tbuckley/cabot-search huggingface dataset:
Response to: ‘Clinical course of COVID-19 in patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine’ by Carbillon <i>et al</i>
Authors: Maximilian F Konig, Milena Gianfrancesco, Jinoos Yazdany, Philip C Robinson
Journal: Annals of the Rheumatic Diseases (2020)

We thank Carbillon et al for their correspondence.1 The use of hydroxychloroquine (HCQ) in pregnant women with systemic lupus erythematosus (SLE) is not controversial.2 3 Similar to its primary role in the prophylaxis and treatment of SLE, discontinuation of HCQ in pregnancy has been linked to increased disease activity and glucocorticoid use in women with lupus.4–6 Given its benefit and preferable safety profile, the continuation of baseline HCQ therapy in pregnant women with lupus is recommended to maintain disease remission,2 3 regardless of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) status. In contrast, there is currently no evidence to suggest that baseline use of HCQ in pregnant women with lupus is protective of SARS-CoV-2 infection or severe COVID-19.

The authors adequately summarise our findings …
以积极心态和处理技巧面对情绪化的病人和家属
Authors: 王滟
Journal: BMJ (2012)

临床思维是医疗诊治工作的核心,医生采集并判断病人的主诉症状、体征,去伪存真,分辨主次及其间的相关性,同时参考各种检测结果,结合自己的专业知识和临床工作经验,做出正确的诊断和治疗.在现代医学模式要求医生关注病人的精神心理健康的同时,医疗工作本身也要求医生要有很高的心理品质.良好的心理环境是医生工作所必需的,但临床实际工作中往往会遇到各种来自病人或家属的干扰,医生应该如何应对,以顺利完成正常的医疗工作呢?
Analysis of germline mutations in Chinese colorectal cancer patients with next-generation sequencing.
Authors: Jing Gao, Hua Ren, Haiyan Liao, Luo Hai, Yuwei Cong, Xiaochen Zhao, Yuezong Bai
Journal: Journal of Clinical Oncology (2020)

e13651 Background: Colorectal cancer (CRC) remains one of the leading causes of morbidity and mortality around the world. Familial cancer syndromes are common in CRC, inherited syndromes including Lynch syndrome (LS), familial adenomatous polyposis (FAP), and MutY human homolog (MUTYH)-associated polyposis (MAP) were well defined. But still, there are not well-established evidence between other several genes and CRC risk. Expanded multi-gene testing may be an alternative to find out the underlying mechanism for genetic susceptibility. Our study aims to assess the germline alternation landscape of Chinese CRC patients. Methods: We performed hybrid capture-based next-generation sequencing (NGS) of 381 genes on tissues from patients with CRC between January 01, 2017 and December 02, 2019 in 3D Medicines database. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: 1360 CRC patients were included for analysis, in which 95 (7.0%) patients harbored pathogenic (80/95) and likely pathogenic (15/95) germline mutations in 28 cancer predisposition genes. 33 subjects had pathogenic variants associated with Lynch syndrome (15 mutations in MLH1, 9 mutations in MSH2, 6 mutations in MSH6, 3 mutations in PMS2, respectively). 8 subjects had pathogenic variants associated with FAP (3 APC), MAP (3 MUTYH) and Li-Fraumeni syndrome (2 TP53). In addition, 14 pathogenic mutations in moderate penetrance genes (5 ATM, 3 BLM and 6 CHEK2) were found. The frequency of pathogenic BRCA mutations were 1 alternation in BRCA1 and 3 alternations in BRCA2. Conclusions: 7.0 % of patients with Chinese CRC carried germline cancer susceptibility gene mutations. Multi-gene testing would provide references for assessing genetic susceptibility and managing increased surveillance.
Development of inclusion criteria of community-based palliative care
Authors: Ruiyun Zhang, Wenqun Cao, Jun Miao
Journal: BMJ (2019)

Objective
To explore the inclusion criteria of community-based palliative care service.


Methods
From July 2017 to September 2017, three rounds of Delphi consultation for development of inclusion criteria of community-based palliative care was conducted. With judgment sampling method, 23 senior executives and managers from 6 pilot units of palliative care service in Shanghai were selected and invited to participate in the consultation, which included the importance, coercion and completeness of the inclusion criteria. According to the consulting results, the inclusion criteria of community palliative care services was developed.


Results
The median age of experts was 35 years (29-55 years, with a quartile spacing of 7 years). The average working experience of experts was (13.7±7.5) years, in which that for palliative care was (4.1±1.6) years. The authority coefficient was 0.82, and the Kendall coordination coefficient was 0.337 (P<0.01) for the importance of inclusion criteria. In the developed criteria, the four mandatory inclusion criteria were patient needs, the provision ability of community health service centers, compliance with legal requirements and compliance with the concept of palliative care service; and the five non-mandatory inclusion criteria were heavy needs and demands, high cooperation from patients and their families, high satisfaction of patients and their families, within the scope of community health service centers and clinical guidelines for the operations.


Conclusion
The experts of this research have high enthusiasm and authority, and the developed inclusion criteria of community palliative care service contents are reasonable and feasible. This studymay provide reference for setting up the contents adjustment mechanism of community-based palliative service.


Key words: 
Delphi technique; Community health services; Palliative care
Immunogenomic classification of gastric cancer based on the tumor microenvironments expression of PD-L1 and CD8+ T-cell infiltration.
Authors: Yu Chen, Gang Chen, Jia-ni Xiong, Bin Lan, Xuan Gao, Liu Jun, Jin Lin, Yaping Xu, Yan-Fang Guan, Ling Chen, Li-zhu Chen, Xuefeng Xia, Zengqing Guo
Journal: Journal of Clinical Oncology (2020)

e16578 Background: Previous data has shown that a positive response to immunotherapy usually relies on active interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). The aim of this study was to classify gastric cancer (GC) subsets based on the TME immune status according to the expression of PD-L1 and infiltration of CD8+ T cells. Methods: One hundred and eighty-six tumor tissue from gastric cancer patients with a curative D2 gastrectomy were examined for evaluating PD-L1 and CD8+ T cells status using histopathologic analysis. The molecular characteristics of 289 GC samples in TCGA network were further analyzed to distinguish the genetic features of four immune subtypes depending on the presence of PD-L1/CD8+T cell. Results: GC samples were categorized into four types, type I (CD8+/PD-L1+, 60.3%), II (CD8-/PD-L1-, 11.8%), III (CD8-/PD-L1+, 0%), and IV (CD8+/PD-L1-, 27.9%), basing on PD-L1/CD8 expression. The PD-L1 expressing level was geographically associated with the intensity of CD8+ T cell infiltration which was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.003 and p = 0.006). Distinct patterns of genetic profile were described in four types of GC from TCGA database. Type I and III which PD-L1 were overly expressed had comparatively higher MSI and TMB, with EBV mainly enriched in Type I, whereas CIN was more likely to occur in PD-L1 aberrant types II and IV. SNV analysis illustrated higher gene mutations in oncogenes (PIK3CA and ERBB2), and in DNA damage repair related pathway, such as PRKDC, ATM, and SWI/SNF complexes (e.g. ARID1A) in Type I. However, TP53 mutations tend to enrich in Type II and IV. Similar results were obtained by transcriptome analysis. Conclusions: The genetic features of four immune subtypes proof that PD-L1 and CD8+ T cells status are reasonable immunogenomic classification of gastric cancer. SNV analysis prompts a potential mechanism for effectiveness of immunotherapy in Type I patients. Overall, the results may be useful for the development of clinical treatments for the blockade of immune checkpoints.
在工作中体现人文关怀
Authors: 曾昭耆
Journal: BMJ (2012)

医学是高科技与人文科学的高度结合体,近年高科技成果的发展却使医生对医学的人文特性的观念逐渐淡化.医生的行为举止、语言表达、对待病家的态度和沟通技巧能力等对疾病、医疗结果等都有重要影响,医生应加强个人的医德素养,端正医风,提高对临床医学社会性和人文性的认识.当前医患矛盾原因复杂,医生加强人文观念更显重要.加强我国医学人文教育刻不容缓。
企业开展全科医师岗位培训模式探讨
Authors: 李秀搂, 张凯, 陈英
Journal: BMJ (2004)

为了提高基层医务人员理论知识和技能水平,满足社区卫生服务的人才需求,我们利用企业三甲医院和医学院临床教学医院的优势,根据医生要求和社区卫生服务工作实际需要,与卫生部全科医学培训中心联合举办了两期全科医师岗位培训班,报告如下。
Phase Ib trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy and a CDK4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC).
Authors: Seth Andrew Wander, Dejan Juric, Jeffrey G. Supko, Douglas Scott Micalizzi, Laura Spring, Neelima Vidula, Maureen Beeler, Karleen R. Habin, Elene Viscosi, Donna Michelle Fitzgerald, Lauren Scarpetti, Elizabeth Tripp, Rachel Hepp, Beverly Moy, Steven J. Isakoff, Leif W. Ellisen, Aditya Bardia
Journal: Journal of Clinical Oncology (2020)

1066 Background: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), with an anti-estrogen, are the standard of care for HR+/HER2- MBC. Insights from patient biopsies and preclinical analysis suggest that AKT1 activation can provoke CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may provide clinical benefit. Methods: TAKTIC is an open-label phase Ib trial exploring the combination of the AKT1 inhibitor, ipatasertib (ipat), with an aromatase inhibitor (Arm A), fulvestrant (Arm B), or the triplet combination (Arm C) of fulvestrant + ipat + palbociclib (palbo). The primary objective is to evaluate the safety and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an interim analysis from the triplet combination (Arm C). Results: As of 1/31/2020, 25 pts have enrolled, including 12 on Arm C, all of whom received prior CDK4/6i (median no of prior lines = 5.5, range 2-7). Along with fulvestrant, 3 pts received ipat at 200mg + 125mg palbo, 7 pts received 300mg + 125mg palbo, and 2 pts received 400mg + 100mg palbo. To date, 8/12 pts remain on treatment including 2 with partial response, 3 with stable disease, 3 with restaging studies pending and 4 with progressive disease. The triplet combination was well tolerated. Grade 3 toxicities included reduced WBC (8/12), reduced neutrophil count (11/12), reduced lymphocyte count (2/12) and single instances of transaminitis, rash, and reduced platelet count. The only grade 4 toxicity was reduced neutrophil count (4/12). There were no DLTs observed and no discontinuations due to toxicity. Mean steady state pharmacokinetic parameters for ipat were similar to historical data from single agent trials suggesting that combined treatment with palbo + fulvestrant did not affect the pharmacokinetics of ipat. Updated analysis will be presented at the meeting. Conclusions: The triplet combination of endocrine therapy with CDK 4/6i and AKTi appears to be well tolerated in heavily pre-treated pts, with a subset demonstrating signs of clinical benefit. The trial demonstrates how insights into the molecular mechanisms of CDK4/6i resistance could be leveraged into actionable therapeutic regimens for HR+/HER2- MBC. Clinical trial information: NCT03959891 .
A phase Ia/Ib, dose-escalation/expansion study of BI 907828 in combination with BI 754091 and BI 754111 in patients (pts) with advanced solid tumors.
Authors: Anthony W. Tolcher, Navid Hafez, Noboru Yamamoto, Jaehong Park, Rolf Grempler, Anthony G. Lucarelli, Mehdi Lahmar, Bushi Wang, Mrinal M. Gounder
Journal: Journal of Clinical Oncology (2020)

TPS3660 Background: Preclinical data show that the combination of a murine double minute 2–tumor protein 53 (MDM2–TP53) antagonist with anti-PD-1 and anti-LAG3 antibodies produces an anti-tumor effect in multiple tumor types. This Phase Ia/Ib study aims to determine the safety, recommended dose for expansion (RDE), and preliminary efficacy of BI 907828, a MDM2–TP53 antagonist, with BI 754091, an anti-PD-1 antibody, and BI 754111, an anti-LAG-3 antibody, in a variety of TP53 wild-type cancers. Methods: In Phase Ia (dose escalation), ~30 pts with a confirmed diagnosis of any unresectable, advanced/metastatic solid tumor, irrespective of TP53 mutation status, will be enrolled. Pts will receive one dose of BI 907828 every 21 days (Q3W), at a starting dose of 10 mg orally, plus BI 754091 and BI 754111 (240 mg and 600 mg, respectively, Q3W, intravenously). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control. The primary endpoint is the maximum-tolerated dose of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle. Secondary endpoints include pharmacokinetics and DLTs in the treatment period (to determine the RDE). In Phase Ib (dose expansion), pts with previously treated, unresectable, advanced/metastatic TP53 wild-type tumors with ≥1 measurable target lesion will be enrolled into four expansion cohorts (1: NSCLC; 2: melanoma; 3: well-differentiated/dedifferentiated liposarcoma or undifferentiated pleomorphic sarcoma; 4: hepatocellular carcinoma). The RDE of BI 907828 will be administered with fixed doses of BI754091 and BI 754111 (Q3W). In the NSCLC cohort only, pts will be randomized to one of three arms: RDE of BI 907828 + 240 mg BI 754091 + 600 mg BI 754111 (arm A, 32 pts); 240 mg BI 754091 + 600 mg BI 754111 (arm B, 32 pts); RDE of BI 907828 + 240 mg BI 754091 (arm C, 16 pts). The primary endpoint is objective response (OR, per RECIST 1.1). Secondary endpoints include OR (per iRECIST), disease control (per RECIST 1.1 and iRECIST), progression-free survival (PFS), PFS rate at 12 and 24 weeks (cohort 3), and safety. Phase Ib will include at least 140 evaluable pts (80 pts in cohort 1 and 20 pts each in cohorts 2–4). Clinical trial information: NCT03964233 .
Super-MSI: CfDNA-based pan-cancer microsatellite instability detection.
Authors: Xiaomeng Sun, Xiaohong Xu, Rongbo Lin, Guodong Zhao
Journal: Journal of Clinical Oncology (2020)

e13672 Background: Microsatellite instability (MSI) is a molecular subtype found in many cancers, which is often associated with the benefits of immunotherapy. However, the application of traditional testing strategies (such as PCR or IHC) is largely limited due to their dependencies on sufficient tumor tissues. Here, we introduced Super-MSI, a cfDNA-based pan-cancer MSI detection method using next-generation sequencing (NGS). Methods: 5500 detectable microsatellite loci from 250 white blood cells (WBCs) and 29 PCR-validated MSI-H tissue samples were sequenced and characterized, while the former represented for MSS pattern, and the later, for MSI-H. 91 microsatellite loci with the most variable motif repeat numbers between patterns were filtered and the Super-MSI method was established. Plasma samples were collected from 608 patients with known MSI status assessed by PCR (593 MSS and 15 MSI-H) to validate the method. All samples were sequenced with a 642-gene panel, and initial microsatellite reads count distributions were profiled by MSIsensor. Results: We characterized each microsatellite locus by REF alleles (MSI-H:WBC ratio less than 1) and ALT alleles (MSI-H:WBC ratio more than 20), then defined the sum of ALT alleles frequency in WBC group as the baseline for each candidate locus. For plasma samples with unknown MSI status, hypergeometric distribution and FDR calibration were employed to assess the difference of ALT alleles frequency between the WBC baseline and plasma samples. Locus with FDR adjusted p-value less than 0.05 was defined as an unstable locus based on prior knowledge, and negative log-transformed FDR-p was defined as MSscore for the locus. The plasma sample with both unstable microsatellite proportion larger than 20% and total MSscore larger than 270 was defined as MSI-H, and contrariwise, MSS. For all evaluable samples in the validation cohort, Super-MSI showed high sensitivity and specificity of 60% (9/15) and 100% (593/593) for an overall accuracy of 99.0% (602/608), superior to its kind bMSISEA (83.5%, 106/127) and Guardant360 (98.4%, 934/949). Within LOD of 0.5% maxAF (approximately 1% ctDNA fraction), Super-MSI was able to detect 81.8% (9/11) of MSI-H samples, demonstrating high concordance with tissue-based PCR tests. Conclusions: Super-MSI can genotype pan-cancer patients with blood cfDNA samples and give highly accurate MSI evaluation with 81.8% sensitivity and 100% specificity above 1% ctDNA fraction.
DNA methylation profile in unknown cancer origin identification: A multi-class classification model.
Authors: Jianing Yu, Yuanyuan Hong, Pei Zhihua, Tiancheng Han, Song Xiaofeng, Xue Song, Wang Xiaoqing, Zhang Zhuo, Weizhi Chen, Ji He
Journal: Journal of Clinical Oncology (2020)

e13554 Background: Approximately 3-5% of human cancers are cancer of unknown primary (CUP). Treatment of a cancer patient is largely dependent on the tumor origin. Therefore, identification of the tumor origin can improve the survival of patients with CUP. We developed a multi-class classification model using DNA methylation profile as biomarker to determine the primary site of CUP. Methods: We split 7,082 primary tumor samples of 19 cancers and 679 normal samples of 15 tissues from TCGA into a 75% training set and a 25% testing set to develop the classification model. We started with multiple support vector machine (SVM) models, and then combined them into an optimal multi-class ensemble model. Predictors included tumor-specific markers and tissue-specific markers, which were filtered by comparing between groups. Only the training samples were used for feature selection and model development. A validation dataset consisting of 150 primary tissues, 54 metastasis tissues, 105 plasma samples with known cancer site origins from 12 classes was generated in house by a self-designed panel. Performance was measured by area under the curve (AUC) using the one-vs-all approach. Results: 7,453 tumor-specific and 1,533 tissue-specific markers were selected for model construction. AUCs of all cancer types were high in TCGA training and testing set (AUC≥0.96 for all classes). In our validation tissues, esophageal cancer, pancreatic cancer, colorectal cancer, lung adenocarcinoma, breast cancer and liver cancer achieved high AUC in both primary (0.83, 0.83, 0.82, 0.82, 0.80 and 0.79 respectively) and metastasis (0.74, 0.92, 0.86, 0.61, 0.92 and 0.65 respectively). Lung adenocarcinoma, colorectal cancer, liver cancer, breast cancer and esophageal cancer even achieved high AUC in the plasmas. Conclusions: Performance of our model in tissue and plasma samples indicated the potential clinical application of DNA methylation profile in unknown cancer origin identification.
3rd-line anaplastic lymphoma kinase (ALK) inhibitors (ALKi) in advanced non-small cell lung cancer (aNSCLC): Real-world comparison to non-ALKi therapy.
Authors: Natalie Maimon, Elizabeth Dudnik, Yakir Rottenberg, Noa Popovits-Hadari, Noam Asna, Mira Wollner, Alona Zer, Maya Gottfried, Moshe Mishaeli, Yulia Rovitsky-Gelis, Anastasiya Lobachov, Amir Onn, Damien Urban, Mor Tal Moskovitz, Jair Bar
Journal: Journal of Clinical Oncology (2020)

e21685 Background: ALKi represent the standard 1 st - and 2 nd -line treatment (Tx) for ALK+ aNSCLC patients (pts). The value of ALKi in the 3 rd -line setting is unclear. We retrospectively assessed the real-world impact of a 3 rd -line ALKi vs. non-ALKi Tx in ALK+ aNSCLC pts. Methods: Consecutive ALK+ aNSCLC pts were identified in the working databases of 7 Israeli oncology centers; pts receiving any systemic Tx beyond 2 different ALKi were selected for the comparative analysis. Pts whose immediate next Tx line (post-2 nd -ALKi) was a 3 rd ALKi (Group (Gr) A) were compared to pts whose immediate next Tx line (post-2 nd -ALKi) was non-ALKi Tx (Gr B), in terms of overall survival (OS) and time to next Tx line (TNT). Results: 158 consecutive ALK+ aNSCLC pts diagnosed in January 2011 - March 2019 were included, median follow up from diagnosis of aNSCLC was 41 months (mo) (IQR 8-45). Median OS from aNSCLC diagnosis was 56 mo (95% CI 36-66). Post-2 nd -ALKi line was a 3 rd ALKi for 23 pts (Gr A) and a non-ALKi Tx for 10 pts (Gr B). 7 of Gr B (70%) received ALKi as a later line Tx. Median OS after initiation of post-2 nd -ALKi Tx was 27 mo (95% CI, 7-NA) for Gr A vs. 16 mo (95% CI, 7-NA) for Gr B; p-non-significant (NS) with or without adjustment for sex, age, brain metastases. TNT on post-2 nd -ALKi Tx was 6 mo (95% CI, 2-27) for Gr A vs. 2.5 mo (95% CI, 0-NA) for Gr B; p-NS. Conclusions: Following progression on a 2 nd ALKi, OS and TNT were numerically higher for pts receiving a 3 rd ALKi, but statistically NS. Extensive exposure of pts in the non-ALKi Tx Gr to an ALKi at a later stage might have impacted these results. Further studies are required to identify patients likely to benefit from ALKi after progressing on 2 or more ALKi Tx lines. [Table: see text]
Hemostatic spray powder TC-325 in the primary endoscopic treatment of peptic ulcer-related bleeding: multicenter international registry
Authors: Mohamed Hussein, Durayd Alzoubaidi, Miguel-Fraile Lopez, Michael Weaver, Jacobo Ortiz-Fernandez-Sordo, Paul Bassett, Johannes W. Rey, Bu Hussain Hayee, Edward Despott, Alberto Murino, Sulleman Moreea, Philip Boger, Jason Dunn, Inder Mainie, David Graham, Daniel K. Mullady, Dayna S. Early, Krish Ragunath, John T. Anderson, Pradeep Bhandari, Martin Goetz, Ralf Kiesslich, Emmanuel Coron, Laurence B. Lovat, Rehan Haidry
Journal: Endoscopy (2020)

Abstract Background Upper gastrointestinal bleeding (UGIB) is a leading cause of morbidity and is associated with a 2 % – 17 % mortality rate in the UK and USA. Bleeding peptic ulcers account for 50 % of UGIB cases. Endoscopic intervention in a timely manner can improve outcomes. Hemostatic spray is an endoscopic hemostatic powder for GI bleeding. This multicenter registry was created to collect data prospectively on the immediate endoscopic hemostasis of GI bleeding in patients with peptic ulcer disease when hemostatic spray is applied as endoscopic monotherapy, dual therapy, or rescue therapy. Methods Data were collected prospectively (January 2016 – March 2019) from 14 centers in the UK, France, Germany, and the USA. The application of hemostatic spray was decided upon at the endoscopist’s discretion. Results 202 patients with UGIB secondary to peptic ulcers were recruited. Immediate hemostasis was achieved in 178/202 patients (88 %), 26/154 (17 %) experienced rebleeding, 21/175 (12 %) died within 7 days, and 38/175 (22 %) died within 30 days (all-cause mortality). Combination therapy of hemostatic spray with other endoscopic modalities had an associated lower 30-day mortality (16 %, P &lt; 0.05) compared with monotherapy or rescue therapy. There were high immediate hemostasis rates across all peptic ulcer disease Forrest classifications. Conclusions This is the largest case series of outcomes of peptic ulcer bleeding treated with hemostatic spray, with high immediate hemostasis rates for bleeding peptic ulcers.