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Background/Aims: Barrett’s esophagus (BE), defined by the presence of intestinal metaplasia (IM) on histology, is thought to be the only identifiable precursor lesion for esophageal adenocarcinoma (EAC). Recent studies have suggested the possibility of an alternate, non-IM associated EAC that is a more aggressive form of EAC with worse survival. Among EAC patients, we aimed to compare survival of patients with and without IM at the time of diagnosis. Methods: This was a retrospective cohort study of all patients with histologic confirmed EAC evaluated at a tertiary care center from 2013 to 2019. Cases were categorized according to the presence or absence of IM on histologic specimens (Group I—IM-EAC and Group II—non-IM-EAC). We compared demographic characteristics, clinical stage, therapy, and survival between the 2 groups using the Chi-square and ANOVA tests (for categorical and continuous variables, respectively). We used Cox proportional hazards regression to determine the association of IM with overall survival, adjusting for sex, age at diagnosis, tumor location, histologic grade, and clinical stage. Results: A total of 475 patients were included in this analysis (mean age 64.8 years [SD 10.8], 89% white) and 109 (23.0%) had no evidence of IM. Compared with IM-EAC (Group I), individuals in the non-IM-EAC group were younger ( P = .01) and had a greater proportion of patients diagnosed with advanced disease (49.5 vs 20.2% for stage 4, P < .001). These patients were less likely to undergo endoscopic therapy alone (0.92% vs 29.78%, P < .001) or surgery alone (0 vs 9.84%, P = .001). On multivariable analysis, the presence of IM-EAC was associated with improved overall survival compared to non-IM-EAC (HR 0.69, 95% CI 0.49-0.96). Additional factors associated with poor survival was increasing stage of diagnosis (HR 6.49: 95% CI 3.77-11.15 for stage 4, HR 2.19: 95% CI 1.25-3.84 for stage 3, HR 2.04: 95% CI 0.98-4.25 for stage 2 compared to stage 1) and more advanced histologic stage (HR 2.00, 95% CI 1.26-3.19) for poorly/undifferentiated compared to well differentiated). Conclusions: EAC without the presence of IM on histology was associated with worse survival compared to those with IM. Future prospective studies with detailed molecular sequencing are required to clarify if 2 separate phenotypes of EAC exist (IM-EAC and non-IM-EAC). If confirmed, this may have significant implications for screening and management strategies.

Abstract Background and aims Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard‐of‐care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin‐dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive. Approach and results Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy‐induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine. Conclusions As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.

SummaryBackgroundNeoplasia detection rate, the proportion of Barrett's oesophagus patients with high‐grade dysplasia or oesophageal adenocarcinoma detected at index surveillance endoscopy has been proposed as a quality metric. However, the correlation between neoplasia detection rate and a clinically relevant outcome like post‐endoscopy Barrett's neoplasia remains unknown. Post‐endoscopy Barrett's neoplasia refers to the rate of high‐grade dysplasia or oesophageal adenocarcinoma on repeat endoscopy within one year of an index screening examination revealing non‐dysplastic Barrett's oesophagus or low‐grade dysplasia.AimTo assess correlation between neoplasia detection rate and post‐endoscopy Barrett's neoplasia.MethodsWe performed a systematic search of multiple databases from date of inception to June 2021 to identify cohort studies reporting both neoplasia detection rate and post‐endoscopy Barrett's neoplasia. Data from each study were pooled using a random effects model, and their correlation assessed using meta‐regression. Heterogeneity was assessed and a priori planned subgroup analyses were conducted.ResultsTen studies with 27 894 patients with Barrett's oesophagus were included. The pooled neoplasia detection rate and post‐endoscopy Barrett's neoplasia were 5.0% (95% CI: 3.4%‐7.1%, I2 = 97%) and 19.6% (95% CI: 10.1%‐34.7%, I2 = 96%), respectively. Meta‐regression revealed a statistically significant inverse relationship between the two variables (coefficient −3.50, 95% CI: −4.63 to −2.37, P < 0.01). With every 1% increase of neoplasia detection rate, post‐endoscopy Barrett's neoplasia decreased by 3.50%. Heterogeneity was high despite adjusting for study quality and performing several subgroup analyses.ConclusionWe observed a statistically significant inverse correlation between neoplasia detection rate and post‐endoscopy Barrett's neoplasia. Additional studies are needed to further validate this correlation.

Objectives: Identification of gene variants of stroke subtypes is important for the development of tailored ischemic stroke therapies among various ethnic groups. Valid and reliable determination of ischemic stroke subtype is essential for achieving this goal and to standardize a classification scheme across multi-center studies and different populations. Causative Classification System for Ischemic Stroke (CCS) is a novel computerized subclassification tool developed to improve reliability and accuracy of classifying stroke types. The CCS algorithm relies on both phenotypic and causative stroke variables. A Hispanic subset of the SiGN, an important and distinct target population with greater risk of certain stroke subtypes, was evaluated with Trial of Org 10172 in Acute Stroke Treatment (TOAST) and CCS and the agreement between the two classification systems was analyzed. Methods: Over 6000 subjects at 15 sites across US and Europe were enrolled, with TOAST and CCS locally adjudicated. Blood collection and central data quality control (10% central readjudication) were performed on all participants. A subset of Hispanics was analyzed for the purpose of this study and the agreement between the TOAST and CCS were assessed by kappa statistic. Findings: Hispanics (n=595, 10.9%) compared to non-Hispanics (n=5457) were more likely to be younger (63.7 vs. 64.0), male (55% vs. 46%) and have fewer of the traditional stroke risk factors HTN (54% vs. 64%), Afib (11% vs. 14%), DM(23% vs. 25%), CAD(16% vs. 20%) and smoking(19% vs. 22%). While the TOAST showed no differences between stroke subtypes for Hispanic vs. non-Hispanics, in CCS, Hispanics were classified with more of large vessel (22% vs. 20%), cardioembolic (37% vs. 30%) and small vessel strokes (13% vs. 9%) and fewer with undetermined etiology (28% vs. 40%) as compared to non-Hispanics. TOAST and CCS offered moderate correlation across all stroke types in Hispanics: kappa of 0.66 for large artery atherosclerosis, 0.58 for cardioembolic, and 0.58 for small artery occlusion. Conclusion: CCS offers a more sensitive and accurate system for subphenotyping of strokes in Hispanics who tended to have relatively fewer risk factors and unclassified strokes. Further studies correlating the two classification systems and their relation to genotyping data are warranted.

Background: The Stroke Genetics Network (SiGN) funded by the NINDS aims to identify genetic risk factors in ischemic stroke using whole-genome association studies (GWAS). High quality phenotyping is crucial to successful application of GWAS. As a heterogenous disorder, stroke poses specific challenges. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification is a broadly used, but its validity is challenged especially when performed by multiple investigators with differing interpretations of the system. The Causative Classification System for Ischemic Stroke (CCS) system is a new, web-based, and computerized algorithm that integrates clinical, diagnostic, and etiologic stroke characteristics in an evidence-based manner ( ccs.mgh.harvard.edu ) to generate subtypes. Methods: In planning the SiGN proposal, a sample of 20 coded charts were collected from a subset of participating studies to assess feasibility of central adjudication and comparability to study-specific TOAST. Two central adjudicators reviewed all records and generated TOAST and CCS subtypes. These were compared to study-specific TOAST subtype and the CCS phenotype generated for SiGN by local trained adjudicators. CCS data is now available for 7134 included cases using both a 5 and a 7 category system as defined in the table . Results: All 4 phenotypes were available for 115 ischemic stroke cases from 6 studies in SiGN. Basic demographics were 54% women, 63% white, and median age between 65-74. Table 1 provides the agreement between the various subtypes. Table 2 describes the types of disagreement. Conclusions: Central adjudication with only two adjudicators and curated medical records yielded more consistent subtyping independent of phenotyping system. The agreement for TOAST was higher than published rates by independent groups (∼0.50). In contrast, the agreement for CCS was lower than previously published (0.85-0.95). Site adjudicators' familiarity with TOAST and inexperience with CCS may contribute. Although CCS is an automated algorithm and has a number of user friendly features, our findings suggest that formal training and certification process before starting to use CCS may be worthwhile to achieve optimal benefit from the system.

Background: American Heart Association/American Stroke Association recommends treatment of eligible acute ischemic stroke patients with intravenous rtPA <60 minutes from emergency department arrival. Purpose: A quality improvement project was designed to reduce the door to needle times for intravenous rtPA administration at Mayo Clinic Florida. We hypothesized that workflow changes in emergency department evaluation of suspected stroke patients would decrease door to needle times. The goal was to treat >75% of patients eligible for IV t-PA within 60 minutes of ED arrival. Methods: We utilized LEAN methods to develop a project charter, identify stakeholders, and visually map the emergency department clinical workflow. Prior to project initiation, suspected stroke patients were taken upon arrival to an exam room for clinical evaluation followed by transport to the CT scanner and return to the exam room for decision-making and rtPA administration. The clinical workflow was changed to obtain patient weight immediately upon arrival, abbreviated patient assessment and lab draws outside of the CT scanner in a holding bay and performing CT scanning prior to transport to an examination room for decision making and rtPA administration. Results: In a 12 month period preceding project initiation, 29 patients were treated with rtPA, 55 % were treated <60 minutes of emergency department arrival. In the 11 month period following implementation of CT scanning prior to neurological evaluation, 57 patients were treated with rtPA, 80 % were treated in <60 minutes of emergency department arrival. The mean door to needle time was reduced from 66 minutes to 46 minutes following the clinical workflow change. No patients experienced clinical deterioration at the time of CT scanning. Conclusions: Non-contrast head CT scan be safely performed prior to comprehensive neurological evaluation and reduces door-to-needle times for intravenous rtPA administration in eligible stroke patients. Validated process improvement paradigms such as LEAN have the potential to reduce door to needle times and improve patient outcomes.

Purpose: The safety of revascularization for asymptomatic carotid stenosis, and the efficacy of medical therapy for stroke prevention have improved. Therefore, results of prior randomized trials may not apply to current treatment decisions. The NINDS-funded CREST-2 will compare carotid endarterectomy and intensive medical therapy (IMT) versus IMT alone (n=1240), and carotid stenting and IMT versus IMT alone (n=1240) in asymptomatic patients with≥70% stenosis. Materials & Methods: CREST-2 consists of two parallel randomized clinical trials to be conducted at a target of ≈120 centers, including within NINDS StrokeNet. The composite primary outcome is stroke or death during the peri-procedural period or ipsilateral ischemic stroke thereafter up to 4 years. Blinded assessment of cognition will be done periodically. Centrally directed IMT includes tight control of blood pressure (systolic target <140 mm Hg) and cholesterol (LDL target <70 mg/dl) as well as lifestyle coaching. Results: As of June 12, 2015, 94 centers have been approved by the Site Selection Committee. Credentialing is ongoing, with 198 approved surgeons and 64 approved interventionists; 124 additional conditionally approved interventionists will be able to submit additional cases for review under the CREST-2 Registry. The Centers for Medicare and Medicaid will offer CAS reimbursement for Registry enrollees. As of June 12, 2015, there are 39 actively enrolling centers, and 37 patients have been randomized. Conclusion: CREST-2 is designed to identify the best approach for asymptomatic carotid stenosis. The first patient was randomized in December, 2014. An update will be provided regarding the numbers of patients randomized, centers certified, as well as surgeons and interventionists fully approved. Registration: ClinicalTrials.gov Identifier: NCT02089217

Background and aim The use of endoluminal flow diversion in bifurcation aneurysms has been questioned due to the potential for complications and lower occlusion rates. In this study we assessed outcomes of endovascular treatment of intracranial sidewall and bifurcation aneurysms with flow diverters Methods In July 2020, a literature search for all studies utilizing endoluminal flow diverter treatment for sidewall or bifurcation aneurysms was performed. Data were collected from studies that met our inclusion/exclusion criteria by two independent reviewers and confirmed by a third reviewer. Using random-effects meta-analysis the target outcomes including overall complications (hematoma, ischemic events, minor ischemic stroke, aneurysm rupture, side vessel occlusion, stenosis, thrombosis, transient ischemic stroke, and other complications), perioperative complications, and follow-up (long-term) aneurysm occlusion were intestigated. Results Overall, we included 35 studies with 1084 patients with 1208 aneurysms. Of these aneurysms, 654 (54.14%) and 554 (45.86%) were classified as sidewall and bifurcation aneurysm, respectively, based on aneurysm location. Sidewall aneurysms had a similar total complication rate (R) of 27.12% (95% CI, 16.56%–41.09%), compared with bifurcation aneurysms (R, 20.40%, 95% CI, 13.24%–30.08%) (p = 0.3527). Follow-up angiographic outcome showed comparable complete occlusion rates for sidewall aneurysms (R 69.49%; 95%CI, 62.41%–75.75%) and bifurcation aneurysms (R 73.99%; 95% CI, 65.05%–81.31%; p = 0.4328). Conclusions This meta-analysis of sidewall and bifurcation aneurysms treated with endoluminal flow diverters demonstrated no significant differences in complications or occlusion rates. These data provide new information that can be used as a benchmark for comparison with emerging devices for the treatment of bifurcation aneurysms.