Showing papers by "Hebron University published in 2020"
TL;DR: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type.
Abstract: Background The efficacy and safety of the anti–programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line trea...
773 citations
TL;DR: This paper aims to provide a history of colorectal surgery in Italy and Spain over the past 50 years and some of the techniques used in that time have changed significantly.
Abstract: 1Department of Biomedical Sciences, Humanitas University, Via Manzoni 113 20089 Rozzano Milan, 2Division of Colon and Rectal Surgery, Humanitas Clinical and Research Hospital, Via Manzoni 56 20089 Rozzano Milan, 3Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania ‘Luigi Vanvitelli’, Naples, Italy, and 4Colorectal Unit, Vall d’Hebron University Hospital, Barcelona, Spain (e-mail: antonino.spinelli@hunimed.eu)
682 citations
University of Las Palmas de Gran Canaria1, Hebron University2, University of Sydney3, University of Wollongong4, Sanford Health5, Sunnybrook Health Sciences Centre6, Ben-Gurion University of the Negev7, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico8, University of California, Los Angeles9, University of Turin10, Kansai Medical University11, Merck & Co.12, University of Milan13
TL;DR: First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.
Abstract: PURPOSEIn KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-plati...
609 citations
Institut Gustave Roussy1, Hebron University2, Ludwig Maximilian University of Munich3, Erasmus University Rotterdam4, University of Verona5, Memorial Sloan Kettering Cancer Center6, University of Texas MD Anderson Cancer Center7, Harvard University8, University Hospital Heidelberg9, Université Paris-Saclay10, Paris Descartes University11, European Society for Medical Oncology12
TL;DR: ESMO recommends routine use of NGS on tumour samples in advanced non-squamous NSCLC, prostate cancers, ovarian cancers and cholangiocarcinoma, and develops multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development.
535 citations
Katholieke Universiteit Leuven1, New Generation University College2, Yale Cancer Center3, Seoul National University Bundang Hospital4, Pontifical Catholic University of Chile5, Yonsei University6, Samsung Medical Center7, Universidad del Desarrollo8, University of Chile9, Harvard University10, Northwestern University11, City of Hope National Medical Center12, University of California, San Francisco13, University of California, Los Angeles14, Merck & Co.15, Hebron University16
TL;DR: This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed.
Abstract: Importance Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need. Objective To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater. Design, Setting, and Participants The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017. Interventions Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2twice daily), or chemotherapy plus placebo, every 3 weeks. Main Outcomes and Measures Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater. Results A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03;P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17;P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02;P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively. Conclusions and Relevance This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested. Trial Registration ClinicalTrials.gov Identifier:NCT02494583
500 citations
Cornell University1, Memorial Sloan Kettering Cancer Center2, Hebron University3, University of Texas MD Anderson Cancer Center4, University of California, San Francisco5, University of Wisconsin-Madison6, Harvard University7, University of Chicago8, Mayo Clinic9, University of Washington10, Johns Hopkins University11, Seoul National University Hospital12, Trinity College, Dublin13, University of Arizona14, University of Southern California15, Agios Pharmaceuticals16, University of Manchester17, Fudan University18
TL;DR: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivOSidenib was well tolerated, and this study shows the clinical benefit of targeting IDH1 mutations in advanced,IDH1-mutant cholangiocarcinoma.
Abstract: Summary Background Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma. Methods This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov , NCT02989857 . Findings Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8–10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6–4·2] vs 1·4 months [1·4–1·6]; hazard ratio 0·37; 95% CI 0·25–0·54; one-sided p Interpretation Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. Funding Agios Pharmaceuticals.
494 citations
TL;DR: Those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib.
Abstract: Background Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with ALK-positive non–small-cell lung cancer ...
474 citations
Vanderbilt University Medical Center1, Mario Negri Institute for Pharmacological Research2, Marche Polytechnic University3, University of L'Aquila4, Hebron University5, University of Alcalá6, Vita-Salute San Raffaele University7, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico8, Georgetown University9, University of Lausanne10, Academy for Urban School Leadership11, University of Parma12, Guangdong General Hospital13, Erasmus University Medical Center14, Aix-Marseille University15, Stanford University16, Vanderbilt University17
TL;DR: With an ongoing global pandemic of COVID-19, the data suggest high mortality and low admission to intensive care in patients with thoracic cancer and whether mortality could be reduced with treatment in intensive care remains to be determined.
Abstract: Summary Background Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies. Methods The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data. Findings Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8–75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0–1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00–3·62), being a current or former smoker (4·24, 1·70–12·95), receiving treatment with chemotherapy alone (2·54, 1·09–6·11), and the presence of any comorbidities (2·65, 1·09–7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11–9·06) was associated with increased risk of death. Interpretation With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference. Funding None.
473 citations
TL;DR: Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status.
Abstract: PURPOSEPatients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiv...
334 citations
Memorial Sloan Kettering Cancer Center1, Harvard University2, Hebron University3, Meir Medical Center4, University of Lausanne5, University of Toronto6, University of Las Palmas de Gran Canaria7, National Taiwan University8, Paul Sabatier University9, Istanbul Medeniyet University10, University of Michigan11, Merck & Co.12, Yonsei University13
TL;DR: Pembrolizumab plus EP significantly improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus EP as first-line therapy for patients with ES-SCLC, and these data support the benefit of pembrolIZumab in ES-sCLC.
Abstract: PURPOSEPembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus e...
320 citations
University of California, San Francisco1, University of Pennsylvania2, Cleveland Clinic3, Vita-Salute San Raffaele University4, Stony Brook University5, Washington University in St. Louis6, University Hospital of Basel7, Hebron University8, University of Warmia and Mazury in Olsztyn9, University of Münster10, Novartis11, University of Basel12
TL;DR: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide, and this data indicates that this drug should be considered as a second-line treatment for relapsing multiple sclerosis.
Abstract: Background Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activ...
University of Bologna1, University of Sydney2, Westmead Hospital3, University of Picardie Jules Verne4, University of Lausanne5, Hebron University6, University of Milan7, University Hospital of Lausanne8, National University of Singapore9, Universidade Federal do Rio Grande do Sul10, Vita-Salute San Raffaele University11, University of Insubria12, Queen Mary University of London13, Barts Health NHS Trust14, University of Sassari15
TL;DR: Diagnostic, treatment and outcome details of 49 COVID-19 patients with concurrent or previous tuberculosis from 8 countries show varied clinical profiles.
Abstract: Diagnostic, treatment and outcome details of 49 COVID-19 patients with concurrent or previous tuberculosis from 8 countries show varied clinical profileshttps://bit.ly/369ZGGu
Hebron University1, Tri-Service General Hospital2, University of California, Los Angeles3, University of Ulsan4, Harvard University5, Institut Gustave Roussy6, Northwestern University7, Sunnybrook Health Sciences Centre8, University of Helsinki9, Kaohsiung Medical University10, National Cheng Kung University11, Li Ka Shing Faculty of Medicine, University of Hong Kong12, Katholieke Universiteit Leuven13, University of Texas Southwestern Medical Center14, National Taiwan University15, Mackay Memorial Hospital16, Gunma University17
TL;DR: N+C significantly improved PFS and time to intervention for CNS disease versus L+C and no new N+C safety signals were observed.
Abstract: PURPOSENALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capec...
TL;DR: How the seven comprehensive cancer centers of Cancer Core Europe have organized their healthcare systems at an unprecedented scale and pace to make their operations ‘pandemic proof’ is reported.
Abstract: The current COVID-19 pandemic challenges oncologists to profoundly re-organize oncological care in order to dramatically reduce hospital visits and admissions and therapy-induced immune-related complications without compromising cancer outcomes. Since COVID-19 is a novel disease, guidance by scientific evidence is often unavailable, and impactful decisions are inevitably made on the basis of expert opinions. Here we report how the seven comprehensive cancer centers of Cancer Core Europe have organized their healthcare systems at an unprecedented scale and pace to make their operations 'pandemic proof'. We identify and discuss many commonalities, but also important local differences, and pinpoint critical research priorities to enable evidence-based remodeling of cancer care during the COVID-19 pandemic. Also, we discuss how the current situation offers a unique window of opportunity for assessing the effects of de-escalating anticancer regimens, which may fast-forward the development of more-refined and less-toxic treatments. By sharing our joint experiences, we offer a roadmap for proceeding and aim to mobilize the global research community to generate the data that are critically needed to offer the best possible care to patients.
Harvard University1, Beth Israel Deaconess Medical Center2, Rambam Health Care Campus3, Hebron University4, Translational Genomics Research Institute5, Tel Aviv University6, Rabin Medical Center7, Sheba Medical Center8, Tel Aviv Sourasky Medical Center9, Mayo Clinic10, Washington University in St. Louis11, Samsung Medical Center12, Ochsner Medical Center13, Hospital Universitario La Paz14, Complutense University of Madrid15, University of Navarra16, Hebrew University of Jerusalem17, Merck & Co.18, NewYork–Presbyterian Hospital19, Cornell University20
TL;DR: Results from the phase IIa COMBAT trial combining CXCR4 and PD-1 inhibition in patients with metastatic cancer show encouraging clinical responses in association with enhanced antitumor immune activation.
Abstract: Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials. Results from the phase IIa COMBAT trial combining CXCR4 and PD-1 inhibition in patients with metastatic cancer show encouraging clinical responses in association with enhanced antitumor immune activation.
European Institute of Oncology1, The Royal Marsden NHS Foundation Trust2, Carlos III Health Institute3, University of Valencia4, University of Milan5, University of Alcalá6, Curie Institute7, Claude Bernard University Lyon 18, Netherlands Cancer Institute9, Heidelberg University10, Leipzig University11, Cliniques Universitaires Saint-Luc12, University of Lausanne13, Hebron University14, University of Ioannina15, University of Geneva16, Université Paris-Saclay17, Harvard University18, Duke University19, National University of Singapore20, Université libre de Bruxelles21, Lund University22, Institut Gustave Roussy23, Vita-Salute San Raffaele University24
TL;DR: An international consortium to develop expert consensus statements related to cancer management during the severe acute respiratory syndrome coronavirus 2-related disease (COVID-19) pandemic agreed on 28 consensus statements that can be used to overcome many of the clinical and technical areas of uncertainty.
University of Colorado Boulder1, Yonsei University2, Samsung Medical Center3, National Taiwan University4, Chungbuk National University5, Seoul National University Hospital6, University of Oldenburg7, Hebron University8, University of Manchester9, Yale Cancer Center10, Millennium Pharmaceuticals11, The Royal Marsden NHS Foundation Trust12, Institute of Cancer Research13
TL;DR: Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.
Abstract: PURPOSEBrigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizo...
TL;DR: The role of intratumoral heterogeneity is highlighted, focusing on the clinical and biological ramifications this phenomenon poses, and how understanding the involved drivers and functional consequences can provide novel insight needed to confront the problem of therapeutic resistance in tumors.
Abstract: In this review, we highlight the role of intratumoral heterogeneity, focusing on the clinical and biological ramifications this phenomenon poses. Intratumoral heterogeneity arises through complex genetic, epigenetic, and protein modifications that drive phenotypic selection in response to environmental pressures. Functionally, heterogeneity provides tumors with significant adaptability. This ranges from mutual beneficial cooperation between cells, which nurture features such as growth and metastasis, to the narrow escape and survival of clonal cell populations that have adapted to thrive under specific conditions such as hypoxia or chemotherapy. These dynamic intercellular interplays are guided by a Darwinian selection landscape between clonal tumor cell populations and the tumor microenvironment. Understanding the involved drivers and functional consequences of such tumor heterogeneity is challenging but also promises to provide novel insight needed to confront the problem of therapeutic resistance in tumors.
Humanitas University1, University of Cartagena2, University of Genoa3, Hebron University4, University of Veterinary Medicine Vienna5, University of Helsinki6, Autonomous University of Barcelona7, University of Paris8, University of Montpellier9, Erasmus University Rotterdam10, Universidad Autónoma de Nuevo León11, Mayo Clinic12, Kırıkkale University13, University of São Paulo14, University of South Florida15, San Juan de Dios Educational Foundation16, University of Marburg17, Nippon Medical School18, Federal University of Paraná19, University of Missouri–Kansas City20, Royal Children's Hospital21, Tan Tock Seng Hospital22, I.M. Sechenov First Moscow State Medical University23, Medical University of Vienna24, Johns Hopkins University School of Medicine25, Charité26
TL;DR: A thorough and updated critical appraisal of the most frequently used diagnostic tests, both in vivo and in vitro, and discusses skin tests, challenges, and serological and cellular in vitro tests, and provides an overview of indications, advantages and disadvantages of each in conditions such as respiratory, food, venom, drug, and occupational allergy.
TL;DR: Dostarlimab was associated with clinically meaningful and durable antitumor activity with an acceptable safety profile for patients with deficient mismatch repair endometrial cancers that have progressed after prior platinum-based chemotherapy.
Abstract: Importance Deficient mismatch mutation repair mechanisms may sensitize endometrial cancers to anti-programmed death 1 (PD-1) therapies. Dostarlimab (TSR-042) is an investigational anti-PD-1 antibody that binds with high affinity to the PD-1 receptor. Objective To assess the antitumor activity and safety of dostarlimab for patients with deficient mismatch repair endometrial cancer. Design, setting, and participants This ongoing, open-label, single-group, multicenter study began part 1 on March 7, 2016, and began enrolling patients with deficient mismatch mutation repair endometrial cancer on May 8, 2017. Median follow-up was 11.2 months (range, 0.03 [ongoing] to 22.11 [ongoing] months; based on radiological assessments). Statistical analysis was performed July 8 to August 9, 2019. Interventions Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, treatment discontinuation, or withdrawal. Main outcomes and measures The primary end point was objective response rate and duration of response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Results As of the data cutoff, 104 women (median age, 64.0 years [range, 38-80 years]) with deficient mismatch mutation repair endometrial cancers were enrolled and treated with dostarlimab. Of these, 71 had measurable disease at baseline and at 6 months or more of follow-up and were included in the analysis. There was a confirmed response in 30 patients (objective response rate, 42.3%; 95% CI, 30.6%-54.6%); 9 patients (12.7%) had a confirmed complete response, and 21 patients (29.6%) had a confirmed partial response. Responses were durable; the median duration of response was not reached (median follow-up was 11.2 months). The estimated likelihood of maintaining a response was 96.4% at 6 months and 76.8% at 12 months. Anemia (3 of 104 [2.9%]), colitis (2 of 104 [1.9%]), and diarrhea (2 of 104 [1.9%]) were the most common grade 3 or higher treatment-related adverse events. Conclusions and relevance In this nonrandomized trial, dostarlimab was associated with clinically meaningful and durable antitumor activity with an acceptable safety profile for patients with deficient mismatch mutation repair endometrial cancers after prior platinum-based chemotherapy. Trial registration ClinicalTrials.gov identifier: NCT02715284.
University of Washington1, Valparaiso University2, University of Pécs3, University of Milan4, Monash University5, Alfred Hospital6, University of Pennsylvania7, Washington University in St. Louis8, University of Cape Town9, Shanghai Jiao Tong University10, Johns Hopkins University11, Stanford University12, Case Western Reserve University13, University of Cambridge14, Christian Medical College & Hospital15, University of Texas Health Science Center at Houston16, University of California, San Francisco17, Henry Ford Health System18, Katholieke Universiteit Leuven19, Oakland University20, University of Lausanne21, University of Pittsburgh22, Vanderbilt University Medical Center23, Baylor College of Medicine24, El Bosque University25, Hebron University26, Humanitas University27, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico28, Université libre de Bruxelles29, Pennsylvania State University30, University of Ottawa31, North Shore University Hospital32, Ronald Reagan UCLA Medical Center33, Emory University34, University of Rochester35, University of Manitoba36
TL;DR: These protocols are intended to assist clinicians in the management of patients with both intracranial pressure (ICP) and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management.
Abstract: Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place. Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting. We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms. These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference.
TL;DR: Migrants had lower mortality, probably because of their younger age and lower number of co-morbidities, however, in settings where advanced forms of TB frequently occur and are caused by drug-resistant strains of M. tuberculosis, higher mortality rates can be expected in young individuals.
TL;DR: The pathogenesis and the possible role played by drugs such as: antimalarials, anti-IL6,anti-IL-1, calcineurin and JAK inhibitors, corticosteroids, immunoglobulins, heparins, angiotensin-converting enzyme agonists and statins in severe COVID-19 are discussed.
Medical University of Silesia1, Academy of Medical Sciences, United Kingdom2, Charles University in Prague3, National and Kapodistrian University of Athens4, Imperial College London5, French Institute of Health and Medical Research6, University of Calgary7, University of Ostrava8, King's College London9, Nil Ratan Sircar Medical College and Hospital10, Indira Gandhi Institute of Medical Sciences11, University of Alberta12, University Hospitals of Leicester NHS Trust13, Hebron University14, Jagiellonian University Medical College15, Medical University of Łódź16, Flinders Medical Centre17, University of Wolverhampton18, University of Perugia19, St. Vincent's Health System20, Medical University Plovdiv21, Icahn School of Medicine at Mount Sinai22, Baylor University Medical Center23, Queen Elizabeth II Health Sciences Centre24, Hebrew University of Jerusalem25, University of Bologna26, Princess Margaret Cancer Centre27, University of Texas Southwestern Medical Center28, Harvard University29
TL;DR: This phase 3, randomised, open-label trial aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortzomib and dex amethas one in patients with previously treated multiple myeloma.
TL;DR: Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events.
Abstract: Summary Background HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane. Methods The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3·6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , NCT02924883 , and the study has been completed. Findings Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8·5 months (IQR 6·1–11·5) for patients assigned atezolizumab and 8·4 months (5·3–11·1) for those assigned placebo. Median progression-free survival was 8·2 months (95% CI 5·8–10·7) for patients assigned atezolizumab versus 6·8 months (4·0–11·1) for those assigned placebo (stratified hazard ratio 0·82, 95% CI 0·55–1·23; p=0·33). The most common grade 3 or worse adverse events were thrombocytopenia (17 [13%] among 132 patients who received atezolizumab vs three [4%] among 68 who received placebo), increased aspartate aminotransferase (11 [8%] vs two [3%]), anaemia (seven [5%] vs 0), neutropenia (six [5%] vs three [4%]), and increased alanine aminotransferase (six [5%] vs two [3%]). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome). Interpretation Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer. Funding F Hoffman-La Roche.
TL;DR: This work provides a practical strategy to reorganize pathways of emergency and elective colorectal surgery during the COVID‐19 pandemic, which is challenging healthcare systems at a global level.
Abstract: Aim The current COVID-19 pandemic is challenging healthcare systems at a global level. We provide a practical strategy to reorganize pathways of emergency and elective colorectal surgery during the COVID-19 pandemic. Method The authors, all from areas affected by the COVID-19 emergency, brainstormed remotely to define the key-points to be discussed. Tasks were assigned, concerning specific aspects of colorectal surgery during the pandemic, including the administrative management of the crisis in Italy. The recommendations (based on experience and on the limited evidence available) were collated and summarized. Results Little is known about the transmission of COVID-19, but it has shown a rapid spread. It is prudent to stop non-cancer procedures and prioritize urgent cancer treatment. Endoscopy and proctological procedures should be performed highly selectively. When dealing with colorectal emergencies, a conservative approach is advised. Specific procedures should be followed when operating on COVID-19-patients, using dedicated personal protective equipment and adhering to specific rules. Some policies are described, including minimally-invasive surgery. These policies outline the strict regulation of entry/ exit into theatres and operating building as well as advice on performing procedures safely to reduce risk of spreading the virus. It is likely that a reorganization of health system is required, both at central and local levels. A description of the strategy adopted in Italy is provided. Conclusion Evidence on the management of patients needing surgery for colorectal conditions during the COVID-19 pandemic is currently lacking. Lessons learnt from healthcare professionals that have managed high volumes of surgical patients during the pandemic could be useful to mitigate some risks and reduce exposure to other patients, public and healthcare staff.
TL;DR: LBA4 is a phase 3, randomized open-label study evaluating the efficacy and safety of pembrolizumab (pembro) versus standard of care chemotherapy ± bevacIZumab o...
Abstract: LBA4Background: KEYNOTE-177 (NCT02563002) is a phase 3, randomized open-label study evaluating the efficacy and safety of pembrolizumab (pembro) versus standard of care chemotherapy ± bevacizumab o...
TL;DR: The genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers, with RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to m CRPC.
Abstract: The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; CDK12 5%; ATM 4%) were commonly detected. TP53, BRCA2, and CDK12 mutations were markedly more common than described in the TCGA cohort. Patients with RB1 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, RB1, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.
TL;DR: Higher risk of death from COVID-19 among patients with cancer was correlated with male sex, greater age, presence of multiple comorbidities, advanced-stage disease, and active disease; there was no association between risk and anticancer treatment.
Abstract: The SARS-Cov-2 pandemic significantly impacted on oncology practice across the globe. There is uncertainty as to the contribution of patients' demographics and oncological features on severity and mortality from Covid-19 and little guidance as to the role of anti-cancer and anti-Covid-19 therapy in this population. In a multi-center study of 890 cancer patients with confirmed Covid-19 we demonstrated a worsening gradient of mortality from breast cancer to haematological malignancies and showed that male gender, older age, and number of co-morbidities identifies a subset of patients with significantly worse mortality rates from Covid-19. Provision of chemotherapy, targeted therapy and immunotherapy did not worsen mortality. Exposure to antimalarials was associated with improved mortality rates independent of baseline prognostic factors. This study highlights the clinical utility of demographic factors for individualized risk-stratification of patients and support further research into emerging anti-Covid-19 therapeutics in SARS-Cov-2 infected cancer patients.
Beth Israel Deaconess Medical Center1, Mayo Clinic2, University of Michigan3, Memorial Sloan Kettering Cancer Center4, University of Texas MD Anderson Cancer Center5, Case Western Reserve University6, Cooper University Hospital7, Hebron University8, Yale Cancer Center9, Georgetown University10, University of Texas Health Science Center at San Antonio11, University of Washington12, Allegheny Health Network13, American Society of Clinical Oncology14, Beaumont Health15
TL;DR: Recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes are developed based on a systematic review of the literature and a formal consensus process.
Abstract: PURPOSETo develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes.METHODSThe American Society of Clinical Oncology, American So...