Photosensitizing antihypertensive drug use and risk of cutaneous squamous cell carcinoma.

BACKGROUND: Many antihypertensive drugs (ADs) are photosensitizing, heightening reactivity of the skin to sunlight. Photosensitizing ADs have been associated with lip cancer, but whether they impact the risk of cutaneous squamous cell carcinoma (cSCC) is unknown. OBJECTIVES: To examine the association between AD use and cSCC risk among a cohort of non-Hispanic white individuals with hypertension enrolled in a comprehensive integrated healthcare delivery system in northern California (n = 28 357). METHODS: Electronic pharmacy data were used to determine exposure to ADs, which were classified as photosensitizing, nonphotosensitizing or unknown, based on published literature. We identified patients who developed a cSCC during follow-up (n = 3010). We used Cox modelling to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Covariates included age, sex, smoking, comorbidities, history of cSCC and actinic keratosis, survey year, healthcare utilization, length of health plan membership and history of photosensitizing AD use. RESULTS: Compared with nonuse of ADs, risk of cSCC was increased with ever having used photosensitizing ADs (aHR = 1·17, 95% CI 1·07-1·28) and ever having used ADs of unknown photosensitizing potential (aHR = 1·11, 95% CI 1·02-1·20), whereas no association was seen with ever having used nonphotosensitizing ADs (aHR = 0·99; 95% CI 0·91-1·07). Additionally, there was a modest increased risk with an increased number of prescriptions for photosensitizing ADs (aHR = 1·12, 95% CI 1·02-1·24; aHR = 1·19, 95% CI 1·06-1·34; aHR = 1·41, 95% CI 1·20-1·67 for one to seven, eight to 15 and ≥ 16 fills, respectively). CONCLUSIONS: These findings provide moderate support for an increased cSCC risk among individuals treated with photosensitizing ADs.

Hydrochlorothiazide use is strongly associated with risk of lip cancer.

BACKGROUND: The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. OBJECTIVES: To study the association between use of hydrochlorothiazide and squamous cell carcinoma of the lip. METHODS: We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63 067 population controls using a risk-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for predefined potential confounders obtained from demographic, prescription and patient registries. RESULTS: Ever-use of hydrochlorothiazide was associated with an adjusted OR for SCC lip cancer of 2.1 (95% confidence interval (CI): 1.7-2.6), increasing to 3.9 (95%CI: 3.0-4.9) for high use (≥25 000 mg). There was a clear dose-response effect (P < 0.001), with the highest cumulative dose category of hydrochlorothiazide (≥100 000 mg) presenting an OR of 7.7 (95%CI: 5.7-10.5). No association with lip cancer was seen with use of other diuretics or nondiuretic antihypertensives. Assuming causality, we estimated that 11% of the SCC lip cancer cases could be attributed to hydrochlorothiazide use. CONCLUSIONS: Hydrochlorothiazide use is strongly associated with an increased risk of lip cancer.

Barbiturates and lung cancer in humans.

In a hypothesis-generating study looking for possible carcinogenic effects of drugs in humans, each of three barbiturates (pentobarbital sodium, phenobarbital, and secobarbital sodium) showed a statistically significant association with the subsequent development of lung cancer, with relative risks ranging from 1.5 to 2.8. Further analysis showed that the association was not explained by the increased prescription of barbiturate drugs shortly before the diagnosis of lung cancer or by an association of barbiturate use with cigarette smoking. Much of the data did not support a causal relationship. Neither a relation of lung cancer to duration or intensity of use not one between barbiturate use and a specific histologic type could be demonstrated.

Initial screening for carcinogenicity of commonly used drugs.

Computer-stored drug-dispensing data for 143,574 outpatients were used to identify users of various medicinal drugs during the 4-year period beginning in July 1969. These patients were followed through 1976 for the development of cancer. This report presents the results of screening analyses for 95 commonly used drugs and drug groups in relation to 56 primary cancer sites and combinations of sites. Statistically significant positive or negative associations with at least one site were found for 53 drugs. Some of these associations were undoubtedly due to chance sampling variation; some confirmed previous reports; some suggested interesting new hypotheses concerning possible drug effects or other etiologic or preventive factors. Further study is required before conclusions as to causality can be reached. Although the duration of follow-up in this study is relatively short so far, the absence of associations for many of the drugs studied provides some provisional assurance of their lack of carcinogenic effects.

Screening for possible drug carcinogenicity: second report of findings.

Cancer development was followed up through 1978 in 143,574 outpatients who were identified on the basis of computer-stored drug-dispensing data as users of various medicinal drugs during the 4-year period starting in July 1969. Screening analyses were repeated for the 95 most commonly used drugs and drug groups, which were reported previously after a shorter follow-up, and it was found that several drug-cancer associations had either gained or lost statistical significance since the report. Screening of 120 additional less commonly used drugs revealed one negative and 43 positive drug-cancer associations. A few of these associations suggested interesting new hypotheses about possible drug effects, but further study is required before conclusions on causality can be drawn. The absence of association with cancer for many drugs provides some provisional assurance for the absence of carcinogenicity, but further follow-up is needed to rule out later effects.

Breast cancer and serum cholesterol.

Recent studies have suggested a role for dietary fat in the etiology of breast cancer. The relation of serum cholesterol and other serum lipid measures to breast cancer incidence was investigated in a cohort of 95, 179 women who had multiphasic health checkups from 1964 through 1972. Through 1977, 1,035 new breast cancer cases occurred in over 752,000 person-years of follow-up. Age-adjusted incidence rates were 1.45, 1.37, 1.31, and 1.40/1,000 person-years from the lowest to the highest quartile of serum cholesterol level, respectively. Similarly, no statistically significant relation was detected between beta-lipoprotein or total lipids and breast cancer. The sample size was sufficiently large to have detected a relative risk of 1.4 or larger with a probability of 99.9% at the 0.05 level of significance. The expected relation od breast cancer to established risk factors was confirmed by univariate analysis, and serum cholesterol and breast cancer were not associated after simultaneous consideration of nine other risk factors by multivariate analysis. These data suggest that the postulated causal relation between dietary fat and breast cancer does not act via an effect on circulating lipid levels.

Prostate-specific antigen as predictor of prostate cancer in black men and white men.

BACKGROUND: The increasing incidence of prostate cancer creates complex issues in health care management and cost containment. There is a need to evaluate serial measurements of prostate-specific antigen (PSA) as a marker for long-term risk of clinically important prostate cancer (stages B through D). PURPOSE: We used a nested case-control design within a retrospective cohort study to evaluate serial PSA concentrations in relation to subsequent prostate cancer diagnoses. METHODS: Participants included 40 black and 96 white men with subsequent diagnoses of prostate cancer and 84 black and 100 white men without such diagnoses (control subjects) in a multiphasic health screening program conducted by the Kaiser Permanente Medical Care Program of Northern California. Serial serum samples were collected 1.5-23 years before prostate cancer diagnosis. RESULTS: Median serum PSA concentrations, specific for age and subsequent cancer status, were similar in blacks and whites. Concentrations in control subjects increased exponentially with age, with a doubling time of 24.9 years. Concentrations in men with stage A cancer were similar to those in control subjects. Until about 13 years before diagnosis, PSA in men with subsequent cancer stages B through D increased exponentially with age, with a doubling time similar to that of control subjects. Thereafter, the PSA concentrations increased exponentially, with a doubling time of 4.3 years. Rapid increase in PSA concentration started about 1.5 years earlier for men with stage D cancer than for men with stage B or C cancer. The single PSA measurement drawn closest to diagnosis was a more sensitive marker of stages B through D cancer within the next 7 years than was any index of change that also took account of earlier PSA readings. CONCLUSIONS: These data suggest that 1) age-specific PSA concentrations are similar in black men and white men and 2) current PSA concentration, specific for age, outperforms changes in past concentrations in identifying the man who will develop stage B, C, or D cancer within 7 years, albeit at the cost of a slightly higher rate of false-positive results. This interpretation needs confirmation in other data containing many serial PSA measurements within a few years of diagnosis.

Appendectomy, appendicitis, and large bowel cancer.

A cohort of 167,561 persons who received multiphasic health checkups were followed up for cancer development. A history of appendectomy showed slightly negative nonsignificant associations with the development of cancer of the colon, rectum, and all sites combined. By inference, the relation of appendicitis with these cancers was also inverse. Upper 95% confidence limits were compatible only with small positive associations of appendectomy and appendicitis with these cancers. These data do not support the view that removing the appendix increases cancer risk by diminishing immunocompetency. A link between appendicitis and large bowel cancer has been noted in intersociety correlations and has been hypothesized to be due to prevention of both by a high-fiber diet. However, appendicitis does not appear to be a useful predictor of large bowel cancer within a developed society.

Screening prescription drugs for possible carcinogenicity: eleven to fifteen years of follow-up.

Using computerized pharmacy records from 1969 to 1973 for a cohort of 143,574 members of the Kaiser Permanente Medical Care Program, we have been testing associations of 215 drugs or drug groups with subsequent incidence of cancer at 56 sites. This paper presents findings with follow-up through 1984. There were 227 statistically significant (P less than 0.05, two-tailed) associations: 170 positive, 57 negative. Some were undoubtedly chance findings; others were likely due to confounding by unmeasured covariables. However, several associations suggested hypotheses for further studies and/or the need for continued observation. Most notable among findings not previously reported were associations of several antibiotics, both oral and topical, with lung cancer. These associations could not be explained by indications for drug use or by differences in smoking habits between users and nonusers, and suggest a possible link between the occurrence of bacterial infections and risk for cancer. In general, our results continue to suggest that most medications used during that period did not affect cancer incidence substantially. However, for less frequently prescribed medications, our power to detect moderate increases in cancer risk was quite low.

Serum glucose levels and alcohol-consumption habits in a large population.

Using information from approximately 100,000 multiphasic check-ups performed in these facilities, we have found an association between alcohol-drinking habits and serum glucose values one hour after an oral challenge with 75 gm. of glucose. There was a positive dose-response relation between reported alcohol intake and serum glucose level over the most common range of alcohol intake. Serum glucose levels were highest in the group who consumed six to eight alcoholic drinks per day. However, among those who said they took nine or more drinks per day, mean serum glucose levels were significantly lower than in the six-to-eight-drink group. These relations persisted when the analysis was controlled for the effects of age, sex, race, adiposity, time since last food intake, time of day, previously known diabetes, and previously known liver disease. A search of the literature failed to uncover a complete explanation for these phenomena.

Mentholated cigarette use and lung cancer.

BACKGROUND: Menthol combustion produces carcinogenic compounds such as benzo[a]pyrenes. Mentholated cigarettes are much more commonly smoked by black individuals than by white individuals. The incidence of lung cancer is much higher (60%) in black men than in white men, but it differs little by race in women. We examined the association of mentholated cigarette use with lung cancer in men and women because mentholated cigarette use could help to explain the higher incidence rate of lung cancer in black men than in white men. METHODS: The study population consisted of 11,761 members of the Northern California Kaiser Permanente Medical Care Program, Oakland (5771 men and 3990 women), aged 30 to 89 years, who underwent a multiphasic health checkup in 1979 through 1985 and reported that they were current cigarette smokers who had smoked for at least 20 years. Data were collected about current cigarette brand, duration of mentholated cigarette use, and other smoking characteristics. Follow-up for incident lung cancer cases (n = 318) was carried out through 1991. RESULTS: The relative risk of lung cancer associated with mentholation compared with nonmentholated cigarettes was 1.45 in men (95% confidence interval, 1.03 to 2.02) and it was 0.75 in women (95% confidence interval, 0.51 to 1.11), adjusted for age, race, education, number of cigarettes smoked per day, and duration of smoking. Further adjustment for tar content and self-reported smoking intensity characteristics did not substantially alter the estimate of relative risk. A graded increase in risk of lung cancer with increasing duration of mentholated cigarette use was present in men. CONCLUSION: This study suggests that there is an increased risk of lung cancer associated with mentholated cigarette use in male smokers but not in female smokers.

Opportunities for research in dermatologic epidemiology.

This report is based on a number of papers presented at the March 1993 Scientific Workshop on the Epidemiology of Skin Diseases, sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. It focuses on opportunities in dermatologic epidemiology identified at the workshop and discusses these opportunities in the context of health maintenance organizations as sites for data collection, problems to be expected, and the potential contribution of dermatologic epidemiology.

Alcohol, tobacco, and hypertension.

In many studies of diverse populations it has been found that persons drinking relatively large amounts of alcohol tend to have higher blood pressures. In the Kaiser-Permanente study of about 87,000 persons, this alcohol-blood pressure association was not attributable to demographic characteristics, adiposity, reported salt use, smoking, or coffee consumption, nor could it be explained by underreporting of alcohol consumption. If the relationship is a causal one, the pathogenesis is not yet established; direct mechanisms or the effects of withdrawal from alcohol are possible explanations. The Kaiser-Permanente data suggest that about 5% of hypertension in the general population may be due to the consumption of three or more alcoholic drinks per day. Alcohol use shows a positive relation to some sequelae of hypertension but not others; the outstanding exception is coronary heart disease which is negatively related to alcohol intake, probably through different mechanisms. In most studies, cigarette smokers have shown similar or slightly lower blood pressures than non smokers. The degree to which this is due to the thinner body build of smokers, on the average, is not well established; nor is the degree to which a stronger negative relation of smoking to blood pressure might be masked by concomitant alcohol use.

Psychiatrically-diagnosed depression and subsequent cancer.

In a follow-up of up to 19 years, 923 patients with some form of depression diagnosed in a psychiatry clinic showed a slightly elevated risk of developing cancer in comparison with the other members of a cohort of 143,574 persons who received prescriptions from a pharmacy (Standardized morbidity ratio, 1.21; 95% confidence interval 0.95-1.53). When cancers diagnosed in the first 2 years after the diagnosis of depression were ignored, the risk increased somewhat (Standard morbidity ratio, 1.38; 95% confidence interval, 1.06-1.76). A subgroup of these depressed patients who had multiphasic health checkups were more apt to be of white race, unmarried, and users of postmenopausal estrogens if females than a matched comparison group of multiphasic examinees. These differences probably explain much of the group's excess cancers, most of which were located in the breast, endometrium, and skin (both melanoma and nonmelanoma). This study lends little if any support to the hypothesis that depression predisposes to cancer occurrence.

Cigarette smoking and risk of non-Hodgkin's lymphoma subtypes.

We examined the hypothesis that cigarette smoking increases the risk of non-Hodgkin's lymphoma (NHL) subtypes in a cohort of approximately 253,000 members of the Kaiser Permanente Medical Care Program, ages 16-84 years, who completed a self-administered questionnaire during the period 1964-1991 that ascertained smoking history. Using information from the Surveillance, Epidemiology, and End Results cancer registry that operates in the area and the Kaiser Permanente cancer registry, we identified 674 incident cases of NHL through 1993. We observed a positive association between smoking and risk of follicular lymphoma (compared with nonsmokers: former smokers, relative risk = 1.9 with 95% confidence interval = 1.2-2.9; current smokers, relative risk = 1.4 with 95% confidence interval = 0.9-2.2), although the strength of the association did not increase consistently with increasing duration and intensity of smoking. We observed no relationship between smoking status and the risks of small cell lymphocytic, diffuse, or high-grade lymphoma, nor was smoking related to the risk of all histological types of NHL combined. These results give limited evidence for a relationship between smoking and the risk of follicular lymphoma.

Barbiturates, smoking, and bladder cancer risk.

Phenobarbital treatment has been observed to be negatively associated with bladder cancer risk in a few studies. It has been suggested that phenobarbital may induce drug-metabolizing enzymes that detoxify the bladder carcinogens found in cigarette smoke. We examined the relationship of barbiturate use to bladder cancer risk and the potential modifying effect of cigarette smoking in a large cohort of Kaiser Permanente Medical Care Program members with computerized pharmacy prescriptions and smoking information. Newly diagnosed bladder cancers were identified among individuals in the study cohort by linkage with data from cancer registries. The overall standardized incidence ratio associated with barbiturate use was 0.71 [95% confidence interval (CI), 0.51-0.99]. Among current smokers, former smokers, and never smokers, the standardized incidence ratios were 0.56 (95% CI, 0.23-1.16), 0.68 (95% CI, 0.27-1.40), and 1.04 (95% CI, 0.48-1.98), respectively. Although our estimates were imprecise, the finding of an inverse association between barbiturate treatment and bladder cancer risk only among current and former cigarette smokers is consistent with the hypothesis that treatment with these medications induces drug-metabolizing enzymes that deactivate bladder carcinogens found in cigarette smoke.

Seasonal variation in vitamin D, vitamin D-binding protein, and dehydroepiandrosterone: risk of prostate cancer in black and white men.

Our previous study provided evidence that higher serum levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1, 25-D), might possibly slow the progression of subclinical to clinically significant prostate cancer in both black and white men, especially after age 57. This paper extends the prior study by contrasting seasonal variation in 1,25-D and its precursor, 25-hydroxyvitamin D (25-D), in case and control subjects. In addition, the risk of prostate cancer is related to serum levels of vitamin D-binding protein (VDBP) and total dehydroepiandrosterone and to polymorphic variation in VDBP. The expected elevated summer levels of 25-D were seen in case and control subjects and, as expected, 1,25-D did not vary throughout the year in the control subjects. Unexpectedly, lower case levels of 1,25-D were limited largely to the summer months (P = 0.01) in both black and white cases and to cases greater than or equal to the median age of 57 years. Levels of VDBP and dehydroepiandrosterone and the frequencies of VDBP polymorphisms were similar in case and control subjects, although striking differences were seen in allelic frequencies in black and white men. These observations provide additional evidence that vitamin D metabolism may impact the risk of prostate cancer.

Can hematuria be a predictor as well as a symptom or sign of bladder cancer?

In a case-control study of urinalysis screening in the prevention of death from bladder cancer, hematuria was present in a higher proportion of cases than controls as long as five or six years before the diagnostic evaluation that led to the diagnosis of bladder cancer. In a separate cohort study data base that permitted the follow-up of 1046 persons with a physician's diagnosis of hematuria, 11 cases of bladder cancer were diagnosed more than two (mean 7.4) years after the hematuria diagnosis (4.3 cases expected; age-sex standardized morbidity ratio, 2.5; 95% confidence interval, 1.3-4.5). Bladder cancer was ruled out initially by cystoscopy in 8 of the 11 cases. Although we cannot be certain that preexisting bladder cancer or bladder cancer risk factors did not cause the bleeding, we hypothesize that hematuria can be a predictor as well as a manifestation of bladder cancer, based on a tendency for bladder mucosa with premalignant changes to bleed. The implications for screening and clinical practice remain to be determined.

Helicobacter pylori, pepsinogen, and risk for gastric adenocarcinoma.

The objective of this project was to determine the association of Helicobacter pylori infection and serum pepsinogen levels on subsequent risk for gastric adenocarcinoma. This nested case-control study was set in a large health maintenance organization. One hundred thirty-six cases of gastric adenocarcinoma and 136 matched controls without adenocarcinoma from a large cohort that had contributed serum in the 1960's were studied. The presence of IgG against H. pylori had previously been determined by enzyme-linked immunosorbent assay. Serum levels of pepsinogens I and II were ascertained by radioimmunoassay. In a sample of subjects, the presence of antiparietal cell antibodies was determined by immunofluorescent antibody assay (Nichols Laboratory). There were 98 cases of adenocarcinoma of the antrum, body, or fundus (distal cancers) and 30 of the cardia or gastroesophageal junction (proximal cancers). By univariate analysis, H. pylori infection [odds ratio (OR), 3.6; P < 0.001] and serum pepsinogen I < 50 ng/ml (OR = 2.9; P = 0.003) were both associated with development of distal cancer. In multivariate analysis, there was interaction between the two variables; H. pylori in the absence of low pepsinogen I was independently associated with cancer (OR, 2.4; P = 0.04) but low pepsinogen I in the absence of H. pylori infection was not associated with cancer (OR, 0.8; P > 0.5). In combination, however, H. pylori infection and a low pepsinogen I were associated with a marked increase in the risk of developing distal malignancy (OR, 10.0; P = 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

5 alpha-reductase activity and prostate cancer: a case-control study using stored sera.

We report a nested case-control study of serum biomarkers of 5 alpha-reductase activity and the incidence of prostate cancer. From a cohort of more than 125,000 members of the Kaiser Permanente Medical Care Program who underwent multiphasic health examinations during 1964-1971, we selected 106 incident prostate cancer cases. A control was pair matched to each case on age, date of serum sampling, and clinic location. Serum levels of total testosterone, free testosterone, androsterone glucuronide, and 5 alpha-androstane-3 alpha,17 beta androstanediol glucuronide (3 alpha-diol G) were measured on the stored samples and scored as quartiles. Potential confounders included alcohol, smoking, and body mass index. The adjusted odds ratios and 95% confidence intervals for a one quartile score increase were 1.00 (0.75-1.34) for total testosterone, 1.14 (0.86-1.50) for free testosterone, 1.13 (0.84-1.53) for androsterone glucuronide, and 1.16 (0.86-1.56) for 3 alpha-diol G. A limitation of this study is that there are two different 5 alpha-reductase isoenzymes, only one of which is expressed in high levels within the prostate, yet both of which may affect serum biomarkers. Since the two isoenzymes are encoded on different chromosomes, variation in one would act as an independent source of measurement error in any analysis of serum biomarker effects of the other. Consequently, the odds ratios may be underestimated and the study, although negative, cannot exclude the previously hypothesized possibility that a positive relationship between intraprostatic 5 alpha-reductase activity and prostate cancer may exist. A clinical trial to test this hypothesis is under way.