Iron can cause oxidative stress and DNA damage, and heme iron can catalyze endogenous formation of N-nitroso compounds, which are potent carcinogens. Dietary iron promotes esophageal cancer incidence in animal studies and has been identified as a growth factor for Helicobacter pylori, an established risk factor for stomach cancer.
We conducted a population-based case-control study of adenocarcinoma of the esophagus (n=124) and stomach (n=154) and 449 controls in Nebraska. Heme iron and total iron intake were estimated from a food-frequency questionnaire and databases of heme and total iron. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) adjusted for known risk factors.
Esophageal cancer was positively associated with higher intakes of heme iron (ORQ4 vs. Q1 =3.04, 95% CI 1.20–7.72; p-trend=0.009) and total iron from meat sources (ORQ4 vs. Q1 =2.67, 95% CI 0.99–7.16; p-trend=0.050). Risk of stomach cancer was elevated among those with higher intakes of heme iron (ORQ4vs.Q1=1.99, 95% CI 1.00–3.95, p-trend=0.17) and total iron from meat (OR=2.26, 95% CI 1.14–4.46; p-trend=0.11). Iron intake from all dietary sources was not significantly associated with risk of either cancer.
Our results suggest that high intakes of heme and iron from meat may be important dietary risk factors for esophageal and stomach cancer and may partly explain associations with red meat.
Iron; heme iron; nutrition; esophageal cancer; stomach cancer
Fumonisin B1 (FB1), a mycotoxin that contaminates corn in certain climates, has been demonstrated to cause hepatocellular cancer (HCC) in animal models. Whether a relationship between FB1 and HCC exists in humans is not known. To examine the hypothesis, we conducted case-control studies nested within two large cohorts in China; the Haimen City Cohort and the General Population Study of the Nutritional Intervention Trials cohort in Linxian. In the Haimen City Cohort, nail FB1 levels were determined in 271 HCC cases and 280 controls. In the General Population Nutritional Intervention Trial, nail FB1 levels were determined in 72 HCC cases and 147 controls. In each population, odds ratios and 95% confidence intervals (95%CI) from logistic regression models estimated the association between measurable FB1 and HCC, adjusting for hepatitis B virus infection and other factors. A meta-analysis that included both populations was also conducted. The analysis revealed no statistically significant association between FB1 and HCC in either Haimen City (OR=1.10, 95%CI=0.64–1.89) or in Linxian (OR=1.47, 95%CI=0.70–3.07). Similarly, the pooled meta-analysis showed no statistically significant association between FB1 exposure and HCC (OR=1.22, 95%CI=0.79–1.89). These findings, although somewhat preliminary, do not support an associated between FB1 and HCC.
fumonisin; hepatocellular carcinoma; cohort study; China; epidemiology
Background & Aims
Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) has been reported to reduce risks for esophageal adenocarcinoma (EAC) and esophagogastric junctional adenocarcinoma (EGJA). However, individual studies have been too small to accurately assess the effects of medication type, frequency, or duration of use. We performed a pooled analysis to investigate these associations.
We performed a pooled analysis of 6 population-based studies within the Barrett's and Esophageal Adenocarcinoma Consortium to evaluate the association between NSAID use and the risk of EAC and EGJA, using uniform exposure definitions. We collected information from 6 studies (5 case-control and 1 cohort), with a total of 1226 EAC and 1140 EGJA cases, on aspirin and/or NSAID use. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate adjusted logistic regression models and then pooled using a random effects meta-analysis model.
Compared to non-users, individuals who have used NSAIDs had a statistically significant, reduced risk of EAC (OR=0.68; 95% CI, 0.56–0.82); they also appeared to have a reduced risk of EGJA (OR=0.84; 95% CI, 0.68–1.03). Similar reductions in risk were observed among individuals who took aspirin or non-aspirin NSAIDs. The highest levels of frequency (≥daily) and duration (≥10 years) of NSAID use were associated with an approximately 40% reduction in risk for EAC: OR=0.56 (95% CI, 0.43–0.73; P-trend, <.001) and OR=0.63 (95% CI, 0.45–0.90; P-trend, 0.04), respectively.
Although reverse causation could, in part, explain the inverse association observed between NSAID use and EAC risk, pooled analysis indicates a role for NSAIDs in prevention of adenocarcinomas of the esophagus and esophagogastric junction.
BEACON; Esophageal Neoplasm; Stomach Cancer; Anti-Inflammatory Agent
The role of human papillomavirus (HPV) in the causation of esophageal squamous cell carcinoma is unclear. We examined the associations between esophageal squamous cell carcinoma and 28 centrally measured HPV serological markers in serum from six existing case–control studies conducted in regions with differing background risks of esophageal cancer.
We used centralized multiplex serology to test serum samples from 1561 case subjects and 2502 control subjects from six case–control studies for antibodies to the major HPV capsid protein (L1) and/or the early proteins E6 and/or E7 of eight high-risk, two low-risk, and four cutaneous HPV types. Study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression with adjustment for smoking, alcohol consumption, and other potential confounders. Pooled odds ratios and 95% confidence intervals were calculated using either a linear mixed-effects approach or a joint fixed-effects approach. All statistical tests were two-sided.
We found statistically significant associations between esophageal squamous cell carcinoma and antibodies to E6 for HPV16 (OR = 1.89, 95% CI = 1.09 to 3.29, P = .023) and HPV6 (OR = 2.53, 95% CI = 1.51 to 4.25, P < .001) but not for other tested HPV types. There were no statistically significant associations between esophageal squamous cell carcinoma and antibodies to E7 for any of the tested HPV types. Simultaneous seropositivity for HPV16 E6 and E7 was rare (four case subjects, two control subjects; OR = 5.57, 95% CI = 0.90 to 34.35; P = .064). We also found statistically significant associations between esophageal squamous cell carcinoma and capsid antibodies for the high-risk mucosal type HPV33 L1 (OR = 1.30, 95% CI = 1.00 to 1.69; P = .047) and the low-risk mucosal types HPV6 (OR = 1.22, 95% CI = 1.05 to 1.42; P = .010) and HPV11 (OR = 1.30, 95% CI = 1.09 to 1.56, P = .0036).
We found limited serological evidence of an association between esophageal squamous cell carcinoma and HPV in the populations studied. Although HPV does not appear to be an important risk factor for esophageal squamous cell carcinoma, we cannot exclude the possibility that certain HPV types may be involved in a small subset of cancers.
Drinking maté, common in southern South America, may increase the risk of esophageal squamous cell carcinoma (ESCC). In 2006, we found high but variable polycyclic aromatic hydrocarbon (PAH) content in commercial yerba maté samples from eight Brazilian brands. The PAH content of new samples from the same brands, purchased in 2008, and four brands from a single manufacturer processed in different ways, obtained in 2010, were quantified to determine whether PAH concentration was still high, PAH content variation was brand specific, and whether processing method affects PAH content of commercial yerba maté. Concentrations of individual PAHs were quantified using gas chromatography/mass spectrometry with deuterated PAHs as internal standards. Median total PAH concentration was 1500 ng/g (range: 625 to 3710 ng/g) and 1090 ng/g (621 to 1990 ng/g) in 2008 and 2010 samples, respectively. Comparing 2006 and 2008 samples, some brands had high PAH concentrations in both years, while PAH concentration changed considerably in others. Benzo[a]pyrene concentrations ranged from 11.9 to 99.3 ng/g and 5.11 to 21.0 ng/g in 2008 and 2010 samples, respectively. The 2010 sample processed without touching smoke had the lowest benzo[a]pyrene content. These results support previous findings of very high total and carcinogenic PAH concentrations in yerba maté, perhaps contributing to the high incidence of ESCC in southern South America. The large PAH content variation by brand, batch and processing method suggests it may be possible to reduce the content of carcinogenic PAHs in commercial yerba maté, making it a healthier beverage.
Polycyclic Aromatic Hydrocarbons; Yerba Maté; Carcinogens; Esophageal Cancer; Benzo(α)pyrene; Processing Method; Lifestyle
Oral bisphosphonate use has increased dramatically in the USA. Recent case reports have suggested a link between bisphosphonate use and esophageal cancer, but this is yet to be robustly investigated.
To investigate the association between bisphosphonate use and esophageal cancer.
Design, setting and participants
Data were extracted from the UK General Practice Research to compare the incidence of esophageal and gastric cancer in a cohort of patients treated with oral bisphosphonates between January 1996 and December 2006 to a control cohort not treated with these drugs. Cancers were identified from relevant Read\OXMIS codes in the patient’s clinical files. Cox proportional hazards modelling was used to calculate hazard ratios (HRs) and 95% CIs for esophageal and gastric cancer risk in bisphosphonate users compared to non bisphosphonate users, with adjustment for potential confounders.
Main outcome measure
The HR for the risk of esophageal and gastric cancer in the bisphosphonate users compared to the non bisphosphonate users.
There were 41,826 members in each cohort; 81% female, mean (SD) age, 70.0 (11.4) years, excluding patients with under 6 months follow-up. 116 esophageal or gastric cancers (79 esophageal) occurred in the bisphosphonate cohort and 115 (72 esophageal) in the control cohort. Mean follow-up time was 4.5 and 4.4 years in the bisphosphonate and control cohorts, respectively. There was no difference in combined esophageal and gastric cancer risk between the cohorts for any bisphosphonate use; adjusted HR (95% CI), 0.96 (0.74, 1.25) or esophageal risk alone; adjusted HR (95% CI), 1.07 (0.77, 1.49). There was also no difference in esophageal or gastric cancer risk by level of bisphosphonate intake.
This large study does not provide evidence for an increased risk of esophageal (or gastric) cancer in persons using oral bisphosphonates.
Bisphosphonates; esophageal cancer; gastric cancer; epidemiology
Oesophageal cancers rank as the eighth most common cancer and the sixth most common cause of cancer death, worldwide. Gastric atrophy, as determined by a low serum pepsinogen I/II ratio, may be associated with an increased risk of oesophageal squamous cell carcinoma (OSCC). Ghrelin, a hormone which, like pepsinogen, is produced in the fundic glands of the stomach, may be a sensitive and specific marker of gastric atrophy, but its association with OSCC is not known.
To examine the relationship between baseline serum ghrelin concentration and subsequent risk of OSCC, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. 82 cases of OSCC were matched (1:1) by age and date of blood draw to controls from the ATBC study. Serum ghrelin was measured by radioimmunoassay. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression with adjustment for potential confounders.
For those individuals in the lowest quartile of serum ghrelin, compared to those in the highest, the multivariate odds ratio of subsequent OSCC was 6.83 (95% CI: 1.46, 31.84). These associations were dose dependent (P for trend = 0.005 for both), and independent of the effects of low pepsinogen I/II ratio (a marker of gastric fundic atrophy) and Helicobacter pylori infection. The significance of these associations remained even for individuals developing OSCC up to 10 years after baseline ghrelin measurement, though they become attenuated after 10 years.
Lower baseline concentrations of serum ghrelin were associated with an increase in risk of OSCC. Further studies are needed to confirm this finding in other populations and to explore the role of ghrelin in the aetiology of OSCC.
ghrelin; oesophageal squamous cell carcinoma; atrophy
To investigate the relation of physical activity to head and neck cancer.
We prospectively examined the association between physical activity and head and neck cancer in 487,732 men and women who, at baseline in 1995–1996, were 50–71 years old and free of cancer and emphysema. Follow-up occurred through December 31, 2003.
During follow-up, 1,249 participants developed head and neck cancer, of which 42.0%, 18.9%, and 32.5% were located in the oral cavity, pharynx, and larynx, respectively. In analyses adjusted for age and gender, the relative risks (RR) of head and neck cancer for increasing frequency of physical activity (0, < 1, 1–2, 3–4, and ≥ 5 times per week) were 1.0 (reference), 0.76, 0.66, 0.57, and 0.62 (95%-CI=0.52–0.74), respectively (p for trend<0.001). After multivariate adjustment including smoking, the relation was attenuated and became statistically non-significant (RR comparing extreme physical activity categories=0.89, 95%-CI=0.74–1.06; p for trend=0.272). In analyses of head and neck cancer subtypes, the corresponding RRs for cancers of the oral cavity, pharynx, and larynx were 0.98 (95%-CI=0.75–1.29), 0.70 (95%-CI=0.45–1.08), and 0.82 (95%-CI=0.59–1.13), respectively.
Our findings suggest that physical activity is unlikely to play an important role in the prevention of head and neck cancer.
Head and neck cancer; oral cavity cancer; pharynx cancer; larynx cancer; physical activity
Incidence of esophageal adenocarcinoma (EAC) has increased rapidly over the past forty years and accumulating evidence suggests that obesity, as measured by body mass index (BMI), is a major risk factor. However, it remains unclear whether abdominal obesity is associated with esophageal and gastric adenocarcinoma.
Cox proportional hazards regression was used to examine associations between overall and abdominal obesity with EAC and gastric adenocarcinoma among 218,854 participants in the prospective NIH-AARP cohort.
253 incident EAC, 191 gastric cardia adenocarcinomas, and 125 gastric non-cardia adenocarcinomas accrued to the cohort. Overall obesity (BMI) was positively associated with EAC and gastric cardia adenocarcinoma risk (highest [≥35 kg/m2] versus referent [18.5–<25 kg/m2]; hazard ratio (HR) 95% confidence interval (95% CI); 2.11 (1.09–4.09) and 3.67 (2.00–6.71), respectively). Waist circumference was also positively associated with EAC and gastric cardia adenocarcinoma risk, (highest versus referent; HR (95% CI) 2.01 (1.35–3.00) and 2.22 (1.43–3.47), respectively), whereas waist-to-hip ratio (WHR) was positively associated with EAC risk only (highest versus referent; HR (95% CI) 1.81 (1.24–2.64)); persisted in patients with normal BMI (18.5–<25 kg/m2). Mutual adjustment of WHR and BMI attenuated both, but did not eliminate the positive associations for either with risk of EAC. In contrast, the majority of the anthropometric variables were not associated with adenocarcinomas of the gastric non-cardia.
Overall obesity was associated with a higher risk of EAC and gastric cardia adenocarcinoma, whereas abdominal obesity was found to be associated with increased EAC risk; even in people with normal BMI.
adenocarcinoma; epidemiology; esophageal cancer; gastric adenocarcinoma; obesity
To evaluate the association of polycyclic aromatic hydrocarbon (PAH) exposure in esophageal epithelial tissue and esophageal squamous cell carcinoma (ESCC) case status in an ESCC case-control study in a high-risk population in northeastern Iran.
Immunohistochemical staining of tissue microarrays (TMAs) of non-tumoral esophageal biopsies from ESCC cases and control subjects. Immunohistochemistry was performed using monoclonal antibodies 8E11 and 5D11, raised against benzo[a]pyrene (B[a]P) diol epoxide (BPDE)-I-modified guanosine and BPDE-I-modified DNA, respectively. Staining intensity was quantified by image analysis, and the average staining in three replicates was calculated.
Rural region in northeastern Iran.
Cases were patients with biopsy-proven ESCC. Controls were GI clinic patients with no endoscopic or biopsy evidence of ESCC.
Main outcome measure
Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between antibody staining intensity and ESCC case status.
Cultured ESCC cells exposed to B[a]P in vitro showed dose-dependent staining with 8E11, but not with 5D11. With 8E11, sufficient epithelial tissue was available in the TMA cores to analyze 91 cases and 103 controls. Compared to the lowest quintile of 8E11 staining in the controls, adjusted ORs (95% CIs) for the 2nd to 5th quintiles were 2.42, 5.77, 11.3, and 26.6 (5.21–135), respectively (P for trend < 0.001). With 5D11, 89 cases and 101 controls were analyzed. No association between staining and case status was observed (ORs (95% CIs) for the 2nd to 5th quintiles were 1.26, 0.88, 1.06, and 1.63 (0.63–4.21), P for trend = 0.40).
Dramatically higher levels of 8E11 staining were observed in non-tumoral esophageal epithelium from ESCC patients than from control subjects. This finding strengthens the evidence for a causal role for PAHs in esophageal carcinogenesis in northeastern Iran.
esophageal squamous cell carcinoma; polycyclic aromatic hydrocarbons; immunohistochemistry; tissue microarray
Esophageal cancer has a strikingly uneven geographical distribution, resulting in focal endemic areas in several countries. One such endemic area is in western Kenya. We conducted a retrospective review of all pathology-confirmed malignancies diagnosed at Tenwek Hospital, Bomet District, between January 1999 and September 2007. Tumor site, histology, sex, age, ethnicity, and location of residence were recorded. Cases were analyzed within and outside a traditional catchment area defined as ≤ 50 km from the hospital. Since 1999, the five most common cancer sites were esophagus, stomach, prostate, colorectum, and cervix. Esophageal cancer accounted for 914 (34.6%) of the 2643 newly diagnosed cancers, and showed increasing trends within and outside the catchment area. Fifty-eight (6.3%) patients were ≤ 30 years old and 9 (1%) were ≤ 20 years old; the youngest patient was 14 at diagnosis. Young cases (≤30) were more common among patients of Kalenjin ethnicity (9.2%) than among other ethnicities (1.7%) (odds ratio (95%CI) 5.7 (2.1–15.1)). This area of western Kenya is a high-risk region for esophageal cancer, and appears unique in its large proportion of young patients. Our findings support the need for further study of both environmental and genetic risk factors for esophageal cancer in this area.
Esophageal cancer; Kenya; age of onset; ethnicity
Coffee is one of the most widely consumed beverages, but the association between coffee consumption and the risk of death remains unclear.
We examined the association of coffee drinking with subsequent total and cause-specific mortality among 229,119 men and 173,141 women in the National Institutes of Health–AARP Diet and Health Study who were 50 to 71 years of age at baseline. Participants with cancer, heart disease, and stroke were excluded. Coffee consumption was assessed once at baseline.
During 5,148,760 person-years of follow-up between 1995 and 2008, a total of 33,731 men and 18,784 women died. In age-adjusted models, the risk of death was increased among coffee drinkers. However, coffee drinkers were also more likely to smoke, and, after adjustment for tobacco-smoking status and other potential confounders, there was a significant inverse association between coffee consumption and mortality. Adjusted hazard ratios for death among men who drank coffee as compared with those who did not were as follows: 0.99 (95% confidence interval [CI], 0.95 to 1.04) for drinking less than 1 cup per day, 0.94 (95% CI, 0.90 to 0.99) for 1 cup, 0.90 (95% CI, 0.86 to 0.93) for 2 or 3 cups, 0.88 (95% CI, 0.84 to 0.93) for 4 or 5 cups, and 0.90 (95% CI, 0.85 to 0.96) for 6 or more cups of coffee per day (P<0.001 for trend); the respective hazard ratios among women were 1.01 (95% CI, 0.96 to 1.07), 0.95 (95% CI, 0.90 to 1.01), 0.87 (95% CI, 0.83 to 0.92), 0.84 (95% CI, 0.79 to 0.90), and 0.85 (95% CI, 0.78 to 0.93) (P<0.001 for trend). Inverse associations were observed for deaths due to heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections, but not for deaths due to cancer. Results were similar in subgroups, including persons who had never smoked and persons who reported very good to excellent health at baseline.
In this large prospective study, coffee consumption was inversely associated with total and cause-specific mortality. Whether this was a causal or associational finding cannot be determined from our data. (Funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.)
Cigarette smoking is associated with esophageal adenocarcinoma (EAC), esophagogastric junctional adenocarcinoma (EGJA) and esophageal squamous cell carcinoma (ESCC), and alcohol consumption with ESCC. However, no analyses have examined how delivery rate modifies the strength of odds ratio (OR) trends with total exposure, i.e., the impact on the OR for a fixed total exposure of high exposure rate for short duration compared with low exposure rate for long duration.
The authors pooled data from 12 case-control studies from the Barrett’s Esophagus and Esophageal Adenocarcinoma Consortium (BEACON), including 1,242 (EAC), 1,263 (EGJA) and 954 (ESCC) cases and 7,053 controls, modeled joint ORs for cumulative exposure and exposure rate for cigarette smoking and alcohol consumption, and evaluated effect modification by sex, body mass index (BMI), age and self-reported acid reflux.
For smoking, all sites exhibited inverse delivery rate effects, whereby ORs with pack-years increased, but trends weakened with increasing cigarettes/day. None of the examined factors modified associations, except for ESCC where younger ages at diagnosis enhanced smoking effects (P<0.01). For EAC and EGJA, ORs with drink-years exhibited inverse associations in <5 drinks/day consumers and no association in heavier consumers. For ESCC, ORs with drink-years increased, with trends strengthening with greater drinks/day. There was no significant effect modification, except for EAC and EGJA where acid reflux mitigated the inverse associations (P=0.02). For ESCC, younger ages at diagnosis enhanced drinking-related ORs (P<0.01).
Patterns of ORs by pack-years and drink-years, delivery rate effects and effect modifiers revealed common as well as distinct etiologic elements for these diseases.
alcohol drinking; risk model; smoking
Iodine concentrates in gastric tissue and may act as an antioxidant for the stomach. We previously showed that self-reported goiter was associated with significantly increased risk of gastric noncardia adenocarcinoma (GNCA) and non-significantly increased risks of gastric cardia adenocarcinoma (GCA) and esophageal squamous cell carcinoma (ESCC) in a prospective case-cohort study in a high-risk population in China. Negatively correlated with iodine levels, serum thyroglobulin (Tg) is a more sensitive biomarker of iodine deficiency than goiter. This study aimed to determine whether baseline serum Tg was also associated with development of GNCA, GCA, and ESCC in the same cohort, the Linxian General Population Nutrition Intervention Trial. Sera from approximately 200 subjects of each case type and 400 non-cases were tested for serum Tg concentration using appropriate assays. Tg was modeled as sex- and assay-specific quartiles in Cox regression models adjusted for age, smoking, alcohol, Helicobacter pylori status, pepsinogens I/II ratio, family history, and commune of residence. In the final combined analysis, participants in the highest quartile of serum Tg, compared to those in the lowest quartile, had adjusted Hazard Ratios of 0.88 (95% confidence interval 0.50–1.52), 1.14 (0.63–2.05), and 0.78 (0.47–1.31) for GNCA, GCA, and ESCC, respectively. Using serum Tg, a sensitive biomarker of iodine deficiency, we found no association between serum Tg concentrations and risk of these upper gastrointestinal (UGI) cancers in the study population. Our results do not support the hypothesis that iodine deficiency, as assessed by serum Tg, is associated with an increased risk of UGI cancers.
iodine deficiency; esophageal cancer; gastric cancer; thyroglobulin; China
The aim of this study was to investigate whether dietary fat and meat intakes are associated with reflux esophagitis (RE), Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). In this all-Ireland case-control study, dietary intake data was collected using a food frequency questionnaire in 219 RE patients, 220 BE patients, 224 EAC patients, and 256 frequency-matched controls between 2002 and 2005. Unconditional multiple logistic regression analysis was used to examine the association between dietary variables and disease risk using quartiles of intake, to attain odds ratios (OR) and 95% confidence intervals (95%CI), while adjusting for potential confounders. Patients in the highest quartile of total fat intake had a higher risk of RE (OR=3.54; 95%CI=1.32–9.46) and EAC (OR=5.44; 95%CI=2.08–14.27). A higher risk of RE and EAC was also reported for patients in the highest quartile of saturated fat intake (OR=2.79; 95%CI=1.11–7.04; OR=2.41; 95%CI=1.14–5.08, respectively) and monounsaturated fat intake (OR=2.63; 95%CI=1.01–6.86; OR=5.35; 95%CI=2.14–13.34, respectively). Patients in the highest quartile of fresh red meat intake had a higher risk of EAC (OR=3.15; 95%CI=1.38–7.20). Patients in the highest category of processed meat intake had a higher risk of RE (OR=4.67; 95%CI=1.71–12.74). No consistent associations were seen for BE with either fat or meat intakes. Further studies, investigating the association between dietary fat and food sources of fat are needed to confirm these results.
adenocarcinoma; Barrett’s esophagus; dietary fat; epidemiology; meat
Previous studies indicate that the population attributable risk of bladder cancer for tobacco smoking is 50–65% in men and 20–30% in women and that current cigarette smoking triples bladder cancer risk relative to never smoking. Over the last 30 years, incidence rates have remained stable in the United States (men: 123.8/100,000 person-years to 142.2/100,000 person-years; women: 32.5/100,000 person-years to 33.2/100,000 person-years), yet changing smoking prevalence and cigarette composition warrant revisiting risk estimates for smoking and bladder cancer in more recent data.
To evaluate the association between tobacco smoking and bladder cancer.
Design, Setting, and Participants
Men (n=281,394) and women (n=186,134) of the NIH-AARP cohort completed a lifestyle questionnaire and were followed from 1995 through Dec 31, 2006. Previous prospective cohort studies of smoking and incident bladder cancer were identified by systematic review and pooled using fixed effects models with heterogeneity assessed by I2.
Main outcome measures
Hazard ratios (HR), population attributable risks, and number needed to harm (NNH).
During 4,518,938 years of follow-up, incident bladder cancer occurred in 3,896 men (144.0/100,000 person-years) and 627 women (34.5/100,000 person-years). Former smokers (119.8/100,000 person-years, HR: 2.22, 95%CI: 2.03–2.44, NNH: 1,250) and current smokers (177.3/100,000 person-years, HR: 4.06, 95%CI: 3.66–4.50; NNH: 727) had higher risks of bladder cancer than never smokers (39.8/100,000 person-years). In contrast, the summary risk estimate for current smoking in seven previous studies (initiated from 1963–1987) was 2.94 (95%CI: 2.45–3.54; I2=0.0%). The population attributable risk for ever smoking in our study was 0.50 (95%CI: 0.45–0.54) in men and 0.52 (95%CI: 0.45–0.59) in women.
Compared to a pooled estimate of US data from cohorts initiated between 1963 and 1987, relative risks for smoking in the more recent NIH-AARP cohort were higher, with population attributable risks for women comparable to those for men.
Background and aims
Alcohol intake is a strong and well-established risk factor for esophageal squamous cell carcinoma (ESCC), but the association with esophageal adenocarcinoma (EA) or adjacent tumors of the esophagogastric junction (EGJA), remains unclear. Therefore, we determined the association of alcohol intake with ESCC, EA, and EGJA in nine case-control studies and two cohort studies of the Barrett’s Esophagus and Esophageal Adenocarcinoma Consortium (BEACON).
Materials and methods
We collected information on alcohol intake, age, sex, education, body mass index, gastroesophageal reflux, and tobacco smoking from each study. Along with 10,854 controls, 1,821 EA, and 1,837 EGJA, seven studies also collected ESCC cases (n=1,016). Study-specific odds ratios (OR) and 95% confidence intervals (CI) were calculated from multivariate-adjusted logistic regression models for alcohol intake in categories compared to non-drinkers. Summary risk estimates were obtained by random effects models.
We observed no increase in risk of EA or EGJA for increasing levels of any of the alcohol intake measures examined. ORs for the highest frequency category (≥7 drinks per day) were 0.97 (95% CI = 0.68-1.36) for EA and 0.77 (95% CI = 0.54-1.10) for EGJA. Suggestive findings linked moderate intake (e.g. 0.5 to <1 drinks per day) to decreased risk of EA (OR = 0.63 95% CI = 0.41-0.99) and EGJA (OR = 0.78; 95% CI = 0.62-0.99). In contrast, alcohol intake was strongly associated with increased risk of ESCC (OR for ≥7 drinks per day= 9.62, 95%CI=4.26-21.71).
In contrast to ESCC, higher alcohol consumption was not associated with increased risk of either EA or EGJA. The apparent inverse association observed with moderate alcohol intake should be evaluated in future prospective studies.
Alcohol Drinking; Esophageal Neoplasms; Stomach Neoplasms; Epidemiology
To investigate the association between iron intake and iron status with Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC).
220 BE patients, 224 EAC patients, and 256 frequency-matched controls completed a lifestyle and food frequency questionnaire, and provided serum and toenail samples between 2002 and 2005. Using multiple logistic regression, odds ratios (OR) and 95% confidence intervals (95%CI) were calculated within quartiles of intake/status.
Comparing the fourth to the first quartile, ferritin (OR 0.47; 95%CI: 0.23, 0.97) and transferrin saturation (OR 0.41; 95%CI: 0.20, 0.82) were negatively associated with BE; whilst total iron binding capacity was positively associated per 50 µg/dl increment (OR 1.47; 95%CI: 1.12, 1.92). Comparing the fourth to the first quartile, iron intake (OR 0.50; 95%CI: 0.25, 0.98), non-heme iron intake per 10 mg/day increment (OR 0.29; 95%CI: 0.08, 0.99), and toenail iron (OR 0.40; 95%CI: 0.17, 0.93) were negatively associated with EAC; whilst heme iron intake was positively associated (OR 3.11 95%CI: 1.46, 6.61).
In contrast to the hypothesis that increased iron intakes and higher iron stores are a risk factor for BE and EAC, this study suggests that higher iron intakes and stores may have a protective association with BE and EAC, with the exception of what was found for heme iron intake.
adenocarcinoma; Barrett's esophagus; epidemiology; ferritin; iron
Cancers 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.
498 oesophageal squamous cell carcinomas (OSCC) and 255 gastric cardia adenocarcinomas (GCA) were matched by age and sex to 947 individuals from the wider cohort. We calculated hazard ratios (HR) and 95% confidence intervals (95% CI) using the case-cohort estimator for the Cox proportional hazards models, stratified on age and sex, with adjustment for potential confounders.
Higher 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, 0.98) and 0.59 for GCA (95% CI: 0.38, 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.
Higher 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.
oesophageal squamous cell carcinoma; gastric cardia cancer; hazard ratio; cysteine
Gastric cancer incidence rates are consistently lower in women than men in both high and low‐risk regions worldwide. Sex hormones, such as progesterone and estrogen, may protect women against gastric cancer.
To investigate the association of menstrual and reproductive factors and gastric cancer risk.
These associations were prospectively investigated in 73 442 Shanghai women. After 419 260 person‐years of follow‐up, 154 women were diagnosed with gastric cancer. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models adjusted for age, body mass index, education, income, and cigarette use.
No associations were observed between gastric cancer risk and age of menarche, number of children, breast feeding, or oral contraceptive use. In contrast, associations were observed with age of menopause (HR 0.80 per five‐year increase in menopausal age, 95% CI 0.66–0.97), years of fertility (participants with less than 30 years of fertility were at increased risk compared with those with 30–36 years of fertility, HR 1.90, 95% CI 1.25–2.90), years since menopause (HR 1.26 per five years, 95% CI 1.03–1.53), and intrauterine device use (HR for users 1.61, 95% CI 1.08–2.39).
These results support the hypothesis that female hormones play a protective role in gastric cancer risk.
stomach neoplasms; cohort studies; prospective studies; hormones
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.
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.
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.
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).
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.
Cancers of the upper gastrointestinal tract remain a substantial cause of morbidity and mortality worldwide. Ghrelin is a hormone produced in the oxyntic glands of the stomach, and under conditions of chronic inflammation and atrophy, serum ghrelin concentrations decrease. However, the relationship between ghrelin and the risk of gastric and esophagogastric junctional cancers has not been investigated.
We conducted a nested case–control study within the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine the relationship between serum ghrelin concentration and the risk of gastric noncardia adenocarcinoma (GNCA) and esophagogastric junctional adenocarcinoma (EGJA). Data from 261 GNCA patients, 98 EGJA patients, and 441 control subjects were analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression with adjustment for potential confounders. Lag analysis was also performed to investigate the temporal nature of the associations between baseline serum pepsinogen I and ghrelin in GNCA and EGJA patients. All statistical tests were two-sided.
Lower concentrations of serum ghrelin were statistically significantly associated with an increased risk of both GNCA (adjusted OR = 1.75, 95% CI = 1.49 to 2.04; P < .001) and EGJA (adjusted OR = 1.56, 95% CI = 1.28 to 1.89, P < .001). A multivariable model found that the risk of both GNCA and EGJA were statistically significantly increased for those individuals in the lowest quartile of serum ghrelin levels compared with those in the highest quartile (OR of GNCA = 5.63, 95% CI = 3.16 to 10.03; OR of EGJA = 4.90, 95% CI = 2.11 to 11.35). The statistical significance of these associations remained even after restricting the analysis to those patients who developed cancer more than 10 years after baseline serum ghrelin measurements.
Low baseline concentrations of serum ghrelin were associated with a statistically significant increase in the risk of GNCA and EGJA, suggesting a potential role for gastric hormones in carcinogenesis.
Published studies suggesting a relationship between vitamin D and some common cancers sparked interest in the association of vitamin D with head and neck cancers. Prolonged darker months in Finland are associated with lower levels of ultraviolet B radiation, raising concerns about low vitamin D levels.
We used a nested case-control study in the prospective Alpha-Tocopherol Beta Carotene (ATBC) Study of male smokers in Finland, to examine the relationship between serum 25(OH)D and risk of developing squamous cancers of the head and neck. Using conditional logistic regression we calculated the multivariate adjusted odds ratio (OR) and confidence interval (CI) comparing those with serum 25(OH)D adequate levels of 50–<75 nmol/L to those <25.0.
We identified incident cancers of the oral cavity (n=134), pharynx (n=48), and larynx (n=158). Median serum vitamin D was 31 nmol/L (interquartile range 21–48), which is below the 50 nmol/L cutoff considered adequate for bone and overall health. Comparing those with serum 25(OH)D below 25 nmol/L to those 50–<75 nmol/L as the referent, the OR was 1.35 (95% CI: 0.53, 3.43, p-trend=0.65) for overall head and neck cancers. Stratification by cancer sub-sites of the oral cavity, pharynx and larynx (p-trend= 0.93, 0.78, 0.26 respectively) or by season of blood draw also showed no association.
Our study showed no association between serum 25(OH)D and risk of head and neck cancers.
This study does not support the hypothesis that greater vitamin D exposure would reduce the risk of developing head and neck squamous cancers.
Head and neck/oral cancers; Diet; alcohol; smoking; and other lifestyle risk factors; vitamin D; Cohort; Finland
While gastric noncardia adenocarcinoma (GNCA) incidence rates in the US have decreased, the rates of gastric cardia adenocarcinoma (GCA) and esophageal adenocarcinoma (EADC) have increased. Obesity increases the risks of GCA and EADC, and the associations may be partially mediated by insulin resistance. A few case-control studies have shown an association between diabetes and an increased risk of EADC.
We prospectively examined the association between diabetes and upper gastrointestinal (UGI) cancers in a cohort of 469,448 people in the US, ages 50-71 at baseline. Cox proportional hazards regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for diabetes and UGI cancers, controlling for multiple potential confounders, including body mass index (BMI).
We observed no association of self-reported diabetes with risk of EADC, HR (95%CI) = 0.98 (0.73-1.31), esophageal squamous cell carcinoma (ESCC), HR (95%CI) = 1.02 (0.60-1.74), or GNCA, HR (95%CI) = 0.98 (0.70-1.37). However, diabetes was significantly associated with an increased risk of GCA, HR (95%CI) = 1.89 (1.43-2.50). The significant association between diabetes and risk of GCA remained after adjustment for BMI, HR (95%CI) = 1.70 (1.28-2.26) and did not differ by BMI strata (pinteraction =0.83). The significant association was unchanged when restricting to only overweight subjects (BMI 25 - ≤30), HR (95%CI) = 1.83 (1.18-2.85).
We found a significant association between self-reported diabetes and increased risk of GCA.
Our results suggest that the metabolic and hormonal changes related to diabetes may play a role in the etiology of GCA independently from BMI.
Esophageal adenocarcinoma; gastric adenocarcinoma; diabetes; BMI
Identifying people at higher risk of having squamous dysplasia, the precursor lesion for esophageal squamous cell carcinoma (ESCC), would allow targeted endoscopic screening.
We used multivariate logistic regression models to predict ESCC and dysplasia as outcomes. The ESCC model was based on data from the Golestan Case-Control Study (total n=871; cases=300), and the dysplasia model was based on data from a cohort of subjects from a GI clinic in Northeast Iran (total n=724; cases=26). In each of these analyses, we fit a model including all risk factors known in this region to be associated with ESCC. Individual risks were calculated using the linear combination of estimated regression coefficients and individual-specific values for covariates. We used cross-validation to determine the area under the curve (AUC) and to find the optimal cut points for each of the models.
The model had an area under the curve of 0.77 (95% CI: 0.74–0.80) to predict ESCC with 74% sensitivity and 70.4% specificity for the optimum cut point. The area under the curve was 0.71 (95% CI: 0.64–0.79) for dysplasia diagnosis, and the classification table optimized at 61.5% sensitivity and 69.5% specificity. In this population, the positive and negative predictive values for diagnosis of dysplasia were 6.8% and 97.8%, respectively.
Our models were able to discriminate between ESCC cases and controls in about 77%, and between individuals with and without squamous dysplasia in about 70% of the cases. Using risk factors to predict individual risk of ESCC or squamous dysplasia still has limited application in clinical practice, but such models may be suitable for selecting high risk individuals in research studies, or increasing the pretest probability for other screening strategies.