N

: 1945

76 VOLUME 76
1 E SUPPLEMENT NUMBER 1
2014 2014

19

...
17 - 21 2014

PROCEEDINGS
19th ANNUAL SEMINAR
OF CONTINUING MEDICAL EDUCATION
OF EVANGELISMOS GENERAL HOSPITAL
ATHENS 17 - 21 FEBRUARY 2014

NOSOKOMIAKA CHRONIKA
Official publication of the Scientific Society
of Evangelismos Hospital
 ()

19

...

17 - 21 2014
...

. :

. :
. :
:
. :
. . .
. : E. . .
. : . . .
. : . . .
. . . .
. . . .
. . .
. . .
. . .
. : . . .
. : . . .
. : . .
.
.
.
. . .
. . .
. . .
. .
. .
. : . .
. : . .
. . .
. . .
. . .
. . .
. . .
. . .
. . .
. .
. .
. .
. : . .
. : . .
. . .
. . .
. . .
. . .
. . .
. .

TYG-MA-01 October 2010

.
TYGACIL PFIZER HELLAS ..

PFIZER HELLAS A.E.

. M .
. : 210 6785800 website: www.pfizer.gr
ADV_EPORATIO_20.7x27.5_4-13_Layout 1 2/4/13 2:30 AM Page 1

EPORATIO ADV 2/3-11

Eporatio

Epoetin theta

EVA Pharmaceuticals Hellas S.A.

. 166A & 2, 151 26 , , : +30 2107279099, www.tevapharm.com
: ratiopharm GmbH ( TEVA)
Ecalta-MA 01-October 2010

PFIZER HELLAS A.E.

. M 243, 154 51 . , . : 210 6785800


...(.....)
4547,10676 76
.:2132045102,2132041744 1
Email:sseh@evaggelismoshosp.gr& 2014
sseh.evaggelismos@gmail.com
Web:www.evaggelismoshosp.gr

ARDS

.__________________________________7
.__________________________________________10



.__________________________________25
.,.__________________________________27

ISSN:22414150 :A
.___________________________________37
:
.______________________________________________40

.______________________________________________51
:,;
.,.____________________________________58

._____________________________________________71

.________________________________________________79


.____________________________________________85
:;
.____________________________________________93
:

.____________________________________________110

...
6
.:2132045102 .,.________________________114
Email:sseh.evaggelismos@gmail.com

:

._______________________________________137
:
.
.......
... .._____________________________________139

, 76, 1, 2014 1


.________________________________________________________________156
.____________________________________________________________________________158

,
.,.,.______________________________________167
.,._______________________________________________________________169

.._________________________________________________________________ 185
.,._____________________________________________________________187

.______________________________________________________________196
..__________________________________________________________________________200

3
.___________________________________________________________________ 217

._________________________________________________________________________ 220

.________________________________________________________________________ 247

.____________________________________________________________________________ 255

.____________________________________________________________________________261

:VS
._______________________________________________________________291

._______________________________________________________________________________ 293

._____________________________________________________________________________302

.______________________________________________________________________________322

C:

.________________________________________________________________________________331

._______________________________________________________________________________343

.,.______________________________________________________________349

.___________________________________________________________________________372

._________________________________________________________________________379

, 76, 1, 2014 2


._______________________________________________________________393
.__________________________________________________________________________394

.________________________________________________________________________409

()
,
.M,.,.,._______________________________________________426
:
.__________________________________________________________________________440

.._________________________________________________________________452

._______________________________________________________________________________465

CLOSTRIDIUMDIFFICILE
._______________________________________________________________467
._______________________________________________________________________________469

HIV
.,.,.,.,.___________________________471

.___________________________________________________________________________492

;
._________________________________________________________________________502

._________________________________________________________________________504

.________________________________________________________________576
.______________________________________________________________________582

.__________________________________________________________________________585

.,._________________________________________________________________591

.,.,._______________________________________________________611
mitraclip
._____________________________________________________________________________618

, 76, 1, 2014 3


()
.,.__________________________________________________________626
;
.,.____________________________________________________________________642
(CTA);;
.______________________________________________________________________________655
(R)
._________________________________________________________________________661
(RV)
.,.______________________________________________________________ 668
.
.___________________________________________________________________________674

._____________________________________________________________________675
._______________________________________________________________________________677

.,.__________________________________________________________________688
College of American Pathologists (CAP
2012/13)AmericanJointCommitteeonCancer(AJCC/2010)
.,.______________________________________________________________735
:

.______________________________________________________________________________ 746

.,.____________________________________________________________________ 751

/
.__________________________________________________________________________759

.___________________________________________________________________________771

.____________________________________________________________________793

._____________________________________________________________________________795

._______________________________________________________________________________810

PHI
.___________________________________________________________________830
._____________________________________________________________________________832

.___________________________________________________________________________847

MALT:
.______________________________________________________________________________863

, 76, 1, 2014 4


Alzheimer
._______________________________________________________________________________877

._______________________________________________________________________________886

._____________________________________________________________________________897

.________________________________________________________________ 899
.,.,._________________________________________________ 901

.___________________________________________________________________________911

.________________________________________________________________________ 913
4PROGRPNGAL
:
:4ProGRP
._______________________________________________________________________________ 945
,NGAL
.____________________________________________________________________________ 966

.__________________________________________________________________________ 970

:
.____________________________________________________________________ 985
.,.,.________________________________________________________ 987

.__________________________________________________________________________1000

, 76, 1, 2014 5

,
.


,
.
..
,
, . . , , . . ,
, . . ,
, , . . ,
,
,
, .. . .
, ,

.
.
, . . ,
.
,
.
. .

VitaCongress-. & .
..

: MSD, ROCHE HELLAS, PFIZER, SANOFI, AMGEN, ASTELLAS
PHARMACEUTICALS, , ANIMUS, MEDRONIC, TEVA, ELPEN, ABBOTT,
BAXTER, BOEHRINGER INGELHEIM, COLOPLAST, GENESIS PHARMA,
GLAXOSMITHKLINE, NOVARTIS, ROCHE DIAGNOSTICS & DEMO.

,

.

.
.. .....
...

, 76, 1, 2014 6


ARDS

, MSc, ,
...

:
: 6936666093
-mail: katdim72@yahoo.gr

(Acute Respiratory
Distress Syndrome, ARDS) (Acute Lung Injury, ALI)

,
. 40-60%,

,
(.. ).
ARDS - Osler-
.
ARDS Ashbaugh Petty 1967.
12 ,
, ,
.
: (7) (12) (60%).
, ,
ARDS.

.
ALI/ARDS 1994
. (ATS)
(ESICM) 1994,

, 76, 1, 2014 7
 ALI ARDS.
(AECC) ,
ARDS : . , .
(PaO2/FiO2<200), .
, .
[
(PCWP)<18mmHg]. AECC
ALI,
ARDS
(PaO2/FiO2<300).
, ,
,
18 . , ESISM,
ATS SCCM,
(expert panel)
ARDS ,

2012 ARDS. , ALI,
1
ARDS, ,
PCWP
, PEEP: 5 mm Hg
.
,
.
ARDS
( )
.

1. James A. Russell Keith R. Walley.
. , 2004.
2. Ashbaugh D, Bigelow D, Petty T, Levine B (1967). "Acute respiratory distress in
adults". Lancet 1967;2(7511):319323.

, 76, 1, 2014 8
3. Bernard G, Artigas A, Brigham K, Carlet J, Falke K, Hudson L, Lamy M, Legall J,
Morris A, Spragg R (1994). "The American-European Consensus Conference on
ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial
coordination". Am J Respir Crit Care Med 1994;149:818824.
4. Phua J, Stewart TE, Ferguson ND. Acute respiratory distress syndrome 40 years
later: time to revisit its definition. Crit Care Med 2008;36(10):2912-2921.
5. The ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin
definition. JAMA 2012;307(23):2526-2533.

, 76, 1, 2014 9
 ALI/ARDS

, MSc, , 8 , ...

:
: 2132041800
-mail: karistinakif@yahoo.gr

:
ALI/ARDS,
.
,
ALI/ARDS, ()
. -:
2007
2008.
24 . ALI/ARDS
-
(AECC). score APACHE II SOFA
24 .
,
. :
317 . , 61 (19,2%)
ALI/ARDS. 56,25 20,65 69,53%
. APACHE II SOFA score
26,64 7,43 10,9 3,77 (p<0,001).
ALI/ARDS 58,33% 65% .
- 34,43%
ALI/ARDS (O.R:2.29, 95%
1,12-4,71, p=0.024).
(39,34%, p<0,001).


ALI/ARDS. : 19,2 %

, 76, 1, 2014 10
 ALI/ARDS. -
34,43%
ALI/ARDS.
(58,33%) (65%).
ALI/RDS,
.

ALI/RDS,
, ,
ALI/ARDS
.
, 76, 1, 10-24, 2014.
: ALI/ARDS, ,

SUMMARY
Introduction-Objective: The incidence and mortality of ALI/ARDS remain high
although substantial progress has been made in the understanding of epidemiology
and pathogenesis of the syndromes. The aim of this study was identification of the
incidence, risk factors and the outcome (mortality) of ALI/ARDS, in patients admitted in
the intensive care unit (ICU) of a General Hospital of Athens. MaterialMethods: This
study was conducted in adult ICU of a General Hospital in Athens between May 2007
and April 2008. Included were all patients admitted for more than 24 hours in ICU. All
patients with ALI/ARDS were identified using American European Consensus
Conference definitions. Acute Physiological And Chronic Health Condition II (APACHE
II) and Sepsis- related Organ Failure Assessment (SOFA) were calculated on the first
day of patients admission. Demographic data, biological indicators and length of stay
in ICU were also included. Measurements and Results: A total of 317 patients were
admitted in ICU. Of all admissions, 61 patients (19.2%) experienced ALI/ARDS. The
median age of those patients, was 56.25 20.65 with the 69,53% of them being men.
The median (range) APACHE and SOFA score at the admittion, was 26.64 7.43 and
10.9 3.77 respectively (p<0.001). Mortality for ALI/ARDS patients was found at
58.33% for the ICU and at 65% for the Hospital. Severe Sepsis or Septic Shock was
present in the 34.43% of ALI/ARDS patients and identified as the main risk factor for
ALI/ARDS (O.R:2.29, 95% confidence interval 1.12-4.71, p=0.024). The major source

, 76, 1, 2014 11
of infection was the respiratory system (39.34%, p<0.001). Hemodiafiltration and
highest dose of vasopressors or inotropic agents were independent risk factors most
strongly associated with death from ALI/ARDS. Conclusion: In this one-year study,
19.2% of all patients admitted in ICU of a General Hospital in Athens experienced
ALI/ARDS. Severe Sepsis or Septic Shock was present in the 34.43% of ALI/ARDS
patients and identified as the main risk factor for ALI/ARDS. Mortality was found high
for the ICU (58.33%) and also for the Hospital (65%). Finally, as independent risk
factors most strongly associated with death from ALI/ARDS, were the use of
hemodiafiltration and the highest dose of vasopressors or inotropic agents. The
absolute necessity of a large scale study is pointed out for the registration of clinical
factors which can lead to ALI/ARDS, incidence and mortality for these syndromes, with
need of the instituition for a united plan of on time identification and confrontation of
ALI/ARDS and nosologic entities which can cause the development of the syndromes.
Nosokomiaka Chronika, 76, Supplement 1, 10-24, 2014.
Key words: ALI/ARDS, ICU, incidence

()

,

.
(Acute Respiratory Distress Syndrome-ARDS).1,3,4,5.
ARDS - Osler-
.
ARDS Ashbaugh 1967.
12 11 48 ,
, ,
.2
.
ALI/ARDS
1994 .
(ATS) (ESICM)
1994
(ALI) ARDS. (AECC)

, 76, 1, 2014 12
 , ALI ARDS,

18mmHg,
.
(PO2)
(FiO2), (PO2 / FiO2),
300 mmHg ALI 200 mmHg ARDS.

ARDS1,3,.
ALI/ARDS

ALI 1
1000 , 74%
, ARDS.
() 190.000 ALI
74.000
25 .

. , ALI/ARDS
2 3,5
4,5,6,7.

ALI/ARDS ,

.

ALI/ARDS
() .

-

2007
2008.
.

, 76, 1, 2014 13

,
24 , ALI/ARDS
, .

24 .
24 ,

.
: .

(, ),
( (
) <70 mm Hg), ,
, ,
, , (Gram (+) Gram
(-) ,
APACHE II SOFA, 24 ,
, .

ALI/ARDS
(AECC):
,
18mmHg
.
(2) (FiO2), PO2/FiO2,
300 ALI 200 ARDS.

.
.

, 76, 1, 2014 14

,
(%)
.
Pearsons chi-square
Fishers exact,
, Students t-test Mann-
Whitney, .
.
,
Bonferroni, p<0,001.
ALI/ARDS,

p<0,05.
STATA, ver.9.

A
317 .
57,69 17,67 , 69,40% .
35,0% , 34,1%
30,9%
.
17,67 23,01 .

19,2 % ALI/ARDS. 47,54%
, 18,03%
34,43%

32,03%, 37,89% 30,08%
ALI/ARDS p=0,009. ,
ALI/ARDS
(p=0,345).
APACHE II SOFA 24
ALI/ARDS
ALI/ARDS (26,64 7,43 10,9 3,77 20,11 7,59 7,64

, 76, 1, 2014 15
3,58 , p<0,001) ( 1).
ALI/ARDS
ALI/ARDS (58,33%
24,71% , p<0,001). ALI/ARDS

ALI/ARDS (65% 30,59%, p<0,001).
<=70 mm Hg ALI/ARDS
ALI/ARDS (68,85% 37,89%, p<0,001).
ALI/ARDS
ALI/ARDS (77,05% 37,50% , p<0,001).
>15 mcg/Kg >0,1
mcg/Kg >0,1 mcg/Kg ALI/ARDS
ALI/ARDS (65,57% 25,39% , p<0,001).
ALI/ARDS
ALI/ARDS (96,72% 71,09%
, p<0,001). , -
ALI/ARDS
ALI/ARDS, 34,43% 9,74 ( p< 0,001).
ALI/ARDS
ALI/ARDS (39,34% 14,84%, p<0,001). ,
ALI/ARDS
ALI/ARDS (55,74% 23,44%, p<0,001).
, ,
ALI/ARDS

ALI/ARDS (26,23% 8,20% , p<0,001).

, 76, 1, 2014 16
 1. ALI/ARDS
ALI-ARDS

Std Std
Mean Mean p
Deviation Deviation
58,03 17,29 56,25 20,65 0,534
17,29 23,82 19,27 19,31 0,550
BMI (kg/m2) 26,42 5,63 27,63 7,34 0,157
PACH Score 20,11 7,59 26,64 7,43 <0,001
SOFA Score 7,64 3,58 10,9 3,77 <0,001

ALI/ARDS, ( 2):

ALI/ARDS 2,41 ( 141%)
(R: 2,41, p=0,021),
(1 44 ),
, - ,
.

2. : ALI/ARDS

Odds [95%
p
Ratio ]
Dopamine>15Mcg adren>1 noradr>1
2,41 1,14 5,08 0,021

(1 44 ) 0,98 0,96 0,99 0,008
6,04 1,32 27,60 0,020
- 2,29 1,12 4,71 0,024
: 2,19 1,07 4,49 0,033

ALI/ARDS 2,29 ( 129%),
(O.R: 2,29, p=0,024)
, 1 (
44 ), .
, 2,19
( 119%) ALI/ARDS,
(O.R: 2,19, p=0,033),

, 76, 1, 2014 17
 , 1
, -
.

() ALI/ARDS ( 3):
5,60 ( 460%)
ALI/ARDS,
(O.R: 5,60, p=0,040)
(dopamine>15 mcg adren>1 noradrenaline >1).
(dopammine>15>
adren>1 noradrenaline >1), 3,84 ( 284%)
(O.R:
3,84, p=0,028), .

ARDS .
National Heart and Lung Task
Force () 1972 ARDS , 75
100.000 . 20 ,
1,5-4,5 ARDS
100.000 /.
1992, ALI ARDS ,
AECC.
AECC, ARDS 13-23
100.000 / ALI 18
100.000 /.
Seattle () 1972,
ARDS 59 100.000 /
ALI 79 100.000 /.
ALI/ARDS
,
-
1,5,6,7, 8,9,10,11
.
ALI/ARDS 19%

, 76, 1, 2014 18
 24 . ALI/ARDS
58,33%,
65%.
- 34,43%
ALI/ARDS.
ALI/ARDS (19%)
Irish Critical Care
Trials Group (2008), 19%.
14 (n=1029) ( ALI/ARDS)
(58 17 56,25 2 0,65
) (62% 69%
) 12
(ARF)
(FINNALI -2009), Rita L. .
7,15 3,3% ALI ARDS .

ALI/ARDS
, ARDS
,
,
ALI/ARDS12.
15 ,
ALI/ARDS ( , )
, ,
ALI/ARDS . To
58,33% 65%
. , Leonard (1995)
ARDS 62%13.
40% Luhr
(1999)14 ,
(n=13,346) Bersten et al (2002)15
.

,

, 76, 1, 2014 19
 ALI/ARDS,
.
run-Buisson , (ALIVE study-2004)
76 10 (n=3485)
49% ALI/ARDS16. Irish Critical Care Trials Group
(2008) 32%,
12
ALI/ARDS .
.. ALIVE,
ALI/ARDS (mean Vt =7,0ml/kg Vt
=8,0-10ml/kg ALIVE).
6,3 16,4 15,8
ALIVE 17,67 23,01 . ,
, SOFA score test
ALI/ARDS 8,8 4,1, SOFA score test

8,27 3,8312. FINNALI (2009)
26 (n=2670)
47% ARDS 15.




.
34%
ALI/ARDS (n=317).
Irish Critical Care Trials Group (2008)12
35% (n=1029) ALI/ARDS
Bersten D, et al (2002)15
35%.
Leonard , (1995)
45% ARDS13.
,


ALI/ARDS.

, 76, 1, 2014 20

( , , -
),
.
,

.
.
.


.

,
(.
, ),

,
,

ALI/ARDS, (.. , , ).

3. : ALI/ARDS ()

Odds [95%
p
Ratio ]
Dopamine>15Mcg adren>1
3,84 1,16 12,71 0,028
noradr>1
5,60 1,08 29,05 0,040

20
ALI/ARDS,

ALI/ARDS, .
ALI/ARDS
. ALI/ARDS

, 76, 1, 2014 21
 .
ALI/ARDS
.
ALI/ARDS 19%
, 58,33% 65%
.
-
34,43% ALI/ARDS.
ALI/ARDS
, ,
, (1
44 ), ,
.
ALI/ARDS,
, .


, .
,
,
,

.

, ,
,
ALI/ARDS, ,

.
,
ALI/ARDS
.

, 76, 1, 2014 22

1. James A. Russell Keith R. Walley.
. , 2004.
2. Ashbaugh D, Bigelow D, Petty T, Levine B. Acute respiratory distress in adults.
Lancet. 1967;2(7511):319323.
3. Bernard G, Artigas A, Brigham K, et al. The American-European Consensus
Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical
trial coordination. Am J Respir Crit Care Med 1994;149(3 Pt 1):818824.
4. Jaime F, Avecillas, MD, Amado X, et al. Clinical Epidemiology of Acute Lung Injury
and Acute Respiratory Distress Syndrome: Incidence, Diagnosis, and Outcomes.
Clin Chest Med. 2006;27:549-557.
5. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute
lung injury. N Engl J Med 2005;353(16):1685-1693.
6. Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of
the acute respiratory distress syndrome. N Engl J Med 2003;348(8):683-693.
7. Davidson TA, Rubenfeld GD, Caldwell ES, et al. The effect of acute distress
syndrome on long-term survival. Am J Respir Crit Care Med 1999;160(6):1838-
1842.
8. Mason: Murray & Nadels Textbook of Respiratory Medicine, 4th ed. 2005
Saunders, MD, Ph.D. An Imprint of Elsevier.
9. Lorraine B. Ware, MD., Michael A. Matthay, MD. The Acute Respiratory
Syndrome. New England Journal of Medicine 2000; 342,18:1334-1349.
10. Rubenfeld GD, Herridge MS. Epidemiology and Outcomes of Acut Lung Injury.
Chest 2007;131:554-562.
11. Garber BG, Hbert PC, Yelle JD, et al. Adult respiratory distress syndrome: A
systematic overview of incidence and risk factors. Critical Care Medicine
1996;24(4):687-695.
12. Irish Critical Care Trials Group. Acute lung injury and acute respiratory distress
syndrome in Ireland: a prospective audit of epidemiology and management. Crit
Care 2008;12(1):R30.Epub 2008 Feb 29.
13. Linko R, Okkonen M, Pettit V, et al. Acute Respiratory Failure in intensive care
units. FINNALI: a prospective cohort study. Intensive Care Med 2009;35:1352-
1361.

, 76, 1, 2014 23
14. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal
volumes as compared with traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308.
15. Zilberberg MD, Epstein SK. Acute lung injury in the medical ICU: comorbid
conditions, age, etiology, and hospital outcome. Am J Respir Crit Care Med
1998;157:1159-1164.
16. Bersten AD, Edibam C, Hunt T, et al. Incidence and Mortality of Acute Lung Injury
and the Acute Respiratory Distress Syndrome in Three Australian States. Am J
Respir Crit Care Med. 2002:165(4):443-448.
17. Brun-Buisson C, Minelli C, Bertolini G, et al. Epidemiology and outcome of acute
lung injury in European intensive care units. Results fron the ALIVE study.
Intensive Care Med 2004;30:51-56.

, 76, 1, 2014 24


.
, ...

.: 6944520791
-mail: georgk1@otenet.gr

,
. ,
,
,
,
.
,
1940.

.
, ,

.
14,1 2012
,
16 2020.



.
, CDC ( Centers for
Disease Control and Prevention)

, 76, 1, 2014 25


, .

,
.
, ,
,
.
,


.

, 76, 1, 2014 26


. 1, . 2
1
, MSc, cPhd, ..,
2
, ..

:
.
: 6947832131
E-mail: gsdiras@yahoo.gr

,
.
,
Crohn.
,

.
.


.
.

.

,
,
.
,
.
,

,

, 76, 1, 2014 27
 .
, 76, 1, 27-36, 2014.
: , , ,

SUMMARY
SIDIRAS G. OUZOUNIDOU A. Risk and safety factors in the handling of
cytostatic medicines by the nurses. The use of cytostatic medicines has increased
in recent years as it is not only the patients with malignancies that receive cytostatic
medicines. Indications for the use of cytostatics are extended beyond oncological
diseases such as rheumatoid arthritis and Crohn's disease . Also today the diagnosis
of cancer is much faster than in the past, which has resulted in patients to receive
more cycles of chemotherapy and for longer periods of time. Result of this is the
increase in the number of workers who handle cytostatic medicines. All employees
who are directly or indirectly involved in handling cytostatic agents are in danger of
being exposed to potentially mutagenic agents. Chemotherapeutic agents constitute a
real occupational hazard for health care professionals. The existing legislation
provides for special arrangements and precautions to be taken for the safety of
workers handling cytostatic medicines. Employees must be aware of, and to adhere to
the basic principles of protection of personnel who manage cytostatic medicines,
whether they are nurses, or doctors, or pharmacists or cleaning staff, who must be
aware of how to properly collect such waste. The personnel must have received the
appropriate training, in order to meet with success and safety in the use of cytostatic
medicines. The monitoring of exposure levels of nurses, who handle cytostatic
medicines is of paramount importance for the assessment of the actual size of the
occupational hazards of these workers, as well as the detection and prognosis of the
adverse reactions and harmful effects on their health. Nosokomiaka Chronika, 76,
Supplement 1, 27-36, 2014.
Key words: security, risks, chemotherapeutic medicines, nurse

. ,
,
.

, 76, 1, 2014 28
 ,
Crohn.
(),

(Endoxan),
1,2
,
, ,
.


.3
' ,

.
, (nitrogen mustard),
Hodgkin.3,4
,
,

. ,
,
.3
OSHA (Occupational Safety & Health Administration)
.
, ,
.5

(
6
).

.
, , ,

, 76, 1, 2014 29
, , .
.
, .7
, , , ,
, , ,
.7

. ,
, (
), , .

, ,
, 48
.8,9
Lancet ,
,
(
) Ames. 90%
.
( )
, .10
,
. 14
, 9

11
.
.12
, , ,
, , , ,
.13
.4,13

,
, , .3,14

, 76, 1, 2014 30

. ,
.
.15 ,
,
.15
.
,
,
.
.16
, ,
.15
.15,17
.
,
.14
.

.15 , (BCNU),
(IFE), thiotepa (Thioplex) (ENDOXAN)
.4
,
OSHA
.
.

.

.15

(American Society of Health-System
Pharmacists)
, (Occupational Safety & Health Administration)

, 76, 1, 2014 31
 (Oncology Nursing Society)

. ,

.
, .18,19
2008, (American Society of
Clinical Oncology ) (Oncology
Nursing Society)
. ,
,
.20
, ,
, ,
, ,
,
.


20
.

.21
, ,
19 50
. ,
.



.22
DNA
comet assay.

, 76, 1, 2014 32
 . Ursini et al
DNA
DNA.23
, , ,
Ursini, DNA
.24,25,26,27


.
Sessink Bos
,

.28

, ,
. Florence Nightingale,
.
,
.
,
.
.
,
.


, , .
,
.
,
,

.

, 76, 1, 2014 33

.

1. Ben-Ari E. Dual purpose: some cancer therapies used to treat autoimmune

disease, J Natl Cancer Inst 2004, 96(8):577-579.
2. Weinman S. Nonsurgical treatment of an ectopic pregnancy with methotrexate, J
Emerg Nurs 1996, 22(6):597-599.
3. What is chemotherapy? American Cancer Society Web site.
http://www.cancer.org/docroot/ETO/content/ETO_1_4X_What_Is_Chemotherapy.a
sp. Accessed May 14, 2011.
4. Connor TH. Hazardous anticancer drugs in health care, Ann NY Acad Sci 2006,
1076:615-623.
5. OSHA technical manual: controlling occupational exposure to hazardous drugs.
OSHA Web site. http://osha.gov/dts/osta/otm/otm _vi/otm_vi_2.html. Accessed
May 14, 2011.
6. ISOPP standards of practice: safe handling of cytotoxics. J Oncol Pharm Pract
2007, 13 Suppl:1-81.
7. Polovich M, White J, Kelleher L. Chemotherapy and Biotherapy Guidelines and
Recommendations for Practice, 2nd ed, Pittsburgh, PA: Oncology Nursing Society,
2005.
8. Gambrell J, Moore S. Assessing workplace compliance with handling of
antineoplastic agents, Clin J Oncol Nurs 2006, 10(4):473-477.
9. Coyle B. Handling hazardous drugs, Am J Nurs 2004, 104(2):104.
10. Kromhout H, Hoek F, Uitterhoeve R, et al. Postulating a dermal pathway for
exposure to antineoplastic drugs among hospital workers. Applying a conceptual
model to the results of three workplace surveys, Annals of Occupational Hygiene
2000, 44(7):551-560.
11. Harrison, B. (2001) Risks of handling cytotoxic drugs. In M.C. Perry (Ed.), The
chemotherapy source book. (3rd Ed, p:566-582). Philadelphia, PA. Lippincott,
Williams, & Wilkins.
12. Martin S, Larson E. Chemotherapy-handling practices of outpatient and office-
based oncology nurses, Oncol Nurs Forum 2003, 30(4):575-581.
13. Snively A. Patient and provider safety with the infusion process, Session presented
at: ONS 33rd Annual Congress, May 16, 2008, Philadelphia, PA.

, 76, 1, 2014 34
14. Yarbo CH, Frogge MH, Goodman M. Cancer Nursing Principles and Practice, 5th
ed, Sudbury, MA: Jones and Barlett Publishing, 2005.
15. Connor TH, McDiarmid MA. Preventing occupational exposures to antineoplastic
drugs in health care settings, CA Cancer J Clin, 2006, 56(6):354-365.
16. Testa A, Giachelia M, Palma S. Occupational exposure to antineoplastic agents
induces a high level of chromosome damage: lack of an effect of GST
polymorphisms, Tox Appl Pharm 2007, 223:46-55.
17. Onteyn M. Update on safe handling of hazardous drugs, session presented at ONS
31st Annual Congress, August 5, 2006, Boston, MA.
18. Occupational Safety & Health Administration 2007. www.osha.gov
19. Connor T, Shults M, Fraser M. Determination of the vaporization of solutions of
mutagenic antineoplastic agents at 23 and 37 IC using a desiccators technique,
Mutat Res 2000, 470:8592.
20. Jacobson J, Polovich, M, McNiff, K, et al. American Society of Clinical
Oncology/Oncology Nursing Society Chemotherapy Administration Safety
Standards, Oncology Nursing Forum 2009, 36(6):651-658.
21. Boughattas AB, Bouraoui S, Debbabi F et al.. Genotoxic risk assessment of nurses
handling antineoplastic drugs, Ann Biol Clin (Paris) 2010, 68(5):545-553.
22. Barbieri A, Nucci MC, Sabatini L et al. Occupational exposure to antineoplasmatic
drugs in a hospital setting: biological and environmental monitoring, Epidemiol Prev
2005, 29(5-6 Suppl):87-90.
23. Ursini CL, Cavallo D, Colombi A et al. Evaluation of early DNA damage in
healthcare workers handling antineoplasmatic drugs, Int Arch Occup Environ
Health, 2006, 80(2):134-140.
24. Rekhadevi PV, Sailaja N, Chandrasekhar M et al. Genotoxicity assessment in
oncology nurses handling anti-neoplastic drugs, Mutagenesis 2007, 22(6):395-401.
25. Cornetta T, Padua L, Testa A et al. Molecular biomonitoring of a population of
nurses handling antineoplastic drugs, Mutat Res. 2008, 638(1-2):75-82.
26. Yoshida J, Kosaka H, Tomioka K et al. Genotoxic risks to nurses from
contamination of the work environment with antineoplastic drugs in Japan, J Occup
Health. 2006, 48(6):517-522.
27. Sasaki M, Dakeishi M, Hoshi S et al. Assessment of DNA damage in Japanese
nurses handling antineoplastic drugs by the comet assay, J Occup Health. 2008,
50(1):7-12.

, 76, 1, 2014 35
28. Sessink PJ, Bos RP. Drugs hazardous to healthcare workers, Evaluation of
methods for monitoring occupational exposure to cytostatic drugs. Drug Saf. 1999,
20(4):347-359.

, 76, 1, 2014 36


. , MD, PhD, AGAF

... --

:
: 2132041604
E-mail: gjmantzaris@gmail.com

.
(overuse), (underuse) (misuse)
/ .

.

2001:


.
, , , ,
(STEEEP: Safe, Timely,
Efficient, Evidence-based, Effective, and Patient-centered Healthcare),
,
.

.

( ) .
/

, 76, 1, 2014 37
 .
,


. ( Mallory-Weiss),
( Cameron),
, Dieulofoy, .
50 (
, . ,
, )
. ,

(
)

.
/ ,


,
. ,
, ,



. (
, ),


, ,
.

(evidence based Medicine)
.

, 76, 1, 2014 38
 25
,

,


.
, ,
.
,



.

1. Institute of Medicine Committee on Quality of Health Care in America NAP, 2001.
2. Porter ME, Teisberg EO. How physicians can change the future of health care.
JAMA 2007;297:11031111.

, 76, 1, 2014 39
 :

,
..

:
: 2107201609, 6947305481
E-mail: nikos_kiriakos@yahoo.gr

() ,
Treitz. 48 160
100.00 . 80%
,
.
,

Mallory-Weiss, , Dieulafoy
. 10%,

.
, ,
,
,
,
. , 76,
1,40-50, 2014.
: , , , ,

SUMMARY
KYRIAKOS N. Upper gastrointestinal bleeding: diagnostic evaluation. Each year,
hundreds of thousands of patients suffer from acute upper gastrointestinal bleeding
(UGIB), which by definition arises from a site proximal to the ligament of Treitz. Its
incidence ranges from 48160 cases per 100,000 adults per year and causes
significant morbidity and mortality. UGIB commonly presents with hematemesis and/or
melena. In cases of severe UGIB, hematochezia (bright red or maroon colored blood
per rectum) can be found. Depending on the speed of blood loss, hemodynamic status
, 76, 1, 2014 40
may be affected in different ways. In patients with mild to modest blood loss over a
longer duration of presentation, anemia, malaise and postural changes in pulse and
blood pressure are common. Peptic ulcer disease usually constitutes slightly over 50%
and esophagogastric varices 1520%. The other important conditions leading to UGIB
include Mallory-Weiss tear, angiodysplasias and vascular ectasias, Dieulafoys lesion
and tumors of the upper gastrointestinal tract. In as many as 20% of patients, the
diagnosis cannot be ascertained. Rapid assessment and resuscitation should precede
the diagnostic evaluation in unstable patients with severe bleeding. Risk stratification
is based on clinical assessment and endoscopic findings. Following adequate
resuscitation, management is directed to identify the lesion and identify the high-risk
patient who is likely to require early endoscopic or surgical treatment. Early upper
endoscopy (within 24 hours of presentation) is recommended in most patients
because it confirms the diagnosis with a sensitivity of about 90% and allows for
targeted endoscopic treatment. When the source cannot be detected via upper
endoscopy, bleeding scans and angiogram can be performed to find the source of
bleeding. Nosokomiaka Chronika, 76, Supplement 1, 40-50, 2014.
Key words: bleeding, melena, peptic ulcer, varices, endoscopy

() ,
Treitz.
48-160 100.00 1,2.
2%
, 300000
,
1,3
7-10 % . 80%
4,
5. 1
6.
10%4,

.

, 76, 1, 2014 41


.
, .

( , , ), (
), . ,
5-15% , (
)
( 1000ml ).

,

(5-10%) .
, ,

.
, ,

.

1. ()

* (%)
62%
8%
6%

, , Dieulafoy,
10%

Mallory-Weiss 4%
2%
8%
* :

(), ,

, 76, 1, 2014 42
 ,
.


,

,

,
,
.
,
, ,
.
,
.

() .
, ,
.
, 16%
7.
,

42-84%8.

,
. ,

,
.

(
) 9.

, 76, 1, 2014 43

,
(ASGE)
:
1. ,
2. , ,
3. 10.
,
.

90-95%11. ,
. , ,
24
. ,
,
10.


.
, ,
,
, .
. 15% 30%
4%.

.
. Forrest ( 2)

12.
(,
)
.

, 76, 1, 2014 44
 ,
.
/

, , .
30-40%
13.
70%
14. , ,


15.

2. Forrest

(%) (%) (%)

Ia 18 55 11
(spurting)

Ib 17 55 11
(oozing)
IIa 17 43 11

IIb 20 22 7

IIc 42 10 3

III 18 5 2

MalloryWeiss
.
, 0,5-5
.
(, ,
)
,
.

, 76, 1, 2014 45

,
(..
Osler-Rendu-Weber,
Ehlers-Danlos blue rubber bleb naevus).
(GAVE), water melon stomach
,
16. ,
(30%), ,
17.
H Dieulafoy
,

.
18.
, .

()
.
3-4 ,
19.

, ,
.
, 20,21.
, , .

.
, 22.

Vater . ,
ERCP, ,
0,5-2% 23.

, 76, 1, 2014 46

90%
24,25.
, ,
, 25,
,
Dieulafoy26
, .
.

60% . 5 Fr
.
,
25. ,
, ,

.

0.5 ml/min 3. ,

. ,
,
.

.
. Ettorre et al.

, (72%)
27. .

, 99
,
(0,1-0,4ml/min).

, 76, 1, 2014 47

24 ,
28.
, ,
,

.

:
1. Longstreth GF. Epidemiology of hospitalization for acute upper gastrointestinal
hemorrhage: a population based study. Am J Gastroenterol 1995; 90:206210.
2. Rockall TA, Logan RF, Devlin HB, et al. Incidence of and mortality from acute
upper gastrointestinal hemorrhage in the United Kingdom. Screening Committee
and Members of the National Audit of Acute Upper Gastrointestinal Hemorrhage.
BMJ 1995;311:222226.
3. Martins N, Wassef W. Upper gastrointestinal bleeding. Curr Opin Gastroenterol
2006; 22:612619.
4. Barkun A, Bardou A, Kuipers E et al. International Consensus Recommendations
on the Management of Patients with Non-variceal Upper Gastrointestinal Bleeding.
Ann Intern Med 2010; 52:101113.
5. Kasem AM, Kamal T, Chandra NN, et al. Management of acute upper
gastrointestinal bleeding in a district hospital. J Laparoendosc Adv Surg Tech
2006; 16:355361.
6. Rockall TA, Logan RF, Devlin HB, et al. Risk assessment after acute upper
gastrointestinal hemorrhage. Gut 1997; 38:316321.
7. Gilbert D, Silverstein F, Tedesco F et al. The national ASGE survey on upper
gastrointestinal bleeding. Endoscopy in upper gastrointestinal bleeding. Gastroint
Endosc 1981; 27:94102.
8. Palamidessi N, Sinert R, Falzon L, et al. Nasogastric aspiration and lavage in
emergency department patients with hematochezia or melena without
hematemesis. Acad Emerg Med. 2010;17:126-32
9. Wilkins T, Khan N, Nabh A et al Diagnosis and management of upper
gastrointestinal bleeding. Am Fam Physician 2012; 85:469476.
10. Eisen GM, Dominitz JA, Faigel DO, et al. An annotated algorithmic approach to
upper gastrointestinal bleeding. Gastrointest Endosc 2001; 53:853858.

, 76, 1, 2014 48
11. Cappell MS, Friedel D. Acute nonvariceal upper gastrointestinal bleeding:
endoscopic diagnosis and therapy. Med Clin NA 2008; 92:511550.
12. Forrest JA, Finalyson N, Shearman DJ. Endoscopy in gastrointestinal bleeding.
Lancet 1974;2(7877):394397.
13. Park EJ, Jang JY, Lee JE et al. The risk factors for bleeding of fundal varices in
patients with liver cirrhosis. Gut Liver.2013; 7:704711.
14. D Amico G, De Franchis R, Cooperative study group- Upper digestive bleeding in
cirrhosis. Post therapeutic outcome and prognostic indicators. Hepatology 2003;
38:599612.
15. Turon F, Casu S, Hernndez-Gea V et al. Variceal and other portal hypertension
related bleeding. Best Pract Res Clin Gastroenterol. 2013; 27:649664.
16. Sebastian S, O Morain CA, Buckley MJ. Review article: current therapeutic
options for gastric antral vascular ectasia. Aliment Pharmacol Ther 2003; 18:157
165.
17. Selinger CP, Ang YS. Gastric antral vascular ectasia (GAVE): An update on
clinical presentation, pathophysiology and treatment. Digestion 2008; 77:131
137.
18. Jamanca-Poma Y, Velasco-Guardado A, Piero-Prez C et al. Prognostic factors
for recurrence of gastrointestinal bleeding due to Dieulafoy's lesion. World J
Gastroenterol. 2012; 18:57345738.
19. Guner A, Mentese U, Kece C et al. A rare and forgotten diagnosis of
gastrointestinal bleeding: primary aortoduodenal fistula. BMJ Case Rep. 2013 pii:
bcr2013008712. doi: 10.1136/bcr-2013-008712
20. Lino M, Kuribayashi S, Imakita S et al. Sensitivity and specificity of CT in the
diagnosis of inflammatory abdominal aortic aneurysms. J Comput Assist Tomogr
2002; 26:10061012.
21. Acosta RD, Wong RK. Differential diagnosis of upper gastrointestinal bleeding
proximal to the ligament of Trietz. Gastrointest Endosc Clin N Am. 2011; 21:555
566.
22. Chin MW, Enns R. Hemobilia. Curr Gastroenterol Rep. 2010; 12:121129.
23. MillerMand Smith TP. Angiographic diagnosis and endovascular management of
nonvariceal gastrointestinal hemorrhage. Gastroenterol Clin NA 2005;34:735752.
24. Lefkovitz Z, Cappell MS, Kaplan M, et al. Radiology in the diagnosis and therapy
of gastrointestinal bleeding. Gastroenterol Clin 2000; 29:489512.

, 76, 1, 2014 49
25. Concha R, Amaro R, Barkin J, et al. Obscure gastrointestinal bleeding: diagnostic
and therapeutic approach. J Clin Gastroenterol 2007; 413:242251.
26. Burke SJ, Golzarian J, Weldon D, et al. Nonvariceal upper gastrointestinal
bleeding. Eur Radiol 2007;17:17141726.
27. Ettorre GC, Francioso G, Garribba AP, et al. Helical CT angiography in
gastrointestinal bleeding of obscure origin. Am J Roentgenol 1997;1 68:727731.
28. Khan O, Singh P, Archibald A et al The role of labelled red blood cell scintigraphy
in the detection of acute gastrointestinal bleeding. West Indian Med J.
2000;49:298301.

, 76, 1, 2014 50
 :

. .
,
...

:
: 6977720281
E-mail: pkaratzas@hotmail.com

,
.
. H

, , ,
, .
60
.
(.. ,
)
, .

.
. -

(). ,

.

.


. , 76, 1, 51-57,
2014.

, 76, 1, 2014 51
 : , , ,
, ,

SUMMARY
KARATZAS SP. Upper Gastrointestinal Bleeding: From the Emergency
Department to the Ward. Resuscitation based on the possible cause. The goals
of managing a patient with acute GI bleeding are first 1) to resuscitate (resuscitation);
second, 2) control active bleeding; and third, 3) to prevent recurrence of hemorrhage.
The importance of resuscitation in the initial management of gastrointestinal bleeding
cannot be over-emphasized. Significant GI bleeding is indicated by syncope,
continuous hematemesis and tachycardia, significant drop in systolic blood pressure,
postural hypotension and requirement of blood or intravenous fluid to maintain blood
pressure. Patients over age 60 and with multiple underlying diseases are at higher risk
of negative outcomes. Those admitted for other medical problems (e.g. heart or
respiratory failure, or cerebrovascular bleed) and who develop gastrointestinal
bleeding during hospitalization also exhibit a higher risk of dying from the condition.
Vital signs should be closely monitored. In patients with hypovolaemic shock, central
venous pressure and hourly urine output should be observed. Volume replacement,
correction of bleeding diathesis (coagulopathy), and emptying the stomach of gastric
contents by nasogastric tube should be considered. Pre-endoscopic pharmacologic
therapy using proton pump inhibitors or somatostatin should be considered on an
individual basis. Following adequate resuscitation, management is directed to identify
the lesion and identify the high-risk patient who is likely to require early endoscopic or
surgical treatment. Nosokomiaka Chronika, 76, Supplement 1, 51-57, 2014.
Key words: bleeding, resuscitation, bleeding disorders, proton pump inhibitors,
somatostatin.

.
,
, , ,
. 60
.

, 76, 1, 2014 52
 ,
, .

.
.

().

.
()
() .


.

. (2) (16G)

.
. )
120mmHg, 70mmHg, ) 0,5ml/Kg/h, ) 2 ) Lac
2,5.
.
( , , )
.
,
.
10g/dl,
7g/dl.
b 7g/dl
,
7 9 g/dl1,2.
79 g/dl
1012g/dL3.

, 76, 1, 2014 53
 8,2g/dL
4. ,
, ,
,
(ARDS), .
.

.

,
,
.

. - 5
371
(Placebo)
5, ,
.

(cost-effective).
6.

: ) , )
)
.

, 7.

.
INR 1.8
8. R 1.5

, 76, 1, 2014 54
 .
INR
, .
INR 2.5.
,
INR 1,5 6

,
, , 9.

. ()

. 380

10.

(cost effective)
11.
- 2006 5
(Randomized Control Trials, RCTs)

( , ,
)
1/3 12.
.


.
,
.


13.

, 76, 1, 2014 55
 .

14-17.
.

.

, :
1. (2) (G16)
2.
3. /
4.
5.
6.
7.

1. Barkun A, Bardou M, Kuipers EJ, et al. International consensus recommendations

on the management of patients with non-variceal upper gastrointestinal bleeding.
Ann Intern Med 2010; 152: 101113.
2. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper
gastrointestinal bleeding. N Eng J Med 2013; 386:11-21.
3. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled
clinical trial of transfusion requirements in critical care. Transfusion Requirements
in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med
1999; 340:409417.
4. Bellotto F, Fagiuoli S, Pavei A, et al. Anemia and ischemia: myocardial injury in
patients with gastrointestinal bleeding. Am J Med 2005; 118:548551.
5. Barkun A, Bardou M, Martel M, et al. Prokinetics in acute upper GI bleeding: a
metaanalysis. Gastrointest Endosc 2010; 72:11381145.
6. Winstead NS, Wilcox CM. Erythromycin prior to endoscopy for acute upper
gastrointestinal haemorrhage: a cost-effectiveness analysis. Aliment Pharmacol
Ther 2007; 26:13711377.

, 76, 1, 2014 56
7. Barkun A, Bardou M Gralnek I, et al. Impact of elevated INR and of low platelet
count on outcomes in acute upper GI bleeding (UGIB). Gastroenterology 2009;
136 (suppl 1):A605
8. Baradarian R, Ramdhaney S, Chapalamadugu R, et al. Early intensive
resuscitation of patients with upper gastrointestinal bleeding decreases mortality.
Am J Gastroenterol 2004; 99:619622
9. Choudari CP, Rajgopal C, Palmer KR. Acute gastrointestinal haemorrhage in
anticoagulated patients: diagnoses and response to endoscopic treatment. Gut
1994; 35:464 466.
10. Lau JWY, Lau JY, Leung WK, et al. Omeprazole before endoscopy in patients with
gastrointestinal bleeding. N Engl J Med 2007; 356:1631 1640.
11. Tsoi KK, Lau JY, Sung JJ. Cost-effectiveness analysis of high-dose omeprazole
infusion before endoscopy for patients with upper-GI bleeding. Gastrointest
Endosc 2008; 67:1056 1063.
12. Naumovski-Mihalic S, Katicic M, Colic-Cvlje V, et al. Intravenous proton pump
inhibitor in ulcer bleeding in patients admitted to an intensive care unit [Abstract
W1578]. Gastroenterology 2005; 128: A641.
13. Sung JJY, Chung SCS, Chan KL, et al. Octreotide versus emergency
sclerotherapy in the treatment of acute variceal haemorrhage. Lancet 1993; 342:
6376341.
14. Corley DA, Cello JP, Adkission W. et al. Octreotide for acute esophageal variceal
bleeding: a meta-analysis. Gastroenterol 2001; 120:946 954.
15. Waler S, Kreichgauer HP, Bode JC. Terlipressin vs somatostatin in bleeding
esophageal varices: a controlled double-blind study. Hepatology 1992; 15:1023
1030.
16. Avgerinos A, Nevens F, Raptis S, et al. Early administration of somatostatin and
efficacy of sclerotherapy in acute oesophageal variceal bleeds: The European
Acute Bleeding Oesophageal Variceal Episodes (ABOVE) randomized trial.
Lancet 1997; 350:14951499.
17. Cales, P, Masliah, C, Bernard, B, et al. Early administration of vapreotide for
variceal bleeding in patients with cirrhosis. French Club for the Study of Portal
Hypertension.N Engl J Med 2001; 344:2328.

, 76, 1, 2014 57

? ? ?

1, 2
1
, ... ,
2

:
: 6936702720
E-mail: march193@yahoo.com

.

.
( 1 24 ),
, ( 6
) .
( ,
) . ;E

24
24 7 , .
, 76, 1, 58-70, 2014.
: . ,

SUMMARY
ARCHAVLIS E, KONTOU M. Upper gastrointestinal bleeding. Urgent endoscopy,
To whom? When? How? Upper gastrointestinal bleeding remains a disease, still
associated with high mortality. Endoscopy is nowadays a cornerstone in the
management of a patient with it. Several studies have shown that an urgent
endoscopy , within the first 24 hours after presentation , can improve the outcome of
the patient, but an even more urgent one ( within the first 6 hours after presentation )
did not add any benefit to those gained by an endoscopy within the above interval.
Controversial issues remain the administration of various drugs before endoscopy
(such as proton pump inhibitor or prokinetics) and nasogastric aspiration. The need

, 76, 1, 2014 58
that every hospital that is going to treat such patients has to have a dedicated
endoscopic team, available 24 hours each day, 7 days a week and must have the
necessary room , endoscopic and other instruments, is well documented.
Nosokomiaka Chronika, 76, Supplement 1, 58-70, 2014.
Key words: upper gastrointestinal bleeding, urgent endoscopy, timing, peptic ulcer

30

1,2
() .

(). ,


3.
, ,
,
4

. .
( , ,
). (
, ). (
)
.

.

, ,
, .


,
. ,


, 24 24 7 .

, 76, 1, 2014 59

(
) .
, 24
,
5,6.
(
)


7-10,


( Blatchfordscore .
24

( )
. 750

30 . 10 %
25% 72
11. 71%
24. 2

, 63% ,
12.

24 7 .
6750
. 50%
24

13.
1675 , 75%
24 90%

, 76, 1, 2014 60
24 (1 48 ).14
on-call
,
,
.



14.

( 2-12 )

( 1 24). .

( 2 ).
15.
( )
1 12 24 16,
( 6 )
24 .
17.

.
(
)
, .

12 18 .

10

.
.

, 76, 1, 2014 61

( ,
). , 40
- 60%
19. Hong Kong
placebo ,
() (19
28%)
20
.

.
, ,
. ( 2223 )

(37 46% ),
(
11.7% 8.7%)21. ,
,
,
10

.

( )
( ).
5 ,
,

,
10
.
1.33 1.18
.22

.

, 76, 1, 2014 62


.

. ,

.

.


.

23.
,
.
,

24
. ,
42%,
91% 92% 64%
.
,
,
24.
,
20%
50%
25.
.

.
3
5
26.

, 76, 1, 2014 63

27.

,

10,28.

.


.

.
. ,
,
,

.

().


.
, ,

,
.

, ,
,
.
,

, 76, 1, 2014 64
 .
(
)
.

, .

,
.
.


.
(2.21 2.26 )

(30 vs 34%).29 ,
.
30,31.

,
, ,
.32


.

.


.
, ,

.
.

, 76, 1, 2014 65
.
,
.
,


Vater, .

.
,
.

.

,
,
.
, .
,
.
.


.
.
.
,
.
,
,
.
,


().

, 76, 1, 2014 66

.

(
) .
,
,
.
,
4,10.
,
,

(35% vs 0%).33

1. Graham DY. Limited value of early endoscopy in the management of acute upper
gastrointestinal bleeding. Prospective controlled trial, Am J Surg 1980, 140:284
290.
2. Peterson WL, Barnett CC, Smith HJ et al. Routine early endoscopy in upper-
gastrointestinal-tract bleeding: a randomized controlled trial, N Engl J Med 1981,
304:925929.
3. Cook DJ, Guyatt GH, Salena BJ et al. Endoscopic therapy for acute non variceal
upper gastrointestinal hemorrhage: a meta-analysis, Gastroenterology 1992,
102:139148.
4. Barkun AN, Martel M, Toubouti Y et al. Endoscopic hemostasis in peptic ulcer
bleeding for patients with high-risk lesions: a series of meta-analyses, Gastrointest
Endosc 2009, 69:786799.
5. Spiegel BM, Vakil NB, Ofman JJ. Endoscopy for acute nonvariceal upper
gastrointestinal tract hemorrhage: is sooner better? A systematic review, Arch
Intern Med 2001;161:13931404.
6. Spiegel BM. Endoscopy for acute upper GI tract hemorrhage: sooner is better.
Gastrointest Endosc 2009, 70:236239.

, 76, 1, 2014 67
7. Barkun A, Bardou M, Marshall JK. Nonvariceal Upper GIBCCG. Consensus
recommendations for managing patients with nonvariceal upper gastrointestinal
bleeding, Ann Intern Med 2003, 139:843857.
8. British Society of Gastroenterology. Non-variceal upper gastrointestinal
haemorrhage: guidelines, Gut 2002, 51Suppl 4:iv16.
9. Adler DG, LeightonJA, DavilaRE et al. ASGE guideline: The role of endoscopy in
acute non-variceal upper-GIhemorrhage, Gastrointest Endosc 2004, 60:497504.
10. Barkun AN, Bardou M, Kuipers EJ et al. International consensus recommendations
on the management of patients with nonvariceal upper gastrointestinal bleeding,
Ann Intern Med 2010, 152:101113.
11. Sung JJ, Barkun A, Kuipers EJ et al. Intravenous esomeprazole for prevention of
recurrent peptic ulcer bleeding: a randomized trial, Ann Intern Med 2009, 150:455
464.
12. Cooper GS, Kou TD, Wong RC. Use and impact of early endoscopy in elderly
patients with peptic ulcer hemorrhage: a population-based analysis, Gastrointest
Endosc 2009, 70:229235.
13. Hearnshaw SA, Logan RF, Lowe D et al. Use of endoscopy for management of
acute upper gastrointestinal bleeding in the UK: results of a nationwide audit, Gut
2010, 59:10221029.
14. da Silveira EB, Lam E, Martel M, et al. The importance of process issues as
predictors of time to endoscopy in patients with acute upper-GI bleeding using the
RUGBE data, Gastrointest Endosc 2006, 64:299309.
15. Schacher GM, Lesbros-Pantoflickova D, Ortner MA et al. Is early endoscopy in the
emergency room beneficial in patients with bleeding pepticulcer? A fortuitously
controlled study, Endoscopy 2005, 37:324328.
16. Targownik LE, Murthy S, Keyvani L et al. The role of rapid endoscopy for high risk
patients with acute nonvariceal upper gastrointestinal bleeding, Can J
Gastroenterol 2007, 21:425429.
17. Sarin N, Monga N, Adams PC. Time to endoscopy and outcomes in upper
gastrointestinal bleeding, Can J Gastroenterol 2009, 23:489-493.
18. Trawick EP, Yachimski PS. Management of non-variceal upper gastrointestinal
tract hemorrhage: Controversies and areas of uncertainty, World J Gastroenterol
2012, 18:1159-1165.
19. Van Leerdam ME. Epidemiology of acute upper gastrointestinal bleeding, Best
Pract Res Clin Gastroenterol 2008, 22:209224.

, 76, 1, 2014 68
20. Lau JY, Leung WK, Wu JC et al. Omeprazole before endoscopy in patients with
gastrointestinal bleeding, N Engl J Med 2007, 356:16311640.
21. Sreedharan A, Martin J, Leontiadis GI et al. Proton pump inhibitor treatment
initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding, Cochrane
Database Syst Rev 2010, 7:CD005415.
22. Winstead NS, Wilcox CM. Erythromycin prior to endoscopy for acute upper
gastrointestinal haemorrhage: a cost-effectiveness analysis. Aliment Pharmacol
Ther 2007, 26:13711377.
23. Lee SD, Kearney DJ. A randomized controlled trial of gastric lavage prior to
endoscopy for acute upper gastrointestinal bleeding, J Clin Gastroenterol 2004,
38:861865.
24. Witting MD, Magder L, Heins AE et al. Usefulness and validity of diagnostic
nasogastric aspiration in patients without hematemesis, Ann Emerg Med 2004,
43:525352.
25. Cuellar RE, Gavaler JS, Alexander JA et al. Gastrointestinal tract hemorrhage. The
value of a nasogastric aspirate, Arch Intern Med 1990, 150:13811384.
26. Aljebreen AM, Fallone CA, Barkun AN. Nasogastric aspirate predicts high-risk
endoscopic lesions in patients with acute upper-GI bleeding, Gastrointest Endosc
2004, 59:172178.
27. Marmo R, Koch M, Cipolletta L et al. Predictive factors of mortality from
nonvariceal upper gastrointestinal hemorrhage: a multicenter study, Am J
Gastroenterol, 2008, 103:16391647.
28. Tera A, Sarko J. Just say no: gastric aspiration and lavage rarely provide benefit,
Ann Emerg Med 2010, 55:365366.
29. Shaheen AA, Kaplan GG, Myers RP. Weekend versus weekday admission and
mortality from gastrointestinal hemorrhage caused by peptic ulcer disease, Clin
Gastroenterol Hepatol 2009, 7:303310.
30. Dorn SD, Shah ND, Berg BP et al. Effect of weekend hospital admission on
gastrointestinal hemorrhage outcomes, Dig Dis Sci 2010, 55:16581666.
31. Ananthakrishnan AN, McGinley EL, Saeian K. Outcomes of weekend admissions
for upper gastrointestinal hemorrhage: a nationwide analysis, Clin Gastroenterol
Hepatol 2009, 7:296302.
32. Tsoi K, Pang S, Chiu P et al. The risk of ulcer-related death in relation to hospital
admission on public holidays: a cohort study on 10.428 cases of upper

, 76, 1, 2014 69
 gastrointestinal bleeding, Presentation #891p, Digestive Disease Week New
Orleans, 2010.
33. Jensen DM, Kovacs TO, Jutabha R et al. Randomized trial of medical or
endoscopic therapy to prevent recurrent ulcer hemorrhage in patients with
adherent clots, Gastroenterology 2002, 123:407-413.

, 76, 1, 2014 70
 :

,
... - -

:
: 6944274277
E-mail : achristidou@hotmail.gr

.
24 .
,
.
, (
).
, .
,

.

, .
spray, clips .
, 76, 1, 71-78, 2014.
: , , , ,

SUMMARY
CHRISTIDOU A. Methods of endoscopic hemostasis. Endoscopy is considered the
cornerstone of upper gastrointestinal bleeding treatment. In the majority of patients
presenting with hematemesis or melena it must be performed within 24 hours following
admission to the hospital. Peptic ulcer disease, erosive disease and esophageal
varices due to portal hypertension are the commonest causes of upper gastrointestinal
bleeding. Endoscopic treatment is recommended for lesions with substantial risk of

, 76, 1, 2014 71
rebleeding (active bleeding, high-risk stigmata). Hemostatic methods include injection
of hemostatic substances, thermal and mechanical techniques. In non-variceal upper
gastrointestinal bleeding the combination of injection therapy with thermal or
mechanical methods is superior to injection monotherapy and comparable to thermal
or mechanical monotherapy. In acute variceal bleeding, endoscopic band ligation is
the preferred form of endoscopic therapy due to fewer complications compared to
injection sclerotherapy. Novel agents like hemospray and newer endoscopic clipping
and suturing devices have recently been added to the therapeutic armamentarium.
Nosokomiaka Chronika, 76, Supplement 1, 71-78, 2014.
Key words: upper gastrointestinal bleeding, peptic ulcer, varices, hemostasis,
endoscopy

()
.
(31-67%), (7-31%)
(4-20%). Mallory-Weiss,
, 1.

6%-8%,
,
1,2.
,
.

. (80%)
. ()
.
10% (
) 20%
24-72 .
.

, 76, 1, 2014 72
24 ,
3.

Forrest ( 1).

1. FORREST

FORREST

CLASS % %

Ia/Ib* 18 55

IIa 17 43

IIb 17 22

IIc 20 10

III 42 5

* a: (spurting) , b: (oozing)

,

2,3.
,

( )4.

3 :
(, ,
, , , histoacryl, )
(heater probe, cold probe, ,
, Argon Plasma Coagulation (APC), NdYag Laser)
( clips, ,
endoloops, , ).

,
.
, 76, 1, 2014 73
1.

. (1:10.000)
.
NaCl . ,
.
,
, , , .
,
()
5.
-
.
, ,
(
)6,7,8,9
2.

() 90% 10,11.

,
12.
histoacryl.

2.
.

, .

(heater probe, cold probe,
) (APC, Laser).
heater probe Cold probe, ,
, APC Laser.
13,14.

, 76, 1, 2014 74
NdYAG Laser (). APC

15.

16.

3.

,
.
, clips (hemoclip, triclip), clips

, 17.

.

, 12,18.

Dieulafoy.

4. /
- ,
.


. , ,
, ,
2,6,7,8.
/-

8.

5.

hemospray.

, 76, 1, 2014 75
 .
95%
Forrest Ia b19.
clip, Over-The-Scope Clip (OTSC),

.
.
clip 20.

, .

21.

1. Van Leerdam ME, Vreeburg EM, Rauws EA, et al. Acute upper GI bleeding: did
anything change? Time trend analysis of incidence and outcome of acute upper GI
bleeding between1993/1994 and 2000. Am J Gastroenterol 2003; 98:1494-1499.
2. Barkun AN, Martel M, Toubouti Y, et al. Endoscopic hemostasis in peptic ulcer
bleeding for patients with high-risk lesions: a series of meta-analyses. Gastrointest
Endosc. 2009; 69:786799.
3. Barkun AN, Bardou M, Kuipers EJ, et al. International consensus
recommendations on the management of patients with nonvariceal upper
gastrointestinal bleeding. Ann Intern Med. 2010; 152:101113.
4. North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices.
Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and
esophageal varices. N Engl J Med 1988; 319:983989.
5. Cappell MS. Medscape. Therapeutic endoscopy for acute upper gastrointestinal
bleeding. Nat Rev Gastroenterol Hepatol. 2010; 7:214229.
6. Laine L, McQuaid KR. Endoscopic therapy for bleeding ulcers: an evidence-based
approach based on meta-analyses of randomized controlled trials. Clin
Gastroenterol Hepatol 2009; 7:3347.
7. Marmo R, Rotondano G, Piscopo R, et al. Dual therapy versus monotherapy in the
endoscopic treatment of high-risk bleeding ulcers: a meta-analysis of controlled
trials. Am J Gastroenterol 2007; 102:279289.

, 76, 1, 2014 76
8. Sung JJ, Tsoi KK, Lai LH, et al. Endoscopic clipping versus injection and thermo-
coagulation in the treatment of non-variceal upper gastrointestinal bleeding: a
meta-analysis. Gut 2007; 56:13641373.
9. Vergara M, Calvet X, Gisbert JP. Epinephrine injection versus epinephrine injection
and a second endoscopic method in high risk bleeding ulcers. Cochrane Database
Syst Rev. 2007:CD005584.
10. de Franchis R, Primignani M. Endoscopic treatments for portal hypertension.
Semin Liver DIs 1999; 19:439-455.
11. Sarin SK, Kumar A. Sclerosants for variceal sclerotherapy: a critical appraisal. Am
J Gastroenterol 1990; 85:641-649.
12. Laine L, el-Newihi HM, Migikovsky B, et al. Endoscopic ligation compared with
sclerotherapy for the treatment of bleeding esophageal varices. Ann Intern Med
1993;119:17.
13. Llarch J, Bordas JM, Salmeron JM, et al. A prospective randomized trial of heater
probe thermocoagulation versus injection therapy in peptic ulcer hemorrhage.
Gastrointest Endosc 1996; 43:117122.
14. Chau CH, Siu WT, Law BK, et al. Randomized controlled trial comparing
epinephrine injection plus heater probe coagulation versus epinephrine injection
plus argon plasma coagulation for bleeding peptic ulcers. Gastrointest Endosc
2003; 57:455461.
15. Havanond C, Havanond P. Argon plasma coagulation therapy for acute non-
variceal upper gastrointestinal bleeding. Cochrane Database Syst Rev.
2005:CD003791.
16. Nagata S, Kimura S, Ogoshi H, et al. Endoscopic hemostasis of gastric ulcer
bleeding by hemostatic forceps coagulation. Dig Endosc. 2010; 22 Suppl 1:S22
25.
17. Lin HJ, Lo WC, Cheng YC, Perng CL. Endoscopic hemoclip versus triclip
placement in patients with high-risk peptic ulcer bleeding. Am J Gastroenterol.
2007; 102:539543.
18. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of
esophageal variceal bleeding. A meta-analysis. Ann Intern Med 1995; 123:280
287.
19. Sung JJ, Luo D, Wu JC, et al. Early clinical experience of the safety and
effectiveness of Hemospray in achieving hemostasis in patients with acute peptic
ulcer bleeding. Endoscopy 2011; 43:291-295.

, 76, 1, 2014 77
20. Kirschniak A, Subotova N, Zieker D, et al. The Over-The-Scope Clip (OTSC) for
the treatment of gastrointestinal bleeding, perforations, and fistulas. Surg Endosc
2011; 25:2901-2905.
21. Chiu PW, Hu B, Lau JY, et al. Endoscopic plication of massively bleeding peptic
ulcer by using the Eagle Claw VII device: a feasibility study in a porcine model.
Gastrointest Endosc 2006; 63:681-685.

, 76, 1, 2014 78
 .

, Sc , ,

:
:2132041638
E-mail: elenivienna@gmail.com

,
12
.
, 5%.
,
.
,

.



. , 76, 1, 79-
84, 2014.
: , ,

SUMMARY

VIENNA E. The role of the nurse in the management of patients with upper GI
bleeding. Bleeding from the proximal gastrointestinal system may be due to lesions
localized in the oesophagus, stomach and the duodenum and is a leading cause for
emergency hospital admission. Despite significant progress in the diagnosis and
management of these conditions mortality remains stable, around 5%. Upper GI

, 76, 1, 2014 79
bleeding is manifested clinically as melaena associated or not with haematemesis.
However, the prognosis is based not only on clinical signs indicative of massive blood
loss but also, on specific endoscopic criteria. Immediate assessment of patients in
critical condition is based on vital signs and signs associated with advanced liver
diseases or systemic diseases; urgent supportive intervention consists of rapid fluid
and blood replacement which falls amongst other to the responsibility of the nursing
staff as an integral part of a multidisciplinary team of experts. Furthermore, duties of
the nursing staff in the Emergency Department and in the Endoscopy Suite are
supervision of a rapid and effective cleansing of the stomach from blood, a readily
available and fully equipped Endoscopic Suite (with endoscopic instruments,
medications, and endoscopic accessories), close monitoring of the vital signs and any
other sedation- or procedure-related adverse events during the endoscopy, during
recovery from the endoscopy, and assurance that the patients leave the Endoscopy
Suite in good condition for further treatment in the Wards. Close co-operation of the
Endoscopy Staff with the endoscopist is essential to optimize endoscopy and quality of
care for the patient in order to reduce morbidity and/or mortality of severe upper
gastrointestinal bleeding. Nosokomiaka Chronika, 76, Supplement 1, 79-84, 2014.
Key words: nurse, endoscopy, upper gastrointestinal bleeding

()
, 12.

8%
1-2
. 47 116
100.000 ,
.
,
5%
.
71 44% 60 .

, 76, 1, 2014 80


50% 3-5.
. 80% ,

6.
.
20%

5.
.
Mallory Weiss (
), ,
.

7. -
.
.

30-40%.
,
.

3.
. ,

, 76, 1, 2014 81
 (, )
.
, ,
.

24
3-4.
.

.

(spurting)

(oozing)

, 76, 1, 2014 82
 ,
3,5.

8.
,
,
.

. >100
min, <100/70mmHg > 2mmHg
. 2
.
.

,
,
.

.
.

.


.
Ligator
. ( 18-20cc)


. /

clips Argon Plasma Coagulator (APC).

.

, 76, 1, 2014 83

.

1. Longstreth GF. Epidemiology and outcome of patients hospitalized with acute

lower gastrointestinal hemorrhage. A population-based study. Am J Gastroenterol
1997; 92:419-424.

2. Crooks CJ, West J, Card TR. Upper gastrointestinal heamorrhage and deprivation:
a nationwide cohort study of health inequality in hospital admissions. Gut. 2012;
61(4):514-512.

3. Barkun AN, Bardou M, Kuipers EJ, et al. International Consensus Upper

Gastrointestinal Bleeding Conference Group. International consensus
recommendations on the management of patients with nonvariceal upper
gastrointestinal bleeding. Ann Intern Med 2010; 152(2):101-113.

4. Halland M, Young M, Fitzgerald MN, et al. Characteristics and outcomes of upper

gastrointestinal hemorrhage in a tertiary referral hospital. Dig Dis Sci 2010;
55:3430-3435.

5. Barkun A, Sabbah S, Enns R, et al. The Canadian Registry on nonvariceal upper

gastrointestinal bleeding and endoscopy. ndoscopic hemostasis and proton pumb
inhibition are associated with improved outcomes in a real-life setting. Am J
Gastroenterol 2004; 99:1238-1246.

6. Well J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of pectic

ulcer bleeding. BMJ 1995; 310:827-830.

7. D Amigo G, De Franchis R, Cooperative Study Group. Upper digestive bleeding in

cirrosis. Post-therapeutic outcome and prognostic indicators. Hepatology 2003;
38:599-612.

8. Smith G.D. The management of acute upper gastrointestinal bleeding. Nurs Times.
2004;100(26):40-43.

, 76, 1, 2014 84
 .
.

.
, ...

:
: 6972094009
E-mail: markoc@otenet.gr

O
PPIs
: 80 mg 8 mg/ 72
.


2 placebo. ,

, ,
,
.
,

. .


.
. .

,

.
,

, 76, 1, 2014 85
 .
2-4
.
.
cyanoacrylate.

. , 76, 1, 85-92,
2014.
: , , ,
,

SUMMARY

MARKOGLOU K. Upper GI bleeding: Management after endoscopy and

indications of second look endoscopy. Patients with high risk stigmata following
endoscopic therapy should be given high-dose bolus and continuous infusion proton
pump inhibitors. Four randomized trials have shown decreased rebleeding and in
some cases reduced need for surgery compared with H2-receptor antagonists or
placebo. Moreover, the proton pump inhibitor therapy reduces rates of rebleeding
and mortality in high risk patients and even suggested a trend toward decreased
rebleeding in patients with low-risk stigmata. Both the rational for the use of proton
pump inhibitors and the existing data suggest that the improvement in rebleeding can
be achieved by using intravenous omeprazole or pantoprazole 80mg bolus followed by
8mg/h for 72 hours after endoscopic therapy. Patients considered at low risk for
rebleeding after endoscopy can be fed within 24 hours and should be tested for
Helicobacter pylori. If infection is present eradication therapy should be given. Routine
second look endoscopy is not recommended. Scheduled repeated endoscopy after
initial successful treatment did not improve outcomes compared with second
endoscopy performed only on recurrent hemorrhage. In case of rebleeding a second
attempt at endoscopic therapy is recommended and surgical consultation should be
sought for patients who have failed endoscopic therapy. Somatostatin and octreotide
do not improve outcomes therefore there is no need to use them in the routine
management of patients with acute nonvariceal upper GI bleeding.

In patients with current bleeding from esophageal varices, endoscopic variceal ligation
is superior to endoscopic sclerotherapy. Ligation should be performed every 2 to 4

, 76, 1, 2014 86
weeks until the varices are eradicated. Concomitant beta blocker therapy is
recommended. Sclerotherapy is reserved for patients who fail ligation. Endoscopic
treatment for obliteration of gastric varices after an episode of hemorrhage is not
recommended, as there are not sufficient data. Nosokomiaka Chronika, 76,
Supplement 1, 85-92, 2014.
Key words: upper GI bleeding, second-look endoscopy, PPI.s

, ,
,

.

H PPIs
,

1992 - 2007 ,
,
1. , ,



1. PPIs

. 2 PPIs
.

80 mg PPIs bolus 8 mg/h

72 2.

PPIs 72


3,4,5,6. ,

, 76, 1, 2014 87
 ,
.

2.

7.

,
8. test
9.
test
. ,
, .
.

2.
.

, ,

,
.

10,11. H Levin

.
. 15%

12.
.

,

, 76, 1, 2014 88
 .

.

H
24,

13.
Mallory-Weiss,
, ,
, , 2.

.


14.

,
.
.


,
15.

.
-16,
,
,
. -
17.

, 76, 1, 2014 89
 15
2-4 . O
6-12
.

, , cyanoacrylate

,
.

.

cyanoacrylate .
18.

1. Sreedharan A, Martin J, Leondiadis GI, et al. Proton pump inhibitor treatment,

initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding.
Cochrane Database System Rev 2010; CD005415 .

2. Barkun A, Bardou M, Marshall K. for the Nonvariceal Upper GI Bleeding

Consensus. Consensus Recommendations for Managing Patients with
Nonvariceal Upper Gastrointestinal Bleeding . Ann Intern Med 2003; 139:843-857.

3. Lau JY, Sung JJ, Lee KK. Effect of intravenous omeprazole of recurrent bleeding
after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000; 343:310-
316.

4. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor treatment for acute
peptic ulcer bleeding . Cochrane Database System Rev 2006; CD002094.

5. Sung JJ, Barkun A, Kuipers EJ, et al. Intravenous esomeprazole for prevention of
re-current peptic ulcer bleeding: A randomized trial. Ann Intern Med 2009;
150:455-464.

6. Laine L, McQaid KR. Endoscopic therapy for bleeding ulcers. An evidence based
approach based on meta-analyses of randomized controlled trials. Clinical
Gastroenterol Hepatol 2009; 7:33-47.

, 76, 1, 2014 90
7. Lai KC, Hui WM, Wong WM, et al. Treatment of helicobacter pylori in patients with
duodenal ulcer hemorrhage-a long term randomized controlled study. Am J
Gastroenterol. 2000; 95:2225-2232.

8. Riemann JF, Schilling D, Schauwecker P, et al. Cure with omeprazole plus

amoxicillin versus long-term ranitidine therapy in helicobacter pylori-associated
peptic ulcer bleeding. Gastrointest Endosc 1997; 46:299-304.

9. Houghton J, Ramamoorthy R, Pandya H, et al. Human plasma is directly

bacteriocidal against Helicobacter pylori in vitro, potentially explaining the
decreased detection of Helicibacter pylori during acute upper GI bleeding.
Gastrointest Endosc 2002; 55:11-16.

10. Singer AJ, Richman PB, Kowalska A, et al. Comparison of patient and practitioner
assassements of pain from commonly performed emergency department
procedures. Ann Emerg Med 1999; 033:652-658.

11. Palamidessi N, Sinert R, Falzon L, et al. Nasogastric aspiration and lavage in

emergency department patients with hematochezia or melena, without
hematemesis. Acad Emerg Med 2010; 17:126-132.

12. Cuelar RE, Gavaler JS, Alexander JA, et al. Gastrointestinal tract hemorrhage.
The value of a nasogastric aspirate. Arch Intern Med 1990; 150:1381-1384.

13. Laine I, Cohen H, Brodhead J, et al. Prospective evaluation of immediate versus

delayed refeeding and prognostic value of endoscopy in patients with upper
gastrointestinal hemorrhage. Gastroenterology 1992; 102:314-316.

14. Messmann H, Schaller P, Andus T, et al. Effect of programmed endoscopic follow-

up examinations on the rebleeding rate of gastric or duodenal peptic ulcers
treated by injection therapy: A prospective randomized controlled trial. Endoscopy
1998; 30:583-589.

15. Lau JY, Sung JJ, Lam YH, et al. Endoscopic retreatment compared with surgery in
patients with recurrent bleeding after initial endoscopic control of bleeding ulcers.
N Engl J Med 1999; 340:751-756.

16. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for the
treatment of esophageal varices bleeding: a meta-analysis. Ann Intern Med 1995;
123:280-287.

, 76, 1, 2014 91
17. De la Penna J, Brullet E, Hernandez- Sanchez E. Variceal ligation plus nadolol
compared with ligation for variceal rebleeding: A multicenter trial. Hepatology
2005; 41:572-578.

18. ASGE Guideline: the role of endoscopy in the managementof variceal

hemorrhage, updated July 2005. Gastrointest Endosc 2005; 62:651-654.

, 76, 1, 2014 92

:

, ...

: 2132041801
Email: iliopoulosv@hotmail.com

()
,
. ,
/ Mallory-
Weiss. 80%85% , ,
, .
.
, 20%35%
5%10%
.

.
, ,
.
, ,
, ,
()
. ,
,
. , ,
10%.
.
,

.
, 76, 1, 93-109, 2014.

, 76, 1, 2014 93
 : , , ,

SUMMARY
ILIOPOULOS E.: Acute upper gastrointestinal hemorrhage. Surgical therapy: to
whom and when. Acute upper gastrointestinal bleeding (UGIB) is a common clinical
problem with diverse manifestations, depending on the cause, magnitude and whether
bleeding is trivial or massive. The most common causes are peptic ulcer disease,
esophageal varices, erosive gastritis/duodenitis and Mallory-Weiss syndrome. In 80%-
85% of patients with non-variceal bleeding this is self-limited, while the rest of the
patients require a therapeutic intervention. Endoscopy is the cornerstone of UGIB
diagnosis and management. About 20%-35% of patients undergoing urgent
endoscopy, require endoscopic hemostasis and 5%-10% of these, need an operative
intervention due to ongoing or recurrent bleeding. The operative strategy is
determined by the cause and location of bleeding as well as the patients general
condition. The primary goal is the control of bleeding and secondary, if it is allowed by
the patients general condition, the definite management of the underlying disease.
Duodenal ulcer hemorrhage is treated by ligation of the bleeding vessels, ulcer
sewing, truncal vagotomy and pyloroplasty or by truncal vagotomy, antrectomy
(including the ulcer) and gastrojejunostomy or gastroduodenostomy. Because of high
incidence of malignancy, gastric ulcers require partial gastrectomy, or excision, truncal
vagotomy and pyloroplasty. Postoperative mortality remains high, exceeding 10%.
This is because patients are older, with serious co-morbid illnesses, and are unable to
withstand surgery after major blood loss and hypotension. Other rare causes of
bleeding require more specialized operations, while the recent years, the role of
surgery in the management of bleeding related to portal hypertension has been
significantly limited. Nosokomiaka Chronika, 76, Supplement 1, 93-109, 2014.
Key words: upper gastrointestinal bleeding, gastric/duodenal ulcer, surgical treatment

()
. 50150 100000
.
Treitz, , , .
,
, ,

, 76, 1, 2014 94
 . ,
)
, 20% )
, 80% .
,
/ ( 1).

1. ()

(%)
* 62%
8%
6%

, , Dieulafoy,
10%

Mallory-Weiss 4%
2%
8%
: , *

)
)
)

. 80%85%
, ,
. ,
, 20%35%
. 10%
10%20% 2472
.
, 5%10%, 2%3%

.

, 76, 1, 2014 95

.

.
.

,

,
,
().
2.

()

.

:
1.
90%95%
2.
3. ,
4.
.

, 76, 1, 2014 96
 2.

> 60





>100/
<100mmHg

3.
,
. , ,
4, ,

.
,

.
,
, ,
:





,
.

.

, 76, 1, 2014 97
 ,

, )


) .

3.

6
* 8 10

.

2

,
,



3
* ^ 1

2
, ,
72 . 2

75% ,
.

, 76, 1, 2014 98
 4.

(10%)

,
, , .
,
, . ,

(permissive hypotension),

.
.
, ,
.
,
, 2 .
,
,
,
,
.


Forrest ( 5),

, 76, 1, 2014 99
 .
(>2cm),
.

5. Forrest 21

(%) (%)

Ia 55 11
(spurting)
Ib (oozing) 55 11

IIa 43 11

IIb 22 7

IIc 10 3

III 5 2

1.
2.
3. ,

, 76, 1, 2014 100



.

, ,
.
,
().
,
Billroth II
Billroth I,
( 1). ,
()
() .
U
,
, .
,

Billroth I
Billroth II.
,
.
,
.

Billroth I Billroth II
1. , Billroth I

, 76, 1, 2014 101


( 2).

V


V

2. Johnson

:
10%
( )


,
() (
V).

30% 20% .
,

, 76, 1, 2014 102


Billroth I Billroth II.
(/)
Billroth I
Billroth II.
.
. 2
5 cm

Billroth I (
Pauchet/Shoemaker, 3). ,
,
(tongue-shaped resection)
Roux-en-Y ( Csendes, 3).
( Kelling-Madlener, 3)
, ,
.
.
Mallory Weiss
Mallory-Weiss, 90%
75% .
50-80% .
,
50% .
. ,
.
.

, 76, 1, 2014 103


3. IV.
. Pauchet, . Kelling-Madlener, . Csendes

Stress (stress gastritis)

.
. ,
(Curlings ulcers), (Cushings ulcers)
.
.

,
. .
.
, 60%.
Dieylafoy

(d=13mm).
6cm .
. ,
.
,
(tattooing).
. .

, 76, 1, 2014 104


(Watermelon stomach).

. .

.

,
. .
.

.

, . 1%
.
3
.

.
.
3 4 12, ,
. .
,
,
.
.25

.
, .
. ,
.
Vater. ,

.

, 76, 1, 2014 105

 (Hemosuccus pancreaticus)
.

. .
.
,
.


2% .
.
48 .
. .
3% ,
.

.
1-2cm.
.
30%
30% .
.

(vasopressin, somatostatin or octreotide).

( ).
90%.
.
Sengstaken-Blakemore Minnesota.
50% .
TIPS (Transjugular Intrahepatic Portosystemic Shunt)
95% .
- , ,
TIPS . ,
.

, 76, 1, 2014 106

 , .
- (Distal Sleno-Renal Shunt, DSRS)
-
( 4). DSRS,
,
.
,
, , ,
, .
DSRS

. , Child A
DSRS 5%6%,
15% 3 85% 75% .24

.
. ,

(4%).

4. ( Warren)

, 76, 1, 2014 107



.
.
,
/, .

1. Lu Y, Loffroy R, Lau JYW, et al: Multidisciplinary management strategies for acute
non-variceal upper gastrointestinal bleeding. Br J Surg 2012; 101:e3450.
2. Rockey DC: Gastrointestinal bleeding. Gastroenterol Clin North Am 2005;34:581
588.
3. Barkun AN, Bardou M, Kuipers EJ, et al: International consensus
recommendations on the management of patients with non-variceal upper
gastrointestinal bleeding. Ann Intern Med. 2010;152:101-113.
4. Dulai GS, Gralnek IM, Oei TT, et al: Utilization of health care resources for low-risk
patients with acute non-variceal upper GI hemorrhage: an historical cohort study
Gastrointest Endosc 2002; 55:321327.
5. Tsoi KK, Ma TK, Sung JJ: Endoscopy for upper gastrointenstinal bleeding: How
urgent is it? Nat Rev Gastroenterol Hepatol 2009; 6:463-469.
6. Sarin N, Monga N, Adams PC: Time to endoscopy and outcomes in upper
gastrointestinal bleeding. Can J Gastroenterol 2009; 23:489493.
7. Tavakkolizadeh A, Ashley SW. Acute gastrointestinal hemorrhage In: Sabiston
Textbook of Surgery: The Biological Basis of Modern Surgical Practice, Townsend
CM, Beauchamp RD, Evers BM, et al ed. Elsevier Saunders, Philadelphia 2012.
8. Lassen A, Hallas J, Schaffalitzky de Muckadell OB: Comlicated and uncomplicated
peptic ulcers in a Danish county 1993 2002: A populationbased cohort
study Am J Gastroenterol 2006;101:945953.
9. Sung JJ: Marshall and Warren Lecture 2009: Peptic ulcer bleeding: An expedition
of 20 years from 19892009 J Gastroenterol Hepatol 2010;25:229233.
10. Mahvi DM, Krantz SB. Stomach In: Sabiston Textbook of Surgery: The Biological
Basis of Modern Surgical Practice, Townsend CM, Beauchamp RD, Evers BM, et
al ed. Elsevier Saunders, Philadelphia, 2012.

, 76, 1, 2014 108

11. Cheng EY, Hiatt JR, Busuttil RW. Portal hypertension: the role of shunting
procedures, In: Current Surgical Therapy, Cameron JL, Cameron AM, ed. Elsevier
Saunders, Philadelphia 2014.
12. Henderson MJ. Multidisciplinary approach to the management of portal
hypertension, In: Shackelford's Surgery of the Alimentary Tract, Yeo CJ, ed.
Elsevier Saunders, Philadelphia 2013.

, 76, 1, 2014 109



, ,
...

:
: 6947570301
-mail: vtsaousis@hotmail.com

20
.
, ,
,
,
,

,
.

:





.


. -
,
,

.
,
1948,

, 76, 1, 2014 110

 1983 , ,

15% 6%.


.

/ ,
.
.


, ,
, ( 5 )
(). 1
. 2
. 3

4
.
( 1,2).
43%
, . 85%
3 4. 76%
3 4 37%
.
. 17,2 26,9
7,77,7 (p<0,01). 18% , 25%
4% .

. :
1. ,

,
.

, 76, 1, 2014 111

 2.
, .

.

.
.
Rockall score system (, , ,
, )
,
()
(standardized mortality ratio, SMR).


.
.
:



.

24


,
.

1. Warthin T, Warren R, Wissing E. Combined medical and surgical management
of upper gastrointestinal hemorrhage N Engl J Med. 1949;241:473478.
2. Hunt P.S, Francis JK, Hanski J, et al. Reduction in mortality from upper
gastrointestinal haemorrhage. Med J. Aust 1983;2:552555.

, 76, 1, 2014 112

3. Lee JG, Turnipseed S, Romano PS, et al. Endoscopy-based triage significantly
reduces hospitalization rates and costs of treating upper GI bleeding: a
randomized controlled trial. Gastrointest Endosc 1999;50:755761.
4. Cooper G, Chak A, Connors A, et al. The effectiveness of early endoscopy for
upper gastrointestinal hemorrhage. Med Care 1998;36:462474.
5. Spiegel BMR, Vakil NB, Ofman JJ. Endoscopy for acute nonvariceal upper
gastrointestinal tract hemorrhage: Is sooner better? A systematic review. Arch
Intern Med 2001;161:13931404.
6. Rollhauser C, Fleischer DE. Current status of endoscopic therapy for ulcer
bleeding. Best Pract Res Clin Gastroenterol 2000;14:391410.
7. Barkun A, Bardou M, Marshall JK. Consensus recommendations for managing
patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med
2003;139:843857.
8. Sandel MH, Kolkman JJ, Kuipers EJ, et al. Nonvariceal upper gastrointestinal
bleeding: differences in outcome for patients admitted to internal medicine and
gastroenterological services. Am J Gastroenterol 2000;95:23572362.
9. Baradarian R, Ramdhaney S, Chapalamadugu R, et al. Skoczylas L, Wang K,
Rivilis S, et al. Early Intensive Resuscitation of Patients with Upper
Gastrointestinal Bleeding Decreases Mortality. Am J Gastroenterol 2004;99:619
622.
10. Hampers Mj, Surgenor SD, Spanjian K, et al. ICU care for patients with
gastrointestinal bleeding: Impact on cost and outcome. Clin Intensive Care
2002;13:109113.
11. Kapur K, Green j, Turner R, et al. Auditing mortality from upper gastrointestinal
haemorrhage: impact of a high dependency unit. J R Coll Physicians (Lond)
1998;32:246250.
12. Sanders DS, Perry MJ, Jones SGW, et al. Effectiveness of an upper-
gastrointestinal haemorrhage unit: A prospective analysis of 900 consecutive
cases using the Rockall score as a method of risk standardisation. Eur J
Gastroenterol Hepatol 2004;16:487494.

, 76, 1, 2014 113



. , MD, PhD1, . , MD, PhD2

1
. o , 2
-, ...

:
.
: 2132043164, 6986488412
E-mail: cpapaste@gmail.com

. ,
, ,
,
,
. , -,
, ,
,
.


.

,
.

. ,
, ,
, ,

.
,

, 76, 1, 2014 114


,
- ,
. , 76,
1, 114-136, 2014.
: , ,
,

SUMMARY
PAPASTERIADES CH, KITSIOU V. The immunological paradox of pregnancy.
Mammals embryos bear antigens both of paternal and maternal origin. The paternal
antigens of the embryos could be considered foreign to the mothers immune system
(semi-allograft) and should mount an immune response leading to immunological
rejection of the embryos. But, despite these genetic dissimilarities that should lead to
immunological rejections, as it is seen in transplantation, human embryos are usually
carried to term and healthy babies are born. This phenomenon has long been
considered as the immunological paradox of pregnancy and raises the questions of
how the mothers immune system is diverted so as to permit cohabitation with the
foreign body. Several decades of research have shown that multiple cooperative fetal
and maternal systems contribute to the uteroplacental immune privilege. These
systems include production of several soluble immunosuppressive molecules in the
uterus and the placenta and strict regulation of the molecules expressed on or by
placental trophoblast cells which are in direct contact with maternal blood and tissue.
The immunological paradox of pregnancy appears to be extremely complex and
despite the vast body of knowledge about the subject many questions still need
answers. In particular, the role of the innate immune system both in the periphery
and in the decidua in successful pregnancy has until now been underexposed.
Understanding of the immune status alterations during pregnancy will help to explain
and prevent immunological abortions, to explain several mothers and fetus disorders
during pregnancy, as well as to facilitate assisted reproductive technologies.
Nosokomiaka Chronika, 76, Supplement 1, 114-136, 2014.
Key words: immunology in pregnancy, embryos survival, fetus as an allograft

, 76, 1, 2014 115



-
, (),
- ( ).

,
- (.. , ).1
,
() ()
() ,
.
, ,
, , ,
( )
( ) ()
. ,
, .
- ,
50% -
- .
,
, , , ,
,
. ,
,
.
.2



. , ,

.

, 76, 1, 2014 116

 ,
. , ,
, ,
. ,


- . ,

,
, .

Nobel Sir Peter
Medawar,
.3 Medawar
-: 1) 2)
3)
4) 5)
.
1)
2)

3)

.

Medawar, , : 1) ,
,
2)
3)


,
.

, 76, 1, 2014 117


.

, .
,
(trophectoderm)
(inner cell mass) .
( )
,
,
.
, .
(decidualization)
.

.4 10
,
.
,

.5 ,
,

. :
(villous cytotrophoblast-vCTB)
(syncytialized trophoblast-sTB). vCTB
,
, ,
: , ,
, ,
. ,
( Hofbauer),
,

.

, 76, 1, 2014 118

 ,
(extravillous cytotrophoblast - xvCTB),
. vCTB

. ,
xvCTB
.
, .
,
. ,
,
. , xvCTB
,
.6,7 ,


.


. ( 1,2,3)

. (, ,
, )
-
.
.


1971 AG Voisin, o
, , ,
.8 (
)

, 76, 1, 2014 119

 . ( )
,
.
. ,
, ,
.
,
-
.9
1980 Tom Wegmann
,
, GM-CSF (granulocyte macrophage colony
stimulating factor), TGF- (transforming growth factor) IL-3.10
., Th1/Th2
, Th2 (IL-4, IL-5, IL-10)
Th1 (IL-2, IFN-). Th2
,

.11 Th2

. , , Th2
, ,
. ,
( ,

Th2), .

Th2

. IFN-, Th1
,

.12 ,

, 76, 1, 2014 120

 ,
.13

Th2, Th1 ,
(IL-12, IL-15, IL-18), ,
.
Th1 (. IL-12)
Th2 (IL-10)
, .
(..
(hCG), , (relaxin)),
,
. .. Th2
hCG ,
.
Th2 ,
Th1
.14

Th2 ,

, .
,
,

.15

)
,
, ,

,
.16 .. , ,
Th2 , T

, 76, 1, 2014 121

.17 ,
, TGF- ,

,
,
.18 , IL-10
Th2 .19
)

,
/ .
:
: (MHC),
, , Fc
, , . ,
,
, .20
:
Th2 , CD1d
.
, T NK
.21
:

Th2 . (heat shock
proteins-hsp), 1 (pregnancy specific b1-
glycoprotein - psB1G) MHC HLA-G
,
IL-10 Th2 .22,23
LIF-R, LIF (leukemia
inhibitory factor). LIF,
, ,
Th2 .24
, hCG,
. ,

, 76, 1, 2014 122

 , PIBF (progesterone
induced blocking factor), IL-4
, Th2 .25
HLA-G:
, , , HLA-G
, .
, HLA (HLA-A,-B,-C)
(HLA-DR,-DQ,-DP)
.
.26 , HLA
.
HLA (HLA-A,-B) (HLA-DR, -DQ, -
DP) . ,
, HLA

. ,
, ,
HLA HLA-C,
(HLA-E,-F,-G). HLA
, ,

. , HLA-G
.
xvCTB , HLA-G mRNA
HLA-G , sTB vCTB
HLA-G mRNA, HLA-G .
, HLA-G sTB .
, HLA-G5 ,

.
HLA-G

,
. :
) ( ),

, 76, 1, 2014 123

) () ,
) , )
, )

. , HLA-G
-
,
.6,27
)
, ,
: ) ,
(dendritic cells-
DCs) ) , DCs
.28
, ,
DCs
.

.
. ,
,

.29
)



.15.
,
.
,
,

.
(APCs):

, 76, 1, 2014 124

 ( CD14+MHC II+), (DC CD83+)
(CD83-) .


, APCs.
,

.
(decidual-d) 20-30%
,
.
,
, .
.30,31
(dendritic cells-DCs)

.
.32
:
, ,

. ,
.
: , CD8+
CD4+ .
,

,
MHC/ .33 ,
CD8+ (CD8+ T
)

.29
:
. , MHC

, 76, 1, 2014 125

 .
HLA
(class I-like) . V
,
.
V ,
V 9/V 2 TcR.
V .4V
Th2. ,
PIBF (progesterone induced blocking factor),
in vivo.25
,
.34
: (Tregs
CD4+CD25+) .35,36
,

, de novo
37
.
: )


(IL-10, TGF) ) ,
CTLA 4 ,
indoleamine 2,3 deoxygenase (IDO),

.38 ,

.39
:

CD1 , ,
, h2 .21
)

, 76, 1, 2014 126


, :
Indoleamine 2,3 deoxygenase (IDO),
, ,
(
)
.40
, Fas/FasL,
. FasL (CD95-
L) , ( Fas-CD95) ,

, Fas-CD95.41
)
,
.

. , DAF (Decay Accelerating Factor-
DAF) MCP (Membrane Cofactor Protein-MCP),
C3 C4 . DAF-CD55
C3
C3
. MCP-CD46 (TLX-Trophoblast-Lymphocyte Cross-
Reactive Antigens)
C3b C4b .
, CD59,
MAC (Membrane Attack Complex-MAC),
.
, ,

.42
)

, .43
,
,

, 76, 1, 2014 127

 ,
, .
in
vitro. , in vivo
.
,
( )
- .44,45

1990,
,
(dNK).46


.
. 90%
CD3-CD56+brightCD16-.
CD56
.
.
,

(monocyte chemotactic protein-3, eotaxin, fractlakine, macrophage inflammatory
protein 1-b, 6Ckine, IL-8, hemofiltrate CC chemokine-1 4, macrophage-derived
chemokine).47

.
,
.
, 2

. ,
.
,
.

, 76, 1, 2014 128

 , 70%
.
.48

,
. ,
,
, IFN-,
, .
, ,


.12
, dNK
,
Th2 ,
.49,50
, dNK
:
KIR (Killer Immunoglobulin-like Receptors-KIR),
-C (C-type lectin family CD94/NKGs),
ILTs LIRs (Immunoglobulin-like Transcripts-ILTs)
NCRs (Natural Cytotoxicity Receptors-NCRs) .
, dNKs HLA
.
HLA
G , HLA C,
. ,
HLA-G HLA-C
dNK .
,
.
,
(Th1 )
(Th2

, 76, 1, 2014 129

).51 ,

. , dNK
,
dNK .
, dNK
.52 dNK

dNK HLA ,
.

, KIR
(inhKIR) , HLA-C ,

.53 ,
inhKIR, HLA-C ,
inhKIR
dNK HLA-C .
-
dNK ,
.

,
,
,
. ,54
, ,
, , , ,

-
.

,
.

, 76, 1, 2014 130

 ,
, , .

1. 6-7
1.
2. ( )
3.
4.
5. ( )
( ,
- )

2.

(American Journal of Obstetrics and Gynecology Volume 195, Issue 1, July 2006,
Pages 2939)

, 76, 1, 2014 131

 3.
( ,
- )

1. . . . 20
, 22-24 2004.
2. Papasteriades C, Varla-Leftherioti M. The immune paradox of pregnancy. Anosia
2009; Suppl: 74-82.
3. Medawar PB. Some immunological and endocrinological problems raised by the
evolution of viviparity in vertebrates. Symp Soc Exp Biol. 1953;44:320338.
4. Burton GJ, Hempstock J, Jauniaux E. Oxygen, early embryonic metabolism and
free radical-mediated embryopathies. Reprod Biomed Online. 2003 Jan-
Feb;6(1):84-96.
5. Bulmer JN, Pace D, Ritson A. Immunoregulatory cells in human decidua:
morphology, immunohistochemistry and function. Reprod Nutr Dev.
1988;28(6B):1599-613.
6. Hunt JS. Stranger in a strange land. Immunol Rev. 2006 Oct;213:36-47.
7. Rossant J, Cross JC. Placental development: lessons from mouse mutants. Nat
Rev Genet. 2001 Jul;2(7):538-548.
8. Voisin GA. Immunological facilitation, a broadening of the concept of the
enhancement phenomenon. Prog Allergy. 1971;15:328-485.
9. Chaouat G, Voisin GA, Escalier D. Facilitation reaction (enhancing antibodies and
suppressor cells) and rejection reaction (sensitized cells) from the mother to the
paternal antigens of the conceptus. Clin Exp Immunol. 1979 Jan;35(1):13-24.
10. Wegmann TG. Placental immunotrophism: maternal T cells enhance placental
growth and function. Am J Reprod Immunol Microbiol. 1987 Oct;15(2):67-69.
, 76, 1, 2014 132
11. Wegmann TG, Lin H, Guilbert L. Bidirectional cytokine interactions in the maternal-
fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today.
1993 Jul;14(7):353-356.
12. Ashkar AA, Di Santo JP, Croy BA. Interferon gamma contributes to initiation of
uterine vascular modification, decidual integrity, and uterine natural killer cell
maturation during normal murine pregnancy. J Exp Med. 2000;192(2):259-270.
13. Chaouat G, Lede-Bataille N, Dubanchet S. TH1/TH2 paradigm in pregnancy:
paradigm lost? Cytokines in pregnancy/early abortion: reexamining the TH1/TH2
paradigm. Int Arch Allergy Immunol. 2004;134(2):93-119.
14. Carp H, Torchinsky A, Fein A. Hormones, cytokines and fetal anomalies in habitual
abortion. Gynecol Endocrinol. 2001;15(6):472-483.
15. Thellin O, Coumans B, Zorzi W. Tolerance to the foeto-placental 'graft': ten ways to
support a child for nine months. Curr Opin Immunol. 2000;12(6):731-737.
16. Mellor AL, Munn DH. Immunology at the maternal-fetal interface: lessons for T cell
tolerance and suppression. Annu Rev Immunol. 2000;18:367-391.
17. Piccinni MP, Giudizi MG, Biagiotti R. Progesterone favors the development of
human T helper cells producing Th2-type cytokines and promotes both IL-4
production and membrane CD30 expression in established Th1 cell clones. J
Immunol. 1995;155(1):128-133.
18. Robertson SA. Seminal plasma and male factor signaling in the female
reproductive tract. Cell Tissue Res. 2005;322(1):43-52.
19. Kelemen K, Paldi A, Tinneberg H. Early recognition of pregnancy by the maternal
immune system. Am J Reprod Immunol. 1998;39(6):351-355.
20. Varla-Leftherioti M. MHC and other antigens at the fetomaternal interface. In: Lukic
ML, Colic M, Mostarica-Stojkovic M, Cuperlovic K eds. Immunoregulation in Health
and Disease. Experimental and clinical aspects. Academic Press Limited, 1997:
367-381.
21. Boyson JE, Rybalov B, Koopman LA. CD1d and invariant NKT cells at the human
maternal-fetal interface. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13741-
13746.
22. Clark DA. Signaling at the fetomaternal interface. Am J Reprod Immunol.
1999;41(3):169-173.
23. Clark DA, Arck PC, Chaouat G. Why did your mother reject you? Immunogenetic
determinants of the response to environmental selective pressure expressed at the
uterine level. Am J Reprod Immunol. 1999;41(1):5-22.

, 76, 1, 2014 133

24. Kojima K, Kanzaki H, Iwai M. Expression of leukaemia inhibitory factor (LIF)
receptor in human placenta: a possible role for LIF in the growth and differentiation
of trophoblasts. Hum Reprod. 1995;10(7):1907-1911.
25. Szekeres-Bartho J, Barakonyi A, Polgar B. The role of gamma/delta T cells in
progesterone-mediated immunomodulation during pregnancy: a review. Am J
Reprod Immunol. 1999;42(1):44-48.
26. . (HLA) .

3 , 26-29
2009.
27. Le Bouteiller P. HLA-G and local placental immunity.Gynecol Obstet Fertil. 2003
Sep; 31(9):782-5.
28. . . 2008; 4,
: 112-116.
29. Erlebacher A, Vencato D, Price KA. Constraints in antigen presentation severely
restrict T cell recognition of the allogeneic fetus. J Clin Invest. 2007;117(5):1399-
1411.
30. Mizuno M, Aoki K, Kimbara T. Functions of macrophages in human decidual tissue
in early pregnancy. Am J Reprod Immunol. 1994;31(4):180-188.
31. Kmmerer U. Antigen-presenting cells in the decidua. Chem Immunol Allergy.
2005;89:96-104.
32. Laskarin G, Kmmerer U, Rukavina D. Antigen-presenting cells and materno-fetal
tolerance: an emerging role for dendritic cells. Am J Reprod Immunol.
2007;58(3):255-267.
33. Jiang SP, Vacchio MS. Multiple mechanisms of peripheral T cell tolerance to the
fetal "allograft". J Immunol. 1998;160(7):3086-3090.
34. Psarra K, Kapsimali V, Tarassi K, et al. TCRgammadelta + T lymphocytes in
unexplained recurrent spontaneous abortions. Am J Reprod Immunol.
2001;45(1):6-11.
35. Heikkinen J, Mttnen M, Alanen A. Phenotypic characterization of regulatory T
cells in the human decidua. Clin Exp Immunol. 2004;136(2):373-378.
36. Sasaki Y, Sakai M, Miyazaki S. Decidual and peripheral blood CD4+CD25+
regulatory T cells in early pregnancy subjects and spontaneous abortion cases.
Mol Hum Reprod. 2004;10(5):347-353.

, 76, 1, 2014 134

37. Zhao JX, Zeng YY, Liu Y. Fetal alloantigen is responsible for the expansion of the
CD4(+)CD25(+) regulatory T cell pool during pregnancy. J Reprod Immunol.
2007;75(2):71-81.
38. Saito S, Sasaki Y, Sakai M. CD4(+)CD25high regulatory T cells in human
pregnancy. J Reprod Immunol. 2005;65(2):111-120.
39. Zenclussen AC, Gerlof K, Zenclussen ML. Abnormal T-cell reactivity against
paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced
CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model.
Am J Pathol. 2005;166(3):811-822.
40. Mellor AL, Chandler P, Lee GK. Indoleamine 2,3-dioxygenase,
immunosuppression and pregnancy. J Reprod Immunol. 2002;57(1-2):143-150.
41. Zorzi W, Thellin O, Coumans B. Demonstration of the expression of CD95 ligand
transcript and protein in human placenta. Placenta. 1998;19(4):269-277.
42. Girardi G. Complement inhibition keeps mothers calm and avoids fetal rejection.
Immunol Invest. 2008;37(5):645-659.
43. , , .
.
1996;8(2):132-139.
44. Bell SC, Billington WD. Anti-fetal allo-antibody in the pregnant female. Immunol
Rev. 1983;75:5-30.
45. Mowbray J, Jalali R, Chaouat G. Maternal response to paternal trophoblast
antigens. Am J Reprod Immunol. 1997;37(6):421-426.
46. King A, Loke YW, Chaouat G. NK cells and reproduction. Immunol Today.
1997;18(2):64-66.
47. Jones RL, Hannan NJ, Kaitu'u TJ. Identification of chemokines important for
leukocyte recruitment to the human endometrium at the times of embryo
implantation and menstruation. J Clin Endocrinol Metab. 2004;89(12):6155-6167.
48. Trundley A, Moffett A. Human uterine leukocytes and pregnancy. Tissue Antigens.
2004;63(1):1-12.
49. Clark DA, Arck PC, Jalali R. Psycho-neuro-cytokine/endocrine pathways in
immunoregulation during pregnancy. Am J Reprod Immunol. 1996;35(4):330-337.
50. Chaouat G, Tranchot Diallo J, Volumenie JL. Immune suppression and Th1/Th2
balance in pregnancy revisited: a (very) personal tribute to Tom Wegmann. Am J
Reprod Immunol. 1997;37(6):427-434.

, 76, 1, 2014 135

51. E. Konsta, V. Kitsiou, K. Psarra, V. Kapsimali, T. Athanassiades, D. Kouniaki, V.
Stamati, S. Dendrinos, G. Kreatsas, C. Papasteriades Two different approaches
for the study of NK cells receptors in unexplained recurrent spontaneous abortions
(URSA) Book, Title: 2nd European Congress of Immunology (ECI), 2009, p.73-75,
Medimond International Proceedings.
52. Varla-Leftherioti M. The significance of the women's repertoire of natural killer cell
receptors in the maintenance of pregnancy. Chem Immunol Allergy. 2005;89:84-
95.
53. Varla-Leftherioti M. Role of a KIR/HLA-C allorecognition system in pregnancy. J
Reprod Immunol. 2004;62(1-2):19-27.
54. . .
, 2013.

, 76, 1, 2014 136



...

:
: 2132041928
E-mail: sdmentzelopoulos@yahoo.com

*
,
1-5/1000 .

( )
( ).
-
.
-

,
5-10%.
.

( 51 mm,
100/).
(
).


.

.

, 76, 1, 2014 137

 , . ,
( 1 / 3-5 1
/ 6-10 ) . , ,
(
) stress shock
(
). -

.
,
. , / / shock

, ,
,

/ shock
(..
70%),
shock. , 76, 1, 137-138,
2014.
: , ,
, , , -1 ,
, , ,

, 76, 1, 2014 138



N.
,
...

:
/: 44, 106 76
E-mail: myparara@yahoo.gr

, 6 ,
, -
. , .
,
, , 5-10
.
, ,
,
.
, ,
4-6000 . .
. .
, . ,
,
. ,
, .
, , ,
, .
, ,
. ,

1/2 .
,
, .
, 76, 1, 2014 139

,
.
!!
,
.
,
:
. ,
.
. ,
. , A N
E, (, , ,
) ,
, 12.
, ,
,
,
.

, .
, ,
,
.

, ,
.
, ,
.
,
, ,
.
,
. , , , .

, 76, 1, 2014 140

 Wertheimer
(Gestait) , ,
, ,
.
,
:
1.
2. /
3.
4.
5.
6.
7. /
8.
9.
10. /
11.
12.
13.
14.
15. /
16.
17.
18. /
19.
20.
21.
22.

, , ,
, CYRIL CONNOLY- -
, ,
-
, , , .
, , , ,
, ,
.
:
. ,

.
, .

, 76, 1, 2014 141

 , , ,
,
, .
.
,
, , ,
. , ,
, ,
.
, ,
, , MCV, Fe
, , 12 .
, , .

, MayGrunwald-Giemsa
( , -
) .

,
. , G6-PD,
.
. ,

. , , , , ,
,
.
,
,
, , ,
, , ,
, , ,
.
,
,
(2) ( ,

, 76, 1, 2014 142

) . , ,

, , :
1. - ( )
2. ( )
3. - ( )
4. ( )
5. (
)
6. MCV - -
(
Biermer)
7. - ( )
8. - (

).
9. - ,

( Moschowitz)
10. ( Evans)
11. -
(
)

.
,
, ,
.
,
: , , ,
, .
, ,
, .
. ,

, 76, 1, 2014 143

 , ,
, , ,
, - , .

-
,
, ,
. , ,
.
, :
A. , ( ,
.)
B. , , , , ,
,
. , , ,
, .
. , ,

, ,
, :
I. , ,
,
, ,
, .
II. , ,
, ,
, (
, ,
WolfParkinson White, ).
III. , ,


,
.

, 76, 1, 2014 144

IV. , ,
,

, .
V. , ,
:
) ( , ,
)
) ( ,
, )
) / ( ,
, ).
VI. , , :
) -,
)
)
)
) , ,
.
,
-:
, , .

, ,
. (2)
.
, Lege artis
.

:
) ( , , )

)
) ( )

, 76, 1, 2014 145

 ) /
) , , , ,

)
.
,
, , :
1. -
2.
3.
4.
5.
6. Wegener
7. .
, ,
, ,
. ,
.
,
,
, .
,


, ,
.
, , ,
:
) 2
) 2
) ,
, :
1) ,
2) ,
,

, 76, 1, 2014 146

 3)

4)
.
, , ,
, ,
, ,
.

, , , .
, ,
.
, ,
,
- .
,
,
., ,
, , , .


,
, .

.
, ,
.

.

, ,
.
. : ,

, 76, 1, 2014 147

, , , , , , ,
, .
,

.
, ,
.
.
(, ,
, Crohn, ,
, , ).
, .

.
, .
,
,
, Saint (15-35%)
,
.
.
, ,
,
. .. , , , Addison,
, .
,
/,
.

.
,
. Crohn

.

, 76, 1, 2014 148


. ,
.

, ,
,
. . ,
. , ,
.
-
. , .
, ,
.. Zollinger-Ellison
Whipple
1-2-. , ,
, 5
, , 12,
,
.

,
.
, .
, , , ,
,
.
,
,
. ,
.
, ,
, Paget, ,
. , ,
SLE , ,

, 76, 1, 2014 149

, , , ,
Sjogren, , , Reiter
.
,
.
2 , ,

.
:
1.
,
(, ,
, , , ..)
2.
.
:
I.

II.
,
, 1980.
,
, ,
, ,
, , , ,
.
,
, Lyme,
, , ...

,
, ,
!

, 76, 1, 2014 150

 ,
.
. ,
,
(.. ,


).
:
1. (, , , )
2.
3.
.
, ,
, . , ,
, , ,
Shock.
,
,
.

, .

.
, , ,
, ,
.

,
.
,

, , , .

, 76, 1, 2014 151

 , ,
, ,
.
. ,
, SLE, , , ..
,
.
,
, , ,
, , ,
, , ,
.
,
.

, CT- SCAN .
, , , , ,
.
. ,

.

,
.
,
:
) ,

) ,
, ,

.
,
, ,
.

, 76, 1, 2014 152

 ,
,
. ,
,
.
,

)

) 2
) , ,
,
) , ,
... /,
/
.
.
,
, .
.
/, /
,
.
,
, , ,
, .
,


, , ,
.
, .
, , ,
.

, 76, 1, 2014 153

 ,
.
,

.
,
, ,
, .
, ,
, ,
, ,
.

, ,
, .

, , 24,
.

(depasse)
. ,
, v
.
. ,
,
. ,
,
, ... , ,
:
)

) ,
,

, 76, 1, 2014 154

 )
, ,
, ,
.
.
10 15 20 ,
.

, ,
, , . (3 .)

, .
,
. ,
,
.
, 20
,
, -
, 3 .
, ,
,

.
,
, , ,

.

, 76, 1, 2014 155



, ,
...

:
: 6972243882, 2107201791
-mail: giannakidoumary@yahoo.gr

.

.

, ,
,
- .


,
.


.

,
,
.

, 76, 1, 2014 156


, , ,
,
. ,

,
, , .

.
:


.

- .
, 24
.


,

, .

, 76, 1, 2014 157

 / :
?

, , ...

:
: 6932564494
E-mail: stavros.kajaani@gmail.com

.
,
,
.

, .



. , 76, 1, 158-166,
2014.
: , , -,
-

SUMMARY
TSITIRIDIS S. Escorts/relatives of patients in the hospital: problem or solution?
Global economic recession has led in cost saving strategies and methods to reduce
human resources costs from sectors less productive and profitable, such as health
care industry. Greek health system crumbles under weight of crisis, a system that had
already been for decades mismanaged and overpriced. As a result, austerity and
painful measures were taken, such as health budget cuts, hiring freeze and
abolishment of positions in health care system, but all these strategies in reality
aggravated the downward of health system performance and the already existing
problems. Social structures and the role of family in Greece permit the development of
a health care network around the patient of minimum quality control. The question that

, 76, 1, 2014 158

arises though is whether patient's care assistants can really help nursing service by
working subsidiary or if their presence create new problems or making worse the
already existing ones. Nosokomiaka Chronika, 76, Supplement 1, Nosokomiaka
Chronika, 76, Supplement 1, 158-166, 2014.
Key words: patient-escorts, relatives in hospital, relatives-patient benefits

.

, ,
,
.
2006 1000
3,7 8,1 . 2009
3,21 1000 .
.

, .1,2
,
,

5.



.

20 ,
(1397/1983)
,
.

, 76, 1, 2014 159

 ,
. ,

24 ,
.
Sapountzi-Krepia et al (2006)
( ), 78,80%

82% 24 24.

,
17 .2
,
, ,
.
, ,

.
, ,

,
1.2.

2
:
1. ,
.
2.
3.
4.

.
.

, 76, 1, 2014 160

 2.4

,
.
:
:
,

, .
,
.
:

.

.
:
,

.
:

(, ). ,
, ,
,
, .
(
) .
:


.
,

.

, 76, 1, 2014 161

 / :
,
,
. ,


.
:
.

.
,

.
, , .
:


:
.
, , ,
.

.
:

.
.
/:


,
.

, 76, 1, 2014 162

 2,3,4,6

,
.
:
:

.
,
.
..
.
:

.
,
, .
,
.

,
.
:


.

. , ,


.
.
: ,
,
.

, 76, 1, 2014 163

 .
,

.


.

.
:
- -
.
?

?
:
.
.
:
,
-

.
:


.

,
.

.
,
,
.

, 76, 1, 2014 164



/ .

2

, :
:

.
,

.

.
:
. .


. ,


.
.
: ,
. ,

. ,
. ,
,

,
.
.

, 76, 1, 2014 165


,
,
,
.
,
(),
.

( ..
), (

).
,


.

1. , , , .
: , 2012,
. 10-12.
2. , , .
? , ( )
, 2009.
3. , , .
, , 2011, 28(4):555.
4. , ,
, .2071/92 123/92 .. 47
5. www.aboutyouth.gr/el/service_1107.html
6. www.eae.gr/new/%20%20%20.pdf

, 76, 1, 2014 166



1, 2, 3
1
, MSc, PhD, , 2 ,
, 3 ,
...

:

: 6944434250, 2132041194, 2132045377
-mail: pmangoulia@gmail.com

30 .

,
20 . ,
,

(..
), .
-
20 .
,
,
,
, , .
-
,

.
,
.
, 76, 1, 2014 167

. ,

.


.

, 76, 1, 2014 168

 ,

1, 2
1
, MSc, PhD, , 2 ,
, ...

:

: 6944434250, 2132041194, 2132045377
-mail: pmangoulia@gmail.com

: 30
. ,
,
. :

, .
: ,

: , ,
,
. :
,
,
. , 76,
1, 169-184, 2014.
: , , , ,

SUMMARY
MANGOULIA P, OUZOUNIDOU A. Legal, Ethical and Deontological Issues in
Liaison Psychiatry. BACKGROUND: In the last 30 years, a lot of work has been
done on the development of Medical Ethics. The recognition of personal value,
autonomy and experience, along with the refutation of medical paternalism have
contributed to these changes. OBJECTIVES: To review the Greek and international
bibliography and legislation on legal, ethical and deontological issues in Liaison
Psychiatry. LITERATURE REVIEW: Breaking bad news, informed consent, autonomy,

, 76, 1, 2014 169

confidentiality, medical errors and prescribing medications for non-approved uses are
some of the most common legal, ethical and deontological issues in Liaison
Psychiatry. CONCLUSIONS: Psychiatrists have an obligation to follow the law and
ethics and consulting health care personnel in order to increase the quality of care.
Nosokomiaka Chronika, 76, Supplement 1, 169-184, 2014.
Key words: Liaison Psychiatry, ethics, deontology, confidentiality, autonomy

30 .

,
20 . ,
,

(..
), .1
-
20 . ,
,
.
,
, .

,
.2
,
,
,
, ,
.3
-
,

.4
. ,

, 76, 1, 2014 170


, .


.5
,
.6

.
,
.

. ,

.7


.8

.
.

,
.9
, ,

.

( ) .
,

.

.

, 76, 1, 2014 171


, , ..
.
. , ,
.1
,
.
,
. 1
:
.

( ).
,
. ,
( ),
.10
,
:
, , ,

.

.11 ,
. ,

.12

.
. ,

, 76, 1, 2014 172

 . .


.11
,
, ,
, ,


.


.
,
. , ,
: ) , )
, )
, ) )
. ,

.11

,
.

.13
,
. ,
.
,
,

, .. . ,
,
,

, 76, 1, 2014 173

 , ,
.11

20
, .
,
.
, ,
,

,
.11
, .
,
. ,
, .14

,
.15,16 .

.

. ,
.


.

(competency)
17
(decision making capacity). ,
,
.18
,

, 76, 1, 2014 174

 . ,

. ,

. , ,
.8

( 2005) 12:

.19 , 4
8 : , ,
.19
,
.
. ,
.
, ,
.8


.
,
( ) .
,
.
, .. ,

.
,
,
.8


(
).

, 76, 1, 2014 175


,
, .
,
, ,20

.9,21,22,23,24

.25,26
(WPA),
(1983), (1989) (1996),
, -
,
.3

,
, (
Bournewood . ). ,
,
. 11
,

. ,

(advance
directives).11
, ,
( ,
).27

.
,

.8,10,11,24,28

, 76, 1, 2014 176


,


. ,

(living wills).29
,
.8



( ,
127, 128 129 ).3
, 128:
10
.
.
10
( 129 ).30

.


.9

- ,

.

,
. ,
,

, 76, 1, 2014 177

 ,

.

,

,
. ,


.24 ,

.
.25


. .

, , .8
, ,
.31,32
, .. ,
,
, HIV
.., .
,
,
,
.
. 8,9,11,33
,
.

.8

, 76, 1, 2014 178

 ,
371, .1, ():10 ,
, , , , /,
..,
, ,


.
(371) , . 4, :10

,
,
.
212, .2, :10
1 ( )
, ()
,
.

, .

(..
),
.
. .19
,
.8

,

.34 ,

, 76, 1, 2014 179

 ,
AIDS.35

330 , :

. , ,
28:
,
,
, , .8,36

. (Institute of Medicine)


.36

.
. ,


.
,
.

,
,
.8

()
.
.24

, 76, 1, 2014 180

 . ,
.37 ,

.

, (.1851/1987, .
2161/1993, . 3982/1987).3 1 :

. ,

.
, ,
, .30

. ,

,
( ).

25,26
, .
, ,
38 placebo
39. ,
, .

, .
- ,
,
, , .
.8

.

, 76, 1, 2014 181


, .17
,
,
.
,
,
.

1. Fulford KWM, Bloch S. Psychiatric ethics: codes, concepts, and clinical skills. In:
New Oxford Textbook of Psychiatry, M.G. Gelder, J.J. Lopez-Ibor, N. Andreasen,
ed. Oxford University Press, New York 2001.
2. Welsh S, Deahl MP. Modern psychiatric ethics. Lancet 2002;19:253-255.
3. . . , , 2004.
4. Ben-Sira Z. Affective and instrumental components in the physician-patient
relationship: an additional dimension of interaction theory. J Hlth Soc Behav
1980;21:170.
5. , . -
. 2002;82:44-56.
6. , . .
: , . , . , . , .
, 2009.
7. Lubit RH, Ladds B, Eth S. Ethics in psychiatry. In: Comprehensive Textbook of
Psychiatry, B.J. Sadock, V.A. Sadock, 8th ed. Lippincott Williams and Wilkins,
Philadelphia 2005.
8. , . -
. : , . , . , . ,
. , 2009.
9. Brooke PS. Legal and ethical guidelines for safe practice. In: Foundations of
Psychiatric Mental Health Nursing: A Clinical Approach, E.M. Varcarolis, M.J.
Halter, 6th ed. Saunders Elsevier, Missouri 2010.
10. . : . , -
, 1986.

, 76, 1, 2014 182

11. . .
: , . , . , . , .
, . , 2011.
12. Cummings JL, Coffey CE. Neurobiological basis of behavior. In: Textbook of
Geriatric Neuropsychiatry, C.E. Coffey, J.L. Cummings, ed. American Psychiatric
Press, Washington DC 1994.
13. Joseph DI, Onek J. Confidentiality in psychiatry. In: Psychiatric Ethics, S. Bloch, S.
Green, P. Chodoff, 3rd ed. Oxford University Press, London 1999.
14. Walter H. Neurophilosophy of free will: From libertarian illusions to a concept of
natural autonomy. MIT, Cambridge, 2001.
15. Reich W. Psychiatric diagnosis as an ethical problem. In: Psychiatric Ethics, B.P.
Chodoff, S. Green, 3rd ed. Oxford University Press, Oxford, 2005.
16. Meynen G. Free will and psychiatric assessments of criminal responsibility: A
parallel with informed consent. Med Health Care and Philos 2010;13:313-320.
17. Schneider PL, Bramstedt KA. When psychiatry and bioethics disagree about
patient decision making capacity (DMC). J Med Ethics 2006;32:90-93.
18. Howe, E. Ethics in Psychiatry. Psychiatry 2008;6:15-23.
19. .
, . 287, 28 2005.
20. Margolin J, Witztum E. Mental health legislation: An unavoidable necessity or a
harmful anachronism. Isr J Psychiatry Relat Sci 2006;219-230.
21. Latha KS. The noncompliant patient in psychiatry: The case for and against
covert/surreptitious medication. Mens Sana Monogr 2010;8:96-121.
22. Singh AR. Covert treatment in Psychiatry: Do no harm, true, but also dare to care.
Mens Sana Monogr. 2008 Jan-Dec; 6(1): 81109.
23. Petrini C. Ethical considerations for evaluating the issue of physical restraint in
psychiatry. Ann Ist Super Sanita 2013;49:281-285.
24. Philbrick KL, Rundell JR, Netzel PJ et al. Clinical manual of psychosomatic
medicine: A guide to consultation-liaison psychiatry. 2nd ed. American Psychiatric
Publishing, Washington, DC, 2012.
25. Simon RI. Legal and ethical issues. In: The American Psychiatric Publishing
Textbook of Consultation-Liaison Psychiatry: Psychiatry in the Medically Ill, M.G.
Wise, J.R. Rundell, 2nd ed. American Psychiatric Publishing, Washington, DC
2002.

, 76, 1, 2014 183

26. Simon RI, Schindler BA, Levenson JL. Legal issues. In: The American Psychiatric
Publishing Textbook of Psychosomatic Medicine, J.L. Levenson, ed. American
Psychiatric Publishing, Washington, DC 2005.
27. . . , , 2005.
28. Naudts K, Ducatelle C, Kovacs J et al. Euthanasia: The role of the psychiatrist.
BJP 2006;188: 405-409.
29. Arboleda-Florez J. The ethics of forensic psychiatry. Curr Opin Psychiatry 2006;19:
544-546.
30. . . : , . , .
, 3 . , 2010.
31. Lubit RH, Ladds B, Eth S. Ethics in psychiatry. In: Comprehensive Textbook of
Psychiatry, B.J. Sadock, V.A. Sadock, 8th ed. Lippincott Williams and Wilkins,
Philadelphia 2005.
32. Sankar P, Moran S, Merz J F et al. Patient perspectives on medical confidentiality:
A review of the literature. J Gen Intern Med 2003;18:659-669.
33. Joseph DI, Onek J. Confidentiality in Psychiatry. In: Psychiatric Ethics, S. Bloch, S.
Green, P. Chodoff, 3rd ed. Oxford University Press, London 1999.
34. , . : ;
2010;72:419-429.
35. Graf J, Von Den Driesch A, Koch KC, et al. Identification and characterization of
errors and incidents in a medical intensive care unit. Acta Anaesthesiol Scand
2005; 49:930-939.
36. Advancing Quality Improvement Research. Challenges and opportunities-
workshop summary. Board of Health Care Services, Institute of Medicine,
Washington, DC, 2007.
37. Macbeth JE, Wheeler AM, Sither JW et al. Legal and risk management issues in
the practice of Psychiatry. Psychiatrists Purchasing Group, Washington, DC, 1994.
38. Tan JOA, Koelch M. The ethics of psychopharmacological research in legal
minors. Child Adolesc Psychiatry Ment Health 2008;2:39.
39. Young SN, Annable L. The ethics of placebo in clinical psychopharmacology: The
urgent need for consistent regulation. J Psychiatry Neurosci 2002;27:319-321.

, 76, 1, 2014 184



- , Msc (c)
TE, , ...

:
: 6973392734
E-mail: efintzo@yahoo.gr

.

.
, ,
.

.
.

.


.

.

, , .

.

, 76, 1, 2014 185


.
. .
,
.

,
,
.
, , ,
.
.
,
,
.


. ,
.
.
.

3 ,
.

,
.

, 76, 1, 2014 186



1, 2
1,2
, ,
... -

:

: 6949515298
-mail: mariavasiliou78@gmail.com

,
.
, , , ,
.
Harken. ,

, . ,
. ,
, Carlens
Pearson,
. ,

. .
.


.
1. . .

,
. /

, 76, 1, 2014 187

. /
: , ,
,
,
,
.
2,5%.
, 76, 1, 187-195, 2014.
: , ,

SUMMARY
VASILIOU , STAVROPOULOU V. Mediastinoscopy. Mediastinoscopy is a surgical
procedure that is used to inspect the body area called mediastinum. The mediastinum
is a part of the thorax that contains the heart, the thymus, the esophagus, the trachea,
some nerves and lymph nodes. The surgical inspection of the mediastinum was
initially done by Harken. It was thought that the presence of infiltrated lymph nodes
excluded the chance of a successful excision and a good prognosis for the patient, in
case of lung cancer. The validity of that theory was proved fifty years later. The
cervical mediastinoscopy, as we know it today, was developed by Carlens in Sweden
and was spread in North America by Pearson. This procedure was proved as the most
useful means of estimating the existence of a metastatic disease in the mediastinum.
Thereby the importance of the spread and the level of the lymph nodes led to the
creation of an international lymph node map. The cervical mediastinoscopy is
conducted with general anesthesia and for this reason the patient must be properly
prepared for the surgery. The preparation might involve the interruption of
anticoagulants for a few days before the surgery. The patient must not eat or drink
anything for a specific period of time before the surgery. The surgical procedure is as
follows: The surgeon does a 1cm section over the suprasternal notch. Then he inserts
the videomediastinoscope. The camera of the videomediastinoscope sends pictures to
a computer, that allows the surgeon to see and take samples from the lynch nodes.
The role of the nurses is very important in mediastinoscopy. They must be well-trained
and know well the surgical tools, such as: the videomediastinoscope and its set up
process, the biopsy forceps the special suctions that are adjusted to the
videomediastinoscope. They must know the procedures and constantly satisfy the

, 76, 1, 2014 188

needs of the surgeons accurately and rapidly. This is achieved by offering the proper
tools and by receiving and managing properly each extruded tissue from the patient
that comes to the table. The cervical mediastinoscopy is a low risk surgery and the
complications are below 2.5%. Nosokomiaka Chronika, 76, Supplement 1, 187-195,
2014.
Key words: mediastinoscopy, lymph nodes, videomediastinoscope

,
, .
,
, .

. , , ,
.
H Harken1.

Jackson .

, .
,
() ().
.

. -
(NSCLC)
(SCLC)2. - (NSCLC),
, (SCLC)
.
.


.
I II
.

, 76, 1, 2014 189

 ( 3),

.
26%
,
. ,
, Carlens
Pearson,
. ,

.

. :
1.
/,
2. ,
3.
4.
.

( )
( )
, ,

, ,
, .

, 76, 1, 2014 190

 ,
2,3,4,5,6,7. Mountain-Dresler modification(1997)
from Naruke/ATS-LCSG Map
: ( 2L 2R),
(4L 4R),
(station 7) ( 1).

1. (Mountain-Dresler)

.

. 1. .
,
,
,
( 2,3).
. ,

.
, .
,

, 76, 1, 2014 191

 , ,

, .

.
: , 2
2 .
,
. , ,
, , .

2.

3.

.

5 6. Ginsberg ,

, 76, 1, 2014 192

, .
,
.
.

,
,
, , .
, .
20.000 2,5%,
0,5%.1
.

.
10 ,
. ,
, ,
, .
, ,
, , , ,
.

, .

, ,
,
.


.

. ,

, 76, 1, 2014 193

 .


3.

,
. ,
.


.
, , ,
, , ,
, .
,
,
.
,
.
, , ,

, .

,


.
,
.

2,5%.

, 76, 1, 2014 194


1. . . . Lung cancer network. ,
2010;13-17.
2. . , . , . . M-
- . ,
2008; 70, 2: 132-135.
3. , . :
,
.

, 76, 1, 2014 195



, MSc, PhD, ,
...

:
: 6973793489
Email: kongiakoumidakis@gmail.com

,
.
,
(evidence based practice)
,

.
1,
.

,
, ,
.

.1

, 76, 1, 2014 196



1. ,

, ,
,

.1 , , ,

,
. , 2010
51,4 ,2
2007 8.333 100.000 ,3
2006 731.900 .4
,


, . ,

, 76, 1, 2014 197


,

.5

,
.5 , ,


,
,
.1
,
,
,
,
,

, . ,

,
, .6
,

.
,

, ,
.
, , ,
. ,
,
,
.

, 76, 1, 2014 198


1. .
,
. , , , 2012.
2. Centers for Disease Control and Prevention (CDC). Inpatient Surgery. 2010. CDC
Web Site. Available at: http://www.cdc.gov/nchs/fastats/insurg.htm. Assessed
Friday 17, 2014.
3. WHO/Europe, European HFA Database. Health Care Activities: Inpatient Surgical
Procedures. 2009. European Hospital and Healthcare Federation Web Site.
Available at: http://www.hope.be/03activities/quality_eu-hospitals/key_figures/11-
hospital_activities-inpatient_surgical_procedures.pdf. Assessed Friday 17, 2014.
4. Lafortune G, Balestat G, Durand A, OECD Health Division. Comparing activities
and performance of the hospital sector in Europe: how many surgical procedures
performed as in patient and day cases? OECD 2012. OECD Web Site. Available
at: http://www.oecd.org/health/Comparing-activities-and-performance-of-the-
hospital-sector-in-Europe_Inpatient-and-day-cases-surgical-procedures.pdf.
Assessed Friday 17, 2014.
5. .
.
, , , 2007.
6. Beyea S. The value of a Clinical Information Infrastructure. In: Perioperative
Nursing Data Set: The perioperative nursing vocabulary, SC Beyea, ed. AORN,
United States of America, 2002.

, 76, 1, 2014 199



- , Msc (c)
TE, , ...

:
.: 6973392734
Email: efintzo@yahoo.gr

,
.
,
, ,

,
.
, .
.
, , .
. .
, , .
, , .
, . ,
, , .
.
, .
.
.

, , ,
. ,
.

, 76, 1, 2014 200

 .
, , ,
, , , /, ,
, .
, ,
, .
, 76, 1, 200-216, 2014.
: , ,

SUMMARY
INTZOGLOU E-D. The use of information as a means to or efficacy. The operation
room (OR) nurse holds a discreetly invisible part within the operation room and as this
part needs managerial skills in handling different specialties and scientific groups in
the operation room or within the hospital in general, the OR nurse is required to be
trained in numerous and various subjects. The training begins at the operation room
as the newly acquired nurse enters for the first time and continues accordingly; with
great intensity at first so as to master the aseptic technique and at a later stage, where
the OR nurse will be gradually trained in all surgical specialties. This way the OR
nurse will have acquired, at the same time, all the required skills and knowledge
needed to grow professionally. This is inevitable due to the information overdose of
the profession. Information is the key to todays modern society for knowledge, news
and professional success. Communication is the sole path to information. Despite the
interdependent relation between information and communication, they both defer
respectively. Communication is perception. Information is logic. It has no character
and cannot be shaped by feelings, virtue, values, expectations and apprehension. t
needs to be brief, precise, sufficient and true. Therefore, when the question who
takes part in any communication? arises, two factors are to be taken into account.
First, the person, who wishes to be heard, takes part in the communication. Second,
the person seeks for the desired information. Thus, there are various sources, where
anyone can look for information. All these sources are means of communication.
Surviving within the information era, will depend on a combination of technological and
strategic ideas. The nursing staff of a hospital must use communication to positively
encourage quality, independence, objectivity and patient service. Many times,
communication errors cause discontentment with work environment. Communication
systems are strong and determinant of success within the organization. A successful

, 76, 1, 2014 201

interaction within the OR requires leadership, management plan, common grounds,
information exchange, PC networks, personal relationship, common experiences,
mutual needs and common future. The OR staff, as an asset, has more value when it
is guided, enriched and actively participates in the OR operation. Nosokomiaka
Chronika, 76, Supplement 1, 200-216, 2014.
Key words: information, communication, perioperative nurse

. ,
. 1

. ,
,
,
. ,
,
,
.

.

,
,

.
,
,
. 2

.

, 76, 1, 2014 202

 .
,
,
,
,
.
, , 2
.

.

.3

, , ,
, , ,
.

;
.
information, 15 informare ,
.4
,
,
, .
, , ,
, .

. ,
:
4

1.
, .
2. ,
, .
3. , :

, 76, 1, 2014 203

 ,
, ( ,
, )






(, ,
)

( )

, (pattern theory)
/
, , .
, ,
, ,
,
.
,
. ,
. ,
( ), .
5. , ,
, .

( ), .
, , 4

.
. ,
,
, .
, 76, 1, 2014 204

,
4.
, + = .

. , ,
Ferdinand de Saussure5,
. ,

. , ,
.
.

.
,
, ,
, :4
1.
2.

3. ( )


, ,
. ,

, ,
. , ,
(characters tokens). 4
(transmission),
(storage) (processing),
.
C. S. Pierce C. W. Morris

: 4

, 76, 1, 2014 205

 1. (syntactic level):
:

,
,

,
.
2. (semantic level):
:
,
, , ,
,
.
,
,

.
,

.
5 (semantics), ,

(syntactics of information), , ,
.
3. (pragmatic level):
.
,
, , /
,
,
,
(predictions), .

: 4

, 76, 1, 2014 206

 (, ,

)
,

.
Beynon-Davies
, ,
, .
(, , )
(carrier)
(medium), .
,
.

(signals).

4.
.

,
.
.
. .
. .,
.
, . ,
7
.
6.
,
. 6.
,
.

, 76, 1, 2014 207


. .
,
:8



.
:8
1.
2.
3. -
.

.
.
(message) (encoding)
(sender) ()
(channels) (receiver), (decoding).
.
(feedback) 8,9.
(communication) .
10, ,
. ,
70%
(, , , ),

8.
,
. . .
.
, , .7
.
.
,

, 76, 1, 2014 208

.
, ,
. ,

.
7.
.
. .

. ,
7,10.

.

.

, ,
(5-20%)
8.

. , ,
, .
. ,
,
.
( ),
,
,
. , , ,
,
,
, 8.
Carl Jung1,11
, , .
Jung

, 76, 1, 2014 209

 . ,
12.
Jung
. ,
, , , ,
, .

.
:1,11




,
, , ,
, , .

,
.
,
. ,
, , .

.
.

,
13.
,
, ,
, .
,
. ,
, ,
.

, 76, 1, 2014 210


, ,
13.

. ,
(overhead pages)
, .
, .
.
,
.
,
.

,
( )13.
, , ,
, ,
, ,
.
,

. 13.

,
.
, ,
:14
.
.


,
,
, ,

, 76, 1, 2014 211

 ,
, .
,
.

,
, ,
.
, 10
Competency (1996),
:14


-










,
.
16 ,
,
.
, ,
. ,
,
, ,
, ,
.

, 76, 1, 2014 212


,
,
kolb.14 ,
.
.
:
.
( ).
, ,
, .

,
, .
.


.
.
, , , .
.
. , .

.

.


.
H kolb
.
,
,

, . 2

, 76, 1, 2014 213




,
.
15

, ,
.

,
, .
,
,
.
,
.
, ,
,
,


.
,
,

.
,



.
:

, 76, 1, 2014 214

 :

.
Time Out: Time Out

.
:

.
.

,
,
.
, .

. ,
, ,
. ,
, , , /, ,
,
.7
,
.

1. . ,
, , 2013.
2. . ,
,
, , , 2013.
3. . . , , Interbooks,
2001.
4. http://el.wikipedia.org.

, 76, 1, 2014 215

5. James Gleick, , , 2011.
6. Russell C. Swansburg, R. J. Swansburg,
, 2 , , 1999.
7. Saunders S, Why good communication skills are important for theatre nurses.
Nurs Times. 2004;100(14):42-44.
8. . , , ,
2008.
9. . . , -
, , 2006.
10. Elizabeth Cvetic, MS, RN, CNOR, Communication in the Perioperative Setting
AORN Journal Volume 94, Issue 3 , Pages 261-270, September 2011.
11. . , , , 2010.
12. Sandra Lee Smith, RN, BSN, CNOR, Managing Up Can Improve Teamwork in
the OR, AORN Journal Volume 91, Issue 5 , Pages 576-582, May 2010.
13. Ronald . Gabel, Operating Room Management,
, , Mediforce,
2001.
14. . ,
, 2003.
15. ,
( ).
... (WHO)
(..), 2009.
16. Daniel Goleman, , 15
, , 2000.

, 76, 1, 2014 216



Dr
, ' , ...

:
: 6942408808
E-mail: vaidakismanolis@gmail.com

. ,
,
.
,
, .
,
(, , )
. ,
, , , ,
,
,
.
.

65 .
65
.
65 7%
. 80 .
,
, :

, 76, 1, 2014 217


.
,

. ,
. 65
,
.
3.5, 1.5
.
,
,
. ,
,
.
, , .

.
.


.

,
.1

.
.
,
, .2
2 .. :
,
,
, ,

, 76, 1, 2014 218

 ,
.3

1. . . www.dent.uoa.gr. [ 3/1/14].
2. . .
www.books.eudoxus.gr [ 3/1/14].
3. . . . 7.
. 107. . , 2002.

, 76, 1, 2014 219



Dr.

, ...

:
: 6944690525
-mail: tkontopoulou @yahoo.gr

.
/,

.
, (),
(delirium),
, , /,
, .

.
, , ,
, .
,

- , ,
, , , ,
.
/
.
.
,

, (
),

, 76, 1, 2014 220

 . ,

.

. , 76,
1, 220-246, 2014.
: , ,

SUMMARY

KONTOPOULOU T. Internal diseases of advanced age. Diseases of advanced age

cover a wide range. Geriatric syndromes/conditions are special entities related to
advanced age. Impairment of daily living activities, decline in cognitive function
(dementia), delirium, polypharmacy or improper medical prescribing, frequent falls,
reduced mobility/immobilization, malnutrition, susceptibility to infections, frailty are
some examples of geriatric syndromes / conditions. The diseases of the elderly have
different characteristics compared to those of other age groups. They differ in
prevalence and incidence, in the clinical symptoms and signs, in the diagnostic
procedure, in the therapeutic choices, in the outcome and in the rehabilitation.
Frequent diseases encountered in the elderly and needing medical assistance are
thromboembolic disease, electrocardiographic abnormalities meaning or not
underlying heart disease-, heart failure, pneumonia due to oropharyngeal aspiration,
renal failure, anemia, allergic diseases and pruritus, hypertension, diabetes mellitus
and dyslipidemia. Adverse consequences of geriatric syndromes/conditions and
diseases are repeated hospitalizations and a poor quality of life of the elderly. The
geriatrician has often to come up against difficult geriatric dilemmas. He has to take
serious decisions: what is the optimal degree of therapy intensification; if he will make
use of all diagnostic and therapeutic possibilities of modern medicine; if he will take
into account the old patients often suffering from dementia- consent; who will share
the responsibility together with the physician to decide about the elderlys life and
health. The life prolongation of an old patient by all means being indifferent to his loss
of dignity or to his desires remains a matter of speculation. The Hippocratic to benefit
or, at least, to do no harm can prove to be a good guide for the geriatrician.
Nosokomiaka Chronika, 76, Supplement 1, 220-246, 2014.
Key words: age, geriatrics, elderly

, 76, 1, 2014 221



.
5 ..
:
, , ,
, , , , , ,
, , ,
, , , 1.

I. /

1.

. , , ,
, .
,
, , ,
, ,
.

,
.2 ,

.3

2.

3. (delirium)

, ,
.
.

, 76, 1, 2014 222

 .
, ,
, ,
.
, ,
, .

.
18.8% 14
.
25-30%.4

.

. ,
.

.
. - -
. 5

4.

2.8 5.0 .
3 4 .


.

.
18
42% .6

.7

, 76, 1, 2014 223



.7

5.

.
, , ,
.
,
.
.8
25- D
, ,
. 800-1000 IU D
.9

6.

, ,

.


.

(, , ),
( , ),
( , ,
), (
), (, ), ,
, ,
(
, ).

: ,
, ,

, 76, 1, 2014 224

 ,
, ,
.

.

,
,

. ,

.
(
) .

.10

7.

.
5-10% 50%
.
.
, ,
,
. , ,

.

.
, , ,
.

: ,
, , ,
.

30% 20% .

, 76, 1, 2014 225

 .
, .
.
.

.
,
.
.

.

,
.

. 5-13% 60-70 11-50%
80 .
.
.11

. ,

. ,

.

:
.
.
. .
.

, 76, 1, 2014 226

. .
.
. ,
,
.

.
(MK 2866), ,

.
. .

. 9

8.

, -
-,
- .

.


.
.
40% 85 20% 65.

.

(Pneumo 23)
65, .
' .
(,
) -
65.

5-20% '
.

, 76, 1, 2014 227

 60
,
, . .

- -,

.
.

39-75%,
50%.

62%
69% 2003-2005 65-74
80.12

9.

3 5 :
, , ,
.
.13

II.

1.

.
75
18%.

>16% 80
2% .
70% 70,
55% 70 .

,
.

, 76, 1, 2014 228

 .

. ,
, ,

75.

. d-dimers
67% 40 ,
10% 80, .

. ,

.

,

. 65
.

.
.
.

.

75.
75
( )
, ,
, , ,
, ,
.
.

, 76, 1, 2014 229

.
. fondaparinux
' .

.14

2.

, , ,
Q/QS, .

.

.

.
.
,
.

,
.15

3.

. 80%
65 .
.

.
25%.

.
:

.

, 76, 1, 2014 230

 , ,
.

.

. Cardiovascular Health Study
7% 65,
1/4 80.
,
.

.


. ,

,
.

.

,
. 1/3 65
1 10
, .
,
-
- .


.
.
, -
,
.

, 76, 1, 2014 231


17.5% >65 , >85 42.9%.

.
, .

.

. ,

.

.16

4.

.
( )


.
. >30%
, 60-80% , 13%
65 >51% .
'
.
.
- -,
,
.

.
>3%
.

, 76, 1, 2014 232


,
-.

gram(-) .

, .17

5.

.18
,
. , 75 41%
, 20% 17%.13

.
.18

, ,

.
:
, ,
.

,
.
,
.

.
(
/ )19
.

, 76, 1, 2014 233


.
. , 65

! , , -
.

.

,
.
, ,
,
,
.18 ,
,

' .13

.18

6.

12g/dl
13g/dl . 65
10%
50% . '
.
: , ,
, ,
.
.
70.
.20

12 ,
.

, 76, 1, 2014 234

 12 12 <150pmol/L
12 <150pmol/L >13mol/L
>0.4mol/L (
6).

12 .
B12.
40% 80
.
, , 2
, ,
, Sjogren
12 .
Biermer 20-50% 12 .
,
.
Schilling test
. 12
.

12
.
,
. 12 ,
, .
12 . 21

, , , .
. 20

7. -

5-10%.

.
.
, ,

, 76, 1, 2014 235

 ,
.

, D
.

65 5.4-10.7%
6-10%.
. ,
( )
.
C1 - -
.

(0.1-2.2%)
. 65
5% 26% 40-65 69% 16-39 .

,

. 10%
,
.
,
,
.

1 ,
,
, .

, ,
, , ,
22
.

65
.
, , .

, 76, 1, 2014 236

 .
.
.22

. ,
. (
)
.23

8.

65
50-75%. 75
75%. Framingham
20-25 85%
55
.

.

.
.
,
.

, (
,
Cox-2) .

, .
,
.24

(ESH) (ESC) 2013
160 mmHg
(1).

, 76, 1, 2014 237

(HYVET) <160 mmHg

.

80
<140 mmHg
. 80
150-140 mmHg,
.
,
.

80 .
,
.

.25

9.

. '
:
, , ,
.

. ,
. 40% 65
2 .
,
>200mg/dl 2 ,
<126mg/dl 60 .

,

.26


. 25%

, 76, 1, 2014 238

 1/4
, 10 , ,
50% .
,
,
.
.

, ,
,
.

.
, , ,
, .
.

.
. 30%
10% .
,
.27

2014
(ADA)

.

. ,
,
.
<7,
, ,
, .
.
,

, 76, 1, 2014 239

 ( 5
).
,
, .

. ' ,
.
.
( )

, .

.
,
. DPP-4
, .
GLP-1.28

10.

- -

.29

2013
(ACC) (AHA)
75
. 75

.

75 .
,
, -, ,
,
.

, 76, 1, 2014 240

 75 ,
.
' .30

III. /

1.

10% 65 '

.
.

/

.
1/3
. 1/3
.
/


' ,
.3

.

.
' ,
,
.

.
/
, ' .

, 76, 1, 2014 241

 . ,
' 10
.
,

, .
' .31

2.

: '
.
.
,

.32

IV.

.

.


.
-
-
.
- ,
, -
.

.
,
;
;
; ;

, 76, 1, 2014 242

 ,
.

. .
, 7 .. :
' '
. .
' ' . ,
.
, ' ' ' .
.
. ' '
, ' .
.33 ,
, 5 ..
.34-35
:
.
.36-37

.

.38

3. Hippocrates. Aphorisms III, Loeb Classical Library, vol IV, p:132-135, London,
1992.

4. Takata Y, Ansai T, Soh I et al. High level activities of daily living and disease
specific mortality during a 12-year followup of an octagenarian population,
Clinical Interventions in Aging 2013, 8:721.

5. Buurman BM, Hoogerduijn JG, Haan de RJ et al. Geriatric Conditions in Acutely

Hospitalized Older Patients: Prevalence and One-Year Survival and Functional

, 76, 1, 2014 243

 Decline, PloS ONE 2011, 6(11):e26951.

6. Isfandiati R, Harimurti K, Setiati S et al. Incidence and Predictors for Delirium in

Hospitalized Elderly Patients: a Retrospective Cohort Study, Acta Med Indones-
Indones J intern Med 2012, 44(4):290-297.

7. Attard A, Ranjith G, Taylor D. Delirium and its treatment, CNS Drugs 2008,
22(8):631-634.

8. Bakken MS, Ranhoff AH, Engeland A et al. Inappropriate prescribing for older
people admitted to an intermediate-care nursing home unit and hospital wards,
Scand J Prim Health 2012, 30:169-175.

9. Chang C-B, Chen J-H, Wen C-J et al. Potentially inappropropriate medications in
geriatric outpatients with polypharmacy: application of six sets of published explicit
criteria, Brit J Clin Pract 2011, 72(3):482-489.

10. Ziere G, Dieleman JP, Hofman A et al. Polypharmacy and falls in the middle age
and elderly population, Br J Clin Pharmacol 2005, 61(2):218-223.

11. Morley JE. Undernutrition in older adults, FAM PRACT 2012, 29:i89-93.

12. Laksmi PW, Harimurti KH, Setiati S et al. Management of Immobilization and its
Complication for Elderly, Acta Med IndonesIndones J Intern Med 2008,
40(4):233-240.

13. Morley JE. Sarcopenia in the elderly, FAM PRACT 2012, 29:i44-48 [Accessed
2/12/2013].

14. National Consensus on Geriatric Immunization 2011. Acta Med IndonesIndones

J Intern Med 2012, 44(1):78-91.

15. Jassal SV, Watson D. Dialysis in Late Life: Benefit or Burden, Clin J Am Soc
Nephrol 2009, 4:2008-2012.

16. Lacut K, Le Gal G, Mottier D. Primary prevention of venous thromboembolism in

elderly medical patients, Clinical Interventions in Aging 2008, 3(3):399-411.

17. Rabunal-Rey R, Monte-Secades R, Gomez-Gigirey A et al. Electrocardiographic

abnormalities in centenarians: impact on survival, BMC Geriatrics 2012, 12:15.

18. Dodson JA, Chaudry SI. Geriatrics conditions in heart failure, Curr Cardiovasc
Risk Rep 2012, 6(5):404-410.

19. Cabre M, Serra-Prat M, Palomera E et al. Prevalence and prognostic implications

of dysphagia in elderly patients with pneumonia, AGE 2010, 39:39-45.

, 76, 1, 2014 244

20. Kooman JP, Cornelis T, Van der Sande FM, et al. Renal Replacement Therapy in
Geriatric End-Stage Renal Disease Patients: A Clinical Approach, Blood Purif
2012, 33:171-176.

21. , , . ,
2013, 25( ):23-25.

22. Thein M, Erschler WB, Artz AS et al. Diminished Quality of Life and Physical
Function in Community-Dwelling Elderly with Anemia, Medicine 2009, 88(2):107-
114.

23. Andres E, Loukili NH, Noel E et al. Vitamin B12 (cobalamin) deficiency in elderly
patients, Can Med Assoc J 2004, 171(3):251-259.

24. Cardona V, Guilarte M, Luengo O et al. Allergic diseases in the elderly, Clin Transl
Allergy 2011, 1:11.

25. , . , www.iatrikionline.gr/
Derma_54/11.htm [Accessed 25/12/2013].

26. Kithas PH, Supiano MA. Practical recommendations for treatment of hypertension
in older patients, Vasc Health Risk Manag 2010, 6:561-569.

27. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the
management of arterial hypertension, Eur Heart J 2013, 34:2159-2219.

28. Chang AM, Halter JB. Aging and insulin secretion, Am J Physiol Endocrinol Metab
2003, 284:E7-E12.

29. Kim KS, Kim SK, Sung KM et al. Management of Type 2 Diabetes Mellitus in
Older Adults, Diabetes Metab J 2012, 36:336-344.

30. ADA. Standards of Medical Care in Diabetes2014, Diabetes Care 2014,

37(Sup.1):S14-S80.

31. Houston DK, Ding J, Lee JS et al. Dietary Fat and Cholesterol and Risk of
Cardiovascular Disease in Older Adults: the Health ABC Study, Nutr Metab
Cardiovasc Dis 2011, 21(6):430-437.

32. Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA Guideline on the
Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in
Adults; A Report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines, JACC doi
10.1016/j.jacc.2013.11.002 [Accessed 29/12/2013].

33. Takahashi PY, Haas LR, Quigg SM et al. 30-day hospital readmission of older
, 76, 1, 2014 245
 adults using care transitions after hospitalization: a pilot prospective cohort study,
Clinical Interventions in Aging 2013, 8:729-736.

34. Bilotta C, Bowling A, Nicolini P et al. Older people's Quality of Life (OPQOL)
scores and adverse health outcomes at a one-year follow-up. A prospective cohort
study on older outpatients living in the community in Italy, Health and Quality of
Life Outcomes 2011, 9:72.

35. 29. 2 West. :

, , .
. www.greek-language.gr [Accessed 31/12/2013].

36. , . 301, : Murrray G, Oxonii, 1973.

37. . .
, . 255. . , 2004.

38. , . 669-672, : Murrray G, Oxonii, 1973.

39. . . : , ,
, , 2002.

40. Hippocrates. Epidemics I. Loeb Classical Library, vol. I, p. 165. London, 1992.

, 76, 1, 2014 246

 :

. .
, , ...

:
: 2132041294
-mail: avlonari1@gmail.com

, ,
.
.
. ,
.

.

. , ,
, .
.
.
. ,
76, 1, 247-254, 2014.
: , , ,

SUMMARY
PAPAGEORGIOU GM. Depression in old age and dementia: Contemporary facts.
Depression in the elderly is characterized by specific symptoms such as apathy,
hypochondriasis but also reduced depressive affect, as opposed to adults. The
cognitive burden on this is different from that of dementia. Prognosis is worse than that
of adults and is characterized by a high co-morbidity. CVA, diabetes or lung disease
often coexists with it. Treatment is similar to that of adults but it is recommended to
avoid drugs with potential interactions. They have to be given in lower doses. The
behavioral and psychological symptoms coexist simultaneously and independently

, 76, 1, 2014 247

with the cognitive ones in demented patients. These are primarily excitation, delirium,
psychosis, sleep disorders, anxiety and depression that accompany dementia. There
are differences in the cognitive function of the depression proper, and dementia is,
characterized by insidious onset and large mnemonic gaps. Characterized by insidious
onset and large mnemonic gaps. The emergence of such symptoms makes the
prognosis of dementia worse. Interventions are either pharmacological or non-
pharmacological or internment in a closed geriatric facility. Nosokomiaka Chronika,
76, Supplement 1, 247-254, 2014.
Key words: depression, psychological symptoms, dementia, elderly

.

2020 .

. .
.

.
,
. , .
() .
,
1. Prince

.
( )
( ).
,
/ .2


.
(, )
. ,
, ,

, 76, 1, 2014 248

 .
:

, ,

1.

.
.
: , ,
, , ,
.
: , ,
.
, ,
, .

.
.
.
, Alzheimer
. , ,

, 76, 1, 2014 249

 ,
3
2.

2.



&

( 3).

3.

- ( )
-
. Cushing

Ca++

/
;
. Parkinson
/. Alzheimer L

Ca
AIDS

. ,

, 76, 1, 2014 250

 20% 6 4.

.
,
SSRIs , ,
.
.
,
.

.

( ).
,
:
,
, ,
.

.
: : , ,
, (, ),
, , (
),
, . ,
: , ,
.

, .5

,
. ,
-.

. ,

, 76, 1, 2014 251

 ,
.
,
. , ,
6.

4.
: :


,
, ,
,
,

5.

,
,
.
( 73% :
.


, .
, .
.
, . .
(12-49%)
.

, 76, 1, 2014 252

,
.
.
: ,
.


, ,
.
.
,
(..
). :
:
, .
: , ,
.
,
. ,
,
.
.
,
.
(, , )
- .

.
(Mc Shane et al,1997).


.
. , ,
( ) ,
.

, 76, 1, 2014 253


.

B
1. Blazer DG. Depression in late Life:Review and Commentary. J Gerontol Med Sci
2003;58A:249-265.
2. Prince MJ, Beekman ATF, Deeg DGH et al. Depression Symptoms in late life using
the EURO-D Scale:effect of Age,Gender and Marital Status in 14 European
Centers. Br J Psychiatry 1999;174:339-345.
3. Baldwin R. Depression in Later Life. Oxford University Press, Oxford 2010 pp. 3-
35.
4. Alexopoulos GS. Depression in the Elderly. Lancet, 2005;365:1961-1970.
5. Brodaty H. Alzheimer . E.
, 2003, . 51-69.
6. Wragg RE, Jeste DV. Overview of Depression and Psychosis in Alzheiemers
Disease. Am J Psychiatry 1989;146:577-587.
7. Lyketsos CG, Carillo MC, Ryan MJ, et al. Neuropsychiatric Symptoms in
Alzheimers Disease . Alzheimers & Dementia 2011;7: 532-539.
8. Geda , Schneider LC, Gitlin LN, et al. Neuropsychiatric symptoms in
Alzheimers disease: Past progress and anticipation of the future. Alzheimers &
Dementia 2013;9:602-608.

, 76, 1, 2014 254

 3

. .
, ,
...

:
: 2132041729
-mail: cgarn@otenet.gr

,
.

.
,
, ,

, ,
, ,
.

(load sharing devices),
-
.

.
, 76, 1, 255-260, 2014.
: , ,
, , ,

SUMMARY
GARNAVOS C. Osteoporotic fractures. Fractures associated with osteoporosis are
of the most common problems of Health Services worldwide, as their number
increases despite advances in prevention and treatment of osteoporosis. Classic

, 76, 1, 2014 255

locations of the body that suffer osteoporotic fractures are the hip, the spinal column
and wrist. Many osteoporotic fractures are treated conservatively with rest and splints
but in many occasions operative intervention is unavoidable for the patients to regain
their pre-fracture physical status and independence. However, the weak bone makes it
difficult to achieve a stable bone-implant construct and general weakness of the
patient often prevents reduction of load on the injured extremity during healing. By
development of load-sharing implants and less invasive techniques the results
following fixation of osteoporotic fractures has improved. Enhancement of the strength
of the cancellous bone that surrounds the metallic implant by bioactive materials and
synthetic bone grafts has also contributed towards better treatment outcomes. In
recent years prosthetic replacement has been increasingly used for peri-arthicular
fractures with specially designed prostheses that could offer a more stable construct
for faster mobilization of the injured patients. Nosokomiaka Chronika, 76,
Supplement 1, 255-260, 2014.
Key words: osteoporotic fractures, conservative treatment, operative treatment,
intramedullary nailing, graft augmentation, arthroplasty

, ,
.
, 80%
.

.
2.5
, 400.000 200.000
, 17
1.
,
() .
,

. ,
, 15% 33%

, 76, 1, 2014 256

, , ,
2.

(4% ), (<2
, 4%; >4 , 6.1%)
. (10
27%, 40%)3.
4.

, , .
23.9% 15.1% ,
, 2
5.

,
, 6.
,
, (1% - 9%)
7.


,
(BMD). BMD

8. BMD
. ,

. ,

50 .

.
, .

,

, 76, 1, 2014 257

 .


.


- . ,

. ,


.
,

.
,

. /
,
.

,
.
,
,
.


, .



.

.

, 76, 1, 2014 258


,
,
. ,
,
,
.

.



.
(dynamic implants)


.



.

.
:
,

.
- -
.
-
.
,

.

, 76, 1, 2014 259


1. National, OsteoporosisFoundation. Clinicians Guide to the Prevention and
Treatment of Osteoporosis.
http://wwwnoforg/professionals/cliniciansguide_formasp, 2008.
2. Dharmarajan TS, Banik P. Hip fracture. Risk factors, preoperative assessment, and
postoperative management. Postgrad Med 2006;119:3138.
3. Paksima N, Koval KJ, Aharanoff G, et al. Predictors of mortality after hip fracture: a
10-year prospective study. Bull NYU Hosp Jt Dis 2008;66:111117.
4. Melton LJ, 3rd. Adverse outcomes of osteoporotic fractures in the general
population. J Bone Miner Res 2003;18:11391141.
5. Lyles KW, Schenck AP, Colon-Emeric CS. Hip and other osteoporotic fractures
increase the risk of subsequent fractures in nursing home residents. Osteoporos
Int 2008;19:12251233.
6. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical
fractures and mortality after hip fracture. N Engl J Med 2007;357:17991809.
7. Petrella RJ, Jones TJ. Do patients receive recommended treatment of
osteoporosis following hip fracture in primary care? BMC Fam Pract 2006;7:31.
8. Dawson-Hughes B, Tosteson AN, Melton LJ, 3rd, et al. Implications of absolute
fracture risk assessment for osteoporosis practice guidelines in the USA.
Osteoporos Int 2008;19:449458.

, 76, 1, 2014 260

 3 .

. .
, , ...

:
: 6944435467
-mail: zoublios@hol.gr

65
. 20 ,
20% . 50% 70%
.



.

.
,

. , 76, 1, 261-
290, 2014.
: , ,

SUMMARY
ZOUBLIOS CD. Cancer in the elderly. Cancer is a disease with high incidence in
older patients. Older patients are a growing part of our population. Data about the care
of these patients are limited because there is underrepresantation of older patient on
clinical trials. We need to increase our understanding about the optimal care for this
population. As a consequence we need to include more older patients in clinical trials,
after a comprehensive geriatric assessment. Nosokomiaka Chronika, 76,
Supplement 1, 261-290, 2014.
Key words: elderly, cancer, geriatric

, 76, 1, 2014 261



. , ,
65 .

. 65
11
15 65 1,2.
60% 70%
65 3.
,
, .
(US Bureau of the Census),
1,4. 1900
65 3,1
. 100 , 2000
10 35 .
20 2030
70,2 , 20,1% .
65
.
10 90 85
38%, 75 84
23%, 65 74
2%4. 2030 85
1 .
, 100 .
72.000 2000. 2050
834.000 5.
,
.

.
,
.

, 76, 1, 2014 262


7,8,9.
345

,
10.



.


11-18.
, ,
.
, .
65
.

.


.

.

.
(comprehensive geriatric
assessment)
.

,
,
.
.

, 76, 1, 2014 263

 164 1993 1996
16.396 . 25%
65 . 15 ,
.
9% 65,
19.
1993
1996. 58%
65 , 22%
65 20.

. 23.000
500 .
65 75 .
65 .

75 . 11% 5%
75.
, 2,7%
75 21.

, CALGB
65
65
.
,
, , .

(51% <
65 35% > 65 . P= 0,06).
, ,
(56% , 50% . P=0,67).

.
. (1)

, 76, 1, 2014 264

 (2)
22.




.23 ,
.
.

, ,
.

. ,
,
. ,

,
24.


. ,


.
DNA, ,
24.
, ,
,
. ,
,
.

. , 507
75 ,

, 76, 1, 2014 265

 . 75 79 35%,
95-99 20% 16%.

67% 75-90 41%
95 .
25.

, .
30.
,
.
,
(stress)26.

,
.
.

,
, /
.

.
, , , ,
, ,
, , ,
.

, , ,

.
.
25% 50%.

, 76, 1, 2014 266

 10% 15%27-29.


.
25% 30% ,
.
1% 50
1mL/minute/year 4027, 29.
,
naive , 26.

. '

30.
31.

,
, ,
, ,
32,33
.
,

.

34.

(, , , , uracil-
tegafur, capecitabine, ..)
.
,
.
, , , , ..
.

, 76, 1, 2014 267

 (
).
35,36.

.


,
.

, (..
) 37,33.
(, )
.


.
, ,
,
, 38,35.

.

(.. , , , , ,
). ,
, ,
, .

"" (frail)
,
, , ,

, 76, 1, 2014 268

, . 10% 25% 65
"".
""
39.
"
, ,

".

. ,
,
.

"" .
,
,
.

"". Cohen .
"" .
-6 C- .
D-dimers . -6 D-dimers
39,40.

"" : >85 ,
, ,
( ,
), (,
, )41.

.

.
Balducci Santa41,
, ,

, 76, 1, 2014 269

 .
.

.



.

.
, . ,
455 70
, ,
. 12,3

42. , ,

43.
,

.
,
44.

.
45.
1208 ,
, .
.
46.
.

, 76, 1, 2014 270

 191 80 , 94%
.
77% 81%
. 6%
, ,
47.

48,49. ,

, -,
.
,
,

. ,

.

.

. 3 : < 50, 50
69 >70.

,
. ,
, .

50. 2 .

51.

.

, 76, 1, 2014 271

 .
,
.

, ,
52. , (fit elderly),

, . (frial
elderly)
. ,
,
53-56.

. , ,
. ,
57. .
(Performance status)

(Performance
Status, PS). .
Karnofsky Performance Satus (KPS) Eastern Coopeative Oncology
Group (ECOG).
.
, PS (. ECOG > 2, KPS<60)

. PS
58.



.

, 76, 1, 2014 272

 , ,

.


.
:
1. 59.
2. 60.
3.
61-63.
4.
63-64.
5. 65.
6. 65.


,
.


, ,
, , ,
, .


.
(Karnofsky, ECOG)
,
62.

(Activities of Daily Living, ADL)
(Instrumental Activities of Daily
Living, IADL)66,67.

, 76, 1, 2014 273

 ()
,
, .
()

, , ,
.

. ...
9745 ,

68.
303
65 ,
17% 59%
69.
()

, Karnofsky ECOG.
363 65
< 2 ECOG
9% 38% .62.

80 .

566
- 70
.60 ,
.

.

. 83
70

, 76, 1, 2014 274

 (
),
ECOG < 2,
59.
(comorbidity)


70.
71.


72.

936 40 84
.
20
4
73.


. 70 -

Charlson 2
274,75.

.
203
(
Charlson) ( ECOG )
76. ,

.


.

, 76, 1, 2014 275

 .
77.
,

, 78.


. , Alzheimer,

79.
,




.

.

(BMI) 80-84.
4714 65
5% 80.
7527 70
19,4 Kg/m2 ( 10%
) 81.

3047 12
85
ECOG .

. ,
, ,
.
(0% 5%) .

, 76, 1, 2014 276

 , BMI

.
.


86, 87
,
,
.
3% 25%86.

.


88.


.
, , .

.

89-91.


.
,
92-
97
.
, , ,
, ,
, ,
94.
Karnofsky,
( ) .

, 76, 1, 2014 277

 , ,
, (, ,
, LDH, ) ,
93.


.
,
Get Up And Go97.

. , non
Hodgkin ,
. , ,
.

,
,
,
98.
65 70 ,
.

.
, , ,
99.
,
.
, .
,
.
.
HER2,
.

, 76, 1, 2014 278


( ), ,
,
.
( ), 100,101.
.
, , > 65
, , .
,
, ,
.

,

.
,
, ,
.
,

.
,
.

70%
65 .

.

.

/
.

, 76, 1, 2014 279

 65
,
.
,

.
, ,
.
,

,
.
,
.

, SN-38
. ,
70 102,103.

,
.


() 70 .

.
, ,

.

. , ,
104,105.
,

.

, 76, 1, 2014 280


,
.

106.


. ,
.

(EGFR)
EGFR..
EGFR,

(gefitinib, erlotinib), .
EGFR,
,
. ,
,
.
, , ,
, .


() 70 .

.
, .
,
, ,
107,108.
109,110.

1. Yansik R. Cancer burden in the aged. Cancer 1997;80:1273-1283.

, 76, 1, 2014 281

2. Yansik R. Aging and cancer in America: demographics and epidemiologic
perspectives. Hematol Oncol Clin North Am 2000;14:17-23.
3. Ries EM, Kosary CL, Hankey BF, et al (eds). SEER Cancer Statistics Review. In:
National Cancer Institute. Bethesda, MD; 1975-2000.
4. US Bureau of the Census. Census 2000 Summary File 1; The 65 years and over
population.
5. Day JC. Bureau of the Census. 1996. Population projections of the United States
by age, sex, race, and Hispanic origin: 1995 to 2050. Current population reports,
P25-1130. Washington, DC: Bureau of the Census; 1996.
6. Centers for Disease Control and Prevention. United States life tables, 1997.
National Vital Statistics Reports, {Serial online] 1999;47(28).
http://www.cdc.gov./nchs/data/nvsr/nvsr47_28.pdf (assesed month, day, year).
7. Hutchins LF; Unger JM; Crowley JJ; Coltman CA Jr; Albain KS.
Underrepresentation of patients 65 years of age or older in cancer-treatment
trials. N Engl J Med 1999;341(27):2061-2067.
8. Yee KW; Pater JL; Pho L; et al. Enrollment of older patients in cancer treatment
trials in Canada: why is age a barrier? J Clin Oncol. 2003;21(8):1618-1623.
9. Trimble EL; Carter CL; Cain D; et al. Representation of older patients in cancer
treatment trials. Cancer 1994;74(7 Suppl):2208-2214.
10. Kumar A, Soares HP, Balducci L, et al. Treatment tolerance and efficacy in
geriatric oncology: a systematic review of phase III randomized trials conducted
by five National Cancer Institute-sponsored cooperative groups. J Clin Oncol.
2007;25(10):1272-1276.
11. Christman K; Muss HB; Case LD; et al. Chemotherapy of metastatic breast
cancer in the elderly. The Piedmont Oncology Association experience [see
comment], JAMA 1992;268(1):57-62.
12. Hurria A, Leung D, Trainor K, et al. Factors influencing treatment patterns of
breast cancer patients age 75 and older. Crit Rev Oncol Hematol.
2003;46(2):121-126.
13. Mandelblatt JS, Hadley J, Kerner JF, et al. Patterns of breast carcinoma
treatment in older women: patient preference and clinical and physical
influences. Cancer 2000;89(3):561-573.
14. Newcomb PA, Carbone PP. Cancer treatment and age: patient perspectives. J
Natl Cancer Inst. 1993;85(19):1580-1584.

, 76, 1, 2014 282

15. Merchant TE, McCormick B, Yahalom J; et al. The influence of older age on
breast cancer treatment decisions and outcome. Int J Radiat Oncol Biol Phys.
1996;34(3):565-570.
16. Bergman L, Dekker G, van Leeuwen FE, et al. The effect of age on treatment
choice and survival in elderly breast cancer patients. Cancer. 1991;67(9):2227-
2234.
17. Bergman L, Kluck HM, van Leeuwen FE, et al. The influence of age on treatment
choice and survival of elderly breast cancer patients in south-eastern
Netherlands: a population-based study. Eur J Cancer 1992;28A(8-9):1475-1480.
18. Schrag D, Cramer LD, Bach PB, et al. Age and adjuvant chemotherapy use after
surgery for stage III colon cancer. J Natl Cancer Inst 2001;93(11):850-857.
19. Hutchins LF, Unger JM, Crowley JJ, et al. Unterrepresentation of patients 65
years of age or older in cancer-treatment trials. N Engl J Med 1999;341:2061-
2067.
20. Yee K, Pater JL, Pho L, et al. Enrollment of elderly patients in cancer treatment
trials in Canada. Proc Annu Meet Am Soc Clin Oncol 2001:1564.
21. Trimble EL, Carter CL, Cain D, et al. Representation of older patients in cancer
treatment trials. Cancer 1994;74:2208-2214
22. Kemeny MM, Muss HB, Kornblith AB, et al. Barriers to participation of older
women with breast cancer in clinical trials Proc Annu Meet Am Soc Clin Oncol
2001:2371.
23. Miller RA. The biology of aging and longevity. In: Hazzard WR, Blass JP, Ettinger
WH, et al, editors. Principles of geriatric medicine and gerontology. New York:
McGrow-Hill; 1999. p.3-19.
24. Cohen HJ. Oncology and aging: general principls of cancer in the elderly. In:
Hazzard WR, Blass JP, Ettinger WH, et al, editors. Principles of geriatric
medicine and gerontology. New York: McGrow-Hill; 1999 p.117-130.
25. Stanta G, Campagner L, Cavallieri F, et al. Cancer of the oldest old: what we
have learned from autopsy studies. Clin Geriatr Med 1997;13: 55-68.
26. Cohen HJ. Cancer in the older population: physiology of aging. American Society
of Clinical Oncology Curiculum 2002.
27. Vestal RE. Aging and pharmacology. Cancer 1997;80:1302-1310.
28. Avorn J, Gurwitz JH. Principles of pharmacology. In: Cassel C, Cohen JH,
Larson EB, et al, editors. Geriatric medicine. 3rd ed. Springer-Verlag: 1997, p.
55-70.

, 76, 1, 2014 283

29. Lichtman SM, Villani G. Chemotherapy in the elderly: pharmacologic
considerations. Cancer Control 2000;7:548-556.
30. Baraldi-Junkins CA, Beck AC, Rothstein G, Hematopoiesis and cytokines:
relevance to cancer and aging. Hematol Oncol Clin North Am 2000;14:45-61.
31. Sehl M, Sawhney R, Naeim A. Physiologic aspects of aging: impact on cancer
management and decision making, part II. Cancer J 2005;11:461-473.
32. Triggs EJ, Nation RLL. Pharmacokinetics in the aged: A review. Journal of
Pharmacokinetics and Biopharmacology, 1975;3:387-418.
33. Greenblatt DJ, Sellers EM, Shader RI. Drug disposition in old age. NEJM,
1982;306:1081-1088.
34. Shaw PG. Common pitfalls in geriatric drug prescribing. Drugs, 1982;23:324-328.
35. Cohen HJ. Clinical aspects of cancer in the elderly. In: Pullman B, TsoPOP,
Schneider EL, eds. Interrelationship among ageing, cancer and differentiation.
Dordrecht: Reidel, 1985;15-21.
36. Hutchins LF, Lipschitz DA. Cancer clinical pharmacology and ageing. Clinics in
Geriatric Medicine, 1987;3:483-503.
37. McLachlan MSF. The aging kidney. Lancet;ii:143-146.
38. Ho PC, Triggs EJ, Drug therapy in the elderly. Australian and New Zealand
Journal of Medicin, 1984;14:179-190.
39. FriedLP, Walston J. In: Hazzard WR, Blass JP, Ettinger WH, et al, editors.
Principles of geriatric medicine and gerontology. New York: McGrow-Hill; 1999,
p.1387-1402.
40. Cohen HJ. In search of the underlying mechanisms of frailty. J Gerontol A Bio Sci
Med Sci 2000;55:M706-708.
41. Balducei L, Stanta G. Cancer in the frail patient: a coming epidemie. Hematol
Oncol Clin North Am 2000;14:235-250.
42. Bates T, Pennessy M, Rilley DL, et al. Breast cancer in the elderly: surgery
improves survival: the results of a cancer research campain trial. Proc Annu Meet
Am Soc Clin Oncol 2001:1533.
43. Kenemy MM, Busch-Deverreaux E, Merriam LT, et al. Cancer surgery in the
elderly. Hematol Oncol Clin North Am 2000;14:169-192.
44. Poon RT, Law WL, Chu KW, et al. Emergency resection and primary
anastomosis for left-sided obstruction colorectal carcinoma in the elderly. Br J
Surg 1998;85:1539-1542.

, 76, 1, 2014 284

45. Zacharian B, Balducci L. Radiation therapy of the older patient. Hematol Oncol
Clin North Am 2000;14:131-167.
46. Pignon D, Gregor A, Schaake Koning C, et al. Age has no impact on acute and
late toxicity of curative thoracic radiotherapy. Radiother Oncol 1998;46:239-248.
47. Zacharia B, Balducci I, Venkattaramanabalaji GV, et al. Radiotherapy for cancer
patients aged 80 and older: a study of effectiveness and side effects. Int J Radiat
Oncol Biol Phys 1997;39:1125-1129.
48. Armitage JO, Potter JF. Aggressive chemotherapy for diffuse histiocytic
lymphoma in the elderly: increased complications with advanced age. Journal of
the American Geriatric Society, 1984;32:269-273.
49. Gelman RS, Taylor SG. CMF chemotherapy in women more than 65 years old
with advanced breast cancer: the elimination of age trends in toxicity by using
doses besed on creatinine clearance.Journal Clinical Oncology, 1984;2:1404-
1413.
50. Christman K, Muss HB, Case LD, et al. Chemotherapy of metastatic breast
cancer in the elderly. The Piedmont Oncology Association Experiance. JAMA
1992;268:57-62.
51. Giovanazzi-Bannon S, Rademaker A, Lai G, et al. Treatment tolerance of elderly
patients entered onto phase II clinical trials: an Illinois Cancer Center Study. J
Clin Oncol 1994;12:2447-2452.
52. Chrischilles EA, Pendergast JF, Kahn KL, et al. Adverse events among the
elderly receiving chemotherapy for advanced non-small-cell lung cancer. J Clin
Oncol 2010;28:620-627.
53. Rockwood K, Stadnyk K, MacKnight C, et al. A brief clinical instrument to classify
frailty in elderly people. Lancet 1999;353:205-206.
54. Repetto L, Comandini D, Mammoliti S. Life expectancy, comorbidity and quality
of life: the treatment equation in the older cancer patients. Crit Rev Oncol
Hematol 2001;37:147-152.
55. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a
phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146.
56. Balducci L, Stanta G. Cancer in the frail patient. A coming epidemic. Hematol
Oncol Clin North Am 2000;14:235-250.
57. National Comprehensive Cancer Network (NCCN) guidelines. Available at:
www.nccn.org (Accessed on November 12, 2013).

, 76, 1, 2014 285

58. Rodin MB, Mohile SG. A practical approach to geriatric assessment in oncology.
J Clin Oncol 2007;25:1936-1944.
59. Freyer G, Geay JF, Touzet S, et al. Comprehensive geriatric assessment
predicts tolerance to chemotherapy and survival in elderly patients with advanced
ovarian carcinoma: a GINECO study. Ann Oncol. 2005;16(11):1795-1800.
60. Maione P, Perrone F, Gallo C, et al. Pretreatment quality of life and functional
status assessment significantly predict survival of elderly patients with advanced
non--small-cell lung cancer receiving chemotherapy: a prognostic analysis of the
multicenter italian lung cancer in the elderly study. J Clin Oncol
2005;23(28):6865-6872.
61. Balducci L, Extermann M. Management of cancer in the older person: a practical
approach. Oncologist 2000;5(3):224-237.
62. Repetto L, Fratino L, Audisio RA, et al. Comprehensive geriatric assessment
adds information to Eastern Cooperative Oncology Group performance status in
elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin
Oncol 2002;20(2):494-502.
63. Extermann M, Meyer J, McGinnis M, et al. A comprehensive geriatric intervention
detects multiple problems in older breast cancer patients. Crit Rev Oncol
Hematol 2004;49(1):69-75.
64. Chen H, Cantor A, Meyer J, et al. Can older cancer patients tolerate
chemotherapy? A prospective pilot study. Cancer. 2003;97(4):1107-1114.
65. Rao AV, Hsieh F, Feussner JR, et al. Geriatric evaluation and management units
in the care of the frail elderly cancer patient. J Gerontol A Biol Sci Med Sci.
2005;60(6):798-803.
66. Katz S. Assessing self maintenance: Activities of daily living, mobility and
instrumental activities of daily living. J Am Geriatr Soc 1983;31:721-727.
67. Lawton MP, Brody EM. Assessment of older people: Self-maintaining and
instrumental activities of daily living. Gerontologist 1969;9:179-186.
68. Stafford RS, Cyr PL. The impact of cancer on the physical function of the elderly
and their utilization of health care. Cancer. 1997;80(10):1973-1980.
69. Prevalence of functional disability among elderly patients with cancer. Serraino
D; Fratino L; Zagonel V. Crit Rev Oncol Hematol. 2001;39(3):269-273.
70. Extermann M, Aapro M. Assessment of the older cancer patient. Hematol Oncol
Clin North Am 2000;14:63-77.

, 76, 1, 2014 286

71. Yancik R. Cancer burden in the aged: an epidemiologic and demographic
overview. Cancer 1997;80:1273-1283.
72. Welch HG, Albertsen PC, Nease RF, et al. Estimating treatment benefits for the
elderly: the effect of competing risks. Ann Intern Med 1996;124:577-584.
73. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of
women with primary breast cancer. Ann Intern Med 1994;120:104-110.
74. Frasci G, Lorusso V, Panza N, et al. Gemcitabine plus vinorelbine versus
vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J
Clin Oncol 2000;18:2529-2536.
75. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic
comorbidity in longitudinal studies: development and validation. J Chron Dis
1987;40(5):373-383.
76. Extermann, M, Overcash, J, Lyman, GH, et al. Comorbidity and functional status
are independent in older cancer patients. J Clin Oncol 1998;16:1582-1587.
77. Wolfson C, Wolfson DB, Asgharian M, et al. A reevaluation of the duration of
survival after the onset of dementia. N Engl J Med 2001;344:1111-1116.
78. Gupta SK, Lamont EB. Patterns of presentation, diagnosis, and treatment in
older patients with colon cancer and comorbid dementia. J Am Geriatr Soc
2004;52:1681-1687.
79. Gorin SS, Heck JE, Albert S. Treatment for breast cancer in patients with
Alzheimer's disease. J Am Geriatr Soc 2005;53:1897-1894.
80. Newman AB, Yanez D, Harris T, et al. Weight change in old age and its
association with mortality. J Am Geriatr Soc 2001;49:1309-1318.
81. Grabowski DC, Ellis JE. High body mass index does not predict mortality in older
people: analysis of the Longitudinal Study of Aging. J Am Geriatr Soc
2001;49:968-979.
82. Wallace JI, Schwartz RS, LaCroix AZ, et al. Involuntary weight loss in older
outpatients: incidence and clinical significance. J Am Geriatr Soc 1995;43:329-
337.
83. Reynolds MW, Fredman L, Langenberg P, et al. Weight, weight change, mortality
in a random sample of older community-dwelling women. J Am Geriatr Soc
1999;47:1409-1414.
84. Landi F, Onder G, Gambassi G, et al. Body mass index and mortality among
hospitalized patients. Arch Intern Med 2000;160:2641-2644.

, 76, 1, 2014 287

85. Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to
chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J
Med 1980;69:491-497.
86. Kua J. The prevalence of psychological and psychiatric sequelae of cancer in the
elderly-how much do we know?. Ann Acad Med Singapore 2005;34:250-256.
87. Vinokur AD, Threatt BA, Vinokur-Kaplan D, et al. The process of recovery from
breast cancer for younger and older patients. Changes during the first year.
Cancer 1990;65:1242-1252.
88. Seeman TE, Berkman LF, Kohout F, et al. Intercommunity variations in the
association between social ties and mortality in the elderly. A comparative
analysis of three communities. Ann Epidemiol 1993;3:325-335.
89. Avorn J, Gurwitz JH. Geriatric Medicine: Springer-Verlag; 1997.
90. Lichtman SM, Villani G. Chemotherapy in the elderly: pharmacologic
considerations. Cancer Control 2000;7:548-556.
91. Vestal RE. Aging and pharmacology. Cancer 1997;80:1302-1310.
92. Freyer G, Geay JF, Touzet S, et al. Comprehensive geriatric assessment
predicts tolerance to chemotherapy and survival in elderly patients with advanced
ovarian carcinoma: a GINECO study. Ann Oncol 2005;16:1795-1800.
93. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy
toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age
Patients (CRASH) score. Cancer 2012;118:3377-3386.
94. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older
adults with cancer: a prospective multicenter study. J Clin Oncol 2011;29:3457-
3465.
95. Extermann M, Bonetti M, Sledge GW, et al. MAX2--a convenient index to
estimate the average per patient risk for chemotherapy toxicity; validation in
ECOG trials. Eur J Cancer 2004;40:1193-1198.
96. Ramjaun A, Nassif MO, Krotneva S, et al. Improved targeting of cancer care for
older patients: a systematic review of the utility of comprehensive geriatric
assessment. J Geriatr Oncol 2013;4:271-281.
97. Soubeyran P, Fonck M, Blanc-Bisson C, et al. Predictors of early death risk in
older patients treated with first-line chemotherapy for cancer. J Clin Oncol 2012;
30:1829-1834.

, 76, 1, 2014 288

98. Bastiaannet E, Liefers GJ, de Craen AJ, et al. Breast cancer in elderly compared
to younger patients in the Netherlands: stage at diagnosis, treatment and survival
in 127,805 unselected patients. Breast Cancer Res Treat 2010;124:801-807.
99. Carlson RW, Moench S, Hurria A, et al. NCCN Task Force Report: breast cancer
in the older woman. J Natl Compr Canc Netw 2008;6 Suppl 4:S1.
100. Calle R, Pilleron JP, Schlienger P, et al. Conservative management of operable
breast cancer: ten years experience at the Foundation Curie. Cancer 1978;
42:2045-2053.
101. Weissberg JB, Prosnitz LR. Treatment of early breast cancer with primary
radiation therapy: rationale, results, and techniques. Bull N Y Acad Med
1982;58:203-213.
102. Rougier P, Van Cutsem E, Bajetta E, et al. Randomised trial of irinotecan versus
fluorouracil by continuous infusion after fluorouracil failure in patients with
metastatic colorectal cancer. Lancet 1998;352:1407-1412.
103. Fuchs CS, Moore MR, Harker G, et al. Phase III comparison of two irinotecan
dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin
Oncol 2003;21:807-814.
104. Frh M, Rolland E, Pignon JP, et al. Pooled analysis of the effect of age on
adjuvant cisplatin-based chemotherapy for completely resected non-small-cell
lung cancer. J Clin Oncol 2008;26:3573-3581.
105. Pepe C, Hasan B, Winton TL, et al. Adjuvant vinorelbine and cisplatin in elderly
patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J
Clin Oncol 2007;25:1553-1561.
106. Hardy D, Liu CC, Cormier JN, et al. Cardiac toxicity in association with
chemotherapy and radiation therapy in a large cohort of older patients with non-
small-cell lung cancer. Ann Oncol 2010;21:1825-1833.
107. Pallis AG, Shepherd FA, Lacombe D, Gridelli C. Treatment of small-cell lung
cancer in elderly patients. Cancer 2010;116:1192-1200.
108. Ardizzoni A, Favaretto A, Boni L, et al. Platinum-etoposide chemotherapy in
elderly patients with small-cell lung cancer: results of a randomized multicenter
phase II study assessing attenuated-dose or full-dose with lenograstim
prophylaxis--a Forza Operativa Nazionale Italiana Carcinoma Polmonare and
Gruppo Studio Tumori Polmonari Veneto (FONICAP-GSTPV) study. J Clin Oncol
2005;23:569-575.

, 76, 1, 2014 289

109. Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the
plasma-concentration-versus-time curve-based carboplatin plus standard-dose
intravenous etoposide in elderly patients with small-cell lung cancer. J Clin Oncol
1999;17:3540-3545.
110. Okamoto H, Watanabe K, Kunikane H, et al. Randomized phase III trial of
carboplatin(C) plus etoposide (E) vs. split doses of cisplatin (P) plus etoposide
(E) in elderly or poor-risk patients with extensive disease small cell lung cancer
(abstract #7010). J Clin Oncol 2005.

, 76, 1, 2014 290



. .
, ...

:
: 2132041634
E-mail: info@eligast.gr

.

,

, ,
, , .

, .

. ,
, ,

. 20%
.
,
, ,

.

7-10 .
,

, 76, 1, 2014 291

. ,

,
.
, 5
20%.
, .
,

,
,

.

, 76, 1, 2014 292

 :

, , ...

:
: 2132041609
E-mail: nikos.viazis@gmail.com

.

,
,
, , , .

, .

. ,
, ,

. 20%
.
.
7-10 .
,
.
,
,

.
.
,
,
1-2
,

, 76, 1, 2014 293

 . , 76, 1,
293-301, 2014.
: , ,

ABSTRACT
The prevalence of colonic diverticulosis appears to be increasing throughout the world,
probably because of changes in lifestyle. It is common in developed countries and is
slightly more common in the United States than in Europe. In contrast, it is rare in
Africa. Diverticular disease is characterized by the presence of sac-like protrusions
(diverticula) that form in the colon wall when the mucosa and submucosa herniate
through defects in the muscle layer of the wall. Although most people with colonic
diverticulosis have no symptoms, about 25% will eventually have an episode of
symptomatic diverticular disease and up to 5% will have an episode of acute
diverticulitis (an acute inflammation of the colonic diverticula). Diverticular bleeding is
another complication of colonic diverticulosis, but in contrast to diverticulitis, its
prevalence is very low. Abdominal CT is valuable for diagnosing colonic diverticulitis,
but nowadays uncomplicated diverticulitis is more frequently diagnosed by endoscopy.
As regards treatment, for outpatients, broad-spectrum antibiotics are usually given for
710 days. Various antibiotics may be used in the treatment of acute diverticulitis,
ranging from ampicillin to third-generation cephalosporins and ciprofloxacin in
combination with and metronidazole, since we need adequate coverage against gram-
positive, gram-negative aerobicanaerobic bacterial strains. Current guidelines
recommend admission to hospital, with intravenous antibiotic treatment and bowel
rest, if the patient is unable to take oral therapy or is affected by severe comorbidity, or
if the patients condition does not improve with outpatient therapy. After an acute
episode of diverticulitis has resolved, patients are generally advised to maintain a
high-fibre diet to optimize their bowel movements. According to guidelines by the
American Society of Colon and Rectal Surgeons and others elective resection should
be considered after 1 or 2 well-documented episodes of diverticulitis, depending on
the severity of the attack and the age and medical fitness of the patient.
Nosokomiaka Chronika, 76, Supplement 1, 293-301, 2014.
Key words: diverticular disease, colonoscopy, antibiotics

, 76, 1, 2014 294



1.


, ,
, 2,3.

, ,
, , 4.


, 5.

-
1.
10% ,
..., , .
2,3. 40 ,
5% 20% 5 50% 65
80% 9 4,5.

.
95% 2.
, 2.

,

.

5.

, 76, 1, 2014 295

, , ,

. 20%
5-7.

,
. ,
, , ,
5-9.

. ,
,
, ,
.

.

94% 81%
6,7.
, , ,
.
1.5%
,
8,9.

7-10 10.
,
10-15. ,

. ,

, 76, 1, 2014 296

 ,
16.
, 5
20%17,18. ,
(.. ) ,

.
,
19-22.
,
, ,
gram- gram-
23. 800
mg/ 10 ,
24-26.
.
2 , /
,

+ 27-40.

,

,
,

41-44.

.
. ,
.
,

, 76, 1, 2014 297

 .

.

1. Weizman AV, Nguyen GC Diverticular disease: epidemiology and management.

Can J Gastroenterol 2011;25:385-389.
2. Tursi A, Papagrigoriadis S. Review article: the current and evolving treatment of
colonic diverticular disease. Aliment Pharmacol Ther 2009;30:532-456.
3. Shahedi K, Fuller G, Bolus R, et al. Progression from incidental diverticulosis to
acute diverticulitis [abstract]. Gastroenterology 2012;142(Suppl 1):144.
4. Etzioni DA, Mack TM, Beart RW Jr, et al. Diverticulitis in the United States: 1998
2005: changing patterns of disease and treatment. Ann Surg 2009;249:210-217.
5. Jung HK, Choung RS, Locke GR III, et al. Diarrhea-predominant irritable bowel
syndrome is associated with diverticular disease: a population-based study. Am J
Gastroenterol 2010;105: 652-661.
6. Ambrosetti P. Acute diverticulitis of the left colon: value of the initial CT and timing
of elective colectomy. J Gastrointest Surg 2008;12:1318-1320.
7. van Randen A, Lamris W, van Es HW, et al. OPTIMA Study Group. A
comparison of the accuracy of ultrasound and computed tomography in common
diagnoses causing acute abdominal pain. Eur Radiol 2011;21:1535-1545.
8. Ghorai S, Ulbright TM, Rex DK. Endoscopic findings of diverticular inflammation in
colonoscopy patients without clinical acute diverticulitis: prevalence and
endoscopic spectrum. Am J Gastroenterol 2003;98:802-806.
9. Tursi A, Elisei W, Giorgetti GM, et al. Inflammatory manifestations at colonoscopy
in patients with colonic diverticular disease. Aliment Pharmacol Ther 2011;33:358-
365.
10. Tursi A. Diverticular disease: a therapeutic overview. World J Gastrointest
Pharmacol Ther 2010;1:27-35.
11. Lahat A, Yanai H, Menachem Y, et al. The feasibility and risk of early colonoscopy
in acute diverticulitis: a prospective controlled study. Endoscopy 2007;39:521-524.
12. Rafferty J, Shellito P, Hyman NH, et al. Practice parameters for sigmoid
diverticulitis. Dis Colon Rectum 2006;49:939-944.
13. Schechter S, Mulvey J, Eisenstat TE. Management of uncomplicated acute
diverticulitis: results of a survey. Dis Colon Rectum 1999;42:470-475.

, 76, 1, 2014 298

14. World Gastroenterology Organisation Practice Guidelines: Diverticular disease.
Milwaukee (WI): World Gastroenterology Organisation; 2007. Available:
www.worldgastroenterology.org/assets/downloads/en/pdf/guidelines/07_diverticula
r_disease.pdf (accessed 2012 July 19).
15. Stollman NH, Raskin JB. Diagnosis and management of diverticular disease of the
colon in adults. Ad Hoc Practice Parameters Committee of the American College of
Gastroenterology. Am J Gastroenterol 1999;94:3110-3121.
16. Broderick-Villa G, Burchette RJ, Collins JC, et al. Hospitalization for acute
diverticulitis does not mandate routine elective colectomy. Arch Surg
2005;140:576-581.
17. Anaya DA, Flum DR. Risk of emergency colectomy and colostomy in patients with
diverticular disease. Arch Surg 2005; 140:681-685.
18. Binda GA, Arezzo A, Serventi A, et al. Italian Study Group on Complicated
Diverticulosis (GISDIC). Multicentre observational study of the natural history of
left-sided acute diverticulitis. [published erratum appears in Br J Surg
2012;99:600]. Br J Surg 2012;99:276-285.
19. Crowe FL, Appleby PN, Allen NE, et al. Diet and risk of diverticular disease in
Oxford cohort of European Prospective Investigation into Cancer and Nutrition
(EPIC): prospective study of British vegetarians and non-vegetarians. BMJ
2011;343:d4131.
20. Peery AF, Barrett PR, Park D, et al. A high-fiber diet does not protect against
asymptomatic diverticulosis. Gastroenterology 2012;142:266-272.
21. Unl C, Daniels L, flrouenraets BC, et al. A systematic review of high-fibre dietary
therapy in diverticular disease. Int J Colorectal Dis 2012;27:419-427.
22. Strate LL, Liu YL, Syngal S, et al. Nut, corn, and popcorn consumption and the
incidence of diverticular disease. JAMA 2008;300:907-914.
23. Bianchi M, Festa V, Moretti A, et al. Meta-analysis: long-term therapy with rifaximin
in the management of uncomplicated diverticular disease. Aliment Pharmacol Ther
2011;33:902-910.
24. Zullo A, Hassan C, Maconi G, et al. Cyclic antibiotic therapy for diverticular
disease: a critical reappraisal. J Gastrointestin Liver Dis 2010;19:295-302.
25. Maconi G, Barbara G, Bosetti C, et al. Treatment of diverticular disease of the
colon and prevention of acute diverticulitis: a systematic review. Dis Colon Rectum
2011;54:1-1326-1338.

, 76, 1, 2014 299

26. Scarpignato C, Pelosini I. Experimental and clinical pharmacology of rifaximin, a
gastrointestinal selective antibiotic. Digestion 2006;73(Suppl 1):13-27.
27. Elli L, Roncoroni L, Bardella MT, et al. Absence of mucosal inflammation in
uncomplicated diverticular disease. Dig Dis Sci 2011;56:2098-2103.
28. Simpson J, Sundler F, Humes DJ, et al. Post inflammatory damage to the enteric
nervous system in diverticular disease and its relationship to symptoms.
Neurogastroenterol Motil 2009;21:847-858.
29. Humes DJ, Simpson J, Smith J, et aL. Visceral hypersensitivity in symptomatic
diverticular disease and the role of neuropeptides and low grade inflammation.
Neurogastroenterol Motil 2012;24: 318-e163.
30. Tursi A, Elisei W, Giorgetti GM, et al. Persistence of endoscopic and histological
inflammation are risk factors of diverticulitis recurrence after attack of acute
uncomplicated diverticulitis [abstract]. Gastroenterology 2011;140(Suppl 1):S-61.
31. Tursi A, Joseph RE, Streck P. Expanding applications: the potential usage of 5-
aminosalicylic acid in diverticular disease. Dig Dis Sci 2011;56:3112-3121.
32. Kruis W, Meier E, Schumacher M, et al. Treatment of painful diverticular disease of
the colon with mesalamine: a placebo-controlled study [abstract]. Gastroenterology
2007;132:A-191.
33. Tursi A, Brandimarte G, Daffin R. Long-term treatment with mesalazine and
rifaximin versus rifaximin alone for patients with recurrent attacks of acute
diverticulitis of colon. Dig Liver Dis 2002;34:510-515.
34. Tursi A, Brandimarte G, Giorgetti GM, et al. Balsalazide and/or high-potency
probiotic mixture (VSL#3) in maintaining remission after attack of acute,
uncomplicated diverticulitis of the colon. Int J Colorectal Dis 2007;22:1103-1108.
35. Stollman N, Magowan S, Shanahn F, et al. Efficacy of delayed-release
mesalamine in the prevention of GI symptoms following acute diverticulitis: results
of the DIVA trial. Am J Gastroenterol 2010;105(Suppl 1):139.
36. Parente F, Bargiggia S, Prada A, et al. Randomised multicentre pilot double-blind
placebo-controlled study evaluating the efficacy and safety of mesalazine in the
prevention of recurrence of diverticulitis: interim analysis after 24-month follow-up.
Dig Liver Dis 2011;43(Suppl 1):135.
37. Gaman A, Teodorescu R, Georhescu EF, Abagiu M. Prophylactic effects of
mesalamine in diverticular disease [abstract]. Falk Symposium 2011;178:13.
38. Yan F, Polk DB. Probiotics and immune health. Curr Opin Gastroenterol
2011;27:496-501.

, 76, 1, 2014 300

39. Tursi A, Brandimarte G, Giorgetti GM, et al. Mesalazine and/or Lactobacillus casei
in preventing recurrence of symptomatic uncomplicated diverticular disease of the
colon: a prospective, randomized, open-label study. J Clin Gastroenterol
2006;40:312-316.
40. Annibale B, Maconi G, Lahner E, et al. Efficacy of Lactobacillus paracasei sub.
paracasei F19 on abdominal symptoms in patients with symptomatic
uncomplicated diverticular disease: a pilot study. Minerva Gastroenterol Dietol
2011;57:13-22.
41. Tursi A. Antibiotics and probiotics in the treatment of diverticular disease. J Clin
Gastroenterol 2011;45(Suppl 1):4652. Stocchi L. Current indications and role of
surgery in the management of sigmoid diverticulitis. World J Gastroenterol 2010;
16:804-817.
42. Egger B, Peter MK, Candinas D. Persistent symptoms after elective sigmoid
resection for diverticulitis. Dis Colon Rectum 2008; 51:1044-1048.
43. Narayan R, Floch MH. Microscopic colitis as part of the natural history of
diverticular disease. Am J Gastroenterol 2002;97(1 Suppl):S112-113.
44. Cianci R, Iacopini F, etruzziello L, et al. Involvement of central immunity in
uncomplicated diverticular disease. Scand J Gastroenterol 2009;44:108-115.

, 76, 1, 2014 301



.
,
...

:
: 6944333740
Email: lakiotisgreg@gmail.com

(diagnostic laparoscopy DL)
, , ,
87%100%
. ,
(Therapeutic laparoscopy TL)
,
.
:
, ,
, , ,
, ,

() .
, 1)
- ; 2)
; 3)
/; 4)
;

. ,
.
, ,
, .

, 76, 1, 2014 302

 ,

,
.
, 76, 1, 302-321, 2014.
: , , ,

SUMMARY
Lakiotis GT. Laparoscopy and acute abdomen. The improvement in surgical
decision-making for patients with abdominal pain, but with uncertain diagnosis, using
diagnostic laparoscopy (DL) has improve now the diagnostic accuracy in a high
percentage of patients (87-100%), and has decrease the negative and non-therapeutic
rates of laparotomy. Once the diagnosis is established the surgeon may proceed with
laparoscopic treatment if indicated and technically possible or if laparoscopic
treatment is not technically possible, may minimize the length of the abdominal
incision by positioning the incision directly over the site of the disease process.
Conditions amenable to therapeutic laparoscopy include appendicitis, perforated
peptic ulcer, diverticulitis, small bowel obstruction, acute cholecystitis, and acute
pancreatitis, incarcerated ventral and inguinal hernia. Bedside laparoscopy in the ICU
is safe and accurate for evaluating patients with suspected intestinal ischemia or intra-
abdominal sepsis. But who should perform emergency laparoscopic procedures?
What should the selection criteria be? What about the cost are and is patient outcome
actually better with laparoscopy? Only randomized trials can answer these questions.
Every surgeon has to decide the best approach according to his or her own
experience, the particular clinical situation, his/her proficiency with the various
techniques and the specific organizational setting in which he/she is working. These
guidelines have been developed to help surgeons with their decisions in the very
difficult situation of emergency surgery. Nosokomiaka Chronika, 76, Supplement 1,
302-321, 2014.
Key words: laparoscopy, urgent laparoscopy, acute abdomen, acute abdominal pain

, 76, 1, 2014 303


-

.
1902 Kelling.
1910
Jacobaeus 1928 Klark Bruhl.
1980

. H
: (1) ,
, -
, (2)
, (3) , (keyhole)
(4)
.
(minimal access surgery,
MAS) 1.


, , ,
, .

,
.

80 90


.
(/)
(computer aided diagnosis CAD), ,
20%
, 75%2.
,

, 76, 1, 2014 304

 ,
.
, ,
4% ,
8%, 23% 71%
.
,
.
,
3.
,
, 20%
40% .
,
13-17%.


,
.

.
/ (CAD),
.

,
,
4.

.
86% ,
,
.
96%.
,

, 76, 1, 2014 305

 .

,
.

()

,
().
:
) .
) .
) .

, ,
. :
1) "look and see"
2) " "wait and see".

(), 19% 0%4.
()
22%, 8% ()
. ,
39% 15%
.

, 5,27.

()



, ,

23%40% ,

, 76, 1, 2014 306

 . ,


.
,
3/4
100%.
,


.
Fitz-Hung and Curtis (
)6 ,
,
, .

, ,
,
.
, ,



.
(SAGES)
SAGES, ,
, ,
. ,
.
:
1. ( ),
2. ( Fitz-Hugh-Curtis ),
3. ,
4. ,

, 76, 1, 2014 307

 5.

6. ,
7. ,
8. ,
9. .
,
7.


.

.
,
, .
.
,
5% 22%2,6 .
20
96%.
,
22%.

,
9.


-,
8.


,
.
.

, 76, 1, 2014 308

, Fitz-Hughes-Curtis .

.
,
. ,
,

.
,
, , .
,
,
, :
:
,
.
,
(second look).
:
,
.
:
.
,
.

,
.
.
:
. ,
,
.
:
, ,

, 76, 1, 2014 309

 .
.
:

.
, Meckel .
,
7.

ASCOI,
SIC, SICUT EAES, ,
2005,
10.


(). ,
.
.
.

,

.
,
.
,

.
11.
, , 11

. ,
Calot.

, 76, 1, 2014 310

 ,
,
.

.

: 4-7 6-12
.

.
17.5% (13.9%25%) ,
,
45%. (United States Medical Claims
Data System) 75% 66 , ,
(71% 29% ).
.
38%
2 9,5%
4,4% .

, : ,
,
. 53
,
,

13.
.

.
. mini
.


.

, 76, 1, 2014 311


.
- (endoscopic retrograde clolangio-
pancreatography, ERCP),
(endoscopic ultra sound, EUS), (magnetic resonance MR)
( >90%) .

, ,
(-
) .
,
.

14
APACHE CT .
. ERCP ERCP
.

.
14
.
15,
16.
.

.
(, )
.

.


().

.
,

, 76, 1, 2014 312

 ,
.
>6-8 L
.
.
,
,
(US, CT), ,
. (>13%)
(9%)
11%26% 17.
,
. 3 trocar
(one port).
.
(NSAP)

7
18. .
, 90%100%,
36%95%, 0-8%
ICU.
. ,
wait and see,
81% 87% (28% 36%),
.
NSAP.
()

,
. .
, .
100%
, 86%
. .

, 76, 1, 2014 313

 ,
.
. Boey
(<90mmHg), ASA II-V
>24,
(Boeys score 01). ,
Manheim Peritonitis Index
(MPI) , APACHE II. > 70
> 10mm. ,


.
.
shock
.
3,7%5,3% 1,6%2%,
.
19. ;
.
, ,
.
,
.
.


Hinchey
. .
(
)
. H
Hinchey:

a
IIb

, 76, 1, 2014 314


IV
I IIa:

.
IIb III .

, . H
.

IV.

.
, ,
, .

,
>90%,
,
, , .
,
3-6 ,
>50% ()20.
III
(, , )
.

.
IV, , ,
, ,
.
() ( )

. O
75% .

, 76, 1, 2014 315

 (12% 18% ),
21.
50-60%, <50%
.
, (SAGES)22.
50% 88%,
0%50%.
.
: >4.,
, 24
, .

,
.
/
TEP (totally extraperitoneal) TAPP (transabdominal pre-
peritoneal)
. 0,29%2,9%
10-15%
(), >5% .
23
61,3, 3,8 , 0,28%, 10,3%,
1,8%, 5,1% 0,9%.
: (0,2%),
(0,15%), 0,6%, 0,3%,
0,3% 5,8%, 7 .
.

, 11,250%.

/ .
-
,
.

, 76, 1, 2014 316

 ,
24.
(Ventral Hernia).

,
.
.

,
>4cm, >24 ,
>6 , 25.
,
.

3 ,
, , .

, ,
, , ,
,
-
, ,

.

, 3cm, ,
.
.


.
()
H ,
.
50% , (non occlusive)

, 76, 1, 2014 317

 20%30% 5%15% .
(59%93%)
.26
93,3% 95,9%
.
, (, ,
) ( ,
), (nonocclusive) .
,

()27. (laparoscopic second-look),
(surgical second-look)
28.

H
,
. ,
,
,

.

.
.
(hernioscopy),

.
()

, ,
,
(), ,
.
,

, 76, 1, 2014 318

 (second look) .

,
.
, .


.
II-III .

() ,
.

, ,
.
.

.
.

, ,

.
.

.

1. Forde KA, Treat MR. The role of peritoneoscopy (laparoscopy) in the evaluation of
the acute abdomen in critically ill patients. Surg Endosc 1992;6:219221.
2. Adams ID, Chan M, Clifford PC, et al. Computer aided diagnosis of acute
abdominal pain: A multicenter study. Br Med J 1972;2:913.
3. Mueller BA, Daling JG, Moore DE, et al. Appendectomy and the risk of tubular
infertility. N Engl J Med 1986;315:15061508.

, 76, 1, 2014 319

4. Paterson-Brown S, Eckerseley JRT, Sim AJ et al. Laparoscopy as an adjunct to
decision-making in the acute abdomen. Br J Surg 1986;73:10221024.
5. Spirtos NM, Eisenkop SM, Spirtos TW, et al. Laparoscopy as a diagnostic aid in
cases of suspected appendicitis. Its use in women of reproductive age. Am J
Obstret Gynecol 1987;156:9094.
6. Wood JJ, Bolton JP, Cannon SR. Biliary-type pain as a manifestation of genital
tract infection: The Curtis-Fitz and Hugh syndrome. Br J Surg 1982;69:251253.
7. Jonathan M. Sackier. Emergency Laparoscopy. In The SAGES MANUAL,
Fundamentals of Laparoscopy and GI Endoscopy, Carol E.H. Scott-Conner, ed
Springer, New York, 1999.
8. Berci G, Sackier JM, Paz Partlow M: Emergency Laparoscopy. Am J Surg
1991;161:332-335.
9. Memon MA, Fitztgibbons RJ. Laparoscopy for abdominal pain. Surg Clin North Am
1977;6:13331353.
10. Guide Lines evidence of effectiveness of laparoscopy in acute abdomen. EAES
Consensus 2011, Surg Endosc 2012;26:21342164.
11. Boo YJ, Kim WB, Kim J et.al. Systemic immune response after open versus
laparoscopic cholecystectomy in acute cholecystitis: a prospective randomized
study. Scand J Clin Lap Invest 2007;67:207214.
12. Borzellino G, Sauerland S, Mimicozzi AM, et al. Laparoscopic cholecystectomy for
severe cholecystitis. A meta - analysis of results. Surg Endosc 2008;22:815.
13. Winbladh A, Gullstrand P, Svanvik J et al, systematic review of cholecystostomy
as a treatment option in acute cholecystitis. HBB (Oxford) 2009;11:183193.
14. Hirota M, Takada T, Kawarada Y et al. Guidelines for the management of acute
pancreatitis: severity assessment of acute pancreatitis. J Hepatobiliary Pancreat
Surg 2006;13:3341.
15. Adamson GD, Cuschieri A, Multimedia article. Laparoscopic infracolic
necresectomy for infected pancreatic necrosis. Surg Endosc 2003;17:1675.
16. Horvath KD, Kao LS, Wherry KL, et al. A technique for laparoscopic-assisted
percutaneous drainage of infected pancreatic necrosis and pancreatic abscess.
Surg Endosc 2001;15:12211225.
17. Navez B, Therasse A. Should every patient undergoing laparoscopy for clinical
diagnosis of appendicitis have an appendicectomy? Acta Chir Belg 2003; 103:87
89 17. Society of American Gastrointestinal and Endoscopic Surgeons (SAGES)

, 76, 1, 2014 320

 Guidelines for diagnostic laparoscopy practice/clinical guidelines. SAGES, Los
Angeles 2007.
18. Lau H. Laparoscopic repair of perforated peptic ulcer: a meta-analysis. Surg
Endosc 2004;18:10131021.
19. Myers E, Hurley M, OSullivan et al. Laparoscopic peritoneal lavage for
generalized peritonitis due to perforated diverticulitis. Br J Surg 2008;95:97101.
20. Farinella E, Cirocchi R, La Mura F, et al. Feasibility of laparoscopy for small bowel
obstruction. World J Emerg Surg 2009;4:3 doi: 10.1186/1749-7922-4-3.
21. SAGES Diagnostic laparoscopy guidelines. Surg Endosc 2008;22:13531383.
22. Ishihara T, Kubota K, Eda N et al. Laparoscopic approach to incarcerated inguinal
hernia. Surg Endosc 1996;10:11111113.
23. Sgourakis G, Radtke A, Sotiropoulos GC et al. Assessment of strangulated
content of the spontaneously reduced inguinal hernia via hernia sac laparoscopy:
preliminary results of a prospective randomized study. Surg Laparosc Endosc
Percutan Tech 2009;19:133137.
24. Landau O, Kyzer S. Emergency laparoscopic repair of incarcerated incisional and
ventral hernia. Surg Endosc 2004;18:13751376.
25. Zamir G, Reisman P. Diagnostic laparoscopy in mesenteric ischemia. Surg
Endosc 1998;12:390393.
26. Yanar H, Taviloglu K, Ertecin C et al.Planned second look laparoscopy in the
management of acute mesenteric ischemia. World J Gastroenterol 2007;13:3350
3353.
27. Paterson S,Brown H, Dudley A.F. The acute Abdomen. In: Laparoscopic Surgery,
Ballantyne-Leahy-Modlin ed. Saunders Co, Philadelphia USA, 1994.

, 76, 1, 2014 321



, PhD,
-,
...

:
: 2132041631
Email: evanbalis@yahoo.co.uk

Gustav Killian 1897

63 .
.
Ikeda
.

30 , ,

.


.
, 76, 1, 322-330, 2014.
: , ,
,

SUMMARY
BALIS E. Interventional bronchoscopy. The otolaryngologist Gustav Killian
performed the first rigid bronchoscopy in 1897 when he removed a piece of pork bone
from the bronchus of a 63 years old farmer. His efforts were greatly aided by discovery
of the anaesthetising effect of locally applied cocaine. Flexible bronchoscopy was

, 76, 1, 2014 322

made possible by discovery of the optical properties of glass fibres by Ikeda who was
also instrumental in the development of the videoscope. The flexible bronchoscope
has become the diagnostic instrument of choice, for the diagnosis and the treatment,
of endobronchial lesions during the last 30 years as it is less invasive, does not require
a general anaesthetic and provides superior visualisation of smaller peripheral
airways. Despite the great development in flexible bronchoscopy, the last two decades
rigid bronchoscopy has been rekindled by the development of various therapeutic
tools for the management of both benign and malignant central airway obstruction.
Nosokomiaka Chronika, 76, Supplement 1, 322-330, 2014.
Key words: flexible bronchoscope, rigid bronchoscope, interventional bronchoscopy,
airway obstraction.

,
, .
: )

)

.
,
( ,
),
.
, ,
, , ,
, , , .


(TBNA), (EBUS & REBUS),
(ENB), ,
, , Laser, , ,
, , ,
, .

, 76, 1, 2014 323



EBUS
REBUS. EBUS ( )
,
,
.

.

(85-95% &100% ),
1, 2. REBUS (
)

.
, , 3.

(400-600nm)
.

,
.
4.

.

.

.

5, 6.

,
( ), (

, 76, 1, 2014 324

), (. Wegener, ,
), (. )
.
.

, ,

7.


,
,
, ,
, , ,
(Lung Volume
Reduction)8, 9.
Laser
Laser Nd:YAG
Laser. ()
.
, .


.
,

8-10.
Argon plasma coagulation(APC)

( , , )
. APC
.
.
Laser .
laser

, 76, 1, 2014 325

 laser
(Stents).
.

8-10.

(-200C -400C) (
), ,
(cryoadhesion).
(cryotherapy) 8-10 .
, , , (
) .
-
.
,
, -
, ,
.
30%
.
.
N2O 2 9,11,12.
(stents)


,
.
, .

. ,

.

.

, 76, 1, 2014 326


13-15.

Laser.

( ) .
192
I (Low Dose Rate)
(High Dose Rate). 60%
.
,
, , , 0,5%.
,
, , 5-15%9,16, 17.


,


.
Photofrin II ( )
(630
nm) .

. 48
.
, 9.


,
2- .
, .

, 76, 1, 2014 327

 .
18, 19.


,
.
,


.
) , ) , )
) 20.

.


.

1. Rintoul RC, Skwarski KM, Murchison JT, et al. Endobronchial and endoscopic
ultrasound-guided real-time fine-needle aspiration for mediastinal staging. Eur
Respir J 2005;25:416421.
2. Yasufuku K, Chiyo M, Koh E, et al. Endobronchial ultrasound guided
transbronchial needle aspiration for staging of lung cancer. Lung Cancer
2005;50:347354.
3. Schuhmann M, Bostanci K, Bugalho A, et al. Endobronchial ultrasound-guided
cryobiopsies in peripheral pulmonary lesions: a feasibility study. Eur Respir J.
2014;43(1):233-239.
4. Haussinger K, Becker H, Stanzel F, et al. Autofluorescence bronchoscopy with
white light bronchoscopy compared with white light bronchoscopy alone for the
detection of precancerous lesions: a European randomised controlled multicentre
trial. Thorax 2005;60:496503.

, 76, 1, 2014 328

5. Becker HD, Herth F, Ernst A, et al. Bronchoscopic biopsy of peripheral lung
lesions under electromagnetic guidance. A pilot study. J Bronchol 2005;12:913.
6. Gildea TR, Mazzone PJ, Karanak D, et al. Electromagnetic navigation diagnostic
bronchoscopy. A prospective study. Am J Respir Crit Care Med 2006;174:982
989.
7. Ayers ML, Beamis JF Jr. Rigid bronchoscopy in the twentyfirst century. Clin Chest
Med 2001;22:355-364.
8. Wahidi MM, Herth FJF, Ernst A. State of the art: interventional pulmonology.
Chest 2007;131:261274.
9. Bolliger CT, Mathur PN, Beamis JF, et al. ERS/ATS statement on interventional
pulmonology. Eur Respir J 2002;19:356373.
10. Breen D, Mallawathantri S, Bezzi A, et al. Follow up and outcome of patients with
carcinoma in situ treated by endobronchial laser a series. Eur Respir J
2008;32:Suppl.52, 593s.
11. Babiak A, Hetzel J, Krishna G, et al. Transbronchial Cryobiopsy: A New Tool for
Lung Biopsies. Respiration 2009;78:203208.
12. Maiwand O, Glynne-Jones R, Chambers J, et al. Direct cryosurgery for inoperable
metastatic disease of the lung. Ann Thorac Surg 2006;81:718721.
13. Ernst A, Majid A, Feller-Kopman D, et al. Airway stabilization with silicone stents
for treating adult tracheobronchomalacia: a prospective observational study. Chest
2007;132:609616.
14. Gildea TR, Downie G, Eapen G, et al. A prospective multicenter trial of a self-
expanding stent in malignant airway obstruction. J Bronchol 2008;15:221224.
15. Dooms C, De Keukeleire T, Janssens A, et al. Performance of fully covered self-
expanding metallic stents in benign airway strictures. Respiration 2009;77:420
426
16. Ung YC, Yu E, Falkson C, et al. The role of high dose rate brachytherapy in the
palliation of symptoms in patients with non-small-cell lung cancer: a systematic
review. Brachytherapy 2006;5:189202.
17. Hennequin C, Bleichner O, Tredaniel J, et al. Long-term results of endobronchial
brachytherapy: a curative treatment? Int J Radiat Oncol Biol Phys 2007;67:425
430.
18. Cox G, Miller JD, McWilliams A, et al. Bronchial thermoplasty for asthma. Am J
Respir Crit Care Med 2006;173:965969.

, 76, 1, 2014 329

19. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after
bronchial thermoplasty. N Engl J Med 2007;356:13271337.
20. Emmanuil P, Koufos N, Koulouris N, et al. Bronchoscopic lung volume reduction in
advanced pulmonary emphysema: the safety and efficacy of novel methods.
Pneumon 2012;25(1):36-50.

, 76, 1, 2014 330



C:
.

, , ...

:
: 6944849534
-mail: sxinama@gmail.com

H C (standard of care, SOC)

50% 1.
1,
2
, (boceprevir, BOC, Victrelis)
(telaprevir, TPV, Incivo). , ,
, - (Direct Acting
Antivirals, DAAs) NS3/4A .
- ,
- .
HCV 1
.

, ,
.
C 1
.
, 76, 1, 331-342, 2014.
: , , C

, 76, 1, 2014 331

 SUMMARY
SCHINA . Developments in Hepatitis C: Drugs and future treatments. Drugs
available. The standard of care therapy of chronic hepatitis C (SOC) is the
combination of pegylated interferon and ribavirin with efficacy rate of 50% for genotype
1. In order to improve the effectiveness of treatment for genotype 1, two new drugs,
belonging to the class of protease inhibitors, were released in the last two years,
boceprevir (BOC, Victrelis ) and teleprevir (TPV, Incivo ). These drugs, are
administered as tablets, belong to the class of direct antivirals (direct acting antivirals,
DAAS) and act by inhibiting the NS3/4A viral protease. They have strong antiviral
activity, but should always be administered in combination with pegylated interferon-
alpha and ribavirin. Have been approved for treatment only in patients with HCV
genotype 1 and significantly increase the likelihood of SVR in this group of patients.
However, this significant improvement in SVR is accompanied by additional and more
serious side effects, including anemia, increased treatment costs and significant
interactions with other drugs. It is obvious that the treatment of patients with chronic
hepatitis C, genotype 1, is becoming more complex and requires more effort for proper
patient selection and optimal implementation. Nosokomiaka Chronika, 76,
Supplement 1, 331-342, 2014.
Key words: triple therapy, protease inhibitor, hepatitis C

C
. 1-3%
.

. ,
( , Sustained Virological Response, SVR) .

. 1
.

C (FN, IntronA Roferon-A),
(Peg) IFN (Peg-IFN-2a, Pegasys, Peg-IFN-2b,
PegIntron), (RBV, Copegus Rebetol)
, (boceprevir, BOC, Victrelis telaprevir, TPV, Incivo).

, 76, 1, 2014 332

H C (standard of care, SOC)
Peg-IFN,
50% 1.
1
2 2011, ,
(boceprevir, BOC, Victrelis) (telaprevir, TPV,
Incivo). , ,
, - (Direct Acting Antivirals,
DAAs) NS3/4A . -
,
- ,
. HCV
1
. ,

40%-45% 68-75% , 25%-30%
75%-88% , 7%-15% 52%-59%
5% 33%-38%
. ,
, 24
48 47%-58%
.

,
.
C 1

.


, 2013, .

1 /
(HCV RNA>800 000IU/mL) ,
, RVR, HCV RNA 4

, 76, 1, 2014 333

.
IL28B,
IL28B (TT CT).

, ADVANCE, REALIZE
ILLUMINATE. 750 mg (2 375 mg)
3 ( 8 ).
1125 mg (3 375 mg)
2 ( 12 ).
12
12 36
. (RGT, response guided
therapy)
HCV RNA 4 12 24
.
HCV RNA > 1000 IU/m L 4 12 /
RNA 24.
(nave)
ADVANCE
(A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients
with Telaprevir)

. =1088 C
1,
:
T 750 mg 8
8 ,
(T8/PR)
T 750 mg 8
12 ,
(T12/PR)
48 (PR48)

, 76, 1, 2014 334


(eRVR, HCV RNA < 25 IU/mL 4 12)
24, eRVR,
24
48 . eRVR 57%
58% T8/PR T12/PR
(RGT, response guided therapy).
SVR
8 12
(69% 75% vs 44%). E 35% 37%
T8/PR T12/PR , 24%
PR48. , 5% 7% T8/PR
T12/PR TVR .

REALIZE
(Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes)

/ . = 663 1
SVR . :
(354 ), (124 )
(184 ). :
12
, 36
(T12PR48)
4 (lead in period),

12 , 32
(lead in-T12PR48)
48 (PR48).
SVR
(SVR 64% T12PR48, 66% lead in-
T12PR48 17% PR48). SVR
:
- (83% T12PR48 , 88% T12PR48 24% PR48)
- (59% , 54%, 15%)

, 76, 1, 2014 335

 - (29% , 33% , 5% ).
143 , SVR

(49%
8%). 4% 5%
2% 3% ,
PR48 .
ILLUMINATE
540 1,
SVR 24
48 eRVR,
HCV RNA < 25 IU/mL 4 12). eRVR
20
, 24 48 . eRVR 352
(65%), 322 24 48 .
eRVR 48 .
SVR 72%, 7%
18% ( ) .
eRVR , SVR 24
(92 %) SVR 48
(88%).

M
SPRINT-
2 RESPOND 2.
PEG/RBV (lead in period)
.
(RGT, response guided
therapy). , HCV RNA
8 24 28 ,
4
24 .
48 . BOC 800 mg (4
200 mg) 3 ( 7-9 ).

, 76, 1, 2014 336

 HCV RNA
>100 IU/mL 12 24 .
(nave)
SPRINT-2
1. N=938
159 .
lead-in, 4 . o lead-in,
:
1: , ,
44
2: ,
24 , 20
HCV RNA o
8 24
3: ,
44
HCV RNA 24
. , SVR 40%, 67%, 68%
1, 2, 3, . SVR

1. , SVR 23%, 42% 53%
. SVR 1 3
, 2 3 . 44%
2 HCV RNA 8
24 28 . SVR
97% 87% , .
IL28B (CC)
SVR CT .
SVR
,
, 1b 1 .
56-57% HCVRNA 8
RGT. 88-90% SVR.

RESPOND-2

, 76, 1, 2014 337

 403

. .
SPRINT-2,
lead-in .
:
1: , ,
44 .
2: ,
32 , 12
HCV RNA
8 , 12.
3: ,
44 .
HCV RNA 12.
61% 1, 22% 2
18% 3. , SVR
.
SVR 7%, 40%
52% 1, 2 3 , SVR 29%, 69%
75% .

lead-in
1 (SOC),
. ,
HCV RNA < 1 log10 4
SVR 0%, 33% 34% 1, 2 3
, 1 log10 SVR 25%,
73% 79% . , o
IL28B SVR .

, (43%-46% vs 20%). 41%-
46% 21% . ,
(0%-3%).

, 76, 1, 2014 338


PEG/RBV. ,
, , ,
, ,
, ,
.
.
.
( EPO)
. PEG-IFN/RBV IDEAL

SVR SVR.
,
,
SVR
. ,

.

BOC
(18,6 VS 12%). , CUPIC
212 (93% Child Pugh A)
44,3% 1,4% .

: <100 000/mm3 <35g/L.

(51,4%)
SVR 12 (27%).

.

(DDIs)
H
.

, 76, 1, 2014 339

 p- P450 3A4/5
50% .

.
,
www.hep - druginteractions .org .

1. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis
C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study.
Gastroenterology 2006;131:997.
2. Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha-
2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in
patients. Hepatology 2007; 46:631.
3. Forestier N, Reesink HW, Weegink CJ, et al. Antiviral activity of telaprevir (VX-
950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology 2007;
46:640.
4. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and
ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360:1827.
5. Hzode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or
without ribavirin for chronic HCV infection. N Engl J Med 2009; 360:1839.
6. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated
chronic HCV infection. N Engl J Med 2010; 362(14):1292.
7. Muir AJ, Poordad FF, McHutchison JG, et al. Retreatment with telaprevir
combination therapy in hepatitis C patients with well-characterized prior treatment
response. Hepatology 2011; 54:1538.
8. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously
untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364:2405.
9. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N
Engl J Med 2011; 364:2417.
10. Pol S, Roberts SK, Andreone P, et al. Efficacy and safety of telaprevir-based
regimens in cirrhotic patients with HCV genotype 1 and prior
peginterferon/ribavirin treatment failure: Subanalysis of the realize phase III study.
Hepatology 2011; 54:374A.

, 76, 1, 2014 340

11. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir
combination treatment for hepatitis C virus infection. N Engl J Med 2011;
365:1014.
12. Zeuzem S, Sulkowski MS, Zoulim F, et, al. Long-term follow-up of patients with
chronic hepatitis C treated with tepalprevir in combination with peginterferon alfa-
2a and ribavirin: Interim analysis of the EXTEND study. Hepatology 2010;
52:436A.
13. Foster GR, Hzode C, Bronowicki JP, et al. Telaprevir alone or with peginterferon
and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not
genotype 3 infections. Gastroenterology 2011; 141:881.
14. Gottwein JM, Scheel TK, Jensen TB, et al. Differential efficacy of protease
inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease
recombinant viruses. Gastroenterology 2011; 141:1067.
15. Benhamou Y, Moussalli J, Ratziu V, et al. Telaprevir activity in treatment-naive
patients infected hepatitis C virus genotype 4: a randomized trial. J Infect Dis
2013; 208:1000.
16. Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus
core region and genetic variation near the interleukin 28B gene predict viral
response to telaprevir with peginterferon and ribavirin. Hepatology 2010; 52:421.
17. Marcellin P, Forns X, Goeser T, et al. Telaprevir is effective given every 8 or 12
hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic
hepatitis C. Gastroenterology 2011; 140:459.
18. Malcolm BA, Liu R, Lahser F, et al. SCH 503034, a mechanism-based inhibitor of
hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances
the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents
Chemother 2006; 50:1013.
19. Susser S, Welsch C, Wang Y, et al. Characterization of resistance to the protease
inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 2009;
50:1709.
20. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease
inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive
patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label,
randomised, multicentre phase 2 trial. Lancet 2010; 376:705.
21. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV
genotype 1 infection. N Engl J Med 2011; 364:1195.

, 76, 1, 2014 341

22. Poordad F, Bronowicki JP, Gordon SC, et al. Factors that predict response of
patients with hepatitis C virus infection to boceprevir. Gastroenterology 2012;
143:608.
23. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic
HCV genotype 1 infection. N Engl J Med 2011; 364:1207.
24. Sullivan JC, De Meyer S, Bartels DJ, et al. Evolution of treatment-emergent
resistant variants in telaprevir phase 3 clinical trials. Clin Infect Dis 2013; 57:221.
25. Sherman KE, Sulkowski MS, Zoulim F, et al. Follow-up of SVR durability and viral
resistance in pateints with chronic hepatitis C treated with telaprevir-based
regimens: Interim analyis of the EXTEND study. Hepatology 2011; 54:485A.
26. Sarrazin C, Reesink HW, Zeuzem S, et al. Retreatment with telaprevir/PEG-
IFN/RBV after a short exposure to telaprevir in phase I studies: Interim results
from a phase IIIb rollover trial (C219). Hepatology 2011; 54:377A.
27. Howe JA, Qiu P, Ogert RA, et al. Frequencies of Resistance-Associated Amino
Acid Variants Detected by 454 Sequencing During Combination Treatment With
Boceprevir Plus Pegintron (Peginterferon Alfa-2b)/Ribavirin in HCV (GT1)-Infected
Subjects. EASL 46th Annual Meeting. March 30th - April 3rd, 2011. Berlin,
Germany.
28. Hzode C, Fontaine H, Dorival C, et al. Triple therapy in treatment-experienced
patients with HCV-cirrhosis in a multicentre cohort of the French Early Access
Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013; 59:434.

, 76, 1, 2014 342

 -

, ,
...

:
: 6945467053
-mail: mfmela@hotmail.com

C 3% .

. 10%
, 30% .
C 1, 40%
26 .
( )
1,

-
.
. FDA (Food and Drug Administration)
Simeprevir .
Sofosbuvir FDA
-
HCV . Faldaprevir .

,
. , 76,
1, 343-348, 2014.
: C, , simeprevir, faldaprevir, sofosbuvir

SUMMARY
MELA M. Chronic hepatitis C-novel therapies that are due to be released.
Hepatitis C virus (HCV) affects approximately 3% of the world population. The current
standard of care for treatment of HCV is a combination of pegylated interferon and
ribavirin. Approximately 10% of patients will stop treatment and 30% of patients

, 76, 1, 2014 343

require dose reduction because of side effects. For genotype 1 HCV-infected patients,
only 40% of patients will achieve undetectable viral load 26 weeks posttreatment. The
new DAAs (Direct Acting Antivirals) that are used last 3 years for triple therapies in
genotype 1 patients (Boceprevir and Telaprevir), have raised the eradication of the
virus in certain patients but those who are in greater need-cirrhotics or with advanced
fibrosis and those with poor response in prior therapies respond less well to the new
agents. Therefore, novel therapies are eagerly awaited. FDA (Food and Drug
Administration) has recently approved Simeprevir as add-on therapy to the standard of
care. Sofosbuvir only last month got its approval from the FDA as add-on and as per
os treatment together with ribavirin for some groups of HCV patients. Faldaprevir
approval is awaited. In Greece, the entrance of these new drugs in the drug market
may take some time but their high effectiveness together with the excellent safety
profile will repay the waiting. Nosokomiaka Chronika, 76, Supplement 1, 343-348,
2014.
Key words: hepatitis C, antivirals, simeprevir, faldaprevir, sofosbuvir

H C (HCV),
,
. 10 ,
C -
(PEG-IFNa) (RBV).
(SVR-Sustained Virological Response),
, 50%-60% . ,
(40%-50%) 1.
. ,
HCV ,
. ,
1 4, 48 ,
SVR ( 1: 40%-45%, 4: 45%-65%)
2 3 (SVR 75%-80%),
24 2.

CV ,
HCV
. 2011,

, 76, 1, 2014 344

 (DDAs-Direct Acting Antivirals),
1 HCV.
HCV
.
) DDAs
, )

, ) 1, )
)
.
,
.
,
1 (1 ).
Simeprevir ( 2013
), Faldaprevir
Sofosbuvir.

SIMEPREVIR (SMV) 3.
- (Quest-1) placebo
1 (12-13% ), SMV
(X1) PEF-IFN RBV (PR) 12
12 ( Response Guided Therapy
HCV RNA<25IU/ml 4 12) 24
. PR 48 .

30% R
(BOC) (TPR).
BOC TPR, RGT (85%)
95%
. ,
,
PR (58% 29%).
1. 1a

, 76, 1, 2014 345

 20% 1b
(Q80K) 3.

FALDAPREVIR (FDV) 4.
(STARTVerso 1&2)
FDV 120 140mg, 1 , PR
(PR).
120mg 12 RGT
( HCV RNA<25IU/ml 4
8) 12 PR 12
FDV " 24 PR.
24 48
RGT FDV
12 .
PR.
. 25%
( 2 ) PR
FDV 120mg4.

.
SMV, ,

. FDV
PR, .
, 3,5.

SOFOSBUVIR (SOF)
HCV
, ,
1 (400mg), (
) ,
CYP3A/4 .

3000 .
SOF .
1 1 6 ( Neutrino)6

, 76, 1, 2014 346

 controls (327 )
SVR 60%. ,
RGT, 3 PR
:
BMI, ( IVDU),
>90 000 > 1000/mm3. SOF
90%.
. 5 6,
4 1 90%.
, , 100%
(EOT: End Of Treatment) 12 ,
80% (81% 1),
55%.
PR,

.
HCV
.
Fission7, 2 3,
SOF RBV 12
PR 24 . 3 (20%
) . SOF RBV
99% EOT
67% 12 SVR
. 2
SOF RBV PR
(97 78%).
3,
56% 63% PR
1/3 .

SOF. .
RBV
.
PEG-IFN. , 2 3,

, 76, 1, 2014 347

 2 (97% )
, 3
.
3,

3 SOF RBV 24 ,
12 ( Valence)
8
.
( ).
2 ,
. 24
SVR12 90%
3.

HCV.
SOF, SVR
1,4,5,6 12 , ,
.
2
3
.

1. Cholongitas E, Papatheodoridis GV. Review article: novel therapeutic options for

chronic hepatitis C. Aliment Pharmacol Ther 2008;27(10):866-884.
2. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. J
Hepatol 2011;55:245-264.
3. Jacobson I et al. EASL 2013, Abstract 1425.
4. Jensen DM AASLD 2013. Abstract
5. anns M et al. EASL 2013 Abstract 1413.
6. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
7. Gane E, EASL 2013 oral #5.
8. Zeuzem AASLD 2013 #1085 .

, 76, 1, 2014 348



()

. 1, . 2
1
, 2 ,
...

:
.
: 2132041822
E-mail: chsfont@yahoo.com

, .

.
(-TNFa, -CD20, -IL6R), (TNF-R
, CTLA4), (IL-1aR, ,
) (
).
-Fa (infliximab, etanercept, adalimumab
golimumab, certolizumab pegol), IL-1(IL-1RA,
anakinra), IL-6(tocilizumab),
IL-12/23 (ustekinumab),
IL-1 (Canakinumab)
- (CTLA4-Ig, abatacept),
CD20 - (rituximab),
Blys (belimumab),

RANKL (Denosumab). o
.
.

, 76, 1, 2014 349

 ,

.

.
.
, 76, 1, 349-371, 2014.
: , ,

SUMMARY
SFONTOURIS C, CHRYSOCHOOU E. Biological agents for the treatment of the
rheumatic diseases in the clinical practice. In recent years new therapies have
been revealed in the management of rheumatic diseases, the so-called biological
therapies. Tumor necrosis factor-a plays a central role in the inflammatory response.
Thus, its blockade with the anti-TNF agents (infliximab, etanercept, adalimumab,
certolizumab pegol and golimumab) has turned into the most important tool in the
management of a variety of disorder. The biological therapies include also Anakinra
(an interleukin-1 receptor antagonist, Tocilizumab (an Interleukin-6 (IL-6) receptor
antagonist), Ustekinumab (an Interleukin-12/23 blocker), Canakinumab (an interleukin-
1 blocker), Abatacept (a selective costimulation modulator with inhibitory activity on T
lymphocytes), Rituximab (an antibody against CD20 antigen of B-cells), Belimumab (a
B-lymphocyte stimulator -specific inhibitor) and Denosumab (an antibody to receptor
activator of nuclear factor kappa-beta ligand (RANKL)). The first biological agents
were approved initially for treatment of rheumatoid arthritis. These agents are
administered often in combination with standard immunosuppressants, who have a
critical role in the treatment of rheumatic diseases. Nosokomiaka Chronika, 76,
Supplement 1, 349-371, 2014.
Key words: biologics, rheumatic diseases, treatment

1. (A-TNFa
) .
1.1. A-TNFa ()
- TNFa
. -Fa
: (infliximab, Remicade)

, 76, 1, 2014 350

 Fa, (etanercept, Enbrel)
Fa,
(adalimumab,Humira) Fa,
Fab TNFa
(Certolizumab pegal, cimzia),
TNFa
(Golimumab,Simponi).
O TNF-a .

. TNF-a
-
.
. . TNF-a
, : 1(IL-1), IL-6,
IL-8, GM-CSF1,2. TNF-a () :
RANK-RANKL (receptor activated
nuclear factor kB ligand) ,
, ,
.
.

.

(MHC HLA). To T

CD80/86
CD28, .
TNF-a, IF, IL-
1, IL-6.
.
CTLA4
, CD80/86
CD28.
.

, 76, 1, 2014 351



.
3.

(DMARDs), . 4
4.
(7,5-25 mg
). (Arava 10-20 mg ),
(Salopyrine 2-3gr ), - (Neoral Sandimmune, 2,5-5 mg/kg
), (Plaquenil 200-400 mg ),
( ) 10mg, 25mg 50mg .

.
5,6.
.


ACR/20/ 50/70, DAS28, o
(,CRP).
.
-TNFa 2
4-6
. 60-70%
.
7,8,9,10.


11.
7,
12
-TNFa 2
DMARDs
4-6 . DAS28
> 5,1 -TNFa.

, 76, 1, 2014 352

 -TNFa
,
( 20 ),
, , CRP,
anti-CCP
HLA-DRB1*0401 HLA-DRB*0404.
, , ,
12
, ,
13.
( , ),
( infliximab) .
-TNFa HIV, HBV, HCV
, ,
anti-dsDNA
.

-TNFa

Mantoux. >5 mm.
9
. -TNFa
.
-TNFa
.
,
, .
-
(Registries). ACR 20%

.
-TNFa ,
DAS28 1,2
3 , (DAS28<3,2) 6
. .

, 76, 1, 2014 353

 -TNFa
.
(infliximab-adalimumab), DMARDs,
-TNFa
DMARD .
-TNFa .
30%. 5-6%
.
, 69% -TNFa
3,2 14. -TNFa
(anakinra, tocilizumab abatacept, rituximab).
1.2 A-TNFa


,
15.
(), , ,
.

.
.
HLA-B27.

. ,
, .
.
( ) 20-25% .
,
,
.
( ) ( Crohn, ).
IgA .
TNF .
(IL-1, IL-6, IL-8,
GM-CSF). (ICAM-1).

, 76, 1, 2014 354

 ,
.
TNFa
(TNFa-mRNA )16.

.

TNFa15,16.
.
BASDAI (Bath Ankylosing Spondylitis
Disease Activity Index) ASDAS (Ankylosing Spondylitis Disease Activity
Score).
BASFI (Bath Ankylosing Spondylitis Functional Index).
BASI (Bath Ankylosing Spondylitis Mobility Index).
ASAS (Assessment in
Ankylosing Spondylitis) ASAS 5 6. , 20% 5
6 : 1. , 2.
, 3.BASFI, 4. ,
5.CRP, 6..BASMI. -TNF
16-24
.
. 12
-TNF 4
, BASDAI 4
.
(
), .
4

7,5 mg . ,
, .

: infliximab 5 mg/kg 0,2,6 8
, etanercept 50 mg , adalimumab 40 mg
15 golimubab 50mg , certolizumab pegol 400mg

, 76, 1, 2014 355

 0,2,4, 200mg .
.
16.

.
:
-TNFa ;
;
; , DMARDs

16,25.
1.3 A-TNFa
- TNFa
.
(case reports).
, ,
Still , , -
, , -Behcet,
, Takayasu, Kawasaki, ,
, ,
(TRAPS, -IgD, CINCA), SAPHO, ,
, ,
.
7 infliximab ( 4 , 3
). . 4
. -TNFa
ANA, anti-DNA, aCL26.
etanercept 75%
27,28. Sjgren
etanercept ,
29. Sjgren ,
, , infliximab
30.
Still
(tanercet,Infliximab, Adalimumab)31.

, 76, 1, 2014 356


infliximab 32. ,
<<lupus like>>
infliximab.
-TNFa
. infliximab Wegener

.
() . etanercept
Wegener 180 27 ,
72,5% ,
. infliximab
etanercept Wegener33.
-Behcet
, ,
.

. infliximab
34,35 .
35
infliximab
etanercept adalimumab 36-38.
, ,
infliximab39,40.
15
etanercept41.
, infliximab 40
( MRI). 3 mg/kg 10 1 mg/kg
. ,
50%.
etanercept 25 mg, 3 2
42,43.

2. Y
-1 (ANAKINRA, IL-1RI) .

, 76, 1, 2014 357

2.1. IL-1
anakinra
H IL-1, TNF-a,
44,45.

.
:
,
( IL-6 TNF-a) (IL-8),
, RANKL (receptor
activator of NF- ligand), ,
,
(NO, COX-2, PAF).
IL-1 TNF
.

IL-1 , IL-1,
,
IL-1 (IL-1 receptor antagonist, IL-1ra).

,

.
anakinra IL-1ra

.
Eastgate
IL-146,47 , IL-1
IL-1
IL-1 48.
,
2001 FDA

, DMARDs.

, 76, 1, 2014 358

 anakinra
ACR20, ACR50, ACR70
placebo ,
,
49,50,51. G. Karanikolas et al.
, 53.
,

100 mg
.
63-81%
, , 5-8%.
2.2. anakinra

anakinra
,
, . ,
Still, IL-1
, ,
IL-1 54,55,
56, 57,
( TRAPS, anti-TNF58,59,
, 60, FCAS (familial cold autoinflammatory
syndrome, )61,
NOMID (neonatal onset multisystem inflammatory disease,
)62 Muckle-Wells63.
- Behcet64,
65 Schnitzler66.

3. CD20 -
(RITUXIMAB, ANTI-CD20) .
3.1 Rituximab
(rituximab, Mabthera)
CD20 . CD20
- -

, 76, 1, 2014 359

 .
.


.

(RF). RF

67.
rituximab .
: 1)
(CDCC, complement-dependent cytotoxicity), 2)
(ADCC, antibody dependent
cytotoxicity), 3) . rituximab
, 6-18 67.
rituximab 1 gr 0, 15 6
.
68,69 ACR50 43% 15%.
anti-TNFa .

-TNFa
. rituximab anti-TNFa
anti-TNFa 70.

Mantoux .
HBsAg
lamivudine 100 mg . Ra test
-CCP .
.
3.2 Rituximab

,
71 .
ANCA+ 72,73 (
Sjgren

, 76, 1, 2014 360

 ,
,
,
).

4. CTLA-4 -
(ABATACEPT, CTLA-4-IGG)

HLA:
( 1)
.
- CD28
CD80/D86 . -
CTLA-4
CD80/86. CTLA-4/CD80/CD86
.
CD28/CD80/CD86
.
abatacept (Orencia) CTLA-
4 IgG1 CD28 CD80/86.
DNA hamster.

.
.
10 mg/kg 0, 15, 30 4 .
abatacept
TNFa DMARDs
74. -Fa
anakinra 75,76.
CTLA-4
77.
, , TBC
-TNFa .
DMARDs
.

, 76, 1, 2014 361

 IL-6 (Tocilizumab)

IL-6
.
.
78.
4-8mg/Kg
.

DAS 28>5,1 DAS 28>3,2 2
. >2
DMARDS
. Tocilizumab
79

.
.
IL12/23. Ustekinumab (STELARA)
ustekinumab IgG1
IL-12/23
DNA.
.
. 45mg 0,
45mg 4 12
80.
, .
,
(), , , ,
, , .
.
L-1. Canakinumab (ILARIS)
To canakimumab IgG1,
-1.
(CAPS)81,
(FCAS),

, 76, 1, 2014 362

 Muckle-Wells
( NOMID)
2 .
82.
.
. 150mg
>40Kg, <40Kg 2mg/Kg, 8
. 4mg/Kg (max
300mg) >7,5Kg 4 .
.

, , ,
.
( ),
.
A - Belimumab
(BENLYSTA)
o Belimumab IgG1
(BLyS).
,

.
,
83.

.

.
Belimumab ANCA-
Sjogren84.
10mg/Kg
2 3
4 .
.
.

, 76, 1, 2014 363

 , >5%
( , , , ,
, , ) , , , , ,
, . .
(Denosumab)

IgG2
RANKL (receptor activator of nuclear factor kb ligand).


. 6 .
.
.
( FREEDOM)
85.

, D86.
.
,

.

1. Sandy JS. Inflammation 3rd ed, 1999, 433-441.

2. Friedland JS, Shattock R, Remick DG, et al. Mycobacterial 65-kD heat shock
protein induces release of proinflammatory cytokines from human monocytic
cells. Clin Exp Immunol 1993;91:58-62.
3. Fuchs HA, Kaye JJ, Callahan LF. Evidence of significant radiographic damage in
rheumatoid arthritis within the first 2 years of disease. J Rheumatol 1989;16:585-
591.
4. Lard LR, Visser H, Speyer I, et al. Early versus delayed treatment in patients with
recent onset rheumatoid arthritis: comparison of two cohorts who received
different treatment strategies. Am J Med 2001;111:446-451.

, 76, 1, 2014 364

5. Weinblatt ME, Kremer JM, Coblyn JS, et al. Pharmacokinetics, safety and
efficacy of combination treatment with methotrexate and leflunomide in patients
with active rheumatoid arthritis. Arthritis Rheum 1999;42:1322-1328.
6. O Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with
methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a
combination of the three medications: results of a two year randomized, double-
blind, placebo controlled trial. Arthritis Rheum 2002;46:1164-1170.
7. Smolen JS, Han C, Bala M, et al. Evidence of radiographic benefit of treatment
with infliximab plus methotrexate in rheumatoid arthritis patients who had no
clinical improvement: A detailed subanalysis of data from the anti-tumor necrosis
factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum
2005;52:1020-1030.
8. Landewe R, van der Heidje D, Klareskog L, et al. Disconnect between
inflammation and joint destruction after treatment with etanercept plus
methotrexate. Results from the trial of etanercept and methotrexate with
radiographic and patient outcomes. Arthritis Rheum 2006;54:3119-3125.
9. Van der Heidje D, Landewe R, van Hollenhoven R, et al. Level of radiographic
damage and radiographic progression are determinants of physical function: a
longitudinal analysis of the TEMPO trial. Ann Rheum Dis 2008;67:1267-1270.
10. Smolen JS, van der Heijde DM, Aletaha D, et al. Progression of radiographic joint
damage in rheumatoid arthritis: Independence of erosions and joint space
narrowing. Ann Rheum Dis 2009; 68(10):1535-1540.
11. Ramirez-Herraiz E, Escudero Vilaplana V, Alanon-Plaza E, et al. Efficiency of
adalimumab, etanercept and infliximab in rheumatoid arthritis patients: dosing
patterns and effectiveness in daily clinical practice. Clin. Exp.Rheumatol
2013;31(4):559-565.
12. .
2013.
13. Lin J Ziring D, Desai S, Kim S, et al. TNFa blockadein human diseases An
overview of efficacy and safety. Clinical immunology 2008:126;13-30.
14. Finc h A, Simard JF, Gabay C et al. Evidence for differential acquired drug
resistance to anti-tumor necrosis factor agents in rheumatoid arthritis. Ann
Rheum Dis 2006;65:746-752.
15. Braun J, Brandt J, Listing J, et al. Biologic therapies in the spondyloarthritis: New
opportunities, new challenges. Curr Opin Rheumatol 2003;15:594-597.

, 76, 1, 2014 365

16. Lin J, Ziring D, Desai S, et al. TNFa blockade in human disease: An overview of
efficacy and safety. Clinical Immunology 2008:128;13-30.
17. Braun J, Brandt J, Listing J, et al. Two year maintenance of efficacy and safety of
infliximab in the treatment of ankylosing spondylitis. Ann Rheun Dis 2005:64;229-
234.
18. Braun J, Baraliakos X, Brandt J, et al. Persistent clinical response to the anti-
TNF-antibody infliximab in patients with ankylosing spondylitis over 3 years.
Rheumatology (Oxford) 2005:44;670-676.
19. Davis JC Jr, Van Der Heijde D, Braun J, et al. Recombinant human tumor
necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a
randomized controlled trial. Arthritis Rheum 2003;48:3230-3236.
20. Calin A, Dijkmans BA, Emery P, et al. Outcomes of a multicentre randomised
clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis
2004;63:1594-1600.
21. Van der Heidje D, Kivitz A, Schiff MH, et al. Efficacy and safety of adalimumab in
patients with ankylosing spondylitis: results from a multicenter, randomized,
double-blind, placebo-controlled trial. Arthritis Rheum 2006;54:2136- 2146.
22. Baraliakos X, Listing J, Brandt J, et al. Clinical response to discontinuation of
anti-TNF therapy in patients with ankylosing spondylitis after 3 years with
continuous treatment with infliximab. Arthritis Res Ther 2005;7:R437-R444.
23. Baraliakos X, Listing J, Rudwaleit M, et al. Safety and efficacy of readministration
of infliximab after long term continuous therapy and withdrawal in patients with
ankylosing spondylitis. J Rheumatol 2007;34: 510-515.
24. Davis JC, van der Heidje D, Braun J, et al. Efficacy and safety of up to 192 weeks
of etanercept therapy in patients with ankylosing spondylitis. Ann Rheum Dis
2008;67:346-352.
25. Heiberg MS, Koldingsnes W, Mikkelsen K, et al. The comparative one-year
performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid
arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal,
observational, multicenter study. Arthritis Rheum. 2008;59(2):234-240.
26. Aringer M, Graninger WB, Steiner G, et al. Safety and efficacy of tumor necrosis
factor alpha blockade in SLE: an open-label study. Arthritis Rheum
2004;50(16):3161-3169.
27. Chikanza IC. Juvenile Rheumatoid Arthritis: therapeutic perspectives. Pediatrics Drugs
2002;4(5): 335-348.

, 76, 1, 2014 366

28. Ilovite NT. Current treatment of juvenile rheumatoid arthritis. Pediatrics 2002;109(1):109-
115.
29. Zandbelt MM, de Wilde P, van Damme P, et al. Etanercept in the treatment of
patients with primary Sjgren's syndrome: a pilot study. J Rheumatol.
2004;31(1):96-101.
30. Pessler F, Monash B, Rettig P, et al. Sjgren syndrome in a child: favourable
response of the arthritis to TNFa blockade. Clin Rheumatology 2006;25(5):746-
748.
31. Fautrel B, Sibilia J, Mariette X, Combe B; Club Rheumatismes et Inflammation.
Tumor necrosis alpha blocking agents in refractory adult Stills disease: an
observational study of 20 cases. Ann Rheum Dis 2005;64(2):262-266.
32. Bargagli E, Galeazzi M, Bellisai F, et al. Infliximab Treatment in a Patient with
Systemic Sclerosis Associated with Lung Fibrosis And Pulmonary Hypertension.
Respiration. 2008;75(3):346-349.
33. Hellmich B, Lamprecht P, Gross WL. Advances in the therapy of Wegener's
granulomatosis. Curr Opin Rheumatol. 2006;18(1):25-32.
34. Sfikakis PP, Theodossiadis PG, Katsiari CG, et al. Effect of infliximab on sight-
threatening panuveitis in Behcet's disease. Lancet 2001;358(9278):295-296.
35. Markomichelakis N, Delicha E, Masselos S, and Sfikakis PP. Intravitreal
infliximab for Sight-Threatening Relapsing Uveitis in Behcet Disease A pilot Study
in 15 Patients. Am J Ophthalmol September 2012:154(3):534-541.
36. Andonopoulos AP, Meimaris N, Daoussis D, et al. Experience with infliximab
(anti-TNF alpha monoclonal antibody) as monotherapy for giant cell arteritis. Ann
Rheum Dis. 2003;62(11):1116.
37. Seton M. Giant cell arteritis in a patient taking etanercept and methotrexate. J
Rheumatol. 2004;31(7):1467.
38. Tan AL, Holdsworth J, Pease C, et al. Successful treatment of resistant giant cell
arteritis with etanercept. Ann Rheum Dis 2003;62(4):373-374.
39. Metya S, Arkfeld DK, Forrester DM, et al. Infliximab treatment of familial
Mediterranean Fever and its effect on Secondary Amyloidosis. J Clin Rheumatol
2004;10(3):134-137.
40. Daysal S, Akcil G, Goker B, et al. Infliximab therapy in a patient with familial
Mediterranean fever and chronic hip arthritis. Arthritis Rheum 2005;25(1):83-87.
41. Sakallioglu O, Duzova A, Ozen S. Etanercept in the treatment of arthritis in a patient with
familial Mediterranean fever. Clin Exp Rheumatol 2006;24(4):435-437.

, 76, 1, 2014 367

42. Korhonen T, Karppinen J, Malmivaara A, et al. Efficacy of infliximab for disc
herniation-induced sciatica: one-year follow-up. Spine. 2004;29(19):2115-2119.
43. Genevay S, Stingelin S, Gabay C. Efficacy of etanercept in the treatment of acute,
severe sciatica: a pilot study. Ann Rheum Dis. 2004;63(9):1120-1123.
44. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood 1996;87:2095-
2147.
45. Dayer JM. The pivotal role of interleukin-1 in the clinical manifestations of
rheumatoid arthritis. Rheumatology 2003;42(Suppl. 2):ii3-iiA10.
46. Eastgate JA, Symonns JA, Wood C, et al. Plasma levels of interleukin-1-alpha in
rheumatoid arthritis rheumatology. 1991; 30: 295-297.
47. Ghivizzani FC, Kang R, Georgescu HI, et al. Constitutive intra-articular
expression of human IL-1 following gene transfer to rabbit synovium produces
all major pathologies of human rheumatoid arthritis. J Immunol 1997;159:3604-
3612.
48. Bresnihan B, Cobby M. Clinical and radiological effects of anakinra in patients
with rheumatoid arthritis. Rheumatology 2003;42(Suppl. 2):ii22ii28.
49. Cohen S, Hurd E, Cush J, et al. Treatment of Rheumatoid Arthritis With Anakinra,
a Recombinant Human Interleukin-1 Receptor Antagonist, in Combination With
Methotrexate. Results of a Twenty-FourWeek, Multicenter, Randomized,
Double-Blind, Placebo-Controlled Trial. Arthritis Rheum 2002;46:614-624
50. Fleischmann RM, Schechtman J, Bennett R, et al for the 990757 Study Group
Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist (r-metHuIL-
1ra), in Patients With Rheumatoid Arthritis. A Large, International, Multicenter,
Placebo-Controlled Trial. Arthritis Rheum. 2003;48:927-934.
51. Fitzgerald AA, LeClercq SA, Yan A and Homik JE. Rapid responses to anakinra
in patients with refractory adult-onset Stills disease. Arthrits Rheum
2005;52:1794-1803
52. Loft AG, Tarp U, Thomsen BS. Anakinra in the treatment of rheumatoid arthritis.
Ugeskr Laeger. 2003;165(39):3720-3724.
53. Karanikolas G, Charalampopoulos D, Vaiopoulos G, et al. Adjunctive anakinra in
patients with active rheumatoid arthritis despite methotrexate, or leflunomide, or
cyclosporine-A monotherapy: a 48week, coparative, prospective study
Rheumatology 2008;47:1384-1388.
54. Maier J, Birkenfeld G, Pfirstinger J, et al. Effective treatment of steroid refractory
adult-onset Still's disease with anakinra. J Rheumatol. 2008;35(5):939-941.

, 76, 1, 2014 368

55. Ilowite N, Porras O, Reiff A, et al. Anakinra in the treatment of polyarticular-
course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a
randomized multicenter study. Clin Rheumatol. 2008 Sep 3. [Epub ahead of
print].
56. Verbsky JW, White AJ. Effective use of the recombinant interleukin 1 receptor
antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid
arthritis. J Rheumatol 2004;31:2071-2075.
57. McGonagle D, Tan AL, Shankaranarayana S, et al. Management of treatment
resistant inflammation of acute on chronic tophaceous gout with anakinra. Ann
Rheum Dis. 2007;66(12):1683-1684.
58. McGonagle D, Tan AL, Madden J, et al. Successful treatment of resistant
pseudogout with anakinra. Arthritis Rheum. 2008;58(2):631-633.
59. Sacr K, Brihaye B, Lidove O, et al. Dramatic improvement following interleukin
1beta blockade in tumor necrosis factor receptor-1-associated syndrome
(TRAPS) resistant to anti-TNF-alpha therapy. J Rheumatol. 2008;35(2):357-358.
60. Gattorno M, Pelagatti MA, Meini A, et al. Persistent efficacy of anakinra in
patients with tumor necrosis factor receptor-associated periodic syndrome.
Arthritis Rheum. 2008;58(5):1516-1520.
61. Roldan R, Ruiz AM, Miranda MD and Collantes E. Anakinra: new therapeutic
approach in children with Familial Mediterranean Fever resistant to colchicine.
Joint Bone Spine. 2008;75(4):504-505.
62. Ross JB, Finlayson LA, Klotz PJ, et al. Use of anakinra (Kineret) in the treatment
of familial cold autoinflammatory syndrome with a 16-month follow-up. J Cutan
Med Surg. 2008;12(1):8-16.
63. Hedrich CM, Fiebig B, Sallmann S, et al. Good response to IL-1beta blockade by
anakinra in a 23-year-old CINCA/NOMID patient without mutations in the CIAS1
gene. Cytokine profiles and functional studies. Scand J Rheumatol.
2008;37(5):385-389.
64. Yamazaki T, Masumoto J, Agematsu K, et al. Anakinra improves sensory
deafness in a Japanese patient with Muckle-Wells syndrome, possibly by
inhibiting the cryopyrin inflammasome. Arthritis Rheum. 2008;58(3):864-868.
65. Botsios C, Sfriso P, Furlan A, et al. Resistant Behet disease responsive to
anakinra. Ann Intern Med. 2008;149(4):284-286.
66. Wendling D, Govindaraju S, Prati C, et al. Efficacy of anakinra in a patient with
refractory relapsing polychondritis. Joint Bone Spine. 2008;75(5):622-624.

, 76, 1, 2014 369

67. Dybowski F, Sepp N, Bergerhausen HJ and Braun J. Successful use of anakinra
to treat refractory Schnitzler's syndrome. Clin Exp Rheumatol. 2008;26(2):354-
357.
68. Cohen SB. Updates from B-cell trials: efficacy. J Rheum 2006;33(suppl 77):12-
17.
69. Emery P, Fleischmann RM, Filipowicz-Sosnowska A, et al. The efficacy and
safety of rituximab in patients with active rheumatoid arthritis despite
methotrexate treatment: results of a phase IIb double-blind, placebo-controlled,
dose-ranging trial (DANCER). Arthritis Rheum 2006;54:1390-1440.
70. Cohen S, Emery P, Greenwald M, et al. Efficacy and safety of rituximab in active
rheumatoid arthritis patients who experience an inadequate response to one or
more anti-TNF therapies (REFLEX study). Arthritis Rheum 2006;54:2793-2806.
71. Finckh A, Ciurea A, Brulhart L, et al. B cell depletion may be more effective than
switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis
patients with inadequate response to anti-tumor necrosis factor agents. Arthritis
Rheum 2007;56:1417-1423.
72. Bertsias G, Boumpas DT. Update on the management of lupus nephritis: let the
treatment fit the patient. Nat Clin Pract Rheumatol. 2008;4(9):464-472.
73. Gomez-Puerta JA, Quintana LF, Stone JH, et al. B-cell depleting agents for ANCA
vasculitides: a new therapeutic approach. Autoimmun Rev 2012;(9):646-652.
74. Charles P, Neel A, Tieulie N, et al. Rituximab for induction and maintenance
treatment of ANCA-associated vasculitides: a multicentre retrospective study on
80 patients. Rheumatology 2013 (epub ahead of print).
75. Genovese MC, Schiff M, Luggen M, et al. Efficacy and safety of the selective co-
stimulation modulator abatacept following 2 years of treatment in patients with
rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor
therapy. Ann Rheum Dis 2008;67:547-554.
76. Weinblatt M, Combe B, Covucci A, et al. Safety of selective costimulation
modulator abatacept in rheumatoid arthritis patients receiving background
biologic and non biologic disease-modifying antirheumatic drugs. Arthritis Rheum
2006; 54:2807-2816.
77. Weinblatt M, Schiff M, Goldman A, et al. Selective costimulation modulation using
abatacept in patients with active rheumatoid arthritis while receiving etanercept: a
randomised clinical trial. Ann Rheum Dis 2007;66:228-234.

, 76, 1, 2014 370

78. Axmann R, Herman S, Zaiss M, et al. CTLA-4 directly inhibits osteoclast
formation. Ann Rheum Dis Ann Rheum Dis. 2008;67(11):1603-1609.
79. Dhillon S. Inbtravenous Tocilizumab: A review of its use in adults with rheumatoid
arthritis. Biodrugs 2013 (Epub ahead of print).
80. Navarro G, Taroumian S, Barosso N, et al. Tocilizumab in rheumatoid arthritis: A meta
analysis of efficacy and selected clinical conundrums. Semin Arthritis Rheum 2013
(Epub ahead of print).
81. Zaghi D, Krueger GG, Callis Duffin K. Ustekinumab: a review in the treatment of plaque
psoriasis and psoriatic arthritis. J Drugs Dermatol 2012;11(2):160-167.
82. Kuemmerle-Deschner JB, Haug I. Canakinumab in patients with cryopyrin-
associated periodic syndrome: an update for clinicians. Ther Adv Musculoskelet
Dis, 2013;5(6): 315-329.
83. .Fanouriakis A, Karantanas A, Fragouli E, et al. Control of flares and relief of
urate burden with canakinumab and targeted uratelowering therapy in
tophaceous gouty arthritis. Rhematology (Oxford) 2013 (Epub ahead of print).
84. Ginzler EM, Wallace DJ, Merrill JT, et al; The LBSL02/99 Study Group. Disease
control and safety of Belimumab plus standart Therapy over 7 years in patients
with systemic lupus erythematosus. J Rheumatol 2013 (epub ahead of print).
85. Furuta S, Jayne D. Emerging therapies in antineutrophil cytoplasm antibody-
associated vasculitis. Curr OpinRheumatol 2014;26(1):1-6.
86. Cumming SR.San Martin S, Mc Clung MR, Siris ES, et al FREEDOM Trial
Denosumab for prevention of fractures in postmenopausal women with
osteoporosis. N. Engl Med 2009;361(8):756-765.
87. John Sharp, Wayne Tsu Li, Peter Ory, et al. Denosumab prevents metacarpal
shaft cortical bone loss in patients with erosive rheumatoid arthritis. Arthritis Care
and Research 2010;62;537-544.

, 76, 1, 2014 371



, ...

:
: 2132041609
E-mail: ikanastassiou@yahoo.gr

infliximab, adalimumab, certolizumab pegol
Crohn
. infliximab
adalimumab
() , certolizumab pegol
.
,
,
, ,
.
,
.
,

.
, .
,
. 12
, .
, 76, 1, 372-378, 2014.
: Crohn, , .

ABSTRACT
ANASTASIOU J. Biological therapies for inflammatory bowel diseases. There is
evidence that infliximab, adalimumab, and certolizumab pegol are effective for

, 76, 1, 2014 372

maintenance of remission in patients with Crohns Disease who have a clinical
response to induction therapy. Infliximab and adalimumab are currently approved for
use in Inflammatory Bowel Disease in many countries, while certolizumab pegol is not
approved in the European Union. All currently available anti-TNF therapies aiming to
treat Inflammatory Bowel Disease appear to have similar efficacy and adverse-event
profiles, so the choice depends on availability, route of delivery, patient preference,
cost and national guidance. The loss of response to anti-TNF therapy should lead to
re-evaluation of disease activity, exclusion of complications and discussion of surgical
options with the patient. For active disease, reduction in interval between doses, or
dose escalation are appropriate strategies before switching to another agent.
Switching is an effective strategy, but reduces future therapeutic options. For
intolerance, especially if severe, switching to an alternative anti-TNF agent is
appropriate. Response to a third anti-TNF therapy occurs in some patients and may
be an appropriate option, although surgical options should also be considered and
discussed. Primary lack of response may be determined within 12 weeks and an
alternative anti-TNF agent tried for active disease. Nosokomiaka Chronika, 76,
Supplement 1, 372-378, 2014.
Key words: Crohns disease, ulcerative colitis, biologic agents, biological therapies

Crohn
(). Crohn
,
,
. :


,
.


.
INFLIXIMAB
Infliximab (75% / 25%
) anti-TNFa . TNFa

, 76, 1, 2014 373


. Infliximab
, Crohn ,

5,10 20 mg/kg Infliximab.
.
Crohns Disease Activity Index, [CDAI] -100 ),
,
Crohns Disease Activity Index, [CDAI] 70 .

Crohn Crohns Disease Activity Index, [CDAI]
<150 . , 81%, 50% 64%
( Crohns Disease Activity Index, [CDAI]
70 ) 4 (p<0.001
Infliximab placebo). , 33%
Infliximab 4% placebo (p=0.005).
Infliximab
, 37%
1. Infliximab,
10 mg/kg 8 placebo. 44
, 53% Infliximab 20%
(p=0.013)2.
ACCENT I3
Infliximab . , 573
5mg/kg Infliximab 0,
CDAI ( score 70
25% score). 335 (58%)
(3) : )
2 6 8 ( 1), ) Infliximab 5 mg/kg
2 6 8 ( 2) ) 5 mg/kg
2 6 10 mg/kg 8 ( 3).
46 . 14 ,
,
Infliximab 5,10 15 mg/kg 1,2
3. 30 , 21% 1 , 39% 2

, 76, 1, 2014 374

(p=0.003), 45% 3 (p=0.0002) ,
19, 38
(p=0.002) 54 (p=0.0002) .

54 2 3 (29%) 1
(9%). .
,
ACCENT I,


( )
,
4
Infliximab
Crohn. ACCENT II, 306
( 3 )
(induction therapy) 3 Infliximab (5mg/kg).
(195) 10 14 87
placebo Infliximab
(5mg/kg) 8 54.

Infliximab placebo (>40 vs 14 wk, p<0.001). ,
54, 36% Infliximab 19%
placebo (p=0.009)5.
Infliximab
6.
Infliximab ( HACA, human anti-chimeric antibodies)
3,7,

7,8. 30% Infliximab
, 9.
Infliximab
10.
Infliximab ,
,

, 76, 1, 2014 375

 , ,
,
,
non-Hodgkin ,
11.

ADALIMUMAB
Adalimumab
IgG1
TNFa.
IgG1 .
CLASSIC I, 299 Crohn
Infliximab Adalimumab . 160 mg 80 mg 2
, 36% 4
, 12% (p<0.05)12.
GAIN Adalimumab
anti-TNF , Crohn,
Infliximab (
Infliximab). (n=325) 160 mg 80 mg
Adalimumab placebo 2 . 21%
Adalimumab 7% ,
4 (p<0.001)13.
CLASSIC I,
, anti-TNF
,
.

CERTOLIZUMAB PEGOL
Certolizumab pegol anti-TNFa ,
400 200 mg. WELCOME
Certolizumab pegol
Infliximab (
)14.
Certolizumab pegol, 0,2 4 329 400
mg 2 4 24 .

, 76, 1, 2014 376

 39.2%
. 29.2% (Certolizumab
pegol 4 ) 30.4% (Certolizumab pegol 2 )
.
,
, Certolizumab pegol
,
Infliximab.

1. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric
monoclonal antibody cA2 to tumor necrosis factor alpha for Crohns disease.
Crohns Disease cA2 Study Group. N Engl J Med. 9 Oct 1997;337:10291035.
2. Rutgeerts P, D Haens G, Targan S, et al. Efficacy and safety of retreatment with
anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohns
disease. Gastroenterology 1999;117:761769.
3. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn
s disease: the ACCENT I randomised trial. Lancet. 2002;359:15411549.
4. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with
infliximab is superior to episodic treatment for the healing of mucosal ulceration
associated with Crohns disease. Gastrointest Endoscopy 2006; 63:433442
5. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for
fistulizing Crohn s disease. N Engl J Med 2004;350:876885.
6. Domnech E, Hinojosa J, Nos P, et al. Clinical evolution of luminal and perianal
Crohn s disease after inducing remission with infliximab: how long should patients
be treated? Aliment Pharmacol Ther. 2005;22:11071113.
7. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term
efficacy of infliximab in Crohns disease. N Engl J Med. 2003;348:601608.
8. Farrell RJ, Alsahli M, Jeen Y-T, et al. Intravenous hydrocortisone premedication
reduces antibodies to infliximab in Crohns disease: a randomized controlled trial.
Gastroenterology. 2003;124:917924.
9. Rutgeerts P, Van Assche G, Vermeire S. Review article: Infliximab therapy for
inflammatory bowel disease--seven years on. Aliment Pharmacol Ther.
2006;23:451463.

, 76, 1, 2014 377

10. Lmann M, Mary J-Y, Duclos B, et al. Infliximab plus azathioprine for steroid-
dependent Crohns disease patients: a randomized placebo-controlled trial.
Gastroenterology. 2006;130:10541061.
11. Colombel J-F, Loftus EV Jr, Tremaine WJ, et al. The safety profile of infliximab in
patients with Crohns disease: the Mayo clinic experience in 500 patients.
Gastroenterology. 2004;126:1931.
12. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor
monoclonal antibody (adalimumab) in Crohns disease: the CLASSIC-I trial.
Gastroenterology 2006;130:323333.
13. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn
disease previously treated with infliximab: a randomized trial. Ann Intern Med.
2007;146:829838.
14. Sandborn WJ, Vermeire S, D Haens et al. Welcome: a randomized, double-blind,
controlled trial comparing cerolizumab pegol 400 mg every 2 weeks with every 2
weeks with every 4 weeks for maintenance of response and remission in patients
with moderate to severe Crohns Disease with secondary failure to Infliximab.
Gastroenterology 2009;136 (S1):A27.

, 76, 1, 2014 378



. . .
-, ,
..

:
: 2104973006, 2104969583
: 6974568777
E-mail: dranastas@yahoo.gr

,
,
.
, ,

.
,
.
,
. , 76,
1, 379-392, 2014.
: , -TNF-, IL-12, IL23,

SUMMARY
ANASTASIADIS GH. Biological therapies in dermatology. This review summarizes
the use of biologic drugs in dermatology. The main indication for the biological
therapies is moderate to severe psoriasis vulgaris. In the pathogenesis of this disease
there is convincing evidence for the role of T cells and inflammatory molecules like
TNF-a and IL-12, IL-23 etc. So we describe the indications, contraindications and side
effects of these drugs. Current guidelines recommendations are written in this review
and we describe also the off-label use of biological drugs in other except psoriasis
dermatological diseases. Nosokomiaka Chronika, 76, Supplement 1, 379-392,
2014.
Key words: biologic drugs, anti-TNF-a, IL-12, IL-23, psoriasis

, 76, 1, 2014 379



.
, ,
,
,
.

( 1922)
(1980) (Toxic
Epidermal Nekrolysis)
(Fas) (FasL)

.
DNA
,

, ( , ,
, ),

, ,
( )

( ) -
(-)
.

,
ximab
infliximab - Rituximab , zumab
Omalizumab, umab

, 76, 1, 2014 380

 adalimumab, ustekinumab
cept
etanercept, Rilonacept

:
(
) ,
.

.

CD28 , 6
-TNF
, infliximab .
,

.

-


:
(MHC I)
,
h2 (IL-4,5,6,9,10,13),
h1
cells.

-:
- / / (3
1 )
:
- (CTCL) 50-75%
( a-IVa)

, 76, 1, 2014 381

 Kaposi - 70-100%
-Behcet


, ,

.
:

-
,
,
-
-
.

-
. ()

.

-, ,
.
-
h1 (IFN-, TNF-, IL-2)
-
-.
- -
.
- ,

.

, 76, 1, 2014 382


1. ( )
6
10%

, PASI 10 .
- BSA (Body Surface Area) >10%
- PASI (Psoriasis Area Severity Index) >10 infliximab (Remicade) >20
- DLQI (Dermatological Life Quality Index) >10 infliximab (Remicade)
>20

( alefacept)
, ,
2.
( D)
( )
( C )
( B)
Behcet ( C)
ANCA ( C)
PASI score
Psoriasis Area Severity Index (PASI)
.
PASI score
, 0
72 .

PASI SCORE-
PASI SCORE=0,1AH (E+I+D) +0,2AU (E+I+D)+0,3AT(E+I+D)+0,4AL(E+I+D)
A=area, H=head, U=upper extremities, T=trunk, L=lower extremities.

0 6, .
0% : 0
< 10% : 1

, 76, 1, 2014 383

10-29% : 2
30-49% : 3
50-69% : 4
70-89% : 5
90-100% : 6
:
E=erythema, I=infiltration, D=desquamation 0
4 (=0, =1, =2,
=3, =4)
PASI SCORE 0-72

INFIXIMAB
IgG1 TNF-,

.
: ( 1998).
: INFLIXIMAB 5mgr/Kg
2 ,
2, 6 8 .
PASI-75 -
PASI SCORE 75% - 10 80% , 24 82%,
50 60%
(INFLIXIMAB adalimumab)

ETANERCEPT, .

ETANERCEP
Fc IgG1
p75 TNF-.
TNF- .
: ( 1998).
: 50mgr 12
50mgr 25mgr
.

, 76, 1, 2014 384

 PASI-75 49% 12 45-54%
24 .

ADALIMUMAB (HUMIRA)
adalimumab anti- TNF-
( 2002).
IgG1, TNF- ,
, ,
.
:
.
: 80mgr , 1 40mgr
40mgr 2 .
PASI-75: 80%
12 64% 60 .
.

USTEKINUMAB
IgG1
interleukin 12 23,
.
IL-12 CD4 NK , 1
(TNF- interferon-), IL-23
IL-17 (Th17-
cells) IL-23 .
ustekinumab p40
, ,
-, .
:
( 1998).
: 45 mgr (90 mgr
100Kg) 0, 4, 12 .

, 76, 1, 2014 385

 PASI-75 12 67% (
72% ),
2024 .
15 (
PASI 50) rebound ,
.

ustekinumab :
,


.
etanercept
12 .

ETANERCEPT : 3
INFLIXIMAB : 8-9,5
ADALIMUMAB : 14
USTEKINUMAB : 3
OMALIZUMAB : 26

5

ANTI-TNF-
anti-TNF- (etanercept adalimumab)
, ,
.
infliximab 2
, 20%
3% .
, ,

.

, 76, 1, 2014 386

 infliximab

.
infliximab etanercept
()
.
-TNF-
.

,
,
.
( ,
, Pnuemocystis
carinii, ).
infliximab
adalimumab . 20
6810 anti-TNF- 12
30
.

:



C, HIV ,

mantoux

, 3 6 ,
, , mantoux
, .

, 76, 1, 2014 387



( D) 10
-
TNF- ( infliximab)


( ) 30
infliximab 69%
, 6 21%
31% .
adalimumab etanercept.

-TNF-
(Sneddon-Wilkinson syndrome) Sweet.
( C ) H
infliximab
Crohn . 70

-TNF .
50%
.
,
,
.

.
-TNF
,
.
( B) TNF
, -
TNF .
infliximab

, 76, 1, 2014 388


. etanercept
.

, -TNF
.
.
Behet ( C)
etanercept infliximab 45%
. Behet,
.
ANCA ( C). TNF
ANCA
Wegener. -TNF
,
,
.

(case reports) -TNF
.
etanercept ,
Wegener, 6
etanercept.
.
-TNF
, 75%
.
,
.
() ( C)
-TNF .

. 6
-TNF
.

, 76, 1, 2014 389

 ,
( )
infliximab etanercept .

( ).
3 (),
infliximab ( 3 5
mgr/Kg ) ( ).

OMALIZUMAB (XOLAIR)
,
IgE ,
Fc- IgE (FCRI),
, .

IgE.
Omalizumab :
12 .

Latex
150300mg 4

323
, H1-, 12
ISS (itch severity score) placebo.
24
,
0,1%
,

- RITUXIMAB
RITUXIMAB IgG1
CD20,
.

, 76, 1, 2014 390


3, -
CD4+ -.
:

rituximab 375mgr/m2 8
. 70%
20%.
,

. ( B)
rituximab
70%

:

-, , (
rituximab 375mgr/m2 IV )

( C)
ANCA+ A ( C).
rituximab
,
. 80% 1


.

(, , ) 1
,


rituximab


, 76, 1, 2014 391
 Stevens Johnson

INTEREUKIN 1 RECEPTOR ANTAGONIST

H Interleukin 1 .
,
, ,
,
.
Anakinra (Kineret 100mgr SC )
IL-1 IL-1
, (IL-1ra)
Rilonacept (160mgr SC/)
, IL-1 (IL-1rb)
(IL-1ra)
,
Still
(cryopyrin-associated autoinflammatory syndromes),
Muckle-Wells
- .

1. SM Breathnach, CH Smith, RJG Chalmers, et al. Systemic Therapy In: Rooks
Textbook of Dermatology, Burns T, Breathnach S, Cox N et al ed. Willey-
Blackwell Publishing Ltd UK 2010.
2. Richardson SK, Gelfand JM. Immunobiologicals, Cytokines and Growth factors in
Dermatology In: Fitzpatricks Dermatology, Goldsmith LA, Katz SI, Barbara A.
Gilchrest B A, et al ed. McGraw-Hill Co USA, 2012.
3. Reich K, Burden AD, Eaton JN et al. Efficacy of Biologics in the treatment of
Moderate to Severe Psoriasis. A Network Meta-analysis of Randomized Trials, Br J
Dermatol 2012;166:179-188.
4. Jackson JM, Callen JP. Immunomodulators In: Dermatology, Bolognia JL, Jorizzo
JL, Schaffer ed. Elsevier, China 2012.

, 76, 1, 2014 392



(HALITOSIS)

, ...

:
: 2132041168
-mail: odontiatriko@evaggelismos-hosp.gr

.
. 80-90%
.. , ,
, ..
, .
( ),
, ..
.
, Gram
,
,
(Votalite Sulphur Compounds- VSCs),
(CH3SH) (H2S).
.

. ,
,
12 /. ,
.

, 76, 1, 2014 393

 (Halitosis)
-

,
, ...

:
: 2132041359, 6980752914
-mail: popied@otenet.gr

:

(halitosis). : Medline, PubMed,
EMBASE, Google Scholar Cohrane Database of Systematic Reviews
, , ,
,
2009 2013. : halitosis

25% .
80-90%

. 10%-20%

, , ,
, ..
(pseudo-halitosis -)

. -
.
(Votalite Sulphur Compounds, VSCs) ..
, , BANA ,
.
.

. :
,

, 76, 1, 2014 394

 .
, 76, 1, 394-408, 2014.
: , halitosis, , , -

SUMMARY
DAMASKINOS P. Bad Breath (Halitosis). Aetiopathogenesis and management.
Objectives: This work reviews the current knowledge of aetiology and treatment of
bad breath (halitosis). Methodology: The following databases were used to identify
studies for this review; Medline, Pub Med, EMBASE and Cochrane Database
Systematic Reviews for reviews and clinical trials and the key words used were: bad
breath, halitosis, aetiopathogenesis, management, halitophobia. There was no
language restriction. Because of the plethora of articles revealed, only articles
published during the last five years (2009-2013) were included in this review.
Discussion: Bad breath or halitosis is called the unpleasant exhaled odour from the
mouth irrespective of its aetiopathogenesis and origin and it concerns around 25% of
the population. The majority of bad breath comes from the oral cavity (80-90%)
because of caries; periodontal disease, pericoronitis, tongue coating, unclean
dentures etc. and patients seek help primarily from dentists. Only a mere 10-20% is
associated with systematic disease i.e. diabetes, kidneys disease, hepatic
encephalopathy, lung cancer, and disorders from the gastrointestinal tract. Besides
genuine halitosis in some cases patients may have pseudo-halitosis (or halitophobia)
of psychological nature, and complain for bad breath while this is not recognized by
others. The patients should be referred for psychological treatment. Measurement
methods for bad breath, used to reveal volatile sulfur compounds include organoleptic
measurement, gas chromatography, BANA et al. The appropriate treatment depends
on the aetiopathogenesis; new treatment methods include probiotics and inoculation
against pathogenic bacteria. Conclusions: Bad breath impacts severely a persons
social life and quality of life. People with halitosis develop low self esteem and social
isolation. Nosokomiaka Chronika, 76, Supplement 1, 394-408, 2014.
Key words: Bad breath, halitosis, aetiopathogenia, management, malodor, pseudo-
halitosis, halitophobia

, 76, 1, 2014 395


halitosis, mal odour bad
breath, ox ore ozostomia,
.
(genuine halitosis) - (pseudo-halitosis
- -)
( ) ( , ,
)1,2,3,4.

.
.
80-90%

.
10%-20%
, ,
..
3,4. , Gram ,


(Votalite Sulphur Compounds- VSCs),
(CH3SH) (H2S) .
.

,
, ,
3,4.

(2009-2013)
(halitosis).

Medline,
Pub Med, EMBASE, Google Scholar Cochrane Database of Systematic Reviews
, , ,

, 76, 1, 2014 396

 ,
, 2013.
(1/2009 12/2013).
,

37 ( 1).
1.
( 2009 2013)

Short term clinical efficacy of new meridol Halitosis tooth

Wilhelm D et al (5)
Chomyszyn-Gajewska,
Skrzypek(6)
Dadamio et al (7)
Marsicano et al (8)
and tongue gel in combination with a tongue cleaner to 2013
reduce oral malodor
Halitosis-diagnosis and treatment 2013
The role of toothpastes in oral malodor management 2013
Gastroesophageal reflux, dental erosion and halitosis in
2013
epidemiological surveys

Tooth brushing versus tooth brushing plus tongue

Kuo YW et al (9) 2013
cleaning in reduction halitosis and tongue coating.

Interdental brushing for the prevention and control of

Poklepovic et al (10) 2013
periodontal diseases and dental caries in adults

Clinical trial of oral malodor treatment in patients with

Pham et al (11) 2013
periodontal diseases

Effect of chewing gums containing the probiotic bacterium

Keller MK et al (12) 2012
Lactobacillus reuteri on oral malodour
Zalewska et al (13) Halitosis- a common medical and social problem 2012
Anilkumar and Monisha (14) Role of friendly bacteria in oral health-a short review 2012
Rao et al (15) Probiotics in oral health-a review 2012
Bollen and Beikler (3) Halitosis; the multidisciplinary approach 2012
Zautner AE (16) Adenotonsillar disease 2012
Blom et al (17) The effect of mouth rinses on oral malodor 2012
Halitology (breathe odour: aetiopathogenesis and
Scully C, Greenman J (2) 2012
management)

Recurrent rhinolithiasis: a case report and review of the

Dogan et al (18) 2012
literature
Tablets containing a cysteine protease, actinidine, reduce
Nohno K et al (19) 2012
oral malodor: a crossover study
Oral piercing and its complications in two Serbian youths:
Pejcic et al (20) 2012
a case report and review of the literature
Contemporary views on etiology and pathogenesis of
Chomyszyn-Gajeweska (21) 2012
halitosis

, 76, 1, 2014 397

 The effect of zinc acetate and magnolia bark extract
Porciani PF and Grandini S
chewing gum on votalite sulfur-containing compounds in 2012
(22)
the oral cavity

Halitosis; an overview of epidemiology, etiology and

Rosing and Loesche (23) 2011
clinical management
Porter SR (24) Diet and halitosis 2011
Campisi et al (25) Halitosis: could be more than mere bad breath? 2011
Effectiveness of mechanical tongue cleaning on breath
Van der Sleen et al (26) 2010
odour and tongue coating.....
Tangerman and Winkel (27) Extra-oral halitosis 2010
Ongole and Shenoy (28) Halitosis; much beyond oral malodor 2010
Some evidence shows certain mouth rinses can reduce
Kumar and Byrne (29) 2010
halitosis
Armstrong et al (30) Halitosis: a review of the current literature 2010
Flichy-Fernandez et al (31) Probiotic treatment in the oral cavity; an update 2010
The correlation of organoleptic and instrumental halitosis
Brunner et al (32) 2010
measurements
.
(4) 2009

Bonifait et al (33) Probiotics for oral health; myth or reality? 2009
De Souza et al (34) Interventions for cleaning dentures in adults 2009
Measurement and biological significance of the volatile
Tangerman A (35) 2009
sulfur compounds hydrogen sulfide....

Vaccines and photodynamic therapies for oral microbial-

Liu et al (36) 2009
related diseases
Prevalence of halitosis in the population of the city of
Bornstein et al (37) 2009
Bern, Switzerland

, ,
(
) ( , ).
80-90%
10-20% .


: ,
. , ,
, ,
, ,

, 76, 1, 2014 398

 (, )
1,2,3,4,20,30.

: ,
, , ,
. , ,
,
.
, 10 20%,
.

: ( ),
(, , )
,
, ,
, ,

2,3,4,27,30.

,
(.. Sjogren), , , stress,
.. , , ,
, , ,
, , Parkinson,
( 2)3,30,38.

- (PSEUDO-HALITOSIS)
(HALITOPHOBIA)

,
. - (pseudo-halitosis)
(halitophobia) . ,
.
,
2,3,4,30,37.

, 76, 1, 2014 399


10 ,
.

2.
.
3,30,38,39

Cyclizine, chlorpheniramine, Benadryl, Claritin,

Zyrtec
Zoloft, Flexaryl, Elavil
Anzemet, Domperidone, Omeprazol
Albuterol aerosol, Norvasc, Prinivil, Aldomet/

beta-blockers-clonidine-methyldopa
Levodopa, Artane, Symmetrel, Comtan, Azilect/
Parkinson
procyclidine - benzatropine
Dicyclomine
Zoloft, Lexapro, Bupropion/ clozapine-

chlorpromazine
Amytal, Lunesta, Valium (,

)
Atrovent (ipratropium), Combivent (ipratrorium
() /albuterol)
Detrol LA/Oxybulynin, tolrerodine tartrate

Ipratropium, tiotropium
Soma, Flexeril, Skelaxin, Robaxin
Cytotoxic

Nicorette

Frovatriptan Succinne

Reductil

/ atropine , tropicamide

, 76, 1, 2014 400


: )
( ), ) , )
BANA ) .
.

2,5 10
.
0 ( ) 5 ( )
( 3).

3.
0 53,4,30

0

1

2
3

4


5

. ,

, ...


.

.
(Benzol-arginine-naphthyl-amide)

, 76, 1, 2014 401

 .
.

. ,
Polyromonas gingivalis, Bacteroids forsythus, Treponema
denticola
.

Halimeter Interscan Co. Chatsworth, CA, Breathtron.

(Peptostreptococcus, Bacteroids, Fusobacterium)
(, , .)

( 4). , Polyromonas
gingivalis, Treponema denticola, Porphyromonas endodontali (gram ,
)
.
,

(VSCs) (H2S),
, (CH3SH), (CH3)2S :
, , .
( ) ( )3,4,30

.

.., , ,
, .
.

.

,
.

, 76, 1, 2014 402

 4.
3,4
(VSCs)
Peptosteptococcus anaerobius
Micros prevotii
Eubacterium limosum H2S
Bacteroides spp.
Centipedia periodontii
Prevotella intermedia
Prevotella loescheii
Porphyromonas gingivalis H2S
Treponema denticola
Selenomonas artermidis
Fusobacterium nucleatum
Fusobacterium periodonticum CH3SH
Eubacterium spp.
Bacteroides spp.
Treponema denticola
Porphyromonas gingivalis CH3SH
Porphyromonas endodontalis
Prevotella melaninogenica
Tanerella forsythensis
Eikenella corrodens
Solobacterium moorei
Treponema forsythensis
Centipeda periodontii
Atopobium parvulum

.
,
, , ,
3,4,30.

2,3,31.

, 76, 1, 2014 403

 -,

.


.
.

,
.

. (80%90%)
1,2,3,4,5,30.

15% 50%.
15%, 15%20% (
70%), 25%, 28%, 25%
43% 50% () 32,5%1,2,3,4,32,37.
(VSCs) (H2S),
, (CH3SH), (CH3)2S :
, , ,
,
.
( ) ,
BANA .
,
3,4,30.
Halimeter, Fresh Kiss
Halitox Halimeter
Fresh Kiss32.

30.

, 76, 1, 2014 404

 .

.
.
.


. Wilhelm et al, 2013, meridol
( )
.
5.
,

, 22.
, ..
, , , ,
, , , ,
, , ,
, 2,3,4,16,18,19,25,30,
.

, 28%3 40%60%4,
.
. -
(halitophobia)
.
-

.
.

25%
.

, 76, 1, 2014 405

 ,
.


.

1. van Steenberghe D & Rosenberg M (Editors) 1996; Bad Breath. A multidisciplinary

research. Leuven University Press.
2. Scully, C. and Greenman, J. Halitology (breath odour: aetiopathogenesis and
management). Oral Diseases, 2012; 18: 333345.
3. Bollen CML& Beikler T. Halitosis: the multidisciplinary approach. nternational
Journal of Oral Science 2012; 4: 5563
4. B, . .
. 2009; 63:83-93.
5. Wilhelm D, Himmelmann A, Krause C. Short term clinical efficacy of new meridol
HALITOSIS tooth & tongue gel in combination with a tongue cleaner to reduce oral
malodor J Clin Dent. 2013; 24:12-19.
6. Chomyszyn-Gajewska M, Skrzypek A. Halitosis--diagnosis and treatment. Przegl
Lek. 2013; 70:65-68.
Dadamio J, Laleman I, Quirynen M. The role of toothpastes in oral malodor
management. Monogr Oral Sci. 2013; 23:45-60.
7. Marsicano JA; de Moura-Grec PG; Bonato R C.S et al. Gastroesophageal reflux,
dental erosion, and halitosis in epidemiological surveys: a systematic review
European Journal of Gastroenterology & Hepatology: 2013; 25:135-41
8. Kuo YW; Yen M; Fetze S; et al. Tooth brushing versus tooth brushing plus tongue
cleaning in reducing Halitosis and tongue coating: A systematic review and meta-
analysis. Nursing Research. 2013; 62:422-429.
9. Poklepovic T, Worthington HV, Johnson TM, et al. Interdental brushing for the
prevention and control of periodontal diseases and dental caries in adults.
Cochrane Database Syst Rev 2013:CD009857.
10. Pham T.A.V, Ueno M, Zaitsu T, et al Clinical trial of oral malodor treatment in
patients with periodontal diseases. J Periodont. Res 2011; 46: 722-729.

, 76, 1, 2014 406

11. Keller MK, Bardow A, Jensdottir T, et al. Effect of chewing gums containing the
probiotic bacterium Lactobacillus reuteri on oral malodour. Acta Odontol Scand.
2012; 70:246-50.
12. Zalewska A, Zatonski M, Jablonka- Strom A, et al. Halitosis- a common medical
and social problem. Acta gastro-enterologica Belgica 2012; 75:300-309.
13. Anilkumar K & Monisha AL. Role of friendly bacteria in oral health - a short review
Oral Health Prev Dent. 2012; 10:3-8.
14. Rao Y, Lingamneni B, Reddy D. Probiotics in oral health-a review. J N J Dent
Assoc. 2012; 83:28-32.
15. E Zautner, A. Adenotonsillar disease. Recent Patents on Inflammation & Allergy
Drug Discovery. 2012;6(2),121-129.
16. Blom T, Slot D, Quirynen M.et al: The effect of mouth rinses on oral malodor: a
systematic review. International Journal of Dental Hygiene, 2012; 10:209222.
17. Dogan M, Dogan DA, Duger C,et al. Recurrent rhinolithiasis: a case report with
review of the literature West Indian Med. J. 2012; 61:760-763.
18. Nohno K, Yamaga T, Kaneko M and et al. Tablets containing a cysteine protease,
actinidine, reduce oral malodor: a crossover study. J. Breath Res. March 6 017107.
19. Pejcic A, Kojovic D, Mirkovic D. Oral piercing and its complications in two Serbian
youths: a case report and review of the literature. West Indian Med J. 2012;
61:838-843.
20. Chomyszyn-Gajeweska. Contemporary views on etiology and pathogenesis of
halitosis Przegl Lek. 2012; 69:1293-1296.
21. Porciani PF and Grandini S. The effect of zinc acetate and magnolia bark extract
chewing gum on votalite sulfur-containing compounds in the oral cavity. J Clin
Dent. 2012; 23:76-79.
22. Rosing CK and Loesche W. Halitosis: an overview of epidemiology, etiology and
clinical management Braz Oral Res. 2011; 25:466-471.
23. Porter SR. Diet and halitosis. Curr Opin Clin Nutr Metab Care. 2011; 14:463-468.
24. Campisi G, Musciotto A, Di Fede O, et al. Halitosis: could be more than mere bad
breath? Intern Emerg Med. 2011; 6:315-319.
25. Van der Sleen MI, Slot DE, Van Trijffel E, et al. Effectiveness of mechanical tongue
cleaning on breath odour and tongue coating: a systematic review Int J Dent Hyg.
2010; 8:258-268.
26. Tangerman A, Winkel EG. Extra-oral halitosis: an overview. J Breath Res. 2010;
4:017003.

, 76, 1, 2014 407

27. Ongole R & Shenoy N. Halitosis; much beyond oral malodor. Kathmandu Univ Med
J (KUMJ). 2010; 8:269-275.
28. Kumar SKS & Byrne G. Some evidence shows certain mouth rinses can reduce
halitosis. JADA 2010; 141:1008-1009.
29. Armstrong BL, Sensat ML, Stoltenberg JL. Halitosis: a review of the current
literature. J Dent Hyg. 2010; 84:65-74.
30. Flichy-Fernndez AJ, Alegre-Domingo T, Pearrocha-Oltra D, et al. Probiotic
treatment in the oral cavity; an update. Med Oral Patol Oral Cir Bucal. 2010;
15:e677-680.
31. Brunner F, Kurmann M, Filippi A. The correlation of organoleptic and instrumental
halitosis measurements. Schweiz Monatsschr Zahnmed. 2010; 120:402-408.
32. Bonifait L, Chandad F, Grenier D. Probiotics for oral health; myth or reality? J Can
Dent Assoc. 2009; 75:585-590.
33. de Souza RF, de Freitas Oliveira Paranhos H, Lovato da Silva CH, et al.
Interventions for cleaning dentures in adults. Cochrane Database of Systematic
Reviews 2009, Issue 4. Art. No.: CD007395.
34. Tangerman A. Measurement and biological significance of the volatile sulfur
compounds hydrogen sulfide, methanethiol and dimethyl sulfide in various
biological matrices. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;
877:3366-3377.
35. Liu PF, Zhu WH, Huang CM. Vaccines and photodynamic therapies for oral
microbial-related diseases. Curr Drug Metab. 2009; 10:90-94.
36. Bornstein MM, Kislig K, Hoti BB, et al. Prevalence of halitosis in the population of
the city of Bern, Switzerland. Eur J Oral Sci. 2009; 117:261-267.
37. The Merck Manual of Diagnosis and Therapy. Seventeenth Edition, 1999.
Centennial Edition. Editors M.H. Beers and R. Berkow. Published by Merck
Research Laboratories. Whitehouse Station, N.J. . 239-241 751.

, 76, 1, 2014 408



( )

.
...
, ...

:
: 6977421460
E-mail: efizori@gmail.com

- -
,
,
. ,
,
, William Gull (1860) Charles Lasegue (1870). ,
,
.
,
: 1. , 2. , 3. .
,

, ,
. , 76,
1, 409-425, 2014.
: , ,

SUMMARY
TRIANTAFYLLOU V. Anorexia nervosa. Anorexia nervosa is a dramatic and, in up
to 19% cases, life-threatening eating disorder and from this point of view, a real
nightmare for families and doctors. The disorder is presented with various forms for
thousands of years, but the most precise description of it has been given by William

, 76, 1, 2014 409

Gull in 1869. The prevalence of the disorder increased substantially since 1950s.
Despite the rapid progresses and new findings in medicine and biology in the last thirty
years, the problem of the disorders cause and medical treatment is remaining
unsolved. All our experience about clinical management of this syndrome is that, the
only stable and pragmatic treatment is 1) feeding 2) feeding and 3) feeding. The
present paper is an overview of the latest and most important concepts about the
causes of the syndrome and the appropriate therapeutical practices that require the
cooperation of many medical and nursing specialties. Nosokomiaka Chronika, 76,
Supplement 1, 409-425, 2014.
Key words: anorexia, eating disorder, life-threatening

1689, Richard Morton,
, ' ,
1.

1800, ,
, William Gull (1860) Charles Lasegue (1870).
,
.
,
1.
W. Gull, ,
: ,
.
,
.
Lasegue
,
,
,
,
1,2.
1800, ,
, , , .

, 76, 1, 2014 410

 ,
2.
20 ,
.
, ,
, .
,
Hilde Bruch (1950) 2.
'60,
. . , Gerald Russel, 1979,
, ..,
.
..,
,

,
1.

,
,
, .

,
() .

, ,
, .
..,
,
. ,
, , , ,
1.
, ,
1%.

, 76, 1, 2014 411

 1:3. ,
life style 1.
19%
3.
(3) ,
, ,
4.

.

.


.
, :
)
)
50% ..
, 500 ,
.


.
8
(12-16 ),
25 .

, .
,
- .
C.

.
,

, 76, 1, 2014 412


.

. , ,

,


. ,
4.

.
, :
( )
- (
)

, , ...
.
,
, ,
.

, ,
,
12.

1. :
)
(, , , )10
) ,
, ,
(.. Daf-2)

, 76, 1, 2014 413

 ) (

)5,6
)
1, 2 2C5
) UCP2 & UCP3, ,
.
1, 2 13.

.
50%
7.
2. :
)
. /
..
, - .
) ,
.
)
,
(, , )
.
)

.
)
.
,
, ,

.
) ( )
) ... ,
.

, 76, 1, 2014 414

 10
1.
( .. , )
2. (
, ) .
3. , ,
,
4.

,
, .
,
.

,
-
10.
1. :
)
) ( ,
,
, ,
)
2. :
)
)
)


, , ,
.

.
.

, 76, 1, 2014 415

 ,
,

.

.
, ,
, , , ,
,
.

, ,
,
.

,
Eriksson.


.
, , ,

.

,
, , ,
.

.
.
' ,
,
, .

, 76, 1, 2014 416

 , ,
.
.
, ,

.
.. , ..
, ,

.

,
-
.
.
, ..
( ),
( ).

,
,
,
.
..,
,
. ,
. ,
, ,
1.


. .
,
.

, 76, 1, 2014 417


, , .

.

4.
:
)
.
)
,
.
) , ,
, , ,
, .
ICD-10 :
) ,
15%

)
)
- .
) --

)

DSM9.
: ,
, ,
.

, 76, 1, 2014 418


. ,

.

,
.


.

,
:
23.
24. (
, , )
3)

( - ) .
:



,



4.
,
.

.

, :
: , , ,

, 76, 1, 2014 419

...: , Qtc ,
: - (),
: ,
: =>
=>
(rT3),
, , , ,

: => ,

: , (
), , ,

: , , ,

: ,

.
.
,
( 19%)
12.


,
15 .


18 .
,
12 '

, 76, 1, 2014 420

 2 '
.


.
70% ,

4
.

30%
, 30% , 30%
10% .
.
50%
, .
12:
)

)
)
)
)
) 25
.

( 4 ) :
1.
2.
3.
4.

, 76, 1, 2014 421


-:
1. , ,
.
2. ,
, , ,
..
3.
,
,
.
4.
.
5. 5
.

.

24 ,
(, ,
...),
.
20% ,
. ,
. 10%-15%
.
,
85% .
, ,
DSM,
1.
,
24 .

, 76, 1, 2014 422



, .

.
, 1,5 kg .

' , '
.
70%, 1500
,
500 3500 ( )
2500 5000
.

, ,
.

,
,
14,
. ,
.
50-100 mg
13.

:
-


: ) )

, 76, 1, 2014 423

 :
1)

2)

11.

: ..= N A

1. Kaplan & Suddock's: Comprehensive Textbook of Psychiatry n: Eating

Disorders Vol I: 2002-2023, 8th Edition, 2004 Lippincott Williams & Wilkins.
2. Jean-Luc Venisse: H 1987.
3. Sullivan PF: Mortality in anorexia nervosa. Am J Psychiatry 1995, 152(7): 1073-
1074.
4. APA Work group on Eating Disorders: Practice Guidelines for the treatment of
patients with eating disorders (revision). Am J Psychiatry 2000, 157 (Suppl 1): 1-
39.
5. Levitan RD, Kaplan HS,Masellis M, Basile et al. Polymorphism on the serotonin
5HT1B receptor gene (HTR1B) associated with minimum lifetime body-mass index
in women with bulimia nervosa. Biol Psychiatry 2001, 50(8): 640-643.
6. Vink T, Hinney A, van Elburg AA et al. Association between an agouti-related
protein gene polymorphism and anorexia nervosa Mol Psychiatry 2001, 6(3): 325-
328.
7. Grice DE, Halmi KA, Fichter MM et al. Evidence for a susceptibility gene for
anorexia nervosa on chromosome 1. Am J Hum Gen 2002, 70(3): 787-792.
8. Lambe EK, Katzman DK, Mikulis DJ, et al. Cerebral gray matter volume deficits
after weight recovery from anorexia nervosa. Arch Gen Psychiatry 1997, 54(6):
537-542.
9. Westen D, Hamden-Fischer J. Personality profiles in eating disorders; rethinking
the distinction between Axis I and Axis II. Am J Psychiatry 2001, 158(4): 547-562.
10. Fairburn CG, Cooper Z, Doll HA, Welch SL. Risk factors for anorexia nervosa:
three integrated case-control comparisons. Arch Gen Psychiatry 1999, 56: 468-
476.
11. Agras WS, Walsh BT, Fairburn CG et al. A multicenter comparison of cognitive-

, 76, 1, 2014 424

 behavioral therapy and interpersonal psychotherapy. Arch Gen Psychiatry 2000,
54: 459-465.
12. Ratnasuriya RH, Eisler I, Szmuker GI, Russel GF. Anorexia nervosa: outcome and
prognostic factors after 20 years. Br J Psychiatry 1991, 158: 495-502.
13. Birmingham CL, Goldner EM, Bakan R. Controlled trial of zinc supplementation in
anorexia nervosa. Int J Eat Disord 1994, 15: 251-255.
14. Bergh C, Eriksson M, Lindberg G, Sodersten P. Selective Serotonin Reuptake
Inhibitors in anorexia nervosa. Lancet 1997, 348(9023): 334-340.

, 76, 1, 2014 425



1, 2, 1, 1
1
, 2, (),
...

:

: 6939746814
E-mail: labrini_mitsi@hotmail.com

Here, at whatever hour you come, you

will find light and help and human
kindness.

,
.

1.
Albert Schweitzer,
Lambarene Albert
Schweitzer (1875-1965)

:
,
.
() ,
. :

, ,
,
. -:
12

, 76, 1, 2014 426

 (Medline, Scopus, Med.Consult).

. :

,
.

.
, 76, 1, 426-439, 2014.
: , , ,

SUMMARY
Introduction: Basic principle of the development of all the health systems worldwide
is the emergency treatment of the acute cases at the right time, at the right place and
by the appropriate personnel.The emergency rooms (ERS) are responsible for the
welcoming , the stabilization and the treatment to the patients. Aim: The purpose of
this study is to present an adequate view of the ERS in our hospital according to
European standards, through the historical flashback, the mission of the ERS itself,
the planning, the logistics and the personnel working on it. Material-Method: For this
study international and Greek bibliography was used from 12 sources. These articles
were found through valid databases (Medline, Scopus, and MedConsult). Also, tables
and diagrams were used which concern both the planning and the logistics of the ERS
too. Results: The proper and orderly function of the ERS depends both on the correct
spatial distribution of the building, the sufficient material needed and the highly trained
staff. We believe, that specifically in the ERS of our hospital with certain interventions
mainly on the spatial planning of the building, we will keep on providing high quality
care to the patients. Nosokomiaka Chronika, 76, Supplement 1, 426-439, 2014.
Key words: emergency rooms (ERS), planning, equipment, quality of health services

,
.

, 76, 1, 2014 427


.1

, .



.
(triage)
2
.

, ,

.

,
3.



.


4.

1.1.


().
Accident and Emergency Departments A &E Departments Emergency
rooms (ERS) Emergency Departments(EDS)5

1.2.

, 76, 1, 2014 428

 1961: ...

1968: (American
College of Emergency Physicians)6
1980:
...
1990: (BAEM)
1993: ()
2003: ( 2010
110 )
2009:
()

1.3.

3

2.1.

.

7 :


,
, 8
..

2.2.-

. ,
.

, 76, 1, 2014 429
.
.9


100 1.0003.

2.3.
2889/02-03-2001
10 :
-
-


( )





-

2.4.

,
10.(1)

6 1/200
3 1/400
2
2 1/200
4 1/200
- 4 1/100
2 1/200
2 1/400

, 76, 1, 2014 430

 4 1/200
1 1/400
2 1/400
- 1 1/400
6 1/100
6 1/100
1 1/400
1 1/400
2 1/200
1
2 1/400
(,,) 2

1.

3. -

:11

.
,
.
,
.
, ,
.
,
..

(4/.4472/20-01-2003) :
(1) ...

,
...
(1)
(1) ...

, 76, 1, 2014 431

 ,
...

:
(1)
(2)
(4)

12
(1) (10)
,
100
(6) (10) .

4.


,
.
, 899
.
2013 40.163,
.
850
, 1.000 24
. 30
30-35 .

4.1.
2
:
- :
1 ( , , )

triage

, 76, 1, 2014 432

 ( )

(, , , , , , ,
, , , , )

wc
wc
wc

4.2.

,
.
,

.
triage , ,
,
.

, 76, 1, 2014 433

 triage 2
.

,

.

,
,
.



.


.


.

.
:, ,
, ,


, ,

.
, ,


.
.

, 76, 1, 2014 434

 ,

.



.



.
,
.
,


.

.

4.3.

. :
(39)

(7)
(11)
(5)
(6)
(4)
(2)

scoop

, 76, 1, 2014 435





(4) -
(4) -
(200)
(10)

(4)



(50)
.



,


Bpap

4.4.
4 ,2
, 18 , 1 , 15 .

8 , 6

. 2
1
, ,
.
9,

, 76, 1, 2014 436

 1000 .
2 .

.
(1) (4) , (2) , (1) , (1) .
.

.

.
,
.
,
.

.

1. Walsh M & Kent A Accident & Emergency Nursing: A new approach, er

department, 4th edition London: Butterworth Heinemann Ltd, 2003;2-14.
2. Innes GM & Sosnow PL The Emergency department fast track En: Saluzzo RF,
Mayer TA et al (eds.) Emergency department management, Principles et
Applications, St. Louis, Misouri: Mosby, 1997;256-258.
3.

. . , 1989.
4. Putsep E, Structure and operation of the emergency department,putsep, Modern
Hospital International Planning Practices, Hospital buildings Design and
construction, London: Lloyd-Luke,1981.
5. ,
,
, 1, , ,
Mediforce, 2005.

, 76, 1, 2014 437

6. BAEM &FAEM=British Association for Emergency Medicine &the Faculty of
Accident and Emergency Medicine , The way ahead Joint Document Final
Draft London, 2004.
7. 517/1991 ,
, , 202/.
8. ,
: ,2001;7-10.
9. , , , , 5,
-, (
),
(), , 2002.
10. 2889/02-03-2001< ...
> { 8 (.5), 6 (.4)} 37/.
11. 87/1986
32/.
12.
, ,
, 2001,

, 76, 1, 2014 438

 2.

, 76, 1, 2014 439


-

.
,
...

:
: 6977971186
Email: spyroskolias@yahoo.gr

, ,


.
40
,

.
,
,
,
,
. ,
(medical triage), ,
,
,
.
, 76, 1, 440-451, 2014.
: , ,

SUMMARY
ARVANITAKIS NP: Organization and function of modern emergency department.
In no other aspect of living, but in life-threatening circumstances, could be best
communicated the significance and outstanding admiration attributed to medicine
among the other applied sciences. With the needs that led to the founding of the
precursors of the contemporary emergency departments, back in the late 40s, still not

, 76, 1, 2014 440

only ongoing but also multiplying, the vital role of emergency departments is more
than evident nowadays. For a number of firm and difficult to cope with reasons, having
to do with the each time different national health system itself on the one hand and
with the patients own choices on the other hand, the number of patients visiting the
emergency departments (ERs) worldwide is growing rapidly, while the ERs
themselves are declining. Thus, the introduction of medical triage, despite all its
setbacks, first used on the battlefield centuries ago, along with the autonomous and
separate development and evolution of the emergency medicine specialty, are the
milestones of providing high level medical support under every circumstance.
Nosokomiaka Chronika, 76, Supplement 1, 440-451, 2014.
Key words: emergency department, triage, emergency medicine

-

,

, ,


.
,
.
-
- ,
, ,
-,
,

,
( ),
.

,
- 5 15 ,

, 76, 1, 2014 441

 - 1, ,

,
- -
2,3, -
spot diagnosis4. ,
(accidents rooms) ()
(emergency rooms)
, 19445.
,
,
- ,
,


, ,
,
,
,
,
-
-
6.

,
, ,


, ,
,

. ,

, 76, 1, 2014 442

 2007,
116 ,
, 2008, 7% ,
124 ,
7.

1998 20098.

(
, ),
, , ,
,
.
, ,
,
,


,

.
,

, ,
,
9. ,
, , , ,
, ) ,
, , ) ,
, )

, )


, 10, )

, 76, 1, 2014 443

 , ) ,
, , , 11,
)
, )
,
,
,
, ,
,
.
,

,
HIV , lifestyle
( ) .. 2,
, overcrowding congestion
,
.
- , ,
triage,
- 12 (Dominique Jean Larrey, 1766-1842),
,
, ,
,
,
, ,
, . 1900 14-9-200713.

, ,
, ,
14.
,

, 76, 1, 2014 444

 1990
, :
, ,
15.
, ,
,
(pre-hospital triage),

/ (at scene triage), ,
(on
arrival triage).
, (. ),

, ,
, / ,
,
,
,
,
.
, , ,
, ,
, ,
.

, ,

, (Australasian Triage Scale)16,
, (Canadian Emergency Department Triage
and Acuity Scale)17, (Manchester Triage
Scale)18, (Emergency Severity Index)19.
-
, , 1,
()
, 5, ,

, 76, 1, 2014 445

 . ,
, ,
,
20,
68% 21. (... -
-), , ,
,
,

22,23, ..
.

, ,
,
,
(inappropriate
non-urgent visits),
( 8%)
24. , ,
, , , ,

.
.

,
- ,
,
.
,
, 1961, ,
,

, 76, 1, 2014 446

, . , ,

, , ,

, ,
.
,
,
,
25.
,
, 1972
, ,
1979, 23
. , . ,
1993 1995 . ,

( 2005/36/) -
()26.
, ,

,
27.
,
. , ,
.

,
,
, -,

,
,
, , , , ,

, 76, 1, 2014 447

 ,
, 28.

29 ,
,
30,
,
(.. , ),
-
.

31.

,
...: (
-,
,
, -
- ,
,
-
,
, -
- .
,
,
13.
,


,
,
, ,
,
,

, 76, 1, 2014 448

 ,
32.

1. Javetz , Melnick J, Adelberg E. .

, .
, , .
2. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival
in patients with severe sepsis or septic shock in whom early goal-directed therapy
was initiated in the emergency department. Crit Care Med. 2010; 38:1045-1053.
3. Perman SM, Goyal M, Gaiesky DF, Scand J. Trauma Resusc Emerg Med Initial
emergency department diagnosis and management of adult patients with severe
sepsis and septic shock 2012;20:41( http://www.sjtrem.com/content/20/1/41)
4. . , , .
. , , 1991.
5. Kellerman AL, Martinez R. The ER, 50 years on. N Engl J Med, 2011; 364:2278
2279.
6. International Federation for Emergency Medicine. IFEM Definition of Emergency
Medicine in http://www.ifem.cc/About_IFEM.aspx.
7. Institute of Medicine Committee on the Future of Emergency Care in the United
States Health System. Hospital Based emergency care: At the breaking point.
Washington, DC: National Academic Press, 2006.
8. He J, Hou X, Toolo S, et al. Demand for hospital emergency departments: a
conceptual understanding World J Emerg Med 2011; 2:253261
9. American College of Emergency Physicians: Definition of an emergency service.
http://www.acep.org/content.aspx?id=29162
10. Somerson SW, Markovchick VJ, Development of the triage In: Emergency
Department Management Saluzzo RF, Mayer TA, Strauss RW et al eds. Mosby,
St. Louis, Missouri, 2010
11. Waldrup RD, Harper DE, Mandry C, Prospective assessment of triage in an urban
emergency department South Med J, 1997; 90:12081212
12. Trauma.org: History of trauma: Dominique-Jean Larrey. In.
http://www.trauma.org/archive/history/prehospital.html
13. K , B, .
1900, 14 2007

, 76, 1, 2014 449

14. Rocovich C, Patel T Emergency. Department visits: Why Adults choose the
emergency room over a primary care physician during regular office hours. World
J Emerg Med 2012; 3:9197
15. Mengert TJ, Eisenberg MS, Copass MK. .
- . , ,
1997
16. Australasian College for Emergency Medicine: Guidelines on the implementation of
the Australasian triage scale in the emergency department Document No:24
Approved: Nov 00, Last Revised: Nov 13 Version No: 03. In:
https://www.acem.org.au/getattachment/d19d5ad3-e1f4-4e4f-bf83
7e09cae27d76/G24-Implementation-of-the-Australasian-Triage-Scal.aspx
17. Murray M, Bullard M, Grafstein E. Revisions to the Canadian Emergency
Department and Acuity Scale Implementation guidelines Can J Emerg Med 2004;
6:421427
18. Macway-Jones K, Marsden J, Windle J. Manchester Triage Group: Emergency
Triage, Blackwell Publishing Inc, Harayana, 2006.
19. Gilboy N, Tanabe T, Travers D, et al. Emergency Severity Index (ESI): A Triage
Tool for Emergency Department Care, version 4. Implementation Handbook 2012
Edition. AHRQ Publications No 12-0014. Rockville, MD. Agency for Healthcare
Research and Quality. November 2011.
20. Parenti N, Letizia M, Reggiani B, et al. Effect of a triage course on quality of rating
triage codes in a group of university nursing students: a before-after observational
study World J Emerg Med 2013; 4: 2025
21. McLean S: 2001 ENA National Benchmark Guide: Emergency Departments. Des
Plaines IL: Emergency Nurses Association 2001.
22. Travers DA, Waller AE, Bowling JM, et al. Five-level triage system is more effective
than three-level in tertiary emergency department. J Emerg Nur 2002; 28:395400
23. Wuerz RC, Milne LW, Eitel DR, et al. Reliability and validity of a new five-level
triage instrument. AcadEmerg Med 2000; 7:236242
24. van der Linden MC, van den Brand CL, van der Linden N, et al. Rate,
characteristics, and factors associated with high emergency department utilization
Int J Emerg Med. 2014;7: in: http://www.intjem.com/content/7/1/9
25. Suter RE Emergency medicine in the United States: a systematic review World J
Emerg Med 2012; 3:510

, 76, 1, 2014 450

26. Directive 2005/36/EC of the European Parliament and of the Council. Official
Journal of the European Communities L 255, 30.09.2005, p.22-142.
27. Working Group of the European Society for Emergency Medicine (EUSEM).
European Curriculum for Emergency Medicine. May 2008.
28. Aacharya RP, Gastmans C, Denier Y. Emergency department triage: an ethical
analysis, BMC Emergency Medicine 2011, 11-16.
29. , , , et al.
. .,
, 4, 1, 21004: 30-32.
30. BAEM & FAEM (2004) = British Association for Emergency Medicine (BAEM) & the
Faculty of Accident and Emergency Medicine (FAEM) (2004). The Way Ahead
Joint Document Final Draft London: BAEM FAEM.
31. , ,
, Mediforce, ,
2005.
32. Goeranson KE, De Waern M, Lindmarker P. Patients pathway to emergency care:
is the emergency department their first choice. European Journal of Emergency
Medicine 2013; 20:4550.

, 76, 1, 2014 451


...

1, 2
1
, . , 2 , . ,
... ...

:
: 6932461683
E-mail : ansmirnis@gmail.com

, ,
.
,
,
.

.
. , 76,
1, 452-464, 2014.
: , , ,

SUMMARY
YDRAIOS E, SMYRNIS A. Modern management of poly-trauma patient in E.R.
Trauma remains the primary cause of death in industrialized countries. Despite major
improvements in the management strategies for multiple trauma patients, there are
fields like ideal resuscitation and blood transfusions that raise controversies. Fields
like post traumatic coagulopathy are new in the multitrauma patient resuscitation. The
aim of this review is to address these controversies. Nosokomiaka Chronika, 76,
Supplement 1, 452-464, 2014.
Key words: trauma, multiple trauma patients, transfusion protocols, post traumatic
coagulopathy

, 76, 1, 2014 452


- ,
...
,

,
40% .
5,06 ( 9% ),
14.000 .
,
.
4,87% , 42,65%
.

. ,

.

- -
:
50%

1,2.
,
3. 30%
4 2
, .
()

. 20%
4 ( 2 4
) , ,

3-5.

, 76, 1, 2014 453

 1.

(responder)

1

Damage control
(nonresponder)
Second looks
2-4

510 Time-window of opportunity

> 10 No surgery!

> . 3

,
,
: ()
,

3-6
1. (primary survey)
(ATLS protocol),
2. "damage control
.
3.

/ .
4. delayed primary surgery -
( .. ,
...).

, 76, 1, 2014 454

 ( PRIMARY SURVEY)


6,7.


,
/ .

(Triage).
,

7,8.

(Golden hour)
golden hour shock

, ATLS
70 ,
9,10.

damage control,
11,12.

ATLS
A = ,
B =
C = ,

D = -
E = , ,
, .

,
MARCH :

, 76, 1, 2014 455

M = Massive haemorrhage control
A = Airway with cervical spine control
R = Respiration (Breathing)
C = Circulation
H = Head, spinal cord & other injuries

2. 13,14


2,5 mmol/l


> 1 ml/kg/h

40% .
ATLS ,

.
15,16.
ATLS
3:1,
,
- .

17-19.

(tourniquets).
, ,
:
1. :
,

19,20.

, 76, 1, 2014 456

 2. :

u/s fast D.P.L. 21,22.
3. :
( 5 lt),
.
(80%) nonresponders,
.

,
, , 22-24.
damage control,
,
,

25-27.
Permissive hypotension (- )

shock - -
.

, ,
.

28-30.
,
,

.


,
31-33.

, 76, 1, 2014 457

 33-40%
,
.
.

shock 34-37 .

, damage control ,
ATLS, ,
38,39.

.
(PT, aPTT, INR)
, .

in vitro pH s 37C
40,41.
(r-TEG)


,
,
,
38-41.


,
ATLS
42. .
RBC
,
> 30%.
, Hb 710 g/dl
43,44.

, 76, 1, 2014 458

 ,
, (FFP)
45.

INR

.
1:1 (FFP:RBC).
46,47.
Stahel .
6h first hit 24h
.
1:2 1:3 (RBC : FFP)
36,48,49.
,
.
50 x 109/L, 100 x 109/L
, . Gunter .
PLT:RBC 1:5
50.
< 100mg/dl (1g/L). (..aXIII)
.

VII (rFVIIa)
51,52.

10 RBC 24.


.
.

,
53-58.

, 76, 1, 2014 459



. (damage control surgery),


.

.

1. Gebhard F, Huber-Lang M. Polytrauma--pathophysiology and management

principles. Langenbecks Arch Surg 2008; 393(6):825831.
2. Scalea TM. Damage control for torso trauma. Hosp Med 2005; 66(2):8487.
3. Soreide K. Three decades (1978-2008) of Advanced Trauma Life Support
(ATLS) practice revised and evidence revisited. Scand J Trauma Resusc Emerg
Med 2008; 16(1):19.
4. Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: a
reassessment. J Trauma 1995; 38(2):185193.
5. Beekley AC. Damage control resuscitation: a sensible approach to the
exsanguinating surgical patient. Crit Care Med 2008; 36(7 Suppl):S267274.
6. Keel M, Trentz O. Pathophysiology of polytrauma. Injury 2005; 36(6):691709.
7. Stahel PF, Heyde CE, Ertel W. Current concepts of polytrauma. management. Eur
J Trauma 2005; 31:200211.
8. Cothren CC, Moore EE. Emergency department thoracotomy for the critically
injured patient: objectives, indications, and outcomes. World J Emerg Surg 2006;
1:4.
9. Lee JC, Peitzman AB. Damage control laparotomy. Curr Opin Crit Care 2006;
12(4):346350.
10. Kragh JF, Jr., Walters TJ, Baer DG, et al. Survival with emergency tourniquet use
to stop bleeding in major limb trauma. Ann Surg 2009; 249(1):17.
11. Loveland JA, Boffard KD. Damage control in the abdomen and beyond. Br J Surg
2004; 91(9):10951101.
12. Stahel PF, Schneider P, Buhr HJ, et al. Emergency management of thoracic
trauma [German]. Orthopade 2005; 34(9):865879.

, 76, 1, 2014 460

13. Moore EE, Burch JM, Franciose RJ, et al. Staged physiologic restoration and
damage control surgery. World J Surg 1998; 22(12):11841190; discussion
11901181.
14. Rotondo MF, Zonies DH. The damage control sequence and underlying logic.
Surg Clin North Am 1997; 77(4):761777
15. Rotondo MF, Schwab CW, McGonigal MD, et al. Damage control: an approach
for improved survival in exsanguinating penetrating abdominal injury. J Trauma
1993; 35(3):375382; discussion 382373.
16. Moore FA, McKinley BA, Moore EE. The next generation in shock resuscitation.
Lancet 2004; 363:19881996.
17. Rossaint R, Cerny V, Coats TJ, et al. Key issues in advanced bleeding care in
trauma. Shock 2006; 26(4): 322331.
18. Watters JM, Tieu BH, Differding JA, et al. A single bolus of 3% hypertonic saline
with 6% dextran provides optimal initial resuscitation after uncontrolled
hemorrhagic shock. J Trauma 2006; 61(1):7581.
19. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an
overview of epidemiology, clinical presentations, and therapeutic considerations.
J Trauma 2006; 60 (Suppl. 6):S3S11.
20. Johnson JW, Gracias VH, Schwab CW, et al. Evolution in damage control for
exsanguinating penetrating abdominal injury. J Trauma 2001; 51(2):261269;
discussion 269271.
21. Jaunoo SS, Harji DP. Damage control surgery. Int J Surg 2009; 7(2):110113.
22. Kortbeek JB, Al Turki SA, Ali J, et al. Advanced trauma life support, 8th edition,
the evidence for change. J Trauma 2008; 64(6):16381650.
23. Bickell WH, Wall MJJ, Pepe PE, et al. Immediate versus delayed fluid
resuscitation for hypotensive patients with penetrating torso injuries. N Engl J
Med 1994; 331:11051109.
24. Bender R, Breil M, Heister U, et al. Hypertonic saline during CPR: Feasibility and
safety of a new protocol of fluid management during resuscitation. Resuscitation
2007; 72(1):7481
25. Catrambone JE, He W, Prestigiacomo CJ, et al. The use of hypertonic saline in
the treatment of post-traumatic cerebral edema: a review. Eur J Trauma Emerg
Surg 2008; 34:397409.
26. Maybauer DM, Maybauer MO, Traber DL. Resuscitation with hypertonic saline in
burn shock and sepsis. Crit Care Med 2006; 34(6):18491850.

, 76, 1, 2014 461

27. Rizoli SB, Rhind SG, Shek PN, et al. The immunomodulatory effects of
hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic
shock: a randomized, controlled, double-blinded trial. Ann Surg 2006;
243(1):4757.
28. Shaz BH, Dente CJ, Harris RS, et al. Transfusion management of trauma
patients. Anesth Analg 2009; 108(6):17601768.
29. Stahel PF, Smith WR, Moore EE. Hypoxia and hypotension, the lethal duo in
traumatic brain injury implications for prehospital care. Intensive Care Med
2008; 34:402404.
30. McIntyre L, Hebert PC, Wells G, et al. Is a restrictive transfusion strategy safe for
resuscitated and critically ill trauma patients? J Trauma 2004; 57:563568.
31. Pascual JL, Maloney-Wilensky E, Reilly PM, et al. Resuscitation of hypotensive
headinjured patients: is hypertonic saline the answer? Am Surg 2008;
74(3):253259.
32. Doyle JA, Davis DP, Hoyt DB. The use of hypertonic saline in the treatment of
traumatic brain injury. J Trauma 2001; 50(2):367383.
33. Forsyth LL, Liu-DeRyke X, Parker D, Jr., et al. Role of hypertonic saline for the
management of intracranial hyper- tension after stroke and traumatic brain injury.
Pharmacotherapy 2008; 28(4):469484.
34. Theusinger OM, Spahn DR, Ganter MT. Transfusion in trauma: why and how
should we change our current practice? Curr Opin Anaesthesiol 2009;
22(2):305312.
35. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism,
identification and effect. Curr Opin Crit Care 2007; 13(6):680685.
36. Stahel PF, Moore EE, Schreier SL, et al. Transfusion strategies in post injury
coagulopathy. Curr Opin Anaesthesiol 2009; 22(2):289298.
37. MacLeod JB, Lynn M, McKenney MG, et al. Early coagulopathy predicts mortality
in trauma. J Trauma 2003; 55(1):3944.
38. Kashuk JL, Moore EE, Le T, et al. Noncitrated Whole Blood Is Optimal for
Evaluation of Postinjury Coagulopathy With Point-of-Care Rapid
Thrombelastography. J Surg Res. 2009;156(1):133-138.
39. Plotkin AJ, Wade CE, Jenkins DH, et al. A reduction in clot formation rate and
strength assessed by thrombelastography is indicative of transfusion
requirements in patients with penetrating injuries. J Trauma 2008; 64(2
Suppl):S6468.

, 76, 1, 2014 462

40. Bartal C, Yitzhak A. The role of thromboelastometry and recombinant factor VIIa
in trauma. Curr Opin Anaesthesiol 2009; 22(2):281288.
41. Salooja N, Perry DJ. Thrombelastography. Blood Coagul Fibrinolysis 2001;
12(5):327337.
42. Spahn DR, Rossaint R. Coagulopathy and blood component transfusion in
trauma. Br J Anaesth 2005 95(2):130139.
43. Maegele M, Lefering R, Yucel N, et al. Early coagulopathy in multiple injury: an
analysis from the German Trauma Registry on 8724 patients. Injury 2007;
38:298304.
44. Scalea TM, Bochicchio KM, Lumpkins K, et al. Early aggressive use of fresh
frozen plasma does not improve outcome in critically injured trauma patients.
Ann Surg 2008; 248:578584.
45. Criddle LM. Recombinant factor VIIa and the trauma patient. J Emerg Nurs 2006;
32(5):404408.
46. Duchesne JC, Hunt JP, Wahl G, et al. Review of current blood transfusions
strategies in a mature level I trauma center: were we wrong for the last 60 years?
J Trauma 2008; 65(2):272276; discussion 276278.
47. Grottke O, Henzler D, Rossaint R. Use of blood and blood products in trauma.
Best Pract Res Clin Anaesthesiol 2007; 21(2):257270.
48. Roberts I. The CRASH-2 trial of an antifibrinolytic agent in traumatic
haemorrhage: an international collaboration. Indian J Med Res 2007; 125(1):57.
49. Kashuk JL, Moore EE, Johnson JL, et al. Postinjury life threatening
coagulopathy: is 1:1 fresh frozen plasma: packed red blood cells the answer? J
Trauma 2008; 65(2):261270; discussion: 270261.
50. Gunter OL, Jr., Au BK, Isbell JM, et al. Optimizing outcomes in damage control
resuscitation: identifying blood product ratios associated with improved survival. J
Trauma 2008; 65(3):527534.
51. Shuja F, Shults C, Duggan M, et al. Development and testing of freeze-dried
plasma for thetreatment of trauma-associated coagulopathy. J Trauma 2008;
65:975985.
52. Stein DM, Dutton RP, Hess JR, et al. Low-dose recombinant factor VIIa for
trauma patients with coagulopathy. Injury 2008; 39(9):10541061.
53. Schreiber MA, Perkins J, Kiraly L, et al. Early predictors of massive transfusion in
combat casualties. J Am Coll Surg 2007; 205(4):541545.

, 76, 1, 2014 463

54. 54.Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products
transfused affects mortality in patients receiving massive transfusions at a
combat support hospital. J Trauma 2007; 63(4):805813.
55. Cotton BA, Gunter OL, Isbell J, et al. Damage control hematology: the impact of
a trauma exsanguination protocol on survival and blood product utilization. J
Trauma 2008; 64(5):11771182; discussion 11821173.
56. Riskin DJ, Tsai TC, Riskin L, et al. Massive transfusion protocols the role of
aggressive resuscitation versus product ratio in mortality reduction. J Am Coll
Surg. 2009; 209:198205.
57. Blackbourne LH. Combat damage control surgery. Crit Care Med 2008; 36
(Suppl. 7):S304310.
58. Fox CJ, Gillespie DL, Cox ED, et al. The effectiveness of a damage control
resuscitation strategy for vascular injury in a combat support hospital: results of a
case control study. J Trauma 2008 64(2 Suppl):S99-106; discussion S106107.

, 76, 1, 2014 464



,
, ...

:
: 2132041468
-mail: k.letsas@mail.gr

.

.


(90% ).
1.5% 50-59
23.5% 80-89 .
CHA2DS2VASc score. CHA2DS2VASc score
>1 .

HASBLED
score.
. ,
,
. dabigatran
etexilate rivaroxaban, apixaban edoxaban


.
,

, 76, 1, 2014 465
.
,
,
( dabigatran etexilate)
.

.
, 76, 1, 465-466, 2014.
: ,

, 76, 1, 2014 466



CLOSTRIDIUM DIFFICILE

-, ,
...

:
: 6974174636
-mail: beleselina@yahoo.com

Clostridium difficile (C. difficile infection CDI)

()

( , , ,
1,2.
To C. difficile 1935
Gram , (
). (-),

.

, , ,
, , shock.
, , , ,
, , , , , .
C.
difficile 3.
H CDI : )
, ) , ) C. difficile, )

, 76, 1, 2014 467

 )
.
C. difficile ,
(),
( PCR)
4,5.
CDI C. difficile

(

Gram ,
)6.
( ,
, , ,
) C. difficile
CDI .

1. Dodek PM, Norena M, Ayas NT et al. Length of stay and mortality due to
Clostridium difficile infection acquired in the intensive care unit. J Crit Care 2013,
28(4): 335-340.
2. Khanafer , Tour , Chambrie C et al. Predictors of Clostridium difficile infection
severity in patients hospitalised in medical intensive care. World J Gastroenterol
2013, 19: 8034-8041.
3. Micek ST, Schramm G, Morrow L et al. Clostridium difficile infection: a multicenter
study of epidemiology and outcomes in mechanically ventilated patients. Crit Care
Med 2013, 41(8): 1968-1975.
4. Bobo LD, Dubberke ER, Kollef M. Clostridium difficile in the ICU: the struggle
continues. Chest 2011, 140(6): 1643-1653.
5. Cohen SH et al. Infect Control. Clin Epidemiol 2010, 315: 431.
6. Bartsch SM, Umscheid CA, Fishman N et al. Is fidaxomicin worth the cost? An
economic analysis. Clin Infect Dis. 2013, 57(4): 555-561.

, 76, 1, 2014 468

 Clostridium difficile

.
, , ...

:
: 6974508199
-mail: ldoukagr@yahoo.gr

Clostridium difficile -

.
C. difficile , ,
, . C. difficile
,
.
C. difficile
.
,
, C. difficile
NAP1/BI/027.
: Clostridium difficile

.
10 15 , ,
. 10 25 %
C. Difficile.
C. difficile.
.
, ,
, , , ,
.
.
:
.
( )

, 76, 1, 2014 469

 (GDH) PCR.
.
C. difficile
.
.
:

.
(Grade 2B). CDI 125 mg
10 14 (Grad1B).
500 mg
(Grade 2C). fidaxomicin
,
.
.
, 500 mg
500 mg (Grade 2C).
(Grade 2C)
. tapering
fidaxomicin, (Grade 2B).
20,000 cells/microL 2.2 4.9
meq/L (Grade 1B).
. ,
, ,
. ,
76, 1, 469-470, 2014.
: clostridium difficile, ,

, 76, 1, 2014 470



HIV

1, 1, , MSc,
PhD2, 1, , MD3
1
, ,
2
, ,
3
, ...

:

: 6977 718184, 213 2041194, 213 2041294
-mail: dr.gerasimos@gmail.com

,
.
... ,

( ).
30 HIV (+) , 26 62 .

, (State Anxiety Inventory-
STAI) (Beck Depression Inventory-BDI).
(=14, 46.7%) -
, 70% (=21)
40% (=12)
. 40 , 2

. ,
.

, 76, 1, 2014 471

 . , 76,
1, 471-491, 2014.
: HIV , AIDS, , ,

SUMMARY
GOUTZAMANIS G, ANDREOU E, MANGOULIA P, DIMOU S, ALEXANDRAKOU P.
HIV and Psychiatric Disorders. Epidemiological studies have shown that there is a
high prevalence of psychiatric disorders in HIV (+) patients, especially mood and
anxiety disorders. The aim of the study is to investigate the prevalence of psychiatric
disorders in HIV (+) patients at the Evaggelismos General Hospital of Athens, to
examine the factors associated with these disorders and to treat these disorders (drug
therapy and/or psychotherapy). The sample of this pilot study consisted of 30 HIV (+)
men, aged 26-62 years old. Study instruments included the State Anxiety Inventory
(STAI), the Beck Depression Inventory (BDI) and a set of items on general information
of the sample (demographic and personal characteristics). Half of the participants
(=14, 46.7%) had comorbid somatic illness and suicide ideation, while 70% (=21)
had moderate to severe depression with or without psychotic symptoms and 40%
(=12) were drug addicted. At the 2nd psychiatric assessment (after 40 days),
participants were found to have lower anxiety and depression rates and higher
compliance with HIV medication. Therefore, the role of the psychiatrist is very
important, especially regarding the compliance of HIV patients with their treatment and
the suicide prevention. Nosokomiaka Chronika, 76, Supplement 1, 471-491, 2014.
Key words: HIV, AIDS, psychiatric disorders, depression, anxiety

.
: . , ,

(DSM-IV, ICD 10), . , .
/
, .
, .
. .
(WHO):

, 76, 1, 2014 472



.2
,
ICD-10 (International Classification of Diseases),
:
1. .
2.
.
3. , .
4. .
5. , .
6.
.
7. .
8. .
9.
10.
.3

HIV+
1) : .
, . , . .
.

10-20% 30-40% .
: , ,
, ,
.
,
AIDS/HIV+ 30%-40%.
. : ,
.

, 76, 1, 2014 473

. :
.
. 5% 65
( 5% ). 50-60%
Alzheimer 15-30% .4 HIV
(HAD) ,
. HAD 15-20% AIDS.5
1990-1992 21,1/1000 HAD, 1995-1997
14,1/1000 .6 1999, HAART
HAD 5-10%.7
2)
:
,
.4
2011 4769
12-64 . 86%
, 38% 4.8% 3.
(13.3%) (3.9%).8
,
16,7%.9 , Witchen et
al, 3,4% ,
1.2%.10 HIV+
3-12%.11 ,
2% - 19%.11
3) , :
10
1,2%.
(
1000 ) 0,2-0,5, / 1,4:1,
15-35 (
3-5 ).3
, ,

.4 ()
8% HIV
.

, 76, 1, 2014 474


HIV
, .4,12
4)
:
) :
, , ,
, , ,
, , , ,
, , , ,
, , , . 10-
25% 5-12% .13
HIV+, 50% ,14,15 (
) ,
.

.. , , ,
.12
,
.
) : X
,
.4 I
0,3-1.5% II 0,4-5%.
, ,
, , , , ,
, , , ,
.4 IV/AIDS
()
HIV ,
HAART(Highly Active Antiretroviral Therapy)
.16 , (
, )
, , ,

, 76, 1, 2014 475

 .16,17 HAART
.
) :

5-6% .18
5) .
,
.18,19 :
1. ( ) 0,4-3,8%
.
2. : (1,3-6%),
(0,5-13,3%) (5,4-11,3%)
3. (0,7 - 44%)
4. (, 2,3 - 13,1%)
5. (1-3%), ) , )

6.
7.
8.
HIV +
15,8%,
11-25% 42%.19,20
HIV+ -
.

V (+)
AIDS , ,
-
. Stuart E. Nichols , 1983,
, ,
.
( )
.21
, , HIV , ,
N (), - ,

, 76, 1, 2014 476


. (

,
gp120 tat), .
(50% AIDS),22
1/3
22
V (HAND-HIV associated
Neurocognitive disorders). ,
( ).
(MND-Mild Neurocognitive
Disorder) V (HAD- HIV
Associated Dementia).12
HAD , , , ,
, , .

. , , ,
, , ,
, . HAD
, ,
,
, (, , ),
.12,22, 23 HAD

22
.

(CT MRI ).12 ,
. HAD
, ,
.22
,
HIV .

,

, 76, 1, 2014 477

 . ,
1) , 2)
, 3)
, 4)
HIV .

(, ), ,
.
() : 1)
HIV , 2)
, 3)
4)
.24 , ART(antiretroviral therapy),
(
HAND).25 HAD
, , , ( HIV
) .26,27
HAD.27 H ,
.26
.28
, HAART.26 ,
,
. (SSRIs)

,
.29 - -

() ,
.30 ,

(NNRTIs) P450,
,
, (
31).32
(SRIs)

, 76, 1, 2014 478

 , .25
.33
-
.34

HIV ,
AIDS.24

, ,
.35
HIV .28
.
( ).36
,
CYP3 ART .32
H Y,

HIV.24 HIV
.16 ,

,37,38
.39,40
, HIV
, -
o HIV , ,
.41
HIV

.42 - ,
, 41
HIV ,
, .

,
.43

, 76, 1, 2014 479

 (, , ,
).41
.41
,
.41
delirium,

.44
,
,
, .

, .45 H (Efavirenz)
() ,46
.47

,
HIV,
.
HAD.48

DAART (Directly Administered Antiretroviral Therapy),
.49
(cART)
50% HIV .22,50

.51 ,

cART .52,53,54
cART.55
HIV , 15-50% AIDS
ART, 10,5% (
).12,22 ART
RT
( , ),12,22,48

, 76, 1, 2014 480


.
.56
(
, )
. ,
HIV (ART)

, ,
( ) . ,

HAND ,
(screening),
.57

.
- ,

,
.

,
,
.

,

( ).

, 76, 1, 2014 481



SPSS 20.0.
. ,
Kolmogorov-Smirnov
test. =0.05.
Pearson

.
()

(linear regression analysis).

(dummy variables).

30 HIV (+) , 26 62 ,
(N=28, 93.3%) (=26, 86.7%).
(=14, 46.7%) -
, 70% (=21)
40% (=12)
( 1).

,
(State Anxiety Inventory-STAI)58,59
(Beck Depression Inventory-BDI).60,61 ,



,
. ,
, 40 .

, 76, 1, 2014 482

 1.
N(%) / mSD

26 (86.7%)
4(13.3%)

1 (3.3.%)
12 (40%)
7 (23.3%)
10 (33.3%)

28 (93.3%)
1 (3.3%)
1 (3.3%)
-
14 (46.7%)
16 (53.3%)

14 (46.7%)
16 (53.3%)

3 (10%)
27 (90%)

7 (23.3%)
23 (76.7%)

8 (26.7%)
22 (73.3%)

12 (40%)
18 (60%)
39.80 9.44
AIDS 66.20 63.41
anti-HIV 45.80 49.36

6.7% (=2), 26.7%

(=8) , .
73.3% (N=22) (anti-HIV) , 30% (=9)
.
, 76, 1, 2014 483
 . anti-HIV
. 80%
,
( 2).

2.
anti-HIV
N(%) / mSD

2 (6.7%)
5 (16.7%)
10 (33.3%)
6 (20%)
4 (13.3%)
2 (6.7%)
1 (3.3%)

( )
2 (6.7%)
2 (6.7%)
3 (10%)
1 (3.3%)
anti-HIV

13 (43.3%)
9 (30%)
anti-HIV 8 (26.7%)
anti-HIV

16 (53.3%)
anti-HIV 8 (26.7%)
6 (20%)

( ),

. 1 (STAI: 114.88 26.61),
73.3% (=22), 40 (STAI: 94 17.79),
43.3% (=13). ,
BDI 28.27 11.06 1 , 19.12 4.67 40

, 76, 1, 2014 484

. 40

( 3).

3. (STAI)
(BDI) 1 40
STI 1 (=26) 40 (=17)
minimum 39 38
maximum 148 120
mSD 114.88 26.61 94 17.79
4 (13.3%) 4 (13.3%)
22 (73.3%) 13 (43.3%)
BDI 1 (=30) 40 (=17)
minimum 1 11
maximum 44 26
mSD 28.27 11.06 19.12 4.67
2 (6.7%)
6 (20%) 11 (36.7%)
6 (20%) 6 (20%)
12 (40%)
4 (13.3%)

( BDI)
anti-HIV (p=.047),
(p<.001), ,
(p=.014) (p=.035),
anti-HIV .
70.7% BDI
. , ( STAI )
BDI ,
(p<.001). 42.4% STAI
( 4). , BDI
(r=.41, p=.001) STAI (r=.65, p<.001).

, 76, 1, 2014 485

 4. BDI STAI
95%
B
p-value

BDI
4.399 0.527 -9.844 18.641

-0.067 0.047 -0.132 -0.001
anti-HIV
STAI 0.248 0.000 0.134 0.362

-9.496 0.014 -16.856 -2.135

-7.352 0.035 -14.120 -0.584

anti-HIV
9.581 0.010 2.610 16.552

STAI

72.356 0.000 49.861 94.850

BDI 1.494 0.000 0.760 2.228

,
. 1995,
HAART, .

.
,
AIDS .
.

.

, ,
,
, . , ,

, 76, 1, 2014 486

 AIDS
.

1. . , , , 2000.
2. World Health Organization (WHO). Primary Prevention of Mental Neurological
and Psychiatrical Disorders, Geneva, 1998.
3. World Health Organisation (WHO). The ICD10 Classification of Mental and
Behavior disorders, clinical description and diagnostic Guidelines, Geneva, 1992.
(. , )
, , 1993.
4. , , . ,
, , 2013.
5. Simpson DM. Human immunodeficiency virus-associated dementia: review of
pathogenesis, prophylaxis, and treatment studies of zidovudine therapy, Clin
Infect Dis. 1999;29:19-34.
6. Dore GJ, Correll PK, Li Y et al. Changes to AIDS dementia complex in the era of
highly active antiretroviral therapy, AIDS, 1999;13:1249-1253.
7. Sacktor NC, Lyles RH, Skolasky RL et al. Combination antiretroviral therapy
improves psychomotor speed performance in HIV-seropositive homosexual men:
Multicenter AIDS Cohort Study (MACS), Neurology, 1999;52:1640-1647.
8. .
, , 2010.
9. Merikangas KR, McClair VL. Epidemiology of substance use disorders, Hum
Genet 2012, 131:779-789.
10. Wittchen HU, Jakobi F, Rehm J et al. The size and burden of mental disorders
and other disorders of the brain in Europe 2010, Eur Neuropsychopharm 2011,
21:655-679.
11. Rabkin JG. Prevalence of psychiatric disorders in HIV illness, Int Rev Psychiatry
1997, 8:157-166.
12. OweLarsson B, Sall L, Salamon E et al. HIV infection and psychiatric illness,
African J Psychiatry 2009, 12:115-128.
13. Lykouras L, Gournellis R. Psychotic delusional major depression: new vistas, Cur
Psychiatry Rep 2009, 5:1-28.
14. Ickovics JR, Hamburger ME, Vlahov D eta al. Mortality, CD4 cell countdecline,

, 76, 1, 2014 487

 and depressive symptoms among HIV- seropositive women: longitudinal analysis
from the HIV Epidemiology Research Study, JAMA 2001, 285:1466-1474.
15. orrison MF, Petitto JM, Ten Have T et al. Depressive and anxiety disorders in
women with HIV infection, Am J Psychiatry 2002, 159:789-796.
16. Ellen SR, Judd FK, Mijch AM et al. Secondary mania in patients with HIV
infection, Aust N Z J Psychiatry 1999, 33(3):353-360.
17. Nakimuli-Mpungu E, Musisi S, Mpungu SK et al. Primary mania versus HIV-
related secondary mania in Uganda, Am J Psychiatry 2006, 163(8):1349-1354.
18. . , , , 2006.
19. Sewell MC, Coggin KJ, Rabkin JG et al. Anxiety Syndromes and symptoms
among men with AIDS, Psychosomatics 2000, 41(4):294-300.
20. Kelly B, Raphael B, Judd F, et al. Posttraumatic stress disorder in response to
HIV infection, Gen Hosp Psychiatry 1998, 20(6):345-352.
21. Nichols SE and Ostrow DG (eds). Psychiatric Implications of Acquired Immune
Deficiency Syndrome, Washington, American Psychiatric Press, 1984.
22. McArthur JC, Haughey N, Gartner S et al. Human immunodeficiency virus-
associated dementia: an evolving disease, J Neurovirol 2003, 9(2):205-221.
23. Navia BA, Jordan BD, Price RW. The AIDS dementia complex: Clinical features,
Ann Neurol 1986, 19(6):517-524.
24. Hinkin CH, Castellon SA, Atkinson JH et al. Neuropsychiatric aspects of HIV
infection among older adults, J Clin Epidemiol 2001, 54(Suppl 1):S44-52.
25. Judd F, Komiti A, Chua P et al. Nature of depression in patients with HIV/AIDS,
Aust N Z J Psychiatry 2005, 39(9): 826-832.
26. Dube B, Benton T, Cruess DG et al. Neuropsychiatric manifestations of HIV
infection and AIDS, J Psychiatry Neurosci 2005, 30(4):237-246.
27. Wojna V, Nath A. Challenges to the diagnosis and management of HIV dementia,
AIDS Read 2006, 16(11):615-616, 621-4, 626.
28. Olley EO, Zeier MD, Seedat S et al. Posttraumatic stress disorder among
recently diagnosed patients with HIV/AIDS in South Africa, AIDS Care 2005,
17(5):550-557.
29. Repetto AL, Petitto JM. Psychopharmacology in HIV-infected patients,
Psychosom Med 2008, 70(5):585-592.
30. Tsai AC, Karasic DH, Hammer GP, et al. Directly Observed Antidepressant
medication Treatment and HIV Outcomes Among Homeless and Marginally
Housed HIV-Positive Adults: Randomized Controlled Trial, American J of Public

, 76, 1, 2014 488

 Health 2013, 103(2):308-315.
31. De Silva KE, Le Flore DB, Marston BJ et al. Serotonin syndrome in HIV-infected
individuals receiving antiretroviral therapy and fluoxetine, AIDS 2001, 15(10):
1281-1285.
32. Tseng AL, Foisy MM. Significant interactions with new antiretrovirals and
psychotropic drugs, Ann Pharmacother 1999, 33(4):461-473.
33. Elliott AJ and Roy-Byrne PP. Mirtazapine for depression in patients with human
immunodeficiency virus, J Clin Psychopharmacol 2000, 20(2):265-267.
34. Olatunji BO, Mimiaga MJ, OCleirigh C et al. Review of treatment studies of
depression, Psychosom Med 2008, 70:539-545.
35. Peretta P, Nisita C, Zaccagnini E et al. Psychopathology in 90 consecutive human
immunodeficiency virus-seropositive and acquired immune deficiency syndrome
patients with mostly intravenous drug use history, Compr Psychiatry 1996,
37(4):267-272.
36. Omonuwa T, Goforth HW, Preudhomme X et al. The pharmacologic management
of insomnia in patients with HIV, J Clin Sleep Med 2009, 5:251-262.
37. Letendre SL, Woods SP, Ellis RJ et al. Lithium improves HIV-assosiated
neurocognitive impairment, AIDS 2006, 20(14):1885-1888.
38. Schifitto G, Peterson DR, Zhong J et al. Valproic acid adjunctive therapy for HIV-
associated cognitive impairment: a first report, Neurology 2006, 66(6):919-921.
39. Romanelli F, Jennings HR, Nath A, et al. Therapeutic dilemma: the use of
anticonvulsants in HIV- positive individuals, Neurology 2000, 54:1404-1407.
40. Cozza KL, Swanton EJ, Humphreys CW. Hepatotoxicity with combination of
valproic acid, ritonavir and nevirapine:a case report, Psychosomatics 2000,
41:452-453.
41. Dolder CR, Patterson TL, Jeste DV. HIV,psychosis and aging: past, present and
future, AIDS 2004, 18(Suppl 1):S35-S42.
42. Sewell DD. Schizophrenia and HIV, Schizophr Bull 1996, 22(3):465-473.
43. Koutsilieri E, Sopper S Scheller C et al. Parkisonism in HIV dementia, J neural
Transm 2002, 109(5-6):767-775.
44. Menza MA, Murray GM, Holmes VF et al. Decreased extrapyramidal symptoms
with intravenous haloperidol, J Clin Psychiatry 1987, 48:278-280.
45. Foster R, Olajide D, Everall IP. Antiretroviral therapy-induced psychosis: case
report and brief review of the literature, HIV Med 2003, 4:39-144.
46. Gatch MB, Kozlekov A, Huang R et al. The HIV Antiretroviral Drug Efavirenz has

, 76, 1, 2014 489

 LSD-Like Properties, Neuropsychopharmacology 2013, 38:2373-2384.
47. Product information. Sustiva (efavirenz), Princeton, NJ: Bristol-Myers Squibb Co,
June 2012.
48. Anthony IC, Bell JE. The Neuropathology of HIV/AIDS, Int Rev Psychiatry 2008,
20(1):15-24.
49. Ing EC, Bae IW et al. Medication Persistence of HIV-infected Drug Users on
Directly Administered Antiretroviral Therapy, AIDS Behav 2013, 17(1):113-121.
50. Crum NF, Riffenburgh RH, Wegner S et al. Comparisons of causes of death and
mortality rates among HIV- infected persons: analysis of the pre, early, and late
HAART(highly active antiretroviral therapy) eras, J Acquir Immune Defic Syndr
2006, 41(2):194-200.
51. Bae JW, Guyer W, Grimm K et al. Meditation persistence in the treatment of HIV
infection: a review of the literature and implications for the future clinical care and
research, AIDS 2011, 25(3):279-290.
52. Lima VD, Geller J, Bangsberg DR et al. The effect of adherence on the
association between depressive symptoms and mortality among HIV-infected
individuals first initiating HAART, AIDS 2007, 21(9):1175-1183.
53. Mellins CA, Havens JF, McDonnell C et al. Adherence to antiretroviral
medications and medical care in HIV-infected adults diagnosed with mental and
substance abuse disorders, AIDS 2009, 21(2):168-177.
54. De Lorenze GN, Satre DD, Quesenberry CP et al. Mortality after diagnosis of
psychiatric disorders and co-ocurring substance use disorders among HIV-
infected patients, AIDS Patient Care STDs 2010, 24(11):705-712.
55. Springer SA, Dushaj A, and Azar MM. The Impact of DSM-IV Mental Disorders on
Adherence to Combination Antiretroviral Therapy Among Adult Persons Living
with HIV/AIDS: A Systematic Review, AIDS Behav 2012, 16:2119-2143.
56. Robertson KR, Su Z et al. Neurocognitive effects of treatment interruption in
stable HIV-positive patients in an observational cohort, Neurology 2010,
74(16):1260-1266.
57. Clifford DB and Ances BM The challenge of HIV associated neurocognitive
disorder, The Lancet Infectious Diseases 2013,13(11):976-986.
58. Spielberger CD. Manual for the State-Trait Anxiety Inventory (STAI), Consulting
Psychological Press, Palo Alto, CA, 1983.
59. Fountoulakis KN, Papadopoulou M, Kleantous S et al. Reliability and
psychometric properties of the Greek translation of the State-Trait Anxiety

, 76, 1, 2014 490

 Inventory form: Preliminary data, Ann Gen Psychiatry 2006, 5:1-10.
60. Beck AT, Ward CH, Mendelson M et al. An inventory for measuring depression,
Arch Gen Psychiatry 1961, 4: 561-571.
61. . Beck .
, , 1987.

, 76, 1, 2014 491



, MSc
& -,
...

:
: 2102710470, 6931199996
-mail: stamatakis_s@yahoo.gr

.
4 : 1.
() ()
1992.
. : )
, )
, )
, , )
() )
(, ,
). 2.
()
. : )
, ) , ) , ) ,
) ) . 3. PRAKSIS
()
,
.
.

, 76, 1, 2014 492

. 4. .
2009
,
. Aids
Healthcare Foundation (AHF) Athens Checkpoint.
HIV. ,
76, 1, 492-501, 2014.
: , , HIV, ,

SUMMARY
STAMATAKIS S. Psychosocial interventions to HIV (+) people. This work focuses
on the main psychosocial interventions to HIV (+) people in Greece. These
interventions come from 4 leading Organizations: 1.Hellenic Centre for Disease
Control and Prevention (HCDCP) is a private law entity and has operated since
1992. It is supervised and funded directly by the Ministry of Health and Social
Solidarity. Its main purposes are: a) to protect and promote public health, b) the
epidemiological surveillance of infectious diseases, c) support research programs to
collect, review and disseminate scientific data, d) the operation of Infectious Diseases
Units in hospitals and e) psychosocial Support to vulnerable population (immigrants,
homosexuals, injecting drug users). 2.The Centre for Life is a Non-Governmental
Organization (NGO) that provides psychosocial services to HIV (+) people and their
families. Its main services are: Psychological and Social Support, b) Free Legal
Support, c) Drop-in-Centre, d) Info Centre, e) Prevention Program and f) Buddy
Program. 3.PRAKSIS is an independent NGO, which has as its main goal the
creation, application and implementation of humanitarian and medical action. It
activates all across Greece and especially in the two major centers of Athens and
Thessaloniki. The main goal is to combat the social and economic exclusion of socially
vulnerable groups and to defense their base civil and social rights. 4. Positive Voice
is the Association of HIV (+) people in Greece. It was founded in 2009 and its main
purpose is to defend the rights of HIV (+) people and to promote social acceptance,
solidarity and support of these groups. Positive Voice with the financial funding of AHF
(Aids Healthcare Foundation) created Athens Checkpoint project, which provides rapid
tests for HIV. Nosokomiaka Chronika, 76, Supplement 1, 492-501, 2014.
Key words: psychosocial interventions, support, HIV, homosexuals

, 76, 1, 2014 493


( ) 1992 ,
& .
& .
HIV/AIDS
, , &
().
, :
) 1
HIV ,
( & )
(, ),
. 13
, 132 (-,
, ).
.
)

(1,5 )
. ,
&
. ,
& &
.
18 .
&
, ,
, , ,
& HIV
,

.
65.000 .
.
3.000 .

, 76, 1, 2014 494

 &

,
&
.
HIV/AIDS :
, ,
(street work),
& ,
promo-stand CD
HIV 15-18 .
&
&
.
, ,
, .
& ,
, , ,
, ,
, . ..
34.000
. 2013

.
& .
& Athens
Checkpoint, .

()

2009
.

. 5
.

, 76, 1, 2014 495

 1,5 .
. 1/2/2012 30/11/2013
63 .
9 . ,
23-47 .
: )
, )
, )
, )
, )
, ) .
668
131 . 5
. 668 35
, 4 52
, .
131 112 (85%) 19 (15%).
, 107 24 .
, 60%
, 20% (
) .

.
,
. , 55
11
.

&
1991 , ,

HIV/AIDS, .

HIV/AIDS.

, 76, 1, 2014 496

 :
( & ,
- &
)
(
,
)
(
, ,
, ,
)
/-/
.

(5 )
: , ,
HIV/AIDS (15 )
Info Centre - (
)
(
, , - 13
)
Positive:
HIV/AIDS, (15 )
Internet-Site: HIV/AIDS (4 )


(17 )
:70

&
[

, 76, 1, 2014 497


-

PRAKSIS
PRAKSIS ( , &
)
,
. :



,



, , /,
, , , ,
, ,
, , , .
2 , & ,
. ,
.
&
.
PRAKSIS 1996 2
16 .
PRAKSIS ,
2007
aids.
, 2010 24
&
, .

, 76, 1, 2014 498

2010 HIV ,
PRAKSIS.
(rapid test)
20 .
2012 PRAKSIS
HIV .
-
HIV,
.
, ,

HIV
.
&
,
.
,


. , PRAKSIS

.

. 2009
,
HIV,
. ,

.
, & ids,
HIV.
HIV
, HIV
.

, 76, 1, 2014 499

Athens Checkpoint
Athens Checkpoint.
HIV
.
, HIV
. Athens Checkpoint
HIV,
. 45
15 , 15 15
. HIV
(western blot).
, ,
. rapid tests
0,1%.
:
HIV


PEP ( )

&
.
Athens Checkpoint 2.500
. AHF (AIDS
Healthcare Foundation).

HIV/AIDS
www.hiv.humanism.gr (blog )
www.hiv.gr (, , free
press10%)
www.hivaids.gr (
)
www.keelpno.gr & ()
www.thebody.com (HIV/AIDS resource)

, 76, 1, 2014 500

 www.cdc.gov Centers of Disease Control and Prevention (CDC)
www.eatg.org European AIDS Treatment Group (EATG)
www.who.int/hiv World Health Organization (WHO)
www.unaids.org UNAIDS

1. Bor R, Miller R & Perry L. A systems approach to AIDS counseling, Journal of
Family Therapy 1989, 11:77-86.
2. Miller R. & Bor R AIDS. A Guide to Clinical Counselling, 1989, London, Science
Press.
3. Van Dyk A. HIV Aids. Care & Counselling. A multidisciplinary approach, 2005,
South Africa, Pearson Education.
4. Vass A. AIDS. A plague in us, 1986, Venus Academica.
5. Walker G. In the Midst of Winter, 1991, London, W.W.Norton & Company.
6. & AIDS, HIV, 2011,
.

, 76, 1, 2014 501



.
, ,
, ...

:
T: 2132041829
E-mail: ioanniskoutsouv@yahoo.gr

.
.

,
.
(-
).
20 ,
,
.

.
,
,
.
,

,

..
,
,
, 76, 1, 2014 502
 ,


,


. , 76,
1, 502-503, 2014.
: , , .

, 76, 1, 2014 503



Dr. .
...

:
: 2132041824
E-mail: michaelvaslamatzis@gmail.com

, ,
.
6 > 6
,
, .
1932.
,
,
.
, ,
,
,
,
: )

, ) carcinoma in situ
, ) ,
.
: ) , , )
> 4
.


, 76, 1, 2014 504
 ,
.
,
,

. , ,
, .
, 76, 1, 504-575, 2014.
: , ,
, , , , ,

SUMMARY
VASLAMATZIS M.M. Multiple Primary Malignant Neoplasms in Cancer Patients.
Patients with malignant solid tumours may present with more than one primary lesion,
at the interval less than 6 months of the initial lesion [synchronous multiple primary
cancer (MPLC)] or may develop a second primary cancer, more than six months,
mainly, after the treatment of the primary cancer (metachronous MPLC). The criteria
for classifying a tumor as second primary malignancy have remained consistent since
they were first proposed in 1932. Second primary neoplasms, are a major cause of
mortality and serious morbidity among cancer survivors successfully cured of their first
cancer. Multiple etiologies may lead to a cancer survivor subsequently being
diagnosed with an second primary neoplasm including radiotherapy for the first
cancer, unhealthy lifestyle behaviors, genetic factors, aging, or an interaction between
any of these factors. Patients presenting with more than one malignant neoplastic
lesions at the same time must fulfill strict criteria to be classified as having
synchronous MPLC: a) Both lesions must be malignant and the second malignant
lesion must not represent a metastasis from the first lone, b) Different histology or
origin from a separate focus of carcinoma in situ and c) Same histology, but the
lesions are anatomically distinct. The second primary tumors are considered
metachronous if: a) The histology is different or b) They are the same histology and
there is a four year or greater interval between the cancers with no evidence of
systemic metastases. This systematic review, evaluates diagnostic criteria for multiple
primary tumours in cancer patients and updates on the current information regarding
mechanisms and risk of developing second primary malignancies in patients with solid

, 76, 1, 2014 505

tumors, with a particular focus on previous chemo or /and radiotherapy, smoking,
lifestyle, and environmental factors, clinical characteristics, pathological features,
staging procedures, molecular biology, genetics, treatment related factors, appropriate
screening and surveillance programs mainly at-high risk subpopulation. Many
systematic reviews and meta-analysis demonstrated that cancer survivors received
more frequent screening for second primary malignant neoplasms, than non-cancer
controls. Nosokomiaka Chronika, 76, Supplement 1, 504-575, 2014.
Key words: multiple primary malignant neoplasms, cancer, solid tumours, patients,
synchronous, metachronous, diagnosis, treatment, outcome

,
DNA
, (
) .
,
1,2
.
, ,
. Billroth 1889 3. , ,
, 1932 4:
1. , ,
.
2. 2 cm,
.
, 5 .
3. .
,
,
.
.
, 1.104.269 ,
10 1990,
0.734% - 11.7% 5. ,
,

, 76, 1, 2014 506

 2,6
19% 34%, .
,
7.

,
.

/
,
, .

2 .
,
(..
), ,
.
() (..
,
, ).

, ,
,
. ( )
/ (Standardized
Incidence Ratio)

.
/ [Standardized Incidence Ratio
(SIR)],
[Standardized Mortality Ratio] 8.
,
2
/
2 ..

, 76, 1, 2014 507

 Hodgkin /
.
(relative risk)
/ . SR
-. ,
- 5
.
,
.

,

.

,
,
,
9
() . SIR
/ (confidence interval)

Poisson 10.

SIR
(
) . : .
,
,
( 1),
( ).

.
,
, .

, 76, 1, 2014 508


- , -
, .


,
, .
1 .
,
, p1, p2,
pKA. :
k
= pi.IAi
i=1

p1, p2,pK, 1 , .

( )
pij, i= 1, k, j= 1, kB, o:

kB
p. = pij
j=1

k
p.j = pij
j=1

SIR .

(..


).

, 76, 1, 2014 509


.

.
,

.

. SIR
SIRB/A O


. :

SIRB/A = ijqijIBj / ijpijIBj

qij
k kB . :
10

qij = pij IAi / ijpij IAi --- , i=1, kA; j=1, kB

SIRB/A = ijpij IAiIBj (ijpij IAi) (ijpij IBj)- = 1 + K2AB,

K2AB
:

K2AB = -1 -1pij(Iai-)(j -)
ij

,
/
()
11
.

, 76, 1, 2014 510

 , field cancerization,
12.
,
, , ,

. , ,
,
, ,
,
glutathione S-transferases,
cytochrome P450, N-acetyl transferase
sulfotransferase.
, 2, 13.
,
14, 15
.
, 6
,
16.

PET/ CT SCANNING

PET / CT
,
/
. Li Ka Shing Faculty of Medicine, Hong
Kong 1/10/2009 30/9/2010 1522 PET / CT scans
.
7 ,
.
,
,
FDG , ,
. 7
, , 17.

, 76, 1, 2014 511


-
(,
, , ), ,
,
.
, , , (<6
18
, 6 ) . SIR 2.18 (95% CI,
19
2.15 - 2.21), .

,
.
EpsteinBarr human papilloma
20,21
.
, ,
, ,
,
22
. (
) ,
,
. ,
,
,
23
. field cancerization
, ,
,
19,24-27
. Cancer
Registry Taiwan, 1986 2008, , 9.996
93.891 (80010 , 13881 )
, 20-90 .
,
< > 6 ,
.
53.3 13.0 . (63.9
11.5) (49.8 12.7),

, 76, 1, 2014 512


5.3 .
2.71 3.95

57.33 12.59 .
,

(covariate analysis).

(Cox proportional
hazards model),
.
,
. Taiwan,
,
.
KaplanMeier,
(log-rank test <0.01) ,
. ,
(regression analysis),
(HR 2.59, CI 95%: 2.53 -
2.65) (HR 2.34, CI 95%: 2.28 - 2.40) ,
.
(39%),
, 11%.

(0.46 0.06) (0.37
0.05).
, ,
28
,

, , ,
.
, ,
, 29.

, 76, 1, 2014 513

 National Comprehensive Cancer Network (NCCN),
,
()
, , , ,
30
. ,
, , ,
(, , /
)
(.. EBV HPV) .
,
56.02 10.75 ,
63.5 12.71 28.
,
. H
,
,
,.
,
. , ,
,
.

31,32.
,
( ) .

,
.

4%
. ,
.
Lugol's iodine
, ( ),
, 33.

, 76, 1, 2014 514


,
, ,
,
34.

1.
, ,
,
35,36:
1. , .
2. , ,
.
3. .
4. , in situ.
5. .
6. ,
, (2 3)
, .


FDG-PET, ,
.
,
,
37,38
.
,
, () ,
,
39.

, .
, ,
, ,

, 76, 1, 2014 515

 .
1, ,
,
( )
1 .
2
, IV.

, ,
.

, .

, ,
,
, ,
FDG PET. ,
, ,
, ,
, .

(
) , ,
. ,

,
,
34, 40
PET scanning .
467
.
. van Rens MT et al,
5
41%, , 19%.

1,75 .

, 76, 1, 2014 516

 ,
(p<0.005).
Tanvetyanon T, et al 52
(95% CI, 45.6 - 63.7). 1 2
, 0 41-44.

, ,
:
1. ,
2. ,
3. .
,
,


45-48
.


, 246 (10-101
).
,
.
. 20 46 .
84% - 97%. grade
.
,
49-53
.
,
,
, 34.

2.

,

, 76, 1, 2014 517

 ,
34.
,
.
,
,
, 4
39. , ,
,
,
, 34.
,
, ,
.
58%
20%, 14%,
, 8% 54-
56.
, ,
.

,
(7th edition) TNM 57. :
1. ,
, 3
,
2. , ,
, 4
.
,

,
58.

, 76, 1, 2014 518



1% - 2% ,
59.
, 6% -
3.5
, . 13
7
60.
,
, , 48 .
2/3 , 39.

61
, .
,

,
,
(1.62/100
-) placebo (1.30/100 -), p = 0.29.
, .
30%, 24%
20%, , ,
62.
2/3
,
1/3 . ,
,
39
.
,
45
, < 3 cm .

, 61 .
5
10 51% 20% 43. , ,

, 76, 1, 2014 519

 161 , 5 61%,
. , >2 cm
.
29%.
( ) lower
forced expiratory volume in 1 second,
. ,
63
.
,
, .

,
.
Cisplatin, standard of care ,
.
,
, , ,
.
. ,
,
4 cm 64.
,
42
, .

, .

.

, ,
.

, 76, 1, 2014 520



, ,
65
.

, .

,
.
, .
1927
, 1951 - 2004.
, 152 169 .
1971 2009, 145
, 132 . 112
781
20
1075 .

(31 ), (26 )
(12 ). SIRs
13.7 (95% confidence interval 11.3-16.5).
,
,
66.

...
. ,
67
6.000 100.000 , 2006 .

, 76, 1, 2014 521

 68
, 1/100.000 ,
,
, ...
,
,
68-77
.
, ,
,
D,
78
. ,
, ,
, DNA
.

79.
,
, /
UV ,
. ,
..., ,
, D,
.
: , ,
D
, 80, 81.


> 10%
50% 82.
,
,
..., Nurses' Health Study (NHS) Health
Professionals' Follow-up Study (HPFS). ,
,
20 .

, 76, 1, 2014 522

 HPFS 46.237 1986
2008 (833496 - ), NHS, 107.339
1984 2008 (2.116.178 - ). 36.102
29.447
, . Cox
proportional hazard models [relative risks (RRs)]
95% [confidence intervals (CIs)].

, (RR = 1.11; 95% CI 1.051.18)
(RR = 1.20; 95% CI 1.151.25).
176 182 100,000 .

15% 26%
, ,
.
Bonferroni,


(RR = 1.99, 116/100.000 - )
(RR = 1.19,
87/100.000 - ), (RR = 1.32,
22/100.000 - ) (RR = 2.58,
79/100.000 - ). , UV-index,
79
, .
,
D ,
83
.
in situ
,
, ,
79
.

,
84
.
MC1R, NHS HPFS,

, 76, 1, 2014 523

 ,
,
85.

(RR = 17.0, 95% CI
14.419.8) ,
86

, 14
. (11/14) ,
RR 14.1
14.6 . ,

, .
,
, , ,
87
, .
,
88
. ,
,
DNA ,
89,90
.
nucleotide excision repair (NER)
DNA DNA.
DNA, , UV
, benzo(a)pyrene diolepoxide (BPDE)-DNA
. NER
,
, ,
,
77
. ,
DNA
, .
NER , .
91
, , ,

, 76, 1, 2014 524

 NER,
, ,
92
. DNA
,
,
.
DNA ,
93,94
. DNA

. ,
( )

DNA 95.
NER DNA, ,
UV
BPDE-DNA ,
,
NER .
NER,
,
.
.
,
.

96

, ..,
. UV
,
97
.
UV

, ,
98 99,100
. .

, 76, 1, 2014 525

UV ,
, 101.

1. Hodgkin

,
102
.
103,104
Hodgkin .
, ,
() non-Hodgkin lymphomas (NHL)
105-107
.
,

108,109:
1. ( ),
2.
3. ,
4.
, Hodgkin,
, ,
.

6q21 110.
11 , (
)
Hodgkin, :
1. 10 -80 ,
2. Non-Hodgkin lymphomas 3 35 ,
3. (, , , , ,
) > 2 .
, 40-
90/10000 , .
11-18% 15 , 20% 28% 20 25 ,

, 76, 1, 2014 526

109
. Hodgkins
5 10 ,
( ),
, 14
111-113
20 30 .
.
, , NHL
5, 7.3 12.2 , , Hodgkins
114
.
Hodgkin (HL), :
1. 2498 Stanford 1960 1995.
, , HL
1980 1995,
111.
2. 1319 HL, ,

(RR 6.1)
(RR 4.0).
, 111.
3. 5798 HL
1963 2001, RR

(RR 3.9),
(RR 2.0). ,
, NHL .
,
, ,
> 25 108.
,
Hodgkin
, .

Hodgkin.
(mechlorethamine, vincristine, procarbazine,
prednisone) .

, 76, 1, 2014 527

 2-3% 10-15
.
.
,

6%-9% 10-15 .
,
,
Hodgkin
,
10%-15% 40
. ,
,
40 .
Hodgkin mechlorethamine,
, .
, cyclophosphamide
mechlorethamine, chlorambucil, melphalan, lomustine
(CCNU) thiotepa .
, 5 / 7
. 50%
().

, ,
,
. , ,

. 15
Hodgkins, 0 0.6%
16.5%. .
.
40
.
Hodgkins, ,
:

, 76, 1, 2014 528


,
40 ,
( IV),
116, 117.
5
10 , , .
10,
117.
10 1990,
,
118
, topoisomerase II.
,
, 10 1990
119-121
.
Hodgkin ,
, ,
,
, .

109,116,117,122-127.
1. MOPP: 15 > 10%. > 6
MOPP MOPP, 20 60
3 5
6 MOPP.
mechlorethamine procarbazine,
.

mechlorethamine, chlorambucil,
, melphalan cyclophosphamide,
,
.
2. ABVD: 15 < 1%. ,
doxorubicin epipodophyllotoxins (teniposide, etoposide)
.

, 76, 1, 2014 529


10 1980, MOPP/ABVD MOPP
MOPP (2.1% 6.4%
Constine LS, et al., ).
3. BEACOPP: 5
BEACOPP COPP/ABVD (2.5%
0.6% 0.4%, ).
4. Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine,
bleomycin, etoposide, prednisone ):
256 .

epipodophyllotoxins
128,129
. 1

epipodophyllotoxins.
1994
, ,
217 Hodgkin
( .
,
).

67 (12-224) .
217 , 96(44.3%)
(41 MOPP, 37 MOPP/ABVD, 10 CMOPP 8 ClVPP).
43(19.8%) (MOPP +
20, MOPP/ABVD + 15 CMOPP ClVPP +
8). 19 .
10 : 8
70 Hodgkins, , NHL,
,,
.
2.4% 6 , 3.2% 10
130.

, 76, 1, 2014 530

 1. 2
epipodophyllotoxins.
Epipodophyllotoxins
Mechlorethamine, Procarbazine,

Ifosfamide, Cyclophosphamide, Etoposide, Teniposide

Nitrosureas
t(11q23), t(8;21), t(3;21),

-5, -7, del(5q), del(7q) inv(16), t(8;16), t(15;17),

t(9;22)
1% - >20% 2% - 12%
,
, ,
L-asparaginase,

, : p53, NF- CYP3A4

1, GSTT1
,



3-9 1-6


: 1, 2, 4, 5
FAB



>

HD, NHL, ,
, ,


,

RAS
: Felix CA. Chemotherapy- related second cancers. p. 137-164. Friedman DL and
Meadows AT. Pediatric tumors. p. 235-256. In: Neugat AI, Meadows AT, Robinson E.
Multiple Primary Cancers. Ed. Lippincott Williams & Wilkins. Philadelphia, Baltimore,
New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo, 1999.

1999
2 ,
2.
, ,

131.

, 76, 1, 2014 531

 2. 2
Hodgkin
/
(CI=95%)
85/27.1 3.1(2.6-3.7)
8/0.4 20.5(10.3-37.4)
22/0.8 25.9(17.6-37.2)
2/0.3 7.4(1.3-24.1)
53/29.9 1.8(1.4-2.3)
9/3.8 2.4(1.3-4.2)
... 6/3.8 1.6(0.7-3.2)
10/3.6 2.8(1.5-4.8)
4/0.2 20.0(6.9-46.8)
- 4/1.4 2.8(1.0-6.5)
2/0.8 2.5(0.4-8.2)
9/5.9 1.5(0.8-2.6)
2/0.5 4.0(0.7-13.1)
7/
= , = .
: Munker R, Grtzner S, Hiller E, et al. Second malignancies after Hodgkin's
disease: the Munich experience. Ann Hematol 1999, 78: 544-554.

, , ,
Mauch PM . 794 Hodgkins
-
1969 1988
(489 ) +
(305 ). 147
.
604 , 117,
44, 26
3.
/ ABVD.
114
10.7 . 2

3.

, 76, 1, 2014 532

 3. 2
Hodgkin Mauch PM .
/
(CI=95%)
72/12.9 5.6(4.4-7.0)
8/0.12 66.2(28.1-130.7)
10/0.54 18.4(8.6-33.8)
1/0.11 9.0(0.22-50.3)
53/11.3 4.76(3.6-6.1)
13/1.99 6.5(3.5-11.2)
... 10/2.03 4.9(2.3-9.1)
8/1.77 4.5(1.9-8.9)
6/0.13 44.5(16.3-97.3)
- 4/0.7 5.7(1.4-14.4)
3/0.74 4.1(0.8-11.9)
3/2.9 1.0(0.2-3.1)
6/1.1 5.6(2.1-12.3)
: Mauch PM, Kalish LA, Marcus KC, et al. Second malignancies after treatment for
laparotomy staged IA-IIIB Hodgkins disease: long-term analysis of risk factors and
outcome. Blood 1996, 87: 3625-3632.

, 1507
..., > 65.000
Hodgkin.

,
, . 14
10472
Hodgkin, 1940-1987. SIR
2 2.7 (
95%, 2.5-3.0), 24 ( 95%, 20-29),
NHL 5.6 ( 95%, 3.9-7.9).
2

(SIR =26,

, 76, 1, 2014 533

 95%, 14-45)
(SIR =12, 95%, 7.7-18).

, 14 (
95%, 5.6-35) procarbazine, chlorambucil, vinblastine
115
MOPP . 2
2000
1253 <40
14.1 . 137 2
19.4
( = 7.0, 95%, 5.9-8.3).
2 25 27.7%
132
. 2
4.9, 6.9 12.7 Hodgkin,
31-39 , 21-30 20 .

40 ,
40-49 ( 27.9, 4.2
, p=0.0001).
2
,

+ ( 9.4 4.7 , p=
0.004). ,
10000 20 ,
221
91% .
<16 2
40 .
114,133
17 458

,

. 109.

, 76, 1, 2014 534

,
HL 134.
HL non-
Hodgkin lymphoma (NHL), .
NHL, ,
132,135
HL 1.6% 15 ,
136
. HL
, 78%
137.

Hodgkin .
5 Hodgkin
, .
(8.1-34, ),
Netherlands Cancer Institute
NHL / (4.1% 4%, 20 ).
2 NHL 2
HL, .
2 NHL .
NHL,
,
,
.
HL 2
NHL, . NHL
HL, ,
... . NHL
Hodgkin :

HL.
, NHL
. British National
Lymphoma Investigation.
,
, .

, 76, 1, 2014 535

 HL,
. 1986,
NHL Hodgkin,
, Ebstein- Barr.
Ebstein - Barr
,
2
Hodgkin 115.
, International Database on Hodgkin's
Disease, 12.411 6.7 .
106 NHL
( 28.2 5 - 9 , 120
15 - 19 ). 15
138
: 45.4 5 - 9 .
NHL
HL
. 55.6 9.8,
139
. NHL
0.3% 3.8%
140.
NHL
10, Hodgkin
141.
Hodgkin Hodgkin
, 20
,
142.
HL,
50% - 66% , .
,
.
,
143
.
1.5 4.5
141,
12

, 76, 1, 2014 536

144, 145, 146, 147, 148
. 9% 13%,
15 - 20 18% - 26% 30 113.
148.
HL
, , ,
, , , ..., ,
, ,
, 109.
() HL () NHL
,

.
,
HL, ,
. , ,
5 20
146,149
. ,
de novo .
187
22.648 HL, 178.431 de
150
novo NSCLC . ,
/
151
.
NHL
HL 152.

1.5 114,151. 1 2/ 10000 HL
153, 13/ 10000 ... 114. HL,
30 16
,
. <20, 20 - 29, 30, 34, 22
154
3.5%, .
,
151,155
. 4 Gy,
, 3.2

, 76, 1, 2014 537

(95% CI: 1.4-8.2), <4 Gy,
.
156
40 Gy . MOPP,
, .
tamoxifen,
.
109
tamoxifen placebo .
, ,

157,158
.
, ,
(30 40 ) ,
150, 154
20% -25% .
, Surveillance, Epidemiology, and End Results (SEER),
2645 HL < 35
, 1973
2000 5 .
, , ,
(79%)
159
.
, ,
. MRI, ,
67%, 68%, 94% 94%, 93% 90%
, Harvard Medical School.
8 10 Hodgkin's
40 160.
American Cancer Society American College of Radiology Society for
Breast Imaging
10 30 , , MRI
161-163.
HL.
1 3/ 10.000 , ,
, 2% ,
,
Hodgkin's.

, 76, 1, 2014 538

 33 67 790
164
20 4 , .
, ,
, 109.
..., 6/ 10.000
, , , 10% ,
. ,
5
20 . ,
HL. HL
...
5519 HL,
...,
(RR = 3.3), l (RR = 1.7),
.
19.882 , 1953 2003.
89, 0.39% (95% CI 0.28% - 0.50%) 15
0.92% (95% CI 0.70% - 1.13%) 30 . ,

, procarbazine dacarbazine.
...,
...,
SEER. ,
. 209 HL
... ( 105 , 35 ,
30 , 21 18 )
484.165 ... 165-167.

HL, 2
. 2 4/ 10000
104,114.
HL
. 2567
. 5 HL.
18.1 , 13 (8

, 76, 1, 2014 539

, 5 ), 27.7 .
HL 26

3.5 / 10000 , .
, , HL 31
, 168.

.
2. Hodgkins

NHL 169, 170, 171, 172, 173.
Ewing
, 65 , 8
NHL, - ,
, IIA, (=1), International
prognostic index, 7 CHOP14 (cyclophosphamide,
hydroxydaunomycin hydrochloride, vincristine prednisolone), 2
colony-stimulating factor.
NHL.
Ewing , , , .
,
CD99. FISH 22q12.
EWS,
EWS-FLI1,
174
Ewing .
Ewing , , 80% <20
175
> 30 .
Ewing, , ,
176-185
, 20 .
Ewing, NHL,
,
176,183

. St Jude Children's
Research Hospital 6 11 183 <21 ,

, 76, 1, 2014 540

 ,
Ewing 183.

,
.
2.456 <60 , NHL,
British National Lymphoma Investigation
, 1973 2000. 123
. Relative risk (RR)
,
Ewing (RR = 1.3; 95% CI, 1.1 - 1.6), (RR = 8.8; 95% CI,
5.1 - 14.1) (RR = 1.6; 95% CI, 1.1 - 2.3).
, ,
.

(RR = 10.5; 95% CI, 5.0 -19.3) (RR
= 13.0; 95% CI, 5.2 - 26.7).
, : (RR =
1.9; 95% CI, 1.1 - 3.1) (RR = 2.1; 95% CI, 1.1 - 3.6), 172.
170
,
, NHL, .
/ ,
, (Standardized incidence ratios, /)
77.876
NHL, 1973 2001,
National Cancer Institute's Surveillance, Epidemiology, and End Results Program.
5638 ,
(O/E, 1.14; P < 0.001).

(RR = 1.04;
95% CI, 0.98-1.10; P = 0.21). ,
,
, , (P
< 0.05). HL < 25 ,

, 76, 1, 2014 541

( O/E, 2.1; P < 0.05,
O/E, 4.51, P < 0.05).
(O/E, 1.12 . 1.15,
). , NHL,

(O/E, 0.85; P < 0.05), < 25 ,
HL
( O/E, 2.1; P < 0.05,
O/E, 4.51, P < 0.05).

EWING
HL
Ewing, 12
Ewing, ,
. ,
,
,
176,178,181-183
.
Ewing, ,
, , topoisomerase II,
174.

,
,
186-
, ,
188
.

EGFR
KRAS
-

,

, ,

, 76, 1, 2014 542

 . EGFR
KRAS,
, ,
.
.
,
.
(EGFR)/RAS/RAF/MEK/MAPK
,
.
EGFR
KRAS,
status. 10/2002
3/2012, 205
, 98
107, . EGFR
IHC (immunohistochemistry / )
1+ ( ), 2+ ( ) 3+ (
). DNA
KRAS.

EGFR
KRAS .
, EGFR
KRAS. EGFR 140 167 (83.8%)
, KRAS 88,
205 (42.9%) .
, EGFR
(P = 0.028), (P <
0.001) (P < 0.001). KRAS
,
189.

, 76, 1, 2014 543


BARRETT

Barrett ,
190
30 . 10 ,
,
, Barrett 191.
,
192
1.4 .

, ,
2
.
,
, .
cyclooxygenase-2,

193
.
(aspirin sulindac)
.
PET-CT
, ,
, ,
194
(FOLFOX
FOLFIRI) 20%
195.

-



1.5
3 ... 196.

, 76, 1, 2014 544


,

, .
1.
-. ;
,
1.3/100.000
.
,

. ,
, .
Department of Surgery, KCVA Medical Center, Kansas City, MO, USA,
2006- 2011, 11
.

.
, ,

197.
2.

, 2013,
35
.
C. Department of
Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

. , ,
, 198.
3. GISTs

(Gastrointestinal stromal tumors, GISTs),
,

, 76, 1, 2014 545

 199
, 4.5% - 33%.
GISTs ,
, Carney.
GISTs
(47%), (9%), (7%), (6%),
(5%), (5%),
(3%), (3%), (2%),
(1%) (7%).
imatinib mesylate, 2002, FDA
. imatinib mesylate,
tyrosine kinase KIT,
BCR-ABL, ARG, PDGFR PDGFR.

,
GISTs imatinib , ,

. , ,
GISTs Imatinib
2002-2009,
7.07%, 1.15% (P=0.030) 1992-2001
200
.
(P=0.023)
imatinib.
,
Imatinib (P=0.030),
, Imatinib 201,202.
12/2001-12/2009,
10% GIST, imatinib
203.
4.

15
, 1.8% - 5%
204.
, 9% - 24%

, 76, 1, 2014 546


205, 206
.
,
,
,
.
,
.
,
, , ,

,
,
205-209
. , 50%
, ,
,
, 210,211.

31 37 , ,
/ 206,208.
, (> 65 ),
, ,
Helicobacter pylori,
,
()
212, 213, 214
.

, ,
. ,
78
10 207.
Korean Association of Internal Medicine Division of
Gastroenterology, Department of Internal Medicine, Presbyterian Medical Center,
Jeonju, 1/2008 12/2011 512 , 66 (23
211
90) , .

, 76, 1, 2014 547

 , ,
Moertel, : 1.
, 2. ,
3.
,
215
.
, ,

, . 15.6 (1 - 52)
, ,
66 (12.9%) 13 (2.5%)
. > 65
(p = 0.012). 2/3
,
.
,
, 31 ,
3%.
,
, ,
3
6 12 .
, ,
, , 211.

10 , ,
207, 210, 216, 217 217
. ,
,
10 .
, 10
211
, ,
10 ,
, > 65 ,
.

, 76, 1, 2014 548

 , ,
:
1. ,
15.6 .
,
.
2. , :
3. ,
( / piecemeal,
).
4. < 1 .
5.
, , .
5.


,
,
6% - 14%
218, 219
.
,
, , ,
. , ,
220
.

Moertel 215.
,
[endoscopic mucosal resection (EMR)],
[submucosal dissection (ESD)] ,
,
221,222
.
,
,
, ,
,

, 76, 1, 2014 549

 . ,
,
,
, ,
146 , 1194
.
1989 - 2008,
.
Brinkman [Brinkman Index (BI)]
223, 224
,
. ,
(BI < 400) (BI 400).
,
. < 22.8, 22.8-45.5 > 45.5 gr,
,
, .
, Fishers exact test Pearsons 2
test.
(Logistic regression analysis)
Kaplan-Meier.
, , ,
10.9% .
, :
(68.0 64.3 , P <
0.001), (81.5% 67.1%, P < 0.001), (P =
0.020) (P = 0.005).
,
(P = 0.046), (68.3%
55.5%), (P = 0.011),
(80.8% 64.6%, P < 0.001)
(P = 0.034).
, ,
,
, (P = 0.052, P = 0.347,
P = 0.595, P = 0.805, P = 0.559 P = 0.408, ).

, 76, 1, 2014 550

 , ,
, ,
, , Japanese
Classification of Gastric Carcinoma - 3rd English edition 225

(P = 0.052, P = 0.347, P = 0.595, P = 0.805, P = 0.559, P = 0.408 P =
0.200, ). 9
,

, (OR = 1.93,
95% CI: 1.27-2.99, P = 0.002) (OR = 1.86, 95% CI: 1.07-3.32, P = 0.028).
146 ,


.
219
.


226.
10 52%
227
.
1.5 3.5 ,
219, 228
Ras p53 .
, ,
, ,
, .


229, 230, 231 232
, ,
219
, ()
, .

,
, ,
, .
, 3 5

, 76, 1, 2014 551

 ( 90%), ,
219,233.

.
,
: 1. , 2
, 3.
: , .

, , 4. (
, ...)
, ,
( ) , 5.

,
, , 6.

,
, ,
( )

.
, ,
, ,
, , .
,
,
210
2.4% - 14% 5 .
233-235
.
,
,
,
235,236.
6.

, 76, 1, 2014 552


.
, ), ... (, ,
, ), ( ,
237-242
, ) .
,
243-246.
.
2013 70
247
, ,
243,248.
. ,
.
IV,
2013 247.

1. Vaslamatzis M, Alevizopoulos N, Petraki C, et al. Second primary neoplasms

(SPN) in cancer patients. 39th Annual Meeting of the American Society of Clinical
Oncology, (ASCO), Chicago, Illinois, 31 May 3 June 2003. Proceedings of
A.S.C.O.2003, Volume 22, page 891, No 3581.
2. Gupta A, Chauhan B, Rangarajan, et al. Oesophageal carcinoma presenting with
a synchronous asymptomatic colon carcinoma. Indian J Med Paediatr Oncol.
2013; 34(2):117120. doi: 10.4103/0971-5851.116202.
3. Billroth T. Die Allgemeine Chirurgische Pathologie and Therapie. In: Reimer G,
Editor. 51 Vorlesungen-Ein Handbuch fur Studierende and Artze. 14. xx. Vol. 8.
Berlin: Auflage; 1889. p. 712.
4. Warren S, Gates O. Multiple primary malignant tumors. A survey of the literature
and a statistical study. Am J Cancer 1932; 16:1358.
5. Demandante CG, Troyer DA, Miles TP. Multiple primary malignant neoplasms:
Case report and a comprehensive review of the literature. Am J Clin Oncol. 2003;
26:7983.
6. Koutsopoulos AV, Dambaki KI, Datseris G, et al. A novel combination of multiple
primary carcinomas: Urinary bladder transitional cell carcinoma, prostate
adenocarcinoma and small cell lung carcinoma: Report of a case and review of

, 76, 1, 2014 553

 the literature. World J Surg Oncol. 2005;3:51., Published online 2005 July 26. doi:
10.1186/1477-7819-3-51.
7. Artac M, Bozcuk H, Ozdogan M, et al. Different clinical features of primary and
secondary tumors in patients with multiple malignancies. Tumori. 2005; 91:317
320.
8. Breslow NE, Day NE. Statistical methods in cancer research. II. The design and
analysis of cohort studies. IARC Sci Publ 1987; 82:65-72.
9. Schoenberg BS, Myers MH. Statistical methods for studying multiple primary
malignant neoplasms. Cancer 1977; 40:1892-1898.
10. Begg CB. Methodological and statistical considerations in the study of multiple
primary cancers. p. 13-26. In Neugat AI, Meadows A, Robinson E. Multiple
Primary Cancers. Ed. Lippincott Williams & Wilkins. Philadelphia, Baltimore, New
York, London, Buenos Aires, Hong Kong, Sydney, Tokyo, 1999.
11. Hemminki K, Boffetta P. Multiple primary cancers as clues to environmental and
heritable causes of cancer and mechanisms of carcinogenesis. IARC Sci Publ.
2004; 157:289297.
12. Carey TE. Field cancerization: Are multiple primary cancers monoclonal or
polyclonal? Ann Med. 1996; 28:183188.
13. Kotnis A, Kannan S, Sarin R, Mulherkar R. Case-control study and meta-analysis
of SULT1A1 Arg213His polymorphism for gene, ethnicity and environment
interaction for cancer risk. Br J Cancer. 2008; 99:13401347.
14. Aydiner A, Karadeniz A, Uygun K, et al. Multiple primary neoplasms at a single
institution: Differences between synchronous and metachronous neoplasms. Am J
Clin Oncol. 2000; 23:364370.
15. Luciani A, Balducci L. Multiple primary malignancies. Semin Oncol. 2004; 31:264
273.
16. Kilciksiz S, Gokce T, Baloglu A, et al. Characteristics of synchronous- and
metachronous-type multiple primary neoplasms: A study of hospital-based cancer
registry in Turkey. Clin Genitourin Cancer. 2007; 5:438445.
17. Chun-Sing W, Nan-Jie G, Yiu-Ching C. Prevalence of synchronous second
primary malignancy: identification using whole body PET/CT imaging. Clin
Imaging. 2013 Nov 6. pii: S0899-7071(13)00229-5. doi:
10.1016/j.clinimag.2013.09.001. [Epub ahead of print]].

, 76, 1, 2014 554

18. Samant S, Posner MR, Brockstein BE, et al. Second primary malignancies in
patients with head and neck cancers. www.Uptodate.com. Literature review
current through: Nov 2013. |This topic last updated: v 27, 2012.]
19. Morris LGT, Sikora AG, Patel SG, et al. Second Primary Cancers After an Index
Head and Neck Cancer: Subsite-Specific Trends in the Era of Human
PapillomavirusAssociated Oropharyngeal Cancer. J Clin Oncol 2011; 29:739
746.
20. Raab-Traub N. Epstein-Barr virus in the pathogenesis of NPC. Semin Cancer Biol
2002; 12:431441.
21. Forte T, Niu J, Lockwood GA, Bryant HE. Incidence trends in head and neck
cancers and human papillomavirus (HPV)-associated oropharyngeal cancer in
Canada, 19922009. Cancer Causes Control 2012; 23:13431348.
22. Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet
2008; 371:16951709.
23. van der Schroeff MP, van de Schans SA, Piccirillo JF, et al. Conditional relative
survival in head and neck squamous cell carcinoma: Permanent excess mortality
risk for long-term survivors. Head Neck 2010; 32:16131618.
24. van Oijen MG, Slootweg PJ. Oral field cancerization: carcinogen-induced
independent events or micrometastatic deposits? Cancer Epidemiol Biomarkers
Prev 2000; 9:249256.
25. Chen MC, Chen PT, Chan CH, et al. Second primary esophageal or lung cancer
in patients with head and neck carcinoma in Taiwan: incidence and risk in relation
to primary index tumor site. J Cancer Res Clin Oncol 2011; 137:115123.
26. Morris LG, Sikora AG, Hayes RB, et al. Anatomic sites at elevated risk of second
primary cancer after an index head and neck cancer. Cancer Causes Control
2011; 22:671679.
27. Chen PT, Kuan FC, Huang CE, et al. Incidence and patterns of second primary
malignancies following oral cavity cancers in a prevalent area of betel-nut
chewing: a population-based cohort of 26,166 patients in Taiwan. Jpn J Clin Oncol
2011; 41:13361343.
28. Liao LJ, Chou HW, Wang CT, et al. The Impact of Second Primary Malignancies
on Head and Neck Cancer Survivors: A Nationwide Cohort Study. PLoS One.
2013;8(4):e62116. Published online 2013 April 16. doi:
10.1371/journal.pone.0062116. PMCID: PMC3628575.

, 76, 1, 2014 555

29. Chung CS, Lee YC, Wang CP, et al. Secondary prevention of esophageal
squamous cell carcinoma in areas where smoking, alcohol, and betel quid
chewing are prevalent. J Formos Med Assoc 2010; 408421.
30. Pfister DG, Ang K, Brockstein B, et al. NCCN Practice Guidelines for Head and
Neck Cancers. Oncology 2000; 14:163194.
31. Stewart FA. Re-treatment after full-course radiotherapy: is it a viable option? Acta
Oncol 1999; 38(7):855-862.
32. Duprez F, Madani I, Bonte K, et al. Intensity-modulated radiotherapy for recurrent
and second primary head and neck cancer in previously irradiated territory.
Radiother Oncol 2009; 93(3):563-569. doi: 10.1016/j.radonc.2009.10.012. Epub
2009 Nov 16.
33. Dulguerov N, Dulguerov P. The indication of panendoscopy in the search for
synchronous and metachronous head and neck cancer. Rev Med Suisse. 2013;
9(400):1770, 1772-1774.
34. Thomas E. Stinchcombe TE, Carr S, Loo BW Jr., et al. Multiple primary lung
cancers. www.uptodate.com. This topic last updated: v 13, 2013.
35. Kozower BD, Larner JM, Detterbeck FC, Jones DR. Special treatment issues in
non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed:
American College of Chest Physicians evidence-based clinical practice guidelines.
Chest 2013; 143(5 Suppl):e369S-399S. doi: 10.1378/chest.12-2362.
36. NCCN Guidlines Version 1.2014 Non-Small Cell Lung Cancer
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
37. Detterbeck FC, Jantz MA, Wallace M, et al. Invasive mediastinal staging of lung
cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest.
2007 Sep;132(3 Suppl):202S-220S.
38. De Leyn P, Lardinois D, Van Schil P, et al. European trends in preoperative and
intraoperative nodal staging: ESTS guidelines. J Thorac Oncol 2007; 2(4):357-
361.
39. Shen KR, Meyers BF, Larner JM, et al. Special treatment issues in lung cancer:
ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;
132:290S - 305S.
40. Finley DJ, Yoshizawa A, Travis W, et al. Predictors of outcomes after surgical
treatment of synchronous primary lung cancers. J Thorac Oncol. 2010;5(2):197-
205. doi: 10.1097/JTO.0b013e3181c814c5; 5:197.

, 76, 1, 2014 556

41. Rosengart TK, Martini N, Ghosn P, Burt M. Multiple primary lung carcinomas:
prognosis and treatment. Ann Thorac Surg 1991; 52(4):773-778; discussion 778-
779.
42. van Rens MT, Zanen P, Brutel de La Rivire A, et al. Survival in synchronous vs.
single lung cancer: upstaging better reflects prognosis. Chest. 2000; 118(4):952-
958.
43. Rea F, Zuin A, Callegaro D, et al. Surgical results for multiple primary lung
cancers. Eur J Cardiothorac Surg 2001; 20(3):489-495.
44. Tanvetyanon T, Finley DJ, Fabian T, et al. Prognostic factors for survival after
complete resections of synchronous lung cancers in multiple lobes: pooled
analysis based on individual patient data. Ann Oncol 2013; 24(4):889-894. doi:
10.1093/annonc/mds495. Epub 2012 Nov 7.
45. Carr SR, Schuchert MJ, Pennathur A, et al. Impact of tumor size on outcomes
after anatomic lung resection for stage 1A non-small cell lung cancer based on the
current staging system. J Thorac Cardiovasc Surg 2012; 143(2):390-397. Epub
2011 Dec 9.
46. Shirvani SM, Jiang J, Chang JY, et al. Comparative effectiveness of 5 treatment
strategies for early-stage non-small cell lung cancer in the elderly. Int J Radiat
Oncol Biol Phys 2012; 84(5):1060-1070. doi: 10.1016/j.ijrobp.2012.07.2354. Epub
2012 Sep 11.
47. Haasbeek CJ, Palma D, Visser O, et al. Early-stage lung cancer in elderly
patients: a population-based study of changes in treatment patterns and survival
in the Netherlands. Ann Oncol 2012; 23(10):2743-2747. Epub 2012 May 2.
48. Dupuy DE. Treatment of medically inoperable non-small-cell lung cancer with
stereotactic body radiation therapy versus image-guided tumor ablation: can
interventional radiology compete? J Vasc Interv Radiol 2013; 24(8):1139-1145.
Epub 2013 Jun 21.
49. Sinha B, McGarry RC. Stereotactic body radiotherapy for bilateral primary lung
cancers: the Indiana University experience. Int J Radiat Oncol Biol Phys 2006;
66(6):1120-1124.
50. Matthiesen C, Thompson JS, De La Fuente Herman T, et al. Use of stereotactic
body radiation therapy for medically inoperable multiple primary lung cancer. J
Med Imaging Radiat Oncol 2012; 56(5):561-566.

, 76, 1, 2014 557

51. Creach KM, El Naqa I, Bradley JD, et al. Dosimetric predictors of chest wall pain
after lung stereotactic body radiotherapy. Radiother Oncol 2012; 104(1):23-27.
Epub 2012 Mar 3.
52. Griffioen GH, Lagerwaard FJ, Haasbeek CJ, et al. Treatment of multiple primary
lung cancers using stereotactic radiotherapy, either with or without surgery.
Radiother Oncol 2013; 107(3):403-408. Epub 2013 Jun 6.
53. Chang JY, Liu YH, Zhu Z, et al. Stereotactic ablative radiotherapy: a potentially
curable approach to early stage multiple primary lung cancer. Cancer 2013;
119(18):3402-3410. doi: 10.1002/cncr.28217. Epub 2013 Jun 24.
54. Wakelee HA, Bernardo P, Johnson DH, Schiller JH. Changes in the natural history
of nonsmall cell lung cancer (NSCLC)--comparison of outcomes and
characteristics in patients with advanced NSCLC entered in Eastern Cooperative
Oncology Group trials before and after 1990. Cancer 2006; 106(10):2208-2217.
55. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell
lung cancer in the United States over the last 30 years: analysis of the
surveillance, epidemiologic, and end results database. J Clin Oncol 2006;
24(28):4539-4544.
56. Nakamura H, Saji H. A worldwide trend of increasing primary adenocarcinoma of
the lung. Surg Today 2013, Jun 11. [Epub ahead of print].
57. Goldstraw P. The 7th Edition of TNM in Lung Cancer: what now? J Thorac Oncol
2009; 4(6):671-673.
58. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study
of Lung Cancer/American Thoracic Society/European Respiratory Society:
international multidisciplinary classification of lung adenocarcinoma: executive
summary. Proc Am Thorac Soc 2011;8(5):381-385. doi: 10.1513/pats.201107-
042ST.
59. Lou F, Huang J, Sima CS, et al. Patterns of recurrence and second primary lung
cancer in early-stage lung cancer survivors followed with routine computed
tomography surveillance. J Thorac Cardiovasc Surg 2013; 145(1):75-81;
discussion 81-82. Epub 2012 Nov 3.
60. Tucker MA, Murray N, Shaw EG, et al. Second primary cancers related to
smoking and treatment of small-cell lung cancer. Lung Cancer Working Cadre. J
Natl Cancer Inst 1997; 89(23):1782-1788.
61. Dijkman BG, Schuurbiers OC, Vriens D, et al. The role of (18)F-FDG PET in the
differentiation between lung metastases and synchronous second primary lung

, 76, 1, 2014 558

 tumours. Eur J Nucl Med Mol Imaging 2010; 2010; 37(11):2037-47. 20doi:
10.1007/s00259-010-1505-2. Epub 2010 Jun 10.
62. Karp DD, Lee SJ, Keller SM, et al. Randomized, Double-Blind, Placebo-
Controlled, Phase III Chemoprevention Trial of Selenium Supplementation in
Patients With Resected Stage I Non-Small-Cell Lung Cancer: ECOG 5597. J Clin
Oncol 2013; 31(33):4179-4187. doi: 10.1200/JCO.2013.49.2173. Epub 2013 Sep
3.
63. Hamaji M, Allen MS, Cassivi SD, et al. Surgical treatment of metachronous
second primary lung cancer after complete resection of non-small cell lung cancer.
J Thorac Cardiovasc Surg 2013; 145(3):683-690; discussion 690-691.145:683.
64. ... (Adjuvant)
: ?
,
, 13-16 2010, . 118-123.
65. https://subscriptions.nccn.org/gl_login.aspx?ReturnURL=http://www.nccn.org/prof
essionals/physician_gls/pdf/nscl.pdf-accessed 3/21/2013. (Accessed on March 21,
2013.
66. MacCarthy A, Bayne AM, Brownbill PA, et al. Second and subsequent tumours
among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer.
2013; 108(12):2455-2463. doi: 10.1038/bjc.2013.228. Epub 2013 May 14.
67. Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, et al.
Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch
Dermatol 2010; 146: 283287.
68. Lewis KG, Weinstock MA. Trends in nonmelanoma skin cancer mortality rates in
the United States, 1969 through 2000. J Invest Dermatol 2007; 127:23232327.
69. Frisch M, Melbye M. New primary cancers after squamous cell skin cancer. Am J
Epidemiol 1995;141:916922
70. Frisch M, Hjalgrim H, Olsen JH, Melbye M. Risk for subsequent cancer after
diagnosis of basal-cell carcinoma. A population-based, epidemiologic study. Ann
Intern Med 1996; 125:815821.
71. Wassberg C, Thorn M, Yuen J, et al. Second primary cancers in patients with
squamous cell carcinoma of the skin: a population-based study in Sweden. Int J
Cancer 1999; 80:511515.

, 76, 1, 2014 559

72. Milan T, Pukkala E, Verkasalo PK, et al. Subsequent primary cancers after basal-
cell carcinoma: a nationwide study in Finland from 1953 to 1995. Int J Cancer
2000; 87:283288.
73. Hemminki K, Dong C. Subsequent cancers after in situ and invasive squamous
cell carcinoma of the skin. Arch Dermatol 2000; 136:647651.
74. Troyanova P, Danon S, Ivanova T. Nonmelanoma skin cancers and risk of
subsequent malignancies: a cancer registry-based study in Bulgaria. Neoplasma
2002; 49:8185.
75. Nugent Z, Demers AA, Wiseman MC, et al. Risk of second primary cancer and
death following a diagnosis of nonmelanoma skin cancer. Cancer Epidemiol
Biomarkers Prev 2005; 14:25842590.
76. Chen J, Ruczinski I, Jorgensen TJ, et al. Nonmelanoma skin cancer and risk for
subsequent malignancy. J Natl Cancer Inst 2008; 100:12151222.
77. Song F, Qureshi AA, Edward L. Giovannucci EL, et al. Risk of a Second Primary
Cancer after Non-melanoma Skin Cancer in White Men and Women: A
Prospective Cohort Study. PLoS Med. 2013; 10(4):e1001433. Published online
2013 April 23. doi: 10.1371/journal.pmed.1001433 PMCID: PMC3635863.
78. Garland CF, Garland FC, Gorham ED, et al. The role of vitamin D in cancer
prevention. Am J Public Health 2006; 96:252261.
79. Song F, Qureshi AA, Edward L. Giovannucci EL, et al. Risk of a Second Primary
Cancer after Non-melanoma Skin Cancer in White Men and Women: A
Prospective Cohort Study. PLoS Med. 2013; 10(4):e1001433. Published online
2013 April 23. doi: 10.1371/journal.pmed.1001433 PMCID: PMC3635863.
80. Tuohimaa P, Pukkala E, Scelo G, et al. Does solar exposure, as indicated by the
non-melanoma skin cancers, protect from solid cancers: vitamin D as a possible
explanation. Eur J Cancer 2007; 43:17011712.
81. Grant WB. Re: Nonmelanoma skin cancer and risk for subsequent malignancy. J
Natl Cancer Inst 2009; 101:210; author reply 210211.
82. Wheless L, Black J, Alberg AJ. Nonmelanoma skin cancer and the risk of second
primary cancers: a systematic review. Cancer Epidemiol Biomarkers Prev 2010;
19:16861695.
83. Ma Y, Zhang P, Wang F, et al. Association between vitamin D and risk of
colorectal cancer: a systematic review of prospective studies. J Clin Oncol 2011;
29:37753782.

, 76, 1, 2014 560

84. Kahn HS, Tatham LM, Patel AV, et al. Increased cancer mortality following a
history of nonmelanoma skin cancer. JAMA 1998; 280:910912.
85. Nan H, Xu M, Kraft P, et al. Genome-wide association study identifies novel
alleles associated with risk of cutaneous basal cell carcinoma and squamous cell
carcinoma. Hum Mol Genet 2011; 20:37183724.
86. Royle JA, Baade PD, Joske D, et al. Second cancer incidence and cancer
mortality among chronic lymphocytic leukaemia patients: a population-based
study. Br J Cancer 2011; 105:10761081.
87. Hemminki K, Jiang Y, Steineck G. Skin cancer and non-Hodgkin's lymphoma as
second malignancies. Markers of impaired immune function? Eur J Cancer 2003;
39:223229.
88. Stacey SN, Sulem P, Jonasdottir A, et al. A germline variant in the TP53
polyadenylation signal confers cancer susceptibility. Nat Genet 2011; 43:1098
1103.
89. Li C, Wang LE, Wei Q. DNA repair phenotype and cancer susceptibilitya mini
review. Int J Cancer 2009; 124:9991007.
90. Rastogi RP, Richa, Kumar A, et al. Molecular mechanisms of ultraviolet radiation-
induced DNA damage and repair. J Nucleic Acids 2010: 592980, 32 pages.
91. Mitchell D, Paniker L, Godar D. Nucleotide excision repair is reduced in oral
epithelial tissues compared with skin. Photochem Photobiol 2012; 88:10271032.
92. Gospodinov A, Ivanov R, Anachkova B, Russev G .Nucleotide excision repair
rates in rat tissues. Eur J Biochem 2003; 270:10001005.
93. Welcsh PL, Schubert EL, King MC. Inherited breast cancer: an emerging picture.
Clin Genet 1998; 54:447458.
94. Scully R, Livingston DM. In search of the tumour-suppressor functions of BRCA1
and BRCA2. Nature 2000; 408:429432.
95. Kitagishi Y, Kobayashi M, Matsuda S. Defective DNA repair systems and the
development of breast and prostate cancer (Review). Int J Oncol 2012; 42(1):29-
34. doi: 10.3892/ijo.2012.1696. Epub 2012 Nov 14. Review. PMID: 23151935
96. Finn OJ. Immuno-oncology: understanding the function and dysfunction of the
immune system in cancer. Ann Oncol 2012; 23 Suppl 8:viii69.
97. Cramer DW, Finn OJ. Epidemiologic perspective on immune-surveillance in
cancer. Curr Opin Immunol 2011; 23:265271.
98. Narayanan DL, Saladi RN, Fox JL. Ultraviolet radiation and skin cancer. Int J
Dermatol 2010; 49:978986.

, 76, 1, 2014 561

99. Welsh MM, Karagas MR, Applebaum KM, et al. A role for ultraviolet radiation
immunosuppression in non-melanoma skin cancer as evidenced by gene-
environment interactions. Carcinogenesis 2008; 29:19501954.
100. Murphy GM. Ultraviolet radiation and immunosuppression. Br J Dermatol
2009;161(Suppl 3):9095.
101. Schwarz T, Schwarz A. Molecular mechanisms of ultraviolet radiation-induced
immunosuppression. Eur J Cell Biol 2011; 90:560564.
102. Travis LB. The epidemiology of second primary cancers. Cancer Epidemiol
Biomarkers Prev 2006; 15:2020-2026.
103. Hancock SL, Tucker MA, Hoppe RT, et al. Breast cancer after treatment of
Hodgkin's disease. J Natl Cancer Inst 1993; 85:25-31.
104. Bhatia S, Robinson LL, Oberlin O, et al. Breast cancer and other second
neoplasms after childhood Hodgkin's disease. N Engl J Med 1996; 334:745-751.
105. Arseneau JC, Sponzo RW, Levin DL, et al. Nonlymphomatous malignant tumors
complicating Hodgkin's disease. Possible association with intensive therapy. N
Engl J Med 1972; 287(22):1119-1122.
106. Bonadonna G, De Lena M, Banfi A, Lattuada A. Secondary neoplasms in
malignant lymphomas after intensive therapy. N Engl J Med 1973; 288(23):1242-
1243.
107. Canellos GP, Arseneau JC, DeVita VT, et al. Second malignancies complicating
Hodgkin's disease in remission. Lancet 1975; 1(7913):947-949.
108. Swerdlow AJ, Higgins CD, Smith P, et al. Second cancer risk after chemotherapy
for Hodgkin's lymphoma: a collaborative British cohort study. J Clin Oncol 2011;
29(31):4096-4104. doi: 10.1200/JCO.2011.34.8268. Epub 2011 Oct 3).
109. Mauch PM, Freedman A, Connor RF. Second malignancies after treatment of
classical Hodgkin lymphoma: www.uptodate.com. This topic last updated: t 10,
2013.).
110. Best T, Li D, Skol AD, et al. Variants at 6q21 implicate PRDM1 in the etiology of
therapy-induced second malignancies after Hodgkin's lymphoma. Nat Med 2011;
17(8):941-943. doi: 10.1038/nm.2407.
111. Ng AK, Bernardo MP, Weller E, et al. Long-term survival and competing causes of
death in patients with early-stage Hodgkin's disease treated at age 50 or younger.
J Clin Oncol 2002; 20(8):2101-2108.

, 76, 1, 2014 562

112. Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al. Long-term cause-
specific mortality of patients treated for Hodgkin's disease. J Clin Oncol 2003;
21(18):3431-3439. Epub 2003 Jul 28.
113. Hodgson DC, Gilbert ES, Dores GM, et al. Long-term solid cancer risk among 5-
year survivors of Hodgkin's lymphoma. J Clin Oncol 2007; 25(12):1489-1497.
Epub 2007 Mar 19.
114. Mauch PM, Kalish LA, Marcus KC, et al. Second malignancies after treatment for
laparotomy staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors
and outcome. Blood 1996; 87(9):3625-3632.
115. , . .
Hodgkin. : 2000.
: , 2000, . 133-197.
116. Delwail V, Jais JP, Colonna P, Andrieu JM. Fifteen-year secondary leukaemia risk
observed in 761 patients with Hodgkin's disease prospectively treated by MOPP
or ABVD chemotherapy plus high-dose irradiation. Br J Haematol 2002;
118(1):189-194.
117. Schonfeld SJ, Gilbert ES, Dores GM, et al. Acute myeloid leukemia following
Hodgkin lymphoma: a population-based study of 35,511 patients. J Natl Cancer
Inst 2006; 98(3):215-218.
118. Kobayashi Y, Hayashi Y, Ozawa K, Asano S. HRX gene rearrangement in
secondary acute lymphoblastic leukemia. Leuk Lymphoma 1995; 17:391-399.
119. Pedersen-Bjergaard J, Philip P, Larsen SO, et al. Therapy-related myelodysplasia
and acute myeloid leukemia. Cytogenetic characteristics of 115 consecutive cases
and risk in seven cohorts of patients treated intensively for malignant diseases in
the Copenhagen series. Leukemia 1993; 7:1975-1986.
120. Quesel B, Kantarjian H, Bjergaard JP, et al. Therapy-related acute myeloid
leukemia with t(8;21), inv(16), and t(8;16). A report on 25 cases and review of the
literature. J Clin Oncol 1993; 11:2370-2379.
121. Pui CH, Relling MV, Rivera GK, et al. Epipodophyllotoxin-related acute myeloid
leukemia. A study of 35 cases. Leukemia 1995; 9:1990-1996.
122. Canellos GP. Can MOPP be replaced in the treatment of advanced Hodgkin's
disease? Semin Oncol 1990; 17(1 Suppl 2):2-6.
123. Devereux S, Selassie TG, Vaughan Hudson G, et al. Leukaemia complicating
treatment for Hodgkin's disease: the experience of the British National Lymphoma
Investigation. BMJ 1990; 301(6760):1077-1080.

, 76, 1, 2014 563

124. Sandoval C, Pui CH, Bowman LC, et al. Secondary acute myeloid leukemia in
children previously treated with alkylating agents, intercalating topoisomerase II
inhibitors, and irradiation. J Clin Oncol 1993; 11(6):1039-1045.
125. Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose
BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's
disease. N Engl J Med 2003; 348(24):2386-2395.
126. Constine LS, Tarbell N, Hudson MM, et al. Subsequent malignancies in children
treated for Hodgkin's disease: associations with gender and radiation dose. Int J
Radiat Oncol Biol Phys 2008; 72(1):24-33. doi: 10.1016/j.ijrobp.2008.04.067.
127. Koontz MZ, Horning SJ, Balise R, et al. Risk of therapy-related secondary
leukemia in Hodgkin lymphoma: the Stanford University experience over three
generations of clinical trials. J Clin Oncol 2013; 31(5):592-8. doi:
10.1200/JCO.2012.44.5791. Epub 2013 Jan 7, Mauch PM, Freedman A, Connor
RF. Second malignancies after treatment of classical Hodgkin lymphoma:
www.uptodate.com. This topic last updated: ct 10, 2013.
128. Felix CA. Chemotherapy- related second cancers. p. 137-164. In: Neugat AI,
Meadows AT, Robinson E. Multiple Primary Cancers. Ed. Lippincott Williams &
Wilkins. Philadelphia, Baltimore, New York, London, Buenos Aires, Hong Kong,
Sydney, Tokyo, 1999.
129. Friedman DL and Meadows AT. Pediatric tumors. p. 235-256. In: Neugat AI,
Meadows AT, Robinson E. Multiple Primary Cancers. Ed. Lippincott Williams &
Wilkins. Philadelphia, Baltimore, New York, London, Buenos Aires, Hong Kong,
Sydney, Tokyo, 1999.
130. Economopoulos Th, Stathakis N, Alexopoulos C, et al. Second malignancies
following treatment for Hodgkins disease: A Greek experience. Haematologica
1994;79:273-276.
131. Munker R, Grtzner S, Hiller E, et al. Second malignancies after Hodgkin's
disease: the Munich experience. Ann Hematol 1999; 78:544-554.
132. van Leeuwen FE, Klokman WJ, vant Veer MB, et al. Long-term risk of second
malignancy in survivors of Hodgkins disease treated during adolescence or young
adulthood. J Clin Oncol 2000; 18:487-497.
133. Sankila R, Garwicz S, Olsen JH, et al. Risk of subsequent malignant neoplasms
among 1641 Hodgkins disease patients diagnosed in childhood and adolescence:
a population-based cohort study in the five Nordic countries-Association of the

, 76, 1, 2014 564

 Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and
Oncology. J Clin Oncol 1996; 1442-1446.
134. van Leeuwen FE, Chorus AM, van den Belt-Dusebout AW, et al. Leukemia risk
following Hodgkin's disease: relation to cumulative dose of alkylating agents,
treatment with teniposide combinations, number of episodes of chemotherapy,
and bone marrow damage. J Clin Oncol 1994; 12(5):1063-1073.
135. Tucker MA, Coleman CN, Cox RS, et al. Risk of second cancers after treatment
for Hodgkin's disease. N Engl J Med 1988; 318(2):76-81.
136. Swerdlow AJ, Douglas AJ, Hudson GV, et al. Risk of second primary cancers after
Hodgkin's disease by type of treatment: analysis of 2846 patients in the British
National Lymphoma Investigation. BMJ 1992; 304(6835):1137-1143.
137. Rueffer U, Josting A, Franklin J, et al. Non-Hodgkin's lymphoma after primary
Hodgkin's disease in the German Hodgkin's Lymphoma Study Group: incidence,
treatment, and prognosis. J Clin Oncol 2001; 19(7):2026-2032.
138. Henry-Amar M. Second cancer after the treatment for Hodgkin's disease: a report
from the International Database on Hodgkin's Disease. Ann Oncol 1992; 3(Suppl
4):117-128.
139. Swerdlow AJ, Douglas AJ, Vaughan Hudson G, et al. Risk of second primary
cancer after Hodgkin's disease in patients in the British National Lymphoma
Investigation: relationships to host factors, histology and stage of Hodgkin's
disease, and splenectomy. Br J Cancer 1993; 68(5):1006-1011.
140. Bennett MH, MacLennan KA, Vaughan Hudson G, Vaughan Hudson B. Non-
Hodgkin's lymphoma arising in patients treated for Hodgkin's disease in the BNLI:
a 20-year experience. British National Lymphoma Investigation. Ann Oncol 1991;
2(Suppl 2):83-92.
141. Zarate-Osorno A, Medeiros LJ, Longo DL, Jaffe ES. Non-Hodgkin's lymphomas
arising in patients successfully treated for Hodgkin's disease. A clinical, histologic,
and immunophenotypic study of 14 cases. Am J Surg Pathol 1992; 16(9):885-895.
142. , , , , ,
. Hodgkin Hodgkin
. 8
. 1
1992. , .5, 7.
143. Nyandoto P, Muhonen T, Joensuu H. Second cancer among long-term survivors
from Hodgkin's disease. Int J Radiat Oncol Biol Phys 1998; 42(2):373-378.

, 76, 1, 2014 565

144. Rodriguez MA, Fuller LM, Zimmerman SO, et al. Hodgkin's disease: study of
treatment intensities and incidences of second malignancies. Ann Oncol 1993;
4(2):125-131.
145. Biti G, Cellai E, Magrini SM, et al. Second solid tumors and leukemia after
treatment for Hodgkin's disease: an analysis of 1121 patients from a single
institution. Int J Radiat Oncol Biol Phys 1994; 29(1):25-31.
146. Foss Abrahamsen A, Andersen A, Nome O, et al. Long-term risk of second
malignancy after treatment of Hodgkin's disease: the influence of treatment, age
and follow-up time. Ann Oncol 2002; 13(11):1786-1791.
147. Pulte D, Gondos A, Brenner H. Long-term survival of patients diagnosed with non-
Hodgkin lymphoma after a previous malignancy. Leuk Lymphoma 2009;
50(2):179-186. doi: 10.1080/10428190802645061.
148. Castellino SM, Geiger AM, Mertens AC, et al. Morbidity and mortality in long-term
survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor
Study. Blood 2011; 117(6):1806-1816. doi: 10.1182/blood-2010-04-278796. Epub
2010 Oct 29.
149. van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiotherapy and
smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 1995;
87(20):1530-1537.
150. Milano MT, Li H, Constine LS, Travis LB. Survival after second primary lung
cancer: a population-based study of 187 Hodgkin lymphoma patients. Cancer
2011; 117(24):5538-5547. doi: 10.1002/cncr.26257. Epub 2011 Jun 20.
151. De Bruin ML, Sparidans J, van't Veer MB, et al. Breast cancer risk in female
survivors of Hodgkin's lymphoma: lower risk after smaller radiation volumes. J Clin
Oncol 2009; 27(26):4239-4246. doi: 10.1200/JCO.2008.19.9174. Epub 2009 Aug
10.
152. Swerdlow AJ, Barber JA, Hudson GV, et al. Risk of second malignancy after
Hodgkin's disease in a collaborative British cohort: the relation to age at treatment.
J Clin Oncol 2000; 18(3):498-509.
153. Swerdlow AJ, Barber JA, Horwich A, et al. Second malignancy in patients with
Hodgkin's disease treated at the Royal Marsden Hospital. Br J Cancer 1997;
75(1):116-123.
154. Aisenberg AC, Finkelstein DM, Doppke KP, et al. High risk of breast carcinoma
after irradiation of young women with Hodgkin's disease. Cancer 1997;
79(6):1203-1210.

, 76, 1, 2014 566

155. Basu SK, Schwartz C, Fisher SG, et al. Unilateral and bilateral breast cancer in
women surviving pediatric Hodgkin's disease. Int J Radiat Oncol Biol Phys 2008;
72(1):34-40. doi: 10.1016/j.ijrobp.2008.04.068.
156. van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiation dose,
chemotherapy, and hormonal factors in breast cancer following Hodgkin's
disease. J Natl Cancer Inst 2003; 95(13):971-980.
157. Chen J, Lee RJ, Tsodikov A, et al. Does radiotherapy around the time of
pregnancy for Hodgkin's disease modify the risk of breast cancer? Int J Radiat
Oncol Biol Phys 2004; 58(5):1474-1479.
158. , Ma YP, van Leeuwen FE, Cooke R, et al. FGFR2 genotype and risk of radiation-
associated breast cancer in Hodgkin lymphoma. Blood 2012 Jan 26; 119(4):1029-
1031. doi: 10.1182/blood-2011-10-383380. Epub 2011 Dec 5.
159. Dores GM, Anderson WF, Beane Freeman LE, et al. Risk of breast cancer
according to clinicopathologic features among long-term survivors of Hodgkin's
lymphoma treated with radiotherapy. Br J Cancer 2010; 103(7):1081-1084. doi:
10.1038/sj.bjc.6605877. Epub 2010 Sep 14.
160. Sung JS, Lee CH, Morris EA, et al. Screening breast MR imaging in women with a
history of chest irradiation. Radiology Radiology. 2011; 259(1):65-71. doi:
10.1148/radiol.10100991. Epub 2011 Feb 15.PMID: 21325032 [PubMed - indexed
for MEDLINE].
161. Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of MRI and mammography for
breast-cancer screening in women with a familial or genetic predisposition. N Engl
J Med 2004; 351(5):427-437.
162. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for
breast screening with MRI as an adjunct to mammography. CA Cancer J Clin
2007; 57(2):75-89.
163. Lee CH, Dershaw DD, Kopans D, et al. Breast cancer screening with imaging:
recommendations from the Society of Breast Imaging and the ACR on the use of
mammography, breast MRI, breast ultrasound, and other technologies for the
detection of clinically occult breast cancer. J Am Coll Radiol 2010 Jan; 7(1):18-27.
doi: 10.1016/j.jacr.2009.09.022.
164. Sankila R, Garwicz S, Olsen JH, et al. Risk of subsequent malignant neoplasms
among 1,641 Hodgkin's disease patients diagnosed in childhood and
adolescence: a population-based cohort study in the five Nordic countries.

, 76, 1, 2014 567

 Association of the Nordic Cancer Registries and the Nordic Society of Pediatric
Hematology and Oncology. J Clin Oncol 1996; 14(5):1442-1446.
165. van den Belt-Dusebout AW, Aleman BM, Besseling G, et al. Roles of radiation
dose and chemotherapy in the etiology of stomach cancer as a second
malignancy. Int J Radiat Oncol Biol Phys 2009; 75(5):1420-1429. doi:
10.1016/j.ijrobp.2009.01.073.).
166. Youn P, Li H, Milano MT, et al. Long-term survival among Hodgkin's lymphoma
patients with gastrointestinal cancer: a population-based study. Ann Oncol 2013
Jan; 24(1):202-208. doi: 10.1093/annonc/mds218. Epub 2012 Jul 31.
167. Morton LM, Dores GM, Curtis RE, et al. Stomach cancer risk after treatment for
Hodgkin lymphoma. J Clin Oncol 2013 Sep 20;31(27):3369-3677. doi:
10.1200/JCO.2013.50.6832. Epub 2013 Aug 26.
168. De Bruin ML, Burgers JA, Baas P, et al. Malignant mesothelioma after radiation
treatment for Hodgkin lymphoma. Blood 2009 Apr 16; 113(16):3679-3681. doi:
10.1182/blood-2008-10-184705. Epub 2009 Feb 20.).
169. Brennan P, Scelo G, Hemminki K, et al. Second primary cancers among 109,000
cases of non-Hodgkin's lymphoma. Br J Cancer 2005; 93:159-166.
170. Tward JD, Wendland MM, Shrieve DC, et al. The risk of secondary malignancies
over 30 years after the treatment of non-Hodgkin lymphoma. Cancer
2006;107:108-115.
171. Moser EC, Noordijk EM, van Leeuwen FE, et al. Risk of second cancer after
treatment of aggressive non-Hodgkin's lymphoma; an EORTC cohort study.
Haematologica 2006; 91:1481-1488.
172. Mudie NY, Swerdlow AJ, Higgins CD, et al. Risk of second malignancy after non-
Hodgkin's lymphoma: A British Cohort Study. J Clin Oncol 2006; 24:1568-1574.
173. Hemminki K, Lenner P, Sundquist J, et al. Risk of subsequent solid tumors after
non-Hodgkin's lymphoma: effect of diagnostic age and time since diagnosis. J Clin
Oncol 2008; 26:1850-1857.
174. Hiramoto , Kobayashi , Nomoto J. et al. Ewing Sarcoma Arising After
Treatment of Diffuse Large B-cell Lymphoma. Jpn. J. Clin. Oncol. 2013, 43 (4):
417-421. doi: 10.1093/jjco/hyt011 First published online: March 8, 2013.
175. Ushigome U, Machinami R, Sorensen PH. Ewing Sarcoma/primitive
neuroectodermal tumor (PNET). In: Fletcher CDM, Unni KK, Mertens F, editors.
World Health Organization Classification of Tumors. Pathology and Genetics of
Tumors of Soft Tissue and Bone. Lyon, France: IARC Press; 2002:298-300.

, 76, 1, 2014 568

176. Zoubek A, Simonitsch I, Panzer-Grumayer ER, et al. Ewing tumor after treatment
of Ki-1+ anaplastic large cell lymphoma. Therapy-associated secondary neoplasm
or unrelated coincidence? Cancer Genet Cytogenet 1995; 83:5-11.
177. Davis M, Brownell M, Watson W, Kennaugh R, Russo J. Primitive
neuroectodermal tumor following successful treatment of Hodgkin's disease. Am J
Hematol 1995; 48:205-206.
178. Aparicio J, Segura A, Montalar J, et al. Secondary cancers after Ewing sarcoma
and Ewing sarcoma as second malignant neoplasm. Med Pediatr Oncol 1998;
30:259-260.
179. Loning L, Zimmermann M, Reiter A, et al. Secondary neoplasms subsequent to
Berlin-Frankfurt-Mnster therapy of acute lymphoblastic leukemia in childhood:
significantly lower risk without cranial radiotherapy. Blood 2000; 95:2770-2775.
180. Bhatia S, Sather HN, Pabustan OB, et al. Low incidence of second neoplasms
among children diagnosed with acute lymphoblastic leukemia after 1983. Blood
2002; 99:4257-4264.
181. Bisogno G, Sotti G, Nowicki Y, et al. Soft tissue sarcoma as a second malignant
neoplasm in the pediatric age group. Cancer 2004; 100:1758-1765.
182. Kim GE, Beach B, Gastier-Foster JM, et al. Ewing sarcoma as a second malignant
neoplasm after acute lymphoblastic leukemia. Pediatr Blood Cancer 2005; 45:57-
59.
183. Spunt SL, Rodriguez-Galindo C, Fuller CE, et al. Ewing sarcoma family tumors
that arise after treatment of primary childhood cancer. Cancer 2006; 107:201-206.
184. Henderson TO, Whitton J, Stovall M, et al. Secondary sarcomas in childhood
cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl
Cancer Inst 2007; 99:300-308.
185. Osone S, Hosoi H, Tanaka K, et al. A case of a Ewing sarcoma family tumor in the
urinary bladder after treatment for acute lymphoblastic leukemia. J Pediatr
Hematol Oncol 2007; 29:841-844.
186. Pothuri B, Ramondetta L, Martino M, et al. Development of endometrial cancer
after radiation treatment for cervical carcinoma. Obstet Gynecol 2003; 101:941-
945.
187. West JG, Qureshi A, West JE, et al. Risk of angiosarcoma following breast
conservation: a clinical alert. Breast J 2005; 11:115-123.

, 76, 1, 2014 569

188. Rubino C, Shamsaldin A, Le MG, et al. Radiation dose and risk of soft tissue and
bone sarcoma after breast cancer treatment. Breast Cancer Res Treat 2005;
89:277-288.
189. Huang CW, Tsai HL, Chen YT, et al. The prognostic values of EGFR expression
and KRAS mutation in patients with synchronous or metachronous metastatic
colorectal cancer. BMC Cancer. 2013; 13(1):599. doi: 10.1186/1471-2407-13-599.
190. Sontag SJ, Schnell TG, Chejfec G, et al. Barrett's oesophagus and colonic
tumours. Lancet. 1985; 1:946949.
191. Laitakari R, Laippala P, Isolauri J. Barrett's oesophagus is not a risk factor for
colonic neoplasia: A case-control study. Ann Med. 1995; 27:499502.
192. Watanabe Y, Tsutsui M, Takeda S, et al. A case of esophageal cancer associated
with colon cancer successfully treated with combination chemotherapy of
FOLFOX and concurrent radiotherapy. Gan To Kagaku Ryoho. 2009; 36:2439
2441.
193. Morgan G, Vainio H. Barrett's oesophagus, oesophageal cancer and colon
cancer: An explanation of the association and cancer chemopreventive potential
of non-steroidal anti-inflammatory drugs. Eur J Cancer Prev. 1998; 7:195199.
194. Suzuki S, Nishimaki T, Suzuki T, Kanda T, et al. Outcomes of simultaneous
resection of synchronous esophageal and extraesophageal carcinomas. J Am Coll
Surg. 2002; 195:2329.
195. Weber WA, Ott K, Becker K, NE, et al. Prediction of response to preoperative
chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic
imaging. J Clin Oncol. 2001; 19:30583065.
196. Mahmood H, Faheem M, Mahmood S, Irfan J. Adenocarcinoma of rectum as
second primary cancer after treatment of endometrium cancer. J Coll Physicians
Surg Pak. 2013; 23(6):434-436. doi: 06.2013/JCPSP.434436.
197. Shenoy S. Gastrointestinal carcinoids and colorectal cancers: Is it a paracrine
effect? Tumori. 2013; 99(4):141e-143e. doi: 10.1700/1361.15111.
198. Jung KS, Chun KH, Choi GH, et al. Synchronous development of intrahepatic
cholangiocarcinoma and hepatocellular carcinoma in different sites of the liver with
chronic B-viral hepatitis: two case reports. BMC Res Notes. 2013 Dec 7;6:520.
doi: 10.1186/1756-0500-6-520.
199. Agaimy A, Wnsch PH, Sobin LH, et al. Occurrence of other malignancies in
patients with gastrointestinal stromal tumors. Semin Diagn Pathol 2006; 23:120-
129.

, 76, 1, 2014 570

200. Giuliani J and Bonetti A. Gastrointestinal stromal tumors and second primary
malignancies before and after the introduction of imatinib mesylate. Chin J Cancer
Res. 2013; 25(5):486487.
201. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in
metastatic melanoma. JAMA 2011; 305:2327-2334.
202. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib
mesylate in patients with metastatic melanoma harboring c-Kit mutation or
amplification. J Clin Oncol 2011; 29:2904-2909.
203. Kanda T, Ishikawa T, Hirota S, et al. Prospective observational study of imatinib
therapy in Japanese patients with advanced gastrointestinal stromal tumors: long-
term follow-up and second malignancy. Jpn J Clin Oncol 2012; 42:578-585.
204. Takeda J, Toyonaga A, Koufuji K, et al. Early gastric cancer in the remnant
stomach. Hepatogastroenterology 1998; 45:1907-1911.
205. Seo JH, Park JC, Kim YJ, et al. Undifferentiated histology after endoscopic
resection may predict synchronous and metachronous occurrence of early gastric
cancer. Digestion 2010; 81:35-42.
206. Han JS, Jang JS, Choi SR, et al. A study of metachronous cancer after
endoscopic resection of early gastric cancer. Scand J Gastroenterol 2011;
46:1099-1104.
207. Nakajima T, Oda I, Gotoda T, et al. Metachronous gastric cancers after
endoscopic resection: how effective is annual endoscopic surveillance? Gastric
Cancer 2006; 9:93-98.
208. Kato M, Nishida T, Yamamoto K, et al. Scheduled endoscopic surveillance
controls secondary cancer after curative endoscopic resection for early gastric
cancer: a multicentre retrospective cohort study by Osaka University ESD study
group. Gut 2013 Oct; 62(10):1425-1432. doi: 10.1136/gutjnl-2011-301647. Epub
2012 Aug 21.
209. Yoo JH, Shin SJ, Lee KM, et al. How can we predict the presence of missed
synchronous lesions after endoscopic submucosal dissection for early gastric
cancers or gastric adenomas? J Clin Gastroenterol 2013; 47:e17-e22.
210. Nasu J, Doi T, Endo H, et al. Characteristics of metachronous multiple early
gastric cancers after endoscopic mucosal resection. Endoscopy 2005; 37:990-
993.

, 76, 1, 2014 571

211. Jang MY, Cho JW, Oh WG, et al. Clinicopathological characteristics of
synchronous and metachronous gastric neoplasms after endoscopic submucosal
dissection. Korean J Intern Med 2013; 28.687-693
http://dx.doi.org/10.3904/kjim.2013.28.6.687.
212. Hasuo T, Semba S, Li D, et al. Assessment of microsatellite instability status for
the prediction of metachronous recurrence after initial endoscopic submucosal
dissection for early gastric cancer. Br J Cancer 2007; 96:89-94.
213. Semba S, Hasuo T, Satake S, et al. Prognostic significance of intestinal claudins
in high-risk synchronous and metachronous multiple gastric epithelial neoplasias
after initial endoscopic submucosal dissection. Pathol Int 2008; 58:371-377.
214. Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter pylori on
incidence of metachronous gastric carcinoma after endoscopic resection of early
gastric cancer: an open-label, randomised controlled trial. Lancet 2008; 372:392-
397.
215. Moertel CG, Bargen JA, Soule EH. Multiple gastric cancers: review of the
literature and study of 42 cases. Gastroenterology 1957; 32:1095-1103.
216. Tada M, Higaki S, Matsumoto Y, et al. Strip biopsy: its problems and measures
implied by a long-term follow-up study (simultaneous and metachronous multiple
cancers). Stomach Intest 1993; 28:1441-1451.
217. Kobayashi M, Narisawa R, Sato Y, et al. Self-limiting risk of metachronous gastric
cancers after endoscopic resection. Dig Endosc 2010; 22:169-173.
218. Ribeiro U, Jorge UM, Safatle-Ribeiro AV, et al. Clinicopathologic and
immunohistochemistry characterization of synchronous multiple primary gastric
adenocarcinoma. J Gastrointest Surg. 2007; 11:233239.
219. Isobe , Hashimoto , Kizaki J, et al. Characteristics and prognosis of
synchronous multiple early gastric cancer. World J Gastroenterol. 2013 Nov 7;
19(41):7154-7159. doi: 10.3748/wjg.v19.i41.7154. PMID: 24222960 [PubMed - in
process].
220. Borie F, Plaisant N, Millat B, et al. Treatment and prognosis of early multiple
gastric cancer. Eur J Surg Oncol. 2003; 29:511514.
221. Kitano S, Shiraishi N, Uyama I, et al. for Japanese Laparoscopic Surgery Study
Group. A multicenter study on oncologic outcome of laparoscopic gastrectomy for
early cancer in Japan. Ann Surg. 2007; 245:6872.
222. Isomoto H, Shikuwa S, Yamaguchi N, et al. Endoscopic submucosal dissection
for early gastric cancer: a large-scale feasibility study. Gut. 2009; 58:331336.

, 76, 1, 2014 572

223. Brinkman GL, Coates EO. The effect of bronchitis, smoking, and occupation on
ventilation. Am Rev Respir Dis. 1963; 87:684693.
224. Ichinoe M, Mikami T, Hara A, et al. Background submucosal cysts in early gastric
cancer cases have unique clinicopathologic features suggestive of postgastritis
and significant smoking association. Am J Clin Pathol. 2007; 128:746752.
225. Japanese Gastric Cancer Association. Japanese classification of gastric
carcinoma: 3rd English edition. Gastric Cancer. 2011; 14:101112.
226. Nitta T, Egashira Y, Akutagawa H, et al. Study of clinicopathological factors
associated with the occurrence of synchronous multiple gastric carcinomas.
Gastric Cancer. 2009; 12:2330.
227. Ruol A, Parenti A, Zaninotto G, et al. Intestinal metaplasia is the probable
common precursor of adenocarcinoma in Barrett esophagus and adenocarcinoma
of the gastric cardia. Cancer. 2000; 88:25202528.
228. Yaghoobi M, Bijarchi R, Narod SA. Family history and the risk of gastric cancer. Br
J Cancer. 2010; 102: 237242.
229. Nomura A, Grove JS, Stemmermann GN, Severson RK. A prospective study of
stomach cancer and its relation to diet, cigarettes, and alcohol consumption.
Cancer Res. 1990; 50:627631.
230. La Vecchia C, Negri E, Franceschi S, Gentile A. Family history and the risk of
stomach and colorectal cancer. Cancer. 1992; 70:5055.
231. Ji BT, Chow WH, Yang G, et al. The influence of cigarette smoking, alcohol, and
green tea consumption on the risk of carcinoma of the cardia and distal stomach
in Shanghai, China. Cancer. 1996; 77:24492457.
232. Morita M, Kuwano H, Baba H, et al. Multifocal occurrence of gastric carcinoma in
patients with a family history of gastric carcinoma. Cancer. 1998; 83:13071311.
233. Otsuji E, Kuriu Y, Ichikawa D, et al. Clinicopathologic characteristics and
prognosis of synchronous multifocal gastric carcinomas. Am J Surg. 2005;
189:116119.
234. Takenaka R, Kawahara Y, Okada H, et al. Risk factors associated with local
recurrence of early gastric cancers after endoscopic submucosal dissection.
Gastrointest Endosc. 2008; 68:887894.
235. Choi J, Kim SG, Im JP, et al. Lymph node metastasis in multiple synchronous
early gastric cancer. Gastrointest Endosc. 2011; 74:276284.

, 76, 1, 2014 573

236. Fujita T, Gotohda N, Takahashi S, et al. Clinical and histopathological features of
remnant gastric cancers, after gastrectomy for synchronous multiple gastric
cancers. J Surg Oncol. 2009; 100:466471.
237. Vaslamatzis M, Petraki C, Petraki K, et al. Small cell carcinoma of the urinary
bladder: Clinical, clinicopathological, immunohistochemical and ultrastructural
characteristics in five cases., 23rd Congress of the European Society for Medical
Oncology 6-10/11/1998, Athens Greece. Annals of Oncology 1998, Volume 9,
(Supplement 4), Page 65, No 310.
238. Petraki C, Vaslamatzis M, Petraki K, et al. Small cell carcinoma of the urinary
bladder: Clinicopathological, immunohistochemical and ultrastructural study in five
cases. 13th World Congress of the International Academy of Pathology 18-
23/10/1998, Nice, France. Archives D Anatomie et de Cytologie Pathologiques.
Clinical and Experimental Pathology 1998, Volume 46, Page 430, No 607.
239. Petraki C, Vaslamatzis M, Petraki K, et al. Prostate cancer with small-cell
morphology: An immunophenotypic subdivision. Scandinavian Journal of Urology
and Nephrology 2005, Vol 39:455-463.
240. Wong Y, Jack RH, Mak V, et al. The epidemiology and survival of extrapulmonary
small cell carcinoma in South East England, 1970-2004. BMC Cancer 2009;
9:209. doi: 10.1186/1471-2407-9-209.
241. Ochsenreither S, Marnitz-Schultze S, Schneider A, et al. Extrapulmonary small
cell carcinoma (EPSCC): 10 years multidisciplinary experience at Charit.
Anticancer Res 2009; 29:3411-3415.
242. Brennan SM, Gregory DL, Stillie A, et al. Should extrapulmonary small cell cancer
be managed like small cell lung cancer? Cancer 2010; 116:888-895.
243. Haider K, Shahid RK, Finch D, et al. Extrapulmonary small cell cancer: a
Canadian provinces experience. Cancer 2006;107:2262-2269.
244. Lee SS, Lee JL, Ryu MH, et al. Extrapulmonary small cell carcinoma: single
center experience with 61 patients. Acta Oncol 2007; 46: 846-851.
245. Cicin I, Karagol H, Uzunoglu S, et al. Extrapulmonary small-cell carcinoma
compared with small-cell lung carcinoma: a retrospective single-center study.
Cancer 2007; 110:1068-1076.
246. Vaslamatzis MM, Kompoti M, Alevizopoulos ND, et al. Multiple primary malignant
neoplasms in patients with Small Cell Lung Cancer.. 11th Central European Lung
Cancer Conference (CELCC). Ljubljana, Slovenia, 12-14/6/2008. Editor 2008 by

, 76, 1, 2014 574

 Monduzzi Editore S.p.A. MEDIMOND Inc, International Proceedings Division, pp
73-82.
247. Matt L, Limjoco T, and Sehgal R. A Case of Small Cell Cancer of the Breast in a
Male with Synchronous Stage IV Non-Small Cell Lung Carcinoma. Rare Tumors.
2013; 5(3):e52. Published online 2013 September 24. doi: 10.4081/rt.2013.e52.
248. Jundt G, Schulz A, Heitz Ph, et al. Small cell neuroendocrine (oat cell) carcinoma
of the male breast. Virchows Arch A Pathol Anat Histopathol 1984; 404: 213-221.

, 76, 1, 2014 575



. .
..

:
./: 210 6919912
.: 6973795493
-mail: vsevastianos@gmail.com

, 11%
1.
,
31%,
0,6%2-5.
3
,
>25% >0,5 mg/dL
3,6,7. >0,5
mg/dL
,
>25%
2.

2% ,
0 90%

( ,
3,6,8-11
) / ( 1, 2) .

, 76, 1, 2014 576

 - , ,
11.



( 1)7,8,12,13.

, , .
24
, 3 5
10-14 10,11. ( 0,4-2%)
, .
(<400 ml 24) 24
2-5 .
5-10 14-21
6,10,11. ,
,
, .

(<1%)10,11.

,
,
50% 14.
, , ,
,
.
GFR (eGFR) 7
,
,
.
.

,

, 76, 1, 2014 577

 .
, ,
2.

11.
1-1,5 ml/kg/ iv
6 6
, 150
ml/10.
,
.
(
500 ml 2500 ml 1 24
).
N- (NAC) ,

, NO.
NAC 6.


.
, -
,

.

, 76, 1, 2014 578

 1.

, ,
<40%,
, ( )



, , ,

>70




, , ,
, , ,

2.


Diatrizoate ( )
Iothalamate ( )

Iopamodol ( )
Iomeprol ( )
Iopentol ( )
Iobiditrol ( )
Iohexol ( )
Ioversol ( )
Iopromide ( )
Ioxilan ( )
Ioxaglate ( )
- ( )
Iodixanol ( )

, 76, 1, 2014 579

 1.
.

1. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. American journal

of kidney diseases: the official journal of the National Kidney Foundation.
2002;39(5):930-936.
2. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A
cohort analysis. JAMA: the journal of the American Medical Association.
1996;275(19):1489-1494.
3. Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, et al. Incidence and
prognostic importance of acute renal failure after percutaneous coronary
intervention. Circulation. 2002;105(19):2259-2264.
4. Shlipak MG, Heidenreich PA, Noguchi H, Chertow GM, Browner WS, McClellan
MB. Association of renal insufficiency with treatment and outcomes after

, 76, 1, 2014 580

 myocardial infarction in elderly patients. Annals of internal medicine.
2002;137(7):555-562.
5. Best PJ, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, et al. The impact of
renal insufficiency on clinical outcomes in patients undergoing percutaneous
coronary interventions. Journal of the American College of Cardiology.
2002;39(7):1113-1119.
6. Pannu N, Wiebe N, Tonelli M. Prophylaxis strategies for contrast-induced
nephropathy. JAMA: the journal of the American Medical Association.
2006;295(23):2765-2779.
7. Maeder M, Klein M, Fehr T, Rickli H. Contrast nephropathy: review focusing on
prevention. Journal of the American College of Cardiology. 2004;44(9):1763-1771.
8. Parfrey P. The clinical epidemiology of contrast-induced nephropathy.
Cardiovascular and interventional radiology. 2005;28 Suppl 2:S3-11.
9. Tepel M, Aspelin P, Lameire N. Contrast-induced nephropathy: a clinical and
evidence-based approach. Circulation. 2006;113(14):1799-1806.
10. Gleeson TG, Bulugahapitiya S. Contrast-induced nephropathy. AJR American
journal of roentgenology. 2004;183(6):1673-1689.
11. Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. Journal of the
American Society of Nephrology: JASN. 2000;11(1):177-182.
12. Morcos SK. Contrast media-induced nephrotoxicity-questions and answers. The
British journal of radiology. 1998;71(844):357-365.
13. Barrett BJ. Contrast nephrotoxicity. Journal of the American Society of Nephrology:
JASN. 1994;5(2):125-137.
14. Luft D, Schmulling RM, Eggstein M. Lactic acidosis in biguanide-treated diabetics:
a review of 330 cases. Diabetologia. 1978;14(2):75-87.

, 76, 1, 2014 581



, , ...

:
: 6944774434
-mail: ageorgako@gmail.com

:
, .
,
.

10-14% .
,
. :
( >
25% > 0,5 mg/dl ),
.
,
0,3 mg% .

,
.

, , ,
, .
.
.
( ).
:
, ,
. 24
,
.

, 76, 1, 2014 582

 . :

,
, , , ..
,
.
, -, .

(48-72 ).
. .
/
-
.

3 4.
5
. :
,
, -
, ,

. , 76, 1, 582-584, 2014.
: , ,
.

1. Cohan Rh, Dunnick NR. Intravascular contrast media: Adverse reactions, Am J
radiol 1987, 149:616-618.
2. Nash K, Haffez A, Hou S. Hospital acquired renal insufficiency, Am J Kidney Dis
2002, 39:930-936.
3. Rihal CS, Textor Sc, Grill DE et al. Incidence and prognostic importance of acute
renal failure after percutaneous coronary intervention, Circulation 2002, 105:2259-
2264.

, 76, 1, 2014 583

4. Shlipak G. Heidenreich PA, Noguchi H et al. Association of renal insufficiency
with treatment and outcomes after myocardial infarction in elderly patients, Ann
Intern Med 2002, 137:556-562.
5. David C. :
(), Comprehensive , .1, ,
, 2013, 5:95-96.
6. Pannu N, Tonelli M, Alberta Disease Net work. Prophylaxis Strategies for
contrast- induced nephropathy, JAMA 2006, 295:2765-2779.
7. Parfrey P. The clinical epidemiology of contrast indused nephropathy, Cardiovasc
Intervent Radiol 2005, 28 (Suppl 2): S3-S11.
8. Tepel M, Aspelin P, Lameire N. Contrast Induced Nephropathy: a clinical and
evidence based approach, Circulation 2006, 113:1799-1806.
9. Gleeson TG, Bulugahapitiya S. Contrast indused nephropathy, Am J Roentgenol
2004, 183:1673-1689.
10. , .
, 2009, 21(4):302-315.
11. Rudnick MR, Goldfarb S, Wexler L et al. Nephrotoxicity of ionic and nonionic
contrast media in 1196 patients: a randomized trial, Kidney Int 1994, 45:259-265.
12. Barret BJ. Contrast nephrotoxicity, J Am Soc Nephrol 1994, 5:125-137.
13. Murphy ME, Tublin ME, Li S. Influence of contrast media on the response of rat
renal arteries to endothelin and nitric oxide: influence of contrast media, Invest
Radio 1998, 33: 356- 365.

, 76, 1, 2014 584



Dr. med. .

, --
...
/ EACTS Academy

:
: 6932704255
E-mail: kallatha@otenet.gr

,
. IIIA (N2)
. ( 1). 2
, .
-
. , .
, 2 3
: 1. , 2. 3. .
,

. , ,
,
2 , .
: (bulky), (extranodal),
(fixed), (multistation).
( 2) ,
. ,
2 ,

,

, 76, 1, 2014 585

 ,
(PET) . ,
, (EUS) /
(EBUS)
,
2 1,

Will Rogers- 2.

2
.
Leuven3
. ,
2 ,
, 5
33%. 36% 34%,
4-5.
, 2 ?
Goldstraw , 876
NSCLC, ,
,
26% , 6,
Cerfolio ,
4,7% 2 7. , Al-
Sarraf 2008, 16% ,
,
2 8.

, 76, 1, 2014 586

 1.

2. 2

,
,
9.

, 76, 1, 2014 587

 , 2 , ,
,
. 5
2, , ,
30%.
Valerie Rusch, 199610.
, ,
(R0 ) 35% 2
11.
, , 5
<5%12.
2 (2 , ,
5),
. ,
.
,
,

13. ,
. ,

, -
14. ,

(EGFR)15,
16,

. , ,
,
.
, ,

, .

, 76, 1, 2014 588

 3. , 2 ,

1. De Leyn P, Lardinois D, Van Schil PE, et al. ESTS guidelines for preoperative
lymph node staging for non-small cell lung cancer. Eur J Cardiothorac Surg 2007;
32:1-8.
2. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration
and new diagnostic techniques as a source of misleading statistics for survival in
cancer. N Engl J Med 1985; 312:1604-1608.
3. Decaluw H, De Leyn P, Vansteenkiste J, et al. Surgical multimodality treatment for
baseline resectable stage IIIa-N2 non-small cell lung cancer. Degree of mediastinal
lymph node involvement and impact on survival. Eur J Cardio horac Surg 2009;
36:433-439.
4. Betticher DC, Hsu Schmitz SF, Ttsch M, et al. Swiss Group for Clinical Cancer
Research (SAKK). Prognostic factors affecting long-term outcomes in patients with
resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II
study. Br J Cancer 2006; 94:1099-1106.
5. Eberhardt W, Wilke H, Stamatis G, et al. Preoperative chemotherapy followed by
concurrent chemoradiation therapy based on hyperfractionated accelerated

, 76, 1, 2014 589

 radiotherapy and definitive surgery in locally advanced non-small-cell lung cancer:
mature results of a phase II trial. J Clin Oncol 1998; 16:622-634.
6. Goldstraw P, Mannam GC, Kaplan DK, et al. Surgical management of non-small-
cell lung cancer with ipsilateral mediastinal node metastasis (N2 disease). J Thorac
Cardiovasc Surg 1994; 107:19-27; discussion 27-28.
7. Cerfolio RJ, Bryant AS, Eloubeidi MA. Routine mediastinoscopy and esophageal
ultrasound fine-needle aspiration in patients with non-small cell lung cancer who
are clinically N2 negative: a prospective study. Chest 2006; 130:1791-1795.
8. Al-Sarraf N, Aziz R, Gately K, et al. Pattern and predictors of occult mediastinal
lymph node involvement in non-small cell lung cancer patients with negative
mediastinal uptake on positron emission tomography. Eur J Cardiothorac Surg
2008; 33:104-109.
9. Allen MS, Darling GE, Pechet TT, et al. Morbidity and mortality of major pulmonary
resections in patients with early-stage lung cancer: initial results of the randomized,
prospective ACOSOG Z0030 trial. Ann Thorac Surg 2006; 81:1013-1019;
discussion 1019-20.
10. Rusch VW. Surgical Treatment of Patients With N2 Disease. Semin Radiat Oncol
1996; 6:76-85.
11. Detterbeck F. What to do with Surprise N2?: intraoperative management of
patients with non-small cell lung cancer. J Thorac Oncol 2008; 3:289-302.
12. Detterbeck FC, Jones DR. Surgical treatment of stage IIIa (N2) non-small cell lung
cancer. In: Detterbeck FC, Rivera MP, Socinski MA, et al. eds. Diagnosis and
Treatment of Lung Cancer: An Evidence-Based Guide for the Practicing Clinician.
Philadelphia, PA: W. B. Saunders, 2001; 244-256.
13. Rusch VW, Asamura H, Watanabe H, et al. On Behalf of the Members of the
IASLC Staging Committee. The IASLC Lung Cancer Staging Project: a proposal for
a new international lymph node map in the forthcoming seventh edition of the TNM
Classification for Lung Cancer. J Thorac Oncol 2009; 4:568-577.
14. Di Costanzo F, Mazzoni F, Micol Mela M, et al. Bevacizumab in non-small cell lung
cancer. Drugs 2008; 68:737-746.
15. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008;
358:1160-1174.
16. Olaussen K.A, Dunant A, Fouret P, et al. IALT Bio Investigators. DNA repair by
ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.
N Engl J Med 2006; 355:983-991.

, 76, 1, 2014 590



1, 2
1
, 2
...

:

: 6972284083
-mail: xanthoula_k@hotmail.com

, , , .

.

.
.
,

.

, , ,
,

.
,
.
,
, ,
, .
, 76, 1, 591-610, 2014.
: , , , ,

, 76, 1, 2014 591

 SUMMARY
KAFETZI D., BACHARIOU A. The importance of fundoscopy in patients with blood
malignancies and solid tumors f the eye. Fundoscopy is the only examination method
that makes inner structures of the body, such as vessels, nerves and deep tissues,
visible to the human eye. This gives us the opportunity to set the diagnosis in a variety
of diseases that affect those deep structures. Notable examples are the malignancies
of the blood and the solid tumors of the eye. Blood malignancies are systemic
diseases that may have eye involvement. Eye involvement is either due to direct
evasion of eye tissues by neoplastic disease, or because of the spread of a systemic
manifestation also to the eye tissues. Fundoscopy and thoroughly conducted
ophthalmological examination constitute a necessary tool to set the diagnosis and deal
with the eye manifestations of blood malignancies, but also they may help to set an
early diagnosis of recurrence, thus leading to an early treatment and a better
prognosis for those patients. Solid eye tumors develop either as a primary cancer
growth of ophthalmic tissues, or they represent a distant metastasis of a primary tumor
elsewhere in the body. The most common primary solid eye tumors are retinoblastoma
and melanoma of the eye, and metastasis to the ophthalmic tissues can be seen
commonly in breast and lung cancer, and less commonly in kidney, gastrointestinal
tract and skin cancer. Rarely prostate cancer can develop ophthalmic solid
metastases. Nosokomiaka Chronika, 76, Supplement 1, 591-610, 2014.
Key words: leukemia, lymphomas, retinoblastoma, melanoma, fundoscopy

,
.
:
, , (
), (
), ,
( 1).

, 76, 1, 2014 592

 1:

,

.

.

.
,
.

, , ,
(),
1,2, (Graft Versus
Host Disease-GVHD), 1,3.
, ,
3. ,
.

. ,
, "
" Liebreich 18634,5.

, 76, 1, 2014 593


.

. .

. .
,
, ,
, ( 2)4,6.

2.

.
70%
7.
8 ( 3),
( 4).
,
.

( Roth) ( 5).
, -
9. ,
.
10.

.
11.
(cotton wool spots) ( 6),

, 76, 1, 2014 594

 ,
12 ( 7).

3. tortuosity

4. .

5. Roth

, 76, 1, 2014 595

 6. cottonwool

7.
.

.
,
13.
12.

. 13%18% .
,

14.

. , , ,
,
, , IV VI.

, 76, 1, 2014 596

 3,15,16,17.
.
, ,
( 8). ,
18,19,20,21.

8.

GVH .

.

, ,
, .
,
( 9), (Candida, Aspergillus), , 22.
( , )

22
.
. Candida albicans
,
.

( 10)22.
,
, 12

, 76, 1, 2014 597

 ( 11). ,
.

9.
.

10. Candida.

11. (
)

,
.
15,23,24.

,

, 76, 1, 2014 598

 25,26. ,
,

25.
,
.

,
,
,
.

. Hodgkin
Non-Hodgkin 27. Hodgkin
, Non-Hodgkin
28
55% 29. ,
.
:
, ,
.

.
(Primary Vitreo
Retinal LymphomaPVRL)
(Primary Central Nervous System Lymphoma-
PCNSL), 30.
80% .
,
. PVRL
(floaters)31 ( 12)

, 32 ( 13).
31,
33 ( 14)

, 76, 1, 2014 599

34 ( 15) 35,36 ( 16).

PVRL .

12. ,
.

13.
.

14.

, 76, 1, 2014 600

 15.

16. .

, .
.


.
,

, . ,
.
( 17).
,
. ,

"salmon" patch.

, 76, 1, 2014 601

 17.

,
, . ,
37.
,
37.
-,
37.


.
, .

. 38.
1 15.000 20.000 5%
. ( 18)
. (40%)
, (60%)
.
.

.
,

, 76, 1, 2014 602


. ,
.

18 -

(75%)
(25%), ,
.
,
,
. .

( 19)

( 20).
,
.
36 ( 21).


38.
.

19.

, 76, 1, 2014 603


,
.
,
, .
.

.

39,40. 80%
.

20.

21.

().
, 76, 1, 2014 604
 , ,
. ,
,
(.. , ).
,
, ,
( )
..
, ,
,
.

( 22).

42. ()

( 23)36. Bruch
( 24.).
43,44.

22. .

, 76, 1, 2014 605

 23.

24.
Bruch

.
.
45.
,
.
.
,

.
-
, .

, 76, 1, 2014 606

 .
( 25).
30%
30% 36.
( 26).

25. ,
.

26. ,
( )

,
, .
.
, .

1. Rosenthal AR. Ocular manifestations of leukemia: a review. Ophthalmology, 1983;

90:899-905
2. Wu L, Calderon M, Hernandez G, et al. Bilateral exudative retinal detachment as
the first sign of relapsing acute myelogenousleukaemia. Clin Exp Ophthalmol,
2006; 34:623-625.
3. Sharma T, Grewal J, Gupta S, et al. Ophthalmic manifestations of acute
leukaemias: the ophthalmologists role. Eye, 2004; 18: 663-672.

, 76, 1, 2014 607

4. Campos-Campos LE, Mendoza-Altamirano L, Prez RX, et.al. Alteraciones
oculares en pacientes peditricos con leukemia aguda. Rev Mex Oftalmol 2004;
14:287-290.
5. Guyer DR, Sch, Schachat AP, Vitale S, et al. Leukemic retinopathy. Relationship
between fundus lesions andhematologic parameters at diagnosis. Ophthalmology,
1989; 96:860-864.
6. Mc Manaway JW, Neely JE. Choroidal and orbital leukemic infiltrate mimicking
advanced retinoblastoma. J Pediatr Ophthalmol Strabismus, 1994; 31:394-296.
7. Kincaid MC, Green WR. Ocular and orbital involvement in leukemia. Surv
Ophthalmol, 1983; 27:211-232.
8. Mesa F, Cordovs L, Garca M, et. Al. Manifestaciones oculars comopresentacin
de recada de leukemia agudalinfoblstica de clulas T. Arch Soc Canar Oftal
2003; 14:91-94.
9. Abdelouahed K, Laghmari M, Tachfouti S, et. al. Leucmieaigulymphoblastique
T/Lymphomelymphoblastiqueorbitaire chez lenfant. J Fr Ophtalmol, 2005; 28:197-
200.
10. Kuwabara T, Aiello L. Leukaemic military nodule in retina. Arch Ophthalmol, 1964;
72:494497.
11. Schworm HD, Nasemann JE, Schriever S. Subretinalhypopyon in
prolymphocyticleukaemia.Br J Ophthalmol. 1995; 79:863864.
12. Kanski JJ, Bowling B .Retinal Vascular Disease. In Clinical Ophthalmology A
Systemic Approach. R. Gabbedy, ed. Saunders Co, London 2011.
13. Jampol LM, Goldberg MF, Busse B. Peripheral retinal micro aneurysms in chronic
leukaemia. Am J Ophthalmol, 1975; 80:242 248.
14. Nikaido H, Mishima H, Ono H, et al. Leukemic involvement of the optic nerve. Am
J Ophthalmol 1988; 105:294-298.
15. Ribera JM, Ortega JJ. Leucemial infoideaguda. In: Hematologa, 2003: pp 1029-
1042.
16. Lin YC, Wang AG, Yen MY, et al. Leukaemic infiltration of the optic nerve as the
initial manifestation of leukaemic relapse.Eye 2004;18:546-550.
17. Mayo GL, Carter JE, McKinnon SJ. Bilateral optic disk edema and blindness as
initial presentation of acute lymphocytic leukemia. Am J Ophthalmol
2002;134:141-142.

, 76, 1, 2014 608

18. Mateo J, Abarzuza R, Nez E, et al. Infiltracin bilateral del nervioptico enun
caso de leukemia aguda linfoblstica de clulas T en remisin. Arch Soc Esp
Oftalmol 2007; 82:167-170.
19. Joshi L, Taylor SRJ, Large O, et al. A case of optic neuropathy after short-term
linezolid use in a patient with acute lymphocytic leukemia. Clin Infect Dis 2009;4
8:73-74..
20. Bhatt UK, Gregory ME, Madi MS et al. Sequential leukemicinfiltration and human
herpervirus optic neuropathy in acute lymphoblasticleukemia.Journal of AAPOS
2008;12:200-202.
21. Cleveland KO, Gelfand MS. Optic neuropathy following linezolid use in a patient
with acute lymphocytic leukemia. Clin Infect Dis 2009: 49:645646.
22. Bandyopadhyay S, Das D, Das G, Gayen S. Unilateral optic nerve infiltration as an
initial site of relapse of acute lymphoblastic leukemia in remission. Oman J
Ophthalmol 2010; 3:153-154.
23. Ribera JM. Tratamiento de la leukemia aguda linfoblastica del adulto, In:
Hematologia clnica 5th ed. Sans-Sabrafen S, Besses C, Vives JL. 2006; 451-
460.
24. Ortega JJ. Leucemias agudas infantiles. In: Hematologa clnica 5th ed. Sans-
Sabrafen S,Besses C, Vives JL. 2006; 437-450.
25. Kim J, Chang W, Sagong M. Bilateral serous retinal detachment as a presenting
signof acute lymphoblastic leukemia. Korean J Ophthalmol, 2010;24(4):245-248.
26. Yang HK, Yu HG. Acute lymphoblastic leukemia manifesting as acute Vogt-
Koyanagi-Harada disease. Korean J Ophthalmol. 2009;23(4):325-328.
27. Sbeity MH, Coupland S, Loeffler KU. High-grade malignant B-celllymphoma of the
retina in a patient with concomitant gastric MALT lymphoma. Graefes Arch Clin
Exp Ophthalmol 2007; 45:448450.
28. Valvassori GE, Sabnis SS, Mafee RF, et al. Imaging of orbital lymphoproliferative
disorders. RadiolClin North Am. Jan 1999; 37:135-150.
29. Shields AJ, Shields LC, Scartozzi R. "Survey of 1264 patients with orbital tumors
and simulating lesions". Ophthalmology 2004; 111(5): 9971008.
30. Peer J, Hochberg FH, Foster CS. Clinical review: Treatment of vitreoretinal
lymphoma. OculImmunolInflam 2009;17(5):299-306.
31. Char DH, Ljung BM, Miller T, et al Primary intraocular lymphoma (ocular reticulum
cell sarcoma) diagnosis and management. Ophthalmology 1988; 95:625-630.

, 76, 1, 2014 609

32. Gass JD, Sever RJ, Grizzard WS, et al. Multifocal pigment epithelial detachments
by reticulum cell sarcoma. A characteristic funduscopic picture. Retina
1984;4:135-143.
33. Gass JD, Trattler HL. Retinal artery obstruction and atheromas associated with
non-Hodgkins large cell lymphoma (reticulum cell sarcoma). Arch Ophthalmol
1991; 109:1134-1139.
34. Michelson JB, Michelson PE, Bordin GM, et al. Ocular reticulum cell sarcoma.
Presentation as retinal detachment with demonstration of monoclonal
immunoglobulin light chains on the vitreous cells. Arch Ophthalmol 1981; 99:1409-
1411.
35. Purvin V, Van Dyk HJ. Primary reticulum cell sarcoma of the brain presenting as
steroid-responsive optic neuropathy. J Clin Neuro-ophthalmol 1984; 4:15-23.
36. Kanski JJ, Bowling B .Ocular Tumors In: 7th ed. Clinical Ophthalmology A
Systemic Approach, R. Gabbedy, ed. Saunders Co, London 2011.
37. Coupland SE, Damato B. Understanding intraocular lymphomas. Clin Exp
Ophthalmol 2008;36:564-578.
38. Abramson DH, Schefler AC. Update on retinoblastoma. Retina. 2004;24:828848.
39. Fontanesi J, Pratt C, Meyer D, et al. Asynchronous bilateral retinoblastoma: the
St. Jude Children's Research Hospital experience. Ophthalmic Genet.
1995;16:109112.
40. Aerts I, Pacquement H, Doz F, et.al. Outcome of second malignancies after
retinoblastoma: a retrospective analysis of 25 patients treated at the Institut Curie.
Eur J Cancer. 2004; 40:1522-1529.
41. Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term
survivors of retinoblastoma. J Natl Cancer Inst. 1993;85:11211128.
42. Kumar, Vinay (2009). "Uvea: Neoplasms". Robbins and Cotran Pathologic Basis of
Disease, Professional Edition. (8th ed.). Philadelphia, PA: Elsevier.
43. Yanoff M, et al. Ophthalmology. 3rd ed. Edinburgh, U.K.: Mosby Elsevier; 2009.
44. Intraocular (eye) melanoma treatment (PDQ). National Cancer Institute.
http://www.cancer.gov/cancertopics/pdq/treatment/intraocularmelanoma/patient.
Accessed June 5, 2012.
45. , ., . et. Al.
.21
, 2006, p335-336.

, 76, 1, 2014 610



1, ,
1
, 2 , 3
, & , ...

:
: 6936136215
-mail: pdedeilias@gmail.com

, 1960.


.
,
.
,
/.


.
,

.

,
,
/ .
.
, 76, 1, 611-617, 2014.

, 76, 1, 2014 611

 : , ,
, .

SUMMARY
DEDEILIAS P, ARGIRIOU M, CHARITOS C. Aortic valve replacement with
sutureless self-anchoring biological valve. Since 1960 when the first aortic valve
replacement with cardiopulmonary bypass was performed this type of surgery remains
the gold standard for the treatment of symptomatic aortic valve stenosis. Although
through the years various valves have been designed the basic technique of
implantation remains more or less the same. Numerous disadvantages have been
related to this technique namely prolonged bypass time and its consequences, as well
as patient-prosthesis mismatch, being the most important especially in recent years
with an increase to the ageing population requiring surgical treatment of aortic valve
stenosis. In this era a new sutureless, stentless self-anchoring biological prosthesis
has been proposed with very promising characteristics. This type of valve combines
the benefits of open valve replacement and transcatheter devices. Initial reports
describe decreased ischemic and bypass time, decreased stroke rate and
paravalvular leaks and satisfactory avoidance of mismatch. We describe the technique
and present our initial experience. Nosokomiaka Chronika, 76, Supplement 1, 611-
617, 2014.
Key words: sutureless aortic valve replacement, stentless valve, Perceval S,
minimally invasive aortic valve replacement.

1952

1. 1960


2,3,4.
5.

60

, 76, 1, 2014 612

 60
(Class IIa, level C)6.

.
,
.
,
60-90 .
.

,
.

,

(patientprosthesis mismatch)7.

8.

.

:
1. .
2.
Ross.
3.
(Manouguian).
,
,

9,10,11.

, 76, 1, 2014 613

 ,

12.

.

13.
,

. ,
,
,
14 ( 1).
3
40 4

( 2).

1. ,

, 76, 1, 2014 614

 2.
...
(2013) , ,
15
Euroscore > 6
( SVP). 20

( BVP). ,
1,



.

, , .

.

,
, . ,
, , ,

, 76, 1, 2014 615


. ,
,
.
.

1. ...

SVP BVP
P
(n = 15) (n = 20)

(n) 15 20

(MO ) 78 75

/ 5/10 9/11
max gradient
8810.5 8912.5
(cm/sec)

max gradient
23.519.20 24.519.90 0.670
(cm/sec)

(cm2) 1.50.3 1.10.5 0.002

(min) 149.3815.22 206.6442.85 p<0.001

CPB time (min) 73.758.12 120.3628.31 p<0.001

(min) 405.50 8615.86 p<0.001

13/15 2/20

0/15 1/20*

SVP , BVP
* :

, 76, 1, 2014 616


1. Hufnagel CA, Harvey WP. The surgical correction of aortic regurgitation
preliminary report. Bull Georgetown Univ Med Cut 1953; 6:60-63.
2. Shioho M, Sezai Y, Sezai A, et al. Long-term results of the cloth-covered Starr-
Edwards ball valve. Am Thorac Surg 2005 ;80:204-209.
3. Oxenham H, Bloomfield P, Wheathey DJ, et al. Twenty-year comparison of a
Bjork-Shiley heart-valve with porcine bioprosthesis. Surg Forum 1979 ;30:235-
242.
4. Emery RW, Krogh CC, Jones DJ, et al. Five-year follow-up of the ATS mechanism
heart-valve. J Heart Valve Dis 2004 ;13:231-237.
5. Gott VL, Alejo DE, Cameton DE. Mechanical heart-valves: 50 years of evolution.
Am Thorac Surg 2003; 76:S2230-9.
6. Guidelines on the management of valvular heart disease (reunion 2012).
European Heart J 2012; 33:2451-2496.
7. Rahimtoola SH. The problem of prosthesis-patient mismatch. Circulation 1978;
58:20-24.
8. Mothy D, Dumesuil JG, Echahidi N, Mathieu P. Impact of prosthesis-patient
mismatch on long-term survival after aortic valve replacement: influence of age,
obesity and left ventricular dysfunction. JACC 2009; 53:39-47.
9. Manouguian S, Seyblod-Epting W. Patch enlargement of the aortic valve ring by
extending the aortic incision to the anterior mitral leaflet. J Thorac Cardiovasc
Surg 1979; 78:402-412.
10. Goutinho GF, Correia PM, Pauperio G, et al. Aortic root enlargement does not
increase the surgical risk and short-term patient outcome. Eur J Cardiothorac Surg
2011; 40:441-447.
11. Kulik A, Al-Saigh M, Chan V, et al. Enlargement of the small aortic root during
aortic valve replacement: is there a benefit? Ann Thorac Surg 2008; 85:94-101.
12. Shrestha M, Folliguet T, Meuris B, et al. Sutureless Perceval S aortic valve
replacement: a multicenter prospective pilot trial. J Heart Valve Dis 2009; 18:11.
13. Shrestha M, Maeding I, Kffler K, et al. Aortic valve replacement in geriatric
patients with small aortic roots: are sutureless valves the future? Interactive
Cardiovasc & Thorac Surg 2013; 17:778-783.
14. Santorpino G, Pfeiffer S, Pollari F, et al. Left ventricular mass regression after
sutureless implantation of the Perceval S aortic valve bioprosthesis: preliminary
results. Interact Cardiovasc & Thorac Surg 2014;38-42.

, 76, 1, 2014 617


itraClip (edge-to-edge-repair)

', K ...

:
: 6972081810
E-mail: dstal@otenet.gr

H (MR)

.
MR, . ,
2%
MR
. MitraClip


,
MR
(eart team).
MitraClip

. , 76,
1, 618-625, 2014.
: MitralClip, edge-to-edge repair, ,

SUMMARY
STALIKAS D. Percutaneous mitral valve repair using the MitraClip system. Mitral
regurgitation (MR) is the most common type of heart valve insufficiency in the US and
the second most frequent valve disease requiring surgery. There are more than four
million patients with significant MR, and the prevalence increases with increasing age.
Surprisingly, only 2% are being surgically treated and a large portion of MR patients
are left untreated due to ineligibility for surgical treatment or concerns about surgical

, 76, 1, 2014 618

risk. MitraClip is the world's first percutaneous mitral valve repair therapy available
with an excellent safety profile and clinically important results providing an option for
select patients with significant, symptomatic, degenerative MR who have been
determined to be at prohibitive risk for mitral valve surgery by a heart team.wo trials
are now underway to evaluate the safety and efficacy of the use of the MitraClip
device for the treatment of significant functional MR in heart failure patients.
Nosokomiaka Chronika, 76, Supplement 1, 618-625, 2014.
Key words: MitraClip, mitral regurgitation, percutaneous mitral valve repair

, , ,
.

.
/
(
) flail
, (
)
.
H (MR)

.
MR,
9,3%
75 1. , 2% ( 30.000 )
2 MR

3.
,
, MR
( ).
,

(class I)

, 76, 1, 2014 619

 (class b)4.
,

.

MR, edge-to-edge mitral clip (Abbott
Vascular, Menlo Park, CA)

Alfieri . (1992)
2-P2
5. MitraClip CE Mark
2008,
10.000
2013 ( 1).

EVEREST II Feldman et al (2011) 279
(3-4+) (MR)
2:1
(n = 184) (n = 95)
.
MR
.
,
MR (3-4+) 12 .

30 . 12 ,
55 %
73 % .
6%,
20 % 2 % MR (3-4+) 21% 20 % .
15%
48%
30 . 12
, NYHA .

, 76, 1, 2014 620


12 ,
6.

1. Mitral clip system.

4
EVEREST II

, 76, 1, 2014 621

 39,8%
53,4% (p = 0.070).
, 17,4% 17,8% (p = 0,914)
MR (3-4+) 21,7% 24,7% (p = 0.745)
MV 24,8% 5,5% ( <0,001) 4.
,

MR. ,
,

- MR 7.
Whitlow .(2012) EVEREST II High Risk Registry
mitral clip 78

(MR 3-4+) 12 %.
, MR ( 3 +)
,

MitraClip (n = 36).
96 % .
30
MitraClip (7,7 % 8,3%)
MitraClip (76% 55%).
mitral clip 78 % MR 2 +.
172 ml 140ml,
82 ml 73 ml. NYHA III / IV 89 %
I / II 74%. QoL
0,59 0,32.
, MitraClip MR


12 .

8.

, 76, 1, 2014 622


EVEREST II mitral clip 2008
CE mark
, R.
80
. registries
,
.
ACCESS-U registry (Maisano et al, 2013)
MitraClip 99,6%. 19 (3,4%)
30 Kaplan-Meier 1
81,8%. MR
(NYHA) 12 36 (6,3%)
, MitraClip
9.
PERMIT-CARE (
)
(Auricchio et al, 2011), TRAMI ( registry mitral clip 1400 )
(Baldus et al, 2012), GRASP (
clip) (Grasso et al, 2013), MitraSwiss registry (Srder et al, 2013),
(Rudolph et al, 2011)10-15
,
EVEREST II, high risk EVEREST registry,
MitraClip
MR,

. ,


MR
.
MR,

.

, 76, 1, 2014 623

 COAPT
RESHAPE-HF ,
MitraClip /
_>3+
.
COAPT RESHAPE - HF

MitraClip
MR.

1. Nkomo VT, Gardin JM, Skelton TN et al. Burden of valvular heart diseases: a
population-based study, Lancet 2006; 368(9540):1005-1011.
2. Gammie JS, Sheng S, Griffith BP, et al. Trends in mitral valve surgery in the
United States: results from the Society of Thoracic Surgeons Adult Cardiac
Surgery Database, Ann Thorac Surg 2009;87(5):1431-1437, discussion 1437-
1439.
3. Mirabel M, Iung B, Baron G et al. What are the characteristics of patients with
severe, symptomatic, mitral regurgitation who are denied surgery? Eur Heart J
2007;28(11):1358-1365.
4. Joint Task Force on the Management of Valvular Heart Disease of the European
Society of Cardiology, European Association for Cardio-Thoracic Surgery,
Vahanian A et al. Guidelines on the management of valvular heart disease
(version 2012), Eur Heart J 2012;33(19):2451-2496.
5. Alfieri O, Maisano F, De Bonis M, et al. The double-orifice technique in mitral valve
repair: a simple solution for complexproblems, J Thorac Cardiovasc Surg
2001;122(4):674-681.
6. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral
regurgitation, N Engl J Med 2011;364(15):1395-1406.
7. Mauri L, Foster E, Glower DD et al. 4-year results of a randomized controlled trial
of percutaneous repair versus surgery for mitral regurgitation, J Am Coll Cardiol
2013;62(4):317-328.
8. Whitlow PL, Feldman T, Pedersen WR et al. Acute and 12-month results with
catheter-based mitral valve leaflet repair: the EVEREST II (Endovascular Valve
Edge-to-Edge Repair) High Risk Study, J Am Coll Cardiol 2012;59(2):130-139.

, 76, 1, 2014 624

9. Maisano F, Franzen O, Baldus S et al. Percutaneous mitral valve interventions in
the real world: early and one year results from the ACCESS-EU, a prospective,
multicenter, non-randomized post-approval study of the MitraClip(R) therapy in
Europe, J Am Coll Cardiol, Published online ahead of print June 6, 2013.
10. Auricchio A, Schillinger W, Meyer S et al. Correction of mitral regurgitation in
nonresponders to cardiac resynchronization therapy by MitraClip improves
symptoms and promotes reverse remodeling, JACC 2011;58(21):2183-2189.
11. Schillinger W, Hunlich M, Baldus S et al. Acute outcomes after MitraClip therapy in
highly aged patients: results from the German TRAnscatheter Mitral valve
Interventions (TRAMI) Registry, EuroIntervention 2013;9(1):84-90.
12. Armoiry X, Brochet E, Lefevre T et al. Initial French experience of percutaneous
mitral valve repair with the MitraClip: a multicentre national registry, Arch
Cardiovasc Dis 2013;106(5):287-294.
13. Rudolph V, Lubos E, Schluter M et al. Aetiology of mitral regurgitation differentially
affects 2-year adverse outcomes after MitraClip therapy in high-risk patients, Eur J
Heart Fail 2013;15(7):796-807.
14. Frerker C, Schafer U, Schewel D et al. Percutaneous approaches for mitral valve
interventions--a real alternative technique for standard cardiac surgery? Herz
2009;34(6):444-450.
15. Masson JB, Webb JG. Percutaneous treatment of mitral regurgitation. Circ
Cardiovasc Interv 2009;2(2):140-146.

, 76, 1, 2014 625



( )

. 1, . 2
1
, 2 ,
..

:
: 2132041972-3
E-mail: johnkalog@yahoo.gr

, .

.
,
(d-dimers).

. ,

(. , )
-.
10%
( ,
, ).

.
( )
. ,
76, 1, 626-641, 2014.
: - ,

, 76, 1, 2014 626

 SUMMARY
KALOGEROPOULOS J, KOLOFOUSI C. The role of chest x-ray in the diagnosis
of pulmonary embolism. Acute pulmonary embolism refers to embolic occlusion of
the main pulmonary artery or its branches. It is a common vascular disease of
thrombotic or non-thrombotic etiology, with high morbidity and mortality without early
treatment with anticoagulants. The diagnosis of pulmonary embolism is based on an
algorithm that indicates which imaging study best fits every individual patient
depending on the clinical possibility and the laboratory tests (D-dimers). Overall, the
imaging method of choice is Computed Tomographic Angiography (CTA), which has
the highest negative prognostic value. Nevertheless, chest x-ray is still an important
tool used for the exclusion of other diseases (such as pneumothorax and pneumonia)
that may mimic pulmonary embolism clinically, as well as for the interpretation of
ventilation-perfusion lung scans (V-Q Scan). In the majority of cases, the radiographic
features are non-specific and only in about 10% of patients there are signs in chest x-
rays with a relatively high specificity but low sensitivity for pulmonary embolism (these
include decreased vascularity in the peripheral lung, enlargement of the central
pulmonary artery, pleura-based infarcts). Chronic pulmonary embolism is a rare
complication of acute pulmonary embolism, which usually leads to severe pulmonary
hypertension and cor pulmonale. The diagnosis is based basically on CTA and Digital
Subtracted Angiography (DSA). Radiographs are non-specific. Nosokomiaka
Chronika, 76, Supplement 1, 626-641, 2014.
Key words: acute-chronic pulmonary embolism, chest x-ray

H
()
( 1).
(>90%)
( )
, .
() () (Deep
Venous Thrombosis- DVT) ,
(Venous Thromboembolism-VTE).1,2
70%
3, , 50%
4. ,

, 76, 1, 2014 627


(, , , .).5
500-600.000 /.
60 , 3
.2

1. :
() / ().

, ( 1).1 ,
20%
( ).6

,
(~30%),

.
, ( d-dimers)
.

, 76, 1, 2014 628

 1. .

. ,
, - .
, , , ,
80%.2,5
2 (Wells score Geneva score)
,
.7,8

d-dimers
,
98%-100%.
. ,
d-dimers 100%
.9 ,
d-dimers
(, , )
.

, 76, 1, 2014 629

 , d-dimers

15% .
,
.9

.
.
:

-






( 2). , ,

.

9
(88% PIOPED) .
: 2,5
1. (.
, )
2. -

-, /
.2

: , ,
, ( 2).1,2,5,10

, 76, 1, 2014 630

 , <10%,
,
( Westermark),
( Fleischner) ( 3)

( Hampton) ( 4) ( 3).1,2,5,10

2. .

D-dimer
.
>40 <40
COPD /
/

V/Q Scan

CT

DSA

COPD: Chronic Obstructive Pulmonary Disease=

V/Q Scan: -
DSA: Digital Subtraction Angiography=

, 76, 1, 2014 631

 2. .

.

3. .
-
Westermark ( )

- Fleischner ( ).

, 76, 1, 2014 632

 4. .

( Hampton).

3.

% % PPV NPV

Westermark 14 92 38 76

Hampton 22 82 29 76

10 87 21 74

36 70 28 76

20 85 30 76

PPV: Positive Predictive Value=

NPV: Negative Predictive Value=

.
, ( ),
,
.
,

, 76, 1, 2014 633

 .5


.2
.
,

.2

.


( 4).

4:

.
:

,
.
, , ,
( ).

, 76, 1, 2014 634

 , , ,
.
.
( 5).11


1%-3%
20% .12 ,
, . ,
,
. ,

.13
O
1-2 ,
,
.
,
( 6).13

5:
. :
. :
.,
.

, 76, 1, 2014 635

 6: 2
. ()

,
().

80%.

. ,
.14
,
. ,
(
).
, ,
,
( 7).15

.
,
, , ,
.

, 76, 1, 2014 636

 ,
.11 ,
.16

7: .

. ()
.

,
,
,
.17

,
.
.
,
.
/ .

.
, ,
.

, 76, 1, 2014 637

 ,
,
,
( 8).2

8: .

( ).

.
, .
, 2-5
( 9).18

9:

.




.

().

, 76, 1, 2014 638


,
. , ,
,
.5,11

()
. ,
,
.
,
( 10).5

10:
. ( )
,

.

,

( 11).

.

, 76, 1, 2014 639

 ,
.11

11: .
() .. ()
.

1. Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and

management of acute pulmonary embolism: The Task Force for the Diagnosis and
Management of Acute Pulmonary Embolism of the European Society of Cardiology
(ESC). Eur Heart J 2008;29:2276-2315.
2. . , , ,
, 2012.
3. Kearon C. Natural history of venous thromboembolism. Circulation 2003;107(23
Suppl.1):122-130.
4. Moser KM, Fedullo PF, LitteJohn JK, et al. Frequent asymptomatic pulmonary
embolism in patients with deep venous thrombosis. JAMA 1994;271:223-225.
5. Han D, Lee KS, Franquet T, et al. Thombotic and nonthrombotic pulmonary arterial
embolism: spectrum of imaging. Radiographics 2003;23:1521-1539.
6. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes
in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet
1999:1386-1389.
7. Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the
bedside without diagnostic imaging: management of patients with suspected

, 76, 1, 2014 640

 pulmonary embolism presenting to the emergency department by using a simple
clinical model and d-dimer. Ann Intern Med 2001;135:98-107.
8. Le Gal G, Righini M, Roy P, et al. Prediction of pulmonary embolism in the
emergency department: The revised Geneva Score. Ann of Intern Med
2006;144:165-171.
9. Stein PD, Woodard PK, Weg JG, et al. Diagnostic pathways in acute pulmonary
embolism: recommendations of the PIOPED II Investigators. Radiology
2007;242:15-21.
10.Jean K, Smita P. Acute Pulmonary Embolism. Radiol Clin N Am 2010;48:31-50.
11.Rossi SE, Goodman PC, Franquet T. Nonthrombotic pulmonary emboli.AJR Am J
Roentgenol 2000;174:1499-1508.
12.Richards RR. Fat embolism syndrome. Can J Surg 1997;40:334-339.
13.Feldman F, Ellis K, Green WM. The fat embolism syndrome. Radiology
1975;114:535-542.
14.Burrows A, Khoo SK. The amniotic fluid embolism syndrome: 10 years experience
at a major teaching hospital. Aust N Z J Obstet Gynaecol 1995;35:245-250.
15.Fidler JL, Patz EF, Ravin CE. Cardiopulmonary complications of pregnancy:
radiographic findings. AJR Am J Roentgenol 1993;161:937-942.
16. Franquet T, Gimenez A, Prats R, et al. Thrombotic microangiopathy of pulmonary
tumors: a vascular cause of tree-in-bud pattern on CT. AJR Am J Roentgenol
2002;179:897-899.
17.Orebaugh SL. Venous air embolism: clinical and experimental considerations. Crit
Care Med 1992;20:1169-1177.
18. Chung JW, Park JH, Im JG, et al. Pulmonary oil embolism after transcatheter oily
chemoembolization of hepatocellular carcinoma. Radiology 1993;187:689-693.

, 76, 1, 2014 641


;

. 1, . 2
1
, 2,
...

:

: 2132045660, 6974313935
Email: ddcokkinos@yahoo.gr

.
, ,
.


. , 76,
1, 642-654, 2014.
: , , ,

SUMMARY
COKKINOS DD. ANTYPA GE. Urgent ultrasound of the lower extremity veins.
How useful is it? Ultrasound examination of the lower extremity veins is a routine
practice for detecting deep vein thrombosis during the assessment of patients with
pulmonary embolism suspicion. This article studies symptoms of thrombosis, anatomy
and terminology of lower extremity veins, as well as advantages and disadvantages of
ultrasound in this field. It also suggests examination protocols depending on the
severity and location of symptoms and examines the role of ultrasound in guidelines
for diagnosing deep vein thrombosis and pulmonary embolism. Nosokomiaka
Chronika, 76, Supplement 1, 642-654, 2014.
Key words: ultrasound, veins, thrombosis, pulmonary embolism

, 76, 1, 2014 642



,
.

(),
.
, , ,
,
.

, ,

50%, 90%
1. ,
.
,
.
-
- ,
.
, ,

. ,
,
Baker, , ,
, , ,
, , , -
3-5.

, ,
.

, 76, 1, 2014 643

 20-46%6, 7 14% .
,
. (20% , 3%
) ,
. .
, (
),
.
5 . .

( 1). , ,
, (11-23%
)8,9.

1. ()
() () .

2002. ,

, ( )
10
(International Interdisciplinary Consensus

, 76, 1, 2014 644

Committee on Venous Anatomical Terminology) ,
, .
,
Terminologia Anatomica11,12,
13-15. Terminologia Anatomica

(Federative Committee
on Anatomical Terminology-FCAT)
(International Federation of Associations of Anatomists-IFAA), 199810
.
,
12.

,
(B-
mode imaging), Doppler (Colour Doppler flow imaging)
(Doppler spectral analysis).
( 1-2 ),
.
B-mode ,
. ,
.
( )16
. ,
,
.
Valsalva
.
, ,

( 2). ,
( 3). ,

, 76, 1, 2014 645

( 4).
.

2. : ( )

(LFA) .

3. :
() .

, 76, 1, 2014 646

 4. : ()
() .
.

,
, ,
(.. ).

()
. , ,

( ).
,
,
1.

.
. ,
.
95%
98%2, .

, 76, 1, 2014 647

, ,
60% 80%1. ,
100% . , 1,6%
17.

.
(American College of
Radiology Standard for Performance of the Peripheral Venous Ultrasound
Examination),
, , 18,
.
1-2 .
(
- ). ,
, ,
.
19,3% 82,7%19.
,
. , ,
.

,
.
,
, 20,21.
1. 20%
19,22.
,
1.

(
) (
),

, 76, 1, 2014 648

 22, 54%.
,
22,3% 23. ,
1.

.
,
. ,

:
,
3.
,
,
( 5).
. ,
(>3 ) 1.
, 1
24,25
.

.
D-dimers
26.

.
1%27,28. ,
,

.

, 76, 1, 2014 649

 5. : ()
( )
.

, ,
.
. 3 .

29,30.
.
, ,
31.
.

.
, 6 , 48%
14%
, 76, 1, 2014 650
 2.
.

. ,
.

.
. ,
.
.
, .
,
.
. ,
. , ,
,

1.

.
,
,
.
(American College of Radiology Appropriateness Criteria for Clinical
Condition: Suspected Lower Extremity Deep Vein Thrombosis)
18. 32
,
.
33,
. ,

, 50% 34. ,
. ,

, 76, 1, 2014 651

 ,
.

,
.
, , ,
. ,
.
,
,

. ,
.

1. Bluth EI. Leg Swelling with Pain or Edema. In: Ultrasonography in Vascular
Disease. A Practical Approach to Clinical Problems. Bluth EI, Benson CB, Ralls
PW, Siegel MJ (editors). 2nd ed. Thieme, New York, Stuttgart 2008.
2. Cronan JJ. Venous thromboembolic disease. The role of US. Radiology 1993;
186: 619-630.
3. Hirsh J, Hull RD. Venous thromboembolism: natural history, diagnosis and
management. In: Hirsh J, Hull RD (editors). Diagnosis of Venous Thrombosis.
Boca Raton, FL: CRC Press 1987: 23-28.
4. Lutter KS, Kerr TM, Roedersheimer LR, et al. Superficial thrombophlebitis
diagnosed by duplex scanning. Surgery 1991; 110(1): 42-46.
5. Swett HA, Jaffe RB, MIff EB. Popliteal cysts: presentation as thrombophlebitis.
Radiology 1975; 115(3): 613-615.
6. Screaton NJ, Gillard JH, Berman LH, et al. Duplicated superficial femoral veins: a
source of error in the sonographic investigation of deep vein thrombosis.
Radiology 1998; 206(2): 397-401.
7. Cronan JJ. Venous duplex US of the lower extremities: effect of duplicated femoral
veins. Radiology 1998; 206(2): 308-309.

, 76, 1, 2014 652

8. Chengelis DL, Bendick PJ, Glover JL, et al. Progression of superficial venous
thrombosis to deep vein thrombosis. J Vasc Surg. 1996; 24(5): 745-749.
9. Jorgensen JO, Hanel KC, Morgan AM, et al. The incidence of deep venous
thrombosis in patients with superficial thrombophlebitis of the lower limbs. J Vasc
Surg 1993; 18(1): 70-73.
10. Bundens WP, Bergan JJ, Halasz NA, et al. The superficial femoral vein: a
potentially lethal misnomer. JAMA 1995; 274:1296-1298.
11. Federative Committee on Anatomical Terminology. Terminologia Anatomica-
International Anatomical Terminology. Thieme, Stuttgart 1998.
12. Caggiati A, Bergan JJ, Gloviczki P, et al. Nomenclature of the veins of the lower
limbs: an international interdisciplinary consensus statement. J Vasc Surg 2002;
36: 416-422.
13. Agur AMR, Lee MJ. Grants atlas of anatomy. 10th ed. Philadelphia, Pa: Lippincott
Williams & Wilkins, 1999; 317.
14. Moore KL, Agur AMR. Essential clinical anatomy. 2nd ed. Philadelphia, Pa:
Lippincott Williams & Wilkins, 2002; 344.
15. Clemente CD. Anatomy: a regional atlas of the human body. 3rd ed. Baltimore,
Md: Urban & Schwarzenberg, 1987.
16. Perlin SJ. Pulmonary embolism during compression US of the lower extremity.
Radiology 1992; 184(1): 165-166.
17. Theodorou SJ, Theodorou DJ, Kakitsubata Y. Sonography and venography of the
lower extremities for diagnosing deep vein thrombosis in symptomatic patients.
Clin Imaging 2003; 27(3): 180-183.
18. American College of Radiology Standard for Performance of the Peripheral
Venous Ultrasound Examination. Reston, VA: ACR; 1933.
19. Fraser JD, Anderson DR. Venous protocols, techniques, and interpretations of the
upper and lower extremities. Radiol Clin North Am 2004; 42(2): 279-296.
20. Righini M, Paris S, Le Gal G, et al. Clinical relevance of distal deep vein
thrombosis. Review of literature data. Thromb Haemost 2006; 95(1): 56-64.
21. Galanaud JP, Kahn SR, Khau Van Kien A, et al. [Epidemiology and management
of isolated distal deep venous thrombosis]. [Article in French]. Rev Med Interne
2012; 33(12): 678-685.
22. Pezzullo JA, Perkins AB, Cronan JJ. Symptomatic deep vein thrombosis:
diagnosis with limited compression US. Radiology 1996; 198(1): 67-70.

, 76, 1, 2014 653

23. Maki DD, Kumar N, Nguyen B, et al. Distribution of thrombi in acute lower
extremity deep venous thrombosis: implications for sonography and CT and MR
venography. AJR Am J Roentgenol 2000; 175(5): 1299-1301.
24. Fiessinger JN, Huisman MV, Davidson BL, et al. Ximelagatran vs low-molecular-
weight heparin and warfarin for the treatment of deep vein thrombosis: a
randomized trial. JAMA 2005; 293(6): 681-689.
25. Gurewich V. Ximelagatran-promises and concerns. JAMA 2005; 293(6): 736-739.
26. Ginsberg JS. Management of venous thromboembolism. N Engl J Med 1996; 12;
335(24): 1816-1828.
27. Cronan JJ. Controversies in venous ultrasound. Semin Ultrasound CT MR 1997;
18: 33-38.
28. Naidich JB, Torre JR, Pellerito JS, et al. Suspected deep venous thrombosis: is
US of both legs necessary? Radiology 1996; 200(2): 429-431.
29. Rose SC, Zwiebel WJ, Nelson BD, et al. Symptomatic lower extremity deep
venous thrombosis: accuracy, limitations, and role of color duplex flow imaging in
diagnosis. Radiology 1990; 175(3): 639-644.
30. Foley WD, Middleton WD, Lawson TL, et al. Color Doppler ultrasound imaging of
lower-extremity venous disease. AJR Am J Roentgenol 1989; 152(2): 371-376.
31. Cronan JJ, Dorfman GS, Scola FH, et al. Deep venous thrombosis: US
assessment using vein compression. Radiology 1987; 162(1 Pt 1): 191-194.
32. The Royal College of Radiologists. Making the best use of clinical radiology
services: Referral Guidelines, sixth edition. London: The Royal College of
Radiologists, 2007.
33. .
. , 2011.
34. Needleman L, Polak J. Suspected lower extremity deep vein thrombosis. In:
American College of Radiology Appropriateness Criteria for Imaging and
Treatment Decisions. Reston VA: ACR; 1995: CV-8.1-8.6.6/j.revmed.2012.05.012.

, 76, 1, 2014 654

 :

.
, , - &
, ..

: 2107201748
-mail- jimexarhos@yahoo.com

( )
.
PIOPED II
.
, ,

.
, 76, 1, 655-660, 2014.
: ,

SUMMARY
EXARHOS DN. Pulmonary Embolism: Role of Multidetector computed
tomography. Investigators recommend stratification of all patients suspected of
having pulmonary embolism according to an objective probability evaluation. A
negative D-dimer result with a low or moderate probability clinical assessment can
safely exclude pulmonary embolism. If pulmonary embolism is not excluded, CT
angiography and venography is recommended by 77% of the PIOPED II investigators,
CT angiography alone is an option. In patients with discordant clinical and CT
findings, further evaluation depends on clinical judgment. In pregnant women,
pulmonary scintigraphy is recommended by 69% of the investigators as the first
imaging examination. Nosokomiaka Chronika, 76, Supplement 1, 655-660, 2014.
Key words: pulmonary embolism, multidetector computed tomography.

, 76, 1, 2014 655


H o
.
.
, .
,
. , ,


.


Wells .
,
,
. , 96-
100% 86-89% , 94-
100% 92-96% .
-
, <5% 10% ,

40%.


D-dimers.

O PIOPED II
(Prospective Investigation of Pulmonary Embolism Diagnosis)1.

.
1. D-dimer rapid ELISA2
2. E .
3.
77% PIOPED II

, 76, 1, 2014 656

 4.
3.
5. ,
.
6.
.

.
1. D-dimer rapid ELISA
2. E ,
.
3. ,
77% .
4.
.
5.
.
6. .

.
1. D-dimers

.
.
2. 77%
.
3.

(-)
.
4.
.

, 76, 1, 2014 657


. 5

.



( 0.3mmol/kg)4.
B. E 6

.
3ml/kg/hr
1ml/kg/hr 6 .
-
.
.
.
.
D-dimers 33% PIOPED II
69%
.
10-50mGy 0.28mGy.
. 7
D-dimers
31%
69%
.
.
U/S

30% PIOPED II.

.

, 76, 1, 2014 658


8
1.
2.
3.
4. ( , ,
, ,
).
5. - , .

, ,
. Dual
- .

-

9.

B
1. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for
acute pulmonary embolism. N Engl J Med 2006;354(22):2317-2327.
2. Van Belle A, Buller HR, Huisman MV, et al. Effectiveness of managing suspected
pulmonary embolism using an algorithm combining clinical probability, D-dimer
testing, and computed tomography. JAMA 2006;295(2):172-179.
3. Wittram C, Liu B, Callahan RJ, et al. An estimate of the radiation dose received per
patient for the investigation of pulmonary venous thromboembolism based on the
PIOPED data (abstr). In: Radiological Society of North America Scientific Assembly
and Annual Meeting Program. Oak Brook Ill: Radiological Society of North America,
2005;464.
4. Remy-Jardin M, Bahepar J, Lafitte JJ, et al. Multi-detector row CT angiography of
pulmonary circulation with gadolinium-based contrast agents: prospective
evaluation in 60 patients. Radiology 2006;238(3):1022-1035.
5. Chertow GM. Prevention of radiocontrast nephropathy: back to basics. JAMA
2004;291(19):2376-2377.

, 76, 1, 2014 659

6. Mathews S. Imaging pulmonary embolism in pregnancy: what is the most
appropriate imaging protocol? Br J Radiol 2006;79(941):441-444.
7. Stein P, Woodard P, Weg J, et al. Diagnostic pathways in Acute Pulmonary
Embolism: Recommendations of the PIOPED II Investigators. Radiology
2007;242:15-21.
8. Castaner E, Gallardo X, Ballesteros E, et al. CT diagnosis of chronic pulmonary
thromboembolism. Radiographics 2009; 29(1):31-50.
9. Johnson T. Dual Energy CTA Lung Perfusion (PE). Dual Source CT Imaging.
Springer-Medzin Verlag, 2005.

, 76, 1, 2014 660



, -
.. A.

:
: 6977597095
-mail: katiatav@yahoo.com

.
, (CTA)
. , .


.
, 76, 1, 661-667, 2014.
: , ,

SUMMARY
TAVERNARAKI E. MRA of the pulmonary artery for the diagnosis of pulmonary
embolism. Pulmonary embolism is an important cause of death in the industrialized
world. In symptomatic patients with a clinical suspicion f a pulmonary embolus, the
currently accepted imaging reference standard is CT angiography (CTA).
Unfortunately, the patient is exposed to ionizing radiation. In this study, we review the
effectiveness of magnetic resonance angiography (MRA) as an alternative method for
detection of pulmonary embolism. Nosokomiaka Chronika, 76, Supplement 1, 661-
667, 2014.
Key words: pulmonary embolism, magnetic resonance angiography, pulmonary
artery.

1,2. ,
(CTA) 3,4,5.

, 76, 1, 2014 661

 -
.
, 6
.
1-5mSv.
50mSv

,7
. ,

8.
,


.
9.
(PIOPED III)9 , ,

.
. ,


. 10,
(steady-
state precession) perfusion
.

(body multichannel
phased array coil) . 20 G
.
1.5 : 3D GRE T1
(Vasc TOF SPGR) (TR=3.4ms, TE=1.2ms, flip angle=25,
FOV=36cm, slice thickness=2.4mm, bandwidth 83.3Hz, 40slices per slab)10.
timing run

, 76, 1, 2014 662

 .
0.1mmol/kgr
3ml/sec 15ml
3ml/sec. .
workstations
.
.
,
1
11.

- PERFUSION
SEQUENCE UNENHANCED (SSFP) 2D ANGIOGRAPHY
Perfusion
3D Fast SPGR
(TR=2ms, TE=0.8ms, flip angle=20, FOV=48cm, slice thickness=6.4mm interpolated
to3.2mm, bandwidth 142.9Hz)10.
,
7 .
0.1mmol/kgr 5ml/sec 15ml
3ml/sec . ,
(subtraction)
.
unenhanced (SSFP) 2D
angiography
, 6 .
(TR=3.1ms, TE=1.3ms, flip angle=60, FOV=42cm, slice
thickness=1.4mm, bandwidth 125Hz).
TR=2.9ms, TE=1.2ms, slice
thickness=5mm10.

(PIOPED III)9
, ,

, 76, 1, 2014 663

 .
(CTA, D-Dimer,
, ) Wells.
78%
99% .
,
92% 96% . 91-98%
97-82%.
79%, 50% 0% - . ,
52% .
(67%), artifact (36%), wrap artifact (4%), parallel
imaging artifact (2%). ,

.
11
3
,
97% . 97.4%.

.

- ,
-
. ,
-
1,12,13.

(unenhanced angiography 2D steady-state-free precession- SSFP)

10.
,
.
. ,
14.

, 76, 1, 2014 664

 perfusion.
, 75% 79.3%
,
10. ,

RV/LV diameter ratio PE perfusion MRI
index15. ,
84% 55-73%
14.

-
.
,
.
15-21sec.

. ,
, ,
, 15.
: /
(<80mm Hg )/ , ,
24, ,
, ,
<60ml/min/1.73m, , ,
, ..9.

.
.
,
- ,
, .
-

, 76, 1, 2014 665


. ,
.

1. Van Beek EJ, Kuijer PM, Buller HR et al. The clinical course of patients with
suspected pulmonary embolism. Arch Intern Med 1997; 157:2593-2598.
2. Silverstein MD, Heit JA, Mohr DN et al. Trends in the incidence of deep vein
thrombosis and pulmonary embolism: a 25-yer population based study. Arch
Intern Med 1998; 158:585-593.
3. Ferretti GR, Bosson JL, Buffaz PD et al. Acute pulmonary embolism: role of helical
CT in 164 patients with intermediate probability at ventilation-perfusion
scintigraphy and normal results at duplex US of the legs. Radiology 1997;
205:453-458.
4. Stein PD, Woodard PK, Weg JG et al. Diagnostic pathways in acute pulmonary
embolism: recommendations of the PIOPED II investigators. Am J Med 2006;
119:1048-1055.
5. Perrier A, Roy PM, Sanchez O et al. Multidetector-row computed tomography in
suspected pulmonary embolism. N Engl J Med 2005; 352:1760-1768.
6. Qaseem A, Alguire P, Dallas P. et al. Appropriate use of screening and diagnostic
tests to foster high value, cost-conscious care. Ann Intern Med 2012; 156:147-
149.
7. Pearce MS, Salotti JA, Little MP, et al. Radiation exposure from CT scans in
childhood and subsequent risk of leukemia and brain tumors: a retrospective
cohort study. Lancet 2012; 380:499-505.
8. Li X, Samei E, Segars WP et al. Patient-specific radiation dose and cancer risk for
pediatric chest CT. Radiology 2011; 259:862-874.
9. Stein PD, Chenevert TL, Fowler SE et al. Gadolinium enhanced magnetic
resonance angiography for pulmonary embolism: a multicenter prospective study
(PIOPED III). Ann Intern Med 2010; 152:434-443.
10. Revel MP, Sanchez O, Lefort C. et al. Diagnostic accuracy of unenhanced,
contrast enhanced perfusion and angiographic MRI sequences for pulmonary
embolism diagnosis: results of independent sequence readings. Eur Radiol ;
2013:23:2374-2382.

, 76, 1, 2014 666

11. Schiebler M, Nagle S., Francois C et al. Effectiveness of MR Angiography for the
primary diagnosis of acute pulmonary embolism: clinical outcomes at 3months and
1 year. J Magn Reson Imaging; 2013:38:914-925.
12. Glassroth J. Imaging of pulmonary embolism: too much of a good thing? JAMA
2007; 298:2788-2789.
13. Wofford JL, Wells MD, Singh S. Best strategies for patient education about
anticoagulation with wafwarin: a systematic review. BMC Health Serv Res 2008;
8:40.
14. Kalb B, Sharma P, Tigges S, et al. MR imaging of pulmonary embolism: diagnostic
accuracy of contrast-enhanced 3D MR pulmonary angiography, contrast-
enhanced low-flip angle 3D GRE and non enhanced free-induction FISP
sequences. Radiology 2012; 263:271-278.
15. hno Y, Koyama H, Matsumoto K, et al. Dynamic MR Perfusion imaging:
capability for quantitative assessment of disease extent and prediction of outcome
for patients with acute pulmonary thromboembolism. J Magn Reson Imaging 2010;
31:1081-1091.

, 76, 1, 2014 667

 (MRV) ,

. . , .
, ,
...

:
.
: 2132041255
E-mail :benakis@hotmail.gr

. - ,
.

. ,


.
.
,
. , 76,
1, 668-673, 2014.
: , ,

SUMMARY
BENAKIS SV, TAVERNARAKI E. MR Venography of the lower extremities:
current status and future directions for the diagnosis of PE/DVT. Venous
thromboembolism (VTE) is a disease that causes high morbidity and mortality in the
population. At present the first-line imaging test for a suspected pulmonary embolism
(PE) is computed tomography (CT) pulmonary angiography, and ultrasonography is
widely used for the diagnosis of deep-vein thrombosis (DVT). Although these
modalities are proven to be safe and accurate, unresolved issues remain, such as
whether CT scanning in patients with a suspected PE should be extended to the legs.
Another issue is the diagnosis of recurrent DVT. Magnetic resonance imaging (MRI)

, 76, 1, 2014 668

offers a number of advantages in the imaging of VTE. Recent developments of
scanning protocols with shorter acquisition times, sometimes complemented by
navigator gating or making use of endogenous contrast, offer new perspectives for the
use of MRI. Nosokomiaka Chronika, 76, Supplement 1, 668-673, 2014.
Key words: MR venography, pulmonary embolism, deep vein thrombosis

,
. ,
(), -

.
.
-
, -
.
,
.
,
.
, ,
.
, .

.
-,
90.
(MRDTI-direct thrombus imaging),
,
.
- ,
,
.
,
,

, 76, 1, 2014 669

 ,
,
(3Tesla),
- ,

.
,
, ,
.

.
,

(, -),
, .
,
( )
.

.
. , ,
,
.
1
,
.
,
.

phase-contrast TOF (time of flight).

, .

, 76, 1, 2014 670

 ,
.
,
.
, ,
.
(3Tesla),
.

1:
,

First Technique /Gold Sensitivi Specifici

N Year Patients
author standard ty ty
Upper and lower Phase contrast/ Contrast
Erdman 100 1990 90 100
extremity venography
Phase contrast and cine 100
Evans 61 1993 Lower extremity 100
MR Contrast venography
Carpent Time of flight Contrast
85 1993 Lower extremity 100 96
er venography/US
Time of flight/ Contrast 98
Spritzer 199 1993 Lower extremity 97
venography
Time of flight Contrast 98
Dupas 25 1995 Pelvic vein 100
venography/US
Lower extremity 100
Laissy 37 1996 or pulmonary Time of flight /US 100
embolism
Phase contrast and cine
Evans 75 1996 Lower extremity 100 100
MR/ US
Time of flight /Contrast
Catalano 43 1997 Lower extremity 100 94
venography
MRDTI /Contrast
Fraser 101 2002 Lower extremity 100 100
venography
VESPA /Contrast
Fraser 55 2003 Lower extremity 100 97
venography
bSSFP /Contrast
Cantwell 24 2006 Lower extremity 100 98
venography
Westerb
43 2008 Lower extremity MRDTI/ US 95 100
eek
Upper and lower HASTE /Gadolinium
Pedrosa 24 2009 100 91
extremity enhanced MRV
J. Magn. Reson. Imaging 2010;32:1302-1312
DTI (direct thrombus imaging),
,

, 76, 1, 2014 671


, , .
.

.
(gadofosveset trisodium),
,
,
-,
, .

1. Barth MM, Smith MP, Pedrosa I, et al. Body MR imaging at 3.0 T: Understanding
the opportunities and challenges. Radiographics 2007;27:1445-1462.
2. Perazella MA, Rodby RA. Gadolinium-induced nephrogenic systemic fibrosis in
patients with kidney disease. Am J Med 2007;120:561-562.
3. Pleszewski B, Chartrand-Lefebvre C, Qanadli SD, et al. Gadolinium-enhanced
pulmonary magnetic resonance angiography in the diagnosis of acute pulmonary
embolism: a prospective study on 48 patients. Clin Imaging 2006;30:166-172.
4. Ersoy H, Zhang H, Prince MR: Peripheral MR angiography. J Cardiovasc Magn
Reson 2006;8:517-528.
5. Habibi R, Krishnam MS, Lohan DG, et al. High-spatial-resolution lower extremity
MR angiography at 3.0 T: contrast agent dose comparison study. Radiology
2008;248:680-692.
6. Rofsky NM, Johnson G, Adelman MA, et al. Peripheral vascular disease evaluated
with reduced-dose gadolinium enhanced MR angiography. Radiology
1997;205:163-169.
7. Klessen C, Hein PA, Huppertz A, et al. First-pass whole-body magnetic resonance
angiography (MRA) using the blood-pool contrast medium gadofosveset trisodium:
comparison to gadopentetate dimeglumine. Invest Radiol 2007;42:659-664.
8. Fenchel M, Doering J, Seeger A, et al. Ultrafast whole-body MR angiography with
two-dimensional parallel imaging at 3.0 T: feasibility study. Radiology
2009;250:254-263.
9. Miyazaki M, Lee VS: Nonenhanced MR angiography. Radiology 2008;248:20-43.

, 76, 1, 2014 672

10. Stalder AF, Russe MF, Frydrychowicz A, et al. Quantitative 2D and 3D phase
contrast MRI: optimized analysis of blood flow and vessel wall parameters. Magn
Reson Med 2008;60:1218-1231.

, 76, 1, 2014 673

 .

' , , ,
, ... '

:
o: 2132041072
E-mail: tkratimenos@gmail.com

1967
2003
FDA .
,
,
, .
,
,
2006
.
'' ''
,
25-30 (
) ,
.
,
,
,
. , 76,
1, 674, 2014.
: ,

, 76, 1, 2014 674



. .
, &
...

::
T: 2132041261
E-mail: eplesia@hotmail.com

.

.
, .
3 ,
,
,
,
.
.


(EFIC).
, 1 5 .
75.000.000 . 7 , 1/5
20 1/3 .
1 3
, 40%
, 1 6 ! 64%
.

.

, 76, 1, 2014 675
 .

.

,

, .
,
,
.
,

, .



, .

.

, 76, 1, 2014 676



, MD, PhD
, & ,
...

:
: 6977-297272
E-mail: diondiplas@hotmail.com

, .
20% .

.
,

,
..
,
,
,
.

.
,

. , 76,
1, 677-687, 2014.
:

, 76, 1, 2014 677

 SUMMARY
DIPLAS D. Chronic pain. Chronic pain is a pervasive problem that affects the patient,
their significant others, and society in many ways. WHO estimates that 20% of
individuals worldwide have some degree of chronic pain. The presence of chronic pain
has both direct health-care and associated indirect (e.g., disability payments, lost
productivity) costs. For most of those affected, the presence of chronic pain
compromises all aspects of their lives and the lives of their significant others. Despite
important advances in understanding of the neurophysiology of pain, the increasing
availability of advanced diagnostic procedures, and the application of sophisticated
therapeutic modalities and approaches, currently available treatments for chronic pain
rarely result in complete resolution of symptoms. Chronic non-cancer pain is typically
defined as pain lasting longer than 3 months or beyond the expected period of healing
of tissue pathology. Pain severity, however, is not correlated with the amount of
damage and symptoms can persist long after tissue damage from an antecedent injury
resolves. Research suggests that chronic non-cancer pain can develop as a result of
persistent stimulation of or changes to nociceptors due to localized tissue damage
from an acute injury or disease, or damage to the peripheral or central nervous
system, or both (e.g. painful diabetic neuropathy, post-stroke pain, spinal cord injury),
which might not be readily detectable with currently available diagnostic technologies.
Mechanisms underlying chronic pain include a complex interaction of physiological,
emotional, cognitive, social, and environmental factors. Treatment options include
pharmacological approaches; interventional techniques including nerve blocks,
surgery, implantable drug-delivery systems, and spinal-cord stimulators; exercise and
physical rehabilitation; psychological treatments; interdisciplinary treatment; and
complementary and alternative treatments. In view of the complex nature of chronic
pain, treatment often necessitates use of a blend of different approaches. Nosokomiaka
Chronika, 76, Supplement 1, 677-687, 2014.
Key words: chronic pain.

()1
.

,
.

, 76, 1, 2014 678


( , ..) 210
. .
26-49
2.
. International
Association for the Study of Pain (IASP) 2010-2011
:
100 .
80% .
70% .
2,1
.

80-85%
.

90% .


.

1979 IASP
,
.
: () (-
).
, ,
, .
.. ,
, , ..
, .
3-6
, ,

, 76, 1, 2014 679



3-6 3. ,

,


.
.
,
,

.

(nocipetion). . ,

4 .
(transduction) .

(), , +,
, , , , ,
.
(transmission)
.

.
, .. .

,
. (perception)
( , ,
), (modulation)

, 76, 1, 2014 680

 , .
.

(,
),
4.

, , .
(nociceptive)

. ,
, ,

. , , ,
, , . C .
C . , , ,
, .
, ..

. ,
, , ,
..


() ().
,
, ,
, , 5.
( ),
( , ,
), (, ),
( ),

, 76, 1, 2014 681


().

.
,

().
,
, , ,
, HIV, ..
(
, , , ), (
HIV ), (, ),
(, ),
( ,
), , ,
, CRPS I II, .
,


.
,
.

.
, .
.
( , )
.

,

. .

, 76, 1, 2014 682

 .
:
) .

,
, ,
.
,
, , .
) , .
) , .
.
) ,
().
) 6.

, ,
( ), (,
, ..), .


.
(, , ,
, ), ( 0
10 ), (visual
analog scale), (
), MPQ (The McGill Pain Questionnaire)
..
D4 .

.
. ,
, , , .

, 76, 1, 2014 683


,

.
.
,
( )
7.
:
(, , -
):
, .. 8.
( ): , , ,
, , , , ..:

..
9.
(, ,
, 2 , , ,
, , ..)
(, )
(, ..).
Ca

.

10.

.

Na
.
-
. (,
..) .

, 76, 1, 2014 684

 .
, ,

.
...,
: (1) :
, (2) : , (3)
: .

.

11.
,

.

.
97%

: 41%, 23%,
13%, 9%, 6%, 4%, 4%,
2%.

( , ,
, , ),
..

, (TENS), ,
, , ,
(biofeedback), ..
Lancet12 2011
Medline 2000 2010, Embase (2000-
2010) Cochrane (2005-2010)
, :

, 76, 1, 2014 685


188% 1996 2005 .


175% 1997 2006,


.

, , ,
..

.
,
.

.

,
,
,
.

1. Gureje O. Persistent pain and well-being: a World Health Organization Study in

Primary Care. JAMA 1998; 280:147-151.
2. Maniadakis N, Gray A. The economic burden of back pain in the UK. Pain 2000;
84:95-103.
3. Turk DC, Okifuji A. Pain terms and taxonomies of pain. In: Bonicas Management
of Pain SM Fishman, JC Ballantyne and JP Rathmell eds, Lippincott Williams &
Wilkins, New York 2009
4. Kingdom RT, Stanley KJ, Kizior RJ. (.: .
, : . ). , 2002.
5. . . (www.myoskeletiko.com).

, 76, 1, 2014 686

6. , , , , .
. , 2006.
7. Kroenke K, Krebs EE, Bair MJ. Pharmacotherapy of chronic pain: a synthesis of
recommendations from systematic reviews. Gen Hosp Psychiatry 2009; 31:206-
209.
8. Vo T, Rice AS, Dworkin RH. Non-steroidal anti-inflammatory drugs for
neuropathic pain: how do we explain continued widespread use? Pain 2009;
143:169-171.
9. . . :
, , , , ,
. , 2006
10. Verdu B, Decosterd I, Buclin T, et al. Antidepressants for the treatment of chronic
pain. Drugs 2008; 68:2611-2632.
11. Stein C, Reinecke H, Sogatz H. Opioid use in chronic non-cancer pain:
guidelines revisited. Curr Opin Anaesthesiol 2010; 23:598-601.
12. Turk DC, Wilson HD, Cahana A. Treatment of chronic non-cancer pain. Lancet
2011; 377(9784):2226-2235.

, 76, 1, 2014 687



. 1, . 2
1
, 2
, ...

:
.
: 2132043138
E-mail :gandreou_ore@yahoo.gr

-
.
, .
,
. , -

. ,
; ,

: 1. , 2.
, .. ,
3.
.

. ,

, organ specific

, .
- (organ specific)

, 76, 1, 2014 688

 .
(SLE),
DNA, ,
-
. Goodpasture,

. ,

. , 76, 1, 688-734,
2014.
: , , ,

SUMMARY
ANDREOUG, VOURLAKOUC. Autoimmune diseases-Histological diagnosis.
Immune reactions against self-antigensautoimmunity are an important cause of
certain diseases in humans. A growing number of diseases have been attributed to
autoimmunity but in many the evidence is not firm. Autoantibodies can be found in the
serum of apparently normal individuals, particularly in older age groups. Furthermore,
innocuous autoantibodies are also formed after tissue damage and may serve a
physiologic role in the removal of tissue breakdown products. How, then, does one
define pathologic autoimmunity? Ideally, at least three requirements should be met
before a disorder is categorized as truly due to autoimmunity: 1.Presence of an
autoimmune reaction; 2.Evidence that such a reaction is not secondary to tissue
damage, e.g., resulting from infection, but is of primary pathogenetic significance; and
3.Absence of another well-defined cause of the disease. Similarity with experimental
models of proven autoimmunity is also often used to support this mechanism in human
diseases. Autoimmune disorders may result from tissue injury caused by T cells or
antibodies that react against self-antigens. The autoimmune disorders form a
spectrum, on one end of which are conditions in which the immune response is
directed against a single organ or tissue, resulting in organ-specific disease, and on
the other end are diseases in which the autoimmune reaction is against widespread
antigens, resulting in generalized or systemic disease. Examples of organ - specific
autoimmunity are type I diabetes mellitus and multiple sclerosis. An example of
systemic autoimmune disease is SLE, in which a diversity of antibodies directed
against DNA, platelets, red cells, and protein-phospholipid complexes result in

, 76, 1, 2014 689

widespread lesions throughout the body. In the middle of the spectrum falls
Goodpasture syndrome, in which antibodies to basement membranes of lung and
kidney induce lesions in these organs. In many cases the morphological changes in
tissues biopsies are essential for diagnosis and prognosis of the diseases.
Nosokomiaka Chronika, 76, Supplement 1, 688-734, 2014.
Key words: autoimmune diseases, autoimmunity, inflammation, histological diagnosis

.
, ,
. - -
. -
.
( 1),
.
,
. ,

.
, , ;
,
: (1)
. (2)
, .. ,
(3)
.

.

.
, ,
.

, 76, 1, 2014 690


1,2.
(Direct evidence)

(Indirect evidence)

(Circumstantial evidence)

1.

Hashimoto


Sjogren
Reiter
Goodpasture
()

Graves

;
,
.


. ,
-,
, . ,

.

, 76, 1, 2014 691


, , ,
.
,
3,4.

,
, -.
-.
- -1,2.

, .
.

5,6.
(Direct evidence) ,
,
.
,
. ,
in vitro.


(adoptivetransfer)7,8.

(Indirect evidence). ,

.
, ,
,

.

HLA 3,4.

, 76, 1, 2014 692

 ,
(Circumstantial evidence),
.
,
, HLA,
, 9,10.
.
,
,
11,12.

(autoreactive)

. ,
(Teff) [effector Tcells (Teff)]
(Treg) [regulatory Tcells (Treg)]
- 13,14.
,
,
, 15.

(SLE)
SLE .
, ,
.
SLE, TREX1
(early)
16.
,
, , DHEA ,
,
SLE.
SLE. ,
.
.

, 76, 1, 2014 693


.
SLE
17,18.

(IC).
SLE
IC , ,
. SLE
, phospholipid-beta-2
glycoproteinIcomplex ( - --2).

.
.
19.
SL.


75 %
SLE.
20
.
, ()
,
Silent .
SLE,
(IC),
. , ,
21
. -
SLE,
,
(class) .
(class)
:
, [the International
Society of Nephrology/Renal Pathology Society or World Health Organization class],

, 76, 1, 2014 694


,
22,23.

.

,
.
, 500 mg /
(bland) ,

.
(class) .


(glomerulonephritides). ,
24.

HASHIMOTO
Hashimoto
, , ,

.
Hashimoto
(goitrousform),
HLA-DR5, (atrophicform),
HLA-DR3,

(thyroid peroxidase)
(thyroglobulin) 25.
SLE, ,
Sjogren, 2, Graves, ,
, MALT (80:1)
.
26.

, 76, 1, 2014 695

, ,
.
Hashimoto
. ,
() ,
TSH .
5% .
,
, 27.
Hashimoto
,
, - in vitro.
Hashimoto
.

.
: (aTh2 typeoffunction)

(aTh1 function) 27,28.

Hashimoto. (molecularmimicry)
- (bystander),

HLA
Fas-Fas (Fasligand-
Fasinteraction).
Hashimoto
.

,
. ,
TSH,
,
Riedel29.
. ,

, 76, 1, 2014 696


, emperipolesis.
(intrathyroidal)
27,28.
:
.

().
Hrthle/ /
.
, .
.
,
, ,
, , ...
.
,
(oxyphilic)
(nodularity),
30.

GRAVES (GRAVES DISEASE)

, ,
/pretibialmyxedema [scaly
5-10%
]. , (acropathy),
(clubbing) ,
. .
, , ,
Basedow ( ).
,
,
,
, .
-TSH : 1.Long-

, 76, 1, 2014 697

actingthyroidstimulator(LATS): IgG
TSH (. ). 2.
Graves' . 3. [Thyroid stimulatin
gimmunoglobulins (TSI)], LATS,
TSH. 4., ,
TSH TSH
. 5. (thyroid peroxidase)
(microsomalantigen - )
, (thyroglobulin)
Hashimoto 31,32.
:


.
, ,
.
, ,
, , scallopedmargins (
scalloping fixationartifact),
, ,
. (oncocytes) .
(15%), (13%)
, (grooves)
pseudonuclear (8%), , ,
(7%), (6 %)
psammomabodies (1 %).

(1 %).

- lymphnodesinuses30.
:

.
.

, 76, 1, 2014 698

 PTU .
(Radio active iodine)
, 33.
, ,
(nodularity) (oncocytic) .

(extraorbital) .

34,35
.

.

. ,
, ,
,
.
,

36,37
.,

.
[anti neutrophil cytoplasmic antibodies (ANCA)]
38.
:
Takayasu
(giantcellarteritis).
- ,
Kawasaki,
-
(Churg-Strauss),
(Granulomatosis with polyangiitis Wegeners), ,
Henoch-Schnlein (IgA ),
( ),

, 76, 1, 2014 699

 ,
39.


/ .
, , , ,
, , , , [

(casts) ] .
,
,
.

, .
, ,

.

,
,
, , ANCA,
, .

.
.
:
1.
2. ( )
3.
4.
5.-

.
,
38,40,41
.

, 76, 1, 2014 700

 (Granulomatosis with polyangiitis
Wegener), GPA, ,

.

, -
(ANCA). 85%
GPA ANCA.
Granulomatosis with polyangiitis (GPA)
,
3 (PR3), 70 80%
() 10% .
,
-2 [lysosome associated membrane protein-2 - LAMP-2] ,
.
GPA ,
, 38,42,43.
ANCAs
(, crypticsites)
.
antisense RNA PR3.
, GPA
-.
,
.
ANCA in vivo
ANCA. ANCA

-MPO - 44,45.

IGG4
[IMMUNOGLOBULING4-RELATED DISEASE - IgG4-RD]
G4 (Immunoglobulin
G4-relateddisease - IgG4-RD)
,

, 76, 1, 2014 701

 , 46.
46,47
.
.
()
,
IgG4- ,
- storiform . ,
IgG4 60 70%
IgG4-RD.
, .
(.. ),
.
,
, 1
(IgG4 )
.
( Mikulicz Kttner
). Sjgren,
.
IgG4 IgG4-
relateddisease48. ,
( 2). :
IgG4 (IgG4-RD)
.
49
. IgG4
,
.
, IgG4 50.
IgG4
IgG4-RD.
Castleman, , Churg-Strauss,
51
.
IgG4-RD
1 (IgG4
),

, 76, 1, 2014 702

IgG4,
II (classII)52.
,
(lactoferrin) (carbonic
anhydraseII).
Helicobacter pylori53. ,
,
54. ,
,
.

2. IgG4 (gG4-related disease)

IgG4 (IgG4-related disease)
IgG4 (IgG4-related systemic disease)
gG4 (gG4-syndrome)
gG4 (IgG4-associated disease)
gG4 (IgG4-related sclerosing disease)
gG4 (IgG4-related systemic
sclerosing disease)
gG4 (IgG4-related autoimmune disease)
gG4- (IgG4-positive
multiorgan lymphoproliferative syndrome)
-IgG4 (Hyper-IgG4 disease)
IgG4
(Systemic IgG4-related plasmacytic syndrome)
(Multifocal fibrosclerosis)
(Multifocal idiopathic fibrosclerosis)

Th2
IgE 55. , IgG4-RD
56.
(Tregs)
Tregs,
-10 (IL-10) transforming growth factor (TGF-)

, 76, 1, 2014 703

 . Th2, Tregs, IL-10
IgG4. 40% IgG4-RD
. , IgG4
,
57.
IgG4- (IgG4-RD associated disorders) -
, IgG4-
RD , , 46,56,57:
1 {Type 1 autoimmune pancreatitis (IgG4-
related pancreatitis)}
IgG4 (IgG4-related sclerosing
cholangitis)
Mikulicz {IgG4-
IgG4-related dacryoadenitis and sialadenitis)}
- Sclerosing sialadenitis ( Kttner, IgG4
- IgG4-related
submandibular gland disease)
{Inflammatory orbital
pseudotumor} [IgG4
(IgG4-related orbital
inflammation or orbital inflammatory pseudotumor)]
[Chronic sclerosing dacryoadenitis]
[ , IgG4
(lacrimal gland enlargement, IgG4-related dacryoadenitis)]
[A subset of
patients with idiopathic retroperitoneal fibrosis ( Ormond)]
[IgG4 , IgG4
(IgG4-related retroperitoneal fibrosis, IgG4-related
mesenteritis)]
(Chronic sclerosing aortitis and
periaortitis) [IgG4 (IgG4-related aortitis
or periaortitis)]
Riedel [IgG4 (IgG4-
related thyroid disease)]

, 76, 1, 2014 704

 IgG4
- IgG4-related interstitial pneumonitis and pulmonary inflammatory
pseudotumors [IgG4 (IgG4-related lung
disease)]
IgG4 (IgG4-related kidney disease) [

IgG4
(including tubulointerstitial nephritis and membranous
glomerulonephritis secondary to IgG4-RD)]
IgG4 - IgG4-related hypophysitis
IgG4 - IgG4-related pachymeningitis


. , ,
,
(80%),
(74%), (39%),
56
(22%), (13%) . ,
17%
IgG4-related , , ,
(17%) (9%)
57. IgG4-related
80% .
: IgG4-RD
,
IgG4- ,
, (obliterative phlebitis),
IgG450,55. (
40%) IgG4 ,
50,55.
,
50,55.
IgG4-RD
storiform ,
(cartwheel) ,

, 76, 1, 2014 705

 50
nuclearstreamingartifact .
.
.
.
IgG4-RD ,
. IgG4

, .
, ,
.
prednisone ,
,
IgG4 .
.
,
.
, .
,

. IgG4-RD
.

SJOGREN [Sjgrenssyndrome (SS)]

Sjgrens (SS)
.
SS
.
SS .
SS,
Sicca, (
58
) . , SS
. SS

(extraglandular) 58.

, 76, 1, 2014 706

 SS
.
SS :

, , Ro
/ SSA La / SSB , ,
(hypocomplementemia), - Hodgkin
, .

, ,
, .
, SS

/
.
(extraglandular)
Ro / SSA
,
.

, ,
,
SS
extraglandular .
Mikulicz IgG4:- 1892,
Mikulicz

59,60. 2005
SS
,
-Hodgkin SS59-61.
,
Mikulicz ,
IgG4-relateddisease.
IgG4 IgG4-,

, 76, 1, 2014 707

.
{IgG4 (dacryoadenitis) },
.
IgG4-relateddiseases
(
Kttner), 1 , IgG4 ,
(aortitis).
Mikulicz SS
, .
Mikulicz (, SS
, SS -Hodgkin
(extraglandular) , IgG4
), Mikulicz
.

Mickulicz,
IgG4.
1933, Henrik Sjgren
19 62.
.
Sjgren (kerato conjunctivitis
sicca - KCS) ,
KCS
.
SS
:
KCS


Ro/SSALa/SSB
(MRI)
-
SS.
61:
SS.

, 76, 1, 2014 708


.

.
,
61,63,64.

, .

, 50 4mm2
61,63,64
.
4mm2 SS.
CD4 (+)
.
65.

SS66.
.
, SS

66.
(labial)
focusscore,

200microns. ,
(multisection)
85-94% focusscores
. (multisection
) (94% ).
, ,
,
. ,
SS. -
(diffusescatterings) - ,

, 76, 1, 2014 709


SS.

SS
1980.
American-European Consensus Groupclassification
criteria67,68. , ,
2012 American College of Rheumatology Classification
Criteria for Sjgrens syndrome69.
American-EuropeanConsensusGroupcriteriaforSS [AECG]

SS . ,
SS
SS.
AECG
KCS .
(consensus criteria)
(
anti-Ro/SSAanti-La/SSB)
SS .

AECG ,
.
. :
1.
2.
3. 3.
4.

5.
6. (anti-Ro/SSA / anti-La/SSB).


:

, 76, 1, 2014 710

 / , C,
(AIDS), , ,
(Graft-versus-host disease),
69.
SS

, SS
(consensus rules)
:
anti-Ro/SSA/anti-
La/SSB .
97% 90%.
(
, , , ).
84% 95%.
96% 94%

SS.
SS
SS
(consensusrules)
:

.
:
1.
2.
3.

, (),
, , ,
, 70,71.
ACRclassificationcriteriaforSS

(consensus approach) Sjgrens International

, 76, 1, 2014 711

Collaborative Clinical Alliance (SICCA),
SS.
70,71
(ACR) 2012 .
ACR SS

.
SS.
European League Against Rheumatism.
SS
:
- SSA / anti SSB
1:320
Ocularstainingscore 3 (
)
, focus score 1 /
4 mm2 .
ACR AECG

(, ). ACR/SICCA
,
,
AECG
SS
SS.

SS. SS

/
.
American-European Consensus Group
SS.

, 76, 1, 2014 712

 [AUTOIMMUNE HEPATITIS].
.
( ),
. ,
,
.

.
(autoimmunologic) ,

72,73. 1950,
,
, ,
, ,
. 1992, International
Autoimmune Hepatitis Group ,
74.
.

.
.

: 1 2
1
1

() / (smoothmuscle-ASMA).
anti-actin().
AAA ,
ASMA 1:320 .
ELISA antiactin (IgG -anti F )
.
2
2
,

, 76, 1, 2014 713

 / (ALKM-1) /
(cytosolantigen -ALC-1).
(
variants),
(
).

.


73,75,76
.

2010 [American Association for the Study of Liver Diseases]
72 :
,
.
,
IgG - ,
(, SMA, - LKM - 1, - LC1), interface .

.
( ),

. ( ).

.
, - SLA pANCA
.


. ,

.

.

, 76, 1, 2014 714

 - ,

. ,
,
.
- ( ),
,
.
,
, ,
IgG .
,
. , IgA
1 ,
2 77.
:
:
(portal infiltrate),
, ,

(limitingplate)
( - periportalinfiltrate).
piecemealnecrosis interface
, ,
.
(centrizonal) . 77-79.
(
ductopenia) 25% .
.
,
,
(rosettes)
.
,
.

, 76, 1, 2014 715

 (bridging), ,
(lobule)
, .
IgG

.
: ,
1
, anti-smoothmuscle / anti-actin.
. 76,77.
1
,
(single-stranded) (-ssDNA) (-
double-stranded / -dsDNA) DNA. antineutrophil
() (p-ANCA),

, 1 .

, ANA, ASMA,
SLA/LP, ANCA, ALKM-1 .
, ,
. ,
(cryptogenic)
(cryptogenic) . -

.
(Scoringsystems):
International Autoimmune
Hepatitis Group
.
,
,
, IgG,
74,78,79.

, 76, 1, 2014 716

 : (onepoint), ANA SMA 1:40
(twopoints) ANA SMA 1:80 ( LKM 1:40
SLA ).
IgG: , IgG >
, IgG > 1,10 .
( ,
): (onepoint),
(twopoints),
.
interface ,
/
, emperipolesis (
),
.
,
.
: (twopoints),
. ,
C. ,
, .

,
.

- ,
.
, ,

, .


, -
(bileductpaucity), /

, 76, 1, 2014 717

 (periductular) ,
.
. ()
,
. ,
AMA
.
(I)
. ,

(PBC). , .

(overlapsyndromes) /
/ (
),
.
,
. ,
/
(
)
.
,
. ,
.
:
, ,
, /
, /
, , ,
, C, ,
, , -1-
, Wilson, AIDS,
( ), ,
, (Graft-

, 76, 1, 2014 718

versus-host disease GvHD), (Cryptogenic)
.

(PEMPHIGUS)

/ ,
(acantholysis) - --
(lossofcell-to-celladhesion). ,
(foliaceus) , IgA .
. .
, ,
pemphigusfoliaceus, foliaceus .



() .
80,81.
desmoglein ()

foliaceus .
desmoglein 1
, desmoglein 3
. desmoglein

profile ,

82,83.
(pemphigusvulgaris)
pemphigusfoliaceus.
.
pemphigusfoliaceus
. , ,
. IgA

84,85
.

, 76, 1, 2014 719



,
.

86-88.

[The inflammatory myopathies].

immune-mediated .


. :
1. . 2. (Overlapsyndromes)
. 3. (Inclusion
body myositis). 4..

.
, ,
.

89.

.
, aminoacylt RNA
synthetase (DM)
, (),
overlapsyndromes90,91.
,
,
.
Anti - Jo - 1 (anti-histidylt RNA synthetase),
myositis-specificauto antibodies (MSA)
91,92
PM DM .
30 - Jo - 1

, 76, 1, 2014 720

 92
, . ,
-Jo - 1
93. ,
(myositis-
associated) (specificautoantibodies)
.

,
(perifascicular)
(myofibers)94. ,

.

,
. ,
(perifascicular)
,
95.
DM, (transcripts)
96.
,
(perifascicular)
97.
, (DM),
(PM), [inclusion
bodymyositis (IBM)] ,
- (immune-mediated) .


,
.
DM
.
.
DM

, 76, 1, 2014 721

 .
myositis- specificauto antibodies .
IBM .
(myofibers) /
,
.
IBM,
.
IBM
.
, , cytosolic 5-nucleotidase 1A,
(myonuclear),

IBM.
PM
IBM,
PM DM. PM

. , P, IBM,
,
(type 1 interferon-inducibletranscripts). PM, DM,
(fascicle),
, ,
MHC .
(mediated) CD8 (+)
(myofibers).
(immunemediated necrotizing myopathy)
, ,
,
.
-SRP
.
,
(myofibers).
(endomysial), DM, PM IBM,

, 76, 1, 2014 722

 .
DM, (perifascicular)
.
(myofibers),
95.

.

.
, ,
(inclusionbodymyositis).93,95,98

(endomysial) (myonecrosis).

(CD8-)
(myofibers) MHC-I.
(endomysium),
.
(MRI)
.

91.

, (perifascicular) .
- [ CD4 (+)
-] ,
.
,
.

.
(tubuloreticular) (TRIs)
.
,
(inclusionbodymyositis).

, 76, 1, 2014 723

 - .
,
membranolytic attack complex (MAC),
.

(perifascicular
atrophy-PFA), .
PFA
(endomysial capillary bed).
,
(fascicle). .
, PFA .
CD4 (+)
.
1,
.
(titin),
() . ,
(perifascicular) PFA98,99.
(
- inclusionbodymyositis) ,
.
.

, , Raynaud,
.
-Jo-1 (antit RNA
synthetase) 100.

[connective tissue diseases- (CTD)]
,
(myonecrosis). ,
.
CTD, CTD, CTD,
(overlapsyndrome), .

, 76, 1, 2014 724

CTD .
,
,
.

INCLUSION BODY MYOSITIS

[Sporadic inclusion-body
myositis (s- )] .
,
(CK). s - IBM

. (CD8 -
)
101,102
.
(myelinoid bodies) .
, (basophilicgranules).

Gomori.
(myelinoid bodies).

(CongoRed). ,
Alzheimer.
s - IBM - (beta amyloid),
hyperphosphorylated tauprotein, apolipoprotein E, presenillin 1, prionprotein, -
synuclein ,
, Alzheimer
Parkinson103,104.
,

(myofibers)
(myofibers) . s - IBM

.
, 105,106.

, 76, 1, 2014 725

 PM, DM, IBM
. PM DM . ,
. IBM
.

- MYASTHENIAGRAVIS
gravis ,


(anticholinesterase), .
,
,
, .
. ,
. ,
(myonecrosis).
,
- ,
, .
. 10% gravis,
, (thymomas)
(follicularhyperplasia)
.

(AChR). IgG
(AChR) .
AChR -
.
( Tensilon) (neostigmine) .
, .

1. Rose NR. Autoimmune diseases: tracing the shared threads. Hosp Pract 1997;
32(4):147-154. (1995) 1997;32(4):147-54.

, 76, 1, 2014 726

2. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med 2001; 345(5):340-
350.
3. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies
before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003;
349(16):1526-1533.
4. Rose NR. Predictors of autoimmune disease: autoantibodies and beyond.
Autoimmunity 2008; 41(6):419-428.
5. Anhalt GJ, Labib RS, Voorhees JJ, et al. Induction of pemphigus in neonatal mice
by passive transfer of IgG from patients with the disease. N Engl J Med 1982;
306(20):1189-1196.
6. Burman KD, Baker JR Jr. Immune mechanisms in Graves' disease. Endocr Rev
1985; 6(2):183-232.
7. Drachman DB. How to recognize an antibody-mediated autoimmune disease:
Criteria. In: Immunologic Mechanisms in Neurologic and Psychiatric Disease,
Waksman BH (Ed), Raven, New York 1990. p.183-186.
8. Reichlin M, Brucato A, Frank MB, et al. Concentration of autoantibodies to native
60-kd Ro/SS-A and denatured 52-kd Ro/SS-A in eluates from the heart of a child
who died with congenital complete heart block. Arthritis Rheum 1994;
37(11):1698-1703.
9. Frustaci A, Cuoco L, Chimenti C, et al. Celiac disease associated with
autoimmune myocarditis. Circulation 2002; 105(22):2611-2618.
10. Eaton WW, Rose NR, Kalaydjian A, et al. Epidemiology of autoimmune diseases
in Denmark. J Autoimmun 2007; 29(1):1-9.
11. Mackay IR, Leskovsek NV, Rose NR. Cell damage and autoimmunity: a critical
appraisal. J Autoimmun 2008; 30(1):5-11.
12. Fairweather D, Frisancho-Kiss S, Rose NR. Viruses as adjuvants for
autoimmunity: evidence from Coxsackievirus-induced myocarditis. Rev Med Virol
2005; 15(1):17-27.
13. Grateau G, Duruz MT. Autoinflammatory conditions: when to suspect? How to
treat? Best Pract Res Clin Rheumatol 2010; 24(3):401-411.
14. Panigrahi AK, Goodman NG, Eisenberg RA, et al. RS rearrangement frequency
as a marker of receptor editing in lupus and type 1 diabetes. J Exp Med 2008;
205(13):2985-2994.
15. Nossal GJ. A purgative mastery. Nature 2001; 412(6848):685-686.

, 76, 1, 2014 727

16. Heinlen LD, McClain MT, Merrill J, et al. Clinical criteria for systemic lupus
erythematosus precede diagnosis, and associated autoantibodies are present
before clinical symptoms. Arthritis Rheum 2007; 56:2344-2351.
17. Hochberg MC. Updating the American College of Rheumatology revised criteria
for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;
40(9):p1725.
18. Petri M, Magder L. Classification criteria for systemic lupus erythematosus: a
review. Lupus 2004; 13(11):829-837.
19. Petri M, Orbai AM, Alarcn GS, et al. Derivation and validation of the Systemic
Lupus International Collaborating Clinics classification criteria for systemic lupus
erythematosus. Arthritis Rheum 2012; 64(8):2677-2686.
20. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of
glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004;
65(2):521-530.
21. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of
glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol
2004; 15(2):241-250.
22. Furness PN, Taub N. Interobserver reproducibility and application of the ISN/RPS
classification of lupus nephritis-a UK-wide study. Am J Surg Pathol 2006;
30(8):1030-1035.
23. Yokoyama H, Wada T, Hara A, et al. The outcome and a new ISN/RPS 2003
classification of lupus nephritis in Japanese. Kidney Int 2004; 66(6):2382-2388.
24. Huong DL, Papo T, Beaufils H, et al. Renal involvement in systemic lupus
erythematosus. A study of 180 patients from a single center. Medicine (Baltimore)
1999; 78(3):148-166.
25. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;
348:2646-2655.
26. Kon YC, DeGroot LJ. Painful Hashimoto's thyroiditis as an indication for
thyroidectomy: clinical characteristics and outcome in seven patients. J Clin
Endocrinol Metab 2003; 88(6):2667-2672.
27. Marinkovic T, Garin A, Yokota Y, et al. Interaction of mature CD3+CD4+ T cells
with dendritic cells triggers the development of tertiary lymphoid structures in the
thyroid. J Clin Invest 2006; 116(10):2622-2632.

, 76, 1, 2014 728

28. Matsuoka N, Unger P, Ben-Nun A, et al. Thyroglobulin-induced murine thyroiditis
assessed by intrathyroidal T cell receptor sequencing. J Immunol 1994;
152(5):2562-2568.
29. Kotani T, Umeki K, Hirai K, et al. Experimental murine thyroiditis induced by
porcine thyroid peroxidase and its transfer by the antigen-specific T cell line. Clin
Exp Immunol 1990; 80(1):11-18.
30. Nikiforov Y, Biddinger P, Thompson L, Diagnostic Pathology and Molecular
Genetics of the Thyroid 2nd ed. 2012: (p:43-69)
31. Feig C, Peter ME. How apoptosis got the immune system in shape. Eur J
Immunol 2007; 37 Suppl 1:S61-70.
32. Bossowski A, Czarnocka B, Bardadin K, et al. Identification of apoptotic proteins
in thyroid gland from patients with Graves' disease and Hashimoto's thyroiditis.
Autoimmunity 2008; 41(2):163-173.
33. Tamai H, Kasagi K, Takaichi Y, et al. Development of spontaneous
hypothyroidism in patients with Graves' disease treated with antithyroidal drugs:
clinical, immunological, and histological findings in 26 patients. J Clin Endocrinol
Metab 1989; 69:49-53.
34. Takasu N, Yamada T, Sato A, et al. Graves' disease following hypothyroidism
due to Hashimoto's disease: studies of eight cases. Clin Endocrinol (Oxf) 1990;
33(6):687-698.
35. Kraiem Z, Baron E, Kahana L, et al. Changes in stimulating and blocking TSH
receptor antibodies in a patient undergoing three cycles of transition from hypo to
hyper-thyroidism and back to hypothyroidism. Clin Endocrinol (Oxf) 1992;
36(2):211-214.
36. Langford CA. Chronic immunosuppressive therapy for systemic vasculitis. Curr
Opin Rheumatol 1997; 9:41-47.
37. Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med
2003; 349(2):160-169.
38. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill
Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;
65(1):1-11.
39. Watts RA, Scott DG. Recent developments in the classification and assessment
of vasculitis. Best Pract Res Clin Rheumatol 2009; 23(3):429-443.
40. Deng J, Ma-Krupa W, Gewirtz AT, et al. Toll-like receptors 4 and 5 induce distinct
types of vasculitis. Circ Res 2009; 104(4):488-495.

, 76, 1, 2014 729

41. Phillip R, Luqmani R. Mortality in systemic vasculitis: a systematic review. Clin
Exp Rheumatol 2008; 26:S94-104.
42. Hunder GG, Arend WP, Bloch DA, et al.The American College of Rheumatology
1990 criteria for the classification of vasculitis.Introduction. Arthritis Rheum 1990;
33:1065-1071.
43. Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997; 337:1512-
1523.
44. Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus
methodology for the classification of the ANCA-associated vasculitides and
polyarteritis nodosa for epidemiological studies.Ann Rheum Dis 2007; 66:222-
227.
45. Liu LJ, Chen M, Yu F, et al. Evaluation of a new algorithm in classification of
systemic vasculitis. Rheumatology (Oxford) 2008; 47(5):708-712.
46. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;
366(6):539-551.
47. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-
related autoimmune disease. J Gastroenterol 2003; 38(10):982-984.
48. Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease.
Curr Opin Rheumatol 2011; 23(1):57-66.
49. Okazaki K, Uchida K, Koyabu M, et al. Recent advances in the concept and
diagnosis of autoimmune pancreatitis and IgG4-related disease. J Gastroenterol
2011; 46(3):277-288.
50. Stone JH, Khosroshahi A, Deshpande V, et al. Recommendations for the
nomenclature of IgG4-related disease and its individual organ system
manifestations. Arthritis Rheum 2012; 64(10):3061-3067.
51. Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related
disease (IgG4RD): general concept and details. Mod Rheumatol 2012; 22(1):1-
14.
52. Cheuk W, Chan JK. IgG4-related sclerosing disease: a critical appraisal of an
evolving clinicopathologic entity. Adv Anat Pathol 2010; 17(5):303-332.
53. Deheragoda MG, Church NI, Rodriguez-Justo M, et al. The use of
immunoglobulin g4 immunostaining in diagnosing pancreatic and extrapancreatic
involvement in autoimmune pancreatitis. Clin Gastroenterol Hepatol 2007;
5(10):1229-1234.
54. Okazaki K, Chiba T. Autoimmune related pancreatitis. Gut 2002; 51(1):1-4.

, 76, 1, 2014 730

55. Smyrk TC. Pathological features of IgG4-related sclerosing disease. Curr Opin
Rheumatol 2011; 23(1):74-79.
56. Masaki Y, Dong L, Kurose N, et al. Proposal for a new clinical entity, IgG4-
positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-
related disorders. Ann Rheum Dis 2009; 68(8):1310-1315.
57. Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases.
Am J Surg Pathol 2010; 34(12):1812-1819.
58. Daniels TE, Fox PC. Salivary and oral components of Sjgren's
syndrome.Rheum Dis Clin North Am 1992; 18(3):571-589.
59. Mikulicz JH. Uber eine eigenartige symmetrische Erkrankung der Tranen- und
Mundspeicheldrusen. In: Beitr. Chir. Fortschr, Billroth GT (Ed), Stuttgart, 1892.
p.610-630.
60. Ihrler S, Harrison JD. Mikulicz's disease and Mikulicz's syndrome: analysis of the
original case report of 1892 in the light of current knowledge identifies a MALT
lymphoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 100(3):334-
339.
61. Lee M, Rutka JA, Slomovic AR, et al. Establishing guidelines for the role of minor
salivary gland biopsy in clinical practice for Sjgren's syndrome. J Rheumatol
1998; 25(2):247-253.
62. Sjgren H. Zur Kenntnis der Keratoconjunctivitis sicca. Acta Ophthalomol 1933;
11(suppl II):1-151.
63. Greenspan JS, Daniels TE, Talal N, et al. The histopathology of Sjgren's
syndrome in labial salivary gland biopsies. Oral Surg Oral Med Oral Pathol 1974;
37(2):217-229.
64. Daniels TE, Whitcher JP. Association of patterns of labial salivary gland
inflammation with keratoconjunctivitis sicca. Analysis of 618 patients with
suspected Sjgren's syndrome. Arthritis Rheum 1994; 37(6):869-877.
65. Vivino FB, Gala I, Hermann GA. Change in final diagnosis on second evaluation
of labial minor salivary gland biopsies. J Rheumatol 2002; 29(5):938-944.
66. Radfar L, Kleiner DE, Fox PC, et al. Prevalence and clinical significance of
lymphocytic foci in minor salivary glands of healthy volunteers. Arthritis Rheum
2002; 47(5):520-524.
67. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjgren's
syndrome: a revised version of the European criteria proposed by the American-
European Consensus Group. Ann Rheum Dis 2002; 61(6):554-558.

, 76, 1, 2014 731

68. Vitali C. Classification criteria for Sjgren's syndrome. Ann Rheum Dis 2003;
62(1):94-95.
69. Shiboski SC, Shiboski CH, Criswell L, et al. American College of Rheumatology
classification criteria for Sjgren's syndrome: a data-driven, expert consensus
approach in the Sjgren's International Collaborative Clinical Alliance cohort.
Arthritis Care Res (Hoboken) 2012; 64(4):475-487.
70. Cacoub P, Renou C, Rosenthal E, et al. Extrahepatic manifestations associated
with hepatitis C virus infection. A prospective multicenter study of 321 patients.
The GERMIVIC. Groupe d'Etude et de Recherche en Medecine Interne et
Maladies Infectieuses sur le Virus de l'Hepatite C. Medicine (Baltimore) 2000;
79(1):47-56.
71. Theander E, Jacobsson LT. Relationship of Sjgren's syndrome to other
connective tissue and autoimmune disorders. Rheum Dis Clin North Am 2008;
34(4):935-947.
72. Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of
autoimmune hepatitis. Hepatology 2010; 51(6):2193-2213.
73. Bjrnsson E, Talwalkar J, Treeprasertsuk S, et al. Patients with typical laboratory
features of autoimmune hepatitis rarely need a liver biopsy for diagnosis. Clin
Gastroenterol Hepatol 2011; 9(1):57-63.
74. Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group
Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;
31(5):929-938.
75. O'Brien C, Joshi S, Feld JJ, et al. Long-term follow-up of antimitochondrial
antibody-positive autoimmune hepatitis. Hepatology 2008; 48(2):550-556.
76. Frenzel C, Herkel J, Lth S, et al. Evaluation of F-actin ELISA for the diagnosis of
autoimmune hepatitis. Am J Gastroenterol 2006; 101(12):2731-2736.
77. Hofer H, Oesterreicher C, Wrba F, et al. Centrilobular necrosis in autoimmune
hepatitis: a histological feature associated with acute clinical presentation. J Clin
Pathol 2006; 59(3):246-249.
78. Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of
autoimmune hepatitis. Hepatology 2008; 48(1):169-176.
79. Chandhok N, Silveira MG and Keith D Lindor. Comparing the simplified and
international autoimmune hepatitis group criteria in primary sclerosing cholangitis.
Gastroenterol Hepatol (NY): 2010; 6(2): 108-112.

, 76, 1, 2014 732

80. Mihai S, Sitaru C. Immunopathology and molecular diagnosis of autoimmune
bullous diseases. J Cell Mol Med 2007; 11(3):462-481.
81. Sitaru C, Zillikens D. Mechanisms of blister induction by autoantibodies. Exp
Dermatol 2005; 14(12):861-875.
82. Hertl M, Eming R, Veldman C. T cell control in autoimmune bullous skin
disorders. J Clin Invest 2006; 116(5):1159-1166
83. Tsuruta D, Ishii N, Hamada T, et al. IgA pemphigus. Clin Dermatol 2011;
29(4):437-442.
84. Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: Clinical
manifestations. J Dtsch Dermatol Ges 2011; 9(10):844-856.
85. Feng S, Zhou W, Zhang J, et al. Analysis of 6 cases of drug-induced pemphigus.
Eur J Dermatol 2011; 21(5):696-699.
86. Torchia D, Romanelli P, Kerdel FA. Erythema multiforme and Stevens-Johnson
syndrome/toxic epidermal necrolysis associated with lupus erythematosus. J Am
Acad Dermatol 2012; 67(3):417-421.
87. Amagai M. Pemphigus. In: Dermatology, 3rd ed, Bolognia JL, Jorizzo JL,
Schaffer JV, et al. (Eds), Elsevier, 2012. Vol 1, p.461.
88. Payne AS, Stanley JR. Pemphigus. In: Fitzpatrick's Dermatology in General
Medicine, 8th ed, Goldsmith LA, Katz SI, Gilchrest BA, et al. (Eds), McGraw Hill,
2012. Vol 1, p.586.
89. Hoogendijk JE, Amato AA, Lecky BR, et al. 119th ENMC international workshop:
trial design in adult idiopathic inflammatory myopathies, with the exception of
inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands.
Neuromuscul Disord 2004; 14(5):337-345.
90. van der Meulen MF, Bronner IM, Hoogendijk JE, et al. Polymyositis: an
overdiagnosed entity. Neurology 2003; 61(3):316-321.
91. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003;
362:971-982.
92. Pedrol E, Grau JM, Casademont J, et al. Idiopathic inflammatory myopathies.
Immunohistochemical analysis of the major histocompatibility complex antigen
expression, inflammatory infiltrate phenotype and activation cell markers. Clin
Neuropathol 1995; 14(3):179-184.
93. Jego G, Pascual V, Palucka AK, et al. Dendritic cells control B cell growth and
differentiation. Curr Dir Autoimmun 2005; 8:124-139.

, 76, 1, 2014 733

94. Amato AA, Barohn RJ. Evaluation and treatment of inflammatory myopathies.J
Neurol Neurosurg Psychiatry 2009; 80(10):1060-1068.
95. Grable-Esposito P, Katzberg HD, Greenberg SA, et al. Immune-mediated
necrotizing myopathy associated with statins. Muscle Nerve 2010; 41(2):185-190.
96. Valiyil R, Casciola-Rosen L, Hong G, et al. Rituximab therapy for myopathy
associated with anti-signal recognition particle antibodies: a case series. Arthritis
Care Res (Hoboken) 2010; 62(9):1328-1334.
97. Miller T, Al-Lozi MT, Lopate G, et al. Myopathy with antibodies to the signal
recognition particle: clinical and pathological features. J Neurol Neurosurg
Psychiatry 2002; 73(4):420-428.
98. Grimley PM, Davis GL, Kang YH, et al. Tubuloreticular inclusions in peripheral
blood mononuclear cells related to systemic therapy with alpha-interferon. Lab
Invest 1985; 52(6):638-649.
99. Norton WL, Velayos E, Robison L. Endothelial inclusions in dermatomyositis. Ann
Rheum Dis 1970; 29(1):67-72.
100. Greenberg SA, Amato AA. Uncertainties in the pathogenesis of adult
dermatomyositis. Curr Opin Neurol 2004; 17:359-364.
101. Greenberg SA. Theories of the pathogenesis of inclusion body myositis. Curr
Rheumatol Rep 2010; 12(3):221-228.
102. Nishino H, Engel AG, Rima BK. Inclusion body myositis: the mumps virus
hypothesis. Ann Neurol 1989; 25(3):260-264.
103. Askanas V, Engel WK. Sporadic inclusion-body myositis and hereditary inclusion-
body myopathies: current concepts of diagnosis and pathogenesis. Curr Opin
Rheumatol 1998; 10(6):530-542.
104. Askanas V, Engel WK. Inclusion-body myositis: newest concepts of pathogenesis
and relation to aging and Alzheimer disease. J Neuropathol Exp Neurol 2001;
60(1):1-14.
105. Askanas V, Engel WK, McFerrin J, et al. Transthyretin Val122Ile, accumulated
Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology 2003;
61(2):257-260.
106. Westaway D, DeArmond SJ, Cayetano-Canlas J, et al. Degeneration of skeletal
muscle, peripheral nerves, and the central nervous system in transgenic mice
overexpressing wild-type prion proteins. Cell 1994; 76:117-129.

, 76, 1, 2014 734

 College of
American Pathologists (CAP 2012/13) American Joint Committee
on Cancer (AJCC/2010)

. 1, . 2
1
, 2 ,
...

:
: 2132043123
-mail: lohengrin_e@yahoo.gr

.
,
,
,
.
American Joint Committee on Cancer College of American Pathologists,

(consensus). , 76,
1, 735-745, 2014.
: American Joint Committee on Cancer, College of American
Pathologists, TNM.

ABSTRACT
KARAGKOUNIS G, ARGYRAKOS T. Oncological histopathology report
according to American Joint Committee on Cancer (AJCC 2010) and College of
American Pathologists (CAP 2012/13). Modern oncological histopathology reports
are currently being enriched with more information, mainly regarding the staging and
surgical margins of the neoplasms, as well as their molecular profile. This information
predicts the biological behavior, chooses the proper chemotherapeutic treatment and
examines the possibility of an inherited syndrome. The American Joint Committee on
Cancer in tandem with the College of American Pathologists examine such information

, 76, 1, 2014 735

and subsequently report them as worldwide agreements (consensus). Nosokomiaka
Chronika, 76, Supplement 1, 735-745, 2014.
Key words: American Joint Committee on Cancer, College of American Pathologists,
TNM.

E
American Joint Committee on Cancer (AJCC), 1959
International Union
for Cancer Control (UICC),
(consensus)
,
. 1977
2009, 1
2010, 7 .

8 2015, 1
2016, Mahul B. Amin,
Cedars-
Sinai, Los Angeles.
6-8

.
(College of
American Pathologists)
.

AJCC
TNM.

,
, 6 ,
. T
AJCC

, 76, 1, 2014 736


.

:
( )
4 .
c (cT, cN, cM / cTNM)
: , ,
,
.

cN.
:

4
, .
.
p (pT, pN, pM / pTNM).

() (working) .

.


( ) 1 4 (1,2
1 ) 5 9
(.. 1,7 .
2).
:

(neoadjuvant)
. y (y)
p c.

, 76, 1, 2014 737

 cTNM ycTNM
.
:
.
r (rTNM) retreatment.
:
(a).

(R) ()

R residual ( )
: R0
, R1
, R2
, Rx .
:
1. ,
2.

3.
, .
7 1.
, 2.

.
,

,
, R0.

(circumferential surgical margin / CSM)
R1 R2 4b
1/3
R0 4a ( 1).

, 76, 1, 2014 738

 6 4



. ,
2010 (WHO/2010),
(consensus)
.

,
.

1.

,

. AJCC/2010 ,

(Whipple)
,
( 2).

, 76, 1, 2014 739


.
AJCC/2010
,
<1
.

2.

AJCC , International
Society of Urologic Pathology,
. ,
(consensus),
. ,

,

, 1
,
, .

, 76, 1, 2014 740


/
. ,
.
in situ,
,

in situ .
,
,

, .
()
(isolated tumor
cells /ITCs) .
7 2006
, 0,2 mm
.


( MelanA HMB-45)
. ,
,

. ,

, (benign nevic
rests)

, .

: 1. :
2
, 2. : >0,05 mm

, 76, 1, 2014 741

 ( ), 0,3
mm 3. In transit :
2 cm
.
in transit


, (tumor deposits)
, ,
N1c
3
1 2.
,
(CAP), (regional)
,
. ,
,
.
, ITCs
. ,
0,2 mm
200 ITCs pN0(i+).
>0,2 mm <2mm
>200, 1000
pN1mi ().

. Cs 0
, .

2013

, .

,

, 76, 1, 2014 742

 (Food and Drug Administration / FDA),
(
),
()
,
.

MLH1, PMS2, MSH2
MSH6.
:
1. MLH1
PMS2
MLH1 / BRAF (V600E)

(germline) . ,
,
Lynch
(sequencing)
MLH1.
2. MSH2 MSH6
Lynch
(sequencing)
MSH2 ,
MSH6.
3. MSH6
Lynch ( MSH6).
MSH6
,
MLH1/PMS2.
4. PMS2
Lynch ( PMS2).
O
,
<50 ,
.

, 76, 1, 2014 743

 PCR


.
, antiEGFR
KRAS 12,
13 61 ,
146.
,
CAP/2013 .
EGFR:
1. 18 Gly719 19 ()
EGFR.
2. 20 ()
.
3. 20 (Thr790Met)
EGFR
(germline) .
ALK KRAS
,


ALK
in situ ALK.

,
,
(consensus).

.
.

, 76, 1, 2014 744


1. AJCC, CANCER STAGING MANUAL, Seventh Edition, 2010, Springer, New York.
2. College of American Pathologists, Cancer protocols
(http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=/portlet
s/contentViewer/show&_windowLabel=cntvwrPtlt&cntvwrPtlt{actionForm.contentRe
ference}=committees/cancer/cancer_protocols/protocols_index.html&_pageLabel=
cntvwr)

, 76, 1, 2014 745

 - :
.

, , ...

:
T.: 2132043124, 6974603640
e-mail: cmagkou@yahoo.com

.
,
.

.
, ,
, . , 76,
1, 746-750, 2014.
: , , ,

SUMMARY
MAGKOU C. Prognostic-predictive markers and targeted therapy: the role of the
Pathologist in clinical practice. The contribution of Pathology in diagnosis and
therapeutic approach of neoplasms has always been important and still remains
crucial. Nowadays, diagnosis and treatment focus on personalized identification.
Modern molecular methods, prognostic and predictive markers and new therapy
targets have contributed to the personalized approach of patients. The role of the
Pathologist in secure, precise, personalized and effective molecular therapy is
continuously expanding. Nosokomiaka Chronika, 76, Supplement 1, 746-750, 2014.
Key words: neoplasms, prognostic markers, predictive markers, targeted therapy

, 76, 1, 2014 746


.
, ,

,
.
,
.
, ,
, .
1,2,
3, 4 5,
6 ,
-, , ,
, - DNA.
,
.

,

.
.
, ER2
trastuzumab HER2
anti-HER2 . HER2
,
. ,

.
cDNA
RT-qPCR .
,

.

, 76, 1, 2014 747



.
,
, .
1,2,
ER HER2,
, (Ki67)
, , .
ER- ER-,
c-DNA
, , : (luminal A),
(luminal B), HER2 ,
(normal-like) (basal-like). , test
(.. OncotypeDX, Mammaprint)

. ,
,
,
(Circulating tumor cells /CTCs),
, .
3,
: EGFR, HER2, MYC, KRAS, MET, CCND1, CDK4, MET, EML4-ALK
BCL2. ,

. , ,
- . -
EGFR HER2, EML-ALK
hMSH2, TP3,
KRAS, STK11 , p16 APC EML-ALK . EGFR
ALK .
4, (MSI) (
DNA
DNA
(Mismatch Repair System-MMR))

, 76, 1, 2014 748

 90% 10-15%.
SI ,
MSI : ,
,
RAS p53,
. MSI

.

. , 5

o EGFR,
VEGF, PI3K/akt/mTOR,
PSMA. , PTEN PCA3,
. 5 RTK-HRAS-
MAPK, mTOR
, HER2, EGFR, VEGF mTOR.
6,7
:
( /MSI,
PTEN, K-RAS, -catenin FGFR2, ARID1A, CTNNB1,
PIK3CA, PIK3R1) ( p-
53, p16, E-Cadherin,
cerbB-2, /LOH PIK3CA
PPP2R1A), .
6
: i) POLE ultramutated, ii.) MSI
hypermutated, iii) copy number low, iv) copy number high.
DNA , ER/PR, o p53, o
/Ki67, bcl-2 ..
, (ER/PR), o EGFR
, VGFR, PTEN mTOR.

, ,
.

, 76, 1, 2014 749


.

B
1. Weigel MT, Dowsett M. Current and emerging biomarkers in breast cancer:
prognosis and prediction Endocrine-Related Cancer 2010; 17: R245R262
2. Liu Y, Liu Q, Wang T, et al. Circulating tumor cells in HER2-positive metastatic
breast cancer patients: a valuable prognostic and predictive biomarker. BMC
Cancer 2013; 13:202
3. Larsen JE, Minna JD. Molecular Biology of Lung Cancer: Clinical Implications. Clin
Chest Med 2011; 32(4): 703740.
4. Jiang WQ, Fu FF, Li YX, et al. Molecular biomarkers of colorectal cancer:
prognostic and predictive tools for clinical practice. Zhejiang Univ-Sci B (Biomed &
Biotechnol) 2012; 13(9):663-675.
5. Netto GJ. Clinical Applications of Recent Molecular Advances in Urologic
Malignancies: No Longer Chasing a Mirage?. Adv Anat Pathol 2013; 20:175203.
6. The cancer Genome Atlas Network. Integrated genomic characterization of
endometrial carcinoma. Nature 2013; 497 (7447): 67-73.
7. Banno K, Kisu I, Yanokura M, et al. Biomarkers in endometrial cancer: Possible
clinical applications (Review). Oncol Letters 2012; 3: 1175-1180.

, 76, 1, 2014 750

 : .

1, 2
1
, 2 ,
...

:
: 6972012914
E-mail: kouvidouch@yahoo.gr

,
.

. ,

, , .


.
. Barrett


(Goblet) .
Barrett
, .
.
,
( ,
/ , familial adenomatous
polyposis, juvenile polyposis Peutz-Jeghers.

<5 mm,

PANIN-1A, PANIN-1B, PANIN-2 PANIN-3.
(PIN)

, 76, 1, 2014 751

. PIN .

. Bowen
in situ .
, 76, 1, 751-758, 2014.
: , ,

SUMMARY
KOUVIDOU C, THEMELI I. Precancerous lesions: diagnosis and clinical
significance. A precancerous condition is a generalized state associated with a
significantly increased risk of cancer and, if left untreated, can lead to cancer. A
precancerous lesion is morphologically altered tissue in which cancer is more likely to
occur than in its apparently normal counterpart. Intraepithelial neoplasia shows both
architectural and cytological abnormalities. In this presentation we will refer to the
gastrointestinal tract, pancreas, prostate gland and skin. Leukoplakia, a clinical term,
is defined as a white plaque that does not wipe off and cannot be characterized
clinically as any other disease. Erythroplakia is associated with an increased risk of
dysplasia and malignant transformation. Barrett esophagus is a complication of
chronic gastroesophageal reflux and is defined as a change in the esophageal
epithelium of any length that can be recognized at endoscopy and is confirmed to
have intestinal metaplasia by biopsy. The precancerous lesions of stomach are gastric
dysplasia and gastric adenoma. Premalignant lesions of the colon include adenomas,
serrated lesions (hyperplastic polyp, sessile serrated adenoma/polyp and traditional
serrated adenoma), familial adenomatous polyposis, juvenile polyposis and Peutz-
Jeghers syndrome. Pancreatic intraepithelial neoplasias (PanINs) are microscopically
papillary or flat non invasive epithelial neoplasms that are usually <5 mm in diameter
and confined to the pancreatic ducts. PanINs are divided into three grades according
to the degree of cytological and architectural atypia. Prostatic intraepithelial neoplasia
(PIN) consists of architecturally benign acini or ducts lined by atypical cells and is
subclassified into low-grade PIN and high-grade PIN. Low-grade PIN has no clinical
significance. Actinic keratosis is a common intraepithelial neoplasm of sun-damaged
skin characterized by variable atypia of keratinocytes. Bowens disease is a form of
squamous carcinoma in situ and characterized by full-thickness epidermal atypia.
Nosokomiaka Chronika, 76, Supplement 1, 751-758, 2014.
Key words: premalignant lesions, diagnosis, clinical significance

, 76, 1, 2014 752



, .

.
,
, .

. , ,
, HPV 16, 18 EBV.
(2).
2-3 . 2-6%

.

51%
, 40% in
(4, 5).
situ Ca 9% -
.
Barrett



(2).
(goblet)
Barrett ,
(1).

. 50%

(4).
5-8%
0,5-1% Barrett .
3 ,

, 76, 1, 2014 753

 3 (5).

.
.
.

4
2 (1).
:
( 15-20 ),
Menetrier, ,
Peutz-Jeghers, ( , ,
) (2).
: ,
.
,
(low grade) (high grade)
. 50%, 30%
15% .
60-85%.
3 12 1 .

(2).
: 10%
. 3-
40%. >2 .
30% (4).

3 (1).
: 25% 15% screening
. ,
.
<1 1%, 1-2 10%, >2
50% (2).

, 76, 1, 2014 754

 ( ,
/ ):
75% ,
, 1-5 mm >1 cm.
/
. 25%
6%
.
( <1%) (1).
():
.
15% 30
(5).
FAP (Familial adenomatous polyposis): 1/7.000-1/30.000 .

. 90%
( ), 100% (fundic gland
polyps) . APC,
5. .
39 90%
50 .
(2).
Peutz-Jeghers syndrome: 1/50.000 -1/200.000 .
(
)
.
.

, , , .
LKB1/STK11 (1).
Juvenile polyposis syndrome: 10
FAP. 2/3
. (75% )
1-1,5 cm -
.

, 76, 1, 2014 755

 , ,
. SMAD-4 BMPR1A 50-60%
(1).

(PANIN)
<5 mm,
(3).

.

:
PANIN-1A:
PANIN-1B:
PANIN-2: -
PANIN-3: ,
(1).

.
.

(5).

()
. (high-grade)
(PIN)
, PSA ,

.

(6).
3412
p63 . PI 60-70%
20-40% .
10 ,
. ,
3-12 .

, 76, 1, 2014 756

 PIN. low-grade PIN
.

, UV UVB,

(7).
, , ,
, . <1 cm.
50% P53
D1. P16
ras
. 8-20%
.

. 0,1%
(8).

.
.

.
Bowens ( in situ):
(6-8 ), .
erythroplasia Queyrat.
(7).
PUVA UVB
. , , , ,
. 5-8%
. p53
p53. HPV 16 18
(8).

1. Bosman FT, Carneiro F, Hruban RH, Theise ND, Adenocarcinoma of the

oesophagus (p 25-31). Gastric carcinoma (p 48-58). Carcinoma of the colon
and recrum (p. 134-146). Familial adenomatous polyposis (p. 147-151).
Serrated polyps of the colon and rectum and serrated polyposis (p. 160-165).

, 76, 1, 2014 757

 Juvenile polyposis (p. 166-167). Peutz-Jeghers syndrome (p. 168-170). Ductal
adenocarcinoma of the pancreas (p. 281-291). In: WHO Classification of
Tumours of the Digestive System, International Agency for Research on
Cancer, Lyon, 2010.
2. Fenoglio-Preiser CM, Noffsinger AE, Stemmermann GN, Lantz PE, Isaacson
PG. The nonneoplastic esophagus (p. 86-133). Polyposis and hereditary cancer
syndromes (p. 692-734). In: Gastrointestinal Pathology: An Atlas and Text, 3rd
Edition Lippincott Williams & Wilkins, 2008.
3. Odze RD, Goldblum JR.Pancreatic intraepithelial neoplasia (p. 922-923) In:
Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas, 2nd ed,
Saunders Elsevier Inc, Philadelphia, 2009.
4. Mills SE, Carter D, Greenson JK, Reuter VE, Stoler MH. The stomach (p 1279-
1312), Nonneoplastic intestinal diseases (p. 1313-1368) In: Sternberg's
Diagnostic Surgical Pathology, 5th Edition Lippincott Williams & Wilkins, 2010.
5. Houston M, Scott J. The esophagus, stomach, small bowel (p. 585-714) In:
Rosai and Ackermans Surgical Pathology, 10th Edition Mosby Elsevier Inc,
2011.
6. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Prostatic intraepithelial neoplasia
(p.193-198). In: WHO Pathology and Genetics of Tumours of the Urinary
System and Male Genital Organs, International Agency for Research on
Cancer, Lyon, 2004.
7. LeBoit PE, Burg G, Weedon D, Sarasin A, Bowen disease (p. 26-29), Actinic
keratosis (p. 30-33) In: WHO Pathology and Genetics of Skin Tumours
International Agency for Research on Cancer, Lyon, 2006.
8. Barnhill RL, Crowson AN, Magro CM, Piepkorn MW, Actinic keratosis (p.570-
572), Bowen disease (p. 573-576) In: Dermatopathology, 3rd Edition McGraw-
Hill Companies Inc, 2010.

, 76, 1, 2014 758



, PhD
, ...

:
: 2132043202, 6945864782
E-mail: perivolioti@yahoo.gr

,

,
. ,
Gram- , Klebsiella pneumoniae,
Pseudomonas aeruginosa, Acinetobacter baumannii,
. 10%

- -
, 30%
.
, ,
.

,
, ,
.




. , 76, 1, 759-770, 2014.

, 76, 1, 2014 759

 : , Gram- ,

SUMMARY
PERIVOLIOTI E. The problem of multidrug/pandrug nosocomial infections.
Hospital-associated infections have been identified as one of the most serious patient
safety issues in health care. Nosocomial infections more than double the mortality and
morbidity risk for hospitalized patients, resulting in an estimated 20,000 deaths a year.
Nosocomial infections increase the costs of hospitalization in addition to increasing
morbidity and mortality risk. Nosocomial infections due to carbapenem-resistant
Enterobacteriaceae (CRE) or carbapenemase - producing Enterobacteriaceae (CPE)
is emerging as an important challenge in health-care settings. Currently carbapenem-
resistant Klebsiella pneumoniae is the species of CRE most commonly encountered
worldwide and is resistant to almost all available antimicrobial agents. Antimicrobial
resistance is a major problem in the hospital environment. The interpretative reading
of antibiogram and prediction of resistance mechanisms from resistance phenotypes
of bacteria to antimicrobial agents is essential for appropriate antimicrobial treatment
and for taking measures to control the spread of resistance. Nosokomiaka Chronika,
76, Supplement 1, 759-770, 2014.
Key words: nosocomial infections, multidrug-resistant Gram-negative bacteria,
carbapenemaces

, ,
, .

4
37.000. 3.000
,
.
6.4-12.7 1.000.000 .
,
, ,
, .

, 76, 1, 2014 760



. 30-50%
5 : )
, ) , )
, ) , )
.

1. ?
- (Nosocomial health-care-
associated infection)
>48
. -
(non-nosocomial health-care-associated infection)
48 .
- --
.

(Multi Drug Resistant rganisms MDROs)
.
2. (Multi Drug Resistant organisms MDROs)
> 3 ..
- , ,
, , .
(MRSA)
(VRE)
Clostridium difficile
-

3. (Extensive Drug Resistance, XDR)
1-2.
Pseudomonas aeruginosa colistin
Acinetobacter baumannii colistin, tigecycline
(KPC, VIM-1)

, 76, 1, 2014 761

4. - ( Panresistant, PDR)
.
Acinetobacter baumannii
Klebsiella pneumoniae

. ,
,
,
.

(
), ,
.
- 80%

. Gram(-)
,
.
.
10-20%
,

.
.
, , ,
.


.
,
,
,

, 76, 1, 2014 762

 ( , , , )
.


.

.
, , ,
.

Gram(-)
,
.
Gram(-
)
Gram(+),

Gram(-) .

. ,


.

.
, ,
.
Klebsiella pneumoniae
.
Klebsiella pneumoniae 2000
.

Escherichia coli.
Pseudomonas aeruginosa

, 76, 1, 2014 763

 ,
. , ,
(OprD) ,
(AmpC)
,
(efflux pumps)
--,
.
(metallo--lactamaces) VIM, IMP.
Acinetobacter baumannii

,

. Acinetobacter
baumannii .

( OprD),

(
, ).

D Ampler (OXA 23, 58 --).

OXA-58 OXA-23
Acinetobacter baumannii.,

Acinetobacter baumannii ,
. ,

.

--
Gram(-) 3
:

, 76, 1, 2014 764

 1) -
()
2) (PBPs)

3) - (AmpC-)


, D -
.
D ,

(--), ( 1).

1. - Ampler

-

TEM 1, 2, SHV-1 +++

OXA + D

TEM, SHV (.)

++++ A
CTX-M (.)
++++ A
OXA (.)
+ D
PER, BES, GES, IBC
++++ A
SFO, TLA, VEB

AmpC- ACC, ACT, CFE, CMY

0 C
DHA, FOX, LAT,MIR, MOX

IMP, VIM, GIM

SMP ()
0 B
KPC-1, KPC-2, KPC-3
+++ A
OXA-23, OXA-24
+ D
OXA-25, OXA-26
OXA-27, OXA-40, OXA-48

-
,

,
.

, 76, 1, 2014 765

 - ,
.

KPCs (class A), MBLs VIM,
IMP, NDM (class B) OXA-48 (class D).

(Antibiotic Resistance Threats-2013) CDC
,
.
Carbapenem Resistant Enterobacteriacae (CRE)
Klebsiella pneumoniae Escherichia coli
Pseudomonas aeruginosa
Acinetobacter baumannii. , 9.300

CRE 670 (7,2% ).
Acinetobacter baumannii Pseudomonas aeruginosa
7.300 6,8% 6.700 6,5% .
,

(PPS) ECDC 2010 23
19.888 , 3,2%
, 23,4% Pseudomonas aeruginosa 20,4%
Acinetobacter baumannii.
2012 200.770
Klebsiella pneumoniae
Acinetobacter baumannii.

2012 EARSS (European
Antimicrobial Resistance Surveillance System-2011)

Gram(-) Klebsiella, Acinetobacter, Pseudomonas >50%
.
Klebsiella pneumoniae
- KPCs

, 76, 1, 2014 766

---VIM. 2011
Klebsiella pneumoniae OXA-48
Klebsiella
pneumoniae NDM .

Klebsiella pneumoniae
bla VIM-1 bla KPC-2
(MIC)
CLSI EUCAST
( 4 g/ml).
,
. CLSI 2010
2012 (100-S22)
. MIC1 g/ml
MIC0.5 g/ml .


.


.

Gram(-)
. ,

.
-
.

,
.
:
, ,

, 76, 1, 2014 767


,
( )
( ).
Gram ,
,
.

Acinetobacter baumannii, ,

Klebsiella pneumoniae
- , KPCs Klebsiella
pneumoniae.

/
, :
1.
2. (active surveillance)
3.
4.

:
1.

CPE
2. contact precautions

3.

1)
2) (
)

, 76, 1, 2014 768

 3) T (
).

1. Umscheid CA, Mitchell MD, Doshi JA, et al. Estimating the proportion of
healthcare-associated infections that are reasonably preventable and the related
mortality and costs. Infect Control Hosp Epidemiol. 2011; 32(2):101-114.
2. CDC/NHSN surveillance definition of healthcare-associated infection and criteria
for specific types of infections in the acute care settings. Horan TC, Andrus M,
Dudeck MA. Am J Infect Control. 2008; 36(5):309-332.
3. WHO A systemic rewiew of the literature Report on the Burden of Endemic
HealthCare-Associated Infection Worldwide 2011.
4. CDC Antibiotic Resistance Threats in the United States, 2013
(http://www.cdc.gov/drugresistnce/threat-report-2013).
5. Glasner C, Albiger B, Buist G. Carbapenemase-producing Enterobacteriaceae in
Europe: a survey among national experts from 39 countries, February 2013
6.
, ... ( www.keelpno.gr).
7. Miriagou V, Cornaglia G, Edelstein M, et al. Acquired carbapenemases in Gram-
negative bacterial pathogens: detection and surveillance issues. Clin Microbiol
Infect. 2010; 16:112-122.
8. Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing
Enterobacteriaceae. Emerg Infect Dis. 2011; 17:1791-1798.
9. Livermore DM. Multiple mechanisms of antimicrobial resisrance in Pseudomonas
aeruginosa: our worst nightmare?Clin Infect Dis 2002; 34(5):634-640.
10. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: Emergence of
successful pathogen. Clin Microbiol Rev 2008; 21:538-582.
11. Bonomo RA, Szabo D. Mechanisms of multidrug resistance in Acinetobacter
species and Pseudomonas aeruginosa. Clin Infect Dis 2006; 43:49-56.
12. Pournaras S, Ikonomidis A, Markogiannakis A, et al. Heteroresistance to
carbapenems in Acinetobacter baumannii. J Antimicrob Chemother 2005;
55(6):1055-1056.
13. Bulik C, Nikolaou D. Double-Carbapenem Therapy for Carbapenemase-Producing
Klebsiella pneumoniae. Antimicrob Agents Chemother June 2011; 3002-30004.

, 76, 1, 2014 769

14. Giamarellou H, Galani L, Baziaka F, Karaiskos I. Double-Carbapenem regimen for
carbapenemase-producing pandrug-resistant Klebsiella pneumoniae infections: Is
it really effective in humans? Antimicrob Agents Chemother Feb 2013.
15. Souli M, Galani L, Giamarellou H. Emergence of extensively drug-resistant and
pandrug-resistant Gram-negative bacilli in Europe. Euro Surveill. 2008; 13(47) pii:
19045.
16. Paterson DL, Lipman J. Returning to the pre-antibiotic era in the critically ill: the
XDR problem. Crit Care Med 2007; 35:1789-1791.
17. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carba-
penemase-producing bacteria. Lancet Infect Dis 2009; 9:228-236.
18. Peleg AY, Potoski BA, Rea R, et al. Acinetobacter baumannii bloodstream infection
while receiving tigecycline: a cautionary report. J Antimicrob Chemother 2007;
59:128-131.
19. Peleg A, Hooper DC. Hospital-Acquired Infections Due to Gram-Negative bacteria
NEJM 2010; 362:1804-1813.
20. Siegel JD, Rhinehart E, Jackson M, Chiarello L. Management of multidrug-resistant
organisms in health care settings, 2006. Am J Infect Control. 2007;35 (10 Suppl
2):S165-193.

, 76, 1, 2014 770



, MSc,
...

:
: 2132045831, 2132045833
E-mail: kostsofia@gmail.com

.

.

.

.
.

. , 76,
1, 771-792, 2014.
: , , ,

SUMMARY
KOSTOUROU S. Surveillance in hospital setting. Surveillance of hospital acquired
infections is associated with reduction in infections incidence. Monitoring of processes
and outcomes of health care delivery is useful to identify areas where there is a need
to implement preventive interventions. Targeted surveillance based on objectives is
more efficient and feasible than Hospital-wide surveillance. It is recommended each
hospital to tailor its surveillance program based on an assessment of its priorities and
needs. Electronic screening of patients care data is an emerging tool to perform more
easily surveillance activities. The main aim of surveillance remains the avoidance of

, 76, 1, 2014 771

the preventable proportion of healthcare associated infections. Nosokomiaka
Chronika, 76, Supplement 1, 771-792, 2014.
Key words: sureillance, hospital -acquired infections, active surveillance, targeted
surveillance

()
.1,2,3


.1


.4
SENIC
(Study on the efficacy of infection control)
1970. SENIC 6%


32%.5
12-60%

.6

.7,2
, Clostridium difficile
,

.2,8,9,10


.3
,

.3 1997

, 76, 1, 2014 772

2008 ,

,

.
, ,.11

.1,2,3

1.

,


.2
,

.2

, ,
,
.1,2,3
.



.3

.


.1,2,3,14

, 76, 1, 2014 773

2.
2.1


;.
,
, , ,

.

,
.

. .

.1,2,14
.
Centers
for Disease Control and Prevention/CDC.15

(benchmarking)

.1,2,3,14

.1,2
:
, , ,
,
,
. .1,2,3,14
2.2.

.
.2

, 76, 1, 2014 774

2.3
.

,

.1,2,3

- (patient-days).
-
.2

.
(device-days)

.

.2,14
: =
/ .
100 1000
100 1000 -
.2,3
,

.
(, , )
ASA score.2,3,14

.2


3
.
2.4. -

, 76, 1, 2014 775

 ,
.1,2 ,

.12,13

.2

.
, ,
.2
2.5

(...).
.

.16
,

,
.17


.2



.18

3.


, .


.2,14

, 76, 1, 2014 776


.2

(hospital wide surveillance)
.


.


.

.2,3


. (
SENIC) 1990
.5

(targeted
surveillance, surveillance by objectives).1,2,3
,
,
.

.
,


.
.


. 1990

, 76, 1, 2014 777

 ()
.

.1,2

.
: (outcome surveillance)
(process surveillance).1,2
3.1

.2,19
.3
( )
.

.3

.20

. ,


.
3 : , 38c
. 100%
62%
.21



20
.

,

.

, 76, 1, 2014 778



.20 ,

.2,3
,

. .

.

.

.7,15
3.2.

.1

.12

.1,12,19
(bundles)
(audit tools).24,25,26
4 5
.26,27
.

.
, ,

26
.

.7,19

Institute for

, 76, 1, 2014 779

Healthcare Improvement.27,28
,

Clostridium Difficile MRSA.26,29
Clostridium Difficile
5 : 1: , 2:
(
Clostridium Difficile) 3:
( 48h ) 4:
(
) 5:
.30
: 1:
( 1 h ) 2:
(: , clippers
, ), 3:
(<11mmol/L), 4:
>36oC.31


.24,25 ,
,
, , ,
.



.18
. ,
, .
3.3

.

.

, 76, 1, 2014 780


.

.2

(, , .)
flu-like syndrome
.3

4.

.3
.
,
.


.2,33
.
4.1


.
,

.14
.

.
.

.34
CDC 2

, 76, 1, 2014 781


.15,33,35
4.2
.
CDC/NHSN

.15 50%

.2

30
.15

,

,
.




.2


3 ,

.36
4.3

, .

(device-days),
.2

, ,

, 76, 1, 2014 782

 , .


.2

.

.


.37

( , ,
)

.
4.4

(ventilator associated pneumonia /VAP) . VAP
CDC/NHSN
, ,
.15 VAP
(
, ) .


.10 VAP
(
)
.

2006 Minnesota.
VAP
CDC/NHSN ,
>25

, 76, 1, 2014 783

. 459 .
20 VAP 95%
( 100%) 21 VAP.38
4.5

: 1.
2.
3. 4.
5.
.10


.10

.

.2,10

.10

. ,
,
,
, , , .


,
(once positive
always positive).39

.
, ,
.
.

, 76, 1, 2014 784

 .


.


.39
.40
gram+
(metthcillin-resistant-Staphylococcus aureus/MRSA)
(Vancomycin Resistant Enterococcus/VRE)
gram- Klebsiella pneumonia, Acinetobacter baumannii
.


90% VRE, 40-90% MRS Gram-
50%.39


.41


.42

.43
MRSA VRE
.

,
.


.

48h

, 76, 1, 2014 785

 .

.
, , ,
, .
.9

.



. :
, , >48h
, ,
, .
, , ,
, ,
(,
),
, ,
.43

5.



,

.44-49
.
: :
, -- :
,
,
, ,

, 76, 1, 2014 786

: , :

. :
,
, ,

,
.
,

,
.

, a wish list
.

.

.
,

.46


.

.
Pennsylvania ,
ICD-9

.36


.

, 76, 1, 2014 787

 LOINC (logical
observation identifiers names and codes) SNOMED (Systematized
Nomenclature Of Medicine) 144.000
12
.46

.
, ,
.

,
.
, ,

.



.

1. Lee T, Montgomery O, Marx J. Recommended practices for surveillance in

Infection Control and Epidemiology (APIC),Inc. Am J Infect Control 2007; 35:427-
440.
2. Public Health Ontario. Provincial Infectious Diseases Advisory Committee
(PIDAC). Best practices for surveillance of Health care-associated infections in
patient and resident populations. Published: June 2008, second revision: October
2011.
3. Horan T, Gaynes R. Surveillance of nosocomial infections. In: Mayhall CG, ed
Hospital epidemiology and infection control.4th ed, Philadelphia: Lippincott
Williams & Wilkins, 2004; 1659-1702.

, 76, 1, 2014 788

4. Siegel JD, Rhinehart E, Jackson M, Chiarello L; Healthcare Infection Control
Practices Advisory Committee. Management of multidrug-resistant organisms in
healthcare settings, 2006. Available at:
http://www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf.2006. Accessed
July 21. 2013.
5. Haley RW, Culver DH, White JW, et al. The efficacy of infection surveillance and
control programs in preventing nosocomial infection in US hospitals, (SENIC
study). Am J Epidemiol 1985; 121(2):182-205.
6. Harbarth S, Sax H, Gastmeier P. The preventable proportion of nosocomial
infections: an overview of published reports. J Hosp Infect 2003; 54:258-266.
7. Tokars J, Richards C, Andrus M, et al. The changing face of surveillance for
health care-associated infections. CID 2004; 39:1347-1352.
8. Deneve C, Janoir C, Poilane I. New trends in Clostridium difficile virulence and
pathogenesis. International Journal of antimicrobial agents 2009; 33:S24-S28.
9. Gupta N, Limbago B, Patel J et al. Carbapenem-resistant enterobacteriaceae:
CID 2011; 53(1):60-67.
10. Cohen A, Calfee D, Fridkin S. Recommendations for metrics for multidrug-
resistant organisms in healthcare settings: SHEA/HISPAC Position paper. Infect
Control Hosp Epidemiol 2008; 29(10):901-913.
11. Gastmeier P, Sohr D, Schwab F, et al. Ten years of KISS: the most important
requirements for success. J Hosp Infect 2008; 70:S11-16.
12. Lilfored R, Mohammmed M, Spiegelhalter D. Use and misuse of process and
outcome data in managing performance of acute medical care: avoiding
institutional stigma Lancet 2004; 363:1147-1154.
13. Perla R, Peden C, Goldmann D et al. Health-care associated infection reporting:
the need for ongoing reliability and validity assessment. Am J Infect Control 2009;
37:615-618.
14. Centre for Healthcare Related Infection Surveillance and Prevention (CHRISP).
Surveillance manual. Third edition. July 2009.
15. Horan T, Andrus M, Dudeck M. CDC/NHSN surveillance definition of health care-
associated infection and criteria for specific types of infections in the acute care
setting. Am J Infect Control 2008; 36:309-332.
16. Haustein T, Gastmeier P, Holmes A, et al. Use of benchmarking and public
reporting for infection control in four high- income countries. Lancet Infect Dis
2011; 11:471-481.

, 76, 1, 2014 789

17. Weinstein R. Who is steering the ship? External influences on infection control
programs. CID 2008; 46:1746-1750.
18. Harbarth S. What can we learn from each other in infection control? Experience
in Europe compared with the USA. J Hosp Infect 2013; (83):173-184.
19. Pronovost P, Nolan T, Zeger S, et al. How clinicians measure safety and quality
in acute care? Lancet 2004; 363:1061-1067.
20. Liata E, Gaynes R, Fridkin S. Measuring the scope and magnitude of hospital-
associated infection in the United States: the value of prevalence studies CID
2009; 48:1434-1440.
21. Brusaferro S, Regattin L, Faruzzo A, et al. Surveillance of hospital acquired
infections: a model for settings with resource constraints. Am J Infect Control
2006; 34:362-366.
22. Rosenthal V, Maki D, Graves N. The international nosocomial infection control
consortium (INICC): goals and objectives, description of surveillance methods
and operational activities. Am J Infect Control 2008; 36:e1-e12.
23. Guerin K, Wagner J, Rains K, et al. Reduction in central line-associated
bloodstream infections by implementation of a postinsertion care bundle. Am J
Infect Control 2010; 38:430-433.
24. Department of Health. nfection Control Nurses Association (ICNA). Audit tools
for monitoring infection control standards .2004. Available at:
http://www.icna.co.uk/public/downloads/documents/audit_tools_acute.pdf
25. Bryce E, Scharf S, Walker M, et al. The infection control audit: the standardized
audit as a tool for change. Am J Infect Control 2007; 35:27 1-83.
26. Institute for healthcare improvement (IHI). Using care bundles to improve health
care quality. Availlable at:
http://www.ihi.org/knowledge/Pages/ImprovementStories/WhatIsaBundle.aspx.
27. Aboelela S, Stone P, Larson E. Effectiveness of bundled behavioral interventions
to control healthcare-associated infections: a systematic review of the literature. J
Hosp Infect 2007; 66:101-108.
28. Yokoe D, Classen D. Improving patient safety through infection control: a new
healthcare imperative. Infect Control Hosp Epidemiol 2008; 29:S3-S11.
29. Pronovost P, Needham D, Berenholitz S. An intervention to decrease catheter-
related bloodstream infections in the ICU. N Engl J Med 2006; 355:2725-2732.
30. National Health System (NHS). High impact intervention No7. Care bundle to
reduce the risk from Clostridium difficile.2006. Available at:

, 76, 1, 2014 790

 http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/ClostridiumDifficile
/Guidelines/.
31. National Health System (NHS). High impact intervention No4. Care bundle to
prevent surgical site infections. 2006 Available at:
http://www.infectioncontrolmanual.co.ni/index.php?option=com_content&view=ca
tegory&id=137&Itemid=119.
32. Casey A, Elliott T. Progress in the prevention of surgical site infections. Curr Opin
Infect Dis 2009; 22:370-375.
33. Lin M, Bonten M. The dilemma of assessment bias in infection control research.
CID 2012; 54(9):1342-1347.
34. Worth L, McLaws ML. Is it possible to achieve a target of zero central line
associated bloodstream infection? Curr Opin Infect Dis 2012; 25:650-657.
35. Klompas M, Yokoe D. Automated surveillance of health care-associated
infections. Clinical Infectious Diseases 2009; 48:1268-1275.
36. Health Protection Agency. Protocol for surveillance of surgical site infection.
Version 4. July 2008. Available at:
http://www.hpa.org.uk/webc/hpawebfile/hpaweb_c/1194947388966.
37. CDC. Device-associated module. CLABSI. Device-associated bloodstream
infection (CLABSI) events. January 2014.
Available at: http://www.cdc.gov/nhsn/pdfs/pscmanual/4psc_clabscurrent.pdf
38. Klompas M, Kleinman K, Platt R. Development of an algorithm for surveillance of
ventilator-associated pneumonia with electronic data and comparison of
algorithm results with clinician diagnosis. Infect Control Hosp Epidemiol 2008;
29:31-37.
39. Harris A, McGregor J, Furuno J. What infection control interventions should be
undertaken to control multidrug resistant gram-negative bacteria? CID 2006;
43:S57-S61.
40. Bonten MJ, Slaughter S, Ambergen AW, et al. The role of colonization pressure
in the spread of vancomycin-resistant enterococci: an important infection control
variable. Arch Intern Med 1998; 158:1127-1132.
41. Khan a, Dancer S, Humphreys H. Priorities in the prevention and control of
multidrug-resistant enterobacteriaceae in hospitals. Journal of Hospital Infection
2012;82(2):85-93.

, 76, 1, 2014 791

42. Pogorzelska M, Stone P, Larson E. Wide variation in adoption of screening and
infection control interventions for multidrug-resistant organisms: a national study.
Am J Infect Control 2012; 40: 696-700.
43. Public Health Ontario. Provincial Infectious Diseases Advisory Committee
(PIDAC). Annex A: Screening, testing and surveillance for antibiotic resistant
organisms (AORS) in all health care settings. Available at:
http://www.publichealthontario.ca/en/eRepository/PIDAC-
IPC_Annex_A_Screening_Testing_Surveillance_AROs_2013.pdf
44. Greene L, Cain T et al. APIC position paper: The importance of surveillance
technologies in the prevention of health care-associated infections. Am J Infect
Control 2009; 37:510-513.
45. Hedden J, Wright MO, Fuss E. Leveraging surveillance technology to benefit the
practice and profession of infection control. Am J Infect Control 2008; 35:S7-11.
46. Hota B, Jones R, Schwartz D. Informatics and infectious diseases: what is the
connection and efficacy of information technology tools for therapy and health
care epidemiology? Am J Infect Control 2008; 36:S47-56.
47. Woeltje K, Lautenbach E. Informatics and epidemiology in infection control. Infect
Dis Clin N Am 2011; 25:261-270.
48. Jhung M, Banerjee S. Administrative coding data and health care-associated
infections CID 2009; 49:949-955.
49. Perla R, Peden C, Goldmann D, et al. Health-care associated infection reporting:
the need for ongoing reliability and validity assessment. Am J Infect Control 2009;
37:615-618.

, 76, 1, 2014 792

 :

. .
,
(), ,
...

: 213 2041242, 6973202228
E-mail: drkarag@gmail.com

.
, , , . (
)
.
(
) .
Candida Aspergillus.
.
Candida C.albicans.
-albicans ,
.
.
Candida .
C.parapsilosis, . To
90% A.fumigatus.
() .
.
,
.
: ,
.
.
.
(13)--D-.

, 76, 1, 2014 793

 , ,
(pre-emptive) .
, ,
.

, . , 76,
1, 793-794, 2014.
: , , ,
,

, 76, 1, 2014 794

 .

.
, ,
...

:
: 6974798334
E-mail: nkaltsas@hotmail.com

,
2012

. :
,
, (
) ,
,

. , 76, 1, 795-
809, 2014.
: , , 2012,

SUMMARY
KALTSAS P. Severe sepsis and septic shock. Starting before the ICU. The 2012
Surviving Sepsis Campaign introduced several important changes in their
recommendations for the treatment of severe sepsis and septic shock. The use of
protocolized quantitative resuscitation with specific physiologic targets, preferential
use of crystalloids (with or without albumin) for volume resuscitation, preferential use
of norepinephrine, addition of lactate clearance as a marker of tissue hypoperfusion, a
decreased emphasis on the use of corticosteroids, and recommendations on timing of
antimicrobials, as well as the importance on administration of broad spectrum
antibiotics are among the most relevant changes for emergency physicians to

, 76, 1, 2014 795

integrate into their practice. Nosokomiaka Chronika, 76, Supplement 1, 795-809,
2014.
Key words: severe sepsis, septic shock, guidelines 2012, emergency physicians

1991 Bone 1. 20
,
,
.
,
.

,

.
(Surviving Sepsis Campaign-SSC).
, 2
2012,
.




.

1991
3 2001
:
1. :
:
:
- >38.3o C < 36o C
- > 90/min

, 76, 1, 2014 796

 -
-
- (>20 ml/kg 24)
- ( >140 mg/dL)
:
- (>12.000 ) (<4.000 )
- >10%
- CRP (>2 SD )
- (>2 SD )
:
- ( <90 mmHg, MAP <70 mmHg)
> 40 mmHg
:
- (pO2/FiO2 <300)
- (<0,5 ml/kg/ 2
)
- > 0,5 mg/dL
- (INR >1,5 APTT >60 s)
- ( )
- (PLT <100.000 )
- ( > 4 mg/dL)
:
- (> 1 mmol/L)
-
2. :
(
):
-
-
- (< 0,5 ml/kg/ 2
)
- (ALI) pO2/FiO2 <250

- (ALI) pO2/FiO2 <200

, 76, 1, 2014 797

 - > 2,0 mg/dL
- > 2,0 mg/dL
- < 100.000
- INR >1,5
3. :

. <90 mmHg, MAP <60
mmHg >40 mmHg
.

.
300 100.000 4.
50% .
25%
, shock
50%. 2010
(http://www.sepsis.gr/SOCIETY%20GR.pdf)

35,3% 67,2% .
37% 49,2% .


- status
. 5 2003 32%
51,1% . 2003
Martin6 7

. ,

, ,
, , ,

, 76, 1, 2014 798


.

,
2012 2.
GRADE (Grading of
Recommendations Assessment, Development and Evaluation system)
(grade 1) (grade 2).
(grade A),
(grade B), (grade C), (grade D) .
,
, :

.


.
,
,

.
, 2,
:
1. ,
.
2.
6
,
.
( 1)

, 76, 1, 2014 799

 1. 2012
(Surviving
Sepsis Campaign-SSC).
o 3



30 ml/kg > 4 mmol/L
6
( )
>65 mmHg
(
) >4 mmol/L: CVP ScvO2
*
* : CVP > 8mm Hg, ScvO2 > 70%

1.


8.
9.


10.


(grade 1C).


.

s (ungraded).

,

.

, 76, 1, 2014 800



(ungraded).
, ,

.
2.

( ) .



(grade 1B). 11
, ,


(grade 1B).

,
(grade 2C).

( )
30 mL/kg
(grade 1C).

.
,
,

.
3.


,
(, )

, 76, 1, 2014 801

 . ,
,
(> 45 )
(grade 1C). a 12


. 2012

(grade 1B)
(grade 1C).



,
. T
(care bundle)
3
.

45
.

,
2
( )
.

.
. ( )
, , ,

(grade 1C).


.

, 76, 1, 2014 802



.
,
,
.


/ .
, ,
2
- , , , .

13,
.
4.
2012
14,15 o

.

(
> 4 mmol/L).

. 6

(grade 1C):
8-12 mm Hg
> 65 mm Hg
> 0,5 mL/kg
ScvO2 70% SvO2 65%

:
,
,

, 76, 1, 2014 803

 ScvO2 SvO2
.


(grade 2C).


3 6
.

;
5.
2 2012
.
65
mmHg (grade 1C)

(ungraded).
1 (grade 1B)
.
16

(grade
2C).
(grade 1A)


(grade 2B)
0,03 U/min ,
17. ( 0,03 U/min)

(ungraded).
6.
20
g/kg

, 76, 1, 2014 804

 (grade 1C).


(grade 1C) ScvO2
.
7.


.
7,0 g/dL.

,
7,0 g/dL
7,0-9,0 g/dL (grade 1B)

(grade
1B)
(grade 2B).


10.000/mm3
20.000/mm3 .
(> 50.000/mm3)
,
(grade 2D).
8.
-18

,
.

.
(grade 1D).

, 76, 1, 2014 805

 .
200 mg
(grade 2C).
(grade
2D).
9.

.
(
)
12 .

(
, , ).
12
(grade 1C).

.


(ungraded).



(grade 2B).


:

(ubgraded)
10.

,
.
19 (<110 mg/dL)

, 76, 1, 2014 806

 ( <180 mg/dL)

. :

> 180 mg/dL 2 .
< 180 mg/dL, < 110 mg/dL
(grade 1A). 1-2

4 (grade 1C)
11.


20.


pH
<7,15 (grade 2B)

1. American College of Chest Physicians/Society of Critical Care Medicine

Consensus Conference: definitions for sepsis and organ failure and guidelines for
the use of innovative therapies in sepsis, Crit Care Med 1992, 20:864-874.
2. Dellinger RP, Levy MM, Rhodes A et al. Surviving Sepsis Campaign Guidelines
Committee including the Pediatric Subgroup. Surviving sepsis campaign:
international guidelines for management of severe sepsis and septic shock 2012,
Crit Care Med 2013, 41:580-637.
3. Levy MM, Fink MP, Marshall JC et al. 2001 SCCM/ESICM/ACCP/ATS/SIS
International Sepsis Definitions conference, Crit Care Med 2003, 31:1250-1256.
4. Angus DC, Linde-Zwirble WT, Lidicker J et al. Epidemiology of severe sepsis in the
United States: analysis of incidence, outcome, and associated costs of care, Crit
Care Med 2001, 29:1303-1310.
5. Esteban A, Frutos-Vivar F, Ferguson ND et al. Sepsis incidence and outcome:
contrasting the intensive care unit with the hospital ward, Crit Care Med 2007,
35:1284-1289.

, 76, 1, 2014 807

6. Martin GS, Mannino DM, Eaton S et al. The epidemiology of sepsis in the United
States from 1979 through 2000, N Engl J Med 2003, 348:1546-1554.
7. Kumar G, Kumar N, Taneja A et al. Milwaukee Initiative in Critical Care Outcomes
Research Group of Investigators. Nationwide trends of severe sepsis in the 21st
century (2000-2007), Chest 2011, 140:1223-1231.
8. Levy MM, Dellinger RP, Townsend S et al. The Surviving Sepsis Campaign: results
of an international guideline-based performance improvement program targeting
severe sepsis, Intensive Care Med 2010, 36:222-231.
9. Nguyen HB, Corbett SW, Steele R et al. Implementation of a bundle of quality
indicators for the early management of severe sepsis and septic shock is
associated with decreased mortality, Crit Care Med 2007, 35:1105-1112.
10. Moore LJ, Jones SL, Kreiner LA et al. Validation of a screening tool for the early
identification of sepsis, J Trauma 2009, 66:1539-1546.
11. Bayer O, Reinhart K, Sakr Y, et al. Renal effects of synthetic colloids and
crystalloids in patients with sepsis: a prospective sequential comparison, Crit Care
Med 2011, 39:1335-1342.
12. Kumar A, Roberts D, Wood KE et al. Duration of hypotension before initiation of
effective antimicrobial therapy is the critical determinant of survival in human septic
shock, Crit Care Med 2006, 34:1589-1596.
13. Kumar A, Zarychanski R, Light B. Early combination antibiotic therapy yields
improved survival compared with monotherapy: a propensity matched analysis, Crit
Care Med 2010, 38:1773-1785.
14. Jones AE, Focht A, Horton JM et al. Prospective external validation of the clinical
effectiveness of an emergency departmentbased early goal directed therapy
protocol for severe sepsis and septic shock, Chest. 2007, 132:425-432.
15. Trzeciak S, Dellinger RP, Abata NL et al. Translating research to clinical practice: a
1-year experience with implementing early goal-directed therapy for septic shock in
the emergency department, Chest 2006, 129:225-235.
16. De Backer D, Biston P, Devriendt J et al. Comparison of dopamine and
norepinephrine in the treatment of shock, N Engl J Med 2010, 362:779-789.
17. Dunser M, Mayr AJ, Tura A et al. Ischemic skin lesions as a complication of
continuous vasopressin infusion in catecholamineresistant vasodilatory shock:
incidence and risk factors, Crit Care Med 2003, 31:1394-1398.

, 76, 1, 2014 808

18. Sligl W, Milner DJ, Sundar S et al. Safety and efficacy of corticosteroids for the
treatment of septic shock: a systematic review and metaanalysis, Clin Infect Dis
2009, 49:93-101.
19. Finfer S, Chittock DR, Su S et al. Intensive versus conventional glucose control in
critically ill patients, N Engl J Med 2009, 360:1283-1297.
20. Mathieu D, Neviere R, Billard V et al. Effects of bicarbonate therapy on
hemodynamics and tissue oxygenation in patients with lactic acidosis: a
prospective, controlled clinical study, Crit Care Med 1991, 19:1352-1356.

, 76, 1, 2014 809



, ...

:
: 6972265361
E-mail: zdor40@otenet.bf

,
. 7%

350.000 .
. -
16
- 11.
1000
.

() .


. ,

()
(non invasive prenatal diagnosis-NIPD).
20

(in vitro fertilization-IVF)
. NIPD

, 76, 1, 2014 810

 DNA
(cell free fetal DNA-cffDNA) .
NIPD
. , 76,
1, 810-829, 2014.
: , ,
, ,

SUMMARY

DORIZA Z. The contribution of molecular control in prenatal and preimplantation

genetic diagnosis of hemoglobinopathies. The hemoglobinopathies are the most
common monogenic disorders worldwide. The -globin gene cluster, is located near
the telomere of the sort arm of chromosome 16 and the globin gene cluster is
located on the sort arm of chromosome 11.Over 1000 mutation within or around the
and globin genes have been observed, affecting either the quantity or quality of the
globin chains synthesized. The prenatal diagnosis (PND) for hemoglobinopathies
based on molecular analysis of trophoblast or amniocyte DNA. Disadvantages with
conventional PND include invasive fetal sampling and the need to terminal affected
ongoing pregnancies. New developments are directed towards improving both timing
and-or safety of procedures. Preimplantation genetic diagnosis (PGD) avoids the need
to terminate affected pregnancies, through identification and selective transfer of
unaffected in vitro fertilization (IVF) embryos. Approaches towards non-invasive PND
(NIPD) through analyzing fetal cells or free fetal DNA present in the circulation of
pregnant women, are a focus of ongoing research .Overall, PND,PGD and NIPD
represent valuable reproductive option for couple at risk for having a child affected
with a severe inherited disease. Nosokomiaka Chronika, 76, Supplement 1, 810-
829, 2014.
Key words: hemoglobinopathies, monogenic disorders, prenatal diagnosis (PND),
preimplantation genetic diagnosis (PGD), non-invasive prenatal diagnosis (NIPD).

.O

, 76, 1, 2014 811

 Hb,
( )
Hb (Hbs, Hbc, ..).
1
270
( 1,2,3,4).

Distribution of b-thalassemia
1. .

1. .

thalassemia
Distribution of -thalassemia

2. 3.
HbS,E,C

, 76, 1, 2014 812

4.

4
(1).
-
- .
Hb( 2 2 ):97%,Hb 2 ( 2 2 ):2,2-3,3%
HbF( 2 2 ):<2%

,
.
.
.
- -.

, 76, 1, 2014 813

1. .

. 1500 3 (exon)
2 (ivs) ( 3).

. ( 2)
16
( 2 ), ( 2 , 1 ),
( 1 , 2 , 1 )
.
1 2 (98,5%)
2
1 2 .

( 2) 11

, 76, 1, 2014 814

 ,
(G, ), ,
().

2. .

300
. 200
. (35
) ( 4) (
1).

1. .
> 300


-
(~200 ) (~80 )
(~35 ) (~20 )

-
-,
, RNA ( 5).

(.. , CCAA
CACCC) 5 (5 UT4).

, 76, 1, 2014 815


.
50
RNA.
,
.
-
RNA
.

5. - DNA

, 76, 1, 2014 816

 3. (11p) -.
-(IVS)-(Exon).

4. .

5. .

, 76, 1, 2014 817

 80
- (20
) ( 6).

( 5).

.

6. .

( 8,9,9,9).

, ( )
.

25% .
1 2 / 1 2 . - ,
-, -
( 7).
.

, 76, 1, 2014 818

 7. (
-).

8. .

9. 9. 2
2

, 76, 1, 2014 819

 9. 2 3

:
,

.
: (1) , (2)
, (3) .


() .

3,4 .

: (1)
( ) , (2)
,
,(3) (4)
.

1. Southern blot & RFLP
2. DNA (Manual sequencing)
3. Oligonucleotide hybridization

, 76, 1, 2014 820

4. Polymerase Chain Reaction (PCR)

.
.
.
:
1. ASO
.
2. ARMS
.
3. RE-PCR .
:
1. gap-PCR 5 ( Southern blot).

PCR 6 .

.

DNA
. .
. :
DGGE
7 .
dHPLC 8 .
,

sequencing.
PCR ,
, , .


sanger sequencing
, MLPA 9,10 (Multiplex ligation-dependant probe
amplification)
.

, 76, 1, 2014 821

 sanger sequencing .

.
,

.
MLPA (Multiplex ligation-dependant probe amplification)

( Southern blotting).
, PCR,
.

O :
HRMA 11 (post-PCR High Resolution Melting Analysis)
Real-time PCR 12
Genotyping microarrays 13
,
,
.

:







(18 -20 ..) (16 -18 ..)
(10 -12 ..).


(2%)
, .

, 76, 1, 2014 822


(-PGD) ( 2).

,
.
, ()
.
,
.
3 ( 6-8 ) ( 7),
2-3
, .

7. .

, 76, 1, 2014 823

 (PGD)

1 2

1 2

, 76, 1, 2014 824


-. 3 -
.

NIPD

-cell free fetal DNA (cffDNA)
cell free fetal RNA (cffRNA) ( 8)

14 .

, (fetal-
NRBCs).

8. cell free fetal DNA-RNA.

.


15 ( 9).

, 76, 1, 2014 825

 9. .

(CFFDNA-
CFFRNA)
cffDNA 3-20%
fDNA 16 .
(<200-300bp) fDNA.
cffDNA- fDNA

:
1. Rhesus D Rhesus D
,
2. ,

3. .

, ,

.
,

, 76, 1, 2014 826


,
.

2. ,
(PGD) NIPD.
PGD NIPD

2 3

( 7



)

~2%
(
, :

,

)

>99% >99%



:
,




.

:



.

.


.

, 76, 1, 2014 827


1. Weatherall DJ. Thalassaemia:the long road from bedside to genome, Nat
Rev Genet 2004, 5:625-631.
2. Bernini LF, Harteveld CL. Alpha thalassaemia.Baillieres, Clin Haematol
1998, 11:53-90.
3. Loukopoulos D, Antsaklis A, Aleporou-Marinou V et al. Prenatal diagnosis
of beta-thalassaemia;the greek experience, Birth Defects Orig Artic Ser
1982, 18:293-301.
4. Kanavakis E, Traeger-Synodinos J, Vrettou C et al. Prenatal diagnosis of
the thallasaemia syndromes by rapid DNA analytical methods, Mol Hum
Reprod 1997, 3:532-538.
5. Harteveld CL, Kleanthous M, Traeger-Synodinos J et al. Prenatal diagnosis
of hemoglobin disorders: present and future strategies, Clin Biochem 2009,
42:1767-1779.
6. Saiki RK, Scharf S, Faloona F et al. Enzymatic amplification of beta-globin
genomic sequences and restriction site analysis for diagnosis of sickle
cellanaemia, Science 1985, 230:1350-1354.
7. Losekoot M, Fodde R, Harteveld CL et al. Denaturing gradient gel
electrophoresis and direct sequencing of PCR amplifield genomicDNA: a
rapid and reliable diagnostic approach to beta thalassaemia, Br J Haematol
1990, 76:269-274.
8. ODonovan MC, Oefner PJ, Roberts SC et al. Blind analysis of denaturing
high-performance liquid chromatography as a tool for mutation detection,
Genomics 1998, 52:44-49.
9. Schouten JP, McElgunn CJ, Waaijer R et al. Relative quantification of 40
nucleic acid sequences by multiplex ligation-dependent probe amplification,
Nucleic Acid Res 2002, 30:e57.
10. Harteveld CL, Voskamp A, Phylipsen M et al. Nice unknown
rearrangements in 16p13.3 and 11p15.4 causing alpha-and beta-
thalassaemia characterized by high resolution multiplex ligation-dependent
probe amplification, J Med Genet 2005, 42:922-931.
11. Reed GH, Kent JO, Wittwer CT. High-resolution DNA melting analysis for
simple and efficient molecular diagnostics, Pharmacogenomics 2007,
8:597-608.

, 76, 1, 2014 828

12. Vrettou C, Traeger-Synodinos J, Tzetis M et al. Rapid screening of multiple
beta-globin gene mutations by real time PCR on the LightCycler:
application to carrier screening and prenatal diagnosis of thalassaemia
syndromes, Clin Chem 2003, 49:769-776.
13. Cremonesi L, Ferrari M, Giordano PC et al. An overview of current
microarray-based human globin gene mutation detection methods,
Hemoglobin 2007, 31:289-311.
14. Hahn S, Jackson LG, Kolla V et al. Noninvasive prenatal diagnosis of fetal
aneuploidies and mendelian disorders: new innovative strategies, Expert
Rev Mol Diagn 2009, 9:612-613.
15. Kavanagh DM, Kersaudy-Kerhoas M, DhariwalRS et al. Current and
emerging techniques of fetal cell separation from materal blood, J
Chromatogr B Analyt Technol Biomed Life Sci 2010, 878:1905-1911.
16. Lo YM, Corbetta N, Chamberlain PF et al. Presence of fetal DNA in
maternal plasma and serum, Lancet 1997, 350:445-448

, 76, 1, 2014 829



:
PHI
(PROSTATE HEALTH INDEX)

,
,
...

:
: 2132043084, 6947937855
E-mail: biochem@evaggelismos-hosp.gr

(PSA) (PROPSA)
(PSA)
( screening test)
. PSA 4ng/ml (cut-off)
. (cut-
offs) PSA ,
PSA < 4ng/ml
.
, PSA .
PSA < 10 ng/ml
25% .
PSA
, (free PSA, fPSA).
PSA 4-10 ng/ml PSA (fPSA/totalPSA ratio),

.
o
fPSA, proPSA. [-2]proPSA p2PSA
. PSA 2-10 ng/ml
p2PSA

, 76, 1, 2014 830

 fPSA/totalPSA
ratio, .

, PHI (PROSTATE HEALTH INDEX)

Catalona ., 2011,
[-2]proPSA/ fPSA x PSA1/2
PHI,
PSA 2-10 ng/ml.
PHI [-
2]proPSA , .
(cut-off) 21,3.

, PHI
(PROSTATE HEALTH INDEX)
PSA 2-10 ng/ml, ,
PHI .
95% PHI 16% ratio fPSA/PSA
8,4% (p= 0.015), [-2]proPSA 7,6% , PSA 6,5% fPSA 3,5%.
( 90%, 85% 80%) PHI
ratio fPSA/PSA.
PHI Gleason score
. ,
Gleason score 7 26,2%, 28,2%, 30,1%, 42,1%
PHI 0-24,9 25-34,9 35-54,9 55 ( p=0.013).H AUC (
area under the curve) PHI ( 0,724) AUC ratio
fPSA/PSA (0,670) Gleason score 4+3
Gleason score.

PHI
,

50 PSA 2-10 ng/ml
.

, 76, 1, 2014 831

 (Phi)

Ph.D. EurClinChem, , ...

:
: 6973998440
E-mail: pch-cris@hotmail.com

(PCa)
.
(PSA)
, . PSA
,
,
,
.
PSA.
, PSA, (PSA
Density), (PSA Velocity)
(Free PSA). H

(Phi). O
(Phi)
DRE,
PSA 2-10ng/ml. 90%
19%
(PSA, Free PSA/Total PSA %Free PSA).
Phi
,
.
. , 76, 1, 832-846, 2014.
: , (PSA),
(Phi)

, 76, 1, 2014 832

 SUMMARY
PSACHOULIA CH. Evaluation of prostate health index (Phi). The cancer of the
prostate gland (PCa) is worldwide the second more common malignancy in men. The
PSA levels measurements in blood serum as diagnostic tool of prostatic cancer,
increased the diagnostic possibility of the disease in early stages. But, PSA
(Prostate-specific Antigen) should not be considered as an ideal tumor marker, as it
can also be increased in benign prostate disorders as prostatitis and benign prostate
hyperplasia, with the consequence of running the risk of false positive results and
unnecessary biopsies. Many efforts have been made to improve the reliability of PSA
as a tumor marker, such as the correlation of PSA levels with the prostate tumor
(PSA Density), the speed of change in time (PSA Velocity) and the levels of non-
bound forms of (free PSA). The latest recommendation regards to the application of a
mathematical model (formula), which identifies prostate health index (Phi). The
prostatic health index (Phi) can be considered as a reliable indicator for detecting
patients with prostate malignancy, negative digital rectal examination (DRE) and total
PSA levels in the range of (2-10) g/l. The prostatic health index (Phi) sensitivity of 90%
can prevent the 19% of prostate biopsies done, after assessing the already
applied markers (PSA, free PSA/total PSA or % free PSA). The clinical relevancy of a
detected malignancy can be assessed depending on the Phi values, since it offers the
highest detectability of an aggressive prostate cancer. Furthermore, it is the most
significant prognostic marker for biopsy in early stage. Nosokomiaka Chronika, 76,
Supplement 1, 832-846, 2014.
Key words: cancer of the prostate gland, Prostate-specific Antigen (PSA), prostatic
health index (Phi)

E
(PCa)
,
1. ,
(2012). ...,
2. ,
,
2000.
,
3.

, 76, 1, 2014 833

 (PSA)
,
, .
PSA ,
,
,
.

PSA. , PSA,
(PSA Density), (PSA Velocity)
(Free PSA). H
, ,

(Phi).
(31,1%)
PSA (10,8%) % FreePSA (19,8%), .
,

( , 18,8%).

(PROSTATE SPECIFIC ANTIGEN-PSA)

PSA
(PCa) 1986, ..
38KDa. ,
,
. ,
106ng/ml. , ,
,
, ,
test PSA. H
PSA < 4ng/ml ( 1).
( -
.) ,
10ng/ml .
PSA 2 10ng/ml 25,5%

, 76, 1, 2014 834


10-35% 4,5.
PSA
,
, PSA
PSA , ,
(PCa)
,
,
3,6.

1. PSA.

PSA :

PSAD (PSA Density)

PSA
, PSAD ( PSA)
PSA .

, 76, 1, 2014 835

PSAV (PSA Velocity)
PSA

.
PSA
PSA,
19927. PSA
,
.
PSA ,
.
, PSA 2ng/ml
.
, PSA,
, :
1. 50 PSA (0,1-20) ng/ml,
20% 8.
2. PSA 2ng/ml, 14%
, 30%
9.
3. ,
50%
10.
,
.

, National Academy of
Clinical Biochemistry (NACB)3, PSA,
. ...
50
PSA
(Digital Rectal Examination, DRE).
PSA
PSA
.

, 76, 1, 2014 836

 PSA .
PSA , .
PSA
(NACB).
PSA
,
,
.
PCa
o . 10
( - - ).
,
.
,
,
PSA.
PSA
PSA (Total PSA)
PCa test
PSA. PSA ,
, 1- (ACT)
2- (AMG). 1-
PSA Complexed PSA. PSA
PSA (Free PSA). Total PSA
Complexed PSA Free PSA (
2).
Free PSA
(Ratio) Free PSA /Total PSA ( 3)
12
Free PSA PSA (% Free PSA) ( 4) .
Free PSA/Total PSA % Free PSA
PCa
, ,
test PSA. H
( 5).

, 76, 1, 2014 837

 2. PSA11

3. (Ratio) Free PSA/Total PSA

4. % Free PSA11

, 76, 1, 2014 838

 5. Total PSA Free
PSA/Total PSA (Ratio). British Association of Urological Surgeons June 1997.

free PSA
Free PSA Benign
PSA (BPSA), intact PSA (iPSA) ProPSA ( 6) 13,14.

,
Free PSA.
BPSA iPSA
ProPSA .

, 76, 1, 2014 839

 6. Free PSA.

ProPSA
ProPSA , [-5,-7] , [-4] , [-2]
, , ,
, [-2] ProPSA p2PSA
( 7).

7. ProPSA

[-2]
ProPSA Beckman Coulter,
.
PSA 2-10ng/ml,
[-2]ProPSA (%[-2] ProPSA) Free PSA,
, % Free PSA
PSA. [-2] ProPSA

, 76, 1, 2014 840

 15,16. [-2] ProPS
% Free PSA .

(PROSTATE HEALTH INDEX- Phi)

Phi

.

Phi

PSA
(Free PSA) [-2] ProPSA Free PSA,
, .
2012, FDA (Food and Drug Administration) ...,
Phi
(American Urological Association, 07 May 2013).

,

, .
2010
,

,
Phi, .

17,18,19,20,21 Phi
, ,
ROC (AUC),
Total PSA, % Free PSA ( Free PSA/Total PSA X 100),
PSAD, [-2]ProPSA, %[-2] Pro PSA ( [-2]ProPSA Free PSA X 100).
22
AUC=0,72 Phi, AUC=0,63 [-2]ProPSA, AUC=0,6 % Free PSA,
AUC=0,56 Total PSA.

, 76, 1, 2014 841



.
90% ( ).
31,1% Phi
19,8% % Free PSA
10,8% PSA
90%
.

.
90% ( )
43% Phi
39% [-2]ProPSA
20% % Free PSA
90%
.
, Phi 2,5
.
Total PSA (2-10)g/l.
Phi
0-22,9
23-44,9
> 45
Phi > 55
23,24

90% Total PSA (2-10) g/l.

Phi 55 52,6%, 4,7
.
Phi 25 11%, 20.
Phi Gleason score .
Phi

, Gleason score20.

, 76, 1, 2014 842

 Phi
Gleason score 7, Gleason score <7
P=0,0018.

Phi.
Phi > 55, 1,6
Gleason score 723.
Phi Gleason
score 7, Tumor stage T3, Tumor volume > 0,5ml
21.
Phi PSA 2-10ng/ml
Phi ,
PSA 2-10 ng/ml.

18,8% 18.
Phi < 27

.
27< Phi < 55
Phi

9,8%-50,1%.



3,9%-28,9%.
Phi > 34,225.
52,6% , 1,6
Phi 55
Gleason score 7 .

Phi>81 91% 22.

O (Phi)

DRE, PSA 2-10ng/ml.
90%

.

, 76, 1, 2014 843

 90% 19%
(PSA, Free
PSA/Total PSA % Free PSA).
Phi
,

.

Phi. , ,
, ,

( ) .

1. Ann WH, Lilian T, Devesa SS. International trends and patterns of prostate cancer
incidence and mortality. Int. J. Cancer 2000, 85: 60-67.
2. Jemal A, Siegel R, Ward E et al. Cancer statistics 2007. CA Cancer J Clin 2007,
57: 43-66.
3. Sturgeon CM, Duffy MJ, Stenman UH et al. National Academy of Clinical
Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers
in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers. Clin Chem 2008,
54: 11-79.
4. Catalona WJ, Partin AW, Slawin KM et al. Use of the percentage of free prostate-
specific antigen to enhance differentiation of prostate cancer from benign prostatic
disease: a prospective multicenter clinical trial. J Am Med Assoc 1998, 279: 1542-
1547.
5. Fillela X,Gimenez N. Evaluation of [-2] proPSA and Prostate Health Index (phi) for
the detection of prostate cancer: a systematic review and meta- analysis. Clin
Chem and Lab Medicine 2012, 51: 729-739.
6. Graham J, Baker M, Macbeth F et al. Diagnosis and treatment of prostate cancer:
summary of NICE guidance. BMJ 2008, 336: 610-612.
7. Carter HB, Pearson JD Metter EJ et al. Longitudinal evaluation of prostate-specific
antigen levels in men with and without prostate disease. JAMA 1992, 267: 2215-
2220.

, 76, 1, 2014 844

8. Soletormos G, Semjonow A, Sibley PE, et al. Biological variation of total prostate-
specific antigen: a survey of published estimates and consequences for clinical
practice. Clin Chem 2005, 51: 1342-1351.
9. Bruun L, Becker C, Hugosson J et al. Assessment of intra-individual variation in
prostate-specific antigen levels in a biennial randomized prostate cancer
screening program in Sweden. Prostate 2005, 65: 216-221.
10. Bunting PS, DeBoer G, Choo R et al. Intraindividual variation of PSA, free PSA
and complexed PSA in a cohort of patients with prostate cancer managed with
watchful observation. Clin Biochem 2002, 35: 471-475.
11. Abbot % Free PSA, Physician Monograph 2004 Abbot Laboratories.
12. Roddam AW, Duffy MJ, Hamdy FC et al. Use of prostate-specific antigen (PSA)
isoforms for the detection of prostate cancer in men with a PSA level of 2-10 ng/
ml: systematic review and meta-analysis. Eur Urol 2005, 48: 38-399.
13. Mikolajczyk SD, Marks LS, Partin AW et al. Free prostate-specific antigen in
serum is becoming more complex. Urology 2002, 59: 797-802.
14. Mikolajczyk SD, Marker KM, Millar LS et al. A truncated precursor form of
prostate-specific antigen is a more specific serum marker of prostate cancer.
Cancer Res 2001, 61: 6958-6963.
15. Skradski V, Ladurner M, Pichler R et al [-2] proPSA is an early marker for prostate
cancer aggressiveness. Prostate cancer and prostatic diseases. ct 2013.
16. Lazzeri M, Abrate A, Lughezzani G et al Relationship of Chronic Histologic
Prostatic Inflammation in Biopsy Specimens With Serum Isoform [-2] proPSA
(p2PSA), % p2PSA, and Prostate Health Index in Men With a Total Prostate-
specific Antigen of 4-10 ng / mL and Normal Digital Rectal. Examination Urology
2013.10.16.
17. Guazzoni G, Nava L, Lazzeri M et al. Prostate-specific antigen (PSA) isoform
p2PSA significantly improves the prediction of prostate cancer at initial extended
prostate biopsies in patients with total PSA between 2.0 and 10 ng/ml: results of a
prospective study in a clinical setting. Eur Urol. 2011, 60(2): 214-222.
18. Prostate Health Index (PHI), A more precise blood test, outperforms traditional
PSA screening in predicting clinically significant prostate cancer, American
Urological Association, 07 May 07 2013.
19. Lazzeri M, Haese A, de la Taille A et al. Serum isoform [-2] proPSA derivatives
significantly improve prediction of prostate cancer at initial biopsy in a total PSA
range of 2-10 ng/ml: a multicentric European study. Eur Urol 2013, 63: 986-994.

, 76, 1, 2014 845

20. Catalona WJ, Partin AW, Sanda MG et al. A multi-center Study of [-2] Pro-
Prostate-Specific Antigen (PSA) in combination with PSA and free PSA for
prostate cancer detection in the 2.0 to 10.0 ng/ml PSA range. J Urol 2011, 185:
1650-1655.
21. Stephan C, Vincendeau S, Houlgatte A et al. Multicenter evaluation of [-2]
proprostate-specific antigen and the prostate health index for detecting prostate
cancer. Clinical Chemistry 2013, 59: 306-314.
22. Vincendau S, Stephan C, Houlgatte A et al. The Beckman Coulter prostate health
index (phi)* increases the specificity of detection of prostate cancer and may
reduce the number of negative biopsies, 2011.
23. Guazzoni G, Lazzeri M, Nava L, et al. Preoperative prostate-specific antigen
isoform p2PSA and its derivatives, % p2PSA and prostate health index, predict
pathologic outcomes in patients undergoing radical prostatectomy for prostate
cancer. Eur Urol 2012, 61: 455-466.
24. Catalona WJ, Partin AW, Sanda MG et al. A multicentre study of [-2] pro-prostate
specific antigen combined with prostate specific antigen and free prostate specific
antigen for prostate cancer detection in the 2.0 10.0 ng/ml prostate specific
antigen range. J Urol 2011, 185: 1650-1655.
25. Fillela X, Gimenez N. Evaluation of [-2] proPSA and Prostate Health Index (phi)
for the detection of prostate cancer: a systematic review and meta-analysis. Chim
Chem Lab Med 2013, 51: 729-739.

, 76, 1, 2014 846



-:


. , MD, PhD

-, ...

:
T: 2132043180
-mail: alextsir@gmail.com

,
,
. ,

.
, ()
, DNA (dsDNA) ()


,
,
. ,


/,
.
,
,

,
.
ANA

, 76, 1, 2014 847

 ,

().

,

, . , 76,
1, 847-862, 2014.
: , ,

SUMMARY
TSIROGIANNI A. Proposed algorithm for autoantibodies detection in systemic
autoimmune diseases. The autoantibodies (Aab) are important biomarkers not only
to confirm the diagnosis of the respective systemic autoimmune disease but also to
diagnose the disease without the typical clinical manifestations or at very early stage.
Furthermore, Aab determinations are used for prognostic purposes and for monitoring
of disease activity or response to therapy. In particular, results of serologic tests for
antinuclear antibodies (ANA) and antibodies to specific nuclear antigens such as
double stranded DNA (dsDNA) and extractable nuclear antigens (ENA) play an
important role in diagnostic approach of systemic rheumatic diseases (SRD).The
increasing frequency at which autoimmune disorders are observed worldwide, in
association to technological evolution used over the recent years in autoantibody
detection, has led to an increase in the number of tests ordered and performed. In the
current health care setting, which demands also reductions in costs, it is crucial to
apply for a more rational use of the available autoantibody testing panel, which takes
into account the optimal cost-benefit parameter and does not, in any way, compromise
the healthcare quality offered. Taking into account the demands of every day clinical
practice as well as several aspects of the laboratory workflow, mainly the methodology
applied, diagnostic guidelines are proposed which target not only on avoiding
needless testing but also on achieving the most comprehensive approach in
evaluating autoimmune disorders. Consideration is given to appropriate use of ANA
screening test in the initial evaluation of patients with symptoms of a SRD,
identification of clinical entities in which the ANA test is required to establish a disease
diagnosis and confirmation of patients suspected of having Systemic Lupus
Erythematosus (SLE). Beside standardization of Aab detection methods and quality

, 76, 1, 2014 848

management efforts, the improvement of diagnostic value of Aab depends on further
development and application of diagnostic algorithms, in daily clinical practice.
Nosokomiaka Chronika, 76, Supplement 1, 847-862, 2014.
Key words: autoantibodies, systemic autoimmune diseases, diagnostic algorithms

100
, 5-10%
.


, ,
,
,
1.

,
.
,
,
, 2,3,4.


,
5. Y.
Shoenfeld ,
,
,

6.
()
()
(screening test)
.
,

, 76, 1, 2014 849

 , ,
:

DNA, (dsDNA, ssDNA, ds/ssDNA), DNP, RNA, RNA

1, 2, 2, 3, 4


nRNP ,Sm, Ro (SSA), La(SSB), Scl-70, Jo-1, PCNA, PL-7, PL-12,


, , .Golgi, , ,

(screening test) ,
,
(IIF), (
Hep-2 ,
, HeLa
, .)7.
Hep- 2
:
, -dsDNA
.
,

.
, (- Sm,
- U1-nRNP, -SSA/Ro, -SSB/ La).
, DNA
(Scl-70), U3-RNP, RNA .

.
, /
,

, 76, 1, 2014 850


().
,
, , , . Golgi,
RNPs, (Jo-1) (,
, ).
, (
, ).

( ),
.
,

, 76, 1, 2014 851

, , ,
(ELISA), (immunoblotting),
(RIA) (immunoprecipitation).

( --,
--, --, / ),
, ,
( ,
), (, , ).
(
, /
),
8.
,
,
. DNA
, , (extractable nuclear antigens)
dsDNA , /
9.( 1)
DNA (dsDNA)
-DNA ,
DNA (DNA ) DNA
(DNA ) / 10. DNA in vivo
, DNA
.
-dsDNA
, ,
,
DNA.
-dsDNA DNA ,
, , , DNA11.
-dsDNA , ,
,
. ,

, 76, 1, 2014 852

 -dsDNA
, .
-dsDNA
(ACR 1997)
. ,
-dsDNA 55%
.
9,3 1 ( 2,7 )
12.
, -dsDNA
. -
dsDNA ,
. H -dsDNA,
,
,
13.
-
dsDNA DNA / in situ

,
,
-, 14.

- dsDNA , :
1. Crithidia luciliae
2. ELISA dsDNA
3. (RIA) ( Farr)

Crithidia lucilae.
, ,
, DNA.
, ,


.

, 76, 1, 2014 853

 RIA, , -dsDNA
,

ELISA,
.
,
, RIA IIF.

, RIA , ELISA
. RIA
Crithidia
ELISA,
. , ELISA
,
-ssDNA ,
dsDNA ssDNA.
, -dsDNA ELISA
, .
-dsDNA
.
-dsDNA , ELISA
, .
, -dsDNA 30% -
,
ELISA15.
()

, (
snRNP/ scRNP). RNA
.
, ,
(Extractable
Nuclear Antigens, ENA).

, 76, 1, 2014 854

 U1RNP Sm
-
, DNA
RNA.

. 1966 Tan Kunkel
DNA.
Sm (Smith)
, . -Sm
D / ,
E, F G ,
20- 30%
16.
To 1971, Mattioli Reichlin
, ,
RNA,

RNA . RNA-
nRNP,
.
RNA URNA RNA U
. -U1RNP
U1-70K U1-A U1-C17.
M N
. ,
30- 40% ,
, Raynaud, ..
Ro/ SSA, La/ SSB
1958 Jones ,
Sjogren,
. 1961, Anderson .
Sjogren,
SjT SjD.

,

, 76, 1, 2014 855

Ro La . ,
SjD Ro
SjT La .
.Sjogren (SSA, SSB) 1975 Alspargh Tan.
Ro /SSA La/ SSB
60 KD 50 KD ,
-Ro

(52KD).
-Ro (35- 50%)
Sjogren (60%), .
, ,
( )
C3 C4 18.

(Ro52/Ro60)
.
-La -Ro
Sjogren (40- 60%) ( 10-
15%). 19, - -
La/SSB ,
, .
J-1
()

.
()
. 1980 Nishikai Reichlin

( ) .
,
. ,
Jo-1 30,8% ,
(4,6%), .
J-1 IIF,

, 76, 1, 2014 856

-Jo-1 ,
.
52-64 KD
120- 150 KD,
tRNA. , ,
-tRNA , (tRNA ,
, , , ), -SRP (anti-signal recognition
particle), -Mi-2, -PM/Scl20.
Scl-70 ( )
( )

,

.
1975 Tan Rodnan

/, Scleroderma-1 (Scl-1). -

. , SDS PAGE
70 KD,
Scleroderma-70 (Scl-70).
Shero .
Scl-70 DNA- I,
DNA,
100 KD, 67KD,
.
Scl-70 21.
,
70- 75% .
4- 18%
( CREST) 5% Raynaud
.

, 22.

, 76, 1, 2014 857

 ,

,
,
5.
,
, EASI, (European
Autoimmunity Standardization Initiative)
. ,


,
.
, EASI

6,8,23.

, Ep-2

1:40 , 1:160

-dsDNA ,
, RIA ( Farr),
Elisa. Elisa

Elisa Farr
-dsDNA
- -
(. Sjgren, )
,
, Elisa -

U1-RNP

, 76, 1, 2014 858

 ,
, ,

,


. ( 2).
,

.

,

.
, ,


25.

1.
,
% %
93 57
Sjogren 48 52
85 54
/ 61 63
Raynaud 64 41
50 44

-dsDNA 57 97
-Sm 25 99
-U1RNP 12 96
-SSA/Ro .Sjogren, 8-70 87
-SSB/La .Sjogren, 16-40 94
-Scl70 20 100
-Jo1 / 30 100

, 76, 1, 2014 859

 2: ()
(Kumar Y . 2009)

1. Aziz KA, Faizal AA. The role of the clinical laboratory in the diagnosis and
monitoring of connective tissue diseases. Saudi Med J. 2004;25(12):1796-1807
2. Wiik AS. Anti-nuclear antibodies: clinical utility for diagnosis, prognosis,
monitoring, and planning of treatment strategy in systemic immunoinflammatory
diseases. Scand J Rheumatol 2005;34:260-268.
3. .
() .
2007;24(1):320-327.
4. Bizzaro N. Autoantibodies as predictors of disease: the clinical and experimental
evidence. Autoimmun Rev 2007;6:325-33.

, 76, 1, 2014 860

5. Smolen JS, Steiner G, Tan EM. Standards of care: the value and importance of
standardization Arthritis Rheum. 1997;40:410-412.
6. Shoenfeld Y, R. Cervera, M. Haass, et al. EASI The European Autoimmunity
Standardization Initiative: a new initiative that can contribute to agreed diagnostic
models of diagnosing autoimmune disorders throughout Europe. Ann. N. Y. Acad.
Sci. 2007;1109:138-144.
7. Kumar Y, Bhatia and Minz RW. Antinuclear antibodies and their detection
methods in diagnosis of connective tissue diseases: a journey revisited, Diagnostic
Pathology 2009;4:1-10.
8. Tozzoli R, Bizzaro N, Tonutti E, et al. Guidelines for the laboratory use of
autoantibody tests in the diagnosis and monitoring of autoimmune rheumatic
diseases. Am J Clin Pathol. 2002;117:316-324.
9. Lyons R, Narain S, Nichols C, et al. Effective use of autoantibody tests in the
diagnosis of systemic autoimmune disease. Ann N Y Acad Sci. 2005;1050:217-
228.
10. Tan EM. Special antibodies for the study of systemic lupus erythematosus.
Arhtritis Rheum. 1982;25:753-756.
11. Smeenk RJ. Methodological update detection of antibodies to dsDNA: current
insights into its relevance. Clin Exp Rheumatol 2002;20:294-300.
12. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies
before the clinical onset of systemic lupus erythematosus, Engl J Med. 2003 Oct
16;349(16):1526-1533.
13. Esdaile JM, Abrahamowicz M, Joseph L, et al. Laboratory tests as predictors of
disease exacerbations in systemic lupus erythematosus. Why some tests fail.
Arthritis Rheum 1996;39:370-378.
14. Hamann D, Smeenk R, Autoantibodies Shoenfeld Y, Gerschwin ME, Meroni PL.
2nd Edition Elsevier 2007;159-167.
15. Haugbro K, Nossent JC, Winkler T, et al. Anti-dsDNA antibodies and disease
classification in antinuclear antibody positive patients: the role of analytical
diversity. Ann Rheum Dis. 2004;63(4):386-394.
16. Neuenkirchen N, Chari A, Fischer U. Deciphering the assembly pathway of Sm-
class U snRNPs. FEBS Lett 2008;582:1997-2003.
17. Will CL, Luhrmann R. Spliceosomal UsnRNP biogenesis, structure and function.
Curr Opin Cell Biol 2001;13:290-300.

, 76, 1, 2014 861

18. Tappeiner G, Hintner H, Scholz S, et al. Systemic lupus erythematosus in
hereditary deficiency of the fourth component of complement. J Am Acad Dermatol
1982;7:66-79.
19. Tzioufas , Routsias J. Idiotype, anti-idiotype network of autoantibodies:
Pathogenetic considerations and clinical application. Autoimmunity Reviews
2010;9: 631633.
20. Targoff IN. Autoantibodies and their significance in myositis, Current
Rheumatology Reports 2008;10(4):333-340.
21. Shero JH, Bordwell B, Earnshaw WC. High titers of autoantibodies to
topoisomerase I (Scl-70) in sera from scleroderma patients. Science.
1986;14:737740.
22. Reveille JD, Solomon DH. American College of Rheumatology, Committee on
Immunological Testing Guidelines Evidence-based guidelines for the use of
immunologic laboratory tests: anti-centromere, Scl-70 and nucleolar antibodies.
Arthritis Rheum, Arthritis Care & Research 2003;49(3):399412.
23. Wiik A, Cervera R, Haass M, et al. European attempts to set guidelines for
improving diagnostics of autoimmune rheumatic disorders. Lupus 2006;15:391-
396.
24. Kumar Y, Bhatia , Minz RW. Antinuclear antibodies and their detection methods
in diagnosis of connective tissue diseases: a journey revisited, Diagnostic
Pathology 2009; 4:1.
25. .
2012; 74(1):25-29.

, 76, 1, 2014 862



:
MALT :

,
...

:
o: 2132041542
E-mail: gkanellis73@gmail.com

MALT - Hodgkin

. -
(Helicobacterpylori,
HP).
,
. MALT
,

(WHO2008)
. , MALT
,
in situ (FISH)
, t(11;18),
. MALT
,
.

,
,
. , 76,
1, 863-876, 2014.

, 76, 1, 2014 863

 : MALT, ()

SUMMARY
KANELLIS G. Gastric MALT lymphoma: New challenges. Gastric MALT lymphoma
is an indolent non Hodgkin B-cell lymphoma from the marginal zone cell of the
mucosa-associated lymphoid tissue (MALT). It is a rather rare B-cell lymphoma and
its pathogenesis is correlated with Helicobacter pylori (HP) infection of the stomach.
In recent studies, mechanisms of lymphoma pathogenesis involve HP and its strands,
and the lymphoma microenvironment as well.The diagnosis is made on a gastric
biopsy specimen, with the use of an array of immunohistochemical markers and
according to the diagnostic criteria set by the World Health Organization (WHO 2008)
in its revised classification of tumors of the Hematopoietic and lymphoid tissues.
Additionally, a number of chromosomal aberrations are observed in gastric MALT
lymphoma. In particular, the t(11;18) translocation is of great interest, because it is
associated with resistance in antibiotic therapy and it is detected via fluorescence in
situ hybridization (FISH) on the biopsy tissue. The therapy of choice is HP eradication
with antibiotics. In case of drug resistance other approaches are used such as
radiotherapy or systematic chemotherapy. In conclusion, the new data emerging
concerning possible new lymphomatogenesis mechanisms and the evaluation of the
established ones give rise to new therapeutic possibilities for the complete cure of this
lymphoma. Nosokomiaka Chronika, 76, Supplement 1, 863-876, 2014.
Key words: gastric MALT lymphoma, Helicobacter pylori (HP)

E

(WHO 2008),
MALT -

,
MALT:
Extra nodal marginal zone lymphoma of ucosa-ssociated Lymphoid Tissue MALTl
ymphoma, (ICD-O 9699/3)1,2.
MALT
,
( ).

, 76, 1, 2014 864


1.

MALT 7%,
, Hodgkin
. 35%
, 66% MALT

(Helicobacter pylori, HP)3.

57 .
, 68% 11% ,

, 8% 2% 4.

MALT
MALT
,
.
,
5 .


2008 (WHO 2008)2 .
:

MALT
-, (
),
.
~ 33% .

, /

, 76, 1, 2014 865

 (lymphoepitheliallesion), ,
MALT 2.
,
(follicular colonization)6,7.

.
(sheets),
- .

MALT
-CD20+, CD79a+, CD5-, CD10-,CyclinD1-,CD23-/+,CD43+/-
.
.
-
,
t(11;18)(q21;q21)API2/MALT1
in situ (FISH).


( / ),
:
1. -
2. -

(..
, ).
3. t(11;18)(q21;q21)API2/MALT1.

.

1.

MALT HP 8.

, 76, 1, 2014 866


.
, HP, Gram ,
9
, pH
.
MALT . ,

70% ALT ,
10. ,
MALT
, Veneto 11.
, MALT 12.

in vitro

- CD40-CD40L13. ,
MALT
14. ,

80% 15.

MALT

-. , Cag+ H
16. CagA , ,
.

16, IV,
-17. - CagA

-
, MALT
17.

, 76, 1, 2014 867

2.
-
.
(..
: ,
, , ).
,
:
( ..
).

18.
MALT , ,

.
2. -
-
( 1).
h1-(CD3+, CD4+, CD8-, FOXP3-, CD25-) ,
TNF, - (IFN-)
,
FAS.
Th1-
MALT 19. MALT
-
CD40
h1-. h1-
Th1- - 13, 20-22
.
,

23
h1- .
Th1-
-
. MALT . ,
, h1-

, 76, 1, 2014 868

 -

- FAS-FAS-ligand 22. ,
, ,
h1- -
. -
22,24,25.

1. -

-

(tumorpromoting)
?
CD8+


CD4+ Th2

-

CD4+ Th1



CD4+ Th17
-

CD4+ Tregs

2. ( 2)
( MALT ),
- - ,
.
,
/ - .

.
26 -3
, ) h1/Th2-
, ) ( ), )

, 76, 1, 2014 869

 ( ), )
( ) )
.
2. (mastcells)


.
E MALT ,
APRIL.
, TNF, -.
, ,
- h1-27.

2.

-
(tumorpromoting)


. : ,

, ,

( IL-12 &IFN-I) ,

.
-


: ,

,

-

3. ( 3)
MALT
.
MALT

, 76, 1, 2014 870

 ,
, ( 3) .

3. MALT

-

t(11;18)(q21;q21) ~25% , ~45%, ~

API2-MALT1 15%, ~ 2%, /~0%.
NF-kB*
t(1;14)(p22;q32)
1-3%
IGH- BCL10

t(14;18)(q32;q21) ~ 10%. .
IGH-MALT1 , ,

MALT .
, ,
.
t(3;14)(p14.1;q32) 29% MALT,
IGH-FOXP1 DFS
DLBCL.

.
t(3;14)(q27;q32)
1-2%
IGH-BCL6
:
3, 12, 18,

50%-65% ,
3q27 MALT DLBCL.
.

18 ~ 40%

t(11;18) (q21;q21) API2/MALT1,

100% ,

MALT 25% 28,29.
t(11;18) - API2
(apoptosis inhibitor-2) 11 C- MALT1 (MALT
lymphoma associated trans location) 18.

, 76, 1, 2014 871

 MALT

,
H
MALT
. , , MALT
29,30.
t(11;18)
, -
31-34.
4.

,
, MALT
35,36.

,
MALT ESMO37
+
10-14 . 6
34. -
(
).
+ -
38.
/
. -


3,33. t(11;18)
3,34. ,
, rituximab
, ,
, 37.

, 76, 1, 2014 872


MALT -
, -.

.


, ,
.

,
.

1. Isaacson PG. Exranodal Marginal Zone Lymphoma: MALT Lymphoma. In: Jaffe
ES, Harris NL, Vardiman JW, Campo E, Arber DA, editors. Hematopathology. St
Luis: Elsevier; 2011. p. 291-305.
2. Isaacson PG, Chott A, Nakamura S, Muller-Hermelink HK, Harris NL, Swerdlow
SH. Extranodal marginal zone lymphoma of mucosa associated lymphois tissue
(MALT lymphoma). In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA,
Stein H, et al., editors. WHO Classification of Tumours of Haematopoietic and
Lymphoid Tissues. Lyon: IARC; 2008. p. 214-219.
3. Bertoni F, Coiffier B, Salles G, et al. MALT lymphomas: pathogenesis can drive
treatment. Oncology. 2011;25(12):1134-1142, 1147.
4. Papaxoinis G, Fountzilas G, Rontogianni D, et al. Low-grade mucosa-associated
lymphoid tissue lymphoma: a retrospective analysis of 97 patients by the Hellenic
Cooperative Oncology Group (HeCOG). Annals of oncology : official journal of the
European Society for Medical Oncology / ESMO. 2008;19(4):780-786.
5. Bertoni F, Zucca E. State-of-the-art therapeutics: marginal-zone lymphoma.
Journal of clinical oncology : official journal of the American Society of Clinical
Oncology. 2005;23(26):6415-6420.
6. Isaacson PG, Spencer J. Malignant lymphoma of mucosa-associated lymphoid
tissue. Histopathology. 1987;11(5):445-462.

, 76, 1, 2014 873

7. Isaacson PG, Wotherspoon AC, Diss T, et al. Follicular colonization in B-cell
lymphoma of mucosa-associated lymphoid tissue. The American journal of
surgical pathology. 1991;15(9):819-828.
8. Sagaert X, De Wolf-Peeters C, Noels H, et al. The pathogenesis of MALT
lymphomas: where do we stand? Leukemia. 2007;21(3):389-396.
9. Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection
and the risk of gastric carcinoma. The New England journal of medicine.
1991;325(16):1127-1131.
10. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, et al. Helicobacter pylori-
associated gastritis and primary B-cell gastric lymphoma. Lancet.
1991;338(8776):1175-1176.
11. Doglioni C, Wotherspoon AC, Moschini A, et al. High incidence of primary gastric
lymphoma in northeastern Italy. Lancet. 1992;339(8797):834-835.
12. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and
gastric lymphoma. The New England journal of medicine. 1994;330(18):1267-71.
13. Hussell T, Isaacson PG, Crabtree JE, et al. The response of cells from low-grade
B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter
pylori. Lancet. 1993;342(8871):571-574.
14. Enno A, O'Rourke J, Braye S, et al. Antigen-dependent progression of mucosa-
associated lymphoid tissue (MALT)-type lymphoma in the stomach. Effects of
antimicrobial therapy on gastric MALT lymphoma in mice. The American journal of
pathology. 1998;152(6):1625-1632.
15. Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary low-grade B-
cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication
of Helicobacter pylori. Lancet. 1993;342(8871):575-577.
16. Hatakeyama M, Higashi H. Helicobacter pylori CagA: a new paradigm for bacterial
carcinogenesis. Cancer science. 2005;96(12):835-843.
17. Lin WC, Tsai HF, Kuo SH, et al. Translocation of Helicobacter pylori CagA into
Human B lymphocytes, the origin of mucosa-associated lymphoid tissue
lymphoma. Cancer research. 2010;70(14):5740-5748.
18. Meads MB, Hazlehurst LA, Dalton WS. The bone marrow microenvironment as a
tumor sanctuary and contributor to drug resistance. Clinical cancer research : an
official journal of the American Association for Cancer Research. 2008;14(9):2519-
2526.

, 76, 1, 2014 874

19. Riedel S, Kraft M, Kucharzik T, et al. CD4+ Th1-cells predominate in low-grade B-
cell lymphoma of gastric mucosa-associated lymphoid tissue (MALT type).
Scandinavian journal of gastroenterology. 2001;36(11):1198-1203.
20. Hussell T, Isaacson PG, Crabtree JE, et al. Helicobacter pylori-specific tumour-
infiltrating T cells provide contact dependent help for the growth of malignant B
cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. The
Journal of pathology. 1996;178(2):122-127.
21. Greiner A, Knorr C, Qin Y, et al. Low-grade B cell lymphomas of mucosa-
associated lymphoid tissue (MALT-type) require CD40-mediated signaling and
Th2-type cytokines for in vitro growth and differentiation. The American journal of
pathology. 1997;150(5):1583-1593.
22. D'Elios MM, Amedei A, Manghetti M, et al. Impaired T-cell regulation of B-cell
growth in Helicobacter pylori--related gastric low-grade MALT lymphoma.
Gastroenterology. 1999;117(5):1105-1112.
23. Bergman MP, D'Elios MM. Cytotoxic T cells in H. pylori-related gastric
autoimmunity and gastric lymphoma. Journal of biomedicine & biotechnology.
2010;2010:104918.
24. Lehours P, Zheng Z, Skoglund A, et al. Is there a link between the
lipopolysaccharide of Helicobacter pylori gastric MALT lymphoma associated
strains and lymphoma pathogenesis? PloS one. 2009;4(10):e7297.
25. Lehours P, Dupouy S, Bergey B, et al. Identification of a genetic marker of
Helicobacter pylori strains involved in gastric extranodal marginal zone B cell
lymphoma of the MALT-type. Gut. 2004;53(7):931-937.
26. Tang D, Lotze MT. Tumor immunity times out: TIM-3 and HMGB1. Nature
immunology. 2012;13(9):808-810.
27. Munari F, Lonardi S, Cassatella MA, et al. Tumor-associated macrophages as
major source of APRIL in gastric MALT lymphoma. Blood. 2011;117(24):6612-
6616.
28. Remstein ED, Dogan A, Einerson RR, et al. The incidence and anatomic site
specificity of chromosomal translocations in primary extranodal marginal zone B-
cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in North
America. The American journal of surgical pathology. 2006;30(12):1546-1553.
29. Ye H, Liu H, Attygalle A, et al. Variable frequencies of t(11;18)(q21;q21) in MALT
lymphomas of different sites: significant association with CagA strains of H pylori
in gastric MALT lymphoma. Blood. 2003;102(3):1012-1018.

, 76, 1, 2014 875

30. Nakamura S, Ye H, Bacon CM, et al. Clinical impact of genetic aberrations in
gastric MALT lymphoma: a comprehensive analysis using interphase fluorescence
in situ hybridisation. Gut. 2007;56(10):1358-1363.
31. Chuang SS, Lee C, Hamoudi RA, et al. High frequency of t(11;18) in gastric
mucosa-associated lymphoid tissue lymphomas in Taiwan, including one patient
with high-grade transformation. British journal of haematology. 2003;120(1):97-
100.
32. Inagaki H, Nakamura T, Li C, et al. Gastric MALT lymphomas are divided into
three groups based on responsiveness to Helicobacter Pylori eradication and
detection of API2-MALT1 fusion. The American journal of surgical pathology.
2004;28(12):1560-1567.
33. Dreyling M, Thieblemont C, Gallamini A, et al. ESMO Consensus conferences:
guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell
lymphoma, peripheral T-cell lymphoma. Annals of oncology : official journal of the
European Society for Medical Oncology / ESMO. 2013;24(4):857-877.
34. Ruskone-Fourmestraux A, Fischbach W, Aleman BM, et al. EGILS consensus
report. Gastric extranodal marginal zone B-cell lymphoma of MALT. Gut.
2011;60(6):747-758.
35. Oka T, Sato H, Ouchida M, Utsunomiya A, et al. Cumulative Epigenetic
Abnormalities in Host Genes with Viral and Microbial Infection during Initiation and
Progression of Malignant Lymphoma/Leukemia. Cancers. 2011;3(1):568-581.
36. Ushijima T, Hattori N. Molecular pathways: involvement of Helicobacter pylori-
triggered inflammation in the formation of an epigenetic field defect, and its
usefulness as cancer risk and exposure markers. Clinical cancer research : an
official journal of the American Association for Cancer Research. 2012;18(4):923-
929.
37. Zucca E, Copie-Bergman C, Ricardi U, et al. Gastric marginal zone lymphoma of
MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-
up. Annals of oncology : official journal of the European Society for Medical
Oncology / ESMO. 2013;24(Suppl 6):vi144-148.
38. Wirth A, Gospodarowicz M, Aleman BM, et al. Long-term outcome for gastric
marginal zone lymphoma treated with radiotherapy: a retrospective, multi-centre,
International Extranodal Lymphoma Study Group study. Annals of oncology :
official journal of the European Society for Medical Oncology/ESMO.
2013;24(5):1344-1351.

, 76, 1, 2014 876



Alzheimer

, PET/CT

:
: 6947721324, 2106597067
E-mail: npianou@yahoo.gr

,
, .
Alzheimer (AD) 2/3 .
: 1)

- () 2) -
(Neurofibrillary angles-NFTs). ,
.


() AD. H - (FDG)
.
AD ,
. ,
FDG-PET AD
, Lewy Body.
FDG-PET AD ,
,
(posterior cingulate gyrous). FDG ,

, 76, 1, 2014 877


AD.
:1. Aminonapthalenes, 2. Benzothiazoles, 3.
Stilbenes 4. Imidazopyridines.
, NFTs,
. AD
)
) . ,
76, 1, 877-885, 2014.
: N Alzheimer, , FDG, , NFTs

SUMMARY
PIANOU . What's New in the Department of Nuclear Medicine; Nuclear
Medicine Diagnostic tests in Neurology. Alzheimer's Disease. Dementia is an
irreversible neurodegenerative disease, which is characterized by a loss of cognitive
ability, affecting a large number of patients. The Alzheimers disease (AD) accounts for
2/3 incidents of dementia. Histopathologic features that characterize the disease are:
1) the colloidal aggregates between neurons called amyloid deposits (Ab) and 2) the
bundles of fibrils into neurons (Neurofibrillary Tangles -NFT's). The diagnosis is
primarily clinical, but it is placed with certainty only after histological confirmation at
autopsy. There are a few positron emitting radiopharmaceuticals which have been
used in Positron Emission Tomography Imaging (PET) for the diagnosis of AD. The
fluoro-deoxy-glucose (FDG) is the most widely used PET radiopharmaceutical in
clinical practice. The characteristic pattern in the development of AD is that as the
amyloid deposits increase, the glucose metabolism is reduced in specific brain
regions. Thus, the FDG-PET may be used for the differential diagnosis between AD
from normal degeneration due to age, from frontotemporal dementia and dementia of
Lewy Body particles. In FDG-PET imaging , the AD is characterized by decreased
metabolism in the temporal lobe, the parietal lobe and the posterior cingulate gyrous.
Besides FDG however, attempts are being made recently to develop new PET
radiopharmaceuticals for the diagnosis of AD. There are four different categories of
radiopharmaceuticals for this purpose: 1. Aminonapthalenes, 2. Benzothiazoles, 3.
Stilbenes and 4. Imidazopyridines. These radiopharmaceuticals show selective uptake
either in Ab plaques, or NFT's, depending on the category to which they belong. The
expected utilities of PET imaging of AD are a) the early detection of high-risk patients

, 76, 1, 2014 878

for AD, who are candidates for treatment and b) to assess the response to treatment.
Nosokomiaka Chronika, 76, Supplement 1, 877-885, 2014.
Key words: Alzheimers Disease, , FDG, Amyloid deposits, NFTs.

, 2030
63 . , 114
. 2050.
,
, .
:
1. Lewy Bodies (DLB)
2. (VaD)
3. (FTLD)
4. Creutzfeldt-Jacob
5. Parkinson
6.
7.
8.
9.
10. Alzheimer
Alzheimer
Alzheimer (AD) 2/3 .
: 1)

- () 2) -
(Neurofibrillary angles-NFTs)1.
AD ,
, (Mini-Mental state examination)
tau.

.

, 76, 1, 2014 879

 . ,
AD
.
AD


(Positron Emission Tomography) AD1.

, NFTs.
- (FDG)
H - (18-F-FDG)
. FDG
,
,

.
AD
,
2. , FDG-PET
AD ,
(FTLD) Lewy Body.
FDG-PET
, AD
, ,
,
(posterior cingulate gyrous),

.
FTLD FDG-PET
,
. , Lewy Body
. FDG-PET
AD ( 55%-70%),
(75%-80%)3, 4.

, 76, 1, 2014 880

 Alzheimer
FDG ,
AD.

AD :
1.
2.
3. - ()
4.

5.
6. .
:1.
Aminonapthalenes, 2. Benzothiazoles, 3. Stilbenes 4. Imidazopyridines.

: C11 F18. ,
C11 (T1/2=20min)
(on site cyclotron),
F18 (T1/2=110min),

,
F18 .
Aminonapthalenes
2-1-6-
dimethylamino-2-naphthyl ethylidene malononitrile (18-F-FDDNP).
in-vivo University of
California.
NFTs,
.

( target/background),
Pi ( ),
,
( naproxen ibuprofen),

, 76, 1, 2014 881


5.
Benzothiazoles
Pittsburg
Compound B (PiB) C11 ([-methyl-11C]2-(4-methylaminophenyl)-6-
hydroxybenzothiazole). PiB -,
. 2002
Uppsala
.
,
. , PiB
, NFTs6.
PiB , BBB,
BBB,
in-vivo .
PiB-
90% AD,
,
. ,
30%-40%
, 80 ,
, 7.
C11 PiB- 86%
(MCI) AD
92% AD.

8.
Flutemetamol (18-F-3 F-PiB) C11 PiB,
F18,
.
C11 PiB, BBB
.
93% 9.
Stilbenes

, 76, 1, 2014 882

 Florbetaben (18F-AV1), (trans-4-(N-methylamino)-4=-{2-[2-(2-[18F] fluoro-
ethoxy)-ethoxy]-ethoxy}-stilbene), Stilbenes.
Pi,
, FTLD
, (
PiB) 10.
18F-AV1
, 80% 91%
AD11.
Imidazopyridines
Florbetapir (18F-AV45), (E)-4-(2-(6-(2-(2-(2-18F-fluoroethoxy) ethoxy)
ethoxy) pyridine-3-yl) vinyl)-N-methylbenzenamine,
Imidazopyridines. PiB,
.
2007, 2010
(
) .
- -
BBB12.
FDG
Florbetapir FDG
AD, Florbetapir FDG
(95% 89% ), (95%
86% )13.
PiB FDG C11-
PiB FDG
,
14.
, ,

MCI AD. ,
, PiB
, ,
15.
-

, 76, 1, 2014 883

 AD
)
( ,
AD), ) .

Appropriate Use Criteria for Amyloid PET
2013 16:
MCI
AD
,


( <65 ).

AD
:


AD
MCI AD

.

.

1. Vallabhajosula S. Positron Emission Tomography Radiopharmaceuticals for

Imaging Brain Beta-Amyloid. Semin Nucl Med 2011; 41:283-299.
2. Nordberg A. Amyloid imaging in Alzheimers disease. Curr Opin Neurol 2007;
20:398402.
3. Hoffman JM, Welsh-Bohmer KA, Hanson M, et. al. FDG PET imaging in patients
with pathologically verified dementia. J Nucl Med 2000; 41:19201928.
4. Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in
evaluation of dementia: Regional brain metabolism and long-term outcome.JAMA
2001; 286:2120 2127.

, 76, 1, 2014 884

5. Agdeppa ED, Kepe V, Liu J, et al: Binding characteristics of radiofluorinated 6-
dialkylamino-2- naphthylethylidene derivatives as positron emission tomography
imaging probes for beta-amyloid plaques in Alzheimers disease. J Neurosci
21:RC189, 2001.
6. Ikonomovic MD, Klunk WE, Abrahamson EE, et al: Post-mortem correlates of in
vivo PiB-PET amyloid imaging in a typical case of Alzheimers disease. Brain
2008; 131:1630-1645.
7. Abella H. Report from SNM: Molecular Imaging, PET imaging of brain chemistry
bolsters characterization of dementias June 16, 2009 |
8. Rowe CC, Ellis KA, Rimajovae M, et al: Amyloid imaging results from the
Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol
Aging 2010; 31:1275-1283.
9. Vandenberghe R, Van Laere K, Ivanoiu A, et al. F-flutemetamol amyloid imaging
in Alzheimer disease and mild cognitive impairment: a phase 2 trial. Ann Neurol
2010; 68: 319329.
18
10. Becker G, Ichise M, Barthel H, et. al. PET Quantification of F-Florbetaben
Binding to -Amyloid Deposits in Human Brains JNM, Vol 54, 5, May 2013.
11. Barthel H, Gertz H-J, Dresel S, et al. Cerebral amyloid- PET with florbetaben
(1F) in patients with Alzheimers disease and healthy controls: a multicentre
phase 2 diagnostic study. Lancet Neurol 2011; 10: 424435.
12. Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging beta-
amyloid pathology. JAMA 2011; 305: 275283.
13. Newberg A, Arnold S, Wintering N, et. al. Initial Clinical Comparison of 18F-
Florbetapir and 18F-FDG PET in Patients with Alzheimer Disease and Controls
Philadelphia, Pennsylvania J Nucl Med 2012; 53:902907
14. Lowe V, Kemp B, Jack C, et. al Comparison of 18F-FDG and PiB PET in Cognitive
Impairment. J Nucl Med 2009; 50:878886.
15. Zhang S, Han D, Tan X, et. al. Diagnostic accuracy of 18F-FDG and 11C-PIB-PET
for prediction of short-term conversion to Alzheimers disease in subjects with mild
cognitive impairment. Int J Clin Pract, February 2012; 66(2):185198.
16. Johnson KA, Mimoshima S, Bohnen NI, et. al. Appropriate Use Criteria for
Amyloid PET: A Report of the Amyloid Imaging Task Force, the Society of Nuclear
Medicine and Molecular Imaging, and the Alzheimers Association. J Nucl Med
2013; 54:476490.

, 76, 1, 2014 885

 :
:

, MSc, PhD,
, ...

:
: 2132041365
E-mail: lskoura@yahoo.gr

. ,
low-grade ,
high-grade
. high-grade ,

, . , MRI
CT,
,
. PET
,
. PET
PET/CT [18F]FDG
,
.
[18F]FDG-,
, [18F]FDG,
, .
, [18F]FDG,
,
, .
11
[ C] (MET),
[18F]-- (FET), [18F]- (FLT) [18F].
[18F]FDG-PET
,

, 76, 1, 2014 886

 [18F]FDG ,
,
. [18F]FDG
, MET FET
. , 76,
1, 886-896, 2014.
: , , , 18F-

SUMMARY
SKOURA E. Brain tumors. Malignant gliomas and metastatic tumors are the most
common brain tumors. Neuroimaging plays a significant role clinically in the imaging
of low-grade tumors. Imaging is performed for the evaluation of recurrent disease and
for monitoring anaplastic transformation into high-grade tumors. In high-grade and
metastatic tumors, the imaging challenge is to distinguish between recurrent tumor
and treatment-induced changes, such as radiation necrosis. Conventional imaging
methods such as MRI and CT provide superior structural detail but have poor
specificity in identifying viable tumors in the brain treated with surgery, radiation, or
chemotherapy. Molecular imaging with PET provides additional metabolic information
of the tumor, both for patient management as well as for evaluation of newly
developed therapeutics. PET and PET/CT imaging using the tracer [18F]FDG have
become a success story for many tumors of the body, it has unfavorable
characteristics in brain tissue due to its high uptake in normal brain tissue. Due to the
sub-optimal specificity and sensitivity of [18F]FDG, the search for non-FDG brain tumor
PET radiotracers has been increasing during the past decade in order to improve the
diagnostic accuracy. The most promising non-FDG brain tumor radiotracers include
radioactively labeled nucleoside and amino-acid analogues, tracers of fatty acid
metabolism and hypoxia, as well as receptor ligands of various kinds. The most widely
used non-FDG radiotracers include [11C]methionine (MET), [18F]fluoroethyl-l-tyrosine
(FET), [18F]fluorothymidine (FLT) and [18F]choline. Although [18F]FDG-PET still plays a
role for assessment of tumor grade and dedifferentiation of gliomas over time, amino
acid tracers are vastly superior to [18F]FDG for most indications, as tumor delineation,
assessment of recurrence and therapy response. The selective advantages of these
radiotracers, compared to [18F]FDG, are varying, but MET and FET appears to be the

, 76, 1, 2014 887

most useful dedicated glioma radiotracers. Nosokomiaka Chronika, 76, Supplement
1, 886-896, 2014.
Key Words: glioma; brain tumors; positron emission tomography; 18F-
fluorodeoxyglucose

1%-2% .
.
(WHO), 3 :
, 1.

-grading: low-grade WHO grades I , high-
grade, WHO grades III IV. 3 low-grade :
(grade I), (grade II),
(grade II). high-grade
( grade III)
(grade IV) 1.


/ (),
. ,

,
. MRI
-gold standard, .
MRI
,
2. ,
, ,
. MRI
, ,
. ,
MRI, , -
3. PET,

, 76, 1, 2014 888

 ,
, MRI CT.
[18F]FDG
. [18F]FDG
high-grade
. low-grade
4,5. ,
[18F]FDG-6. [18F]FDG
(background),
,
.
,
, low-grade
high-grade, .
[18F]FDG low-grade
,
.

PET,

[18F]FDG, [11C]- (MET),
11 11 18
C-, C- , F-
(FET).
,
. ,
-18 (18F), [18F]FET
-11(11C) ,
18 11
F (110 min) C (20 min). , [18F]FET
11
on-site . C-
MET [18F]FET, ,
7,8,9.
PET :

,
10,11

, 76, 1, 2014 889


12,13
14,15
:
1.
[18F]FET
( )
,
16. low-grade
17.

1.6
1.5 [18F]FET 11
C-MET, ,
18,19
. ,

80%. , 25% low-grade
,
low-grade . [18F]FET
,
low- high-grade .
high-grade
low-grade , PET.
MRI-
:
MRI
8,16,19.
,
,
, 20,21. ,

, , MRI CT11,22. ,


3,23.

, 76, 1, 2014 890

2.
MRI
. ,

9. , [18F]FET-PET

.
100% 93%,
13.
3.
,
[18F]FET-PET.
[18F]FET-PET
24,25.
[18F]FET PET MRI14. ,
[18F]FDG
26,27.
4.

.
, grade II28,29,30.

[18F]FDG .

31,32. , grade III grade IV
. ,
[18F]FDG
31,33.
PET


,

.

, 76, 1, 2014 891

 , [18F]Fluoroazomycin arabinoside-[18F]FAZA
[18F]Fluoromisonidazole-[18F]FMISO,
.
34,35.
, [18F]Fluorothymidine-
[18F]FLT . [18F]FLT
1 DNA.
Ki-67
[18F]FDG36. [18F]FLT
[18F]FDG
. , [18F]FLT

37,38.

. ,

,
11 18
. C F
39-41. [18F]

42.
,
43. avb3
,
44. avb3
18F-Galacto-RGD45,47.

1. Kleihues P, Cavenee WK, eds. World Health Classification of Tumors: Pathology

and Genetics-Tumors of the Nervous System. New York, NY: Oxford University
Press; 2000.
2. Benard F, Romsa J, Hustinx R. Imaging gliomas with positron emission
tomography and single-photon emission computed tomography. Semin Nucl Med
2003; 33: 148-162.

, 76, 1, 2014 892

3. Grosu AL, Weber WA, Astner ST et al. 11C-methionine PET improves the target
volume delineation of meningiomas treated with stereotactic fractionated
radiotherapy. Int. J. Radiat. Oncol. Biol. Phys 2006; 66: 339-344.
4. Padoma MV, Said S, Jacobs M, et al. Prediction of pathology and survival by FDG
PET in gliomas. J Neurooncology 2003; 64: 227-237.
5. De White O, Levivier M, Violon P, et al. Prognostic value of positron emission
tomography with [18F]fluoro-2-D-glucose in the low-grade glioma.
9. J Neurosurg 1996; 39: 470-477.
6. Olivero WC, Dulebohn SC, Lister JR. The use of PET in evaluating patients with
primary brain tumors: is it useful? J Neurol Neurosurg Psychiatry 1995; 58: 250-
252.
7. Langen KJ, Jarosch M, Muhlensiepen H, et al. Comparison of fluorotyrosines and
methionine uptake in F98 rat gliomas. Nucl. Med. Biol 2003; 30: 501-508.
8. Pauleit D, Floeth F, Tellmann L, et al. Comparison of O-(218F-fluoroethyl)-
Ltyrosine PET and 3123I-iodo-a-methyl-LtyrosineLtyrosine SPECT in brain
tumors. J. Nucl. Med 2004; 45: 374381.
9. Popperl G, Gotz C, Rachinger W, et al. Value of O-(2-[18F]fluoroethyl)- L-tyrosine
PET for the diagnosis of recurrent glioma. Eur J Nucl Med Mol 2004; 31:1464-
1470.
10. Goldman S, Levivier M, Pirotte B, et al. Regional methionine and glucose uptake
in high-grade gliomas: a comparative study on PET-guided stereotactic biopsy. J.
Nucl Med 1997; 38: 1459-1462.
11. Pirotte B, Goldman S, Dewitte O, et al. Integrated positron emission tomography
and magnetic resonance imaging-guided resection of brain tumors: a report of 103
consecutive procedures. J. Neurosurg 2006; 104: 238-253.
12. Van Laere K, Ceyssens S, Van Calenbergh F, et al. Direct comparison of 18F-
FDG and 11C-methionine PET in suspected recurrence of glioma: sensitivity,
inter-observer variability and prognostic value. Eur J Nucl 2005; Med Mol Imaging
2005; 32: 39-51.
13. Rachinger W, Goetz C, Popperl G, et al. Positron emission tomography with O-(2-
[18F]fluoroethyl)-l-tyrosine versus magnetic resonance imaging in the diagnosis of
recurrent gliomas. Neurosurgery 2005 ; 57 : 505-511.
14. Nariai T, Tanaka Y, Wakimoto H , et al. Usefulness of L-[methyl-11C] methionine
positron emission tomography as a biological monitoring tool in the treatment of
glioma. J Neurosurg 2005; 103: 498-507.

, 76, 1, 2014 893

15. Wyss M, Hofer S, Bruehlmeier M, et al. Early metabolic responses in
temozolomide treated low-grade glioma patients. J Neurooncol 2009; 95: 87-93.
16. Pauleit D, Floeth F, Hamacher K, et al. O-(2-[18F]fluoroethyl)-L-tyrosine PET
combined with MRI improves the diagnostic assessment of cerebral gliomas.
Brain 2005; 128: 678-687.
17. Jacobs AH, Kracht LW, Gossmann A, et al. Imaging in neurooncology. NeuroRx
2005; 2: 333-347.
18. Herholz K, Holzer T, Bauer B, et al. 11C-methionine PET for differential diagnosis
of low-grade gliomas. Neurology 1998; 50: 1316-1322.
19. Floeth FW, Pauleit D, Wittsack H-J, et al. Multimodal metabolic imaging of
cerebral gliomas: positron emission tomography with [18F]fluoroethyl-L-tyrosine
and magnetic resonance spectroscopy. J Neurosurg 2005; 102: 318-327.
20. Kracht LW, Miletic H, Busch S, et al. Delineation of brain tumor extent with
10. [11C]L-methionine positron emission tomography: local comparison with
stereotactic histopathology. Clin Cancer Res 2004; 10: 7163-7170.
21. Pirotte B, Goldman S, Massager N, et al. Comparison of 18F-FDG and 11C-
methionine for PET-guided stereotactic brain biopsy of gliomas. J Nucl Med 2004;
45: 1293-1298.
22. Ogawa T, Shishido F, Kanno I, et al. Cerebral glioma: evaluation with methionine
PET. Radiology 1993; 186: 4553.
23. Nuutinen J, Sonninen P, Lehikoinen P, et al. Radiotherapy treatment planning and
long-term follow-up with [11C]methionine PET in patients with low-grade
astrocytoma. Int J Radiat Oncol Biol Phys 2000; 48: 4352.
24. Popperl G, Goldbrunner R, Gildehaus FJ, et al. O-(2-[18F]fluoroethyl)-L-tyrosine
PET for monitoring the effects of convection-enhanced delivery of paclitaxel in
patients with recurrent glioblastoma. Eur J Nucl Med Mol Imaging 2005; 32: 1018-
1025.
25. Popperl G, Gotz C, Rachinger W, et al. Serial O-(2-[18F]fluoroethyl)-L-tyrosine
PET for monitoring the effects of intracavitary radioimmunotherapy in patients with
malignant glioma. Eur J Nucl Med Mol Imaging 2006; 33: 792-800.
26. Brock CS, Young H, OReilly SM, et al. Early evaluation of tumour metabolic
response using [18F]fluorodeoxyglucose and positron emission tomography: a
pilot study following the Phase II chemotherapy schedule for temozolomide in
recurrent high-grade gliomas. Br J Cancer 2000; 82: 608-615.

, 76, 1, 2014 894

27. De Witte O, Levivier M, Violon P, et al. Prognostic value positron emission
tomography with [18F]fluoro-2-deoxy-Dglucose in the low-grade glioma.
Neurosurgery 1996; 39: 470-476.
28. Ceyssens S, Van Laere K, de Groot T, et al. [11C]methionine PET,
histopathology, and survival in primary brain tumors and recurrence. AJNR Am. J.
Neuroradiol 2006; 27: 1432-1437.
29. Ribom D, Smits A. Baseline 11C-methionine PET reflects the natural course of
grade 2 oligodendrogliomas. Neurol. Res. 2005; 27: 516521.
30. Smits A, Westerberg E, Ribom D. Adding 11C-methionine PET to the EORTC
prognostic factors in grade 2 gliomas. Eur J Nucl Med Mol Imaging 2008; 35: 65-
71.
31. Alavi JB, Alavi A, Chawluk J et al. Positron emission tomography in patients with
glioma. A predictor of prognosis. Cancer 1998; 62: 1074-1078.
32. Kim CK, Alavi JB, Alavi A, Reivich M. New grading system of cerebral gliomas
using positron emission tomography with F-18 fluorodeoxyglucose. J. Neurooncol
1991; 10: 85-91.
33. Padma MV, Said S, Jacobs M, et al. Prediction of pathology and survival by FDG
PET in gliomas. J Neurooncol 2003; 64: 227-237.
34. Roelcke U, Leenders KL. PET in neurooncology. J Cancer Res Clin Oncol 2001;
127: 2-8.
35. Bruehlmeier M, Roelcke U, Schubiger PA, Ametamey SM. Assessment of hypoxia
and perfusion in human brain tumors using PET with 18F-fluoromisonidazole and
15O-H2O. J Nucl Med 2004; 45: 1851-1859.
36. Choi SJ, Kim JS, Kim JH, et al. [18F]3-deoxy-3-fluorothymidine PET for the
diagnosis and grading of brain tumors. Eur J Nucl Med Mol Imaging 2005; 32:
653-659.
37. Chen W, Cloughesy T, Kamdar, N et al. Imaging proliferation in brain tumors with
18F-FLT PET: comparison with 18F-FDG. J Nucl Med 2005; 46: 945-952.
38. Chen W, Delaloye S, Silverman DH, et al. Predicting treatment response of
malignant gliomas to bevacizumab and irinotecan by imaging proliferation with
[18F]fluorothymidine positron emission tomography: a pilot study. J Clin Oncol
2007; 25: 4714-4721.
39. Kwee SA, Ko JP, Jiang CS, et al. Solitary brain lesions enhancing at MR imaging:
evaluation with fluorine 18 fluorocholine PET. Radioloy 2007; 244: 557-565.

, 76, 1, 2014 895

40. Mertens K, Slaets D, Lambert B, et al. PET with (18F)-labelled choline-based
tracers for tumour imaging: a review of the literature. Eur J Nucl Med Mol Imaging
2010; 37: 2188-2193.
41. Lam WW, Ng DC, Wong WY, et al. Promising role of [18F]fluorocholine PET/CT
vs [18F]fluorodeoxyglucose PET/CT in primary brain tumors-early experience. Clin
Neurol Neurosurg 2011; 113: 156-161.
42. Vanpouille C, Le Jeune N, Kryza D, et al. Influence of multidrug resistance on
(18F)F-FCH cellular uptake in a glioblastoma model. Eur J Nucl Med Mol Imaging
2009; 36: 1256-1264.
43. Beer AJ, Schwaiger M. Imaging of integrin avb3 expression. Cancer Metastasis
Rev 2008; 27: 631-644.
44. Schnell O, Krebs B, Wagner E, et al. Expression of integrin avb3 in gliomas
correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol
2008; 18: 378-386
45. Beer AJ, Haubner R, Sarbia M, et al. Positron emission tomography using
[18F]Galacto-RGD identifies the level of integrin avb3 expression in man. Clin.
Cancer Res 2006; 12: 3942-3949.
46. Beer AJ, Grosu AL, Carlsen J, et al. [18F]galacto-RGD positron emission
tomography for imaging of avb3 expression on the neovasculature in patients with
squamous cell carcinoma of the head and neck. Clin Cancer Res 2007; 13: 6610-
6616.
47. Schnell O, Krebs B, Carlsen J, et al. Imaging of integrin avb3 expression in
patients with malignant glioma by [18F] galacto-RGD positron emission
tomography. Neuro Oncol 2009; 11: 861-870.

, 76, 1, 2014 896

 -
.

, MD1, , MD3,
, PhD2, , MD, PhD2,
, MD, PhD2, , MD, PhD1
1
PET/CT, ... ,
2
. ,
, , ... ,
3
, 251 ,

:

: 6973986896
-mail: drougasdim@gmail.com

coma recovery scale (CRS-R) ,
(PVS)
(MCS)
.

.
,
(fMRI) (FDG PET)
PVS MCS,
MCS , MCS+
MCS-. PVS MCS
Coma Recovery Scale(CRS-R) PET
18F - (FDG PET) fMRI.

voxel (voxel-based mutual co-registration)
. (fMRI),
(FDG PET)
(CRS-R).
o fMRI 18F
FDG PET.
(CRS-R)

, 76, 1, 2014 897

 MCS PVS. H
- (multi-modality) MCS
PVS .


, .
, 76, 1, 897-898, 2014.
: o (18F-FDG PET),
(PVS), (MCS), COMA
RECOVERY SCALE-REVISED (CRS-R)

, 76, 1, 2014 898



.
,
, ... .

:
: 2132041825
E-mail: stsagara@otenet.gr

()
International Diabetes Federation (IDF) 2030
7,8%
1.
, .
,
1 2
,
.

.
,
.
4
.
1976, , Pickup Keen2
1.

. 15 ,
, ,

, 76, 1, 2014 899

 . FDA
375.000
2007, 3.

( ).


24 .

.

1. Wild S, Roglic G, Green A, et al. "Global prevalence of diabetes: Estimates for the
year 2000 and projections for 2030". Diabetes Care 2004; 27(5):10471053.
2. Pickup JC, Keen H, Parsons JA, et al. Continuous subcutaneous insulin infusion:
an approach to achieving normoglycaemia. BMJ 1978; 1:204-207.
3. Insulin Infusion Pumps Panel Information. US Food and Drug Administration,
General Hospital and Personal Use Medical Devices Panel; March 2010.

, 76, 1, 2014 900

 :

1, 2, . 3
1
, 2 , 3
, , ...

:
: 2132041826
E-mail: vasilopharis@yahoo.gr

() .

.

. ,
1
2 .
HbA1c,
,
,
.
,
HbA1c, ,
, .
, .
,
.
,
. , (
- ), ,
. , 76, 1,
901-910, 2014.
: , , ,

, 76, 1, 2014 901

 SUMMARY
VASILOPOULOS C, TSIRONA S, TSAGARAKIS S. What is the new in
Endocrinology? Insulin pumps. The prevalence of Diabetes Mellitus (DM) is
escalating worldwide. Novel therapies and management strategies are needed to
reduce associated morbidity. Aggressive blood glucose lowering using conventional
insulin replacement regimens is limited by the risk of hypoglycemia. Nowadays the use
of insulin pumps seems to be the new therapeutic strategy in the treatment of type 1
DM and in some patients with type 2 who are insulin dependent. Data show the
beneficial effect of these pumps in lowering the HbA1c levels, as long as leading to
less variability of glucose levels during the day and causing fewer episodes of
hypoglycemia, compared to the multiple daily injections protocol. It is mostly indicated
in patients who cannot reach the goal of glucose levels, who have increased HbA1c,
people who exercise a lot, those who have often episodes of hypoglycemia or dawn
phenomenon, children and pregnant women. Besides their effectiveness, they also
have some disadvantages. Insulin deficiency might be caused in a few minutes and
ketoacidosis in a few hours, in the case of interruption of insulin infusion. Blood
glucose levels should often be measured and patients should be properly trained.
Recently, a novel insulin pump (closed loop- artificial pancreas) seems to be the new
treatment option. Nosokomiaka Chronika, 76, Supplement 1, 901-910, 2014.
Key words: diabetes mellitus, insulin pump, treatment, closed loop

: ,
. (
Teflon) , 72 ,
, .
( ) :
1) , ,
,
24,
, ,

1.

, 76, 1, 2014 902

2)
(bolus). bolus
:
(normal) , square
wave dual wave

.( 1).

1. bolus

3) ,
(correction doses).
.

bolus ,
. 2
( 36% ,
53% CH 829 Kcal , coca cola) ,
bolus.
wizard .
,
,
,
,
( ),
(
). .

, 76, 1, 2014 903

 bolus
2 bolus: 50% bolus , 50% bolus 90
bolus 2 hours (square wave bolus)

dual wave bolus (70% ,and 30% bolus over 2

hrs)

2.
bolus

(),
2i.
,

monitor (real time)
, 5 . monitor
4 .
.
-,
.
() .

.
bolus -,
(bolus)
,
-.

, 76, 1, 2014 904

 .
.
5 15

.

.

, , ,
, ,
. -
,

. ,
.
.
.
,
.
,
.
.
5
.

, ..
.

, 2 .

Hba1c3.
.

.

, 76, 1, 2014 905

 Patch Pump (Omnipad)
.
2-3 . reservoir

.
. (
)
bolus .
.

2003,

Hb1c, -
Hb1c (8,5% )

4.
HbA1C, ,
, , ,
,
.

5:

, ,

.
( .
).
.

.
.

.

, 76, 1, 2014 906

 .

,
.

:

24
16. DCCT
124 1
90% 6,5 ,
HbA1c 0,2-0,4% (p<0,001)
7. M 320 1

- 6 ,
HbA1c
18 , .
2 HbA1c
8%, 6 8.
Bruttomesso 2008 cross over 39 ,

9.
10 11
. , Monami et
al HbA1C

12. Holmes
bA1c

,
13.

, 76, 1, 2014 907


,
. , ,

. ,
. ,
, .

. , .

.
.
,
, ,
- (
, ).

,
, ,
,
.

.

( ). To
: ,


.
17 14. 16
,
,
24,
15.

, 76, 1, 2014 908



.

1. Scheiner G, Boyer BA. Characteristics of basal insulin requirements by age and

gender in Type-1 diabetes patients using insulin pump therapy. Diabetes Res Clin
Pract. 2005; 69(1):14-21.
2. Bergenstal RM, Tamborlane WV, Ahmann A, et al. Effectiveness of Sensor-
Augmented Insulin-pump therapy in type 1 Diabetes. N Eng J of Med 2010;
363:311-320.
3. Bergenstal RM, Klonoff DC, Garg SK, et al. ASPIRE In-Home Study Group.
Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J
Med. 2013; 369(3):224-232.
4. The clinical effectiveness and cost effectiveness of insulin pump therapy' (NICE
technology appraisal guidance 57) issued in February 2003.
5. Tanenberg: The Insulin Pump Book, MiniMed 1995:21-30.
6. Pick Up, Keen H. Continuous subcutaneous Insulin infusion at 25 years evidence
base for the expanding use of insulin pump therapy in type 1 diabetes. Diabetes
care 2002; 25(3):593-598.
7. he Diabetes Control and Complications Trial research Group. Implementation of
treatment protocols in Diabetes Control and Complications Trial. Diabetes Care
1995; 18:361-376.
8. Peyrot M, Rubin RR, Frias JP. Association between improved glucose control and
patient reported outcomes after initiation of insulin pump therapy in patient with
type 2 diabetes mellitus. Diabetes Technol. Ther. 2011; 13(4):471-476.
9. Bruttomesso D, Crazzolara D, Maran A, et al. In Type 1 diabetic patients with good
glycaemic control, blood glucose variability is lower during continuous
subcutaneous insulin infusion than during multiple daily injections with insulin
glargine. Diabetes Medicine 2008; 25(3):326-332.
10. Bode BW, Steed RD, Davidson PC Reduction in severe hypoglycemia with long-
term continuous subcutaneous insulin infusion in type I diabetes. Diabetes Care
1996; 19:324-327.

, 76, 1, 2014 909

11. Liebl A, Renner R, Hepp KD, et al. Continuing education forum in diabetes in
general practice. Differentiation of types of diabetes Exp. Clin. Endocrinol.
Diabetes 2000; 108(Suppl 1):153.
12. Monami M, Lamanna C, Marchionni N, et al. Continuous subcutaneous insulin
infusion versus multiple daily insulin injections in type 1 diabetes: a meta-analysis.
Acta Diabetol. 2010; 47(Suppl 1):77-81.
13. Holmes VA, Young IS, Patterson CC, et al. Optimal glycemic control pre-
eclampsia, and gestational hypertension in women with type 1 diabetes in the
diabetes and pre-eclampsia intervention trial. Diabetes Care 2011; 34(8):1683-
1688.
14. Weinzimer SA, Steil Gm, Swan KL, et al. Fully Automated Closed-Loop Insulin
Delivery Versus Semiautomated Hybrid Control in Pediatric Patients With Type 1
Diabetes Using an Artificial Pancreas MD13 Diabetes Care 2008; 31(5):934-939.
15. Horvoka R. Artificial pancreas improves glucose control with less ypoglycemia.
Australian Internet Governance Forum Oct 2013, Melbourne.

, 76, 1, 2014 910



, MD, MSc, M.D.(res),

& , ,
...

:
: 2132041131
E-mail: japostol@otenet.gr

- (-cell receptor, BCR)
-
,
-. BCR,

LYN, SYK, .
CR -.
-
(activated B cell-like, ABC)
(DLBCL),
(germinal B cell-like, GCB),
BCR,
F- PI3K . ,
,
(knockdown) BCR,
F- .
.
ABC DLBCL
, . bench to
bedside ,
2/3 .

, 76, 1, 2014 911

 -
BCR
,
(CLL) (MCL).
ibrutinib ( BTK) idelalisib ( PI3K),
CLL/MCL ,
, . ,
ibrutinib
MCL. ,

.

().


. , 76,
1, 911-912, 2014.
: , - ,

1. Davies RE, Ngo VN, Lenz G et al. Chronic active B-cell receptor signalling in
diffuse large B-cell lymphoma, Nature 2010, 463: 88-92.
2. Roschewski M, Staudt LM, Wilson WH. Diffuse-large B-cell lymphoma-treatment
approaches in the molecular era, Nat Rev Clin Oncol 2014, 11:12-23.
3. Byrd JC, Furman RR, Coutre SE et al. Targeting BTK with ibrutinib in relapsed
chronic lymphocytic leukemia, N Engl J Med 2013, 369:32-42.
4. Wang ML, Rule S, Martin P et al. Targeting BTK with ibrutinib in relapsed or
refractory mantle-cell lymphoma, N Engl J Med 2013, 369:507-516.
5. Furman RR, Sharman JP, Coutre SE et al. Idelalisib and rituximab in relapsed
chronic lymphocytic leukemia, N Engl J Med 2014, Jan 22. [Epub ahead of print]
6. Gopal AK, Kahl BS, de Vos S et al. PI3K inhibition by idelalisib in patients with
relapsed indolent lymphoma, N Engl J Med 2014, Jan 22. [Epub ahead of print]

, 76, 1, 2014 912



T

()

. . 1, . . 2
1
-, , 2-,
, , ..

:
. .
: 6944868352
-mail: nalevizopoulos@gmail.com

,
. ,
, .

.
-
,

. , 76, 1, 913-944, 2014.
: , ,

SUMMARY
ALEVIZOPOULOS D, LASKARAKIS M. From the molecular information to the
therapeutic challenge in lung cancer patients. Lung cancer is an extremely
heterogeneous malignant neoplasm including variants with differing genetic, biological,
and clinical properties, implying different response to treatment. Molecular analysis of
lung cancer tissues reveal the therapeutic targets of all the newer anticancer therapies
so that the most effective treatment may be decided. Molecular information drive to
targeted therapies usage, which selectively target molecular pathways, responsible for
the malignant phenotype of lung cancer cells. This selectivily targeted drug choice

, 76, 1, 2014 913

cause fewer toxic effects on normal cells and tend to best antitumor activity.
Nosokomiaka Chronika, 76, Supplement 1, 913-944, 2014.
Key words: lung cancer, molecular therapy, targeted drugs

(), ()
80% ,
.
20%,


,

1,2.

(),
() ,

.
,
,
-
,
3,4. ,

,
.:

(EGFR),
(VEGF) (ALK).
,
,
.

, 76, 1, 2014 914

 -


,
,
-
5,6.

-,

,
.
. C-erb B 1, EGFR
EGFR ( HER-1 c-erb B1),
HER-2 (c-erb B2)
HER-3 HER-4. EGFR 170 kDa
(repeats) ,
C- .
EGFR EGF
(transforming growth factor alpha TGFa).
EGFR ()

. EGFR
()7-10.
EGFR
11-13 14-16.
() EGFR
, ,
7-
9
.
EGFR , ,
, -17.
Erb-B
- (mitogen-activated protein kinase
MAPK) ,

, 76, 1, 2014 915

 3 (phosphatidylinositol 3-kinase) P13K-AKT
janus (JAKS) .
118.

1. EGFR 18

. HER-2 (c-erb B-2)

HER-2
19-21. ,
VEGFmRNA VEGF,
HER-2 22.
. K-ras
Ras
.
K-ras
23-25.
K-ras
26,27. K-ras
,

, 76, 1, 2014 916

 , wild
type K-ras28.
V. C-met (HGF)
Met c-met,

(Hepatocyte Growth Factor HGF). HGF
,
(Extra Cellular Matrix ECM).

29. HGF
30.

EGFR .
V. p53
p53 1713.1
,
G1 . p53

DNA guardian of the
genome31. (point mutations) p53

20% 60% 32,33
34.

p53
28.
VI. ERCCI RRMI
ERCCI (Excision Repair Cross Complementation group1) RRMI
(Ribonucleotide Reductase subunit M1) DNA
. RRMI
PTEN
(phosphatase and tension deleted on chromosome TEN)
35.
, ERCCI RRMI
36.

, 76, 1, 2014 917

 ,
37-39.
.
VII. (MMPs)
(TIMPs)


40. TIMP-1
41. MMPs

42-44. MMP9
EGFR 45.
VIII. EML-4-ALK
(ALK) ,
46.
4,

(EML4-ALK), ,
:
,
. ALK
EGFR K-ras 47,48.
ALK in situ (FISH)49,50.
EML4-ALK
,
ALK.
IX. -


51.
(FGF),
(VEGF), 8 (1L-8)
(PD-ECGF) 252
, .

, 76, 1, 2014 918

 2. VEGF/VEGFR
52

,
.

:
I.
EGFR (erlotinib, gefitinib).
II. EGFR (cetuximab).
III. (bevacizumab).
IV. ALK (crizotinib).

.1.
(EGFR TKIs)
, , ,
,
.
EGFR,

.
EGFR ,

, 76, 1, 2014 919


, ,
.
EGFR, gefitinib erlotinib

. 53-57
58,
erlotinib gefitinib.
, ,
.
,
EGFR K-ras.
EGFR
, K- ras
59,60.
erlotinib
- 61.
,
EGFR.
EGFR ( 19,
L858R 21)
erlotinib gefitinib62-68.
(ER-beta),
69. Nose et al
2009 EGFR
ER-beta,
EGFR
ER-beta69.
K-ras
EGFR [70-
74]. erlotinib placebo58,
K-RAS
erlotinib75.
K-RAS
EGFR72.

, 76, 1, 2014 920


EGFR 76.

EGFR TKIs
HER-2, ACT
( EGFR)
- (Epithelial Mesenchymal Transition ),
E-cadherin vimentin77-81.
ICACT 2012 Rosell et al
, BRCA1mRNA
erlotinib82.

EGFR

, EGFR
[83-86].
IPASS83, 1217

, gefitinib
. (<10
pack years 0 pack years 15 ).
(Progression Free Survival PFS)
gefitinib ,
(Overall Survival OS)
, 87. EGFR
60% .

gefitinib ( PFS 9.5
6.3 ).
(European Medical Association )
gefitinib
EGFR, IPASS.
OPTIMAL86
154 EGFR
erlotinib .

, 76, 1, 2014 921

 erlotinib (13.1 4.6
).
TORCH
EGFR
EGFR ,
88.

EGFR

,
erlotinib , ,
,
.
gefitinib89-92.

EGFR .

EGFR.

EGFR s
,
EGFR ,
. :
I. EGFR
790 (790), 50%
93-96.
II. , 20%
97-99.

100.

GFR

EGFR ,
EGFR

, 76, 1, 2014 922

101.
102-103.

Stevens-Johnson .
58 104.
,
, ,
.
104-105.

,
EGFR,
EGFR.
,
EGFR 106.

2. CUXIMAB

EGFR, (MoAb) Cetuximab.
Cetuximab EGFR
, EGF,
,

107.
Yi-Fan Hsu et al,
Cetuximab [108].
549 wild
type EGFR K-ras , in
vivo, Cetuximab

.
3108.
Cetuximab
b IV109-110.

, 76, 1, 2014 923

 FLEX b IV
- +/- cetuximab.
EGFR.
Cetuximab ,
(Overall Survival OS): OS 11.3 10.1
,
109. Cetuximab
,
,
, 111.

3. cetuximab108

(BMS-099 TRIAL)
, cetuximab
, 110.
, cetuximab
,
bevacizumab112.
, FLEX,
cetuximab

EGFR /106.

, 76, 1, 2014 924

3. BVACIZUMAB
(VEGF),

51. -
113-115.
VEGF, ,
116-118.
, VEGF, .
,
, ,
(MOAb) Bevacizumab, VEGF,
VEGFR. Bevacizumab
ECOG119,
b + IV Performance Status (PS) 0-1,
,

+/- Bevacizumab 15mg/Kgr ( Sandler).
Bevacizumab
12.3 10.3 6.2
4.5 .
Bevacizumab ,
,
70 ,
120.

, ,
121. Bevacizumab
grade 3 4. ,
Bevacizumab

122.
AVAiL, b + IV,
ECOG PS 0 1, -
Bevacizumab 7,5mg/Kgr Bevacizumab 15mg/Kgr placebo.

, 76, 1, 2014 925

Bevacizumab,
123-124.
ATLAS Bevacizumab
erlotinib Bevacizumab

Bevacizumab.


. erlotinib
Bevacizumab 4,8 3,7
Bevacizumab
125.
, PS ,
Bevacizumab

106.

4. NA ALK - CRIZOTINIB
ALK 3-13% 47.
ALK , -
, Crizotinib.
C-MET,
ALK.
in vivo in vitro,
G1-S126.
ASCO 2010 Bang Y et al,
Crizotinib 82
EML4-ALK. , ,
95% .
57%
72%.
, ,
( /), ,
QT127.

, 76, 1, 2014 926


255 ALK (+) FISH,
(US FDA)
2011 Crizotinib
, ALK (+) 128.
95% IV, 5% IIIb
94%
76% , .
55% 8 Crizotinib
250mg, p.o. Crizotinib
(
) ALK (+) 129.
ALK
Crizotinib130.

ME
1. EGFR
,
gefitinib erlotinib .
,
EGFR, EGFR s.

797 EGFR,
EGFR, 790131.

Neratinib (HKI-272)132 (BIBW 2992) Afatinib133
EGFR HER-2. ASCO 2012 James Yang et al
, ,
LUX-Lung 3 , 354 IIIb IV ,
EGFR, Afatinib
.
.
8 ,
11.1 6.9 Afatinib
.

, 76, 1, 2014 927

EGFR, 19 L858R, ,
13.6 6.9 134.

2. HGF
HGF,

EGFR.
PHA-665752135 HGF HGF
HGF NK4136.
3. Figitumumab
Figitumumab
1 (IGF-1R),
. ,
( ) +/-
Figitumumab. .
137.

. E HER-2
HER-2,
.
, . ,
HER-2 Trastuzumab,
HER-2 (+) ,
HER-2,
.
Trastuzumab,
138.

. A .

.
.
1. Ramucirumab
Ramucirumab VEGFR-2,

, 76, 1, 2014 928

 IV ,
139.
, .
140.
2.
Cediranib
VEGFR-1,2,3, (PDGFR),
FGFR-1 c-kit41-142.
/,
, 143.
, ,
Cediranib 30mg . K
,
-. Cediranib

144.
Sorafenib
, VEGFR-2 VEGFR-3,
PDGFR-B v-Raf FLT-3 c-kit.
ESCAPE
, .

145.
Sunitinib
Sorafenib,
,
VEGFR-1, 2, 3, PDGFR c-kit FLT-3146.
,
,
,
. 23.4
12 147.
,
52.

, 76, 1, 2014 929


Motesanib,
VEGFR-2,3 PDFGR-b c-kit148,149.
, Axitinib, VEGFR-1,2,3
PDGF-b, ,
,
, .
14.8 4.9 150.

52.
3.

. Bordezomib 26S
.
.
,
11 151. ,
, bordezomib bordezomib
, 152.
, , .

, ,
, ,
-.
, 153,
(GM-CSF). GM-
CSF G-
VAX, 154,155,

, 156.

,
, 80% .
, ,

, 76, 1, 2014 930

 .
.
-
, ,
.
, EGFR,
erlotinib gefitinib ALK , crizotinib,
, ,
, .
EGFR, Cetuximab,
VEGF, Bevacizumab, ,
. ,
.

,
, .

1. American Cancer Society Cancer Facts and Figures, 2010. Atlanta, GA:
American Cancer Society; 2010.
2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin.
2010;60:277300.
3. Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of Phase III trials
for patients with advanced non-small-cell lung cancer: sobering results. J Clin
Oncol. 2001;19(6):17341742.
4. Carney DN. Lung cancer time to move on from chemotherapy. N Engl J Med.
2002;346(2):126128.
5. Salgia R., Skarin AT. Molecular abnormalities in lung cancer. J Clin Oncol 1998;
16:1207.
6. Devereux TR, Taylor JA, Barrett JC. Molecular mechanisms of lung
cancer.Interaction of environmental and genetic factors.Giles F. Filley Lecture.
Chest 1996;109:14S.
7. Salomon DS, Brandt R, Ciardiello F., et al: Epidermal growth factor-related
peptides and their receptors in human malignancies. Crit Rev Oncol Hematol
1995;19:183-232.

, 76, 1, 2014 931

8. Woodburn JR: The epidermal growth factor receptor and its inhibition in cancer
therapy. Pharmacol Ther 1999;82:241-250.
9. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy.
Oncogene 2000;19:6550-6565.
10. Rusch V, Baselga J, Cordon-Cardo C, et al: Differential expression of the
epidermal growth factor receptor and its lingands in primary non-small cell lung
cancers and adjacent bening lung. Cancer Res 1993;53:2379-2385.
11. Volm M, Rittgen W, Drings P. Prognostic value of ERBB-1, VEGF, cyclin A.,
FOS, JUN and MYC in patients with squamous cell lung carcinomas. Br J Cancer
1998;77:663-669.
12. Brabender J, Danenberg KD, Metzer R, et al. Epidermal growth factor receptor
and HER2-neu mRNA expression in non-small cell lung cancer is correlated with
survival. Clin Cancer Res 2001;7:1850-1855.
13. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Epidermal growth factor receptor
in non-small-cell lung carcinomas: correlation between gene copy number and
protein expression and impact on prognosis. J. Clin Oncol 2003;21:3798-3807.
14. Rusch V, Klimstra D, Venkatraman E, et al. Overexpression of the epidermal
growth factor receptor and its ligand transforming growth factor alpha is frequent
in resectable non-small cell lung cancer but does not predict tumor progression.
Clin Cancer Res 1997;3:515.
15. Pastorino U, Andreola S, Tagliabue , et al. Immunocytochemical markets in
stage I lung cancer: relevance to prognosis. J Clin Oncol 1997;15:2858-2865.
16. Reissmann PT, Koga H, Figlin RA, et al. Amplification and overexpression of the
cyclin D1 and epidermal growth factor receptor genes in non-small-cell lung
cancer. Lung Cancer Study Group. J Cancer Res Clin Oncol 1999;125:61-70.
17. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: Correlation
with clinical response to gefitinib therapy. Science 2004;304:1497-1500.
18. Charpidou A, Blatza D, Anagnostou V and Syrigos KN. EGFR Mutations in Non-
small cell lung cancer-Clinical Implications. In vivo 2008; 22:529-536.
19. Kern JA, Schwartz DA, Nordberg JE, et al. p185neu expression in human lung
adenocarcinomas predicts shortened survival. Cancer Res 1990;50:5184-5187.
20. Tateishi M, IshidaT, Mitsudomi T, et al. Prognostic value of c-erbB-2 protein
expression in human lung adenocarcinoma and squamous cell carcinoma. Eur J
Cancer 1991;27:1372-1375.

, 76, 1, 2014 932

21. Shi D, He G, Cao S, et al. Overexpression of the c-erbB-2/neu-encoded p185
protein in primary lung cancer. Mol Carcinog 1992;5:213-218.
22. Yen L, You XL, Al Moustafa AE, et al. Heregulin selectively upregulates vascular
endothelial growth Factor secretion in cancer cells and stimulates angiogenesis.
Oncogene 2000;19:3460-3469.
23. Siebos RJ, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a
prognostic marker in adenocarcinoma of the lung. N Engl J Med 1990;323:561-
565.
24. Rodenhuis S, Slebos RJ. Clinical significance of ras oncogene activation in
human lung cancer. Cancer Res 1992;52:2665s-2669s.
25. Graziano SL, Gamble GP, Newman NB, et al. Prognostic significance of K-ras
codon 12 mutations in patients with resected stage I and II non-small-cell lung
cancer. J Clin Oncol 1999;17:668-675.
26. Rosell R, Li S, Skacel Z, et al. Prognostic impact of mutated K-ras gene in
surgically resected non-small cell lung cancer patients. Oncogene 1993;8:2407-
2412.
27. Huncharek M, Muscat J, Geschwind JF. K-ras oncogene mutation as a
prognostic marker in non-small cell lung cancer: a combined analysis of 881
cases. Carcinogenesis 1999;20:1507-1510.
28. Tsao MS, Aviel-Ronen S, Ding K, et al. Prognostic and predictive importance of
p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer. J Clin
Oncol 2007;25:5240-5247.
29. Ichimura E, Maeshima A, Nakajima T,et al. Expression of c-met/HGF receptor in
human non-small cell lung carcinomas in vitro and in vivo and its prognostic
significance. Jpn J Cancer Res 1996;87:1063-1069.
30. Siegfried JM, Weissfeld LA, Luketich JD, et al. The clinical significance of
hepatocyte growth factor for non-small cell lung cancer. Ann Thorac Surg
1998;66:1915-1918.
31. Lane DP. Cancer. P53, guardian of the genome. Nature 1992;358:15-16.
32. Chambers AF, MacDonald IC, Schmidt EE, et al. Steps in tumor metastasis: new
concepts from intravital videomicroscopy. Cancer Metastasis Rev 1995;14:279-
301.
33. Ahrendt SA, Hu Y, Buta M, et al. p53 mutations and survival in stage I non-small-
cell lung cancer: results of a prospective study. J Natl Cancer Inst 2003;95: 961-
970.

, 76, 1, 2014 933

34. Tammemagi MC, McLaughlin JR, Bull SB. Meta-analyses of p53 tumor
suppressor gene alterations and clinicopathological features in resected lung
cancers. Cancer Epidemiol Biomarkers Prev 1999;8:625-634.
35. Gautam A, Li ZR, Bepler G.RRM1-induced metastasis suppression through
PTEN-regulated pathways.Oncogene 2003;22:2135-2142.
36. Zheng Z, Chen T, Li , et al. DNA synthesis and repair genes RRM1 and ERCC1
in lung cancer. N Engl J Med 2007;356:800-808.
37. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small cell
lung cancer and cisplatin based adjuvant chemotherapy. N Engl J Med
2006;355:983-991.
38. Ceppi P, Volante M, Novello S, et al. ERCC1 and RRM1 gene expressions but
not EGFR are predictive of shorter survival in advanced non-small cell lung
cancer treated with cisplatin and gemcitabine. Ann Oncol 2006;17:1818-1825.
39. Holm B, Mellemgaard A, Skov BG. Different impact of excision repair cross-
complementation group 1 on survival in male and female patients with inoperable
non-small-cell lung cancer treated with carboplatin and gemcitabine. J Clin Oncol
2009;27:4254-4259.
40. Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM. Matrix
metalloproteinases:biologic activity and clinical implications. J Clin Oncol
2000;18:1135-1149.
41. Ponton A, Coulombe B, Skup D. Decreased expression of tissue inhibitor of
metalloproteinases in metastatic tumor cells leading to increased levels of
collagenase activity. Cancer Res 1991;51: 2138-2143.
42. Pritchard SC, Nicolson MC, Lioret C, et al. Expression of matrix
metalloproteinases 1,2,9 and their tissue inhibitors in stage II non-small cell lung
cancer: implications for MMP inhibition therapy. Oncol Rep 2001;8:421-424.
43. Passlick B, Sienel W, Seen-Hibler R, et al. Overexpression of matrix
metalloproteinase 2 predicts unfavourable outcome in early stage non-small cell
lung cancer. Clin Cancer Res 2000;6:3944-3948.
44. Herbst RS, Yano S, Kuniyasu H, et al. Differential expression of E-cadherin and
type IV collagenase genes predicts outcome in patients with stage I non-small
cell lung carcinoma. Clin Cancer Res 2000;6:790-797.
45. Cox G, Jones JL, OByrne KJ. Matrix metalloproteinase 9 and the epithelial
growth factor signal pathway in operable non-small cell lung cancer. Clin Cancer
Res 2000;6:2349-2355.

, 76, 1, 2014 934

46. Wasik MA. et al. Anaplastic lymphoma kinase (ALK)-induced malignancies: novel
mechanisms of cell transformation and potential therapeutic approaches. Semin
Oncol. 2009;36(2 Suppl 1):S2735.
47. Soda M. et al. Identification of the transforming EML4-ALK fusion gene in non-
small-cell lung cancer. Nature. 2007;448(7153):561566. doi:
10.1038/nature05945
48. Shaw AT. et al. Clinical features and outcome of patients with non-small-cell lung
cancer who harbor EML4-ALK. J Clin Oncol. 2009;27(26):42474253. doi:
10.1200/JCO.2009.22.6993.
49. Martelli MP, Sozzi G et al. EML4-ALK rearrangement in non-small cell lung
cancer and non-tumor lung tissues. Am J Pathol 2009; 174:661-670.
50. Boland JM, Erdogan S, et al. Anaplastic lymphoma kinase immunoreactivity
correlates with ALK gene rearrangement and transcriptional up-regulation in non-
small cell lung carcinomas. Hum Pathol 2009; 40:1152-1158.
51. OByrne KJ, Dalgleish AG, Browning MJ, et al. The relationship between
angiogenesis and the immune response in carcinogenesis and the progression of
malignant disease. Eur J Cancer 2000; 36:151-169.
52. Ballas Marc S and Abraham Chachoua. Rationale for targeting VEGF, FGF and
PDGF for the treatment of NSCLC. Onco Targets Ther. 2011; 4: 43-58.
53. Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor
response and survival with erlotinib in patients with non-small cell lung cancer. J
Clin Oncol 2004; 22:3238-3247.
54. Janne PA, Gurubhagavatula S, Yeap BY, et al.Outcomes of patients with
advanced non-small cell lung cancer treated with gefitinib (ZD1839, Iressa) on a
expanded acess study. Lung Cancer 2004; 44:221-230.
55. Gandara DR, West H, Chansky K, et al.Bronchiolalveolar carcinoma: a model for
investigating the biology of epidermal growth factor receptor inhibition. Clin
Cancer Res 2004: 10:4205s-4209s.
56. Miller VA, Kris MG, Shah N, et al. Bronchioalveolar pathologic subtype and
smoking history predict sensitivity to gefitinib in advanced non-small cell lung
cancer. J Clin Oncol 2004: 22:1103-1109.
57. West HL, Franklin WA, McCoy J, et al. Gefitinib therapy in advanced
bronchioalveolar carcinoma: Southwest Oncology Group Study S0126. J Clin
Oncol 2006: 24:1807-1813.

, 76, 1, 2014 935

58. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously
treated non-small cell lung cancer. N Engl J Med 2005: 353:123-132.
59. Wu CC, Hsu HY, Liu HP, et al. Reversed mutation rates of KRAS and EGFR
genes in adenocarcinoma of the lung in Taiwan and their implications. Cancer
2008; 113:3199-3208.
60. Marks JL, Broderick S, Zhou Q, et al. Prognostic and therapeutic implications of
EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol
2008; 3:111-116.
61. Hamilton M, Wolf JL, Rusk J, et al. Effects of smoking on the pharmacokinetics of
erlotinib. Clin Cancer Res 2006; 12:2166-2171.
62. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in
lung cancers from never smokers and are associated with sensitivity of tumors
to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004; 101:13306-13311.
63. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth
factor receptor underlying responsiveness of non-small-cell lung cancer to
gefitinib.N Engl J Med 2004; 350:2129-2139.
64. Paez JG, Janne PA, Lee JC, et al EGFR mutations in lung cancer: correlation
with clinical response to gefitinib therapy.Science 2004; 304:1497-1500.
65. Tokumo M, Toyooka S, Kiura K, et al .The relationship between epidermal growth
factor receptor mutations and clinicopathologic features in non small cell lung
cancers. Clin Cancer Res 2005; 11:1167-1173.
66. Cappuzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and
protein and gefitinib sensitivity in non small cell lung cancer. J Natl Cancer Inst
2005; 97:643-655.
67. Yang CH, Yu CJ, Shih JY,et al. Specific EGFR mutations predict treatment
outcome of stage IIIB/IV patients with chemotherapy nave non-small cell lung
cancer receiving first line gefitinib monotherapy. J Clin Oncol 2008; 26:2745-
2753.
68. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor
receptor mutations in lung cancer. N Engl J Med 2009; 361:958-967.
69. Nose N, Sugio K, Oyama T, et al. Association between estrogen receptor-beta
expression and epidermal growth factor receptor mutation in the postoperative
prognosis of adenocarcinoma of the lung. J Clin Oncol 2009; 27:411-417.
70. Eberhard DA,Johnson BE, Amler LC, et al. Mutations in the epidermal growth
factor receptor and in KRAS are predictive and prognostic indicators in patients

, 76, 1, 2014 936

 with non-small-cell lung cancertreated with chemotherapy alone and in
combination with erlotinib. J Clin Oncol 2005; 23:5900-5909.
71. Aviel-Ronen S, Blackhall FH, Shepherd FA,et al. K-ras mutations in non-small
cell lung carcinoma: a review. Clin Lung Cancer 2006; 8:30-38.
72. Massarelli E, Varella-Garcia M, Tang X, et al. KRAS mutation is an important
predictor of resistance to therapy with epidermal growth factor receptor tyrosine
kinase inhibitors in non small cell lung cancer. Clin Cancer Res 2007; 13:2890-
2896.
73. Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic K-ras
mutations as a mechanism associated with resistance to EGFR-targeted agents:
a systematic review and meta-analysis of studies in advanced non-small cell lung
cancer and metastatic colorectal cancer. Lancet Oncol 2008; 9:962-972.
74. Scheider CP, Heigener D, Schott-von-Romer K, et al. Epidermal growth factor
receptor-related tumor markers and clinical outcomes with erlotinib in non-small
cell lung cancer: an analysis of patients from german centers in the TRUST
study. J Thorac Oncol 2008; 3:1446-1453.
75. Tsao M, Zhu C, Sakurada A, et al. An analysis of the prognostic and predictive
importance of K-RAS mutation status in the National Cancer Institute of Canada
Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of
non-small-cell lund cancer. J Clin Oncol 2006; 24:365s.
76. Park S, Holmes-Tisch aj, Cho EY, et al. Discordance of molecular biomarkers
associated with epidermal growth factor receptor pathway between primary
tumors and lymph node metastasis in non-small cell lung cancer. J Thorac Oncol
2009; 4:809-815.
77. Cappuzo F, Varella-Garcia M, Shigematsu H, et al. Increased HER-2 gene copy
number is associated with response to gefitinib therapy in epidermal growth
factor receptor-positive non-small cell lung cancer patients. J Clin Oncol 2005:
23:5007-5018.
78. Cappuzo F, Magrini E, Ceresoli GL, et al. Akt phosphorylation and gefitinib
efficacy in patients with advanced non-small cell llung cancer. J Natl Cancer Inst
2004; 96:1133-1141.
79. Thiery JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev
Cancer 2002; 2 : 442-454.
80. Thomson S, Buck E, Petti F, et al. Epithelial to mesenchymal transition is
adeterminant of sensitivity of non-small cell lung carcinoma cell lines and

, 76, 1, 2014 937

 xenografts to epidermal growth factor receptor inhibition. Cancer Res 2005;
65:9455-9462.
81. Yauch RL, Januario T, Eberhard DA, et al. Epithelial versus mesenchymal
phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in
lung cancer patients. Clin Cancer Res 2005; 11:8686-8698.
82. Rosell et al. Cancer Translational Research. (www.icact.com, 23th 2012).
83. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in
pulmonary adenocarcinoma. N Engl J Med 2009; 361:947-957.
84. Mitudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in
patients with non small cell lung cancer harbouring mutations of the epidermal
growth factor receptor (WJTOG34405): an open label, randomized phase 3 trial.
Lancet Oncol 2010; 11:121-128.
85. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non
small cell lung cancer with mutated EGFR. N Engl J Med 2010; 362:2380-2388.
86. Zhou,C, Wu, Y, Chen, G, et al. Efficacy results from the randomized phase III
OPTIMAL (ctong 0802) study comparing first-line erlotinib versus carboplatin plus
gemcitabine in Chinese advanced non-small cell lung cancer patients with EGFR
activating mutations. Lancet Oncol 2011 Aug;12(8) 735-742.
87. Yang, C, Fukuoka, M, Mok,TS,et al. Final overall survival results from phase III
IPASS study. J Clin Oncol 2011 Jul 20;29(21)i 2866-2874.
88. Gridelli, C, Butts C, Ciardiello R, et al. International multicenter randomized
phase III study of first-line erlotinib (E) followed by second-line cisplatin plus
gemcitabine (CG) versus first-line CG followed by second line E in advanced
non-small cell lung cance: The TORCH trial. Clin Lung Cancer 2008 Jul;9(4):235-
238.
89. Herbst RS, Prager D, Hermann R, et al.TRIBUTE: a phase III trial of erlotinib
hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy
in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23:5892-5899.
90. Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in
combination with cisplatin and gemcitabine in advanced non-small-cell lung
cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007; 25:1545-
1552.
91. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with
gemcitabine and cisplatin in advanced non-small cell lung cancer : a phase III
trial-INTACT 1. J Clin Oncol 2004; 22:777-784.

, 76, 1, 2014 938

92. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel
and carboplatin in advanced non-small cell lung cancer: a phase III trial-INTACT
2. J Clin Oncol 2004; 22:785-794.
93. Kosaka T, Yatabe Y, Endoh H, et al. Analysis of epidermal growth factor receptor
gene mutation in patients with non-small cell lung cancer and acquired resistance
to gefitinib. Clin Cancer Res 2006; 12:5764-5769.
94. Balak MN, Gong Y, Riely GJ, et al. Novel D761Y and common secondary T790M
mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with
acquired resistance to kinase inhibitors. Clin Cancer Res 2006; 12:6494-6501.
95. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of
non-small-cell lung cancer to gefitinib. N Eng J Med 2005; 352 :786-792.
96. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas
to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase
domain.PLoS Med 2005 Epub2005 Feb 22.
97. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without
T790M mutations in EGFR mutant lung tumors with acquired resistance to
gefitinib or erlotinib. Proc Natl Acad Sci USA 2007; 104:20932-20937.
98. Engelman JA, Zejnuallahu K, Mitsudomi T, et al. MET amplification leads to
gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;
316:1039-1043.
99. Cipriani NA, Abidoye OO, Vokes E,et al. MET as a target for treatment of chest
tumors. Lung Cancer 2009 ; 63: 169-179.
100. Cappuzo F, Marchetti A, Skokan M, et al. Increased MET gene copy number
negatively affects survival of surgically resected non-small-cell lung cancer
patients. J Clin Oncol 2009 ; 27 :1667-1674.
101. Herbst RS, LoRusso PM, PurdomM,et al. Dermatologic side effects associated
with gefitinib therapy: clinical experience and management.Clin Lung Cancer
2003; 4:366-369.
102. Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted
agents:is there a silver lining? J Clin Oncol 2005: 23: 5235-5246.
103. Wacker B, Nagrani T, Weinberg J, et al. Correlation between development of
rash and efficacy in patients treated with the epidermal growth factor receptor
tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res
2007; 13:3913-3921.

, 76, 1, 2014 939

104. Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial pneumonia and
gefitinib. Lancet 2003; 361:137-139.
105. Makris D, Scherpereel A, Copin MC, et al. Fatal interstitial lung disease
associated with oral erlotinib therapy for lung cancer. BMC Cancer 2007; 7:150.
106. Rogerio C Lilenbaum. Targeted agents in the initial systemic treatment of
advanced non-small cell lung cancer (www.uptodate.com ), 2011.
107. Minna JD, Peyton MJ, Gadzar AF. Gefitinib versus cetuximab in lung cancer:
round one. J Natl Cancer Inst 2005; 97: 1168-1169.
108. Hsu et al. Complement activation mediates cetuximab inhibition of non-small cell
lung cancer tumor growth in vivo. Molecular cancer 2010 Jun 7; 9:139.
109. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients
with advanced non small cell lung cancer (FLEX) : an open label randomized
phase III trial. Lancet 2009; 373:1525-1531.
110. Lynch TJ, Patel T, Dreisbach L, et al. Cetuximab and first-line taxane/carboplatin
chemotherapy in advanced non-small cell lung cancer: results of the randomized
multicenter phase III trial BMS099. J Clin Oncol 2010; 28:911-917.
111. Gatzemeier U, von Pawel J, Vynnychenko I, et al. First-cycle rash and survival
in patients with advanced non-small cell lung cancer receiving cetuximab in
combination with first-line chemotherapy: a subgroup analysis of data from the
FLEX phase III study. Lancet Oncol 2011; 12:30-37.
112. U.S. National Institutes of Health, Clinical Trials .gov http://www.clinicaltrials.gov//
113. Ohta Y, Nozaki Z, Nozawa H, et al. Thepredictive value of vascular endothelial
growth factor and nm23 for the diagnosis of occult metastasis in non-small cell
lung cancer. Jpn J Cancer Res 2001; 92:361-366.
114. OByrne KJ, Koukourakis MI, Giatromanolaki A, et al. Vascular endothelial growth
factor, platelet derived endothelial cell growth factor and angiogenesis in non-
small-cell lung cancer. Br J Cancer 2000; 82:1427-1432.
115. Harpole DH Jr, Richards WG, Herdon JE 2nd,et al. Angiogenesis and molecular
biologic substaging in patients with stage I non-small cell lung cancer. Ann
Thorac Surg 1996; 61:1470-1476.
116. Han H, Silverman JF, Santucci TS, et al. Vascular endothelial growth factor
expression in stage I non small cell lung cancer correlates with neoangiogenesis
and a poor prognosis. Ann Surg Oncol 2001; 8:72-79.
117. Yuan A, Yu CJ, Kuo SH, et al. Vascular endothelial growth factor 189 m RNA
isoform expression specifically correlates with tumor angiogenesis,patients

, 76, 1, 2014 940

 survival and postoperative relapse in non-small cell lung cancer. J Clin Oncol
2001; 19:432-441.
118. Fontanini G, Lucchi M, Vignati S, et al. Angiogenesis as a prognostic indicator of
survival in non-small cell lung carcinoma: a prospective study. J Natl Cancer Inst
1997; 89:881-886.
119. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with
bevacizumab for non-small cell lung cancer. N Eng J Med 2006; 355;2542-2550.
120. Ramalingam SS, Dahlberg SE, Langer CJ, et al. Outcomes for elderly,advanced-
stage non-small cell lung cancer patients treated with bevacizumab in
combination with carboplatin and paclitaxel: analysis of Eastern Cooperative
Eastern Group Trial 4599.J Clin Oncol 2008; 26;60-65.
121. Sandler AB, Schiller JH, Gray R, et al. Retrospective evaluation of the clinical and
radiografick risk factors associated with severe pulmonary hemorrhage in first-
line advanced unresectable non-small cell lung cancer treated with carboplatin
and paclitaxel plus bevacizumab.J Clin O ncol 2009; 27:1405-1412.
122. Dahlberg SE, Sandler AB, Brahmer JR, et al. Clinical course of advanced non-
small cell lung cancer patients experiencing hypertension during treatment with
bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J
Clin Oncol 2010; 28;949-954.
123. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus
gemcitabine with either placebo or bevacizumab as first-line therapy for non
squamous non-small-cell lung cancer: AVAiL. J Clin Oncol 2009; 27:1227-1234.
124. Reck M,von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-
gemcitabine and bevacizumab or placebo as first line therapy for non-squamous
non-small cell lung cancer: results from a randomized phase III trial (AVAiL). Ann
Oncol 2010; 21:1804-1809.
125. Kabbinavar FF, Miller VA, Johnson BE,et al. Overall survival (OS) in ATLAS, a
phase IIIb trial comparing bevacizumab (B) therapy with or without erlotinib (E)
after completion of chemotherapy (chemo) with B for first-line treatment of locally
advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) J Clin
Oncol. 2010; 28(15s) Abstract 7526.
126. Christensen JG, Zou HY et al. Cytoreductive antitumor activity of PF-2341066, a
novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models
of anaplastic large-cell lymphoma. Mol Cancer Ther 2007; 6:3314.

, 76, 1, 2014 941

127. Bang Y. et al. Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-
positive patients with non-small cell lung cancer (NSCLC) J Clin Oncol (Meeting
Abstracts) 2010;28(18_suppl):3.
128. Food and Drug Administration.
http://www.acessdata.fda.gov/drugsatfda_docs/label/2011/202570s000lbl.pdf.
129. NIH clinical trials database: http://clinicaltrials.gov. An investigational drug PF-
02341066 is being studied versus standard of care in patients with advanced
NSCLC with-specific gene profile involving the ALK Gene.
130. Choi YL, Soda M, et al. EML4-ALK mutations in lung cancer that confer
resistance to ALK inhibitors. N Engl J Med 2010; 363:1734-1739.
131. Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor
may circumvent acquired resistance to gefitinib. Proceedings of the National
Academy of Sciences of the United States of America. 2005;102(21):76657670
132. Sequist LV, Besse B, Lynch TJ, et al. Neratinib, An irreversible pan-ErbB
receptor tyrosine kinase inhibitor: results of a phase II trial in patients with
advanced non-small-cell lung cancer. Journal of Clinical Oncology. 2010;
28(18):30763083.
133. Eskens FA, Mom CH, Planting AS, et al. A phase I dose escalation study of
BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1
(EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in
patients with advanced solid tumours. British Journal of Cancer. 2008;98(1):80
85.
134. Yang J. et al (2012), Lux-Lung3 randomized open label phase III study of Afatinib
versus pemetrexed and cisplatin as first line tratment for patients with advanced
adenocarcinoma of the lung harboring EGFR activating mutations ASCO 2012,
Abstract LBA 7500.
135. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to
gefitinib resistance in lung cancer by activating ERBB3 signalling. Science. 2007;
316(5827):10391043.
136. Wang W, Li Q, Yamada T, et al. Crosstalk to stromal fibroblasts induces
resistance of lung cancer to epidermal growth factor receptor tyrosine kinase
inhibitors. Clinical Cancer Research. 2009;15(21):66306638
137. Jassem J, Langer CJ, Karp DD, et al. Randomized, open label, phase II trial of
figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and

, 76, 1, 2014 942

 carboplatin in patients with non-small cell lung cancer (NSCLC). J Clin Oncol.
2009 May 20; 27 (15):2516-2522
138. Gatzemeier U, Groth G, Butts C, et al. Randomized phase II trial of gemcitabine-
cisplatin with or without trastuzumab in HER2-positive non-small cell lung
cancer.Ann Oncol 2004; 15:19.
139. .www.clinicaltrialsgov. Protocol 14T-MC-JVBA 9 (C) A Randomized, Double-
Blind, Phase 3 Study of Docetaxel and Ramucirumab versus Docetaxel and
Placebo in the treatment of Stage IV NSCLC Following Disease Progression after
One Prior Platinum-Based Therapy.
140. Camidge DR, Ballas MS, Dubey S, et al. A phase II, open-label study of
ramucirumab (IMC-1121B), an IgG1 fully human monoclonal antibody (MAb)
targeting VEGFR-2, in combination with paclitaxel and carboplatin as first-line
therapy in patients (pts) with stage IIIb/IV non-small cell lung cancer (NSCLC) J
Clin Oncol. 2010;28(15s) Abstract 7588.
141. Nikolinakos P, Heymach JV. The tyrosine kinase inhibitor cediranib for non-small
cell lung cancer and other thoracic malignancies. J Thorac Oncol. 2008;3(6 Suppl
2):S131S134.
142. Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally
bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase
inhibitor for the treatment of cancer. Cancer Res. 2005; 65(10):43894400.
143. Goss GD, Arnold A, Shepherd FA, et al. Randomized, double-blind trial of
carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced
non-small-cell lung cancer: NCIC Clinical Trials Group BR24 study. J Clin Oncol.
2010;28(1):4955.
144. Gadgeel SM, Wozniak A, Edelman MJ, et al. Cediranib, a VEGF receptor 1, 2,
and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung
cancer (NSCLC) J Clin Oncol. 2009; 27(15S) Abstract e19007.
145. Scagliotti G, Novello S, von Pawel J, et al. Phase III study of carboplatin and
paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin
Oncol. 2010;28(11):18351842.
146. Sun L, Liang C, Shirazian S, et al. Discovery of 5-[5-fluoro-2-oxo-1,2-
dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-
diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular
endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med
Chem. 2003;46(7):11161119.

, 76, 1, 2014 943

147. Socinski MA, Novello S, Brahmer JR, et al. Multicenter, Phase II trial of sunitinib
in previously treated, advanced non-small-cell lung cancer. J Clin Oncol. 2008;
26(4):650656.
148. Polverino A, Coxon A, Starnes C, et al. AMG 706, an oral, multikinase inhibitor
that selectively targets vascular endothelial growth factor, platelet-derived growth
factor, and kit receptors, potently inhibits angiogenesis and induces regression in
tumor xenografts. Cancer Res. 2006; 66(17):87158721.
149. Blumenschein GR, Kabbinavar FF, Menon H, et al. Randomized, open-label
phase II study of motesanib or bevacizumab in combination with paclitaxel and
carboplatin (P/C) for advanced nonsquamous non-small cell lung cancer
(NSCLC) J Clin Oncol. 2010; 28(15s):7528.
150. Schiller JH, Larson T, Ou SH, et al. Efficacy and safety of axitinib in patients with
advanced non-small-cell lung cancer: results from a Phase II study. J Clin Oncol.
2009; 27(23):38363841.
151. Davies AM, Chansky K, Lara PN, et al. Bortezomib plus gemcitabine/carboplatin
as first-line treatment of advanced non-small cell lung cancer: a phase II
Southwest Oncology Group Study (SO339). J Thorac Oncol 2009; 4: 87-92.
152. Fanucchi MP, Fossella FV, Belt R, et al. Randomized phase II study of
bortezomib alone and bortezomib in combination with docetaxel in previously
treated advanced non-small cell lung cancer. J Clin Oncol 2006; 24:5025-5033.
153. Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells
engineered to secrete murine granulocyte-macrophage colony-stimulating factor
stimulates potent, specific and long lasting anti-tumor immunity. Proc Natl Acad
Sci USA 1993; 90:3539-3543.
154. Salgia R, Lynch T, Skarin A, et al. Vaccination with irradiated autologous tumor
cells engineered to secrete granulocyte-macrophage colony-stimulating factor
augments antitumor immunity in some patients with metastatic non-small cell
lung carcinoma. J Clin Oncol 2003; 21:624-630.
155. Nemunaitis J, Sterman D, Jablons D, et al. Granulocyte-macrophage colony-
stimulating factor gene-modified autologous tumor vaccines in non-small cell lung
cancer. J Natl Cancer Inst 2004; 96; 326-331.
156. Schiller J, Nemunaitis J, Ross H, et al. A phase 2 randomized study of GM-CSF
gene-modified autologous tumor vaccine (CG8123) with and without low-dose
cyclophosphamide in advanced stage non-small cell lung cancer (NSCLC). Lung
Cancer 2005; 49: S91.

, 76, 1, 2014 944



.
: 4 ProGRP

. -, PhD, EurClinChem,
, , ..

:
: 2132043087
E-mail: lakyriou@otenet.gr

1 () CA
125, .
,
WFDC2 (4)
. 4
.
, .
WFDC .
4

, CA 125.
.
. , 1
, , (-)
(NSE),
. (GRP)
-
-. ,
.
.
GRP proGRP,

, 76, 1, 2014 945

 proGRP (31-98)
. proGRP
-, NSE .
proGRP, NSE SCC
,
proGRP. , 76, 1, 945-965,
2014.
: , 4 , 4,
WFDC2, CA 125, ROMA, ,
, ProGRP, GRP, , NSE,
,

SUMMARY
KYRIOU-MALLIS L. Novel tumor markers: HE4 and ProGRP. The contribution of
the Biochemistry Dpt. Up to now CA 125 is considered as the 1st choice marker for
epithelial ovarian cancer (EC), despite of its relatively low diagnostic sensitivity and
specificity. The research for more efficacious tumor markers for EOC revealed an
amplification of the WFDC2 gene of the human epididymis protein (HE4) in these
cancers. HE4 is overexpressed mainly in serous and endometrioid EOC. It is normally
expressed in the epithelium of the upper respiratory, the genitourinary and the
reproductive system. The genes of the WFDC family presumably share a role in
natural immunity. Determination of HE4 levels in serum and urine is performed
through a chemiluminescent immunoassay. The diagnostic sensitivity and specificity of
HE4 is superior to CA 125 both in general and in early stages of EOC. It correlates
well with stage and grade of EOC. However, renal impairment increases HE4 levels.
Respectively, NSE (neuron specific enolase) is at present the 1st choice marker for
small cell lung carcinoma (SC-LC), a cancer of neuroendocrine origin. It has been
found that the gastrin-releasing peptide (GRP) is expressed in SC-LC cells and is a
strong mitogenic factor in SC-LC cell lines. It is normally expressed in the central
nervous system, the gastrointestinal and the respiratory tract. GRP has a vasodilatory
role in the lung and is produced by the lung neuroendocrine cells. The unstable GRP
molecule generates from its stable precursor proGRP, the carboxyterminal peptide
proGRP (31-98) of which is determined in serum or plasma through a
chemiluminescent immunoassay. As a tumor marker, proGRP outperforms NSE in

, 76, 1, 2014 946

early stages of SC-LC, while its combination with NSE and SCC (squamous cell
carcinoma antigen) results in an algorithm useful in the histological subtyping of LC.
Increase of proGRP levels is also caused by renal impairment. Nosokomiaka
Chronika, 76, Supplement 1, 945-965, 2014.
Key words: tumor markers, human epididymis protein 4, HE4, WFDC2, CA 125,
ROMA algorithm, epithelial ovarian cancer, EOC, progastrin-releasing peptide,
ProGRP, GRP, neuron specific enolase, NSE, small cell lung cancer, lung cancer

. 4
() 1-2%
,
,
. 5
1. 2009
38%,

2.
80, 1
CA 125 ,
, . CA
125
: () (
/ , ,
, ),
() , .
, - , , -
-, () , . 50%
I, 80-90% III IV 3.



. , CA 125,
.

, , , , ,

, 76, 1, 2014 947

 CA 72-4 . ( 1)4,5. 4
6, 7.

1.
.
. (4)
LOE(5)


CA125 III



I, II


Inhibin IV
HLA-G / V
TATI / IV, V
,
CASA / IV

TPA / IV
CEA / IV
LPA IV, V
PAI-1 / V
Interleukin-6 / IV
Kallikreins 5, 6, ,
7, 8, 9, 10, 11, , / IV, V
13, 14, 15
hCGcf III, IV
Prostasin / IV
Osteopontin / III, IV


HE4 , III, IV


Mitogen-
/
activated / V

protein kinase
Insulin-like
growth factor
binding / / IV
protein2
(IGFBP-2)
RSF-1 / / V
NAC-1 / / V
(LOE=level of evidence)

, 76, 1, 2014 948


-
Mabs -
, cDNA microarrays.
WFDC2,
, 8, 9, 10.
WFDC2
, 4 (Homo sapiens
epididymis specific),
11, 12
. WFDC2
14 20q12-13.1
4 (WFDC WAP-type Four Disulphide
Core Domain, WAP= Whey Acidic Protein),
13.
WFDC (whey)
. WAP (domains) ,
,
, .. (Peptidase Inhibitor
3-PI3) SLPI (Secretory Leucocyte Protease Inhibitor). 4

8. ,
4
,
4 , ,
(splicing) 14.
4, SLPI,
, .
WFDC

, .
SLPI
(immunomodulatory)
.

. WFDC

, 76, 1, 2014 949

 semenogelin 1 2
(SEMG1, SEMG2)15,16,17. , WAP
, SLPI, PS20 ( WFDC1) 4
,
, , , , ,
18, 19 .

4, MUC16 (CA 125)
, ,
,
, 20.
4 WFDC2 13 kD
, (domains) WFDC,
20-25 kD21. 4
-
-
22,23. 4
(30-70% )
(10-20% )22,24a ( 2)24b.
, 425:
1.
, CA 125 ,
24a, 26. ( 1)
2. 200827
CA125, SMRP, HE4, CA72-4, , , , EGFR
ERBB2, 72,9% ( 95%),
CA 125 76,4%.
3. CA 125,
( ),


( ).
4.
. 4
,

, 76, 1, 2014 950

 4 , CA 125,
26,28,29.
5. . 4 CA 125
.
. 4 CA 125
, , 25,30.
6. ,
28,
26.

2.
.
30-70% 24a,24b.

.
- low grade
BRAF, KRAS, ERBB2


(5-20%) KRAS
-Catenin, PTEN, MSI,CTNNB1,
(10-20%)
PIK3CA
Brenner
(3-10%)
RIK3CA
high grade
p-53, CCNE1

()
(1%)
.
.
.
. Leydig Sertoli
.
( , , -
)

, 76, 1, 2014 951

 1. ROC (Receiver Operating Characteristic) AUC
(Area Under Curve) CA 125 HE4
24a.

4 CA 125
,
. ~10%
48,15,26.

4, SCC
ProGRP31,32,33.

. ,
.
4 FDA
.
RMI
(Risk of Malignancy Index), CA 125,
,
ROMA (Risk of Ovarian Malignancy Algorithm),

, 76, 1, 2014 952

CA 125, 4 34. FDA
ROMA.
,
1 2500 ,
75% ~99,7%,
PPV (Positive predictive value) 10%.
,
4 ,
PPV 25.
4
(CMIA, Chemiluminescent
Microparticle Immunoassay) Architect i2000SR Abbott
pmol/L. 95%
<70 pmol/L, 95%
4 < 140 pmol/L.
. proGRP-
() ~29%
.
, 13%,
.
, (-) -
(-), . -
3 (,
, )
35,36,37,38. - ,
,
- .
39.
- ~ 20-25%
, ,
()
. (NSE),
, 1 -.
NSE ,
,

, 76, 1, 2014 953

 . - CEA, SCC
(TPA CYFRA 21.1).
GRP (gastrin-releasing peptide)

, 40,41. GRP
.
GRP, ,
, .

,
41,42.
GRP
, , ,
43,44. GRP

(). ( GRP)
. , ( GRP)
,
45.46.
GRP

(-),
- GRP42.

,
, , , , -
44,47,48,49. 199150 51 GRP
-. GRP
mRNA, , , ,
, 44.
GRP ,
proGRP, 44,52 ( 2). pre-proGRP
, (native) GRP (1-27),
(28-30),

, 76, 1, 2014 954

 (31-98) (
mRNA).
proGRP (t1/2 19-28
), GRP (t1/2 ~2 ),
proGRP54,55,
-,
56,57,58. proGRP
proGRP (31-98),
54.
-, proGRP:
1. ,
, ,
proGRP
NSE39,59.
. , ,
proGRP
39.
2. - 22 , 6759
, - (pooled)
72%
93%.
proGRP 28% -,
7%60 ( 3)39.
3. NSE SCC, -,
( 3, 4, 5)61,62.

, 76, 1, 2014 955

 2. - proGRP53. pre-proGRP (148
) proGRP (125 )
.

GRP (1-27)-Gly - GRP(1-27)-amide.
GRP (31-125)
.

, ,

, proGRP
-(39) (
4).
proGRP ( 350 pg/ml)
.
,
( 80 pg/ml), ,
( 150 pg/ml)39 ( 4)(59).

, 76, 1, 2014 956

Sensitivity (%)

ProGRP (pg/mL)

3. proGRP
100% -
,
-39.

4. proGRP ,
( , , )
59.
3.
.

, 76, 1, 2014 957


(-)
proGRP
CEA
NSE
(-)
: CYFRA 21.1, CEA, SCC
CYFRA 21.1
SCC : CEA, CYFRA 21.1
CEA
: CYFRA 21.1 , CEA

4.
61.

- -

-



H
CEA
NSE ,
ProGRP -
CK-BB
CgA -
CYFRA21.1
TPA -
NCAM , -
LDH
SCC+NSE+

ProGRP
: O=, =, = , =
, = , = ,
- =

, 76, 1, 2014 958

 5. ,
,
SCC+proGRP+NSE62.

Molina R. Tumor Markers in Lung Cancer: Theory and Practice. Abbott Laboratories.
2011

proGRP
(CMIA Chemiluminescent
Microparticle Immunoassay) Architect i2000SR Abbott
pg/ml. proGRP
FDA. 95% <63 pg/ml
<65 pg/ml . proGRP
63,64,65.
<3
. proGRP , ,
, 64.

, 76, 1, 2014 959

 ,
.

1. American Cancer Society (ACS) 2011

http://www.cancer.org/Cancer/OvarianCancer/DetailedGuide/ovariancancer-
key-statistics. Accessed 10 July 2011 at 2151cdt.
2. Le T, Giede C, Salem S. Initial evaluation and referral guidelines for
management of pelvic/ovarian masses. JOGC 2009, 230: 668-673.
3. Molina R, Escudero JM, Aug JM et al. HE4 a novel tumour marker for ovarian
cancer: comparison with CA 125 and ROMA algorithm in patients with
gynaecological diseases. Tumour Biol. 2011, 32(6): 1087-1095.
4. Diamandis EP, Hoffman BR, Sturgeon CM. National Academy of Clinical
Biochemistry Laboratory Medicine Practice Guidelines for the Use of Tumor
Markers. Clin Chem 2008, 54: 1935-1939.
5. Sturgeon CM, Duffy MJ et al. National Academy of Clinical Biochemistry.
National Academy of Clinical Biochemistry laboratory medicine practice
guidelines for use of tumor markers in testicular, prostate, colorectal, breast,
and ovarian cancers. Clin Chem 2008, 54(12): e11-79.
6. Huhtinen K, Suvitie P, Hiissa J et al. Serum HE4 concentration differentiates
malignant ovarian tumours from ovarian endometriotic cysts. Br J
Cancer. 2009,100(8): 1315-1319.
7. Hamed EO, Ahmed H, Sedeek OB et al. Significance of HE4 estimation in
comparison with CA125 in diagnosis of ovarian cancer and assessment of
treatment response. Diagn Pathol. 2013, 8: 11.
8. 8.HellstrmI, Rayrcraft J, Hayden-Ledbetter M et al. The HE4 (WFDC2) protein
is a biomarker for ovarian cancer? Cancer Res 2003, 63: 3695-3700.
9. Ono K, Tanaka T, Tsunoda T et al. Identification by cDNA microarray of genes
involved in ovarian carcinogenesis. Cancer Res 2000, 60: 5007-5011.
10. Welsh J, Zarrinkar P, Sapinoso L et al. Analysis of gene expression profiles in
normal and neoplastic ovarian tissue samples identifies candidate molecular
markers of epithelial ovarian cancer. Proc Natl Acad Sci USA, 2001, 98: 1176-
1181.

, 76, 1, 2014 960

11. Kirchhoff C, Habben I, Ivell R and Krull N. A major human epididymis-specific
cDNA encodes a protein with sequence homology to extracellular proteinase
inhibitors. Biol Reprod 1991, 45: 350-357.
12. Kirchhoff C. Molecular characterization of epididymal proteins. Rev Reprod 1998,
3: 86-95.
13. Clauss A, Lilja H, Lundwall A. A locus on human chromosome 20 contains several
genes expressing protease inhibitor domains with homology to whey acidic
protein. Biochem J 2002, 368: 233-242.
14. Chhikara N, Saraswat M, Tomar AK et al. Human Epididymis Protein-4 (HE-4): A
Novel Cross-Class Protease Inhibitor. PLoS ONE 2012, 7(11): e47672.
15. Galgano M, Hampton G and Frierson H. Comprehensive analysis of HE4
expression in normal and malignant human tissues. Modern Pathology 2006, 19:
847-853.
16. Wilkinson TS, Roghanian A, Simpson AJ and Sallenave J-M. WAP domain
proteins as modulators of mucosal immunity. Biochem Soc Trans 2011, 39: 1409-
1415.
17. Ferreira Z, Seixas S, Andrs AM et al. Reproduction and immunity-driven natural
selection in the human WFDC locus. Mol Biol Evol 2013, 30(4): 938-950.
18. Bouchard D, Morisset D, Bourbonnais Y, Tremblay GM.Proteins with whey-acidic-
protein motifs and cancer. Lancet Oncol 2006, 7(2): 167-174.
19. Clauss A, Ng V, Liu J et al. Overexpression of elafin in ovarian carcinoma is driven
by genomic gains and activation of the nuclear factor kappaB pathway and is
associated with poor overall survival. Neoplasia 2010, 12(2): 161-172.
20. O' Shannessy DJ, Jackson SM, Twine NC et al. Gene expression analyses
support fallopian tube epithelium as the cell of origin of epithelial ovarian cancer.
Int J Mol Sci. 2013, 14(7): 13687-13703.
21. ingle L, Singleton V, Bingle CD. The putative ovarian tumour marker gene HE4
(wfdc2) is expressed in normal tissues and undergoes complex alternative splicing
to yield multiple isoforms. Oncogene 2002, 21: 2768-2773.
22. Drapkin R, von Horsten HH, Lin Y, Mok SC et al. Human epididymis protein4
(HE4) is a secreted glycoprotein that is overexpressed by serous and endometroid
ovarian carcinomas. Cancer Res 2005, 65: 2162-2169.
23. Hellstrom I, Heagerty PJ, Swisher EM et al. Detection of the HE4 protein in urine
as a biomarker for ovarian neoplasms. Cancer Lett 2010, 296: 43-48.

, 76, 1, 2014 961

24. A. Hamed EO, Ahmed H, Sedeek OB et al. Significance of HE4 estimation in
comparison with CA125 in diagnosis of ovarian cancer and assessment of
treatment response. Diagn Pathol 2013, 23: 8:11.
. , .
. biomagazine.gr 2013, 14,
http://www.biomagazine.gr/index.php/site/article/15/2/BIO%20Health/thewries-
proeleyshs-kai-pathogeneshs-twn-epithhliakwn-ogkwn-twn-wothhkwn
25. Li J, Dowdy S, Tipton T et al. HE4 as a biomarker for ovarian and endometrial
cancer management. Expert Rev Mol Diagn 2009, 9(6): 555-566.
26. Escudero JM, Auge JM, Filella X et al. Comparison of serum human epididymis
protein 4 with cancer antigen 125 as a tumor marker in patients with malignant
and nonmalignant diseases.Clin Chem 2011, 57(11): 1534-1544.
27. Moore RG, Brown AK, Miller MC et al. The use of multiple novel tumor biomarkers
for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol
Oncol 2008, 108(2): 402-408.
28. Moore RG, Brown AK, Miller MC et al. Utility of a novel serum tumor biomarker
HE4 in patients with endometrioid adenocarcinoma of the uterus. Gynecol Oncol
2008, 110(2): 196-201.
29. Hallamaa M, Suvitie P, Huhtinen K et al. Serum HE4 concentration is not
dependent on menstrual cycle or hormonal treatment among endometriosis
patients and healthy premenopausal women. Gynecol Oncol 2012,125(3): 667-
672.
30. Dong L, Chang XH, Ye X et al. The values of serum human epididymis secretory
protein 4 and CA(125) assay in the diagnosis of ovarian malignancy. Zhonghua Fu
Chan Ke Za Zhi 2008, 43(12): 931-936.
31. Duk JM, Voorst Vader PC, Ten Hoor KA et al. Elevated levels of squamous cell
carcinoma antigen with a benign disease of the skin. Cancer 1989, 64: 1652-
1656.
32. Cases A, Filella X, Molina R et al. Tumor markers in chronic renal failure and
hemodialysis patients. Nephron 1991, 57(2): 183-186.
33. Molina R, Auge JM, Alicarte J et al. Pro-gastrin-releasing peptide in patients with
benign and malignant diseases. Tumour Biol. 2004, 25(1-2): 56-61.
34. Moore RG, Jabre-Raughley M, Brown AK et al. Comparison of a novel multiple
marker assay vs the Risk of Malignancy Index for the prediction of epithelial

, 76, 1, 2014 962

 ovarian cancer in patients with a pelvic mass. Am J Obstet Gynecol 2010, 203(3):
228.
35. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2009. CA Cancer J
Clin. 2009, 59(4):225-249.
36. Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J
Med. 2004, 350(4):379-392. Review
37. Schiller JH. Current standards of care in small-cell and non-small-cell lung cancer.
Oncology 2001, 61 (Suppl 1): 3-13.
38. Stupp R, Monnerat C, Turrisi AT 3rd et al. Small cell lung cancer: state of the art
and future perspectives. Lung Cancer 2004, 45(1): 105-117.
39. Stieber P. Pro-Gastrin-Releasing Peptide (ProGRP)-A Diagnostic Biomarker for
Small-Cell Lung Cancer. Chin J Lung Cancer 2009, 12(3): 183-186.
40. McDonald TJ, Jornvall H, Nilsson G et al. Characterization of a gastrin releasing
peptide from porcine non-antral gastric tissue. Biochem Biophys Res Commun
1979, 90: 227233.
41. Bunnett N 1994 Gastrin releasing peptide. In: Walsh JH, Dockray GJ, eds. Gut
peptides. Raven Press, New York; p 423-455.
42. Cuttitta F, Carney DN, Mulshine J et al. Bombesin-like peptides can function as
autocrine growth factors in human small-cell lung cancer. Nature 1985, 316: 823
826.
43. Ischia J, Patel O, Shulkes A, Baldwin GS. Gastrin-releasing peptide: different
forms, different functions. Biofactors. 2009, 35(1): 69-75.
44. Patel O, Shulkes A, Baldwin GS. Gastrin-releasing peptide and cancer. Biochim
Biophys Acta-Rev Cancer 2006,1766: 23-41.
45. Degan S, Lopez GY, Kevill K, Sunday ME. Gastrin-releasing peptide, immune
responses, and lung disease. Ann N Y Acad Sci. 2008, 1144: 136-47.
46. Zhou S, Potts EN, Cuttitta F, Foster WM, Sunday ME. Gastrin-releasing peptide
blockade as a broad-spectrum anti-inflammatory therapy for asthma. Proc Natl
Acad Sci USA 2011, 108(5): 2100-2105.
47. Preston SR, Miller GV, Primrose JN. Bombesin-like peptides and cancer. Crit Rev
Oncol Hematol 1996, 23:225238.
48. Moody TW, Chan D, Fahrenkrug J, Jensen RT Neuropeptides as autocrine
growth factors in cancer cells. Curr Pharm Des 2003, 9: 495509.
49. Patel O, Dumesny C, Giraud AS, Baldwin GB, Shulkes A. Stimulation of
proliferation and migration of a colorectal cancer cell line by amidated and glycine-

, 76, 1, 2014 963

 extended gastrin-releasing peptide via the same receptor. Biochem Pharmacol
2004, 68: 2129-2142.
50. Sunday ME, Choi N, Spindel ER et al. Gastrin-releasing peptide gene expression
in small cell and large cell undifferentiated lung carcinomas. Hum Pathol 1991,
22(10): 1030-1039.
51. Yamaguchi K, Abe K, Kameya T et al. Production and molecular size
heterogeneity of immunoreactive gastrin-releasing peptide in fetal and adult lungs
and primary lung tumors. Cancer Res. 1983, 43(8): 3932-3939.
52. C Dumesny, O Patel, S Lachal et al. Synthesis, Expression and Biological Activity
of the Prohormone for Gastrin Releasing Peptide (ProGRP) Endocrinology 2006,
147(1): 502509.
53. Patel O, Dumesny C, Shulkes A, Baldwin GS. C-terminal fragments of the gastrin-
releasing peptide precursor stimulate cell proliferation via a novel receptor.
Endocrinology 2007, 148(3): 1330-1339.
54. Aoyagi K, Miyake Y, Urakami K et al. Enzyme immunoassay of immunoreactive
progastrin-releasing peptide(31-98) as tumor marker for small-cell lung carcinoma:
development and evaluation. Clin Chem 1995, 41(4):537-543.
55. Yamaguchi K, Aoyagi K, Urakami K et al. Enzyme-linked immunosorbent assay of
pro-gastrin-releasing peptide for small cell lung cancer patients in comparison with
neuron-specific enolase measurement. Jpn J Cancer Res. 1995, 86(7): 698-705.
56. Sunaga N, Tsuchiya S, Minato K et al. Serum pro-gastrin-releasing peptide is a
useful marker for treatment monitoring and survival in small-cell lung cancer.
Oncology 1999, 57:143148.
57. Ide A, Ashizawa K, Ishikawa N et al. Elevation of serum pro-gastrin-releasing
peptide in patients with medullary thyroid carcinoma and small cell lung
carcinoma. Thyroid 2001, 11:10551061.
58. Yashi M, Muraishi O, Kobayashi Y et al. Elevated serum progastrin-releasing
peptide (3198) in metastatic and androgen-independent prostate cancer patients.
Prostate 2002, 51: 84-97.
59. Oremek GM, Sauer-Eppel H, Bruzdziak TH. Value of tumour and inflammatory
markers in lung cancer. Anticancer Res. 2007, 27(4A): 1911-1915.
60. Tang JH, Zhang XL, Zhang ZH et al. Diagnostic value of tumor marker pro-
gastrin-releasing peptide in patients with small cell lung cancer: a systematic
review. Chin Med J (Engl). 2011, 124(10): 1563-1568.

, 76, 1, 2014 964

61. Harmsma M, Schutte B, Ramaekers FC. Serum markers in small cell lung cancer:
Opportunities for improvement. Biochim Biophys Acta. 2013, 1836(2): 255-272.
62. Molina R, Aug JM, Bosch X et al. Usefulness of serum tumor markers, including
progastrin-releasing peptide, in patients with lung cancer: correlation with
histology. Tumour Biol. 2009, 30(3): 121-129.
63. Yoshimura T, Fujita K, Kawakami S et al. Stability of pro-gastrin-releasing peptide
in serum versus plasma. Tumour Biol 2008, 29(4): 224-230.
64. Nordlund MS, Bjerner J, Warren DJ et al. Progastrin-releasing peptide: stability in
plasma/serum and upper reference limit.Tumor Biol 2008, 29(3): 204-210.
65. Kim HR, Oh IJ, Shin MG et al. Plasma proGRP Concentration is Sensitive and
Specific for Discriminating Small Cell Lung Cancer from Nonmalignant Conditions
or Non-small Cell Lung Cancer. J Korean Med Sci 2011, 26: 625-630.

, 76, 1, 2014 965

 , NGAL

,
,
...

:
: 2132043084, 6947937855
E-mail: biochem@evaggelismos-hosp.gr

(ACUTE KIDNEY INJURY- AKI)

.
( )
.
:
(.. )
(.. , )
(.. ,
).

.
,

(ACUTE KIDNEY INJURY- AKI)

RIFLE , (SCr)
24. KDIGO :
:
SCr 0.3 mg/dl 48
SCr 1.5 (baseline),
7
< 0.5 ml/kg/h 6.

, 76, 1, 2014 966

 (AKD), (AKI)
(CKD)

.
(AKD),
( CKD).
, (CKD) ,
, ,
() (AKD)
. AKD.
AKD CKD.

.
RCPE UK Consensus Conference on Management of acute
kidney injury: the role of fluids, e-alerts and biomarkers (6-17 2012,
)

, ,
(baseline). 24
.
,
.
()

(, , )
.
, ,
. ,
, .

G1 ,
.

DNA,
.

, 76, 1, 2014 967



. :
1.NGAL: Neutrophil gelatinase associated lipokalin
2.KIM-1: Kidney injury molecule-1
3.IGFBP7: Insulin-like growth factor-binding protein 7
4.TIMP-2: Tissue inhibitor of metalloproteinases 2

NEUTROPHIL GELATINASE ASSOCIATED LIPOCALIN (NGAL)

25kDa
, ,
. NGAL Henle
.
NGAL (uNGAL)
. ,
, , IgA
.
,

.
NGAL
,
.

1. Krumholtz JS, Carvalhal GF, Ramos CG, et al. Prostate specific antigen cutoff of
2.6ng/ml for prostate cancer screening is associated with favorable pathologic
tumor features.Urology. 2002;60(3):469-473.
2. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer
among men with a prostate specific antigen level < or = 4.0 ng per milliliter. N Engl
J Med. 2004;350(22):2239-2246.
3. Lilja H,Christensson A, Dahlen U, et al.Prostate- specific antigen in serum occurs
predominantly in complex with 1-antichymotripsin.Clin Chem.1991;37(9):1618-
1625.

, 76, 1, 2014 968

4. Catalona WJ, Partin AW, Slawin KM, et al.Use of the percentage of free prostate-
specific antigen to enhance differentiation of prostate cancer from benign prostatic
disease: a prospective multicenter clinical trial.Jama.1998;279(19):1542-1547.
5. Catalona WJ, Bartch G, Rittenhouse HG,et al.Serum pro prostate specific antigen
improves cancer detection compared to free and complexed prostate specific
antigen in men with prostate specific antigen 2 to 4 ng/ml.J Urol.2 003;170(6 Pt
1):2181-2185.
6. Catalona WJ, Bartch G, Rittenhouse HG,et al. Serum pro prostate specific antigen
preferentially detects aggressive prostate cancers in men with 2 to 4ng/ml prostate
specific antigen.J Urol. 2004;171(6 Pt 1):2239-2244.

, 76, 1, 2014 969

 HE4, Pro GRP, NGAL

1, 2
1
-, MD, MSc,
2
-,
, ...

:

:6974992097
-mail: aplaskarakis@gmail.com

,
,
. ,
,
, ,
. ,
,
.
,
HE4 (Human Epididymis Protein 4 gene) ProGRP (Pro-
gastrin-releasing peptide).
,
, ,
, NGAL (Neutrophil gelatinase-associated lipocalin).
, 76, 1, 970-984, 2014.
: , , , ,

SUMMARY
LASKARAKIS , ALEVIZOPOULOS . Novel biomarkers HE4, ProGRP, NGAL
and their clinical role. Ovarian cancer is one of the most common reproductive
cancers and has the highest mortality rate amongst gynecologic cancers. This is due
to the fact that most diagnoses occur in the late, metastatic stages of the disease, thus
making early diagnosis a top priority. The same need seems to exist for lung cancer,
which is the most frequent and deadly malignancy worldwide, with the majority of

, 76, 1, 2014 970

patients presenting with inoperable advanced disease. Over the last few years,
several novel biomarkers for these types of cancer have been discovered. Two of the
most important are the human epididymis protein (HE)4 gene and the progastrin-
releasing peptide (ProGRP). Aim of this article is to present the clinical role of these
two biomarkers ,along with that of the neutrophil gelatinase-associated lipocalin
(NGAL), a novel biomarker which seems to be related with acute renal injury and
some types of cancer. Nosokomiaka Chronika, 76, Supplement 1, 970-984, 2014.
Key words: biomarker, HE4, ProGRP, NGAL, cancer

,
1.

(), 2009 , 21.550 ,
, 14.600 , ,
()2.
, 20%
3.
, ,
, 25% ,
4.

.
screening test,
5.
HE43.
()
, ,
, 6,7.
, ,
()
() , 15% 6.

,

, 76, 1, 2014 971

 8.
,
, neuron specific enolase (NSE) pro-gastrin
releasing peptide (ProGRP)9,10,11,12.

, ,
.
, ,
, ,
13.
NGAL (neutrophil gelatinase- associated
lipocalin)14.
, NGAL, ,

,
,
15,16,17.
, .

,
, 125 (Ca125),
1981 Bast et al., ,
80% , 18,19,20.
, ,
,
3. ,
,
, ,
, 21. Ca125

, ,
32 , 34 31
, 84,4% 66,3,
22. Ca125 ,

, 76, 1, 2014 972

 , ,
23. ,
screening test ,
24.
,
, ,
. , ,
30 35 U/ml Ca125
,
screening test23,18. ,
, .

4-
4, (WFDC2),
Kirchhoff et al. 25,26.
4 mRNA, , ,
, ,
real time PCR27. 4
,25,28,29
, 3.
, , 67 ,
90% 76% 30.
, HE4
. , HE4,
,
, ,
31.
, 4
, ,
Ca125, ,
32,33, 4, Ca125,
, .
screening ,
,
, Ca125,

, 76, 1, 2014 973

 94%. , Ca125
,
,
Ca125 (76,4% 72,9%)30.
4 ,
, ,
,
Ca125 ROMA test (Risk of Ovarian Malignancy Algorithm)
(FDA), 201134.
NCCN,
35,36,37.

ProGRP
,
,
(), (),
. ,
(CEA), 200 KDa,
(40KDa), CYFRA 21-1,
, 38,39,40.
, (neuron specific enolase - NSE),
. , ,
, ,
, ,
, 41,42,43. ,
, 80%
, 20%-30%
[9]. , ,
(ProGRP), ,
,
,
NSE,
44,45,10,11,12. ,
, 46,47,48. ProGRP
,

, 76, 1, 2014 974

 , 162 , 37
, 88 37 .
CEA, CYFRA21-1, NSE ProGRP. NSE ProGRP,
, ,
( P<0,0001),
, , performance status.
, ,
NSE ProGRP , ProGRP
78,4% 48,6% NSE.
, , NS, ProGRP,
,
49. ProGRP
, ,

.

NGAL
2 24P3 Neutrophil gelatinase-associated
lipocalin (NGAL), ,
,
,
, .
,
,
50,51.
NGAL , ,
52-61, 62 17.

NGAL
NGAL
, , -
[63], 64 ,
65.
66,67.
NGAL ,

, 76, 1, 2014 975

 , ,
NGAL , , ,
(P<0,0001)68,69.
, NGAL 70.
NGAL ,
. ,
NGAL HENLE71.
NGAL ,

72. NGAL
GFR, 73.

,
74.

NGAL K
NGAL
. ,
, grade I ,
75,76.77.
, NGAL
,
HER-2,
NGAL 78,75,79.
NGAL, ,
78. , NGAL
,
80.
,
81.
, NGAL,
,
,
82. NGAL ,
( ),

, 76, 1, 2014 976

 CEA CA19-982. ,
, NGAL
EGFR, ERLOTINIB83.

,
, HE4
, ProGRP
NGAL
,
,

.
,
screening tests,
, , ,

1. E. Banks. The epidemiology of ovarian cancer. In Ovarian Cancer: Methods and

Protocols, J.M. S. Bartlett, Ed.,Humana Press, Totowa, NJ, USA, 2000.
2. United States Cancer Statistics 2002 Incidence and Mortality, 2005,
http://seer.cancer.gov/csr/1975 2006/results single/sect 01 table.01.pdf.
3. N. Urban and C. Drescher, Potential and limitations in early diagnosis of ovarian
cancer. In Ovarian Cancer: State of the Art and Future Directions in Translational
Research, G. Coukos, A. Berchuck, and R. Ozols, Eds., pp. 314, Springer, New
York, NY, USA, 2008.
4. Badgwell D and Bast RC. Early detection of ovarian cancer, DiseaseMarkers, vol.
23, no. 5-6, pp. 397410, 2007.
5. Mor G, Visintin I, Lai Y, et al. Serum protein markers for early detection of ovarian
cancer, Proceedings of the National Academy of Sciences of the United States of
America, vol. 102, no. 21, pp. 76777682, 2005.
6. American Cancer Society Cancer Facts and Figures, 2010. Atlanta, GA: American
Cancer Society; 2010.
7. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin.
2010;60:277300.

, 76, 1, 2014 977

8. Ettinger DS: Overview and state of the art in the management of lung cancer.
Oncology 18:3-9, 2004.
9. Slodkowska J, Zych J, Szturmowicz M, et al. Neuroendocrine phenotype of non-
small cell lung carcinoma: immunohistological evaluation and biochemical study.
Int J Biol Markers 2005;20:217-226.
10. Takada M, Kusunoki Y, Masuda N, et al. Pro-gastrin-releasing peptide (31-98) as
a tumour marker of small-cell lung cancer: comparative evaluation with neuron-
specific enolase. Br J Cancer 1996;73:1227-1232.
11. Lamy PJ, Grenier J, Kramar A et al: Pro-gastrinreleasing peptide, neuron-specific
enolase and chromogranin A as serum markers of small cell lung cancer. Lung
Cancer 2000;29:197-203.
12. Molina R, Auge JM, Filella X,et al. Pro-gastrin-releasing peptide (proGRP) in
patients with benign and malignant diseases: comparison with CEA, SCC, CYFRA
21-1 and NSE in patients with lung cancer. Anticancer Res 2005;25(3A):1773-
1778.
13. Bonventre JV, Vaidya VS, Schmouder R,et al. Next-generation biomarkers for
detecting kidney toxicity, Nature Biotechnology, vol. 28, no. 5, pp. 436440, 2010.
14. Fassett RG, Venuthurupalli SK, Gobe GC,et al. Biomarkers in chronic kidney
disease: a review, Kidney International, vol. 80, pp. 806821, 2011.
15. Kjeldsen L, Johnsen AH, Sengelov H, et al. Isolation and primary structure
ofNGAL, a novel protein associated with human neutrophil gelatinase, Journal of
Biological Chemistry, vol. 268, no. 14, pp. 1042510432, 1993.
16. Mishra J, Qing MA, Prada A, et al. Identification of neutrophil gelatinase-
associated lipocalin as a novel early urinary biomarker for ischemic renal injury,
Journal of the American Society of Nephrology, vol. 14, no. 10, pp. 25342543,
2003.
17. Bolignano D, Donato V, Lacquaniti A et al. Neutrophil gelatinase-associated
lipocalin (NGAL) in human neoplasias: a new protein enters the scene. Cancer
Lett. 2010;288:1016.
18. Goonewardene TI, Hall MR, Rustin GJ. Management of asymptomatic patients on
follow-up for ovarian cancer with rising CA-125 concentrations. Lancet Oncol.
2007;8:813821.
19. Bast RC Jr, Feeney M, Lazarus H, et al. Reactivity of a monoclonal antibody with
human ovarian carcinoma. J Clin Invest. 1981;68:13311337.

, 76, 1, 2014 978

20. Kabawat SE, Bast RC Jr, Bhan AK, et al. Tissue distribution of a coelomic-
epithelium-related antigen recognized by the monoclonal antibody OC125. Int J
Gynecol Pathol. 1983;2:275285.
21. Gupta D. and Lis CG, Role of CA125 in predicting ovarian cancer survivala
review of the epidemiological literature, Journal of Ovarian Research, vol. 2, no. 1,
article no. 13, 2009.
22. Nakae M, Iwamoto I, Fujino T, et al. Preoperative plasma osteopontinlevel as a
biomarker complementaryto carbohydrate antigen 125 in predicting ovarian
cancer, Journal of Obstetrics and GynaecologyResearch, vol. 32, no.3, pp. 309
314, 2006.
23. Skates SJ, Jacobs IJ, and Knapp RC, Tumor markersin screening for ovarian
cancer, in Ovarian Cancer: Methodsand Protocols, J.M. S.Bartlett,Ed., pp. 6173,
Humana Press,Totowa, NJ, USA, 2000.
24. Helzlsouer KJ, Bush TL, Alberg AJ,et al.Prospective study of serum CA-125 levels
as markers of ovarian cancer, Journal of the American Medical Association, vol.
269, no. 9, pp. 11231126, 1993.
25. Kirchhoff C, Habben I, Ivell R, Krull N. A major human epididymis specific cDNA
encodes a protein with sequence homology to extracellular proteinase inhibitors.
Biol Reprod. 1991;45:350357.
26. Bingle L, Singleton V, Bingle CD. The putative ovarian tumour marker gene HE4
(WFDC2), is expressed in normal tissues and undergoes complex alternative
splicing to yield multiple protein isoforms. Oncogene. 2002;21:27682773.
27. Li Jinping, Dowdy Sean et al. HE4 as a biomarker for ovarian and endometrial
cancer management. Expert Rev Mol Diagn. 2009;9(6):555-566.
28. Schummer M, Ng WV, Bumgarner RE, et al. Comparative hybridization of an array
of 21 500 ovarian cDNAs for the discovery of genes overexpressed in ovarian
carcinomas, Gene, vol. 238, no. 2, pp. 375385, 1999.
29. Hellstrom I and Hellstrom KE. SMRP and HE4 as biomarkers for ovarian
carcinoma when used alone and in combination with CA125 and/or each other,
Advances in Experimental Medicine and Biology, vol. 622, pp. 1521, 2008.
30. Moore RG, Brown AK, Miller MC et al. The use of multiple novel tumor biomarkers
for the detection of ovarian carcinoma in patients with a pelvic mass, Gynecologic
Oncology, vol. 108, no. 2, pp. 402408, 2008.

, 76, 1, 2014 979

31. Scholler N, Crawford M, Sato A et al. Bead-based ELISA for validation of ovarian
cancer early detection markers, Clinical Cancer Research, vol. 12, no. 7, pp.
21172124, 2006.
32. Hellstrom I and Hellstrom KE. SMRP and HE4 as biomarkers for ovarian
carcinoma when used alone and in combination with CA125 and/or each other,
Advances in Experimental Medicine and Biology, vol. 622, pp. 1521, 2008.
33. Hellstrom I, Raycraft J, Hayden-Ledbetter M et al. The HE4 (WFDC2) protein is a
biomarker for ovarian carcinoma, Cancer Research, vol. 63, no. 13, pp. 3695
3700, 2003.
34. www.Fda.gov, FDA clears a test for ovarian cancer September 6 2011.
35. Jacob F, Meier M, Caduff R, et al. No benefit from combining HE4 and Ca 125 as
ovarian tumour markers in a clinical setting. Gynecol Oncol. 2011;121:487-491.
36. Molina R, Escudero JM. HE4 a novel tumour marker for ovarian
cancer.Comparison with Ca 125 and ROMA algorithm in patients with
gynaecological diseases. Tumour Biol. 2011;32:1087-1095.
37. Van Gorp T, Despiere E, Despierre E, et al. HE4 and Ca 125 as a diagnostic test
in ovarian cancer, prospective validation of the risk of ovarian Malignancy
Algorithm. Br. J Cancer 2011;104:863-870.
38. Paone G, De Angelis G, Greco S,et al. Evaluation of response to chemotherapy in
patients affected with non-small cell lung cancer by means of three tumour
markers elaborated by discriminant analysis. Respir Med 1997;91(6):361-367.
39. Oremek GM and Seiffert UB: Cyfra 21-1 ein geeigneter Tumormarker in der
Diagnostik nichtkleinzelliger Bronchialkarzinome. Med Welt 47: 335-338, 1996.
40. Pujol JL, Boher JM, Grenier J et al. Cyfra 21-1, neuron-specific enolase and
prognosis of nonsmall cell lung cancer: prospective study in 621 patients. Lung
Cancer 2001;31:221-231.
41. Kaiser E, Kuzmits R, Pregant P, et al. Clinical biochemistry of neuron specific
enolase. Clin Chim Acta 1989183: 13-31.
42. Cooper EH: Neuron-specific enolase. Int J Biol Markers 19949: 205-210.
43. Stieber P, Arousson AC, Bialk P, et al. Tumour markers in lung cancer. Anticancer
Res 1999;19:2785-2820.
44. Schneider J, Philipp M, Salewski L et al. Progastrin releasing peptide (ProGRP)
and neuron-specific enolase (NSE) in therapy control of patients with small-cell
lung cancer. Clin Lab 2003;49:35-42.

, 76, 1, 2014 980

45. Schneider J, Philipp M, Velcovsky HG, et al. Progastrin releasing peptide
(ProGRP), neuron-specific enolase(NSE), carcinoembryonic antigen (CEA) and
cytokeratin 19- fragments (CYFRA 21-1) in patients with lung cancer in
comparison to other diseases. Anticancer Res 2003;23: 885-894.
46. Niho S, Nishiwaki Y, Goto K, et al. Significance of serum pro-gastrin-releasing
peptide as a predictor of relapse of small cell lung cancer: comparative evaluation
with neuron-specific enolase and carcinoembryonic antigen. Lung Cancer
2000;27:159-167.
47. Shibayama T, Ueoka H, Nishii K, et al. Complementary roles of progastrin-
releasing peptide (ProGRP) and neuron-specific enolase (NSE) in diagnosis and
prognosis of small-cell lung cancer (SCLC). Lung Cancer 2001;32:61-69.
48. Pujol JL, Quantin X, Jacot W, et al. Neuroendocrine and cytokeratin serum
markers as prognostic determinants of small cell lung cancer. Lung Cancer
2003;39:131-138.
49. Nisman B, Biran H, Ramu N, et al. The Diagnostic and Prognostic Value of
ProGRP in lung cancer. Anticancer Research 2009;29:4827-4832.
50. Flower DR. Experimentally determined lipocalin structures. BiochimBiophys Acta.
2000;1482:4656.
51. Flower DR, North AC, Sansom CE. The lipocalin protein family: structural and
sequence overview. Biochim Biophys Acta. 2000;1482:924.
52. Mussap M, Degrandi R, Fravega M, et al. Acute kidney injury in critically ill infants:
the role of urine Neutrophil Gelatinase-Associated Lipocalin (NGAL). J Matern
Fetal Neonatal Med. 2010;23(Suppl 3):7072.
53. Devarajan P. Review: neutrophil gelatinase-associated lipocalin: a troponin-like
biomarker for human acute kidney injury. Nephrology (Carlton). 2010;15:419428.
54. .Kunzendorf U, Haase M, Rolver L, et al. Novel aspects of pharmacological
therapies for acute renal failure. Drugs. 2010;70:10991114.
55. Moore E, Bellomo R, Nichol A. Biomarkers of acute kidney injury in anesthesia,
intensive care and major surgery: from the bench to clinical research to clinical
practice. Minerva Anestesiol. 2010;76:425440.
56. Chaudhary K, Phadke G, Nistala R, et al. The emerging role of biomarkers in
diabetic and hypertensive chronic kidney disease. Curr Diab Rep. 2010; 10:3742.
57. Bolignano D, Coppolino G, Lacquaniti A, et al. From kidney to cardiovascular
diseases: NGAL as a biomarker beyond the confines of nephrology. Eur J Clin
Invest. 2010;40:273276.

, 76, 1, 2014 981

58. Prabhu A, Sujatha DI, Ninan B, et al. Neutrophil gelatinase associated lipocalin as
a biomarker for acute kidney injury in patients undergoing coronary artery bypass
grafting with cardiopulmonary bypass. Ann Vasc Surg. 2010;24:525531.
59. Rosner MH. Urinary biomarkers for the detection of renal injury. Adv Clin Chem.
2009;49:7397.
60. Di GA, Giuffrida C, Carpinteri G, et al. Neutrophil gelatinase-associated lipocalin: a
novel biomarker for the early diagnosis of acute kidney injury in the emergency
department. Eur Rev Med Pharmacol Sci. 2009;13:197200.
61. Soni SS, Ronco C, Katz N, et al. Early diagnosis of acute kidney injury: the
promise of novel biomarkers. Blood Purif. 2009;28:165174.
62. Bolignano D, Coppolino G, Donato V, et al. Neutrophil gelatinase associated
lipocalin (NGAL): a new piece of the anemia puzzle? Med Sci Monit.
2010;16:RA131RA135.
63. Nomura I, Gao B, Boguniewicz M, et al. Distinct patterns of gene expression in the
skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis. J
Allergy Clin Immunol. 2003;112:11951202.
64. Mallbris L, OBrien KP, Hulthen A, et al. Neutrophil gelatinase-associated lipocalin
is a marker for dysregulated keratinocyte differentiation in human skin. Exp
Dermatol. 2002;11:584591.
65. Van Dyke TE, Schweinebraten M, Cianciola LJ, et al. Neutrophil chemotaxis in
families with localized juvenile periodontitis. J Periodontal Res. 1985; 20:503514.
66. Ding L, Hanawa H, Ota Y, et al. Lipocalin-2/neutrophil gelatinase-B associated
lipocalin is strongly induced in hearts of rats with autoimmune myocarditis and in
human myocarditis. Circ J. 2010;74:523530.
67. Yndestad A, Landro L, Ueland T, et al. Increased systemic and myocardial
expression of neutrophil gelatinase-associated lipocalin in clinical and
experimental heart failure 1. Eur Heart J. 2009;30:12291236.
68. Anwaar I, Gottsater A, Hedblad B, et al. Endothelial derived vasoactive factors and
leukocyte derived inflammatory mediators in subjects with asymptomatic
atherosclerosis. Angiology. 1998;49:957966
69. Sahinarslan A, Kocaman SA, Bas D, et al. Plasma neutrophil gelatinase-
associated lipocalin levels in acute myocardial infarction and stable coronary
artery disease. Coron Artery Dis. 2011;22:333338.

, 76, 1, 2014 982

70. Lee SY, Kim DH, Sung SA, et al. Sphingosine-1-phosphate reduces hepatic
ischaemia/reperfusion-induced acute kidney injury through attenuation of
endothelial injury in mice. Nephrology (Carlton ). 2011;16:163173.
71. Hvidberg V, Jacobsen C, Strong RK, et al. The endocytic receptor megalin binds
the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity
and mediates its cellular uptake. FEBS Lett. 2005;579:773777.
72. Schmidt-Ott KM, Mori K, Kalandadze A, Li JY, et al. Neutrophil gelatinase-
associated lipocalin-mediated iron traffic in kidney epithelia. Curr Opin Nephrol
Hypertens. 2006; 15:442449
73. Viau A, El KK, Laouari D, et al. Lipocalin 2 is essential for chronic kidney disease
progression in mice and humans. J Clin Invest. 2010;120:40654076.
74. Han WK, Wagener G, Zhu Y, et al. Urinary biomarkers in the early detection of
acute kidney injury after cardiac surgery. Clin J Am Soc Nephrol. 2009;4:873882.
75. Bauer M, Eickhoff JC, Gould MN, et al. Neutrophil gelatinase associated lipocalin
(NGAL) is a predictor of poor prognosis in human primary breast cancer. Breast
Cancer Res Treat. 2008; 108:389397.
76. Santin AD, Zhan F, Bellone S, et al. Gene expression profiles in primary ovarian
serous papillary tumors and normal ovarian epithelium: identification of candidate
molecular markers for ovarian cancer diagnosis and therapy. Int J Cancer.
2004;112:1425.
77. Cho H, Kim JH. Lipocalin2 expressions correlate significantly with tumor
differentiation in epithelial ovarian cancer. J Histochem Cytochem. 2009;57:513
521.
78. Nacht M, Ferguson AT, Zhang W, et al. Combining serial analysis of gene
expression and array technologies to identify genes differentially expressed in
breast cancer. Cancer Res.1999;59:54645470
79. Stoesz SP, Friedl A, Haag JD, et al. Heterogeneous expression of the lipocalin
NGAL in primary breast cancers. Int J Cancer. 1998;79:565572.
80. Miyamoto T, Kashima H, Suzuki A, et al. Laser-capturedmicrodissection-
microarray analysis of the genes involved in endometrial carcinogenesis: stepwise
up-regulation of lipocalin2 expression in normal and neoplastic endometria and its
functional relevance. Hum Pathol. 2011;42:12651274.
81. Sun Y, Yokoi K, Li H, et al. NGAL expression is elevated in both colorectal
adenoma-carcinoma sequence and cancer progression and enhances
tumorigenesis in xenograft mouse models. Clin Cancer Res. 2011;17:43314340.

, 76, 1, 2014 983

82. Wang HJ, He XJ, Ma YY, et al. Expressions of neutrophil gelatinase-associated
lipocalin in gastric cancer: a potential biomarker for prognosis and an ancillary
diagnostic test. Anat Rec (Hoboken). 2010;293:18551863. [
83. Krysan K, Cui X, Gardner BK, et al. Elevetated neutrophil-associated lipocalin
contributes to erlotinib resistance in non small cell lung cancer. Am J Transl. Res
2013;5 (5); 481-496.

, 76, 1, 2014 984



.
, &

:
: 2132045553
E-mail: skorfias@otenet.gr

-.

: 1) , 2)
3)
.

: )
, )
, )
,
) (, ,
, )
.
: i)
ii)
: , ,
, , , ,
, , , ,
..

, 76, 1, 2014 985

 -,
, ,
.

, 76, 1, 2014 986

 :

. 1, . 2, . 3
1
. 2
3
,
, ...
.

:

: 2107229250
E-mail: stranjal@otenet.gr

, , , -
, .
, , ,
.
.
()
, () , ()
()
(, , , ).
/
/ .
, 76, 1, 987-999, 2014.
: , , ,

SUMMARY
STRANJALIS G, KORFIAS S, LIOUTA E. Contemporary Management of
Intracranial Tumors Intracranial tumors present with certain clinical, imaging, surgical
and histological peculiarities. In contrast with other tumors, the total or subtotal
resection depends not only on their histological origin, but also on their localization.
Very often Neurosurgery is confronted with patients who sustain benign tumors in
eloquent areas and hence no prospect of total resection. In this review we present the
clinical, imaging and surgical characteristics of the most frequent intracranial tumors.
Moreover, we describe the current progress in the preoperative neuropsychological
diagnosis, the new structural and functional neuro-imaging techniques, the surgical
management (intraoperative imaging) and the other therapeutic modalities such as
, 76, 1, 2014 987
radiotherapy, chemotherapy, and brachytherapy. The above contemporary-
comprehensive management of brain tumors offers an early and precise diagnosis, as
well as, a safer surgical approach, both of which are essential for an improved clinical
outcome. Nosokomiaka Chronika, 76, Supplement 1, 987-999, 2014.
Key words: brain tumors, intracranial tumors, CNS tumors, neurosurgery

. ,
, ,

1-7. ,

.. , , ,
.
.
,
, .
,
, ,
, . ,
7-10 2000 - 2500
( )
.

1,2,4-10
() : 50 %
(, ,
, , , ), ()
: 20 %, () : 10 % (
), () : 8-9 %, () : 4-5 %, )
: 5 % (, , , ,
, , , , .)

1,11-22

, 76, 1, 2014 988


.
.

, , ,
, , , , ,
.
.. ()
(), ,
, .

( , , ,
, -, ) ( /
, / , -, ),
.

(, , , ,
, , , ).

,
. ,
, , .


(, ) 3,23-25.

(fMRI)
24,25.

(
, )
.

, 76, 1, 2014 989

 ,
, fMRI,
,

.
,


3,4. ,
.

.
,
.

, 3,4,24,25.

12,26

, .
, ,
.
, -
( )
,
.
. ()

.
,

, ,
-,
,
,

, 76, 1, 2014 990

 ,
(, , ).
.

. ,
, .

2,11,23-28


,

23-26. ,
. , ,
,
,
. , ,
,
,
, (..
, - )2,23,24,27,28.

. ( ,
)
.
, ,


(image-guided neurosurgery). ,
,
( , ),
( -, -
,
).

, 76, 1, 2014 991

 1,2,3,13,18-20,23,27,28,
( 50 %
)
1,4.
, , ,
.
( )
( )
.
, ,
. (
), -
( ).

1,2,4-8,29.
4-8,10,30,31. 1,10,32,33,34-36.
.

1,2,7,19,28.
(low-grade) ,
4-
6,31,32,34,37-39
. 2.5-5 %,
7-15 %34,39.
, :
,


(, 22,29,
-Gliadel30-32 -
2,33,34,37,38).

1,2,4-6
8-12 % .

. ,

, 76, 1, 2014 992


,
.
,
,
, ,
. ,
,
. ,

( ).

, :


.

(41 %). (12 %), (11 %), (9 %),
(7 %).
.
.
2 . ,
( )
(Ommaya Rickham),
.

1,4-6
15-20 %
9,10,39,40.
..
(, )39,40. .
, ,
.
(< 3 cm)
( knife).

, 76, 1, 2014 993

, .

35,36.

1,2,4-10
-


(-, , Cushing),
,
. - .
-
(-), (
) ( Cushing).
, ,
.
( 2-3 ) ( ),
,
.
.
,
,
,

. 1 % .
.
(, ,
). ,
( )
1-6.

(
Schwann).
( ).

, 76, 1, 2014 994

 4 % .
80-90 .
, ,
, .

3-4 .
, ,
(7 ),
.
60-70 %
30 % .
2.5-3 .

,
. 2
. , ,
1,2,4-6.
3 .

1 % . 20 %
.
, (60 %),
(germinomas)
. , ,
, , .
.
Sylvius

.
,
.
(
).
1,2,4-6.

, 76, 1, 2014 995

 () .
1 % .
, .
1,2,4-6.
() .
( 50% ).

. 2 3 1,2,4,5.
() .
.
3 100 % 3. 5
50-60 %.
,
1,2,4,5.
() . .
. ,
. ,
1,2,6-8.

, , ,

( , , )

,
,
/ ,
, ( -knife,
cyberknife x-knife), , ,

.

1. Sherman GH, Hoes K. Neurosurgery for brain tumors. Update on recent

technological advances. Curr Neurol Neurosci Rep 2011;11:313-391.

, 76, 1, 2014 996

2. Vassal M, Rigau V, Duffau H. Surgical management of diffuse low-grade gliomas.
Acta Neurochir 2013;10:200-212.
3. Duffau H. The huge plastic potential of adult brain. New insights in glioma surgery.
Cortex 2013;15:1-13.
4. Youmans D: Neurological Surgery. Tumors. 4th Edition. Saunders. Volume IV.
2493-3188, 2011.
5. Lindsay K, Bone I: Neurology and Neurosurgery Illustrated. 3rd Edition. Churchill
Livingstone, 1997.
6. Kaye A, Black P: Operative Neurosurgery. Tumors. 1st Edition. Churchill-
Livingstone. Volume I-II. 2000.
7. De Angelis: Medical Progress: Brain Tumors. Review articles. N Eng J Med
2001;344:114-123.
8. Kleihues P, Cavenee WQ: eds. Pathology and genetics of tumors of the nervous
system. WHO classification of tumors. Lyon, France: IARC Press, 2000.
9. Surawicz TS, McCarthy BJ, et al: Descriptive epidemiology of primary brain and
CNS tumors: Results from the Central Brain Tumor Registry of the United States,
1990-1994. Neurooncol 1999;1:14-25.
10. Radhakrishnan K, Mokri B et al: The trends in incidence of primary brain tumors in
the population of Rochester, Minnesota. Ann Neurol 1995;37:67-73.
11. Patel TR, Yu JB, Piepmeier JM. Role of neurosurgery and radiation therapy in the
management of brain tumors. Hematol Oncol Clin North Am 26:757-77, 2012
12. Forsy PA, Posner JB: Headaches in patients with brain tumors: a study of 111
patients. Neurology 1993;30:211-216.
13. Scott JN, Rewscatle NB: Which glioblastoma multiform patient will become a long-
term survivor? A population-based study. Ann Neurol 1999;46:183-188.
14. Bampoe J, Bernstein M.:The role of surgery in low grade gliomas. J Neurooncol
1999;42:259-269.
15. Recht LD, Lew R, Smith TW: Suspected low grade glioma: is deferring treatment
safe? Ann Neurol 2000;31:431-436.
16. Karim ABMF, Maat B, et al: A randomized trial on dose response in radiation
therapy of low-grade cerebral glioma: European Organization for Research and
Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys
1996;36:549-556.
17. Karim ABFM, Cornu P, et al: Immediate postoperative radiotherapy in low grade
glioma improves progression free survival, but not overall survival: preliminary

, 76, 1, 2014 997

 results of an EORTC / MRC randomized phase III study. Prog Proc Am Soc Clin
Oncol 1998;17:400.
18. Hess KR: Extent of resection as a prognostic variable in the treatment of gliomas. J
Neurooncol 1999;42:227-231.
19. Fadul C, Wood J, Thaler H, et al: Morbidity and mortality of craniotomy for excision
of supratentorial gliomas. Neurology 1988;38:1374-1379.
20. McCormack BM, Miller DC, et al: Treatment and survival of low grade astrocytoma
in adults 19771988. Neurosurgery 1992;31:636-642.
21. Bauman G, Lote K, et al: Pretreatment factors predict overall survival for patients
with low-grade glioma: a recursive partitioning analysis. Int J Radiat Oncol Biol
Phys 1999;45:923-929.
22. Suh JH, Barnett GH: Brachytherapy for brain tumor. Hematol Oncol Clin North Am
1999;13:635-650.
23. DeWitt Hamer PC, Robles SG. Impact of intraoperative stimulation brain mapping.
J Clin Oncol 2012;30:2559-2565.
24. Beez T, Boge K, Wager M, et al. Awake surgery for gliomas. Acta Neurochir
2013;155:1301-1308.
25. Klein M, Duffau H, DeWitt Hamer PC. Cognition and resective surgery for diffuse
glioma. J Neurooncol 2012;108:309-318.
26. Kuhnt D, Bauer M, Ganslandt O. Functional imaging:where do we go from here ?.
J Neurosurg Sci 2013;57:1-11.
27. Sanai N, Berger M. Glioma extent of resection and outcome. Neurosurgery
2008;62:752-765.
28. Terakawa Y, Yordanova YN, Tate MC et al. Surgical management of multicentric
low-grade gliomas: functional and oncological outcome. J Neurosurg
2013;118:1169-1175.
29. Tokuuye K, Akine Y, et al: Fractionated Stereotactic radiotherapy of small
intracranial malignancies. Int J Radiat Oncol Biol Phys 1998;42:989-994.
30. Fine HA, Dear KB, Loffler JS, et al: Meta-analysis of radiation therapy with and
without adjuvant chemotherapy for malignant gliomas in adults. Cancer
1993;71:2585-2597.
31. De Angelis LM, Burger PC, et al: Malignant glioma: who benefits from adjuvant
chemotherapy? Ann Neurol 1998;44:691-695.

, 76, 1, 2014 998

32. Huncharek M, Muscat J, et al: Multi-drug versus single agent chemotherapy for
high grade astrocytoma: results of a meta-analysis. Anti-cancer Res 1998;18:4693-
4697.
33. Ram Z, Culver KW, et al: Therapy of malignant brain tumors by intratumoral
implantation of retroviral vector-producing cells. Nat Med 1997;3:1354-1361.
34. Reardon DA, Akabani G, Coleman RE et al: Phase II trial of murine I-labeled
antitenascin monoclonal antibody administered into surgically sreated resection
cavities of patients with malignant glioma. J Clin Oncol 2002;20:1389-1397.
35. Brainstein JB: Meningiomas: the decision not to operate. Neurology 1997;48:1459-
1462.
36. Chamberlain MC: Adjuvant combined modality therapy for malignant meningiomas.
J Neurosurg 1996;84:733-736.
37. Dunn I, Black P: The Neurosurgeon as local oncologist: Cellular and molecular
neurosurgery in malignant glioma tyherapy. Neurosurgery 2003;52:1411-1424.
38. Rand RW, Kreitman RJ, Patronas N, et al: Intratumoral administration of
recombinant interleukin in patients with high-grade glioma. Clin Cancer Res
2000;6:2157-2165.
39. Bondy M, Ligon BL. Epidemiology and etiology of intracranial meningiomas: a
review. J Neurooncol 1996;29:197-205.
40. Kleihues P, Burger PC, et al: Histological typing of tumors of the central nervous
system. 2nd ed. Berlin, Germany: Springer-Verlag, 1993.

, 76, 1, 2014 999



' , , ,
, ...

:
o: 2132041072
E-mail: tkratimenos@gmail.com

5%-10% 65-
79

, 5%.

,
, - ,
, ,
30- (1%-2%).
,
, ,
( )
.


. , 76,
1, 1000, 2014.
: ,

, 76, 1, 2014 1000