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Detection of Doxorubicin Cardiotoxicity in

Patients with Sarcomas by Indium-ill
Antimyosin Monoclonal Antibody Studies
Ignasi Carrió, Antonio Lopez-Pousa, Montserrat Estorch, David Duncker, Lluis Bemá,Gustavo Tones and
Luis de Andrés

Departmentr ofNuclear Medicine and Medical Oncolo@, Hospital de Sant Pau, Barcelona, Spain

is widely used to treatthese tumorswith variabledoses and

Toassess myocardialcelldamagedueto doxorubicsn cardiotox administration regimens. Bolus injection every 3 wk up to
icity,we prospectivelystudied30 patientswith sarcomaswho the classic safe cumulative dose of 450 mg/in2is the most
were receMngchemotherapy,indudingdoxorubicin.Sixteen common regimen of administration. Continuous infusion of
patientsweretreatedby continuousinfusionover72 hr and 14 doxorubicin over 72 hr is an alternative method, which
patientsweretreatedby bolusinjection.Antimyosinstudiesand may reduce the incidence of congestive heart failure and
leftventricularejectionfraction(LVEF)measurementswereper may permit the administrationof higher cumulative doses
formedbeforechemotherapyandat intermediateandmaximal
(1,2).
cumulativedoses.MyOcardial antimyosinuptakewasquantified
by a heart-to-lung ratio (HLR). Myocardial antimyosin uptake
Cardiotoxicity is the most deleterious effect of this drug.
@ was observedin all patientsat 240-300 mg/ms ejection Its appearance may produce irreversible and often fatal
fractionwas still maintained.Sevenpatientspresentedwith a congestive heart failure, thus limitingthe total cumulative
decreaseof 10%inabsoluteejectionfractionunitsat420-600 dose achievable (3—5).Detection of cardiotoxicity is there
mg/rn2.Fryeof these patients had mildcongestive heart fallure.
fore crucial in the managementof these patients and serial
Al patientswho presentedwitha decreasein LVEF 10%at ejection fraction measurements have become the standard
420-600 mg/rn2hadincreasedantimyosinuptakewithHLR method to monitor these patients during chemotherapy.
I .90 at a cumulative dose of 240-300 mg/me. p@fi@e@wI@
Chemotherapy is usually discontinued ifthere is a decrease
weretreatedwith continuousinfusionhad lessantim@sinup
in 10 absolute ejection fractionunits to an ejection fraction
take than those who were treatedwifi, bolus administration
(mean HLR of 1.70 ±0.09 versus HLR of 2.01 ±0.16 at a
of 40%or less (6). With use of this strategy, incidence and
cumulativedoseof 240-300 mg/rn2,p < 0.01; HLRof 1.86 ± severity of heart failure can be significantly reduced. How
0.12 versus HLR of 2.32 ±0.34 at a cumulative dose of 420- ever, a more sensitive method capable to identify patients
@ 600mg/me, < 0.01).Twoof 16patientstreatedbycontinuous at risk of significantejectionfractiondeteriorationduring
infusionand5 of 14patientstreatedbybolusinjectionpresented chemotherapy could still be useful, because these patients
witha decreasein ejectionfraction 10%.LVEFafterchemo could benefit from changes in the schedule of administra
therapyin the infusiongroupwas 56% ±5% and 48% ±8% tion to avoid heart failure.
(p < 0.05)in the bolusgroup.Antimyosinstudiesare helpfulin Indium-111-antiinyosinantibody studies allow in vivo
theassessmentofdoxorubidncardiotoxicity. Intenseantimyosin noninvasive detection of myocardial damage. Binding
uptakeat intermediatecumulativedosesidentifiespatientsat
of this antibody to intracellularmyosin takes place only
risk of cardiotoxioltybeforeejectionfractiondeteriorates.Pa
tientswithsarcomastreatedbycontinuousinfusionpresentwith when sarcolemmal disruption occurs and the cell is irre
lessantimyosinuptakethanthosetreatedwith bolusinjection, versibly damaged (7). Antimyosin studies have been
indicatinglessseverecardiOtoXicity. shown to be sensitive in the detection of myocyte cell
damage in a variety of conditions (7—10).
We have recently
J Nuci Med1993;34:1503-1507 shown that the morphologic damage in the myocytes
present in doxorubicin toxicity can be detected by antimy
osin scans (11), that intensity of antimyosin uptake relates
to the cumulative dose of doxorubicin (12) and that anti
oxorubicin is one of the most effective chemothera myosin uptake precedes ejection fraction deterioration
peutic agents in the treatmentof patients with sarcomas. It (11,12).
This study was undertaken to assess cardiotoxicity in
patients with sarcomas treated with doxorubicin and to
Received Nov.10,1992;revIsionaccepted
Apr.14,1993.
Forcorrespondence MD,NuclearMedicine compare bolus administrationwith a continuous infusion
or reprintsconta@IgnatiCarrió,
Unit,Hospital
de SaMPau,PareCIar@ 167,08025Barcelona,
Spain. technique.

DetectingDoxorut@cin
Cardiotoxicity
•
Car@ó
at al. 1503
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A B C

FIGURE 1. Mtimyo&nscansof patients

withsarcomastreatedwithdoxorubicin.
(A)
Normalstudy beforechemotherapy.(B)
Study obtainedat 240-300 mg/rn2.(C)
Studyobtainedat420-600mg/rn@.Notethe
increasingmyocardlalantlmyosinuptake
with the increasingcumulativedose of
doxorubicin.

METHODS heart by average counts per pixel in the lungs. A cutoff point of
>1.58 (normal value 1.46 ±0.4 + 3 s.d.) was used to define
Patlenta abnormalstudies(9,13).
Weprospectivelystudied30patientswithsarcomas:soft-tissue
sarcoma (22 patients) and osteosarcoma (8 patients). Regimens Statistical AnalysIs
utilizing doxorubicin were based on chemotherapeutic protocol Resultsare expressedas mean ±s.d. of the meanwith nonpa
(including dacarbazine, cyclophosphamide and vincristine) and rametric analysis of groups using the Mann-Whitney and
disease status. All patients had normal baseline ejection fraction. Wilcoxontests andone-wayANOVA.Regressionanalysiswas
None of the patientshad a historyof hypertension,previous used to assess correlation between variables. Chi-square analysis
cardiac disease or had received previous chemotherapy or mcdi was used when appropriate.The statisticalpackagefor social
astinal radiotherapy. All patients had adequate hepatic and renal sciences (SPSS/PC) was used.
function; none of them had evidence of central nervous system,
mediastinal or cardiac metastases. Informed consent was ob
RESULTS
tamed from all patients. Doxorubicin was administered every 3-4
wk at a dose of 60 mg/rn2.Sixteen patientswere treatedby LVEFMeasurements
andAntimyosinStudl.s
continuousinfusionover 72 hr and 14 patients were treated by LVEF before chemotherapy was 61% ±7%, 59% ±6%
bolus injection. Antimyosin studies and left ventricular ejection at 240—300
mg/m2(p = ns) 52% ±8%(p < 0.01) at 420—600
fraction (LVEF) measurements were performed before chemo mg/m2. Seven patients presented with a decrease of 10%
therapy, at intermediate cumulative doses (240—300mg/m2) and at in absolute ejection fraction units at 420—600
mg/rn2.Five
maximal cumulative doses (420-600 mg/m2)of doxorubicin. of these seven patients had mild congestive heart failure.
Patientswere examinedby the studycardiologistat baseline None of the patients presented with severe congestive
and when the scans were performed.Symptomaticcongestive heart failure. Antimyosin studies were normal in all pa
heart failure was defined as mild ifthird heart sound gallop or rales
tientsbeforechemotherapy
(HLR 1.39±0.06).Myocar
in less thanhalfthe lungfieldswere present,or severeif major
dial antimyosin uptake was observed in all patients at 240—
pulmonary edema or cardiogenic shock were present (3).
300 mg/m2 (mean HLR of 1.85 ±0.19, p < 0.01) and in all
Ejection Fraction Measurements patients at 420-600 mg/m2 (HLR 2.08 ±0.33, p < 0.001)
After in vivo red blood cell labeling with 25 mCi of @Tcand (Figs. 1—3,
Table 1).
with the patients supine, gated blood-pool scans were acquired All patients who presented with a decrease in LVEF
with a large field of view camera (Siemens Orbiter ZLC with a 10%at 420-600 mg/m2had increased antimyosin uptake
high-resolutioncollimatorlinkedto a SiemensMicrodeltacorn with HLR 1.90 at a cumulative dose of 240-300 mg/rn2.
puter)in the LAO 30°—50°
projectionand 5°—10°
caudaltilt to
Eight patients with HLR 1.90 at 240-300 mg/rn2 did not
providethe best separationbetweenbothventriclesand atria.The
@ cardiaccycle was separated into 30 64 x 64frames,with a mini present a decrease in LVEF 10%;seven of them had a
mum of 300,000 counts collected in each frame. Data were stored decrease in LVEF between 5% and 10% (Table 1).
on magneticdiskfor subsequentanalysis.LVEFwas measured Bolus AdmInistration and Continuous Infusion
usinga semiautomaticedgedetectionandcountstechniquewith a LVEFwas similar in both groups at a cumulative dose of
varying region of interest (ROl). Fourier phase and amplitude
images were generated to help trace ROIs.
240-300 mg/rn2 (59% ±6% versus 58% ±7%). LVEF
significantly decreased in both groups at a cumulative dose
Antimyosin Studl•s of 420—600mg/rn2(Table 1, Figs. 2, 3). LVEF in the bolus
Antimyosinstudieswere performedwithina week of LVEF group was significantly lower than that observed in the
measurements. R11-D10-Fab-DTPA (0.5 mg, Centocor Europe, infusion group (48%±8%versus 56% ±5%, p < 0.05). A
Leiden,TheNetherlands)labeledwith2 mCiof @In was admin decrease in LVEF 10% was observed in two patients
istered by slow intravenous injection. Planar scans were obtained
treatedby continuous infusion (one had symptoms of mild
48hrlaterusingarnediun-energy
collimator
witha20%window
congestive heart failure) and in five patients treated by
centered on both peaks of ‘DInat a preset time of 10 mm. Scans
were storedin 128 x 128 frames.The presenceof antirnyosin bolus injection (four had symptoms of mild congestive
uptake in the heart was assessed by app@ng a quantitative heart failure).
method (13). This consisted of drawinga ROl on the heart and Patients treated with continuous infusion had less an
lungs on the anterior view of the thorax. A heart-to-lung ratio tirnyosin uptake than those treated with bolus administra
(HLR) was obtained by dividing average counts per pixel in the tion: HLR of 1.70 ±0.09 versus HLR of 2.01 ±0.16 at a

1504 TheJournalof NuclearMedicine•

Vol.34 •
No.9 •
September1993
 Downloaded from jnm.snmjournals.org by on April 19, 2020. For personal use only.

A B
@1@IU

c80• @3. $
.2 $ ..
@6o. S I ;
C S , S
S C . I

0
@4O- S I 2
I
E

@
@@2O-

C I I
@1.5

1-
I
0 200-300 400400 (mg/m2) 0 240-300 420400 (mg,m2)
Bolus admInIstration BolusadmInIstration
FiGURE 2. Ejectionfractionmeasurements(A) and antirnyosinuptake (B) in patientstreatedwitha bolusInjection.

cumulative dose of 240—300mg/rn2, p < 0.01; HLR of 1.86 associated with low incidence and a benign course of
±0.12 versus HLR of 2.32 ±0.34 at a cumulative dose of doxorubicin-induced congestive heart failure. After reach
420—600 mg/rn2, p < 0.01 (Figs. 2, 3). ing a total cumulative dose of 500 mg/rn2,however, addi
The response rate observed in the group of patients tional treatment with doxorubicin produces a rapidly in
treatedby continuous infusionwas similarto thatobserved creasing incidence of clinically significant cardiornyopathy
in the group of patients treated by bolus injection. Of 16 (1). This has led to the use of a fixed maximal dose of
patients treated by continuous infusion, a complete re 450—550mg/rn2 of doxorubicin in most chemotherapeutic
sponse was observed in one patient, a partialresponse was protocols, althoughsome patients may develop cardiomy
observed in fourpatients andone patienthad stable disease opathy at lower cumulative doses. Cessation of doxorubi
after chemotherapy. Of 14 patients treated by bolus injec cin administrationat a fixed cumulativedose, however, has
tion, a complete response was observed in one patient, a important clinical implications. In a large series of patients
partial response was observed in three patients and two with a variety of cancers, Van Hoff et al. (14) showed that
patients had stablediseaseafter chemotherapy. patients in whom chernotherapyhad been stopped at a
cumulative dose of 550 mg/rn2could be in complete remis
DISCUSSION sion (19%), in partialremission (28%)or be stable (39%).
The appearance of cardiornyopathyis the most serious Their results suggested that these remissions could have
toxic effect of doxorubicin and is the one that limits its use been prolonged with additional administrationof doxoru
for extended periods of time. Therefore, new chernother bicin. Patients who could tolerate higher doses could ben
apy regimens and alternativeanthracyclinederivatives are efit from additionaltreatment.
under development with the aim of renderingsimilarther Important attempts to reduce doxorubicin cardiotoxicity
apeutic benefit with less cardiotoxicity. Serial resting have been made by modifying the schedule of administra
LVEF measurements provide effective management of the tion. Since doxorubicin cardiotoxicity depends on peak
majority of cancer patients under doxorubicin therapy. plasma levels (15), several continuous infusion regimens
Monitoring resting LVEF with gated blood-pool scans is have been proposed. Initial studies suggested decreased

A B
bc 3.5

@8o .

1.0 1 1 1 j2.5
140 12 C
S
I
@ @A@2: I I
___________________ I I
0 200-300 400-100 (mg/m2) 0 240-300 420-500 (mg/m2)
Continuous InfusIon ContinuousInfusion

FiGURE 3. Ejectionfractionmeasurements(A@and antimyosinuptake (B) In patientstreatedwithcontinuousInfusion.

Detecting Doxowbicin Cardiotoxicity•

Carnóat al. 1505
 Downloaded from jnm.snmjournals.org by on April 19, 2020. For personal use only.

TABLE I
Resultsof MtimyosinStudies(HLR)and LVEFMeasurements
in all Patients
@BolusInfusionBolusInfusionBolusInfusionHLRLVEFHLRLVEFHLRLVEFHLRLVEFHLRLVEFHLRLVEF1.45521.34791.956
BeforechemotherapyAt 240-300mg/mefr@

1.43 58 1.64 60 1.81 60

45Mean±s.d. 1.3750 551.84461.65 1.9254 512.00481.90 2.1048
1.39±0761±71.40±.0561±72.01±1658±71.70±.0959±62.32±.3448±81.86±.1256±5

cardiotoxicity with similar antitumoral effect using con functional impairment can be detected by conventional
stant infusion by ambulatory pump delivery systems (16), methods (4,5). Our results show that anthnyosin studies
although contradictory data were subsequently reported can detect cell damage before LVEF deterioration is ob
(17,18). In a clinical studywith soft-tissue sarcomas, Ham served. At intermediatecumulative doses, a certain degree
dam et al. (2) showed that continuous infusion of doxoru of myocardial cell damage is detected in antimyosin stud
bicin may provide the same antitumoral effect with a re ies, whereas ejection fraction is still maintained. Patients
duced incidence of congestive heart failure. In addition, it with more intense antimyosinuptake at that time tend to be
has to be taken into account that prolonged exposure of those with more severe functional impairmentwith addi
tumors with small growth fractions, such as soft-tissue tional doxorubicin administration, whereas patients with
sarcomas, to cytotoxic agents might result in more tumor less intense antimyosin uptake at intermediatedoses seem
cell necrosis. Our results show that continuous infusion of to be those with less functional impairmentover time.
doxorubicin results in less intense antimyosin uptake as The ability of antimyosin studies to assess the time
compared to bolus administration. This indicates more se course of myocyte damage has been tested in other clinical
vere myocyte damage with bolus administration,although conditions. In heart transplant rejection and myocarditis,
not always to the extent necessary to deterioratefunction. antimyosin studies also have proven to be highly sensitive
This difference in cardiotoxicity between bolus administra in detectingvariations in active myocyte damage over time
tion and continuous infusion is better assessed with a corn (8,19). It has been shown in these conditions that the
bination of antimyosin scans and ejection fraction mea degree of antimyosin uptake relates to the extension and
surements. At intermediate cumulative doses, functional severity of myocyte damage and that it can be reliably
status ofboth groups was similar, although patients treated quantified in terms of HLRs (10,13). We used the same
with a bolus injection had more increased antimyosin up quantitative approach in our study and found that when a
take. At maximal cumulative doses, patients treated with certain degree of myocyte damage has been reached, as
bolus injection presented with more severe functional im shown by a certain degree of antimyosin uptake (HLR
pairrnent, resulting in an incidence of mild congestive heart 1.90), a significant decrease in ejection fraction and symp
failure at maximal cumulative doses which is similar to that torns of overt heart failure are more likely to occur.
found in other series of patients treated with doxorubicin It is still not clear if this early detection of cardiotoxicity
(1,3). may influencemanagementstrategies. Although serialrest
Detection of those patients at risk for cardiomyopathy ing LVEF measurementswill remainthe method of choice
before ejection fraction deteriorates could be of interest, to monitorcardiotoxicity, it is possible thatby usinga more
since those patients could benefit frornalternative admin sensitive test, such as antimyosin scans, drug administra
istration regimens to avoid or delay significant functional tion could be individuallytailored to reduce the incidence
impairment. LVEF measurements seem not to be sensitive and severity of cardiotoxicity (20). In view of our results,
enough to detect patients at risk of significantcardiotoxic it seemsreasonablethat antimyosin studiesmight comple
ity at an early stage.This is in keepingwith the conceptof ment LVEF measurements in some circumstances. For
the need for a certain critical mass of cell damage before example, a complementary approach could be helpful for

1506 The Journal of Nuclear Medicine•

Vol. 34 •
No. 9 •
September 1993
 Downloaded from jnm.snmjournals.org by on April 19, 2020. For personal use only.

individual management of patients with previous risk fac
tors or for patients who are potential candidates for future
repeated doxorubicinadministration.Althoughthe progno
sis for patients with advanced or metastatic soft-tissue
sarcomas is still poor, this may be particularlyrelevant in
young patients with responsive tumors who might benefit
from further doxorubicin administration.Recently, it has
been shown in children treated with doxorubicin for acute
lymphoblastic leukemia that decreased contractility may
occur several years afterchemotherapy (21). An unexpect
edly high incidence of late cardiac abnormalities in these
children was reported in that study. It is possible that early
detection of cardiotoxicity in these circumstances could
prompt changes in the schedule of administration which
could result in decreased cardiotoxicity over time.
We conclude that antimyosin studies are helpful in the
assessment of doxorubicin cardiotoxicity. Intense antimy
osin uptake (HLR 1.90) at intermediate cumulative
doses identifies patients at risk of cardiotoxicity before
LVEF deteriorates. Antimyosin studies provide a new
quantitative method to compare different administration
regimens. Patients with sarcomas treated by continuous
infusion present with less antimyosin uptake than those
treated with bolus injection, thus indicating less severe
cardiotoxicity.
ACKNOWLEDGMENTS
Supported by grant DGICYT PM89-0125 and by a research
grant from Amersham Ibérica.
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EDF@ORIAL
Antimyosin Posftivity in Doxorubicin Cardiotoxicity: Earlier
Than the Conventional Evidence
e classical symptom of chest and enzyme elevation are the tell-tale the detection of an acute myocardial
pain almost invariably offers an accompaniments. However, the clas infarction (1—7).The high predictive
indication of acute myocardial infarc sical symptoms and diagnostic meth values of normal and abnormalscans
tion. Electrocardiographic changes ods arenot foolproof. The needfor an confirmed the clinical utility of the
accurate diagnostic method for the procedure in patients with equivocal
ReceivedJune22,1993;revIsionaoceØed June
detection of ischernic necrosis led to diagnosis resulting from inadequate or
22.1993. development of antimyosin scin uninterpretable clinical or electrocar
For correspondenceor repdntscontnot Ban M
tigraphy.The imagingproceduredem diographic alterations (8). These stud
Khaw,PhD,205Mugar,
BouveCOflegeOfPharmnoy,
Northeastern
University,
360HuntIngton
Ave.,Boa onstratedhigh diagnostic accuracy for ies establishedthe lack of sarcolem
ton,MA02115.

Detecting DoxorubicinCardiotoxicity•
Carnóat al. 1507
 Downloaded from jnm.snmjournals.org by on April 19, 2020. For personal use only.

Detection of Doxorubicin Cardiotoxicity in Patients with Sarcomas by

Indium-111-Antimyosin Monoclonal Antibody Studies
Ignasi Carrió, Antonio Lopez-Pousa, Montserrat Estorch, David Duncker, Lluis Berná, Gustavo Torres and Luis de Andrés

J Nucl Med. 1993;34:1503-1507.

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