tbuckley/cabot-search huggingface dataset:
Experience of immune-related adverse events associated with ipilimumab and nivolumab in a single center.
Authors: Bernardo Leon Rapoport, Teresa Smit, Ronwyn van Eeden
Journal: Journal of Clinical Oncology (2017)

91 Background: Anti-programmed cell death receptor-1 (PD-1) and anti-CTLA4 antibodies represent an effective anti-cancer. Ipilimumab and nivolumab can induce immune-related adverse events (IrAEs). These IrAEs affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Life-threatening and fatal irAEs have been reported; adequate diagnosis and management are essential. Methods: A retrospective review of data from 40 patients (pts) records were used to describe the IrAE’s associated with 15 pts treated with ipilimumab and 25 pts treated with nivolumab. Results: A total of 40 pts (25 males and 15 females) were included in the analysis. The median age was 63 years (range 30 - 85 years). The performance status (PS) ranged from 0 to 2, with a median PS of 1. In total, 3 pts with metastatic melanoma, 18 with non small cell lung cancer (NSCLC), 2 with renal cell carcinoma and 2 with Hodgkin’s disease were treated with nivolumab and 15 with metastatic melanoma received ipilimumab. A total of 167 cycles of nivolumab (median = 4, range 1-16) and 60 cycles of ipilimumab (median = 4 cycles, range 1-4 cycles) were administered. Seven IrAEs are described in 19 pts treated with ipilimumab. These include endocrinopathy in 3 pts (hypophysitis in pt and hyphothyroidsm in 2 pts), colitis in 3 pts (1 required infliximab) and hepatitis in 1 pt. Among the pts treated with nivolumab 7 IrAEs were documented. These included pneumonitis in 2 pts, skin rash in 3 pts, mild diarrhea in 1 pt and mild uveitis in 1 pt. Additionally, 3 chest infections were documented including a case of pulmonary tuberculosis in a pt with NSCLC. Conclusions: Anti-PD1 and anti-CTLA4 antibodies can induce a plethora of irAEs. Colitis was more common with ipilimumab while pneumonitis more common with nivolumab. The knowledge of IrAE’s will allow prompt diagnosis and improve the management resulting in decreased morbidity.
187P Nivolumab-related immune-related adverse events in advanced NSCLC predict therapeutic objective response
Authors: J. Rogado, V. Pacheco Barcia, B. Vera, P. Toquero, R. Mondejar, A.I. Ballesteros Garcia, O. Donnay, N. Romero Laorden, R. Colomer Bosch, J.M. Sánchez-Torres
Journal: Journal of Thoracic Oncology (2018)
An incidental finding on a knee radiograph
Authors: James Russell, Joanna Farrant
Journal: BMJ (2018)

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Variations and delays in COPD care warrant new targets, says college
Authors: Eliza Slawther
Journal: BMJ (2018)

Doctors have called for greater collaboration across hospital teams to ensure that patients with chronic obstructive respiratory disease (COPD) get the most appropriate care promptly after finding that over half of patients are waiting too long for pulmonary rehabilitation.

Two audits from the Royal College of Physicians presented a picture of the organisation, resourcing, and care of patients with COPD in 182 hospitals in England and Wales in 2016, updating similar audits carried out in 2014 (which looked at care in 2013).12

They found that only 54% of hospitals provided access to smoking cessation services in 2016 compared with 63% in 2013. Even then only a quarter of …
Different rates of progression and mortality in patients with chronic kidney disease at outpatient nephrology clinics across Europe
Authors: Katharina Brück, Kitty J. Jager, Carmine Zoccali, Aminu K. Bello, Roberto Minutolo, Kyriakos Ioannou, Francis Verbeke, Henry Völzke, Johan Arnlöv, Daniela Leonardis, Pietro Manuel Ferraro, Hermann Brenner, Ben Caplin, Philip A. Kalra, Christoph Wanner, Alberto Martinez Castelao, Jose Luis Gorriz, Stein Hallan, Dietrich Rothenbacher, Dino Gibertoni, Luca De Nicola, Georg Heinze, Wim Van Biesen, Vianda S. Stel
Journal: Kidney International (2018)
81P The influence of comorbidity on health utility score (HUS) and health-related quality of life (HRQoL) in small cell lung cancer (SCLC) compared to non-small cell lung cancer (NSCLC)
Authors: A. Vedadi, S. Shakik, M.C. Brown, W. Xu, F.A. Shepherd, N. Leighl, P.A. Bradbury, G. Liu, G. O'kane
Journal: Journal of Thoracic Oncology (2018)
Mutational load (ML) and T-cell-inflamed microenvironment as predictors of response to pembrolizumab.
Authors: Razvan Cristescu, Robin Mogg, Mark Ayers, Andrew Albright, Erin Murphy, Jennifer Yearley, Xinwei Sher, Xiaoqiao Liu, Michael Nebozhyn, Jared K. Lunceford, Andrew K. Joe, Jonathan Cheng, Elizabeth R. Plimack, Patrick Alexander Ott, Tanguy Y. Seiwert, Terrill K McClanahan, Andrey Loboda, David Ross Kaufman
Journal: Journal of Clinical Oncology (2017)

1 Background: ML is associated with response to anti CTLA-4 and PD-1/L1 immunotherapies in some cancers, likely due to increased tumor antigenicity via generation of neoepitopes not subject to central immune tolerance. An IFNγ centric gene expression profile (GEP), characteristic of a T cell inflamed microenvironment, is also related to response to PD-1/PD-L1 therapies. The association between ML and outcome, and independent predictive values of ML and GEP in pembrolizumab treated patients across 21 tumor types were assessed. Methods: Whole exome and RNA sequencing were performed on FFPE specimens pooled from 2 multicohort advanced solid tumor trials (KEYNOTE 012 [n = 39] and 028 [n = 80]). The previously defined GEP score is a weighted sum of normalized expression values for 18 genes. ML and neoantigen analysis tools included GATK, MuTect and NetMHC. Statistical testing was adjusted for multiple testing. ML and GEP association was also explored in Moffitt and TCGA datasets. Results: ML and neoantigen load were significantly associated with objective response (OR) (AUROC = 0.76 and 0.78; p = 0.0036 and 0.0083, respectively). Median numbers of mutations were 180 in responders and 61 in nonresponders. The overall response rate (ORR) in all patients was 15%. At a ML cutoff of 102 (based on ROC Curve YoudenIndex), the ORR was 32.3% (prevalence 31.0%; NPV 92.8%). GEP was also significantly associated with OR (AUROC = 0.76; p = 0.0071). ML and GEP were modestly correlated (r = 0.28), consistent with associations between ML and GEP in Moffitt (r = 0.11) and TCGA databases (r = 0.29). When jointly modeled, ML was significantly associated with response (p = 0.0078) after adjusting for GEP (also significant; p = 0.0251). Data from additional patients will also be presented. Conclusions: These data show that ML and GEP are independently predictive biomarkers of response to pembrolizumab in multiple tumor types, suggesting that tumor antigenicity and T cell infiltration may provide complementary information for expected pembrolizumab activity. As measures of distinct, yet common features of a PD-1 checkpoint blockade responsive tumor, ML and GEP may have utility in characterizing responses to anti PD-1 and other cancer immunotherapies. Clinical trial information: NCT01848834; NCT02054806.
Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): a national cross-sectional study
Authors: Chen Wang, Jianying Xu, Lan Yang, Yongjian Xu, Xiangyan Zhang, Chunxue Bai, Jian Kang, Pixin Ran, Huahao Shen, Fuqiang Wen, Kewu Huang, Wanzhen Yao, Tieying Sun, Guangliang Shan, Ting Yang, Yingxiang Lin, Sinan Wu, Jianguo Zhu, Ruiying Wang, Zhihong Shi, Jianping Zhao, Xianwei Ye, Yuanlin Song, Qiuyue Wang, Yumin Zhou, Liren Ding, Ting Yang, Yahong Chen, Yanfei Guo, Fei Xiao, Yong Lu, Xiaoxia Peng, Biao Zhang, Dan Xiao, Chung-Shiuan Chen, Zuomin Wang, Hong Zhang, Xiaoning Bu, Xiaolei Zhang, Li An, Shu Zhang, Zhixin Cao, Qingyuan Zhan, Yuanhua Yang, Bin Cao, Huaping Dai, Lirong Liang, Jiang He
Journal: The Lancet (2018)
Weak sharing of genetic association signals in three lung cancer subtypes: evidence at the SNP, gene, regulation, and pathway levels
Authors: Timothy D. O’Brien, Peilin Jia, Neil E. Caporaso, Maria Teresa Landi, Zhongming Zhao
Journal: Genome Medicine (2018)

There are two main types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has many subtypes, but the two most common are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These subtypes are mainly classified by physiological and pathological characteristics, although there is increasing evidence of genetic and molecular differences as well. Although some work has been done at the somatic level to explore the genetic and biological differences among subtypes, little work has been done that interrogates these differences at the germline level to characterize the unique and shared susceptibility genes for each subtype. We used single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) of European samples to interrogate the similarity of the subtypes at the SNP, gene, pathway, and regulatory levels. We expanded these genotyped SNPs to include all SNPs in linkage disequilibrium (LD) using data from the 1000 Genomes Project. We mapped these SNPs to several lung tissue expression quantitative trait loci (eQTL) and enhancer datasets to identify regulatory SNPs and their target genes. We used these genes to perform a biological pathway analysis for each subtype. We identified 8295, 8734, and 8361 SNPs with moderate association signals for LUAD, LUSC, and SCLC, respectively. Those SNPs had p < 1 × 10− 3 in the original GWAS or were within LD (r2 > 0.8, Europeans) to the genotyped SNPs. We identified 215, 320, and 172 disease-associated genes for LUAD, LUSC, and SCLC, respectively. Only five genes (CHRNA5, IDH3A, PSMA4, RP11-650 L12.2, and TBC1D2B) overlapped all subtypes. Furthermore, we observed only two pathways from the Kyoto Encyclopedia of Genes and Genomes shared by all subtypes. At the regulatory level, only three eQTL target genes and two enhancer target genes overlapped between all subtypes. Our results suggest that the three lung cancer subtypes do not share much genetic signal at the SNP, gene, pathway, or regulatory level, which differs from the common subtype classification based upon histology. However, three (CHRNA5, IDH3A, and PSMA4) of the five genes shared between the subtypes are well-known lung cancer genes that may act as general lung cancer genes regardless of subtype.
Phenotypic subtypes as a novel validated prognostic classification system for patients with colorectal cancer.
Authors: Antonia K. Roseweir, James Hugh Park, Sanne ten Hoorn, Arfon GMT Powell, Campbell SD Roxburgh, Donald C McMillan, Paul G. Horgan, Louis Vermeulen, Joanne Edwards
Journal: Journal of Clinical Oncology (2018)

625 Background: There has been enormous effort to develop a prognostic genomic classification of colorectal cancer (CRC). As a result, mismatch repair (MMR) status was established as a prognostic marker in addition to TNM-staging. Phenotypic subtypes were recently proposed that stratified patient survival, however their clinical utility had not been compared to other proposed classification systems including consensus molecular subtypes (CMS) or current prognostic markers including MMR status. Methods: Three patient cohorts, a pilot cohort of 237 stage I-III CRC patients, a validation cohort of 879 stage I-III CRC patients, and the AMC-AJCCII-90 cohort with 81 stage II colon cancer patients were utilised to investigate associations between phenotypic subtypes, MMR status, CMS and patient survival. Results: In the pilot cohort, phenotypic subtype stratified cancer-specific survival (P &lt; 0.001). In the validation cohort, phenotypic subtype stratified overall (p = 0.003) and cancer-specific survival (CSS, p &lt; 0.001) independent of tumour location. MMR status associated with right-sided colon cancer (p &lt; 0.001), therefore further analysis was restricted to this subset of patient (n = 380). The immune subtype had the highest MMR deficiency (p = 0.001). Phenotypic subtype (p &lt; 0.001) more effectively stratified CSS than MMR status (p = 0.023). Furthermore, in left-sided colon cancer (p = 0.007) and rectal cancer (p &lt; 0.001) only phenotypic subtype stratified CSS. Phenotypic subtype and not MMR status was independently prognostic in the full cohort (p &lt; 0.001) and right-sided colon cancer (p &lt; 0.001). In the AMC-AJCCII-90 cohort phenotypic subtypes aligned with CMS (p &lt; 0.001) and stratified overall survival better than CMS (p = 0.125 v p = 0.487 respectively). Conclusions: Phenotypic subtype is a more effective prognostic classification than CMS and MMR status. Phenotypic subtypes should be incorporated alongside MMR status as a clinical aid for the prognosis of patients with CRC.
BRAF and MEK Inhibitors Increase PD-1-Positive Melanoma Cells Leading to a Potential Lymphocyte-Independent Synergism with Anti–PD-1 Antibody
Authors: Martina Sanlorenzo, Igor Vujic, Arianna Floris, Mauro Novelli, Loretta Gammaitoni, Lidia Giraudo, Marco Macagno, Valeria Leuci, Ramona Rotolo, Chiara Donini, Marco Basiricò, Pietro Quaglino, Maria Teresa Fierro, Silvia Giordano, Maria Sibilia, Fabrizio Carnevale-Schianca, Massimo Aglietta, Dario Sangiolo
Journal: Clinical Cancer Research (2018)

Abstract Purpose: BRAF and MEK inhibitors (BRAF/MEKi) favor melanoma-infiltrating lymphocytes, providing the rationale for current combinatorial trials with anti–PD-1 antibody. A portion of melanoma cells may express PD-1, and anti–PD-1 antibody could have a direct antitumor effect. Here, we explore whether BRAF/MEKi modulate rates of PD-1+ melanoma cells, supporting an additional—lymphocyte-independent—basis for their therapeutic combination with anti–PD-1 antibody. Experimental Design: With data mining and flow cytometry, we assessed PD-1, PD-L1/2 expression on melanoma cell lines (CCLE, N = 61; validation cell lines, N = 7) and melanoma tumors (TCGA, N = 214). We explored in vitro how BRAF/MEKi affect rates of PD-1+, PD-L1/2+ melanoma cells, and characterized the proliferative and putative stemness features of PD-1+ melanoma cells. We tested the functional lymphocyte-independent effect of anti–PD-1 antibody alone and in combination with BRAF/MEKi in vitro and in an in vivo immunodeficient murine model. Results: PD-1 is consistently expressed on a small subset of melanoma cells, but PD-1+ cells increase to relevant rates during BRAF/MEKi treatment [7.3% (5.6–14.2) vs. 1.5% (0.7–3.2), P = 0.0156; N = 7], together with PD-L2+ melanoma cells [8.5% (0.0–63.0) vs. 1.5% (0.2–43.3), P = 0.0312; N = 7]. PD-1+ cells proliferate less than PD-1− cells (avg. 65% less; t = 7 days) and are preferentially endowed with stemness features. In vivo, the direct anti-melanoma activity of PD-1 blockage as monotherapy was negligible, but its association with BRAF/MEKi significantly delayed the development of drug resistance and tumor relapse. Conclusions: BRAF/MEKi increase the rates of PD-1+ melanoma cells that may sustain tumor relapse, providing a lymphocyte-independent rationale to explore combinatory strategies with anti–PD-1 antibody. Clin Cancer Res; 24(14); 3377–85. ©2018 AACR.
Multiple Myeloma in Russia (First Results of the Registration Trial)
Authors: Larisa P. Mendeleeva, Maxim V. Solovev, Anna Alexeeva, Ochsana Ochirova, Naida Baygishieva, Imisa Baygishieva, Svetlana Beliaeva, Tatiana V Shelekhova, Varvara Bogova, Elena Borisenkova, Irina Verkhoglyad, Valentine Molostvova, Elena Volodicheva, Elena Voronova, Valery Lapin, Elena Gribanova, Taras Gritsenko, Igor Davydkin, Olga Dianova, Marina Kosinova, Yury Dunaev, Natalia Esefyeva, Ekaterina Zotina, Anna Zarubina, Elena Kirillova, Ekaterina Kalinovskay, Yana Tsinchenko, Kamil D Kaplanov, Mariya Shirokova, Taniana Kaporskaia, Marina Kiseleva, Marina Kozmina, Tatiana Konstantinova, Ekaterina Krupkina, Elena Kuznetcova, Guzaliya Gaynullina, Ekaterina Lisina, Natalia Mashnina, Svetlana Osjnihina, Svetlana Menshikova, Mikhail Mikhalev, Olga Samoilova, Dmitry Morozov, Islam Nakastoev, Maria Novikova, Zhanna Davydova, Elena Patrakova, Natalya Popova, Natalia Rachkova, Irina Rekhtina, Marina Savinova, Tatiana Pospelova, Natalia Skvortsova, Irina Sokolova, Nadezhda Stepanova, Tatyana Sycheva, Elena Tarasenko, Ekaterina Filatova, Valeriy Voytsekhovskiy, Lyudmila Anchukova, Maria Frolova, Anna Khazieva, Elena Martynova, Evgeniy Vasiliev, Tatyana Ksenzova, Ilmil Shackirov, Valery Savchenko
Journal: Blood (2017)
Identifying treatment options for triple negative breast cancer patients using RNA-sequencing.
Authors: Gitte Pedersen
Journal: Journal of Clinical Oncology (2017)

31 Background: In the context of diagnostics, RNA is proxy for proteins and proteins are typically targets for drugs; e.g. breast cancer is typically driven by over-expression of various hormone receptors and Her2. In the current standard-of-care setting there is no measurement of mutations. Furthermore, all the markers for response to the new immune therapies are expressed as mRNA. Approximately 15% of the breast cancer patients are triple negative. Due to the poor outcome of chemo, standard-of-care guidelines (NCCN) suggests doctors encourage the patient to enroll in clinical trials. However, with more than 2000 ongoing trials in breast, which trial could potentially benefit the patient? Methods: Using the RNA-seq data from the TCGA study, we analyzed more than 120 triple negative datasets. Results: We found at least one over-expressed checkpoint inhibitor target in almost all the patients, suggesting that if you analyzed for all of the checkpoint targets, it would be possible to find a clinical study for these patients. Furthermore, when we analyzed over-expressed tumor antigens, we realized that it would be possible to design sophisticated combination trials with this information. In addition, we identified patients that were BRCAwt with an impaired DNA repair pathway; e.g. some had BRCA silencing and could potentially benefit from PARP inhibitors. Finally, a small number of patients overexpressed the androgen receptor for which there is a drug approved for prostate cancer. Conclusions: Compared to DNA analysis, tumor RNA profiling has the potential to guide a much broader set of drugs and treatment approaches including immunotherapy and chemotherapy. Messenger RNA (mRNA) analysis can reveal tumor antigens and drug targets expressed by cancer cells, as well as the vital status of the tumor microenvironment including immune response, the integrity of DNA repair mechanisms, and the engagement of angiogenesis and other cancer-related pathways.
Correction to: A statistical framework for analyzing deep mutational scanning data
Authors: Alan F. Rubin, Hannah Gelman, Nathan Lucas, Sandra M. Bajjalieh, Anthony T. Papenfuss, Terence P. Speed, Douglas M. Fowler
Journal: Genome biology (2018)

After publication of our article [1] it was brought to our attention that a line of code was missing from our program to combine the within-replicate variance and between-replicate variance. This led to an overestimation of the standard errors calculated using the Enrich2 random-effects model.
Cancer epigenetics and effector T cells in immunotherapy and chemotherapy.
Authors: Weiping Zou
Journal: Journal of Clinical Oncology (2017)

17 Background: The tumor microenvironment is comprised of immune cells that have been reprogrammed by active tumor-mediated processes to defeat tumor-specific immunity and promote tumor growth in a highly effective manner. Previous studies have helped define the nature of immune responses in the tumor microenvironment, and provide new insights into designing novel immune therapies to target the immune suppressive mechanisms including Tregs and inhibitory B7 family members (e.g. PD-L1/PD-1) and treat patients with cancer. However, the mechanisms controlling tumor immune phenotype and biological phenotype, and their relevance in cancer therapy are not well understood. Methods: Using human colon and ovarian cancer as our models, we have studied the cross-talk between immune cell subsets and tumor/stem cells, and between immunogenic and oncogenic pathways in the tumor microenvironment, and its impact on tumor immunity and therapy. Results: In patients with colon and ovarian cancer as our models, we demonstrate that Th22 cells and myeloid derived suppressor cells (MDSCs) regulate tumor stemness via epigenetic mechanisms. Furthermore, we found that histone modification and DNA methylation repress the tumor production of Th1-type chemokines, and subsequently determine effector T cell trafficking to the tumor microenvironment, affect tumor progression, and therapeutic efficacy of checkpoint blockade and adoptive T cell transfusion, chemotherapy and patient outcome. Conclusions: Epigenetic silencing of Th1-type chemokine is a novel tumor immune evasion mechanism. Selective epigenetic reprogramming alters T cell landscape in cancer and may enhance clinical efficacy of cancer therapy.
Acute Metam Sodium Poisoning Caused by Occupational Exposure at a Flower Farm — Uganda, October 2016
Authors: Susan Nakubulwa, Joy Kusiima, Daniel Kadobera, Joan N. Mutyoba, Alex R. Ario, Bao-Ping Zhu
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

On October 25, 2016, media reports alerted the Uganda Ministry of Health to an outbreak of >80 cases of vomiting, syncope, and acute diarrhea among workers at a flower farm in central Uganda; 27 workers were hospitalized. On November 1, an investigation was undertaken by the Uganda Public Health Fellowship Program.* A case-control study found that working inside greenhouse 7, which had been fumigated with the organosulfur compound metam sodium the night of October 13, was strongly associated with illness. Employees who worked in this greenhouse during October 14-21 reported a strong "suffocating" smell in the greenhouse. Investigation revealed that, in violation of safety protocols, workers did not properly cover the soil after fumigation, allowing vapors to become trapped inside the greenhouse. The farm management, unaware of the lapse, failed to inform workers to avoid the vicinity of the fumigation. Respiratory protective measures were not routinely available for workers, which likely contributed to the severity and extent of the outbreak. Although metam sodium is generally considered to be of low risk when used according to manufacturer's instructions (1), occupational exposure in the absence of recommended safety measures can have serious health consequences. The investigation highlighted the importance of identifying potential occupational hazards to workers, as well as establishing safety protocols in occupational settings, training workers at risk, such as pesticide sprayers and flower pickers,† and ensuring enforcement of safety protocols. After this outbreak, the farm management reviewed, revised, and trained the workers on safety protocols to prevent future outbreaks.