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Implausibly high algorithm-identified cancer incidence within a new user study after medication initiation may result from increased healthcare utilization (HU) around initiation ("catch-up care") that increases diagnostic opportunity. Understanding the relationships between HU prior to and around initiation and subsequent cancer rates and timing is important to avoiding protopathic bias.We identified a cohort of 417 458 Medicare beneficiaries (2007-2014) aged ≥66 initiating an antihypertensive (AHT) after ≥180 days of non-use. Initiators were stratified into groups of 0, 1, 2-3, and ≥4 outpatient visits (OV) 60-360 days before initiation. We calculated algorithm-identified colorectal cancer (aiCRC) rates stratified by OVs and time since AHT initiation: (0-90, 91-180, 181-365, 366-730, and 731+ days). We summarized HU -360/+60 days around AHT initiation by aiCRC timing: (0-29, 30-89, 90-179, and ≥180 days).AiCRC incidence (311 per 100 000 overall) peaked in the first 0-90 days, was inversely associated with HU before initiation, and stabilized ≥180 days after AHT initiation. Catch-up care was greatest among persons with aiCRCs identified30 days in follow-up. Catch-up care magnitude decreased as time to the aiCRC date increased, with aiCRCs identified ≥180 days after AHT initiation exhibiting similar HU compared with the full cohort.Lower HU before-and increased HU around AHT initiation-seem to drive excess short-term aiCRC incidence. Person-time and case accrual should only begin when incidence stabilizes. When comparison groups within a study differ by HU, outcome-detection bias may exist. Similar observations may exist in other settings when typical HU is delayed (e.g., cancer screening during SARS-CoV-2).

Risk of conventional adenomas and serrated polyps at year 1 associated with categories of circulating serum high sensitivity C-reactive protein levels.

Aspirin has been shown to protect against colorectal neoplasms; however, the optimal chemopreventive dose and underlying mechanisms are unclear. We aimed to study the relationship between prostanoid metabolites and aspirin's effect on adenoma occurrence. We used data from the Aspirin/Folate Polyp Prevention Study, in which 1,121 participants with a recent adenoma were randomized to placebo or two doses of aspirin (81 or 325 mg/d) to be taken until the next surveillance colonoscopy, anticipated about 3 years later. Urinary metabolites of prostanoids (PGE-M, PGI-M, and dTxB2) were measured using liquid chromatography/mass spectrometry or GC/NICI-MS in 876 participants near the end of treatment follow-up. Poisson regression with a robust error variance was used to calculate relative risks and 95% confidence intervals. PGE-M, PGI-M, and dTxB2 levels were 28%, 37%, and 60% proportionately lower, respectively, in individuals who took 325 mg of aspirin compared with individuals who took placebo (all P < 0.001). Similarly, among individuals who took 81 mg of aspirin, PGE-M, PGI-M, and dTxB2 were, respectively, 18%, 30%, and 57% proportionally lower compared with placebo (all P < 0.005). None of the metabolites or their ratios were statistically significantly associated with the risk of adenoma occurrence. The effect of aspirin in reducing adenoma risk was independent of prostanoid levels. Aspirin use is associated with lower levels of urinary prostanoid metabolites. However, our findings do not support the hypothesis that these metabolites are associated with adenoma occurrence, suggesting that COX-dependent mechanisms may not completely explain the chemopreventive effect of aspirin on colorectal neoplasms. Cancer Prev Res; 8(11); 1061–8. ©2015 AACR.

Supplementary Table 1. Urinary PGE-M, PGI-M and dTxB2 by subject characteristics*, the Aspirin/Folate Polyp Prevention Study. Supplementary Table 2. Urinary PGE-M, PGI-M and dTxB2* by subject characteristics in the placebo group, the Aspirin/Folate Polyp Prevention Study. Supplementary Table 3. Urinary PGE-M, PGI-M and dTxB2 ratios by aspirin treatment group, the Aspirin/Folate Polyp Prevention Study. Supplementary Table 4 Urinary PGE-M, PGI-M and dTxB2 levels (ng/mg creatinine) by aspirin and folic acid treatment group, the Aspirin/Folate Polyp Prevention Study. Supplementary Table 5. Association of adenoma occurrence during study treatment with the ratios of urinary prostanoids, the Aspirin/Folate Polyp Prevention Study. Supplementary Table 6. Association adenoma occurrence during study treatment with urinary PGE-M, PGI-M and dTxB2 levels in the placebo group, the Aspirin/Folate Polyp Prevention Study. Supplementary Table 7. Association adenoma occurrence during study treatment with urinary PGE-M, PGI-M and dTxB2 levels in men, the Aspirin/Folate Polyp Prevention Study. Supplementary Table 8. Association adenoma occurrence during study treatment with urinary PGE-M, PGI-M and dTxB2 levels in women, the Aspirin/Folate Polyp Prevention Study.

Epithelial–mesenchymal transition (EMT) is thought to be an important mechanism of cancer cell metastasis. Clinical measurement of EMT markers in primary tumors could improve risk stratification and treatment decisions by identifying patients who potentially have metastatic disease. To evaluate the potential of EMT markers that could be used for risk stratification for patients with colorectal cancer, we conducted a systematic review of studies (N = 30) that measured at least one of a selection of EMT markers in primary tumors and patient outcomes. Fifteen of 30 studies (50%) reported at least one statistically significant result supporting a role for one of the selected EMT markers in identifying patients at risk for worse outcomes. Importantly, however, we identified design inconsistencies that limited inferences and prevented meta-analysis of data. We offer a number of recommendations to make future studies more informative and standardized, including consistent sampling of different parts of the primary tumor, larger sample sizes, and measurement of both protein and RNA expression of a given EMT marker in the same tumors. Strengthening the literature per our recommendations could facilitate translating EMT markers to clinical use. Cancer Epidemiol Biomarkers Prev; 23(7); 1164–75. ©2014 AACR.

PDF - 51KB, Shows diagnosis and procedure codes used in the Danish health registries.

PDF file - 98K, This file presents the set of search terms we used as applied to PubMed. It provides information about the structure of the search and how it could be adapted to search for studies of EMT markers and patient outcomes in tumor sites other than colorectal cancer.

PDF - 80K, Family Health Promotion Project: Baseline Questionnaire used in trial.

PDF - 64KB, Supplementary table showing results for stroke subtypes.

Background: An association between colorectal cancer and acute myocardial infarction (AMI) and stroke has been suggested, but evidence is conflicting.Method: We conducted a population-based cohort study (1978–2010) of the association between AMI/stroke and colorectal cancer by linking nationwide Danish registries. We calculated standardized incidence ratios (SIR) of colorectal cancer after AMI/stroke as the ratios of observed to expected incidence.Results: A total of 297,523 patients with AMI (median age, 69.4 years; 64% men) were followed for a median of 3.1 years (range, 0–33 years) and 4,387 developed colorectal cancer [SIR, 1.08; 95% confidence interval (CI), 1.05–1.11; P < 0.001]. In the first year of follow-up, the SIR was 1.85 (95% CI, 1.73–1.98; P < 0.001), whereas it was 0.98 (95% CI, 0.95–1.02; P = 0.318) in the second and subsequent years. We followed 246,998 patients with stroke (median age, 72.4 years; 52% men) for a median of 2.9 years (range, 0–33 years) and 3,035 developed colorectal cancer (SIR, 1.04; 95% CI, 1.00–1.07; P = 0.053). In the first year of follow-up, the SIR was 1.42 (95% CI, 1.31–1.53; P < 0.001), whereas it was 0.96 (95% CI, 0.93–1.00; P = 0.072) thereafter. We found no difference between the SIRs for ischemic and hemorrhagic stroke. The increased one-year relative risks for AMI and stroke corresponded to a 0.3% absolute risk.Conclusions: Our findings reflect detection of occult cancer at the time of the vascular event. The lack of increased risk after one year suggests that an association based on shared risk factors or chronic inflammation is unlikely.Impact: In patients with AMI/stroke, the diagnostic workup including screening for colorectal cancer should follow that of the general population. Cancer Epidemiol Biomarkers Prev; 22(11); 1994–9. ©2013 AACR.

Background: Individuals with a strong family history of colorectal cancer have significant risk for colorectal cancer, although adherence to colonoscopy screening in these groups remains low. This study assessed whether a tailored telephone counseling intervention can increase adherence to colonoscopy in members of high-risk families in a randomized, controlled trial.Methods: Eligible participants were recruited from two national cancer registries if they had a first-degree relative with colorectal cancer under age 60 or multiple affected family members, which included families that met the Amsterdam criteria for hereditary non-polyposis colon cancer (HNPCC), and if they were due for colonoscopy within 24 months. Participants were randomized to receive a tailored telephone intervention grounded in behavioral theory or a mailed packet with general information about screening. Colonoscopy status was assessed through follow-up surveys and endoscopy reports. Cox proportional hazards models were used to assess intervention effect.Results: Of the 632 participants (ages 25–80), 60% were female, the majority were White, non-Hispanic, educated, and had health insurance. Colonoscopy adherence increased 11 percentage points in the tailored telephone intervention group, compared with no significant change in the mailed group. The telephone intervention was associated with a 32% increase in screening adherence compared with the mailed intervention (HR, 1.32; P = 0.01).Conclusions: A tailored telephone intervention can effectively increase colonoscopy adherence in high-risk persons. This intervention has the potential for broad dissemination to healthcare organizations or other high-risk populations.Impact: Increasing adherence to colonoscopy among persons with increased colorectal cancer risk could effectively reduce incidence and mortality from this disease. Cancer Epidemiol Biomarkers Prev; 23(4); 601–10. ©2014 AACR.

Supplementary Tables and Methods.

ECT2 is an activator of RHO GTPases that is essential for cytokinesis. In addition, ECT2 was identified as an oncoprotein when expressed ectopically in NIH/3T3 fibroblasts. However, oncogenic activation of ECT2 resulted from N-terminal truncation, and such truncated ECT2 proteins have not been found in patients with cancer. In this study, we observed elevated expression of full-length ECT2 protein in preneoplastic colon adenomas, driven by increased ECT2 mRNA abundance and associated with APC tumor-suppressor loss. Elevated ECT2 levels were detected in the cytoplasm and nucleus of colorectal cancer tissue, suggesting cytoplasmic mislocalization as one mechanism of early oncogenic ECT2 activation. Importantly, elevated nuclear ECT2 correlated with poorly differentiated tumors, and a low cytoplasmic:nuclear ratio of ECT2 protein correlated with poor patient survival, suggesting that nuclear and cytoplasmic ECT2 play distinct roles in colorectal cancer. Depletion of ECT2 reduced anchorage-independent cancer cell growth and invasion independent of its function in cytokinesis, and loss of Ect2 extended survival in a KrasG12D Apc-null colon cancer mouse model. Expression of ECT2 variants with impaired nuclear localization or guanine nucleotide exchange catalytic activity failed to restore cancer cell growth or invasion, indicating that active, nuclear ECT2 is required to support tumor progression. Nuclear ECT2 promoted ribosomal DNA transcription and ribosome biogenesis in colorectal cancer. These results support a driver role for both cytoplasmic and nuclear ECT2 overexpression in colorectal cancer and emphasize the critical role of precise subcellular localization in dictating ECT2 function in neoplastic cells.Significance:ECT2 overexpression and mislocalization support its role as a driver in colon cancer that is independent from its function in normal cell cytokinesis.

Supplementary Figures S1-S4

Background Despite highly effective therapies, many children develop medically refractory ulcerative colitis (UC) and undergo proctocolectomy with ileal pouch–anal anastomosis (IPAA). We sought to determine the incidence, risk, and burden of pouchitis in the first 2 years following the final stage of IPAA in pediatric UC patients. Methods Within the IQVIA Legacy PharMetrics Adjudicated Claims Database, we identified pediatric patients with UC who underwent proctocolectomy with IPAA between January 1, 2007, and June 30, 2015. We utilized International Classification of Diseases–Ninth Revision–Clinical Modification or International Classification of Diseases–Tenth Revision–Clinical Modification codes to identify patients with UC and Current Procedural Terminology codes to identify colectomy and IPAA. Continuous variables were compared using t tests and Wilcoxon rank sum testing, while categorical variables were compared using chi-square testing. Results A total of 68 patients with an IPAA were identified. In the first 2 years following IPAA, the cumulative incidence of pouchitis was 54%. Patients with pouchitis required more outpatient visits in the first 2 years after IPAA (mean 21.8 vs 10.2; P = .006) and were more likely to be hospitalized compared with patients without pouchitis (46% vs 23%; P = .045). Patients with pouchitis also demonstrated higher mean total costs in year 1 and year 2 ($27 489 vs $8032 [P = .001] and $27 699 vs $6058 [P = .003], respectively). Conclusions Our findings confirm the high incidence of pouchitis demonstrated in earlier single-center studies of pediatric patients undergoing proctocolectomy with IPAA for UC. Identification of risk factors for pouchitis would be useful to optimize early intervention.

Background Fatigue is a disabling symptom in patients with inflammatory bowel disease (IBD). Its prevalence, mechanism, and impact remain poorly understood. We determined changes in fatigue status over time and identified predictors of incident or resolving fatigue. Methods This was a prospective study nested within the IBD Partners cohort. Participants prospectively completed the Multidimensional Fatigue Inventory and the Functional Assessment of Chronic Illness Therapy-Fatigue at baseline, 6 months, and 12 months. A Functional Assessment of Chronic Illness Therapy-Fatigue score ≤43 defined significant fatigue. Multivariable regression models using baseline covariates were used to identify risk factors for incident fatigue at 6 months and to predict the resolution of fatigue. Results A total of 2429 patients (1605 with Crohn disease, 824 with ulcerative colitis) completed a baseline assessment, and 1057 completed a second assessment at 6 months. Persistent fatigue (at baseline and at 6 months) was the most common pattern, affecting two-thirds (65.8%) of patients. One-sixth (15.7%) of patients had fatigue at 1 timepoint, whereas fewer than one-fifth (18.5%) of patients never reported fatigue. Among patients not fatigued at baseline, 26% developed fatigue at 6 months. The strongest predictor of incident fatigue was sleep disturbance at baseline (odds ratio, 2.91; 95% confidence interval, 1.48–5.72). In contrast, only 12.3% of those with fatigue at baseline had symptom resolution by month 6. Resolution was more likely in patients with a diagnosis of ulcerative colitis, quiescent disease, and an absence of significant psychological comorbidity. Conclusions Fatigue is common in patients with IBD. However, only a few fatigued patients experience symptom resolution at 6 or 12 months, suggesting the need for novel interventions to ameliorate its impact.

Background The comparative effectiveness of trimodality therapy vs definitive chemoradiation for treating locally advanced esophageal cancer in older adults is uncertain. Existing trials lack generalizability to older adults, a population with heightened frailty. We sought to emulate a hypothetical trial comparing these treatments using real-world data. Methods A cohort of adults aged 66-79 years diagnosed with locally advanced esophageal cancer between 2004 and 2017 was identified in the Surveillance Epidemiology and End Results–Medicare database. The clone-censor-weight method was leveraged to eliminate time-related biases when comparing outcomes between treatments. Outcomes included overall mortality, esophageal cancer–specific mortality, functional adverse events, and healthy days at home. Results A total of 1240 individuals with adenocarcinomas and 661 with squamous cell carcinomas were identified. For adenocarcinomas, the standardized 5-year risk of mortality was 73.4% for trimodality therapy and 83.8% for definitive chemoradiation (relative risk [RR] = 0.88, 95% confidence interval [CI] = 0.82 to 0.95). Trimodality therapy was associated with mortality risk reduction for squamous cell carcinomas (RR = 0.87, 95% CI = 0.70 to 1.01). The 1-year incidence of functional adverse events was higher in the trimodality group (adenocarcinomas RR = 1.40, 95% CI = 1.22 to 1.65; squamous cell carcinomas RR = 1.21, 95% CI = 1.00 to 1.49). Over 5 years, trimodality therapy was associated with 160 (95% CI = 67 to 229) and 177 (95% CI = 51 to 313) additional home days in individuals with adenocarcinomas and squamous cell carcinomas, respectively. Conclusions Compared with definitive chemoradiation, trimodality therapy was associated with reduced mortality but increased risk of function-related adverse events. Discussing these tradeoffs may help optimize care plans.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are thought to protect against colorectal adenoma (CRA) development. We aimed to further understand the underlying mechanisms by examining the relationships between ω-3 PUFAs and the gut microbiota on CRAs. We assessed the mucosal microbiota via bacterial 16S rRNA sequencing among 217 CRA cases and 218 controls who completed PUFA intake questionnaires. The overall microbial composition was assessed by α-diversity measurements (diversity, richness, and evenness). Global metabolomics was conducted using a random subset of case–control pairs (n = 50). We compared microbiota and metabolite signatures between cases and controls according to fold change (FC). Odds ratios (OR) and confidence intervals (CI) were estimated from logistic regression for associations of ω-3 PUFAs and the microbiota with CRAs. We observed an inverse association between overall ω-3 PUFA intake and CRAs, especially for short-chain ω -3 PUFAs (OR = 0.45, 95% CI: 0.21, 0.97). Such inverse associations were modified by bacterial evenness (p-interaction = 0.03). Participants with higher levels (FC > 2) of bile acid-relevant metabolites were more likely to have CRAs than the controls, and the correlation between bile acids and bacterial diversity differed by case–control status. Our findings suggest that ω-3 PUFAs are inversely associated with CRA development, and the association may be modified by gut microbiota profiles.

Since the early 2010s, neoadjuvant chemoradiation followed by esophagectomy (trimodal therapy) has been a recommended treatment for patients diagnosed with locally advanced esophageal cancer. However, it may also add treatment-related toxicity, particularly for older adults with significant comorbidity and frailty burdens. We examined contemporary patterns of care in older adults, which have not been well characterized.We used the Surveillance Epidemiology and End Results-Medicare database to identify a cohort of US adults aged 66 years and older diagnosed with incident locally advanced esophageal cancer between 2004 and 2017. Calendar year age-standardized percentages of treatment receipt were calculated. Joinpoint regression was used to detect temporal trends in treatment receipt. Descriptive associations between patient factors and treatment were assessed. Trend analyses quantified how the percentage of trimodal and definitive chemoradiation (no surgery) patients receiving cisplatin-based, carboplatin-based, and other chemotherapy regimens evolved over time.In total, 4332 adults aged ≥66 years with locally advanced esophageal cancer were included. The age-standardized percentage of patients receiving trimodal therapy increased from 16.7% in 2004 to 26.1% in 2017 (annual percent change = 3.5%; 95% confidence interval [CI], 0.7%-6.4%) in adenocarcinomas and from 7.3% in 2004 to 9.1% in 2017 (annual percent change = 0.4%; 95% CI, -4.1%-5.1%) in squamous cell carcinomas. By 2017, definitive chemoradiation became the most frequently used treatment modality for adenocarcinomas (49.8%; 95% CI, 43.5-56.0) and squamous cell carcinomas (59.5%; 95% CI, 50.8-68.2). Patients with higher comorbidity and frailty burdens were less likely to be treated with trimodal therapy. Amongst patients receiving chemoradiation as part of their treatment, a large and swift channeling away from cisplatin and towards carboplatin-based regimens was observed.In practice, definitive chemoradiation is the most commonly received treatment by older adults with locally advanced esophageal cancer. Four out of five older adults do not receive trimodal therapy, some of whom are potentially undertreated.

BACKGROUND AND OBJECTIVEMicroscopic colitis is a relatively common cause of chronic diarrhea and may be linked to luminal factors. Given the essential role of the microbiome in human gut health, analysis of microbiome changes associated with microscopic colitis could provide insights into the development of the disease.METHODSWe enrolled patients who underwent colonoscopy for diarrhea. An experienced pathologist classified patients as having microscopic colitis (n=52) or controls (n=153). Research biopsies were taken from the ascending and descending colon, and the microbiome was characterized with Illumina sequencing. We analyzed the associations between microscopic colitis and microbiome with a series of increasingly complex models adjusted for a range of demographic and health factors.RESULTSWe found that alpha-diversity was significantly lower in microscopic colitis cases compared to controls in the descending colon microbiome. In the descending colon, a series of models that adjusted for an increasing number of co-variates found taxa significantly associated with microscopic colitis, including Proteobacteria that was enriched in cases and Collinsella enriched in controls. While the alpha-diversity and taxa were not significantly associated with microscopic colitis in the ascending colon microbiome, the inference p-values based on ascending and descending microbiomes were highly correlated.CONCLUSIONOur study demonstrates an altered microbiome in microscopic colitis cases compared to controls. Because both the cases and controls had diarrhea, we have identified candidate taxa that could be mechanistically responsible for the development of microscopic colitis independent of changes to the microbial community caused by diarrhea.Significance of this studyWhat is already known about this subject?Microscopic colitis is a common cause of chronic diarrhea. The exact etiology of microscopic colitis is unknown, but the gut microbiome is considered to play an important role.Prior studies have reported microbial changes associated with microscopic colitis, but the results are not consistent. Prior studies have generally involved small numbers of patients, fecal samples, and comparison to healthy controls.What are the new findings?The microbiome was altered in microscopic colitis patients.Microscopic colitis was associated with lower alpha-diversity, increase of inflammation related taxa and decrease of Collinsella in the descending colon microbiome independent of diarrhea status.The changes of microbial features were consistent between ascending and descending colon microbiomes, but with smaller changes in the ascending colon microbiome.How might it impact on clinical practice in the foreseeable future?The altered microbial communities in patients with microscopic colitis suggest that the patients might benefit from prevention or treatment with live biotherapeutic products.

ECT2 is an activator of RHO GTPases that is essential for cytokinesis. In addition, ECT2 was identified as an oncoprotein when expressed ectopically in NIH/3T3 fibroblasts. However, oncogenic activation of ECT2 resulted from N-terminal truncation, and such truncated ECT2 proteins have not been found in patients with cancer. In this study, we observed elevated expression of full-length ECT2 protein in preneoplastic colon adenomas, driven by increased ECT2 mRNA abundance and associated with APC tumor-suppressor loss. Elevated ECT2 levels were detected in the cytoplasm and nucleus of colorectal cancer tissue, suggesting cytoplasmic mislocalization as one mechanism of early oncogenic ECT2 activation. Importantly, elevated nuclear ECT2 correlated with poorly differentiated tumors, and a low cytoplasmic:nuclear ratio of ECT2 protein correlated with poor patient survival, suggesting that nuclear and cytoplasmic ECT2 play distinct roles in colorectal cancer. Depletion of ECT2 reduced anchorage-independent cancer cell growth and invasion independent of its function in cytokinesis, and loss of Ect2 extended survival in a KrasG12D Apc-null colon cancer mouse model. Expression of ECT2 variants with impaired nuclear localization or guanine nucleotide exchange catalytic activity failed to restore cancer cell growth or invasion, indicating that active, nuclear ECT2 is required to support tumor progression. Nuclear ECT2 promoted ribosomal DNA transcription and ribosome biogenesis in colorectal cancer. These results support a driver role for both cytoplasmic and nuclear ECT2 overexpression in colorectal cancer and emphasize the critical role of precise subcellular localization in dictating ECT2 function in neoplastic cells. Significance: ECT2 overexpression and mislocalization support its role as a driver in colon cancer that is independent from its function in normal cell cytokinesis.

Background: The most common complication following ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC) is pouchitis. Our study aimed to investigate the relationship between histopathologic findings of ileitis, granuloma, or transmural inflammation on the colectomy specimen of patients with clinically and endoscopically diagnosed UC and the development of pouchitis within the first 2 years after IPAA. Methods: We performed a retrospective cohort study evaluating patients undergoing colectomy with IPAA for UC between January 1, 2004 and December 31, 2016. Bivariate analyses were conducted to evaluate the relationship between clinical factors and the development of pouchitis. We performed multivariate logistic regression to evaluate the relationship between histologic, clinical, and demographic factors at the time of colectomy and subsequent development of pouchitis. Results: Among 626 patients, pouchitis occurred in 246 (39%). Patients with primary sclerosing cholangitis were more likely to develop pouchitis (adjusted odds ratio [aOR] 2.81, 95% confidence interval [CI] 1.02–7.72), as were patients with a family history of inflammatory bowel disease (aOR 1.75, 95% CI 1.11–2.77). Histologic findings of ileitis, granuloma, or transmural inflammation were not associated with an increased odds of developing pouchitis (aOR 0.70, 95% CI 0.45–1.08). Discussion/Conclusion: Patients with ileitis, granulomas, or transmural inflammation at the time of colectomy were not at greater risk for development of pouchitis in the 2 years after IPAA. These pathological findings should not preclude IPAA for UC.

BACKGROUND AND AIMS: Confounding is a major concern in nonexperimental studies of endoscopic interventions and can lead to biased estimates of the effects of treatment. Propensity score methods, which are commonly used in the pharmacoepidemiology literature, can effectively control for baseline confounding by balancing measured baseline confounders and risk factors and creating comparable populations of treated and untreated patients. METHODS: We propose the following 5-step checklist to guide the use and evaluation of propensity score methods: (1) select covariates; (2) assess covariate balance in risk factors before propensity score implementation; (3) estimate and implement the propensity score in the study cohort; (4) re-assess covariate balance in risk factors after propensity score implementation; and (5) critically evaluate differences between matched and unmatched patients after propensity score implementation. We then apply this checklist to an endoscopy example using a study cohort of 411 adults with newly diagnosed eosinophilic esophagitis (EoE), some of whom were treated with esophageal dilation. RESULTS: We identified 156 patients, aged 18 and older, who were treated with esophageal dilation, and 255 patients who were nondilated. We successfully matched 148 (95%) dilated patients to nondilated patients who had a propensity score within 0.1, based on patient age, sex, race, self-reported food allergy, and presence of narrowing at baseline endoscopy. Crude imbalances were observed before propensity score matching in several baseline covariates, including age, sex, and narrowing; however, propensity score matching was successful in achieving balance across all measured covariates. CONCLUSIONS: We provide an introduction to propensity score methods, including a straightforward checklist for implementing propensity score methods in nonexperimental studies of treatment effectiveness. Moreover, we demonstrate the advantage of using the typical patient characteristics table as a simple but effective diagnostic tool for evaluating the success of propensity score methods in an applied example of esophageal dilation in EoE.

This article reviews epidemiological evidence of heritability and putative mechanisms in diverticular disease, with greatest attention to 3 recent studies of genetic associations with diverticular disease based on genome-wide or whole-genome sequencing studies in large patient cohorts. We provide an analysis of the biological plausibility of the significant associations with gene variants reported and highlight the relevance of ANO1, CPI-17 (aka PPP1R14A), COLQ6, COL6A1, CALCB or CALCA, COL6A1, ARHGAP15, and S100A10 to colonic neuromuscular function and tissue properties that may result in altered compliance and predispose to the development of diverticular disease. Such studies also identify candidate genes for future studies. Keywords: Diverticulum, Diverticulitis, Diverticular Hemorrhage

Background & Aims Increasing rates of young-onset colorectal cancer (CRC) have attracted substantial research and media attention, but we know little about racial disparities among younger adults with CRC. We examined racial disparities in young-onset CRC by comparing CRC incidence and relative survival among younger ( Methods Using data from the Surveillance, Epidemiology, and End Results program of cancer registries, we estimated CRC incidence rates (per 100,000 persons 20–49 years old) from 1992 through 2014 for different periods (1992–1996 vs 2010–2014) and races (white vs black). Relative survival was calculated as the ratio of observed survival to expected survival in a comparable cancer-free population. Results From 1992–1996 to 2010–2014, CRC incidence increased from 7.5 to 11.0 per 100,000 in white individuals and from 11.7 to 12.7 per 100,000 in black individuals. The increase in rectal cancer was larger in whites (from 2.7 to 4.5 per 100,000) than in blacks (from 3.4 to 4.0 per 100,000); in the 2010–2014 period, blacks and whites had similar rates of rectal cancer. Compared with whites, blacks had smaller increases in relative survival with proximal colon cancer but larger increases in survival with rectal cancer (from 55.3% to 70.8%). Conclusion In an analysis of the Surveillance, Epidemiology, and End Results database, we found racial disparities in incidence of young-onset CRC and patient survival for cancer of the colon but minimal difference for rectal cancer. Well-documented and recent increases in young-onset CRC have largely been due to increases in rectal cancer, especially in whites.

Background Gastrointestinal diseases account for considerable health care use and expenditures. We estimated the annual burden, costs, and research funding associated with gastrointestinal, liver, and pancreatic diseases in the United States. Methods We generated estimates using data from National Ambulatory Medical Care Survey, National Hospital Ambulatory Medical Care Survey, Nationwide Emergency Department Sample, National Inpatient Sample, Kids’ Inpatient Database, Nationwide Readmissions Database, Surveillance, Epidemiology, and End Results program, National Vital Statistics System, Centers for Disease Control Wide-ranging Online Data for Epidemiologic Research, MarketScan Commercial Claims and Encounters data, MarketScan Medicare Supplemental data, United Network for Organ Sharing registry, Medical Expenditure Panel Survey, and National Institutes of Health. Results Gastrointestinal health care expenditures totaled $119.6 billion dollars in 2018. Annually, there were more than 36.8 million ambulatory visits for gastrointestinal symptoms and 43.4 million ambulatory visits with a primary gastrointestinal diagnosis. Hospitalizations for a principal gastrointestinal diagnosis accounted for more than 3.8 million admissions with 403,699 readmissions. A total of 22.2 million gastrointestinal endoscopies were performed and 284,844 new gastrointestinal cancers diagnosed. Gastrointestinal diseases and cancers caused 255,407 deaths. The National Institutes of Health supported $3.1 billion dollars (7.5% of the NIH budget) for gastrointestinal research in 2020. Conclusion Gastrointestinal diseases are responsible for millions of health care encounters and hundreds of thousands of deaths which annually costs billions of dollars in the US. To reduce the high burden of gastrointestinal diseases, focused clinical and public health efforts, supported by additional research funding, are warranted.

Pouchitis, the most common long-term complication after colectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC), can lead to increased health care costs and diminished quality of life.1 In this study, we aimed to compare the total costs among patients diagnosed with pouchitis in the first 2 years after an IPAA with those among patients who were not diagnosed with pouchitis, using a large administrative claims database. Additionally, we aimed to investigate the specific drivers of cost among patients with an IPAA during the 2-year study period, including inpatient hospitalizations, emergency department visits, and pharmacy-related costs.

Background Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite. Methods Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite. Results Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27; P = .04). Conclusion In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.

Background & Aims Despite the increased numbers of older adults with inflammatory bowel diseases (IBDs), there are few studies regarding the safety and effectiveness of IBD treatments in older adults. The aim of this study was to compare the safety and effectiveness of anti–tumor necrosis factor (TNF)-α agents and vedolizumab in older adults with IBD. Methods We conducted a retrospective cohort study using an active comparator, new-user design for adults age 65 years and older with IBD initiating anti–TNF-α agents and vedolizumab in the Medicare claims database from 2014 to 2017. The primary safety outcome was infection-related hospitalization (excluding intra-abdominal and perianal abscesses). Co-primary outcomes to estimate effectiveness were IBD-related hospitalization, IBD-related surgery, and new corticosteroid use 60 days or more after biologic initiation. We performed propensity score weighting to control for confounding and estimated adjusted hazard ratios and 95% CIs using standardized morbidity ratio–weighted variables. Results We identified 1152 anti–TNF-α new users and 480 vedolizumab new users. The median age was 71 years in both cohorts and 11% were age 80 years or older. Crohn’s disease patients comprised 54% of the anti–TNF-α cohort and 57% of the vedolizumab cohort. There was no significant difference in demographics, health care utilization, or frailty in both cohorts. More than half of both cohorts had a Charlson comorbidity index of 2 or higher. Vedolizumab users had a decreased risk of infection-related hospitalization (adjusted hazard ratio, 0.47; 95% CI, 0.25–0.86). There was no significant difference in the outcomes approximating effectiveness. Conclusions Older IBD patients treated with vedolizumab had a lower risk of infection-related hospitalization compared with those initiating anti-TNFs. We observed no difference in effectiveness defined by hospitalizations, surgery, or new corticosteroid use.

e16093 Background: The comparative effectiveness of trimodal therapy versus definitive chemoradiation for older adults with locally advanced esophageal cancer is uncertain. Only two randomized trials have considered this comparison, and older adults and patients with adenocarcinomas were underrepresented. Older adults have greater frailty and may not benefit from adding surgery to chemoradiation. Methods: A cohort of adults 66-79 years of age diagnosed with incident locally advanced esophageal cancer between 2004 and 2017 was identified using the Surveillance Epidemiology and End Results-Medicare database. We used observational data to emulate a hypothetical trial comparing trimodal therapy and definitive chemoradiation. Outcomes included overall mortality, esophageal cancer-specific mortality, functional adverse events, and healthy days at home. Results: The study population included 1,240 individuals with adenocarcinomas and 661 with squamous cell carcinomas. Amongst older adults diagnosed with adenocarcinomas, the five-year risk of mortality was 73.4% (95% CI: 69.1–77.4) in the trimodal therapy group and 83.8% (95% CI: 78.6–87.2) in the definitive chemoradiation group (RR= 0.88, 95% CI: 0.82–0.95). Amongst older adults diagnosed with squamous cell carcinomas, the five-year risk of mortality was 62.6% (95% CI: 50.9–73.5) in the trimodal therapy group and 72.3% (95% CI: 67.6–76.3) in the definitive chemoradiation group (RR= 0.87, 95% CI: 0.70–1.01). Results for all outcomes are presented in the Table. Conclusions: Trimodal therapy was associated with lower mortality than definitive chemoradiation. The benefits were smaller than suggested by prior observational studies. These findings can be used with clinical expertise and patient preferences to enhance shared decision-making. [Table: see text]

Background & Aims This study compared the effectiveness of the Specific Carbohydrate Diet (SCD) to the Mediterranean diet (MD) as treatment for Crohn's disease (CD) with mild to moderate symptoms. Methods Adult patients with CD and with mild-to-moderate symptoms were randomly assigned 1:1 to consume the MD or SCD for 12 weeks. For the first 6 weeks, participants received prepared meals and snacks according to their assigned diet. After 6 weeks, participants were instructed to follow the diet independently. The primary outcome was symptomatic remission at week 6. Key secondary outcomes at week 6 included fecal calprotectin (FC) response (FC 50% among those with baseline FC >250 μg/g) and C-reactive protein (CRP) response (high-sensitivity CRP 50% reduction from baseline among those with high-sensitivity CRP >5 mg/L). Results The study randomized 194 patients, and 191 were included in the efficacy analyses. The percentage of participants who achieved symptomatic remission at week 6 was not superior with the SCD (SCD, 46.5%; MD, 43.5%; P = .77). FC response was achieved in 8 of 23 participants (34.8%) with the SCD and in 4 of 13 participants (30.8%) with the MD (P = .83). CRP response was achieved in 2 of 37 participants (5.4%) with the SCD and in 1 of 28 participants (3.6%) with the MD (P = .68). Conclusions The SCD was not superior to the MD to achieve symptomatic remission, FC response, and CRP response. CRP response was uncommon. Given these results, the greater ease of following the MD and other health benefits associated with the MD, the MD may be preferred to the SCD for most patients with CD with mild to moderate symptoms. ClinicalTrials.gov Identifier: NCT03058679

Background Outpatient diverticulitis is commonly treated with either a combination of metronidazole and a fluoroquinolone (metronidazole-with-fluoroquinolone) or amoxicillin-clavulanate alone. The U.S. Food and Drug Administration advised that fluoroquinolones be reserved for conditions with no alternative treatment options. The comparative effectiveness of metronidazole-with-fluoroquinolone versus amoxicillin-clavulanate for diverticulitis is uncertain. Objective To determine the effectiveness and harms of metronidazole-with-fluoroquinolone versus amoxicillin-clavulanate for outpatient diverticulitis. Design Active-comparator, new-user, retrospective cohort studies. Setting Nationwide population-based claims data on U.S. residents aged 18 to 64 years with private employer-sponsored insurance (2000 to 2018) or those aged 65 years or older with Medicare (2006 to 2015). Participants Immunocompetent adults with diverticulitis in the outpatient setting. Intervention Metronidazole-with-fluoroquinolone or amoxicillin-clavulanate. Measurements 1-year risks for inpatient admission, urgent surgery, and Clostridioides difficile infection (CDI) and 3-year risk for elective surgery. Results In MarketScan (IBM Watson Health), new users of metronidazole-with-fluoroquinolone (n = 106 361) and amoxicillin-clavulanate (n = 13 160) were identified. There were no differences in 1-year admission risk (risk difference, 0.1 percentage points [95% CI, -0.3 to 0.6]), 1-year urgent surgery risk (risk difference, 0.0 percentage points [CI, -0.1 to 0.1]), 3-year elective surgery risk (risk difference, 0.2 percentage points [CI, -0.3 to 0.7]), or 1-year CDI risk (risk difference, 0.0 percentage points [CI, -0.1 to 0.1]) between groups. In Medicare, new users of metronidazole-with-fluoroquinolone (n = 17 639) and amoxicillin-clavulanate (n = 2709) were identified. There were no differences in 1-year admission risk (risk difference, 0.1 percentage points [CI, -0.7 to 0.9]), 1-year urgent surgery risk (risk difference, -0.2 percentage points [CI, -0.6 to 0.1]), or 3-year elective surgery risk (risk difference, -0.3 percentage points [CI, -1.1 to 0.4]) between groups. The 1-year CDI risk was higher for metronidazole-with-fluoroquinolone than for amoxicillin-clavulanate (risk difference, 0.6 percentage points [CI, 0.2 to 1.0]). Limitation Residual confounding is possible, and not all harms associated with these antibiotics, most notably drug-induced liver injury, could be assessed. Conclusion Treating diverticulitis in the outpatient setting with amoxicillin-clavulanate may reduce the risk for fluoroquinolone-related harms without adversely affecting diverticulitis-specific outcomes. Primary funding source National Institutes of Health.

BACKGROUND AND AIMS Anesthesia services for endoscopic procedures have proliferated with the promise of increased comfort and safety. Cirrhosis patients are higher risk for sedation, yet limited data are available describing anesthesia complications in this population. APPROACH AND RESULTS This cross-sectional study utilized the National Anesthesia Clinical Outcomes Registry, a multicenter quality-improvement database from 2010 to 2015. Patients with cirrhosis undergoing an endoscopy were identified by International Classification of Diseases, Ninth Revision (ICD-9)/Current Procedures Terminology (CPT) codes. The outcome of interest was serious anesthesia-related complication defined as cardiovascular, respiratory, neurological, drug related, patient injury, death, or unexpected admission. A mixed-effects multivariate logistic regression model determined odds ratios (ORs) between variables and serious complications, adjusting for potential confounders. In total, 9,007 endoscopic procedures were performed among patients with cirrhosis; 92% were esophagogastroduodenoscopies. The majority (81%) were American Society of Anesthesiologists (ASA) class ≥3, and 72% had a history of hepatic encephalopathy, ascites, varices, hepatorenal syndrome, or spontaneous bacterial peritonitis identified by ICD-9/CPT codes. In total, 87 complications were reported, 33 of which were serious. Frequency of serious complications was 0.4% or 378.6 per 100,000 procedures (95% confidence interval [CI], 260.8, 531.3). The majority of serious complications were cardiovascular (21 of 33), including 15 cardiac arrests. Serious complications were significantly associated with ASA 4/5 (OR, 3.84; 95% CI, 1.09, 13.57) and general anesthesia (OR, 4.71; 95% CI, 1.20, 18.50), adjusting for age, sex, ASA class, anesthesia type, inpatient status, portal hypertension history, and variable complication reporting practices. CONCLUSIONS Anesthesia complications among endoscopic procedures in cirrhosis are rare overall. Serious complications were predominantly cardiac and associated with sicker patients undergoing general anesthesia. The complexity of end-stage liver disease may warrant more intensive care during endoscopic procedures, including anesthesia monitoring.

Background Prior studies have identified racial disparities in the treatment and outcomes of inflammatory bowel disease (IBD). These disparities could be secondary to differences in biology, care delivery, or access to appropriate therapy. The primary aim of this study was to compare medication use among Medicaid-insured black and white patients with IBD, given uniform access to gastroenterologists and therapies. Methods We analyzed Medicaid Analytic eXtract data from 4 states (California, Georgia, North Carolina, and Texas) between 2006 and 2011. We compared the use of IBD-specific therapies, including analyses of postoperative therapy among patients with Crohn disease (CD). We performed bivariate analyses and multivariable logistic regression, adjusting for potential confounders. Results We identified 14,735 patients with IBD (4672 black [32%], 8277 with CD [58%]). In multivariable analysis, there was no significant difference in the odds of anti-tumor necrosis factor use by race for CD (adjusted odds ratio [aOR] = 1.13; 95% confidence interval [CI], 0.99-1.28] or ulcerative colitis (aOR = 1.12; 95% CI, 0.96-1.32). Black patients with CD were more likely than white patients to receive combination therapy (aOR = 1.50; 95% CI, 1.15-1.96), and black patients were more likely than white patients to receive immunomodulator monotherapy after surgery for CD (31% vs 18%; P = 0.004). Conclusions In patients with Medicaid insurance, where access to IBD-specific therapy should be similar for all individuals, there was no significant disparity by race in the utilization of IBD-specific therapies. Disparities in IBD treatment discussed in prior literature seem to be driven by socioeconomic or other issues affecting access to care.