MYXŒDEMA—POSSIBLE SIDE-EFFECT OF LITHIUM ?

427

CYCLOPHOSPHAMIDE PLUS EMETINE IN LUNG CANCER

SIR,-One of us (K. M.) has seen described by Dr. Street (Aug. 19, p.

of the cases has been and 381) most impressed by case 4 (male, 64, oat-cell carcinoma), whose " quality of life " has been very considerably enhanced. Unfortunately, in our hands treatment with cyclophosphamide 400 mg. intravenously daily for ten days and emetine 1-5 mg. per kg. intravenously on alternate days for ten days has not led to any improvement, but this may well be because we have treated only patients who have already had radiotherapy. If emetine in some way sensitises the tumour to antitumour

therapy-either radiotherapy

or

some

chemotherapy-it

would be reasonable to give the drug at the time of radiotherapy, and a trial in conjunction with Dr. Brinkley in the radiotherapy department has begun. Concurrently, work to try and confirm Dr. Street’s results with cyclophosphamide is also in progress. St. Giles’ Hospital, London SE5 7RN.

Microscopic appearance of testicular morphology in prepubescent boys. (a) Normal: immature tubules lined by Sertoli cells and containing spermatogonia; connective tissue shown is scanty;

hasmatoxylin and eosin, x 250 (reduced to two-thirds). (b) testis of the 6-year-old boy treated with cyclophosphamide: abundant fibroconnective-tissue stroma with distortion and disarray of small testicular tubules; hsematoxylin and eosin, x 250 (reduced to

two-thirds).

Comment

al.5 described azoospermia and oligospermia aged 24-44 years who had received cyclophosphamide. Testicular biopsy revealed no spermatogenesis in 4 of 5 of these patients. Testicular atrophy was also observed. Kumar et al. studied testicular biopsies in 8 males aged 17-48 who had received cyclophosphamide for nephrotic syndrome. Again, testicular atrophy was observed in all patients. Our patient is the first prepubescent male with apparent cyclophosphamide-induced testicular atrophy to be reported. Possibly other prepubescent males treated with this drug may not show as striking testicular changes as observed in this one case, and studies of more cases are needed. Although it is difficult to predict the long-term effects of cyclophosphamide on testicular morphology and function in prepubescent males, the changes observed in this patient would suggest that, with the severe degree of atrophy and fibrosis present, regeneration to functional capacity at puberty would be

Fairley

et

in 31 males

unlikely. We agree with Cameron and Ogg 8 that the risk of sterility in addition to other complications of immunosuppressive therapy in such renal lesions as membranous glomerulonephropathy, focal glomerulosclerosis, membranoproliferative glomerulonephritis, and lupus nephritis may justify a vigorous search for other more effective modes of treatment. Further review of dose and duration of cyclophosphamide in prepubescent males is indicated. In the " steroid-resistant " nephrotic syndrome of minimalchange glomerulopathy of childhood, drugs which apparently do not injure reproductive function, such as azathioprine and mercaptopurine, merit trial. L. R. H. is supported by U.S.P.H.S. AM-53086. Renal

special fellowship

Section,

Department of Pediatrics and the Department of Pathology, University of Wisconsin Medical Center, Madison, Wisconsin 53706, U.S.A.

LAWRENCE R. HYMAN ENID F. GILBERT.

8. Cameron, J. S., Ogg, C. S. Lancet, 1972, i,

1174.

K. R. HYDE K. MARSH W. PERRY.

MYXŒDEMA—POSSIBLE SIDE-EFFECT OF LITHIUM ? communication SIR,-Dr. Myers’s (June 10, p. 1287) prompts us to report five cases of myxoedema which arose during lithium treatment. Case 1.-A 47-year-old woman with no family history of thyroid disease had, since 1953, been admitted several times with endogenous depression and had been treated with imipramine and amitriptyline. In August, 1970, prophylactic lithium carbonate was commenced, and in March, 1971, she complained of tiredness, weight-gain, sensitivity to cold, dry and peeling skin, and hoarseness. No goitre could be found. P.B.I. was 0-08 ttmole per litre (normal 0-32-0-58); 1B 18 nmole per litre (normal 60-148) ; radioactive-iodine uptake 4-6% after 24 hours. She was treated with thyroxine, and lithium treatment was continued. Both treatments were discontinued in August, 1971, when the patient complained of effort angina. In October, 1971, thyroxine treatment was recommenced, and in June, 1972, the P.B.I. was 0-64 nmole per litre, T 165 nmole per litre, and T 0-084 (rel. molc.) (0-7-0-12). Case 2.-A 63-year-old woman with no family history of thyroid disease had been admitted six times since 1955 with a depressive type of manic-depressive psychosis. She had been treated with E.C.T.,

chlorpromazine, meprobamate, chlorproIn December, 1970, prophylactic lithium was commenced. In July, 1971, she complained of tiredness, hoarseness, dry and peeling skin, loss of hair, and weightgain. No goitre could be found. P.B.I. was 0-07 pmole per litre; T4 13 nmole per litre; and radioactive iodine uptake 11-4% after 24 hours. After T.s.H. stimulation uptake values were still thixene, and methyprylone.

low. Lithium treatment was discontinued and she was treated with thyroxine. Thyroid-function tests were soon normal and the patient became euthyroid. Case 3.-A 50-year-old woman with no family history of thyroid disease had been treated since 1969 for manic-depressive psychosis. In November, 1969, prophylactic lithium was commenced, supplemented with chlorprothixene, imipramine, and clomipramine. In January, 1971, the patient complained of dullness of mind, constipation, dry and peeling skin, effort dyspnoea, and weight-gain. No goitre could be found. P.B.I. 0-18 nmole per litre; T4 22 nmole per litre; radioactive iodine uptake 25-3% after 24 hours. There was only minimal response The patient was treated with thyroxine to T.S.H. stimulation. and lithium was continued. The thyroid-function tests soon became normal and the patient euthyroid. Case 4.-A 43-year-old woman with no family history of thyroid disease had, since 1961, been admitted eight times for manic-depressive psychosis, six times in a manic phase and twice in a depressive phase. She had been treated with E.C.T. and with neuroleptics. From July to November, 1971, she had

428

prophylactic lithium, and another course was begun in December, 1971. Before this treatment the patient was clinically euthyroid and there was no goitre (P.B.I. 0-39 tmole per litre; T4 129 nmole per litre; T 0-080 rel. molc.). In May, 1972, the patient complained of tiredness, weight-gain, dry and peeling skin, and loss of hair, and was a classic case of myxcedema. There was no goitre (P.B.I. 0 05 Eunole per litre; T4 26 nmole per litre; T3 0.061 rel. molc.; radioactive-iodine uptake 9-1% after 24 hours). After lithium treatment was discontinued the patient became severely manic, and she is now on thyroxine plus lithium. Case 5.-A 43-year-old woman with no family history of thyroid disease was first admitted in 1965 with reactive depression. She was readmitted in 1970 with the diagnosis of endogenous depression. She had E.c.T., and in March, 1971, prophylactic lithium was commenced. In December, 1971, she was readmitted in a depressive phase. Lithium was continued, supplemented by doxepine and haloperidol. In February, 1972, she was admitted for the fourth time with depression, but this time she was also myxredematous. P.B.I. was 0-18 mole per litre; T4 27 nmole per litre; T 0-061 rel. molc. Lithium was discontinued and the

depression

was

treated with

E.C.T.

The

patient is still hypothyroid. In 1970, before lithium treatment was started, her P.B.I. was 0-46 nmole per litre and serumcholesterol 200 mg. per 100 ml.

reports of myxoedema not been established Such how lithium interferes with thyroid metabolism. knowledge might enable us to predict which patients are at risk of myxoedema on lithium treatment. It now seems essential to examine any patient’s thyroid function before and during lithium treatment. Contrary to Dr. Myers’s experience, we found it necessary in one case to discontinue lithium treatment in order to restore thyroid function to normal. We know of five

published

during lithium treatment.1-5

Lithium Clinic, State Mental

Hospital,

Aalborg, Denmark.

It has

P. A. VESTERGAARD J. C. POULSEN.

PRIMARY CONCERN discussion initiated by Professor Dudley’s SIR,-The article6 is of particular interest to me, since I attended a seminar about a year ago at St. Helier’s, Carshalton, given by Mr. Rodney Smith and Prof. Howard Eddey, at which the English and Australasian approaches to the primary examination were propounded. Professor Dudley very properly begins by attempting to define an objective for training, but then confuses knowledge with training-two vastly different things. Dr. Simpson7 also says " it is necessary to define one’s objectives " and then goes on to assume that this objective is static. This is dangerous, for as Eisenbergsays, " if there is a single leitmotiv of our time, it is a constantly accelerating rate of change ". The objective must be to give the surgeon not only the " factual tools " that Professor Dudley speaks of but also the " conceptual tools " to cope with a rapidly changing subject. This means training the surgeon to think, so that change can be accepted and utilised after critical evaluation. The proposed Australasian syllabus with its six-monthly review will keep the examination up to date, but will that be true of the surgeons who trained some years before ? Having examined the objectives, let us look at the means. Can it be that matters of fundamental theoretical change 1. 2. 3. 4. 5. 6. 7. 8.

Rogers, M. P., Whybrow, P. C. Am. J. Psychiat. 1971, 128, 158. Sedvall, G., Jonsson, B., Petterson, U., Levin, K. Life Sci. 1968, 7, 1257. Shopsin, B., Blum, M., Gershon, S. Compr. Psychiat. 1969, 3, 215. Vestergaard, P. A., Sørensen, T., Poulsen, J. C. Ugeskr. Læg. 1972, 134, 1282. Wiggers, Sv. ibid. 1968, 130, 1523. Dudley, H. A. F. Lancet, 1972, i, 1386. Simpson, M. A. ibid. July 22, 1972, p. 185. Eisenberg, L. Science, 1972, 176, 123.

will occur every six months ? It is unlikely that changes of concept will occur as often as this. Perhaps a list of significant articles might be circulated to candidates for the final fellowship, but this is hardly relevant to those grappling with the basic concepts of a subject. No-one seems to dispute the concept of the primary fellowship as a test of the prospective surgeon’s understanding of the basic sciences. But that this training will have to support him through the fundamental changes which The answer we can expect over forty years is forgotten. does not lie in supplying an up-to-date list of fashionable articles: it lies in training his mind, using the disciplines of the basic sciences to do so. After that, he can approach the technical, factual aspects with a critical mind. Kent and Canterbury Hospital, H. C. O. MARTIN. Canterbury.

SIR,-Professor Lennox (July 8, p. 85) is so experienced multiple-choice testing that one disagrees with him at peril. Nevertheless, his view that multiple-choice papers alone are inadequate is no more than a view and cannot bee substantiated, except by the usual appeal to the concept that oral examinations are " good for both parties ". Good is left undefined, as is so often the case in education. There in

is little doubt that the sum of two assessments is better than either on its own, but it is important to know the value of the terms in the arithmetic before expending a great deal of resource and energy on one that makes a very small increase in the discriminatory power of a technically oriented examination. The evidence available from the Australasian examinations is that the oral does not add enough to make its use worth while. However, as in all things educational, there is need for further study; I hope that in Glasgow the oral will be used as a means of finding out not only whether a confrontation is valid (an absolute statement which cannot be contested) but also whether it is reliable (a relative statement open to considerable doubt). Finally, Professor Lennox seems to have different objectives for the primary than do I. To me it is a means of setting minimum (but not necessarily low) standards rather than of picking winners. Those who sit have already had long experience of examination systems as students. The Australasian behind his objective computer may be preferable and fairer; time and further study will tell. Department of Surgery, Monash University, Alfred Hospital, Prahran, Victoria,

HUGH DUDLEY.

Australia 3181.

SEASONAL VARIATION IN SUICIDE-RATES

SIR,-Within the United States, Dublin1 observed only slight variation in the seasonal patterns of suicide between large cities in the nine geographical regions. The fact that one can observe no systematic variation may be explained partly by the use of figures for one year only (1959), and partly by the combining of the figures for groups of cities within each region. Suicide figures for five large U.S. cities over an extended period of time (that for which data are available) were therefore examined. The cities were chosen on the basis of size, their similar summer temperatures (with the exception of Seattle), and their contrast in winter temperatures (table i). In order to facilitate comparison of the seasonal patterns, the monthly rates for each city were converted to a standardised rate for each city where 100 equalled the average daily rate for the city over the whole year (table 11). The some

1.

Dublin, L. I. Suicide: York, 1963.

a

Sociological and Statistical Study.

New