nuclear magnetic resonance investigations of human ... · the specimens were chosen by resident...
TRANSCRIPT
[CANCER RESEARCH 35, 1326 1332, May 1975)
Nuclear Magnetic Resonance Investigations of Human Neoplasticand Abnormal Nonneoplastic Tissues1
3, 4Joseph C. Eggleston, Leon A. Saryan, and Donald P. Mollis
Department* of Pathology \J. C. E.] and Physiological Chemistry \L. A. S., D. P. H.]. The Johns Hopkins University School of Medicine. Baltimore.Maryland 21205
SUMMARY
A large number of samples of human neoplastic andabnormal nonneoplastic tissues were studied by nuclearmagnetic resonance spectrometry in order to evaluate thepossible role of this technique in the diagnosis of cancer.The spin-lattice magnetic relaxation times (7",) of abnormal
nonneoplastic tissue were longer, in many instances, thanthose of malignant tumors from similar sites, preventingrecognition of the tumors in this manner. The evidence forthe nonspecific nature of the prolongation of 7",in abnormal
tissue is reviewed, and additional limitations of this technique in the diagnosis of cancer are indicated.
INTRODUCTION
Research by Damadian (4), and subsequently by ourgroup (9, 13 15, 19, 20) and by others (3. 11, 22), hasestablished that the NMR5 relaxation times of tissue waterprotons in malignant tumors of experimental animals arelonger than those of the corresponding normal tissues;although some such tumors may have shorter relaxationtimes than normal tissues from other parts of the body (D.P. Mollis, L. A. Saryan, J. C. Eggleston, and H. P. Morris,submitted for publication to Journal of the National CancerInstitute). Similarly, a comparison of human malignanttumors and corresponding normal tissue indicates thatmost, but not all, of the tumors have prolonged relaxationtimes (3, 6-9, 13, 16, 21) and it has been suggested that thisobservation may prove useful in the diagnosis of humancancer (4, 6-8).
The present study represents the 1st comparison of therelaxation times of a large number of benign neoplastic andnonneoplastic abnormal human tissues with those of humancancers and evaluation of this technique in discriminatingcancer from other abnormalities.
MATERIALS AND METHODS
Tissue samples designed to reflect various disease processes were chosen in the Division of Surgical Pathology
1This is Paper 7 in a series on Nuclear Magnetic Resonance Studies ofCancer.
2The results described herein are part of a dissertation to be submittedin partial fulfillment of the requirements for the Ph.D.
'Supported in part by USPHS Contract NO1-CB-4391I and USPHSGrant ÇAI4817 from the National Cancer Institute.
4To whom requests for reprints should be addressed.sThe abbreviation used is: NMR. nuclear magnetic resonance.Received December 19. 1974; accepted February II, 1975.
from specimens removed surgically at The Johns HopkinsHospital. The specimens were chosen by resident anatomical pathologists under the direction of Dr. J. C. Eggleston.The diseases represented in the specimens were knownthrough previous biopsy or frozen section, or because theywere clinically obvious, e.g. gangrenous extremity. Sampleswere selected from areas obviously involved by the diseasein question, and in many instances additional samples weretaken from apparently uninvolved tissue, e.g., normal tissuein an organ resected for cancer. At least 2 separate sampleswere chosen from each area investigated. In this manner, atotal of 279 specimens from 118 separate patients wereobtained.
Specimens weighing 200 mg were packed into cellulosenitrate centrifuge tubes 5 mm in diameter and 40 mm long(Beckman Instruments, Inc., Spinco Division, Palo Alto,Calif.) and inserted into snap-top airtight plastic tubes(Falcon Plastics, Oxnard, Calif.). Tubes containing specimens were left this way at room temperature generally forno longer than 3 hr. In a few cases, specimens were left foras long as 8 hr. Studies on rodent tissue in our laboratoryand by Frey et al. (11), and on human material in ourlaboratory, showed that tissue stored this way showed 7",
decreases of no more than 5% over a 12-hr period.Reproducibility of the 7, measurements on a single specimen was approximately ±5%.
Relaxation time measurements were made using a BrukerSXP pulsed NMR spectrometer (Bruker Magnetics, Inc.,Burlington, Mass.) operating at 24.3 MHz, equipped with a15-inch Varian magnet (VarÃan Associates. InstrumentDivision, Palo Alto, Calif.). Probe temperature was maintained at 23.0 ±1.0°.A standard sample of 5 x 10 4 M
MnCl2, with a TI of 216 msec at the operating frequency,was measured twice daily and was used to correct proportionately measurements made on different days. Variationof the standard from day to day was ordinarily less than 5%and was thought to be due to slight temperature andfrequency differences or variations in the width of the180-degree pulse noted previously (14). 7",was measured by
the null method (13). This method and a number ofalternative methods for 7", measurement was described in
detail (10). The null method for Tl measurement has theadvantage of being very rapid and fairly satisfactory for usein systems possessing a unique 7",. In cases where more than
1 T, value is resolvable, the null method gives only aweighted average value of the relaxation times. This disadvantage can be overcome by utilizing complete plots of themagnetization behavior versus time as described in Ref. 10.
Following the determination of the 7\ value, the same
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N MR o) Human Tissues
tissue on which the measurement had been made was fixedin 10% formalin, processed, and embedded in paraffin.Hematoxylin- and eosin-stained sections, cut at 6 /im, wereexamined by light microscopy to evaluate various aspects ofthe actual tissue being measured.
Measurements of the 7",were made without knowledge of
the type of tissue being examined, and microscopic evaluation of the tissue was made without knowledge of thecorresponding 7", value.
RESULTS
The results are listed in Tables 1 to 6. Tables 1 to 4contain tissue samples either from a single organ, e.g.,breast, or from a group of related organs, e.g., intestinaltract, while those in Tables 5 and 6 have been groupedmerely for convenience and bear no particular relationshipto each other.
Results for a given organ are listed in decreasing order,arbitrarily using the higher (or highest) of the values as thedetermining factor for that set of samples. The T¡formalignant neoplasms are listed to the right of the diagnosis;those for benign neoplasms and nonneoplastic conditionsare listed to the left of the diagnosis.
Two or more separate samples were taken from eachabnormal tissue, and the 7", of each sample is listed.Specifically, 2 or more 7",values given for each diagnosis do
not represent duplicate determinations on the same tissuesample but determinations on each of 2 samples, eachcontaining tissue of the type indicated by the correspondingdiagnosis. Since, in some instances, more than 1 diseaseprocess was sampled from the specimen of a single patient,the patients represented in each group have been numberedand those with more than 1 process sampled are designatedwith an a. Thus any patient so designated will have at least 1other set of determinations listed elsewhere on the table.The identification number was that used in Surgical Pathology for the specimen examined, omitting the prefix 74-.
Breast. The largest number of samples from any singleorgan in the study is that from the breast, with 85 samplesfrom 34 separate patients. As indicated in Table 1, themalignant tumors had 7", values scattered throughout the
range of all samples. The 5 samples giving the highest valueswere all benign, and 4 of them came from patients withoutcancer. The cancer with the lowest value (Patient 29)occurred in an elderly woman whose atrophie breastcontained large amounts of fat into which the tumor hadinfiltrated; the samples of tissue studied consisted solely ofcancer and fat. Similarly, the benign tissues giving very lowvalues contained significant amounts of fat.
Intestinal Tract. The samples were taken from the colon,small intestine, and stomach (Table 2). Seven of the patientswhose colons were studied had carcinoma of the colon,while 2 had inflammatory bowel disease. In those patientswith carcinoma, uninvolved areas of the colon, whensampled, had longer 7", values than did the actual tumor
tissue (Patients I, 3, 6, and 7). One sample, intended to beuninvolved, had a very low value but contained a microscopic focus of cancer (Patient 7). The highest value for any
of the cancers was found in a villous adenoma with in situcarcinoma but no invasive cancer (Patient 2).In the small intestine the longest 7", was in a specimenremoved for small bowel obstruction. Crohn's disease in
both the colon and the intestine, as well as ulcerative colitisin the colon, had a relatively short 7",.
In the stomach the 1 benign specimen, from a stomachremoved for duodenal ulcer disease, had a longer relaxationtime than did the 3 cancers tested.
Genitourinary Tract. The organs from which malignanttumors were sampled were the prostate and the kidney(Table 3). No discrimination between prostatic hyperplasiaand carcinoma could be made by using the 7",values. This is
most dramatically illustrated by Patient 6, who underwentprostatic enucleation for hyperplasia but whose prostatecontained focal unsuspected well-differentiated carcinoma.This carcinoma was present on 1 of the 2 samples chosen torepresent the hyperplasia, and that sample had the shortest7", of the small series. In the kidney the highest value was
obtained from a malignant tumor. However, 2 othermalignant tumors had 7",values that were exceeded by that
of a rejected allograft (Patient 3) as well as by tissueuninvolved by cancer in 2 instances (Patients 1 and 2).
Soft Tissue. Three neural tumors are listed among thesoft tissues (Table 4), since these tumors present clinically asmasses in the soft tissues. Two of these tumors, both benign,gave the highest Tt values of this group. The 3 malignanttumors are interspersed among the benign specimens nearthe upper range of values, the lower range containing severalspecimens with abundant fat.
Various Other Tissues. In the skin (Table 5) the 1malignant tumor had a longer T, than most of thespecimens but shorter than an area of ulcérationtaken froma patient without tumor. In the lung and pleura (Table 5)both empyema and tuberculosis had T, values longer than Iof the 2 carcinomas, and that of the empyema exceededboth. In the lymphoid tissue a hyperplastic tonsil was 2nd inthe series of 5 specimens. The samples listed in Table 6contain only 1 malignant tumor, a myeloma from an area ofpathological fracture, and thus no comparisons can bemade.
DISCUSSION
Obviously, malignant tumors are highly abnormal conditions and it is well known that they show a variety ofabnormalities in the clinical state of the patient, their grossmorphological and radiographie appearances, various biochemical parameters (12), and their histológica!features. Ithas now been shown that in addition malignant tumors inhumans usually have longer spin-lattice 7", than the normal
tissue in which they occur (68, 21); it has been suggestedthat this may be of value in cancer diagnosis and in fact mayprove a better method of classifying tumors than currentmorphological methods (6-8). The distinction betweencancerous and normal tissue is, however, rarely a diagnostic problem. To be of value in this regard, any techniquemust be useful in distinguishing malignant tumors fromvarious benign neoplastic and nonneoplastic abnormalities
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J. C. Eggleston el al.
Table ISpin-lattice relaxation times of various abnormal mammary tissues
Patient123°45(f78°910II123°138°14151617181920212223242526272829303132336°34Identificationno.112219799249410555123324661316426121248510075953233692494100552612957010169123141078327801089610463104721090710530109704327100161058834019619105243409249696144661110827",
(msec)
(benign)731;
687731;657;643:614678;
563663;640663;588656;
537;537;511631:617628:
549607;600600;558532:450522:437501;499498:
380479;
456;444;433479:450474;
469:419469;
445469;409468;258464:417451:438446:
433:426;424289;
195275;196228;
200222;143219:189199;193194;188152;
144DiagnosisLactating
breastFibrocysticdiseaseLobular
hyperplasiaFibrocysticdiseaseFibrocysticdiseaseInfiltrating
lobularcarcinomaFibrocysticdiseaseFibroadenoma
with secretoryactivityFibrocysticdiseaseFibrocysticdiseaseFibrocysticdiseaseIn
situ and infiltrating lobularcarcinomaInfiltratingwell-differentiated scirrhous carci
nomaJuvenilehypertrophyFibrocysticdiseaseFibrocysticdiseaseFibrocysticdiseaseInfiltrating
scirrhouscarcinomaGynecomastiaFibrocystic
diseaseFibrocysticdiseaseFibrocystic
diseaseFibrocysticdiseaseInflammation
and fatnecrosisFibrocysticdiseaseFibrocysticdiseaseFibroadenomaInfiltrating
poorly differentiatedscirrhouscarcinomaFibrocystic
diseaseFibrocysticdiseaseIntraductal
and infiltrating scirrhous carcinomaFibrocystic
disease(fat)Fibrousmastopathy(fat)Fibrousmastopathy(fat)Fibrocystic
disease(fat)Normalbreast(fat)Fat
and connective tissue7",
(msec)
(malignant)657:641549;
479534;274485;
389439;
357246:
190
°Patients having more than I type of specimen. In some instances more than 1disease process was sampledfrom a single patient.
with a high degree of precision and reliability.There is reason to believe from previously published data
that this technique is not sufficiently specific in this regard.In the largest series comparing human tumors with normaltissues (6—8), the authors note in the text that pulmonaryand splenic congestion gave abnormally high 7", values and
that lactating breasts also gave a very high value. The 1malignant testicular tumor studied (could not be distinguished from normal testis) and metastatic melanoma inlymph nodes gave very low values. Three benign tumorswere studied: a leiomyoma, a juvenile fibroadenoma ofskeletal muscle (sic), and a uterine fibroadenoma. The 1st 2had T, values longer than at least 1 malignant tumor of softtissue, as did a 4th benign tumor, a benign neurilemoma
listed in Table 10 under "Cancers of Nerve" (8). Although
it is stated that cancers of the lung, breast, and adrenalcould be distinguished from normal tissues (6, 8), thesestatements are based on mean determinations rather thanindividual values. In fact, 3 of 5 normal lungs had valuesexceeding 2 cancers (or conversely, 2 cancers fell within thenormal range), the 1 adrenal carcinoma fell below 2 normals and above the other 3, and 1 of the 6 normal breastsequaled or exceeded 2 of the cancers; the other 5 normalbreasts gave very low values, suggesting that largeamounts of fat were present. One of 4 cancers previouslystudied in our laboratory could not be distinguished fromuninvolved (but abnormal) lung tissue (13). This overlapof values is well illustrated in a study of a variety of abnor-
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NMR of Human Tissues
Table 2Spin-lattice relaxation limes of various abnormal ¡issuesof intestinal tract
PatientIa21°3«1-456°6°3"7°7"807°98°i2°2°31234Identificationno.9813111739813443098135056107501139611396443012412124129644454796441073932473247108261233611073410410381T,(msec)
(benign)760;
701658;
657658:
600620;
598594555;
548446:433355;
349649590;
577571:563;546683;
549DiagnosisColonNegative
fortumorVillousadenoma with in situcarcinomaAcute
and chronic inflammation. NegativefortumorNegative
fortumorAdenocarcinomaofcolonAdenocarcinomaofcolonAdenocarcinomaofcolonNegative
fortumorAdenocarcinomaofcolonAdenocarcinomaofcolonInflammation;
negative fortumorAdenocarcinomaofcolonNormal
colonOnefocus of adenocarcinoma ofcolonUlcerative
colitisGranulomatouscolitis (Crohn'sdisease)Small
intestineNonspecificchronicinflammationAdenocarcinoma
ofjejunumNormaljejunumCrohn'sdiseaseStomachChronic
gastritis and parietal cellhyperplasiaAdenocarcinomaofstomachAdenocarcinomaofstomachAdenocarcinomaof stomach7",
(msec)
(malignant)700:
684644:614639:
632624;629:624612:594607:
600573;
343512630:617610:595544:515476;
470
°See Table I, Footnote a.
malities of the thyroid gland in which multiple samples ofeach lesion were examined (21). Five of the 10 carcinomason which histological confirmation was available had 1 ormore 7", values within the benign range (<700 msec), and
6 of the 27 benign conditions had at least 1 value greaterthan 700 msec, in 2 instances not associated with tissuenecrosis.
Recently, Damadian and Cope (5) have studied therelaxation times 7",and 7",beat patterns of potassium (39K)in various tissues. With a "malignancy index," derived fromthe TI of water and an assumed 39K oscillation index foreach tissue, they could separate all malignant tumors of thelung from all normal lungs, and they suggest that increasingthe number of nuclei studied would improve cancer diagnosis. The beat pattern seen in all malignant specimensexamined was assumed to occur in the lung tumors (whichwere not so examined); on this basis the observed 7",values
for the lung tumors were simply doubled, the beat patternalso occurred in normal small intestines and in 1of 5 normalkidneys, and no abnormal nonneoplastic tissue was studied.
In the present study a large number of abnormal tissues,some representing actual problems in cancer diagnosis, wereexamined by NMR spectrometry. As indicated in thepreceding tables, the relationship between the Tl values ofthe cancers and the other tissues did not allow recognition ofthe cancers in this manner. There are several reasons for thisvariable relationship.
The most significant factor lies in the cause of theprolongation of 7",values determined in this manner. There
is now abundant evidence indicating that this prolongationis largely the result of a phenomenon by no means specificfor cancer, namely an increase in the amount of water in thetissue. Studies clarifying this aspect of the problem havebeen published by many groups, and the correlation betweenwater content and relaxation time is now well established onan experimental and theoretical basis (1,2, 14, 16, 17, 19).
In addition, there are several serious practical problemsin the use of 7", values in the diagnosis of human cancer,
many of which are illustrated in the following tables. Thefirst of these lies in the variable and heterogeneous nature ofthe tissue in which the tumor occurs, particularly withregard to the amount of fat present. The breast cancer whichgave the lowest 7"i value in this series (Table I, Patient 29)
occurred in an elderly woman whose breast was atrophieand consisted largely of fat. The tumor could not be entirelyseparated from the fat, even in the surgically removedtumor, and this undoubtedly lowered the Tt value of thespecimen. This variability will be a problem not only in thebreast but in other soft tissues as well.
In addition the variable components of different malignant tumors, many of which are not themselves malignant,may also give unreliable results even within the same organ.The vascularity of tumors, the amount of supportingstroma, the number of accompanying inflammatory cells.
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7. C. Eggleston et al.
Table 3Spin-lattice relaxation times of various abnormal tissues of the genitourinary system
Patient123456°76"1"2°1«342-5123i1«I'11•
See TableIdentifica
tionno.9520952111189519610056951095069510249911264249933731229911264992111199110055057100709450945028291,
Footnote a.T,
(msec)(benign)688;
600551:545395344;
332640;
579613:599573:439469:
456791:686701:640465:
440585:
5555034X4331:325DiagnosisProstaleHyperplasia
andinflammationPoorlydifferentiated carcinoma ofprostatePoorlydifferentiated carcinoma ofprostateHyperplasiaPoorly
differentiated carcinoma ofprostateHyperplasiaHyperplasiaWell-differentiated
adenocarcinoma of prostateKidneyTransitional
cell carcinoma ofpelvisInterstitialinflammationChronicpyelonephritisAcutely
rejectedallograftIrradiatedWilm's tumor withmaturationHypernephromaChronic
glomerulonephritisTestesNormal
testesNormaltestesAtrophyBladderLeiomyomaUrethraNormal
urethraLeiomyomaUterusLeiomyomaTable
47~,
(msec)(malignant)686:661671:627526;
526342700;
635549;
497530;493Spin-lattice
relaxation times of various abnormal softtissuesPatient123456«76°89101112131415161718Identifica
tionno.112841047397919937114093886334438862646981426751107295459505110189514410410478104997",
(msec)(benign)1159;
1082838:548731:585696:
620621:614563;
552556:
499;409;397555:512438:427;414:414408;
352374;327220;195207:201204:
181152:149149;
146DiagnosisPlexiform
neurofibromaNeurofibromaMetastatic
carcinoma ofbreastMarkedinflammationGranulationtissueSkeletal
muscle with inflammation;negativefortumorInflammation
andscarringSquamouscarcinoma oftongueGanglioneuromaRadiation
ulcerMetastaticcarcinoma from unknown pri
maryAtrophyand scarring ofmuscleGangrenous
muscleGangrenewithabscessesFat
and connectivetissueFatand skeletalmuscleNormal
omentumLipomaNormal
fatT,
(msec)(malignant)760:731561:544508;
473
" See Table I. Footnote a.
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N MR of Human Tissues
Table 5Spin-lattice relaxation times of various abnormal tissues
PatientIdentifica
tion no.TI (msec)(benign) Diagnosis
7", (msec)
(malignant)
Skin1" 11135 474:425 Ulcération
2 9483 Metastatic carcinoma of breast 456:3523 10970 432:414 Normal skin4 10177 422:409 Chronic inflammation5 11139 401:384 Scarring and hyperkeratosis1" 11135 346:334 Chronic inflammation
6 10459 302:296 Focal inflammation
Lung and pleura
1 11257 771:741 Empyema2 9762 Adenocarcinoma of lung 656:6443 3375 573:503 Tuberculosis4" 10300 Adenocarcinoma of lung 3664" 10300 270 Lung; negative for tumor
Lvmphoid tissue
1 9574 Metastalic carcinoma of colon 706:3252 10927 662:616 Inflamed hyperplastic lonsil3 9933 Metastatic transitional cell carcinoma 658:3664 3261 Metastatic squamous carcinoma 539:5395 4549 Metastatic carcinoma of colon 426:407
Salivary glands
1 2893 603:596 Benign mixed tumor2 9934 497:497 Benign mixed tumor3 11188 Adenoid cystic carcinoma 462:451
1«23249811572498432:403427:
392ThyroidPapillary
carcinoma ofthyroidNodulargoiterNormal
thyroid693:
664
' See Table 1, Footnote a.
Table 6Spin-lattice relaxation limes of various abnormal tissues
PatientIdentifica
tion no.
7", (msec)
(benign) Diagnosis
7", (msec)
(malignant)
Synovium1 11314 569:507 Reactive synovium2 9513 487:487 Inflammation and scarring3 10436 470:458 Scarring and foreign reaction4 10738 372:365 Pigmented villonodular synovitis5 10321 322:280 Synovium and bone chips
Spleen
1 11022 567:519 Normal spleen2 4090 533:516; Chronic congestion
487:482
Miscellaneous
1 11067 610:548 Thrombus (aortic aneurysm)2 10910 Myeloma in marro» 554:4313 3192 551:515 Chronic cholecystitis4 3489 424:392 Thrombus5 10172 265:263 Gunshot wound of liver
and the amount of hemorrhage and/or necrosis in the tissuemay well significantly alter the 7~, value. In addition,different portions of the tumor may have different 7", values
for reasons not so obvious. The values in the precedingtables have been arranged according to the highest singledetermination, but there is occasional significant variationin the 2 (or more) specimens taken from the same lesion, for
reasons not always apparent on microscopic examination.Averaging the values would result in a different orderingof the specimens but would not permit identification of thecancers.
Similarly, the amount of tumor present in a givenspecimen will determine the 7, value when done by the nullmethod, since both the normal tissue and the tumor are
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J. C. Eggleston et al.
measured. This is particularly significant in biopsies donebefore removal of the tumor or in instances such as needlebiopsy of the liver or other organs. Thus a biopsy specimenfrom an organ with a normal range of 450 to 550 mseccontaining 90% normal tissue with a 7", of 450 msec and10% tumor with a 7", of 1000 msec would have a value
within the normal range (485 msec). Examples of this typeof problem are seen in Table 2 (Patient 7 under "Colon")and Table 3 (Patient 6 under "Prostate") where microscopic foci of cancer were undetected by magnetic spec-trometry.
Finally, even in those instances where spectrometryindicates a "malignant tumor," this information is not
sufficiently specific to guide appropriate therapy. Obviously, a primary sarcoma, a metastatic carcinoma, and alymphomatous mass require quite different therapeuticapproaches, yet all are malignant tumors and may presentin a similar fashion. Since NMR is currently done on tissueremoved from the patient and thus suitable for microscopicexamination, no additional information is obtained from the7", determination.
We recognize that some of the difficulties mentionedabove, such as the effect of the intermixture of fat or othertypes of nonmalignant tissues with malignant tissues couldbe overcome by the determination of the 7\ values from ahigh-resolution NMR spectrum using an inversion-recoverymethod (10) rather than the null method. In addition, it isconceivable that further development of the NMR zeug-matography technique (18) could permit spatial resolutionof foci of cells of different relaxation times present in aspecimen of tissue. In our view the most optimistic prognosis would suggest that such refinements might permit alimited but possibly important role for NMR in screeningorgans such as breasts for foci of abnormal cells having longTVs. The direct use of NMR 7", measurements for cancer
diagnosis is clearly not feasible, however, because of thelack of specificity.
We feel that prolongation of the spin-lattice relaxationtime is largely the result of increased water content of thetissue examined, a factor in no way specific for cancer, andthat it is further significantly affected by variable factorsoccurring in clinical diagnostic situations. The data presently available indicate that this technique does not providea valuable primary or adjunct method of cancer diagnosis,and classification of tumors in this manner does not seemrealistic.
ACKNOWLEDGMENTS
We acknowledge helpful discussions with Dr. Jeffrey L. Czeisler andJames S. hconomou and the proficient technical assistance of Deborah M.
Cox.
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1975;35:1326-1332. Cancer Res Joseph C. Eggleston, Leon A. Saryan and Donald P. Hollis Neoplastic and Abnormal Nonneoplastic TissuesNuclear Magnetic Resonance Investigations of Human
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