Steven D. Mark

Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China

Esophageal cancer incidence and mortality rates in Linxian, China are among the highest in the world. We examined risk factors for esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC), and gastric noncardia cancer (GNCC) in a population‐based, prospective study of 29,584 adults who participated in the Linxian General Population Trial. All study participants completed a baseline questionnaire that included questions on demographic characteristics, personal and family history of disease, and lifestyle factors. After 15 years of follow‐up, a total of 3,410 incident upper gastrointestinal cancers were identified, including 1,958 ESCC, 1,089 GCC and 363 GNCC. Cox proportional hazard models were used to estimate risks. Increased age and a positive family history of esophageal cancer (including ESCC or GCC) were significantly associated with risk at all 3 cancer sites. Additional risk factors for ESCC included being born in Linxian, increased height, cigarette smoking and pipe smoking; for GCC, male gender, consumption of moldy breads and pipe smoking; and for GNCC, male gender and cigarette smoking. Protective factors for ESCC included formal education, water piped into the home, increased consumption of meat, eggs and fresh fruits and increased BMI; for GCC, formal education, water piped into the home, increased consumption of eggs and fresh fruits and alcohol consumption; and for GNCC, increased weight and BMI. General socioeconomic status (SES) is a common denominator in many of these factors and improving SES is a promising approach for reducing the tremendous burden of upper gastrointestinal cancers in Linxian.

Histological precursors of oesophageal squamous cell carcinoma: results from a 13 year prospective follow up study in a high risk population

Background: Oesophageal squamous cell carcinoma (OSCC) has a very poor prognosis, which is largely due to late diagnosis. Successful early detection strategies will require identification of clinically relevant precursor lesions that can be targets for screening and treatment. Aims: To identify the clinically relevant histological precursors of OSCC. Subjects: A cohort of 682 endoscoped patients from a high risk rural population in Linxian, China. Methods: Subjects were endoscoped and biopsied at baseline and followed for 13.5 years. We estimated the relative risk of developing OSCC for each of the initial histological diagnoses using Cox proportional hazards regression models. Results: A total of 114 (16.7%) patients developed OSCC during the follow up period. After adjusting for potential confounding factors, relative risks (95% confidence intervals) for incidence of this tumour, by initial histological diagnosis, were: normal 1.0 (reference), oesophagitis 0.8 (0.2–3.2), basal cell hyperplasia 1.9 (0.8–4.5), mild dysplasia 2.9 (1.6–5.2), moderate dysplasia 9.8 (5.3–18.3), severe dysplasia 28.3 (15.3–52.3), and carcinoma in situ 34.4 (16.6–71.4). Conclusions: In this study, squamous dysplasia and carcinoma in situ were the only histological lesions associated with a significantly increased risk of developing OSCC within 13.5 years after endoscopy. There was no evidence that oesophagitis predisposed to this tumour. Increasing grades of dysplasia were strongly associated with increasing risk, indicating that the histological grading was clinically meaningful. The follow up experience of severe dysplasia and carcinoma in situ was equivalent, suggesting that this distinction is not clinically relevant. Documenting these precursor lesions of OSCC should assist in the development of effective prevention, early detection, and treatment strategies for this disease.

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 pre-menopausal 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 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.

Prospective study of tooth loss and incident esophageal and gastric cancers in China

AbstractObjective: 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.

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.

A pooled analysis of thyroid cancer studies. V. Anthropometric factors

AbstractObjective: 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.

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.

Helicobacter pylori and oesophageal and gastric cancers in a prospective study in China

In a cohort of 29 584 residents of Linxian, China, followed from 1985 to 2001, we conducted a case–cohort study of the magnitude of the association of Helicobacter pylori seropositivity with cancer risk in a random sample of 300 oesophageal squamous cell carcinomas, 600 gastric cardia adenocarcinomas, all 363 diagnosed gastric non-cardia adenocarcinomas, and a random sample of the entire cohort (N=1050). Baseline serum was evaluated for IgG antibodies to whole-cell and CagA H. pylori antigens by enzyme-linked immunosorbent assay. Risks of both gastric cardia and non-cardia cancers were increased in individuals exposed to H. pylori (Hazard ratios (HRs) and 95% confidence intervals=1.64; 1.26–2.14, and 1.60; 1.15–2.21, respectively), whereas risk of oesophageal squamous cell cancer was not affected (1.17; 0.88–1.57). For both cardia and non-cardia cancers, HRs were higher in younger individuals. With longer time between serum collection to cancer diagnosis, associations became stronger for cardia cancers but weaker for non-cardia cancers. CagA positivity did not modify these associations. The associations between H. pylori exposure and gastric cardia and non-cardia adenocarcinoma development were equally strong, in contrast to Western countries, perhaps due to the absence of Barretts oesophagus and oesophageal adenocarcinomas in Linxian, making all cardia tumours of gastric origin, rather than a mixture of gastric and oesophageal malignancies.

Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers.

We prospectively examined the relation between pretrial serum vitamin D status and risk of oesophageal and gastric cancers among subjects who developed cancer over 5.25 years of follow-up, including 545 oesophageal squamous cell carcinomas (ESCC), 353 gastric cardia adenocarcinomas, 81 gastric noncardia adenocarcinomas, and an age- and sex-stratified random sample of 1105 subjects. The distribution of serum 25(OH)D was calculated using the known sampling weights. For the cohort as a whole, the 25th, 50th, and 75th percentile concentrations of 25(OH)-vitamin D were 19.6, 31.9, and 48.7 nmol l−1, respectively, and we found that higher serum 25(OH)D concentrations were associated with monotonically increasing risk of ESCC in men, but not in women. Comparing men in the fourth quartile of serum 25(OH)D concentrations to those in the first, we found a hazard ratio (HR) (95% confidence interval (CI)) of 1.77 (1.16–2.70), P trend=0.0033. The same comparison in women had a HR (95% CI) of 1.06 (0.71–1.59), P trend=0.70. We found no associations for gastric cardia or noncardia adenocarcinoma. Among subjects with low vitamin D status, higher serum 25(OH)D concentrations were associated with significantly increased risk of ESCC in men, but not in women. Further refinements of the analysis did not suggest any factors, which could explain this unexpected result.