Methionine is needed for protein synthesis and for conversion to S-adenosylmethionine, which is the predominant biologic methyl group donor, and a precursor inpolyamine synthesis and transsulfuration pathway. Cancercells are dependent on the external supply of methionine(5—7),and the transmethylationrateis high in tumor cells(8). The difference in the rates of uptake of amino acidsbetween transformed and nontransformed cells may be2.5—3.5-fold(9).

The aim ofthis investigation was to study the uptake ofL-[methyl-' ‘C]methionine(‘1C-methionine) and FDG innon-Hodgkin's lymphoma (NHL), and to study the correlation between histology, proliferative activity, and kinetics and accumulation of ‘‘C-methionineand FDG inNHL.

MATERIALS AND METHODS

PatientsPatients admitted consecutively to Turku University Central

Hospital with the diagnosisof lymphoma who were willingtoundergoPET imagingwerestudied.Four patientshad high-gradelymphoma, five intermediate-grade, and five low-grade lym

phoma (Table 1). Patient 1 1 had maturity onset-type diabetes,

while the remaining patients had normal blood sugar levels.Histologywas classifiedaccordingto the WorkingFormulation(10).

There was no therapy given to those patients with primarylymphoma prior to the PET study. The patients who relapsedhad been without any therapyfor at least 1 yr, except Patients 6,7,8,and 10.Patients6 and7 receivedradiotherapyandthelastfractionwasgiven 1.5mo beforethe PET study.The lymphomatumors were largein both casesand they increasedin sizeafterradiotherapy. These two patients died of their lymphoma a fewmonths after the PET study. Patient 8 received the last prednisolone dose 1 mo and the last chlorambucile dose 1.5 mo beforethe PET study. Patient 8 had a low-gradetumor whose size hadnot changedduringthe therapybut startedto growaftercessationofthe treatment.Patient 10 receivedthreedoses of chemotherapywith a combination ofcyclophosphamide, vincristine, doxorubi

cm, and prednisolone. There was a 1-mo period after the lasttherapy and the tumor continued to grow all the time despite the

therapy. This patient died 1 mo after the PET study.

The fraction of cells in the S-phase was determined by DNA

Uptakeof L-[methyl-11C]methionine(11C-methionine)and[18F]-2-fiuoro-2-deoxy-D-glucose(FDG)was studiedwith PETin14 patientswith non-Hodgkin'slymphomas.The low molecularweight fractionof venousplasmaseparatedby fast gelfiltrationwas used as the input functionfor 11C-methioninestudies,and traceraccumulationwas analyzedaccordingtoPatlakandGjedde.Theaverageuptakerateof 11C-methioninewas 0.0775 ±0.0245 min1 (s.d.) and of FDG 0.0355 ±0.0293 min1, 11C-methionine uptake rate being significantlyhigher than that of FDG (p < 0.01). Carbon-i 1-methionineaccumulatedstronglyin all but one of the lymphomas.FDGaccumulatedclearlyin lymphomasof high-grademalignancy,whereas two intermediate-and three low-grade malignantlymphomashada poor uptakerate.The tumor/plasmaratioof both 11C-methionineandFDGincreasedfaster in highandintermediate-gradelymphomasthaninlow-gradelymphomas,but there was considerableoverlapbetweenthe histologicgrades.Carbon-i1-methionineseemsto be preferablein detectingtumors,whileFDGwas superiorto 11C-methionineindistinguishing the high-grade malignant lymphomas from theothergrades.

J NucI Med 1991; 32:1211—1218

he positron-emitting radiopharmaceutical [18F]-2-fluoro-2-deoxy-D-glucose (FDG) has been successfully usedin studies on glucose metabolism in vivo (1). Phosphorylation by hexokinase of 2-deoxy-D-glucose, an analog ofD-glucose, produces 2-deoxy-D-glucose 6-phosphate,which is a relatively poor substrate for the subsequentmetabolic steps and is considered to be metabolicallytrapped intracellularly (2,3). In neoplastic tissues, the activity of glucose 6-phosphatase is low (1,4). The rate atwhich FDG accumulates in tumor tissue thus dependsessentially on the tracer transport and hexokinase activityof the cells.

Methionine metabolism is also altered in cancer (5).

Received Jul. 10, 1990; revision accepted Dec. 17, 1990.For reprints contact: Sirkku Leskinen-Kaflio, MD, Department of Oncology

and RadiOtherapy, Turku Lk@iVerSityCentral Hospital, 20520 Turku, Finland.

1211Uptakeof 11C-MethionineandFDG•Leskinen-Kallioet al

Uptake of Carbon- 11-Methionine andFluorodeoxyglucose in Non-Hodgkin's

Lymphoma: A PET StudySirkku Leskinen-Kallio, Ulla Ruotsalainen, Kjell Nâgren,Mika Teräs,and Heikki Joensuu

Department ofOncology and Radiotherapy and Turku Medical Cyclotron-PET Center, Turku University Central Hospital,Turku,Finland, and Medical CyclotronLaboratory, UniversityofTurku, Turku,Finland

TABLE I@!@tientCharacteristics

Lesionsize Tumor(cm) @ca@on

Patientno.Age/SexHistologicsubtype156/M10

x 5 x 3Neck PLymphoma, centrocytic-centroblastic,GIl261/M0,

5 x 1, 54x0,5Eyelids l.a.PLymphoma,

centrocyticdiffuse,GI342/F2,

5 x 72x2x2Neck l.a.PLymphoma,

centroblasticumdiffuse,GIl454/F5

x 3 x 3Axilla PLymphoma, centrocyticdiffuse,GII562/M5x 4

4 x 3AxilIa l.a.ALymphoma,centrocytic-centroblas

tic follicular,GI673/M7x 5

5x5AbdomenALymphoma, immunoblastic,GIII741/M14

x 10 x 5Neck ALymphoma, lymphoblastic,GIII858/M5x 4 x 2Neck RLymphoma, lymphocyticdiffuse,

GI964/M4x 2

3x23 x 2,5Neck

I.a.PLymphoma,lymphocytic

diffuse,GI1075/F4

x 4AxilIa ALymphoma, immunoblastic,GIII4x4

4x5NeCkR1181/F7 x 6Neck ALymphoma, smalllymphocyticdif

fuse, GI1253/F4x 4Neck PLymphoma, smallIymphocyticdif

fuse,GI1374/F5x 3Inguinal re

gionPLymphoma,centrocytic-centroblas

tic,GIl1455/F5x 2, 5Inguinal re

gionPLymphoma,centrocytic-centroblas

ticdiffuse,GIIM

= male,F= female,P= studiedatpresentation,R= studiedatrelapse,G= grade,andl.a.= lesionon boths@es.

flow cytometry from deparaffinized tissue sections in 13 patients(11). The preparation of a single-cell suspension from paraffinembeddedtissuewas done accordingto a slightmodificationofthe method described by Hedley et al. (12). Flow cytometry wasdone with a FACStarflowcytometer(Becton-DickinsonImmunocytornetrySystems,Mountain View, CA) as described elsewhere using a double-analysis method in which all samples areanalyzedat leasttwice(13). The intervalbetweenthe biopsyandPET was 2 mo, except for Cases 6 and 11 which were obtained 6mo and 12 mo, respectively, before the study. Because the diseasehad been stable without any treatment, the S-phase value wasaccepted in the study.

All subjects had a light, protein-poor breakfast before scanning,and a light lunch between@ ‘C-methionineand FDO studies.Written informed consent was obtained from all patients. Thestudy was approved by the Ethical Committee of Turku University Central Hospital.

PET ImagingCarbon-i l-methionine and FDG were synthesized at the

TurkuMedicalCyclotron Laboratoryas describedelsewhere(14-16). The radiochemical purity of ‘‘C-methionine ranged from

90%to98%,exceptin onecase(Patient13),whereit was82%.the radiochemical purity of FDG was over 97%, except in twocases,Patients6 and 9, whereit was 78%and 88%,respectively.The radiochemicalimpurityconsisted ofa triacetylatedprecursor

of FDG. The fraction of mannose was 14% with a deviation of5%.

Transmission scans were recorded for attenuation correction.

Aftertransmissionscanning, ‘‘C-methionine(125—300MBq) wasinjected into a peripheral vein of the upper extremity. On thesameday,FDG (230—340MBq)wasinjectedintravenouslyabout4 hr after ‘‘C-methionineinjection.A newtransmissionscanwasperformed before the FDG injection. Following the injections,sequentialimageswererecordedfor40 mm in the ‘‘C-methioninestudies and for 60 mm in the FDG studies using an ECATScanner 931/08-12 (17). The scanner acquires 15 contiguousslicessimultaneouslywith a slice thicknessof 6.7 mm and fullwidth at half maximum is 6.1 mm transaxially in the center ofthe field of view.

The tumors were positioned by palpation, except for oneabdominallymphoma,wherea computed tomographicscanwasused.

Blood SamplingFrequent venous blood samples were taken from an antecu

bital vein contralateral to the injection site. The hand and armwere warmed up with a pad thermostated to +40°C.The bloodsampleswere immediatelycentrifuged,and radioactivityof theplasma was determined. When@ 1C-methioninewas used as thetracer, the low molecular weight fraction of plasma taken at 10,20, 40, and 60 mm after injection was separated by fast gel

1212 The Journalof NuclearMedicine•Vol. 32 •No. 6 •June 1991

Patient Histologicno. grade S-phase%

Uptakerate(K)SUV

MetFDGMethionineFDGI

II8.10.09870.04155.79.12II4.3nnnn3II10.90.04990.01454.53.24II5.60.07240.02938.47.75I7.5nd0.0470nd11.06

Ill13.40.10270.08599.119.47III20.00.10330.02695.98.88Ind0.06450.00983.91.99I3.60.05370.01315.53.710

IIInd0.1026nd7.6ndI1 I10.30.03570.00913.92.312

I 5.60.08940.02181 1.74.713III11.40.08120.10479.613.814II5.90.03360.02212.34.5.

Total plasma activity is used as the inputfunction.n

= No clearaccumulation,the K valuewas notcalculated,seetext.nd= Notdetermined.

filtrationwith SephadexPD-l0 columns(PharmaciaFine Chemicals,Sweden)for radioactivitymeasurements(18).

Regions of InterestRegionsofinterest (ROIs)wereselectedto representthe tumor

area of high accumulation.ROIs were not directlycompared toconventional imaging, but clinical radiologic images were usedfor reference together with palpation. The tumors were of asufficientsize (Table 1). for easy localizationand positioning.The minimum number of pixels in a ROl was 43. Relativestandard deviation ofthe ROIs was under 15% in the last framesof the studies. Two or more tumors of four patients were evalu

ated, but the time-activitycurvesof differentROIs drawn in thehot spots of the tumors were so similar that we decided to usethe averageof thesecurvesin analysis.

Kinetical and Statistical AnalysisA graphical approach according to Patlak et a!. and Gjedde

(19,20) was used to analyze the kinetics of ‘‘C-methionineandFDG uptake. In this method normalized plasma time values areplotted on the horizontal, and tissue activity values divided byplasmaactivityvalueson the verticalaxis(Figs.2—4):

x(T) = ,f C@(t)dt/C,(T)

y(T) = C@(T)/C,(T),

whereC@(t)is plasmaconcentration oftracer at time t, T is framemean time after injection,and C@(T)is tracer concentration oftumor tissue at time T. When y(T) is plotted against x(T) astraightlinewitha slopeofK@(influxconstant)isobtained,whichrepresents the accumulation rate of the tracer in the irreversiblecompartment.

The influx constant was calculated from the 5—7last datapoints in the Patlakcurve representingthe evaluationtime from15 mm till the end of the study (40 mm in the ‘‘C-methioninestudy and 60 mm in the FDO study).

Standardized uptake values (SUV) were also calculated foreach patient:

SUV = tumor activity/(dose/patient'sweight),

where tumor activity is the activity measured in the PET studyand dose is the injectedtracer dose.

The K@-valuesand SUVscould not be calculatedfor Patient 2because the tumors were not visible in the PET images and areferencestudy could not be done becauseof the patient's poorcondition. The ‘‘C-methionineuptake in Patient 5 and the FDGuptake in Patient 10 could not be studied becauseof technicalproblems.

The K@of ‘‘C-methionineand FDG were compared by Wilcoxon's rank sum test for unpaired data (Mann-Whitney'stest).K@-valuesand S-phase fractions were compared by calculatingPearson'scorrelationcoefficientand by cluster-analysis.P valuesare two-tailed.

RESULTS

Carbon-l 1-methionine accumulated in all but one ofthe lymphomas(Table 2). The patient without clear uptake(Patient 2) had intermediate-gradelymphoma with tumors0.5 x 1.5 and 4 x 0.5 cm in diameter in both upper eyelids,and the high accumulation of ‘‘C-methiomnein the lacrimal glands may have impaired the detection of lymphoma in this case.

FDG accumulated in all high-grade lymphomas (n =3). In two of the five intermediate-gradeandthreeof thefive low-grade malignant lymphomas, FDG uptake ratewas low (K@< 0.02, Table 2). Since the accumulation andpharmacokinetics of FDG in Patients 6 and 9 who werestudied with a batch of FDG containing triacetyiglucalwere in agreement with that found in the other patients,these results were considered valid and included in thestudy.

The uptake rate of ‘‘C-methioninein lymphoma was

TABLE 2Uptakeof 11C-MethionineandFDGby Non-Hodgkin'sLymphoma

Uptake of 11C-Methionineand FDG •Leskinen-KalIloet al 1213

,--.ci,,—.Gii.—.

6iii

Low MolecularTABWeightFractLE3

ion of Total P1asmaActivityPatient304060no.mmmmmm10.750.550.4020.800.580.3230.890.870.5140.840.790.715———60.710.580.2870.670.500.3280.860.79—91

.00.810.63100.750.560.3711———120.750.710.601

30.730.690.61

4

2

n

higher than that of FDG (p < 0.01, Table 2). The averageuptake rate of' ‘C-methioninewas 0.0775 ±0.0245 (s.d.)min' and of FDG 0.0355 ±0.0293 min'. The averageSUV for ‘‘C-methioninewas 6.7 ±2.8 and for FDG 7.5±5.3 (Table 2).

Accumulation of both tracers was generally homogeneous, but two high-grade lymphomas (Cases 6 and 7, Table1, Fig. 1) had clearly heterogeneous uptake of both tracerswith areas of very low uptake. The areas of low traceractivity, probably caused by tumor necrosis (Fig. 1), weredisregarded when tracer accumulation was assessed.

More than one tumor of Patients 3, 6, 9, and 10 (Table1) were imaged. The time-activity curves of the differenttumors in the individual patients were very similar (Fig.2) and were regarded to be caused by the disease of thesame kind. The average of these time-activity curves wasincluded in the analysis.

The proportion of radioactivity in the low molecularweight fraction of the plasma was 79% ±9% (s.d.) at 30mm, 67% ±12% at 40 mm, and 48% ±15% at 60 mmafter injection of ‘‘C-methionine(Table 3). When the lowmolecular weight fraction ofplasma radioactivity was used

as the input function, the curve C@(T)/C,@,(T)versus plasmatime in the Patlak analysis became linear, which indicatesthat there is net influx of the tracer into the cells.

The tumor/plasma ratio C@(T)/C,,(T)of both ‘‘C-methionine and FDG increased faster in high- and intermediate-grade lymphomas when compared to low-gradelymphomas (Figs. 3—4).There was, however, considerableoverlap between the histologic grades (Fig. 5).

The uptake rate of' ‘C-methioninetended to be higherin lymphomas with a large S-phase fraction (r = 0.62, n =9). The uptakerateofFDG correlatedpoorlywiththesizeofthe S-phase fraction (r = 0.29, n = 11), because in threecases the measured 5% was clearly higher than expectedfrom FDO accumulation (Figs. 6—7).The SUV of “C-methionine did not correlate at all with S-phase fraction(r = —0.0052, n = 9). The correlation coefficient was 0.40(r, n = 11) for FDG SUV and S-phase. The correlationbetween K@and SUVs was quite good, for ‘‘C-methioniner = 0.62 and for FDG r = 0.91.

In the FDG study, the high-gradelymphomas (Cases 6and 13) were one group in cluster analysis (FDG SUV,FDG K@and S-Phase as factors). When results from bothâ€â€˜C-methionine and FDG studies were included in the

- AXILLA TUMOR

NECKTUMORw

E

UC

TIME AFTER INJECTION(minI

FIGURE2. Time-activitycurvesof 11C-methioninestudyofPatient10with bothaxillary(tumor)andnecktumors(necktumor)fromimmunoblasticlymphoma.

A B@@

Cn(T) €Cp IT)

lCIMETHIO@1NESTUDY

14

12

Cn(T) @Ccp I TI

ic

FIGURE3. (A)AveragePatlak graphsof 11C-methionineaccumulation rate for lowgrade(GI),intermediate-grade(GII),andhigh-grade(GIII)lymphomas.Standarddeviationisindicatedwith bars.Case2 isexduded. (B) IndividualPatlakslopes of 11C-methionineaccumulation.Patientnumberisin the end of each slope.

20 40 60 80

j@Cp)t)dt MIN

Cp(T)

20 40 60 80 100 120 140

pitCp)t)dt

1214 The Journalof Nudear Medicine•Vol. 32 •No. 6 •June 1991

FIGURE1. (A)PETimageofPatient6.Carbon-i1-methionine accumulation isclearlyseenin the largepartiallynecrotictumorin the abdomenconsistingof immunoblasticlymphoma(high-grade).Thenecroticpart of the tumor does not accumulatemethionine.The imageissummedup over 15—40mm postmnjection.The inJecteddoseof @C-methioninewas 260MBq.Totalcountsof the imagewas7 xi0@.(B)CT scan fromthe same plane.

cluster analysis, Patients 6 and 13 were distinguished asone group. When only ‘‘C-methioninestudy was concerned, Patients 6, 7, 12, 13, 1, and 4 were in the samegroup. In cluster analysis, FDG seems to be better indistinguishing the high-grade tumors from the other lymphoma tumors.

DISCUSSION

Selenium-75-methionine was reported to accumulate inlymphoma more than 20 yr ago (21), but selenate andselenite alone enter lymphoma if administered intravenously (22). An increased accumulation of ‘‘C-methionineand a correlation between histology and ‘‘C-methionineuptake have been reported for brain and lung tumors (23—29). High accumulation of methionine has also been detected in prolactinomas (30).

A weak correlation between ‘‘C-methionineuptake andhistology was found in this study. The uptake rate of “C-methionine in lymphoma tumor tissue is higher than thatof FDG. Carbon-i i-methionine is also taken up by thenormal pancreas and liver (31), salivary glands (32), andbone marrow, which impairs its role as a tumor-seekingtracer.

FIX; has been found to accumulate in lymphoma in afew cases (33,34). In these reports,the uptake ofFDG hasnot, however, been analyzed in terms of lymphoma grading. The present findings suggest that the uptake rate ofFIX; is more rapid in high-grade lymphomas (Fig. 4), and

that low-grade lymphomas may not always become visiblein the PET images (Table 2). One out of three high-gradetumors had a very low uptake of FDG (Case 7, Tables 1and 2, Fig. 5). This tumor was partly necrotic, which mayimpair the uptake ofFDG, and only the average metabolicrate oftumor cells is assessed in PET studies, although thehot spots are under observation.

The rate of FDG uptake studied by PET has beenreportedto correlatewith tumor grade(35,36) and survival(37-39) in patients with brain tumors, although thesefindings have been criticized (40). The rate ofFDG uptakeinto lung tumor tissue is increased in comparison withnormal lung tissue, but there appears to be little correlationbetween the tumor type and the rate of FIX) uptake (41).There is also increased accumulation of FDG in colorectaltumors (42,43), breastcancer (44), head and neck tumors(45), thyroid cancer(46), and in abdominal abscesses (47).

Arterial samples should be taken, if entirely correctinformation about input function is needed (48). Venoussamples taken from a heated hand vein can, however,approximate the arterialmeasurements (49).

Standardizing the tumor uptake to blood activity hasthe advantage of permitting the comparison of uptakekinetics of different tracers, while SUVs cannot be compared between two tracers because of the different biodistribution of the tracers.

The low molecular weight fraction of plasma does notconsist only of ‘‘C-methioninebut also of other active

FIGURE4. (A)AveragePatlak graphs of FDG accumulation rate for low-grade (G I),intermediate-grade(G II), andhigh-grade(G III) tymphomas.Standarddeviationis indicatedwith bars. (B) Individual Patlakslopesof FDGaccumulation.Patientnumberis in the end ofeachslope.

A@ FDG-STUDY B

6

S@@cJJJ.

Cp(T)@ ci..LIiCp I TI

2 )Gi)0)

@@ 3@0 5@0@

j'Cp)t)dt MiNCp)T)

FDG - STUDY

J'Cp(t)dt MN

Uptake of @C-Methionineand FDG •Leskinen-Kallioet al 1215

FDG STUDY

. S

S

x. 0

0 S

. MO

* 0x

0.1.30.100•x••007x0x0x0040x0

00•0.01!°

4 8 1216 2024S-PHASE%

(CI METHIONINESTUDY

••

0

* •

0

*0

0

A B l@CJMETHION1NE•

•

*x

•• 0

0 •

• 0

x@0 X o

* *0

0

(tIMETHIONINE STUDY FDG STUDYFIGURE5 (A) K@.valuesof@C-methionineand FDG in

non-Hodgkin'slymphomaaccording to histologic grade.ResultsfromPatient2 withuncertain accumulationdue toproximity of the Iarcimal glandsare not shown, and the Kvalueof @C-methionineaccumulation rate of Patient 11where only total plasma wasavailable is not included. (B)SINs of @C-methionineandFDGstudies.

12

10

SUV8

6

4

2

K,

ci cii ciii ci cii ciii ci cii ciii ci cii ciii

light molecules, such as serine (18). The fraction of proteinfree ‘‘C-labeledmethionine ofthe total plasma radioactivity measured with high-pressure liquid chromatographyhas been reported to be about 71% at 30 mm after injectionand about 36%at 60 mm postinjection (50), values whichare about 10%smaller than the ones we obtained by thefast gel filtration method. Serine is not transportedacrossthe blood-brain barrier as fast as methionine (51), but thetransportsystem in cancer cell plasma membrane is nonspecific and the uptake of serine may be of significance.

The graphicalanalysis method ofPatlak et al. (19) is anestablished method to assess the rate of FDG uptake. Thismethod formerly has been applied to ‘‘C-methionine(52,53). Although the kinetics of ‘‘C-methionine transportthrough plasma membranes is not the same as that ofFDG, there was a net influx of the tracer into the tumorand the method appears to be of value in ‘‘C-methioninestudy.

The local blood flow and blood volume may vary indifferent tumors and affect the accumulation of tracers.The mean blood flow in human lymphomas has beenreported to be 35 ±21 ml/min/lOO g, which is higher

FIGURE6. Correlationof Kr-valuesof @C-methionineuptakeand S-phasefractionsin ninepatientswithnon-Hodgkin'slymphoma,r = 0.62.Symbolsasin Figure3.

than for carcinomas (54). There is also no significantcorrelation between the size of the tumor and the localblood flow.

NHL is a disease ofheterogeneous clinical presentation.Low-grade malignant lymphomas have a prolonged clinical course, typically of several years, whereas high-grademalignant lymphomas may be fatal within a few weeks.Both histology and the size of S-phase fraction are associated with survival in NHL. However, there are difficultiesin the determination of histology, such as interobservervariability(55). Proliferationby cytometry is, on the otherhand, disturbed by cell debris and a lack of knowledgeabout cell cycle time (56).

The membrane transport systems used in the uptake ofnutrients (e.g., of sugars and amino acids) is frequentlyenhanced in transformed cells. Similar changes may occurduring increased cell proliferation stimulated by, for cxample, growth factors or mitogens (57). Although onlysecondarily related to the malignant phenotype, the ratesofglucose and amino acid metabolism are probably closelyrelated to the proliferation rate of lymphoma. Tumorsmay, however, be heterogeneous not only macroscopically

FiGURE7. Correlationof Kr-valuesof FDGuptakeand5-phasefractionin 11 patientswithnon-Hodgkin'slymphoma,r =0.29. Symbolsare as definedin Figure3.

0.120

0.100

0.080

0.060

0.040

0.020

0.120

0.100

0.080

K10.060

0.OLO

0.020

K,

4 8 1216 2024S-PHASE%

1216 The Journal of Nuclear Medicine@ Vol. 32 •No. 6@ June 1991

(our Cases 6 and 7), but also at a microscopic and at ametabolic level, in which cases only the average metabolicactivity will be measured by PET. PET and FDG mayserve as an alternative to assess tumor grades, especiallywhen there is uncertainty about the histologic grade.

ACKNOWLEDGMENTSThe authors acknowledge the support of Professor Eeva Nord

man and Professor Uno Wegelius, and thank Dr. Heikki Minn,Dr. Aapo Ahonen, and Dr. Robert Paul for fruitfuldiscussions,Dr. Karl-Ove Soderströmfor reexamination of the histologictumor samples,Meija Haaparanta-Solin,MSc and the TurkuMedicalCyclotronLaboratoryfor providingthe FDG, as wellasthe personnel of the nuclear medicine department for accuratework in collecting the data.

The studywas financiallysupportedby grantsfromthe FinnishCancer Society and the Arvo and Inken Suominen Foundation.

REFERENCESI. Gallagher BM, Fowler iS, Gutterson NI, et al. Metabolic trapping as a

principle of radiopharmaceutical design: some factors responsible for thebiodistribution of I'8F12-deoxy.2-fluoro-D-glucose. J Nuci Med 1978;19:1154—1161.

2. SoIsA,CraneRK.Substratespecificityofbrainhexokinase.J Bid Cheml954;210:581—595.

3. Bessell EM, Thomas P. The effect of substitution at C-2 of D-glucose 6-phosphate on the rate of dehydrogenation by glucose-6-phosphate dehy.drogenase (from yeast and from rat liver). Biochem J 1973;131:83—89.

4. Weber 0. Enzymology of cancer cells (second of two parts). New Engi JMed 1977:296:541—551.

5. Hoffman RM. Altered methionine metabolism, DNA methylation andoncogenic expression in carcinogenesis. Biochem Biophys Ada 1984;738:49—87.

6. Stern PH, Wallace CD, Hoffman RM. Altered methionine metabolismoccurs in all members of a set of diverse human tumor cell lines. I CellPhysioll984;l 19:29—34.

7. Wheatley DN. On the problem oflinear incorporation ofamino acids intocell proteins. Experientia 1982;38:818—820.

8. Stern PH, Hoffman RM. Elevated overall rates of transmethylation in celllines from diverse human tumors. In Vitro 1984;20:663—670.

9. IsselbacherKi. Increased uptake ofamino acids and 2-deoxy-D-glucose byvirus-transformedcells in culture. Plvc Nat Acad Sd USA 1972;69:585—589.

10. The non-Hodgkin's Lymphoma Pathologic Classification Project. NationalCancer Institute sponsored study of classifications of non-Hodgkin's lymphomas. Summary and description ofa Working Formulation for clinicalusage.Cancer1982;49:2112—2135.

I I. ioensuuH, Klemi Pi, KorkeilaE. Prognosticvalueof DNA ploidyandproliferative activity in Hodgkin's disease. Am J Clin Patho! l988;90:670—673.

I2. Hedley DW. FriedlanderML, TaylorIW, RuggCA, Musgrove EA. Methodfor analysis of cellular DNA content of paraffin-embedded pathologicalmaterial using flow cytometry. JHistochem Cytochem 1983;3l:l333—1335.

13. Joensuu H, Kiemi Pi. DNA aneuploidy in adenomas of the endocrineorgans.Am J Paihol1988;132:145—151.

14. Ungstrom B, Antoni 0, Gullberg P, et al. Synthesisof L- and D-[methylI ‘Cjmethionine. J Nuc/Med 1987;28: 1037—1040.

15. NãgrenK, Aho K, Bergman i, et al. ‘‘C-methyliodide: routine productionand use in preparationofsome ‘‘C-labelledradiopharmaceuticalsfor PETin Turku. In: Brenner M, Bergman i, Brenner R, Lill 3-0, ManngArd P,eds. The Abo Akademi accelator laboratory triennal report 1987—1989.Turku, 1990:76—81.

16. Haaparanta M, BergmanJ, Solin 0, et al. A remotely controlled systemfor the routine synthesisof *F.2.fluoro.2-deoxy.D-glucose.Nuclearmedi:in 1984:2l(suppl):823—826.

I7. Spinks Ti, iones 1, Gilardi MC, Heather iD. Physical performance of thelatest generation of commercial positron scanner. IEEE Trans Nuci Scil988;35:72l—725.

l8. Lundqvist H, StàlnackeC-G, Làngstrom B, iones B. Labelled metabolites

in plasma after iv. administration of [‘‘Ch3]-L-methionine.In: Greits T,Widen L, Ingvar D, eds. The metabolism ofthe human brain studied withpositronemissiontomography.New York: Raven Press;1985:233—240.

19. PatlakCS, BlasbergRG, FenstermacheriD. Graphical evaluation of bloodto-brain transfer constants from multiple-time uptake data. J Cereb BloodFlow Metab 1983;3:1—7.

20. Gjedde A. High- and low-affinity transport of D-glucose from blood tobrain.JNeurocheml981;36:1463—l47l.

21. Herrera NE, Gonzalez R, Schwartz RD, Diggs AM, Bclsky i. Se-75-methionine as a diagnostic agent in malignant lymphoma. J Nuci Med1965;6:792—804.

22. Spencer RP, Montana 0, Scanlon GT, Evans OR. Uptake of selenomethionine by mouse and human lymphomas, with observations on selenite andselenate. J Nuci Med 1967;8:l97—208.

23. BustanyP, Chatel M, DerlonJM, et al Braintumor proteinsynthesisandhistologicalgrades:a study by positron emission tomography(PET) andC-I l-L-methionine. J Neurooncol 1986;3:397—404.

24. Schober 0, Meyer 0-i, Duden C, et al. Die Aufnahme von Aminosàurenin Hirntumoren mit der Positronen-Emissionstomographie als Indikatorfürdie Beurteilung von Stoffwechselaktivitat und Malignitàt.FortschrROntgenstr 1987;147:503—509.

25. MosskinM, von Hoist H, BergstromM, et al. Positron emissiontomography with ‘‘C-methionineand computed tomography of intracranialtumours compared with histopathologic examination of multiple biopsies.Ada Radiol1987;28:673—681.

26. Ericson K, Lilja A, Bergstrom M, et al. Positron emission tomography with(I―Cjmethyl)-L-methionine, ([“CJ-D-glucose,and [‘@GaJEDTAin supratentorial tumors. J Comput Assist Tomogr 1985;9:683—689.

27. BergstromM, Collins VP, Ehnn E, et al. Discrepanciesin brain tumorextent as shown by computed tomography and positron emission tomography using [@GaJEDTA, [“CJGlucose,and [“Cjmethionine.I ComputAssist Tomogr l983;7:l062—1066.

28. Fujiwaral, MatsuzawaT, Kubota K, et al. Relationshipbetween histologictype of primary lung cancer and carbon-I l-L-methionine uptake withpositron emission tomography. J NuciMed 1989;30:33—37.

29. Kubota K, Matsuzawa 1, Ito M, et al. Lung tumor imaging by positronemission tomography using C-ll-L-methionine. J Nucl Med 1985;26:37-42.

30. Bergstrom M, Muhr C, Lundberg P0, et al. In vivo study of amino aciddistribution and metabolism in pituitary adenomas using positron emissiontomography with D-' ‘C-methionineand L-' ‘C-methionine.I Compul Assist Tomogr l987;l 1:384—389.

31. Syrota A, Duquesnoy N, Paraf A, Kellershohn C. The role of positronemission tomography in the detection of pancreatic disease. Radiology1982;143:249—253.

32. Syrota A, Collard P. ParafA. Comparison of ‘‘C-L-methionineuptake bythe parotid gland and pancreas in chronic pancreatitis studied by positronemission tomography. Gut 198324:637—641.

33. Paul R. Comparison of fluorine-18-2-fluorodeoxyglucose and gallium-67-citrate imaging for detection oflymphoma. J NuciMed 1987;28:288—92.

34. Kuwabara Y, Ichiya Y, Otsuka M, et al. High I'@F]FDGuptake in primarycerebral lymphoma: a PET study. J Comput Assist Tomogr 1988;12:47-48.

35. DiChiro0, DeLaPazRL, BrooksRA,et al. Glucoseutilizationof cerebralgliomas measured by (‘8Fjfluorodeoxyglucoseand positron emission tomography. Neurology 1982;32:1323—1329.

36. DiChiro 0. Positron emission tomography using [‘9@fluorodeoxyglucosein brain tumors—a powerful diagnostic and prognostic tool. Invest Radiol1986;22:360—37l.

37. Patronas Ni, DiChiro 0, Kufta C, et al. Prediction of survival in gliomapatients by means of positron emission tomography. J Neurosurg1985;62:816—822.

38. Alavi JB, Alavi A, Chawluk J, et al. Positron emission tomography inpatients with glioma—a predictor of prognosis. Cancer I988;62:1074—1078.

39. DiChiro 0, Hatazawa i, Katz DA, Rizzoli HV, De Michele Di. Glucoseutilization by intracranial meningeomas as an index of tumor aggressivityand probability ofrecurrence: a PET study. Radiology 1987;164:521—526.

40. Tyler JL, Diksic M, Villemure J-G, et al. Metabolic and hemodynamicevaluation of gliomas using positron emission tomography. J Nucl Med1987;28:l123—1133.

41. Nolop KB, Rhodes CG, Brudin LH, et al. Glucose utilization in vivo byhuman pulmonaryneoplasms.Cancer 1987;60:2682—2689.

42. Yonekura, Y, Benua RS, Brill AB, et al. Increased accumulation of 2-deoxy-2-('@FJfluoro-D-glucose in liV@metastases from colon carcinoma. J

Uptake of @C-Methionineand FDG@ Leskinen-Kallioet al 1217

NuclMed 1982;23:l133—I137.43. StraussLG,CloriusiH, SchlagP.et al. Recurrenceof colorectaltumors:

PET evaluation. Radiology l989;170:329—332.44. Minn H, Soini I. [‘8FjFluorodeoxyglucosescintigraphy in diagnosis and

follow-up of treatment in advanced breast cancer. Eur I Nuci Med1989;15:61—66

45. Minn H, ioensuu H, Ahonen A, Kiemi P. Fluorodeoxyglucose imaging amethod to assess the proliferative activity of human cancer in vivo. Comparison with DNA flow cytometry in head and neck tumors. Cancerl988;6l:1776—1781.

46. ioensuu H, Ahonen A. Imaging of metastases of thyroid carcinoma withfluorine-18-fluorodeoxyglucose. J NuclMed 1987;28:910—914.

47. Tahara 1, Ichiya Y, Kuwabara Y, et al. High [‘8F]fluorodeoxyglucoseuptake in abdominal abscesses: a PET study. J Compul Assist Tomogr1989;13:829—831.

48.GreeniH, EllisFR,ShallcrossTM,BramleyPN.Invalidityofhandheatingas a method to arterialize venous blood. C/in Chem l990;36:719—722.

49. Abumrad NN, Rabin D, Diamond MP, Lacy WW. Use of a heatedsuperficial hand vein as an alternative site for the measurement of aminoacid concentration and for the study of glucose and alanine kinetics inman. Metabolism 198l;30:936—940.

(con:inuedfrom page 5A)

50. Ishiwata K, Hatazawa J, Kubota K, et al. Metabolic fate ofL-[methyl-' ‘C]methionine in human plasma. Eur I NuclMed 1989;15:665—669.

51. Oldendorf WH. Brain uptake of radiolabeled amino acids, amines andhexosesafterarterialinjection.Am J Physiol197l;22l:1629—1639.

52. Hatazawa i, Ishiwata K, Itoh M, et al. Quantitative evaluation of LImethyl-C-l l]methionine uptake in tumor using positron emission tomography. JNuclMed l989;30:l809—18l3.

53. Bergstrom M, Muhr C, Lundberg P0, Bergstrom K, Lundqvist H, IJngström B. Amino acid metabolism in pituitary adenomas. Ada Radio!l986;26(suppl 369):4l2—4l4.

54. MäntylaMi. Regional blood flow in human tumors. Cancer Res1979;39:2304—2306.

55. De Wolf-PeetersC, Caillou B, Diebold i, et al. Reproducibilityandprognostic value of different non-Hodgkin's lymphoma classifications:study based on the clinicopathologic relations found in the EORTC trial(20751).EurJ CancerC/inOncoll985,2l:579—584.

56. ialkanen 5, ioensuu H, Klemi PJ. Prognostic value oflymphocyte homingreceptor and S-phase fraction in non-Hodgkin's lyinphoma. Blood1991:1549—1556.

57. Ruddon RW. Cancer biology, second edition. New York, Oxford: OxfordUniversity Press; 1987:216.

ACQUIS@ON INFORMATiON:A 66-yr-old male was admittedfor resection of a rightatrial mass. A ventilation-perfusion scan was performed preoperatively to evaluate progressive hypoxemia. The perfusion phase demonstrates myocardialuptake of ““Tc-MAA,indicating a right-to-left shuntmade apparent by a large photopenic area surroundingthe heart. An echocardiogramdemonstrateda solidmass occupying the right atrium and a pericardial effusion, non-Hodgkin's lymphoma with invasion of theatrial septum was found at surgery.

TRACER:Technetium-99m-MAA

Intravenous

DL@ .J..

S@ 7 —n C1@-@ ;i;'ci I Pfl@M

1218 The Journal of Nuclear Medicine@ Vol. 32@ No. 6@ June 1991

FIRST IMPRESSIONS

ROUTE OF ADMIN1ITRATION:

IN$TRUMENTATION:ADAC Genesys Camera

CONTRIBUTORIW.H. McCuskey, MD and E. Turbiner, DO

INSTITUTION:Mercy Hospital of Pittsburgh, Pittsburgh, PA