tbuckley/cabot-search huggingface dataset:
Detection of actionable gene mutations in breast cancer by amplicon-based next-generation sequencing liquid biopsy.
Authors: Jing Shan Lim, Yukti Choudhury, Wai Min Phyo, Chaitanya Gupta, Yiliang Ho, Carina Tay, Yuki Sim, Wei Shuen Ng, Min-Han Tan, Janice Tsang, Hui Ti See
Journal: Journal of Clinical Oncology (2020)

1035 Background: The PI3K-inhibitor, alpelisib, was approved for the treatment of hormone receptor (HR)-positive, HER2-negative breast cancers with PIK3CA mutations based on findings from the SOLAR-1 trial. PIK3CA-positivity in tumor tissue was 29% (341/1172), but was only 15% (177/1172) in plasma cell-free DNA (cfDNA). The lower mutation detection rate observed in cfDNA may limit the clinical application of liquid biopsy in breast cancer. Amplicon-based next-generation sequencing (NGS) approach may confer improved sensitivity, allowing more effective profiling. We conducted a study to evaluate the use of this technology. Methods: Plasma cfDNA from 113 breast cancer patients (82.3% metastatic) underwent real-world testing in a CAP and ISO15189 accredited central laboratory. We analysed genetic alterations in cfDNA using an amplicon-based NGS technology. The presence of PIK3CA and other mutations relevant to breast cancer were correlated to molecular subtypes and treatment histories. Results: At least one mutation was detected in 70.8% of cases. Mutations were more frequent in metastatic cases (77.4%) compared to non-metastatic cases (27.3%). Across all patients, mutations in PIK3CA (33.6%), TP53 (32.7%), ESR1 (22.1%), GATA3 (7.1%) and ERBB2 (7.1%) were most frequently detected, in accordance with tumor tissue genotyping studies. PIK3CA mutations were more common in HR+ HER2- patients (44.4% vs 28.6% of other patients). Among PIK3CA-mutant cases, multiple PIK3CA mutations were present in 18.4% of cases, and hotspot mutations H1047R (34.2%), E542K (26.3%) and E545K (15.8%) were most frequent. An association was seen between PIK3CA mutation and prior treatment with CDK4/6 inhibitors (palbociclib, ribociclib) or mTOR inhibitor (everolimus), with 58% of PIK3CA-mutant cases having received these treatment previously compared to only 20% of PIK3CA-wild type (wt) cases. In addition, 75% of previously treated ESR1-mutant cases had specifically received hormonal treatment, compared to 60 % of ESR1-wt cases that received any treatment. Conclusions: We report similar PIK3CA mutation frequencies (~30%) with amplicon-based NGS on cfDNA compared to tumor tissue testing in breast cancer. Importantly, other driver mutations were also observed at similar frequencies as external tissue studies, implying high sensitivity as the primary reason for performance. This supports the clinical utility of an amplicon-based NGS-based approach to liquid biopsy for the sensitive detection of actionable mutations in breast cancer.
Streamlined human antibody generation and optimization by exploiting designed immunoglobulin loci in a B cell line
Authors: Hidetaka Seo, Hitomi Masuda, Kenjiro Asagoshi, Tomoaki Uchiki, Shigehisa Kawata, Goh Sasaki, Takashi Yabuki, Shunsuke Miyai, Naoki Takahashi, Shu-ichi Hashimoto, Atsushi Sawada, Aki Takaiwa, Chika Koyama, Kanako Tamai, Kohei Kurosawa, Ke-Yi Lin, Kunihiro Ohta, Yukoh Nakazaki
Journal: Cellular and Molecular Immunology (2020)

Monoclonal antibodies (mAbs) are widely utilized as therapeutic drugs for various diseases, such as cancer, autoimmune diseases, and infectious diseases. Using the avian-derived B cell line DT40, we previously developed an antibody display technology, namely, the ADLib system, which rapidly generates antigen-specific mAbs. Here, we report the development of a human version of the ADLib system and showcase the streamlined generation and optimization of functional human mAbs. Tailored libraries were first constructed by replacing endogenous immunoglobulin genes with designed human counterparts. From these libraries, clones producing full-length human IgGs against distinct antigens can be isolated, as exemplified by the selection of antagonistic mAbs. Taking advantage of avian biology, effective affinity maturation was achieved in a straightforward manner by seamless diversification of the parental clones into secondary libraries followed by single-cell sorting, quickly affording mAbs with improved affinities and functionalities. Collectively, we demonstrate that the human ADLib system could serve as an integrative platform with unique diversity for rapid de novo generation and optimization of therapeutic or diagnostic antibody leads. Furthermore, our results suggest that libraries can be constructed by introducing exogenous genes into DT40 cells, indicating that the ADLib system has the potential to be applied for the rapid and effective directed evolution and optimization of proteins in various fields beyond biomedicine.
Training of senior residents for attending ward-round: a pilot study at Peking Union Medical College Hospital
Authors: Yang Jiao, Xiaoming Huang, Xuejun Zeng, Fengchun Zhang
Journal: BMJ (2019)

A questionnaire survey was conducted among 14 senior residents or fellows who received the  ward-round training in Department of General Internal Medicine of Peking Union Medical College Hospital during the period from January 2015 to September 2018. The attitudes and suggestions towards the training program, and to what extent they benefited from the program were assessed. Based on Visual Analog Scale (VAS), the mean score on general training improvement was (8.29±1.25). The self-reported benefits in decision making, teaching skills and leadership of residents participating in the  ward-round training program were significantly higher than those receiving regular rotating and training (t=5.53, 7.78, 13.00; P<0.01). Eight respondents suggested that the training frequency could be increased from once a week to at least twice a week and 10 respondents wished that the supervisors could give feedback on their decision-making performance as quickly as possible after the  round. The training program attending ward-round by senior resident facilitates to improve the competency of rotating senior residents, which may be worth extending to more hospitals.

Key words: 
Standardized training; Senior resident; Leadership
Clinical activity of MCLA-128 (zenocutuzumab), trastuzumab, and vinorelbine in HER2 amplified metastatic breast cancer (MBC) patients (pts) who had progressed on anti-HER2 ADCs.
Authors: Erika Paige Hamilton, Thierry Petit, Barbara Pistilli, Anthony Goncalves, Ana Alexandra Ferreira, Florence Dalenc, Fatima Cardoso, Monica M. Mita, Vincent O. Dezentjé, Luis Manso, Stephanie L. Graff, Francois Clement Bidard, Philippe Georges Aftimos, Santiago Escrivá, Noemia Afonso, Ernesto Wasserman, Kees Bol, Viktoriya Stalbovskaya, Anastasia Vliet, Thomas Bachelot
Journal: Journal of Clinical Oncology (2020)

3093 Background: MCLA-128 (zenocutuzumab ), a HER3 pathway inhibitor, is a humanized bispecific full-length IgG1 antibody targeting both HER2 and HER3 with enhanced ADCC activity. The unique Dock &amp; Block mechanism inhibits HER3 from interacting with its ligands and targets HER2 at a different epitope than trastuzumab, blocking HER2/HER3 dimerization and downstream PI3K/AKT/mTOR signaling. In MBC, HER3 overexpression and/or HER3 ligand upregulation are important drivers leading to trastuzumab resistance, indicating a role for MCLA-128. Preclinical activity was seen in HER2+ breast models when MCLA-128 was combined with trastuzumab. Furthermore, single agent MCLA-128 showed consistent antitumor activity in heavily pretreated HER2+ MBC pts. A phase 2, open-label study explored the MCLA-128/trastuzumab plus vinorelbine triplet in an MBC population. Methods: This open-label trial planned for up to 40 evaluable women with HER2+/amplified MBC progressing on up to 5 anti-HER2 lines including trastuzumab, pertuzumab and an anti-HER2 ADC. Pts received MCLA-128 (750 mg, 2h IV), trastuzumab (8 mg/kg loading, then 6 mg/kg) and vinorelbine (25 mg/m², D1 and 8), q3w. A safety run-in of MCLA-128 + trastuzumab ± chemotherapy was performed. Disease control rate (DCR; RECIST 1.1, per investigator), best overall response (BOR), overall response rate (ORR), safety, and PK are evaluated. Data cutoff was 14Nov2019. Results: 28 pts with a median 3 lines (range 2-5) of anti-HER2 therapy (metastatic setting) and 3 (range 1-6) metastatic sites, received a median of 5 (range 1-17) MCLA-128 cycles. Among 26 pts evaluable for efficacy, 20 patients had CR/PR/SD as BOR; DCR was 77% (90%CI: 60-89) with 1 confirmed CR and 4 PRs (2 unconfirmed). Common related AEs (all grades; G3-4) were neutropenia/neutrophil count decrease (61%; 46%), diarrhea (61%; 4%), asthenia/fatigue (46%; 0), nausea (29%; 0). No clinically significant LVEF decline was seen. At the end of cycle 1, mean trough levels of MCLA-128 was 19.1 µg/mL, and mean terminal half-life was 112 h (n = 8-11). Data on the primary endpoint, clinical benefit rate at 24 weeks, and biomarkers will be provided. Conclusions: The triplet MCLA-128-based combination is active in heavily pretreated pts with HER2+/amplified MBC. The regimen is safe and well tolerated with a manageable AE profile mostly related to the chemotherapy component. Clinical trial information: NCT03321981 .
Current status of occupational hygiene habits and Helicobacter pylori infection of domestic service personnel in a Shanghai community
Authors: Yuan Fang, Guo-xing Ding, Ai-bin Gu
Journal: BMJ (2013)

To explore the current status of occupational hygiene habits and Helicobacter pylori(Hp) infection of domestic service personnel in a Shanghai community and propose the community control measures. A total of 76 domestic service personnel and employers were selected into the investigation and control groups. And they answered questionnaire and received 14C-urea breath test. The career duration of 65% domestic service personnel were over 3 years. Home-based services accounted for 45%. The number of 49% part-time service accounted for two or more. And 84% of them dined together with service families. The difference of occupational hygiene habits and awareness of Hp infection had no statistical significance (P>0.05). The rate of Hp infection of domestic service personnel was 50% vs. 38% for control group (χ2=2.162, P=1.141). Their consistent rate was 62%(Kappa=0.237). A high risk of Hp infection spread within or between the families is correlated with the professional behaviors of domestic service personnel. Eradication therapy for an existing patient should be started as early as possible and occupational practices standardized.


Key words: 
Occupational hygiene; Helicobacter pylori
Outpatient Treatment at Home for Medicare Beneficiaries During and After the COVID-19 Pandemic
Authors: Justin E. Bekelman, Ezekiel J. Emanuel, Amol S. Navathe
Journal: JAMA (2020)

On April 30, 2020, the Centers for Medicare & Medicaid Services (CMS) released an unprecedented emergency policy waiver to increase capacity in response to coronavirus disease 2019 (COVID-19): Hospital outpatient departments can now relocate health care services to off-campus sites or even into Medicare beneficiaries' homes.For the duration of the public health emergency, these relocated services will be reimbursed at the higher outpatient prospective payment system rates rather than the typical physician fee schedule rates for new off-campus sites, an increase of approximately 40% for similar outpatient services. 1Both the relocation and payment waivers will terminate when the Department of Health and Human Services withdraws the emergency declaration at the end of the COVID-19 pandemic, although how that will be decided is unclear.Even though most of the new waivers offer the potential for innovations in home-based health care delivery, care in the home is not new.Patients prefer to receive medical treatments at home, if available, rather than in health care facilities.For many clinical conditions, care at home is as safe and effective as at other sites and is less costly.For instance, home infusion
Survival outcomes of neoadjuvant versus adjuvant chemotherapy in early-stage pancreatic adenocarcinoma: A subgroup analysis of the National Cancer Database.
Authors: Rohit Kumar, Shruti Bhandari, Sunny R K Singh, Sindhu Janarthanam Malapati, Adam Rojan
Journal: Journal of Clinical Oncology (2020)

e16777 Background: Early-stage disease is diagnosed in 10-20% of patients with pancreatic adenocarcinoma (PAC). The current standard of care is upfront surgery followed by adjuvant chemotherapy (AC). The administration of the latter may be limited due to postoperative complications. The aim of this study is to determine the subgroups of patients with early-stage PAC who derive maximum benefit of neoadjuvant chemotherapy (NAC). Methods: Using the National Cancer Database 2004-15, we identified 20,003 patients with clinical stage I or II PAC who had surgery and received chemotherapy in any sequence. The baseline characteristics were compared using Pearson's chi‐square test between patients who received NAC versus AC. A separate multivariate Cox-proportional Hazard regression analysis was done for each subgroup to identify patients with the maximum survival benefit from NAC. Hazard ratio (HR) &lt; 1 connotes survival benefit in favor of NAC. Results: Of the study population, 24% of the patients received NAC. The patients in the NAC group had more PAC of head (80% vs 73%), stage II disease (72% vs 53%), CA19-9 levels 50 U/ml (66% vs 59%), multiagent chemotherapy (68% vs 27%) and were treated at an academic facility (66% vs 52%) compared to the AC group. The p-value was &lt; 0.001 for all comparisons. The age and sex distribution were similar in both groups. On multivariate survival analysis in the overall population, NAC had improved survival compared to AC (HR 0.88 95%CI 0.82-0.93, p &lt; 0.001). Subgroup multivariate survival analysis is shown in the table. Conclusions: In early stage PAC, there is a trend towards survival benefit of NAC compared to AC in most subgroups. The maximum benefit is seen in younger patients with Stage II disease, high CA19-9 levels and fewer comorbidities who receive multiagent chemotherapy. This finding may partly be explained by better tolerability of preoperative compared to postoperative chemotherapy. A randomized clinical trial is needed to establish the optimal chemotherapy timing in patients with early-stage PAC who are treated with curative intent. [Table: see text]
Novel biomarker panel based on cellular and soluble checkpoint proteins for PD-1/PD-L1 blockade treatment efficacy.
Authors: Hiroki Nagai, Ganepola A.P. Ganepola, Jin Lee, Eli Kirshner, Kevin C. Wood, Thomas J. Rakowski, Jason Suh, Eleonora Teplinsky, Alysha Insinga, John R Rutledge, David H Chang
Journal: Journal of Clinical Oncology (2020)

3045 Background: Although anti-PD-1/PD-L1 therapy has become one of the standard treatments for advanced cancers, its low treatment efficacy (10-30%) has remained a major issue. We sought to perform a detailed immune profiling of cells and soluble proteins in order to characterize key regulators and signaling molecules and identify therapeutic targets and biomarkers that may improve treatment efficacy and diagnosis. Methods: This observational study enrolled 49 advanced cancer patients treated with PD-1/PD-L1 blockade monotherapy. Treatment response was assessed by RECIST 1.1. PBMC and plasma samples were collected at baseline and every 6 weeks following initial treatment. Immune profiling of PBMC was done by multi-parametric flow cytometer, and t-SNE analysis was used to identify key immune subtypes. Soluble proteins were evaluated by LUMINEX assays. Cut-off values were determined by ROC curve analysis. Results: Three unique subtypes of immune cells were identified. The population of CD11c + HLA-DR low CD80 + CD86 − CD274 + cells (regDC) at baseline was significantly higher in patients with progressive disease (PD, n=28) than in patients showing clinical benefit (non-PD, n=21; p=0.030). The higher regDC population also correlated with higher levels of IL-8, IL-10, CXCL1, CXCL5, and CXCL11 in plasma. The population of CD4 + CD25 + CD62L + T cells (Treg) was also higher in PD patients (p&lt;0.001). A unique subtype of CD4 + CD28 − T cell, however, was higher in non-PD patients (p&lt;0.001). For the soluble proteins, the levels of sLAG-3 and sGITR in plasma correlated with better clinical outcome in low regDC patients (p=0.004 and 0.044, respectively). The combined biomarker panel (cellular and protein markers) yields high sensitivity (90.5 %) and specificity (82.1 %) for predicting treatment efficacy. Disease control rate (DCR) and median progression free survival (PFS) are shown in the Table. Conclusions: To our knowledge, this pilot study is the first to detect three immune cell subtypes, regDC, Treg and CD4 + CD28 − cells, associated with clinical outcome in the treatment of PD-1/PD-L1 blockade. Profiling of immune cell subtypes and soluble immune checkpoint proteins can serve to identify therapeutic targets and biomarkers for treatment efficacy. We will report the data with further enrollment. [Table: see text]
睡眠呼吸暂停低通气综合征的诊断及鉴别诊断
Authors: 王丽, 韩芳
Journal: BMJ (2005)

一、睡眠呼吸暂停的相关概念 睡眠呼吸暂停(sleep apnea, SA) 指睡眠时间歇性发生的口鼻呼吸气流消失持续10 s以上.SA分为阻塞性(OSA)、混合性(MSA)及中枢性(CSA)3种.OSA指上气道完全阻塞,呼吸气流消失但胸腹呼吸运动仍存在;发生CSA时,呼吸气流及胸腹部的呼吸运动均消失;MSA兼有二者的特点,一般先出现CSA,接着为OSA.三者常出现在同一患者的睡眠过程中,但以其中的一种为主.睡眠呼吸暂停低通气综合征(SAHS)指由于睡眠时频发呼吸暂停导致低氧血症和睡眠紊乱,从而引起的一系列病理生理改变及日间不适症状.以阻塞性睡眠呼吸暂停低通气综合征 (OSAHS)最为常见,其次为中枢性,混合性在成人中少见[1]。
Mental distress and mental health services receipt in foreign-born survivors of cancer: A national health interview survey analysis.
Authors: Melaku A Arega, Edward Christopher Dee, Vinayak Muralidhar, Paul L. Nguyen, Idalid Ivy Franco, Nina Niu Sanford, Brandon Arvin Virgil Mahal
Journal: Journal of Clinical Oncology (2020)

e19001 Background: There is a greater burden of mental illness, in survivors of cancer compared with the general population. Though mental health interventions may reduce mental distress and improve subsequent oncological outcomes, there are disparities in mental health service (MHS) receipt in immigrant populations. Therefore, we examined contemporary patterns of mental distress and mental health service receipt by immigrant status in cancer survivors in the United States. Methods: Data are collected in non-institutionalized civilian adults by the US National Health Interview Survey. For this study, harmonized data of participants reporting a cancer diagnosis were extracted from the Integrated Health Interview Series from 2009-2018. Sample weight-adjusted estimates of mental distress were defined by the validated Kessler 6 (K6). MHS receipt in the past 12 months was estimated, stratified by K6 status. Multivariable logistic regression defined adjusted odds ratios (AOR) and 95% confidence intervals (95CI) for the odds of MHS receipt, with birth status (US vs. non-US) as the primary independent variable of interest. Results: Among 14,653 adult survivors of cancer and 207,018 adults without cancer, 4.16% vs. 3.01% had K6 &gt;13, respectively (AOR 0.96, 95CI 0.87-1.07, P = 0.504). Among survivors of cancer, younger age, female sex, and white race were associated with K6&gt;13, while factors associated with lower MHS receipt included non-US born status, non-white race, and older age. The distribution of severe mental illness (K6&gt;13) did not differ by place of birth. However, non-US birth status was associated with lower MHS receipt among survivors of cancer with K6 &lt; 13 (5.61% vs 8.15%, AOR 0.67, 95CI 0.49-0.92, P = 0.013), and there was a greater disparity among those with K6&gt;13 (9.43% vs 37.8%, AOR 0.19, 95CI 0.08-0.45, P &lt; 0.001) (P interaction = 0.002). Conclusions: In this large contemporary cross-sectional survey, though there was a similar distribution of mental distress in survivors of cancer based on birth status, non-US born adults with severe mental distress (K613) were 81% less likely to receive MHS relative to US born adults. These data suggest that immigrant survivors of cancer who suffer from severe mental distress may be a greater risk not receiving appropriate MHS, which could lead to subsequent adverse outcome. Given the demonstrated gap in use of MHS in non-US born adults with cancer and severe mental distress, increased efforts are needed to screen for mental illness and the need for MHS in immigrant populations.
Combination of monalizumab and cetuximab in recurrent or metastatic head and neck cancer patients previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors.
Authors: Roger B. Cohen, Jessica Ruth Bauman, Sebastien Salas, A. Dimitrios Colevas, Caroline Even, Didier Cupissol, Marshall R. Posner, Gautier Lefebvre, Esma Saada-Bouzid, Maureen Bernadach, Tanguy Y. Seiwert, Alexander T. Pearson, Franceline Calmels, Robert Zerbib, Pascale Andre, Federico Rotolo, Agnès Boyer-chammard, Jerome Fayette
Journal: Journal of Clinical Oncology (2020)

6516 Background: Monalizumab is a first-in-class immune checkpoint inhibitor targeting Natural Killer Group 2A (NKG2A), which is expressed on subsets of Natural Killer (NK), gd T and tumor-infiltrating CD8 + T cells. NKG2A blockade promotes innate anti-tumor immunity mediated by NK and CD8 + T cells and enhances NK cell antibody-dependent cell-mediated cytotoxicity induced by cetuximab. In a Phase I study, the combination of monalizumab and cetuximab was well tolerated. In an initial expansion cohort 1 of 40 patients (pts) who had progressed after platinum-based therapy, we reported an overall response rate (ORR) of 27.5%, a 4.5 month median PFS and an 8.5 month median OS. In a subset of patients (n=18) previously treated with PD-(L)1 inhibitors (IO), corresponding results were 17%, 5.1, and 14.1 months, respectively (ESMO 2019). Here we present data from a second expansion cohort 2 (n=40) conducted specifically in the post-IO setting to independently confirm the cohort 1 results. Methods: Eligible patients had R/M SCCHN previously treated with platinum and a PD-(L)1 inhibitor. Pts received monalizumab 750 mg q2weeks and cetuximab according to the label until progression or toxicity. Cohort 2 was designed as a confirmatory multicenter single arm phase II study, with a pre-planned total of 40 patients. The primary endpoint was ORR assessed per RECIST 1.1. Results: As of January 31, 2020, 40 pts have been treated in cohort 2. Median follow-up is 7.3 months (range, 1.9-13.6+). Eight (8) pts have a confirmed partial response (PR); ORR is 20% [95% confidence interval: 11-35]. Median time to response is 1.6 months [1.6-5.3]. At the time of data analysis, 3 pts were still in PR and 3 pts had stable disease continue on treatment. PFS and OS are still immature. Conclusions: In pts previously treated with platinum and PD-(L)1 inhibitors, the combination of monalizumab and cetuximab demonstrated promising activity. The second extension cohort confirmed prospectively the ORR reported in cohort 1. A randomized phase III trial of monalizumab and cetuximab is planned in this platinum and IO-pretreated SCCHN population. Clinical trial information: NCT02643550 .
Survival of Patients With Angina Pectoris Undergoing Percutaneous Coronary Intervention With Intracoronary Pressure Wire Guidance
Authors: Sebastian Völz, Christian Dworeck, Björn Redfors, Pétur Pétursson, Oskar Angerås, Li-Ming Gan, Matthias Götberg, Giovanna Sarno, Dimitrios Venetsanos, Per Grimfärd, Robin Hofmann, Jens Jensen, Fredrik Björklund, Mikael Danielewicz, Rickard Linder, Truls Råmunddal, Ole Fröbert, Nils Witt, Stefan James, David Erlinge, Elmir Omerovic
Journal: Journal of the American College of Cardiology (2020)