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 Barrett's oesophagus and oesophageal adenocarcinomas in Linxian, making all cardia tumours of gastric origin, rather than a mixture of gastric and oesophageal malignancies.
Helicobacter pylori; oesophageal cancer; gastric cancer; China
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
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.
vitamin D; oesophageal cancer; gastric cancer; cohort study; China
Thousands of people in central Asia die every year from gastric cardia adenocarcinoma (GCA). GCA arises in the transformation zone between the esophagus and the stomach, similar to cervical and oropharyngeal carcinoma, which arise in areas with transformation zone characteristics. The analogous biology of the gastric cardia to the cervix and oropharynx, where human papillomavirus (HPV) is known to cause cancer, raises the possibility that GCA could be an HPV-associated cancer. Given the availability of an effective HPV vaccine and its potential to prevent HPV-associated cancer, we decided to evaluate the prevalence of HPV DNA in GCA.
We collected tumor tissue from 144 histopathologically-confirmed GCA patients at Yaocun Commune Hospital, Linxian, China, with rigorous attention to prevent DNA contamination. We tested for the presence of HPV DNA in fresh-frozen tumor specimens using PCR with sensitive L1, E6, and E7-based primers.
DNA was adequate, as indicated by β-globin positivity, in 108 cases. Of these, all (100%, 95% confidence interval: 97%–100%) were negative for HPV DNA
These results suggest that HPV does not contribute to gastric cardia carcinogenesis in north central China.
Since GCA does not appear to be an HPV-associated cancer, prophylactic HPV vaccination is unlikely to affect rates of GCA in China.
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.
oesophageal cancer; precursor lesions; squamous dysplasia; China; follow up study
In the last decades, the incidence of oesophageal and gastric cardia adenocarcinoma has increased rapidly in the Western world. We investigated the association between body mass index (BMI), height and risk of oesophageal and gastric cardia adenocarcinoma.
The Netherlands Cohort Study was initiated in 1986. All participants (n = 120 852), aged 55–69 years, completed a self administered questionnaire. Cases were identified through annual record linkage with the Netherlands Cancer Registry. After 13.3 years of follow‐up, excluding the first follow‐up year, complete data from 4552 subcohort members, 133 oesophageal and 163 gastric cardia adenocarcinomas were available for case‐cohort analyses. Incidence rate ratios (RRs) and corresponding 95% confidence intervals were estimated using Cox proportional hazard models.
The RRs (95% CI) of oesophageal adenocarcinoma were 1.40 (0.95 to 2.04) and 3.96 (2.27 to 6.88) for overweight (BMI 25.0–29.9 kg/m2) and obese subjects (BMI ⩾30.0 kg/m2), respectively, compared to subjects with normal weight (BMI 20.0–24.9 kg/m2). For gastric cardia adenocarcinoma, these RRs were 1.32 (0.94 to 1.85) and 2.73 (1.56 to 4.79). Also change in BMI during adulthood was positively associated with the risk of oesophageal and gastric cardia adenocarcinoma (p trend 0.001 and 0.02, respectively), while no association was found with BMI in early adulthood (p trend 0.17 and 0.17, respectively). None of the tumour types investigated was significantly associated with height.
These results confirm higher risks of oesophageal and gastric cardia adenocarcinoma with increasing BMI. This implies that the increasing prevalence of obesity may be one of the explanations for the rising incidence of oesophageal and gastric cardia adenocarcinoma in the Western world.
cohort study; oesophageal cancer; stomach cancer; risk factors; body mass index
Use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of gastric or oesophageal adenocarcinomas. We examined the association between self-reported use of aspirin or non-aspirin NSAIDs in the earlier 12 months and gastric non-cardia (N=182), gastric cardia (N=178), and oesophageal adenocarcinomas (N=228) in a prospective cohort (N=311 115) followed for 7 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) come from Cox models adjusted for potential confounders. Use of any aspirin (HR, 95% CI: 0.64, 0.47–0.86) or other NSAIDs (0.68, 0.51–0.92) was associated with a significantly lower risk of gastric non-cardia adenocarcinoma. Neither aspirin (0.86, 0.61–1.20) nor other NSAIDs (0.91, 0.67–1.22) had a significant association with gastric cardia cancer. We found no significant association between using aspirin (1.00, 0.73–1.37) or other NSAIDs (0.90, 69–1.17) and oesophageal adenocarcinoma. We also performed a meta-analysis of the association between the use of NSAIDs and risk of gastric and oesophageal adenocarcinoma. In this analysis, aspirin use was inversely associated with both gastric and oesophageal adenocarcinomas, with summary odds ratios (95% CI) for non-cardia, cardia, and oesophageal adenocarcinomas of 0.64 (0.52–0.80), 0.82 (0.65–1.04), and 0.64 (0.52–0.79), respectively. The corresponding numbers for other NSAIDs were 0.68 (0.57–0.81), 0.80 (0.67–0.95), and 0.65 (0.50–0.85), respectively.
aspirin; NSAIDs; oesophageal cancer; gastric cancer; cohort; meta-analysis
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
Background and aims: Intestinal metaplasia (IM) at the cardia is likely to be a precursor of cardia cancer. Previous work has shown that it is associated with chronic inflammation attributable to either gastro-oesophageal reflux disease (GORD) or Helicobacter pylori infection. An alternative aetiological factor is bile reflux. Duodenogastric reflux brings about histological changes in the gastric mucosa that can be graded and used to calculate a bile reflux index (BRI). We used the BRI to assess whether reflux of bile plays a part in the development of cardia IM.
Methods: Histological changes in simultaneous gastric antrum and cardia biopsies from 267 dyspeptic patients were independently graded by two pathologists. The association between cardia IM and age, sex, clinical group, H pylori status, increased BRI (>14), and inflammation at the cardia were evaluated using logistic regression.
Results: A total of 226 patients had adequate cardia and antral biopsies; 149 had GORD and 77 had non-ulcer dyspepsia. Cardia IM was present in 66 (29%) patients, of whom 28 (42%) had complete IM. Increasing age, male sex, chronic inflammation, and a high BRI emerged as significant independent associations with cardia IM. Clinical group and H pylori status were not independent risk factors.
Conclusions: Histological evidence of bile reflux into the stomach is associated with cardia IM. This could have an important bearing on carcinogenesis at this site.
bile reflux; intestinal metaplasia; gastric cardia
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
Squamous dysplasia is the precursor lesion for esophageal squamous cell carcinoma (ESCC), and nutritional factors play an important role in the etiology of this cancer. Previous studies using a variety of measures of vitamin D exposure have reached different conclusions about the association between vitamin D and risk of developing esophageal cancer.
We measured serum 25-hydroxyvitamin D (25(OH)D) concentrations in a cross-sectional analysis of 720 subjects from Linxian, China, a population at high risk for developing ESCC. All subjects underwent endoscopy and biopsy and were categorized by presence or absence of histologic squamous dysplasia. We used crude and multivariate adjusted generalized linear models to estimate the relative risk (RR) and 95% confidence intervals (CI) for the association between squamous dysplasia and sex-specific quartiles of serum 25(OH)D concentration.
Two hundred and thirty (32%) of 720 subjects had squamous dysplasia. Subjects with dysplasia had significantly higher median serum 25(OH)D concentrations then subjects without dysplasia, 36.5 and 31.5 nmol/L respectively (Wilcoxon two-sample test p = 0.0004). In multivariate adjusted models, subjects in the highest compared to the lowest quartile were at significantly increased risk of squamous dysplasia, RR (95% CI) = 1.86 (1.35–2.62). Increased risks were similar when examined in men and women separately: Men RR (95% CI) = 1.74 (1.08–2.93); Women RR (95% CI) = 1.96 (1.28–3.18).
Higher serum 25(OH)D concentration was associated with significantly increased risk of squamous dysplasia. No obvious source of measured or unmeasured confounding explains this finding.
Esophageal cancer; Squamous dysplasia; Vitamin D; Serum 25(OH)D; China
Survival trends in oesophageal and gastric cancer need to be updated. A nationwide Swedish population-based study in 1961–2009 was based on registry data.
Relative survival rate, i.e. the ratio of the observed to the expected survival, adjusted for age, sex, and calendar period, and presented with 95% confidence intervals (CI), was the main outcome measure. The expected survival was calculated using the corresponding Swedish general population with no exclusions. The relative survival rates in oesophageal and gastric cardia adenocarcinoma have improved since the 1990s (p for trend <0.001), but not in oesophageal squamous cell carcinoma or gastric non-cardia adenocarcinoma. The relative 5-year survival rates during the two recent periods 1990–1999 and 2000–2008 were 12.5% (95%CI 10.1%–14.9%) and 10.3% (95%CI 8.5–12.0%) for oesophageal squamous cell carcinoma, 12.5% (95%CI 10.1%–14.9%) and 14.6% (95%CI 12.6–16.6%) for oesophageal adenocarcinoma, 11.1% (95%CI 9.6%–12.6%) and 14.3% (95%CI 12.3–16.3%) for gastric cardia adenocarcinoma, and 20.2% (95%CI 19.2%–21.1%) and 19.0% (95%CI 17.7–20.2%) for gastric non-cardia adenocarcinoma. The 3-year survival in tumour stage III in 2004–2008 was about 25% for all four tumour types.
The survival in oesophageal and cardia adenocarcinoma is increasing, but the lack of such increase in oesophageal squamous cell carcinoma and gastric non-cardia adenocarcinoma is a concern.
Data in a regional cancer registry covering a population of 5 million and with an efficiency of registration of over 95% have been used to examine incidence trends in oesophageal and gastric carcinoma. In the West Midlands Region of the UK, during the period 1962 to 1981 the age standardised incidence of gastric carcinoma decreased by 20%. However, an analysis by both histological type and detailed site reveals that while the incidence of distal lesions is diminishing, the incidence of adenocarcinoma of the oesophagus and cardia is increasing. The proximal and distal lesions also exhibit marked differences in social class distribution and sex ratio. The results strongly suggest that the aetiological factors involved for cardia and adjoining sites are different from those for pyloric antrum.
Hormonal factors may influence risk for upper gastrointestinal cancers in women. We examined risk of oesophageal and gastric cancers in relation to reproductive factors in a large UK cohort, the Million Women Study.
Among 1 319 409 women aged on average 56 years at recruitment, 1186 incident cancers of the oesophagus and 1194 of the stomach were registered during 11.9 million person-years' observation. Adjusted relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.
Risks of both oesophageal and gastric cancer were significantly higher in postmenopausal than in pre- or peri-menopausal women (RRs 1.46, 1.07–2.00 and 1.59, 1.15–2.20, respectively; P⩽0.01 for both); and, among postmenopausal women, risk was higher the younger women were at menopause (RR, 95% CI per 5 years younger at menopause 1.18, 1.05–1.34 for oesophageal cancer and 1.18, 1.04–1.34 for stomach cancer, Ptrend=0.01 for both). For factors relating to childbearing, including women's age at first birth, their number of children, and breastfeeding history, the only significant association was a higher risk of oesophageal cancer in nulliparous, compared with parous, women (RR 1.31, 1.11–1.55; P=0.002). When risks for squamous cell and adenocarcinomas of the oesophagus were compared, most did not differ significantly, but statistical power was limited.
Both oesophageal and gastric cancer risks appeared to be related to menopausal status and age at menopause, but there was little consistent evidence for associations with factors related to childbearing.
oesophageal cancer; gastric cancer; menarche; menopause; parity; cohort
The General Population Nutrition Intervention Trial was a randomized primary esophageal and gastric cancer prevention trial conducted from 1985 to 1991, in which 29 584 adult participants in Linxian, China, were given daily vitamin and mineral supplements. Treatment with “factor D,” a combination of 50 μg selenium, 30 mg vitamin E, and 15 mg beta-carotene, led to decreased mortality from all causes, cancer overall, and gastric cancer. Here, we present 10-year follow-up after the end of active intervention.
Participants were assessed by periodic data collection, monthly visits by village health workers, and quarterly review of the Linxian Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the cumulative effects of four vitamin and mineral supplementation regimens were calculated using adjusted proportional hazards models.
Through May 31, 2001, 276 participants were lost to follow-up; 9727 died, including 3242 from cancer (1515 from esophageal cancer and 1199 from gastric cancer). Participants who received factor D had lower overall mortality (HR = 0.95, 95% CI = 0.91 to 0.99; P = .009; reduction in cumulative mortality from 33.62% to 32.19%) and gastric cancer mortality (HR = 0.89, 95% CI = 0.79 to 1.00; P = .043; reduction in cumulative gastric cancer mortality from 4.28% to 3.84%) than subjects who did not receive factor D. Reductions were mostly attributable to benefits to subjects younger than 55 years. Esophageal cancer deaths between those who did and did not receive factor D were not different overall; however, decreased 17% among participants younger than 55 (HR = 0.83, 95% CI = 0.71 to 0.98; P = .025) but increased 14% among those aged 55 years or older (HR = 1.14, 95% CI = 1.00 to 1.30; P = .47). Vitamin A and zinc supplementation was associated with increased total and stroke mortality; vitamin C and molybdenum supplementation, with decreased stroke mortality.
The beneficial effects of selenium, vitamin E, and beta-carotene on mortality were still evident up to 10 years after the cessation of supplementation and were consistently greater in younger participants. Late effects of other supplementation regimens were also observed.
Background and aims: It has been suggested that gastric cardia adenocarcinoma (GCA) is a distinct entity from oesophageal adenocarcinoma (OA). We examined several epidemiological features of GCA and OA in the USA to elucidate differences/similarities between these malignancies.
Methods: Using the database of Surveillance, Epidemiology, and End Results (SEER) program, we examined incidence rates for temporal changes, and ethnic and age distributions, and performed birth cohort analyses for cases with morphologically and histologically confirmed OA or GCA.
Results: The age adjusted incidence rates of OA rose progressively, reaching 1.8 per 100 000 (95% confidence interval 1.7–1.9) during 1987–1991 and 2.5 per 100 000 (2.3–2.6) during 1992–1996. In 1992–1996, Whites were affected five times more than Blacks, and men eight times more than women. A significant increase in incidence occurred among younger persons aged 45–65 years. Irrespective of age, OA was characterised by higher incidence rates among more recent birth cohorts: a 40% increase in incidence for each five year increase in the date of birth—a “birth cohort effect”. On the other hand, the incidence rates of GCA reached their highest level of 3.3 per 100 000 (3.2–3.4) in 1987–1991 and subsequently declined during 1992–1996 to 3.1 per 100 000 (3.0–3.3). Whites were affected twice more than blacks and men five times more than women. Most patients with GCA were older than 60 years with no increase among younger persons and no birth cohort effect (p=0.99).
Conclusion: Several significant epidemiological differences exist between OA and GCA. These differences suggest that these two malignancies are separate entities with different risk factors.
oesophageal adenocarcinoma; gastric cardia adenocarcinoma; gastro-oesophageal reflux disease; epidemiology
Low serum pepsinogen I (PGI) and low pepsinogen I/pepsinogen II ratio (PGI/II ratio) are markers of gastric fundic atrophy. We aimed to prospectively test the association between serum PGI/II ratio and risks of gastric noncardia adenocarcinoma, gastric cardia adenocarcinoma, and esophageal squamous cell carcinoma.
Case-cohort study nested in a prospective cohort with over 15 years of follow-up.
Rural region of the People’s Republic of China.
Men and women aged 40-69 at study baseline.
Main outcome measures
Adjusted hazard ratios and 95% confidence intervals for the association between serum PGI/II ratio and caner risk
Compared to subjects with PGI/II ratio of > 4, those with ≤4 had HRs (95%CIs) of 2.72 (1.77-4.20) and 2.12 (1.42-3.16) for noncardia and cardia gastric cancers, respectively. Risk of both cancers were also increased when other cut points ranging from 3 to 6, or when we used quartile models, or nonlinear continuous models. Risk of ESCC was marginally increased in those with PGI/II ratio ≤4, with HR (95% CI) of 1.56 (0.99-2.47), but quartile models and continuous models showed no increased risk. The nonlinear continuous models suggested that any single cut point collapsed subjects with dissimilar gastric cancer risks, and that using cut points was not an efficient use of data in evaluating these associations.
In this prospective study, we found similar and significantly increased risks of noncardia and cardia gastric adenocarcinomas in subjects with low PGI/II ratio, but little evidence for an association with ESCC risk.
Gastric cancer; Esophageal cancer; Pepsinogen; Case-cohort
In the first cohort study of the question we followed 92 986 (42 663 men and 50 323 women) adult patients hospitalized for asthma in Sweden from 1965 to 1994 for an average of 8.5 years to evaluate their risk of oesophageal and gastric cardia adenocarcinoma. Standardized incidence ratio (SIR) adjusted for gender, age and calendar year was used to estimate relative risk, using the Swedish nationwide cancer incidence rates as reference. Asthmatic patients overall had a moderately elevated risk for oesophageal adenocarcinoma (SIR = 1.5, 95% confidence interval CI, 0.9–2.5) and gastric cardia cancer (SIR = 1.4, 95% CI, 1.0–1.9). However, the excess risks were largely confined to asthmatic patients who also had a discharge record of gastro-oesophageal reflux (SIR = 7.5, 95% CI, 1.6–22.0 and SIR = 7.1, 95% CI, 3.1–14.0, respectively). No significant excess risk for oesophageal squamous-cell carcinoma or distal stomach cancer was observed. In conclusion, asthma is associated with a moderately elevated risk of developing oesophageal or gastric cardia adenocarcinoma. Special clinical vigilance vis-à-vis gastro-esophageal cancers seems unwarranted in asthmatic patients, but may be appropriate in those with clinically manifest gastro-oesophageal reflux. http://www.bjcancer.com © 2001 Cancer Research Campaign
asthma; gastro-oesophageal reflux; adenocarcinoma of the oesophagus and gastric cardia
Objective To examine the hypothesis that risk of oesophageal, but not of gastric or colorectal, cancer is increased in users of oral bisphosphonates.
Design Nested case-control analysis within a primary care cohort of about 6 million people in the UK, with prospectively recorded information on prescribing of bisphosphonates.
Setting UK General Practice Research Database cohort.
Participants Men and women aged 40 years or over—2954 with oesophageal cancer, 2018 with gastric cancer, and 10 641 with colorectal cancer, diagnosed in 1995-2005; five controls per case matched for age, sex, general practice, and observation time.
Main outcome measures Relative risks for incident invasive cancers of the oesophagus, stomach, and colorectum, adjusted for smoking, alcohol, and body mass index.
Results The incidence of oesophageal cancer was increased in people with one or more previous prescriptions for oral bisphosphonates compared with those with no such prescriptions (relative risk 1.30, 95% confidence interval 1.02 to1.66; P=0.02). Risk of oesophageal cancer was significantly higher for 10 or more prescriptions (1.93, 1.37 to 2.70) than for one to nine prescriptions (0.93, 0.66 to 1.31) (P for heterogeneity=0.002), and for use for over 3 years (on average, about 5 years: relative risk v no prescription, 2.24, 1.47 to 3.43). Risk of oesophageal cancer did not differ significantly by bisphosphonate type, and risk in those with 10 or more bisphosphonate prescriptions did not vary by age, sex, smoking, alcohol intake, or body mass index; by diagnosis of osteoporosis, fracture, or upper gastrointestinal disease; or by prescription of acid suppressants, non-steroidal anti-inflammatory drugs, or corticosteroids. Cancers of the stomach and colorectum were not associated with prescription of bisphosphonate: relative risks for one or more versus no prescriptions were 0.87 (0.64 to 1.19) and 0.87 (0.77 to 1.00). The specificity of the association for oesophageal cancer argues against methodological problems in the selection of cases and controls or in the analysis.
Conclusions The risk of oesophageal cancer increased with 10 or more prescriptions for oral bisphosphonates and with prescriptions over about a five year period. In Europe and North America, the incidence of oesophageal cancer at age 60-79 is typically 1 per 1000 population over five years, and this is estimated to increase to about 2 per 1000 with five years’ use of oral bisphosphonates.
Among 185 cases of gastric cancer and 200 controls in Linxian, China, Epstein–Barr virus (EBV) seropositivity was not associated with increased risk of gastric cancer. High EBV nuclear antigen titres were associated with longer survival in cardia cancer cases, possibly due to chance.
EBV; gastric cancer; incidence; survival
BACKGROUND—The relationship between Helicobacter pylori and reflux oesophagitis remains controversial.
AIMS—To evaluate the relationship between H pylori and reflux oesophagitis in a large number of Japanese subjects.
SUBJECTS—A total of 5732 consecutive Japanese subjects during a health screening were enrolled.
METHODS—Gastrointestinal endoscopy was performed on all subjects. We simultaneously measured serum anti-H pylori antibody and pepsinogen as markers of H pylori infection together with gastric atrophy. The risk of reflux oesophagitis was evaluated in relation to these markers, and the results were compared with those of gastric cancer.
RESULTS—Reflux oesophagitis was found in 108 subjects. Both positivity for H pylori antibody (adjusted odds ratio (OR) 0.67 (95% confidence interval 0.45-1.0)) and "low" pepsinogen indicating gastric atrophy (OR 0.35 (0.18-0.68)) were negatively associated with reflux oesophagitis. After subjects were classified into four groups based on positivity or negativity for H pylori antibody and "low" pepsinogen, the prevalence of reflux oesophagitis showed a decreasing trend as H pylori induced gastric atrophy became more severe. The risk of gastric cancer showed an increasing trend, exactly the opposite to that of reflux oesophagitis.
CONCLUSIONS—Analysis of a large series of Japanese subjects revealed a decreasing prevalence of reflux oesophagitis in conjunction with progress of gastric atrophy induced by H pylori infection. This pattern was completely opposite to that of gastric cancer cases. A protective role of H pylori for reflux oesophagitis through the development of gastric atrophy has been suggested.
Keywords: Helicobacter pylori; oesophagitis; gastro-oesophageal reflux disease; atrophic gastritis; gastric cancer
The incidence of oesophageal and gastric cardia adenocarcinoma has increased rapidly over the previous two decades. There has been a rise in the number of younger patients affected, and the disease may be more aggressive and have a worse prognosis in these individuals. Current UK guidelines for urgent cancer referral focus on patients who are over 55 years. This study prospectively compares the referral times and outcome in a cohort of patients diagnosed with oesophagogastric cancer under the age of 55 years with a matched cohort over 55 of age.
PATIENTS AND METHODS
Every patient diagnosed with oesophageal, junctional or gastric cancer under the age of 55 years and every subsequent patient over the age of 55 years was accepted into this study. In all, 17 hospitals participated over a 12-month period. The following data were recorded: duration of symptoms, number of fast-track referrals, duration from GP referral to first hospital visit and stage at presentation. A survival analysis between the two groups was conducted at 2 years after the end of recruitment.
In total, 102 patients under the age of 55 years were diagnosed with oesophagogastric cancer during the study period. There were fewer fast-track referrals from GPs in this group compared to the over 55-year matched cases (29.4% vs 40.2%). Duration of time from GP referral to first hospital visit was significantly longer in the under 55-year group (median 14 days vs 11 days; P = 0.045 Mann-Whitney). Stage at presentation was similar between groups, but a higher proportion of patients under 55 years were offered a curative treatment plan compared to those over 55 years (P < 0.01). Survival analysis conducted at 2 years after the end of recruitment demonstrated a longer median survival in the under 55-year group (348 days vs 248 days; P = 0.03 log rank).
Although there was a longer referral time in patients under the age of 55 years, this had no effect on disease stage at presentation. Patients under the age of 55 years diagnosed with oesophageal or gastric cancer appear to have a better prognosis than those aged over 55 years.
Oesophageal cancer; Outcome; Survival
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.
An intravenous bolus of pentagastrin significantly increased the amplitude and duration of oesophageal body contractions in seven patients with diffuse oesophageal spasm (DES) when compared with five normal subjects (P greater than 0.05). In order to determine whether this stimulation also occurred at physiological gastrin concentrations, the effect of an intravenous infusion of gastrin heptadecapeptide (G17), 25 pmol/kg-h, on oesophageal contractions was studied in DES patients. G17 had no significant effect on the amplitude and duration of oesophageal contractions compared with a saline control. This dose of G17 was near the D50 for gastric acid secretion and produced a rise in serum gastrin concentration comparable with a meal. G17 infusions at doses of 100 and 200 pmol/kg-h increased the amplitude and duration of oesophageal contractions, but the corresponding serum gastrin concentrations were higher than postprandial levels. Thus, endogenous fluctuations in serum gastrin heptadecapeptide, alone, are unlikely to alter oesophageal contractions in DES patients.
AIM: To investigate the relationship between human papillomavirus (HPV) infection and concurrent esophagus and gastric cardia cancer from the same patient (CC) and examine the significance of P16INK4A protein expression.
METHODS: Polymerase chain reaction was used to detect the presence of HPV type16 (HPV16). The expression of P16INK4A protein was detected using immunohistochemistry.
RESULTS: Among the CC specimens, HPV16-DNA was found in eight cases of esophageal squamous cell carcinoma (ESCC) and five cases of gastric cardia adenocarcinoma (GCA), respectively (47% vs 29%), and two of both ESCC and GCA. P16INK4A was highly expressed in both ESCC and GCA. In the HPV-associated positive CC, higher P16INK4A expression was observed in the GCA than in the ESCC (75% vs 25%, P < 0.05).
CONCLUSION: HPV16 as a correlated risk factor may play an important role in the development of ESCC and GCA. P16INK4A may be a screening index in the HPV-associated carcinoma of gastric cardia.
Esophageal squamous cell carcinoma; Gastric cardia adenocarcinoma; Human papillomavirus; Polymerase chain reaction; Immunohistochemistry