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AbstractBackgroundRepresentation trends of women, older adults, and ethnic/racial minorities in randomized controlled trials (RCTs) of atrial fibrillation (AF) are uncertain.MethodsWe systematically reviewed 134 AF related RCTs (phase II and III) encompassing 149,162 participants using Medline and ClinicalTrials.gov through April 2019 to determine representation trends of women, older patients (≥75 years), and ethnic/racial minorities. Weighted data on the prevalence of AF from epidemiological studies were used to compare the representation of the studied groups of interest in AF RCTs to their expected burden of the disease.ResultsOnly 18.7% of the RCTs reported proportion of older patients, and 12.7% RCTs reported ethnic/racial minorities. The proportions of women in RCTs versus general population were 35.2% and 35.1%, of Hispanics were 11.9% and 5.2%, of Blacks were 1.2% and 5.7%, of American Indian/Alaskans were 0.2% and 0.2%, of Asians were 14.2% and 2.4%, of native Hawaiian/Pacific Islanders were 0.05% and 0.1% and of non‐Whites were 19.5% and 22.5%, respectively. The weighted mean age (SD) across the trials was 65.3 (3.2) years which was less than the corresponding weighted mean age of 71.1 (4.5) years in the comparative epidemiological data.ConclusionThe reporting of older patients and ethnic/racial minorities was poor in RCTs of AF. The representation of women and American Indian/Alaskan natives matched their expected population share of disease burden. Hispanics and Asians were over‐represented and Blacks, native Hawaiian/Pacific Islanders and non‐Whites were under‐represented in RCTs of AF.

Abstract Aims Anticoagulants are the mainstay treatment for stroke prevention in patients with non-valvular atrial fibrillation (NVAF), and the CHA2DS2-VASc score is widely used to guide anticoagulation therapy in this cohort. However, utility of CHA2DS2-VASc in NVAF patients is debated, primarily because it is a vascular scoring system, which does not incorporate atrial fibrillation related parameters. Therefore, we conducted a meta-analysis to estimate the discrimination ability of CHA2DS2-VASc in predicting ischaemic stroke overall, and in subgroups of patients with or without NVAF. Methods and results PubMed and Embase databases were searched till June 2020 for published articles that assessed the discrimination ability of CHA2DS2-VASc, as measured by C-statistics, during mid-term (2–5 years) and long-term (>5 years) follow-up. Summary estimates were reported as random effects C-statistics with 95% confidence intervals (CIs). Seventeen articles were included in the analysis. Nine studies (n = 453 747 patients) reported the discrimination ability of CHA2DS2-VASc in NVAF patients, and 10 studies (n = 138 262 patients) in patients without NVAF. During mid-term follow-up, CHA2DS2-VASc predicted stroke with modest discrimination in the overall cohort [0.67 (0.65–0.69)], with similar discrimination ability in patients with NVAF [0.65 (0.63–0.68)] and in those without NVAF [0.69 (0.68–0.71)] (P-interaction = 0.08). Similarly, at long-term follow-up, CHA2DS2-VASc had modest discrimination [0.66 (0.63–0.69)], which was consistent among patients with NVAF [0.63 (0.54–0.71)] and those without NVAF [0.67 (0.64–0.70)] (P-interaction = 0.39). Conclusion This meta-analysis suggests that the discrimination power of the CHA2DS2-VASc score in predicting ischaemic stroke is modest, and is similar in the presence or absence of NVAF. More accurate stroke prediction models are thus needed for the NVAF population.

468 Background: The burden of gastrointestinal (GI) disease is high, costing over $97 billion annually in the United States (U.S.) alone. Yet the methodological rigor and characteristics of trials leading to guideline development are rarely explored. In 2007, the U.S. mandated that all interventional studies (Phase II-IV) register with ClinicalTrials.gov, the largest international clinical trial database. We characterized registered GI trials to identify features associated with early discontinuation, results reporting and increased methodological rigor. Methods: We employed a cross-sectional study design with descriptive, logistic regression, cox regression, time series and survival analyses. We downloaded data for 327 075 studies registered on the Aggregate Analysis of the ClinicalTrials.gov database from October 1, 2007 to December 31, 2019. Trials were excluded if registered prior to 2007 (n=38 111) or for non-interventional study design (n=69 233). After applying GI specific Medical Subject Heading terms to the remaining 219 731 trials, 22 339 trials were identified for manual review. 20 548 trials were found to contain true GI content, representing over seven million patients. Primary exposure variables were trial focus (disease process, anatomical location) and funding (industry, U.S. government, academic). Results: Of the 20 548 GI trials, 6.1% were funded by the U.S. government, 35.6% by industry, and 58.3% by academic institutions. The most studied disease process was neoplasia (42.6% of trials), followed by viral hepatitis (10.8%). The majority of neoplasia trials were funded by academic institutions (60.3%) and studied colorectal neoplasms (31.5%), followed by hepatic (17.9%), pancreatic (15.5%), gastric (12.8%), esophageal (10.6%) and biliary tract (4.9%) neoplasms. U.S. government funded trials had the lowest risk of early discontinuation (adjusted Hazard Ratio 0.63, 95% CI: 0.48-0.83, p<0.001) and the highest rates of results reporting (25%, X2 p<0.001). Among all trials, the majority did not report Data Monitoring Committee (DMC) oversight (58.6%). Only 12% of phase III trials employed a rigorous methodology, which we defined as being randomized, double blinded, multi-site, overseen by a DMC, and having enrolled ≥50 patients. Government sponsored trials had the highest proportion of trials meeting this definition (19%). Academic sponsored trials, constituting the majority of trials overall, had the lowest proportion (5.3%), in part due to not meeting the multi-site criteria. Conclusions: Despite constituting the minority of trials overall, U.S. government funded trials displayed the highest methodological rigor. Stakeholders can look to U.S. government funded trials as a model of improvement, but nevertheless must commit to increasing methodological rigor and results dissemination to strengthen trial findings that guide GI clinical recommendations.

431 Background: Patients (pts) with localized PC do not routinely undergo comprehensive genomic profiling (CGP) unless they develop recurrent or metastatic disease. KRAS is the most frequently mutated gene in PC, however, the impact of different KRAS mutations in localized PC has not been well characterized. We interrogated our genomic database to analyze the KRAS status in PC pts who presented with localized disease at diagnosis (Dx). Methods: We identified PC pts at our institution who underwent CGP utilizing the Foundation One CDx assay and had localized disease at initial Dx; these pts were categorized into resectable/borderline resectable PC (LPC) and locally advanced PC (LAPC). All pts with LPC and LAPC underwent neoadjuvant chemotherapy and chemoradiation prior to possible surgery (all intended therapy - AIT). Tissue from metastatic sites was used for CGP in pts who developed recurrent/metastatic disease before or after completion of AIT. The primary tumor was used for CGP in pts who completed AIT without subsequent relapse or in the absence of adequate metastatic tissue. Effect of each gene on response and survival outcomes was estimated using proportional odds and Cox regression analysis, respectively, adjusting for stage. Results: 75 pts were identified, median age at Dx was 65 years, 59% were male, 65% had a primary tumor in the pancreatic head. 38 (86%) pts with LPC completed AIT compared to 21 (68%) pts with LAPC (p<0.001). KRAS mutation was detected in 95% (71/75) of pts– 94% (67/71) in codon 12 and 6% (4/71) in codon 61. The various KRAS mutations and their association with completion of AIT is summarized in the table. The likelihood of completing AIT did not differ based on KRAS wildtype (WT) vs mutated status (p =1.00), the mutated codon (codon 12 vs. codon 61; p =1.00) or the individual KRAS point mutations (p = 0.7); however, all patients with G12A (N= 1), G12C (N=1), G12L (N=1) and G12R (N=11) mutations completed AIT. KRAS status (mutated vs. WT) and the individual KRAS mutations were not associated with overall survival (OS) after adjusting for stage (p= 0.13 and p = 0.26 respectively). Median OS for patients with LPC and LAPC, was 39 months (mos) and 29 mos respectively. Conclusions: KRAS status and individual KRAS mutations did not have an impact on completing AIT or mOS; however, these findings need to be interpreted with caution due to the inherent biases involved in such analyses. The clinical significance and functional relevance of KRAS G12A, G12C, G12L and G12R mutations, though relatively rare, needs further characterization as well as mechanistic elucidation. [Table: see text]

231 Background: Both peri-operative chemotherapy and neoadjuvant chemoradiation have been shown to improve outcomes in patients (pts) with LA-GEJ CA compared to surgery alone. Rates of post-operative chemotherapy delivery remain suboptimal. Total neo-adjuvant therapy (TNT) in LA-GEJ CA - induction chemotherapy (IC) followed by concurrent chemoradiation (CRT) - may improve systematic delivery of neoadjuvant therapy and result in favorable clinical outcomes. Methods: We retrospectively reviewed medical records of 135 pts with LA-GEJ CA at our institution between 2/2007 and 11/2019; pertinent clinical data were abstracted with Institutional Review Board approval. Patients treated with IC and curative-intent CRT with ≥40 Gy dose of radiation for adenocarcinoma were included in this analysis (N = 59). Doublet or triplet IC regimens utilizing 5-Flurouracil(5-FU), Cisplatin/Oxaliplatin and Docetaxel were commonly administered while combinations of Carboplatin +Paclitaxel or 5-FU + Oxaliplatin were used in CRT. Clinical complete response (CCR) was defined as metabolic imaging and endoscopic biopsies negative for residual malignancy after completion of TNT. Patients were followed from diagnosis to recurrence and overall survival. Survival probabilities were estimated using the Kaplan-Meier method and compared between groups using a log-rank test. Results: Out of 59 evaluable pts, 69% were clinical stage T3, 71% were node positive. 37 pts (63%) underwent surgery, R0 resection rate was 89% (33/37), pathologic complete response (pCR) rate was 19% (7/37). Among the pts who did not undergo surgery, 41% (9/22) opted to forego surgery since they attained a CCR. For the entire cohort, median Disease-Free Survival (mDFS), median Overall Survival (mOS), and 3-yr OS were 2.4 yrs, 4.7 yrs, and 67% respectively. Pts who did not undergo surgery had a mDFS, mOS, and 3-yr OS of 1.5 yrs, 4.2 yrs, and 59% respectively. Median DFS, mOS, and 3-yr OS of patients who underwent surgery were 3.5 yrs, 5.8 yrs and 72% respectively. Patients who achieved a CCR and opted to forego surgery (N = 9) had a 3 -yr DFS of 42% vs 83% for pts (N = 7) who demonstrated a pCR after curative intent tri-modality therapy. (P = 0.0099) Interestingly, the same group that achieved CCR and opted out of surgery had 3yr OS of 89% vs 83% of those who demonstrated a pCR (p = 0.0042). Conclusions: TNT for pts with LA-GEJ CA is associated with high rates of R0 resection as well as excellent DFS and OS compared to historical controls, warranting prospective evaluation. The remarkable DFS and OS in patients who opted to forego surgery due to achieving CCR is reflective of the local and systemic control rendered by this approach. Careful characterization and close longitudinal follow-up of patients who achieve CCR may help identify a subgroup of LA-GEJ CA pts who may benefit from surgery sparing approaches.

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

Abstract Background Data on efficacy of hepatitis-B vaccine (HBV) in patients with inflammatory bowel disease (IBD) is limited. Our aim was to review the literature and perform meta-analysis of available studies to quantify efficacy of HBV in patients with IBD. Methods We conducted a comprehensive search of several databases (inception to July 2020) to identify studies evaluating efficacy of HBV in patients with IBD. Random effects model was used to calculate the pooled rates and I2 percentage values were used to assess the heterogeneity. Results A total of 14 studies (2375 patients) were included. Four data sets were available from 2 studies that compared HBV response in patients with IBD against healthy controls. The pooled odds ratio of HBV response in IBD patients was 0.13 (95% CI, 0.05–0.33, P = 0.001). The pooled proportion of adequate immune response (AIR) was 64% (95% CI, 55–72.1, P = 0.003) from 13 data sets, and effective immune response (EIR) was 39.7% (95% CI, 30.7–49.5, P = 0.04) from 10 data sets. Conclusion Patients with IBD on immunosuppression demonstrated significantly reduced HBV response as compared with general population.

Abstract Aim The 2018 American Heart Association/American College of Cardiology/Multi-Society Cholesterol Guidelines recommended the addition of non-statins to statin therapy for high-risk secondary prevention patients above a low-density lipoprotein cholesterol (LDL-C) threshold of ≥70 mg/dL (1.8 mmol/L). We compared effectiveness and safety of treatment to achieve lower (&lt;70) vs. higher (≥70 mg/dL) LDL-C among patients receiving intensive lipid-lowering therapy (statins alone or plus ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors). Methods and results Eleven randomized controlled trials (130 070 patients), comparing intensive vs. less-intensive lipid-lowering therapy, with follow-up ≥6 months and sample size ≥1000 patients were selected. Meta-analysis was reported as random effects risk ratios (RRs) [95% confidence intervals] and absolute risk differences (ARDs) as incident cases per 1000 person-years. The median LDL-C levels achieved in lower LDL-C vs. higher LDL-C groups were 62 and 103 mg/dL, respectively. At median follow-up of 2 years, the lower LDL-C vs. higher LDL-C group was associated with significant reduction in all-cause mortality [ARD −1.56; RR 0.94 (0.89–1.00)], cardiovascular mortality [ARD −1.49; RR 0.90 (0.81–1.00)], and reduced risk of myocardial infarction, cerebrovascular events, revascularization, and major adverse cardiovascular events (MACE). These benefits were achieved without increasing the risk of incident cancer, diabetes mellitus, or haemorrhagic stroke. All-cause mortality benefit in lower LDL-C group was limited to statin therapy and those with higher baseline LDL-C (≥100 mg/dL). However, the RR reduction in ischaemic and safety endpoints was independent of baseline LDL-C or drug therapy. Conclusion This meta-analysis showed that treatment to achieve LDL-C levels below 70 mg/dL using intensive lipid-lowering therapy can safely reduce the risk of mortality and MACE.