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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.

BackgroundCancers of the upper gastrointestinal tract remain a significant cause of morbidity and mortality. Cysteine, known to be involved in a myriad of immuno-modulatory, anti-oxidant, and anti-carcinogenic pathways, has not been investigated in the aetiology of oesophageal or gastric cancers. To examine the relationship between serum cysteine concentration and risk of these cancers we conducted a nested case–cohort study within the General Population Nutrition Intervention Trial in Linxian, China.Methods498 oesophageal squamous cell carcinomas (OSCCs) and 255 gastric cardia adenocarcinomas (GCAs) were matched by age and sex to 947 individuals from the wider cohort. We calculated HRs and 95% CIs using the case–cohort estimator for the Cox proportional hazards models, stratified on age and sex, with adjustment for potential confounders.ResultsHigher concentrations of serum cysteine were significantly associated with a lower risk of both OSCC and GCA. For those in the highest quartile of serum cysteine, compared to those in the lowest, the multivariate HRs were 0.70 for OSCC (95% CI 0.51 to 0.98) and 0.59 for GCA (95% CI 0.38 to 0.91). These associations were dose dependent (p for trend=0.006 and 0.008, respectively). These inverse associations were not significantly modified by other risk factors, with the exception of age, where a stronger association was noted among persons in the older age strata.ConclusionHigher serum concentrations of cysteine were associated with a significantly reduced risk of OSCC and GCA. Cysteine should be further investigated for its potential as a chemopreventive agent for upper gastrointestinal cancers.

Since 1986, we have been studying a cohort of individuals from a region in China with epidemic rates of gastric cardia cancer and have conducted numerous two-stage studies to assess the association of various exposures with this cancer. Two-stage studies are a commonly used statistical design. Stage one involves observing the outcomes and accessible baseline covariate information on all cohort members, and stage two involves using the stage one observations to select a subset of the cohort for measurements of exposures that are difficult to obtain. When the outcomes are censored failure times, such as in our studies, the most common designs used are the case-cohort and nested case-control designs. One limitation of both these designs is that the estimators of the cumulative hazards, and hence survivals and absolute risks, are biased when some cases are missing the stage two measurements. In our experience, such missingness is present in virtually all two-stage studies that (like ours) use biological specimens to obtain exposure measurements. In earlier work we derived and characterized the efficiency of a class of nonparametric and a class of semiparametric cumulative hazard estimators that are unbiased regardless of whether or not all cases are measured. In this article we limit the presentation of the mathematical derivation of these two classes to aspects important to study design and analysis. We analyze data from a two-stage study that we conducted on the association of Helicobacter pylori infection with incident gastric cardia cancers. We discuss the substantive reasons why we deliberately sampled only 25% of the available cancer cases. Through simulations, we demonstrate that substantial variation in precision exists between unbiased estimators within each class, and express the origin of these differences in terms of parameters familiar to investigators. We describe how preexistent knowledge about these parameters can be used to increase estimator precision, and detail specific strategies for constructing such estimators. Computer code in R that implements these estimators is available from the authors on request.

Standardization, a common approach for controlling confounding in population-studies or data from disease registries, is defined to be a weighted average of stratum specific rates. Typically, discussions on the construction of a particular standardized rate regard the strata as fixed, and focus on the considerations that affect the specification of weights. Each year the data from the SEER cancer registries are analyzed using a weighting procedure referred to as \"direct standardization for age.\" To evaluate the performance of direct standardization, we define a general class of standardization operators. We regard a particular standardized rate to be the output of an operator and a given data set. Based on the functional form of the operators, we define a subclass of standardization operators that controls for confounding by measured risk factors. Using the fundamental disease probability paradigm for inference, we establish the conclusions that can be drawn from year-to-year contrasts of standardized rates produced by these operators in the presence of unmeasured cancer risk factors. These conclusions take the form of falsifying specific assumptions about the conditional probabilities of disease given all the risk factors (both measured and unmeasured), and the conditional probabilities of the unmeasured risk factors given the measured risk factors. We show the one-to-one correspondence between these falsifications and the inferences made from the contrasts of directly standardized rates reported each year in the Annual Report to the Nation on the Status of Cancer. We further show that the \"direct standardization for age\" procedure is not a member of the class of unconfounded standardization operators. Consequently, it can, and usually will, introduce confounding when confounding is not present in the data. We propose a particular standardization operator, the SCC operator, that is in the class of unconfounded operators. We contrast the mathematical properties of the SCC and the SEER operator (SCA), and present an analysis of SEER cancer registry data that demonstrates the consequences of these differences. We further prove that the SCC operator is a projection operator. We discuss how this property can enable the SCC operator to be developed as a method for comparing nested conditional expectations in the same manner as is currently done with regression methods that control for confounding.

Objective: To determine if genetic polymorphisms of CYP1A1, GSTM1, GSTP1, or GSTT1 are associated with an increased risk of developing esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC), or either in a high-risk Asian population. Methods: We conducted a case-cohort analysis with 5 years of prospective follow-up. The analytical cohort contained 642 individuals who participated in either the Dysplasia Trial (DT) or the General Population (GPT) of the Nutrition Intervention Trials conducted in Linxian, China, and included 131 cases of ESCC and 90 cases of GCC. Genotyping analysis was performed on DNA extracted from red blood cells using a PureGene kit (Gentra Systems, Inc., Minneapolis, MN) and real-time PCR analysis amplification (Taq-Man). Relative risks and 95% confidence intervals were estimated using the case - cohort estimator for the Cox proportional hazards models. p-values from nested models with genotyping variables came from score tests. Results: The relative risks for developing ESCC, GCC, or either cancer were calculated in the entire analytic cohort for GSTM1, P1*B (A313G), and T1 and CYP1A1*2A (T3801C) and *2C (A2455G) genotypes, and no significant associations were identified. However, because of the difference in cancer risks between the DT (9.3 cases per 1000 person years) and the GPT (5.3 cases), the analytical cohort was stratified by trial; the DT participants who were heterozygous or homozygous for the variant-allele at CYP1A1*2A had a reduced risk for developing GCC (adjusted RR (95%CI) 0.47 (0.23-1.00) p = 0.037). Conclusions: This study found an association for the CYP1A1*2A variant allele and a reduced risk of GCC in people at high risk for development of this disease. This finding is consistent with previous studies suggesting that substrates for the cytochrome P-450 1A1 metabolic pathway, such as polycyclic aromatic hydrocarbons, may be etiologically significant in this high-risk region.

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 2094 women and 425 men with cancer of the thyroid and, respectively, 3248 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.

Objective: This study examined the relationship between pretrial serum concentrations of retinol, β-carotene, β-cryptoxanthin, and lutein/zeaxanthin and the subsequent risk of developing esophageal squamous cell carcinoma and gastric cardia or non-cardia adenocarcinoma in subjects selected from a randomized nutritional intervention trial in Linxian, China, a region with epidemic rates of esophageal and gastric cardia cancer. Methods: We used a stratified case-cohort design to select cohort members for inclusion in this study. In all we measured serum concentrations of the above vitamins in 590 esophageal, 395 gastric cardia, and 87 gastric non-cardia case subjects as well as in 1053 control subjects. Relative risks (RRs) were estimated using Cox proportional hazards models. Results: Median values in our cohort were low for serum retinol (33.6 μg/dl), β-carotene (4.3 μg/dl), and β-cryptoxanthin (3.5 μg/dl), but were high for lutein/zeaxanthin (40.0 μg/dl). Gastric cardia cancer incidence fell 10% for each quartile increase in serum retinol (RR = 0.90, 95% CI = 0.83-0.99). For esophageal cancer, an inverse association with retinol levels was found only in male non-smokers (RR = 0.79 per quartile increase, 95% CI = 0.63-0.99). For gastric non-cardia cancer, an inverse association was limited to subjects 50 years old or younger (RR = 0.58 per quartile, 95% CI = 0.31-0.96). For β-cryptoxanthin there was a borderline significant protective association for gastric non-cardia cancer (RR = 0.88 per quartile, 95% CI = 0.76-1.0). In contrast, we found the incidence of gastric non-cardia cancer increased (RR = 1.2 per quartile, 95% CI = 1.0-1.3) with increasing concentration of serum lutein/zeaxanthin. Conclusions: In this population, we found that low retinol and high lutein/zeaxanthin concentrations increased the risks of gastric cardia and gastric non-cardia cancer respectively. We found that there were no strong associations between any of the other analytes and any of the cancer sites.

Background: Stroke is the leading cause of death in Linxian, China. Although there is evidence of DNA damage in experimental stroke, no data exist on DNA repair and stroke in human populations. Aim: To assess the risk of stroke conferred by polymorphisms in the DNA repair genes, XRCC1, XPD23 and APE/ref-1 in a cohort of individuals originally assembled as subjects in two cancer prevention trials in Linxian, China. Methods: The subjects for this prospective study were sampled from a cohort of 4005 eligible subjects who were alive and cancer free in 1991 and had blood samples available for DNA extraction. Using real-time Taqman analyses, all incident cases of stroke (n = 118) that developed from May 1996, and an age- and a sex-stratified random sample (n = 454) drawn from all eligible subjects were genotyped. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% CIs. Results: No association was observed between polymorphisms in APE/ref-1 codon 148 and XRCC1*6 codon 194, and stroke. Polymorphisms in XRCC1*10 codon 399 were associated with a significantly reduced risk of stroke (RR 0.59, 95% CI 0.36 to 0.96, p = 0.033), whereas XPD23 codon 312 was associated with a significantly increased risk of stroke (RR 2.18, 95% CI 1.14 to 4.17, p = 0.010). Conclusions: Polymorphisms in DNA repair genes may be important in the aetiology of stroke. These data should stimulate research on DNA damage and repair in stroke.

Objective: To investigate the association between cruciferous and other vegetables and thyroid cancer risk we systematically reanalyzed the original data from 11 case-control studies conducted in the US, Asia, and Europe. Methods: A total of 2241 cases (1784 women, 457 men) and 3716 controls (2744 women, 972 men) were included. Odds ratios (OR) and the corresponding 95% confidence intervals (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. Summary ORs for all studies combined were computed as the weighted average of the estimates from each study. Results: A decreased risk for the highest level of cruciferous vegetable intake, as compared to the lowest, was observed in Los Angeles, Hawaii, Connecticut, southeastern Sweden, Tromsø, and Switzerland; the OR were above unity in Japan and Uppsala, whereas no material association was found in northern Sweden, Italy, or Greece. The OR values for all studies combined were 0.87 (95% CI 0.75-1.01) for moderate and 0.94 (95% CI 0.80-1.10) for high cruciferous vegetables intake. The results were similar in studies from iodine-rich areas and endemic goiter areas, and were consistent when the analysis was restricted to papillary carcinomas and women. The summary OR values for vegetables other than cruciferous were 1.04 (0.88-1.22) for moderate and 0.82 (0.69-0.98) for high consumption. Conclusions: This combined analysis indicates that cruciferous vegetables are not positively related to thyroid cancer risk. Their effect does not seem to be substantially different from that of other vegetables, which appear to be protective on this cancer.

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.