tbuckley/cabot-search huggingface dataset:
High frequency of c-KIT genetic variants in exons 9, 11, 13 and 17 and PDGFRA in exon 18 in gastric GIST tumors.
Authors: Ekaterina P. Omelchuk, Dmitry Yu. Gvaldin, Natalya N. Timoshkina, Liubov Yu Vladimirova, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Dmitry A. Kharagezov, Andrey V. Dashkov, Dmitry O. Kaymakchi, Sergey I. Poluektov, Vladimir E. Kolesnikov, Vladimir A. Dontsov, Roman E. Tolmakh, Sergei A. Ilchenko, Oleg N. Stateshny, Dmitry S. Petrov, Fedor N. Grechkin, Nairi B. Oganyan, Valeriy V. Kolesnikov, Ellada Mirzoyan
Journal: Journal of Clinical Oncology (2020)

e23525 Background: Gastrointestinal stromal tumors (GIST) are rare malignant mesenchymal neoplasms of the gastrointestinal tract, the diagnosis and treatment of which is associated with the presence of mutations in the c-KIT and PDGFRA genes. Purpose of this study was molecular genetic genotyping of GIST according to clinically significant exons of the c-KIT and PDGFRA genes. Methods: The study included patients with an immunohistochemically confirmed diagnosis of GIST who underwent treatment in the RRIO, Rostov-on-Don, for the period 2018-2019 (n = 20, median age 63.5 years, men/women–10 people each, gastric tumors). DNA was isolated from FFPE tissue using the GeneJET FFPE DNA Purification Kit, USA. The presence of mutations in exons 9, 11, 13 and 17 of c-KIT and exon 18 of PDGFRA was detected by Sanger sequencing. Results: Activating mutations in exon c-KIT were detected in 10 ps, including one substitution p.V560E and 4 deletions – p.V559_E561del, p.M552_V555delMYEV, p.W557_V559 &gt; F and p.W557_V559 &gt; C. These mutations cause sensitivity to imatinib. Pathogenic mutations were detected in PDGFRA exon 18: an activating deletion p.I843_D846delIMHD (2 ps) and a substitution p.D842Y, which determines imatinib resistance (2 ps). Thus, 20% of GIST cases are promising for obtaining avapritinib, the first FDA approved drug in 2020 for patients with GIST with a mutation in PDGFRA exon 18. In addition, neutral genetic variants were revealed: in 17 exon c-KIT in 16 patients, benign rs1008658, in PDGFRA 18 exon – rs3830355 (3 ps) and silent mutation p.V824V (3 ps). Conclusions: Genotyping of c-KIT and PDGFRA identified 12 types of clinically significant mutations and, in 80% of cases, the carriage of benign polymorphisms and / or SNPs of unknown clinical significance. As a result, 70% of patients from the South of Russia with GIST may be sensitive to treatment with imatinib and/or avapritinib.
Pathophysiology foundation and clinic management of dyspnea
Authors: Haichao Li
Journal: BMJ (2017)

呼吸困难是一组病因和发病机制不尽相同的呼吸不适的主观感受，呼吸困难受生理、心理、社会和环境因素的影响，其发生机制尚不完全清楚。呼吸困难特征的3种常见类型分别是呼吸用力/费力、空气饥饿感和胸闷，同一患者可有多种机制参与。呼吸困难的病因主要包括呼吸系统源性、心血管系统源性以及心因性疾病。与呼吸系统源性呼吸困难发生相关的主要环节包括呼吸中枢、呼吸泵和气血交换。心血管源性呼吸困难的主要原因包括心力衰竭、贫血和去适应。对呼吸困难病理生理机制的理解有助于呼吸困难的临床诊断和鉴别诊断以及对呼吸困难的正确处理。
Effect of changes in body composition and islet β-cell function on bone mineral density in obese women with normal glucose metabolism at child-bearing age
Authors: Sun-jie Yan, Mei-rong Li, Xi-mei Shen, Li-yong Yang, Song-jing Zhang, Ru-hai Yi, Xiao-fang Yan
Journal: BMJ (2009)

Objective To investigate effects of changes in body composition and pancreas islet β-cell function on bone mineral density(BMD)in obese women with normal glucose metabolism at child-bearing age.Methods Ninety-five obese women with normal blood glucose at child-bearing age were recruited for the study,20 in non-obese group with body mass index(BMI)less than 23,20 in overweightgroup with BMI equal to or more than 23 and less than 25.28 in obesity Ⅰ group with BMI equal to or more than 25 and less than 30.and 27 in obesity Ⅱ group with BMI equal to or more than 30.Their BMD,body fat and lean mass were measured with by dual energy X-ray absorptiometer(DEXA),and intravenous -glucose tolerance test(IVGTT)was performed.Area under the Curve of insulin(AUCins)and acute jnsulin response(AIR)phase were calculated to assess their early insulin secretion.Homeostasis model assessment β-cell function index(HOMA2-%B)and homeostasis model insulin resistance index(HOMA2-IR)were used to assess their β-cell function and insulin resistance.Results Fat and lean mass in the upper and lower extremities.trunk and whole body and BMD in those women increased with increasing of their BMI(P＜0.05),particularly in fat mass.as well as their otller parameters including plasma insulin level at zerominute of IVGTT(IVGTTins0),AUCins.HOMA2-%B and HOMA2.IR(all P＜0.01).BMD in the upper and lower extremities,trunk and whole body showed a positive correlation with BMI,FPG,lean mass and/or fat mass.respectively(P＜0.05).BMD of the trunk and whole body also had a positive correlation with TVGTTins0,AIR,AUCins and HOMA2-IR.respectively(P＜0.05).Results of multivariate linear regression analysis showed that HOMA2-%B and HOMA2-IR correlated with BMD in a linear pattern.As the vailable body composition was added to the regression model.HOMA2 parameters would be removed from the model.Results of partial correlation analysis showed that islet β-cell function did not correlate with BMD after controlling body composition factors.Conclusions Insulin resistance or islet β-cell function compensation accompanied in obese women with main increase in fat mass have little benefit for their BMD,which may reflect indirectly their change in body compositions.Body composition,especially lean nlass,is the most important determinants of BMD in obese women.

Key words: 
Obesity; β-cell function; Body composition; Bone mineral density
Value of postoperative pelvic four-contrast defecography in the patients with outlet obstructive constipation
Authors: Qing-yun Long, Jin-xiang Hu
Journal: BMJ (2010)

Twenty two patients with outlet obstructive constipation (OOC) underwent pelvic fourcontrast defecography preoperatively and postoperatively. Functional outcome and the findings on defecography were analyzed. The inconsistent signs between preoperative and postoperative defecography findings were shown in all patients. Some new abnormal findings, including 5 cases with pelvic floor hernia, 4 with cystocele, 4 with vagina prolapse, 3 with uterine prolapse,2 with rectal prolapsed and 1 with spastic pelvic floor syndrome were present in 5 patients with ineffective surgical treatment and 9 patients with effective surgical treatment. Reduced abnormal signs were showed in the 9 effective patients, but other new abnormalities appeared. The abnormal signs were reduced or disappeared in 8 obviously effective patients and there were no new abnormalities present in those patients. Results indicate that pelvic four-contrast defecography can provide valuable information for patients with OOC postoperatively.

Key words: 
Defecography;  Constipation
FOLFIRINOX de-escalation in advanced pancreatic cancer (aPC): A multicenter real-life study.
Authors: Hortense Chevalier, Angélique Vienot, Astrid Lièvre, Julien Edeline, Farid El Hajbi, Charlotte Peugniez, Dewi Vernerey, Aurelia Meurisse, Pascal Hammel, Cindy Neuzillet, Christophe Borg, Anthony Turpin
Journal: Journal of Clinical Oncology (2020)

4639 Background: FOLFIRINOX (5FU, irinotecan, and oxaliplatin) is a reference first line (L1) of chemotherapy (CT) in fit patients (Pts) with advanced pancreatic cancer (aPC). Limiting toxicities (in particular, neuropathy) are frequent and maintaining quality of life without a lack of efficacy is a crucial need. Modalities and efficacy of maintenance strategy in aPC remain scarcely studied. Our study describes the French practices of a FOLFIRINOX de-escalation and maintenance in a real-life multicentric cohort. Methods: We performed a retrospective multicentric study in 5 French centers. Pts receiving FOLFIRINOX L1 for aPC were recruited between January 2011 and December 2018. FOLFIRINOX de-escalation was defined as stopping oxaliplatin and/or irinotecan in patients without tumor progression, after at least 4 cycles of FOLFIRINOX. Maintenance schedules were oral capecitabine or intravenous (IV) 5FU, FOLFOX or FOLFIRI. Primary endpoint was overall survival (OS). Secondary endpoints were first progression-free survival (PFS1) and, in case of reintroduction of FOLFIRINOX, second progression free survival (PFS2). OS and PFS were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Among the 321 patients included, 147 (46%) received a maintenance therapy. Median age was 60.0 (53-66), 35 (24%) had locally advanced PC and 91 (62%) had metastatic PC. The median number of cycles of FOLFIRINOX was 9.0 (6.0-11.0). Median OS was 16.1 months (95%CI=13.7-20.3). Median PFS1 was 9.4 months (95%CI=8.5-10.4). The preferred maintenance regimen was FOLFIRI in 66 (45%), vs fluoropyrimidine (FP) in 52 (35%) and FOLFOX in 25 (17%). Among 118 Pts who received a maintenance CT with FP or FOLFIRI, there was no difference in PFS1 (median: 10.1 vs 9.0, respectively, p=0.33) or OS (median: 16.6 versus 18.7, p=0.86) between the 2 maintenance regimens. After progression under maintenance CT with FOLFIRI or FP, reintroduction of FOLFIRINOX was performed in 20.2% of Pts, with a median PFS2 of 2.8 months (95%CI=2.0-22.3). The rates of G3-4 toxicity were significantly higher during FOLFIRI maintenance CT than with FP (41% vs 22%, p=0.03), especially neuropathy (73% vs 9%). Conclusions: FOLFIRINOX de-escalation in aPC is largely used in France. Fluoropyrimidine maintenance chemotherapy appears to be as effective as FOLFIRI.
Evaluation of safety, immunogenicity, and preliminary efficacy of PolyPEPI1018 off-the-shelf vaccine with fluoropyrimidine/bevacizumab maintenance therapy in metastatic colorectal cancer (mCRC) patients.
Authors: Joleen Marie Hubbard, Chiara Cremolini, Rondell P. Graham, Roberto Moretto, Jessica L Mitchell, Jaclynn Wessling, Eniko Rita Toke, Zsolt Csiszovszki, Orsolya Lőrincz, Levente Molnar, Eszter Somogyi, Mónika Megyesi, Kata Pantya, József Tóth, Péter Páles, István Miklós, Alfredo Falcone
Journal: Journal of Clinical Oncology (2020)

4048 Background: PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 cancer testis antigens (CTAs) frequently expressed in patients with CRC. Here we report the final results of the phase I study of PolyPEPI1018 vaccine as an add-on to maintenance therapy in mCRC patients. Methods: 11 patients with MSS mCRC were vaccinated with PolyPEPI1018 just after the transition to maintenance therapy with fluoropyrimidine/bevacizumab after first-line combo chemotherapy and bevacizumab. Part A: n = 5, single dose; Part B: n = 6, 3 doses, Q12W. Primary endpoint was safety. Immunomonitoring was performed at both blood and tumor levels, as well as prospectively predicted. Results: The vaccine was well tolerated; most common side effects were transient skin reactions. No vaccine-related SAE occurred. Pre-existing immune responses were boosted by the vaccine for 7/10 patients. De novo responses were also induced, overall, 80% of patients had CD8+ T cell responses against at least 3 CTAs. The magnitude of immune responses as well as the density and the ratio of CD8+/CD3+ tumor infiltrating T cells increased with multiple vaccine doses. Three patients had objective tumor response according to RECIST v1.1: one of them in the single dose group and two of them in the 3 doses group. Both patients in the 3 doses group qualified for curative surgery. One of them had no viable tumor cells in his primary tumor at the time of surgery. Post-trial follow-up revealed PFS of at least 12 months for 3 patients. mPFS was longer for patients receiving multiple doses (9.9 months) compared to single dose (6.1 months). Both measured and predicted multiantigenic immune responses tend to correlate with PFS and tumor volume reduction. Conclusions: PolyPEPI1018 was effective in restoring immunological responses to CTAs in patients’ with spontaneous immunity against. Treatment with PolyPEPI1018 vaccine and maintenance therapy was safe and demonstrated evidence of early clinical activity in MSS mCRC tumors. Data support further randomized trials with PolyPEPI1018. Clinical trial information: NCT03391232 .
Outcome of locally advanced carcinoma of oesophagus: A single institution experience.
Authors: Thianeshwaran S, Sriniivas Bj, Niyati Prakash Sanghavi, Vinu Sarathy, Bhanu Prakash Lalkota, Kiran PK, Nitin Byas, Mansi Shah, Madhusudhan N, Hrishi Varayathu, Lalnun Puii, Diganta Hazarika, Suhail Sayeed Mufti, Basavalinga Sadasivaiah Ajaikumar, Naik Radheshyam
Journal: Journal of Clinical Oncology (2020)

e16507 Background: Oesophageal cancer is the twelfth most common cancer worldwide and seventh leading cause of cancer related death. Neoadjuvant treatment in addition to surgery has shown improved overall survival compared to surgery alone in resectable oesophageal cancer. We aimed to analyse the survival outcome among locally advanced oesophageal carcinoma patients in neoadjuvant setting. Methods: We analysed 37 patients with locally advanced carcinoma of oesophagus from 2015 to 2019 who underwent neoadjuvant chemoradiotherapy followed by surgical excision of tumour. Descriptive analysis was used for demographic data. overall survival and disease free survival was analysed using Kaplan-Meier survival analysis. Results: Our study includes 20 males (54%) and 17 females (45%). Over all consumption of Tobacco and alcohol consumption was found to be 64% and 18% respectively. The most common tumour site in this study was middle oesophagus (56%) followed by lower (37%) and upper (5%). Histopathologically, moderately differentiated squamous cell carcinoma constituted the highest (62%), followed by well differentiated squamous cell carcinoma (21%) and poorly differentiated carcinoma (16%). The pathological stage post chemoradiotherapy was 80%, 50% and 57% for stage I, II and III respectively. Median over all survival is 60 months and no statistical difference in stage I and stage II. Median over all survival for poorly differentiated squamous cell carcinoma is 16 months and lower one third of squamous cell carcinoma is 37 months. Complete pathological response is 42 %. Conclusions: Our study concluded that patients with tobacco and alcohol consumption have poorer survival. Prognosis was worst for patients with lower end oesophagus and poorly differentiated type. Disease free survival was better for patients who achieved complete pathological response when compared to partial responders.
Trial in progress: A phase I study of AMG 199, a half-life extended bispecific T-cell engager (HLE BiTE) immune therapy, targeting MUC17 in patients with gastric and gastroesophageal junction (G/GEJ) cancer.
Authors: Joseph Chao, Elvira Buxó, Andrés Cervantes, Farshid Dayyani, Caio Max Sao Pedro Rocha Lima, Richard Greil, Hanneke W.M. Van Laarhoven, Sylvie Lorenzen, Volker Heinemann, Roman Kischel, Kohei Shitara, Florian Lordick
Journal: Journal of Clinical Oncology (2020)

TPS4649 Background: Prognosis for advanced G/GEJ cancer is poor and new treatment modalities are urgently needed. MUC17 is a transmembrane protein overexpressed and differentially localized on the cell membrane of G/GEJ cancer cells; expression and localization in normal cells is much more limited. AMG 199 is an HLE BiTE immune therapy designed to engage CD3-positive T cells to MUC17-positive G/GEJ cancer cells, mediate redirected tumor cell lysis, and induce T cell activation and proliferation. A clinical trial is being conducted for this novel and targeted immune therapy agent in patients with MUC17-positive G/GEJ cancer. Methods: This is a first-in-human phase 1, open-label, dose escalating study (NCT04117958) evaluating AMG 199 in patients with MUC17-positive G/GEJ cancer. Key eligibility criteria include metastatic or locally advanced unresectable MUC17-positive (as determined by IHC using a central laboratory assay) gastric adenocarcinoma or gastroesophageal junction adenocarcinoma ineligible for curative surgery and relapsed or treatment-refractory following ≥2 lines including a platinum, a fluoropyrimidine, taxane or irinotecan, and an approved vascular endothelial growth factor receptor antibody or tyrosine kinase inhibitor. Patients eligible for human epidermal growth factor receptor 2 (HER2) directed therapy should have received an approved HER2 targeting antibody. Primary endpoints include: dose-limiting toxicities, treatment-emergent or -related adverse events, vital signs, electrocardiogram (ECG), and laboratory changes. Secondary endpoints include: pharmacokinetics of AMG 199, objective response, duration of response, time to progression, 6-month and 1-year progression-free survival, and 1-year and 2-year overall survival. The dose exploration (n = 30) will estimate the maximum tolerated dose and/or recommended phase 2 dose; this will be followed by a dose expansion (n = 40) and evaluation of the benefit/risk profile of AMG 199. The study began enrolling patients in January 2020 and is ongoing. This is the first clinical trial to investigate MUC17 as a potential anti-tumor target. For more information, please contact Amgen Medical Information: medinfo@amgen.com . Clinical trial information: NCT04117958 .
Contribution of specific diseases and injuries to changes in health adjusted life expectancy in 187 countries from 1990 to 2013: retrospective observational study
Authors: 陈鹤, 陈功, 郑晓瑛, 郭岩
Journal: BMJ (2019)

目的
分解和比较1990—2013年306种疾病和伤害对全球187个国家出生时健康调整预期寿命（Health-adjusted life expectancy at birth，HALE0）变化的贡献。


研究设计
回顾性人口学分析，使用了全球疾病负担研究（Global Burden of Diseases，GBD）提供的死亡率和伤残损失生命年率等公开数据，运用了生命表技术、苏利文方法、健康寿命差异分解方法等人口学分析技术。


研究地点
GBD 2013中涵盖的全球、21个地区和187个国家。


研究对象
GBD 2013中187个国家的人口。


主要结局指标
以死亡效应、残疾效应和总效应显示的各种原因对1990—2013年间HALE0变化的贡献。


结果
在1990—2013年，全球HALE0在男性中增长了5.31年，女性中增长了5.73年。国家间HALE0的基尼系数从0.073 6降低为0.062 4，幅度为15.22%。11个国家出现了HALE0下降。除了伯利兹、白俄罗斯和巴拉圭之外，HALE0下降主要是由HIV/AIDS造成的。控制传染病、孕产妇疾病、新生儿疾病和营养类疾病是HALE0增长的最主要原因（56.47%；3.10年），其后是非传染性疾病（NCDs）（30.05%；1.65年）和伤害（13.67%；0.75年）。同时，HIV/AIDS（-0.28年）和糖尿病（-0.12年）对HALE0变化的消极影响最大。HIV/AIDS的负面影响集中在南、西和东部撒哈拉以南非洲，而糖尿病的负面影响则遍及全球21个地区。尽管缺血性心脏病、脑血管病和高血压心脏病等NCDs在高收入地区对HALE0变化具有积极的总效应，但在许多中低收入地区却具有消极的总效应。死亡率下降是HALE0改善的主要原因（5.14年，93.62%），并伴随着出生时带残预期寿命的增长（0.80年）。在层3的163个原因中，只有44个（26.99%）主要通过或仅通过残疾效应影响HALE0变化。


结论
1990—2013年，全球在促进整体人口健康和减少国家间健康不平等方面都取得了一定的成就。在健康政策制定方面，本研究确定了扭转11个国家健康颓势、遏制中低收入国家NCDs流行以及促进全球疾病压缩的疾病和伤害优先干预对象。研究还提供了人口健康变化的疾病和伤害国别分解结果，将会为各国制定政策提供支持。
Abstract 3329: Myocardial Loss of Ets2 Results in Dilated Cardiomyopathy in Adult Mice
Authors: Nata Y Diman, David C Wilkes, Jinghua Chen, Cathy J Hatcher, Trevor J Wilson, Craig T Basson
Journal: Circulation (2009)

Ets2 is a member of the ETS transcription factor gene family. Ets factors regulate the expression of genes encoding cell-cycle regulators, matrix metalloproteinases, cytokeratins, adhesion molecule...
MLsurvival: an automated machine learning tool for survival analysis of cancer patients.
Authors: Wei Zhou, Ji He
Journal: Journal of Clinical Oncology (2020)

e13555 Background: Survival analysis is used to establish a connection between covariates and the time of event with censored data. Compared with traditional statistical methods, machine learning approaches based on sophisticated and effective computational algorithms are more capable for handling complex multi-dimensional medical data. Methods: We developed an automated machine learning tool MLsurvival to analyze survival data of cancer patients, algorithms of which include the statistical cox regression and machine learning based on linear model (elastic net), ensemble model (gradient boosting with least squares or regression trees and random forest) and support vector kernel (linear and non-linear). The workflow of MLsurvival is comprised with four modules: preprocessing (missing data remove or imputation and feature standardization), feature selection (unsupervised multi-statistics and supervised machine recursive feature elimination with cross-validation), modeling (hyperparameter and performance evaluation) and prediction. To evaluate the performance of this tool, we analyzed medical data for 222 hepatocellular carcinoma (HCC) patients at stage II-III who underwent surgical resection and developed five machine learning approach based estimation models for overall survival (OS). Models were trained on 155 patients with 300 features, including clinical information, somatic mutation and copy number variation, and independently validated on the rest 67 patients. Results: The ensemble model of gradient boosting fitted by MLsurvival using 48 selected features for the data of 155 HCC patients possessed the highest mean AUC and C-Index value. For 67 patients in validation set, this model predicted half year mortality of patients with an AUC of 0.9 (95% CI, 0.771-1.029) and one year mortality with an AUC of 0.897 (95% CI, 0.816-0.978). In addition to that, this model was also predictive for the time of recurrence (pvalue &lt; 0.0001). Furthermore, we also utilized this tool in survival analysis for extensive real data from patients with breast, lung, and esophagus cancers, while most of results showed superior accuracy and stable performance. Conclusions: MLsurvial is an automate tool for survival analysis of cancer patients with well performance. The risk scoring system implemented in this tool offers a novel strategy for incorporating multi-dimensional risk factors to predict clinical outcome, contributes to the better understanding of disease background and helps to optimize the clinical follow-up and therapeutic treatment for cancer patients.