Showing papers by "Hebron University published in 2018"
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TL;DR: Authors/Task Force Members: Michele Brignole* (Chairperson), Angel Moya* (Co-chairperson) (Spain), Frederik J. de Lange (The Netherlands), Jean-Claude Deharo (France), Perry M. Elliott (UK), Alessandra Fanciulli (Austria), Artur Fedorowski (Sweden), Raffaello Furlan (Italy), Rose Anne Kenny (Ireland), Alfonso Mart ın (Spain
1,015 citations
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TL;DR: This study demonstrates how a molecularly driven clinical trial can be used to refine the biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
Abstract: Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
517 citations
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Harvard University1, University of Paris2, University of California, San Francisco3, Netherlands Cancer Institute4, Sarah Cannon Research Institute5, Institut Gustave Roussy6, University of North Carolina at Chapel Hill7, University of Milan8, University of Birmingham9, Pinnacle Financial Partners10, Hebron University11, Memorial Sloan Kettering Cancer Center12, University of Pennsylvania13, Utrecht University14, Amgen15, Novartis16, Katholieke Universiteit Leuven17
TL;DR: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer, and highlights the MAPK pathway as a critical target in BRAFv600Ecolorectals and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance.
Abstract: Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only ~5% with BRAFV600E colorectal cancer (CRC) respond. Preclinical studies suggest that lack of efficacy in BRAFV600E CRC is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E CRC. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pre- and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E CRC can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.
396 citations
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University of Ioannina1, Sun Yat-sen University2, University of Ulsan3, National University of Malaysia4, National Taiwan University5, Mayo Clinic6, Zhejiang University7, Yonsei University8, Hospital Kuala Lumpur9, National Health Research Institutes10, University of Texas MD Anderson Cancer Center11, St. Marianna University School of Medicine12, Kanazawa University13, University of Valencia14, Hebron University15, Kobe University16
TL;DR: These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China, Korea, Malaysia, Singapore, Singapore and Taiwan.
386 citations
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Hebron University1, Ruhr University Bochum2, University College London3, University of Florence4, Multiple Sclerosis International Federation5, University of Toulouse6, Vita-Salute San Raffaele University7, University Hospital of Basel8, Medical University of Graz9, University of Düsseldorf10, First Faculty of Medicine, Charles University in Prague11, Technische Universität München12, University of Paris13, Karolinska University Hospital14, Medical University of Łódź15, Istanbul University16, Copenhagen University Hospital17, University of Genoa18, University of Münster19, University of Mainz20
TL;DR: An evidence-based clinical practice guideline for the pharmacological treatment of people with MS, which takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication.
Abstract: Background:Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years There is a need for a reference tool compiling current data to aid professionals in trea
374 citations
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New Generation University College1, University of La Frontera2, Katholieke Universiteit Leuven3, Seoul National University Bundang Hospital4, Hebron University5, University of Ulsan6, University Health System7, Samsung Medical Center8, Russian Academy9, University of Mainz10, Merck Serono11, Merck KGaA12, Paris Descartes University13
TL;DR: Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy, and a Velumab showed a more manageable safety profile than chemotherapy.
355 citations
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TL;DR: Trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer and could be a new treatment option in this population who represent a high unmet medical need.
Abstract: Summary Background Trifluridine/tipiracil showed activity and was well tolerated in a phase 2 study of pretreated patients with advanced gastric cancer done in Japan. We investigated whether the treatment was efficacious compared with placebo in a global population. Methods TAGS was a randomised, double-blind, placebo-controlled, phase 3 trial done in 110 academic hospitals in 17 countries. Patients aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression were eligible for inclusion. Patients were randomly assigned (2:1) via dynamic randomisation from a centralised interactive voice-response system to receive either oral trifluridine/tipiracil (35 mg/m2 twice daily on days 1–5 and days 8–12 every 28 days) plus best supportive care or placebo plus best supportive care. Participants were allocated to groups by study-site personnel. Randomisation was stratified by region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no). Both patients and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov , number NCT02500043 . The trial, including follow-up of all participants, has been completed. Findings Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group. Median overall survival was 5·7 months (95% CI 4·8–6·2) in the trifluridine/tipiracil group and 3·6 months (3·1–4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56–0·85]; one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of any cause occurred in 267 (80%) patients in the trifluridine/tipiracil group and 97 (58%) in the placebo group. The most frequent grade 3 or worse adverse events of any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the trifluridine/tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) in the placebo group. Serious adverse events of any cause were reported in 143 (43%) patients in the trifluridine/tipiracil group and 70 (42%) in the placebo group. One treatment-related death was reported in each group (because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of toxic hepatitis in the placebo group). Interpretation Trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer. Trifluridine/tipiracil could be a new treatment option in this population who represent a high unmet medical need. Funding Taiho Oncology and Taiho Pharmaceutical.
308 citations
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TL;DR: In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations.
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
211 citations
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University of Auvergne1, University of Milano-Bicocca2, Hebron University3, Carlos III Health Institute4, University Medical Center Groningen5, Karolinska Institutet6, Karolinska University Hospital7, Sanjay Gandhi Post Graduate Institute of Medical Sciences8, Uppsala University9, Middlesex University10, University Malaya Medical Centre11, University of Lyon12, St. Michael's Hospital13, University of Angers14
TL;DR: This prospective international prevalence study found that PP was used in 32.9% of patients with severe ARDS, and was associated with low complication rates, significant increase in oxygenation and a significant decrease in driving pressure.
Abstract: INTRODUCTION: While prone positioning (PP) has been shown to improve patient survival in moderate to severe acute respiratory distress syndrome (ARDS) patients, the rate of application of PP in cli ...
184 citations
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Emory University1, Université libre de Bruxelles2, The Feinstein Institute for Medical Research3, Hebron University4, Rush University Medical Center5, Federal University of São Paulo6, St James's University Hospital7, New York University8, Catholic University of the Sacred Heart9, University of California, San Francisco10, Utrecht University11, Brown University12, St George’s University Hospitals NHS Foundation Trust13
TL;DR: While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression ofSepsis.
Abstract: To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock. A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations. Each committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science. The Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction? While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.
182 citations
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Hebron University1, Ruhr University Bochum2, University College London3, University of Florence4, Multiple Sclerosis International Federation5, University of Toulouse6, Università telematica San Raffaele7, University Hospital of Basel8, Medical University of Graz9, University of Düsseldorf10, First Faculty of Medicine, Charles University in Prague11, Technische Universität München12, University of Paris13, Karolinska University Hospital14, Medical University of Łódź15, Istanbul University16, Copenhagen University Hospital17, University of Genoa18, University of Münster19, University of Mainz20
TL;DR: The objective was to develop an evidence‐based clinical practice guideline for the pharmacological treatment of people with MS.
Abstract: Background and purpose:
Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process.
Methods:
This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories – very high, high, low and very low − according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk−benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique.
Results:
A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.
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TL;DR: Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit, and future exploration of galun isertib in pancreatic cancer is ongoing in combination with durvalumab.
Abstract: Galunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined. This was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib–gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers. Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59–1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit. Galunisertib–gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.
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Medical University of Vienna1, Nova Southeastern University2, Odense University Hospital3, Netherlands Cancer Institute4, Hebron University5, National and Kapodistrian University of Athens6, The Royal Marsden NHS Foundation Trust7, Seconda Università degli Studi di Napoli8, Autonomous University of Barcelona9, Vienna General Hospital10, European Society for Medical Oncology11, World Health Organization12
TL;DR: The national actions and the policy recommendations in this paper set forth the vision of its authors for the future of global cancer control at the national level, where the WHO Cancer Resolution must be implemented if the authors are to reduce the cancer burden, avoid unnecessary suffering and save as many lives as possible.
Abstract: The cancer burden is rising globally, exerting significant strain on populations and health systems at all income levels. In May 2017, world governments made a commitment to further invest in cancer control as a public health priority, passing the World Health Assembly Resolution 70.12 on cancer prevention and control within an integrated approach. In this manuscript, the 2016 European Society for Medical Oncology Leadership Generation Programme participants propose a strategic framework that is in line with the 2017 WHO Cancer Resolution and consistent with the principle of universal health coverage, which ensures access to optimal cancer care for all people because health is a basic human right. The time for action is now to reduce barriers and provide the highest possible quality cancer care to everyone regardless of circumstance, precondition or geographic location. The national actions and the policy recommendations in this paper set forth the vision of its authors for the future of global cancer control at the national level, where the WHO Cancer Resolution must be implemented if we are to reduce the cancer burden, avoid unnecessary suffering and save as many lives as possible.
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TL;DR: This approach provides a highly sensitive platform to isolate clinically relevant neoantigen-reactive T cells or their TCRs for cancer treatment.
Abstract: Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TILs) targeting neoantigens can mediate tumor regression in selected patients with metastatic epithelial cancer. However, effectively identifying and harnessing neoantigen-reactive T cells for patient treatment remains a challenge and it is unknown whether current methods to detect neoantigen-reactive T cells are missing potentially clinically relevant neoantigen reactivities. We thus investigated whether the detection of neoantigen-reactive TILs could be enhanced by enriching T cells that express PD-1 and/or T cell activation markers followed by microwell culturing to avoid overgrowth of nonreactive T cells. In 6 patients with metastatic epithelial cancer, this method led to the detection of CD4+ and CD8+ T cells targeting 18 and 1 neoantigens, respectively, compared with 6 and 2 neoantigens recognized by CD4+ and CD8+ T cells, respectively, when using our standard TIL fragment screening approach. In 2 patients, no recognition of mutated peptides was observed using our conventional screen, while our high-throughput approach led to the identification of 5 neoantigen-reactive T cell receptors (TCRs) against 5 different mutations from one patient and a highly potent MHC class II-restricted KRASG12V-reactive TCR from a second patient. In addition, in a metastatic tumor sample from a patient with serous ovarian cancer, we isolated 3 MHC class II-restricted TCRs targeting the TP53G245S hot-spot mutation. In conclusion, this approach provides a highly sensitive platform to isolate clinically relevant neoantigen-reactive T cells or their TCRs for cancer treatment.
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TL;DR: The functional biomarker RAD51 enables the identification of PARPi‐sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2‐related cancers.
Abstract: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2-related cancers. A test to identify additional HRR-deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient-derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2-related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2-related tumors were classified as HRR-deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi-sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2-related cancers.
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TL;DR: Long-term DFS and PFS were similar between groups and patients who achieved tpCR had improved DFS; no new safety signals were identified.
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TL;DR: The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only and no commercial use is authorized.
Abstract: The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oxfordjournals.org).
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University of Pennsylvania1, University of Texas MD Anderson Cancer Center2, Georgetown University3, Vanderbilt University4, University of California, San Francisco5, University of Milan6, National Taiwan University7, Curie Institute8, French Institute of Health and Medical Research9, Ontario Institute for Cancer Research10, University of Paris-Sud11, Hebron University12, Merck & Co.13, Seoul National University14
TL;DR: Pembrolizumab demonstrated promising antitumor activity and a manageable safety profile in patients with advanced, PD-L1-positive SGC.
Abstract: Author(s): Cohen, Roger B; Delord, Jean-Pierre; Doi, Toshihiko; Piha-Paul, Sarina A; Liu, Stephen V; Gilbert, Jill; Algazi, Alain P; Damian, Silvia; Hong, Ruey-Long; Le Tourneau, Christophe; Day, Daphne; Varga, Andrea; Elez, Elena; Wallmark, John; Saraf, Sanatan; Thanigaimani, Pradeep; Cheng, Jonathan; Keam, Bhumsuk | Abstract: ObjectivesTreatment options for patients with unresectable or metastatic salivary gland carcinoma (SGC) are limited. Safety and efficacy of pembrolizumab for SGC expressing programmed death ligand 1 (PD-L1) were explored.Materials and methodsA cohort of patients with advanced, PD-L1-positive SGC was enrolled in the nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors (KEYNOTE-028; NCT02054806). Key inclusion criteria included recurrent or metastatic disease, failure of prior systemic therapy, and PD-L1 expression on ≥1% of tumor or stroma cells (per a prototype immunohistochemistry assay). Patients received pembrolizumab 10 mg/kg every 2 weeks for ≥2 years or until confirmed disease progression or unacceptable toxicity. Primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator review.ResultsTwenty-six patients with PD-L1-positive SGC were enrolled and treated; median age was 57 years, 88% were men, and 74% had received prior therapy for recurrent/metastatic disease. Confirmed objective response rate after median follow-up of 20 months was 12% (95% confidence interval, 2%-30%), with 3 patients achieving partial response; there were no complete responses. Median duration of response was 4 months (range, 4 to 21 mo). Treatment-related adverse events occurred in 22 patients (85%), resulting in discontinuation in 2 patients and death in 1 (interstitial lung disease); those occurring in ≥15% of patients were diarrhea, decreased appetite, pruritus, and fatigue.ConclusionsPembrolizumab demonstrated promising antitumor activity and a manageable safety profile in patients with advanced, PD-L1-positive SGC.
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TL;DR: No difference in disease-free survival was observed between pregnant and nonpregnant patients with ER-positive or ER-negative breast cancer, and reassuring evidence on the long-term safety of pregnancy in breast cancer survivors, including those withER-positive disease is provided.
Abstract: Safety of pregnancy in women with history of estrogen receptor (ER)-positive breast cancer remains controversial. In this multicenter case-control study, 333 patients with pregnancy after breast cancer were matched (1:3) to 874 nonpregnant patients of similar characteristics, adjusting for guaranteed time bias. Survival estimates were calculated using the Kaplan-Meier analysis; groups were compared with the log-rank test. All reported P values were two-sided. At a median follow-up of 7.2 years after pregnancy, no difference in disease-free survival was observed between pregnant and nonpregnant patients with ER-positive (hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.70 to 1.26, P = .68) or ER-negative (HR = 0.75, 95% CI = 0.53 to 1.06, P = .10) disease. No overall survival (OS) difference was observed in ER-positive patients (HR = 0.84, 95% CI = 0.60 to 1.18, P = .32); ER-negative patients in the pregnant cohort had better OS (HR = 0.57, 95% CI = 0.36 to 0.90, P = .01). Abortion, time to pregnancy, breastfeeding, and type of adjuvant therapy had no impact on patients' outcomes. This study provides reassuring evidence on the long-term safety of pregnancy in breast cancer survivors, including those with ER-positive disease.
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TL;DR: Osimertinib was the first third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to receive FDA and EMA approval for metastatic EGFR-mutant non-small-cell lung cancer patients that have acquired the EGFR T790M resistance mutation.
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Université Paris-Saclay1, Huntsman Cancer Institute2, National Institute for Health Research3, University of Navarra4, Institut Gustave Roussy5, Université catholique de Louvain6, MedImmune7, Hoffmann-La Roche8, Amgen9, Pfizer10, Eisai11, Merck & Co.12, Hebron University13, Netherlands Cancer Institute14, Icahn School of Medicine at Mount Sinai15
TL;DR: A European Society for Medical Oncology-sponsored expert meeting was held in Paris on 8 March 2018 with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies.
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TL;DR: Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and past failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors.
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Food and Drug Administration1, University of Colorado Boulder2, Memorial Sloan Kettering Cancer Center3, University of California, San Francisco4, Mayo Clinic5, University of Turin6, Ohio State University7, Brigham and Women's Hospital8, Karolinska University Hospital9, University of Texas MD Anderson Cancer Center10, Bristol-Myers Squibb11, AstraZeneca12, Stanford University13, Children's National Medical Center14, University of Duisburg-Essen15, Hebron University16, Vita-Salute San Raffaele University17, Merck & Co.18, University of Texas Southwestern Medical Center19, European Medicines Agency20, Johns Hopkins University21, Fred Hutchinson Cancer Research Center22, Columbia University Medical Center23, Maastricht University Medical Centre24, Columbia University25, Center for Drug Evaluation and Research26, University of Colorado Denver27, Cornell University28
TL;DR: Given the success of oncogene‐targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes.
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TL;DR: The sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the subclassification of diffuse gliomas facilitates the diagnosis of diffusegliomas in a timely manner to support the surgical and clinical management of patients with brain malignancies.
Abstract: Purpose: Diffuse gliomas are the most common primary tumor of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumor specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumor DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies.Experimental Design: We performed an analysis of IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B gene mutations in two tumor cohorts from The Cancer Genome Atlas (TCGA) including 648 diffuse gliomas. We also performed targeted exome sequencing and droplet digital PCR (ddPCR) analysis of these seven genes in 20 clinical tumor specimens and CSF from glioma patients and performed a histopathologic characterization of the tumors.Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analyzed, into IDH-wild-type glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, and 11.2 years, respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the subclassification of diffuse gliomas.Conclusions: The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A, and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients. Clin Cancer Res; 24(12); 2812-9. ©2018 AACR.
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TL;DR: Clinical, neuroimaging and composite outcome measures for MS, including patient-reported outcome measures, used in both trials and the clinical setting are discussed to help clinicians and researchers navigate through the multiple options encountered when choosing an outcome measure.
Abstract: Increasing numbers of drugs are being developed for the treatment of multiple sclerosis (MS). Measurement of relevant outcomes is key for assessing the efficacy of new drugs in clinical trials and for monitoring responses to disease-modifying drugs in individual patients. Most outcomes used in trial and clinical settings reflect either clinical or neuroimaging aspects of MS (such as relapse and accrual of disability or the presence of visible inflammation and brain tissue loss, respectively). However, most measures employed in clinical trials to assess treatment effects are not used in routine practice. In clinical trials, the appropriate choice of outcome measures is crucial because the results determine whether a drug is considered effective and therefore worthy of further development; in the clinic, outcome measures can guide treatment decisions, such as choosing a first-line disease-modifying drug or escalating to second-line treatment. This Review discusses clinical, neuroimaging and composite outcome measures for MS, including patient-reported outcome measures, used in both trials and the clinical setting. Its aim is to help clinicians and researchers navigate through the multiple options encountered when choosing an outcome measure. Barriers and limitations that need to be overcome to translate trial outcome measures into the clinical setting are also discussed.
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TL;DR: The EmboTrap stent-retriever mechanical thrombectomy device demonstrated high rates of substantial reperfusion and functional independence in patients with acute ischemic stroke secondary to large-vessel occlusions and all-cause mortality at 90 days.
Abstract: Background and Purpose— EmboTrap is a novel stent retriever designed to achieve rapid and substantial flow restoration in acute ischemic stroke secondary to large-vessel occlusions. Here, we evaluated EmboTrap’s safety and efficacy compared with established stent retrievers. Methods— ARISE II (Analysis of Revascularization in Ischemic Stroke With EmboTrap) was a single-arm, prospective, multicenter study, comparing the EmboTrap device to a composite performance goal criterion derived using a Bayesian meta-analysis from the pivotal SWIFT (Solitaire device) and TREVO 2 (Trevo device) trials. Patients at 11 US and 8 European sites were eligible for inclusion if they had large-vessel occlusions and moderate-to-severe neurological deficits within 8 hours of symptom onset. The primary efficacy end point was achievement of modified Thrombolysis in Cerebral Ischemia (mTICI) reperfusion scores of ≥2b within 3 EmboTrap passes as adjudicated by the core laboratory. The primary safety end point was a composite of symptomatic intracerebral hemorrhage and serious adverse device effects. Secondary end points included functional independence (modified Rankin Scale, 0–2) and all-cause mortality at 90 days. Results— Between October 2015 and February 2017, 227 patients were enrolled and treated with the EmboTrap device. The primary efficacy end point (mTICI ≥2b within 3 passes) was achieved in 80.2% (95% confidence interval, 74%–85% versus 56% performance goal criterion; P value, Conclusions— The EmboTrap stent-retriever mechanical thrombectomy device demonstrated high rates of substantial reperfusion and functional independence in patients with acute ischemic stroke secondary to large-vessel occlusions. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02488915.
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Strathclyde Institute of Pharmacy and Biomedical Sciences1, Ecorys2, Radboud University Nijmegen3, Jagiellonian University Medical College4, Harvard University5, European Organisation for Rare Diseases6, University of Liverpool7, Katholieke Universiteit Leuven8, Hawler Medical University9, Imperial College London10, Vilnius University11, NHS Lothian12, University of Medicine, Tirana13, University of Botswana14, Universidade Federal de Minas Gerais15, Sofia Medical University16, National and Kapodistrian University of Athens17, University of Nairobi18, Mokwon University19, University of Namibia20, Ekiti State University21, Norwegian Institute of Public Health22, University of Banja Luka23, Ministry of Health and Social Welfare24, Carol Davila University of Medicine and Pharmacy25, Slovak Medical University26, Hebron University27, Sefako Makgatho Health Sciences University28, Karolinska University Hospital29, Stockholm County Council30, Memorial Hospital of South Bend31, University of Manchester32
TL;DR: The primary aim of this paper is to consider potential ways to optimize the use of new medicines balancing rising costs with increasing budgetary pressures to stimulate debate especially from a payer perspective.
Abstract: Introduction: There is continued unmet medical need for new medicines across countries especially for cancer, immunological diseases and orphan diseases. However, there are growing challenges with funding new medicines at ever increasing prices along with funding increased medicine volumes with the growing prevalence of both infectious diseases and non-communicable diseases across countries. This has resulted in the development of new models to better manage the entry of new medicines, new financial models being postulated as well as strategies to improve prescribing efficiency. However, more needs to be done. Consequently, the primary aim of this paper is to consider potential ways to optimise the use of new medicines balancing rising costs with increasing budgetary pressures to stimulate debate especially from a payer perspective. Methods: A narrative review of pharmaceutical policies and implications, as well as possible developments, based on key publications and initiatives known to the co-authors principally from a health authority perspective. Results: A number of initiatives and approaches have been identified including new models to better manage the entry of new medicines based on three pillars (pre-, peri-, and post-launch activities). Within this, we see the growing role of horizon scanning activities starting up to 36 months before launch, managed entry agreements and post launch follow-up. It is also likely there will be greater scrutiny over the effectiveness and value of new cancer medicines given ever increasing prices. This could include establishing minimum effectiveness targets for premium pricing along with re-evaluating prices as more medicines for cancer lose their patent. There will also be a greater involvement of patients especially with orphan diseases. New initiatives could include a greater role of multicriteria decision analysis, as well as looking at the potential for de-linking research and development from commercial activities to enhance affordability. Conclusion: There are a number of ongoing activities across countries to try and fund new valued medicines whilst attaining or maintaining universal healthcare. Such activities will grow with increasing resource pressures and continued unmet need.
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TL;DR: It is shown how the acquired EGFRG724S mutation induces resistance to third-generation EGFR inhibitors and why the mutant kinase remains susceptible to second-generation inhibitors.
Abstract: The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFRT790M-negative but EGFRG724S-positive subclones and osimertinib resistance. We demonstrate that EGFRG724S limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFRG724S mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFRG724S-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFRG724S-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFRG724S-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.
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TL;DR: Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients.
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TL;DR: A retrospective multicenter cohort study showed no improvement in excellent and independent functional outcomes in mild strokes (NIHSS, <6) receiving thrombectomy irrespective of thrombus location, with increased symptomatic intracerebral hemorrhage rates, consistent with the guidelines recommending the treatment for NIHSS ≥6.
Abstract: Background and Purpose- Endovascular thrombectomy (EVT) is effective for acute ischemic stroke with large vessel occlusion and National Institutes of Health Stroke Scale (NIHSS) ≥6. However, EVT benefit for mild deficits large vessel occlusions (NIHSS, <6) is uncertain. We evaluated EVT efficacy and safety in mild strokes with large vessel occlusion. Methods- A retrospective cohort of patients with anterior circulation large vessel occlusion and NIHSS <6 presenting within 24 hours from last seen normal were pooled. Patients were divided into 2 groups: EVT or medical management. Ninety-day mRS of 0 to 1 was the primary outcome, mRS of 0 to 2 was the secondary. Symptomatic intracerebral hemorrhage was the safety outcome. Clinical outcomes were compared through a multivariable logistic regression after adjusting for age, presentation NIHSS, time last seen normal to presentation, center, IV alteplase, Alberta Stroke Program early computed tomographic score, and thrombus location. We then performed propensity score matching as a sensitivity analysis. Results were also stratified by thrombus location. Results- Two hundred fourteen patients (EVT, 124; medical management, 90) were included from 8 US and Spain centers between January 2012 and March 2017. The groups were similar in age, Alberta Stroke Program early computed tomographic score, IV alteplase rate and time last seen normal to presentation. There was no difference in mRS of 0 to 1 between EVT and medical management (55.7% versus 54.4%, respectively; adjusted odds ratio, 1.3; 95% CI, 0.64-2.64; P=0.47). Similar results were seen for mRS of 0 to 2 (63.3% EVT versus 67.8% medical management; adjusted odds ratio, 0.9; 95% CI, 0.43-1.88; P=0.77). In a propensity matching analysis, there was no treatment effect in 62 matched pairs (53.5% EVT, 48.4% medical management; odds ratio, 1.17; 95% CI, 0.54-2.52; P=0.69). There was no statistically significant difference when stratified by any thrombus location; M1 approached significance ( P=0.07). Symptomatic intracerebral hemorrhage rates were higher with thrombectomy (5.8% EVT versus 0% medical management; P=0.02). Conclusions- Our retrospective multicenter cohort study showed no improvement in excellent and independent functional outcomes in mild strokes (NIHSS, <6) receiving thrombectomy irrespective of thrombus location, with increased symptomatic intracerebral hemorrhage rates, consistent with the guidelines recommending the treatment for NIHSS ≥6. There was a signal toward benefit with EVT only in M1 occlusions; however, this needs to be further evaluated in future randomized control trials.