Showing papers by "Fred Hutchinson Cancer Research Center published in 2016"
Imperial College London1, University of Barcelona2, Keio University3, University of Duisburg-Essen4, Queen's University5, Peter MacCallum Cancer Centre6, University of Michigan7, University of São Paulo8, Yale University9, Northern General Hospital10, University of Caen Lower Normandy11, Fred Hutchinson Cancer Research Center12, University of Oxford13, Memorial Sloan Kettering Cancer Center14, University of Sydney15, Sungkyunkwan University16, Seoul National University17, Kyorin University18, University of Copenhagen19, Nippon Medical School20, Katholieke Universiteit Leuven21, University of Texas MD Anderson Cancer Center22, University of Antwerp23, Hyogo College of Medicine24, University of Western Australia25, Glenfield Hospital26, Cleveland Clinic27, Icahn School of Medicine at Mount Sinai28, University of Turin29, Université libre de Bruxelles30, Juntendo University31, National Cancer Research Institute32, Mayo Clinic33, University of Toronto34, Sinai Grace Hospital35, Netherlands Cancer Institute36, Hiroshima University37, City of Hope National Medical Center38, University of Chicago39, New York University40, Georgetown University41, University of Tokushima42, University of Pisa43, Osaka University44, University of Valencia45, Good Samaritan Hospital46, Military Medical Academy47, Fundación Favaloro48, Autonomous University of Barcelona49, Complutense University of Madrid50, University of Oviedo51, National and Kapodistrian University of Athens52, Rovira i Virgili University53, Autonomous University of Madrid54, Ghent University55
TL;DR: The methods used to evaluate the resultant Stage groupings and the proposals put forward for the 8th edition of the TNM Classification for lung cancer due to be published late 2016 are described.
2,826 citations
Wellcome Trust Sanger Institute1, University of Michigan2, University of Oxford3, University of Geneva4, University of Exeter5, Greifswald University Hospital6, National Research Council7, University of Bristol8, University of Colorado Boulder9, University of Washington10, Fred Hutchinson Cancer Research Center11, SUNY Downstate Medical Center12, Erasmus University Rotterdam13, University of Trieste14, VU University Amsterdam15, King's College London16, South London and Maudsley NHS Foundation Trust17, University of Edinburgh18, Harvard University19, National Institutes of Health20, Harokopio University21, Innsbruck Medical University22, Broad Institute23, Lund University24, University of Helsinki25, Norwegian University of Science and Technology26, University of Cambridge27, University of Minnesota28, Technische Universität München29, University of North Carolina at Chapel Hill30, University of Toronto31, McGill University32, Leiden University33, University of Pennsylvania34, University of Groningen35, Utrecht University36, Churchill Hospital37
TL;DR: A reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies.
Abstract: We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
2,149 citations
University of Cambridge1, Harvard University2, Peking University3, National Institutes of Health4, University of Oxford5, Curtin University6, Australian National University7, Imperial College London8, American Cancer Society9, University of Southern California10, Johns Hopkins University11, University of Sydney12, Vanderbilt University13, Chinese Center for Disease Control and Prevention14, University of Bristol15, Capital Medical University16, Erasmus University Rotterdam17, Yonsei University18, Fred Hutchinson Cancer Research Center19, University of Turin20, University of Glasgow21, University of North Carolina at Chapel Hill22, Shiga University of Medical Science23, Innsbruck Medical University24, International Agency for Research on Cancer25, University of Hong Kong26, Massey University27
TL;DR: The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents and supports strategies to combat the entire spectrum of excess adiposity in many populations.
1,731 citations
TL;DR: It is established that high CAR-T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity, and serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity are identified.
Abstract: BACKGROUND. T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR–T cell products were prepared from unselected T cells.
METHODS. We conducted a clinical trial to evaluate CD19 CAR–T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy.
RESULTS. The defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission, as determined by flow cytometry. We established that high CAR–T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity. Moreover, we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. Risk-stratified CAR–T cell dosing based on BM disease burden decreased toxicity. CD8+ T cell–mediated anti-CAR transgene product immune responses developed after CAR–T cell infusion in some patients, limited CAR–T cell persistence, and increased relapse risk. Addition of fludarabine to the lymphodepletion regimen improved CAR–T cell persistence and disease-free survival.
CONCLUSION. Immunotherapy with a CAR–T cell product of defined composition enabled identification of factors that correlated with CAR–T cell expansion, persistence, and toxicity and facilitated design of lymphodepletion and CAR–T cell dosing strategies that mitigated toxicity and improved disease-free survival.
TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01865617","term_id":"NCT01865617"}}NCT01865617.
FUNDING. R01-CA136551; Life Science Development Fund; Juno Therapeutics; Bezos Family Foundation.
1,548 citations
Broad Institute1, New York University2, Harvard University3, Icahn School of Medicine at Mount Sinai4, Fred Hutchinson Cancer Research Center5, Washington University in St. Louis6, Karolinska Institutet7, Baylor College of Medicine8, University of North Carolina at Chapel Hill9, Vanderbilt University10, National Institutes of Health11
TL;DR: It is demonstrated that proteogenomic analysis of breast cancer elucidates functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.
Abstract: Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.
1,296 citations
Stanford University1, Icahn School of Medicine at Mount Sinai2, Indiana University3, Memorial Sloan Kettering Cancer Center4, Mayo Clinic5, National Institutes of Health6, University of Utah7, Fred Hutchinson Cancer Research Center8, Johns Hopkins University9, NorthShore University HealthSystem10, University of Michigan11, University of North Carolina at Chapel Hill12, University of Turku13, Translational Genomics Research Institute14, Wayne State University15, University of Paris16, Cancer Council Victoria17, University of Melbourne18, University of Ulm19, University of Southern California20, Karolinska Institutet21, Northwestern University22, McGill University23, LSU Health Sciences Center New Orleans24
TL;DR: This work developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, LRT, GERP, SiPhy, phyloP, and phastCons.
Abstract: The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p −12 ) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies
1,295 citations
TL;DR: The frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer and 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis.
Abstract: BackgroundInherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. MethodsWe recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. ResultsA total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [...
1,119 citations
University of Washington Medical Center1, Johns Hopkins University School of Medicine2, Emory University3, University of Washington4, Merck & Co.5, Johns Hopkins University6, University of California, San Francisco7, Fred Hutchinson Cancer Research Center8, Icahn School of Medicine at Mount Sinai9, Yale University10, Stanford University11, Ohio State University12, National Institutes of Health13
TL;DR: First-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56% and effectiveness was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing.
Abstract: BackgroundMerkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. MethodsIn this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti–PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing. ResultsA total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patient...
997 citations
Florida International University1, American Cancer Society2, University of Miami3, Oncology Nursing Society4, George Washington University5, University of Pennsylvania6, City of Hope National Medical Center7, University of North Carolina at Chapel Hill8, University of Toronto9, Fred Hutchinson Cancer Research Center10, University of California, Los Angeles11
TL;DR: Recommendations on surveillance for breast cancer recurrence, screening for second primary cancers, assessment and management of physical and psychosocial long-term and late effects of breast cancer and its treatment, health promotion, and care coordination/practice implications are made.
Abstract: The purpose of the American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline is to provide recommendations to assist primary care and other clinicians in the care of female adult survivors of breast cancer. A systematic review of the literature was conducted using PubMed through April 2015. A multidisciplinary expert workgroup with expertise in primary care, gynecology, surgical oncology, medical oncology, radiation oncology, and nursing was formed and tasked with drafting the Breast Cancer Survivorship Care Guideline. A total of 1,073 articles met inclusion criteria; and, after full text review, 237 were included as the evidence base. Patients should undergo regular surveillance for breast cancer recurrence, including evaluation with a cancer-related history and physical examination, and should be screened for new primary breast cancer. Data do not support performing routine laboratory tests or imaging tests in asymptomatic patients to evaluate for breast cancer recurrence. Primary care clinicians should counsel patients about the importance of maintaining a healthy lifestyle, monitor for post-treatment symptoms that can adversely affect quality of life, and monitor for adherence to endocrine therapy. Recommendations provided in this guideline are based on current evidence in the literature and expert consensus opinion. Most of the evidence is not sufficient to warrant a strong evidence-based recommendation. Recommendations on surveillance for breast cancer recurrence, screening for second primary cancers, assessment and management of physical and psychosocial long-term and late effects of breast cancer and its treatment, health promotion, and care coordination/practice implications are made.This guideline was developed through a collaboration between the American Cancer Society and the American Society of Clinical Oncology and has been published jointly by invitation and consent in both CA: A Cancer Journal for Clinicians and Journal of Clinical Oncology. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by the American Cancer Society or the American Society of Clinical Oncology.
795 citations
TL;DR: Immunotherapy with CD19 CAR-T cells in a defined CD4+/CD8+ ratio allowed identification of correlative factors for CAR-t cell expansion, persistence, and toxicity, and facilitated optimization of lymphodepletion that improved disease response and overall and progression-free survival.
Abstract: CD19-specific chimeric antigen receptor (CAR)–modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4 + /CD8 + ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin’s lymphoma after cyclophosphamide (Cy)–based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had increased CAR-T cell expansion and persistence, and higher response rates [50% complete remission (CR), 72% overall response rate (ORR)] than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR). The CR rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR; n = 11). Cy/Flu minimized the effects of an immune response to the murine single-chain variable fragment component of the CAR, which limited CAR-T cell expansion and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥3 neurotoxicity were observed in 13 and 28% of all patients, respectively. Serum biomarkers, one day after CAR-T cell infusion, correlated with subsequent sCRS and neurotoxicity. Immunotherapy with CD19 CAR-T cells in a defined CD4 + /CD8 + ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of lymphodepletion that improved disease response and overall and progression-free survival.
777 citations
National Institutes of Health1, University of Queensland2, University of Edinburgh3, Columbia University4, Erasmus University Rotterdam5, King's College London6, University of Minnesota7, University of Texas Health Science Center at Houston8, Baylor College of Medicine9, Johns Hopkins University10, Harvard University11, Boston University12, University of Exeter13, Innsbruck Medical University14, University of Düsseldorf15, Stanford University16, University of California, Los Angeles17, United States Department of Veterans Affairs18, Northwestern University19, George Washington University20, University of California, San Diego21, University of Washington22, Fred Hutchinson Cancer Research Center23
TL;DR: Evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors is strengthened and estimates that incorporate information on blood cell counts lead to highly significant associations with all- Cause mortality are demonstrated.
Abstract: Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10-9), independent of chronological age, even after adjusting for additional risk factors (p<5.4x10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.
University College London1, Karolinska Institutet2, Memorial Sloan Kettering Cancer Center3, University of Colorado Denver4, Dresden University of Technology5, Ohio State University6, Fred Hutchinson Cancer Research Center7, Erasmus University Medical Center8, French Institute of Health and Medical Research9
TL;DR: A plethora of new agents — including those targeted at specific biochemical pathways and immunotherapeutic approaches — are now in trial based on improved understanding of disease pathophysiology, providing good grounds for optimism, although mortality remains high especially in older patients.
Abstract: Acute myeloid leukaemia (AML) is a disorder characterized by a clonal proliferation derived from primitive haematopoietic stem cells or progenitor cells. Abnormal differentiation of myeloid cells results in a high level of immature malignant cells and fewer differentiated red blood cells, platelets and white blood cells. The disease occurs at all ages, but predominantly occurs in older people (>60 years of age). AML typically presents with a rapid onset of symptoms that are attributable to bone marrow failure and may be fatal within weeks or months when left untreated. The genomic landscape of AML has been determined and genetic instability is infrequent with a relatively small number of driver mutations. Mutations in genes involved in epigenetic regulation are common and are early events in leukaemogenesis. The subclassification of AML has been dependent on the morphology and cytogenetics of blood and bone marrow cells, but specific mutational analysis is now being incorporated. Improvements in treatment in younger patients over the past 35 years has largely been due to dose escalation and better supportive care. Allogeneic haematopoietic stem cell transplantation may be used to consolidate remission in those patients who are deemed to be at high risk of relapse. A plethora of new agents - including those targeted at specific biochemical pathways and immunotherapeutic approaches - are now in trial based on improved understanding of disease pathophysiology. These advances provide good grounds for optimism, although mortality remains high especially in older patients.
United States Department of Health and Human Services1, Erasmus University Rotterdam2, University of California, Berkeley3, Johns Hopkins University4, Icahn School of Medicine at Mount Sinai5, University of Southern California6, Duke University7, University of Bristol8, University Medical Center Groningen9, University of California, San Francisco10, North Carolina State University11, Karolinska Institutet12, Pompeu Fabra University13, University of Paris14, University of Memphis15, Centre Hospitalier Universitaire de Grenoble16, University of Bergen17, Isfahan University of Medical Sciences18, Brigham and Women's Hospital19, Oslo University Hospital20, Utrecht University21, French Institute of Health and Medical Research22, Norwegian Institute of Public Health23, Johns Hopkins University School of Medicine24, Harvard University25, International Agency for Research on Cancer26, Paris Descartes University27, Michigan State University28, Centre national de la recherche scientifique29, Fred Hutchinson Cancer Research Center30, University of Basel31, Swiss Tropical and Public Health Institute32, Stockholm County Council33, University of Southampton34
TL;DR: This large scale meta-analysis of methylation data identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
Abstract: Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
TL;DR: The accessible chromatin landscape in exhausted CD8+ T cells is defined and shown that it is distinct from functional memory CD8 + T cells, suggesting that exhausted T cells are a distinct lineage.
Abstract: Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1) However, the regulation of gene expression in exhausted T cells is poorly understood Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells
TL;DR: Severe financial distress requiring bankruptcy protection after cancer diagnosis appears to be a risk factor for mortality, according to Cox proportional hazards models.
Abstract: PurposePatients with cancer are more likely to file for bankruptcy than the general population, but the impact of severe financial distress on health outcomes among patients with cancer is not known.MethodsWe linked Western Washington SEER Cancer Registry records with federal bankruptcy records for the region. By using propensity score matching to account for differences in several demographic and clinical factors between patients who did and did not file for bankruptcy, we then fit Cox proportional hazards models to examine the relationship between bankruptcy filing and survival.ResultsBetween 1995 and 2009, 231,596 persons were diagnosed with cancer. Patients who filed for bankruptcy (n = 4,728) were more likely to be younger, female, and nonwhite, to have local- or regional- (v distant-) stage disease at diagnosis, and have received treatment. After propensity score matching, 3,841 patients remained in each group (bankruptcy v no bankruptcy). In the matched sample, mean age was 53.0 years, 54% were men...
TL;DR: It is shown that CAR-T-cell products generated from defined T-cell subsets can provide uniform potency compared with products derived from unselected T cells that vary in phenotypic composition.
Abstract: Adoptive T-cell therapy with gene-modified T cells expressing a tumor-reactive T-cell receptor or chimeric antigen receptor (CAR) is a rapidly growing field of translational medicine and has shown success in the treatment of B-cell malignancies and solid tumors. In all reported trials, patients have received T-cell products comprising random compositions of CD4(+) and CD8(+) naive and memory T cells, meaning that each patient received a different therapeutic agent. This variation may have influenced the efficacy of T-cell therapy, and complicates comparison of outcomes between different patients and across trials. We analyzed CD19 CAR-expressing effector T cells derived from different subsets (CD4(+)/CD8(+) naive, central memory, effector memory). T cells derived from each of the subsets were efficiently transduced and expanded, but showed clear differences in effector function and proliferation in vitro and in vivo. Combining the most potent CD4(+) and CD8(+) CAR-expressing subsets, resulted in synergistic antitumor effects in vivo. We show that CAR-T-cell products generated from defined T-cell subsets can provide uniform potency compared with products derived from unselected T cells that vary in phenotypic composition. These findings have important implications for the formulation of T-cell products for adoptive therapies.
TL;DR: Administration of lymphodepletion chemotherapy followed by CD19-specific chimeric antigen receptor (CAR)-modified T cells is a remarkably effective approach to treating patients with relapsed and refractory CD19(+) B-cell malignancies.
University of Vienna1, University of Edinburgh2, Massey University3, Newcastle University4, University of Copenhagen5, University of Glasgow6, Massachusetts Institute of Technology7, Boston College8, Fred Hutchinson Cancer Research Center9, University of Aberdeen10, San Diego State University11, Institut national de la recherche agronomique12, University of Birmingham13, Agricultural Research Organization, Volcani Center14, University of Jena15, University of Lausanne16, University of Warwick17, University of Amsterdam18, Delft University of Technology19, Temple University20, Technical University of Denmark21, Columbia University22
TL;DR: In this paper, the authors argue that the ability to predict and manage the function of these highly complex, dynamically changing communities is limited, and that close coordination of experimental data collection and method development with mathematical model building is needed to achieve significant progress in understanding of microbial dynamics and function.
Abstract: The importance of microbial communities (MCs) cannot be overstated. MCs underpin the biogeochemical cycles of the earth’s soil, oceans and the atmosphere, and perform ecosystem functions that impact plants, animals and humans. Yet our ability to predict and manage the function of these highly complex, dynamically changing communities is limited. Building predictive models that link MC composition to function is a key emerging challenge in microbial ecology. Here, we argue that addressing this challenge requires close coordination of experimental data collection and method development with mathematical model building. We discuss specific examples where model–experiment integration has already resulted in important insights into MC function and structure. We also highlight key research questions that still demand better integration of experiments and models. We argue that such integration is needed to achieve significant progress in our understanding of MC dynamics and function, and we make specific practical suggestions as to how this could be achieved.
Northwestern University1, University of Oxford2, Fred Hutchinson Cancer Research Center3, University of Porto4, University of California, San Diego5, Temple University6, National Institutes of Health7, University of Minnesota8, University of Nebraska Medical Center9, King's College London10, University of Edinburgh11
TL;DR: It is shown that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.
Abstract: Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.
TL;DR: A phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe finds that using longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV- 1 protection.
Abstract: BackgroundAntiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. MethodsWe conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. ResultsAmong the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0....
TL;DR: Analysis of multiple tumors from men with disseminated prostate cancer indicates that evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.
Abstract: Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.
University of California, Los Angeles1, University of California, Santa Barbara2, University of New Mexico3, University of Southern California4, National Institutes of Health5, Tulane University6, Centre national de la recherche scientifique7, Harvard University8, University of British Columbia9, VA Palo Alto Healthcare System10, Stanford University11, Fred Hutchinson Cancer Research Center12, University of Washington13
TL;DR: Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes.
Abstract: Epigenetic biomarkers of aging (the “epigenetic clock”) have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors. We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue. Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.
TL;DR: The recent genomic characterization of cancers has revealed recurrent somatic point mutations and copy number changes affecting genes encoding RNA splicing factors, which may create novel vulnerabilities in cancer cells that can be therapeutic exploited using compounds that can influence the splicing process.
Abstract: This Review discusses the current genetic and functional links between dysregulated and/or mutated RNA splicing factors and cancer, as well as the therapeutic opportunities presented by alterations in alternative splicing in cancer. The recent genomic characterization of cancers has revealed recurrent somatic point mutations and copy number changes affecting genes encoding RNA splicing factors. Initial studies of these 'spliceosomal mutations' suggest that the proteins bearing these mutations exhibit altered splice site and/or exon recognition preferences relative to their wild-type counterparts, resulting in cancer-specific mis-splicing. Such changes in the splicing machinery may create novel vulnerabilities in cancer cells that can be therapeutically exploited using compounds that can influence the splicing process. Further studies to dissect the biochemical, genomic and biological effects of spliceosomal mutations are crucial for the development of cancer therapies targeted at these mutations.
University of Washington1, University of the Witwatersrand2, Fred Hutchinson Cancer Research Center3, FHI 3604, National Institutes of Health5, South African Medical Research Council6, University of Zimbabwe7, Makerere University8, Centre for the AIDS Programme of Research in South Africa9, University of Cape Town10, University of Pittsburgh11, Johns Hopkins University12, RTI International13, University of California, San Francisco14, Population Council15
TL;DR: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence.
Abstract: (ed from N Engl J Med 2016; DOI: 10.1056/NEJMoa1506110)The objective of this study was to examine the efficacy of dapivirine vaginal rings in providing protection against human immunodeficiency virus type 1 (HIV-1). HIV-1 infection incidence is one of the highest in sub-Saharan Africa.
TL;DR: Understanding the levels and trends of the leading causes of death and disability among children and adolescents is critical to guide investment and inform policies and give guidance to policy makers in countries where more attention is needed.
Abstract: Importance The literature focuses on mortality among children younger than 5 years. Comparable information on nonfatal health outcomes among these children and the fatal and nonfatal burden of diseases and injuries among older children and adolescents is scarce. Objective To determine levels and trends in the fatal and nonfatal burden of diseases and injuries among younger children (aged Evidence Review Data from vital registration, verbal autopsy studies, maternal and child death surveillance, and other sources covering 14 244 site-years (ie, years of cause of death data by geography) from 1980 through 2013 were used to estimate cause-specific mortality. Data from 35 620 epidemiological sources were used to estimate the prevalence of the diseases and sequelae in the GBD 2013 study. Cause-specific mortality for most causes was estimated using the Cause of Death Ensemble Model strategy. For some infectious diseases (eg, HIV infection/AIDS, measles, hepatitis B) where the disease process is complex or the cause of death data were insufficient or unavailable, we used natural history models. For most nonfatal health outcomes, DisMod-MR 2.0, a Bayesian metaregression tool, was used to meta-analyze the epidemiological data to generate prevalence estimates. Findings Of the 7.7 (95% uncertainty interval [UI], 7.4-8.1) million deaths among children and adolescents globally in 2013, 6.28 million occurred among younger children, 0.48 million among older children, and 0.97 million among adolescents. In 2013, the leading causes of death were lower respiratory tract infections among younger children (905 059 deaths; 95% UI, 810 304-998 125), diarrheal diseases among older children (38 325 deaths; 95% UI, 30 365-47 678), and road injuries among adolescents (115 186 deaths; 95% UI, 105 185-124 870). Iron deficiency anemia was the leading cause of years lived with disability among children and adolescents, affecting 619 (95% UI, 618-621) million in 2013. Large between-country variations exist in mortality from leading causes among children and adolescents. Countries with rapid declines in all-cause mortality between 1990 and 2013 also experienced large declines in most leading causes of death, whereas countries with the slowest declines had stagnant or increasing trends in the leading causes of death. In 2013, Nigeria had a 12% global share of deaths from lower respiratory tract infections and a 38% global share of deaths from malaria. India had 33% of the world’s deaths from neonatal encephalopathy. Half of the world’s diarrheal deaths among children and adolescents occurred in just 5 countries: India, Democratic Republic of the Congo, Pakistan, Nigeria, and Ethiopia. Conclusions and Relevance Understanding the levels and trends of the leading causes of death and disability among children and adolescents is critical to guide investment and inform policies. Monitoring these trends over time is also key to understanding where interventions are having an impact. Proven interventions exist to prevent or treat the leading causes of unnecessary death and disability among children and adolescents. The findings presented here show that these are underused and give guidance to policy makers in countries where more attention is needed.
Brigham and Women's Hospital1, Memorial Hermann Texas Medical Center2, University of Cologne3, University of Chicago4, Duke University5, University of California, Davis6, Henry Ford Hospital7, Stanford University8, Fred Hutchinson Cancer Research Center9, University of Würzburg10, University of Strasbourg11, Katholieke Universiteit Leuven12, Rambam Health Care Campus13, University of Alabama at Birmingham14, Masaryk University15, Sheba Medical Center16, Universidade Federal de Minas Gerais17, Charité18, University of Minnesota19, Khon Kaen University20, Prince of Songkla University21, American University of Beirut22, Center for Global Development23
TL;DR: Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B, and can be used for treatment of mucormYcosis and is well tolerated.
Abstract: Summary Background Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. Methods In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response—ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)—according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. Findings Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19–179, range 2–882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). Interpretation Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. Funding Astellas Pharma Global Development, Basilea Pharmaceutica International.
TL;DR: It is shown that although overall survival is significantly prolonged in response to CSF-1R inhibition, tumors recur eventually in >50% of mice, indicating the necessity of combination therapy to expose PI3K signaling dependency in recurrent disease.
Abstract: Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors.
TL;DR: Overall use of dietary supplements remained stable from 1999-2012, use of MVMM decreased, and trends in use of individual supplements varied and were heterogeneous by population subgroups.
Abstract: Importance Dietary supplements are commonly used by US adults; yet, little is known about recent trends in supplement use. Objective To report trends in dietary supplement use among US adults. Design, Setting, and Participants Serial cross-sectional study using nationally representative data from the National Health and Nutrition Examination Survey (NHANES) collected between 1999 and 2012. Participants include noninstitutionalized adults residing in the United States, surveyed over 7 continuous 2-year cycles (sample size per cycle, 4863 to 6213). Exposures Calendar time, as represented by NHANES cycle. Main Outcomes and Measures In an in-home interview, participants were queried on use of supplements in the preceding 30 days to estimate the prevalence of use within each NHANES cycle, and trends were evaluated across cycles. Outcomes included use of any supplements; use of multivitamins/multiminerals (MVMM; defined as a product containing ≥10 vitamins and/or minerals); and use of individual vitamins, minerals, and nonvitamin, nonmineral supplements. Data were analyzed overall and by population subgroup (including age, sex, race/ethnicity, and educational status), and were weighted to be nationally representative. Results A total of 37 958 adults were included in the study (weighted mean age, 46.4 years; women, 52.0% ), with an overall response rate of 74%. Overall, the use of supplements remained stable between 1999 and 2012, with 52% of US adults reporting use of any supplements in 2011-2012 ( P for trend = .19). This trend varied by population subgroup. Use of MVMM decreased, with 37% reporting use of MVMM in 1999-2000 and 31% reporting use in 2011-2012 (difference, −5.7% [95% CI, −8.6% to −2.7%], P for trend P for trend P for trend Conclusions and Relevance Among adults in the United States, overall use of dietary supplements remained stable from 1999-2012, use of MVMM decreased, and trends in use of individual supplements varied and were heterogeneous by population subgroups.
TL;DR: A tamoxifen-inducible liver cancer mouse model with a defined oncogenic driver antigen is developed to follow the activation and differentiation of naive tumor-specific CD8(+) T (TST) cells after tumor initiation and shows dysfunction early during the pre-malignant phase of tumorigenesis.
TL;DR: Reduction in treatment exposure was associated with reduced late mortality among survivors of acute lymphoblastic leukemia and Wilms' tumor and the strategy of lowering therapeutic exposure has contributed to an observed decline inLate mortality among 5-year survivors of childhood cancer.
Abstract: BackgroundAmong patients in whom childhood cancer was diagnosed in the 1970s and 1980s, 18% of those who survived for 5 years died within the subsequent 25 years. In recent decades, cancer treatments have been modified with the goal of reducing life-threatening late effects. MethodsWe evaluated late mortality among 34,033 patients in the Childhood Cancer Survivor Study cohort who survived at least 5 years after childhood cancer (i.e., cancer diagnosed before the age of 21 years) for which treatment was initiated during the period from 1970 through 1999. The median follow-up was 21 years (range, 5 to 38). We evaluated demographic and disease factors that were associated with death from health-related causes (i.e., conditions that exclude recurrence or progression of the original cancer and external causes but include the late effects of cancer therapy) using cumulative incidence and piecewise exponential models to estimate relative rates and 95% confidence intervals. ResultsOf the 3958 deaths that occurred...