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British Journal of Anaesthesia 109 (2): 2539 (2012)

Advance Access publication 15 June 2012 . doi:10.1093/bja/aes176


Can regional anaesthesia for lymph-node dissection improve

the prognosis in malignant melanoma?
A. Gottschalk 1*, G. Brodner 2, H. K. Van Aken 1, B. Ellger 1, S. Althaus 1 and H.-J. Schulze 3
Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Munster, Munster, Germany
Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy and 3 Department of Dermatology, Hornheide Specialist
Hospital, Munster, Germany
* Corresponding author: Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Munster, Albert-Schweitzer-
Campus 1, Building A1, 48149 Munster, Germany. E-mail:

Background. Optimized anaesthetic management might improve the outcome after cancer
Editors key points surgery. A retrospective analysis was performed to assess the association between spinal
Understanding the anaesthesia (SpA) or general anaesthesia (GA) and survival in patients undergoing
impact of anaesthetic surgery for malignant melanoma (MM).
technique on cancer Methods. Records for 275 patients who required SpA or GA for inguinal lymph-node dissection
survival is important. after primary MM in the lower extremity between 1998 and 2005 were reviewed. The follow-up
There is some evidence ended in 2009. Survival was calculated as days from surgery to the date of death or last
that regional techniques patient contact. The primary endpoint was mortality during a 10 yr observation period.
may improve long-term Results. Of 273 patients included, 52 received SpA and 221 GA, either as balanced
outcomes after cancer anaesthesia (sevoflurane/sufentanil, n118) or as total i.v. anaesthesia (propofol/
surgery. remifentanil, n103). The mean follow-up period was 52.2 (SD 35.69) months after
This retrospective study operation. Significant effects on cumulative survival were observed for gender, ASA
of malignant melanoma status, tumour size, and type of surgery (P0.000). After matched-pairs adjustment, no
patients found a differences in these variables were found between patients with SpA and GA. A trend
non-significant trend for towards a better cumulative survival rate for patients with SpA was demonstrated [mean
improved survival after survival (months), SpA: 95.9, 95% confidence interval (CI), 81.2110.5; GA: 70.4, 95% CI,
spinal anaesthesia. 53.6 87.1; P0.087]. Further analysis comparing SpA with the subgroup of balanced
While there are volatile GA confirmed this trend [mean survival (months), SpA: 95.9, 95% CI, 81.2 110.5;
limitations in a volatile balanced anaesthesia: 68.5, 95% CI, 49.6 87.5, P0.081].
retrospective study, this Conclusions. These data suggest an association between anaesthetic technique and cancer
important area clearly outcome in MM patients after lymph-node dissection. Prospective controlled trials on this
warrants further topic are warranted.
Keywords: anaesthesia, general; anaesthesia, spinal; melanoma; surgery; survival
Accepted for publication: 5 March 2012

Cancer is a heterogeneous disease. In most cases, surgeons a high risk of tumour cells spreading during this period.3
can successfully remove the primary tumour, but a large pro- Both cell-mediated and humoural immune responses are ad-
portion of cancer-related deaths are due to the development versely affected by general anaesthesia (GA) and surgical
of metastases rather than directly related to the primary trauma, and this may result in tumour progression. In vitro
cancer. Potentially, curative surgery may contribute to meta- studies have shown dose-dependent alterations in neutro-
static spread: it suppresses the immune system, facilitates phil, monocyte, and lymphocyte functions after exposure to
the growth of pre-existing micrometastases, and allows ma- different anaesthetics.3
lignant cells to disseminate during tumour manipulation.1 2 Spinal anaesthesia (SpA), which for most operations in the
Preventing immunosuppression during the immediate post- lower body provides very good analgesia, attenuates the sur-
operative period might be extremely important, as there is gical stress response and prevents inhibition of the immune

These authors contributed equally to this paper.

This article is accompanied by Editorial III.

& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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BJA Gottschalk et al.

system. In an animal model, it has been shown that innate accordance with DIN EN ISO 9001/2000 as a centre for the
tumour immunity is impaired through inhibition of the cyto- treatment of skin cancer. The melanoma team consists of a
toxic Th1 response of hepatic mononuclear cells after lower combination of specialists, including surgeons, dermatologists,
abdominal surgery. Spinal block attenuates this impairment, pathologists, medical oncologists, and also anaesthesiologists.
thereby inhibiting the promotion of metastatic spread after The hospitals Department of Medical Documentation is re-
surgery.4 5 sponsible for maintaining the database of primary and follow-
A survival analysis of patients with malignant melanoma up information on patients tumour status.
(MM) showed an improved survival rate after primary excision After the primary operation, patients receive annual
of the malignant tumour under local anaesthesia in compari- follow-up examinations, which include an interview, physical
son with GA.6 Sole use of local anaesthesia is, however, often examination, ultrasound of the lymph nodes, and if neces-
not possible in various types of surgery. In addition, there sary a computed tomography scan. If patients do not
have been no prospective clinical trials so far that have appear for the annual follow-up appointment, their family
been adequately powered to assess long-term survival rela- or family practitioner is contacted to obtain information
tive to different anaesthetic techniques, and no definitive about the patients health status.
conclusions can therefore be drawn. An electronic database (megaMANAGER, 2008
The prognostic impact of the type of anaesthesia used for version; megapharm Ltd, St Augustin, Germany) was used
excision of malignant tumours is thus currently a matter of to determine baseline variables (for patient characteristic
controversy. The present retrospective study was therefore factors, tumour, physical condition, risk factors for survival),
carried out to allow improved hypothesis formation regard- surgical variables, and follow-up variables in all patients
ing the long-term effects of anaesthesia. The aim of the treated for MM. The patients charts were also screened for
study was to assess the association between SpA or GA additional information if necessary. The type of anaesthesia
and cancer survival after lymph-node dissection in patients was recorded from the original anaesthesia charts. The
with MM. It was hypothesized that the use of SpA would patients underwent surgery either under SpA with 2.53.0
improve the survival rate in these patients. ml hyperbaric bupivacaine 0.5% or GA. GA was administered
as balanced volatile anaesthesia using isoflurane and sufen-
Methods tanil, or as total i.v. anaesthesia with continuous infusions of
propofol and remifentanil.
After ethical approval for the retrospective study had been
All data were transferred to the SPSS program for statistic-
received (from the ethical committee of the Medical
al analysis (IBM SPSS Statistics, PASWPredictive Analytics
Council of Westphalia-Lippe and from the Medical School of
Software, version 18). The following potential confounders
the University of Munster, Germany), records were reviewed
were tested in the statistical analyses to identify any signifi-
for all patients who had required anaesthesia for inguinal
cant differences between SpA and GA:
lymph-node dissection after primary MM in the lower extrem-
ity between February 1998 and April 2005 at the Department Baseline variables: age, gender, BMI, smoking status,
of Anaesthesia, Intensive Care and Pain Medicine, Hornheide alcohol abuse, ASA status.
Hospital, Munster, Germany. The follow-up period ended in Medical history: myocardial infarction, coronary artery
May 2009. disease, arrhythmias, hypertension, chronic obstructive
A total of 353 surgical records were reviewed. The proce- pulmonary disease (COPD), diabetes, renal insufficiency,
dures included 247 sentinel lymph-node biopsies (SLNBs) liver diseases, coagulopathies, and immunosuppression.
and 101 complete lymph-node dissections (CLNDs), and the Tumour stage: tumour thickness, tumour ulcerations.
type of surgery could not be determined in five records. American Joint Committee on Cancer (AJCC) classifica-
These five operations were excluded from further analyses. tion: Stage 0 melanoma involves the epidermis, but has
Seventy-three operations were identified as duplicatesthat not reached the underlying dermis melanoma in situ.
is, with SLNB followed by CLND in the same patient. In these Stage I melanoma is characterized by tumour thick-
duplicates, the SLNB was excluded and only the CLND was ness, presence and number of mitoses, and ulceration
used for analysis. Records for a total of 275 cases were thus status. There is no evidence of regional lymph-node
analysed: 174 SLNBs (247 73) and 101 CLNDs. Two patients metastasis or distant metastasis. Stage II melanoma
were excluded due to incomplete data sheets lacking import- is characterized by tumour thickness and ulceration
ant information, and 273 patients remained for the final ana- status. There is no evidence of regional lymph-node
lyses. Fifty-two patients received SpA and 221 underwent metastasis or distant metastasis. Stage III melanoma
surgery with GA. GA was administered either as balanced GA is characterized by the level of lymph-node metastasis.
(n118) or as total i.v. anaesthesia (n103) (Fig. 1). There is no evidence of distant metastasis. Stage IV
Hornheide Specialist Hospital is the main national cancer melanoma is characterized by the location of distant
institute for the treatment of skin malignancies in Germany metastases and the level of serum lactate dehydrogenase.
and is one of the major institutes for this type of cancer in Postoperative variables: signs of infection, use of anti-
Europe. The hospital incidence of MM amounted to more biotics, seromas, repeat surgery.
than 1000 patients in 2009. The centre has been certified in Long-term variables: additional malignancies.

Regional anaesthesia and cancer prognosis BJA

Kind of surgery n = 353

SLNB CLND No information

n = 247 n = 101 n=5

Duplicates: Primary cases:

SLNB followed by CLND Only SLNB
n = 73 n = 174
Number of cases

n = 275

Complete data set missing data

n = 273 n=2

Spinal anaesthesia General anaesthesia

Type of anaesthesia

n = 52 n = 221

Balanced volatile anaesthesia Total intravenous anaesthesia

n = 118 n = 103

Fig 1 Flow diagram presenting the enrolment, intervention allocation, and data analysis with numbers of patients in each group. SLNB, sen-
tinel lymph-node biopsy; CLND, complete lymph-node dissection.

Statistics SpA subgroup. The KaplanMeier analysis and subsequent

The primary endpoint of the study was mortality during a log-rank tests were done to compare the survival rate of
postoperative observation period of 10 yr. Survival was calcu- patients in the two groups.
lated as the number of days from the date of surgery to the The following alternative hypothesis was tested in the
date of death or last contact with the patient. matched-pairs analysis: the long-term survival rate after in-
Nominal scale variables were described using relative and guinal lymph-node dissection in MM is different for patients
absolute frequencies. Variables with interval or higher-scale undergoing surgery in SpA in comparison with GA (H0: mgeneral
levels were described as means and standard deviation. anaesthesia mspinal anaesthesia; H1: mgeneral anaesthesia =mspinal

Patient characteristic and physiological basic data were com- anaesthesia). To reduce the risk of type I error, no direction for

pared using Students t-test, the x 2 test, or Fishers test, as the difference was defined, statistical tests were two-tailed,
appropriate. Survival was analysed in two steps using the and a P-value of 0.05 was regarded as significant.
KaplanMeier curves and subsequent log-rank tests.
In the first step, the overall group was analysed for vari- Results
ables that might confound the effects of anaesthesia on sur- A total of 273 patients who required anaesthesia for inguinal
vival. The following variables were included: type of surgery, lymph-node dissection after primary MM in the lower extrem-
tumour thickness, gender, and ASA status. In the second ity between February 1998 and April 2005 at the Department
step using these variables, matched pairs of patients with of Anaesthesia, Intensive Care and Pain Medicine, Hornheide
SpA and GA were built for further statistical analyses. This Specialist Hospital, Munster, Germany, were included in this
was due to the small study group of only 52 patients in the analysis. The follow-up ended in May 2009. The mean follow-up

BJA Gottschalk et al.

time for all patients was 52.2 (SD 35.69) months (with a spontaneously recognize and kill malignant cells. NK cell sup-
minimum of 0 months for patients who died within the first pression is also associated with increased rates of metasta-
month after operation, and a maximum of 122 months for sis. Studies in humans have also shown that low
patients who survived for the whole study period). perioperative levels of NK cell activity are associated with
After testing for confounders of the effects of the type of increased cancer-related morbidity and mortality.8 9
anaesthesia on long-term survival, x 2 analyses comparing The specific anaesthesia approach used is likely to be of
the SpA group (n52) and the GA group (n221) did show relevance, as animal studies have shown that the choice of
a significant difference with regard to gender (P0.021), anaesthetic drugs and techniques has a profound influence
ASA status (P0.004), arrhythmias in the medical history on the immune response and, as a result, on cancer metas-
(P0.033), or coagulopathies (P0.008). There were no sig- tasis.3 In particular, regional anaesthesia, including SpA,
nificant differences with regard to tumour stage, post- reduces the stress response caused by surgery, which is
operative surgical complications, or long-term variables believed to be a mediator of postoperative immunosuppres-
(Tables 13). Patients in the GA group were significantly sion.10 12 This prevents noxious afferent input from reaching
younger than those in the SpA group (P0.003). In addition, the central nervous system. In addition, SpA avoids inhaled
the duration of surgery (P0.026) and hospital stay anaesthetics and reduces the opioid requirements, both of
(P0.007) were significantly longer for patients in the GA which have been shown to decrease the activity of NK
group in comparison with the SpA group (Tables 1 and 3). cells. SpA also effectively blunts the neuroendocrine re-
The Kaplan Meier analysis showed that patients with sponse and thus decreases the production of catechola-
SLNBs had a significantly longer survival in comparison mines, which reduce NK cell activity.3 In a mouse model,
with patients with CLNDs (P0.000). Patients with a higher for example, it has been shown that laparotomy during sevo-
ASA class had a significantly higher risk for a shorter survival flurane anaesthesia significantly increased the number of
after surgery, as did male patients and patients with a liver metastases in comparison with sevoflurane anaesthesia
greater tumour thickness (all P0.000). plus SpA.4 The addition of intrathecal local anaesthetics atte-
Using these variables (type of surgery, ASA status, tumour nuated the suppression of tumoricidal function in hepatic
thickness, gender), matched pairs of the 52 patients with SpA mononuclear cells and thereby reduced tumour metastasis.4
and 52 corresponding patients with GA were built and tested Data from retrospective studies in humans have demon-
once again for the following variables: age, gender, BMI, strated that the long-term outcome for patients undergoing
smoking, alcohol abuse, ASA status, medical history (myocar- cancer surgery is improved if they receive a neuraxial or re-
dial infarction, coronary artery disease, arrhythmias, hyper- gional block. Exadaktylos and colleagues13 reported that
tension, diabetes, COPD, renal insufficiency, liver diseases, the use of paravertebral nerve block in combination with
coagulopathies, immunosuppression), tumour stage GA was associated with a longer cancer-free interval and a
(tumour thickness, tumour ulcerations, AJCC classification), lower incidence of recurrence in patients with breast
postoperative variables such as signs of infection, use of anti- cancer. Another retrospective trial was able to show that
biotics, seromas, and repeat surgery. No significant differ- the epidural technique was associated with a 65% reduction
ences between the groups now remained. However, in biochemical recurrences of prostate cancer, as defined by
differences in the duration of surgery [SpA 59.00 min (SD increased prostate-specific antigen after operation.14 In con-
20.59), GA 71.00 min (SD 35.77) (P0.039)] and length of hos- trast to these results, the use of epidural analgesia for peri-
pital stay [SpA 16.08 days (SD 9.91), GA 21.58 (SD 12.09) operative pain control during colorectal cancer surgery was
(P0.013)] remained significant. not found to be associated with a decreased rate of cancer
A trend towards longer survival in patients in the SpA recurrence; a potential benefit was observed in older
group was now detected [mean survival time for SpA: 95.9 patients.15 These findings suggest that the benefit of region-
months; 95% confidence interval (CI), 81.2 110.5 months; al anaesthesia relative to cancer recurrence, if it exists, may
GA: 70.4 months; 95% CI, 53.6 87.1 months; P0.087] depend critically on the specific cancer type. However, no
(Fig. 2). clinical trials have been conducted to investigate the
effects of SpA on the long-term outcome after cancer
surgery. The data obtained in the present study may
Discussion suggest that SpA perioperatively may improve the long-term
The results of this retrospective study of patients undergoing prognosis for patients with MM. However, only prospective
lymph-node dissection after MM are in accordance with the randomized trials can fully address the relationship
hypothesis that surgery with SpA might improve the long- between regional analgesia and cancer recurrence.
term prognosis in patients with MM. In principle, two different models of cancer are at issue
Animal studies have indicated that immune-response here. On the one hand, the existence of a metastatic
control over the circulation of tumour cells and micrometas- cascade has been proposed, with a number of sequential
tases takes place mainly through cell-mediated immunity. events being required for disseminated cancer to develop.16
The main cell types involved are cytotoxic T lymphocytes, The idea behind this concept is that tumour cells migrate
natural killer (NK) cells, NK T cells, dendritic cells, and macro- through the lymphatic vessels to the lymph nodes and
phages. 7 NK cells are particularly important, as they can then disseminate to distant sites. On the other hand,

Regional anaesthesia and cancer prognosis BJA

Table 1 Patient characteristic data, type of anaesthesia used, and Table 1 Continued
preoperative physical condition
Spinal General P-value
Spinal General P-value anaesthesia anaesthesia
anaesthesia anaesthesia
.6 months 2 (3.8) 8 (3.6)
Gender 0.021 ,6 months 0 (0) 3 (1.4)
Male (%) 24 (46.2) 64 (29.0) Immunosuppression 1.000
Female (%) 28 (53.8) 157 (71.0) (%)
Age (yr) mean (range 58.13 (32/86) 50.64 (4/93) 0.003 No 52 (100) 218 (98.6)
min/max) .6 months 0 (0) 3 (1.4)
ASA classification (%) 0.004 ,6 months 0 (0) 0 (0)
I 7 (13.5) 57 (25.8) Smoking (%) 0.345
II 34 (65.4) 148 (67.0) No 44 (84.6) 172 (77.8)
III 10 (19.2) 16 (7.2) Yes 8 (15.4) 49 (22.2)
IV 1 (1.9) 0 (0) Alcohol consumption 0.179
Coronary artery 0.053 (%)
disease (%) ,1week 45 (86.5) 204 (92.3)
No history 45 (86.5) 211 (95.5) Weekend 1 (1.9) 8 (3.6)
Minimal risk 3 (5.8) 5 (2.3) .1week 1 (1.9) 2 (0.9)
High risk 4 (7.7) 5 (2.3) Daily 5 (9.6) 7 (3.2)
History of myocardial 1.000
infarction (%)
No 51 (98.1) 215 (97.3)
.6 months 1 (1.9) 6 (2.7) Table 2 Oncological data
,6 months 0 (0) 0 (0)
Arrhythmia (%) 0.033 Spinal General P-value
No history 49 (94.2) 217 (98.2) anaesthesia anaesthesia

Bradycardia 0 (0) 1 (0.5) Tumour thickness 1.00

Pacemaker 0 (0) 2 (0.9) (%)

Ventricular 1 (1.9) 1 (0.5) ,2 mm 25 (48.1) 105 (47.5)

arrhythmia 2 mm 27 (51.9) 116 (52.5)
Atrial fibrillation 2 (3.8) 0 (0) Tumour ulcerations 0.321
Hypertension (%) 0.474 (%)

No 37 (71.2) 169 (76.5) No 33 (63.5) 156 (70.6)

Yes 15 (28.8) 52 (23.5) Yes 19 (36.5) 65 (29.4)

Coagulopathy (%) 0.008 AJCC classification 0.472

No history 50 (96.2) 216 (97.7)
No data 0 (0) 1 (0.4)
Over 6 months 0 (0) 5 (2.3)
previously IA 1 (1.9) 6 (2.7)

Within the last 6 2 (3.8) 0 (0) IB 19 (36.5) 70 (31.7)

months IIA 8 (15.4) 39 (17.6)
COPD (%) 0.592 IIB 11 (21.2) 22 (10.0)
No 48 (92.3) 208 (94.1) IIC 2 (3.8) 8 (3.6)
Dyspnoea during 4 (7.7) 11 (5.0) IIIA 5 (9.6) 27 (12.2)
stress IIIB 3 (5.8) 26 (11.8)
Dyspnoea during 0 (0) 2 (0.9) IIIC 3 (5.8) 22 (10.0)
rest IV 0 (0) 0 (0)
Renal failure (%) 0.085 Additional 1.000
No 49 (94.2) 218 (98.6) malignancies (%)
Compensated 3 (5.8) 3 (1.4) No 52 (100) 217 (98.2)
retention Yes 0 (0) 4 (1.8)
Liver failure (%) 1.00
No 52 (100) 220 (99.5)
Yes 0 (0) 1 (0.5)
Diabetes mellitus (%) 0.699 Paget17 proposed the seed and soil hypothesis in order to
No 50 (96.2) 210 (95.0) explain the unusual organ-specific metastatic pattern.
According to the seed and soil theory, which appears to
Continued reflect clinical reality better, metastaseseven from small

BJA Gottschalk et al.

tumoursmay be initiated before the primary tumour is

Table 3 Surgical information diagnosed. The growth of the primary tumour and the
Spinal General P-value
process of metastasis may thus be two autonomous pro-
anaesthesia anaesthesia cesses. In that case, perioperative compromise of the
Duration of 59.00 (20.59) 68.72 (29.57) 0.026
immune system might be fatal, as it might promote the
surgery (min) (SD) growth of micrometastases in distant organs.
status (%) Limitations of the study
Wound infection 0.839 Potential weaknesses of this study, which is retrospective in
No 44 (84.6) 182 (82.4) nature, might be inaccuracies in the written records, with
Yes 8 (15.4) 39 (17.6) important data missing, and the difficulty of controlling
Use of 0.168 bias and confounders. For example, differences in surgical
antibiotics time and hospital stay might be caused by confounders
No 42 (80.8) 156 (70.6) that were not recorded. The results of this study have there-
Yes 10 (19.2) 65 (29.4) fore been used to generate hypotheses and will require con-
Seromas 0.285 firmation with further prospective studies. To minimize the
No 47 (90.4) 184 (83.3) risk for a-error, an alternative hypothesis for a two-sided
Yes 5 (9.6) 37 (16.7) test was selected for statistical analyses. To compensate
Repeat surgery 1.000 for this, a matched case control study design was chosen
No 51 (98.1) 217 (98.2) to adjust for potential confounders and to increase the pre-
Yes 1 (1.9) 4 (1.8) cision of the comparison. The poor prognosis in patients
Hospital stay 16.08 (9.91) 20.81 (11.58) 0.007 with MM, particularly with positive lymph nodes, may also
(days) (SD)
have masked true benefits of regional anaesthesia.18 19
However, this is the largest study to date providing
support for the view that the use of SpA in patients


Type of anasthesia
1: spinal
2: general
1: censored
2: censored
Cumulative survival





0 20 40 60 80 100 120


Fig 2 Kaplan Meier survival curve after adjustment of matched-pairs samples: SpA vs GA.

Regional anaesthesia and cancer prognosis BJA
presenting with MM and undergoing inguinal lymph-node 5 Bar-Yosef S, Melamed R, Page GG, Shakhar G, Shakhar K,
dissection may improve the long-term outcome. Ben-Eliyahu S. Attenuation of the tumor-promoting effect of
The study is not capable of revealing any potential mech- surgery by spinal blockade in rats. Anesthesiology 2001; 94:
1066 73
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6 Schlagenhauff B, Ellwanger U, Breuninger H, Stroebel W,
MM. Long-term prospective studies will be required before it
Rassner G, Garbe C. Prognostic impact of the type of anaesthesia
can be determined whether the choice of anaesthesia tech- used during the excision of primary cutaneous melanoma. Melan-
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9 Brittenden J, Heys SD, Ross J, Eremin O. Natural killer cells and
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10 Freise H, Van Aken HK. Risks and benefits of thoracic epidural
term survival and risk of cancer recurrence will be studied. anaesthesia. Br J Anaesth 2011; 107: 859 68
The data presented here suggest that after lymph-node 11 Liu SS, Block BM, Wu CL. Effects of perioperative central neuraxial
dissection, there may be an association between the anaes- analgesia on outcome after coronary artery bypass surgery: a
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Declaration of interest
13 Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can
None declared. anesthetic technique for primary breast cancer surgery affect re-
currence or metastasis? Anesthesiology 2006; 105: 660 4
Funding 14 Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ.
Anesthetic technique for radical prostatectomy surgery affects
The study was supported solely by departmental funding. cancer recurrence: a retrospective analysis. Anesthesiology
2008; 109: 180 7
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