Showing papers by "Hebron University published in 2021"
University of Washington1, St George’s University Hospitals NHS Foundation Trust2, McMaster University3, Agostino Gemelli University Polyclinic4, Emory University5, Federal University of São Paulo6, Ottawa Hospital7, St Thomas' Hospital8, University of Michigan9, Cooper University Hospital10, University of Kansas11, University of Amsterdam12, United Arab Emirates University13, University of Pittsburgh14, King Saud bin Abdulaziz University for Health Sciences15, University of São Paulo16, University of Minnesota17, Population Health Research Institute18, University of Toronto19, Humanitas University20, University of Kentucky21, Ghent University Hospital22, University of Tokyo23, Peking Union Medical College Hospital24, Hebron University25, Monash University26, Copenhagen University Hospital27, Liverpool School of Tropical Medicine28, Vanderbilt University29, Brigham and Women's Hospital30, Harvard University31, University of Ulsan32, University of Manitoba33, Makerere University34, Faculdade de Medicina de São José do Rio Preto35, Mount Sinai Hospital, Toronto36, Medanta37, University of the Witwatersrand38, New York University39, Washington University in St. Louis40, University of Alberta41, Hennepin County Medical Center42, University of Pennsylvania43, Hebrew University of Jerusalem44, Hadassah Medical Center45, Hochschule Hannover46, Brown University47
TL;DR: The Surviving Sepsis Campaign (SSC) guidelines provide evidence-based recommendations on the recognition and management of sepsis and its complications as discussed by the authors, which are either strong or weak, or in the form of best practice statements.
Abstract: Background
Sepsis poses a global threat to millions of lives. The Surviving Sepsis Campaign (SSC) guidelines provide evidence-based recommendations on the recognition and management of sepsis and its complications.
Methods
We formed a panel of 60 experts from 22 countries and 11 members of the public. The panel prioritized questions that are relevant to the recognition and management of sepsis and septic shock in adults. New questions and sections were addressed, relative to the previous guidelines. These questions were grouped under 6 subgroups (screening and early treatment, infection, hemodynamics, ventilation, additional therapies, and long-term outcomes and goals of care). With input from the panel and methodologists, professional medical librarians performed the search strategy tailored to either specific questions or a group of relevant questions. A dedicated systematic review team performed screening and data abstraction when indicated. For each question, the methodologists, with input from panel members, summarized the evidence assessed and graded the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The panel generated recommendations using the evidence-to-decision framework. Recommendations were either strong or weak, or in the form of best practice statements. When evidence was insufficient to support a recommendation, the panel was surveyed to generate “in our practice” statements.
Results
The SSC panel issued 93 statements: 15 best practice statements, 15 strong recommendations, and 54 weak recommendations and no recommendation was provided for 9 questions. The recommendations address several important clinical areas related to screening tools, acute resuscitation strategies, management of fluids and vasoactive agents, antimicrobials and diagnostic tests and the use of additional therapies, ventilation management, goals of care, and post sepsis care.
Conclusion
The SSC panel issued evidence-based recommendations to help support key stakeholders caring for adults with sepsis or septic shock and their families.
893 citations
University of Washington1, St George’s University Hospitals NHS Foundation Trust2, McMaster University3, Agostino Gemelli University Polyclinic4, Emory University5, Federal University of São Paulo6, Ottawa Hospital7, St Thomas' Hospital8, University of Michigan9, Cooper University Hospital10, University of Kansas11, University of Amsterdam12, United Arab Emirates University13, University of Pittsburgh14, King Saud bin Abdulaziz University for Health Sciences15, University of São Paulo16, University of Minnesota17, Population Health Research Institute18, University of Toronto19, Humanitas University20, University of Kentucky21, Ghent University Hospital22, University of Tokyo23, Peking Union Medical College Hospital24, Hebron University25, Monash University26, Copenhagen University Hospital27, Liverpool School of Tropical Medicine28, Vanderbilt University29, Brigham and Women's Hospital30, University of Ulsan31, University of Manitoba32, Makerere University33, Faculdade de Medicina de São José do Rio Preto34, National Institutes of Health35, Mount Sinai Hospital, Toronto36, Medanta37, University of the Witwatersrand38, New York University39, Washington University in St. Louis40, University of Alberta41, Hennepin County Medical Center42, Royal Brisbane and Women's Hospital43, University of Pennsylvania44, Hebrew University of Jerusalem45, Hochschule Hannover46, Brown University47
TL;DR: The Surviving Sepsis Campaign (SSC) guidelines provide evidence-based recommendations on the recognition and management of sepsis and its complications as mentioned in this paper, which are either strong or weak, or in the form of best practice statements.
Abstract: Background
Sepsis poses a global threat to millions of lives. The Surviving Sepsis Campaign (SSC) guidelines provide evidence-based recommendations on the recognition and management of sepsis and its complications.
Methods
We formed a panel of 60 experts from 22 countries and 11 members of the public. The panel prioritized questions that are relevant to the recognition and management of sepsis and septic shock in adults. New questions and sections were addressed, relative to the previous guidelines. These questions were grouped under 6 subgroups (screening and early treatment, infection, hemodynamics, ventilation, additional therapies, and long-term outcomes and goals of care). With input from the panel and methodologists, professional medical librarians performed the search strategy tailored to either specific questions or a group of relevant questions. A dedicated systematic review team performed screening and data abstraction when indicated. For each question, the methodologists, with input from panel members, summarized the evidence assessed and graded the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The panel generated recommendations using the evidence-to-decision framework. Recommendations were either strong or weak, or in the form of best practice statements. When evidence was insufficient to support a recommendation, the panel was surveyed to generate “in our practice” statements.
Results
The SSC panel issued 93 statements: 15 best practice statements, 15 strong recommendations, and 54 weak recommendations and no recommendation was provided for 9 questions. The recommendations address several important clinical areas related to screening tools, acute resuscitation strategies, management of fluids and vasoactive agents, antimicrobials and diagnostic tests and the use of additional therapies, ventilation management, goals of care, and post sepsis care.
Conclusion
The SSC panel issued evidence-based recommendations to help support key stakeholders caring for adults with sepsis or septic shock and their families.
664 citations
TL;DR: In this article, the authors investigated whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit of first-line nivolumab plus ipilimumab for advanced non-small-cell lung cancer (NSCLC).
Abstract: Summary Background First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit. Methods This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0–1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov , number NCT03215706 . Findings Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4–12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2–16·2] vs 10·7 months [9·5–12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55–0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4–17·0]), median overall survival was 15·6 months (95% CI 13·9–20·0) in the experimental group versus 10·9 months (9·5–12·6) in the control group (HR 0·66 [95% CI 0·55–0·80]). The most common grade 3–4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and febrile neutropenia (14 [4%] vs ten [3%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related. Interpretation Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk–benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC. Funding Bristol Myers Squibb. Translations For the Polish and Russian translations of the Article see Supplementary Materials section.
586 citations
TL;DR: The IMpower010 trial as mentioned in this paper evaluated adjuvant atezolizumab versus best supportive care (observation and regular scans for disease recurrence) in patients with early-stage non-small-cell lung cancer.
450 citations
Harvard University1, University of California, Los Angeles2, Curie Institute3, Université libre de Bruxelles4, Hebron University5, University of Pittsburgh6, Ohio State University7, Memorial Sloan Kettering Cancer Center8, Northside Hospital9, Georgetown University10, Baylor University Medical Center11, Jewish General Hospital12, Queen Mary University of London13, University of North Carolina at Chapel Hill14, University of California, San Francisco15
TL;DR: The Sacituzumab govitecan (SgoVitecan) is an antibody-drug conjugate composed of an antibody targeting the human tro... as mentioned in this paper.
Abstract: Background Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody–drug conjugate composed of an antibody targeting the human tro...
387 citations
University of Göttingen1, Örebro University2, Guy's and St Thomas' NHS Foundation Trust3, King's College London4, Charité5, Claude Bernard University Lyon 16, University of Jena7, Radboud University Nijmegen8, Agence Nationale de la Recherche9, University Hospital Heidelberg10, University of Duisburg-Essen11, University of Amsterdam12, Carlos III Health Institute13, University of Bern14, University of Barcelona15, National and Kapodistrian University of Athens16, Hebron University17, University of Modena and Reggio Emilia18, University of Bonn19, University of Medicine and Pharmacy of Craiova20
TL;DR: The authors reviewed the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels.
325 citations
Institut Gustave Roussy1, Université libre de Bruxelles2, Hospital of the University of Pennsylvania3, Swansea University4, University of Paris5, University of California, Los Angeles6, Seoul National University Hospital7, Ludwig Maximilian University of Munich8, Peter MacCallum Cancer Centre9, University of Auvergne10, Memorial Sloan Kettering Cancer Center11, University of California, San Francisco12, Hebron University13, Queen Mary University of London14, Medical University of Vienna15, Harvard University16, The Royal Marsden NHS Foundation Trust17, University of Milan18, Hebrew University of Jerusalem19
289 citations
Fox Chase Cancer Center1, Yale University2, University of Washington3, Curie Institute4, Cross Cancer Institute5, Duke University6, Hebron University7, Aix-Marseille University8, Bosch9, University of Texas Southwestern Medical Center10, Sarah Cannon Research Institute11, Bristol-Myers Squibb12, Johns Hopkins University13
TL;DR: In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in o... as mentioned in this paper, and showed an improved lung cancer survival.
Abstract: PURPOSEImmunotherapy has revolutionized the treatment of advanced non–small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in o...
266 citations
Rockefeller University1, French Institute of Health and Medical Research2, University of Paris3, Yale University4, National Institutes of Health5, Hebron University6, Autonomous University of Barcelona7, Katholieke Universiteit Leuven8, Shahid Beheshti University of Medical Sciences and Health Services9, University of Health Sciences Antigua10, University of Rome Tor Vergata11, Boston Children's Hospital12, Vita-Salute San Raffaele University13, University of Antioquia14, Universidad de La Sabana15
TL;DR: This article reported very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years with unexplained critical COVID-19 pneumonia.
Abstract: Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.
198 citations
University of Naples Federico II1, The Breast Cancer Research Foundation2, University of Barcelona3, University of Genoa4, University of North Carolina at Chapel Hill5, University of Valencia6, Università Campus Bio-Medico7, Hebron University8, Pontifícia Universidade Católica do Rio Grande do Sul9, Hospital General Universitario Gregorio Marañón10
TL;DR: In this article, the authors collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations: the proportion of HER2low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%).
Abstract: Novel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression.
192 citations
Hebron University1, Katholieke Universiteit Leuven2, Memorial Sloan Kettering Cancer Center3, Imperial College London4, Peter MacCallum Cancer Centre5, Asan Medical Center6, Netherlands Cancer Institute7, Oslo University Hospital8, Sarah Cannon Research Institute9, Hospital General Universitario Gregorio Marañón10, Pfizer11, University of Texas MD Anderson Cancer Center12
TL;DR: PURPOSEBEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus CetuxIMB in patients with BRAFV600E-mutant metastatic...
Abstract: PURPOSEBEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E–mutant metastatic ...
Harvard University1, European Institute of Oncology2, Seoul National University Hospital3, University of Ulsan4, Université Paris-Saclay5, University of Washington6, University of Colorado Denver7, University of Miami8, Hebron University9, Yonsei University10, University of Michigan11, University Hospital Heidelberg12, Georgetown University13, Mayo Clinic14, University of California, Irvine15, University of Texas MD Anderson Cancer Center16
TL;DR: The ARROW study as discussed by the authors evaluated the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC.
Abstract: Summary Background Oncogenic alterations in RET have been identified in multiple tumour types, including 1–2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. Methods ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0–2 (later limited to 0–1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. Findings Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50–71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50–86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. Interpretation Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. Funding Blueprint Medicines.
TL;DR: PURPOSEGlofitamab as mentioned in this paper is a bispecific antibody possessing a 2:1 structure with bivalency for B cells and monovalency for CD3 on T cells.
Abstract: PURPOSEGlofitamab is a T-cell–engaging bispecific antibody possessing a novel 2:1 structure with bivalency for CD20 on B cells and monovalency for CD3 on T cells. This phase I study evaluated glofi...
University of Las Palmas de Gran Canaria1, Sanford Health2, Wayne State University3, Hebron University4, Sunnybrook Health Sciences Centre5, Shaare Zedek Medical Center6, University of Sydney7, University of California, Los Angeles8, Kansai Medical University9, Merck & Co.10, University of Chicago11
TL;DR: Pembrolizumab plus pemetrexed and platinum-based chemotherapy significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) as discussed by the authors.
University of Washington1, St George’s University Hospitals NHS Foundation Trust2, McMaster University3, Agostino Gemelli University Polyclinic4, Emory University5, Federal University of São Paulo6, Ottawa Hospital7, St Thomas' Hospital8, University of Michigan9, Cooper University Hospital10, University of Kansas11, University of Amsterdam12, United Arab Emirates University13, University of Pittsburgh14, King Saud bin Abdulaziz University for Health Sciences15, University of São Paulo16, University of Minnesota17, Population Health Research Institute18, University of Toronto19, University of Kentucky20, Ghent University Hospital21, University of Tokyo22, Peking Union Medical College Hospital23, Hebron University24, Monash University25, Copenhagen University Hospital26, Liverpool School of Tropical Medicine27, Vanderbilt University28, Brigham and Women's Hospital29, University of Ulsan30, University of Manitoba31, Makerere University32, Faculdade de Medicina de São José do Rio Preto33, National Institutes of Health34, Mount Sinai Hospital, Toronto35, Medanta36, University of the Witwatersrand37, New York University38, Washington University in St. Louis39, University of Alberta40, Hennepin County Medical Center41, Royal Brisbane and Women's Hospital42, University of Pennsylvania43, Hebrew University of Jerusalem44, Hochschule Hannover45, Brown University46
TL;DR: The CheckMate 331 trial as discussed by the authors was a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed small-cell lung cancer (SCLC).
Emory University1, Samsung Medical Center2, Washington University in St. Louis3, Duke University4, University of Lausanne5, Hebron University6, Seoul National University Bundang Hospital7, Pontifícia Universidade Católica do Rio Grande do Sul8, Aix-Marseille University9, Bristol-Myers Squibb10, Yonsei University11
TL;DR: In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability as discussed by the authors.
Abstract: PURPOSEIn extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase...
TL;DR: In this paper, the authors evaluated treatment outcomes and safety of mobocertinib in patients with previously treated EGFRex20ins-positive mNSCLC, with a manageable safety profile.
Abstract: Importance Metastatic non–small cell lung cancer (mNSCLC) withEGFRexon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively targetEGFRex20ins mutations. Objective To evaluate treatment outcomes and safety of mobocertinib in patients with previously treatedEGFRex20ins-positive mNSCLC. Design, Setting, and Participants This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreatedEGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treatedEGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort). Interventions Mobocertinib 160 mg once daily. Main Outcomes and Measures The primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety. Results Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash. Conclusions and Relevance In this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treatedEGFRex20ins-positive mNSCLC, with a manageable safety profile. Trial Registration ClinicalTrials.gov Identifier:NCT02716116
University of Copenhagen1, University of Duisburg-Essen2, National and Kapodistrian University of Athens3, Autonomous University of Barcelona4, Hebron University5, Sapienza University of Rome6, University of Montpellier7, Tartu University Hospital8, University of Navarra9, Mersin University10, Leiden University Medical Center11, Ghent University Hospital12, University of L'Aquila13, Charité14, Imperial College London15, Norwegian University of Science and Technology16
TL;DR: In this paper, a European panel of experts has developed a ten-step approach to the diagnosis and management of migraine, which was established by expert consensus and supported by a review of current literature, and the consensus statement is endorsed by the European Headache Federation and the European Academy of Neurology.
Abstract: Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up. In this Consensus Statement, which is endorsed by the European Headache Federation and the European Academy of Neurology, an expert panel provides recommendations for the diagnosis and management of migraine to support clinical decision-making by general practitioners, neurologists and headache specialists.
TL;DR: In this paper, the authors provide a comprehensive overview of the current standard of care that will enable informed clinical management of migraine and explore the outlook of emerging mechanism-based treatments that could address unmet challenges in clinical management.
TL;DR: The design of and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-811 study, which will evaluate the efficacy and safety of pembrolizumab or placebo in combination with trastuzumab and chemotherapy as first-line treatment for patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma, are described.
Abstract: Treatment options for patients with HER2-positive advanced gastric cancer are limited, and the prognosis for these patients is poor. Pembrolizumab has demonstrated promising antitumor activity in patients with advanced gastric or gastroesophageal junction adenocarcinoma as monotherapy, in combination with chemotherapy and in combination with trastuzumab. Combining pembrolizumab with trastuzumab and chemotherapy may therefore provide a benefit for patients with advanced HER2-positive gastric cancer. Here we aimed to describe the design of and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-811 study, which will evaluate the efficacy and safety of pembrolizumab or placebo in combination with trastuzumab and chemotherapy as first-line treatment for patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma. Clinical trial registration: NCT03615326 (ClinicalTrials.gov).
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, National Health Service10, Yale Cancer Center11, University of Parma12, Takeda Pharmaceutical Company13, The Royal Marsden NHS Foundation Trust14
TL;DR: In this article, the authors reported the final efficacy, safety, and exploratory results of the ALTA-1L trial, which is a study of brigatinib in ALK inhibitor-naive advanced ALK-positive NSCLC.
McGill University1, Tianjin Medical University Cancer Institute and Hospital2, University of Occupational and Environmental Health Japan3, Peking University4, Université de Montréal5, University of Chicago6, Curie Institute7, Shanghai Jiao Tong University8, Kindai University9, Harvard University10, Hebron University11, Johns Hopkins University12, Aberdeen Royal Infirmary13, Bristol-Myers Squibb14
TL;DR: The study met its first primary endpoint, demonstrating significa… CheckMate 816 (NCT02998528) meets its firstPrimary endpoint.
Abstract: 8503Background: CheckMate 816 (NCT02998528) is a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo in resectable NSCLC. The study met its first primary endpoint, demonstrating significa...
TL;DR: The OpTIMUM trial as discussed by the authors compared the efficacy of ponesimod and teriflunomide for relapsing multiple sclerosis (RMS) using a randomized clinical trial.
Abstract: Importance To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS). Objective To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. Design, Setting, and Participants This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity. Interventions Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1modulators and a follow-up period of 30 days. Main Outcomes and Measures The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ–RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status. Results For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290;P Conclusions and Relevance In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators. Trial Registration ClinicalTrials.gov Identifier:NCT02425644
University of Bologna1, Medical University of Warsaw2, Institut Gustave Roussy3, Memorial Sloan Kettering Cancer Center4, Hebron University5, Erasmus University Rotterdam6, University of Lausanne7, Vita-Salute San Raffaele University8, University Hospital of Basel9, University of Melbourne10, Istanbul University11, National and Kapodistrian University of Athens12, King's College London13, Mario Negri Institute for Pharmacological Research14, Humanitas University15, Trinity College, Dublin16, University of Erlangen-Nuremberg17, University of Paris18, University of Verona19, Uppsala University20, Aix-Marseille University21, Innsbruck Medical University22, University of Duisburg-Essen23, University of Texas MD Anderson Cancer Center24
TL;DR: The European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs).
TL;DR: In this paper, the authors outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials and integrate these experiences into a common framework to reshape the future design of biology-informed clinical trials.
Abstract: Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Indeed, successful inhibition of BRAF or KRAS in metastatic CRCs driven by activating mutations in these genes requires combinations of drugs that inhibit the mutant protein while at the same time restraining adaptive resistance via CRC-specific EGFR-mediated feedback loops. The emerging paradigm is, therefore, that the intrinsic biology of CRC cells must be considered alongside the molecular profiles of individual tumours in order to successfully personalize treatment. In this Review, we outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials. The integration of these experiences into a common framework will reshape the future design of biology-informed clinical trials in this field.
TL;DR: In this article, the role of children in household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains uncertain, and the authors investigate the dynamics of household transmission.
Abstract: BACKGROUND: The role of children in household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains uncertain. Here, we describe the epidemiological and clinical characteristics of children with COVID-19 in Catalonia (Spain) and investigate the dynamics of household transmission. METHODS: Prospective, observational, multicenter study performed during summer and school periods (1 July-31 October, 2020), in which epidemiological and clinical features, and viral transmission dynamics were analyzed in COVID-19 patients <16 years. A pediatric index case was established when a child was the first individual infected within a household. Secondary cases were defined when another household member tested positive for SARS-CoV-2 before the child. The secondary attack rate (SAR) was calculated, and logistic regression was used to assess associations between transmission risk factors and SARS-CoV-2 infections. RESULTS: The study included 1040 COVID-19 patients <16 years. Almost half (47.2%) were asymptomatic, 10.8% had comorbidities, and 2.6% required hospitalization. No deaths were reported. Viral transmission was common among household members (62.3%). More than 70% (756/1040) of pediatric cases were secondary to an adult, whereas 7.7% (80/1040) were index cases. The SAR was significantly lower in households with COVID-19 pediatric index cases during the school period relative to summer (p=0.02), and when compared to adults (p=0.006). No individual or environmental risk factors associated with the SAR were identified. CONCLUSIONS: Children are unlikely to cause household COVID-19 clusters or be major drivers of the pandemic even if attending school. Interventions aimed at children are expected to have a small impact on reducing SARS-CoV-2 transmission.
TL;DR: Adjuvant platinum-based chemotherapy provides only a modest 5-year survival benefit in fully resected, high-risk early-stage NSCLC and the primary disease-free survival benefit is reported.
Abstract: 8500Background: Adjuvant platinum-based chemotherapy (chemo) provides only a modest 5-year survival benefit in fully resected, high-risk early-stage NSCLC. We report the primary disease-free surviv...
Brigham and Women's Hospital1, University of Vermont2, Harvard University3, Ohio State University4, Hebron University5, St Thomas' Hospital6, Mayo Clinic7, University of Texas MD Anderson Cancer Center8, Stanford University9, Memorial Sloan Kettering Cancer Center10, Hofstra University11, Duke University12, University Hospitals of Cleveland13, Rega Institute for Medical Research14, Katholieke Universiteit Leuven15, Northwestern University16, University of Washington17, Charité18, University of California, San Francisco19, Southern Taiwan University of Science and Technology20, National Cheng Kung University21, Sheba Medical Center22, University of Miami23, University of Florida24, University of Virginia Health System25, University Health Network26, University of California, Los Angeles27, University of Alabama28, Mount Sinai Hospital29, University of Pennsylvania30, University Medical Center Groningen31, King Chulalongkorn Memorial Hospital32, I.M. Sechenov First Moscow State Medical University33, Max Delbrück Center for Molecular Medicine34
TL;DR: In this paper, a multivariable logistic regression model was used to identify predictors of ICPi-AKI and its recovery, and the effect of rechallenge versus no re-challenge on survival was estimated.
Abstract: Background Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results ICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.
University of Washington1, Princess Margaret Cancer Centre2, Hebron University3, University of Texas MD Anderson Cancer Center4, Memorial Sloan Kettering Cancer Center5, University of California, Los Angeles6, Ohio State University7, Institut Gustave Roussy8, Université de Montréal9, Lawson Health Research Institute10, University of California, San Francisco11, Mayo Clinic12, Guy's and St Thomas' NHS Foundation Trust13, Stanford University14, University of Melbourne15, Foundation Medicine16, University of Arizona17, Walter and Eliza Hall Institute of Medical Research18, Imperial College London19
TL;DR: In this paper, a post hoc exploratory biomarker analysis of pre-and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib.
Abstract: ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.