tbuckley/cabot-search huggingface dataset:
Overall survival (OS) with docetaxel (D) vs novel hormonal therapy (NHT) with abiraterone (A) or enzalutamide (E) after a prior NHT in patients (Pts) with metastatic prostate cancer (mPC): Results from a real-world dataset.
Authors: Umang Swami, Jennifer Anne Sinnott, Ben Haaland, Benjamin Louis Maughan, Nityam Rathi, Taylor Ryan McFarland, Manish Kohli, Roberto Nussenzveig, Sumanta K. Pal, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2020)

5537 Background: NHT (A and E) are approved first-line (1L) treatment (Rx) for mPC. After progression on NHT, Rx include either alternate NHT or D. However, OS from a randomized trial comparing NHT vs D after progression on 1L NHT has not been reported. Methods: Pts data were extracted from the Flatiron Health EHR-derived de-identified database. Inclusion: diagnosis of mPC; 1L Rx with single agent A or E only, single-agent Rx with alternate NHT (E or A) or D in second line (2L). Exclusion: &gt; 180 days between date of diagnosis of mPC and date of next visit to ensure Pts were actively engaged in care at data-providing site; Rx with NHT in non-metastatic setting, any prior exposure to D. OS was compared using Cox proportional hazards model stratified by Rx propensity score. Each Pts’ probability of receiving D (rather than NHT) was modeled via a random forest based on Pts and disease characteristics which may drive treatment selection. These included pre-2L Rx ECOG scores, PSA, LDH, ALPH, Hb, age, ICD codes for liver metastasis, diabetes, neuropathy, and heart failure; insurance payer, year of start of 2L Rx, time on 1 L NHT, Gleason score, PSA at the original diagnosis of mPC. Subgroup analyses included 1L Rx duration &lt; 12 mos. Results: 1165 Pts between 2/5/2013 to 9/27/2019 were eligible. Median follow up 8 mos (range 0.1-64.5). Median OS after 1L A was higher with E as compared to D (15.7 vs. 9.4 mos). Median OS after 1L E was higher with A as compared to D (13.3 vs. 9.7 mos) (table). Propensity distributions were overlapping among Rx arms and showed only modest imbalance. In 2L, D had a worse adjusted hazard ratio of 1.29 and 1.35 as compared to E and A respectively (p &lt; 0.05). Similar results were seen with 1L Rx duration of &lt; 12 mos (p &lt; 0.05). Conclusions: These hypothesis-generating data provide real-world OS estimates with 2L D &amp; NHT in mPC. In propensity-stratified analyses, mPC Pts who progressed on NHT had a worse OS with 2L D as compared to alternate NHT. Results were consistent in unadjusted analysis &amp; subgroup analyses of 1L Rx &lt; 12 mos. Results are subject to residual confounding and missingness. After prospective validation these data may aid in Rx sequencing, Pts counselling, and design of future clinical trials in this setting. [Table: see text]
Towards cancer mega-cohorts: A novel homogenization algorithm applied to diverse breast cancer RNA-Seq datasets.
Authors: Talal Ahmed, Mark Carty, Stephane Wenric, Raphael Pelossof
Journal: Journal of Clinical Oncology (2020)

e13507 Background: Recent advances in transcriptomics have resulted in the emergence of several publicly available breast cancer RNA-Seq datasets, such as TCGA, SCAN-B, and METABRIC. However, molecular predictors cannot be applied across datasets without the correction of batch differences. In this study, we demonstrate a homogenization algorithm that allows the transfer of molecular subtype predictors from one RNA-Seq cohort to another. The algorithm only uses cohort-level RNA-Seq summary statistics, and therefore, does not require joint normalization of both datasets nor the transfer of patient information. Using this approach, we transferred a breast cancer subtype (Luminal A, Luminal B, HER2+, Basal) predictor trained on SCAN-B data to accurately predict subtypes from TCGA. Methods: First, we randomly split the TCGA cohort (n = 481 Luminal A, n = 189 Luminal B, n = 73 Her2+, n = 168 Basal) into two sets: TCGA-train and held-out TCGA-test (n = 455 and n = 456, respectively). Second, the SCAN-B cohort (n = 837) was homogenized with the TCGA-train set. Third, a molecular subtype predictor, based on a logistic regression model, was trained on homogenized SCAN-B RNA-Seq samples and used to predict the subtypes of TCGA-test RNA-Seq samples. For baseline comparison, a similar predictor trained on the non-homogenized SCAN-B cohort was tested on the TCGA-test set. The experimental framework was iterated 250 times. Reported P-values reflect a paired one-sided t-test. Results: To quantify model performance, we measured the average F1 score for each tumor subtype prediction from the held-out TCGA test set with and without cohort homogenization. The average F1 scores with vs. without homogenization were: Luminal A, 0.88 vs. 0.85 ( P&lt; 1e-69); Luminal B, 0.74 vs. 0.51 ( P&lt; 1e-183); Her2+, 0.73 vs. 0.53 ( P&lt; 1e-99); Basal, 0.98 vs. 0.97 ( P&lt; 1e-53). Overall, homogenization significantly outperformed no homogenization. Conclusions: We developed a novel homogenization algorithm that accurately transfers subtype predictors across diverse, independent breast cancer cohorts.
Quality of life and its influencing factors in elderly patients with advanced cancer
Authors: Min Yu, Xiaoqin Lu
Journal: BMJ (2017)

Objective
To assess the quality of life and its influencing factors in elderly patients with advanced cancer.


Methods
The quality of life was evaluated with EORTC QLQ-C30 scale Chinese version in 103 elderly patients with advanced cancer in a hospital outpatient clinic of Beijing from July 2013 to July 2014. The overall health, physical function, role function, cognitive function, emotional function, social function and individual symptoms score were assessed. The general information and clinical data of patients were analyzed.


Results
The general score of quality of life in elderly advanced cancer patients was (35.77±21.98). In the domain of function the role functional score was the lowest (36.60±27.97); in the domain of symptoms the tired score was the highest(50.82±30.16), the score of appetite loss was the highest in individual symptoms (39.78±24.32). Educational level, marital status, living condition, medical insurance and the number of comorbidities were correlated with overall health in elderly patients with advanced cancer (P<0.05). Multiple linear regression analysis showed that the educational level (t=2.447, P<0.05), marital status (t=2.118, P<0.05), medical insurance (t=3.770, P<0.05) and overall health status were positively correlated with the quality of life scores; and number of comorbidities (t=-7.157, P<0.05) was negatively associated with the overall quality of life.


Conclusion
The quality of life was generally poor in elderly patients with advanced cancer; and educational level, marital status, medical insurance, comorbidities are important influencing factors.


Key words: 
Quality of life; Cancer; Elderly
Lungful: An observational prospective study to assess the molecular epidemiology of EGFR mutations upon progression on or after first line EGFR-TKI therapy, in real-life clinical settings in Greece.
Authors: Giannis Socrates Mountzios, Dimitrios Mavroudis, Epaminondas Samantas, Anna Koumarianou, Evangelos Georgios Konstantinos Fergadis, Panagiotis Katsaounis, Ilias Athanasiadis, Michalis Karamouzis, Ioannis Boukovinas, Sofia Lampaki, Aggeliki Rapti, Marios E Froudarakis, Stamatia-Eleni Kalampaliki, Eleftheria Anastasopoulou, Alvertos Somarakis, Konstantinos N. Syrigos
Journal: Journal of Clinical Oncology (2020)

e21641 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the gold standard 1 st line strategy for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations (EGFRm), associated with improved survival outcomes and quality of life compared to chemotherapy. Despite the high response rate with first- and second- generation TKIs, most patients develop resistance to treatment and progress. The acquisition of T790M mutation in exon 20 is considered the most common resistance mechanism. This study aims to investigate the molecular epidemiology of EGFR resistance mutations, focusing on T790M in EGFRm NSCLC patients treated with TKIs. Methods: The study included patients with locally advanced/metastatic EGFRm NSCLC who have progressed on or after 1 st line treatment with first- or second- generation TKI. Samples either from plasma-based liquid biopsy and/or tissue re-biopsy were analysed using the Cobas EGFR Mutation Test v2. All patients signed informed consent and were enrolled between July 2017 and September 2019. Statistical analyses were performed using SAS software, Version 9.4. Results: Ninety-six eligible patients were enrolled. At the time of progression, T790M mutation was detected in 16.7%of the patients using plasma-based liquid biopsies. Among patients with negative T790M result, in plasma, tissue re-biopsy was performed in 22,7% with evaluable/valid results in 72.2% of them. T790M mutation was identified in 38.5% of re-biopsy samples. According to Cobas EGFR Mutation test results (combined plasma and tissue), T790M mutation was identified in 21.9% of the patients. Of T790M-positive patients 42.9% had previously received first and 57.1% second generation EGFR-TKI. Conclusions: Results from this study in real world clinical setting in Greece, show that EGFR-T790M acquired resistance positivity rate in plasma is lower compared to previous reports. Moreover, these data underline the challenges of implementing precision medicine using tissue re-biopsy in advanced/metastatic NSCLC. Clinical trial information: D133FR00126. [Table: see text]
Soluble BTN2A1 as a potential predictive biomarker of immune checkpoint inhibitor efficacy in advanced non-small cell lung cancer (NSCLC).
Authors: Philippe Rochigneux, Anne Sophie Chretien, Delphine Rossille, Brice Chanez, Emilien Billon, Stephane Fattori, Romain Corre, Jihane Pakradouni, Anthony Goncalves, Thierry Fest, Anne Madroszyk, Daniel Olive
Journal: Journal of Clinical Oncology (2020)

9561 Background: Medical treatment of lung cancer has irreversibly changed since the development of immune checkpoint inhibitors (ICI). However, immune biomarkers of efficacy are still lacking. Preliminary data in leukemia and pancreatic cancer showed that soluble immune checkpoints are associated with a reduced overall survival (OS). This led us to explore the prognostic and predictive value of soluble immune checkpoints in non-small cell lung cancer (NSCLC) patients treated with chemotherapy or ICI. Methods: We analyzed 90 advanced NSCLC patients. The pilot cohort (Rennes University Hospital, France), included 48 patients treated with platinum doublets (n = 33) or ICI (n = 15) (LOC/11-16 protocol). The confirmation cohort (Paoli-Calmettes Institute) included 42 patients treated with ICI (nivolumab or pembrolizumab) in a longitudinal prospective setting (Immunosup trial, NCT03595813). In both cohorts, enzyme-linked immunosorbent assays (ELISA) were performed in baseline plasma samples for soluble forms of PD-1, PD-L1, global BTN3, BTLA, BTN3-A1 and BTN2A1. Soluble ICI levels were linked to clinical data using Kaplan-Meier, log-rank and Cox proportional-hazards models. Cut-points were determined using maxstat package for survival, R software R 3.6.2. Results: Five soluble immune checkpoints correlated and clustered together in unsupervised analysis (PD-1, PD-L1, global BTN3, BTLA, BTN3-A1), but were not associated with ICI efficacy. In patients treated with ICI, in the pilot and confirmation cohort, a high baseline plasmatic concentration of soluble BTN2A1 was significantly associated with an improved OS (confirmation cohort with a BTN2A1 cut-point of 3.55 ng/ml: HR = 0.30, 95%CI = 0.12-0.74, p = 0.0057, median OS in BTN2A1 low = 7.6 months and median OS in BTN2A1 hi = 19.5 months). On the contrary, in patients treated with chemotherapy, soluble BTN2A1 concentration was not associated with overall survival. Conclusions: In advanced NSCLC patients, a high baseline plasmatic concentration of soluble BTN2A1 was correlated with improved outcomes for ICI, but not for chemotherapy, suggesting that baseline soluble BTN2A1 level is a potential predictive biomarker of ICI efficacy. Additional studies are ongoing to confirm this finding.
Temozolomide-induced hypermutation is associated with high-grade transformation, distant recurrence, and reduced survival after transformation in initially low-grade <i>IDH</i>-mutant diffuse gliomas.
Authors: Nancy Ann Oberheim Bush, Yao Yu, Javier Villanueva-Meyer, Matthew Grimmer, Stephanie Hilz, David Solomon, Serah Choi, Tali Mazor, Chibo Hong, Anny Shai, Joanna J. Phillips, Mike McDermott, Daphne A. Haas-Kogan, Jennie Taylor, Nicholas A. Butowski, Jennifer Clarke, Mitchel Berger, Annette Molinaro, Susan Marina Chang, Joseph Costello
Journal: Journal of Clinical Oncology (2020)

2506 Background: Temozolomide, a commonly used alkylating agent to treat gliomas, can induce somatic hypermutation. The prevalence and clinical implications of this phenomenon are not well characterized. Methods: We used targeted and whole exome sequencing from a cohort of 82 patients with recurrent IDH-mutant low grade gliomas undergoing re-operation to evaluate the prevalence as well as the clinical implications of hypermutation. Results: Hypermutation was identified at transformation in 57% of recurrent gliomas exposed to Temozolomide, 94% of which were transformed to higher WHO grades. All patients who developed hypermutation were exposed to Temozolomide. Hypermutation was associated with transformation to higher WHO grade (OR 12.0 95% CI 2.5 – 115.5, p = 0.002) and shorter survival after transformation (HR 2.1, 95% CI 1.1-4.0, p = 0.018) compared with non-hypermutated transformed tumors, controlling for grade, molecular subtype, age, and prior radiotherapy. Patients with transformation to glioblastoma had poor survival regardless of hypermutation (p = 0.78). Hypermutated tumors were associated with development of discontiguous disease at a significantly higher frequency (p = 0.003), including four cases with spinal dissemination. Conclusions: TMZ-induced hypermutation is associated with high grade transformation, unique patterns of dissemination and shortened survival after transformation. Next generation sequencing should be considered in this patient population. These data have important implications for the management of newly diagnosed and recurrent IDH-mutant low grade gliomas.
如何利用免费的网络医学继续教育资源
Authors: 李蓓, 周宇葵
Journal: BMJ (2006)

网络上的医学继续教育(CME)资源非常丰富.医业网、37℃医学网、HealthAtoZ、MedMatrix、Medscape、Healthweb、MedWorld、Achoo及美国国立卫生研究所、世界许多权威学会或协会主页都提供了继续医学教育和培训信息。
Bridging the Translational Divide in Oncology: In Vivo Testing of Chemo-sensitivity
Authors: Stefan Sleijfer, Martijn Lolkema
Journal: Clinical Cancer Research (2020)

A study was presented in which sarcomas were microinjected simultaneously with several drugs to study the pharmacodynamic response after resection. This platform may represent a future way of probing efficacy of anticancer agents in the relevant model system: human tumors.See related article by Gundle et al., p. 3958.
HPV ctDNA analysis in unresectable recurrent/metastatic oropharyngeal cancer.
Authors: Catherine T Haring, Collin Brummel, Brittany Jewell, Molly Heft Neal, Emily Bellile, Matthew E Spector, Michelle Mierzwa, Francis P. Worden, Muneesh Tewari, Chad Brenner, Paul Swiecicki
Journal: Journal of Clinical Oncology (2020)

6554 Background: There is an increasing incidence of human papillomavirus associated (HPV+) oropharyngeal cancer (OPC). While HPV + portents improved prognosis, survival for patients with unresectable recurrent/metastatic (R/M) OPC remains poor. Extant data suggest that HPV ctDNA levels correlate with disease burden and treatment outcomes in patients with HPV + OPC in the primary setting but scant data exists in the metastatic setting. Objective: To develop a highly precise droplet digital (ddPCR) assay for quantification of plasma HPV ctDNA and to evaluate whether HPV ctDNA predicts treatment response in patients with HPV+ R/M OPC. Methods: Patients with HPV + R/M OPC starting systemic therapy were enrolled in a biorepository in which blood was collected prior to each cycle of therapy. PCR probes were created for the most common high-risk HPV subtypes, 16 and 18. HPV ctDNA was extracted from plasma and quantified with ddPCR. Percent change in HPV ctDNA was calculated after 1 and 2 cycles of treatment. Treatment response was assessed per standard of care or study protocol after 2-3 cycles of treatment. ROC curve analyses were performed. Results: A precise ddPCR assay was developed to identify plasma HPV ctDNA in 10 patients who underwent 16 distinct treatment courses. On ROC curve analysis, percent change in HPV ctDNA after 2 cycles of treatment was predictive of radiographic response (AUC 0.82, p = 0.03). The optimal cutoff point to optimize sensitive and specificity was identified as 30% change in HPV ctDNA (Table). Changes in HPV ctDNA after 1 cycle of treatment were also predictive of radiographic response (AUC 0.82, p = 0.05). Conclusions: Changes in HPV ctDNA may be predictive of treatment response in patients with R/M HPV + OPC. Furthermore, HPV ctDNA predicts response earlier than conventional imaging. While validation is needed, this assay shows promise in identifying poor responders who can be directed early towards clinical trials or alternative therapies. [Table: see text]
Phase II trial of Voyager-V1 (vesicular stomatitis virus expressing human IFNβ and NIS, VV1), in combination with cemiplimab (C) in patients with NSCLC, melanoma, HCC or endometrial carcinoma.
Authors: Mario Sznol, Jose Lutzky, Alex A. Adjei, Steven Francis Powell, Aiwu Ruth He, Manish Patel, Steven O'Day, Naimish B. Pandya, Stephen Kaesshaefer, Monica Reckner, Cheryl Brown, Rosa M Diaz, Luke Russell, Kah Whye Peng, Erol Wiegert, Giuseppe Gullo, Frank A. Seebach, Israel Lowy, Alice Susannah Bexon
Journal: Journal of Clinical Oncology (2020)

TPS3161 Background: VV1 is an oncolytic vesicular stomatitis virus engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and the human sodium iodide symporter (NIS) for virus tracking by SPECT imaging. Cancer cells are often hyporesponsive to IFNβ, enabling the efficient spread of VV1 and resulting in increased oncolysis. Differently from other oncolytic viruses, VV1 is suitable for both intra-tumoral (IT) and/or intra-venous (IV) administration. Despite considerable anti-tumor activity with checkpoint inhibitors (CPI) among some malignancies, long term survival and overall cures remain elusive. Prior Ph 1 studies have shown significant anti-tumor activity among several malignancies when VV1 was administered either as monotherapy or in combination with a CPI, despite progression on prior CPI monotherapy. Furthermore, pre- and post-treatment biopsy evaluations after VV1 treatment have demonstrated T cell infiltration and inflammation in both IT injected and non-injected lesions. Among IV treated patients (pts), IFNβ was detectable in the serum correlating with viral replication, making it an effective biomarker. C is a high-affinity potent human IgG4 anti-PD-1 monoclonal antibody. Though approved for use in cutaneous squamous cell carcinoma, C has shown anti-tumor activity, similar to other CPI, in several other indications. Therefore, VV1 and C could be an attractive combination for the immunotherapy for several solid tumors. This study represents the first clinical evaluation of VV1 in combination with C in pts with advanced solid tumors. Methods: The Ph 2 Simon 2 stage five-arm study of IV administration VV1 in combination with IV C will enroll pts with advanced NSCLC, HCC, melanoma &amp; endometrial cancer. Enrolled pts with NSCLC &amp; melanoma will be recent CPI-progressors, whereas enrolled HCC &amp; endometrial cancer will be CPI-naïve. The study’s objectives include assessment of preliminary anti-tumor activity, safety, &amp; immuno-regulatory activity of the combination. Pts will receive IV VV1 once on D1 and IV C once every 3 weeks until confirmed disease progression or intolerable toxicity. Pts enrolled in one melanoma cohort will also receive IT VV1 administered to palpable lesions. Response will be assessed every 9 weeks per RECIST v1.1. The null hypothesis of each cohort’s ORR will be tested versus a one-sided alternative yielding a Type I error rate of 5% and power of 80%. Cohorts will be expanded based on signal of activity. Clinical trial information: NCT .
Impact of body mass index on survival of medical patients with sepsis: a prospective cohort study in a university hospital in China
Authors: 周庆涛, 王蒙, 李硕, 张静, 马青变, 丁艳苓, 葛洪霞, 沈宁, 郑亚安, 孙永昌
Journal: BMJ (2019)

目的
在内科脓毒症患者中评价体质指数(BMI)对生存情况的影响。


设计
2015年5月至2017年4月进行的单中心前瞻性队列研究。


研究地点
中国的一家大学附属三级医院。


研究对象
共纳入178例在内科重症监护病房（ICU）接受治疗的脓毒症患者。


结局指标
主要研究终点为90天死亡率，次要研究终点为住院死亡率、住ICU时间和住院时间。


结果
患者年龄中位数(四分位范围)为78 (66~84)岁，且77.0%的患者在65岁以上。90天死亡率为47.2%，住院死亡率为41.6%，住ICU时间和住院时间分别为12 (5~22)天和15（9~28）天。Cox回归分析表明序贯器官衰竭（SOFA）评分[危害比（HR）=1.229，P<0.001]、急性生理学与慢性健康状况评价（APACHE）Ⅱ评分(HR=1.050，P<0.001)和BMI (HR=0.940，P=0.029)是90天死亡的独立影响因素。根据BMI将患者分为4组[低体重33例(18.5%)、正常98例(55.1%)、超重36例(20.2%)和肥胖11例(6.2%)]。90天死亡率(66.7%、48.0%、36.1%和18.2%，P=0.015)和住院死亡率(60.6%、41.8%、30.6%和18.2%，P= 0.027) 4组间差异均有统计学意义。Kaplan-Meier生存分析也表明4组间生存率差异有统计学意义(P=0.008)，低体重患者生存率最低。


结论
在中国进行的队列研究表明，BMI是内科脓毒症患者90天生存情况的独立影响因素，BMI越低死亡风险越高。
Discovery of proangiogenic CD44+mesenchymal cancer stem cells in an acute myeloid leukemia patient’s bone marrow
Authors: Huynh Cao, Jeffrey Xiao, Mark E. Reeves, Kimberly Payne, Chien Shing Chen, David J. Baylink, Guido Marcucci, Yi Xu
Journal: Journal of Hematology & Oncology (2020)

Abstract Here, we report a unique acute myeloid leukemia (AML) bone marrow-derived mesenchymal stem cell (MSC) with both mesenchymal and endothelial potential, which we have named Mesenchymal Cancer Stem Cells (MCSCs). These MCSCs are CD90-CD13-CD44+ and differ from MSCs in isolation, expansion, differentiation, immunophenotype, and cytokine release profile. Furthermore, blocking CD44 inhibited the proliferation and cluster formation of early MCSCs with lower ICAM-1 protein levels. Similar CD90-CD44+ cancer stem cells have been reported in both gastric and breast cancers, which grew in floating spheres in vitro and exhibited mesenchymal features and high metastatic/tumorigenic capabilities in vivo. Our novel discovery provides the first evidence that certain AMLs may be comprised of both hematopoietic and stromal malignant cells. Targeting MCSCs and their cytokine release has potential as a novel therapeutic approach in AML.