Showing papers by "Memorial Sloan Kettering Cancer Center published in 2018"
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4 +414 more•Institutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
5,988 citations
TL;DR: New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy, and evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways.
Abstract: The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.
3,736 citations
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4 +183 more•Institutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
3,301 citations
French Institute of Health and Medical Research1, Université Paris-Saclay2, Institut Gustave Roussy3, Pierre-and-Marie-Curie University4, Paris Diderot University5, Memorial Sloan Kettering Cancer Center6, University of Orléans7, Paris Descartes University8, Cornell University9, Aix-Marseille University10
TL;DR: It is found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition, and Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer.
Abstract: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.
3,258 citations
Memorial Sloan Kettering Cancer Center1, University of Texas MD Anderson Cancer Center2, Harvard University3, Fox Chase Cancer Center4, University of Strasbourg5, Queen Mary University of London6, Aarhus University7, Rabin Medical Center8, Tel Aviv University9, University of British Columbia10, Roswell Park Cancer Institute11, Cancer Research UK12, University of Jena13, Pontifícia Universidade Católica do Rio Grande do Sul14, Niigata University15, Complutense University of Madrid16, Cleveland Clinic17, Bristol-Myers Squibb18, Macquarie University19, Johns Hopkins University20, Université Paris-Saclay21
TL;DR: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate‐ and poor‐risk patients with previously untreated advanced renal‐cell carcinoma.
Abstract: Background Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. Methods We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. Results A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follo...
2,984 citations
TL;DR: Tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent were examined and major determinants of clinical outcome were identified and suggested that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.
Abstract: Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.
2,808 citations
TL;DR: The wide range of immune-related adverse effects associated with immune checkpoint blockade can complicate this effective therapy and limit its use in patients with cancer.
Abstract: Side Effects of Immune Checkpoint Blockade The wide range of immune-related adverse effects associated with immune checkpoint blockade can complicate this effective therapy and limit its use in patients with cancer. This review surveys the adverse effects and their management.
2,658 citations
Johns Hopkins University1, University of Michigan2, University of Texas MD Anderson Cancer Center3, Georgetown University4, The Royal Marsden NHS Foundation Trust5, Roswell Park Cancer Institute6, Oncology Nursing Society7, University of Washington8, Memorial Sloan Kettering Cancer Center9, Harvard University10, University of Oklahoma11, American Society of Clinical Oncology12, Ohio State University13, New York University14
TL;DR: Recommendations for specific organ system-based toxicity diagnosis and management are presented and, in general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement.
Abstract: PurposeTo increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapyMethodsA multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline Guideline development involved a systematic review of the literature and an informal consensus process The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017ResultsThe systematic review identified 204 eligible publications Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports Due to the paucity of high-quality evidence on management
2,386 citations
TL;DR: The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD‐L1 expression level of at least 1% and those with a level of less than 1%.
Abstract: Background Nivolumab plus ipilimumab showed promising efficacy for the treatment of non–small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase). Methods We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx...
2,249 citations
TL;DR: A perspective on the basic concepts of convolutional neural network and its application to various radiological tasks is offered, and its challenges and future directions in the field of radiology are discussed.
Abstract: Convolutional neural network (CNN), a class of artificial neural networks that has become dominant in various computer vision tasks, is attracting interest across a variety of domains, including radiology. CNN is designed to automatically and adaptively learn spatial hierarchies of features through backpropagation by using multiple building blocks, such as convolution layers, pooling layers, and fully connected layers. This review article offers a perspective on the basic concepts of CNN and its application to various radiological tasks, and discusses its challenges and future directions in the field of radiology. Two challenges in applying CNN to radiological tasks, small dataset and overfitting, will also be covered in this article, as well as techniques to minimize them. Being familiar with the concepts and advantages, as well as limitations, of CNN is essential to leverage its potential in diagnostic radiology, with the goal of augmenting the performance of radiologists and improving patient care. • Convolutional neural network is a class of deep learning methods which has become dominant in various computer vision tasks and is attracting interest across a variety of domains, including radiology.
• Convolutional neural network is composed of multiple building blocks, such as convolution layers, pooling layers, and fully connected layers, and is designed to automatically and adaptively learn spatial hierarchies of features through a backpropagation algorithm.
• Familiarity with the concepts and advantages, as well as limitations, of convolutional neural network is essential to leverage its potential to improve radiologist performance and, eventually, patient care.
2,189 citations
Memorial Sloan Kettering Cancer Center1, Swiss Institute of Bioinformatics2, Harvard University3, Princeton University4, University of Texas at Dallas5, Washington University in St. Louis6, Institute for Systems Biology7, Bilkent University8, Van Andel Institute9, University of Pennsylvania10, University of Texas MD Anderson Cancer Center11, Mayo Clinic12, Columbia University Medical Center13, Fred Hutchinson Cancer Research Center14, University of California, San Francisco15, University of Michigan16, Peter MacCallum Cancer Centre17, Baylor College of Medicine18
TL;DR: This work charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity.
TL;DR: A phase 1 trial involving adults with relapsed B‐cell ALL who received an infusion of autologous T cells expressing the 19‐28z CAR at the Memorial Sloan Kettering Cancer Center found that patients with a low disease burden before treatment had markedly enhanced remission duration and survival and had a markedly lower incidence of the cytokine release syndrome and neurotoxic events after infusion.
Abstract: Background CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients. Methods We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. Results A total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12....
TL;DR: A blood test that combines protein and DNA markers may allow earlier detection of eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA.
Abstract: Earlier detection is key to reducing cancer deaths. Here, we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1005 patients with nonmetastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69 to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was greater than 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients.
Washington University in St. Louis1, Johns Hopkins University2, Discovery Institute3, Genome Institute of Singapore4, University of Miami5, Broad Institute6, Harvard University7, University of Texas MD Anderson Cancer Center8, Memorial Sloan Kettering Cancer Center9, Cornell University10, University of Cambridge11, Catalan Institution for Research and Advanced Studies12, University of California, Santa Cruz13, Baylor College of Medicine14
TL;DR: This study reports a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations, identifying 299 driver genes with implications regarding their anatomical sites and cancer/cell types.
TL;DR: This work presents a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and shows that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods.
Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
University of Oklahoma1, European Institute of Oncology2, Sungkyunkwan University3, Autonomous University of Barcelona4, University of New South Wales5, University of Bordeaux6, University of Paris-Sud7, Netherlands Cancer Institute8, Edinburgh Cancer Research Centre9, The Royal Marsden NHS Foundation Trust10, University of Toronto11, University of Texas MD Anderson Cancer Center12, Memorial Sloan Kettering Cancer Center13, Medical College of Wisconsin14, Harvard University15, AstraZeneca16
TL;DR: The use of maintenance therapy with olaparib provided a substantial benefit with regard to progression‐free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation, with a 70% lower risk of disease progression or death with olAParib than with placebo.
Abstract: Background Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the o...
University of Alabama at Birmingham1, University of South Florida2, Vanderbilt University3, City of Hope National Medical Center4, Fox Chase Cancer Center5, University Of Tennessee System6, Brigham and Women's Hospital7, Seattle Cancer Care Alliance8, Case Western Reserve University9, Roswell Park Cancer Institute10, Northwestern University11, Harvard University12, University of Nebraska Medical Center13, University of Utah14, Memorial Sloan Kettering Cancer Center15
TL;DR: This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
Abstract: Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
TL;DR: Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, Pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which may inform strategies for future therapeutic development.
Memorial Sloan Kettering Cancer Center1, University College London2, National Taiwan University3, University of Southern California4, University of Ulsan5, Trakya University6, University of Bordeaux7, University of Bologna8, University of Amsterdam9, The Chinese University of Hong Kong10, University of California, San Francisco11
TL;DR: Treatment with cabozantinib resulted in longer overall survival and progression‐free survival than placebo among patients with previously treated advanced hepatocellular carcinoma, and the rate of high‐grade adverse events in the cabozaninib group was approximately twice that observed in the placebo group.
Abstract: Background Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellul...
04 Apr 2018
TL;DR: The most recent edition of the dermoscopic image analysis benchmark challenge as discussed by the authors was organized to support research and development of algorithms for automated diagnosis of melanoma, the most lethal skin cancer.
Abstract: This article describes the design, implementation, and results of the latest installment of the dermoscopic image analysis benchmark challenge. The goal is to support research and development of algorithms for automated diagnosis of melanoma, the most lethal skin cancer. The challenge was divided into 3 tasks: lesion segmentation, feature detection, and disease classification. Participation involved 593 registrations, 81 pre-submissions, 46 finalized submissions (including a 4-page manuscript), and approximately 50 attendees, making this the largest standardized and comparative study in this field to date. While the official challenge duration and ranking of participants has concluded, the dataset snapshots remain available for further research and development.
TL;DR: Nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors, and the tumor mutational burden was predictive of the pathological response to PD‐1 blockade.
Abstract: Background Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non–small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. Methods In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. Results Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed...
Pierre-and-Marie-Curie University1, Paris Descartes University2, French Institute of Health and Medical Research3, Mayo Clinic4, Providence Portland Medical Center5, University of Bern6, University Hospital of Bern7, Radboud University Nijmegen8, University of Erlangen-Nuremberg9, Université catholique de Louvain10, University Health Network11, University of Toronto12, Memorial Sloan Kettering Cancer Center13, Karolinska Institutet14, First Faculty of Medicine, Charles University in Prague15, Humanitas University16, Keio University17, Yamaguchi University18, Kindai University19, Sapporo Medical University20, Kurume University21, Xi'an Jiaotong University22, Qatar Airways23, Oregon Health & Science University24
TL;DR: The immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer and supports the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer.
TL;DR: This review addresses T-cell engineering and synthetic immunity, with a focus on producing durable remissions in patients with treatment-refractory tumors, aboutimeric Antigen Receptor T Cells.
Abstract: Chimeric Antigen Receptor T Cells This review addresses T-cell engineering and synthetic immunity, with a focus on producing durable remissions in patients with treatment-refractory tumors. Toxic e...
National Institutes of Health1, City of Hope National Medical Center2, University of British Columbia3, University of Barcelona4, University of Würzburg5, Bosch6, University of Toronto7, Mayo Clinic8, Alliance for Clinical Trials in Oncology9, Memorial Sloan Kettering Cancer Center10, Cornell University11, Washington University in St. Louis12
TL;DR: Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on “chronic active” B‐cell receptor signaling that is amenable to therapeutic inhibition, and an algorithm was developed and implemented to discover genetic subtypes based on the co‐occurrence of genetic alterations.
Abstract: Background Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell–like [ABC], germinal-center B-cell–like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. Methods We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. Results We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B muta...
TL;DR: A preprocessing pipeline, SEQC, and a Bayesian clustering and normalization method, Biscuit, are developed to address computational challenges inherent to single-cell data and support a model of continuous activation in T cells and do not comport with the macrophage polarization model in cancer.
Yale Cancer Center1, Princess Margaret Cancer Centre2, University of Toronto3, Osaka University4, University of Kansas5, University of Pittsburgh6, Indiana University7, NewYork–Presbyterian Hospital8, Pontifical Catholic University of Chile9, Tel Aviv University10, Sheba Medical Center11, University of California, Los Angeles12, University of Chicago13, Tel Aviv Sourasky Medical Center14, Sanford Health15, University of California, San Francisco16, Memorial Sloan Kettering Cancer Center17, Harvard University18, New Generation University College19, Merck & Co.20, Mayo Clinic21
TL;DR: Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment.
Abstract: Importance Therapeutic options are needed for patients with advanced gastric cancer whose disease has progressed after 2 or more lines of therapy. Objective To evaluate the safety and efficacy of pembrolizumab in a cohort of patients with previously treated gastric or gastroesophageal junction cancer. Design, Setting, and Participants In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016. Median (range) follow-up was 5.8 (0.5-21.6) months. Intervention Patients received pembrolizumab, 200 mg, intravenously every 3 weeks until disease progression, investigator or patient decision to withdraw, or unacceptable toxic effects. Main Outcomes and Measures Primary end points were objective response rate and safety. Objective response rate was assessed by central radiologic review per Response Evaluation Criteria in Solid Tumors, version 1.1, in all patients and those with programmed cell death 1 ligand 1 (PD-L1)–positive tumors. Expression of PD-L1 was assessed by immunohistochemistry. Secondary end points included response duration. Results Of 259 patients enrolled, most were male (198 [76.4%]) and white (200 [77.2%]); median (range) age was 62 (24-89) years. Objective response rate was 11.6% (95% CI, 8.0%-16.1%; 30 of 259 patients), with complete response in 2.3% (95% CI, 0.9%-5.0%; 6 of 259 patients). Median (range) response duration was 8.4 (1.6+ to 17.3+) months (+ indicates that patients had no progressive disease at their last assessment). Objective response rate and median (range) response duration were 15.5% (95% CI, 10.1%-22.4%; 23 of 148 patients) and 16.3 (1.6+ to 17.3+) months and 6.4% (95% CI, 2.6%-12.8%; 7 of 109 patients) and 6.9 (2.4 to 7.0+) months in patients with PD-L1–positive and PD-L1–negative tumors, respectively. Forty-six patients (17.8%) experienced 1 or more grade 3 to 5 treatment-related adverse events. Two patients (0.8%) discontinued because of treatment-related adverse events, and 2 deaths were considered related to treatment. Conclusions and Relevance Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment. Durable responses were observed in patients with PD-L1–positive and PD-L1–negative tumors. Further study of pembrolizumab for this group of patients is warranted. Trial Registration clinicaltrials.gov Identifier: NCT02335411
TL;DR: A novel approach to modelling life expectancy, all-cause mortality and cause of death forecasts —and alternative future scenarios—for 250 causes of death from 2016 to 2040 in 195 countries and territories is provided.
TL;DR: MAGIC as mentioned in this paper is a Markov affinity-based graph imputation of cells that shares information across similar cells, via data diffusion, to denoise the cell count matrix and fill in missing transcripts.
University of Texas MD Anderson Cancer Center1, Memorial Sloan Kettering Cancer Center2, Institut Gustave Roussy3, Cornell University4, Northwestern University5, Ohio State University6, University of Miami7, University of Texas Southwestern Medical Center8, University of California, San Francisco9, Anschutz Medical Campus10, Sarah Cannon Research Institute11, Harvard University12, Centre Hospitalier Universitaire de Bordeaux13, University of Alabama at Birmingham14, Johns Hopkins University15, City of Hope National Medical Center16, Washington University in St. Louis17, Mayo Clinic18, Oregon Health & Science University19, Medical University of South Carolina20, Emory University21, Cleveland Clinic22, Agios Pharmaceuticals23
TL;DR: In patients with advanced IDH1‐mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment‐related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission.
Abstract: Background Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. Methods We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. Results Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%...
TL;DR: It is shown that AF4 can serve as an improved analytical tool for isolating extracellular vesicles and addressing the complexities of heterogeneous nanoparticle subpopulations, and three nanoparticle subsets demonstrated diverse organ biodistribution patterns, suggesting distinct biological functions.
Abstract: The heterogeneity of exosomal populations has hindered our understanding of their biogenesis, molecular composition, biodistribution and functions. By employing asymmetric flow field-flow fractionation (AF4), we identified two exosome subpopulations (large exosome vesicles, Exo-L, 90–120 nm; small exosome vesicles, Exo-S, 60–80 nm) and discovered an abundant population of non-membranous nanoparticles termed ‘exomeres’ (~35 nm). Exomere proteomic profiling revealed an enrichment in metabolic enzymes and hypoxia, microtubule and coagulation proteins as well as specific pathways, such as glycolysis and mTOR signalling. Exo-S and Exo-L contained proteins involved in endosomal function and secretion pathways, and mitotic spindle and IL-2/STAT5 signalling pathways, respectively. Exo-S, Exo-L and exomeres each had unique N-glycosylation, protein, lipid, DNA and RNA profiles and biophysical properties. These three nanoparticle subsets demonstrated diverse organ biodistribution patterns, suggesting distinct biological functions. This study demonstrates that AF4 can serve as an improved analytical tool for isolating extracellular vesicles and addressing the complexities of heterogeneous nanoparticle subpopulations.