775

ACUTE MYELOID LEUKAEMIA AFTER

TREATMENT WITH CYTOSTATIC AGENTS

W. S. A. ALLAN.Pathology Department,

Royal Hospital, Wolverhampton.

SiR,-The letter from Dr. Smit and Dr. Meyler (Sept.26, p. 671) prompts me to record a similar instance.A 70-year-old woman had a cystic left ovarian tumour

removed, together with part of the uterus, to which it wasadherent. Neoplastic tissue was also found in the pouchof Douglas and on the vermiform appendix, and wasremoved. Thiotepa was administered weekly over the next 13months, but was discontinued because of thrombocytopenia.Pancytopenia did not develop at any stage of the treatment.A total of 840 mg. thiotepa was given. 28 months afterher operation she was well, with no sign of recurrence.However, 2 months later she was readmitted with abdominalpain and severe anaemia. Hxmoglobin was 4-4 g. per100 ml., leucocytes 13,400 per c.mm. (75% myeloblasts),and platelets 60,000 per c.mm. Marrow puncture con-firmed the diagnosis of acute myeloblastic leukaemia.She died a few days later, and necropsy confirmed the

presence of leukasmic infiltration of the viscera; there wasno recurrence of the tumour nor metastases. The periodbetween the last administration of thiotepa and the onsetof leukxmia was about 17 months.

TRIETHYLENE TETRAMINE

DIHYDROCHLORIDE IN WILSON’S DISEASE

SIR,-Walshe has described the use of a new chelatingagent, triethylene tetramine dihydrochloride (T.E.T.A.), inthe management of a patient with Wilson’s disease who haddeveloped nephrotic syndrome on D-penicillamine treat-ment. We have investigated the use of this agent for theremoval of copper from a patient with Wilson’s disease whodeveloped severe recurrent leucopenia after treatment withD-penicillamine.The patient was a 13-year-old boy who had a 2-year

history of liver disease. The diagnosis of Wilson’s diseasewas confirmed by the presence of Kayser-Fleischer rings, aserum-caeruloplasmin level of less than 1 mg. per 100 ml.,urinary copper excretion of 340 µg. per 24 hours, and a liver-copper content of 392 µg. per g. wet weight. There were

stigmata of chronic liver disease, which was confirmedhistologically. CEsophageal varices were seen radiologically.There was some degree of hypersplenism as evidenced bythrombocytopenia and a mean white-cell count of 4500 perc.mm. D-penicillamine treatment was started at a dose of1 g. per day, and the patient had a striking cupriuresis of2387 ,g. per 24 hours. However, his white-cell count fellrapidly to below 2500 per c.mm. It rose promptly to theprevious level when D-penicillamine treatment was sus-

pended. Therapy was reinstituted at a dose of 500 mg. perday, with a resultant moderate cupriuresis (1412 g. per24 hours). However, the white-cell count again droppedprecipitously to 2000 per c.mm. Similar effects were notedat a dose of 250 mg. per day. The patient was on no specificchelation therapy for 2 weeks, and the urinary copperexcretion dropped to 94 .g. per 24 hours. At this time he

developed signs of neurological deterioration. For thisreason a trial of T.E.T.A. was begun.Examination of commercial-grade triethylene tetramine by

nuclear magnetic resonance, gas-liquid chromatography, andmass spectrometry revealed a purity with respect to triethylenetetramine of 57%, with two major impurities-1,4-bis(amino-ethyl) piperazine (30%) and 1,(2-aminoethyl-aminoethyl)piperazine (10%). Triethylene tetramine dihydrochloride wasprepared from commercial triethylene tetramine to a purity of

1. Walshe, J. M. Lancet, 1969, ii, 1401.

97% by conversion to the dihydrochloride and repeated fractionalcrystallisation, and fractional distillation of the neutralised

fractions, followed by reconversion to the dihydrochloride. Thismaterial was made into 250 mg. capsules.The patient was then given T.E.T.A. at a dose of 1 g. per

day. The urinary copper excretion increased to 1334 .g.per 24 hours, and the white-cell count remained stable atapproximately 4000 per c.mm. Emission-spectroscopyanalysis of the urine during T.E.T.A. administration revealedno increase in the excretion of iron, manganese, or chromiumbut there was significant increase in zinc excretion (181 /g.per 24 hours before T.E.T.A. to 402 .g. per 24 hours duringT.E.T.A. treatment). No other clinical or biochemicalmanifestations of toxicity were observed during treatmentwith T.E.T.A. After 6 weeks of treatment T.E.T.A. was dis-

continued, and the patient was recommenced on D-penicil-lamine in a dose of 1 g. per day with no diminution ofwhite-cell count. Copper excretion in the urine increasedto 3020 ju.g. per 24 hours.While D-penicillamine undoubtedly remains the agent of

choice in the treatment of Wilson’s disease, it is evidentthat the new agent, T.E.T.A., has a place in the treatment ofpatients in whom D-penicillamine produces a toxic reaction.

This work was supported in part by U.S.P.H.S. Grant FR 69.The T.E.T.A. was administered under Food and Drug Administra-tion IND 6764.

REUBEN S. DUBOISDENIS O. RODGERSONTHOMAS L. SLOVISK. MICHAEL HAMBIDGETHOMAS A. BIANCHI.

Department of Pediatrics,University of Colorado Medical Center,

Denver, Colorado,and

Eastman-Kodak Company,Eastman Organic Chemicals,

Rochester, N.Y.

RECURRENT BACTERIURIA

A. G. MARSHALL.

SIR,-In your editorial on this subject (Sept. 12, p. 554),you confess that you find it difficult to explain the findingsof Kunin et al.1 in terms of a constitutional abnormality.May I be bold enough to direct your attention to somepapers which I have published on this very subject?Briefly, they describe lesions of the renal cortex, based oncongenital vascular abnormality, which are associated withrecurrent infection and hypertension.2-5

COAGULATION ABNORMALITIES IN

GENERALISED HERPES-SIMPLEX

INFECTION OF NEWBORN

SIR,-A hasmorrhagic tendency is a frequent complica-tion of generalised herpes-simplex infection of the newborn,and is often the immediate cause of death. Thrombocyto-penia and hypoprothrombinxmia have been the most

frequently reported coagulation abnormalities, and theyhave been assumed to be due to hepatocellular damage bythe virus and bone-marrow suppression by overwhelminginfection. The purpose of this letter is to draw attention tothe fact that disseminated intravascular coagulation (D.I.C.)may complicate generalised herpes-simplex infection andmay be responsible for fatal haemorrhage in these infants,more often than is generally recognised.The results of coagulation studies in 2 newborn babies

with generalised herpes simplex studied consecutively are

1. Kunin, C. M., Paquin, A. J. in Progress in Pyelonephritis (editedby E. H. Kass). Philadelphia, 1965.

2. Marshall, A. G. Lancet, 1951, ii, 701.3. Marshall, A. G. Br. J. Surg. 1953, 41, 38.4. Marshall, A. G. J. Path. Bact. 1956, 71, 95.5. Marshall, A. G. ibid. 1968, 95, 225.