tbuckley/cabot-search huggingface dataset:
Adherence to breast cancer treatment guidelines according to pathogenic variants in cancer susceptibility genes in a population-based cohort.
Authors: Steven J. Katz, Monica Morrow, Allison W. Kurian
Journal: Journal of Clinical Oncology (2019)

34 Background: Increasing use of germline genetic testing may have unintended consequences on breast cancer treatment. We do not know whether treatment deviates from guidelines for women with pathogenic variants (PV) in cancer susceptibility genes. Methods: SEER data for all women aged ≥20 years, diagnosed with breast cancer in 2014-15 and reported to Georgia and California registries (N=77,588) by December 1, 2016 were linked to germline genetic testing results from 4 laboratories that did nearly all clinical testing. We examined first course of therapy of stage &lt;IV patients who linked to a genetic test: bilateral mastectomy (BLM) in candidates for surgery (unilateral, stages 0-III); post-lumpectomy radiation in those with an indication (all but age ≥70, stage I, hormone receptor (HR)-positive and HER2-negative); and chemotherapy in those without definitive indication (stage I-II, HR-positive, HER2-negative and 21-gene recurrence score &lt;30). We report the percent treated based on multivariable modeling, adjusted for age, race, stage, grade, insurance and socioeconomic status. Results: The table shows that 9% of patients who linked to a genetic test result had a PV (N=1,283). Compared to women with negative results, those with BRCA1/2 PVs were more likely to receive BLM, more likely to receive chemotherapy without definitive indication, and less likely to receive indicated radiation as initial treatment. Lower-magnitude effects were seen with other PVs but not variants of uncertain significance (VUS). Conclusions: In a population-based setting, women with PVs in BRCA1/2 or other cancer susceptibility genes may have higher risk of receiving locoregional and systemic treatment that does not follow guidelines. [Table: see text]
High Throughput Screening, With a Flow Cytometry Automated Platform (Ex vivo Biotech), To Identify Potential Combination Partners, For The JAK 2 Inhibitor Ruxolitinib
Authors: Alicia Arenas, Pilar Hernandez-Campo, Daniel Primo, Santiago Barrio, Rosa M. Ayala, Joan Ballesteros, Joaquín Martínez-López
Journal: Blood (2013)
Maintaining clinical pathways: What does it really take?
Authors: Debra McNeil, Joanna M. Hamilton, Emily Meserve, Victoria Hayne, Laura Holtz, Matthew Wolfson, Dana Milne, David Michael Jackman, Houry Leblebjian, Joseph O. Jacobson, Carole Kathleen Tremonti
Journal: Journal of Clinical Oncology (2019)

305 Background: Building pathways to support clinical decision making is one step, maintaining them is a mountain. Dana-Farber Cancer Institute has built 34 medical oncology (MO) pathways (PWs) and 27 radiation oncology (RO) PWs. These PWs are managed by 28 lead MDs, 8 pharmacists, 6 project managers (PMs), 1 data analyst and 1 coordinator. Once PWs are built, attention shifts to platform and content maintenance. Methods: Maintaining PW clinical and informatics content is complicated and laborious. It requires collaboration amongst clinical and non-clinical experts; these resources form the PW team. PW content is updated quarterly or semi-annually, based on the pace of scientific change in a disease. These review meetings serve as a forum for physicians to review, discuss and revise content. Infrastructure support is provided by the PW team. Supporting the meeting requires a pre-meeting, the formal review meeting, a post meeting, and extensive revisions and content validation along the way. To prepare, PW performance data and emerging relevant evidence is reviewed with the lead MD to establish the meeting agenda. In both MO and RO the PW team is responsible for all content management. Results: We reviewed 6 months of data (2/18-7/18) and analyzed the hours and cost to maintain the pathway portfolio. Conclusions: PW maintenance is costly therefore labor efficiency is critical to overall success. There are 4 strategies for success: building trust; MD engagement; data; and program coordination. The MD/PM relationship is the foundation and consistency is key. MD engagement is crucial; having an influential lead MD sets the tone for the disease center overall. Establishing clear expectations and frequent check-ins keeps the lead MD engaged. Actionable, frequent, and transparent data reports give MDs feedback on their practice patterns. The coordinator is a central point of contact and ensures programmatic execution and success. Though PW maintenance is resource intensive, it facilitates standardized decision-making for the dissemination of cutting-edge cancer care. [Table: see text]
Cascades of Care After Incidental Findings in a US National Survey of Physicians
Authors: Ishani Ganguli, Arabella L. Simpkin, Claire Lupo, Arlene Weissman, Alexander J. Mainor, E. John Orav, Meredith B. Rosenthal, Carrie H. Colla, Thomas D. Sequist
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Incidental findings on screening and diagnostic tests are common and may prompt cascades of testing and treatment that are of uncertain value. No study to date has examined physician perceptions and experiences of these cascades nationally. <h3>Objective</h3> To estimate the national frequency and consequences of cascades of care after incidental findings using a national survey of US physicians. <h3>Design, Setting, and Participants</h3> Population-based survey study using data from a 44-item cross-sectional, online survey among 991 practicing US internists in a research panel representative of American College of Physicians national membership. The survey was emailed to panel members on January 22, 2019, and analysis was performed from March 11 to May 27, 2019. <h3>Main Outcomes and Measures</h3> Physician report of prior experiences with cascades, features of their most recently experienced cascade, and perception of potential interventions to limit the negative consequences of cascades. <h3>Results</h3> This study achieved a 44.7% response rate (376 completed surveys) and weighted responses to be nationally representative. The mean (SE) age of respondents was 43.4 (0.7) years, and 60.4% of respondents were male. Almost all respondents (99.4%; percentages were weighted) reported experiencing cascades, including cascades with clinically important and intervenable outcomes (90.9%) and cascades with no such outcome (94.4%). Physicians reported cascades caused their patients psychological harm (68.4%), physical harm (15.6%), and financial burden (57.5%) and personally caused the physicians wasted time and effort (69.1%), frustration (52.5%), and anxiety (45.4%). When asked about their most recent cascade, 33.7% of 371 respondents reported the test revealing the incidental finding may not have been clinically appropriate. During this most recent cascade, physicians reported that guidelines for follow-up testing were not followed (8.1%) or did not exist to their knowledge (53.2%). To lessen the negative consequences of cascades, 62.8% of 376 respondents chose accessible guidelines and 44.6% chose decision aids as potential solutions. <h3>Conclusions and Relevance</h3> The survey findings indicate that almost all respondents had experienced cascades after incidental findings that did not lead to clinically meaningful outcomes yet caused harm to patients and themselves. Policy makers and health care leaders should address cascades after incidental findings as part of efforts to improve health care value and reduce physician burnout.
Efficacy of Maintenance Therapy after Autologous Hematopoietic Stem Cell Transplantation in High-Risk Aggressive Lymphoma: A Single-Center Prospective Non-Randomized Study
Authors: Yongquan Chen, Zhihong Zheng, Xiaofeng Luo, Jinhua Ren, Haili Geng, Hajji Ally Issa, Zhizhe Chen, Jianda Hu, Ting Yang
Journal: Blood (2018)
Biological Activity and Selectivity for Tpo Receptor of the Orally Bioavailable, Small Molecule Tpo Receptor Agonist, SB-497115.
Authors: Connie Erickson-Miller, Evelyn Delorme, Leslie Giampa, Christopher Hopson, Elizabeth Valoret, Shin-Shay Tian, Stephen G. Miller, Richard Keenan, Jon Rosen, Susan Dillon, Kevin Duffy, Peter Lamb, Juan Luengo
Journal: Blood (2004)
Endocuff vision-assisted vs. standard polyp resection in the colorectum (the EVASTA study): a prospective randomized study
Authors: Guido von Figura, Moritz Hasenöhrl, Bernhard Haller, Alexander Poszler, Jörg Ulrich, Hayley Brown, Mohamed Abdelhafez, Roland M. Schmid, Stefan von Delius, Peter Klare
Journal: Endoscopy (2019)

Abstract Background Cap-assisted colonoscopy is frequently used to facilitate adenoma detection during endoscopy. However, data on how cap assistance influences polyp resection are scarce. We aimed to evaluate the impact of cap assistance with the Endocuff vision device (EVD) on the resection time for colorectal polyps in patients undergoing colonoscopy. Methods A randomized, prospective study was performed in a university hospital in Germany. A total of 250 patients were randomly assigned 1:1 to undergo either colonoscopy with the EVD (EVD arm) or standard colonoscopy without the use of a cap (standard arm). The primary outcome was the average duration of polypectomy. Secondary outcomes included adenoma detection rate, cecal and ileal intubation times, and propofol dosage. Results The use of EVD led to a significant reduction in the median polypectomy time in the EVD vs. standard arm (54 vs. 80 seconds, respectively; P = 0.02). This effect was strongest for polyps ≥ 6 mm. Compared with the standard group, Endocuff assistance also resulted in a shorter cecal intubation time (6 vs. 8 minutes; P = 0.03) and overall colonoscopy time (23 vs. 27 minutes; P = 0.02). In contrast, no difference in withdrawal time was observed. The polyp and adenoma detection rates did not differ significantly between the two groups. Conclusion Endocuff-assisted colonoscopy reduces the duration of polypectomy, which may be due to a more stable scope position during resection. Further studies are needed to investigate whether comparable effects will be seen for other interventions, such as clipping or biopsy sampling.
Capturing discrete complete staging elements in EPIC for new and progressing breast (B) and prostate (P) cancer patients: A quality training program pilot.
Authors: Linda D. Bosserman, Denise Morse, Kathleen McNeese, Ridaa Atcha, Niki Himat Patel
Journal: Journal of Clinical Oncology (2019)

117 Background: Staging is a fundamental quality metric. Entry of discrete elements of staging in the EHR supports &amp; improves efficiencies for clinical notes, therapy summaries, survivorship plans, clinical decision making, pathway use, timely authorizations, clinical trial eligibility evaluations, as well as clinical, financial &amp; quality outcomes. Staging of all new &amp; progressing patients in our EPIC EHR was set as a priority in 2018 but baseline entry through 2018 was below target goals. Methods: A Staging QTP project group was formed &amp; participated in the COH-ASCO QTP Fall training. Baseline capture of staging data in EPIC for campus and community (enterprise) sites for Breast (B) &amp; Prostate (P) patients was collected. QTP processes were used to develop and implement a 12-week pilot with PDSA cycles at weeks 8 and 12. B &amp; P cancer patients seen by 3 B &amp; 2 P medical oncologists (MO), 5B surgeons (S) &amp; 3P urologists (U) agreed to participate in a pilot study. Disease leads determined the elements of complete staging: 9-10 for B &amp; 8 for P. Training was done for all campus APPs &amp; for doctors in the pilot. Follow up by the QTP team was done at clinics during the pilot. Reports were built to capture specific staging elements for B &amp; P patients by doctor. Reports were sent out starting week 9 indicating patients without complete staging with missing elements. A survey about the process was done by participant MDs &amp; APPS weeks 8 &amp; 12. Results: Baseline enterprise wide complete staging in Epic was 6% for B cancer &amp; 3% for P cancer. 6 week PDSA showed capture of complete staging for B-MO &amp; S was 20% and for P-MO &amp; U was 12%. QTP Pilot ends 6/19 &amp; abstract data will be updated for the staging &amp; survey results. Additional results on complete staging for progressing patients is being captured. Conclusions: Complete staging in the EHR requires definition, training, resourcing, leadership support and feedback. Initial results show all new patients had initial staging data entered and complete staging rates increased significantly for new B &amp; P cancer patients before weekly feedback was sent. Analysis of survey results will inform future PDSA cycles &amp; plans for complete staging enterprise wide.
Abstract 373: Regulation of Hypoxia by Chromatin Reader Protein Kinase C Binding Protein 1 (PRKCBP1)
Authors: Kathryn J Schunke, Ralph V Shohet
Journal: Circulation Research (2019)

PRKCBP1 (also known as RACK7 and Zmynd8) is a polyvalent chromatin reader known to cooperatively bind acetylated and methylated nucleosomes. Recently it has been shown to regulate transcription and cancer progression by coordinating histone methylation modifications affecting enhancer and promoter regions of genes. The role of PRKCBP1 in the cardiac myocardium is unexplored. Hypoxia-inducible factor 1α (HIF-1α) upregulation and stabilization is a common feature of both cancer and myocardial ischemia, promoting cellular functions such as proliferation, glucose metabolism and angiogenesis. Here we investigated the mechanism by which PRKCBP1 modulates the cardiac hypoxic response. We hypothesize that PRKCBP1 inhibits the HIF-1 response in the hypoxic heart by reducing enhancer activity of HIF-1 target genes and altering availability of HIF-1 binding sites. We have found that in transgenic mice with a mutation that increases HIF-induced expression of PRKCBP, the effect of induced oxygen-stable HIF is markedly diminished. These mice did not exhibit the typical HIF-1 over-expression phenotype of dilated vessels, increased heart size and reduced ventricular function. Semi-quantitative rtPCR analysis of mouse neonatal cardiomyocytes transfected with CMV-driven expression plasmids for PRKCBP1 and oxygen-stable HIF-1α showed striking reduction of multiple HIF-1 target genes such as PDK1 (45% reduction relative to Ehbp1) compared to the HIF-1α plasmid alone. RNAi mediated knockdown of PRKCBP1 removed this negative regulation (65% increase). Analysis of human PRKCBP1 and HIF-1α ChIP-seq data indicate that PRKCBP1 binds to the enhancer of 78% of HIF-1 regulated genes. ATAC-seq data suggest that PRKCBP1 affects genome-wide chromatin accessibility, with loci-specific modifications at numerous HIF-1 target genes, such as EGLN3. These data suggest that PRKCBP1 may be acting both by modulating enhancer activity in cis - to HIF-1 target genes and by preventing HIF-1 binding to hypoxia response elements of target genes. We have discovered a new regulator of HIF-1 action that modifies the hypoxic response, likely through chromatin remodeling. This new form of regulation may modify the pathophysiology of ischemia and provide new targets for therapy.
Abstract 575: Loss of Function Variant in CYB5R3 Associates With Exacerbated Cardiac Hypertrophy in Mice
Authors: Nolan T Carew, Scott Hahn, Megan P Miller, Kathrine Wood, Patrick H Thideau, Brett A Kaufman, Dennis M McNamara, Adam C Straub
Journal: Circulation Research (2019)

African Americans (AA) are 20 times more likely to be diagnosed with heart failure (HF) before the age of 50 and 2 times more likely to die from heart failure. Previous reports have shown AA with HF have diminished nitric oxide (NO) signaling, a pathway critical for cardiac contractility. NO signals, in part, via binding reduced heme iron (Fe 2+ ) in soluble guanylyl cyclase (sGC) leading to cyclic guanosine monophosphate (cGMP) generation. Recently, our lab reported that cytochrome b5 reductase 3 (Cyb5R3) reduces oxidized sGC heme-iron from the oxidized (Fe 3+ ) to the reduced (Fe 2+ ) state, thereby sensitizing sGC to NO. However, the role of Cyb5R3 in the setting of HF remains elusive. It is known that a high frequency Cyb5R3 T117S single nucleotide polymorphism (23% minor allele frequency) exists and is enriched in individuals with African ancestry. To determine the impact of T117S in HF outcomes, we completed a retrospective study from AHEFT and GRACE trials. Our data show that Cyb5R3 T117S carriers have significantly accelerated time to death/transplant. Additionally, biobank HF samples from AA samples show an enrichment of Cyb5R3 T117S carriers from 0.23 to 0.4. To assess the impact of Cyb5R3 T117S on sGC/cGMP signaling in the heart, ventricular cGMP levels in AA with HF were examined. Pooled Cyb5R3 T117S carriers have significantly decreased cGMP relative to non-carriers. Next, we determined if this variant impacts sGC heme redox state. Using purified protein activity assays, we found that Cyb5R3 T117S results in a 60% loss-of-function and an inability to reduce oxidized sGC. Lastly, to test the in vivo impact of the Cyb5R3 T117S variant in heart failure, we generated a novel Cyb5R3 T117S mouse. Transverse aortic constriction (TAC) studies in Cyb5R3 T117S mice show significantly accelerates cardiac hypertrophy relative to wild-type TAC controls. Taken together, these data suggest Cyb5R3 T117S may be a disease modifying variant that augments hypertrophic signaling through an sGC-dependent mechanism.
Launch of telemedicine in community oncology practice.
Authors: L. Johnetta Blakely, Natalie R. Dickson, Jack William Erter, Carolyn Craig, Holly Bushart, David Stewart, Mary Darden, Ann Ripley, Stacey L Poole, Susan Frailey, Jeffrey Patton
Journal: Journal of Clinical Oncology (2019)

275 Background: Tennessee Oncology (TO) is a community medical, radiation and gynecology oncology practice with 90 physicians and 40 advanced practice providers (APPs) in 33 locations in Tennessee. TO participates in the Oncology Care Model (OCM), a CMMI experimental payment model to improve access, quality of care, patient experience and lower costs. Methods: To promote provider-patient communication to improve outcomes and lower healthcare costs, TO launched a telemedicine pilot. The pilot was designed to understand Tennessee’s rules and regulations, reimbursement policies for Medicare, Medicaid and commercial payers and technology requirements. As survivorship was aligned with clinical workflow, supported by existing technology and required minimal staff training, the Survivorship Program for OCM was selected as proof of concept for telemedicine. Education surrounding Survivorship is required as part of the OCM model. A portion of the MEOS payment was considered as reimbursement for this initiative. The goal was to increase the delivery and review of survivorship documents to eligible breast cancer patients using the telemedicine platform from 0% to 80%. Results: 4000 potential patients were eligible for survivorship visits within TO. The selection was narrowed to include only OCM patients with breast cancer. TO identified 4 APPs who were given special training. TO’s front office staff coordinated scheduling of the technology, provider and space available. There were 99 patients eligible for a Telemedicine visit. 36 patients completed a Telemedicine visit with 23 patients declining. 19 patients did not respond to requests for these visits. 10 patients completed surveys and were 100% satisfied with their visits. The APPs felt Telemedicine visits were more productive than in person visits. Conclusions: Telemedicine is an effective tool for delivery of health care. There are challenges that make this technology difficult to implement such as reimbursement and limitations to the use of technology in elderly. In our pilot we found that the APPs and patients found this to be an effective way of communication and delivery of care. In the future telemedicine could answer some of the shortages in health care delivery and could also improve coordination of care.
Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy
Authors: Rebecca A. Gardner, Francesco Ceppi, Julie Rivers, Colleen Annesley, Corinne Summers, Agne Taraseviciute, Juliane Gust, Kasey J. Leger, Katherine Tarlock, Todd M. Cooper, Olivia C. Finney, Hannah Brakke, Daniel H. Li, Julie R. Park, Michael C. Jensen
Journal: Blood (2019)
Altered RNA Processing in Cancer Pathogenesis and Therapy
Authors: Esther A. Obeng, Connor Stewart, Omar Abdel-Wahab
Journal: Cancer Discovery (2019)

Major advances in our understanding of cancer pathogenesis and therapy have come from efforts to catalog genomic alterations in cancer. A growing number of large-scale genomic studies have uncovered mutations that drive cancer by perturbing cotranscriptional and post-transcriptional regulation of gene expression. These include alterations that affect each phase of RNA processing, including splicing, transport, editing, and decay of messenger RNA. The discovery of these events illuminates a number of novel therapeutic vulnerabilities generated by aberrant RNA processing in cancer, several of which have progressed to clinical development. SIGNIFICANCE: There is increased recognition that genetic alterations affecting RNA splicing and polyadenylation are common in cancer and may generate novel therapeutic opportunities. Such mutations may occur within an individual gene or in RNA processing factors themselves, thereby influencing splicing of many downstream target genes. This review discusses the biological impact of these mutations on tumorigenesis and the therapeutic approaches targeting cells bearing these mutations.
Disease Characteristics and Prognostic Implications Of Cell Surface FLT3 Receptor (CD135) Expression In Pediatric Acute Myeloid Leukemia – A Report From Children’s Oncology Group
Authors: Katherine Tarlock, Todd A. Alonzo, Michael R. Loken, Robert B. Gerbing, Richard Aplenc, Lillian Sung, Susana C. Raimondi, Betsy Hirsch, Samir Kahwash, Amy Heerema-McKenney, Alan S. Gamis, Soheil Meshinchi
Journal: Blood (2013)
Effective Stimulant Dosing in Attention-Deficit/Hyperactivity Disorder—Reply
Authors: Alison S. Poulton, Guy D. Eslick
Journal: JAMA Pediatrics (2019)

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