- Email: [email protected]
AXILLARY SAMPLING AND BREAST CANCER
495 I remain perplexed about The Lancet’s proposal encouraging molecular biological studies on the mechanisms involved in scrapie pathogenesis when the detailed structure of the prion is unknown. So many advances in molecular biology over the past 35 years have been based on understanding the structure of a macromolecule before elucidating the details of its function. Although purification and characterisation of the scrapie agent have been and continue to be a long, difficult, and arduous task, that is no reason to mimimise the significance of such work. Those workers willing to devote their efforts to such a task should be encouraged, not maligned. Perhaps the most disconcerting aspect of the editorial is the confusion surrounding the suggestion attributed to Gajdusekl9 and myself9,2o about the medical implications of studies on prions. Many investigators have suggested that slow viruses or scrapie-likee agents (prions) may be the cause of one or more serious degenerative diseases. However, enthusiasm for this line of investigation has gradually diminished as slow viruses have not been found in diseased tissues and isolation of prions by animal transmission experiments have failed. Such pessimism with respect to prions as possible aetiological agents seems unjustified when the history of human diseases caused by slow viruses is examined. In both subacute sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML), animal inoculation studies were not useful in identifying and isolating the offending slow viruses,21 Other more specialised virological techniques were required to identify the viral pathogens. None of these specialised are available for the identification and isolation of prions. Only purification of the scrapie prion to homogeneity and elucidation of its molecular structure will provide the chemical reagents needed to search for prions in many human degenerative disorders of unknown aetiology.
techniques
Department of Neurology, M-794, University of California, San Francisco, California 94143, U S A.
STANLEY B. PRUSINER
INFLUENZA VACCINE AND DERMATOMYOSITIS
SIR,-The recent interest in the question of an association between influenza vaccine and various neuromuscular disorders leads us to correct a reference which was mis-stated and is now being 1 misinterpreted. When Ehrengut reviewed cases of dermaand vaccination he stated that "Winkelmann2saw tomyositis a 47-year-old female patient with onset of dermatomyositis after a cold vaccine. Winkelmann felt that the immunization was a precipitating factor." When the results were being analysed on the 289 patients with dermatomyositis and polymyositis in the Mayo Clinic study cited above, the abstract for only one patient was coded for a recent immunisation and it was this coded information which I relayed to Ehrengut. However, a recent review of these cases made it clear that this patient had not been injected with influenza vaccine or any other vaccine and we wish to describe the circumstances correctly. In the year before the onset of her dermatomyositis in October, 1947, the patient had received, at various medical facilities, a series of X-ray treatment, antihistiminics, "gland shots", and "cold vaccine" tablets. At that time cold vaccine tablets were used orally for prophylaxis against secondary invaders of "common cold" and were available under a variety of brand names. They consisted of various mixtures of killed bacteria (usually pneumococcus, streptococcus, haemophilus, and micrococcus). These mixtures are now generally regarded as ineffectual for prophylaxis for either 19. Gajdusek DC. Unconventional viruses and the origin and disappearance of kuru. Science 1977; 197: 943-60. 20 Prusiner SB, Groth DF, Bolton DC, Bendheim PC, Bowman KA, Cochran SP, Mayled JJ, McKinley MP. Scrapie prions and degenerative diseases. Ninth Annual Symposium of Barrow Neurological Institute on Infectious Diseases ofthe Central Nervous System (in press). 21. Johnson RT. Viral infections of the nervous system. New York: Raven Press, 1982. 1. Ehrengut W. Dermatomyositis and vaccination. Lancet 1978; i: 1040-41. 2. Winkelmann RK, Mulder DW, Lambert EH, Howard FM Jr, Diessner GR. Course of
dermatomyositis-polymyositis: comparison patients. Mayo Clin Proc 1968; 43: 545-56.
of untreated and cortisone-treated
"colds" or secondary infections. The cold vaccine tablet is unrelated to any of the recent influenza vaccines, and this patient should not be regarded as having had any association with influenza immunisation. Department of Dermatology, Mayo Clinic,
RICHARD K. WINKELMANN
Rochester, Minnesota 55901, U.S.A.
INOSIPLEX FOR SSPE
SIR,-Dr Chalmers and Professor Smith (June 26, p. 1475) see our analysis of inosiplex therapy in subacute sclerosing panencephelitis (SSPE) as a "travesty", since "a group of treated patients with 100% follow-up is being compared with controls in which the great majority of the follow-up information comes only from the dead patients". We think their concern is misplaced. The important issue is not whether the SSPE control patients are dead or alive but whether they reflect the survival characteristics of the population from which they are being sampled. As stated in our article, the lack of consistent follow-up makes it impossible to know if survival of the 150 dead Registry patients accurately depicts survival in the total non-inosiplex-treated SSPE population in the U.S. However, both the Lebanese and Israeli control samples were relatively complete (including most of the SSPE patients in those countries) and adequately followed-up and should therefore be unbiased with regard to the influence of these two potential complicating factors on survival probability in untreated SSPE. Furthermore, the comparison between "a group of treated patients with 100% followup" and two control groups (Lebanese and Israeli), either combined or singular, with comparable follow-up produced the same result and conclusion as the inosiplex/three-control composite comparison. Later, data were made available on an additional 163 U.S. Registry patients, many of whom were alive. These new data, further analysed with refined statistical procedures, generated conclusions that were consistent with those expressed in our article. A final comment on the closing sentence of the first paragraph of the letter by Chalmers and Smith. Clinical studies are often initiated in an open-trial (no randomised controls) format. If these initial studies are conducted on a few patients with a rare and fatal disease and suggest that a drug is safe and possibly effective, then are medical ethics best served by a continuation of the open trial or the implementation of the randomised-control study which gives all patients "an equal chance of getting the better therapy"? We believe that the ethos of medical practice would not be violated by continuing the open trial, since the latter argument ignores the corollary that a randomised study in a fatal disease gives all patients "an equal chance" of getting the therapy that will guarantee their demise. Statistical purity, nevertheless, is clearly allied with the latter choice. Newport Pharmaceuticals International, P.O. Box 1990, Newport Beach, California 92660-0147, U.S.A.
Inc.
CLARENCE JONES
AXILLARY SAMPLING AND BREAST CANCER
SIR,-The letter of Mr Kark and Mr Kissin (Aug. 7,
p. 326) drags into the debate. Their argument is that the most accurate method of staging is "a thorough and complete axillary clearance". Staging is not an end in itself but is to establish the prognosis. Our method of staging by node sampling separates patients into prognostic groups very effectively’ but Kark and Kissin present no data about this. Sampling gives a good estimate of prognosis and even better when combined with other factors.’ Until Kark and Kissin show that axillary clearance improves on the estimation of prognosis their argument is without substance. me
Professorial Unit
of Surgery,
City Hospital,
Nottingham NG5 1.
R. W. BLAMEY
1PB
Haybittle JL, Blamey RW, Elston CW, et cancer. Br J Cancer 1982; 45: 361-66.
al A
prognostic
index in
primary
breast
techniques
Department of Neurology, M-794, University of California, San Francisco, California 94143, U S A.
STANLEY B. PRUSINER
INFLUENZA VACCINE AND DERMATOMYOSITIS
SIR,-The recent interest in the question of an association between influenza vaccine and various neuromuscular disorders leads us to correct a reference which was mis-stated and is now being 1 misinterpreted. When Ehrengut reviewed cases of dermaand vaccination he stated that "Winkelmann2saw tomyositis a 47-year-old female patient with onset of dermatomyositis after a cold vaccine. Winkelmann felt that the immunization was a precipitating factor." When the results were being analysed on the 289 patients with dermatomyositis and polymyositis in the Mayo Clinic study cited above, the abstract for only one patient was coded for a recent immunisation and it was this coded information which I relayed to Ehrengut. However, a recent review of these cases made it clear that this patient had not been injected with influenza vaccine or any other vaccine and we wish to describe the circumstances correctly. In the year before the onset of her dermatomyositis in October, 1947, the patient had received, at various medical facilities, a series of X-ray treatment, antihistiminics, "gland shots", and "cold vaccine" tablets. At that time cold vaccine tablets were used orally for prophylaxis against secondary invaders of "common cold" and were available under a variety of brand names. They consisted of various mixtures of killed bacteria (usually pneumococcus, streptococcus, haemophilus, and micrococcus). These mixtures are now generally regarded as ineffectual for prophylaxis for either 19. Gajdusek DC. Unconventional viruses and the origin and disappearance of kuru. Science 1977; 197: 943-60. 20 Prusiner SB, Groth DF, Bolton DC, Bendheim PC, Bowman KA, Cochran SP, Mayled JJ, McKinley MP. Scrapie prions and degenerative diseases. Ninth Annual Symposium of Barrow Neurological Institute on Infectious Diseases ofthe Central Nervous System (in press). 21. Johnson RT. Viral infections of the nervous system. New York: Raven Press, 1982. 1. Ehrengut W. Dermatomyositis and vaccination. Lancet 1978; i: 1040-41. 2. Winkelmann RK, Mulder DW, Lambert EH, Howard FM Jr, Diessner GR. Course of
dermatomyositis-polymyositis: comparison patients. Mayo Clin Proc 1968; 43: 545-56.
of untreated and cortisone-treated
"colds" or secondary infections. The cold vaccine tablet is unrelated to any of the recent influenza vaccines, and this patient should not be regarded as having had any association with influenza immunisation. Department of Dermatology, Mayo Clinic,
RICHARD K. WINKELMANN
Rochester, Minnesota 55901, U.S.A.
INOSIPLEX FOR SSPE
SIR,-Dr Chalmers and Professor Smith (June 26, p. 1475) see our analysis of inosiplex therapy in subacute sclerosing panencephelitis (SSPE) as a "travesty", since "a group of treated patients with 100% follow-up is being compared with controls in which the great majority of the follow-up information comes only from the dead patients". We think their concern is misplaced. The important issue is not whether the SSPE control patients are dead or alive but whether they reflect the survival characteristics of the population from which they are being sampled. As stated in our article, the lack of consistent follow-up makes it impossible to know if survival of the 150 dead Registry patients accurately depicts survival in the total non-inosiplex-treated SSPE population in the U.S. However, both the Lebanese and Israeli control samples were relatively complete (including most of the SSPE patients in those countries) and adequately followed-up and should therefore be unbiased with regard to the influence of these two potential complicating factors on survival probability in untreated SSPE. Furthermore, the comparison between "a group of treated patients with 100% followup" and two control groups (Lebanese and Israeli), either combined or singular, with comparable follow-up produced the same result and conclusion as the inosiplex/three-control composite comparison. Later, data were made available on an additional 163 U.S. Registry patients, many of whom were alive. These new data, further analysed with refined statistical procedures, generated conclusions that were consistent with those expressed in our article. A final comment on the closing sentence of the first paragraph of the letter by Chalmers and Smith. Clinical studies are often initiated in an open-trial (no randomised controls) format. If these initial studies are conducted on a few patients with a rare and fatal disease and suggest that a drug is safe and possibly effective, then are medical ethics best served by a continuation of the open trial or the implementation of the randomised-control study which gives all patients "an equal chance of getting the better therapy"? We believe that the ethos of medical practice would not be violated by continuing the open trial, since the latter argument ignores the corollary that a randomised study in a fatal disease gives all patients "an equal chance" of getting the therapy that will guarantee their demise. Statistical purity, nevertheless, is clearly allied with the latter choice. Newport Pharmaceuticals International, P.O. Box 1990, Newport Beach, California 92660-0147, U.S.A.
Inc.
CLARENCE JONES
AXILLARY SAMPLING AND BREAST CANCER
SIR,-The letter of Mr Kark and Mr Kissin (Aug. 7,
p. 326) drags into the debate. Their argument is that the most accurate method of staging is "a thorough and complete axillary clearance". Staging is not an end in itself but is to establish the prognosis. Our method of staging by node sampling separates patients into prognostic groups very effectively’ but Kark and Kissin present no data about this. Sampling gives a good estimate of prognosis and even better when combined with other factors.’ Until Kark and Kissin show that axillary clearance improves on the estimation of prognosis their argument is without substance. me
Professorial Unit
of Surgery,
City Hospital,
Nottingham NG5 1.
R. W. BLAMEY
1PB
Haybittle JL, Blamey RW, Elston CW, et cancer. Br J Cancer 1982; 45: 361-66.
al A
prognostic
index in
primary
breast