Anti-Tumor Necrosis Factor Therapy and Risk of Kidney Function Decline and Mortality in Inflammatory Bowel Disease.

Importance: Inflammatory bowel disease (IBD) is associated with adverse clinical outcomes, including chronic kidney disease and mortality, due in part to chronic inflammation. Little is known about the effects of anti-tumor necrosis factor (TNF) therapy on kidney disease progression and mortality among patients with new-onset IBD. Objective: To examine the association of incident use of TNF inhibitors with subsequent decline in kidney function and risk of all-cause mortality. Design, Setting, and Participants: This retrospective cohort study used data from the US Department of Veterans Affairs health care system. Participants were US veterans with new-onset IBD enrolled from October 1, 2004, through September 30, 2019. Data were analyzed from December 2022 to February 2024. Exposures: Incident use of TNF inhibitors. Main Outcomes and Measures: The main outcomes were at least 30% decline in estimated glomerular filtration rate (eGFR) and all-cause mortality. Results: Among 10 689 patients (mean [SD] age, 67.4 [12.3] years; 9999 [93.5%] male) with incident IBD, 3353 (31.4%) had diabetes, the mean (SD) baseline eGFR was 77.2 (19.2) mL/min/1.73 m2, and 1515 (14.2%) were newly initiated on anti-TNF therapy. During a median (IQR) follow-up of 4.1 (1.9-7.0) years, 3367 patients experienced at least 30% decline in eGFR, and over a median (IQR) follow-up of 5.0 (2.5-8.0) years, 2502 patients died. After multivariable adjustments, incident use (vs nonuse) of TNF inhibitors was significantly associated with higher risk of decline in eGFR (adjusted hazard ratio [HR], 1.34 [95% CI, 1.18-1.52]) but was not associated with risk of all-cause mortality (adjusted HR, 1.02 [95% CI, 0.86-1.21]). Similar results were observed in sensitivity analyses. Conclusions and Relevance: In this cohort study of US veterans with incident IBD, incident use (vs nonuse) of TNF inhibitors was independently associated with higher risk of progressive eGFR decline but was not associated with risk of all-cause mortality. Further studies are needed to elucidate potentially distinct pathophysiologic contributions of TNF inhibitor use to kidney and nonkidney outcomes in patients with IBD.

Long-term Patiromer Use and Outcomes Among US Veterans With Hyperkalemia and CKD: A Propensity-Matched Cohort Study.

Rationale & Objective: Patiromer is a potassium binder approved for the long-term management of hyperkalemia. Although patiromer use among patients with advanced chronic kidney disease (CKD) has been shown to reduce the discontinuation of renin-angiotensin-aldosterone system inhibition therapy, it remains unclear whether patiromer can improve clinical outcomes. The aim of this study was to examine the association of long-term patiromer use with clinical outcomes among hyperkalemic patients with CKD. Study Design: This was a longitudinal observational study. Setting & Participants: We evaluated a national cohort of 854,217 US Veterans who had at least 1 serum potassium measurement of ≥5.1 mEq/L and were treated at US Department of Veterans Affairs health care facilities between January 2016 and September 2019. Exposure: The exposure was long-term patiromer use. Outcomes: The outcomes were as follows: (1) composite endpoint of kidney failure with replacement therapy (KFRT) or all-cause death and (2) all-cause death including the post-KFRT period. Analytical Approach: Cox proportional Fine-Gray subdistribution hazard models were used in a propensity-matched cohort. Results: Among 2,004 patients who ever used patiromer during the study period (0.2% of the cohort), 666 met the criteria for long-term patiromer use. We matched 308 long-term patiromer users to 308 nonusers based on propensity scores. The median estimated glomerular filtration rate was 23.5 mL/min/1.73m2, and the median potassium level was 5.2 mEq/L. Approximately 45% were on renin-angiotensin system inhibitor(s) at baseline. During follow-up, 93 patients developed KFRT, and 134 patients died. Long-term patiromer users, when compared to nonusers, experienced a 26% lower risk of the composite outcome (HR, 0.74; 95% CI, 0.53-1.01; P = 0.06) and a 41% lower risk of all-cause mortality (HR, 0.59; 95% CI, 0.41-0.84; P = 0.003). Limitations: The study cohort included mostly male veterans with relatively short follow-up periods. Conclusions: Long-term patiromer use was associated with a lower risk of all-cause mortality among patients with CKD and hyperkalemia. Long-term potassium binder use for hyperkalemia may improve clinical outcomes in CKD. Plain-Language Summary: Hyperkalemia is a common complication of chronic kidney disease (CKD) and can result in the discontinuation of renin-angiotensin-aldosterone system inhibition therapy, a cornerstone of CKD management. Patiromer is a new potassium binder approved for the long-term management of hyperkalemia, but it remains unclear whether patiromer can improve clinical outcomes. We examined a cohort of US Veterans with hyperkalemia between January 2016 and September 2019 and found that patiromer use was uncommon for treating hyperkalemia during this study period. We then matched 308 long-term patiromer users and 308 nonusers based on propensity scores. Long-term patiromer users, when compared to nonusers, experienced a 26% lower risk of the composite outcome and a 41% lower risk of all-cause mortality. These findings indicate that long-term potassium binder use for hyperkalemia may improve clinical outcomes in CKD.

Association of oral iron replacement therapy with kidney failure and mortality in CKD patients.

Background: Oral iron is the predominant route of iron replacement (IRT) but its benefits and safety are unclear in patients with chronic kidney disease (CKD). Methods: We examined the association of oral IRT vs no IRT with end-stage kidney disease (ESKD) and mortality in a national cohort of US Veterans. We identified 17 413 incident new users of oral IRT with estimated glomerular filtration rates <60 mL/min/1.73 m2 and 32 530 controls who did not receive any IRT during 2004-18. We used propensity score-overlap weighting to account for differences in key baseline characteristics associated with the use of oral IRT. We examined associations using competing risk regression and Cox models. Results: In the cohort of 49 943 patients, 1616 (3.2%) patients experienced ESKD and 28 711 (57%) patients died during a median follow-up of 1.9 years. Oral IRT was not associated with ESKD [subhazard ratio (HR) (95% confidence interval, CI) 1.00 (0.84-1.19), P = .9] and was associated with higher risk of all-cause mortality [HR (95% CI) 1.06 (1.01-1.11), P = .01]. There was significant heterogeneity of treatment effect for mortality, with oral IRT associated with higher mortality in the subgroups of patients without congestive heart failure (CHF), anemia or iron deficiency. In patient with blood hemoglobin <10 g/dL oral IRT was associated with significantly lower mortality. Conclusion: Oral IRT was associated with lower mortality only in patients with anemia. In patients without anemia, iron deficiency or CHF, the risk-benefit ratio of oral IRT should be further examined.

Association of iron therapy with incidence of chronic kidney disease.

OBJECTIVE: We investigated the association of oral iron replacement with the incidence of chronic kidney disease (CKD) in a population with normal kidney function to study the effects of iron replacement on the development of new onset CKD. METHODS: In a national cohort of US Veterans with no pre-existing CKD, we identified 33 894 incident new users of oral iron replacement and a comparable group of 112 780 patients who did not receive any iron replacement during 2004-2018. We examined the association of oral iron replacement versus no iron replacement with the incidence of eGFR <60 mL/min/1.73 m2 and the incidence of urine albumin creatinine ratio (UACR) ≥30 mg/g in competing risk regressions and in Cox models. We used propensity score weighing to account for differences in key baseline characteristics associated with the use of oral iron replacement. RESULTS: In the cohort of 146 674 patients, a total of 18 547 (13%) patients experienced incident eGFR <60 mL/min/1.73 m2 , and 16 117 patients (11%) experienced new onset UACR ≥30 mg/g. Oral iron replacement was associated with significantly higher risk of incident eGFR <60 mL/min/1.73 m2 (subhazard ratio, 95% confidence interval [CI]: 1.3 [1.22-1.38], p < .001) and incident albuminuria (subhazard ratio, 95% CI: 1.14 [1.07-1.22], p < .001). CONCLUSION: Oral iron replacement is associated with higher risk of new onset CKD. The long-term kidney safety of oral iron replacement should be tested in clinical trials.

Mediation analysis of racial disparities in triple-negative breast cancer incidence among postmenopausal women.

BACKGROUND: Triple-negative breast cancer (TNBC) is disproportionately higher in Black women relative to White women. The objective of this study was to examine to what extent the association between race/ethnicity and risk of TNBC is mediated by potentially modifiable factors. METHODS: A total of 128,623 Black and White women aged 50-79 years from the Women's Health Initiative were followed for a mean of 15.8 years. 643 incident TNBC cases (92 Black women and 551 White women) were confirmed by medical record review. Mediation analyses were conducted using an approach under a counterfactual framework. RESULTS: Black women had approximately twofold higher risk of TNBC compared with white women (HR = 1.93, 95% CI 1.52-2.45). We observed that 48% of the racial disparity was mediated by metabolic dysfunction defined by having 3 or more cardiometabolic risk factors including elevated waist circumference, having history of diabetes, high cholesterol and hypertension. The racial disparity was not significantly mediated by other factors studied, including socioeconomic, lifestyle or reproductive factors. CONCLUSION: Our study observed that approximately half of the racial disparity between postmenopausal Black and White women in TNBC incidence was driven by metabolic dysfunction.

Predialysis Potassium Variability and Postdialysis Mortality in Patients With Advanced CKD.

INTRODUCTION: Patients with advanced non-dialysis-dependent chronic kidney disease (NDD-CKD) are prone to potassium (K) imbalances due to reduced kidney function. Both hypo- and hyperkalemia are associated with increased mortality; however, it is unclear if K variability before dialysis initiation is associated with outcomes after dialysis initiation. METHODS: We identified 34,167 US veterans with advanced NDD-CKD transitioning to dialysis between October 1, 2007, through March 31, 2015, who had at least 1 K measurement each year over a 3-year period before transition (3-year prelude). For each patient, a linear mixed-effects model was used to regress K over time (in years) over the 3-year prelude to derive K variability (square root of the average squared distance between the observed and estimated K). The main outcomes of interest were 6-month all-cause and cardiovascular mortality after dialysis initiation. Multivariable Cox and Fine-Gray competing risk regression adjusted for 3-year prelude K intercept, K slope (per year), demographics, smoking status, comorbidities, length of hospitalizations, body mass index, vascular access type, medications, average estimated glomerular filtration rate, and number of K measurements over the 3-year prelude were used to assess the association of K variability (expressed as quartiles) with all-cause and cardiovascular mortality, respectively. RESULTS: Higher prelude K variability was associated with higher multivariable-adjusted risk of all-cause mortality but not cardiovascular mortality (adjusted hazard/subhazard ratios [95% confidence interval] for highest quartile [vs. lowest] of K variability, 1.14 [1.03-1.25] and 0.99 [0.85-1.16] for all-cause and cardiovascular mortality, respectively). CONCLUSION: Higher K variability is associated with higher all-cause mortality after dialysis initiation.

Shunt Failure-The First 30 Days.

BACKGROUND: Incontrovertible predictors of shunt malfunction remain elusive. OBJECTIVE: To determine predictors of shunt failure within 30 d of index surgery. METHODS: This was a single-center retrospective cohort study from January 2010 through November 2016. Using a ventricular shunt surgery research database, clinical and procedural variables were procured. An "index surgery" was defined as implantation of a new shunt or revision or augmentation of an existing shunt system. The primary outcome was shunt failure of any kind within the first 30 days of index surgery. Bivariate models were created, followed by a final multivariable logistic regression model using a backward-forward selection procedure. RESULTS: Our dataset contained 655 unique patients with a total of 1206 operations. The median age for the cohort at the time of first shunt surgery was 4.6 yr (range, 0-28; first and third quartile, .37 and 11.8, respectively). The 30-day failure rates were 12.4% when analyzing the first-index operation only (81/655), and 15.7% when analyzing all-index operations (189/1206). Small or slit ventricles at the time of index surgery and prior ventricular shunt operations were found to be significant covariates in both the "first-index" (P < .01 and P = .05, respectively) and "all-index" (P = .02 and P < .01, respectively) multivariable models. Intraventricular hemorrhage at the time of index surgery was an additional predictor in the all-index model (P = .01). CONCLUSION: This study demonstrates that only 3 variables are predictive of 30-day shunt failure when following established variable selection procedures, 2 of which are potentially under direct control of the surgeon.

Risk factors, clinical outcomes, and natural history of uveal melanoma: a single-institution analysis.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. We describe the characteristics of UM patients at a tertiary referral center in the Mid-Southern United States, and explore associations and predictors of outcomes. This is a retrospective cohort study of patients with UM seen at West Cancer Center, from 07/2006 to 08/2017. Clinical characteristics and their relationship to outcomes (time-to-death and metastasis) were explored using Cox regression analysis. We identified 208 patients, 51% males, 97% Caucasians, 80% were symptomatic, with a median follow-up of 2.34 years, IQR (1.01-3.03), of which 19.2% died during follow-up. Metastases were diagnosed in 19% (4 older patients had metastases at diagnosis), 53% of those by surveillance. Without considering metastases as a time-varying covariate, age (HR = 1.06/year, CI 1.0-1.1; p < 0.001), headaches (HR = 5.7, CI 1.6-20.5; p = 0.03), and tumor stage (T) were significant covariates for time-to-death. Tumor stages T3 versus T1 (HR = 6.4; CI 1.5-27.7; p = 0.01) and T4 versus T1 (HR = 5.98; CI 1.3-27.8; p = 0.02) were associated with worse outcomes. When considering metastases as a time-varying covariate (HR = 35.8, CI 17-75.2; p < 0.001), only age remains in the model (HR = 1.04/year; p < 0.001). However, tumor stage (p < 0.001), headaches (p = 0.008), and age (p < 0.001) are associated with time-to-metastasis. One in five patients developed metastasis which was the most influential factor on mortality. Predictors of mortality were metastasis, age, tumor stage, and headache as a reported symptom. Surveillance successfully diagnosed metastatic disease in most patients. Most patients had symptoms preceding their UM diagnosis highlighting an opportunity for earlier recognition of UM.

Association of Cataract Surgery With Mortality in Older Women: Findings from the Women's Health Initiative.

Importance: Previous studies have suggested an association between cataract surgery and decreased risk for all-cause mortality potentially through a mechanism of improved health status and functional independence, but the association between cataract surgery and cause-specific mortality has not been previously studied and is not well understood. Objective: To examine the association between cataract surgery and total and cause-specific mortality in older women with cataract. Design, Setting, and Participants: This prospective cohort study included nationwide data collected from the Women's Health Initiative (WHI) clinical trial and observational study linked with the Medicare claims database. Participants in the present study were 65 years or older with a diagnosis of cataract in the linked Medicare claims database. The WHI data were collected from January 1, 1993, through December 31, 2015. Data were analyzed for the present study from July 1, 2014, through September 1, 2017. Exposures: Cataract surgery as determined by Medicare claims codes. Main Outcomes and Measures: The outcomes of interest included all-cause mortality and mortality attributed to vascular, cancer, accidental, neurologic, pulmonary, and infectious causes. Mortality rates were compared by cataract surgery status using the log-rank test and Cox proportional hazards regression models adjusting for demographics, systemic and ocular comorbidities, smoking, alcohol use, body mass index, and physical activity. Results: A total of 74 044 women with cataract in the WHI included 41 735 who underwent cataract surgery. Mean (SD) age was 70.5 (4.6) years; the most common ethnicity was white (64 430 [87.0%]), followed by black (5293 [7.1%]) and Hispanic (1723 [2.3%]). The mortality rate was 2.56 per 100 person-years in both groups. In covariate-adjusted Cox models, cataract surgery was associated with lower all-cause mortality (adjusted hazards ratio [AHR], 0.40; 95% CI, 0.39-0.42) as well as lower mortality specific to vascular (AHR, 0.42; 95% CI, 0.39-0.46), cancer (AHR, 0.31; 95% CI, 0.29-0.34), accidental (AHR, 0.44; 95% CI, 0.33-0.58), neurologic (AHR, 0.43; 95% CI, 0.36-0.53), pulmonary (AHR, 0.63; 95% CI, 0.52-0.78), and infectious (AHR, 0.44; 95% CI, 0.36-0.54) diseases. Conclusions and Relevance: In older women with cataract in the WHI, cataract surgery is associated with lower risk for total and cause-specific mortality, although whether this association is explained by the intervention of cataract surgery is unclear. Further study of the interplay of cataract surgery, systemic disease, and disease-related mortality would be informative for improved patient care.

The Primary Results of the Treating Adult Smokers at Risk for Weight Gain with Interactive Technology (TARGIT) Study.

OBJECTIVE: To evaluate whether a behavioral weight management program combined with a smoking cessation program delivered via interactive technology could prevent postcessation weight gain. METHODS: Three hundred and thirty young adult smokers, age 18 to 35 years, were randomized to a smoking cessation program alone (comparison group), which included behavioral counseling and nicotine replacement, or to a behavioral weight management program adapted from the Look AHEAD trial plus the same smoking cessation program (intervention group). RESULTS: The Treating Adult Smokers at Risk for Weight Gain with Interactive Technology study randomized 164 participants to the comparison group and 166 participants to the intervention group. On average, the participants gained 0.91 kg after 24 months in the trial (comparison group + 1.45 kg and intervention group + 0.32; P = 0.157). The only variable systematically affecting weight change over time was smoking abstinence, in which those who were abstinent, on average, gained 0.14 kg more per month compared with those who continued to smoke (P < 0.001). In exploratory analyses, the intervention participants who were abstinent at 6 months had numerically smaller weight gains compared with abstinent participants in the comparison group, but these differences were not statistically significant. CONCLUSIONS: Providing an intensive weight gain prevention program combined with a smoking cessation program via interactive technology was not associated with greater long-term weight gain prevention.

Low-Fat Dietary Pattern and Breast Cancer Mortality in the Women's Health Initiative Randomized Controlled Trial.

Purpose Earlier Women's Health Initiative Dietary Modification trial findings suggested that a low-fat eating pattern may reduce breast cancers with greater mortality. Therefore, as a primary outcome-related analysis from a randomized prevention trial, we examined the long-term influence of this intervention on deaths as a result of and after breast cancer during 8.5 years (median) of dietary intervention and cumulatively for all breast cancers diagnosed during 16.1 years (median) of follow-up. Patients and Methods The trial randomly assigned 48,835 postmenopausal women with normal mammograms and without prior breast cancer from 1993 to 1998 at 40 US clinical centers to a dietary intervention with goals of a reduction of fat intake to 20% of energy and an increased intake of fruits, vegetables, and grains (40%; n = 19,541) or to a usual diet comparison (60%; n = 29,294). Results In the dietary group, fat intake and body weight decreased (all P < .001). During the 8.5-year dietary intervention, with 1,764 incident breast cancers, fewer deaths occurred as a result of breast cancer in the dietary group, which was not statistically significant (27 deaths [0.016% per year] v 61 deaths [0.024% per year]; hazard ratio [HR], 0.67; 95% CI, 0.43 to 1.06; P = .08). During the same period, deaths after breast cancer (n = 134) were significantly reduced (40 deaths [0.025% per year] v 94 deaths [0.038% per year]; HR, 0.65; 95% CI, 0.45 to 0.94; P = .02) by the dietary intervention. During the 16.1-year follow-up, with 3,030 incident breast cancers, deaths after breast cancer also were significantly reduced (234 deaths [0.085% per year] v 443 deaths [0.11% per year]; HR, 0.82; 95% CI, 0.70 to 0.96; P = .01) in the dietary group. Conclusion Compared with a usual diet comparison group, a low-fat dietary pattern led to a lower incidence of deaths after breast cancer.

Step Care treatment for smoking cessation.

We compared the effectiveness of a 'stepped care' approach with increasing treatment intensity ('Step Care') to one with repeated treatments ('Recycle') among cigarette smokers interested in quitting smoking. Step 1 of the Step Care intervention consisted of a single counseling session, nicotine patch for six weeks and telephonic contact. For smokers not achieving tobacco abstinence 6 months after randomization with Step 1, the intensity of the intervention increased to four counseling sessions, bupropion sustained-release, nine telephone calls and three mailings (Step 2). For those not achieving tobacco abstinence 12 months after randomization, smokers received six behavioral counseling sessions, nicotine patch and nicotine gum, nine telephone calls and three mailings (Step 3). The Recycle participants received one session of health behavior counseling, six weeks of the nicotine patch and a telephone call at each step. 270 cigarette smokers were randomized. At 24 months after randomization using an intention to treat analysis, no statistically significant difference was observed in prolonged smoking abstinence between the Step Care and Recycle condition (16.9% versus 9.4%; adjusted OR = 1.88; 95% CI 0.88­4.01; P =0.10). Additional research is needed to explore whether a stepped care intervention increases long-term smoking abstinence rates compared with repeating the same intervention.

Age at presentation and management of pediatric intussusception: A Pediatric Health Information System database study.

BACKGROUND: Intussusception is uncommon in children older than 3 years, and use of enema reduction in older children is controversial. We sought to determine whether older children are at greater risk of requiring operative intervention and/or having pathology causing lead points, such that enema reduction should not be attempted. METHODS: The Pediatric Health Information System database was reviewed from January 1, 2009-June 30, 2014. Patients were followed for 6 months from initial presentation or until bowel resection occurred. Successful enema reduction was defined as having radiologic reduction without additional procedures. RESULTS: A total of 7,412 patients were identified: 6,681 were <3 years old, 731 patients were >3 years old. In those >3 years old, 450 (62%) were treated successfully with enema reduction; the rate of patients with a tumor diagnosis was similar in patients <3 years old and patients >3 years old (5% vs 6%, P = .07). The rate of a Meckel's diagnosis was greater in patients >3 years old (2% vs 14%, P < .0001). In patients >3 years old, duration of stay between patients who underwent primary operative therapy versus those who underwent operative therapy after enema reduction was similar (4 days vs 4 days, P = .06). Older age was not associated with increased risk of recurrent admission for intussusception (P = .45). CONCLUSION: Pediatric Health Information System data suggest that enema reduction may be safe and effective for a majority of children even if older than 3 years.

The Recruitment Experience of a Randomized Clinical Trial to Aid Young Adult Smokers to Stop Smoking without Weight Gain with Interactive Technology.

Multiple recruitment strategies are often needed to recruit an adequate number of participants, especially hard to reach groups. Technology-based recruitment methods hold promise as a more robust form of reaching and enrolling historically hard to reach young adults. The TARGIT study is a randomized two-arm clinical trial in young adults using interactive technology testing an efficacious proactive telephone Quitline versus the Quitline plus a behavioral weight management intervention focusing on smoking cessation and weight change. All randomized participants in the TARGIT study were required to be a young adult smoker (18-35 years), who reported smoking at least 10 cigarettes per day, had a BMI < 40 kg/m2, and were willing to stop smoking and not gain weight. Traditional recruitment methods were compared to technology-based strategies using standard descriptive statistics based on counts and proportions to describe the recruitment process from initial pre-screening (PS) to randomization into TARGIT. Participants at PS were majority Black (59.80%), female (52.66%), normal or over weight (combined 62.42%), 29.5 years old, and smoked 18.4 cigarettes per day. There were differences in men and women with respect to reasons for ineligibility during PS (p < 0.001; ignoring gender specific pregnancy-related ineligibility). TARGIT experienced a disproportionate loss of minorities during recruitment as well as a prolonged recruitment period due to either study ineligibility or not completing screening activities. Recruitment into longer term behavioral change intervention trials can be challenging and multiple methods are often required to recruit hard to reach groups.

Efficacy of a Tobacco Quitline in Active Duty Military and TRICARE Beneficiaries: A Randomized Trial.

A higher proportion of military personnel than civilians smoke cigarettes. Few randomized trials of tobacco use interventions have been conducted in the U.S. military. We evaluated the efficacy of a tobacco quitline (QL) in 1298 active duty military personnel, their dependents, reservists, and retirees who smoke cigarettes. Participants were randomized to either a proactive (counselor-initiated) or reactive (participant-initiated) QL intervention for 8 weeks. The proactive condition included up to an 8-week supply of free nicotine replacement therapy, and the reactive condition included a 2-week supply. The primary outcome was 12-month smoking abstinence. The enrolled population was predominantly affiliated with the Air Force and Army. At the end of treatment, proactive treatment was associated with a greater odds of both prolonged (44.22% vs. 24.96%; odds ratio [OR] = 2.4, P < 0.0001) and 7-day point prevalence (49.92% vs. 28.20%; OR = 2.5, P < 0.0001) smoking abstinence, a difference that was maintained for prolonged smoking abstinence at 12 months (22.03% vs. 13.41%; OR = 1.8, P < 0.0001). Our findings provide evidence that a proactive QL with nicotine replacement therapy is highly efficacious among Air Force and Army active duty and TRICARE beneficiaries and would provide an effective telephonic treatment option for this population of smokers.

Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.

IMPORTANCE: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. OBJECTIVE: To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent. EXPOSURES: Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. MAIN OUTCOMES AND MEASURES: Colorectal cancer. RESULTS: Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76). CONCLUSIONS AND RELEVANCE: In this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist.

Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonist of the type 2 G protein coupled receptor for lysophosphatidic acid (LPA2) 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl]benzoic acid (DBIBB) when administered with a postirradiation delay of up to 72 hr reduced mortality of C57BL/6 mice but not LPA2 knockout mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of γ-H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34(+) hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering from the hematopoietic acute radiation syndrome after total-body irradiation. DBIBB represents a drug candidate capable of mitigating acute radiation syndrome caused by high-dose γ-radiation to the hematopoietic and gastrointestinal system.

Association of cancer susceptibility variants with risk of multiple primary cancers: The population architecture using genomics and epidemiology study.

BACKGROUND: Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). METHODS: As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance. RESULTS: A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05-1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04-1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03-1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53). CONCLUSIONS: Our study has identified rs578776 and rs11249433 as risk variants for IMPC. IMPACT: These findings may help to identify genetic regions associated with IMPC risk.

Gene-environment interaction involving recently identified colorectal cancer susceptibility Loci.

BACKGROUND: Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer. Prior research has evaluated the presence of gene-environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279. METHODS: Data on 9,160 cases and 9,280 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR) were used to evaluate the presence of interaction involving the above-listed SNPs and sex, body mass index (BMI), alcohol consumption, smoking, aspirin use, postmenopausal hormone (PMH) use, as well as intake of dietary calcium, dietary fiber, dietary folate, red meat, processed meat, fruit, and vegetables. Interaction was evaluated using a fixed effects meta-analysis of an efficient Empirical Bayes estimator, and permutation was used to account for multiple comparisons. RESULTS: None of the permutation-adjusted P values reached statistical significance. CONCLUSIONS: The associations between recently identified genetic susceptibility loci and colorectal cancer are not strongly modified by sex, BMI, alcohol, smoking, aspirin, PMH use, and various dietary factors. IMPACT: Results suggest no evidence of strong gene-environment interactions involving the recently identified 16 susceptibility loci for colorectal cancer taken one at a time.