tbuckley/cabot-search huggingface dataset:
High-dimensional immune-profiling in cancer: implications for immunotherapy
Authors: Samuel Chuah, Valerie Chew
Journal: Journal for ImmunoTherapy of Cancer (2020)

Immunotherapy is a rapidly growing field for cancer treatment. In contrast to conventional cancer therapies, immunotherapeutic strategies focus on reactivating the immune system to mount an antitumor response. Despite the encouraging outcome in clinical trials, a large proportion of patients still do not respond to treatment and many experience different degrees of immune-related adverse events. Furthermore, it is now increasingly appreciated that even many conventional cancer therapies such as radiotherapy could have a positive impact on the host immune system for better clinical response. Hence, there is a need to better understand tumor immunity in order to design immunotherapeutic strategies, especially evidence-based combination therapies, for improved clinical outcomes. With this aim, cancer research turned its attention to profiling the immune contexture of either the tumor microenvironment (TME) or peripheral blood to uncover mechanisms and biomarkers which might aid in precision immunotherapeutics. Conventional technologies used for this purpose were limited by the depth and dimensionality of the data. Advances in newer techniques have, however, greatly improved the breadth and depth, as well as the quantity and quality of data that can be obtained. The result of these advances is a wealth of new information and insights on how the TME could be affected by various immune cell-types, and how this might in turn impact the clinical outcome of cancer patients . We highlight herein some of the high-dimensional technologies currently employed in immune profiling in cancer and summarize the insights and potential benefits they could bring in designing better cancer immunotherapies.
Predictive value of the modified systemic inflammation score in patients undergoing curative resection of squamous cell carcinoma of the esophagus.
Authors: Mitsuro Kanda, Masahiko Koike, Dai Shimizu, Chie Tanaka, Daisuke Kobayashi, Fuminori Sonohara, Hideki Takami, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2020)

447 Background: Inflammation plays a critical role in the development and progression of cancers. Here we aimed to evaluate the clinical significance of the preoperative modified systemic inflammation score (mSIS) to predict long-term outcomes of patients with esophageal squamous cell carcinoma (ESCC). Methods: We included 443 patients who underwent curative resection of ESCC. The mSIS was formulated according to the serum albumin level (ALB) and lymphocyte-to-monocyte ratio (LMR) as follows: mSIS 0 (ALB ≥4.0 g/dL and LMR ≥3.4), mSIS 1 (ALB &lt; 4.0 g/dL or LMR &lt; 3.4), and mSIS 2 ( ALB &lt; 4.0 g/dL and LMR &lt; 3.4). Results: Patients were categorized into preoperative mSIS 0 (n = 165), mSIS 1 (n = 183), and mSIS 2 (n = 95) groups. Preoperative mSIS was significantly associated with age, preoperative body mass index, and pathological disease stage. The disease-specific survival times of patients in preoperative mSIS 0, 1, and 2 sequentially shortened ( P = 0.009), and mSIS 2 was identified as an independent prognostic factor (hazard ratio 2.63, 95% confidence interval 1.33–5.27, P = 0.0053). In most patient subgroups, the mSIS was associated with greater risk of disease-specific death. A stepwise increase in the prevalence of hematogenous recurrences was directly proportion to the mSIS. When patients were subdivided by mSIS before neoadjuvant treatment, there were no significant differences in disease-specific survival. Conclusions: Our findings demonstrate that the preoperative mSIS may serve as a powerful prognosticator of ESCC that definitively stratifies clinical outcomes as well as a tool for selecting treatment strategies.
Epigenetic Modulation of the Tumor Immune Microenvironment to Potentiate Immune Checkpoint Blockade Therapy
Authors: Johannes Menzel, Joshua C. Black
Journal: Cancer Discovery (2020)

Abstract Summary: Response rates to immune checkpoint blockade (ICB) in KRAS-mutant lung adenocarcinoma remain poor. In this issue of Cancer Discovery, Li and colleagues report an in vivo CRISPR screen of epigenetic regulators of the tumor immune microenvironment that uncovers Asf1a as a tumor-intrinsic suppressor of ICB through suppression of GM-CSF expression. See related article by Li et al., p. 270.
Randomized phase II trial of CAPOX with continuous versus intermittent use of oxaliplatin as an adjuvant chemotherapy after curative resection of stage II/III colon cancer (CCOG-1302 study).
Authors: Masanori Nakamura, Goro Nakayama, Kiyoshi Ishigure, Naoki Mashita, Hiroyuki Yokoyama, Norifumi Hattori, Keisuke Uehara, Suguru Yamada, Masahiko Koike, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2020)

95 Background: The aim of this study was to evaluate the efficacy and safety of CAPOX with intermittent use of oxaliplatin compared to continuous use of oxaliplatin as an adjuvant setting for colon cancer. Methods: Patients with curative resection of stage II or III colon cancer were randomly assigned to receive either CAPOX with continuous use of oxaliplatin (continuous arm: 8 cycles of CAPOX) or CAPOX with intermittent use of oxaliplatin (intermittent arm: 2 cycles of CAPOX→4 cycles of capecitabine→2 cycles of CAPOX). The primary endpoints were frequency of disease-free survival (DFS) rate at 3-year after surgery and peripheral sensory neuropathy (PSN) at 1-year after surgery. The secondary end points included DFS, overall survival (OS), compliance and safety. Results: A total of 200 patients were enrolled. The intent-to-treat and safety population comprised 100 and 99 patients in the continuous arm, and 100 and 98 patients in the intermittent arm, respectively. After a median follow-up period of 39 months, disease recurrence and death occurred in 37 patients (19%) and 8 patients (4%) in the ITT population, respectively. The 3-year DFS was 78% (95% CI, 70-87%) in the continuous arm and 82% (95% CI, 74-90%) in the intermittent arm (HR, 0.80; 95% CI, 0.42-1.52; p = 0.49). In the patients with stage III disease, the 3-year DFS was 76% (95% CI, 66-86%)in the continuous arm and 80% (95% CI, 71-88) in the intermittent arm(HR, 0.75; 95% CI, 0.38-1.51; p = 0.43). The frequencies of PSF at 1-year after surgery were 58% (95% CI, 48-68%) in the continuous arm and 19% (95% CI, 11-26%) in the intermittent arm (p &lt; 0.01), and those at 3-year after surgery were 37% (95% CI, 27-47%) and 9% (3-15%), respectively (p &lt; 0.01). Conclusions: CAPOX with planned intermittent use of oxaliplatin could be equally effective as an adjuvant setting for colon cancer, and substantially reduce long-term PSN and potential improve patient quality of life. Clinical trial information: UMIN 000012535.
Emergence of RAS mutations in patients with metastatic colorectal cancer receiving cetuximab-based treatment.
Authors: Jaw-Yuan Wang, Hsiang-Lin Tsai, Yung-Chuan Sung
Journal: Journal of Clinical Oncology (2020)

208 Background: In management of patients with RAS wild-type mCRC, anti-EGFR therapies have demonstrated clinical benefit. However, the correlation between emergence of RAS mutations in circulating tumor DNA (ctDNA) and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy (NCT03401957). Methods: A total of 39 intention-to-treat (ITT) patients diagnosed with RAS wild-type mCRC, from Cathay General Hospital (CGH) and Kaohsiung Medical University Hospital (KMUH), were analyzed in this study. Of them, 24 were male and 15 were female, with median age of 55 years. Patients received cetuximab-based FOLFIRI or FOLFOX regimen as first-line treatment. Blood samples from enrolled patients were collected before and every 3 months during cetuximab-based treatment and also at disease progression. These blood samples were evaluated for RAS resistance mutations using MassARRAY platform. The primary endpoint is percentage of RAS mutations detected in ctDNA from patients during cetuximab treatment. The correlation between the tumor response of these patients and the emergence of RAS mutations in ctDNA is further analyzed. Results: Between January 2018 and July 2019, 3 (8.3%) of 36 per-protocol (PP) patients subsequently with newly detected ctDNA KRAS/NRAS mutations in their blood samples during the treatment period, and all of three patients developed progressive disease (PD). Of 36 PP patients, 19 (52.8%) patients had complete/partial response (CR/PR), 13 (36.1%) patients had stable disease (SD) and 4 (11.1%) patients had PD. The disease control rate was 88.9% in the present study. Three of 4 PD patients were detected with ctDNA KRAS/NRAS mutations in their blood sample, with time to onset of newly detected ctDNA RAS at 3 and 6 months posttreatment, respectively. Conclusions: In current study, the frequency of RAS mutations in blood samples during the treatment period was 8.3% and all of these 3 patients developed PD. The results of this study will offer substantial, valuable information for anti-EGFR therapeutic strategy in patients with mCRC.
Effect of weight loss in patients with metastatic colorectal cancer treated within the randomized phase III FIRE-3 trial (AIO KRK 0306).
Authors: Lian Liu, Nicole Tonya Erickson, Julian W. Holch, Ingrid Ricard, Alena Britta Gesenhues, Sebastian Theurich, Sebastian Stintzing, Volker Heinemann
Journal: Journal of Clinical Oncology (2020)

87 Background: A subgroup of RAS wild-type metastatic colorectal cancer patients within the FIRE-3 study consisted of 400 patients. Gaining insight into frequency and effects of weight change among patients treated with FOLFIRI plus either cetuximab or bevacizumab was aim of this analysis. Methods: A subgroup of 400 RAS wild-type metastatic colorectal cancer (mCRC) patients of the FIRE-3 trial were evaluated. Linear mixed effect models were fitted to explore the mean evolution of weight over time. The presence of a breakpoint at month 1 was investigated by the addition of an adequate parameter into the model. A linear evolution was supposed from month 1. In this exploratory analysis, patients were grouped into cohorts according to weight change using the cut off ≥ 5%. Kaplan-Meier estimations and median survival times were analyzed using log-rank testing. Hazard ratios and corresponding 95% confidence interval from univariate Cox proportional hazards were followed by a multivariate analysis. Results: Patients lost in average 0.75 kg during the first month of treatment, whereas body weight increased hereafter 0.43 kg per month. Of note, patients older than 65 years lost most body weight at month one (1.35kg) and gained least hereafter (0.20kg per month). Within this population a weight loss of ≥ 5% was observed to be an independent prognostic factor for both PFS after 3 months (HR 1.72, 95% CI 1.26-2.34, P = 0.001) and OS after 3 months (HR 1.754, 95% CI 1.29-2.39, P &lt; 0.001). This remained significant when adjusted for age, sex, ECOG score, primary tumor side and treatment arm. Conclusions: In the overall RAS wild-type population, weight loss is an independent prognostic factor for survival in patients with RAS wild-type metastatic colorectal cancer patients and may predict the frequency of adverse events. Therefore, we assume that early preventative measures targeted at weight maintenance might contribute to improved outcomes among this population.
The immunogenomic difference between Asian and non-Asian esophageal squamous cell carcinoma (ESCC) patients: An analysis of the Cancer Genome Atlas (TCGA) cohort.
Authors: Hung-Yang Kuo, Jhe-Cyuan Guo, Chia-Lang Hsu, Ta-Chen Huang, Chih-Hung Hsu
Journal: Journal of Clinical Oncology (2020)

27 Background: Recently reported global phase 3 trials of immune checkpoint inhibitor (ICI) versus second-line chemotherapy for esophageal cancer revealed that Asian population appear to obtain more benefit from ICI than non-Asian patients even in ESCC subgroups. Whether this observation could be explained by the immunogenomic difference between Asian and non-Asian ESCC remains uncertain. Methods: We retrieved the data of genetic alterations and gene expression profiling from ESCC patients of TCGA dataset, and compared the mutational profiles, immune subtypes, composition of immune cell infiltrates, and T cell-related signatures between Asian and Non-Asian patients with ESCC. Abundance of immune cell infiltrates were estimated by averaging expression values of the corresponding immune cells’ transcriptomic markers defined by Danaher et al. (J Immunother Cancer. 2017; 5:18.). The 6 immune subtypes were adopted from Thorsson et al (Immunity. 2018;48(4):812-830). The T-cell related signatures were determined by averaging the corresponding genes' expression values following previous reports. Results: We retrieved 93 patients with ESCC (Asian: non-Asian= 45: 48) from TCGA database. There is no statistical difference in overall survival between Asian and non-Asian ESCC patients. Higher mutation frequencies of TP53, NFE2L2, ZNF750, and lower mutation frequency of SMARCA4 were seen in Asian patients than in non-Asian patients. As for the immune contexture, we found that the composition of immune cell infiltrate, the distribution of immune subtypes, and a variety of T cell-related gene signatures including the 6-gene interferon-gamma signature, the 10-gene interferon-gamma signature defined by Merck or by Ribas et al, and the 13-gene inflammatory signature defined by Gajewski et al, were not significantly different between Asian and non-Asian groups. Conclusions: Our analysis failed to identify statistically significant difference in the immunogenomics of ESCC tumors between Asian and non-Asian patients in the TCGA cohort. Further immunogenomic studies focusing on patients from Asian countries with high ESCC prevalence are warranted.
Abstract 14232: Predictors of Influenza Vaccination in African American Patients With Coronary Artery Diseases and Heart Failure: Findings From a Large Urban Public Hospital
Authors: Titi Olanipekun, Valery S Effoe, Onaopepo Kola-Kehinde, Rachel Harris, Nicholas Bakinde, Claudia Fotzeu
Journal: Circulation (2018)

Introduction: Patients with cardiovascular disease including coronary artery diseases (CAD) and heart failure (HF) are vulnerable to influenza-related complications and vaccination may improve outc...
哪种用于真菌指/趾甲感染的治疗更好,是口服还是涂抹于指/趾甲的治疗?
Authors: A.K. Gupta, K.A. Foley, R.R. Mays, N.H. Shear, V. Piguet
Journal: British Journal of Dermatology (2020)

甲癣是指/趾甲的真菌感染,更有可能发生在脚趾甲上。在欧洲和北美,约 4.3% 的人发生这种感染。感染约占所有指/趾甲相关疾病的 50%。 现有口服(经口服用)和局部用药(涂抹于皮肤)的药物可用于治疗脚趾甲感染。局部治疗的成功率比口服治疗更低,但口服治疗可能产生副作用或影响其他药物的作用方式。 已发表的临床试验研究并没有直接比较口服和局部治疗。加拿大研究人员开展的这项研究旨在使用称为网络荟萃分析的统计分析来估计口服和局部治疗在真菌治愈(根除真菌感染)和不良事件(副作用)方面的可比性。 作者发现 26 项已发表的研究并包括在分析中。作者希望包括基于器械的治疗(如激光)和联合治疗,但关于这些治疗没有足够数量的随机对照试验。 结果表明,每日使用特比萘芬 250 mg 和伊曲康唑 200 mg 口服治疗与局部治疗相比明显更有可能根除真菌感染。其他口服治疗和方案在治愈真菌方面与局部治疗相似,每种治疗均好于对照组。 就副作用而言,口服和局部用药之间没有差异,这可能是因为在完成这些临床研究之后才报告口服药物的副作用。 本综述表明,患者有可用于脚趾甲真菌感染的安全口服和局部用药选择。 本摘要涉及研究:脚趾甲甲癣单药治疗:系统性综述和网络荟萃分析
Cancer Cell–Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma
Authors: Chenxi Tian, Daniel Öhlund, Steffen Rickelt, Tommy Lidström, Ying Huang, Liangliang Hao, Renee T. Zhao, Oskar Franklin, Sangeeta N. Bhatia, David A. Tuveson, Richard O. Hynes
Journal: Cancer Research (2020)

Abstract The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell–derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SERPINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell–derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell–derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets. Significance: This study provides insights into the biological roles of cancer cell–derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.
COPD clinical control as a predictor of future exacerbations: concept validation in the SPARK study population
Authors: Miriam Barrecheguren, Konstantinos Kostikas, Karen Mezzi, Steven Shen, Bernardino Alcazar, Juan José Soler-Cataluña, Marc Miravitlles, Jadwiga A Wedzicha
Journal: Thorax (2020)

The concept of chronic obstructive pulmonary disease (COPD) control has been proposed to guide treatment decisions in COPD. In this study, we aimed to validate the prospective value of this concept in the SPARK study population. Control was assessed based on COPD stability and impact. Patients with low impact and stability during weeks 1–12 were classified as controlled, and exacerbations were measured during a 52-week follow-up. Of the 2044 patients included a majority were non-controlled (80%), frequently due to high impact. During the follow-up, the rate of moderate/severe exacerbations was significantly lower in controlled patients (rate ratio, 0.56, 95% CI 0.48 to 0.65 p&lt;0.0001) and time-to-first moderate/severe exacerbation was significantly delayed. This study demonstrated an association between control status and risk of exacerbations.
Specialization of mucosal immunoglobulins in pathogen control and microbiota homeostasis occurred early in vertebrate evolution
Authors: Zhen Xu, Fumio Takizawa, Elisa Casadei, Yasuhiro Shibasaki, Yang Ding, Thomas J. C. Sauters, Yongyao Yu, Irene Salinas, J. Oriol Sunyer
Journal: Science Immunology (2020)

Mucosal immunoglobulins of primitive and modern vertebrates evolved to control pathogens and preserve microbiota homeostasis.
Skeletal muscle index (SMI) status and survival in patients undergoing surgery for colorectal cancer (CRC): A longitudinal study.
Authors: Tanvir Abbass, Ross Dolan, Stephen Thomas McSorley, Paul G. Horgan, Donald C. McMillan
Journal: Journal of Clinical Oncology (2020)

175 Background: There is now good evidence that low skeletal muscle index (SMI) using established thresholds is associated with poor survival in patients undergoing surgery for CRC. However, to date few studies have carried out longitudinal analyses. Such studies also inform, the determinants of SMI status. Methods: From prospectively maintained database, pre-operative and 1 year follow up CT scans were analysed at L3 level for SMI (n=794).The relationship between SMI status before and after surgery (both high (n=366)/high then low (n=52)/low then high (n=108) and both low (n=268), clinicopathological parameters and overall survival was analysed. Results: The majority of patients were &gt; 65 years of age (75%), male (56%), ASA&lt;3 (67%), had TNM stage &lt;3 (65%) and were not systemically inflamed (mGPS = 0 in 73%, and NLR &lt;3 in 53%). Patients with low SMI at any time point (before surgery, after surgery, or both) had significantly poorer survival (p&lt;0.001), were more likely to be over 65 years (p&lt;0.001), and with mGPS&gt;0 (p&lt;0.001) than those who had high SMI at both time points. In those patients who were high then low SMI, they had poor survival (p&lt;0.001) and were more likely &gt;65 years old (p&lt;0.001) compared with high high SMI. There was no difference in survival between those with low high SMI compared with low low SMI status (p=0.296). Conclusions: In this longitudinal study, low SMI status was associated with older age, increased systemic inflammatory response and poorer survival whether prior to or following surgery for CRC. Interestingly, surgery did not affect preoperative SMI status in the majority of patients, suggesting that host responses perhaps have a greater effect than the presence of the tumour itself. Reference: Martin L, Birdsell L, Macdonald N, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31: 1539-1547.
ESC Working Group on Coronary Pathophysiology and Microcirculation position paper on ‘coronary microvascular dysfunction in cardiovascular disease’
Authors: Teresa Padro, Olivia Manfrini, Raffaele Bugiardini, John Canty, Edina Cenko, Giuseppe De Luca, Dirk J Duncker, Etto C Eringa, Akos Koller, Dimitris Tousoulis, Danijela Trifunovic, Marija Vavlukis, Cor de Wit, Lina Badimon
Journal: Cardiovascular Research (2020)

Although myocardial ischaemia usually manifests as a consequence of atherosclerosis-dependent obstructive epicardial coronary artery disease, a significant percentage of patients suffer ischaemic events in the absence of epicardial coronary artery obstruction. Experimental and clinical evidence highlight the abnormalities of the coronary microcirculation as a main cause of myocardial ischaemia in patients with 'normal or near normal' coronary arteries on angiography. Coronary microvascular disturbances have been associated with early stages of atherosclerosis even prior to any angiographic evidence of epicardial coronary stenosis, as well as to other cardiac pathologies such as myocardial hypertrophy and heart failure. The main objectives of the manuscript are (i) to provide updated evidence in our current understanding of the pathophysiological consequences of microvascular dysfunction in the heart; (ii) to report on the current knowledge on the relevance of cardiovascular risk factors and comorbid conditions for microcirculatory dysfunction; and (iii) to evidence the relevance of the clinical consequences of microvascular dysfunction. Highlighting the clinical importance of coronary microvascular dysfunction will open the field for research and the development of novel strategies for intervention will encourage early detection of subclinical disease and will help in the stratification of cardiovascular risk in agreement with the new concept of precision medicine.