A clinical trial to evaluate the effect of vitamin C supplementation on in vitro mutagen sensitivity. The University of Texas M. D. Anderson Clinical Community Oncology Program Network.

Mutagen sensitivity, as measured by an in vitro assay, has been described as a risk factor for the development of several tobacco-related epithelial cancers. In vitro studies have indicated that sensitivity to the clastogenic effects of bleomycin on chromosomes was reduced with the introduction of ascorbic acid in a dose-dependent relationship. We report the results of a randomized clinical trial to determine whether increasing levels of oral ascorbic acid could reduce the levels of mutagen sensitivity. For this study, we recruited 228 healthy smokers from 21 centers around the country through the Clinical Community Oncology Program. Each individual was randomly assigned to one of four daily regimens: placebo, 1 g of ascorbic acid, 2 g of ascorbic acid, or 4 g of ascorbic acid. Treatments were administered for 16 weeks. Assessment of mutagen sensitivity was made at baseline and at weeks 4, 16, and 20 (4 weeks after cessation of treatment). Serum ascorbic acid levels were measured at baseline and at weeks 4 and 16. Demographic and risk factor data were collected at baseline and at each-measurement point. Analyses measured the differences of mutagen sensitivity levels across the four treatment arms, as well as investigating the correlation between serum ascorbic acid level and mutagen sensitivity levels in individuals. We did not find a dose-response relationship between ascorbic acid intake and mutagen sensitivity. Additionally, we did not find an association between serum ascorbic acid levels and mutagen sensitivity.

Lung carcinoma in former smokers.

BACKGROUND: A reduction in the risk of lung carcinoma and a lower death rate among former smokers (FS) compared with current smokers (CS) have been documented in numerous U.S. and international studies. The main objective of our study was to compare the differences in demographic and clinical characteristics in groups stratified by smoking status and gender to evaluate the effect of smoking history and cessation on age at lung carcinoma diagnosis and on specific histologic type. METHODS: We conducted a cross-sectional study of lung cancer at The University of Texas M.D. Anderson Cancer Center from January 1986 to December 1990 and from January 1992 to December 1993. This study included 1039 patients age 19-88 with confirmed primary lung carcinoma who responded to self-administered risk factor questionnaires. Among them, 497 patients (47.83%) were CS, 444 patients (42.73%) were FS, 98 patients (9.43%) had never smoked (NS), and 840 patients (80.8%) were heavy smokers (more than 20 pack-years). RESULTS: The median age at lung carcinoma diagnosis for FS was slightly later than that for CS. The histologic type of lung carcinoma for those who had quit smoking more than 20 years previously was not significantly different from that of NS, but was significantly different from that of CS (P < 0.05) and from those who quit smoking fewer than 10 years previously (P < 0.10). CS was a positive predictor for both small cell carcinoma (odds ratio [OR] = 8.79) and squamous cell carcinoma (OR = 2.11) and negatively associated with adenocarcinoma (OR = 0.50), whereas FS was a positive predictor only for small cell carcinoma (OR = 5.50). The variable of pack-years was negatively associated with adenocarcinoma and positively associated with small cell carcinoma in all patients combined and in women, and was also positively associated with squamous carcinoma in all patients after adjustment by smoking status. CONCLUSIONS: These results indicate that smoking cessation or less life-time smoking exposure affects the distribution of specific histologic subtypes of lung cancer, especially for women, and that smoking cessation may postpone the age at which lung cancer occurs.

Correlation between selected environmental exposures and karyotype in acute myelocytic leukemia.

Many bone marrow cytogenetic abnormalities in acute myelogenous leukemia (AML) are tumor specific, clonal, nonrandom, and related to prognosis; it has been hypothesized that they may be markers of exposure to etiological agents. A previous report from our institution revealed several such associations; the purpose of the current study was to determine whether previous findings were present in a new group of patients. Subjects included 84 newly diagnosed AML patients (French-American-British M1 and M2); exposure data were gathered using self-report questionnaires at the time of registration. Two sets of comparisons were made: (a) patients with all (AA) or some (AN) cytogenetically abnormal cells versus those with normal karyotypes (NN) and (b) patients with specific abnormalities [-5/5q-, -7/7q-, +8, t(8;21)] versus all others. Odds ratios (ORs) were 4.64 for the association between prior cytotoxic therapy and -5/5q- and 6.38 for the association with -7/7q-, but were <1.00 for +8 and t(8;21). There were no ORs > 2.0 for specific abnormalities in any of the other exposures evaluated (cigarette smoking, alcohol use, occupational exposure to organic chemicals, paints, or pesticides/herbicides), with the exception of exposure to paints and -7/7q- (OR, 7.50). The ORs for AA/AN versus NN patients were 1.43 and 3.81 for smoking and alcohol use, and weak dose-response trends were present. The most consistent positive associations between the two series were for prior cytotoxic therapy (-5/5q-; -7/7q-), cigarette smoking (AA/AN versus NN) and alcohol use (AA/AN versus NN). Reasoning from the known association between prior cytotoxic therapy and -7/7q-, we would have predicted relatively high ORs (> 4.0) if specific abnormalities acted as markers for the exposures assessed, but none were present. However, in both series, AA/AN patients were more likely to smoke and use alcohol than were NN patients, and weak dose-response patterns were present for both. This finding suggests that both smoking and alcohol use may play a role in the pathogenesis of cytogenetic abnormalities in AML-M1/M2; however, the mechanism by which they work and whether they are involved in the etiology of these diseases remain unclear.

Mutagen sensitivity as a biological marker of lung cancer risk in African Americans.

Cigarette smoking is the major determinant of lung cancer. However, only a fraction of smokers develops lung cancer; genetically determined susceptibility factors seem to play an important role also. Previous case-control studies have shown that in vitro bleomycin-induced mutagen sensitivity is an independent risk factor for head-and-neck cancers, and preliminary data suggest a similar association with lung cancer. However, these studies were almost exclusively performed on Caucasian populations. To test whether ethnic differences in cancer risk are due to differences in mutagen sensitivity, we are using the in vitro mutagen sensitivity assay to conduct a case-control study of mutagen sensitivity and lung cancer risk in low-risk (Mexican-American) and high-risk (African-American) groups. Here we report the results of our ongoing study of 209 African-Americans (90 cases and 119 controls) in the Houston-Galveston area. Mexican-American data will be reported separately as case accrual increases. Predictably, all measures of cigarette smoking status (including intensity, duration, tar content, depth of inhalation, and type of cigarette) were significant predictors of risk. In addition, 55.3% of the cases were mutagen sensitive (defined as > or = 1 break/cell), compared with 24.6% of the controls, with an age-, sex-, and smoking-adjusted odds ratio (OR) of 3.7 (95% confidence limits = 1.4, 9.4). Of interest, higher risks were noted for former smokers (OR = 5.4) compared with current smokers (OR = 3.1) and especially for younger former smokers (< 55 years). By histologic-specific analysis, mutagen sensitivity was significantly associated with risk for adenocarcinoma (OR = 4.8) and squamous cell carcinoma (OR = 8.5).(ABSTRACT TRUNCATED AT 250 WORDS)

A case-control study of nonrandom distribution of bleomycin-induced chromatid breaks in lymphocytes of lung cancer cases.

We used a case-control study design to determine the association between bleomycin-induced chromatid breaks and the risk of lung cancer in general and by specific histopathological types. Lymphocytes from primary blood cultures of 78 controls and 75 cases with 4 histopathological types of lung cancer were treated with 0.03 unit/ml bleomycin for 5 h, and the frequency of induced chromatid breakage and the locations of the breaks were determined in Q-banded preparations. After adjustment for their length, the larger chromosomes had more breaks than the smaller chromosomes in both cases and controls. The cases had significantly more breaks on chromosomes 4 and 5 than the controls did, with odds ratios (ORs) of 4.9 [95% confidence limits (CL), 2.0, 11.7] and 3.9 (95% CL, 1.6, 9.3), respectively. When the lung cancers were classified by histopathological type, adenocarcinomas had significantly more breaks on chromosomes 4 and 5, with ORs of 3.0 (95% CL, 1.0, 8.7) and 3.5 (95% CL, 1.2, 10.7), respectively. For squamous cell carcinoma, the ORs were significantly elevated for breaks on chromosomes 2, 4, and 5 with ORs of 3.5 (95% CL, 1.0, 11.7), 10.2 (95% CL, 2.5, 41.9), and 7.9 (95% CL, 1.9, 32.8). For small cell carcinoma, breaks on chromosomes 2 and 4 showed significantly increased ORs of 33.2 (95% CL, 2.2, 513.3) and 20.4 (95% CL, 1.7, 250.1), respectively. However, no specific chromatid breaks were detected in cases with large cell carcinoma. When the frequency of chromatid breaks at specific regions was calculated, breaks at 4p14, 4q27, 4q31, 5q21-q22, 5q31, and 5q33 were significantly more common in lung cancer cases than in controls. Lung cancer risk had a dose-response relationship with breaks on chromosomes 4 and 5. Cigarette smoking had a strong interaction with breaks on chromosomes 2, 4, and 5. The findings suggest that the susceptibility of particular chromosome loci to mutagenic damage may be a risk factor for specific types of lung cancer.

Lung cancer, smoking patterns, and mutagen sensitivity in Mexican-Americans.

BACKGROUND: Mexican-Americans have lower age-adjusted lung cancer incidence rates than non-Hispanic whites and African-Americans. Since 87% of lung cancers are attributed to tobacco exposure, this difference could be explained partly by lower prevalence of cigarette smoking. However, only a fraction of exposed individuals will develop smoking-related cancer, and genetically determined differences in modulation of environmental exposures could also explain some of this ethnic risk differential in lung cancer incidence in the United States. However, little research on genetic susceptibility has been focused on Hispanic populations in the United States. METHODS: We are conducting a case-control study of lung cancer in a high-risk group (African-Americans) and a low-risk group (Mexican-Americans) to evaluate ethnic differences in mutagen sensitivity by an in vitro assay that quantifies mutagen-induced chromosome breaks in short-term lymphocyte cultures. RESULTS: In the 174 Mexican-Americans (67 lung cancer case patients and 107 control subjects) accrued to date, all measures of cigarette smoking (intensity, duration, nicotine and tar contents, depth of inhalation, and type of cigarette) were significant predictors of lung cancer risk. There were significantly higher risks associated with mutagen sensitivity (defined as > or = 1 break/cell) for both former smokers (odds ratio [OR] = 4.5; 95% confidence interval [CI] = 0.9-21.9) and current smokers (OR = 2.6; 95% CI = 0.6-11.1). Mutagen sensitivity also appeared to be implicated in risk in patients who were less than 55 years old at diagnosis (OR = 15.0; 95% CI = 1.0-228.9) and in those with lower cigarette exposure (OR = 11.0; compared with an OR of 1.7 for the heaviest smokers). The overall OR for mutagen sensitivity adjusted for age, sex, and pack-years of smoking was 2.9 (95% CI = 0.8-9.9). Neither current smoking status nor years of exposure shifted the sensitivity profile of case patients and control subjects. CONCLUSION: Although this study showed higher percentages of nonsmokers among Mexican-Americans than our previously reported data for African-Americans, the Mexican-American case patients were heavier smokers than the African-American case patients. The prevalence of mutagen sensitivity for Mexican-Americans was 64.1% in case patients and 26.2% in control subjects. In African-Americans, mutagen sensitivity was previously reported to be 55.3% in case patients and 24.6% in control subjects. These preliminary data do not support our a priori hypothesis that a lower prevalence of mutagen sensitivity in Mexican-Americans would account for the lower incidence of lung cancer. Mutagen sensitivity, however, is only one of an array of potential susceptibility markers that we are evaluating in this unique population.

Mutagen sensitivity in upper aerodigestive tract cancer: a case-control analysis.

Variability in DNA repair capability may be a determinant of interindividual difference in susceptibility to carcinogenic exposures. A cytogenetic assay which quantifies chromosomal breakage induced by in vitro exposure to a clastogen provides an indirect measure of repair. We report the results of a case-control study of upper aerodigestive tract cancers assessing differences in mutagen sensitivity based on this assay. There were 108 cases with previously untreated squamous cell cancers and 108 age and sex frequency-matched controls selected from blood donors to The University of Texas M. D. Anderson Cancer Center. Sixty-nine% of the cases, compared with 44% of the controls, were classified as mutagen sensitive (breaks per cell > or = 0.8). On multivariate analysis, mutagen sensitivity [odds ratio (OR), 2.5], heavy cigarette smoking (OR, 4.8), and heavy alcohol consumption (OR, 3.1) were associated with significantly increased risk. Stratified analyses showed that the combined effects of cigarette smoking (OR, 8.1) and mutagen sensitivity (OR, 3.2) were suggestive of a multiplicative effect (OR, 23.0). The combined estimate for alcohol use (OR, 3.0) and mutagen sensitivity (OR, 3.0) was 5.8. These data confirm those of a previously published preliminary study of upper aerodigestive cancers and underscore the importance of considering interindividual susceptibility in cancer risk characterization, even for those cancers with well quantified exposures.

Association between family history of cancer and mutagen sensitivity in upper aerodigestive tract cancer patients.

This study evaluated the relationship between family history of cancer and bleomycin-induced mutagen sensitivity. The study included 108 patients who registered at The University of Texas M.D. Anderson Cancer Center from June 1987 to June 1991 with histologically confirmed and previously untreated squamous cell carcinoma of the upper aerodigestive tract. All patients underwent the mutagen sensitivity assay and completed a self-administered risk evaluation questionnaire, including a detailed family history. The patients reported having 650 first-degree relatives, including 54 cases with cancers. The patients were classified as mutagen sensitive (> or = 1 chromosome break/cell) or not mutagen sensitive (< or = 0.99 chromosome breaks/cell). Odds ratios (ORs) were calculated to test for significant associations between mutagen sensitivity and family history of cancer. We found a significant OR (OR = 2.63; 95% confidence interval = 1.06-6.53) for patients who were mutagen sensitive and had one first-degree relative affected with cancer. For mutagen-sensitive patients with two or more first-degree relatives affected with cancer, the OR increased to 6.59 (95% confidence interval = 1.69-25.72). Although 88% of the patients were ever smokers, cigarette smoking was not found to be related to mutagen sensitivity. The study findings suggest that patients who have defective DNA repair capability as evidenced by the mutagen sensitivity assay are significantly more likely to report a family history of cancer than patients who are not mutagen sensitive. Further studies are needed to confirm that mutagen-sensitive individuals have inherited an increased risk of cancer.

Low incidence of familial breast cancer among Hispanic women.

There is a paucity of data on familial patterns of breast cancer among minority populations. This study compared the frequency of cancer in 1,095 first-degree relatives of 50 White, 46 Black, and 49 Hispanic breast-cancer patients referred to The University of Texas M.D. Anderson Cancer Center (United States). Family histories of cancer were derived from a self-administered questionnaire on risk factors. Expected numbers of cancers were calculated from the Connecticut Tumor Registry for White and Black relatives and from the New Mexico Tumor Registry for Hispanic relatives. Family history of a first-degree relative with breast cancer was the most important risk factor for both Black and White patients. Significantly elevated standardized incidence ratios (SIR) for breast cancer were noted among White (SIR = 4.5, 95 percent confidence interval [CI] = 1.2-11.4) and Black (SIR = 4.1, CI = 1.1-10.4) relatives younger than age 45. Despite the small number of Black patients, the combined effect of family history of breast cancer and the relative's age at diagnosis (under 45 years) was associated with an SIR of 7.1 (CI = 1.9-18.1). A deficit of cancer was noted in Hispanic women; only one patient reported having a first-degree relative with breast cancer. These findings, although based on small numbers, suggest that Hispanics have a lower rate of familial breast cancer than Whites and Blacks, and that they may possess protective factors that reduce their risk for breast cancer.

Cancer prevention practices among Texas primary care physicians.

Primary care physicians are uniquely positioned to practice primary and secondary cancer prevention. However, despite a positive commitment, many physicians are pessimistic about the success of their interventions. This study describes the self-reported cancer prevention practices and perceived obstacles of 1600 Texas primary care physicians. These practices differed by primary care specialty and by length of time in practice. Time constraints were uniformly perceived as the leading obstacle to the provision of smoking cessation counseling. High cost, lack of third-party reimbursement, and poor patient compliance were cited as the leading barriers to patient referral for screening mammography. Professional education should stress to physicians that interventions need not be elaborate, expensive, or time consuming, the main purpose being to motivate and reinforce patient behavior. The special challenges of introducing health promotion activities into the clinical setting must be addressed with practical aids such as prompting systems, flowsheets, and computer-based aids for monitoring compliance rates.

Familial patterns of prostate cancer: a case-control analysis.

Epidemiological data have not yet enabled physicians to look beyond age and race to identify men at increased risk for prostate cancer. We conducted a hospital-based case-control study of familial patterns of prostate cancer with self-reported data from a risk-factor questionnaire. There were 385 patients with histologically confirmed prostate cancer, and 385 race and age-matched (+/- 5 years) controls with other cancers. Family history, available for 378 patients and 383 controls, was positive for prostate cancer in 13.0% versus 5.7%, respectively. The difference was significant at p = 0.01. The over-all age-adjusted risk estimate for men with a first-degree relative with prostate cancer was significantly elevated (odds ratio of 2.41), as were the individual risk estimates for having a father or brother with prostate cancer (odds ratio of 2.24 and 2.66). Having a second-degree relative (grandfather or uncle) with prostate cancer also conferred elevated but not statistically significant risk. These data accord well with the few previously published case-control studies of familiarity of prostate cancer. On the basis of these findings, one should consider recommending participation in early detection programs for prostate cancer in a man whose father or brother has had the disease.

Employees' perceptions of an on-site cancer screening clinic.

A 14-question survey was mailed to 355 employees examined during a 5-month period in 1989 in a nurse-administered employee cancer screening clinic at The University of Texas M.D. Anderson Cancer Center in Houston. Almost 60% of the study group (209/355) responded to the survey, which was designed to measure employees' attitudes toward the on-site clinic. Overall, respondents viewed the program very positively, and almost all of those still employed by M.D. Anderson Cancer Center at the time of the survey said they would return for an examination the next year. Between 52 and 80% of respondents reported increasing the practice of self-examinations for cancer. Of the quarter of the study group who identified themselves as being smokers at the time of the screening examination, 63% said they were no longer smoking. Finally, the analysis showed that having registered nurse participants present during screening did not significantly affect employees' willingness to return for an examination the next year. The survey results indicate that employees view the screening program favorably, that the education they receive affects their behavior, and that almost all have a positive attitude about returning for an examination the next year.

Risk profiles of women with cervical neoplasia.

Risk-factor profiles were compared in M.D. Anderson Cancer Center patients with various uterine cervix histologic diagnoses. Intraepithelial neoplasia (n = 171) and condyloma (n = 82) were associated with significantly lower patient age (mean 23.6 and 25.8 years, respectively). In addition, these two groups were lowest in annual income, age at beginning intercourse and at first pregnancy, and highest in percentages of black and Hispanic patients, number of sexual partners, and history of gonorrhea. Women with squamous carcinoma in situ (n = 47), who were about a decade older, exhibited a similar socioeconomic distribution and sexual history. All three groups also reported high prevalences of current smokers, were most likely to use oral contraceptives, and were least likely to use diaphragms or condoms. Patients with invasive squamous cell carcinoma (n = 77) had a mean age of 46.3 years, a large lowest-income constituency, and the highest mean number of pregnancies; they were least likely to have used oral contraceptives. Adenocarcinoma (n = 21) was epidemiologically distinct: a predominance of white woman characterized by high socioeconomic status, elevated body mass index, and non of the liberal sexual practices of the other groups. Primary and secondary prevention strategies must be tailored to the unique needs and socioeconomic status of the young at-risk populations.

Salivary gland cancer. A case-control investigation of risk factors.

Unlike most upper aerodigestive tract cancers, salivary gland cancers are relatively infrequent, are characterized by a diversity of histologic subtypes, and have never been etiologically associated with tobacco exposure. We present the results of a case-control study of risk factors for these cancers, with risk estimates derived from self-administered comprehensive risk-factor questionnaires distributed to patients at The University of Texas M. D. Anderson Cancer Center, Houston. Cases were 64 patients with histologically confirmed salivary gland cancer. Control subjects, randomly selected from the same patient population excluding patients with cancer of the head and neck or nonmelanoma skin cancer, were frequency-matched to the cases by age, sex, and ethnicity to achieve a 2:1 control subjects/cases ratio. On multivariate analysis, prior radiotherapy was a significant risk factor for both men (odds ratio [OR] = 2.1) and women (OR = 2.3). Among women, higher educational attainment (OR = 2.4), alcohol use (OR = 2.0), and hairdye use (OR = 2.5) were also significantly associated with risk. There were no significant differences between cases and control subjects with respect to tobacco exposure or specific occupational or leisure-time exposures. There is biological plausibility for associations with hairdye use and alcohol exposure.

Cigarette smoking patterns in patients after treatment of upper aerodigestive tract cancers.

There is a paucity of data on variables predictive of successful smoking cessation in cancer patients. In this questionnaire-based study, we report the smoking status of 75 patients (46 men, 29 women) with head and neck cancer followed for a minimum of 30 months after definitive therapy. Seventy-one percent of the men and 61% of the women who were current smokers at diagnosis stopped smoking subsequent to diagnosis and treatment. Only 29% and 39%, respectively, continued to smoke, most at decreased intensity. Patients with laryngeal cancer were most likely to have stopped (83%). Conversely, patients with oral cavity cancer were most likely to be continuing smokers (66%). In addition, older age, college education, and lighter smoking habits were somewhat predictive of successful cessation. Fear of recurrent disease and physician advice were the questionnaire-listed incentives most often chosen as contributing to success in cessation. The role health professionals can play in counseling cancer patients to stop smoking is stressed.

Chromosome sensitivity to bleomycin-induced mutagenesis, an independent risk factor for upper aerodigestive tract cancers.

Defective DNA repair capability, measured by enumerating mutagen-induced chromosomal lesions, might explain variable host susceptibility to the action of environmental carcinogens. We compared sensitivity to bleomycin-induced chromosome damage in 75 patients (53 men and 22 women) with previously untreated upper aerodigestive tract malignancies with that in 62 healthy control subjects. Data on tobacco and alcohol use were derived from a detailed, self-administered cancer risk factor questionnaire. Forty-five patients and 13 controls were sensitive to bleomycin-induced mutagenesis (average breaks/cell greater than 0.8). Differential susceptibility was detected in patients categorized by primary tumor location. Odds ratios for chromosome sensitivity were significantly elevated for all sites (odds ratio = 10.3 for pharyngeal cancers, 8.0 for laryngeal cancers, and 3.8 for oral cavity cancers). On logistic regression analysis, chromosome sensitivity remained a strong and independent risk factor after adjustment for potential confounding from age, sex, and tobacco and alcohol use (odds ratio = 4.3, 95% confidence limits = 2.0, 10.2). Despite the small study size and design constraints, the strength of the association with chromosome sensitivity even after adjustment for potential confounders is impressive and suggests a promising avenue for further research. The preventive implications of a valid marker for carcinogen sensitivity are manifold.