Biomedical subjects
S D Mark
Publications and source records attributed to S D Mark.
A pooled analysis of case-control studies of thyroid cancer. VI. Fish and shellfish consumption.
OBJECTIVE: To better understand the role of fish and shellfish on thyroid cancer risk, we systematically re-analyzed the original data from 13 case-control studies conducted in the US, Japan, China, and Europe. METHODS: A total of 2497 cases (2023 women, 474 men) and 4337 controls (3268 women, 1069 men) were considered. Odds ratio (OR) and corresponding 95% confidence interval (CI) were estimated for each study by logistic regression models, conditioned on age and sex, and adjusted for history of goiter, thyroid nodules or adenomas, and radiation. Combined ORs were computed as the weighted average of the estimates from each study. RESULTS: The ORs for the highest level of total fish consumption (three or more times per week) as compared to the lowest one (less than once per week) was above unity in Hawaii, Connecticut, Japan, Norway, Tromsø, and Vaud. Conversely, the ORs for the studies in Los Angeles. Shanghai, southeastern Sweden, Uppsala, northern Sweden, northern Italy, and Athens were below one. The pattern of risk for salt water fish and shellfish was not substantially different from that of total fish. Fish was not associated with thyroid cancer risk in all studies combined (OR = 0.99, 95% CI 0.85-1.2 for moderate, and OR=0.88, 95% CI 0.71-1.1 for high total fish consumption), but there was a suggestion of a protective effect in endemic goiter areas (OR = 0.65, 95% CI 0.48-0.88). CONCLUSION: This combined analysis indicates that relatively elevated fish consumption does not appreciably increase thyroid cancer risk, and may have a favorable influence in areas where iodine deficiency is, or was, common.
Sphingolipids as biomarkers of fumonisin exposure and risk of esophageal squamous cell carcinoma in china.
OBJECTIVE: Ecologic studies of esophageal squamous cell carcinoma (ESCC) have reported an association with consumption of maize contaminated with Fusarium verticillioides, which produce fungal toxins referred to as fumonisins. Fumonisins disrupt sphingolipid metabolism and serum sphingolipids have been proposed as biomarkers of fumonisin exposure. We conducted a prospective nested case-control study to examine the relationship between serum sphingolipids and ESCC incidence. METHODS: Cases and controls were selected from a large prospective trial conducted in Linxian, People's Republic of China. Ninety-eight ESCC cases were randomly selected from the 639 incident ESCC ascertained during the initial 5.25 years of follow-up: 185 controls were also randomly selected based on the distribution of cases among six age and sex strata. Concentrations of sphinganine and sphingosine were determined by high-performance liquid chromatography in serum collected at the study baseline. RESULTS: No significant associations were found between serum sphingosine, sphinganine, or the sphinganine/ sphingosine ratio and ESCC incidence in conditional and unconditional logistic regression models with adjustment for age, sex, tobacco use. and alcohol use. CONCLUSION: Our study is the first prospective study to assess the relationship between sphingolipid levels, as biomarkers of fumonisin exposure, and cancer incidence. We found no significant association between sphingolipid levels and risk of ESCC.
Prospective study of tooth loss and incident esophageal and gastric cancers in China.
OBJECTIVE: To determine the association between tooth loss and the risk of developing esophageal squamous cell carcinoma, gastric cardia adenocarcinoma, or gastric non-cardia adenocarcinoma in a prospective study. METHODS: Cox proportional hazards regression was used to examine these associations in a 28,868-person cohort followed prospectively for 5.25 years. The baseline questionnaire included questions regarding tooth loss, and individuals reporting lost teeth had their teeth counted by study personnel. The analytic cohort included 620 esophagus, 431 gastric cardia, and 102 gastric non-cardia cancer cases. RESULTS: Tooth loss was associated with a significantly elevated risk of developing all three cancers. When examined as median splits, tooth loss was associated with a relative risk (RR) (95% confidence interval, CI) of 1.3 (1.1-1.6) in the esophagus, 1.3 (1.0-1.6) in the gastric cardia, and 1.8 (1.1-3.0) in the gastric non-cardia. Further analysis demonstrated that this increased risk was most strongly associated with the loss of the first few teeth and was primarily confined to the younger members of our cohort. CONCLUSIONS: In this cohort tooth loss increased the risk of developing upper gastrointestinal cancer. We hypothesize that this may be related to alterations in oral bacterial flora and subsequent increases in the in-vivo production of carcinogens such as nitrosamines.
Influence function based variance estimation and missing data issues in case-cohort studies.
Recognizing that the efficiency in relative risk estimation for the Cox proportional hazards model is largely constrained by the total number of cases, Prentice (1986) proposed the case-cohort design in which covariates are measured on all cases and on a random sample of the cohort. Subsequent to Prentice, other methods of estimation and sampling have been proposed for these designs. We formalize an approach to variance estimation suggested by Barlow (1994), and derive a robust variance estimator based on the influence function. We consider the applicability of the variance estimator to all the proposed case-cohort estimators, and derive the influence function when known sampling probabilities in the estimators are replaced by observed sampling fractions. We discuss the modifications required when cases are missing covariate information. The missingness may occur by chance, and be completely at random; or may occur as part of the sampling design, and depend upon other observed covariates. We provide an adaptation of S-plus code that allows estimating influence function variances in the presence of such missing covariates. Using examples from our current case-cohort studies on esophageal and gastric cancer, we illustrate how our results our useful in solving design and analytic issues that arise in practice.
A cross-sectional study of human serum sphingolipids, diet and physiologic parameters.
Sphinganine and sphingosine, the two sphingoid base backbones of sphingolipids, are highly bioactive compounds that are of increasing interest to nutritionists because they occur in food and their metabolism can be altered by fungal toxins that contaminate some foods. Nonetheless, no studies of diet and sphinganine or sphingosine concentrations in serum have yet been reported. Here we describe a cross-sectional study of 265 residents of Linxian, People's Republic of China, which examines potential demographic, physiologic and dietary correlates of serum sphinganine and sphingosine in this population. Median concentrations of serum sphinganine and sphingosine were compared among strata for 29 different variables. For sphinganine, no significant differences were found. For sphingosine, significant differences were seen among strata of age, menstruation status, serum cholesterol, carotenoids, retinol, tocopherols, fresh and dried vegetable and fresh fruit consumption. Using multivariate linear regression with stepwise selection, we found that the significant predictors for serum sphingosine included total tocopherols, age, serum selenium and retinol, with a final R(2) = 0.22; for sphinganine, tooth loss was the sole correlate, with R(2) = 0.015. Analyses using ranked sphingolipid data or principal components analysis, to simplify the food variables, did not materially alter these results. This study represents the largest report of human serum sphingolipid concentrations to date and provides insight into potential explanatory variables that can be incorporated into future studies.
Prospective study of serum selenium levels and incident esophageal and gastric cancers.
BACKGROUND: From March 1986 through May 1991, we conducted a randomized nutritional intervention trial, the General Population Trial, in Linxian, China, a region with epidemic rates of squamous esophageal and adenomatous gastric cardia cancers. We found that participants who received selenium, beta-carotene, and vitamin E had significantly lower cancer mortality rates than those who did not. In the current study, we examined the relationship between selenium levels measured in pretrial (1985) sera from participants and the subsequent risk of developing squamous esophageal, gastric cardia, and gastric non-cardia cancers during the trial. METHODS: This study was designed and analyzed in accord with a stratified case-cohort sampling scheme, with the six strata defined by sex and three age categories. We measured serum selenium levels in 590 case subjects with esophageal cancer, 402 with gastric cardia cancers, and 87 with gastric non-cardia cancers as well as in 1062 control subjects. Relative risks (RRs), absolute risks, and population attributable risk for cancers were estimated on the basis of the Cox proportional hazards models. All statistical tests are two-sided. RESULTS: We found highly significant inverse associations of serum selenium levels with the incidence of esophageal (P: for trend <10(-4)) and gastric cardia (P: for trend <10(-6)) cancers. The RR and 95% confidence interval (CI) for comparison of highest to lowest quartile of serum selenium was 0.56 (95% CI = 0.44-0.71) for esophageal cancer and 0.47 (95% CI = 0.33-0.65) for gastric cardia cancer. The population proportion of these cancers that is attributable to low selenium levels was 26.4% (95% CI = 14.45-38.36). We found no evidence for a gradient of serum selenium associated with incidence of gastric non-cardia cancer (P: for trend =.96), with an RR of 1.07 (95% CI = 0.55-2.08) for the highest to lowest quartile of serum selenium. CONCLUSIONS: Our study supports findings from previous prospective studies and randomized trials that variations in selenium levels affect the incidence of certain cancers. In the United States, where intervention trials of selenium are in the planning stages, consideration should be given to including populations at high risk for squamous esophageal and gastric cardia cancers.
A pooled analysis of thyroid cancer studies. V. Anthropometric factors.
OBJECTIVE: To assess the relation between anthropometric factors and thyroid cancer risk in a pooled analysis of individual data from 12 case-control studies conducted in the US, Japan, China and Europe. METHODS: 2056 female and 417 male cases, 3358 female and 965 male controls were considered. Odds ratios (OR) were derived from logistic regression, conditioning on age, A-bomb exposure (Japan) and study, and adjusting for radiotherapy. RESULTS: Compared to the lowest tertile of height, the pooled OR was 1.2 for females for the highest one, and 1.5 for males, and trends in risk were significant. With reference to weight at diagnosis, the OR for females was 1.2 for the highest tertile, and the trend in risk was significant, whereas no association was observed in males. Body mass index (BMI) at diagnosis was directly related to thyroid cancer risk in females (OR = 1.2 for the highest tertile), but not in males. No consistent pattern of risk emerged with BMI during the late teens. Most of the associations were observed both for papillary and follicular cancers, and in all age groups. However, significant heterogeneity was observed across studies. CONCLUSIONS: Height and weight at diagnosis are moderately related to thyroid cancer risk.
Non-Hodgkin's lymphoma and nitrate in drinking water.
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Evolution of precancerous lesions in a rural Chinese population at high risk of gastric cancer.
The pathogenesis of gastric cancer (GC), particularly of the intestinal type, is thought to involve a multistep and multifactorial process. Our objective was to determine the rates of transition from early to advanced gastric lesions in a population in Linqu County, China, where the GC rates are among the highest in the world. An endoscopic screening survey was launched in 1989-1990 among 3,399 residents aged 34-64 years with precancerous lesions diagnosed from biopsies taken from 7 standard locations in the stomach and from any suspicious sites. The cohort was subsequently followed, with endoscopic and histopathologic examinations conducted in 1994. Logistic regression analysis was used to estimate odds ratios (ORs) of progression to advanced lesions of various levels of severity as a function of age, sex and baseline pathology. The rates of progression were higher among older subjects, among men and among subjects with more extensive gastric lesions. 34 incident GCs were identified during the follow-up period. The ORs of GC, adjusted for age and sex, varied from 17.1, for those with baseline diagnoses of superficial intestinal metaplasia (IM), to 29.3, for those with deep IM or mild dysplasia (DYS) or IM with glandular atrophy and neck hyperplasia, to 104.2, for those with moderate or severe DYS, as compared with subjects with superficial gastritis (SG) or chronic atrophic gastritis (CAG) at baseline. Our prospective study of a high-risk population revealed sharp increases in the risk of GC and advanced precursor lesions according to the severity of lesions diagnosed at the start of follow-up. Int. J. Cancer, 83:615-619, 1999. Published 1999 Wiley-Liss, Inc.
Tyrosine kinase inhibitors block sperm-induced egg activation in Xenopus laevis.
Fertilization of Xenopus laevis eggs triggers a wave of increased [Ca2+]i. The exact signal transduction pathway culminating in this Ca2+ wave remains unknown. To determine whether increases in tyrosine kinase activity are part of this pathway, we microinjected tyrosine kinase inhibitors into unfertilized eggs. Upon fertilization, signs of activation were monitored, such as fertilization envelope liftoff and the Ca2+ wave (for eggs microinjected with lavendustin A). Various concentrations of lavendustin A and tyrphostin B46 were microinjected, as well as inactive forms of these compounds (lavendustin B and tyrphostin A1) to provide negative controls. Peptide A, a 20-amino-acid peptide derived from the SH2 region of pp60(v-src) tyrosine kinase, was also microinjected. Peptide A inhibits tyrosine kinase activity but not PKA or PKG activity. Dose-response curves for lavendustin A, tyrphostin B46, and peptide A show clear inhibition of vitelline envelope liftoff by these three compounds. Confocal imaging of eggs coinjected with lavendustin A and Oregon Green-dextran showed that the Ca2+ wave was inhibited under normal insemination conditions but that the block of the Ca2+ wave could be overcome with very high sperm densities. A phenomenon of small local Ca2+ increases termed "hot spots" seen in lavendustin A containing eggs is also described. Since this inhibition of egg activation by tyrosine kinase inhibitors can be overcome by Ca2+ microinjection, the inhibitors must act on a step in the signal transduction cascade that is upstream of the Ca2+ wave.
A pooled analysis of case-control studies of thyroid cancer. III. Oral contraceptives, menopausal replacement therapy and other female hormones.
OBJECTIVE: The relations between oral contraceptives (OC), hormone replacement therapy (HRT) for menopause, and other female hormone use and thyroid cancer risk was analyzed using the original data from 13 studies from North America, Asia and Europe. METHODS: Based on 2,132 cases and 3,301 controls, odds ratios (OR) and the corresponding 95% confidence intervals (CI) were obtained by conditional regression models, conditioning on study and age at diagnosis, and adjusting for age, radiation exposure and parity. RESULTS: Overall, 808 (38%) cases versus 1,290 (39%) controls had ever used OCs, corresponding to an OR of 1.2 (95% CI 1.0 to 1.4). There was no relation with duration of use, age at first use, or use before first birth. The OR was significantly increased for current OC users (OR = 1.5, 95% 1.0 to 2.1), but declined with increasing time since stopping (OR = 1.1 for > 10 years since stopping). The association was stronger for papillary cancers (OR = 1.6 for current users) than for other histologic types. No significant heterogeneity was observed across studies or geographic areas. Eight studies had data on HRT, for a total of 1,305 cases and 2,300 controls: 110 (8%) cases and 205 (9%) controls reported ever using HRT (OR = 0.8; 95% CI 0.6 to 1.1). The ORs were 1.6 (95% to 0.9 to 2.9) for use of fertility drugs, and 1.5 (95% CI 1.1 to 2.1) for lactation suppression treatment. CONCLUSIONS: The studies considered in these analyses include most of the epidemiological data on the role of exogenous hormone use in the etiology of thyroid cancer, and they provide reassuring evidence on the absence of an association of practical relevance. The moderate excess risk in current OC users, if not due to increased surveillance for thyroid masses among OC users, is similar to that described for breast cancer, and would imply a role of female hormones on thyroid cancer promotion. There was no indication of increased thyroid cancer risk 10 or more years after discontinuing OC use.
A pooled analysis of case-control studies of thyroid cancer. I. Methods.
OBJECTIVE: Because the etiology of thyroid cancer is not well described, we conducted a pooled analysis of all published case-control studies, as well as two identified unpublished studies. This paper describes the major characteristics of the 14 studies included in the analysis, as well as the statistical methods employed. Four studies were conducted in the United States (1 each in Washington State, California, Connecticut and Hawaii), 8 in Europe (3 in Sweden, 2 in Norway, 1 in Switzerland, 1 in Italy and 1 in Greece), and 2 in Asia (1 in China and 1 in Japan). METHODS: The original datasets were obtained and restructured in a uniform format. Data on socio-demographic characteristics, anthropometric measures, smoking and alcohol consumption, history of benign thyroid diseases and of other selected medical conditions and treatments, family history of cancer and of benign thyroid conditions, occupation, residence in endemic goitre areas, and dietary habits were analyzed. For women, we also analyzed menstrual and reproductive factors and use of female hormones. Radiotherapy and, in Japan, exposure to the A-bombs were considered as potential confounding factors. RESULTS: A total of 2,725 cases (2,247 females and 478 males) and 4,776 controls (3,699 females and 1,077 males) were included in this study. Of the cases, 79% were classified as papillary thyroid carcinomas, 14% as follicular, 2% medullary, 1% anaplastic, 1% other histologies, and 3% histological type unknown. Each of the datasets was checked for outliers and consistency. Data were analysed separately by study center, gender, and the two major histologic types (papillary, follicular). Frequency tables and simple statistics were computed for each variable under study. Conditional logistic regression was used to compute odds ratios. For matched studies, the original matching was preserved, whereas, for unmatched ones, five-year age groups were used for matching. Study-specific analyses were computed, and then the data from all the studies were pooled conditioning on study. Heterogeneity between studies, geographic areas and study designs was assessed, and the modifying effect of age was also evaluated.
A pooled analysis of case-control studies of thyroid cancer. II. Menstrual and reproductive factors.
OBJECTIVE: It has been suggested that female hormones, and hence menstrual and reproductive factors, play a role in thyroid cancer etiology. Epidemiological data, however, are limited and inconsistent, partly because of the small number of cases included in each study. To clarify the etiology of thyroid cancer, we conducted a pooled analysis of original data from 14 case-control studies, 4 from the United States, 2 from Asia, and 8 from Europe. METHODS: This analysis included a total of 2,247 female cases of thyroid cancer (80% papillary) and 3,699 control women. Pooled odds ratios (OR) were estimated using logistic regression, conditioning on study and (i) matching sets for individually matched studies, or (ii) quinquennia of age for the other studies. Additional terms for age and history of radiation exposure were included in the regression equations. RESULTS: The OR per year of later menarche was 1.04 (95% confidence interval (CI) 1.0-1.1). Compared to premenopausal women, the OR was 1.3 for women with natural menopause, and 1.8 for those with artificial menopause, but the studies were heterogeneous and the association may be due, at least in part, to diagnostic or ascertainment bias. Parity, spontaneous or induced abortions and history of infertility were not associated with thyroid cancer risk. The OR was above unity in women reporting later age at first birth (OR = 1.1, 95% CI 1.0-1.3 for 5-year delay) and higher in the first years after a birth. CONCLUSIONS: The associations of menstrual and reproductive factors with thyroid cancer risk were generally weak, but appeared stronger among women diagnosed with thyroid cancer at younger ages.
A pooled analysis of case-control studies of thyroid cancer. IV. Benign thyroid diseases.
OBJECTIVE: To obtain more precise estimates of the association between thyroid cancer and benign thyroid diseases and to elucidate the role of potential confounders or effect modifiers. METHODS: The original data from 12 case-control studies from the United States, Asia, and Europe were pooled. Based on 2,094 women and 425 men with cancer of the thyroid and, respectively, 3,248 and 928 control subjects, odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were obtained by conditional regression models, conditioning on study and age at diagnosis, and adjusting for age and radiotherapy. RESULTS: A history of hypothyroidism was not associated with cancer risk (pooled ORs = 0.9, 95% confidence interval, CI: 0.7-1.3 in women and 1.7, 95% CI: 0.3-11.7 in men). ORs for hyperthyroidism were 1.4 (95% CI: 1.0-2.1) in women and 3.1 (95% CI: 1.0-9.8) in men. In women, however, risk was lower in the absence of or after allowance for history of goiter. Pooled ORs for a history of goiter were 5.9 (95% CI: 4.2-8.1) in women and 38.3 (95% CI: 5.0-291.2) in men. Risk for a history of benign nodules/adenomas was especially high (OR = 29.9, 95% CI: 14.5-62.0, in women; 18 cases versus 0 controls in men). The excess risk for goiter and benign nodules/adenomas was greatest within 2-4 years prior to thyroid cancer diagnosis, but an elevated OR was present 10 years or more before cancer. CONCLUSIONS: Goiter and benign nodules/adenomas are the strongest risk factors for thyroid cancer, apart from radiation in childhood.
Factorial trial of three interventions to reduce the progression of precancerous gastric lesions in Shandong, China: design issues and initial data.
In the fall of 1995, 3411 subjects in 13 rural villages in Linqu County, Shandong Province, China, began participating in a blinded, randomized 23 factorial trial to determine whether interventions can reduce the prevalence of dysplasia and other precancerous gastric lesions. One intervention is treatment for infection by Helicobacter pylori with amoxicillin and omeprazole. A second is dietary supplementation with capsules containing vitamin C, vitamin E, and selenium. A third is dietary supplementation with capsules containing steam-distilled garlic oil and Kyolic aged garlic extract. Investigators will evaluate histopathologic endpoints after gastroscopies with biopsies from seven standard sites in 1999. Initial data from pill counts and sampled blood levels of vitamin E, vitamin C, and S-allylcysteine indicate excellent compliance. Subjects have tolerated all interventions well, although 3.1% of those assigned to amoxicillin and omeprazole developed rashes, compared to 0.3% to those in the control group. Preliminary breath tests demonstrate substantial reductions in gastric urease activity, an indication of infection by Helicobacter pylori, among those assigned to amoxicillin and omeprazole.
Do nutritional supplements lower the risk of stroke or hypertension?
Between 1986 and 1991, 29,584 persons took part in a randomized nutritional intervention trial in Linxian, China, an area whose residents had chronically low intakes of several nutrients and high rates of esophageal and gastric cardia cancer as well as stroke. Using a one-half replicate of a 2(4) factorial design, we randomized individuals to one of eight groups which received combinations of four supplements: retinol and zinc (factor A); riboflavin and niacin (factor B); vitamin C and molybdenum (factor C); and beta-carotene, alpha-tocopherol (vitamin E), and selenium (factor D). Deaths that occurred during 5 years of supplementation were ascertained and classified according to cause. At the end of the supplementation period, we measured blood pressure readings and determined the prevalence of hypertension. Participants who received factor D had reductions in total mortality (9%) and total cancer mortality (13%). These individuals also had the largest reduction in stroke mortality (relative risk = 0.91; 95% confidence interval = 0.76-1.07). End-of-trial hypertension, however, was not less prevalent among those receiving factor D. Our findings contrast with the larger reductions in stroke death and hypertension found in a parallel trial of Linxian subjects with esophageal dysplasia who received a multivitamin/mineral supplement, suggesting an effect largely derived from nutrients other than those received in the present study.
Quantitative fluorescence image analysis of DNA content and nuclear morphology on esophageal balloon cytology smears and subsequent development of esophageal and gastric cardia cancer in Linxian, China.
The highest incidences of esophageal and gastric cardia cancer in the world occur in northern China. Chinese scientists have developed esophageal balloon cytology screening to detect these cancers, but traditional cytology is sometimes inadequate to find some early, curable lesions. Several studies suggest that quantitative fluorescence image analysis (QFIA) of DNA ploidy and nuclear morphology may be able to improve upon traditional cytology results. In October 1987, esophageal balloon cytology was performed on 1331 adults in Linxian, China, and all samples were evaluated both by traditional cytology and QFIA. From 1987 to May 1991, 62 new squamous esophageal cancers and 44 new adenocarcinomas of the cardia were identified in this cohort. Proportional hazards models were used to evaluate the relationship of cytological diagnoses and six QFIA variables to subsequent cancer risk. These models showed significant trends for increasing esophageal cancer risk, with increasing values in five of the QFIA variables and with increasing severity of the traditional cytological diagnoses. A comparison of models with only cytology variables versus models with both cytology and QFIA variables indicated that the QFIA provided an important additional predictive value. Persons with both cytological dysplasia and high cellular DNA were 8 times more likely to develop esophageal cancer than were individuals with neither of these conditions. For cardia cancer, associations between QFIA variables or cytological diagnoses and later cancer were more limited. This study suggests that the QFIA variables evaluated here are independent predictors of squamous esophageal cancer and that combining QFIA with traditional cytology can improve prediction of esophageal cancer risk.