Sylvie Bonvalot, Alessandro Gronchi, Cécile Le Péchoux, Carol J Swallow, Dirk Strauss, Pierre Meeus, Frits van Coevorden, Stephan Stoldt, Eberhard Stoeckle, Piotr Rutkowski, Marco Rastrelli, Chandrajit P Raut, Daphne Hompes, Antonino De Paoli, Claudia Sangalli, Charles Honoré, Peter Chung, Aisha Miah, Jean Yves Blay, Marco Fiore, Jean-Jacques Stelmes, Angelo P Dei Tos, Elizabeth H Baldini, Saskia Litière, Sandrine Marreaud, Hans Gelderblom, Rick L Haas
BACKGROUND: Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival. METHODS: EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery...
September 14, 2020: Lancet Oncology
Iosifina P Foskolou, Laura Barbieri, Aude Vernet, David Bargiela, Pedro P Cunha, Pedro Velica, Eunyeong Suh, Sandra Pietsch, Rugile Matuleviciute, Helene Rundqvist, Dominick McIntyre, Ken G C Smith, Randall S Johnson
Cancer immunotherapy is advancing rapidly and gene-modified T cells expressing chimeric antigen receptors (CARs) show particular promise. A challenge of CAR-T cell therapy is that the ex vivo-generated CAR-T cells become exhausted during expansion in culture, and do not persist when transferred back to patients. It has become clear that naive and memory CD8 T cells perform better than the total CD8 T-cell populations in CAR-T immunotherapy because of better expansion, antitumor activity, and persistence, which are necessary features for therapeutic success and prevention of disease relapse...
September 22, 2020: Blood Advances
Wen-Kai Weng, Sally Arai, Andrew Rezvani, Laura Johnston, Robert Lowsky, David Miklos, Judith Shizuru, Lori Muffly, Everett Meyer, Robert S Negrin, Erica Wang, Timothy Almazan, Lynn Million, Michael Khodadoust, Shufeng Li, Richard T Hoppe, Youn H Kim
The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients...
September 22, 2020: Blood Advances
Ben O'Leary, Rosalind J Cutts, Xin Huang, Sarah Hrebien, Yuan Liu, Fabrice André, Sibylle Loibl, Sherene Loi, Isaac Garcia-Murillas, Massimo Cristofanilli, Cynthia Huang Bartlett, Nicholas C Turner
BACKGROUND: There are no established molecular biomarkers for patients with breast cancer receiving combination endocrine and CDK4/6 inhibitor (CDK4/6i). We aimed to determine whether genomic markers in circulating tumor DNA (ctDNA) can identify patients at higher risk of early progression on fulvestrant therapy with or without palbociclib, a CDK4/6i. METHODS: PALOMA-3 was a phase III, multicenter, double-blind randomized controlled trial of palbociclib plus fulvestrant (n = 347) vs placebo plus fulvestrant (n = 174) in patients with endocrine-pretreated estrogen receptor-positive (ER+) breast cancer...
June 17, 2020: Journal of the National Cancer Institute
Christopher Mackintosh, Chen Yuan, Fang-Shu Ou, Sui Zhang, Donna Niedzwiecki, I-Wen Chang, Bert H O'Neil, Brian C Mullen, Heinz-Josef Lenz, Charles D Blanke, Alan P Venook, Robert J Mayer, Charles S Fuchs, Federico Innocenti, Andrew B Nixon, Richard M Goldberg, Eileen M O'Reilly, Jeffrey A Meyerhardt, Kimmie Ng
Importance: Several compounds found in coffee possess antioxidant, anti-inflammatory, and insulin-sensitizing effects, which may contribute to anticancer activity. Epidemiological studies have identified associations between increased coffee consumption and decreased recurrence and mortality of colorectal cancer. The association between coffee consumption and survival in patients with advanced or metastatic colorectal cancer is unknown. Objective: To evaluate the association of coffee consumption with disease progression and death in patients with advanced or metastatic colorectal cancer...
September 17, 2020: JAMA Oncology
Srikala S Sridhar, Normand Blais, Ben Tran, M Neil Reaume, Scott A North, Martin R Stockler, Kim N Chi, Neil E Fleshner, Geoffrey Liu, John W Robinson, Som D Mukherjee, Yasmin Rahim, Eric Winquist, Christopher M Booth, Nghia Trung Nguyen, Emma K Beardsley, Nimira S Alimohamed, Gail T McDonald, Keyue Ding, Wendy R Parulekar
Importance: Treatment options for platinum-refractory metastatic urothelial cancer (mUC) are limited, and outcomes remain poor. Nab-paclitaxel is an albumin-bound formulation of paclitaxel showing promising activity and tolerability in a prior single-arm trial. Objectives: To evaluate the efficacy and safety of nab-paclitaxel vs paclitaxel in platinum-refractory mUC. Design, Setting, and Participants: In this investigator-initiated, open-label, phase 2 randomized clinical trial conducted across Canada and Australia from January 2014 to April 2017, eligible patients had histologically confirmed, radiologically evident mUC of the urinary tract...
September 17, 2020: JAMA Oncology
Sergi Yun, Cristina Enjuanes, Esther Calero, Encarnación Hidalgo, Marta Cobo, Pau Llàcer, José Manuel García-Pinilla, Álvaro González-Franco, Julio Núñez, José Luis Morales-Rull, Paola Beltrán, Cristina Delso, Román Freixa-Pamias, Pedro Moliner, Xavier Corbella, Josep Comín-Colet
AIMS: The role of non-invasive telemedicine (TM) combining telemonitoring and teleintervention by videoconference (VC) in patients recently admitted due to heart failure (HF) ('vulnerable phase' HF patients) is not well established. The aim of the Heart failure Events reduction with Remote Monitoring and eHealth Support (HERMeS) trial is to assess the impact on clinical outcomes of implementing a TM service based on mobile health (mHealth), which includes remote daily monitoring of biometric data and symptom reporting (telemonitoring) combined with VC structured, nurse-based follow-up (teleintervention)...
September 17, 2020: ESC Heart Failure
A Pinter, M Hoffmann, K Reich, M Augustin, K Kaplan, S D Gudjónsdóttir, T Delvin, U Mrowietz
BACKGROUND: Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, 17F, 17C, and 17E. Therapy with fumaric acid esters (FAE) is a well-established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis OBJECTIVES: To compare brodalumab to FAE in terms of clinical efficacy, patient-reported outcomes, and safety in subjects with moderate to severe plaque psoriasis who were naïve to systemic treatment...
September 16, 2020: Journal of the European Academy of Dermatology and Venereology: JEADV
Toshihiko Doi, Masaomi Tajimi, Joji Mori, Hiroya Asou, Koichi Inoue, Karim A Benhadji, Yoichi Naito
Background This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a γ-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. Methods The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28-day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients...
September 16, 2020: Investigational New Drugs
Catherine A Chappell, Kimberly K Scarsi, Brian J Kirby, Vithika Suri, Anuj Gaggar, Debra L Bogen, Ingrid S Macio, Leslie A Meyn, Katherine E Bunge, Elizabeth E Krans, Sharon L Hillier
Background: Hepatitis C virus (HCV) infection is increasing among pregnant women because of the opioid epidemic, yet there are no interventions to reduce perinatal HCV transmission or to treat HCV during pregnancy. Physiological changes in pregnancy alter the pharmacokinetics of some medications; thus, our aim was to compare the pharmacokinetic parameters of ledipasvir 90 mg plus sofosbuvir 400 mg during pregnancy with non-pregnant women. Methods: This was an open-label, phase 1 study of pregnant women with genotype 1 HCV infection and their infants...
September 2020: The Lancet. Microbe
Sadhana Jackson, Eva H Baker, Andrea M Gross, Patricia Whitcomb, Andrea Baldwin, Joanne Derdak, Cecilia Tibery, Jennifer Desanto, Amanda Carbonell, Kaleb Yohay, Geraldine O'Sullivan, Alice P Chen, Brigitte C Widemann, Eva Dombi
Background: Spinal neurofibromas (SNFs) in neurofibromatosis type 1 (NF1) can cause progressive spinal cord compression and neurological dysfunction. The MEK inhibitor selumetinib shrinks the majority of plexiform neurofibromas (PNs) in patients with NF1. We assessed the effect of selumetinib on SNF. Methods: Pediatric and adult patients with NF1 and inoperable PN participating in phase 2 studies of selumetinib for PN were included in this analysis if they had SNF and serial spine magnetic resonance imaging (MRI)...
January 2020: Neuro-oncology advances
Kim Donoghue, Abigail Rose, Simon Coulton, Rachel Coleman, Joanna Milward, Thomas Philips, Colin Drummond, Hilary Little
BACKGROUND: Alcohol dependence is a significant issue contributing to disease burden. Changes in cortisol concentrations during alcohol withdrawal are associated with cognitive deficits and symptoms of depression. Current treatments are only successful for a small proportion of people and do not target cognitive deficits and symptoms of depression experienced by those who are alcohol dependent. The aim of this research is to determine the potential efficacy of mifepristone, a type II glucocorticoid receptor antagonist, to prevent symptoms of depression and cognitive deficits following alcohol detoxification...
September 16, 2020: Trials
Alexander J Schupper, Matthew E Eagles, Sean N Neifert, J Mocco, R Loch Macdonald
After years of research on treatment of aneurysmal subarachnoid hemorrhage (aSAH), including randomized clinical trials, few treatments have been shown to be efficacious. Nevertheless, reductions in morbidity and mortality have occurred over the last decades. Reasons for the improved outcomes remain unclear. One randomized clinical trial that has been examined in detail with these questions in mind is Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1)...
September 14, 2020: Journal of Clinical Medicine
Christoph Boss, John Gatfield, Christine Brotschi, Bibia Heidmann, Thierry Sifferlen, Markus von Raumer, Gunther Schmidt, Jodi T Williams, Alexander Treiber, Catherine Roch
Since its discovery in 1998, the orexin system is of interest to the research community as a potential therapeutic target for the treatment of sleep/wake disorders, stress and anxiety disorders, addiction or eating disorders. It consists of two G-protein-coupled receptors, the orexin 1 and the orexin 2-receptor and two neuropeptides with agonistic effects, the orexin A and the orexin B-peptide. We describe our efforts leading to the identification of a promising set of dual orexin receptor antagonists (DORAs) which subsequently went through physiology-based pharmacokinetic and pharmacodynamic modelling 1 and finally led to the selection of daridorexant ( 93 ) currently in phase 3 clinical trials for the treatment of insomnia disorders...
September 16, 2020: ChemMedChem
Burak Kalin, Yvette van Norden, Michel van Gelder, Dimitri Breems, Johan Maertens, Mojca Jongen-Lavrencic, Annoek E C Broers, Eric Braakman, Tim Grob, Wendelien Zeijlemaker, Gert J Ossenkoppele, Ellen Meijer, Jan J Cornelissen
Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the graft-versus-leukemia effect more effectively, we assessed the feasibility of early initiation of epigenetic therapy with panobinostat and decitabine after allo-HSCT and before donor lymphocyte infusion (DLI) in poor-risk patients with acute myeloid leukemia (AML) or refractory anemia with excess blasts with International Prognostic Scoring System score ≥1...
September 22, 2020: Blood Advances
Tyler Faits, Maura E Walker, Jose Rodriguez-Morato, Huicui Meng, Julie E Gervis, Jean M Galluccio, Alice H Lichtenstein, W Evan Johnson, Nirupa R Matthan
BACKGROUND: Dietary carbohydrate type may influence cardiometabolic risk through alterations in the gut microbiome and microbial-derived metabolites, but evidence is limited. OBJECTIVES: We explored the relative effects of an isocaloric exchange of dietary simple, refined, and unrefined carbohydrate on gut microbiota composition/function, and selected microbial metabolite concentrations. METHODS: Participants [n = 11; age: 65 ± 8 y; BMI (in kg/m2): 29...
September 16, 2020: American Journal of Clinical Nutrition
Vitor DE Mello Netto, Carolina A Flores, Stefano Pallanti
Comorbidity between bipolar disorder (BD) and obsessive-compulsive disorder (OCD) is fairly common, and the treatment of these conditions when comorbid is challenging. Serotonin reuptake inhibitors, the first option for treatment of OCD, can worsen BD symptoms, and mood stabilizers are generally not efficacious for OCD. Our goal in this article is to assess the clinical effectiveness of pharmacotherapies for comorbid BD-OCD in adults. We searched the Medline, Embase, and Cochrane Central Register of Controlled Trials databases on April 30, 2017, and we also searched the reference lists of identified articles...
September 2020: Journal of Psychiatric Practice
Paola Lipone, Edvard Ehler, Marcin Nastaj, Ilona Palka-Kisielowska, Giorgio Cruccu, Andrea Truini, Giorgio Di Loreto, Alessandra Del Vecchio, Ilena Pochiero, Alessandro Comandini, Fabrizio Calisti, Agnese Cattaneo
BACKGROUND: Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy...
September 16, 2020: CNS Drugs
Gabrielle Levin, J Gordon Boyd, Andrew Day, Miranda Hunt, David M Maslove, Patrick Norman, Nicole O'Callaghan, Stephanie Sibley, John Muscedere
INTRODUCTION: Immunological dysfunction is common in critically ill patients but its clinical significance and the optimal method to measure it are unknown. The level of tumor necrosis factor alpha (TNF-α) after ex-vivo whole blood stimulation with lipopolysaccharide (LPS) has been proposed as a possible method to quantify immunological function. We hypothesized that in a cohort of critically ill patients, those with a lower post-stimulation TNF-α level would have increased rates of nosocomial infections (NIs) and worse clinical outcomes...
September 16, 2020: Intensive Care Medicine Experimental
Philippe Gradidge, Merling Phaswana, Katrien Wijndaele, Nigel Crowther, Catherine Draper
Background: Sedentary behaviour is associated with cardiometabolic diseases amongst office-bound workers, mostly through extended sitting and engaging in low-energy-demanding activities during work hours. The aim of this study is to assess the effectiveness of standing desks and healthy messages on cardiovascular parameters in a cohort of office-based workers and to explore the perceptions of these workers about the suitability of this intervention to lower occupation-related sedentariness...
2020: South African Journal of Physiotherapy
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