Johannes Fibiger and his Nobel Prize for the hypothesis that a worm causes stomach cancer.
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Biomedical subjects
Publications and source records attributed to P D Stolley.
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To examine the relation of noncontraceptive estrogen use to the risk of breast cancer among postmenopausal women, the authors conducted a case-control study: 1,686 cases were compared with 2,077 hospital control subjects, of whom 1,120 had non-gynecologic cancers and 957 had nonmalignant (also non-gynecologic) conditions. Data were obtained from 1980 to 1986, by interview of subjects in hospitals in the United States and Canada. The relative risk estimate for any use of replacement estrogens unopposed by progestogens was 1.2 (95% confidence interval (Cl) 1.0-1.4), after adjustment for age and type of menopause; when all known risk factors for breast cancer were taken into account in a multivariate analysis, the estimate was similar. For use of at least 15 years duration, the estimate was 0.9 (95% Cl 0.5-1.9). Most of the unopposed use was of conjugated estrogens: overall, the relative risk (95% Cl) was 1.3 (1.0-1.6); for durations of 15 or more years, it was 0.9 (0.4-1.9); for use of 5 years followed by a latent interval of 15 or more years, it was 1.3 (0.7-2.4); and for current use it was 1.1 (0.7-1.6). There was no evidence of increased breast cancer risk when the conjugated estrogen users were divided according to dose. There was little use of estrogens opposed by progestogens; the relative risk estimate was 1.7 (95% Cl 0.9-3.3). The results of this large study provide no evidence that the use of unopposed conjugated estrogens increases the risk of breast cancer, even after long durations of use or long latent intervals, but the possibility of a modest increase (less than a doubling) could not be excluded. There were insufficient data to evaluate the effects of nonconjugated estrogens and of combined estrogen and progestogen therapy.
In many studies, cigarette smoking has been associated with a small increase in breast cancer risk. The authors evaluated the relation of smoking to breast cancer risk in two case-control studies carried out from 1982 through 1986. In Canada, 607 women with breast cancer and 1,214 controls matched on decade of age and neighborhood were interviewed at home. In the United States, 1,955 cases of breast cancer and 805 controls with other cancers were interviewed in the hospital. In both studies, breast cancer risk was associated weakly with cigarette smoking overall. The odds ratio for women who had smoked 25 or more cigarettes per day as compared with never smokers was 1.2 (95% confidence interval (CI) 0.9-1.6) in the Canadian study and 1.2 (95% Cl 0.9-1.6) in the US study. In both studies, breast cancer risk was more strongly related to commencement of smoking at a young age. Among women who smoked at least 25 cigarettes per day in the most recent year of smoking, the odds ratios for commencement before age 16 years were 1.7 (95% Cl 1.0-2.9) in the Canadian data and 1.8 (95% Cl 1.0-3.4) in the US data, and the odds ratios for commencement at even younger ages were higher. The associations were not explained by duration of smoking, by the time elapsed since commencement, or by factors associated with cigarette smoking such as alcohol consumption or oral contraceptive use. Our findings raise the hypothesis that exposure to cigarette smoke during adolescence may increase a woman's risk of breast cancer. The hypothesis has biologic plausibility: cigarette smoke contains known carcinogens, and the developing breast is especially susceptible to cancer initiation.
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis and tumor growth in the rodent colon. We assessed NSAID use in relation to risk of human large-bowel cancer in a hospital-based, case-control study of 1326 patients with colorectal cancer and 4891 control patients. For regular NSAID use that continued into the year before interview, the multivariate relative risk estimate was 0.5 (95% confidence interval, 0.4 to 0.8); the estimate decreased as the duration of use increased, but the trend was not statistically significant. Similar results were obtained whether cancer or non-cancer controls were used, and the inverse association was apparent for both colon cancer and rectal cancer in men and women and in subjects younger and older than 60 years. Regular NSAID use that had been discontinued at least 1 year previously and non-regular use were not associated with risk. Almost all regular NSAID use was of aspirin-containing drugs. The present data suggest that the sustained use of NSAIDs reduces the incidence of human large-bowel cancer.
R.A. Fisher's work on lung cancer and smoking is critically reviewed. The controversy is placed in the context of his career and personality. Although Fisher made invaluable contributions to the field of statistics, his analysis of the causal association between lung cancer and smoking was flawed by an unwillingness to examine the entire body of data available and prematurely drawn conclusions. His views may also have been influenced by personal and professional conflicts, by his work as a consultant to the tobacco industry, and by the fact that he was himself a smoker.
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We conducted a random-sample survey of homeless children and their mothers residing in Philadelphia (Pa) shelters. One hundred forty-six families were included in the final sample, resulting in an 80% response rate. The aims of the survey were to characterize the child's current and past health status, to determine access to and use of medical services, and to determine the serum erythrocyte protoporphyrin levels and tuberculin skin test status of the children. In addition, psychological tests were administered to both child and parent to assess developmental level and psychological problems. Finally, detailed questions were asked concerning the reasons for the homeless condition. The important reasons for homelessness cited in the survey included physical abuse, substance abuse, disagreements with landlords, and poor living conditions. The children's health problems included a high incidence of reported accidents and injuries, burns, and lead toxicity; the parents suffered from depression, physical abuse, and substance abuse. School-aged children tended to have low scores on tests of expressive vocabulary and word decoding, and preschoolers seemed to be below age expectations in receptive vocabulary and visual motor skills. The findings of this study suggest that homeless children tend to score poorly on developmental and psychological tests and tend to sustain serious burns and accidents. Policy implications of the survey include suggestions for health screening, rehabilitation, and education.
In order to explore a priori hypotheses about drug-induced Stevens-Johnson Syndrome (SJS), a case-control study was initiated using data from COMPASS, a computerized data base consisting of Medicaid claims data. The records of 3.8 million patients in five U.S. states were searched to identify patients with an inpatient diagnosis of ICD-9-CM code 695.1 (erythema multiforme-EM). Out of the total of 367 cases that were identified, primary medical records for 249 were sought and 128 (51.4 per cent) of these were obtained. The remainder could not be obtained because: in 36 (29.8 per cent) the hospital refused to provide medical records; in 33 (27.3 per cent) there were transcription errors; in 20 (16.5 per cent) the state could not translate the identification number, primarily because the patients lost Medicaid eligibility too long before our request; in 27 (22.3 per cent) the hospital could not locate the patient's record; and in 5 (4.1 per cent) there were other reasons. Of those with a medical record, 121 (94.5 per cent) had a skin diagnosis and 109 (85.2 per cent) had a diagnosis compatible with ICD-9-CM code 695.1 specified on their discharge summary. However, in 35 (27.3 per cent) an expert reviewer felt that the discharge diagnosis was incorrect. In 50 (39 per cent) the computer diagnosis was incorrect. Only 19 (14.8 per cent) were judged by the expert reviewer to truly have Stevens-Johnson Syndrome, and an additional 37 (28.9 per cent) were judged to have erythema multiforme minor. Thus, the computerized diagnosis agreed very well with the diagnoses specified on the discharge summary. However, EM is frequently misdiagnosed, ICD-9-CM code 695.1 contains multiple other diagnoses which are not EM, and much of hospitalized EM is EM minor. Thus, studies of SJS cannot be performed except in patients whose medical records are available.
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The relationship of Papanicolaou (Pap) testing and physician visits to stage at diagnosis of cervical cancer was assessed by interviews with 149 women with invasive cervical cancer and 214 women with in situ cervical cancer. A significantly smaller percent of study subjects with invasive disease than in situ disease had at least one Pap test in the 3 years prior to diagnosis (age- and race-adjusted odds ratio: 3.38). The two groups did not differ in visits to a physician for other reasons during this period. Pap testing decreased with increasing age for both groups, but not physician visits. While 65% percent of the subjects with invasive disease aged between 65 and 79 years had never had a Pap test until diagnosis, 88% had seen a physician in the preceding 3 years. Women with regional or distant invasive disease were least likely to have had Pap tests, and, within this group, those aged between 35 and 64 years were also least likely to have seen a physician. Strategies for early detection must reflect missed opportunities and the need to bring those not receiving care into the system.
A case-control study of 293 patients with in situ cervical cancer and 801 community controls was conducted between 1982 and 1984 in five geographic areas in the United States. Relative risk (RR) was elevated among women reporting multiple sexual partners (RR for greater than or equal to 5 partners = 5.0), a history of an abnormal Papanicolaou smear (RR = 5.0), interval since last Papanicolaou smear (RR for greater than or equal to 10-year interval versus 0- to 2-year interval = 4.1), use of oral contraceptives (RR for greater than or equal to 10 years use = 1.4), a history of nonspecific genital infection (RR = 2.6), and smoking (RR for current smokers = 1.9). Risk was low among diaphragm users (RR for greater than 2 years use = 0.5). Neither age at first coitus nor number of births was predictive of risk of in situ disease. Comparisons between this analysis and risk factors previously identified for invasive cervical cancer in this same study indicate that the risk factors were quite similar.
OBJECTIVE: To assess the use of L-tryptophan by patients with eosinophilic fasciitis and compare this with its use by patients with progressive systemic sclerosis (scleroderma). DESIGN: Retrospective and prospective analysis. Six patients with eosinophilic fasciitis were identified retrospectively and two prospectively. Retrospective identification of patients was done by questioning hospital-affiliated rheumatologists and dermatologists and by searching the hospital dermatopathology database. The patients with scleroderma or morphea were prospectively identified by questioning consecutive office patients with these established diagnoses. SETTING: University of Pennsylvania rheumatology and dermatology practices. PATIENTS: Eight patients with eosinophilic fasciitis; 40 consecutive patients with scleroderma (27 with diffuse cutaneous and 13, limited cutaneous disease); 3 patients with morphea. RESULTS OF DATA ANALYSIS: All eight patients with eosinophilic fasciitis had taken L-tryptophan before the onset of their disease. All had myalgias and high peripheral eosinophil counts (most greater than 5000 cells/mm3). Only 1 of 40 patients with scleroderma (no patients with morphea) had used L-tryptophan preceding illness (P less than 0.001 compared with eosinophilic fasciitis). Six patients with eosinophilic fasciitis had taken L-tryptophan for less than 8 months. One patient had taken it for 9 years before developing skin induration. Two patients were newly identified as having hypothyroidism; two developed neuropathy; and two had severe flexion contractures (several occurring in areas without skin induration). Five patients had low-titer antinuclear antibodies, indicating a possible autoimmune process. Most patients had only a partial response to systemic corticosteroid therapy. One patient has had important disease regression in response to isotretenoin therapy that was evident even while she continued to take L-tryptophan. CONCLUSIONS: L-Tryptophan use can lead to eosinophilic fasciitis whereas it does not appear to cause classic scleroderma. The disease process does not automatically remit after discontinuation of L-tryptophan-containing products.
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The relation between diazepam use and breast cancer was explored in two case-control studies. The first (1981-1987) was a hospital-based study in the United States of 3,078 cases of breast cancer, 1,259 controls with other malignancies, and 672 controls with nonmalignant conditions. The relative risk estimates for regular diazepam use (at least 4 days per week for at least 6 months) that antedated the diagnosis of breast cancer by at least 12 months were 1.0 (95% confidence interval (CI) 0.6-1.7) using the cancer controls and 0.8 (95% CI 0.4-1.8) using the noncancer controls. Risk factors for breast cancer were taken into account in the estimates. There was no association for regular use lasting at least 5 years or for regular use that took place exclusively in the recent or more distant past. The second study (1982-1986), conducted in Toronto, Ontario, Canada, was community-based, and included 607 cases of breast cancer and 1,214 neighbor controls selected from municipal voting and census records. After control of confounding, the relative risk estimate for regular diazepam use was 0.8 (95% CI 0.5-1.3). Again, there was no association for long-term, past, or recent regular use. The results of both studies suggest that regular diazepam use does not increase the risk of breast cancer. The findings are strengthened by the similarity of the results using three different control groups--women with cancer, women with nonmalignant conditions, and neighbors.
An unexpected association between history of vasectomy and increased risk of prostate cancer emerged when multiple comparisons were carried out in data collected from 1976-1988 in a US hospital-based case-control study of many diseases and exposures. The association was assessed in detail in these data, in a comparison of 220 men with first episodes of prostate cancer with 571 noncancer controls and 960 cancer controls. The age-adjusted relative risk of prostate cancer was 5.3 (95% confidence interval 2.7-10) when noncancer controls were used and 3.5 (95 percent confidence interval 2.1-6.0) when cancer controls were used. The magnitude of the relative risk estimate appeared to be unrelated to the length of the interval after vasectomy. Allowance for several factors did not alter the estimates, but we did not have information on testosterone level or sexual activity, which may have been confounding factors. The association was stronger among men most likely to have been under more intensive medical surveillance; selective detection of asymptomatic cancer in such men would have led to an excess of cases. Further studies are needed to rule out chance, bias from medical surveillance, and uncontrolled confounding as explanations for the finding.
Feinstein's criticism of epidemiology are summarized and evaluated. His major premises appear to be that methodologic errors inevitably result in false positive associations, that epidemiologists are complacent about methodology, and that epidemiologists encourage overinterpretation of epidemiologic data by the public. We challenge these premises and discuss a number of technical errors that underlie Feinstein's writings: he generally ignores the tendency of nondifferential exposure misclassification to dilute associations; he inappropriately interchanges measure of disease occurrence, which leads him to erroneous assertions regarding differences among studies; and he asserts that absence of a dose-response gradient precludes causality, despite the fact that causal effects need not follow a monotonic dose-response curve over the entire range of exposure. We also challenge his assertions that contradictory results necessarily indicate poor study methods and that prior beliefs of the data collectors inevitably affect study results in ways not apparent in the study methods. Feinstein's approach to the use of epidemiology in policy formulation ignores the need to weigh all evidence and distinguish important from unimportant biases. We illustrate this point by documenting how the use of Feinstein's "scientific standards" in evaluating the evidence linking aspirin to Reye's syndrome would have led to costly errors in medical practice.