Hydralazine and breast cancer.

Hydralazine (CAS: 86-54-4; 1-hydrazinonaphthalazine) is a well-established antihypertensive agent. There are no conclusive data on the drug as a human carcinogen, but one of its metabolites, hydrazine (CAS: 302-01-2), has been shown to be carcinogenic in rats and mice. To assess the relationship of hydralazine to human breast cancer, 3,419 women with breast cancer and 3,219 hospital control subjects were studied. Data were obtained by interview in hospitals in the United States and Canada. A total of 1.4% of the cases and 1.2% of the controls had used hydralazine. Compared with never use, the relative risk (RR) estimate for hydralazine that was first used at least 18 months before admission was 0.9 [95% confidence interval (CI), 0.5-1.7] after risk factors for breast cancer and the use of other antihypertensive drugs and diuretics were taken into account by multivariate analysis. The RR estimate for hydralazine use lasting at least 1 year was 0.9 (95% CI, 0.5-1.7). RR estimates for longer durations of use (up to 5 or more yr), and for use within strata of risk factors for breast cancer, were close to 1.0. The results suggest that hydralazine does not increase the risk of breast cancer in humans in the short term. Whether the risk is increased after latent intervals of many years could not be evaluated.

Risk factors for breast cancer in black women.

Risk factors for breast cancer were examined in black women in a hospital-based case-control study of 529 black women with breast cancer and 589 controls. Late age at menarche was associated with a reduced risk of breast cancer. Women having 5 or more children had a reduced risk relative to that of women with fewer or no children. Late age at first birth was associated with an elevated risk of breast cancer. Among postmenopausal black women, obesity [as measured by body mass index (BMI)] was associated with an increased risk; among premenopausal women, there was no association of breast cancer with BMI. Women whose menopause occurred at or after age 50 were at increased risk relative to those whose menopause occurred earlier. There was no association between number of years of education and breast cancer in black women. History of benign breast disease and history of breast cancer in mother or sisters both were risk factors. The risk factor profile for breast cancer in black women was similar to that observed in whites.

Lack of an elevated risk of malignant melanoma in relation to oral contraceptive use.

Epidemiologic and laboratory data suggest an effect of oral contraceptives (OC) on the risk of malignant melanoma. This relationship was explored in a hospital-based case-control study of 160 women with malignant melanoma and 640 matched controls, all of whom were white and 20-59 years of age. A total of 63 cases (39%) had used OC compared with 270 controls (42%), yielding a relative risk estimate of 0.9 (95% confidence interval: 0.6-1.3). When a number of potential confounding factors were simultaneously controlled, the relative risk estimate was 0.8 (0.5-1.3). For use that lasted 5 or more years the estimate was 0.9 (0.5-1.6). The level of tumor invasion was not related to OC use. The evidence from this study suggests that OC, even when used for 5 or more years, do not increase the risk of malignant melanoma.

Major upper gastrointestinal tract bleeding. Relation to the use of aspirin and other nonnarcotic analgesics.

In a hospital-based case-control study, the risk of a first episode of major upper gastrointestinal tract bleeding in subjects now known to be predisposed was assessed in relation to the use of nonnarcotic analgesics. For aspirin use within the week before the onset of symptoms, the rate ratio estimates, adjusted for potential confounding, were 15 (95% confidence interval, 6.4 to 34) for regular use (at least four days a week) and 5.6 (confidence interval, 2.7 to 12) for occasional use. For aspirin use discontinued at least one week earlier, the estimate was 1.6 (confidence interval, 0.6 to 4.2). There was no evidence that acetaminophen use increased the risk. For the regular use of other analgesics in the week before onset, the adjusted rate ratio estimate was 9.1 (confidence interval, 2.7 to 31); there were insufficient data to evaluate occasional use. The findings suggest that the risk of bleeding is increased substantially by aspirin, even when used occasionally. With the exception of acetaminophen, other nonnarcotic analgesics may also increase the risk, but they remain to be evaluated individually.

Epidemiologic approaches to the study of toxic epidermal necrolysis.

The appropriate epidemiologic strategy for studying the etiology of toxic epidermal necrolysis is determined by the characteristics of the disease, particularly its rarity and the fact that it is caused by numerous drugs. Although information about drugs as risk factors can in principal be obtained from case reports and experimental studies, the former are subject to bias and the latter are impractical because toxic epidermal necrolysis is so rare. Cohort studies are also impractical because of the rarity of the outcome. An automated database, even if based on a large population, can only yield valid results if it is used as the starting point for a case-control study that includes access to the subjects and to the medical records for information to confirm the diagnosis. A population-based case registry can provide a large enough and well-documented series of cases, but does not allow for the valid estimation of risks because it lacks a comparison series. This leaves a case-control study as the only strategy that is both practical and valid. An ongoing international case-control study of toxic epidermal necrolysis and Stevens-Johnson syndrome in relation to the use of drugs is described. Data collection has proceeded in France, Italy, Germany, and Portugal. The study in Germany is conducted within a population-based case registry, and the study in Portugal is also population based; this will allow for the estimation of absolute risks. Data on demographic factors and medical history, a detailed history of drug use in the month before hospital admission, and various other factors are collected by interview of the cases and hospital controls. Cases are confirmed in an independent review process in which the diagnoses, and classification along a spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis, are determined without knowledge of drug use. As of June, 1993, 459 cases and 1299 controls have been enrolled. At the scheduled end of data collection in 1995, the projected totals are 691 cases and 1956 controls. These large numbers will allow for the detailed evaluation of even relatively uncommonly used drugs, for the evaluation of more commonly used drugs in relation to subtypes of toxic epidermal necrolysis/Stevens-Johnson syndrome, and for the comparison of results between countries.

Risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs: The International Agranulocytosis and Aplastic Anemia Study.

The risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs were estimated in a population-based case-control study conducted in Israel and Europe (total population, 23 million). Cardiovascular drug use in the week before onset of illness was compared between 270 patients hospitalized with agranulocytosis and 1870 hospitalized control subjects. Propranolol (relative risk, 2.5), dipyridamole (3.8), digoxin (2.5), and acetyldigoxin (9.9) were significantly associated with agranulocytosis. The excess risks attributable to these drugs ranged from one to three cases per 10 million persons exposed for up to 1 week. Increased risks were also observed for cinepazide (used by six cases and no control subjects), procainamide (7, 1), and aprindine (5, 1); based on crude relative risk estimates, the excess risks for the latter two drugs were approximately three per million persons exposed for up to 1 week. The use of cardiovascular drugs in a 5-month period ending 1 month before hospital admission was compared between 152 patients with aplastic anemia and 2180 control subjects. Furosemide was the only significantly associated drug (relative risk, 3.1); the excess risk attributable to any exposure in a 5-month interval was 1.7 per million.

Nonsteroidal anti-inflammatory drug use in relation to major upper gastrointestinal bleeding.

In a study in the United States, Sweden, and Hungary, 335 cases of gastric bleeding without predisposing factors were compared with 670 control subjects, and 239 cases of duodenal bleeding were compared with 489 control subjects. For aspirin taken at least every other day during the week before the onset of bleeding (regular use), the relative risk of gastric bleeding was 4.4 (95% confidence interval [CI], 2.9 to 6.7); for occasional use, it was 3.3 (95% CI, 2.1 to 5.0). For ibuprofen, the corresponding estimates were 1.0 (95% CI, 0.4 to 2.6) and 1.1 (95% CI, 0.5 to 2.4). For naproxen, the estimate for regular use was 4.0 (95% CI, 1.5 to 11). The estimates for any use of piroxicam (crude estimate), indomethacin, and diclofenac during the week before onset were 18 (95% CI, 4.1 to 83), 1.6 (95% CI, 0.4 to 5.9), and 0.9 (95% CI, 0.2 to 4.2), respectively. The corresponding relative risks of duodenal bleeding were 7.1 (95% CI, 4.2 to 12) and 2.2 (95% CI, 1.3 to 3.7) for the regular and occasional use of aspirin, 2.4 (95% CI, 0.5 to 11) and 0.8 (95% CI, 0.3 to 2.0) for ibuprofen, 12 (95% CI, 2.8 to 54) and 9.9 (95% CI, 2.3 to 44) for naproxen, 17 (95% CI, 3.6 to 79) for any use of piroxicam (crude estimate), and 1.7 (95% CI, 0.2 to 14) for any use of indomethacin. There was a significant trend in the risk of gastric bleeding with increasing dose of regular aspirin use (p = 0.002). The relative risk estimates for the regular use of 325 mg or less were significantly elevated for both gastric and duodenal bleeding at 3.1 and 6.4, respectively.

Estimating risks for matching factors in case-control studies.

Matching for factors such as age and sex is a convenient method for minimizing confounding in case-control studies, but it does not allow inferences about the effects of the matching factors unless case ascertainment is virtually complete and the distribution of the matching factors in the source population is known. When this is so, the effect of a particular factor can be estimated by comparing the population distribution of that factor with what is observed in the case series. Such a comparison, however, may itself be confounded by other factors that are related to both the matching factors and the disease under investigation. This article proposes a method for evaluating matching factors as risk factors, which uses information on the distribution of potential confounders in the reference series and exposure relative risk estimates to adjust the person-time proportionality constant in a Poisson regression model. The method is particularly suited to data sets in which many of the elementary matching strata contain few or no cases and/or controls. It makes use of standard analytic procedures, but requires the estimation of an additional variance-covariance component for the estimated Poisson regression coefficients. Further factors that may confound the relationship between exposure and disease are easily accommodated. The method is demonstrated in two examples: a matched case-control study of drugs in relation to the rare blood dyscrasia, agranulocytosis, that was conducted in Europe and Israel, and a case-control study of ovarian cancer in Australia.

An international collaborative case-control study of severe cutaneous adverse reactions (SCAR). Design and methods.

A multicenter international case-control study has been designed to elucidate the etiology of Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). Although these diseases occur rarely, the morbidity is high and the mortality for TEN is of the order of 30%. These serious dermatologic conditions have often been linked to exposure to drugs. Infective and autoimmune diseases, as well as other non-drug risk factors, have also been postulated to be of importance in increasing the risk. The design and methods are described, with particular attention to the unique challenges for an epidemiologic study of these conditions.

Cigarette smoking in relation to the risk of myocardial infarction in young women. Modifying influence of age and predisposing factors.

We evaluated the relation between myocardial infarction (MI) and cigarette smoking in women 30 to 49 years of age. Among 318 women who had survived recent first infarctions and 1272 age-matched controls, the proportions of cigarette smokers were 83% and 54%, respectively (p < 0.001). The estimated relative risk rose progressively with amount smoked: compared with women who had never smoked, the estimate was 1.8 for smokers of less than 15 cigarettes per day and 6.9 for smokers of 35 or more cigarettes per day. At each level of smoking, the relative increase in risk was greater at younger ages and among those not apparently predisposed from other factors. Although MI is a rare disease in young women, our data indicate that the risks faced by those who smoke heavily are appreciable.

Epithelial ovarian cancer and coffee drinking.

A recent report from a case-control study in Greece suggested that coffee consumption is related to an increase in the risk of ovarian cancer. This hypothesis was examined in a hospital-based case-control study in the US. Information on coffee drinking and other factors was obtained from 290 incident cases of epithelial ovarian cancer and compared with that of 580 controls with non-malignant conditions of acute onset and 476 controls with cancer of other sites. Adjustment was made for the potential confounding effects of several factors, including the major known risk factors for ovarian cancer. The estimated relative risk for drinking five or more cups of coffee per day, relative to none, was 1.1 (95% confidence interval, 0.6-2.0) using the controls with non-malignant conditions and 1.0 (0.5-1.8) using the controls with cancer. The estimates for drinking less than five cups per day were greater than 1.0, but this could have been due to chance. The consumption of decaffeinated coffee and tea also appeared to have no influence on risk. The evidence from this study suggests that, if coffee drinking increases the risk of ovarian cancer, the effect is small.

Case-control study of idiopathic retinal detachment.

A case-control study of idiopathic, rhegmatogenous retinal detachment (IRD) was conducted to investigate potential risk factors for developing IRD. These included some factors reported previously, such as cardiovascular disease, and some not under suspicion, such as cigarette smoking and iris colour. Cases (n = 198) were incident cases of IRD who were hospitalized for surgical repair of their detachments. Controls (n = 655) were patients hospitalized for conditions unrelated to suspected risk factors for IRD. The risk of IRD appeared to increase with increasing age, and the relative risk for self-reported myopes, compared with non-myopes, was elevated (RR = 3.4, 95% CI = 2.3 - 5.0). The relative risk of IRD was decreased in current smokers (RR = 0.5, 95% CI = 0.3 - 0.8); although there was not a significant trend of decreasing relative risk with increasing amount smoked, the estimate was lowest in those who smoked most heavily. Risk did not appear to be related to gender, eye colour, history of myocardial infarction, or history of hypertension.

Use of household pesticides and the risk of aplastic anaemia in Thailand. The Aplastic Anemia Study Group.

BACKGROUND: Aplastic anaemia is a severe blood dyscrasia that is more common in Thailand than in Western countries. Its a etiology remains poorly understood. METHODS: A case-control study was conducted in Bangkok and two rural regions of Thailand. The effect of household pesticides was evaluated among 253 incident cases of aplastic anaemia and 1174 hospital controls. RESULTS: A total of 54% of the cases and 61% of the controls were exposed 1-6 months previously. For most individual household pesticides and for groups classified according to chemical type (organophosphates, pyrethrins, and organochlorines), the relative risk (RR) estimates approximated 1.0; upper 95% confidence limits were below 2.0 for many comparisons. A significant association was observed for exposure to combination products containing dichlorvos and propoxur, with an overall RR estimate of 1.7 (95% confidence interval [CI]: 1.1-2.6); the estimate for regular use was 1.6 (95% CI: 0.9-2.9). CONCLUSIONS: The absence of a higher risk for the regular use of dichlorvos/propoxur reduces the credibility of the apparent association, which could well have been an artefact of multiple comparisons. We conclude that most household pesticides used in Thailand do not appear to increase the risk of aplastic anaemia.

Venous thromboembolism in relation to oral contraceptive use.

The relation of the risk of venous thromboembolism to the use of oral contraceptives was assessed in a hospital-based study of 61 women suffering from a first episode of idiopathic deep vein thrombosis or pulmonary embolism (cases) and 1278 women admitted for trauma or respiratory infections (controls). Twenty (33%) of the cases and 121 (9%) of the controls had used oral contraceptives within the previous month, yielding an age-adjusted relative risk estimate of 8.1 (95% confidence interval 3.7 to 18) for recent users relative to never-users. For women using oral contraceptives containing less than 50 micrograms estrogen, the relative risk estimate was 11 (3.7 to 22); for preparations with 50 micrograms estrogen, it was 5.5 (2.1 to 15); and for preparations with more than 50 micrograms estrogen, it was 11 (3.9 to 30). Past use of oral contraceptives was not associated with an increased risk. The data suggest that the risk of venous thromboembolism is increased for recent oral contraceptive users relative to nonusers, even if women use oral contraceptives containing low doses of estrogen. Confidence intervals were wide, however, so that a reduction in the risk for users of lower dose formulations relative to users of higher dose formulations cannot be ruled out. Selection bias, if present, would have resulted in overestimation of the relative risk, but should not have distorted the comparisons according to dosage.

Breast cancer risk in relation to early oral contraceptive use.

It has been suggested that the risk of breast cancer is increased by oral contraceptive use before the first birth, or by use before age 25, particularly if certain formulations are used. These hypotheses were evaluated in a hospital-based case-control study. A total of 521 patients under age 45 with breast cancer were compared with 521 controls matched for age, time of interview, and geographic area. Oral contraceptive use before the first birth was reported by 155 patients and 137 controls. With allowance for confounding by multivariate analysis, the estimated relative risk was 1.0 (95% confidence interval, 0.6-1.5). The estimate was 1.0 (0.2-3.9) for any use among nulliparous women and 0.6 (0.3-1.3) for use before the first birth among parous women. Use before age 25 was reported by 145 patients and 141 controls, and the multivariate relative risk estimate was 1.0 (0.7-1.6); the results were similar when use of specific formulations was examined. For oral contraceptive use before either the first birth or age 25, the relative risk estimates were compatible with 1.0 for use of five or more years' duration or an interval since first use of at least 15 years. There was also no evidence of an increased risk in any subgroup including those at increased underlying risk because of factors such as a family history of breast cancer or a history of cystic breast disease. The findings suggest that, up to age 45, the risk of breast cancer is not influenced by the use of oral contraceptives before the first birth or before age 25 even if the use lasted for five or more years.

Agranulocytosis in Bangkok, Thailand: a predominantly drug-induced disease with an unusually low incidence. Aplastic Anemia Study Group.

Agranulocytosis, a syndrome characterized by a marked reduction in circulating granulocytes, is strongly associated with medical drug use in Europe and the United States. Unregulated use of common pharmaceutical agents in developing countries has been suspected of causing large numbers of cases of agranulocytosis and deaths, especially among children. To elucidate the incidence and etiology of agranulocytosis in Thailand, a population-based case-control study of symptomatic agranulocytosis that resulted in hospital admission was conducted in Bangkok from 1990 to 1994. An attempt was also made to study the disease in Khonkaen (in northeastern Thailand) and Songkla (in southern Thailand), but there were insufficient cases in the latter regions, and the analysis was confined to subjects from Bangkok. In that region, the overall incidence of agranulocytosis was 0.8 per million per year; there were no deaths. As expected, the incidence was higher in females (0.9 per million), and it increased with age (4.3 per million beyond age 60). Among 25 cases and 529 controls the relative risk estimate for a combined category of all suspect drugs was 9.2 (95% confidence interval = 3.9-21), and the proportion of cases that could be attributed to drug use was 68%. For individual drugs and drug classes the data were sparse; within these limitations, the strongest association appeared to be with antithyroid drugs. One case and three controls were exposed to dipyrone, a drug known to cause agranulocytosis; with such scanty data the risk could not be evaluated. Exposure to pesticides or solvents was not associated with an increased risk. This is the first formal epidemiologic study of agranulocytosis in a developing country. As in the West, most cases are attributable to medical drug use. However, the incidence of agranulocytosis in Bangkok, and apparently, in Thailand as a whole, is unusually low, and the disease does not pose a public health risk.

Survival in commercially insured multiple sclerosis patients and comparator subjects in the U.S.

OBJECTIVE: Compare survival in patients with multiple sclerosis (MS) from a U.S. commercial health insurance database with a matched cohort of non-MS subjects. METHODS: 30,402 MS patients and 89,818 non-MS subjects (comparators) in the OptumInsight Research (OIR) database from 1996 to 2009 were included. An MS diagnosis required at least 3 consecutive months of database reporting, with two or more ICD-9 codes of 340 at least 30 days apart, or the combination of 1 ICD-9-340 code and at least 1 MS disease-modifying treatment (DMT) code. Comparators required the absence of ICD-9-340 and DMT codes throughout database reporting. Up to three comparators were matched to each patient for: age in the year of the first relevant code (index year - at least 3 months of reporting in that year were required); sex; region of residence in the index year. Deaths were ascertained from the National Death Index and the Social Security Administration Death Master File. Subjects not identified as deceased were assumed to be alive through the end of 2009. RESULTS: Annual mortality rates were 899/100,000 among MS patients and 446/100,000 among comparators. Standardized mortality ratios compared to the U.S. population were 1.70 and 0.80, respectively. Kaplan-Meier analysis yielded a median survival from birth that was 6 years lower among MS patients than among comparators. CONCLUSIONS: The results show, for the first time in a U.S. population, a survival disadvantage for contemporary MS patients compared to non-MS subjects from the same healthcare system. The 6-year decrement in lifespan parallels a recent report from British Columbia.

Inheritance and expression of Esterase-1 allozymes in Peromyscus leucopus.

We analyzed inheritance of 5 Es-1 alleles in P leucopus and found them to be co-dominant and segregating from a single autosomal locus, thereby verifying assumptions of Mendelian inheritance implicit in field data. We also described an allele that is 'silent' in hemolysate, but is active in liver extract.