CONTENTS Hepatitis and Leukemia J. P. Fiore M. E. Conrad and J. C. Barton R. A. Neiman M. E. Conrad and J. C Barton Acute Nonlymphocytic Leukemia After Treatment with Radiomimetic Drugs R. R. Reimer and C W. Groppe, Jr. Thrombotic Thrombocytopenic Purpura: Failure of Plasma Infusion and Antiplatelet Agents R. Stern, C J. Cornell, R. Beck, andR. E. Smith Rheumatic Fever in Adults F. G. Aguilar-Torres and L. J. Jackson Zinc Deficiency and Intestinal Bypass Procedures J.A. Garofa/o, E. Strong, andR.A. Good Hypothermia Treatment Needs Controlled Studies F. P. Chinard Eikenella corrodens as Pathogen J. G. Sinkovics, C. Plager, andK. Mills Cimetidine and Impaired Renal Function G. D. Luk, W. J. Luk, and T. R. Hendrix

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989 989 990

Cimetidine and Agranulocytosis F. H. Al-Kawas, B. A. Lenes, andR. A. Sacher Cimetidine and Effect of Warfarin B. A. Wallin, A. Jacknowitz, and P. C Raich Lactation from Tamoxifen in Breast Cancer G. R. Favis, J. B. Alavi, and J. H. Glick Analgesic-Associated Urinary-Tract Tumors K. R. Burnett, J. B. Miller, and E. Greenbaum Lithium and Generic Nonequivalence G. E. Pakes Dialysis and Psoriasis H. Graf, A. Wolf, and H. K. Stummvoll Skin Color and Race in Clinical Medicine M. Gutwein X-Linked Lymphoproliferative Syndrome Registry D. T. Purti/o and J. Hamilton

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Correction: Testicular Neoplasm Review T. Anderson



Letters submitted for publication must be typed double-spaced. Text length must not exceed 500 words, and no more than five references may be used. Complete references must be furnished, as specified in "Information for Authors" (page 1-6). Specific permission to publish should be appended as a postscript. Publication depends on availability of space: We give preference to comment on recent content and to new information. Letters for this section should be concise—the Editor reserves the right to shorten them and make changes that accord with our style.

poorly and selected a group of patients who were destined to live longer and who had more time to develop SGOT elevations.

Hepatitis and Leukemia

In reply: The relatively low incidence of HBsAg among our transfused leukemic patients with transaminase elevations is probably due to the national exclusion of hepatitis B carriers as blood donors and is similar to that in other studies of posttransfusion hepatitis in nonleukemic patients, in which 80% of patients are believed to have non-A, non-B hepatitis (1). Until serologic methods for detection of non-A, non-B hepatitis are developed, tests that detect liver dysfunction must be used for diagnosis. Although abnormalities of the serum alkaline phosphatase and lactic dehydrogenase were seen in our patients, persistent transaminase elevations were used in the study because they are more specific and this is the criterion used in most other recent hepatitis investigations (2). Two consecutive SGOT values greater than 50 m U / m L ( > 3 S D from mean normal values) obtained at least 1 week apart were required for a tentative diagnosis of hepatitis. In our patients, at least one of these values was greater than 70 m U / m L ( > 5 SD from mean values). It is not surprising that post-transfusion hepatitis is usually a mild disease in leukemic patients, with only modest elevations of SGOT and abnormalities in liver biopsy specimens. These findings are similar to those observed in immunosuppressed patients with renal disease who develop hepatitis and in whom the diagnosis is more difficult to challenge because of the concomitant occurrence of HBsAg in blood specimens (3). It is well known that symptomatic icteric hepatitis is much less common in renal dialysis patients than in their families or the personnel who care for them. The hepatitis viruses are probably not directly hepatocytotoxic and require cell-mediated immunocompetence for clinical and histologic manifestations (4). Further, leukemic patients with hepatitis type B and HBsAg in

T o T H E EE>ITOR: I wish to offer several criticisms of the paper by Barton and Conrad in the February issue (1) on possible prolonged survival of leukemic patients who contract hepatitis. The authors use SGOT elevation as the major diagnostic criterion for hepatitis but acknowledge that the causes of mild SGOT elevation in leukemia can be heterogeneous, including leukemic infiltration of the liver and chemotherapeutic drugs. The authors do not state what the mean SGOT elevation was, but apparently an SGOT concentration of 50 m U / m L (normal range, 10 to 40) for more than 1 week was considered elevated. Using such minimally elevated values as criteria would tend to include patients who had SGOT elevations from causes other than hepatitis. The patients who developed SGOT elevations seemed to live longer, but perhaps this was because they had more prolonged treatment with chemotherapeutic drugs, codeine derivatives, or other mildly hepatotoxic drugs. Patients were treated with several different regimens; perhaps these had different hepatotoxic effects. Other liver enzyme tests were not done. The serologic and biopsy results are not convincing. Only two of 36 patients were HBsAg positive. Only 11 patients were studied by biopsy or autopsy, and in no case did the hepatic histology suggest hepatitis. The findings are heavily biased on another count, even if it is allowed that patients with mild SGOT elevations had posttransfusion hepatitis. The initial elevation of SGOT was seen 7.0 + 4.9 weeks after the start of therapy, but by arbitrarily excluding from analysis patients who did not survive the first 6 weeks, the authors have excluded a group of patients who did

J O S E P H P. F I O R E , M . D .

Menorah Medical Center; Kansas City, MO 64110 REFERENCE

1. BARTON JC, C O N R A D ME: Beneficial effects of hepatitis in patients with acute myelogenous leukemia. Ann Intern Med 90:188-190, 1979

Letters and Correction

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their parenchymal liver cells usually have a mild clinical course and histologic changes in biopsy specimens similar to renal dialysis patients and to our leukemic patients with purported nonA, non-B hepatitis. The possibility that drug therapy was responsible for our reported findings was carefully reviewed in each case, even though it was believed unlikely that drug-induced hepatitis would prolong survival. A s have others (5), we saw no worsening of clinical or laboratory findings with continued therapy; this is contrary to the usual observations in drug-associated hepatitis. In addition, the prevalence of transaminase elevations in leukemic patients has markedly increased since the introduction of prophylactic platelet transfusions, with administration of blood products from six to 10 donors several times weekly during induction therapy. Patients who did not survive the first 6 weeks of therapy were excluded to provide a fairer comparison because of the incubation period of hepatitis. It biases the study against our conclusions because the patients who died early did not develop evidence of hepatitis. It could be postulated that if patients live longer they have a greater chance of developing hepatitis. Since the initial elevation of SGOT, however, was seen 7.0 ± 4.9 weeks after initiation of therapy, this does not influence our conclusions. We do not believe it is fortuitous that this is the incubation period for post-transfusion hepatitis. Most of our patients with acute myelogenous leukemia are exposed to hepatitis because of the number of donor units they receive, and those who are immunologically capable of responding to this exposure have a better prognosis. Alternatively, the myelosuppressive effect of hepatitis may have a beneficial effect upon the disease, as has been postulated for 100 years. M A R C E L E. C O N R A D , M . D . J A M E S C. B A R T O N , M . D .

University of Alabama; University Station, Birmingham, A L 35294 REFERENCES 1. K N O D E L L RG, CONRAD ME, DIENSTAG JL, BELL CJ: Etiological spec-

trum of post-transfusion hepatitis. Gastroenterology 69:1278-1285, 1975 2. SURGENOR DM, CHALMERS TC, C O N R A D ME, F R I E D E W A L D WT, G R A D Y GF, HAMILTON M, MOSLEY JW, PRINCE AM, STENGLE JM:

Clinical trials of hepatitis B immune globulin. Development of policies and materials for the 1972-1975 studies sponsored by the National Heart and Lung Institute. N Engl J Med 293:1060-1062, 1975 3. SZMUNESS W, PRINCE AM, G R A D Y GF, M A N N MK, LEVINE RW, FRIEDMAN EA, JACOBS MJ, JOSEPHSON A, RIBOT S, SHAPIRO FL,

STENZEL KH, SUKI WN, VYAS G: Hepatitis B infection. A point-prevalence study in 15 US hemodialysis centers. JAMA 227:901-906, 1974 4. WERNER B, LONDON WT: Host responses to hepatitis B infection: hepatitis B surface antigen and host proteins (editorial). Ann Intern Med 83;113-114, 1975 5. ARMITAGE JO, BURNS CP, K E N T TH: Liver disease complicating the management of acute leukemia during remission. Cancer 41:737-742, 1978

T o THE EDITOR: There is some sensationalism and misrepresentation in the title "Beneficial Effects of Hepatitis in Patients with Acute Myelogenous Leukemia" in the February issue (1). The authors do not provide any data indicating an effect of hepatitis on acute myelogenous leukemia; rather, the data only indicate a quite possibly coincidental relation. The authors themselves, in concluding statements, postulate that the relation is probably more a manifestation of a competent immune system than a result of the hepatitis. Misleading titles such as this one can only detract from the editorial integrity and reputation of your journal. R I C H A R D A. N E I M A N , M.D.

Providence Medical Center; Portland, OR 97213

In comment: The belief that there is a direct beneficial effect of certain infections on leukemia and other hematologic malignancies is not a novel hypothesis but, rather, a century old (1). Temporary improvement in the clinical and hematologic status of patients with acute leukemia was reported during the 19th century and was reviewed by Dock in 1904 (2). Since these reports, there have been well-documented cases in which the progress of leukemia was temporarily interrupted by intercurrent infection (3). Before World War II, this relation was sufficiently well known that some physicians exposed their leukemic patients to the childhood exanthematous viral illnesses in the hope of obtaining a transient remission. Inoculation of humans with viruses to which they had no immunity has been shown to produce objective evidence of tumor regression in patients with hematologic malignancies (4). Interest in this phenomenon has waned because of the increasing availability of effective chemotherapeutic drugs with a more predictable response. This does not, however, alter the probability that certain patients with hematologic malignancies may benefit from an intercurrent infection. We do not believe that either the journal or we owe Dr. Nieman an apology for a misleading title because the content deals with the subject summarized above, and this is discussed and referenced in the publication (References 24-29). We agree with Dr. Nieman that our data provide only a statistical correlation between the development of evidence of hepatitis and an increased probability of remission and survival in acute myelogenous leukemia. Currently, direct proof of a cause-and-effect relationship requires inoculation of a randomized group of patients with live virus, regarded as unconscionable for anyone with a potentially fatal disease. We think it unlikely that the proposed relationship is coincidental because we have recently redemonstrated the correlation in a prospective study of leukemic patients. These data are summarized in the April 1979 issue of Clinical Research. The effects of post-transfusion hepatitis on acute myelogenous leukemia are an important consideration in the treatment of this disease because of the high risk from the large number of units of donor blood and platelets to which these patients are exposed. It is this, rather than sensationalism, that prompted us to publish these findings. An alternative explanation to the possibility that hepatitis had a direct beneficial effect on the leukemia is that patients who fail to show evidence of hepatic dysfunction may do so because they have a less competent immune system (5). This concept is novel in this setting and may explain some of the older data. More information needed to ascertain which of these explanations is most valid probably must await the development of an antigen-antibody method to test for exposure to non-A, non-B hepatitis after transfusion. M A R C E L E. C O N R A D , M . D . J A M E S C. B A R T O N , M . D .

University of Alabama; University Station, Birmingham, A L 35294


1. EISENLOHR C: Neuropathologische Beobachtungen. I. Leucaemia lienalis, lymphatica et medullaris mit multiplen Gehirnnervenlahmungen. Virchows Arch [Pathol AnatJ 73:56-73, 1878 2. DOCK G: The influence of complicating diseases upon leukemia. Am J MedSci 127:563-592, 1904 3. PELNER L, FOWLER GA, N A U T S HC: Effects of concurrent infections and their toxins on the course of leukemia. Acta Med Scand [Suppl] 338:1-47, 1958 4. TIGERTT WD, CROSBY WH, BERGE TO, H O W I E DL, KRESS S, D A N -

GERFIELD HG, BASS JW, FRANK W: The virus of Venezuelan equine encephalomyelitis as an antineoplastic agent in man. Cancer 15:628-632, 1962 5. HERSH EM, G U T T E R M A N JU, MAVLIGIT GM, M C C R E D I E KB, B U R -


1. BARTON JC, CONRAD ME: Beneficial effects of hepatitis in patients with acute myelogenous leukemia. Ann Intern Med 90:188-190, 1979 988

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GESS MA, MATTHEWS A, FREIREICH EJ: Serial studies of immunocompetence of patients undergoing therapy for acute leukemia. / Clin Invest 54:401-408, 1974

Acute Nonlymphocytic Leukemia T o T H E E D I T O R : A l t h o u g h a c u t e l e u k e m i a is a potential l o n g t e r m c o m p l i c a t i o n o f a l k y l a t i n g agent t h e r a p y ( 1 ) , i n t e r a c t i o n s b e t w e e n t h e s e d r u g s a n d radiation t h e r a p y o r r a d i o m i m e t i c d r u g s are p o o r l y u n d e r s t o o d . D o x o r u b i c i n ( a d r i a m y c i n ) is a rad i o m i m e t i c d r u g c a r c i n o g e n i c t o laboratory a n i m a l s ( 2 ) . It is frequently u s e d i n c o n j u n c t i o n w i t h c y c l o p h o s p h a m i d e a n d rad i a t i o n t h e r a p y for v a r i o u s solid t u m o r s . W e h a v e recently evalu a t e d a patient w h o d e v e l o p e d a c u t e l e u k e m i a after s u c h c o m b i n e d m o d a l i t y therapy. A 56-year-old white woman received preoperative pelvic radiation (5000 rad) in February 1976 for an adenosquamous carcinoma of the endometrium. At surgery, her uterus and both ovaries contained tumor, and peritoneal washings were positive for malignant cells. From July 1976 to May 1977 she received 700 mg of intravenous doxorubicin (450 mg/m 2 ) and 12 600 mg of intravenous cyclophosphamide. She subsequently was treated with intermittent oral Cytoxan® from June 1977 to April 1978 when therapy was discontinued. At that time, she had no clinical evidence of uterine carcinoma. In June 1978 a hemogram showed 8.5 g/dL of hemoglobin, 85 000 leukocytes/ mm3 with 52% myeloblasts, and 55 000 platelets/mm 3 . Bone marrow aspiration and biopsy revealed acute myelogenous leukemia. Karyotypic analysis showed no chromosomal abnormalities. The leukemia did not respond to Rubidazone , vincristine, cytarabine, and prednisone or to 5-azacytidine. The patient died in October 1978. Postmortem examination was not permitted. A l t h o u g h c u t a n e o u s ( 3 ) , e s o p h a g e a l ( 3 ) , a n d cardiac ( 4 ) t o x icity m a y b e e n h a n c e d b y c o n c o m i t a n t therapy w i t h d o x o r u b i cin, c y c l o p h o s p h a m i d e , a n d radiation, t h e l e u k e m o g e n i c p o t e n tial o f this c o m b i n a t i o n r e m a i n s t o b e quantitated. W e u r g e careful, l o n g - t e r m f o l l o w - u p o f patients receiving c o m b i n e d m o d a l i t y therapy, particularly a s a n adjuvant t o p o t e n t i a l l y c u rative surgery. R O N A L D R. R E I M E R , M . D . C A R L W. GROPPE, JR., M . D .

Cleveland Clinic Foundation; Cleveland, O H 4 4 1 0 6

cytes; and the hemoglobin was 9.4 g/dL. The patient was transfused with 2 units of packed cells. Hyperglycemia was treated with insulin. Escherichia coli were grown from urine and ampicillin therapy started. Prednisone, 60 mg/daily, was started. On the third day she became disoriented, developed facial paralysis and noticed decreased vibratory sensation in her feet; hemoglobin was 7.7 g m / dL; leukocytes 14 2000/mm 3 ; platelets 6000/mm 3 ; nucleated erythrocytes, 7%; BUN 78 mg/dL; and glucose 250 mg/dL. Partial thromboplastin time, fibrinogen, and prothrombin time were normal. At this point, thrombotic thrombocytopenic purpura was diagnosed and the patient started on aspirin, 4 g, sulfinpyrazone, 400 mg, dipyridamole, 200 mg (all daily), and prednisone was switched to methylprednisolone, 120 mg intravenously. She was transfused with 3 units of packed cells and 4 units of fresh frozen plasma. On the fourth day, she developed transient left hemiparesis, aphasia, stupor, and agitation. Plasmapheresis was done, removing 4 units of her plasma and infusing 6 units of fresh frozen plasma. All antiplatelet agents were withdrawn. On the fifth day a total plasma exchange was attempted, but the patient died after cardiac arrest. Autopsy revealed petechiae in the skin; fibrin, thrombi, and arteriosclerosis in coronary arteries; edema of lungs, myocardium, and liver; and glomerulosclerosis.

Byrnes and colleagues (2) have reported two cases of remission associated with plasma infusion. This finding, which suggested that a deficient factor was replaced with plasma, was supported by Lian's work (3). Hanzlick and colleagues (4) pointed out that the transfusions used by Byrnes may have contained platelets or platelet substances as the active agent(s). Ansell and associates (5) described a patient not improved after fresh frozen plasma exchange but improved after plasmapheresis of 8 units of whole blood without plasma replacement. In our patient steroids, platelet inhibitors, plasma infusion, and plasma exchange were not effective. Plasma products may have some therapeutic role but should not be considered a standard treatment. Multi-institutional controlled trials are needed. R O N A L D STERN, M.D. C O R N E L I U S J. C O R N E L L , JR., M . D . R O B E R T BECK, M . D . R O B E R T E. SMITH, M . D . D a r t m o u t h - H i t c h c o c k M e d i c a l Center; H a n o v e r , N H 0 3 7 5 5


mia after alkylating-agent therapy of ovarian cancer. N Eng J Med 297:177-181, 1977 2. M A R Q U A R D T H, PHILIPS FS, STERNBERG SS: Tumorigenicity in vivo

and induction of malignant transformation and mutagenesis in cell cultures by adriamycin and daunomycin. Cancer Res 36:2065-2069, 1976 3. GRECO FA, BRERETON HD, K E N T H, ZIMBLER H, MERRILL J, JOHN-

SON RE: Adriamycin and enhanced radiation reaction in normal esophagus and skin. Ann Intern Med 85:294-298, 1976 4. M I N O W RA, BENJAMIN RS, GOTTLIEB JA: Adriamycin cardiomyopa-

thy—an overview with determination of risk factors. Cancer Chemother Rep 6:195-201, 1975

Thrombotic Thrombocytopenic Purpura: Failure of Plasma Infusion and Antiplatelet Agents T o T H E E D I T O R : B y r n e s a n d K h u r a n a ( 1 ) h a v e reported t h e successful t r e a t m e n t o f patients w i t h t h r o m b o t i c t h r o m b o c y t o p e n i c purpura u s i n g p l a s m a infusions. Different p r o m i s i n g treatments have been advocated by other authors, yet the mortality rate c o n t i n u e s at a b o u t 7 0 % . N o r e g i m e n h a s b e e n s h o w n by c o n t r o l l e d trials t o b e m o r e effective t h a n a n y o t h e r m e t h o d . A 23-year-old woman with juvenile onset diabetes noted easy bruising 2 days before hospital admission for asymptomatic mild jaundice. Examination showed a temperature of 37.4 °C, petechiae and ecchymosis, mild scleral icterus, and a barely palpable nontender liver. Neurologic findings were normal. Laboratory findings included a hemoglobin level of 11.0 g/dL; reticulocyte count 5%; leukocyte count 12 800/mm 3 with 78% neutrophils and 16% lymphocytes; and platelet count 47 000/mm 3 . Prothrombin and partial thromboplastin times and fibrinogen levels were normal. Other findings included thrombin time of 20 s; fibrin degradation products less than 40 u.g/ dL; glucose 832 mg/dL; total bilirubin 7.1 mg/dL; direct bilirubin 1.9 mg/ dL; alkaline phosphatase 1065 IU/L; aspartate aminotransferase 82 IU/L; GGT 214 IU/L; and blood urea nitrogen (BUN) 66 mg/dL. On the second day the blood smear showed few atypical lymphocytes and markedly decreased platelets (11 000/mm 3 ); the bone marrow aspirate was normocellular with erythrohyperplasia and normal numbers of megakaryo-


1. BYRNES JJ, KHURANA M: Treatment of thrombotic thrombocytopenic purpura with plasma. N EnglJ Med 297:1386-1389, 1977 2. BYRNES JJ, SHOLTIS CM, W H I T E P: Plasma infusion in the treatment of

thrombotic thrombocytopenic purpura, further experience (abstract). Blood 50 (suppl 1):236, 1977 3. LIAN EC-Y, BYRNES JJ, K H U R A N A M, SCHULTZ DR: A platelet aggre-

gating substances in the plasma of a patient with thrombotic thrombocytopenic purpura (TTP) and its inhibition by a factor in normal plasma (abstract). Blood 50 (suppl 1):245, 1977 4. HANZLICK RL, SHAH NT, SENHAUSER DA: Treatments for thrombotic

thrombocytopenic purpura: plasma, vincristine, hemodialysis and exchange transfusions (letter). N Engl J Med 298:971, 1978 5. A N S E L L J, BEASER RS, PECHET L: Thrombotic thrombocytopenic pur-

pura fails to respond to fresh frozen plasma infusion. Ann Intern Med 89:647-648, 1978

Rheumatic Fever in Adults

To THE EDITOR: We read with interest the article by McDanald and Weisman in the December 1978 issue (1) on articular manifestations of rheumatic fever in adults. During our early medical training we saw patients with classic clinical presentation of rheumatic fever. During our first years of postgraduate training in the United States we saw acute rheumatic fever in an older-age-group population, in which the lack of Jones* criteria and minimal if any cardiac manifestations were the rule. We report here the case of an adult patient in whom aseptic meningitis was the initial clinical manifestation of rheumatic fever. A 44-year-old high school sports coach was hospitalized because of an abrupt onset of headache, neck pain with stiffness, and fever. Two weeks before admission he had had an episode of pharyngitis for which he had received a brief course of penicillin. He was febrile (39 °C) with nuchal rigidity, unable to move his neck in any direction. He had no murmurs or gallops. Leukocyte count was 18 000/mm 3 with left shift. Erythocyte sedimentation rate was 60 mm/h. Spinal tap done at admission showed spinal fluid Letters and Correction

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with normal pressure, protein 136 mg/dL, glucose 62 mg/dL, and 2 lymphocytes/mm 3 . Over the next 24 h the patient developed right ankle swelling with overlying erythema. Synovial fluid of the ankle showed a leukocyte count of 33 OOO/mm3 with 87% granulocytes. Over the next 48 h the patient developed migratory poly arthralgias affecting his right shoulder, right knee, and right sternoclavicular joint. A second spinal tap on the third hospital day showed protein of 128 mg/dL, glucose 68 mg/dL, and 4 cells/mm 3 , all of them lymphocytes. Antistreptolysin O titers on Day 1 were 166 Todd units, on Day 4 166, and on Day 12 1250. Antihyaluronidase was 1:4096. On the fourth day treatment with aspirin was begun. Within 72 h the intense synovitis, rigidity, and fever completely subsided. Other tests, including multiple cultures and serologic tests for infectious agents or autoimmune disorders, were negative or nondiagnostic.

the conditioned zinc deficiency induced by surgery can develop into a nutritional zinc deficiency not necessarily accompanied by overt clinical symptoms.

This case illustrates the evolving pattern of rheumatic fever (2). Although rheumatic fever is a multisystem disease and we should expect central nervous system involvement, we were not able to find reports of cases manifesting aseptic meningitis. In addition, our patient is older than those reported by McDanald and Weisman (1) and recently by Mund (3). He also had a prominent involvement of the right sternoclavicular joint and of the cervical spine. The involvement of these joints has been reported to be only 0.5% and 1%, respectively (4). A s was the case with the other patients, he did not have clinically detectable cardiac involvement. Larger numbers of patients with a long-term follow-up will indeed define the clinical spectrum and long-term complications of rheumatic fever in various age groups.

Plasma zinc and copper in obesity and after intestinal bypass. Ann Intern Med 89:491-493, 1978 2. MEYER G: Intestinal bypass and zinc (letter). Ann Intern Med 90:278, 1979

F R A N C I S C O G. A G U I L A R - T O R R E S , M . D . L E O N J. J A C K S O N , M . D .

J O H N A. G A R O F A L O , M . D . ELLIOT STRONG, M.D. R O B E R T A. G O O D , PH.D., M . D .

Memorial Sloan-Kettering Cancer Center; N e w York, N Y 10021 REFERENCES 1. ATKINSON RL, D A H M S WT, BRAY GA, JACOB R, SANDSTEAD HH:


in hair, anorexia, poor growth, and hypogeusia in children. Pediatr Res 6:868-874, 1972 4. SANSTEAD HH: Zinc nutrition in the United States. Am J Clin Nutr 26:1251-1260, 1973 5. F E R N A N D E S G, N A I R M, O N O E K, T A N A K A T, FLOYD R, G O O D RA:

Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice. Proc Natl Acad Sci USA 76:457-461, 1979 6. FRAKER PJ, H A A S SM, LUECKE RW: Effect of zinc deficiency on the

immune response of the young adult A / J mouse. J Nutr 1977


7. LUECKE RW, SIMONEL CE, FRAKER PJ: The effect of restricted dietary

intake on the antibody mediated response of the zinc deficient A / J mouse. J Nutr 108:881-887, 1978

St. Francis Hospital; Milwaukee, WI 53215

Hypothermia Treatment Needs Controlled Studies REFERENCES 1. M C D A N A L D EC, WEISMAN MH: Articular manifestations of rheumatic

fever in adults. Ann Intern Med 89:917-920, 1978 2. SELLERS TF JR: An epidemiologic view of rheumatic fever. Prog CardiovascDis 16:303-322, 1973 3. M U N D DJ: Rheumatic fever in adults (letter). Ann Intern Med 90:435, 1979 4. FEINSTEIN AR, SPAGNUOLO M: The clinical patterns of acute rheumatic fever: a reappraisal. Medicine (Baltimore) 41:279-305, 1962

Zinc Deficiency and Intestinal Bypass Procedures T o T H E EDITOR: In the October 1978 issue, Atkinson and associates (1) indicate that zinc deficiency may be a common finding after intestinal bypass procedures. Meyer (2) further suggests that zinc deficiency should be sought in those patients with markedly depressed appetites, especially when associated with dysgeusia. However, the reports by Hambridge and co-workers (3) on apparent zinc deficiency in children from middle- and upper-income families in the Denver area, as well as the review by Sandstead (4), strongly suggest that zinc deficiency may be commoner than previously suspected in otherwise healthy persons. We have observed that surgery in itself will cause a transient depression in serum zinc levels that can lead to a prolonged or permanent nutritional deficiency of zinc in patients who, before surgery, have either low serum zinc levels or are subclinically zinc-deficient. Zinc deficiency can be subtle and exist in the absence of rash, dysgeusia, or depressed appetite ( H E N K I N R: Personal communication). Our studies (5) and those of Fraker and colleagues (6, 7) have found that depressed immunologic function in experimental animals occurs much earlier in severe zinc deficiency and at levels of zinc intake that very much anticipate the overt evidence of zinc deficiency. We agree with Atkinson and associates that zinc deficiency can occur in patients after intestinal bypass surgery. It should, however, be looked for in all patients undergoing radical surgery, not just those who have markedly depressed appetites with or without dysgeusia, as suggested by Meyer (2). Surgical patients especially prone to develop zinc deficiency are those whose postoperative course is followed by tube feeding. It is during this postoperative period, when the requirements and excretion exceed the daily dietary replacement, that 990

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T o T H E EDITOR: Indicative of current interest in hypothermia are recent publications, including a review (1), articles (2, 3), an editorial (4), and a spate of letters to the editor of this journal in the February issue (5-7) in response to the review (1). Hypothermia is not a new problem, and it is unfortunate there have not yet been adequately constructed series that could permit assessment of the advantages of one rewarming procedure over another. About the only general agreement evident is that the patients should be rewarmed. Available guidelines are based on necessarily limited personal experience and on extrapolations from experiences of others and from animal studies. The issue about which there is (and should be) considerable disagreement is whether to use core rewarming. Several modalities are available for this: peritoneal dialysis, hemodialysis, and cardiopulmonary bypass. Such management may be indicated for some patients but not necessarily for all. There are no data available, for example, that permit a rational decision based on risk-benefit assessment for the use of cardiopulmonary bypass in elderly patients in preference to active external rewarming. It would be unfortunate if patients suffering from hypothermia were to be provided with the expenses and risks of the most advanced technology without any demonstrable benefit. I suggest that it would be appropriate to set up a controlled study, preferably under the auspices of the National Institutes of Health, to determine what means of rewarming are to be applied under what conditions to patients with hypothermia. Also, I wish to point out an eponymic error. The "J" waves in the electrocardiogram are considered "pathognomonic" of hypothermia (1). Osborn's name (frequently misspelled "Osborne" or even "Osbourn") is often used in connection with the "J" waves. I call attention to the article by Tomaszewski (8) in which "J" waves are clearly shown and pointed out as an electrocardiographic abnormality. If "J" waves must be known as an eponym, they should be referred to as "Tomaszewski" waves rather than "Osborn" waves. F R A N C I S P. C H I N A R D , M . D .

New Jersey Medical School; Newark, NJ 07103 REFERENCES

1. REULER JB: Hypothermia: pathophysiology, clinical settings, and management. Ann Intern Med 89:519-527, 1978 2. WELTON DE, MATTOX KL, MILLER RR, PETMECKY FF: Treatment of

profound hypothermia. JAMA 240:2291-2292, 1978 3. C H I N A R D F P : Accidental hypothermia—a brief review. / Med Soc NJ 75:610-614, 1978 4. EDITORIAL: Treating accidental hypothermia. Br Med J 2:1383-1384, 1978 5. R O T M A N H H : Hypothermia (letter). Ann Intern Med 90:273, 1979 6. A R N O L D JW: Hypothermia (letter). Ann Intern Med 90:273, 1979 7. PORTNOI VA: Hypothermia (letter). Ann Intern Med 90:273-274, 1979 8. TOMASZEWSKI W: Changements electrocardiographiques observes chez un homme mort de froid. Arch Coeur 31:525-528, 1938

Eikenella corrodens as Pathogen




(letter). Ann Intern Med 79:900, 1973 2. BROOKS G F , O ' D O N O G H U E JM, RISSING JP, SOAPES K, S M I T H JW:

Eikenella corrodens, a recently recognized pathogen: infections in medical-surgical patients and in association with methylphenidate abuse. Medicine (Baltimore) 53:325-342, 1974 3. D O R F F GJ, JACKSON LJ, R Y T E L MW: Infections with Eikenella


dens. A Newly recognized human pathogen. Ann Intern Med 80:305309, 1974 4. V O N H O F F D D , K I M B A L L RS: Eikenella corrodens infection (letter). Ann Intern Med 81:273-274, 1974 5. L U T W I C K LI: Pancreatic abscess with Haemophilus influenzae and Eikenella corrodens. JAMA 236:2091-2092, 1976 6. G O L D S T E I N EJC, S U T T E R VL, F I N E G O L D SM: Susceptibility of Eikenella

T o T H E EDITOR: The facultative anaerobe Eikenella corrodens is a recognized human pathogen (1-5), but its pathogenicity still requires further documentation. We recently saw two patients who were infected with this microorganism. A 64-year-old man had poorly differentiated neoplasm in peritoneum, mesentery, diaphragm, and lungs. He also had ascites with malignant cells. The primary site was unknown. Unclassifiable sarcoma was suspected, and treatment was begun with vincristine, cyclophosphamide, doxorubicin, and 5-fluorouracil. The patient was anergic, became febrile, and developed pulmonary infiltrates. His sputum grew Klebsiella pneumoniae, Candida albicans, and Candida tropicalis. He became hypoxic (Po 2 48 mm Hg) with C 0 2 retention (Pco 2 80mm Hg). Blood gases improved after intubation and respirator breathing. The patient was given anticoagulation treatment with heparin and received tobramycin and cephalothin. Blood culture grew Eikenella corrodens. Ampicillin was given intravenously instead of cephalothin. The patient defervesced and his blood cultures became sterile. He died with disseminated tumors. A 70-year-old man had left maxillectomy and exenteration of the left orbit for squamous-cell carcinoma. Postoperatively he received intravenous hyperalimentation, dexamethasone, tolbutamide, methicillin, tobramycin, and chloramphenicol. He remained febrile and became obtunded. Left temporal lobe abscess was found and evacuated. Eikenella corrodens was grown from the abscess. The patient received ampicillin intravenously. He improved rapidly and was discharged. In both cases Eikenella corrodens was the major isolate. Both isolates were susceptible to ampicillin. Ampicillin remains the treatment of choice for eikenella infections. Most isolates are susceptible to penicillin G, ampicillin, cefazolin, and cefoxitin but resistant to clindamycin and dicloxacillin, cephalothin, cephalexin, cephapirin, and cefaclor (6). J . G . SlNKOVICS, M.D. C. PLAGER, M.D. K A R E N M I L L S , M.S.

M. D . Anderson Hospital; Houston, T X 77030

corrodens to ten cephalosporins. Antimicrob 641, 1978

Agents Chemother


Cimetidine and Impaired Renal Function T o T H E EDITOR: Even though there is now extensive experience with the use of cimetidine, its use in patients with renal failure is still limited. The manufacturer and others have recommended that the dosage of cimetidine be adjusted when administered to patients with impairment of renal function (1). However, no simple guideline is available, and appropriate attention to the patient's renal status or dosage adjustment, or both, is often not paid. Many reports on possible complications of cimetidine therapy have involved the administration of normal or increased doses of cimetidine to patients with renal failure (2). Other reports, including two articles and one editorial that appeared in the February and March 1979 issues of this journal (3-5), failed even to mention the patients' renal function. We therefore present a preliminary cimetidine-dosage-adjustment nomogram and table as a guide and as a reminder that cimetidine dosage requires adjustment in patients with impaired renal function. Serial blood cimetidine levels were measured after intravenous administration of 300 mg of cimetidine as a 2-min infusion in three patients with varying degrees of renal failure, and the drug half-lives were calculated. Another 13 sets of serial blood levels or half-lives and the corresponding creatinine clearance were obtained from either published literature (1, 6) or Smith Kline & French Laboratories (Personal communications). An elimination constant (K 2 ) was then calculated from the available cimetidine halflife values (T '/ 2 ), at various levels of creatinine clearance (Ccr), by K2 = loge 2 / T , and then plotted. Linear regression analysis showed that K2 = 0.15 + 0.0025 Ccr for Ccr less than 60 mL/min (r = 0.72, P < 0.01) and that K2 = 0.30 for Ccr greater than 60 mL/min. The cimetidine dosages corresponding to the differing K2 values (and

Figure 1 . Cimetidine dosage adjustment nomogram ana" table. A loading dose of 3 0 0 mg of cimetidine is first administered; the maintenance dose, given every 6 h, is then determined by drawing a vertical line f r o m the patient's creatinine clearance (Ccr) to meet the sloping line K2 versus Ccr, and then drawing a horizontal line f r o m the intercept to meet the dosage axis. To use the table, the adjusted maintenance dose is given in the column under the patient's Ccr. Letters and Correction

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hence the corresponding Ccr values) were then calculated by multiplying the normal dose of 300 mg by the corresponding K : /maximal K : , and then plotted (Figure 1, see figure legend for instructions for use).

Because of the limited amount of data available, further studies are needed either to validate this nomogram or to derive a more accurate one. In the meantime, the table given under the nomogram may be a more useful guide. This table is derived from the nomogram, taking into account the intrinsic inaccuracies of the nomogram and the limited data available. The serum creatinine is included because it is more readily available than the creatinine clearance, even though the clearance is preferred. For patients with changing renal function, determining or even "anticipating" the creatinine clearance and later the maintenance dose on a daily basis will be necessary. In patients on hemodialysis, an additional 300-mg dose, given at the end of each dialysis, is recommended (1). We have now used this nomogram in 18 patients with renal failure and four patients on dialysis without adverse effects; and cimetidine levels measured in four patients who were on stable doses for at least 3 d were within therapeutic range (mean peak level, 1 h after a dose of 1.13 jutg/mL; mean lowest level immediately before dose, 0.37 /xg/mL). Despite the initial satisfactory results in our hands, the nomogram and the more practical table can only be considered tentative at present, but they are reminders that cimetidine dosage needs adjustment in patients with renal failure and provide approximate guidelines. In the individual patient, the patient's response, as measured by adequate inhibition of gastric-acid secretion, may be a more accurate method of dosage adjustment. In the difficult patient, blood levels may have to be obtained, the therapeutic level being in the range of 0.5 to 1.5 /xg/mL. Further studies are needed to define more clearly the metabolism and kinetics of cimetidine in patients with renal failure; whether the same cimetidine level has the same effect on gastric-acid secretion; the role of nonrenal mechanisms in cimetidine excretion; the cause of the transient, small, but statistically significant, rise in creatinine after receiving cimetidine; and whether normal or increased levels of cimetidine can cause renal toxicity.

G O R D O N D. LUK, M.D. W E N D Y J. LUK, M.S. T H O M A S R. HENDRIX, M.D. Johns Hopkins University School of Medicine; Baltimore, M D 21205 REFERENCES

1. M A KW, B R O W N DC, MASLER DS, SILVIS SE: Effects of renal failure on blood levels of cimetidine. Gastroenterology 74:473-477, 1978

2. M C M I L L E N MA, AMBIS D, SIEGEL JH. Cimetidine and mental confusion. N Engl J Med 298:284-285, 1978 3. D E GALOCSY C, VAN YPERSELE D E STRIHOU C: Pancytopenia with cimetidine (letter). Ann Intern Med 90:21 A, 1979 4. SILVER BA, B E L L WR: Cimetidine potentiation of the hypoprothrombinemic effect of warfarin. Ann Intern Med 90:348-349, 1979 5. FRESTON JW: Cimetidine and granulocytopemia (editorial). Ann Intern Med 90:264-265, 1979 6. CANAVAN JSF, BRIGGS JD: Cimetidine clearance in renal failure in Cimetidine: Proceedings of the Second International Symposium on Histamine H2—Recptor Antagonists, edited by B U R L A N D WL, SIMKINS M D , Amsterdam-Oxford, Excerpta Medica, 1977, pp. 75-80

Cimetidine and Agranulocytosis T o THE EDITOR: We read with interest the letter by de Galocsy

and van Ypersele de Strihou (1) and the editorial by Freston (2) in the February 1979 issue. Cimetidine has been reported in association with pure agranulocytosis in only two cases (3, 4). The remainder of the cases were granulocytopenia (5, 6) and pancytopenia (1, 7). In addition, the exact association with cimetidine in the cases of agranulocytosis appears far from certain in view of the complex drug therapy in the first case and the long interval before the onset of agranulocytosis in the second. We report a case of agranulocytosis that occurred 28 d after the onset of cimetidine therapy. A 78-year-old white woman was admitted to Georgetown University Hospital on 8 December 1978 with an intertrochanteric fracture of the right hip. Her medical history was significant for alledged alcohol abuse, micronodular cirrhosis, and a seizure disorder for which she had received 300 mg of oral phenytoin (Dilantin®) daily for a 20-year period. The day after admission the patient developed an upper gastrointestinal bleed and was started on 300 mg of intravenous cimetidine every 6 h. On Day 15, an Austin-Moore prosthesis was inserted under general anesthesia. The patient became febrile 3 d after surgery and tombramycin and cefazolin (Ancef®) were begun. Antibiotic therapy was discontinued after 8 d after the development of a pruritic erythematous skin rash. On Day 28 the patient had a spiking temperature of 38 °C. Her medications at that time consisted of Dilantin, cimetidine and spironolactone (Aldactone®). Results of physical examination were unremarkable except for hepatomegaly, ascites, and an erythematous rash over the abdomen, flexor surfaces of the upper extremities, and buttocks. Hematologic and drug administration data are shown in Figure 1. Of note are the normal leukocyte counts on admission, the development of leukocytosis on Day 15, and the documentation of agranulocytosis on Day 28. A bone-marrow aspirate obtained on Day 30 showed a cellular marrow with myeloid hyperplasia, numerous promyelocytes, prominence of eosinophils, and normal erythropoiesis, and megakaryocytes. Cimetidine and Dilantin were withdrawn. Seven days after stopping cimetidine and Dilantin therapy, resolution of the agranulocytosis was noted. Results of liver-function studies were consistent with hepatocellular

Figure 1 . Hematologic changes during therapy in a 78-year-old patient. PRBC's = packed red blood cells, TID = three times a day, q 6 h = every 6 hours, q l 2 h = every 12 hours, BID = twice a day. 992

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damage, and all other laboratory values including cultures and a screen for systemic lupus erythematosus were negative or noncontributory.

In our patient the most likely offending agents causing agranulocytosis are cimetidine and Dilantin. Dilantin has been well documented as a cause of agranulocytosis (8). However, in all previously reported cases, Dilantin-induced agranulocytosis occured within 68 days of starting Dilantin therapy (8). One cannot rule out cimetidine-Dilantin synergism and we suggest that there may be an additive effect of the two potential myelosuppressive drugs in this case. In addition the contribution of abnormal drug clearance secondary to comprised hepatic function cannot be fully evaluated. F I R A S H. A L - K A W A S , M . D . B R U C E A. L E N E S , M . D . R O N A L D A. S A C H E R , M . D .

Georgetown University Hospital; 3800 Reservoir Road, N.W.; Washington, D C 20007

being the only change before the onset of the coagulation problem. A brief letter in the 11 November 1978 British Medical Journal (2) from the medical director of the manufacturer of cimetidine describes an increase of 20% in the prothrombin time of subjects given cimetidine while receiving chronic anticoagulation treatment with warfarin. Our report and that by Silver and Bell point to a considerably greater than 2 0 % increase in the prothrombin time, even in the face of a brief period of cimetidine administration. Such elevations of the prothrombin time (and in our patient also the partial thromboplastin time) can be expected to be associated with significant bleeding problems. The mechanism of this drug interaction is not known at present. We recommend that prothrombin times should be followed more closely, and Coumadin dosage may need to be reduced in patients receiving warfarin and cimetidine concurrently. B R U C E A. W A L L I N , M . D . ART



1. D E GALOCSY C, VAN Y P E R S E L E D E S T R I H O U C: Pancytopenia with cim-

West Virginia University; Morgantown, WV 26506

etidine (letter). Ann Intern Med 90:274, 1979 2. FRESTON JW: Cimetidine and granulocytopenia. Ann Intern Med 90:264, 1979 3. K L O T Z SA, K A Y BF: Cimetidine and agranulocytosis (letter). Ann Intern Med 88:579-580, 1978 4. C R A V E N ER, W H I T T I N G T O N JM: Agranulocytosis four months after cimetidine therapy (letter). Lancet 2:294-295, 1977


5. JOHNSON N, M C I BLACK AE, H U G H E S ASB, C L A R K E SW: Leukopenia

with cimetidine (letter). Lancet 2:1226, 1977 6. U F B E R G M H , BROOKS CM, BOSANAC PR, K I N T Z E L JE: Transient neu-

tropenia in a patient receiving cimetidine. Gastroenterology 1977


7. S E L K E R R G , M O O R E P, L O D O L C E D: Bone-marrow depression with

cimetidine plus carmustine (letter). N Engl J Med 299:834, 1978 8. T S A N M F , M E H L M A N DJ, G R E E N RS, B E L L WR: Dilantin®, agranulo-

cytosis, and phagocytic marrow histiocytes (letter). Ann Intern Med 84:710-711, 1976

Cimetidine and Effect of Warfarin T o THE EDITOR: The report of Silver and Bell in the March issue (1) describes a patient in whom cimetidine appeared to potentiate the hypoprothrombinemic effect of warfarin. We report an additional case of this potentially harmful drug interaction. A 46-year-old white man had coronary artery revascularization in January 1975. He was placed on warfarin sodium (Coumadin®) at a dosage of 7 mg daily. On this dose, his prothrombin time remained stable within 1.7 to 1.9 times control. In September 1978, because of obstruction of both bypass grafts, repeat coronary revascularization was done. He was discharged on Coumadin, 6 mg daily, and cimetidine (Tagamet®), 300 mg four times daily, the latter because of a previous diagnosis of hiatal hernia and gastric ulcer. Two weeks later he had chest pain and was begun on isosorbide dinitrate and propranolol. Five weeks after discharge he noted severe pain in his left anteromedial thigh. He was unable to stand and noted numbness along his left lateral thigh. On admission he was unable to fully extend his hip. Pain was elicited by palpation along the left paravertebral muscles and the left inguinal area. Pertinent laboratory data included hemoglobin, 8.7 g/dL; prothrombin time, 38 s (control, 10.0 s); and partial thromboplastin time, greater than 90 s (control, 24.0 s). Platelet count was 520 000/mm 3 , fibrinogen was normal, and fibrin split products were mildly elevated. Abdominal roentgenogram showed a soft-tissue mass overlying the left iliopsoas muscle, which was confirmed by ultrasound examination. Both cimetidine and Coumadin were withdrawn. Within 48 hours his prothrombin time decreased to 15 s and the partial thromboplastin time to 33 s. His left thigh pain subsided, and he was able to straighten his leg and walk. As in the patient reported by Silver and Bell, our patient was well stabilized on Coumadin with the addition of cimetidine

1. SILVER BA, B E L L WR: Cimetidine potentiation of the hypoprothrombi-

nemic effect of warfarin. Ann Intern Med 90:348-349, 1979 2. F L I N D AC: Cimetidine and oral anticoagulants (letter). Br Med J 2:1367', 1978

Lactation from Tamoxifen in Breast Cancer T o THE EDITOR: Tamoxifen, a new antiestrogen, is considerably active in breast cancer (1). The use of this drug in premenopausal women with breast cancer has been limited and poorly documented; however, the timely communication by Pritchard and associates in the November 1978 issue (2) has further shown that tamoxifen can be beneficial in this group. Undoubtedly, more premenopausal women will be exposed to this drug, and previously unrecognized effects may be observed. We report a new possible side-effect of tamoxifen: lactation in a premenopausal woman. A 31-year-old premenopausal woman who had had four pregnancies and given birth four times sought treatment of a left breast mass that had been shown to be malignant by needle aspiration. Three months before admission, chronic thyroid supplementation was withdrawn when she was found to be euthyroid. The patient had breast fed all of her children, and 8 months before admission she had stopped breast feeding her youngest child whom she had nursed for 10 months continually. Within 2 weeks of stopping breast feeding, milk flow ceased entirely. Findings in a physical examination were essentially normal except for a 2-by-2.5-cm mass in the upper outer quadrant of the left breast and a clinically suspicious axillary node. Chest roentgenograms and bilateral mammograms showed no abnormalities, and results of routine blood and chemistry tests were also normal. A left modified radical mastectomy was done, and pathologic examination showed that the mass was an infiltrating ductal carcinoma and seven of 13 axillary lymph nodes contained tumor. Metastatic work-up was negative. After informed consent, the patient was placed on an Eastern Cooperative Oncology Group protocol and was randomized to receive adjuvant chemotherapy with cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, and tamoxifen (20 mg/d continually). Within a week of starting adjuvant therapy, however, the patient noted the onset of lactation. This continued for several weeks until tamoxifen was withdrawn. At the time lactation became manifest, the patient had taken no other medications except for one 10-mg prochlorperazine (Compazine®) tablet several days previously. Results of repeat blood chemistry examinations, thyroid function tests, and skull films were all normal. During 12 weeks of follow-up since tamoxifen was withdrawn, lactation has not recurred, although she has been continued on chemotherapy and prednisone.

In the absence of other demonstrable causes for lactation in this patient, we suggest that tamoxifen may have induced lactation. Although we can only speculate as to a mechanism of action, information from work with other antiestrogens is helpful. Clomiphene, another antiestrogen, has been shown to cause a rise in gonadotropin secretion (3), probably through blockade of hypothalamic estrogen receptors. If tamoxifen produced the Letters and Correction

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same effect in the presence of a "primed" end organ (such as a breast that had recently supported breast feeding), then lactation might well occur. The fact that antiestrogens have been shown to also suppress lactation (4, 5) does not negate the above hypothetical mechanism, because the lactating purperal woman and our patient exist in differing hormonal milieus, which might alter drug effects. The association of lactation with tamoxifen use has not been previously reported, but this drug has been used infrequently in premenopausal women. Because lactation can be worrisome to all concerned, physicians caring for cancer patients should be aware that tamoxifen may induce lactation in the appropriate patient. G R E G O R Y R. F A VIS, M . D . J A N E B. A L A V I , M . D . J O H N H. G L I C K , M . D .

University of Pennsylvania School of Medicine, Hosptial of the University of Pennsylvania; Philadelphia, P A 19104 REFERENCES

1. LEGHA SS, DAVIS HL, MUGGIA FM: Hormonal therapy of breast cancer: new approaches and concepts. Ann Intern Med 88:69-77, 1978 2. PRITCHARD KI, MEAKIN JW, MYERS RE, SUTHERLAND DJA, MOBBS

BG: Tamoxifen and metastatic breast cancer (letter). Ann Intern Med 89:721-722, 1978 3. NEWTON J, DIXAN P: Site of action of clomiphene and its use as a test of pituitary function. / Obstet Gynaecol Br Commonw 78:812-921, 1971 4. ZUCKERMAN H, CARMEL S: The inhibition of lactation by clomiphene. / Obstet Gynaecol Br Commonw 80:822-823, 1973 5. SHAABAN M: Lactation suppression with tamoxifen. Eur J Obstet Gynecol Reprod Biol 4:167-169, 1975 Analgesic-Associated Urinary-Tract Tumors T o T H E EDITOR: The editorial by Gonwa and associates in the March issue (1) is a very timely and concise summary of the current concepts of analgesic-associated urinary tract tumors (2). One additional and important point concerning this association is brought out in a recent case report of ours that is being prepared for publication. A 65-year-old white man presented with a long history of phenacetin abuse and difficulty in voiding. Microscopic hematuria and pyuria were found, and an infusioh nephrotomographic study showed kidney changes consistent with interstitial nephropathy; no mass lesions were seen. Four months later the patient presented with total gross hematuria, and an identical urographic examination showed a 3-cm filling defect in the left renal pelvis. Results of cystoscopic examination were negative for bladder tumors and urine cytologies were class V-positive. A 2.5-cm grade V transitional cell carcinoma was found in the renal pelvis. This tumor exhibited an unusually rapid growth rate, which may be partially or wholly attributable to the carcinogenic properties of phenacetin. Even in the face of a normal and technically adequate radiographic study, a constant vigil must be maintained in patients with appropriate histories. This should include frequent urographic follow up with cystoscopy and, possibly, selective ureteral cytologic studies. K E I T H R. B U R N E T T , M . D . J. B E R N A R D M I L L E R , M . D . E D W A R D GREENBAUM, M.D.

Veterans Administration Medical Center, Long Beach; Long Beach, CA 90822 REFERENCES

1. GONWA TA, BUCKALEW VM JR, CORBETT WT: Analgesic nephropathy

and urinary-tract carcinoma (editorial). Ann Intern Med 90:432-433, 1979 2. BENGTSSON U, ANGERVALL L: Malignancies of the urinary tract and their relationship to analgesic abuse. Kidney Int 13:107, 1978 Lithium and Generic Nonequivalence T o T H E EDITOR: Lithium carbonate is now marketed in 300-mg dosage forms by five different manufacturers. A liquid form of lithium, as the citrate salt, was also introduced in 1978, with 994

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each teaspoonful providing the lithium equivalent of a 300-mg tablet or capsule. Although the individual manufacturers have provided data showing bioequivalence of their marketed lithium dosage forms (1, 2), little has been published investigating comparative bioavailability of different brands. At this institution, two cases have concerned us in this regard. In one case, a manic-depressive patient who had received 300 mg of a popular brand (Eskalith**) four times daily for 2 months had had three consecutive lithium blood levels of 0.8 m e q / L (therapeutic = 0.5 to 1.0 meq/L) within the first 3 d of admission. A change to a generic brand of lithium t (generic at this institution = Philips Roxane) was made, and within 1 week the lithium blood level dropped to 0.4 m e q / L (two separate readings). In another case, subtherapeutic lithium blood levels were also achieved with a change from a dosage regimen of lithium tablets (Lithane*) to one using generic lithium capsules. These cases illustrate a problem with lithium treatment in which the patient becomes the victim of generic substitution nonequivalency. In-vitro investigations (3) have suggested that in-vivo differences among lithium preparations may be encountered because of different physical characteristics of differently manufactured dosage forms. Solid dosage forms usually contain materials other than the pharmacologically active ingredient (such as filler, lubricants, disintegrating agents). These agents may have a significant effect not only on absorption rate but also on the extent of absorption. Unfortunately, different manufacturers rarely use the same "added" ingredients in formulating their drug product (4, 5). Generic substitution with such pharmacologic agents as vitamins, antihistamines, or antacids would have little effect on the clinical outcome in the treatment of a patient. However, such an interchange of brands of lithium, or any other drug where established blood levels closely correlate with efficacy or toxicity, could result in the patient receiving either too little or too much drug. Thus, patients who are stabilized on a certain brand of lithium carbonate should be told to remain on that brand to avoid alterations in lithium blood levels or possible changes in their mental status. G A R Y E. P A K E S , P H A R M . D .

Brotman Memorial Hospital; Culver City, C A 90230 REFERENCES

1. ROWELL LABORATORIES, INC.: Lithonate9andLithotabs9, Bioavailabil-

ity Report. Baudette, Minnesota, Rowell Laboratories, Inc., 1977, pp. 1-4 2. CALDWELL HC, WESTLAKE WJ, CONNOR SM, FLANAGAN T: A phar-

macokinetic analysis of lithium carbonate absorption from several formulations in man. / Clin Pharmacol 11:349-356, 1971 3. SUGITA ET, STOKES JW, FRAZER A, GROF P, MENDELS J, GOLDSTEIN

FJ, NIEBERGALL PJ: Lithium carbonate absorption in humans. / Clin Pharmacol 13:264-270, 1973 4. VARLEY AB: The generic inequivalence of drugs. JAMA 206:1745, 1968 5. SCHNELLER GH: Hazard of therapeutic nonequivalency of drug products. J Am Pharm Assoc NS 9:455-457, 1969 Dialysis and Psoriasis T o T H E EDITOR: Since the amelioration of psoriasis during dialysis was first described (1), a number of reports of positive effects of dialysis on this troublesome and often therapy-resistant disease have been published (2-7). At present, peritoneal dialysis (5, 6) and hemodialysis (5, 7) are used as therapy in otherwise untreatable cases. To our knowledge there has been no previous report of a psoriatic patient with renal insufficiency in whom chronic hemodialysis showed no positive effect in psoriasis. A 32-year-old man had first had psoriasis vulgaris 14 years previously. Ten years after onset of this disease, albuminuria was discovered, and from that time renal function became continuously worse. Four years later, a cadaveric renal transplantation was done because of end-stage renal failure without previous dialysis therapy. With corticosteroid and azathioprine therapy for immunosuppression, the skin lesions improved to nearly complete remission. Due to irreversible chronic rejection, the transplant had to be removed 2 months later and chronic hemodialysis was started. With the discontinuation of immunosuppressive therapy the psoriasis relapsed, in-

volving the entire integumentum. The same condition recurred when the patient received a second kidney graft from a living donor. This graft was also chronically rejected and had to be removed after 4 months. Since that time the patient has been on chronic hemodialysis. His psoriasis is as bad as it was before onset of his renal disease. Our dialysis technique consisted of three dialyses a week, 6 h each, using a 2.5-g hollow fiber artificial kidney (Cordis Dow, C-DAK), a subcutaneous fistula on the left forearm; heparin is given 10 000 IU as primary dose and 2000 IU continuously. The bath solution contains sodium, 130 meq/L; potassium, 2.0 meq/L; chloride, 103 meq/L; calcium, 3.5 meq/L; magnesium, 2.5 meq/L; and acetate, 35 meq/L, glucose free.

Our experience contradicts the assumption of a "psoriatic factor" that can be removed by dialysis. We cannot state whether the reason our patient did not respond was because of differences of the membranes and the composition of the bath solution used in dialysis treatment. We suggest that case reports dealing with psoriasis treatment and dialysis should contain such information. H E L M U T GRAF, M.D. A X E L WOLF, M.D. H A N S KRISTER STUMMVOLL, M.D.

Second Medical Department, University of Vienna; Vienna, Austria REFERENCES

1. MCEVOY J, KELLY AMT: Psoriatic clearance during hemodialysis. Ulster Med J 45:76-78, 1976 2. TWARDOWSKI ZJ: Abatement of psoriasis and repeated dialysis (letter). Ann Intern Med 86:509-510, 1977 3. MUSTON HL, CONCEICAO S: Remission of psoriasis during haemodialysis. Br Med 71:480-481, 1978 4. SON BT, BAGUIO MS: Dialysis and psoriasis (letter). Ann Intern Med 88:842, 1978 5. BUSELMEIER TJ, KjELLSTRAND CM, DAHL MU, BURGDORF WG, SIMMONS RL, NAJARIAN JS, GOLTZ RW: Treatment of psoriasis with dialysis (abstract) EDTA 15:10, 1978 6. TWARDOWSKI ZJ, NOLPH K D , R U B I N J, A N D E R S O N PC: Peritoneal

dialysis for psoriasis. An uncontrolled study. Ann Intern Med 88:349351, 1978 7. CHUGH KS, N A T H IVS, B E D I TR, PAREEK SK: Dialysis and psoriasis

(letter). Ann Intern Med 88:842-843, 1978

Skin Color and Race in Clinical Medicine

To THE EDITOR: The statement by Rothschild and Hunter (1) that "Skin color as a designation of race is an arbitrary sociologic classification and rarely, if ever, adds to our diagnostic, pathogenic, or therapeutic knowledge" is out and out nonsense. Imagine evaluating a patient with a congenital anemia without knowing the patient's race. The authors applaud those journals that bowdlerize reference to race except in selected instances; such censorship can only interfere with the recognition of whatever role race may have in human disease and is to be deplored. Race is a biologic datum, whatever else men have made of it. The desire to deny that fact, to relegate race to "the social history in the case presentation," is a symptom of the unnatural relation men have toward race today. MICHAEL G U T W E I N , M.D.

Washington University School of Medicine, St. Louis, MO 63110

X-Linked Lymphoproliferative Syndrome Registry

To THE EDITOR: The X-Linked Lymphoproliferative Syndrome Registry was recently established and is funded by the National Cancer Institute. We invite referrals of possible cases of the Xlinked lymphoproliferative syndrome as well as unusual complications associated with infectious mononucleosis. The following criteria may be used to ascertain whether a patient is a candidate for the registry. 1. Phenotypes (1) of the proliferative types including fatal infectious mononucleosis, immunoblastic sarcoma of B cells, immunodeficiency with hyper IgM after infectious mononucleosis, or American Burkitt lymphoma. Aproliferative phenotypes such as agranulocytosis, aplastic anemia, or acquired hypogammaglobulinemia. 2. The phenotypes of X-linked lymphoproliferative syndrome in two or more maternally related males. 3. In affected males, after infection by Epstein-Barr (EB) virus, infected B cells grow spontaneously, saliva transforms cord lymphocytes, and EB virus antibody is usually absent in sera. By studying affected patients and their families we seek to increase knowledge on the cause and pathogenesis of X-linked lymphoproliferative syndrome and ultimately to offer a basis for rational therapeutic intervention. Inquiries should be sent to one of the persons below. D A V I D T. P U R T I L O , M . D . J A N E T H A M I L T O N , M.S.

Department of Pathology, University of Massachusetts Medical Center; Worcester, MA 01605 REFERENCE 1. PURTILO DT, D E F L O R I O D JR, H U T T LM, B H A W A N J, Y A N G JPS,

OTTO K, EDWARDS W: Variable phenotypic expression of an X-linked recessive lymphoproliferative syndrome. N Engl J Med 297:1077-1081, 1977

Correction: Testicular Neoplasm Review

To THE EDITOR: A typographic error was made in the article entitled "Testicular Germ-Cell Neoplasms: Recent Advances in Diagnosis and Therapy" (1) in the March 1979 issue. The first sentence of the last paragraph on p. 380 should read "the results of primary radiation therapy alone in stage Iir* (not stage II as it reads in the text) "nonseminatomous testicular cancer have been exceedingly poor." A major thrust of the presentations by the various discussants is to demonstrate that testicular germ cell neoplasms are sensitive to a wide variety of therapeutic modalities. The lack of good clinical studies comparing various therapeutic modalities has hampered the ability to arrive at a consensus on the most efficacious treatment for the testicular carcinomas. Although radiotherapy alone is not obviously designed to treat stage III disease, as the sentence was meant to demonstrate, Dr. Glatstein's presentation pointed out that radiotherapy for stage I and II disease is an effective modality of therapy. TOM ANDERSON, M.D.

Medicine Branch, National Cancer Institute, National Institutes of Health; Bethesda, MD 20014 REFERENCE


1. ROTHSCHILD H, HUNTER FM: Skin color as a clinical datum (letter). Ann Intern Med 90:280, 1979


lar germ-cell neoplasms: recent advances in diagnosis and therapy. Ann Intern Med 90:373-385, 1979

Letters and Correction

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Rheumatic fever in adults.

LETTERS AND CORRECTION CONTENTS Hepatitis and Leukemia J. P. Fiore M. E. Conrad and J. C. Barton R. A. Neiman M. E. Conrad and J. C Barton Acute Nonl...
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