Citations

AbstractDistal biliary strictures (DBS) are common and may be caused by both malignant and benign pathologies. While endoscopic procedures play a major role in their management, a comprehensive review of the subject is still lacking. Our consensus statements were formulated by a group of expert Asian pancreatico‐biliary interventional endoscopists, following a proposal from the Digestive Endoscopy Society of Taiwan, the Thai Association for Gastrointestinal Endoscopy, and the Tokyo Conference of Asian Pancreato‐biliary Interventional Endoscopy. Based on a literature review utilizing Medline, Cochrane library, and Embase databases, a total of 19 consensus statements on DBS were made on diagnosis, endoscopic drainage, benign biliary stricture, malignant biliary stricture, and management of recurrent biliary obstruction and other complications. Our consensus statements provide comprehensive guidance for the endoscopic management of DBS.

Abstract Background BMS-911543 is an oral, selective small-molecule inhibitor of JAK2 (IC50=1.1nM) with potent anti-proliferative and pharmacodynamic effects in cell lines and in vivo models dependent upon JAK2 signaling. In vitro, BMS-911543 demonstrates high selectivity within the JAK family (JAK1 [IC50=356nM], JAK3 [IC50=73nM] or TYK2 [IC50=66nM]) and across a large kinase panel (at 1 µM concentration of BMS-911543, only 8 of 451 kinases were markedly inhibited [≥67%]) It also has little activity in cells dependent on other JAK family pathways. Anti-proliferative responses were observed with BMS-911543 in colony growth assays using primary progenitor cells isolated from patients with JAK2V617F-positive polycythemia vera (PV) (Leukemia 2012;26:280). Methods In a multicenter phase 1/2a study, BMS-911543 was administered orally using a BID dosing schedule, in patients with high-, intermediate-2 or intermediate-1 risk symptomatic primary or secondary MF (JAK2 WT or mutant) with platelet counts ≥50,000/mm3. Patients were not required to have palpable splenomegaly. The aim of the study is to determine safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of BMS-911543. Safety was assessed using NCI-CTCAE version 4.0. Treatment effect was assessed using the International Working Group (IWG) response criteria, MF-SAF, BFI, physical examination, spleen and liver volume assessment by MRI, bone marrow morphology, karyotype, V617F mutant allele burden, plasma cytokine analysis, circulating CD34+ cells and other molecular parameters. Current status To date, 84 patients have been treated (dose escalation [n=42]; dose expansion [n=42]) and the maximum tolerated dose (MTD) was defined as 200mg BID. The summary below represents an interim data analysis of 36 patients from the dose escalation phase dosed at 5, 10, 20, 40, 80, 120, 160, and 200mg BID. Fifteen of 36 (42%) patients had received prior Jak inhibitors (Jaki) including 3 who had received ≥2 Jak inhibitors. PK, PD, Safety, Tolerability and Efficacy After repeat dosing, greater than dose-proportional increase in the Cmax and AUC, and drug accumulation was observed at doses ≥40mg BID. PD analysis indicated inhibition of JAK/STAT pathway signaling activity in peripheral blood mononuclear cells, and modulation of several soluble peripheral blood proteins including IL-6, EPO and Leptin. Eleven patients (31%) had drug-related AEs. The nine hematological AEs included 3 anemia (1 grade 3 and 2 grade 2); 3 neutropenia (grade 4); and single leukopenia (grade 4), thrombocytopenia (grade 4), and reduction in platelet count (grade 2). Nine non-hematological AEs included 3 nausea (grade1/2); amylase increased (grade 3) and lipase increased (grade 3) one each; and grade 1 fatigue, muscle spasms, insomnia, erectile dysfunction one each. Ten patients (28%) discontinued treatment: 4 were attributed to disease progression, 2 to lack of efficacy, 2 at patient’s request, 1 to poor compliance, and 1 to unrelated AE. Spleen volume reductions (SVR) by MRI were observed in Jaki failure and in Jaki naive patients. Of 11 patients treated at 160 and 200mg, 8 patients (73%) had SVR greater than 35% at 3 months. In contrast, 1 of 4 patients treated at 120mg and none treated below 120mg had SVR greater than 35%. Of the patients treated at 160mg and 200mg, more than 50% had MF-SAF reductions > 50%. Overall, 3 patients (8.3%; 2 treated at 10mg BID and 1 at 200mg BID) had an increase in hemoglobin of ≥2g/dL;. Other signs of clinical activity included reductions in V617F mutant allele burden, leukocytosis, leukoerythroblastosis, circulating CD34+ cells, and LDH. Conclusion BMS-911543 was generally well tolerated and has an acceptable safety and efficacy profile. BMS-911543 induced rapid control of constitutional symptoms, and splenomegaly in patients with symptomatic MF, including those previously treated with one or more Jak inhibitors. Updated data from all 84 patients who have been treated in the dose escalation and ongoing expansion phases, including MRI assessments of spleen and liver volume, V617F mutant allele burden and levels of select plasma cytokines, will be presented.</abstract> Disclosures: Pardanani: JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other; PharmaMar: Clinical trial support, Clinical trial support Other; Sanofi: Clinical trial support, Publication support services, Clinical trial support, Publication support services Other; Bristol Myers Squibb: Clinical trial support Other. Off Label Use: Use of BMS-911543, Ruxolitinib, Momelotinib, Fedratinib and Pomalidomide for treatment of Myelofibrosis in Clinical Trial setting. Roberts:AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, recieves commercial income related to ABT-199, Employee, recieves commercial income related to ABT-199 Other, Employment. Seymour:Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Verstovsek:Incyte Corporation: Research Funding. Yoshitsugu:Bristol-Myers Squibb: Employment, Equity Ownership. Gestone:Bristol-Myers Squibb: Employment, Equity Ownership. Phillips:Bristol-Myers Squibb: Employment, Equity Ownership. Xing:Bristol-Myers Squibb: Employment, Equity Ownership. Peltz:Bristol-Myers Squibb: Employment, Equity Ownership. Lorenzi:Bristol-Myers Squibb: Equity Ownership, Former employment Other. Alland:Bristol-Myers Squibb: Employment, Equity Ownership. Woolfson:Bristol-Myers Squibb: Equity Ownership, Former employment Other.

INTRODUCTION: While esophagectomy is the standard treatment for submucosal (T1b) esophageal adenocarcinoma (EAC) and squamous cell cancer (SCC), many elderly patients -the age group that esophageal cancer tends to affect- are not candidates for surgery. Endoscopic submucosal dissection (ESD) is a minimally invasive procedure that allows for en-bloc resection of early esophageal cancer and allows for precise histopathologic staging of the tumor. ESD could be curative in submucosal cancer without lymph node metastasis, and it allows for precise histopathologic staging. To evaluate the long-term outcomes of ESD in patients with EUS-staged T1b esophageal cancer. METHODS: A retrospective multicenter study was performed at three academic hospitals in the U.S. Patients who underwent ESD with a pre-procedural or post-procedural histopathologic diagnosis of T1b N0 M0 EAC or SCC were included in the study. Data was collected on demographics, tumor and procedure characteristics, procedure pathology, and follow-up. Local recurrence was confirmed by endoscopic findings and pathological analysis. Metastasis was confirmed by cross-sectional imaging. The main outcome was a composite of rate of metastasis and local recurrence. Follow-up time was defined as months from initial procedure to recurrence or last follow-up visit if recurrence-free. A time-to-event analysis was performed to evaluate recurrence. RESULTS: Fifty-two patients underwent ESD (mean age 69.6 years +/-9; 35 males) (Table 1). Based on available comorbidity data, 42% patients were not fit for surgery, as determined by an age-adjusted Charlson Comorbidity Index > 6. Twenty tumors (62%) were found to be HGD or T1a on post-ESD specimen analysis, while one was staged as T2. Nineteen patients were staged as T1b after ESD. Immediately after ESD, 6 patients were referred for surgery, 3 underwent chemoradiation therapy, and 6 radiation alone (Table 2). Patients were followed for a median of 18 months, and the calculated 24-month recurrence rate was 13% (Figure 1). CONCLUSION: This multicenter trial showed that ESD for T1b esophageal cancer can be acceptable for patients who deemed not surgical candidates. However, close follow up is necessary. ESD can also serve as a staging procedure, as our data confirms inaccurate EUS-staging of T1b cancer, with 62% of tumors being down-staged to T1a, as has been previously reported.

INTRODUCTION: The difference in long-term outcomes of endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) for Barrett’s related superficial neoplasia remains unclear. We aimed to compare the rates of local and metachronous recurrence of ESD and EMR in patients with clinically staged BE-associated high-grade dysplasia (HGD) and T1a esophageal adenocarcinoma (EAC). METHODS: Multicenter study at six academic hospitals in the U.S. including patients who underwent ESD for BE-HGD or T1a EAC. Primary outcome was a composite of metastasis and local recurrence rate. A time-to-event analysis was performed to evaluate recurrence. A Kaplan-Meier plot was constructed, and a log-rank test was used to compare the groups. A Cox hazard ratio regression analysis was performed to identify predictors of recurrence. RESULTS: A total of 241 patients were included. 154 underwent EMR, while 84 underwent ESD (Table 1). ESD had higher en bloc (96% vs 33%, P < 0.0001), R0 (76% vs 54%, P = 0.0009) and curative resection rates (75% vs 32%, P < .0001) when compared to EMR. The 24-month local recurrence rate for EMR and ESD was 43% and 11%, respectively ( P = 0.0007) (Figure 1). Significantly more endoscopic resection procedures were required to treat recurrence after EMR compared to after ESD (Table 1). EMR, piecemeal resection, positive margins, and non-curative resection were identified as predictors of recurrence on univariate analysis. En bloc resection remained significant after multivariate analysis (Table 2). CONCLUSION: This multicenter study showed that ESD results in more definitive treatment of BE-associated early neoplasia than EMR, with significant lower recurrence rates and less need for repeat endoscopic therapeutic procedures than EMR.

Background: Mitral stenosis frequently coexists in patients with severe aortic stenosis. Mitral stenosis severity evaluation is challenging in the setting of combined aortic stenosis and mitral stenosis because of hemodynamic interactions between the 2 valve lesions. The impact of aortic valve replacement (AVR) for severe aortic stenosis on mitral stenosis is unknown. This study aimed to assess the effect of AVR on mitral stenosis hemodynamics and the clinical outcomes of patients with severe aortic stenosis with and without mitral stenosis. Methods: We retrospectively investigated patients who underwent surgical AVR or transcatheter AVR for severe aortic stenosis from 2008 to 2015. Mean transmitral gradient by Doppler echocardiography ≥4 mm Hg was identified as mitral stenosis; patients were then stratified according to mitral valve area (MVA, by continuity equation) as >2.0 cm 2 or ≤2.0 cm 2 . MVA before and after AVR in patients with mitral stenosis were evaluated. Clinical outcomes of patients with and without mitral stenosis were compared using 1:2 matching for age, sex, left ventricular ejection fraction, method of AVR (surgical AVR versus transcatheter AVR) and year of AVR. Results: Of 190 patients with severe aortic stenosis and mitral stenosis (age 76±9 years, 42% men), 184 were matched with 362 with severe aortic stenosis without mitral stenosis. Among all mitral stenosis patients, the mean MVA increased after AVR by 0.26±0.59 cm 2 (from 2.00±0.50 to 2.26±0.62 cm 2 , P <0.01). MVA increased in 105 (55%) and remained unchanged in 34 (18%). Indexed stroke volume ≤45 mL/m 2 (odds ratio [OR] 2.40; 95% CI, 1.15–5.01; P =0.020) and transcatheter AVR (OR, 2.36; 95% CI, 1.17–4.77; P =0.017) were independently associated with increase in MVA. Of 107 with significant mitral stenosis (MVA ≤2.0 cm 2 ), MVA increased to >2.0 cm 2 after AVR in 52 (49%, pseudo mitral stenosis) and remained ≤2.0 cm 2 in 55 (51%, true mitral stenosis). During follow-up of median 2.9 (0.7–4.9) years, true mitral stenosis was an independent predictor of all-cause mortality (adjusted hazard ratio, 1.88; 95% CI, 1.20–2.94; P <0.01). Conclusions: MVA improved after AVR in nearly half of patients with severe aortic stenosis and mitral stenosis. MVA remained ≤2.0 cm 2 (true mitral stenosis) in nearly half of patients with severe aortic stenosis and significant mitral stenosis; this was associated with worse survival among patients undergoing AVR for severe aortic stenosis.

Abstract Background: The GALAD score is a serum biomarker–based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison with liver ultrasound for detection of HCC. Methods: A single-center cohort of 111 HCC patients and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) phase II HCC Study were analyzed. Results: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI), 0.93–97], which was higher than the AUC of ultrasound (0.82, P &lt;0.01). At a cutoff of −0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early-stage HCC detection remained high at 0.92 (95% CI, 0.88–0.96; cutoff −1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85–0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single-center cohort, achieving an AUC of 0.98 (95% CI, 0.96–0.99; cutoff −0.18, sensitivity 95%, specificity 91%). Conclusions: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score. Impact: The GALAD score was validated in the United States.