Wang, Kenneth T.

AbstractAlthough endoscopic submucosal dissection (ESD) is associated with higher en-bloc and R0 resection rates than cap-assisted endoscopic mucosal resection (cEMR), its comparative impact on achieving complete remission of dysplasia (CRD) and intestinal metaplasia (CRIM) in BE endoscopic eradication therapy (EET) is not well defined. We aimed to compare the journey of patients from initial endoscopic resection (ER) with ESD and cEMR to achieving CRD and CRIM.Patients undergoing ESD or cEMR followed by ablation for BE neoplasia at two academic institutions in the United States were included. Primary outcomes included CRD and CRIM rates following ER in the two groups. Secondary outcomes included the number of resection/ablative procedures from initial ER to achieving CRD and CRIM. Inverse probability treatment weighting (IPTW) was used to balance confounding variables between groups.A total of 801 patients (606 cEMR, 195 ESD) were included. ESD group patients had higher en-bloc resection rates (ESD 94.4%, cEMR 44.7%). Higher rates of CRD were observed in patients undergoing initial ESD (HR 1.53, P < 0.01). With time-to-event and IPTW analyses, rates of achieving CRD and CRIM were comparable between the groups. There were no significant differences in mean number of endoscopic resection or ablative procedures among patients undergoing initial cEMR resection compared with those treated with initial ESD.Despite larger lesion sizes and more cancers in patients undergoing ESD, the EET journey to achieving CRD and CRIM was comparable to that in patients receiving cEMR. Prospective studies are required to further study differences between these two treatment approaches.

Abstract Frailty is most prevalent among elderly multiple myeloma (MM) patients, and frail patients have a higher risk of poor outcomes due to reduced performance status or comorbidities. This post hoc analysis assessed efficacy and safety of carfilzomib combinations in frail patients with relapsed and/or refractory MM from the phase 3 ASPIRE (carfilzomib [27 mg/m2]-lenalidomide-dexamethasone [KRd27] vs lenalidomide-dexamethasone [Rd]), ENDEAVOR (carfilzomib [56 mg/m2]-dexamethasone [Kd56] vs bortezomib-dexamethasone [Vd]), and ARROW (once-weekly carfilzomib [70 mg/m2]-dexamethasone [Kd70] vs carfilzomib [27 mg/m2]-dexamethasone [Kd27]) studies. A frailty algorithm incorporating age, Charlson comorbidity index, and performance status classified patients as fit, intermediate, or frail. Results are presented for frail patients (ASPIRE, n = 196; ENDEAVOR, n = 330; ARROW, n = 141). In ASPIRE, median progression-free survival (PFS) (hazard ratio; 95% confidence interval) was 24.1 (KRd27) vs 15.9 months (Rd) (0.78; 0.54-1.12); median overall survival (OS) was 36.4 vs 26.2 months (0.79; 0.57-1.08). In ENDEAVOR, median PFS was 18.7 (Kd56) vs 6.6 months (Vd) (0.50; 0.36-0.68); median OS was 33.6 vs 21.8 months (0.75; 0.56-1.00). In ARROW, median PFS was 10.3 (once-weekly Kd70) vs 6.6 months (twice-weekly Kd27) (0.76; 0.49-1.16). In all 3 studies, rates of grade ≥3 treatment-emergent adverse events were consistent with those observed in the primary studies. The ASPIRE, ENDEAVOR, and ARROW primary analyses demonstrated favorable benefit-risk profiles with carfilzomib-containing regimens compared with controls. Across clinically relevant subgroups, including those by frailty status, consistent efficacy and safety were observed with KRd27, Kd56, and weekly Kd70, and treatment with these regimens should not be restricted by frailty status.

Abstract Background Volumetric laser endomicroscopy (VLE) allows for near-microscopic imaging of the superficial esophageal wall and may improve detection of early neoplasia in Barrett’s esophagus (BE). Interpretation of a 6-cm long, circumferential VLE “full scan” may however be challenging for endoscopists. We aimed to evaluate the accuracy of VLE experts in correctly diagnosing VLE full scans of early neoplasia and non-dysplastic BE (NDBE). Methods 29 VLE full scan videos (15 neoplastic and 14 NDBE) were randomly evaluated by 12 VLE experts using a web-based module. Experts were blinded to the endoscopic BE images and histology. The 15 neoplastic cases contained a subtle endoscopically visible lesion, which on endoscopic resection showed high grade dysplasia or cancer. NDBE cases had no visible lesions and an absence of dysplasia in all biopsies. VLE videos were first scored as “neoplastic” or “NDBE.” If neoplastic, assessors located the area most suspicious for neoplasia. Primary outcome was the performance of VLE experts in differentiating between non-dysplastic and neoplastic full scan videos, calculated by accuracy, sensitivity, and specificity. Secondary outcomes included correct location of neoplasia, interobserver agreement, and level of confidence. Results VLE experts correctly labelled 73 % (95 % confidence interval [CI] 67 % – 79 %) of neoplastic VLE videos. In 54 % (range 27 % – 66 %) both neoplastic diagnosis and lesion location were correct. NDBE videos were consistent with endoscopic biopsies in 52 % (95 %CI 46 % – 57 %). Interobserver agreement was fair (kappa 0.28). High level of confidence was associated with a higher rate of correct neoplastic diagnosis (81 %) and lesion location (73 %). Conclusions Identification of subtle neoplastic lesions in VLE full scans by experts was disappointing. Future studies should focus on improving methodologies for reviewing full scans, development of refined VLE criteria for neoplasia, and computer-aided diagnosis of VLE scans.

Abstract Background and study aims Precise staging in T1 esophageal adenocarcinoma (EAC) is critical in determining candidacy for curative endoscopic resection. High-frequency endoscopic ultrasound (EUS) has demonstrated suboptimal accuracy in T1 EAC staging due to insufficient spatial resolution. Volumetric laser endomicroscopy (VLE) allows for high-resolution wide-field visualization of the esophageal microstructure. We aimed to investigate the role of VLE in staging T1 EAC. Patients and methods Patients undergoing endoscopic mucosal resection (EMR) were prospectively enrolled and only T1 EAC cases were included. EMR specimens were imaged using second-generation VLE immediately after resection. VLE images were analyzed for signal intensity by depth and signal attenuation (dB/mm) in both cross-sectional and en-face orientation. A decision tree model was constructed to combine measured VLE parameters and delineate diagnostic thresholds. Results Thirty EMR scans were obtained – 15 T1a specimens from 9 patients and 15 T1b specimens from 11 patients. T1b specimen VLE scans exhibited higher signal intensity (P < 0.0001) and higher signal attenuation compared to T1a specimens (P = 0.03). A combination of signal attenuation and signal intensity at 150 µm depth yielded optimal diagnostic thresholds and an area under the curve (AUC) of 0.77. VLE signal attenuation was significantly associated with grade of differentiation, irrespective of EAC stage. Conclusions VLE signal intensity and signal attenuation are quantitatively distinct in T1a and T1b EAC and associated with grade of differentiation. This is the first study examining the role of VLE for staging of T1 EAC and demonstrates promising diagnostic performance. With further in vivo validation, VLE may serve a role in staging superficial EAC.

114 Background: Clinical staging of early esophageal neoplasia traditionally involves histological confirmation and imaging with endoscopic ultrasound (EUS), CT, and PET which have low sensitivity and specificity for staging esophageal cancer (EC). Endoscopic submucosal dissection (ESD) therapy is traditionally used for treatment, but not diagnosis as it is felt to be technically challenging and have a high risk for complications. We applied a new articulating endoscopic knife that permits safe ESD (ESD-CC) to evaluate early neoplasia with potential curative resection. Methods: We performed a retrospective study of patients undergoing ESD to stage or treat suspected early EC (cT1-T2). Clinical stage was done by EUS, CT, and PET. Two expert GI pathologists reviewed all histology. Lesions were examined with high resolution white light endoscopy and narrow band imaging. ESD was done with 1:200,000 epinephrine and methylene blue dye injection for lifting and staining the submucosal space. A 5mm, scissors-like articulated knife was used to perform ESD and hemostasis. Complications during post-ESD observation or follow-up were recorded. Results: A total of 35 patients who underwent ESD-CC were included with median age 70 (IQR 12), 26 males (74%), and followed for a median 3.4 months (IQR 6.4). This group consisted of 32 potential adenocarcinomas and 3 squamous cell cancers. The clinical Pre-ESD diagnoses were cT1 EC (24, 69%) and suspected EC in Barrett’s esophagus (BE) (11, 31%). The cT1 EC cases had ESD staged at least T1b (5, 21%), T1a (11, 46%), EC in situ (1, 4%), and dysplastic BE (7, 29%). The suspected EC cases had ESD staged at least T1b (1, 9%), T1a (2, 18%), and DBE (8, 73%). ESD-CC up-staged 4 (11%), down-staged 10 (29%), and confirmed prior diagnosis in 21 (60%). No complications including bleeding, perforation, or stricture formation regardless of size of ESD, age of patient, or co-morbidities. Conclusions: Staging of early esophageal cancer can be improved using ESD with an articulating knife, without increase in complications. ESD may be used as a staging modality in early esophageal cancer.

1 Background: Endoscopic resection (ER) is used to treat early esophageal cancers (EAC). With the advent of techniques such as ESD that can remove large lesions en bloc, it is important to determine if performing piecemeal resections of intramucosal cancers is detrimental. Aim: To evaluate the response rates in patients with esophageal intramucosal adenocarcinoma (IMC) who had a single ER (SR) compared to those treated with piecemeal resection (PR). Methods: This is a cohort study of patients being followed in our BE unit. Patients in a prospectively maintained database with EAC from Jan 1998 to Apr 2012 were assessed. IMC was defined as lesions that were intramucosal without extension into the submucosa. All T1a cancers were verified by two expert gastrointestinal pathologists. We compared the tumor characteristics and recurrence rate between the two groups of SR and PR of IMC. Results: A total of 197 IMC (T1a) lesions in 138 patients were identified. 88(44.7%) lesions were performed SR and 109(55.3%) were PR. Mean follow up time were 45 months (IQR 24-70.5) in SR and 39 months (IQR 26-52, P=0.067) in PR. Complete remission were found of 92.1% (81) in SR and of 93.6% (102) in PR (P=0.788) patients. The recurrence rate was 7.9% in the SR patients, and 6.4% in the PR patients (P=0.699). Median time to progression was 12 months in the SR group (IQR 8-23.5) and 11 months in the PR (IQR 8-22) (P=0.765) group. The mean survival duration was 116.3 months in the SR and 89 months in the PR (P=0.079). No statistical difference in 5-year survival rates was found between SR (83.2%) and PR (80.9%) (P=0.082). Cox proportional hazard model analysis showed local recurrence after EMR was not related to number of specimen resected or technique. Conclusions: PR appears to be as effective a therapy as en bloc for esophageal IMC. Using PR does not appear to affect clinical outcomes.

ABSTRACTThe rapid increase and poor survival of esophageal adenocarcinoma (EAC) have led to significant efforts to promote early detection. Given that the premalignant lesion of Barrett's esophagus (BE) is the major known risk factor for EAC, multiple investigators have studied biomarker signatures that can predict malignant progression of BE to EAC. MicroRNAs, a novel class of gene regulators, are small non‐coding RNAs and have been associated with carcinogenesis. MicroRNAs are ideal biomarkers because of their remarkable stability in fixed tissues, a common method for collection of clinical specimens, and in blood either within exosomes or as microRNA‐protein complexes. Multiple studies show potential of microRNAs as tissue and blood biomarkers for diagnosis and prognosis of EAC but the results need confirmation in prospective studies. Although head‐to‐head comparisons are lacking, microRNA panels require less genes than messenger RNA panels for diagnosis of EAC in BE. MicroRNA diagnostic panels will need to be compared for accuracy against global measures of genome instability that were recently shown to be good predictors of progression but require sophisticated analytic techniques. Early studies on blood microRNA panels are promising but have found microRNA markers to be inconsistent among studies. MicroRNA expression in blood is different between various microRNA sub‐compartments such as exosomes and microRNA‐protein complexes and could affect blood microRNA measurements. Further standardization is needed to yield consistent results. We have summarized the current understanding of the tissue and blood microRNA signatures that may predict the development and progression of EAC. J. Cell. Biochem. 117: 1288–1295, 2016. © 2016 Wiley Periodicals, Inc.