Citations

e15567 Background: Esophageal adenocarcinoma (EAC) prognosis is poor and there is a need to identify patients that benefit most from neoadjuvant therapy. To examine the association of various biomarkers with clinical outcomes in neoadjuvant treatment of EAC, we retrospectively evaluated the biomarker expression (TS, ERCC1, TOPO1, PD-L1, PD-1) in patient matched formalin-fixed paraffin-embedded (FFPE) tumor samples. Methods: Immunohistochemistry of TS (TS106/4H4B1) , ERCC1 (Ab. 8F1), TOPO1 (1D6), PD-L1 (both 22c3 and SP142), PD-1 (NAT105), and chromogenic in-situ hybridization (CISH) of Her2 were performed on FFPE samples from 35 patients across 2 institutions at time of EAC diagnosis and after treatment when available. Retrospective clinical data and survival (5/2006-1/2016) was analyzed with a mean follow up of 110 months (range 22-306). Results: Overexpression (pre/post-treatment) of TS (60%/54%), ERCC1 (69%/16%), TOPO1 (74%/50%), PD-1 (54%/63%), PD-L1 (SP142) (2.9%/4%), PD-L1 (22c3) (0%/4%) and amplification of Her2 (18%/23%) were observed. Pretreatment observed PD-L1 levels were lower in our study (3%) when compared to other studies in EAC specimens (35%). Immunohistochemistry and changes observed after chemoradiation are reviewed in Table. No markers had significant correlation with prognosis however TS negative expression showed a non-significant (p=0.15) trend towards improved survival. Conclusions: Analyzing biomarkers in our neoadjuvant EAC cohort demonstrated a lower than expected PD-L1 positivity. In the largest cohort, to our knowledge, of patient matched FFPE tumor samples, we did not observe a statistically significant association between TS, ERCC1, TOPO1, PD-L1, or PD-1 with improved clinical outcomes. [Table: see text]

e15563 Background: Expression of thymidylate synthase (TS), a target of fluoropyrimidine-based (5-FU) chemotherapy, has prognostic value in colorectal adenocarcinoma. Its value as a biomarker in treatment of esophageal adenocarcinoma (EAC) is unknown. With widespread adoption of CROSS trial protocol for treatment of EAC, 5-FU is frequently omitted from regimens. We retrospectively analyzed the association between TS protein expression and clinical outcomes in EAC. Methods: TS expression levels were measured by immunohistochemistry in formalin-fixed paraffin-embedded specimens from 35 primary EAC patients from 2 institutions (range 5/2006-1/2016); at time of diagnosis and surgical resection (33 neoadjuvant chemoradiation and 2 surgery alone). TS expression higher than 1+, 5% was read as positive. Mean follow up was 1323 days (range 263-3677). TS expression correlated with treatment response and survival in patients treated with and without 5-FU therapy (log-rank test, Kaplan-Meier method). Results: In the cohort of 35 patients, 21 patients (60%) had pretreatment positive TS expression. Overall survival (OS) for TS negative patients was 1216 days versus 974 days for TS positive (p = 0.15). In the 23 patients treated with 5-FU, TS-negative patients had a trend towards longer overall survival compared to TS-positive patients, mean OS (1272 days versus 743 days, p = 0.08). In the group of 12 patients not treated with 5-FU, 2 patients showed negative TS staining. Neoadjuvant chemoradiation was performed in 33/35 patients. Downstaging was observed in 69% (9/13) of patients with negative pre-treatment TS levels versus 55% (11/20) in pre-treatment TS positive patients (p = 0.48). In 23 patients treated with 5FU, 9/12 (75%) were downstaged in the TS-negative cohort versus 6/11 (45%) in the TS-positive cohort (p = 0.21). In the 5FU treatment group, complete response was seen in 2 patients with negative TS staining. Conclusions: Low TS expression in EAC patients trended towards improved survival and tumor downstaging, particularly in patients treated with neoadjuvant 5-FU and platinum based therapy. Prospective data and greater patient numbers may be necessary to demonstrate statistical significance.

Abstract Background: Abemaciclib is an orally administered, selective CDK4 & 6 inhibitor dosed on a continuous schedule. In patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), abemaciclib demonstrated clinical activity as monotherapy in MONARCH 1 and efficacy with a generally tolerable safety profile in combination with fulvestrant in MONARCH 2. At the MONARCH 3 (NCT02246621) interim analysis, abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) significantly improved progression-free survival (PFS) (hazard ratio [HR], 0.543; 95% confidence interval [CI], 0.409, 0.723; p=.000021) and objective response rate (ORR) (measurable disease: abemaciclib arm, 59.2%; placebo arm, 43.8%; p=.004) with a generally tolerable safety profile as initial treatment for HR+, HER2- ABC. Here we present the MONARCH 3 results from the preplanned final PFS analysis. Methods: MONARCH 3 is a double-blind, Phase 3 study of abemaciclib/placebo (150 mg, twice daily continuous schedule) + NSAI (1 mg anastrozole or 2.5 mg letrozole, daily) in postmenopausal women with HR+, HER2- ABC who have had no prior systemic therapy for advanced disease. Endocrine therapy (ET) naïve pts or pts with disease relapse >12 months after (neo)adjuvant ET were randomized 2:1 and stratified by metastatic site (visceral, bone-only, or other) and prior ET (aromatase inhibitor, no ET, or other). The primary objective was investigator-assessed PFS. Additional objectives included ORR, clinical benefit rate (CBR), duration of response (DoR), overall survival (OS), and safety and tolerability. The study was powered to 80% at 1-sided α=.025 assuming a HR of 0.67 in favor of abemaciclib + NSAI, with the final analysis at 240 PFS events. Results: 493 pts were randomized to abemaciclib + NSAI (n=328) or placebo + NSAI (n=165). At the final PFS analysis, 246 PFS events had occurred. Abemaciclib + NSAI significantly extended PFS (HR, 0.540; 95% CI, 0.418, 0.698; p=.000002; median: abemaciclib arm, 28.18 vs placebo arm, 14.76 months). PFS was improved across all subgroups. For pts with measurable disease, the ORR was 61.0% in the abemaciclib arm and 45.5% in the placebo arm (p=.003), and the CBR was 79.0% in the abemaciclib arm and 69.7% in the placebo arm (p=.037). The median DoR was 27.39 months in the abemaciclib arm compared to 17.46 months in the placebo arm. OS was immature at the time of analysis. Adverse events were consistent with previous reports. Conclusions: Abemaciclib + NSAI demonstrated a generally tolerable safety profile and was an effective initial treatment for pts with HR+, HER2- ABC, significantly improving PFS and ORR. Citation Format: Matthew P. Goetz, Miguel Martin, Angelo Di Leo, Seock-Ah Im, Ahmad Awada, Tammy Forrester, Martin Frenzel, Joanne Cox, Susana Barriga, Masakazu Toi, Hiroji Iwata, Stephen Johnston. MONARCH 3: Abemaciclib as initial therapy for patients with HR+, HER2- advanced breast cancer - Results from the preplanned final PFS analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT040.

Abstract Background In the past decade, opioid use in the general population of the US has increased dramatically. Concomitantly, opioid-related morbidity and mortality have also risen steeply. The causes of opioid over-prescribing are multifactorial, with pressure from medical agencies, patients, aggressive patient-directed marketing, and use of patient surveys as an evaluation tool to unduly influence medical providers' decision-making. Providers also have significant concerns regarding scrutiny from their medical board and exposure to medicolegal liability. Content To provide the basis for best practice recommendations, several aspects of modern opioid prescribing practice require review. The practicing clinician should be aware of: (a) the pervasiveness of current opioid prescribing within the US; (b) the availability and applicability of clinical tools used to assess patient risk; (c) the new guidelines designed to facilitate appropriate and safe medical use of opioids; (d) the incorporation of clinical tools and best documentation practices to reduce medicolegal exposure. Summary On completion of this review, the reader should be able to recognize the magnitude of the problem of opioid over-prescribing in the US and identify several patient risk factors for opioid misuse, abuse, and/or diversion. Specifically, better familiarity with the recently published CDC guidelines for opioid prescribing will help ensure the adoption of best-use practices that maximize therapeutic efficacy while attenuating the possibility of harm to patients. A thorough review of the legal principles and risk-mitigation strategies relevant to opioid prescribing will also lessen the clinician's exposure to medicolegal liability.

Background Current thermal ablation methods for atrial fibrillation, including radiofrequency and cryoablation, have a suboptimal success rate. To avoid pulmonary vein (PV) stenosis, ablation is performed outside of the PV, despite the importance of triggers inside the vein. We previously reported on the acute effects of a novel direct current electroporation approach with a balloon catheter to create lesions inside the PVs in addition to the antrum. In this study, we aimed to determine whether the effects created by this nonthermal ablation method were associated with irreversible lesions and whether PV stenosis or other adverse effects occurred after a survival period. Methods and Results Initial and survival studies were performed in 5 canines. At the initial study, the balloon catheter was inflated to contact the antrum and interior of the PV. Direct current energy was delivered between 2 electrodes on the catheter in ECG‐gated 100 μs pulses. A total of 10 PVs were treated demonstrating significant acute local electrogram diminution (mean amplitude decrease of 61.2±19.8%). After the survival period (mean 27 days), computed tomography imaging showed no PV stenosis. On histologic evaluation, transmural, although not circumferential, lesions were seen in each treated vein. No PV stenosis or esophageal injury was present. Conclusions Irreversible, transmural lesions can be created inside the PV without evidence of stenosis after a 27‐day survival period using this balloon‐based direct current ablation approach. These early data show promise for an ablation approach that could directly treat PV triggers in addition to traditional PV antrum ablation.

AbstractBackgroundTransvenous lead implantation has multiple drawbacks and complications that can be overcome by epicardial lead placement. We aimed to design percutaneously implanted epicardial leads that are anchored through the transverse sinus (TS).Methods and resultsWe designed a novel multielectrode pacing device with four bipole electrode pairs. The device is advanced through the TS, with both ends externalized out of the pericardium. We tested the prototype in one proof‐of‐concept and 5 additional acute canine experiments.The TS device recorded ventricular and atrial electrograms. The median amplitude of near‐field ventricular electrograms was 3.3 mA (IQR 2.0–4.3) and of near‐field atrial electrograms was 2.1 mA (IQR 1.3–2.2). The median ventricular threshold (N = 30) was 1.1 mA (IQR 0.7–3.1) at a median pulse width of 0.5 ms (IQR 0.5–0.5). The median atrial threshold (N = 10) was 2.4 mA (IQR 1.1–7.8) at a median pulse width of 0.5 ms (IQR 0.5–0.9). Right and left ventricular and atrial pacing morphologies were noted while pacing electrodes adjacent to these chambers. Simultaneous left (LV) and right ventricular (RV) pacing showed reduction in QRS duration from 116 ms (RV) and 105 ms (LV) to 91 ms. On necropsy, the device was located in the TS in all animals. There were TS abrasions in one animal, and no other acute complications.ConclusionsThis study highlights a novel approach to epicardial pacing harnessing the unique anatomy of the transverse sinus as an anchoring point. Placement of this novel transverse sinus device was safe and feasible, with acceptable atrial and ventricular thresholds.