Zhensheng Wang

Helicobacter Pylori Infection is Associated With Reduced Risk of Barrett’s Esophagus: An Analysis of the Barrett’s and Esophageal Adenocarcinoma Consortium

OBJECTIVES: Epidemiological studies of Helicobacter pylori infection and risk of Barretts esophagus (BE) have reported conflicting results. We examined the association between H. pylori infection and BE and sought to determine whether the association is mediated by gastroesophageal reflux disease (GERD) and to identify potential effect modifiers. METHODS: We used individual level data from 1308 patients with BE (cases), 1388 population‐based controls, and 1775 GERD controls in the Barretts and Esophageal Adenocarcinoma Consortium (BEACON). We estimated study‐specific odds ratios (ORs) and 95% CIs using multivariable logistic regression models and obtained summary risk estimates using a random‐effects meta‐analytic approach. We examined potential effect modification by waist‐to‐hip ratio (WHR), body mass index (BMI), and smoking status by conducting stratified analyses. RESULTS: For comparisons with population‐based controls, H. pylori infection was inversely associated with the risk of BE (adjusted OR = 0.44, 95% CI = 0.36‐0.55), with no evidence of between‐study heterogeneity (I2 = 0%). A stronger inverse association between H. pylori and BE was observed among individuals with the CagA‐positive strain (P for interaction = 0.017). We found no evidence of interaction between WHR, BMI, smoking status, and H. pylori infection on the risk of BE. There was no association between H. pylori infection and BE for comparisons with GERD controls (OR = 0.96, 95% CI = 0.67‐1.37; I2 = 48%). CONCLUSIONS: This study provides the strongest evidence yet that H. pylori infection is strongly inversely associated with BE. This effect is probably mediated by a decrease in GERD in infected patients, since the protective effect disappears in patients with GERD symptoms.

Epidemiology of Comorbid Conditions Among Adults 50 Years and Older With Traumatic Brain Injury

Objectives: Aging individuals with traumatic brain injury (TBI) experience multiple comorbidities that can affect recovery from injury. The objective of this study was to describe the most commonly co-occurring comorbid conditions among adults 50 years and older with TBI. Setting: Level I Trauma centers. Participants: Adults 50 years and older with moderate/severe TBI enrolled in the TBI-Model Systems (TBI-MS) from 2007 to 2014 (n = 2134). Design: A TBI-MS prospective cohort study. Main Measures: International Classification of Disease–9th Revision codes collapsed into 45 comorbidity categories. Comorbidity prevalence estimates and trend analyses were conducted by age strata (50-54, 55-64, 65-74, 75-84, ≥85 years). A dimension reduction method, Treelet Transform, classified clusters of comorbidities that tended to co-occur. Results: The 3 most commonly occurring comorbid categories were hypertensive disease (52.6/100 persons), other diseases of the respiratory system (51.8/100 persons), and fluid component imbalances (43.7/100 persons). Treelet Transform classified 3 clusters of comorbid codes, broadly classified as (1) acute medical diseases/infections, (2) chronic conditions, and (3) substance abuse disorders. Conclusion: This study provides valuable insight into comorbid conditions that co-occur among adults 50 years and older with TBI and provides a foundation for future studies to explore how specific comorbidities affect TBI recovery.

Reproductive factors, hormone use and gastric cancer risk: The Singapore Chinese Health Study.

Gastric cancer incidence varies greatly worldwide, but is consistently twice as high in men than in women. The hormone‐related factors hypothesized to be associated with lower risk of gastric cancer in women have not been fully explored in populations with a high background risk of gastric cancer. The Singapore Chinese Health Study (SCHS) is a prospective cohort study in which 34,022 of the participants enrolled between 1993 and 1998 were women between 45 and 74 years of age. Information on reproductive histories, hormone replacement therapy (HRT) and oral contraceptive (OC) use was collected through in‐person interviews at baseline. As of December 31, 2013, 269 incident gastric cancer cases were identified. Multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate gastric cancer risk associations. Older age at natural menopause (≥55 versus <45 years: HRu2009=u20090.50, 95% CI: 0.25–0.99), type of menopause (other versus natural: HRu2009=u20090.48, 95% CI: 0.27–0.87) and greater years of menstrual cycling (fourth versus first quartile: HRu2009=u20090.67, 95% CI: 0.46–0.96) were associated with a decreased risk of gastric cancer. Ever use of OCs and HRT was also associated with reduced risk of gastric cancer; the multivariable‐adjusted HRs (95% CIs) were 0.40 (0.17–0.90) for use of HRT >3 years and 0.67 (0.47–0.94) for ever use of OCs, compared with never use. Reproductive factors associated with a longer window of fertility and the use of exogenous hormones were shown to reduce gastric cancer development in a cohort of Chinese women with a high background risk of gastric cancer.

Telomere length and risk of developing gastric adenocarcinoma: The Singapore Chinese Health Study

BackgroundExtreme telomere length has been previously reported to be associated with increased risk of gastric cancer. However, evidence from prospective studies on a relative large sample size with long-term follow-up to further corroborate previous study findings is meager.MethodsThe association between peripheral blood leukocyte telomere length and risk of gastric adenocarcinoma was prospectively examined in a cohort of 26,540 middle-aged or older Chinese nested in the Singapore Chinese Health Study. Telomere length was determined using a validated qPCR-based method. The Cox proportional regression method was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of gastric adenocarcinoma associated with telomere length after adjustment for potential confounders. Restricted cubic spline analysis was applied to assess the nonlinear relationship between telomere length and gastric cancer risk.ResultsA U-shaped association was found between telomere length and risk of gastric adenocarcinoma (Pnonlinearityxa0=xa00.020). Compared with the second quintile of telomere length, a statistically significant higher risk of gastric adenocarcinoma was associated with either the lowest quintile (HRxa0=xa01.63, 95% CI, 1.07–2.47) or the highest quintile (HRxa0=xa01.55, 95% CI, 0.97–2.47) of telomere length. This U-shaped relationship was more apparent in men and younger individuals.ConclusionsThis is the first prospective study demonstrating a higher risk of gastric cancer to be associated with either extremely short or extremely long telomere length. Short and long telomere length may function differently in the early and late stages of gastric carcinogenesis.

Helicobacter pylori Infection and Gastroesophageal Reflux Disease—Barrett’s Esophagus-Esophageal Adenocarcinoma Sequence: Reply From Authors

i.e., multiple factors that were not taken into consideration in the study design or the analysis of data, but might possibly contribute to EAC pathogenesis. This may have affected the meta-analyses results, due to the inclusion of original papers that did not sufficiently adjust for potential confounders. Moreover, the presence of any heterogeneity, if and when present, was not evaluated in the meta-analyses. We consider [2] that the Hp-I positive association with gastric and colorectal cancers but not with EAC appears to be an inconsistency, and all the above should be the focus of future investigation. There is evidence supporting the sequence GERD–BE–dysplasia–EAC and Hp implication separately in each single step to EAC, at least in certain populations [2, 3]. The effect of Hp on BE varies according to geographic location [2, 3]. Chronic inflammation promotes initiation, invasion, and metastasis of several malignancies, as exemplified by the GERD–BE–EAC sequence [3]. In this respect, two studies reported that Hp-I is common in patients with GERD, and Hp eradication results in adequate control of GERD symptoms and improves esophagitis. Moreover, other authors, previous supporters of the hypothesis that Hp “protects” against GERD, relented, claiming that Hp therapy does not cause or protect against GERD, and recommending Hp eradication in GERD. Besides, there are epidemiologic studies further supporting the above-mentioned data. A large-scale study (~21,000 cases) reported that the decline in Hp-I parallels the reduction in peptic ulcer prevalence, and that the rise in GERD and/or reappearance of GERD following Hp therapy is rare [2]. Malaysians, who for a long time have had a low prevalence of Hp-I, also show a low incidence of GERD, BE and distal esophageal cancers, signifying that Hp-I is not protective against the above mentioned conditions and its absence may be beneficial [2]. Contrary to expectations, patients hospitalized with duodenal ulcers (~61,500 cases) apparently attributed to Hp-I had a 70% increased risk of GERD-related EAC complication [4]. Specifically, evidence further potentiates the consideration that Hp is not “protective” against anything, including GERD [5], and possibly its related complications, including BE and EAC. Hp and/ or Hp-related metabolic syndrome might be involved in GERD–BE–EAC, gastric atrophy-intestinal metaplasia–dysplasia– gastric cancer and colorectal adenoma– dysplasia–colorectal cancer sequences by diverse mechanisms [2, 3]. Hp eradication may inhibit these oncogenic properties, and thus large-scale studies are necessary.

Anti-Hypertensive Medication Use, Soluble Receptor for Glycation End Products and Risk of Pancreatic Cancer in the Women’s Health Initiative Study

Pancreatic cancer is the fourth leading cause of cancer death. Soluble receptor for glycation end products (sRAGE), which is modulated by anti-hypertensive (HT) medications, has been inversely associated with pancreatic cancer. However, the association between commonly used anti-HT medications and risk of pancreatic cancer is unknown. A total of 145,551 postmenopausal women from the Women Health Initiative (WHI) Study were included in analysis. Use of angiotensin converting enzyme inhibitors (ACEi), β-blockers, calcium channel blockers (CCBs) and diuretics was ascertained at baseline (1993–1998). Baseline sRAGE levels were measured among a subset of 2104 participants using an immunoassay. Multivariable Cox proportional hazard regression model was performed to estimate hazard ratios (HRs) and its 95% confidence intervals (CIs) for pancreatic cancer in association with anti-HT medications. Increased risk of pancreatic cancer was found among users of short-acting CCB (HR = 1.66, 95% CI: 1.20–2.28) and long-term (≥3 years) users of short-acting CCB (HR = 2.07, 95% CI: 1.42–3.02) compared to users of other anti-HT medications. Average sRAGE levels were lower in short-acting CCB users than users of other anti-HT medications (1173 versus 1454 pg/mL, p = 0.038). Non-statistically significant reduced risk of pancreatic cancer was found among users of β-blockers (HR = 0.80, 95% CI: 0.60–1.07). Average sRAGE levels were higher in β-blockers users than users of other anti-HT medications (1692 versus 1454 pg/mL, p > 0.05). Future studies are warranted to confirm these findings and elucidate potential mechanisms by which anti-HT medications influence development of pancreatic cancer.

Incidence of gastric cancer in the USA during 1999 to 2013: a 50-state analysis

BackgroundnThe incidence of gastric cancer, while declining in many places worldwide, is characterized by considerable geographical variability. The USA has large racial, ethnic and regional variation; we collected data from all 50 states to better characterize recent changes in gastric cancer incidence nationwide.nnnMethodsnAnnual gastric cancer incidence rates from 1999 to 2013 were extracted from the United States Cancer Statistics (USCS) registry. Secular trends of gastric cancer incidence were examined overall and by sociodemographic factors and states. We used Joinpoint regression to compute annual percent change (APC) and average annual percent change (AAPC) and corresponding 95% confidence intervals (CIs). SEER 13 registries data were extracted to examine the secular trends by cardia and non-cardia gastric cancers.nnnResultsnOverall gastric cancer incidence decreased until 2007 (APC = -1.55, 95% CI: -1.88, -1.21), and remained stable thereafter (APC = -0.32, 95% CI: -0.84, 0.20). However, rates increased among personsu2009<50u2009years of age (AAPC = 0.89, 95% CI: 0.61, 1.16), especially among non-Hispanic white females and Hispanic females. Incidence of non-cardia gastric cancer increased among personsu2009<50u2009years of age (AAPC = 0.69, 95% CI: -0.06, 1.44), whereas rates of gastric cardia cancer remained unchanged. States with rapid increases in high-risk population groups (e.g. Hispanic females agedu2009<50), including California and Texas, had highest annual increases in gastric cancer incidence.nnnConclusionsnDivergent trends for gastric cancer incidence were observed in the USA. Incidence rates, particularly for non-cardia gastric cancer, were stable or increasing among persons aged u2009<50u2009years.

Abstract 1190: Incidence of gastric cancer in the United States during 1999 to 2013: A 50-state analysis

Background: The incidence of gastric cancer while declining in many places worldwide is characterized by considerable geographic variability in incidence rates and temporal trends. The United States has large racial, ethnic, and regional variation; we collected data from all 50 states to better characterize recent changes in gastric cancer incidence in the entire United States. Methods: We extracted data on the annual gastric cancer (ICD-O-3: C16.0-C16.9) incidence rates for the period 1999-2013 from the United Stated Cancer Statistics (USCS) registry, which covers 97% of the population. Both age-adjusted incidence rates and temporal trends of gastric cancer incidence were examined overall, as well as stratified by sociodemographic factors and at the state level. We used Joinpoint regression analysis to compute annual percent change (APC) and average annual percent change (AAPC) and corresponding 95% CIs. Heat maps were created to highlight the temporal trend in age-adjusted incidence rates in each state over three 5-year periods: 1999-2003, 2004-2008, and 2009-2013. As a secondary analysis, we also extracted data from the SEER 13 registries to examine the incidence rates and trends separately for cardia and non-cardia gastric cancers. Results: Overall gastric cancer incidence decreased from 7.64 per 100,000 in 1999 to 6.55 per 100,000 in 2013, decreasing by 1.02% (AAPC=-1.02; 95% CI, -1.28 to -0.76) annually between 1999 and 2013. However, while overall gastric cancer incidence rates decreased (1999-2008 APC=-1.75, 95% CI, -2.02 to -1.47) and then plateaued (2008-2013 APC=-0.24, 95% CI: -0.89, 0.42) among persons aged ≥50 years, the rates increased among persons aged 95% CI, -2.51 to -1.90). Increasing rate of non-cardia cancer helped explain the uprising trend of gastric cancer among aged Conclusions: While gastric cancer, particularly non-cardia, rates have decreased rapidly among persons aged ≥50 years in the United States, the incidence rates among persons aged Citation Format: Zhensheng Wang, Anam Khan, Maya Balakrishnan, Hashem B. El-Serag, Aaron P. Thrift. Incidence of gastric cancer in the United States during 1999 to 2013: A 50-state analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1190.

Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study

Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF) that may influence secondary injury cascades associated with traumatic brain injury (TBI) and predict outcome. We investigated concurrent CSF BDNF and cortisol relationships in 117 patients sampled days 0–6 after severe TBI while accounting for BDNF genetics and age. We also determined associations between CSF BDNF and cortisol with 6-month mortality. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to previously published hypothesized risk for mortality in “younger patients” (<48 years) and hypothesized BDNF production/secretion capacity with these variants. Group based trajectory analysis (TRAJ) was used to create two cortisol groups (high and low trajectories). A Bayesian estimation approach informed the mediation models. Results show CSF BDNF predicted patient cortisol TRAJ group (P = 0.001). Also, GRS moderated BDNF associations with cortisol TRAJ group. Additionally, cortisol TRAJ predicted 6-month mortality (P = 0.001). In a mediation analysis, BDNF predicted mortality, with cortisol acting as the mediator (P = 0.011), yielding a mediation percentage of 29.92%. Mediation effects increased to 45.45% among younger patients. A BDNF*GRS interaction predicted mortality in younger patients (P = 0.004). Thus, we conclude 6-month mortality after severe TBI can be predicted through a mediation model with CSF cortisol and BDNF, suggesting a regulatory role for cortisol with BDNFs contribution to TBI pathophysiology and mortality, particularly among younger individuals with severe TBI. Based on the literature, cortisol modulated BDNF effects on mortality after TBI may be related to known hormone and neurotrophin relationships to neurological injury severity and autonomic nervous system imbalance.

Composite protective lifestyle factors and risk of developing gastric adenocarcinoma: the Singapore Chinese Health Study

Background:Incidence of gastric cancer is the highest in Eastern Asia. Multiple modifiable lifestyle factors have been identified as risk factors for gastric cancer. However, their aggregated effect on the risk of gastric cancer has not been examined among populations with high prevalence of Helicobacter pylori.Methods:A study was conducted to examine the association between multiple lifestyle factors together and the risk of developing gastric adenocarcinoma in the Singapore Chinese Health Study, a prospective cohort of 63u2009257 men and women between 45 and 74 years enroled during 1993–1998. Composite score of cigarette smoking, alcohol consumption, obesity, dietary pattern, and sodium intake at baseline was assessed with hazard ratio (HR) and 95% confidence interval (CI) of gastric adenocarcinoma using Cox regression method.Results:Higher healthy composite lifestyle scores were significantly associated with reduced risk of gastric adenocarcinoma in a dose-dependent manner. Hazard ratios (95% CIs) for total, cardia, and non-cardia gastric adenocarcinoma for the highest (score 5) vs lowest composite score (score 0/1/2) were 0.42 (0.31–0.57), 0.22 (0.10–0.47), and 0.55 (0.39–0.78), respectively (all Ptrend<0.001). These lifestyles together accounted for 48% of total gastric adenocarcinoma cases in the study population. The inverse association was observed in both genders, and remained after exclusion of first 5 years of follow-up.Conclusions:The inverse association between the aggregated healthy lifestyle factors and the risk of gastric adenocarcinoma is in dose-dependent manner in this highly H. pylori-exposed population. These lifestyle factors together may account for up to half of disease burden in this study population.