Serum Total and Isoenzyme Lactate Dehydrogenase Activity in American Burkitt's Lymphoma Patients

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Serum Ttal and Isenzyme Lactate Dehydrgenase Activity American Burkitt's Lymphma Patients GYORGY CSAKO, M.D., IAN T. MAGRATH, M.D., M.R.C.P., AND RONALD J. ELIN, M.D., PH.D. Serum ttal lactate dehydrgenase (LDH) and LDH isenzyme activities were studied 45 American patients with a tissue diagnsis f Burkitt's lymphma.

1 Serum Ttal and Isenzyme Lactate Dehydrgenase Activity American Burkitt's Lymphma Patients GYORGY CSAKO, M.D., IAN T. MAGRATH, M.D., M.R.C.P., AND RONALD J. ELIN, M.D., PH.D. Serum ttal lactate dehydrgenase (LDH) and LDH isenzyme activities were studied 45 American patients with a tissue diagnsis f Burkitt's lymphma. Serum ttal LDH activity crrelated with tumr burden as determed by clical stagg at presentat r clical stage f the disease prcess ("disease status"). Tumr lysis by chemtherapy cnsiderably creased the serum ttal LDH activity. Fr the LDH isenzyme pattern, the largest relative creases were fund with LDH3 and LDH4, whereas the highest isenzyme activities ccurred with LDH and LDH3. Thus, the ttal and isenzyme LDH activities are helpful t evaluate the tumr burden and prgnsis patients with Burkitt's lymphma. (Key wrds: Serum LDH; LDH isenzymes; Burkitt's lymphma) Am J Cl Pathl 19; : 1-1 THE ENZYME lactate dehydrgenase (LDH) is widely distributed amng tissues humans. 10 Necrsis f several different tissues may result an crease f serum ttal LDH activity. Sce the enzyme activity is a cmpsite f five different isenzymes, 9 the prprt f which differs amng the tissues, the pattern f the LDH isenzyme activity with an elevated ttal LDH activity may dicate the tissue r tissues f rig effectg the elevated ttal LDH activity. 13 The serum ttal LDH activity has been shwn t be creased several human malignancies. In particular, a clse crrelat has been fund between serum ttal LDH activity and the tumr burden Burkitt's lymphma patients. 4 ' ' 1416 T date, the distribut f serum LDH isenzymes patients with this rapidly grwg neplasm has nt been studied detail. In this study, we reprt the serum ttal and isenzyme activities f patients with a diagnsis f American Burkitt's lymphma at different stages (presentat, duct f first remiss, remiss, relapse, and pretermal relapse) f the disease. Patients and Methds The frmat fr this study was btaed frm 45 patients admitted t the Pediatric Onclgy Branch (POB) f the Natal Cancer Institute (NCI) f the Natal Institutes f Health (NIH) fr stagg and treat- Received January 13, 19; received revised manuscript and accepted fr publicat March 1, 19. Address reprt requests t Dr. El: Buildg 10, Rm C-306C, Natal Institutes f Health, Bethesda, Maryland //1100/01 $01.10 Clical Chemistry Service, Clical Pathlgy Department, Clical Center and the Pediatric Onclgy Branch, Natal Cancer Institute, Natal Institutes f Health, Bethesda, Maryland ment between January 1, 196 and December 31, 190. In all patients, the diagnsis f Burkitt's lymphma was cnfirmed histlgically by the Labratry f Pathlgy f the NCI. In addit, each patient was required t have ne r mre determats f serum ttal and isenzyme LDH activities perfrmed n the same specimen. At presentat, the median age f the patients was 19 years f age (range f t 49 years) (Fig. 1). Thirty-three f the 45 patients were male and 1 were female (male:female rati f.:1). Frty-three were Caucasian, ne was Oriental, and ne was Black. After explag the prcedures and the nature f treatment vlved, frmed cnsent was btaed frm all patients. Clical stagg f the patients was carried ut accrdg t standard prcedures as described previusly. ' 16 ' 1 ' 0 C/m/aj/ stagg is used here t describe the status f patients at presentat as defed belw, whereas the clical stage f patients durg the disease prcess is referred t as disease status. At the time f presentat, seven patients were classified as havg Stage A disease (sgle extra-abdmal tumr), tw were Stage B (multiple extra-abdmal tumr sites), 1 had Stage C disease (tra-abdmal tumr), 15 were fund t have Stage D disease (tra-abdmal tumr + extra-abdmal vlvement), and fur had Stage AR Burkitt's lymphma (>90% resect f abdmal tumr therwise untreated patients with Stage C disease). Patients were managed accrdg t standard POB prtcls fr nn-hdgk's/burkitt's lymphmas. 119 In sme patients, lcalized tumr was remved surgically prir t chemtherapy. In a few cases, chemtherapy was supplemented by lcal irradiat. Ttal bdy irradiat has been used recently the treatment f patients at the time f relapse. Patients were gruped accrdg t the disease status. The fllwg five ma grups were selected: presentat, duct f first remiss, remiss, relapse, American Sciety f Clical Pathlgists 1 Dwnladed frm n 0 July 01

2 vl. N. 5 SERUM LDH IN BURKJTT'S LYMPHOMA [ 3 and pretermal relapse. Further dissect f sme f the grups ultimately resulted eight grups (Table ). The presentat grup was divided t tw grups based upn the itial serum ttal LDH activity (thse with a ttal LDH activity belw the upper limit f the reference terval f 4 U/L and thse with a value greater than 4 U/L). The relapse grups were subdivided t pretreatment and psttreatment grups. The pretermal relapse grup is cmpsed f thse patients wh were relapse at the time f ttal and isenzyme LDH determat and expired with weeks. If multiple results were available fr a patient at a particular stage the disease prcess, the result with the highest ttal LDH activity was selected fr this study. Each patient culd appear mre than ne grup dependg n the prgress f the disease. This is why 60 patients are listed amng the eight grups with nly 45 the study. The ttal LDH activity was measured spectrphtmetrically at 340 nm by a ketic methd (xidat f L-lactate) with a Sequential Multiple Analyser with Cmputer (SMAC, Technicn Instruments Crprat, Tarrytwn, N.Y )." The five LDH isenzymes (LDH 1-5) were determed by a standard prcedure usg agarse gel electrphresis (Crng Medical and Scientific, Pal Alt, CA 94306). W3 1 r 10 a. 0 6 cr UJ 1 4 i (O J^ i O c 1 AGE OF PATIENTS (yrs) FIG. 1. Age distribut f 45 patients with American Burkitt's lymphma at the time f presentat. 5 c Table 1. Prgnstic Value f Clical Stagg and Serum LDH Levels at Presentat Number f patients Sex f patients Male Female Age f patients (yr) Mean ± SEM Range Stage f disease Stages A + B + AR Stages C + D Ttal LDH (U/L) (Mean ± SEM) Survival* In cmplete remiss! Deceasedft LDH ; 4 U/L ± 3. (3-36) 6 15 ± 16 0 LDH > 4 U/L ± 3.3 (5-34) 1,19 ±3 As f nw, i.e., at the time f preparat f manuscript. Length f fllw-up is cmparable fr the tw grups. t In each case dicates at least a -year survival. tt Mean survival ± SEM =. ± 1.1 mnths, rangg frm 5 t 1 mnths. Serum Ttal LDH Results The seventeen Burkitt's lymphma patients wh were studied at presentat fr LDH were divided t tw grups n the basis f their itial serum ttal LDH activity usg the upper limit f ur reference terval (4 U/L) as the discrimatr. The serum LDH levels with the sex, age, stage f disease, and survival data are presented Table 1. All patients that had a serum ttal LDH activity with the reference terval at presentat survived fr at least tw years and were remiss. Of the ne patients that had a serum ttal LDH activity greater than the reference terval at presentat, six died with ne year. It is als seen frm Table 1 that the frmer grup was cmprised mstly f patients with small tumr burden (Stages A + B + AR), whereas the latter grup cnsisted f patients with larger tumr masses-unresected r, mre frequently, unresectable tra-abdmal tumrs with r withut extraabdmal vlvement (States C + D). The serum ttal LDH activity shwed cnsiderable variats amng the eight grups f Burkitt's lymphma patients (Table ). Therapeutic tervent, whether fr the duct f the first remiss, fr relapse, r fr pretermal relapse, caused a mean elevat f the serum ttal LDH activity f greater than 1,000 U/L. In each f the five patients whm isenzyme levels were estimated at the time f remiss, the serum ttal LDH activity was with the reference 3 6 Dwnladed frm n 0 July 01

3 14 CSAKO ETAL. Table. Serum Ttal and Isenzyme LDH Activities Patients with Burkitt's Lymphma AJ CP ' * Nvember 19 Number f Patients Ttal LDH (U/L)* 1 LDH Isenzymes (rel. %)* Presentat (LDH & 4 U/L) 15 ± 16 (116-4) 1 ± 1 (14-6) 35 ± 1 (31-41) 3 ± (19-33) 11 ± 1 (9-14) (-15) Presentat (LDH > 4 U/L) 9 1,19 ±3 (36-,556) 14 ± (9-) 3 ± (3-4) 9 ± (1-3) 13± 1 (-1) ± (4-0) Induct f first remiss,13 ± 1,354 (51-10,60) 13± (3-19) 35 ±3 (6-4) 3 ±3 (3-4) 14 ± (-6) 6+ 1 (-1) Remiss 5 05 ± 10 (11-41) 0 ± (1-4) 3 ± 1 (3-41) 1 ± 1 (1-3) 1 ± 1 (-13) (-15) Relapse 603 ± 134 (9-1,314) 13 ± (-4) 3 ± (-3) ± (1-34) 1 ± (10-4) 9± 1 (5-13) Relapse + therapy,14 ± 556 (44-5,10) 1 ± (4-16) 31 ±4 (11-40) 9 ±3 (1-39) 0 ±4 (-3) + (1-15) Pretermal relapse 9 4,955 ± 1,90 (46-1,110) 1 ± 1 (9-19) 9 ± (1-3) 9 ± (16-3) 1 ± (1-4) (3-4) Pretermal relapse + therapy 6,90 ±,09 (95-15,0) 14 ± 1 (-19) 35 ± (4-4) 31 ± 3 (19-44) 13 ± (-5) + (1-1) Reference tervalf All patients with LDH. 4 U/Lft ±3 0 ±0 34 ±0 ±0 11 ±0 13 ±0 * Results are expressed as the means ± SEM. Range is given the brackets. t Reference terval (expressed as the.5 and 9.5 percentiles) fr serum ttal LDH was established with healthy Bld Bank dnrs, whereas Cmg's technical bullet data are presented fr ranges f LDH isenzymes. tt All patients wh entered the NIH Clical Center with varius diagnses between January 1, 196 and December and had a serum ttal LDH activity f 4 U/L with simultaneus determat f LDH isenzymes. Fr all isenzymes. SEM is less than 0.5%. terval. Of terest is the fdg that pretermal relapse prir t therapeutic tervent was characterized by a mean serum ttal LDH activity f apprximately 5,000 U/L. The mean serum ttal LDH activity f thse patients the pretermal relapse grup was mre than eight-fld greater than thse patients the relapse grup (Table ). Serum LDH Isenzymes The serum LDH isenzyme patterns were analyzed three ways, i.e., relative percentage (Table ), abslute activities (Fig. ), and as a rati f the LDH isenzyme activity fr a particular stage f the disease versus the cncentrat with cmplete remiss f the disease (Fig. 3). The mean value fr LDH3 was at r exceeded the upper limit f the reference terval five f the eight grups (Table ). The majrity f patients with Burkitt's lymphma wuld have a relative percentage f LDH3 with the reference terval nly at presentat with a nrmal serum ttal LDH activity, durg remiss, and durg relapse withut therapeutic tervent. Thus, an elevat f the relative percentage f LDH3 was characteristic f patients with Burkitt's lymphma. The mean value fr LDH4 was at r abve the upper limit f the reference terval fr three f the fur relapse grups. Only the pretermal psttreatment relapse grup had a relative percentage f LDH4 that was with the reference terval. The mean value fr the relative percentage f LDH 1 was lw the fur relapse grups cmpared with the reference terval. All mean values fr the relative percentage f LDH and LDH5 were with the reference tervals fr the eight grups. The abslute activities f LDH isenzymes are the highest LDH and LDH3 (Fig. ). In the three grups with therapeutic tervent (duct f thefirstremiss, relapse + therapy, and pretermal relapse + therapy) a "flip" the nrmal LDH t LDH3 rati ccurred that the LDH3 cncentrat exceeds that f LDH. In the tw relapse grups withut therapeutic tervent, the activities f LDH and LDH3 are cmparable. In an attempt t determe the relative crease f LDH isenzyme activities Burkitt's lymphma, the isenzyme activity each patient was expressed as the rati t the mean isenzyme activities the grup f patients remiss. The mean values f ratis are shwn Figure 3. Sce the isenzyme activities the presentat grup with LDH ^4 U/L were essen- Dwnladed frm n 0 July 01

Vl. N. 5 SERUM LDH IN BURKITT'S LYMPHOMA 15 O 1.0 r 0.5 0 3.0 Presentat (LDH 4) Presentat (LDH > 4) Relapse + Chemtherapy Pretermal Relapse + Chem/Raditherapy Z I- I- Z Ul z I a.5.0 1.5 1.

4 Vl. N. 5 SERUM LDH IN BURKITT'S LYMPHOMA 15 O 1.0 r Presentat (LDH 4) Presentat (LDH > 4) Relapse + Chemtherapy Pretermal Relapse + Chem/Raditherapy Z I- I- Z Ul z I a Induct f 1st Remiss Pretermal Relapse 0.5- Cmplete Remiss (D(D (D(D (D LDH ISOENZYME FRACTIONS FIG.. Abslute LDH isenzyme activities eight different grups f patients with American Burkitt's lymphma. Mean ± SEM. tially identical t thse the remiss grup, the ratis fr each f the isenzymes are clse t unity and are nt shwn the figure. In fur f the six grups presented Figure 3, the relative crease LDH3 was the largest. In the ther tw grups (relapse and relapse + therapy), LDH4 shwed the largest relative crease. The relative crease f LDH3 and LDH4 is greater than that f the ther three isenzyme fracts fr all six grups. LDH 1 shwed the smallest relative crease each f the six grups. Discuss American Burkitt's lymphma ccurs mst frequently lder children and yung adults. 1,41 In bth African and American patients, Burkitt's lymphma has been fund t shw a higher cidence males than females When cmpared t the classical frm ("jaw sarcma") ccurrg East African patients, 1 American Burkitt's lymphma has been bserved t differ a number f ways, cludg a greater frequency f abdmal tumr and lwer cidence f jaw tumrs The patient ppulat evaluated the present study exhibited the features cnsistent with American Burkitt's lymphma. Burkitt's lymphma is a very rapidly grwg tumr with a clical dublg time estimated t be 66 hurs, and with a ptential dublg time f abut 6 hurs. 51 The high prliferative rate (grwth fract apprachg 100%) 6 cmbed with a high rate f "spntaneus" cell death the tumr (>0% f the rate f cells enterg the DNA synthesis) 5 can expla the series f bichemical abnrmalities like an elevated cncentrat f serum ttal LDH patients presentg with large (usually abdmal) tumrs r thse relapse. Indeed, serum ttal LDH is a useful tl fr assessg prgnsis and fr mnitrg the patients Our data cnfirm the value f this enzymatic dicatr as a crrelate f disease status (Table ). Mrever, as expected, ptent chemtherapy als creased, apparently by enhancg tumr lysis, the LDH cncentrat the serum. The results btaed here n a relatively large number f American Burkitt's lymphma patients have shwn that, where serum ttal LDH is elevated, LDH and LDH3 are the mst abundant isenzyme fracts. In relative percentages, hwever, LDH3 and LDH4 displayed the highest creases when the serum ttal LDH was elevated. The specific crements (active disease/ cmplete remiss ratis fr LDH isenzymes which is expressed U/L) even mre clearly demnstrated that LDH3 and LDH4 are the mst specific markers f Dwnladed frm n 0 July 01

5 16 CSAKO ETAL. A.J.C.P. Nvember 19 RELAPSE + CHEMOTHERAPY 0 w w 10 UJ w Q 40 - PRESENTATION ILDH>4) RELAPSE PRETERMINAL RELAPSE PRETERMINAL RELAPSE + CHEMO/RADIOTHERAPY - 30 q 0 tr 0 L- INDUCTION OF 1ST REMISSION 1 I P 1 LDH ISOENZYME FRACTIONS FIG. 3. The rati (relative crease) f LDH isenzyme activities six different grups f patients with American Burkitt's lymphma (numeratr) cmpared t the mean isenzyme activities f the remiss grup (denmatr). disease status. Sce there is a high nrmal level f LDH, this isenzyme is less useful as a marker f tumr burden. A previus study f a small grup f East African children with Burkitt's lymphma supprts the fdgs f this reprt. I4 An crease LDH3 was nted as beg characteristic fr Burkitt's lymphma by visual examat f electrphresis slides. 14 Recently, Magrath and clleagues analyzed three tumrs frm African Burkitt's lymphma cases. Tw specimens cntaed welldetectable levels f LDH with an isenzyme distribut pattern clsely similar t that seen sera f patients with elevated ttal LDH, that is, shwg the predmance f LDH3 and LDH. The third specimen, fr unknwn reasns, had n measurable LDH activity. Mst recently, high levels f LDH 3 and LDH4 were bserved fresh tumrs and tumr cell les btaed frm American patients with Burkitt's lymphma. 3 The assciat f high serum levels f LDH3, LDH4, and LDH with Burkitt's lymphma is als cnsistent with results btaed n an African Burkitt's lymphma cell le. Accrdg t Trenfield and Masters, 15 Raji lymphma cells grwn vitr shw a fairly cnstant LDH isenzyme pattern thrughut the cell cycle. The authrs nted that LDH3 cntributes relatively mre percentages than LDH and LDH4, which are, turn, much greater than LDH1 and LDH5. In addit, nrmal B cells have greater cncentrats f LDH 3 and LDH4 than thse f the ther isenzymes. 3 There was an terestg "discrepancy" the LDH isenzyme patterns f ur patients with high ttal serum LDH. When the ttal serum LDH was elevated, LDH3 usually exhibited a relatively greater crease than LDH4. In the relapse and relapse + chemtherapy grups, this situat was reversed. Whether this reflects a specific event r just simply the cnsequence f nnspecific factrs (e.g., relatively lw number f patients per grup r different patients different grups) remas t be elucidated. Nevertheless, it is hped that knwledge f the particular LDH isenzyme patterns that are assciated with Burkitt's lymphma will aid the clician t distguish between tumr-related and secndary cmplicats durg the stages f disease when the ttal serum LDH cncentrat is elevated. Acknwledgment. The authrs wish t thank Mrs. Jsia Hagner fr her excellent assistance with the preparat f the manuscript. References 1. Arseneau JC, Canells GP, Banks PM, Berard CW, Gralnick HR, DeVita VT: American Burkitt's lymphma: A clicpath- Dwnladed frm n 0 July 01

6 Vl. N. 5 SERUM LDH IN BURKITT'S LYMPHOMA 1 lgic study f 30 cases. I. Clical factrs relatg t prlnged survival. Am J Med 195; 5: Bierman HR, Hill BR, Rehardt L, Emry E: Crrelat f serum lactic dehydrgenase activity with the clical status f patients with cancer, lymphmas and leukemias. Cancer Res 195; 1: Blatt J, Spiegel RJ, Papadpuls NM, Lazaru SA, Magrath IT, Pplack DG: Lactate dehydrgenase isenzymes nrmal and malignant human lymphid cells. Bld 19; 60: Chen LF, Balw JE, Magrath IT, Pplack DG, Ziegler JL: Acute tumr lysis syndrme. A review f 3 patients with Burkitt's lymphma. Am J Med 190; 6: Iversn OH, Iversn U, Ziegler JL, Blumg AZ: Cell ketics Burkitt's lymphma. Eur J Cancer 194; 10: Iversn U, Iversn OH, Blumg AZ, Ziegler JL, Kyalwasi S: Cell ketics f African cases f Burkitt lymphma. A prelimary reprt. Eur J Cancer 19; : Magrath IT, Janus C, Edwards B, et al: An effective therapy fr bth T- and B-cell lymphmas yung peple. Submitted fr publicat. Magrath I, Lee YJ, Andersn T, et al. Prgnstic factrs Burkitt's lymphma. Imprtance f ttal tumr burden. Cancer 190;45: Markert CL: Lactate dehydrgenase isenzymes: dissciat and recmbat f subunits. Science 1963; 140: Markert CL, Mcller F: Multiple frms f enzymes: tissue, ntgenetic, and species specific patterns. Prc Natl Acad Sci USA 1959; 45: Mrgenstern S, Rush R, Lehman D: Chemical methds fr creased specificity, Advances Autmated Analysis, 19 Internatal Cngress. Vlume 1. Tarrytwn, Mediad Inc. 193, pp Nkrumah FK, Perks IV: Burkitt's lymphma. A clical study f 110 patients. Cancer 196; 3: PapadpulsNM: Clical applicats f lactate dehydrgenase isenzymes. Ann Cl Lab Sci 19; : Shaw B: Studies n serum lactate dehydrgenase Burkitt's lymphma patients durg chemtherapy. East Afr Med J 190: 4: Trenfield K, Masters C: Patterns f synthesis and degradat f lactate dehydrgenase durg the cell cycle f Burkitt's lymphma cells. Int J Bichem 190; 11: Tsks GC, Balw JE, Spiegel RJ, Magrath IT: Renal and metablic cmplicats f undifferentiated and lymphblastic lymphmas. Medice 191; 60: Ziegler JL: Treatment results f 54 American patients with Burkitt's lymphma are similar t the African experience. N Engl J Med 19; 9: Ziegler JL, Blumg AZ, Fass LK, Mrrw RH: Relapse patterns Burkitt's lymphma. Cancer Res 19; 3: Ziegler JL, Deisserth AB, Appelbaum FR, Graw RG Jr: Burkitt's lymphma: a mdel fr tensive chemtherapy. Sem Oncl 19;4: Ziegler JL, Magrath IT: Burkitt's lymphma: Pathbilgy Annual. Edited By HL Iachim. New Yrk, Appletn-Century Crfts, 194, pp Dwnladed frm n 0 July 01

M.J. Guthriel, D.G. Wagner2

EFFECT OF SUPPLEMENTAL PROTEIN OR GRAIN ON INTAKE AND UTILIZATION OF MEDIUM QUALITY PRAIRIE HAY BY STEERS M.J. Guthriel, D.G. Wagner2 and D.C. Weakley3 Stry in Brief Sixteen 1,053 lb tw-year-ld Herefrd