tbuckley/cabot-search huggingface dataset:
Asthma and Obstructive Sleep Apnea: Taking It to Heart
Authors: Muddassir Mehmood
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

the animal models are to the KRT8 hi cells in IPF should be assessed.We must also determine whether AECs permanently arrest or just pause in the early differentiation state, and whether a failure of KRT8 downregulation is causally related to this.Finally, although we propose that persistence of the early differentiation state may represent the ineffectual epithelial regeneration that is widely believed to promote fibrogenesis, whether KRT8/KRT18 hi AEC2s activate fibroblasts should also be examined.During the preparation of this work, an unpublished preprint reported the emergence of a transitional Krt8/Krt18 hi , TGF-b-activated state after lung injury induced by bleomycin (10), which is strikingly similar to the TGF-b-activated Krt8/Krt18 hi transitional cell state we previously identified in the LPS model ( 4).The upregulation of TNF, MYCN, and NRF2 target genes reported in the bleomycin model was also observed in the LPS model (4).Although bleomycin induces fibrosis, the fibrosis eventually resolves and late differentiation, with Krt8/Krt18 downregulation and TGF-b deactivation, ensues (10).The mechanisms underlying AEC2-to-AEC1 differentiation during physiologic regeneration and the manner in which alveolar regeneration may go awry during the pathogenesis of fibrosis have remained fundamental unanswered questions in the field.Here, we demonstrate that physiologic AEC2-to-AEC1 differentiation proceeds via an early differentiation state characterized by TGFb-dependent KRT8/KRT18 upregulation and a late differentiation state characterized by TGF-b deactivation and KRT8/KRT18 downregulation.This regenerative lineage trajectory appears to be conserved in three injury models, which is a significant finding with therapeutic implications.However, in fibrosis, likely owing to persistent TGF-b activation, regenerating AEC2s persist in the KRT8/KRT18 hi early differentiation state.These findings may ultimately lead to novel therapies to promote physiologic regeneration and suppress fibrogenesis in IPF.
Leveraging the integrated EHR for trial matching across a nationwide network.
Authors: Timothy Joseph Yeatman, Mark Watson, Adam Chasse
Journal: Journal of Clinical Oncology (2020)

165 Background: The Guardian Research Network (GRN) is a nationwide consortium of integrated health systems, who share their electronic health records (EHR) to democratize clinical trial access through improvements in “process”. The GRN is a unique-in-class, free-to join, non-exclusive consortium leveraging the digital EHR---including labs, medications, demographics and non-discrete data (all text) data--- mining nightly for clinical trial candidates. Using a suite of NLP and AI tools, the GRN dramatically improves the efficiency of the clinical research staff, by electronically searching all records for the I/E criteria for trials. The GRN uses a central IRB, one contract and legal review, promising to revolutionize the trial accrual process and speed drug development. Methods: With a database of &gt; 1.0M patients, the GRN reviews all active cancer records nightly from &gt; 110 member hospitals to produce lists of trial candidates. Comprehensive electronic screens were filtered by manual reviews to rapidly find best candidates. Results: Our data collected over 10 mo suggest comprehensive electronic queries examining hundreds of thousands of records daily eliminate &gt; 90% of ineligible patients in minutes. Manual review further refines eligible list. This is vastly different from current opportunistic screening approaches that examine only a tiny fraction of potential trial candidates (last week's new patients). Conclusions: The GRN has executed an all-inclusive approach to trial accrual, embedding a scalable database search technology within an integrated trial network. The novel approach seeks to exponentially expand operational capabilities of CTOs with limited staff, review all eligible patients, and solve for a large unmet need for democratizing trial access in the community. [Table: see text]
Declining use of red blood cell transfusions for gastrointestinal cancer surgery: A population-based analysis.
Authors: Jesse Zuckerman, Natalie Coburn, Jeannie Callum, Alyson Mahar, Victoria Zuk, Yulia Lin, Robin McLeod, Alexis F. Turgeon, Emily Pearsall, Guillaume Martel, Julie Hallet
Journal: Journal of Clinical Oncology (2020)

802 Background: Perioperative anemia is common in gastrointestinal (GI) cancer surgery patients and is often treated with red blood cell transfusion (RBCT), which carries risks for inferior oncologic outcomes. Despite level-1 evidence for restrictive transfusion strategies, RBCT use is often not consistent with guidelines leading to a high rate of unnecessary transfusions. Understanding of RBCT use at the population-level is necessary to develop system-level efforts to minimize perioperative RBCT for cancer. We sought to evaluate the secular trends of transfusion in a large North American population. Methods: We conducted a population-based retrospective cohort study of patients undergoing GI cancer resection between 2007-2018 using linked administrative health datasets in Ontario, Canada. Primary outcome was administration of any RBCT during the hospitalization. Temporal RBCT trends were analyzed with Cochran-Armittage tests for trend. Modified Poisson regression assessed trends while controlling for potential confounders. Results: Of 79,764 patients undergoing GI cancer resection, median age was 69 (IQR: 60-78) years old and 55.5% were male. The most frequent cancer site was colorectal cancer (n = 63,243), followed by esophago-gastric (n = 7,307), hepato-pancreato-biliary (n = 6,510), and small bowel (n = 2,704). 30% of patients received RBCT. The proportion of patients transfused decreased from 26.5% in 2007 to 18.9% in 2018 (p &lt; 0.001). This trend remained consistent when stratified by sex, age, cancer type, operative approach, procedure setting, and institution teaching status. After adjusting for patient and institution factors, the time period was associated with receipt of RBCT with a relative risk of 0.94 (95% CI 0.91-0.96) for 2011-14 and 0.75 (95% CI 0.73-0.78) for 2015-2018 compared to the period of 2007-10. Conclusions: Over the 11-year study period, we observed a decrease in RBCT for GI cancer resection. These findings may reflect the dissemination of clinical guidelines and implementation of patient blood management programs. An evaluation of institutional variation and the relationship with outcomes is warranted to identify opportunities for further improvement.
Patterns of gastric cancer metastasis within the United States.
Authors: Joseph Sirody, Amy H. Kaji, Danielle M. Hari, Kathryn Tzung-Kai Chen
Journal: Journal of Clinical Oncology (2020)

329 Background: There are few reports on the epidemiology of gastric cancer metastasis, although outcomes are known to be uniformly poor. Here we describe the patterns of gastric cancer metastasis and treatment in the United States (US). Methods: Patients with gastric adenocarcinoma histologies were identified in the National Cancer Database (NCDB) from 2004-2016. We describe univariate associations between different sites of metastasis and clinicopathologic characteristics and treatment modalities, using the chi-square and Kruskal-Wallis tests. Kaplan Meier curves were constructed for the estimation of overall survival (OS) by metastatic site. Results: Due to changes in the coding of metastatic disease, we were limited to the year 2016 for evaluation of patterns of disease. Twenty-six percent (n = 1228) of gastric cancer patients presented with liver metastases, 20% (n = 941) with distant nodes, 43% (n = 2028) with other distant site metastases (including peritoneum), and the rest to bone, brain or lung. On univariate analysis, when compared to liver metastases, other distant site metastases were significantly more likely to arise from an antral primary site (28% v. 16%); to be of Hispanic origin (16% v. 7%); female (42% v. 29%); associated with signet ring histology (34% v. 6%); lymphovascular invasion (LVI) (58% v. 27%); and tumor grade III/IV (85% vs. 60%) (p &lt; 0.0001 for all). There were no significant differences in how patients with metastatic disease were treated in terms of systemic therapy. With regard to OS, due to how metastatic sites were coded prior to 2016, it was not possible to compare peritoneal metastases against other sites; however, patients with distant nodal disease had improved median overall survival compared to those with any other metastatic site (7.9 v. 5.2 months, p &lt; 0.0001). Conclusions: The majority of US patients with metastatic gastric cancer present with presumed peritoneal disease. Predictive factors for peritoneal metastases vs. liver metastases included adverse prognostic features, including signet ring histology, higher tumor grades, and LVI. Although it was not possible to compare OS of peritoneal disease against other sites, continued follow up is needed, as this may impact future staging.
Consultant who was convicted of downloading images of child sexual abuse is struck off
Authors: Clare Dyer
Journal: BMJ (2020)

A consultant in anaesthesia and critical care has been struck off the UK medical register after being convicted of downloading images of child sexual abuse.1

Officers from the Metropolitan Police’s online child sexual abuse and exploitation unit arrived at Richard Johnson’s Yorkshire home with a search warrant in February 2018, after he mistakenly uploaded an image to a social media site. …
Efficacy and safety of apremilast in patients with moderate to severe plaque psoriasis of the scalp: Results of a phase 3b, multicenter, randomized, placebo-controlled, double-blind study
Authors: Abby S. Van Voorhees, Linda Stein Gold, Mark Lebwohl, Bruce Strober, Charles Lynde, Stephen Tyring, Ashley Cauthen, Howard Sofen, Zuoshun Zhang, Maria Paris, Yao Wang
Journal: Journal of the American Academy of Dermatology (2020)

Many patients with psoriasis are bothered by symptoms in highly visible, pruritic areas, such as the scalp.To evaluate the efficacy and safety of apremilast for moderate to severe scalp psoriasis.This phase 3b, double-blind, placebo-controlled study randomized adults with moderate to severe scalp psoriasis who had inadequate response/intolerance to at least 1 topical scalp psoriasis therapy (NCT03123471). The primary endpoint was the proportion of patients who achieved Scalp Physician Global Assessment response, defined as score of 0 (clear) or 1 (almost clear), with at least a 2-point reduction, at week 16. Secondary endpoints included at least a 4-point improvement from baseline in Whole Body Itch and Scalp Itch Numeric Rating Scales (NRSs) and mean improvement in Dermatology Life Quality Index (DLQI) at week 16.There were 303 randomized patients (placebo: n = 102; apremilast: n = 201). With apremilast, significantly more patients achieved Scalp Physician Global Assessment (43.3% vs 13.7%), Scalp Itch NRS (47.1% vs 21.1%), and Whole Body Itch NRS (45.5% vs 22.5%) response, and significantly greater DLQI improvement was observed versus placebo (-6.7 vs -3.8; all P < .0001). Common adverse events with apremilast were diarrhea (30.5%), nausea (21.5%), headache (12.0%), and vomiting (5.5%).Patients with mild disease were not enrolled.Apremilast showed efficacy for the treatment of moderate to severe scalp psoriasis.
High heart rate at admission as a predictive factor of mortality in hospitalized patients with Lassa fever: An observational cohort study in Sierra Leone
Authors: Nadia Wauquier, Camille Couffignal, Pauline Manchon, Elisabeth Smith, Victor Lungay, Moinya Coomber, Lauren Weisenfluh, James Bangura, Sheik Humarr Khan, Amara Jambai, Aiah Gbakima, Nadezda Yun, Slobodan Paessler, Randal Schoepp, Stephen S. Morse, Jean-Paul Gonzalez, Joseph Fair, France Mentré, Vincent Vieillard
Journal: Journal of Infection (2020)
A randomized controlled phase III multicenter study on dose escalation in definitive chemoradiation for patients with locally advanced esophageal cancer: ARTDECO study.
Authors: Maarten C.C.M. Hulshof, Debby Geijsen, Tom Rozema, Vera Oppedijk, Jeroen Buijsen, Karen J. Neelis, Joost Nuyttens, Maurice Van Der Sangen, Paul Jeene, Janny Reinders, Mark I. van Berge Henegouwen, Jeanin E. van Hooft, Hanneke W.M. Van Laarhoven, Ate Van Der Gaast
Journal: Journal of Clinical Oncology (2020)

281 Background: To analyze the effect of radiation dose escalation to the primary tumor on local control, locoregional control, survival and toxicity in definitive chemoradiation for esophageal cancer. Methods: Patients with clinical stage T2-4, N0-3, M0 carcinoma of the esophagus were randomized between a standard dose of 50.4 Gy/1.8 Gy/5,5 weeks to the tumor and regional lymph nodes (SD) versus the same dose combined with an integrated boost of 0,4 Gy per fraction (total 61,6 Gy) to the primary tumor (HD). Chemotherapy consisted of 6 weekly concurrent carboplatin (AUC 2) and paclitaxel (50 mg/m 2 ) in both arms. The primary endpoint was local progression free survival (LPFS) and 260 patients were needed to detect a difference of 15% (power: 80%). Secondary endpoints were locoregional progression free survival (LRPFS), overall survival (OS) and toxicity. Patients were stratified for histological subtype. Results: Between September 2012 and June 2018, 260 patients were included. Reasons for inoperability were proximal localization and patient preference (44%), comorbidity (30%), unresectable lymph nodes (11%), T4 (5%), local recurrence 2% and combinations (7%). 61% of the patients had a squamous cell carcinoma (SCC) and 39% had an adenocarcinoma (AC). 94% completed radiation treatment and 85% had at least 5 courses chemotherapy. Median follow up time was 45 months. 3-year LPFS was 70% in the SD arm versus 76% in the HD arm (ns). LPFS for SCC and AC was 74% versus 81% and 62% versus 65% for SD and HD, resp. (ns). 3-year LRPFS was 53% and 63% for the SD and HD arm resp. (p = 0.08). 1 year any progression free survival was 60% for SCC and 50% for AC, without a significant difference between SD and HD (p = 0,5). 3-year OS was 41% versus 40% for SD and HD resp. Overall grade 4 and 5 CTC toxicity was 12% and 4% in the SD arm versus 14% and 10% in the HD arm, resp. Conclusions: In definitive chemoradiation for esophageal cancer, radiation dose escalation up to 61,6 Gy to the primary tumor did not result in a significant increase in local control over 50,4 Gy. Numerical improvement of locoregional control after HD was observed with an increase in toxicity and without improving OS. Clinical trial information: NL38343.018.11.
Abstract 12538: Patients With Hypoplastic Left Heart Syndrome Have Abnormal Ascending Aortic Flow Associated With Increased Kinetic Energy Dissipation: Preliminary 4D-Flow MRI Study
Authors: Michal Schäfer, Max Mitchell, Lorna Browne, James Jaggers, Uyen Truong, Brian Fonseca, Dunbar Ivy, Adel Younoszai, Michael DiMaria
Journal: Circulation (2018)

Introduction: Stage I Norwood palliation of hypoplastic left heart syndrome (HLHS) requires extensive reconstruction of the aorta which is most commonly augmented with a pulmonary allograft patch. ...
First-in-human phase I trial of small activating RNA (saRNA) oligonucleotide MTL-CEBPA in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Debashis Sarker, Mikael Sodergren, Elizabeth Ruth Plummer, Bristi Basu, Tim Meyer, Kai-Wen Huang, T.R. Jeffry Evans, Duncan Spalding, Yuk Ting Ma, Daniel H. Palmer, Cheng Ean Chee, David James Pinato, Vikash Reebye, Daniel McVeigh, Nina Raulf, Jenni Vasara, Pinelopi Andrikakou, Robert Habib, David Blakey, Nagy A. Habib
Journal: Journal of Clinical Oncology (2020)

554 Background: MTL-CEBPA is the first saRNA to enter clinical trials and targets the transcription factor C/EBPα, a master regulator of myeloid cell differentiation. We have previously reported a favourable safety profile of MTL-CEBPA given as a single agent QWx3 every 28 days, in patients with HCC (Sarker D et al, ASCO 2018). After discontinuation of MTL-CEBPA, three out of five patients treated with sorafenib off study have had maintained complete radiological response (CR) of 7-18 months duration; 2 patients demonstrated resolution of lung metastases &gt; 1 year. Here we provide updated data on phase 1 patients treated with sorafenib off study as well as subsequent combination cohorts. Methods: MTL-CEBPA 130mg/m 2 QWx3 or BIW and sorafenib 400mg bd were administered to patients with HCC using combination or sequential dosing regimens, in cohorts either tyrosine kinase inhibitor naive or resistant. On treatment liver biopsies evaluated changes in M2 macrophages (CD163). Flow cytometry of peripheral blood determined changes in myeloid cell populations. Results: 12 patients have been treated with MTL-CEBPA co-administered with sorafenib and 14 patients treated with MTL-CEBPA followed by sorafenib (23M/3F, median age 65.5years, range 44-83, ECOG PS 0/1: 18/8). The most common treatment-related AEs (all grades/grade 3) in this group include facial flushing (4/0), raised AST (3/1) raised ALT (2/1), fatigue (5/0), raised ALP (2/0), and anaemia (2/2), diarrhoea (3/0), rash (2/0) and anorexia (1/0). 1 TKI naïve patient in the co-administration cohort has maintained CR at 7 months and two patients have SD (ongoing at 3 &amp; 4 months both in sequential cohort). IHC in the patient with CR has demonstrated 95% reduction in M2 macrophages with significant decrease in frequency of immature CD10- neutrophils (-85.7%; p = 0.0078), PMN-MDSCs (-49.3%; p = 0.00145) and M-MDSCs (-18.4%; P = 0.0072). All responding patients have underlying HBV or HCV. Conclusions: MTL-CEBPA is a novel saRNA targeting myeloid cells which may result in a significantly enhanced oncological response in HCC of viral aetiology. Updated safety and efficacy data will be presented. Clinical trial information: NCT02716012.
Correlation of Epstein-Barr virus-specific cytotoxic T lymphocyte precursors (EBV-CTLp) after tabelecleucel with response and survival in rituximab relapsing or refractory EBV+ post-transplant lymphoproliferative disease (PTLD).
Authors: Blake T. Aftab, Rhine R. Shen, Norma Guzman-Becerra, Yan Sun, Farahnaz Forozan, Susan Prockop, Ekaterina Doubrovina, Richard J. O'Reilly, Xiaoming Li, Minoti Hiremath, Laurence Gamelin, Willis H. Navarro
Journal: Journal of Clinical Oncology (2020)

38 Background: EBV + PTLD is often a fatal disease. Tabelecleucel is an investigational off-the-shelf, allogeneic T-cell immunotherapy specific for EBV antigens. Functional in vivo expansion approximated by a limiting dilution analysis of EBV-CTLp has previously been correlated to clinical response. Methods: We conducted analyses of reported peak circulating EBV-CTLp levels following tabelecleucel administration in correlation to response and safety across two studies (N=42) in rituximab refractory or relapsing EBV + PTLD following HCT or SOT. Results: Two cohorts were defined by the lowest EBV-CTLp quartile (n=11) and the combined upper 3 quartiles (n=31). Twenty-five of 31 subjects (80.6%) in upper quartiles exhibited a clinical response compared to 3 of 11 subjects (27.3%) in the lowest quartile. Eighteen of 20 complete responses and 7 of 8 partial responses demonstrated peak CTLp values in the upper quartiles of the population. Overall survival (OS) rate in subjects exhibiting CTLp values in the upper quartiles was 83.9% (95% CI: 65.5-92.9%) at 1 year and 66.1% (95% CI: 45.9-80.2%) at 2 years, compared to 18.2% (95% CI: 2.9-44.2%) in the lowest quartile over the same periods. OS is commensurate with a hazard ratio of 0.168 in favor of subjects with higher EBV-CTLp (95% CI: 0.067-0.425; Log-Rank Test p-value &lt;0.001). Subjects demonstrating clinical responses experienced median CTLp values of 36.2 CTLp/ml (15.6-155 interquartile range), whereas non-responders exhibited significantly lower (p=0.001, based on Wilcoxon Rank Sum test) median CTLp of 0.07/ml (0.01-5.5 interquartile range). Tabelecleucel was well tolerated across both studies, with a safety profile in each group consistent with the underlying clinical condition of patients. Conclusions: These analyses illustrate the correlation of peak EBV-CTLp to clinical benefit in subjects receiving tabelecleucel. Significant correlation of EBV-CTLp with ORR and OS are consistent with potential use as a functional biomarker for the expansion of EBV-specific T-cells in the treatment of EBV + PTLD in the rituximab refractory/relapsing setting. Clinical trial information: NCT01498484.
Evaluation of adjuvant chemotherapy-associated steatosis in colorectal cancer.
Authors: Michelle (Chae Min) Lee, Ayesha Taqi, Aftab Malik, Raissa Dzulynsky, Amy Di Tomaso, Christine Brezden-Masley
Journal: Journal of Clinical Oncology (2020)

94 Background: Chemotherapy-associated steatosis (CAS) is poorly understood in context of colorectal cancer (CRC). It has been anecdotally observed that CRC patients undergoing chemotherapy appeared to develop steatosis at a higher rate than expected, and that statin therapy may have protective effects against CAS. Here, we sought to evaluate 1) the frequency of CAS in Stage II-III CRC patients; and 2) whether patients on statins throughout adjuvant chemotherapy develop CAS at a lower frequency. Methods: This study retrospectively examined medical records of 267 Stage II-III CRC patients who received adjuvant chemotherapy and were followed up at St. Michael’s Hospital, Toronto, Canada between January 1, 2006 and January 1, 2017. Patient information, relevant co-morbid conditions, statin use, and adjuvant chemotherapy were collected. Baseline and incident steatosis for up to one year from chemotherapy start date was assessed based on imaging reports (CT, ultrasound, MR). Results: Of 267 patients, 78 (29.2%) had steatosis at baseline radiology, prior to treatment with adjuvant chemotherapy. Of the remaining 189 cases, the incidence of steatosis within one year of adjuvant chemotherapy start date was significantly greater in patients who received adjuvant treatment (n = 132) compared to those who did not (n = 57), (39% vs. 23%, p = 0.03). Among patients who underwent chemotherapy, statin use for preexisting hyperlipidemia, a known risk factor for steatosis (n = 39), was associated with a lower incidence of steatosis compared to no statin administration (n = 93), although this result was not significant (31% vs. 42%, p = 0.243). Among statin users, 42.9% of patients treated using oxaliplatin-containing FOLFOX regimen (n = 21) developed steatosis, compared to 20% in patients on a capecitabine regimen (n = 15). There was a trend towards significance, with p = 0.151. Conclusions: Chemotherapeutic treatment of Stage II-III CRC is associated with an increased incidence of steatosis. Statins may protect against acute development of CAS within one year following chemotherapy, particularly with single agent capecitabine. Prospective clinical trials should be considered to assess protective use of statin in this curative patient population.
Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas
Authors: A.J. Schoenfeld, H. Rizvi, C. Bandlamudi, J.L. Sauter, W.D. Travis, N. Rekhtman, A.J. Plodkowski, R. Perez-Johnston, P. Sawan, A. Beras, J.V. Egger, M. Ladanyi, K.C. Arbour, C.M. Rudin, G.J. Riely, B.S. Taylor, M.T.A. Donoghue, M.D. Hellmann
Journal: Annals of Oncology (2020)
Liquid Biopsies for Hepatocellular Cancer and Their Potential in Clinical Practice
Authors: Gary P. Jeffrey, Louisa G. Gordon, Michelle M. Hill, Grant A. Ramm
Journal: Hepatology (2020)

Jeffrey, Gary P. M.D.; Gordon, Louisa G. Ph.D.; Hill, Michelle M. Ph.D.; Ramm, Grant A. Ph.D.Editor(s): Corey, Kathleen E.6; Malhi, Harmeet7 Author Information