tbuckley/cabot-search huggingface dataset:
Publisher Correction: RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice
Authors: Denuja Karunakaran, Adam W. Turner, Anne-Claire Duchez, Sebastien Soubeyrand, Adil Rasheed, David Smyth, David P. Cook, Majid Nikpay, Joshua W. Kandiah, Calvin Pan, Michele Geoffrion, Richard Lee, Ludovic Boytard, Hailey Wyatt, My-Anh Nguyen, Paulina Lau, Markku Laakso, Bhama Ramkhelawon, Marcus Alvarez, Kirsi H. Pietiläinen, Päivi Pajukanta, Barbara C. Vanderhyden, Peter Liu, Scott B. Berger, Peter J. Gough, John Bertin, Mary-Ellen Harper, Aldons J. Lusis, Ruth McPherson, Katey J. Rayner
Journal: Nature Metabolism (2020)
Autophagy and liver cancer
Authors: Xiaojuan Chao, Hui Qian, Shaogui Wang, Sam Fulte, Wen-Xing Ding
Journal: Clinical and Molecular Hepatology (2020)

Autophagy is a highly conserved catabolic process that degrades cytosolic proteins and organelles via formation of autophagosomes that fuse with lysosomes to form autolysosomes, whereby autophagic cargos are degraded. Numerous studies have demonstrated that autophagy plays a critical role in the regulation of liver physiology and homeostasis, and impaired autophagy leads to the pathogenesis of various liver diseases such as viral hepatitis, alcohol associated liver diseases (AALD), non-alcoholic fatty liver diseases (NAFLD), and liver cancer. Recent evidence indicates that autophagy may play a dual role in liver cancer: inhibiting early tumor initiation while promoting progression and malignancy of already formed liver tumors. In this review, we summarized the progress of current understanding of how hepatic viral infection, alcohol consumption and diet-induced fatty liver diseases impair hepatic autophagy. We also discussed how impaired autophagy promotes liver tumorigenesis, and paradoxically how autophagy is required to promote the malignancy and progression of liver cancer. Understanding the molecular mechanisms underlying how autophagy differentially affects liver cancer development and progression may help to design better therapeutic strategies for prevention and treatment of liver cancer.
Phase I Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-positive <i>EGFR</i>-mutant Non–small Cell Lung Cancer
Authors: Helena A. Yu, Luis G. Paz-Ares, James Chih-Hsin Yang, Ki Hyeong Lee, Pilar Garrido, Keunchil Park, Joo-Hang Kim, Dae Ho Lee, Huzhang Mao, Sameera R. Wijayawardana, Ling Gao, Rebecca R. Hozak, Bo H. Chao, David Planchard
Journal: Clinical Cancer Research (2020)

We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant non-small cell lung cancer (NSCLC).This open-label, single-arm phase I study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation.Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with (N = 10) and without central nervous system (CNS) metastasis (N = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6-21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification.Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.See related commentary by Garon, p. 905.
ECO Experts’ consensus on establishing renal cancer healthcare quality measures in Spain.
Authors: Vicente Guillem, Javier Puente, Carlos Camps, Miguel Ángel Climent Durán, Enrique Gallardo Diaz, Aránzazu González del Alba, Martín Emilio Lázaro Quintela, María José Méndez Vidal, Cristina Antón, Fernando Caballero, Francisco J. Campos, Ilse Lugo, Diana Monge, Álvaro Rogado, Irene Santamaría Rodríguez, Alvaro Pinto, Ignacio Duran
Journal: Journal of Clinical Oncology (2020)

220 Background: The ECO Foundation (Excellence and Quality in Oncology) proposes to establish a set of healthcare quality measures (including indicators and standards) for the diagnosis, treatment and follow-up of renal cancer in Spain which all healthcare professionals involved can assume, being suitable for implementation in the continuous improvement process of our healthcare system. Methods: a) International literature review on the quality of healthcare in renal cancer; b) multidisciplinary driving group (9 oncologists with expertise in renal cancer plus 2 methodologists) to identify and choose possible quality measures to be applied in Spain; c) global evaluation of the relevance of these measures through experts’ consensus (Delphi modified by a stratified state panel, n = 55 oncologists specialized in renal cancer); d) selection of definitive measures, according to their feasibility and efficiency (information provided/effort in obtaining it) using a quantitative online priority grid; e) standard wording of the chosen measures: definition, indicator, sources of information, exclusions, clarifications, categorization and acceptable standard. Results: The nominal group proposed 43 quality measures for the Delphi panel. Consensus agreement rate = 84.5% (47/55). The professional consensus was reached on 40 measures (4 structural, 33 in healthcare procedures and 3 in clinical results). Therefore, there is a high level of consensus (93%) among Spanish oncologists who specialize in renal cancer on the content of the healthcare quality measures in the management of renal cancer. The final measures were chosen using a high confidence level (95%) in the unanimity of the experts (oncologists in the driving group) for prioritization depending on the feasibility and efficiency in the healthcare system. Finally, 25 measures were chosen (2 structural, 20 in procedures and 3 in results). Conclusions: The level of consensus and prioritization of measures achieved, will most likely translate in a widespread acceptance and viability for implementation in the National Health System. This could provide a valuable tool for quality assessment and equality in the care of renal cancer patients in Spain.
Development and implementation of an evidence-based malignant hematology clinical pathway program.
Authors: Amanda Brahim, Fernando Manuel Vargas Madueno, Robert Wilkinson, Melissa Hardwick, Yehuda Ethan Deutsch, Jose David Sandoval-Sus, Hugo Francisco Fernandez
Journal: Journal of Clinical Oncology (2020)

304 Background: Clinical pathways provide a means to maximize value-based care for cancer patients. They have been associated with decreased costs and outcome improvements. Our institution entered a transformative partnership with an NCI designated comprehensive cancer center for the treatment of hematologic malignancies. As part of the collaboration, a multidisciplinary task force was established to adapt clinical pathways within our system. Given the multiple new drug approvals for the treatment of Acute Myeloid Leukemia (AML), this was the first pathway created. Methods: The taskforce consisted of physicians, pharmacists, nurses, quality manager, and information technology staff. The group met weekly to draft algorithms in accordance with national guidelines, updated evidence and institutional preferences. Electronic Medical Record (EMR) treatment plans were reviewed in a secondary multidisciplinary workgroup and validated to ensure compliance with the AML pathway. When applicable, specific criteria for use were developed to aid in medication use optimization. The finalized pathway and treatment plans were presented and approved at our clinical standards committee meeting. A chart audit was performed one year after pathway implementation to assess adherence, with a goal of 80% or higher. The results were compared to an audit assessing adherence to best available clinical evidence for the year prior to implementation. Results: The group established a consensus on treatment, laboratory testing, and supportive care, including anti-emetic, anti-microbial, and tumor lysis syndrome (TLS) prophylaxis. Electronic order sets were created for bone marrow biopsies, transfusion support, TLS and febrile neutropenia. Thirty-two EMR treatment plans for AML were built and/or revised, while five were inactivated. A total of 88 patient charts were included in the pathway adherence audit (44 before and 44 after implementation). Pre and post pathway adherence was 64% and 89%, respectively (p=0.006). Deviations were categorized by type (table). Conclusions: AML pathway development and implementation resulted in standardization of treatment regimens, supportive care and higher adherence to institutional evidence based practices. [Table: see text]
Care coordination challenges between a high-volume center and rural physicians treating patients with pancreatic cancer.
Authors: Matthew DePuccio, Natasha Kurien, Angela Sarna, Ann Scheck McAlearney, Aslam Ejaz
Journal: Journal of Clinical Oncology (2020)

58 Background: Pancreatic cancer (PC) patients treated at high-volume centers (HVCs) benefit from specialty services that may not be accessible to rural patients: complex treatment planning, advanced surgical and chemo-radiation options, and multidisciplinary team-based care. As a result, rural PC patients often seek treatment at multiple locations for different episodes of care (i.e., chemotherapy and surgery). The facilitators and barriers to coordinating care between rural physicians and HVCs for rural PC patients treated by both types of providers are not well-understood. Methods: We conducted semi-structured interviews with PC specialists (medical, surgical, and radiation oncologists, n = 9) at a HVC (The Ohio State University) actively treating and co-managing rural PC patients with rural physicians. Using rigorous qualitative methods, two co-authors independently coded the interview transcripts to develop a thematic account of HVC-rural physician care coordination barriers and facilitators. Results: Initial interactions between PC specialists and rural PC patients often require duplication of diagnostic testing (i.e., imaging) due to inadequate transfer of medical records at the time of consultation. This is partly due to inefficient phone communication between HVCs and rural physicians. Such inefficiencies often discourage two-way communication between HVCs and rural physicians, and this can hinder development of a shared understanding of patients’ treatment plans. Specialists suggested a dual-approach may help to improve care coordination in this context: (a) developing better personal relationships with rural physicians to facilitate information-sharing and “closing-the-loop” on patients’ treatment plans; and (b) implementing data systems that permit physicians to share patients’ records across organizations. Several specialists acknowledged the benefit of having a dedicated care coordinator who could help patients connect with specialists, navigate the different healthcare systems, and relay information between providers. Conclusions: Given the challenges that can complicate the PC treatment process for rural patients, it is important to consider opportunities to address these issues. Taking steps to improve efficiency in communication may help facilitate the development of cohesive treatment plans and promote team-based care. Further studies are needed to examine the effects of care coordination interventions, like the use of care coordinators, on improving care for rural PC patients.
Improving the efficiency of same-day ill calls.
Authors: Gregory Bociek, Mary Huerter Wells, Teri Schuldt, Tracy Farrell, Duncan Phillips
Journal: Journal of Clinical Oncology (2020)

56 Background: Burnout is a syndrome whose manifestations include pervasive emotional and physical exhaustion, depersonalization, a lack of motivation and an inability to complete tasks efficiently. We sought to use quality improvement (QI) methodology to approach problems contributing to burnout and workplace stress in our oncology care team. Methods: Through a broad survey of cancer center team members, we identified the coordination of same-day outpatient visits for acutely ill oncology patients as a source of excessive stress for team members across various disciplines including case managers, infusion clinic nurses, advanced practice providers, and physicians. We used the Plan-Do-Study-Act (PDSA) framework to identify a feasible, appropriate intervention to reduce the time required to coordinate visits with the specific aim of reducing the time to schedule an ill patients by 25%. We generated a cause and effect diagram to map the elements involved in the ill call scheduling process, and used a priority/payoff matrix to evaluate possible countermeasures that could streamline the process by re-designing/improving the efficiency of the workflow for scheduling ill calls. Our initial workflow involved paging individual practitioners at three locations. The process led us to the creation of a HIPPA-compliant group text to simultaneously coordinate scheduling of an ill call among/between three campuses in a more collaborative/efficient manner. We tracked time from patient call to time of scheduled appointment pre- and post-test of change (Voalte group text). We also tracked quantity of phone calls required to arrange a visit and perceived frustration with the process. Results: After one PDSA cycle, we found case manager time required to arrange a visit had decreased by 21%, number of calls required by 59% and frustration with the process by 41%. Conclusions: While we did not meet our specific aim of decreasing scheduling time by 25%, we feel use of a QI approach led to an easily implemented, yet effective modification to streamline a previously inefficient and disruptive workflow. The use of QI methodology ensured we understood the baseline process and involved all stakeholders before implementing a change and also ensured we followed data to understand the impact of our intervention on team members. Viewing sources of burnout and workplace frustration through the lens of QI may lead to more consistently high-yield interventions than traditional wellness-based, administrative approaches.
Covid-19: Group of UK and US experts argues for “focused protection” instead of lockdowns
Authors: Jeanne Lenzer
Journal: BMJ (2020)

Thousands of medical practitioners and public health scientists have signed a declaration arguing for an alternative public health approach to dealing with covid-19.The Great Barrington Declaration, 1 published on Monday 5 October, was drawn up by three epidemiologists and public health experts from Harvard, Oxford, and Stanford universities, who describe their approach as "focused protection" of the people most at risk.As of Wednesday 7 October almost 6300 medical practitioners and public health scientists from the US, the UK, and other nations had signed the declaration.
Analysis of Sentinel Node Biopsy and Clinicopathologic Features as Prognostic Factors in Patients With Atypical Melanocytic Tumors
Authors: Andrea Maurichi, Rosalba Miceli, Roberto Patuzzo, Francesco Barretta, Gianfranco Gallino, Ilaria Mattavelli, Consuelo Barbieri, Andrea Leva, Umberto Cortinovis, Elena Tolomio, Milena Sant, Gianpiero Castelli, Leonardo Zichichi, Giovanni Pellacani, Ignazio Stanganelli, Marco Simonacci, Ausilia Manganoni, Corrado Del Forno, Gioachino Caresana, Catherine Harwood, Daniele Bergamaschi, Konstantinos Lasithiotakis, Dorothy Bennett, Vittoria Espeli, Cristina Mangas, Sandra Leoni Parvex, Barbara Valeri, Mara Cossa, Marta Barisella, Alessandro Pellegrinelli, Claudia Miranda, Andrea Anichini, Roberta Mortarini, Odysseas Zoras, Mario Santinami
Journal: Journal of the National Comprehensive Cancer Network (2020)

Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients with AMTs.Clinicopathologic and follow-up data of 238 children, adolescents, and adults with histologically proved AMTs consecutively treated at 12 European centers from 2000 through 2010 were retrieved from prospectively maintained databases. The binary association between all investigated covariates was studied by evaluating the Spearman correlation coefficients, and the association between progression-free survival and all investigated covariates was evaluated using univariable Cox models. The overall survival and progression-free survival curves were established using the Kaplan-Meier method.Median follow-up was 126 months (interquartile range, 104-157 months). All patients received an initial diagnostic biopsy followed by wide (1 cm) excision. Sentinel node biopsy was performed in 139 patients (58.4%), 37 (26.6%) of whom had sentinel node positivity. There were 4 local recurrences, 43 regional relapses, and 8 distant metastases as first events. Six patients (2.5%) died of disease progression. Five patients who were sentinel node-negative and 3 patients who were sentinel node-positive developed distant metastases. Ten-year overall and progression-free survival rates were 97% (95% CI, 94.9%-99.2%) and 82.2% (95% CI, 77.3%-87.3%), respectively. Age, mitotic rate/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss were factors affecting prognosis in the whole series and the sentinel node biopsy subgroup.Age >20 years, mitotic rate >4/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss proved to be worse prognostic factors in patients with ATMs. Sentinel node status was not a clear prognostic predictor.
Glycemic Control and the Risk of Acute Kidney Injury in Patients With Type 2 Diabetes and Chronic Kidney Disease: Parallel Population-Based Cohort Studies in U.S. and Swedish Routine Care
Authors: Yang Xu, Aditya Surapaneni, Jim Alkas, Marie Evans, Jung-Im Shin, Elizabeth Selvin, Alex Chang, Morgan E. Grams, Juan Jesus Carrero
Journal: Diabetes Care (2020)

OBJECTIVE Patients with diabetes and chronic kidney disease (CKD) have increased susceptibility to acute kidney injury (AKI), but mechanisms are unclear. We investigated the association of glycemic control with risk of AKI. RESEARCH DESIGN AND METHODS In two observational cohorts of U.S. (Geisinger Health System, Danville, PA) and Swedish (Stockholm CREAtinine Measurements [SCREAM] project, Stockholm, Sweden) adults with type 2 diabetes and confirmed CKD stages G3–G5 undergoing routine care, we evaluated associations between baseline and time-varying hemoglobin A1c (HbA1c) with the incident AKI (defined as increase in creatinine ≥0.3 mg/dL over 48 h or 1.5 times creatinine over 7 days). RESULTS In the U.S. cohort, there were 22,877 patients (55% women) with a median age of 72 years and estimated glomerular filtration rate (eGFR) 52 mL/min/1.73 m2. In the Swedish cohort, there were 12,157 patients (50% women) with a median age of 77 years and eGFR 51 mL/min/1.73 m2. During 3.1 and 2.3 years of follow-up, 7,060 and 2,619 AKI events were recorded in the U.S. and Swedish cohorts, respectively. The adjusted association between baseline HbA1c and AKI was similar in both cohorts. Compared with baseline HbA1c 6–6.9% (42–52 mmol/mol), the hazard ratio for AKI in patients with HbA1c &amp;gt;9% (75 mmol/mol) was 1.29 (95% CI 1.18–1.41) in Geisinger and 1.33 (95% CI 1.13–1.57) in the Swedish cohort. Results were consistent in stratified analysis, when using death as competing risk, and when using time-varying HbA1c. CONCLUSIONS Higher HbA1c was associated with AKI in adults with type 2 diabetes and CKD, suggesting that improving glycemic control may reduce the risk of AKI.
Icotinib With Concurrent Radiotherapy vs Radiotherapy Alone in Older Adults With Unresectable Esophageal Squamous Cell Carcinoma
Authors: Honglei Luo, Wei Jiang, Li Ma, Peng Chen, Min Fang, Lingyu Ding, Yuhui Hua, Dexi Du, Zhao Jing, Ruifei Xie, Yaqi Song, Jiayang Wang, Rongjing Zhou, Zhifeng Tian, Shixiu Wu
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Palliative radiotherapy (RT) is generally recommended for older patients with esophageal squamous cell carcinoma (ESCC) with poor prognosis. A new combination treatment is therefore needed. <h3>Objective</h3> To assess the efficacy and toxicity of RT plus icotinib vs RT alone in older patients with ESCC. <h3>Design, Setting, and Participants</h3> This randomized, multicenter, open-label, phase II clinical trial was conducted in China, with enrollment between January 1, 2015, and October 31, 2016. Patients aged 70 years or older with clinical stage T2 to T4, N0/1, M0/1a unresectable (because of comorbidities, T4 disease, unresectable lymph node, or refused surgery) ESCC were randomized 1:1 to receive RT plus icotinib or RT alone. Radiation was prescribed at 60 Gy in 30 fractions in both groups, and icotinib was administered at a dosage of 125 mg 3 times a day in the RT plus icotinib group. The last follow-up was completed on June 30, 2019, and data were analyzed from July 1 to September 30, 2019. <h3>Interventions</h3> Patients were randomized to either RT plus icotinib or RT alone. <h3>Main Outcomes and Measures</h3> The primary end point was overall survival (OS). Treatment-related toxic effects were evaluated. Immunohistochemistry was performed to analyze epidermal growth factor receptor (EGFR) expression if available. <h3>Results</h3> A total of 127 patients (median age, 76 years [range, 70-91 years]; 76 men [59.8%]) were enrolled and were eligible for survival analysis. Median OS was 24.0 (95% CI, 22.2-25.8) months in the RT plus icotinib group vs 16.3 (95% CI, 13.8-18.8) months in the RT group (hazard ratio, 0.53; 95% CI, 0.33-0.87;<i>P</i> = .008). No difference was observed in grades 3 or 4 adverse events. Patients with EGFR overexpression had a significantly better median overall survival (not reached vs 16.3 months [range, 2.6-45.1 months];<i>P</i> = .03) in the RT plus icotinib group. <h3>Conclusions and Relevance</h3> In this randomized clinical trial, icotinib plus RT was well tolerated and improved OS in older patients with ESCC relative to RT alone. Patients with EGFR overexpression benefitted more from icotinib with RT. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02375581