tbuckley/cabot-search huggingface dataset:
Physician burnout: An innovative way to find “sanity out of madness” in the infusion center of a cancer institute.
Authors: Sarah Sewaralthahab, Shaunika Thorne, Linda King, Debolina Goswami, Christopher Gallagher, Laura Kaufman, Irina Veytsman
Journal: Journal of Clinical Oncology (2020)

e19246 Background: Physician burnout is affecting over 50% of physicians in the US alone and is related to the high workload, loss of anonymity and a sense of powerlessness in the face of multiple bureaucratic hurdles. The result is physical exhaustion, moral distress, high turnover and increased rates of suicide. Methods: The faculty and staff at Washington Cancer Institute (WCI) were surveyed using AMA/ASCO burnout questionnaire to identify burnout rates. A brainstorming session with staff captured the perceived causes of burnout in a fishbone diagram, and the most prominent cause was noted to be pertaining to delays in the infusion center (IC) related to chemotherapy orders. We tracked causes of delay in starting chemotherapy from 7/23/19 to 8/7/19, and utilizing a Pareto Chart identified that over 80% of the delays were due to missing chemotherapy orders on the day of IC appointment. Process flow charts were developed for all provider teams at WCI noting variations that may be leading to delays. The aim was to decrease the number of missing chemotherapy orders for patients coming to the IC by 50%, decreasing the resultant stress on providers and IC nurses. Results: By retrospective chart review, 6/21/2019 to 8/30/ 2019, an average of 13.18% of patients scheduled to receive chemotherapy at WCI IC had missing orders on the day of the infusion, which resulted in up to a 111-minute delay in starting chemotherapy. This, in turn, resulted in stress/burnout among 42.1% of providers and 55.6% of supportive staff. To remedy the problem, we implemented 4 interventions over two plan-do-study-act (PDSA) cycles. In the first PDSA cycle the process was standardized to obtain necessary labs 48 hours prior to IC appointment and review and sign orders by 2 pm the day prior to IC appointment. Email notifications were also sent to all providers and nurse navigators regarding missing orders 48 hours prior to IC appointment. In the second PDSA cycle we continued with the previous interventions in addition to addressing pharmacy related delays in releasing premedication if dose adjustments of chemotherapy are needed. In the time period of 10/2/2019 to 11/11/2019, two PDSA cycles were implemented and resulted in a decrease in the average number of missing orders on the day of IC appointment to 7% achieving our aim. Conclusions: Using a systems approach to standardize the process promotes a more effective environment in the work place and decreases burnout on physicians and staff.
Defining the mutational landscape of 3,217 primary breast cancer transcriptomes through large-scale RNA-seq within the Sweden Cancerome Analysis Network: Breast Project (SCAN-B; NCT03430492).
Authors: Christian Brueffer, Sergii Gladchuk, Christof Winter, Johan Vallon-Christersson, Cecilia Hegardt, Jari Häkkinen, Anthony M George, Yilun Chen, Anna Ehinger, Christer Larsson, Niklas Loman, Martin Malmberg, Lisa Rydén, Åke Borg, Lao H. Saal
Journal: Journal of Clinical Oncology (2020)

518 Background: Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. The Sweden Cancerome Analysis Network-Breast project (SCAN-B; ClinicalTrials.gov NCT02306096) is a multi-center population-based ongoing prospective observational study elucidating the global transcriptomic profiles for thousands of patients and tumors using RNA sequencing. Since September 2010, over 15,000 patients with breast cancer have been enrolled at 9 hospitals across a wide geography of Sweden, comprising greater than 90% of all eligible patients in the catchment area. Methods: Within SCAN-B, we developed an optimized bioinformatics pipeline for detection of single nucleotide variants and small insertions and deletions from RNA-seq data. From this, we describe the mutational landscape of 3,217 primary breast cancer transcriptomes, and relate it to patient overall survival in a real-world setting (median follow-up 75 months, range 2-105 months). Results: We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such as PIK3CA, TP53, ESR1, and ERBB2, as well as mutation status of key molecular pathways and tumor mutational burden, identify mutations in one or more potentially druggable genes in 85.3% percent of cases, and reveal significant relationships to patient outcome within specific treatment groups. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source interactive web application, SCAN-B MutationExplorer, publicly accessible at http://oncogenomics.bmc.lu.se/MutationExplorer . Conclusions: These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based signatures and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling.
Panel-derived TMB and immune-related GEP are associated with the response to immune checkpoint inhibitors (ICIs) in urothelial cancers.
Authors: Kien Thiam Tan, Shu-Jen Chen, Yi-Lin Hsieh, Yu-Li Su, Yi-hua Jan, Jen Hao Cheng, An Hsu, Wan-Ting Huang, De-Wei Zhuo, Woei-Fuh Wang, Datsen George Wei
Journal: Journal of Clinical Oncology (2020)

e17047 Background: Tumor mutational burden (TMB) and gene expression profile (GEP) have emerged as potential biomarkers for the prediction of response to the immune checkpoint inhibitor (ICI) treatment. An interferon-g gene signature was shown recently to predict ICI response in a pan-cancer setting. For TMB, not only did TMB-high patients experience better clinical outcome with ICI, but panel-derived TMB was also shown to be comparable to the gold standard, TMB derived from whole exome sequencing. Here, we evaluate possible correlations between panel-derived TMB, as well as immune-related GEP, with ICI response in urothelial cancers. Methods: FFPE tumor tissues from 30 patients with urothelial cancers who had previously received ICI as monotherapies or combination with chemotherapies at Kaohsiung Chang Gung Memorial Hospital were retrospectively tested for targeted next-generation sequencing (ACTOnco) and quantitative PCR-based GEP (ACTTME), for the identification of nonsynonymous variants across 440 cancer-associated genes and expression levels of &gt; 90 immune-related genes, respectively. TMB was calculated by using the sequenced regions of ACTOnco to estimate the number of somatic nonsynonymous mutations per megabase of all protein-coding genes. For ACTTME, Cq values were normalized to internal control before group analysis. RECIST criteria were used to categorize tumor response to the treatment. Results: Patients were defined as responders (CR/PR) and non-responders (SD/PD) according to the RECIST criteria. In the ICI monotherapy cohort, the responders (n = 8) had significantly higher TMB than non-responders (n = 15) (Median 16.2 muts/Mb vs. 6.5 muts/Mb, p= 0.0035). In contrast, for the cohort receiving ICI combination therapy, several genes implicated in hypoxia (HIF1A), suppressive cell types (Treg &amp; MDSC) and immune checkpoint (PD-L2) were significantly elevated ( p&lt; 0.05) in the non-responder group by 2 to 8 folds. Conclusions: Despite the fact that the cohort size is small, this study showed panel-derived TMB, as well as immune-related GEP, can potentially serve as predictive biomarkers to identify urothelial cancer patients for immune checkpoint inhibitor therapy.
Perioperative FLOT in elderly patients with resectable gastric cancer: Subgroup analysis from the observational RealFLOT study.
Authors: Elisa Giommoni, Ferdinando De Vita, Irene Pecora, Francesco Iachetta, Antonia Strippoli, Maria Antonietta Satolli, Andrea Spallanzani, Marco Puzzoni, Floriana Nappo, Michele Sisani, Vincenzo Formica, Filippo Giovanardi, Carmelo Pozzo, Michele Prisciandaro, Samantha Di Donato, Luca Pompella, Francesca Salani, Giuseppe Tirino, Daniele Lavacchi, Lorenzo Antonuzzo
Journal: Journal of Clinical Oncology (2020)

4548 Background: The treatment strategy for patients with resectable gastric cancer changed in the last few years with perioperative treatments. FLOT regimen (fluorouracil, oxaliplatin, docetaxel) turned out to be feasible and effective, offering significant improvement in survival outcomes. However, the safety profile of triplet therapies for elderly patients deserves a special attention and, consequently, the best treatment strategy for these patients is still debated. Methods: Focusing on the elderly patient population (age ≥65 years), real-world data from patients with resectable gastric or gastro-oesophageal junction (GEJ) adenocarcinoma (T≥2 and/or N+) enrolled in the observational RealFLOT study were collected. Results: A total of 206 patients with resectable gastric or GEJ adenocarcinoma received perioperative FLOT at 15 Italian centers in routine clinical practice, between September 2016 and September 2019. The median age was 63 years (range 36-77) and 43% of patients enrolled (n = 89) were ≥65 years. Among elderly patients, 46 (52%) received FLOT for at least 4 full-dose cycles in the preoperative phase, 82 (92%) underwent surgery, and 56 (62%) started the postoperative phase. The primary end point of the study, pathological complete response (pCR) rate, was similar among patients aged ≥65 and &lt; 65 (6.7% vs 7.7%, respectively). The distribution of pathological stages did not differ according to age (p = 0.473), and disease-free survival (DFS) is unrelated to the age of patients (log-rank 0.57; p = 0.89). The incidence of grade (G) 3-4 adverse events (AEs) was similar in the two age groups (Table) and the 30-day mortality rates after surgery did not differ according to age. Conclusions: FLOT regimen demonstrated to be feasible and safe in elderly patients since no differences were observed in terms of pCR, DFS and safety profile according to age. [Table: see text]
Intensive lowering of blood lipid level and cardio-and cerebro-vascular diseases
Authors: 仝其广, 胡大一
Journal: BMJ (2004)

1994年以来具有里程碑意义的5项大规模临床试验[北欧辛伐他汀生存研究 (4S)[1]、西苏格兰冠心病预防研究 (WOSCOPS) [2]、胆固醇和冠心病复发事件试验 (CARE) [3]、普伐他汀对缺血性心脏病的长期干预 (LIPID)[4]和空军/得州冠状动脉粥样硬化预防研究 (AFCAPS/TEXCAPS) [5]]充分证明降脂治疗具有能显著减少冠心病事件的巨大益处,奠定了他汀类药物在冠心病防治中的重要地位.随着循证医学的迅猛发展,调脂治疗的观念也在不断更新,认识不断深化.强化降脂是相对于一般降脂而言更为积极的降脂治疗,强调达到目标值或更低.越来越多的证据表明强化降脂可进一步减少高危患者心血管事件的发生,改善生存质量。
A phase Ib study of simmitecan (LP) single-agent and in combination with 5-fluorouracil/leucovorin (5-FU/LV) or thalidomide (T) in patients with advanced solid tumor.
Authors: Jifang Gong, Ting Deng, Jie Li, Ming Lu, Jian Li, Yi Ba, Qiuqiong Yu, Lin Shen
Journal: Journal of Clinical Oncology (2020)

3523 Background: Simmitecan (LP), a novel 9-substituted lipophilic camptothecin derivative, is a potent inhibitor of topoisomerase I with anti-tumor activity single agent or in combination with other anti-tumor agents, i.e. thalidomide or anti-PD-1 antibody in xenograft models. In this phase Ib study (NCT02870036), we evaluate the safety and anti-tumor effects of LP as monotherapy or in combination therapies in patients (pts) with advanced solid tumors. Methods: This open-label, multi-cohort phase Ib study was conducted at 3 academic centers in China. Eligible pts had advanced cancer without standard treatment options. Prior irinotecan treated failure pts was eligible. In the single agent study, enrolled pts was allocated to received intravenous(iv) 50, 80, or 120 mg/m 2 of LP Q2W to determine the safety of LP. After single agent study finished, enrolled pts allocated in LP+5-FU/LV cohorts received 50, 65, or 80 mg/m 2 of LP then LV 400 mg/m 2 and 5-FU bolus at 400 mg/m 2 followed by 5-FU continuous iv of 2400 mg/m 2 Q2W; pts in LP+T cohorts received LP 65 mg/m 2 Q2W + thalidomide 50mg QD or thalidomide 100mg QD, or LP 80 mg/m 2 Q2W + thalidomide 50mg QD. Treatment repeated in 28-day cycles until disease progression or unacceptable toxicity. Results: Between October 2016 to February 2019, 41 pts, median age of 55.1 (range 29-69) years, were enrolled, 13 in LP monotherapy, 10 in LP + 5-FU/LV and 18 in LP + T. Over all, no dose limited toxicity (DLT) occurred. The most common (≥20%) grade 3/4 AE among three regimens was neutropenia (44%, 70% and 89% respectively in LP, LP+5FU/LV and LP+T),and treatment related SAEs were similar, i.e. anemia and febrile neutropenia (11.1% each) in LP, diarrhea (10%) in LP+5-FU/LV, febrile neutropenia (5.6%) in LP+T. Majority of enrolled pts (24/41, 59%) had progressed on prior irinotecan, nevertheless, partial response (PR) was observed in 1 colorectal cancer pt treated with LP 80 mg/m 2 + thalidomide 50mg. Disease control rate (DCR, SD≥12 weeks or CR or PR) were 60%, 80% and 61% and median progress free survival were 2.71, 4.17 and 2.76 months respectively in LP, LP + 5-FU/LV and LP+T cohorts. Conclusions: This study showed the safety profiles are manageable, either LP monotherapy or combination therapies, no DLT or safety concern was elicited in combination compared to single agent, and the LP + 5-FU/LV regimen showed higher DCR. A phase II study in pts with metastatic NEC is on-going to explore safety and efficacy of LP + 5-FU/LV regimen combined with toripalimab, an anti-PD-1 antibody. Clinical trial information: 02870036 .
Immune microenvironment profiling of breast cancer brain metastases using multiplex immunofluorescence.
Authors: Gaia Griguolo, Anna Tosi, Valentina Guarneri, Maria Vittoria Dieci, Susan Fineberg, Annavera Ventura, Luc Bauchet, Jack Jacob, Valerie Rigau, William Jacot, Antonio Rosato, Amelie Darlix, Pier Franco Conte
Journal: Journal of Clinical Oncology (2020)

2526 Background: Despite clinical implications, the complexity of brain metastases (BM) immune microenvironment in breast cancer (BC) patients is poorly understood. Multiplex immunofluorescence (mIF), a novel imaging technique allowing simultaneous visualization and quantification of several IF labeled proteins while maintaining spatial information, holds promise to comprehensively describe BCBM immune microenvironment, potentially providing valuable information to improve treatment. Methods: Clinical data and archival BM samples were collected for 60 BC patients undergoing neurosurgery (2003-2018) at three institutions. BM immune contexture was characterized using a custom mIF panel, including cell subtyping (CD4, CD8, FOXP3, CD68), activation (Granzyme B) and localization (keratin for tumor recognition) markers. Mean immune cell density (cells/mm2) for each sample was determined by digital image analysis and classified in tumor and stroma areas. Associations between immune subpopulations, BC subtype and overall survival from BM diagnosis (OS) were studied. Results: Up to date, 30 BCBM samples have been analyzed; 33% HR+/HER2-, 20% HR-/HER2+, 10% HR+/HER2+, 37% HR-/HER2-. At a median follow-up of 46 months, BC subtype was the only clinical variable associated with OS (longest for HER2+ and shortest for HR-/HER2-, log-rank p = 0.002). In the total sample area, no significant difference in immune cell densities was observed according to BC subtype. In the tumor area, HR+/HER2- tumors showed higher densities of CD8+ and CD68+ cells compared to other subtypes (p = 0.036 and p = 0.016, respectively). In stroma, HR-/HER2- tumors presented numerically higher densities of CD4+ and FOXP3+ cells and higher ratio of CD4/CD8 and FOXP3/CD8 ratio (not statistically significant). Higher CD4/CD8 and FOXP3/CD8 ratio in the stroma was significantly associated with worse OS, even after correction by BC subtype (Table). Conclusions: In BCBM, immune infiltrate differs according to BC subtype. Preliminary results suggest that a more tolerogenic immune microenvironment is associated with worse OS and might represent a target for optimization of immunotherapy for these patients. Updated results for all 60 patients will be presented. [Table: see text]
肠吻合口皮下埋植在肠切除伴严重腹腔感染时的应用
Authors: 高海德, 邢壮杰, 赵晖, 李润生, 郑新, 邓芝徽, 郝国强
Journal: BMJ (2010)

对急诊需要肠切除伴腹腔感染严重的患者,因担心肠切除后吻合口漏的发生而采用一期肠造瘘,二期肠吻合,但肠造瘘给患者心理带来负担,生活带来不便.为此,我院对类似病例行一期病变肠管切除、将肠吻合口置于皮下的术式治疗,取得良好的临床效果.现对我院开展此术式治疗的20例患者的临床资料分析如下。
Effect of modulation of CD3 binding in a PSMAxCD3 T-cell engaging bispecific antibody on maintenance of efficient tumor cell kill and cytokine release.
Authors: Ben Buelow, Kevin Dang, Pranjali Dalvi, Yuping Li, Alexander Cheung, Chiara Rancan, Preethi Sankaran, Duy Pham, Katherine Harris, Laura Davison, Aarti Balasubramani, Starlynn Clarke, Alec Starzinski, Lawrence Fong, Suhasini Iyer
Journal: Journal of Clinical Oncology (2020)

e17583 Background: Castration resistant prostate cancer (CRPC) is an incurable disease and represents a significant unmet need. Prostate specific membrane antigen (PSMA) is a protein highly expressed on the surface of prostate cancer cells; expression has been shown to increase with disease progression. Therapies targeting PSMA, such as anti-PSMA radioligand conjugates, have shown promise in clinical trials, validating this target for CRPC. T-cell recruiting bispecific antibodies (T-BsAbs) have demonstrated potent tumor killing activity against multiple tumor types, but immune-mediated toxicities have hampered T-cell redirecting therapies to date. Using Teneobio’s unique antibody discovery platform, we have developed a CD3xPSMA bispecific antibody (TNB-585) that retains the potent cytotoxicity of other T-BsAbs but with significantly reduced cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated via immunization of our proprietary transgenic animals. Candidate antibodies were selected by repertoire deep sequencing of B-cells from draining lymph nodes, followed by high-throughput gene assembly and recombinant expression. Multiple bispecific antibodies targeting CD3 and PSMA were assembled and evaluated for their ability to selectively activate primary human T-cells and mediate killing of PSMA+ tumor cells in vitro, ex vivo, and in vivo. T-cell activation surface markers, cytokine production, and tumor cell cytotoxicity were measured. Results: In co-culture experiments, primary human T-cells were activated only in the presence of both the bispecifics and PSMA+ cells. These bispecifics mediated potent and selective cytotoxicity against PSMA-positive tumor cells, prostate tumor cell lines, or primary human prostate tumor cells isolated from patients. From among these we identified TNB-585, which showed attenuated binding to CD3. TNB-585 mediated comparable tumor cell cytotoxicity to CD3xPSMA T-BsAbs containing a high affinity anti-CD3 domain but with significantly reduced cytokine production. TNB-585 also showed tumor growth inhibition in xenograft models of prostate cancer in vivo. Conclusions: We have developed a novel CD3xPSMA T-BsAb that mediates T-cell killing of PSMA+ tumor cells with minimal production of cytokines. This molecule may improve safety, efficacy, and offer opportunities for combination therapy to treat CRPC. A Phase 1 clinical trial of this compound in CRPC is scheduled to begin in Q1 2021.
Haemophagocytic lymphohistiocytosis (HLH) in patients with large B-cell lymphoma treated with standard of care (SOC) axicabtagene ciloleucel (Axi-cel).
Authors: Sairah Ahmed, fateeha furqan, Paolo Strati, Jason Westin, Luis Fayad, Frederick B. Hagemeister, Hun Ju Lee, Swaminathan Padmanabhan Iyer, Ranjit Nair, Loretta J. Nastoupil, Simrit Parmar, Maria Alma Rodriguez, Felipe Samaniego, Raphael Steiner, Michael Wang, Chelsea Camille Pinnix, Christopher Flowers, Sandra B. Horowitz, Misha Hawkins, Sattva Swarup Neelapu
Journal: Journal of Clinical Oncology (2020)

8057 Background: HLH is a rare but serious complication of chimeric antigen receptor (CAR) T cell therapy, characterized by severe immune activation, and immune mediated multi-organ failure. Diagnosis is difficult in the context of cytokine release syndrome (CRS) and optimal treatment and outcomes are unclear. Methods: Retrospective, descriptive analysis of patients with relapsed/refractory LBCL treated with SOC axi-cel at MD Anderson Cancer Center between 01/2018 - 10/2019 (data cut-off 12/21/2019). Progression-free survival (PFS) defined as time from axi-cel infusion to progression/death or last follow-up. Diagnosis of HLH per HLH-2004 and CART cell therapy toxicity guidelines (Neelapu, 2018) Results: One hundred and five patients with relapsed/refractory LBCL included, 6 diagnosed with HLH. No significant difference in baseline characteristics, disease stage, international prognostic index or inflammatory markers at baseline between groups, with exception of platelet count which was lower in HLH group 116 [37-129] versus 141 [9-391] (p = 0.07). Development of HLH was early after CART cell infusion at a median 11 days [7 – 78 days] with 3 patients having bone marrow hemophagocytosis; all 6 had abnormalities in liver function tests, fibrinogen, triglycerides, and at least 1 ferritin level &gt; 10,000. CART toxicity in HLH cohort: 4 patients experienced grade 0-1 CRS, and 1 with grade 2 CRS while 3 HLH patients experienced grade 3-4 IEC-associated neurotoxicity syndrome ( ICANS), and 2 patients had grade 0-1 ICANS. Five HLH patients treated with high dose steroids, and tocilizumab; anakinra administered in 2 patients. Four of 6 patients had resolution of HLH with treatment and didn’t require escalation to HLH specific therapy however 1 patient was treated with steroids/etoposide. PFS and overall survival (OS) were significantly shorter in HLH group, PFS 1 months vs 8 months, respectively (p &lt; 0.001) and median OS 2 months vs not reached, respectively (p = 0.001) follow up 10 months (95% CI 8-12 months). One patient died of acute respiratory failure, 2 patients died of HLH and multi-organ failure without progressive disease (PD). Of 3 remaining patients, all had radiographic PD at day 30, 2 of whom died of PD. Conclusions: HLH is likely an underreported complication of CART cell therapy, and patients with HLH have significantly worse outcomes. In this series the majority of patients died of PD, not the syndrome itself. More information is necessary to design treatment strategies that won’t compromise CART outcomes.
Author Correction: Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer
Authors: Kirsten L. Bryant, Clint A. Stalnecker, Daniel Zeitouni, Jennifer E. Klomp, Sen Peng, Andrey P. Tikunov, Venugopal Gunda, Mariaelena Pierobon, Andrew M. Waters, Samuel D. George, Garima Tomar, Björn Papke, G. Aaron Hobbs, Liang Yan, Tikvah K. Hayes, J. Nathaniel Diehl, Gennifer D. Goode, Nina V. Chaika, Yingxue Wang, Guo-Fang Zhang, Agnieszka K. Witkiewicz, Erik S. Knudsen, Emanuel F. Petricoin, Pankaj K. Singh, Jeffrey M. Macdonald, Nhan L. Tran, Costas A. Lyssiotis, Haoqiang Ying, Alec C. Kimmelman, Adrienne D. Cox, Channing J. Der
Journal: Nature Medicine (2020)
缺血性脑卒中急性期的治疗选择
Authors: 刘芳
Journal: BMJ (2009)

缺血性脑卒中又称脑梗死,是指因脑部血液循环障碍、缺血缺氧所致的局限性脑组织的缺血性坏死或软化…,是卒中的主要类型.在我国,随着人口老龄化和高血压、糖尿病等危险因素的增多,缺血性卒中的发病率也在逐渐增高.在急性期选择合理的治疗措施,以降低致残率和死亡率尤为重要。
慢性肾衰竭患者应用头孢米诺钠致脑病二例
Authors: 李建英, 梁青, 杜雅静, 胡维华
Journal: BMJ (2011)

例1 患者女,72岁,因糖尿病肾病、慢性肾衰竭、肺部感染于2008年9月12日由急诊入院.既往无精神病史,无药物过敏史,未行透析治疗.于急诊科给予头孢米诺钠2 g、2次/d静脉滴注,入院后查血尿素氮12.9 mmol/L,肌酐326μmol/L,肌酐清除率(cCr)13.1 ml/min,血清白蛋白32 g/L.遂头孢米诺钠减量至1 g、2次/d,共应用3 d,累积量8 g。