Citations

AbstractThe European Society of Gastrointestinal Endoscopy (ESGE) presents a short list of performance measures for colonoscopy in inflammatory bowel disease (IBD) patients. Current performance measures for colonoscopy mainly focus on detecting (pre)malignant lesions. However, these performance measures are not relevant for all colonoscopy indications in IBD patients. Therefore, our aim was to provide endoscopy services across Europe and other interested countries with a tool for quality monitoring and improvement in IBD colonoscopy. Eight key performance measures and one minor performance measure were recommended for measurement and evaluation in daily endoscopy practice.

Water devoid RF pulses designed by an evolutionary algorithm and AI improve solvent suppression and increase the NMR spectra sensitivity.

AbstractEnteral nutrition (EN) is a vital component of nutrition around the world. EN allows for delivery of nutrients to those who cannot maintain adequate nutrition by oral intake alone. Common questions regarding EN are when to initiate and in what scenarios it is safe. The answers to these questions are often complex and require an evidence‐based approach. The Board of Directors of the American Society for Parenteral and Enteral Nutrition (ASPEN) established an Enteral Nutrition Committtee to address the important questions surrounding the indications for EN. Consensus recommendations were established based on eight extremely clinically relevant questions regarding EN indications as deemed by the Enteral Nutrition Committee. These consensus recommendations may act as a guide for clinicians and stakeholders on difficult questions pertaining to indications for EN. This paper was approved by the ASPEN Board of Directors.

Abstract Background: The kinases ataxia-telangiectasia-mutated-and-Rad3-related (ATR), checkpoint kinase 1 (CHK1) and WEE1 participate in the response to replication stress. Inhibitors of ATR, WEE1 and CHK1 are being tested for antineoplastic activity as monotherapies and in combination with chemotherapy. Although these agents impair cell cycle checkpoints, fork stabilization, origin firing and homologous recombination (HR), little is known about the apoptotic pathways that are engaged and the critical mediators activating cell death mechanisms. The present study utilizes high grade serous ovarian cancer (HGSOC) cell lines and patient derived xenografts (PDXs) to identify the primary mechanism of cell death in ovarian cancer and assess changes involved in the resistance setting after treatment with these inhibitors. Methods: A panel of HGSOC cell lines was examined for responses to ceralasertib (ATRi), prexasertib (CHK1i) or adavosertib (WEE1i) using colony forming assays, immunoblotting and assays for apoptosis. Mechanisms involved in acquired resistance and downstream changes in cell fate were evaluated by generating prexasertib-resistant HGSOC cell lines. Subsequent NGS analysis was performed in the sensitive and resistant pairs. Results: Irrespective of the homologous recombination (HR) status, ovarian cell lines and PDXs underwent cell death during prolonged exposure at clinically achievable concentrations. Treatment of ovarian cancer cell lines with ATRi, CHK1i or WEE1i activated the replication checkpoint, consistent with previously published reports. The subsequent apoptotic response involved PMAIP1 and BCL2L11 upregulation rather than the TNFa-induced death receptor-mediated apoptosis we recently described in acute leukemia (Cancer Res. PMID: 33414171). Additionally, ovarian lines selected for CHK1i resistance failed to die in response to either ATRi or WEE1i. Conclusions: Prexasertib, ceralasertib, and adavosertib exhibit monotherapy activity in both HR deficient and proficient HGSOC cell lines and PDX models. Unlike AML, death receptor mediated apoptosis was not observed; instead, the primary mechanism of cell killing in HGSOC lines involves activation of the mitochondrial apoptotic pathway. Cross-resistance of these DNA damage repair modulators is likely multifactorial and mainly involves diminished replication stress response. Citation Format: Annapoorna Venkatachalam, Kevin L. Peterson, Cristina Correia, Karen S. Flatten, Xianon Hou, Paula A. Schneider, Emily Balczewski, Cordelia McGehee, Rachel M. Hurley, Xue W. Meng, Chance Sine, Rameen Shah, Nicole Vincelettte, Husheng Ding, Hu Li, Saravut (John) Weroha, Scott H. Kaufmann. CHK1 inhibitor prexasertib induces NOXA-dependent apoptosis in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1832.

Abstract Background: Large scale genetic perturbations screens have been instrumental for many key discoveries. In the last decade sequence specific genetic perturbations created RNAi and CRISPR (PMID: 25446316). Recently, specific genome targeting approaches using single guide RNAs (sgRNAs) for the CRISPR-Cas9 system have been repurposed to induce sequence-specific repression or activation of gene expression at a genome-wide scale. Different perturbation approaches have different effects and encompass a trade-off between specificity and duration in establishing a measurable perturbation which can result in different biological readouts. However, bench-side strategies are time consuming and expensive. The method described here aims to build a systems-based computational platform to assess pharmacological and biological perturbations at genome-wide network level.Methods: Our network tool NetDecoder (Nucleic Acids Res. 2016; 44(10):e100) that models genome-wide information flow will be used to build context specific protein-protein interaction networks. These networks will be subsequently subjected to in silico perturbations and their impacts on network properties will be assessed. AVANA and Demeter datasets will be used during method validation procedures. Results: Using publicly available expression datasets we generated context specific Breast Cancer networks and individually manipulated nodes and edges of context-specific networks associated with pharmacological FDA approved targets. Our perturbation networks captured cellular rewiring by engulfing new gene players, alterations of the network size and its connectivity. Conclusions: Our in-silico genome wide perturbation platform provides a flexible approach to fine-tune single and tandem manipulations, allowing for inexpensively monitoring a range of pharmacological interventions using large omics data. Citation Format: Cristina Correia, Choong Yong Ung, Cheng Zhang, Scott H. Kaufmann, Hu Li. A genome wide pharmacological perturbation platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1226.

Abstract Current understandings of individual disease etiology and therapeutics are limited despite great need. To fill the gap, we propose a novel computational pipeline which collects potent disease gene cooperative pathways to envision individualized disease etiology and therapies. Our algorithm constructs individualized disease modules de novo which enable us to elucidate the importance of mutated genes in specific patients and to understand the synthetic penetrance of these genes across patients. We reveal that importance of notorious cancer drivers TP53 and PIK3CA fluctuate widely across breast cancers and peak in tumors with distinct numbers of mutations, and that rarely mutated genes such as XPO1 and PLEKHA1 have high disease module importance in specific individuals. Furthermore, individualized module disruption enables us to devise customized singular and combinatorial target therapies which were highly varied across patients demonstrating the need for precision therapeutics pipelines. As the first analysis of de novo individualized disease modules, we illustrate the power of individualized disease modules for precision medicine by providing deep novel insights on the activity of diseased genes in individuals. Citation Format: Taylor Weiskittel, Cristina Correia, Choong Ung, Cheng Zhang, Hu Li. De novo individualized disease modules reveal the synthetic penetrance of genes and inform personalized treatment regimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 490.

AbstractBackgroundSudden cardiac death (SCD) is common after orthotopic heart transplant (OHT). No clear guidelines for implantable cardioverter defibrillator (ICD) implantation in OHT patients at high risk for SCD currently exist.ObjectivesTo assess the safety, efficacy, and benefit of ICDs and resynchronization therapy post‐OHT. We also provide a systematic review of previous reports.MethodsA retrospective multicenter cohort study within the United States. Patients with ICD post‐OHT between 2000 and 2020 were identified.ResultsWe analyzed 16 patients from 4 centers. The mean standard‐deviation (SD) age was 43 (18) years at OHT and 51 (20) years at ICD implantation. The mean (SD) duration from OHT to ICD implantation was 9 (5) years. The mean (SD) left ventricular ejection fraction (LVEF) was 35% (17%). There were 2 (13%) postprocedural complications: 1 hematoma and 1 death. Mean (SD) follow‐up was 24 (23) months. Survival rate was 63% (10/16) at 1 year and 56% (9/16) at 2 years, with 6/7 of those who died having LVEF < 35% at the time of the ICD implantation. Patients were more likely to receive appropriate therapy if their ICD was implanted for secondary (5/8) rather than primary (0/8) prevention (p = .007). Of those who did, 4 patients survived to 30 days post‐ICD therapy. Severe CAV was not associated with the rate of appropriate therapy.ConclusionsBeneficial outcomes were observed when ICDs were implanted for secondary prevention only, and in patients with higher baseline LVEF. We also observed benefits with resynchronization therapy.

8027 Background: The Connect MM Registry is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed multiple myeloma (NDMM) and one of the largest, longest running MM registries. Long-term survivors (LTS), defined as patients (pts) who have ≥ 8 years of follow-up, comprise a large portion of the Connect MM Registry. The purpose of this analysis was to assess LTS demographic and clinical characteristics. Methods: Adult pts with NDMM (N = 3011) were enrolled from 250 community, academic, and government sites: Cohort 1 from 2009 – 2011 and Cohort 2 from 2012 – 2016. As 99% of LTS were enrolled in Cohort 1, only pts from Cohort 1 were included in this analysis. Pt data were unevaluable if there were missing treatments, disease assessments, or large gaps in activity during follow-up (n = 28). Baseline characteristics, treatment patterns, and quality of life (QoL) form completion rates were examined. Results: At data cutoff (5/17/21), of the 1493 pts in Cohort 1 with evaluable data, 279 were LTS and 1186 were non-LTS. LTS were generally younger and had better performance status at enrollment (Table). Most (66%) LTS received stem cell transplants and few experienced progression within the first 6 months (3%). Top first-line (1L) regimen for LTS was lenalidomide/bortezomib/dexamethasone (31%) vs bortezomib/dexamethasone (22%) in non-LTS. At data cutoff, 73% of LTS were still on treatment at their most recent visit. LTS underwent disease assessments more frequently (2.0 vs 1.3 per year) and had a higher QoL completion rate by year 5 (58% vs 46%). This analysis showed an estimated 8-year survival of 36% vs an observed 8-year survival of 39% from the SEER database. Additional analyses are ongoing. Conclusions: LTS were younger and healthier than non-LTS. Most LTS received triplets at induction, stem cell transplants in 1L, and were less likely to relapse within the first 6 months of treatment than non-LTS. These findings are consistent with what has been observed in MM clinical trials. Further, this analysis demonstrates the value of longitudinal data in the CONNECT MM Registry and provides insights on long surviving pts with MM. Clinical trial information: NCT01081028. [Table: see text]