Colorectal cancer: molecules and populations.
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The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention. (+info)
The differential risk of oral contraceptives: the impact of full exposure history.
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Previous discussions have indicated that the small increases of risk of venous thromboembolism (VTE) associated with newer combined oral contraceptives (third generation, containing desogestrel and gestodene) may be attributed to bias due to cohort effects. In a case-control analysis, this may produce an overestimate of risk of newer preparations. In 10 centres in Germany and the UK, the Transnational Study analysed data from 502 women aged 16-44 years with VTE, and from 1864 controls matched for 5-year age group and region. Information on lifetime exposure history from all subjects was added to the dataset used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17 622 continuous exposure episodes comprising 47 914 person-years of observation, the adjusted hazard ratio (equivalent to odds ratio, OR) of VTE for the comparison of current users of third-generation versus current users of second-generation (primarily levonorgestrel compounds) combined oral contraceptives was 0.8 (0.5 to 1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1 to 2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the Transnational Study data show no evidence for an increased risk of VTE with third- compared with second-generation combined oral contraceptives. (+info)
Effect of cigar smoking on the risk of cardiovascular disease, chronic obstructive pulmonary disease, and cancer in men.
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BACKGROUND: The sale of cigars in the United States has been increasing for the past six years. Cigar smoking is a known risk factor for certain cancers and for chronic obstructive pulmonary disease (COPD). However, unlike the relation between cigarette smoking and cardiovascular disease, the association between cigar smoking and cardiovascular disease has not been clearly established. METHODS: We performed a cohort study among 17,774 men 30 to 85 years of age at base line (from 1964 through 1973) who were enrolled in the Kaiser Permanente health plan and who reported that they had never smoked cigarettes and did not currently smoke a pipe. Those who smoked cigars (1546 men) and those who did not (16,228) were followed from 1971 through the end of 1995 for a first hospitalization for or death from a major cardiovascular disease or COPD, and through the end of 1996 for a diagnosis of cancer. RESULTS: In multivariate analysis, cigar smokers, as compared with nonsmokers, were at higher risk for coronary heart disease (relative risk, 1.27; 95 percent confidence interval, 1.12 to 1.45), COPD (relative risk, 1.45; 95 percent confidence interval, 1.10 to 1.91), and cancers of the upper aerodigestive tract (relative risk, 2.02; 95 percent confidence interval, 1.01 to 4.06) and lung (relative risk, 2.14; 95 percent confidence interval, 1.12 to 4.11), with evidence of dose-response effects. There appeared to be a synergistic relation between cigar smoking and alcohol consumption with respect to the risk of oropharyngeal cancers and cancers of the upper aerodigestive tract. CONCLUSIONS: Independently of other risk factors, regular cigar smoking can increase the risk of coronary heart disease, COPD, and cancers of the upper aerodigestive tract and lung. (+info)
Atrophic and static (neurodevelopmental) schizophrenic psychoses: premorbid functioning, symptoms and neuroleptic response.
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The question of whether schizophrenic-like disorders are neurodevelopmental or degenerative in origin has been argued since the time of Kraepelin. The authors provide evidence for the existence of two etiologically distinct endophenotypes of the psychoses contained within the rubric of familial non-affective psychosis (schizophrenia), one atrophic and the other neurodevelopmental. The atrophic psychosis, identified by progressive ventricular enlargement throughout adult illness, evidences progressive impairment of interests, relationships, and withdrawal from latency through adolescence, with emergence of trait-like negative symptoms which are only marginally responsive to conventional neuroleptics. This psychosis also exhibits delayed response of positive symptoms during neuroleptic treatment, and may also proceed to a praecox dementia in later life. In contrast, a putative neurodevelopmental psychosis, associated with static ventricles during the course of adult illness, also demonstrates preadolescent impairments, but impairments which do not progress to marked negative symptoms. Conventional neuroleptics appear to have little effect (except sedation) on positive symptoms, but appear to induce negative symptomatology and partial disengagement from the burden of persistent psychotic thought processes in such static ventricle psychoses. Thus, separate patterns of illnesses with different prodromal features, different treatment response patterns, and different patterns of residual (negative) symptoms appear to characterize patients with psychosis who have expanding as opposed to stable cerebral-ventricles at doses of neuroleptic at 10 mg haloperidol equivalents/day. (+info)
Analyzing health surveys for cancer-related objectives.
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Large-scale health surveys conducted by government agencies record information on a large number of health-related variables. We review the use of these data for performing analyses that address cancer-related objectives. After describing the conduct of a large-scale health survey (the third National Health and Nutrition Examination Survey [NHANES III]), we discuss some of the issues involved in analyzing data collected in such a survey. In particular, the use of sample weights in the analysis and the importance of accounting for the complex survey design when estimating standard errors are discussed. Six applications are then presented that involve the following: 1) estimating demographic factors associated with snuff use, 2) estimating the association of type of health insurance with the probability of receiving a digital rectal examination, 3) estimating the association of body iron stores with the probability of later developing cancer, 4) estimating the changing rates of mammography screening in the United States between 1987 and 1992, 5) evaluating smoking and alcohol consumption as risk factors for digestive cancer by use of a population-based, case-control study, and 6) evaluating a randomized community-intervention experiment to encourage smoking cessation. These applications use data from the National Health Interview Survey, the NHANES I Epidemiologic Followup Study, the 1986 National Mortality Followback Survey, and the Community Intervention Trial for Smoking Cessation. The availability of public-use data files is discussed for surveys sponsored by the U.S. government that collect health-related information. We demonstrate that statistical methods and computer software are available for analyzing public-use data files of surveys to address different types of cancer-related objectives. (+info)
Alcohol consumption and mortality from all causes, coronary heart disease, and stroke: results from a prospective cohort study of scottish men with 21 years of follow up.
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OBJECTIVES: To relate alcohol consumption to mortality. DESIGN: Prospective cohort study. SETTING: 27 workplaces in the west of Scotland. PARTICIPANTS: 5766 men aged 35-64 when screened in 1970-3 who answered questions on their usual weekly alcohol consumption. MAIN OUTCOME MEASURES: Mortality from all causes, coronary heart disease, stroke, and alcohol related causes over 21 years of follow up related to units of alcohol consumed per week. RESULTS: Risk for all cause mortality was similar for non-drinkers and men drinking up to 14 units a week. Mortality risk then showed a graded association with alcohol consumption (relative rate compared with non-drinkers 1. 34 (95% confidence interval 1.14 to 1.58) for 15-21 units a week, 1. 49 (1.27 to 1.75) for 22-34 units, 1.74 (1.47 to 2.06) for 35 or more units). Adjustment for risk factors attenuated the increased relative risks, but they remained significantly above 1 for men drinking 22 or more units a week. There was no strong relation between alcohol consumption and mortality from coronary heart disease after adjustment. A strong positive relation was seen between alcohol consumption and risk of mortality from stroke, with men drinking 35 or more units having double the risk of non-drinkers, even after adjustment. CONCLUSIONS: The overall association between alcohol consumption and mortality is unfavourable for men drinking over 22 units a week, and there is no clear evidence of any protective effect for men drinking less than this. (+info)
Methylenetetrahydrofolate reductase, diet, and risk of colon cancer.
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Individuals with different forms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, carriers of the C677T mutation versus wild type, show differences in enzyme levels; these differences have been hypothesized to be related to DNA methylation and, perhaps, to the nucleotide pool size. Using data from an incident case-control study, we evaluated the combined effect of dietary intake of folate, methionine, vitamin B6, vitamin B12, and alcohol and various forms of the MTHFR gene on risk of colon cancer. Individuals homozygous for the variant form of the MTHFR gene (TT) had a slightly lower risk of colon cancer than did individuals who were wild type [CC, odds ratio (OR) = 0.8, 95% confidence interval (CI) = 0.6-1.1 for men; and OR = 0.9, 95% CI = 0.6-1.2 for women]. High levels of intake of folate, vitamin B6, and vitamin B12 were associated with a 30-40% reduction in risk of colon cancer among those with the TT relative to those with low levels of intake who were CC genotype. Associations were stronger for proximal tumors, in which high levels of intake of these nutrients were associated with a halving of risk among those with the TT genotype. The inverse association with high levels of these nutrients in those with the TT genotype was stronger among those diagnosed at an older age. Although imprecise, the inverse association with the low-risk diet that was high in folate and methionine and without alcohol was observed for both the TT genotype (OR = 0.4 95% CI = 0.1-0.9) and the CC/CT genotype (OR = 0.6, 95% CI = 0.4-1.0), but this association was not seen with the high-risk diet for either the TT or CC/CT genotype. Although associations were generally weak, these findings suggest that those with differing MTHFR genotypes may have different susceptibilities to colon cancer, based on dietary consumption of folate, vitamin B6, and vitamin B12. (+info)
Glutathione S-transferase M1 and susceptibility to nasopharyngeal carcinoma.
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Genetic polymorphisms for enzymes that metabolize tobacco smoke have been reported to determine susceptibility to several smoking-related cancers, including cancers of the lung, bladder, and head and neck. Glutathione S-transferase M1 (GSTM1) detoxifies benzo(a)pyrene and other carcinogens in tobacco smoke. Approximately 50% of Caucasians lack the GSTM1 gene. Because the most common type of nasopharyngeal cancer (NPC), squamous cell carcinoma, is related to smoking, we sought to determine whether GSTM1 is associated with risk for NPC. Cases (n = 83) were from a population-based study conducted from 1987 to 1993 at five cancer registries in the United States. Random-digit dialing controls (n = 114) were matched to the cases for age, sex, and registry. Subjects participated in a phone interview and blood draw. Absence of GSTM1 was associated with increased risk for NPC (odds ratio = 1.9, 95% confidence interval = 1.0-3.3 for all cases; and odds ratio = 1.7, 95% confidence interval = 0.8-3.5 for squamous cell cases). This relationship was not modified by smoking history, but stronger relationships between glutathione S-transferase and NPC were suggested among subjects who used alcohol more frequently than others, older subjects (50 or more years of age), and women relative to men. These data indicate that absence of GSTM1 moderately increases risk for NPC and add to growing evidence that GSTM1 is a determinant of risk for several smoking-related cancers. (+info)