tbuckley/cabot-search huggingface dataset:
Retrospective study to assess the efficacy and safety of checkpoint inhibitors in advanced urothelial carcinoma in real-world setting.
Authors: Elena Sevillano Fernandez, Javier Puente, Natalia Vidal, Alvaro Pinto, Lourdes Garcia Sanchez, Aldo Fiorini, Luis Enrique Chara Velarde, Irene Nalda Ariza, Javier Cassinello, Angel Rodriguez, Saray Galvan Ruiz, Juan Francisco Rodriguez-Moreno, Arantzazu Barquin, Sergio Ruiz, Paloma Navarro, Monica Yagüe, Enrique Grande, Jesús García-Donas
Journal: Journal of Clinical Oncology (2020)

e17043 Background: Checkpoint Inhibitors (CPI) have become a new standard of treatment in advanced urothelial carcinoma. However, little is known regarding the outcome of patients in daily practice.We aimed to assess tumor response and toxicity of CPIs in a cohort of patients treated in “real world” conditions. In parallel, a comprehensive molecular study in tumor samples from these patients, is ongoing. Methods: We designed an observational retrospective study within the “Grupo Centro” collaborative group. Adult patients diagnosed of metastasic urothelial carcinoma (mUC) and treated with CPIs between 2011-2019 in any of the 20 centers of the group, were eligible. Results: Up to date 100 patients have been included (82% males) with a median age of 74 years (48 -96). In 82% patients primary was bladder cancer. Most common metastasic sites were bone (26%) and liver (16%).With a median follow up of 10,6 months(mo) median progression free survival (mPFS) was 6,6mo (1,4-95,4 range) and median Overall Survival (mOS) was 21.3mo (3,8-121,8). 38% of patients received CPIs in first line(L): atezolizumab:27, pembrolizumab: 10, nivolumab:1. The median number of cycles was 8,2. Up to 51% received platinum-based combinations in first line. 69% (69/100) pts received 2L treatment: 68% with CPIs, 27,5% with chemotherapy and 4% with FGFR inhibitors (as part of a clinical trial). 2L mPFS was 3,5 mo (1,9-25.9). 23% (23/100) patients received 3L, of them 26% (6/23) were treated with CPIs. 3L mPFS:8,3mo(0,4-43,8). As a whole, patients treated with CPI accross different lines, achieved complete response in 8% of the cases, partial response in 18% and stable disease in 15%. Up to 44% of cases presented progressive disease as best response and evaluation was not available in 15%. Most common G1-2 AEs related to immunotherapy were: asthenia:31%,pruritus:16% and anorexia: 9%.10% pts experienced G3-4 toxicity: asthenia G3: 4, diarrhea G3: 1, erythrodysesthesia G3:1, arthromyalgia G3: 1, cardiac arrest G4:1,pneumonitis G4:1,anemia G3:1. Conclusions: This study confirms the efficacy and security of CPIs in real world. Response rates and toxicity profile were comparable to those reported in clinical trials.
An investigation on sleeping conditions and factors related to insomnia in the elderly aged 60 years and over in Shanghai community
Authors: 顾杰, 江孙芳, 祝墡珠, 季建林, 赵耐青
Journal: BMJ (2007)

目的 了解上海市60岁及以上人群的睡眠状况和失眠相关因素.方法 2005年7月至10月,对上海市静安区静安寺街道随机抽取的7个居委2789名60岁及以上居民,进行睡眠情况调查.结果 实际调查2304名,应答率82.61%,失眠患病率14.84%(342/2304).logistic回归分析显示,年龄增长(OR=1.02)、女性(OR=2.20)、睡前饮酒(OR=2.98)、光线(OR=3.89)、噪音(OR=1.95)、糖尿病(OR=1.82)、高血压(OR=1.49)、脑卒中(OR=1.65)、骨质疏松(OR=1.76)和罹患慢性病个数的增长(OR=1.43)均为失眠的危险因素(均P＜0.05).结论 60岁及以上人群失眠患病率较高,失眠的发生与年龄、性别、睡眠习惯、睡眠环境和糖尿病等慢性病有关。
Overall survival (OS) in patients (pts) with advanced breast cancer (ABC) with visceral metastases (mets), including those with liver mets, treated with ribociclib (RIB) plus endocrine therapy (ET) in the MONALEESA (ML) -3 and -7 trials.
Authors: Denise A. Yardley, Arnd Nusch, Yoon Sim Yap, Gabe S. Sonke, Thomas Bachelot, Arlene Chan, Patrick Neven, Dennis J. Slamon, Paul Wheatley-Price, Agnes Lteif, Manu Sondhi, Karen Rodriguez-Lorenc, Anil Gaur, Stephen K. L. Chia
Journal: Journal of Clinical Oncology (2020)

1054 Background: In the Phase III ML-3 (NCT02422615) and ML-7 (NCT02278120) trials, RIB + ET demonstrated a significant OS benefit (ML-3: HR, 0.72, P = 0.00455; ML-7: HR, 0.71, P = 0.00973) over placebo (PBO) + ET in pts with HR+/HER2- ABC (Im et al. N Engl J Med. 2019; Slamon et al. N Engl J Med. 2019). The presence of visceral mets generally portends a poor prognosis, which is especially poor in pts with liver mets (He et al. Ann Oncol. 2019). Here we report OS in pts with visceral mets with a focus on those with liver mets in ML-3 and ML-7. Methods: In ML-3, postmenopausal pts were randomized 2:1 to receive RIB + fulvestrant (FUL) or PBO + FUL as first- (1L) or second-line (2L) treatment. In ML-7, premenopausal pts were randomized 1:1 to receive RIB + ET or PBO + ET (this analysis included only pts who received an NSAI as ET partner to match approved indication). Results: Visceral mets were identified in 293 pts (60.5%) in the RIB arm and 147 (60.7%) in the PBO arm in ML-3 and 150 (44.8%) and 142 pts (42.1%), respectively, in ML-7. In ML-3, the median age of pts with visceral mets was 63 and 65 years in the RIB and PBO arms, and in ML-7 it was 42.5 and 45.0 years, respectively. In ML-3, 214 pts with visceral mets received 1L therapy (RIB, n = 137; PBO, n = 77), while 219 pts received 2L therapy or had early relapse (RIB, n = 151; PBO, n = 68). Lung and liver were the most common sites of visceral mets for pts in ML-3 (49.8% and 44.8%, respectively) and ML-7 (51.4% and 58.2%, respectively). OS HRs in pts with visceral mets were consistent with the benefit in the overall pt populations and suggested a particularly substantial OS benefit in pts with liver mets (HR for liver mets group in ML-3, 0.629 [95% CI, 0.421-0.942]; HR in ML-7, 0.531 [95% CI, 0.321-0.877]; Table). No new safety signals were observed. Conclusions: Approximately half of the pts in ML-3 and ML-7 had visceral mets. The OS data in these pts are consistent with the benefit observed with RIB in the overall populations of each trial. In pts with liver mets, a group with an especially poor prognosis, RIB + ET demonstrated a substantial OS benefit compared with PBO + ET. Clinical trial information: NCT02422615; NCT02278120 . [Table: see text]
Patient-matched tissue and liquid biopsies identify shared and acquired genomic alterations in breast cancer.
Authors: Ethan Sokol, Smruthy Sivakumar, Dexter Jin, Natalie Danziger, Kimberly McGregor, Dean Pavlick, Lucas Dennis, Jeffrey S. Ross, Garrett M. Frampton, Jeffrey Venstrom, Priti Hegde, Luciana Molinero, Steffi Oesterreich, Jon Chung
Journal: Journal of Clinical Oncology (2020)

1050 Background: Liquid biopsy-based comprehensive genomic profiling (CGP) is a minimally invasive approach to potentially identify truncal driver alterations and mechanisms of acquired resistance. However, there are limited data comparing solid tissue and plasma biopsies from the same patient in breast cancer. Methods: CGP was performed on matched tumor tissue and plasma samples from 444 patients with breast cancer (Foundation Medicine, Inc.) to identify short variant mutations and rearrangements in at least 62 genes. ER/PR/HER2 status was abstracted for a subset of patients (n = 273). Patients were primarily ER+/HER2- (58%) with fewer HER2+ (16%) and TNBC (25%). Results: Samples were temporally heterogeneous with a median time between matched tissue-plasma collection of 276 days (interquartile range 45 - 650). Positive percent agreement (PPA) to tissue biopsy was 81.5% with higher PPA for collection interval ≤1y v &gt; 1y (82.5% v 76.5%). PPA was highest in known truncal driver genes ( AKT1, PTEN, BRCA2, BRCA1, TP53, PIK3CA: 85-89% PPA). PPA of tissue to liquid biopsy was 50.5% with strong time dependence (62.4% ≤1y, 37.9% &gt; 1y), presumably due to intervening therapies. Acquired alterations in liquid biopsy were primarily known resistance mechanisms ( ESR1, NF1, ERBB2, PIK3CA, PTEN, TP53, BRCA1, and BRCA2), were often polyclonal, associated with longer collection intervals, and exhibited higher prevalence in the ER+/HER2- subtype (62% ER+/HER2-, 33% HER2+, 42% TNBC). Acquired alterations significantly enriched in ER+ cases included ESR1, NF1, ERBB2 and TP53. For PIK3CA, a PPA of 84.6% was observed with solid as baseline and 79.1% with liquid as baseline; prevalence was similar (36.5% solid, 35.6% liquid). Alpelisib companion diagnostic alterations (CDx) had a similar PPA (84.0% solid, 83.3% liquid). Overall percent agreement (OPA) for PIK3CA CDx in paired samples was 91.4% (406/444). When acquired PIK3CA alterations are observed they tend to be subclonal, co-occur with shared PIK3CA alterations, and consist of rare alterations (E726K, E453K, M1043I). Conclusions: While high PPA to tissue was observed for alterations in truncal driver genes, acquired alterations observed in plasma were frequently polyclonal, often identify potential mechanisms of therapeutic resistance and are, in part, a function of time and intervening treatments relative to tissue CGP. These results demonstrate high PPA to tissue suggesting that liquid biopsy has clinical validity in identifying truncal alterations and can also identify acquired alterations in breast cancer.
Correlation of immunity-related adverse events with survival and response to anti-PD-1 treatment in patients with metastatic melanoma.
Authors: Bozena Cybulska-Stopa, Iwona Lugowska, Marcin Zietek, Anna Dawidowska, Anna Malgorzata Czarnecka, Karolina Piejko, Lukasz Galus, Barbara Ziolkowska, Stanislaw Kieszko, Hanna Kosela-Paterczyk, Tomasz Switaj, Katarzyna Kozak, Pawel Rogala, Natasza Kempa-Kaminska, Jacek Calik, Pawel Teterycz, Elzbieta Staroslawska, Rafal Suwinski, Jacek Mackiewicz, Piotr Rutkowski
Journal: Journal of Clinical Oncology (2020)

e15164 Background: Immunotherapy has become a standard treatment option for metastatic melanoma patients, and the use of anti-programmed cell death-1 monoclonal antibodies (anti-PD-1) has significantly improved the outcomes of this group of patients. Immune related adverse events (irAEs) during anti-PD-1 treatment may present a significant problem. However, irAEs' relationship with overall survival although suggested in single studies was not confirmed in real world data. Methods: Consecutive patients starting treatment between March 2016 and April 2019 with fist line anti-PD-1 (nivolumab or pembrolizumab) for unresectable or metastatic melanoma in 6 comprehensive cancer centers in Poland were enrolled in the study. Baseline patients characteristics and irAEs development during treatment were evaluated to identify predictors of progression-free (PFS) and overall (OS) survival in Cox model. PFS and OS were assessed using Kaplan–Meier method. Results: Overall, 410 patients were included in the present analysis and 107 patients experienced irAEs. Response rate (RR) and disease control rate (DCR) were 36% (148 pts) and 65% (267 pts) respectively. Median PFS and OS were 7.6 (2.8–21.6) and 21.6 (6.7–38.2) months, respectively. In univariate analysis normal LDH level, no brain metastases, ECOG 0 or 1, ≤ 2 number of metastases locations were positive prognostic factors for both OS and PFS. At the same time irAEs occurrence was correlated with longer PFS, OS, RR and DCR (all p &lt; 0.001); moreover high LDH level correlated with irAEs (p = 0.027) development. There was no correlation between irAEs and the number of cycles of anti-PD-1 patients received. Conclusions: Our study showed an association between irAEs and longer survival on anti-PD1 therapy in patients with advanced or metastatic melanoma. An association with irAEs and response to therapy has also been demonstrated.
Neutrophil extracellular traps blockade in combination with PD-1 inhibition in treatment of colorectal cancer metastasis.
Authors: Amblessed Onuma, Jiayi He, Yujia Xia, Hongji Zhang, Dmitry Genkin, George Tetz, Hai Huang, Allan Tsung
Journal: Journal of Clinical Oncology (2020)

e16002 Background: Immune checkpoint inhibitors (ICIs) are currently approved for microsatellite instability-high metastatic colorectal cancer (mCRC) however reported objective response rate to monotherapy range between 28-52%. Neutrophil Extracellular Traps (NETs), an extracellular network of DNA and proteins expelled by neutrophils into the tumor microenvironment, promote CRC metastasis by inducing potent immunosuppressive effects. We hypothesize that targeting this network may improve response rates to immune checkpoint therapy. The purpose of our study is to investigate the effect of combination DNase I treatment, a NET depleting agent, and PD-1 blockade in mCRC progression. Methods: Subcutaneous MC38 (MSI-H adenocarcinoma of the colon) tumors were established in 6-week-old mice. Treatment was initiated six days after tumor inoculation with daily intraperitoneal (i.p) injections of DNase I followed by i.p anti-PD-1 treatment administered every 3 days. Animals were divided into treatment groups: control, DNase alone, anti-PD-1 alone and combination of DNase I with anti-PD-1 (n = 6 mice/ group). Results: Tumors were successfully established after 6 days of inoculation. These tumors expressed high neutrophil infiltration and NETs. To determine the effects of combination therapy on tumor progression, we measured tumor volume and time to progression (TTP). We found that mice treated with combination DNase I and anti-PD-1 had significantly lower mean tumor volume compared to anti-PD-1 alone (1372.68mm 3 vs 2193.20 mm 3 , p-value = 0.043). TTP was higher in the combination group compared to anti-PD-1 treatment alone (median time to progression 22 vs 17 days, p-value = 0.004). Next we sought to determine the mechanism behind this effect by investigating if NETs blockade modulated the tumor microenvironment. We found that treatment with DNase I decreased exhaustion of CD8+ T-cells in the tumor compared to no treatment. Conclusions: Targeting NETs in combination with immune checkpoint inhibition may be an option to improve response rate to immune checkpoint inhibitors through decreasing exhausted CD8+ T-cells.
A phase Ib study of endogenous SLC45A2-specific cytotoxic T cells for the treatment of patients with metastatic uveal melanoma.
Authors: Suzanne Phillips, Gregory Lizee, Courtney Brown, Jacqueline Marie Lara, Roland L. Bassett, Lisa G Beal, Ravi Murthy, Amjad Talukder, David H Hawke, Ivy Lai, Patrick Hwu, Cassian Yee, Sapna Pradyuman Patel
Journal: Journal of Clinical Oncology (2020)

TPS10086 Background: Overall survival (OS) for patients (pts) with advanced uveal melanoma (UM) is poor with a median survival of approximately 12 months. Roughly half of all pts with UM will develop distant metastatic disease despite effective treatment of the primary site. Metastatic UM has a 90% prevalence of liver involvement. Currently, there are no specific FDA-approved treatments for metastatic UM and consensus guidelines recommend participation in a clinical trial. Modern treatments such as checkpoint inhibitors and targeted therapy have less impressive outcomes in UM. Our group has identified peptide epitopes of SLC45A2, a melanosomal transport protein, that is highly expressed in UM and present at very low levels in normal melanocytes. We demonstrated that cytotoxic T cells against SLC45A2 were able to kill HLA-matched UM cell lines. Through the use of enabling technologies, SLC45A2-specific cytotoxic T cells can be isolated and expanded ex-vivo from peripheral blood for use in endogenous T cell (ETC) therapy (a form of adoptive cellular therapy). These activated ETCs can then be infused to traffic to tumor sites. CTLA4 is a T-cell surface protein that binds to B7 with a higher affinity than the costimulatory receptor CD28, providing an inhibitory signal to T-cells. Anti-CTLA4 blockade can divert this inhibition and release the brake on antigen-specific T-cell activation of ETC. We hypothesize that antigen-specific ETCs infused via hepatic artery will be safe and tolerable for UM pts with liver metastasis. Methods: We are conducting a first-in-human clinical trial (NCT03068624 ) of ETC therapy targeting SLC45A2 in combination with anti-CTLA4 in pts with metastatic UM. Pts who express HLA-A*02:01 or A*24:02 undergo apheresis to collect T cells. Their cells then undergo ex vivo cloning and interleukin-21 primed expansion. Hepatic arterial infusion of ETCs will ensure direct localization to the target organ of interest. Conditioning with low-dose cyclophosphamide (300 mg/m2) occurs on Day -2. Hepatic arterial infusion of ETCs on Day 0 is followed by low dose subcutaneous interleukin-2 (IL-2) twice daily for 14 days. The initial dose escalation phase is a 3+3 design with a starting dose level of 3.3 x 10 9 cells/m 2 of ETCs alone. Once the maximum tolerated dose of ETCs is established, the dose expansion phase will include ETCs in combination with anti-CTLA4 (Ipilimumab). The primary objective is to evaluate the safety of this first in human T cell regimen. Secondary objectives are to evaluate the in vivo persistence and anti-tumor efficacy. Clinical trial information: NCT03068624.
ABC of antithrombotic therapy: Venous thromboembolism: pathophysiology, clinical features, and prevention
Authors: Alexander G G Turpie, Bernard S P Chin, Gregory Y H Lip
Journal: BMJ (2002)

Venous thromboembolism is a common complication among hospital inpatients and contributes to longer hospital stays, morbidity, and mortality. Some venous thromboembolisms may be subclinical, whereas others present as sudden pulmonary embolus or symptomatic deep vein thrombosis. Ultrasonic Doppler and venographic techniques have shown deep vein thrombosis of the lower limb to occur in half of all major lower limb orthopaedic operations performed without antithrombotic prophylaxis. Deep vein thrombosis of the lower limb is also seen in a quarter of patients with acute myocardial infarction, and more than half of patients with acute ischaemic stroke. 

Deep vein thrombosis of the lower limb normally starts in the calf veins. About 10-20% of thromboses extend proximally, and a further 1-5% go on to develop fatal pulmonary embolism. Appropriate antithrombotic measures can reduce this complication. Until recently, some clinicians were reluctant to provide such prophylaxis routinely. As unfounded fears of major bleeding complications from anticoagulant regimens wane, preventive treatments are used more often with medical and surgical patients. However, the risk of bleeding can be serious and this has particular bearing in postoperative patients.


Venous thromboembolism can also arise spontaneously in ambulant individuals particularly if they have associated risk factors such as thrombophilia, previous thrombosis, or cancer. However, in over half of these patients, no specific predisposing factors can be identified at presentation. 


Venous thromboembolism often manifests clinically as deep vein thrombosis or pulmonary embolism, and is possibly one of the preventable complications that occur in hospitalised patients
全科医学与医务人员的素质教育
Authors: 吴春容
Journal: BMJ (2004)

素质是一个综合的概念,包括政治素质、思想素质、身体素质、心理素质、业务素质等.医学生的素质教育应该是医学教育的核心,但目前的医学教育明显忽视了医学生的素质教育,这也导致目前的医务人员在基本素质方面有不少缺陷.如何加强医务人员的素质教育,补上素质教育这一课,这已成为医院管理中的一个难题.我们在帮助50多家医院进行营销和发展策划的过程中,应用全科医学的理论和方法,着重在医务人员的素质教育方面做了一些大胆的尝试,取得了非常显著的效果。
Molecular profiling and quantitative image analysis reveal spatial intratumor heterogeneity in TNBC.
Authors: Karuna Mittal, Hongxiao Li, Dennis Wylie, Jaspreet Kaur, Rishab Kolachina, Bikram Sahoo, Guanhao Wei, Michael S Toss, Andrew R. Green, Dhivya Arasappan, Jianchen Yang, Thomas Yankeelov, Shristi Bhattarai, Emad A. Rakha, Keerthi Gogineni, Jun Kong, Jeanne Kowalski, Ritu Aneja
Journal: Journal of Clinical Oncology (2020)

e12536 Background: Triple negative breast cancer (TNBC) is a molecularly complex and heterogeneous subtype with distinct biological features and clinical behavior. Extensive intra-tumor heterogeneity is suspected to be a major cause of therapeutic failure. Spatially-distinct parts of the tumor harbor diverse and divergent clonal populations of cancer cells. Thus it is likely increasing the likelihood that some of those clones resist treatment, expand in numbers and eventually, repopulate the tumor leading to recurrence and spread. Therefore, a deeper understanding of this complexity is fundamental to gaining insights into this clinically important issue. In this study, we used RNA sequencing and machine learning approaches to examine the molecular and phenotypic/cellular profiles of various tumor samples from the same patient tumor to reveal spatial intra-tumor heterogeneity in TNBCs. Methods: We used 34 samples (2-4 samples from each patient tumor) from a total of 11 unique TNBC patients. RNA-sequencing was performed to quantify differential gene expression and machine learning (ML) approaches (deep learning regression modeling) were used to quantify the percentage of tumor and tumor-infiltrating lymphocytes (TILs) in the H&amp;E stained tissue sections. The extent of concordance/discordance between the multiple tumor samples that originated from the same patient was analyzed by analyzing the intra- and inter-patient variance of normalized tumor cell, TIL % and gene expression. We also performed pathway analysis to identify signaling pathways dysregulated within (intra-tumoral heterogeneity) and between tumors (inter-tumoral heterogeneity) and performed molecular subtype analysis. Results: We observed that gene expression variance as higher within-patient (intra-tumor) compared to between-patient (inter-tumor). Tumor samples from 70% of patients showed different molecular subtypes representing extensive intra-tumor heterogeneity. Our ML-based image analysis showed that intra-patient tumor cell and TILs density/percentage variance was greater than inter-patient variance. In addition, patients with high within-patient gene expression variability had a high tumor and TIL variance. Among the within-patient expression variability, the genes associated with the PLK1 and Notch signaling were enriched. Conclusions: Our results suggest that TNBCs exhibit higher intra-tumor gene expression and cellular variance compared to inter-tumor gene expression and cellular variance suggesting higher intra-tumor heterogeneity in TNBCs.
Management of internal hernia after radical gastrectomy for gastric cancer
Authors: Wangxun Jin, Bing Wang, Yunli Zhang, Xinbao Wang, Jianmin Guo, Jiantao Yang, Lingnan Zhang
Journal: BMJ (2019)

A total of 1 789 patients with gastric cancer underwent radical gastrectomy in our hospital from September 2015 to August 2017, internal hernia (IH) developed in 7 cases with a incidence rate of 0.4%. The general condition, the symptoms, imaging findings, treatment methods and prognosis as well as the types of digestive tract reconstruction of patients were retrospective analyzed. There were 4 cases of Petersen′s hernia, 2 cases of jejuno-jejuno mesenteric hernia and 1 case of diaphragm hernia. All patients developed mechanical obstruction. Imaging examination showed mesenteric vessels overriding sign and double whirl sign. Six patients recovered smoothly, 1 patient gave up treatment due to extensive small bowel infarction. It is indicated that the formation of abnormal channels in the abdominal cavity after radical gastrectomy may lead to IH. The mesenteric vessels overriding sign and the double whirl sign are the unique imaging findings of IH after radical gastrectomy. Closing the abnormal channel can prevent the occurrence of IH after gastrectomy.

Key words: 
Stomach neoplasms; Gastrectomy; Intestinal obstruction; Hernia