tbuckley/cabot-search huggingface dataset:
Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing
Authors: Johanna K Sandling, Pascal Pucholt, Lina Hultin Rosenberg, Fabiana H G Farias, Sergey V Kozyrev, Maija-Leena Eloranta, Andrei Alexsson, Matteo Bianchi, Leonid Padyukov, Christine Bengtsson, Roland Jonsson, Roald Omdal, Benedicte A Lie, Laura Massarenti, Rudi Steffensen, Marianne A Jakobsen, Søren T Lillevang, Karoline Lerang, Øyvind Molberg, Anne Voss, Anne Troldborg, Søren Jacobsen, Ann-Christine Syvänen, Andreas Jönsen, Iva Gunnarsson, Elisabet Svenungsson, Solbritt Rantapää-Dahlqvist, Anders A Bengtsson, Christopher Sjöwall, Dag Leonard, Kerstin Lindblad-Toh, Lars Rönnblom
Journal: Annals of the Rheumatic Diseases (2020)

Objectives Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. Methods We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). Results We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. Conclusions Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.
Performance Status Restriction in Phase III Cancer Clinical Trials
Authors: Joseph Abi Jaoude, Ramez Kouzy, Walker Mainwaring, Timothy A. Lin, Austin B. Miller, Amit Jethanandani, Andres F. Espinoza, Dario Pasalic, Vivek Verma, Noam A. VanderWalde, Benjamin D. Smith, Grace L. Smith, C. David Fuller, Prajnan Das, Bruce D. Minsky, Claus Rödel, Emmanouil Fokas, Reshma Jagsi, Charles R. Thomas, Ishwaria M. Subbiah, Cullen M. Taniguchi, Ethan B. Ludmir
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: Patients with good performance status (PS) tend to be favored in randomized clinical trials (RCTs), possibly limiting the generalizability of trial findings. We aimed to characterize trial-related factors associated with the use of PS eligibility criteria and analyze patient accrual breakdown by PS. Methods: Adult, therapeutic, multiarm phase III cancer-specific RCTs were identified through ClinicalTrials.gov . PS data were extracted from articles. Trials with a PS restriction ECOG score ≤1 were identified. Factors associated with PS restriction were determined, and the use of PS restrictions was analyzed over time. Results: In total, 600 trials were included and 238,213 patients had PS data. Of those trials, 527 studies (87.8%) specified a PS restriction cutoff, with 237 (39.5%) having a strict inclusion criterion (ECOG PS ≤1). Enrollment criteria restrictions based on PS (ECOG PS ≤1) were more common among industry-supported trials ( P &lt;.001) and lung cancer trials ( P &lt;.001). Nearly half of trials that led to FDA approval included strict PS restrictions. Most patients enrolled across all trials had an ECOG PS of 0 to 1 (96.3%). Even among trials that allowed patients with ECOG PS ≥2, only 8.1% of those enrolled had a poor PS. Trials of lung, breast, gastrointestinal, and genitourinary cancers all included &lt;5% of patients with poor PS. Finally, only 4.7% of patients enrolled in trials that led to subsequent FDA approval had poor PS. Conclusions: Use of PS restrictions in oncologic RCTs is pervasive, and exceedingly few patients with poor PS are enrolled. The selective accrual of healthier patients has the potential to severely limit and bias trial results. Future trials should consider a wider cancer population with close toxicity monitoring to ensure the generalizability of results while maintaining patient safety.
Comparing characteristics and outcomes of cancer to non-cancer patients admitted to general internal medicine (GIM).
Authors: Lawson Eng, Amol A Verma, Saeha Shin, Afsaneh Raissi, Alejandro Berlin, Christine Brezden, Kelvin K. Chan, Katherine Enright, Genevieve Bouchard-Fortier, Lauren Linett, Melanie Lynn Powis, Haider Samawi, Geoffrey Liu, Monika K. Krzyzanowska, Fahad Razak
Journal: Journal of Clinical Oncology (2020)

21 Background: Cancer prevalence is rising and there is a corresponding increase in hospitalizations across the cancer continuum. However, little is known about the patterns of care and outcomes of cancer inpatients as administrative data may not capture in-hospital details including investigations and medications required for characterization. Understanding how cancer inpatients are managed and their outcomes can help to optimize care delivery. Methods: We conducted a multicenter study of all patients admitted to GIM at seven hospitals (Toronto, Canada) from 2010 to 2017 where we deterministically linked administrative data with each hospital’s electronic information (pharmacy, orders, notes, laboratory/imaging and results) at the patient level. Multivariable regression models compared characteristics and outcomes between cancer and non-cancer patients for the top 5 non-cancer patient discharge diagnoses. Results: Among 230,040 hospitalizations, 15% had cancer listed as an ICD-10 comorbidity. The most common cancer disease sites were gastrointestinal (20%), lung (13%) and leukemia (11%). The most common discharge diagnoses for cancer patients were disease progression (9%), palliative care (6%), pneumonia (4%), leukemia (4%) and lung cancer (4%), while for non-cancer patients were: heart failure (5%), pneumonia (5%), stroke (5%), COPD (5%) and urinary tract infections (5%). In general, compared to non-cancer patients, cancer patients were younger (70 vs 72), had greater length of stay (LOS; 6.4 vs 4.6 days), in-hospital mortality (16% vs 5%), ICU use (12% vs 11%), 30 day re-admission rate (17% vs 10%) and were more likely to receive CTs (64% vs 52%), MRIs (14% vs 12%) and interventional procedures (22% vs 8%) (p &lt; 0.001, all comparisons). When evaluating the top 5 non-cancer patient discharge diagnoses, results (adjusted for age, gender, Charlson comorbidity score and hospital) were similar wherein cancer patients had a higher in-hospital mortality (aOR = 2.02 p &lt; 0.001), 30 day re-admission rate (aOR = 1.09 p = 0.08) and were more likely to receive CTs (aOR = 1.88 p &lt; 0.001), MRIs (aOR = 1.66 p &lt; 0.001) or interventional procedures (aOR = 1.78 p &lt; 0.001), despite similar mean LOS (5.7 vs 5.1 days p = 0.35). Results were similar across discharge diagnoses. Conclusions: Cancer patients represent a unique population on GIM and have higher resource use, mortality and LOS compared to non-cancer patients, with similar trends even for the same non-cancer diagnoses. Specialized models of care for hospitalized cancer patients may be warranted.
Genomic evidence for reinfection with SARS-CoV-2: a case study
Authors: Richard L Tillett, Joel R Sevinsky, Paul D Hartley, Heather Kerwin, Natalie Crawford, Andrew Gorzalski, Chris Laverdure, Subhash C Verma, Cyprian C Rossetto, David Jackson, Megan J Farrell, Stephanie Van Hooser, Mark Pandori
Journal: The Lancet Infectious Diseases (2020)

The degree of protective immunity conferred by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently unknown. As such, the possibility of reinfection with SARS-CoV-2 is not well understood. We describe an investigation of two instances of SARS-CoV-2 infection in the same individual.
A role for intestinal alkaline phosphatase in preventing liver fibrosis
Authors: Yang Liu, Paul M Cavallaro, Byeong-Moo Kim, Tao Liu, Hongyan Wang, Florian Kühn, Fatemeh Adiliaghdam, Enyu Liu, Robin Vasan, Ehsan Samarbafzadeh, Matthew Z Farber, Junhui Li, Meng Xu, Vidisha Mohad, Michael Choi, Richard A Hodin
Journal: Theranostics (2020)

Liver fibrosis is frequently associated with gut barrier dysfunction, and the lipopolysaccharides (LPS) -TLR4 pathway is common to the development of both. Intestinal alkaline phosphatase (IAP) has the ability to detoxify LPS, as well as maintain intestinal tight junction proteins and gut barrier integrity. Therefore, we hypothesized that IAP may function as a novel therapy to prevent liver fibrosis.
Activity and Safety of Geptanolimab (GB226) for Patients with Unresectable, Recurrent, or Metastatic Alveolar Soft Part Sarcoma: A Phase II, Single-arm Study
Authors: Yuankai Shi, Qiqing Cai, Yu Jiang, Gang Huang, Minghong Bi, Baocheng Wang, Yuhong Zhou, Guowen Wang, Hongyan Ying, Zhiwei Tao, Chunmei Shi, Qian Guo, Chao Gao
Journal: Clinical Cancer Research (2020)

Patients with alveolar soft part sarcoma (ASPS) are rare and have few treatment options. We assessed the activity of geptanolimab (GB226), a fully humanized programmed cell death protein 1 antibody, for patients with unresectable, recurrent, or metastatic ASPS.We conducted this multicenter, single-arm, phase II study (Gxplore-005, NCT03623581) in patients aged 18-75 years who had unresectable, recurrent, or metastatic ASPS at 11 sites in China. Patients received intravenous geptanolimab (3 mg/kg) every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by independent review committee (IRC) per RECIST 1.1 in the full analysis set population.Between September 6, 2018 and March 6, 2019, we enrolled and treated 37 patients with 23 (62.2%) having received prior systemic treatment. Fourteen [37.8%; 95% confidence interval (CI), 22.5-55.2] of 37 patients had an objective response assessed by IRC with a 6-month duration of response rate of 91.7%. Median progression-free survival was 6.9 months (95% CI, 5.0-not reached) and disease control was achieved in 32 (86.5%; 95% CI, 71.2-95.5) patients. Three of 37 patients reported grade 3 treatment-related adverse events (TRAEs), including anemia, hypophysitis, and proteinuria [one each (2.7%)]. No grade 4 TRAEs were observed. Two (5.4%) patients discontinued treatment due to TRAEs (one with hypophysitis and one with Mobitz type I atrioventricular block). The baseline percentage of CD4+ T cells was adversely associated with patient response (P = 0.031).Geptanolimab has clinically meaningful activity and a manageable safety profile in unresectable, recurrent, or metastatic ASPS.
Facial Nerve Canal Paraganglioma
Authors: Emina Arsovic, Marion Montava, Jean-Pierre Lavieille, Karel Pacak, Arthur Varoquaux, David Taïeb
Journal: Clinical Nuclear Medicine (2020)

Abstract We report the case of a 72-year-old woman presenting with a progressive left peripheral facial paralysis and a facial canal mass extending through the stylomastoid foramen along the posterior edge of the parotid gland. On MRI, the early and intense enhancement was highly suggestive of paraganglioma but could not rule out a nonossifying hemangioma. Laboratory analysis showed normal plasma metanephrines. On 18 F-FDOPA PET/CT, the mass exhibited a typical paraganglioma feature with a marked tumor uptake. Our case demonstrates that 18 F-FDOPA plays a vital role in this rare entity and can avoid any further confirmatory invasive procedure.
Multidisciplinary care for rural pancreatic cancer patients: Providers’ perspectives about patients’ challenges navigating between rural healthcare settings and high-volume centers.
Authors: Natasha Kurien, Matthew DePuccio, Angela Sarna, Ann Scheck McAlearney, Aslam Ejaz
Journal: Journal of Clinical Oncology (2020)

116 Background: Multidisciplinary care from high-volume centers (HVCs) improves outcomes for patients with pancreatic cancer (PC). However, rural PC patients lack access to high-volume PC specialists, resulting in the need for them to travel to distant HVCs for specialized treatment. The barriers and challenges rural PC patients face when seeking care at distant HVCs is poorly 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 coders independently coded the interview transcripts to develop a thematic account of challenges rural PC patients encounter when receiving care at distant HVCs. Results: PC specialists commonly identified transportation as a major barrier they believed their rural PC patients experienced, and noted both the distance these patients needed to travel and difficulties patients reported in navigating major cities to receive care at HVCs. Similarly, providers commented that rural PC patients and their families reported having difficulty finding affordable lodging near HVCs sometimes resulting in the need for frequent and inconvenient back-and-forth travel between the HVC and the patient’s home. One interviewee stressed the importance of health literacy and the need for providers to improve physician-patient communication as well as provide resources to help rural PC patients better understand their condition and recommended treatment plan. PC specialists also indicated that some rural PC patients had expressed discomfort about contacting physicians outside their in-person clinic visits. They also reported that the possible duplication of services such as diagnostic imaging that could occur may result in increased financial stress for their patients. Conclusions: PC specialists noted several challenges they perceived their rural PC patients may face when navigating care between rural healthcare settings and HVCs. Notably, these challenges may both impact the delivery of high-quality multidisciplinary care and cause additional stress for rural PC patients. Future studies should examine how interventions (e.g., patient navigators, support groups, educational resources) aimed specifically at addressing barriers to multidisciplinary PC care for rural PC patients can be designed and implemented.
CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program
Authors: Fabio Guolo, Luana Fianchi, Paola Minetto, Marino Clavio, Michele Gottardi, Sara Galimberti, Giuliana Rizzuto, Michela Rondoni, Giambattista Bertani, Michela Dargenio, Atto Bilio, Barbara Scappini, Patrizia Zappasodi, Anna Maria Scattolin, Francesco Grimaldi, Giuseppe Pietrantuono, Pellegrino Musto, Marco Cerrano, Stefano D’Ardia, Ernesta Audisio, Alessandro Cignetti, Crescenza Pasciolla, Francesca Pavesi, Anna Candoni, Carmela Gurreri, Monica Morselli, Caterina Alati, Nicola Fracchiolla, Giovanni Rossi, Manuela Caizzi, Fabrizio Carnevale-Schianca, Agostino Tafuri, Giuseppe Rossi, Felicetto Ferrara, Livio Pagano, Roberto Massimo Lemoli
Journal: Blood Cancer Journal (2020)

Secondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT.
Clinical Evidence Supporting US Food and Drug Administration Clearance of Novel Therapeutic Devices via the De Novo Pathway Between 2011 and 2019
Authors: James L. Johnston, Sanket S. Dhruva, Joseph S. Ross, Vinay K. Rathi
Journal: JAMA Internal Medicine (2020)

This cross-sectional study characterizes the premarket clinical evidence supporting clearance of moderate-risk novel therapeutic medical devices by the US Food and Drug Administration.
FRI0076 Reduced toxicity of methotrexate in rheumatoid
Authors: MN Kotevska, M Grlickov, A Pusevski, J Calovski, S Percinkova, N Marina, D Antova, M Trajanoska, E Grlickova
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The aim of the study was to investigate whether folic acid (FA) supplementation in patients with rheumatoid arthritis reduces methotrexate (MTX) toxicity. <h3>Methods</h3> It was a prospective randomised study. Total of 53 patients with RA who had never used methotrexate before, were randomly assigned to receive either MTX alone (group 1) or MTX and 5 mg. folic acid (group 2). Patients were evaluated for treatment toxicity at three monthly intervals for two years. <h3>Results</h3> 1. Significant increases in the hepatic transaminases, ALT and AST, occurred in group 1, over the trial period. 2. After 6 months an increased incidence of nausea in group 1, occurred (43% vs. 7%). 3. More patients withdrew from the study early because of side-effects in group 1 (39% vs. 18% p = 0,025). <h3>Conclusion</h3> Our results indicate that it is inportant to continue FA supplementation long term to avoid patients discontinuing MTX treatment due to side-effects. They aslo suggest that FA supplementation can prevent the changes in AST and ALT.
Real-world evidence for U.S. Food and Drug Administration-approved oncology products, 2015 to 2020.
Authors: Bhakti Arondekar, Mei Sheng Duh, Rachel Bhak, Maral DerSarkissian, Lynn Huynh, Kelsey Wang, Eric Davis, Bryon Wornson
Journal: Journal of Clinical Oncology (2020)

280 Background: Since the 21st Century Cures Act, there has been growing interest in using real-world evidence (RWE) to support regulatory filings for new drugs and indications. The goal of this study was to provide a comprehensive source of RWE use cases of U.S. Food and Drug Administration (FDA) approvals for oncology products. Methods: A systematic review of FDA new drug applications (NDAs) and biologics license applications (BLAs) from 1/2015-2/2020 for approved oncology products was performed. Data on the RWE study were extracted (data source, study design, statistical methods, results), and corresponding FDA comments were synthesized to identify patterns of the FDA’s review. Results: We identified 102 NDAs and BLAs, 8 (8%) of which included RWE, all post-Cures Act (see Table). RWE supporting avelumab, axicabtagene ciloleucel, and avapritinib were received positively and used by the FDA in their approval decision. RWE results were used to provide contextualization to the pivotal trial, rather than statistical comparison. Common data sources included Flatiron (38%) and chart reviews (38%). FDA critiques included lack of a priori study protocol, incomparability with the pivotal trial population and endpoints, and uncontrolled confounding. Conclusions: There have been few examples of RWE in oncology submissions, and most served to complement clinical trial results. To meet FDA standards, RWE studies should be clearly designed and discussed with the FDA and include robust methods to minimize bias. [Table: see text]
Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial
Authors: Olivier Benveniste, Jean-Yves Hogrel, Lisa Belin, Mélanie Annoussamy, Damien Bachasson, Aude Rigolet, Pascal Laforet, Gaëlle Dzangué-Tchoupou, Joe-Elie Salem, Lee S Nguyen, Tanya Stojkovic, Noel Zahr, Baptiste Hervier, Océane Landon-Cardinal, Anthony Behin, Edith Guilloux, Harmen Reyngoudt, Damien Amelin, Akinori Uruha, Kuberaka Mariampillai, Benjamin Marty, Bruno Eymard, Jean-Sébastien Hulot, Steven A Greenberg, Pierre G Carlier, Yves Allenbach
Journal: The Lancet Rheumatology (2020)
'You’re the best liar in the world’: a grounded theory study of rowing athletes’ experience of low back pain
Authors: Fiona Wilson, Leo Ng, Kieran O'Sullivan, J P Caneiro, Peter PB O'Sullivan, Alex Horgan, Jane S Thornton, Kellie Wilkie, Virpi Timonen
Journal: British Journal of Sports Medicine (2020)

Objectives Low back pain (LBP) is common in rowers and leads to considerable disability and even retirement. The athlete voice can help clinicians to better understand sport-related pain disorders. We aimed to capture the lived experience of LBP in rowers. Methods Cross-sectional qualitative study using a grounded theory approach. Adult competitive rowers with a rowing-related LBP history were recruited in Australia and Ireland. Data were collected through interviews that explored: context around the time of onset of their LBP and their subsequent journey, experiences of management/treatment, perspectives around present beliefs, fears, barriers and expectations for the future. Results The 25 rowers (12 women/13 men) who participated were aged 18–50 years; they had a mean 12.1 years of rowing experience. They discussed a culture of concealment of pain from coaches and teammates, and fear of being judged as ‘weak’ because of the limitations caused by LBP. They reported fear and isolation as a result of their pain. They felt that the culture within rowing supported this. They reported inconsistent messages regarding management from medical staff. Some rowers reported being in a system where openness was encouraged—they regarded this a leading to better outcomes and influencing their LBP experience. Conclusions Rowers’ lived experience of LBP was influenced by a pervasive culture of secrecy around symptoms. Rowers and support staff should be educated regarding the benefits of early disclosure and rowers should be supported to do so without judgement.
Characterizing Ionizing Radiation Exposure after T-Cell Depleted Allogeneic Hematopoietic Cell Transplantation
Authors: Christina Cho, Molly Maloy, Sean M. Devlin, Omer Aras, H.R. Castro-Malaspina, Lawrence T. Dauer, Ann A. Jakubowski, Richard J. O'Reilly, Esperanza B. Papadopoulos, Miguel-Angel Perales, Theodore S. Rappaport, Roni Tamari, Marcel R.M. van den Brink, Sergio A. Giralt
Journal: Blood (2017)