CLINICAL-TRIAL POLICY AND TESTICULAR TUMOURS

1185 association between immune dysfunction and V.L.A. in C.S.F. Care should be taken when interpreting the results of studies linking an infectious agent to disease causation; controls for the state of the immune system are required. In summary, a compromised immune system may result in virus-like particles infiltrating the c. s. F. of some patients. This would render an astiological role for v.L.A. in schizophrenia untenable. Neurosciences Program, Medical Center, University of Alabama in Birmingham, Birmingham, Alabama 35294, U.S.A.

DONARD S. DWYER

COMBINATION CHEMOTHERAPY FOR METASTATIC MALIGNANT TERATOMA OF TESTIS

SIR,-With reference leagues (May 5, p. 941)

the paper by Dr Stoter and colwould like to confirm that metastatic teratoma of the testis may be a curable disease. Samuels’ introduction’ of high-dose vinblastine and bleomycin, whilst producing satisfactory tumour regression, was considered by us to be unacceptably toxic. A modification of this regimen at this Institute resulted in a complete remission in 50% of twenty-two patients with metastatic disease. These remissions were generally, however, of short duration, and only four patients are alive and disease-free 2 years after completing treatment. The later report of an increase in both the duration and the incidence of complete remission occasioned by the addition of cis-diammine-dichloroplatinum (cis-P)2 led to a modification in the above chemotherapy to coincide with revision in the timing of radiotherapy. So far

we

to

we

have treated twenty-seven

patients

with

histologically

proven primary and/or metastatic disease. The stage before treatment is given in the table, the staging procedure being a modification of that RESULTS OF COMBINATION THERAPY FOR METASTATIC TERATOMA OF TESTIS

mg/m2, actinomycin as a

D 1.2

mg/m2,

and methotrexate 50

The results are given in the table. Complete remission, maintained for at least 3 months, was achieved in eighteen patients (67%). Five patients subsequently relapsed, but the remainder are alive and disease free, the median duration being 8 months. There was no evidence that one particular histological group was prognostic ally more favourable. Except for vomiting induced by cis-P, toxicity was acceptable, and no drug related death was occasioned by induction chemotherapy. Serious toxicity was observed in four patients (neutropenia and septicxmia in two, decreased transfer factor in two). Although renal toxicity is a common complication of cis-P, in no instance did creatinine clearance fall during induction therapy. Of those patients who have been followed up for 6 months, four have had an increase in serum-creatinine but this has remained within the normal range. It is premature, however, to state whether there will be any long-term renal complications from this particular method of drug administration. Thrombocytopenia (<30xlOVl) was common in patients who had previously received irradiation. This happened 3 or 4 days after therapy began and was attributed to vinblastine. Dose reduction prevented it in subsequent courses. One patient died after the first course of maintenance treatment and this was attributed to methotrexate. One patient had nephritis 6 months after abdominal irradiation but this patient had had 2000 rad to both kidneys during irradiation at another site. In most patients the fields did not include the bulk of the kidneys, but when this was unavoidable full kidney shielding was introduced when the cumulative dose of radiation reached 1600 rad. This particular drug combination is the most effective therapy to date for patients with advanced disease, and in our opinion the addition of irradiation to sites of previous bulk disease may produce additional benefit and is preferable to radical lymphadenectomy. Because of the rarity of this particular tumour, we consider it preferable that patients continue to be managed in specialised centres experienced in the management of cancer patients. We thank Dr M. this renor-t.

J. Garrett for referring three patients included in

Christie Hospital and Holt Radium Institute, Withington, Manchester M20 9BX

of Peckham

et

al. The

Pugh.’

pathological classification adopted was that of ,

Routine pre-treatment investigations consisted of full blood-count, biochemistry profile (SMA 12), chest X-ray, pulmonary-function studies (Dr T. B. Stretton), computerised tomography of chest and abdomen (Prof. I. Isherwood), serum ot-fetoprotein and human chorionic gonadotrophin (B subunit), urea, electrolytes, and creatinine

clearance. The primary treatment was vinblastine 6 mg/m2 i.v. on days 1 and 2, bleomycin 10 mg/m2 i.m. 12-hourly on days 2-4, and cis-P 15 mg/m2 i.v. daily on days 2-6. 2 h before administration of cis-P patients were asked to drink 2 litres of fluid and drug was then administered in 500 ml saline over 30 min. Courses were repeated monthly to a maximum of four courses. In patients with clinically apparent remission, confirmation was sought by repetition of chest X-ray, computerised tomography, and hormone markers. Laparotomy was not considered justifiable. Patients then received irradiation to sites of previous bulk disease (generally, abdominal lymph-nodes) and then six courses of maintenance chemotherapy were given with vinblastine 6 1. Samuels, M. L., Hologe, P. Y., Johnson, D. E. Cancer, 1975, 36, 318. 2 Einhorn, L. H., Donohue, J. Ann. intern. Med. 1977, 87, 293. 3 Peckham, M. J., Hendry, W., McElwain, T. J., Caiman, F. M. M. in Adjuvant Chemotherapy of Cancer (edited by S. S. Salmon, and S. E. Jones); p 306. Amsterdam, 1977. 4. Pugh, R. C. B. in Pathology of the Testis (edited by R. C. B. Pugh); p. 144.

Oxford, 1976.

mg/m2 given

single i.v. push in the outpatient clinic.

PETER WILKINSON ROBERT GIBB GRAHAM READ

CLINICAL-TRIAL POLICY AND TESTICULAR TUMOURS

SiR,-Dr Stoter and colleagues (May 5,

p. 941), in their combination chemotherapy in advanced testicular non-seminoma, and an editorial in the British MedicalJournal of March 31 on testicular tumours, have both drawn attention to encouraging increases in survival in this rare but important group of tumours. The rarity of these tumours and the integrated team approach to therapy that is required have led to the concentration of treatment in just a few centres. The need for frequent and accurate assessment of marker substances for the diagnosis and staging and for monitoring of therapy was highlighted in a multinational letter in The Lancet of Nov. 11, 1978. The role of these oncofetal marker proteins has raised fascinating questions about the basic biology of these tumours, and of tumours in general. These aspects are being studied in several laboratories, often attached to the above centres. Clinical trials in patients with testicular tumours will have to be multicentre and, probably, internationally based if the trials are to be large enough to permit valid conclusions; only about 300 new cases of testicular teratoma are seen in the U.K. each year. American and British treatment of early-stage disease is basically at variance, the Americans often relying on

paper

on

1186 extensive radical retroperitonal lymphadenectomy, whilst British and some other European practice favours routine irradiation to the ipsilateral pelvic and para-aortic nodes for occult and small nodal metastases (stages i and na). The aggressive treatment regimens necessary to salvage patients with metastatic disease have revealed that prior radiotherapy or chemotherapy adversely affects tolerance to treatment and compromises the chance of obtaining the only state which leads to a chance of "cure"-namely, complete remission (c.R.). Hence studies of the treatment of early-stage disease should look to how to reduce the number of cases progressing to advanced (supradiaphragmatic) disease without compromising the bonemarrow reserve in case chemotherapy becomes necessary later. For advanced disease aggressive multiple chemotherapy, followed where appropriate by surgery or radiotherapy, provides the only chance of long-term complete remission. However, we still need to know how far the doses of these sometimes lethally toxic regimens can be reduced without compromising the chance of c.R. Another unanswered question is the role of maintenance therapy. The concept of maintenance therapy has developed from experience in acute lymphatic leuksemia. However, there is some evidence that the biology of teratomas is fundamentally different; in some cases chemotherapy may induce differentiation into benign teratoma and attainment of c.R. alone may be sufficient to give the patient a good chance of cure. Some workers propose to test the maintenance concept in clinical trials. However, the effects of maintenance therapy in terms of long-term somatic damage (e.g., on kidney, bonemarrow, and lung) and of the induction of second (iatrogenically induced) neoplasms are unknown; such a plan needs very careful consideration, and follow-up for life would be mandatory. Proposals for clinical trials, based on national and international cooperation, may soon be sent out by both the urological group of the E.O.R.T.C. and the British Medical Research Council, and urologists and general surgeons should be aware of the need to concentrate treatment of testicular tumours in oncological centres and of the possibility of offering long-term survival to at least 50% of those with advanced disease. This is especially important since our evidence suggests that the incidence of testicular teratoma is increasing. To be effective clinical trials must recruit most cases occurring in a country and a high standard of investigation, substaging, and attention to detail during treatment are essential. Accurate substaging -needed to allow the choice of the most suitable therapydemands close cooperation between many disciplines, and this will be facilitated by following agreed protocols. The choice of the best form of treatment for the individual patient must remain the clinician’s primary responsibility. It must be hoped that proposals for trials will satisfy this requirement and that clinicians will feel willing to enter as many pa-’ tients as they can. University Department of Radiotherapy, Regional Radiotherapy Centre, Cookridge Hospital, Leeds LS16 6QB

P.

J. CORBETT

ANKYLOSING SPONDYLITIS, IMMUNE-RESPONSE-GENES AND MOLECULAR MIMICRY

SIR,-In your otherwise excellent editorial of May 12 on the

molecular-mimicry hypothesis you state that "human analogues for the mouse Ir genes have not been found". However, mouse Ir genes have not been found either. The term "Ir gene" operational definition for the evident demonstration of and low antibody responses in different strains of inbred high animals when immunised with the same dose of antigen. The molecular-mimicry hypothesis could apply equally well to Ir gene systems as to HLA-linked diseases.

is

an

The synthetic polypeptide (T,G)-A-L evokes a high antibody response in H-2b and a low antibody response in H-2k mice.’ This could be explained either by the presence of an immune response (Ir) "gene" in high-responder animals or by molecular similarity between antigen and self molecules of lowresponder animals, thereby producing a lower antibody response. Evidence in favour of the second alternative ("molecular mimicry") has been obtained for the antigens (T,G)-A-L,2 ferritin,3 and Salmonella typhimurium microorganisms.4 The molecular-mimicry hypothesis not only explains the observed HLA frequencies but also provides a possible mechanism for the pathogenesis of gene associated diseases. Individuals possessing HLA-B27 when making antibodies to klebsiella will also be producing anti-self antibodies which could be responsible for the inflammatory lesions of ankylosing spondylitis.5 The molecular similarity between test antigen and self antigen is one of degree and does not imply absence of response, as suggested in the editorial. In B27 negative patients with ankylosing spondylitis, an increased incidence of HLA B7,6 BW22,’ and BW428 has been reported, and every one of these three antigens cross-reacts with B27.9 Thus klebsiella cross-reactivity would appear to be relevant in non-B27 ankylosing spondylitis as well. Finally the strong HLA-B27 association with reactive arthritis following infection with salmonella, shigella, or Yersinia enterocolitica is not unduly surprising since klebsiellas share common antigens with other gram-negative microorganisms. Ankylosing spondylitis could be considered as a form of reactive arthritis following infection by various gram-negative microorganisms. The reactive arthritis would be produced by bacterial antibodies binding to cross-reacting self antigens, thereby acting as tissue damaging autoantibodies, and a similar mechanism appears to operate in rheumatic fever.

Immunology Unit, Department of Biochemistry

Queen Elizabeth College,

ALAN EBRINGER

London W8 7AH

FRENCH WINE AND DEATH CERTIFICATES

SIR,-I share with Dr St. Leger and his colleagues (May 12,

1017) doubts about the fat coronary-disease argument as set by Dr J. Stamler and colleagues. However, there is a gross flaw in St Leger’s own study in respect of low C.H.D. death-

p.

out

rates

in France. Bronte Stewart,

two

decades ago, ascribed the

alleged protection of Frenchmen to olive-oil consumption’" The leading French cardiologist of that day, J. Lenegre, immediately drew attention to the fallacy." French doctors seem to certify coronary deaths when closely time related to recognisable infarctions. Survivors who later die of heart-failure are certified as having some form of chronic myocarditis. When the two death-rates were added France, came more into line with other Western countries. This gross error of labelling is now being studied by the Institut National de la Sante de la Recherche Medicale who report that "mortality from ischaemic heart-disease is at least twice more than that reported in the statistics of causes of death France is a civilised country so this French certification 1. McDevitt, H. O., Sela, M.J. exp.Med. 1965, 122, 517. 2. Ebringer, A., Davies, D. A. L. Nature new Biol. 1973, 241, 144. 3. Deacon, N. J., and others. Br. J. exp. Path. 1978, 59, 644. 4. Wooley, P., Ebringer, A.J. med. Microbiol. (in the press). 5. Ebringer, A. New Sci. 1978,79,865. 6. Kahn, M. A., Kushner, I., Braun, W. E. Arthr. Rheum. 1978,21,528. 7. Safwenberg, J., Domeij-Nyberg, B., Kjallman, M. Scand. J. Rheum 1978,

7,177. 8. Arnett, F. C., Hochberg, M. C., Bias, W. B. Johns Hopkins med. J 1977, 141, 193. 9. Joysey, V. C., Wolf, E. Br. med. Bull. 1978, 34, 217. 10. Bronte Stewart, B. Br. Med. Bull. 1958, 14, 243. 11. Lenegre, J. Revue Pract 1958, 8, 1717 12. Richard, J. L., and others Colloq. Inst. natn. Santé Reche. méd. 1973, 21, 11.