tbuckley/cabot-search huggingface dataset:
A randomized phase III trial of systemic therapy plus early local therapy versus systemic therapy alone in women with de novo stage IV breast cancer: A trial of the ECOG-ACRIN Research Group (E2108).
Authors: Seema Ahsan Khan, Fengmin Zhao, Lawrence J. Solin, Lori J. Goldstein, David Cella, Mark Basik, Mehra Golshan, Thomas B. Julian, Barbara A. Pockaj, Christine A Lee, Wajeeha Razaq, Joseph A. Sparano, Gildy V Babiera, Irene Ang Dy, Sarika Jain, Paula Silverman, Carla Fisher, Amye Juliet Tevaarwerk, Lynne I. Wagner, George W. Sledge
Journal: Journal of Clinical Oncology (2020)

LBA2 Background: About 6% of newly diagnosed breast cancer patients present with Stage IV disease and an intact primary tumor (IPT). Locoregional treatment (LRT) for the IPT is hypothesized to improve survival based on retrospective analyses, but randomized trials have provided conflicting data. We now report the results of E2108, a Phase 3 trial that examined the worth of LRT for the IPT following initial systemic therapy. Methods: Stage IV patients with IPT were registered, treated with optimal systemic therapy (OST) based on patient and tumor characteristics; those who did not progress during 4-8 months of OST were randomized to LRT for the IPT, or no LRT. The primary endpoint was overall survival (OS), with locoregional disease control as a secondary endpoint. Stratified log rank test and Cox proportional hazard model were used to compare OS between treatment groups. Cumulative incidence of locoregional recurrence/progression was estimated and Gray test was used for treatment group comparisons. The trial was designed to detect an improvement in 3 year OS rate from 30% with OST alone to 49.3% for OST+LRT (power 95%, 1-sided alpha 0.05) with full information expected after 152 deaths; the data monitoring committee recommended data release after 80% of full information. Results: 390 patients were enrolled between 2/8/11 and 7/23/15, and received OST. Of these, 256 eligible patients were randomized to either continued OST alone (N = 131) or OST+LRT (N = 125).There were 121 deaths and 43 locoregional progression events after a median follow up 59 months (range: 0-91). There was no significant difference in OS (3-year OS rate 68.4% in OST+LRT vs. 67.9% OST alone arm, stratified log-rank p = 0.63, HR = 1.09, 90% CI: 0.80, 1.49) or in progression-free survival (p = 0.40). The locoregional recurrence/progression was significantly higher in the OST alone arm (3-year rate 25.6% vs 10.2%, Gray test p = 0.003). Health-related quality of life (HRQOL) measured by FACT-B Trial Outcome Index was significantly worse in the OST+LRT arm than OST alone arm at 18 months post randomization (60% completion, Wilcoxon rank sum test p = 0.01), but no difference was observed at time points 6 months (74% completion) or 30 months (56% completion). Conclusions: Early local therapy does not improve survival in patients with de novo metastatic breast cancer and an IPT. Although there was a 2.5-fold higher risk of local disease progression without LRT, LRT of the IPT did not lead to improved HRQOL. Clinical trial information: NCT01242800 .
Stargardt Juvenile Macular Degeneration
Authors: Jin K Oh, Stephen H Tsang
Journal: New England Journal of Medicine (2020)

A 13-year-old boy presented with enlarging blind spots in both eyes. Short-wavelength autofluorescence showed bisretinoid accumulation and atrophy of the retinal pigment epithelium, findings that were consistent with a diagnosis of Stargardt juvenile macular degeneration.
One world, one pandemic, many guidelines: management of liver diseases during COVID-19
Authors: Steven Bollipo, Devika Kapuria, Atoosa Rabiee, Gil Ben-Yakov, Rashid N Lui, Hye Won Lee, Goutham Kumar, Keith Siau, Juan Turnes, Renumathy Dhanasekaran
Journal: Gut (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current global pandemic of COVID-19, which is associated with significant morbidity and mortality.1 As of 26 April 2020, it has infected over three million people worldwide and caused more than 200 000 deaths.2 Chronic liver diseases from HCV, HBV, alcoholism or non-alcoholic fatty liver disease (NAFLD) represent a major disease burden in the world. Around 1.5 billion people have chronic liver diseases worldwide, and it causes around two million deaths per year. While self-resolving elevations of transaminases are reported in 15%–54% of patients with COVID-19, those with more severe disease experience worse liver injury.3–5 An open international registry, SECURE-Cirrhosis, is reporting a mortality rate of 40% among the 118 patients with cirrhosis.6 Thus, patients with chronic liver disease represent a vulnerable population who are at higher risk of acquiring COVID-19 and suffering from its complications.7 8 

International societies, including the American Association for the Study of Liver Diseases (AASLD),9 the European Association for the Study of the Liver (EASL),10 the International Liver Cancer Association (ILCA),11 the Gastroenterological Society of Australia, The Transplantation Society (TTS),12 the American Society of Transplantation Surgeons,13 and the Liver Transplant Society of India,14 have released guidance to aid physicians taking care of patients with chronic liver diseases and liver transplantation. Most of these recommendations are based on expert consensus, as rigorous data are not yet available. We compare these major international recommendations and discuss a consolidated approach to managing liver disease in the setting of COVID-19. We also share our views on the path towards the eventual transition back to normality.

### Recommendations for inpatient care of chronic liver disease during COVID-19

Patients with liver diseases continue to require hospitalisation during the pandemic both for COVID-related and liver-related indications, and attempts should be made to …
Laying straw men to rest: author’s reply to “Urgency and uncertainty: covid-19, face masks, and evidence informed policy”
Authors: Trisha Greenhalgh
Journal: BMJ (2020)

<h3>Abstract</h3> This short paper reports a Bayesian analysis of the publicly available COVID-19 trial results. The analysis casts some doubts on whether the half+full dose regime of the AstraZeneca COVID-19 vaccine is truly more effective than the 2x full dose regime. The 95% posterior interval for the efficacy of the half+full dose regime is 66.6-96.3%, while for the 2x full dose regime it is 39.0-74.8%. Hence, it is possible that in both dosage regimes the vaccine has similar efficacy, around 70%. The estimated efficacy for the Pfizer vaccine is 89.9-97.4% and for Moderna 86.3-97.5%. These results should be interpreted with care though, since this analysis does not account for differences in for instance trial population, COVID-19 testing, and storage requirements for the various vaccines.
Abstract PR06: An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants
Authors: Maria Paz Zafra, Direna Alonso-Curbelo, Sukanya Goswami, Emma M Schatoff, Teng Han, John E. Wilkinson, Lukas E. Dow
Journal: Cancer Research (2020)

Abstract KRAS is the most frequently mutated oncogene in cancer. Tumor sequencing has revealed a complex spectrum of KRAS mutations across different cancer types, yet there is little understanding of how specific KRAS alterations impact tumor in initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R), and colon (KRASG13D) cancers. Induction of each mutation in the developing mouse pancreas reveals striking quantitative and qualitative differences in the degree of ductal transformation and premalignant progression. Further, using organoid models we show that KRASG13D mutants respond to EGFR inhibition, while the antiproliferative effect of KRASG12C-selective inhibitors can be overcome by upstream EGFR signaling. Together, these new mouse strains provide an ideal method for investigating KRAS biology in vivo and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers. This abstract is also being presented as Poster A41. Citation Format: Maria Paz Zafra, Direna Alonso-Curbelo, Sukanya Goswami, Emma M Schatoff, Teng Han, John E. Wilkinson, Lukas E. Dow. An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PR06.
Association of Programmed Cell Death Ligand 1 Expression Status With Receipt of Immune Checkpoint Inhibitors in Patients With Advanced Non–Small Cell Lung Cancer
Authors: Michael S. Leapman, Carolyn J. Presley, Weiwei Zhu, Pamela R. Soulos, Kerin B. Adelson, Rebecca A. Miksad, Daniel J. Boffa, Cary P. Gross
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Initial approval for immune checkpoint inhibitors (ICIs) for treatment of advanced non–small cell lung cancer (NSCLC) was limited to patients with high levels of programmed cell death ligand 1 (PD-L1) expression. However, in the period after approval, it is not known how new evidence supporting efficacy of these treatments in patients with low or negative PD-L1 expression was incorporated into real-world practice. <h3>Objective</h3> To evaluate the association between PD-L1 testing and first-line ICI use. <h3>Design, Setting, and Participants</h3> This retrospective cohort study (January 1, 2011, to December 31, 2018) used a deidentified nationwide electronic health record–derived database reflecting real-world care at more than 280 US community and academic cancer clinics (approximately 800 sites of care). Patients included those with advanced NSCLC without other identifiable variations diagnosed in the period after the US Food and Drug Administration's initial first-line approval of ICIs for patients with high PD-L1 expression (≥50%). <h3>Exposure</h3> First-line ICI treatment. <h3>Main Outcomes and Measures</h3> Patterns of PD-L1 testing and first-line ICI treatment among all patients and patients stratified by tumor histologic type (squamous vs nonsquamous). <h3>Results</h3> A total of 45 631 patients (mean [SD] age, 68.4 [9.6] years; 21 614 [47.4%] female) with advanced NSCLC were included in the study. PD-L1 testing increased from 468 (7.2%) in 2015 to 4202 (73.2%) in 2018. Within a subset of 7785 patients receiving first-line treatment in the period after first-line approval of pembrolizumab, those who received PD-L1 testing had a greater odds of receiving an ICI (odds ratio, 2.11; 95% CI, 1.89-2.36). Among patients with high PD-L1 expression (≥50%), 1541 (83.5%) received first-line ICI treatment; 776 patients (40.3%) with low PD-L1 expression (1%-49%) and 348 (32.3%) with negative PD-L1 expression (0%) also received ICIs. In addition, 755 untested patients (32.8%) were treated with a first-line ICI. The proportion of patients who received ICIs without PD-L1 testing increased during the study period (59 [17%] in quarter 4 of 2016 to 141 [53.8%] in quarter 4 of 2018). <h3>Conclusions and Relevance</h3> In this study, use of first-line ICI treatment increased among patients with advanced NSCLC with negative, low, or untested PD-L1 expression status in 2016 through 2018. These findings suggest that national practice was rapidly responsive to new clinical evidence rather than adhering to regulatory guidance in place at the time.
SARS-CoV-2 infection, clinical features and outcome of COVID-19 in United Kingdom nursing homes
Authors: N.S.N. Graham, C. Junghans, R. Downes, C. Sendall, H. Lai, A. McKirdy, P. Elliott, R. Howard, D. Wingfield, M. Priestman, M. Ciechonska, L. Cameron, M. Storch, M.A. Crone, P.S. Freemont, P. Randell, R. McLaren, N. Lang, S. Ladhani, F. Sanderson, D.J. Sharp
Journal: Journal of Infection (2020)

To understand SARS-Co-V-2 infection and transmission in UK nursing homes in order to develop preventive strategies for protecting the frail elderly residents.An outbreak investigation involving 394 residents and 70 staff, was carried out in 4 nursing homes affected by COVID-19 outbreaks in central London. Two point-prevalence surveys were performed one week apart where residents underwent SARS-CoV-2 testing and had relevant symptoms documented. Asymptomatic staff from three of the four homes were also offered SARS-CoV-2 testing.Overall, 26% (95% CI 22-31) of residents died over the two-month period. All-cause mortality increased by 203% (95% CI 70-336) compared with previous years. Systematic testing identified 40% (95% CI 35-46) of residents as positive for SARS-CoV-2, and of these 43% (95% CI 34-52) were asymptomatic and 18% (95% CI 11-24) had only atypical symptoms; 4% (95% CI -1 to 9) of asymptomatic staff also tested positive.The SARS-CoV-2 outbreak in four UK nursing homes was associated with very high infection and mortality rates. Many residents developed either atypical or had no discernible symptoms. A number of asymptomatic staff members also tested positive, suggesting a role for regular screening of both residents and staff in mitigating future outbreaks.
Molecular and functional extracellular vesicle analysis using nanopatterned microchips monitors tumor progression and metastasis
Authors: Peng Zhang, Xiaoqing Wu, Gulhumay Gardashova, Yang Yang, Yaohua Zhang, Liang Xu, Yong Zeng
Journal: Science Translational Medicine (2020)

An inkjet-printed nanochip integrating multiparametric extracellular vesicle analyses monitors tumor burden via liquid biopsy.
Time to intra-arrest therapeutic hypothermia in out-of-hospital cardiac arrest patients and its association with neurologic outcome: a propensity matched sub-analysis of the PRINCESS trial
Authors: Akil Awad, Fabio Silvio Taccone, Martin Jonsson, Sune Forsberg, Jacob Hollenberg, Anatolij Truhlar, Mattias Ringh, Benjamin S. Abella, Lance B. Becker, Jean-Louis Vincent, Leif Svensson, Per Nordberg
Journal: Intensive Care Medicine (2020)

To study the association between early initiation of intra-arrest therapeutic hypothermia and neurologic outcome in out-of-hospital cardiac arrest. A prespecified sub-analysis of the PRINCESS trial (NCT01400373) that randomized 677 bystander-witnessed cardiac arrests to transnasal evaporative intra-arrest cooling initiated by emergency medical services or cooling started after hospital arrival. Early cooling (intervention) was defined as intra-arrest cooling initiated < 20 min from collapse (i.e., ≤ median time to cooling in PRINCESS). Propensity score matching established comparable control patients. Primary outcome was favorable neurologic outcome, Cerebral Performance Category (CPC) 1–2 at 90 days. Complete recovery (CPC 1) was among secondary outcomes. In total, 300 patients were analyzed and the proportion with CPC 1–2 at 90 days was 35/150 (23.3%) in the intervention group versus 24/150 (16%) in the control group, odds ratio (OR) 1.92, 95% confidence interval (CI) 0.95–3.85, p = .07. In patients with shockable rhythm, CPC 1–2 was 29/57 (50.9%) versus 17/57 (29.8%), OR 3.25, 95%, CI 1.06–9.97, p = .04. The proportion with CPC 1 at 90 days was 31/150 (20.7%) in the intervention group and 17/150 (11.3%) in controls, OR 2.27, 95% CI 1.12–4.62, p = .02. In patients with shockable rhythms, the proportion with CPC 1 was 27/57 (47.4%) versus 12/57 (21.1%), OR 5.33, 95% CI 1.55–18.3, p = .008. In the whole study population, intra-arrest cooling initiated < 20 min from collapse compared to cooling initiated at hospital was not associated with improved favorable neurologic outcome. In the subgroup with shockable rhythms, early cooling was associated with improved favorable outcome and complete recovery.
Existing Drugs Might Treat COVID-19
Authors: Jennifer Abbasi
Journal: JAMA (2020)

Existing Drugs Might Treat COVID-19Drugs already marketed for conditions including schizophrenia might have potential as treatments for coronavirus disease 2019 (COVID-19), a Nature study suggests.In laboratory experiments, 10 pharmaceutical agents that are currently available or in development killed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).But the compounds still need testing in clinical trials to demonstrate safety and efficacy.Additionally, the researchers cautioned that the cough syrup ingredient dextromethorphan had proviral activity.To pinpoint potential therapeutics, the researchers identified protein interactions between SARS-CoV-2 and human cells.The human proteins involved in these interactions are druggable targets, so the next step was to find existing compounds that act on them.The researchers identified 69 agents and tested 47 of them against SARS-CoV-2.The 10 compounds that emerged from these experiments fall into 2 camps.One group interferes with protein transcription, affecting the virus's ability to replicate.The other, which includes the antipsychotic haloperidol, targets sigma-1 and sigma-2 receptors on human cells, disrupting the virus in different ways.Several of these compounds already have US Food and Drug Administration approval as over-the-counter or prescription drugs.The available drugs include 2 antihistamines, the hormone progesterone, and the antimalarial hydroxychloroquine.However, the most promising agent was a preclinical compound called PB28, senior author Nevan Krogan, PhD, of University of California, San Francisco, said in a media briefing.It was 20 times more potent than hydroxychloroquine in the group's experiments.
Knowledge and Practices Regarding Safe Household Cleaning and Disinfection for COVID-19 Prevention — United States, May 2020
Authors: Radhika Gharpure, Candis M. Hunter, Amy H. Schnall, Catherine E. Barrett, Amy E. Kirby, Jasen Kunz, Kirsten Berling, Jeffrey W. Mercante, Jennifer L. Murphy, Amanda G. Garcia-Williams
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

A recent report described a sharp increase in calls to poison centers related to exposures to cleaners and disinfectants since the onset of the coronavirus disease 2019 (COVID-19) pandemic (1). However, data describing cleaning and disinfection practices within household settings in the United States are limited, particularly concerning those practices intended to prevent transmission of SARS-CoV-2, the virus that causes COVID-19. To provide contextual and behavioral insight into the reported increase in poison center calls and to inform timely and relevant prevention strategies, an opt-in Internet panel survey of 502 U.S. adults was conducted in May 2020 to characterize knowledge and practices regarding household cleaning and disinfection during the COVID-19 pandemic. Knowledge gaps were identified in several areas, including safe preparation of cleaning and disinfectant solutions, use of recommended personal protective equipment when using cleaners and disinfectants, and safe storage of hand sanitizers, cleaners, and disinfectants. Thirty-nine percent of respondents reported engaging in nonrecommended high-risk practices with the intent of preventing SARS-CoV-2 transmission, such as washing food products with bleach, applying household cleaning or disinfectant products to bare skin, and intentionally inhaling or ingesting these products. Respondents who engaged in high-risk practices more frequently reported an adverse health effect that they believed was a result of using cleaners or disinfectants than did those who did not report engaging in these practices. Public messaging should continue to emphasize evidence-based, safe practices such as hand hygiene and recommended cleaning and disinfection of high-touch surfaces to prevent transmission of SARS-CoV-2 in household settings (2). Messaging should also emphasize avoidance of high-risk practices such as unsafe preparation of cleaning and disinfectant solutions, use of bleach on food products, application of household cleaning and disinfectant products to skin, and inhalation or ingestion of cleaners and disinfectants.
Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis
Authors: Stefano Indraccolo, Gian Luca De Salvo, Martina Verza, Mario Caccese, Giovanni Esposito, Ilaria Piga, Paola Del Bianco, Marco Pizzi, Marina Paola Gardiman, Marica Eoli, Roberta Rudà, Alba Ariela Brandes, Toni Ibrahim, Simona Rizzato, Ivan Lolli, Vittorina Zagonel, Giuseppe Lombardi
Journal: Clinical Cancer Research (2020)

Preclinical studies show that antiangiogenic therapy exacerbates tumor glycolysis and activates liver kinase B1/AMP kinase (AMPK), a pathway involved in the regulation of tumor metabolism. We investigated whether certain metabolism-related in situ biomarkers could predict benefit to regorafenib in the phase II randomized REGOMA trial.IHC and digital pathology analysis were used to investigate the expression in glioblastoma (GBM) sections of monocarboxylate transporter 1 and 4 (MCT1 and MCT4), associated with OXPHOS and glycolysis, respectively, phosphorylated AMPK (pAMPK), and phosphorylated acetyl-CoA carboxylase (pACC), a canonical target of AMPK activity. The status of each biomarker was associated with clinical endpoints, including overall survival (OS) and progression-free survival (PFS) in patients with relapsed GBM treated either with regorafenib or lomustine.Between November 2015 and February 2017, 119 patients were enrolled (n = 59 regorafenib and n = 60 lomustine) and stratified for surgery at recurrence, and baseline characteristics were balanced. Biomarker analysis was performed in 84 patients (71%), including 42 patients of the regorafenib arm and 42 patients of the lomustine arm. Among all markers analyzed, only pACC showed predictive value in terms of OS. In fact, median OS was 9.3 months [95% confidence interval (CI), 5.6-13.2] for regorafenib and 5.5 months (95% CI, 4.2-6.6) for lomustine for pACC-positive patients, HR, 0.37 (95% CI, 0.20-0.70); log rank P = 0.0013; test for interaction = 0.0453. No statistically significant difference was demonstrated for PFS according to pACC status.We found that AMPK pathway activation is associated with clinical benefit from treatment with regorafenib in relapsed GBM.