tbuckley/cabot-search huggingface dataset:
Pan-Cancer Efficacy of Vemurafenib in <i>BRAF</i>V600-Mutant Non-Melanoma Cancers
Authors: Vivek Subbiah, Igor Puzanov, Jean-Yves Blay, Ian Chau, A. Craig Lockhart, Noopur S. Raje, Juergen Wolf, José Baselga, Funda Meric-Bernstam, Jason Roszik, Eli L. Diamond, Gregory J. Riely, Eric J. Sherman, Todd Riehl, Bethany Pitcher, David M. Hyman
Journal: Cancer Discovery (2020)

Abstract BRAF V600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAFV600 mutations have historically been considered a clear demonstration of tumor lineage context–dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort “basket” study of the BRAF inhibitor vemurafenib in non-melanoma BRAFV600 mutation–positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized. Significance: These data suggest that BRAFV600 mutations lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers, including tumor types in which RAF inhibition is not currently considered standard of care. See related commentary by Ribas and Lo, p. 640. This article is highlighted in the In This Issue feature, p. 627
NRG-GI005 (COBRA): Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer.
Authors: Van K. Morris, Greg Yothers, Scott Kopetz, Samuel A. Jacobs, Peter C. Lucas, Atif Iqbal, Patrick McKay Boland, Dustin A. Deming, Aaron James Scott, Howard John Lim, Norman Wolmark, Thomas J. George
Journal: Journal of Clinical Oncology (2020)

TPS261 Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features as a prognostic factor to assess risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N=1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for no adjuvant chemotherapy will be randomized 1:1 into 2 arms: standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the GuardantHealth LUNAR panel, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. Trial accrual is anticipated across all US and Canadian cooperative groups.NCT#: 04068103. Support: U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: 04068103.
PSMA expression in the neo-vasculature of solid tumors
Authors: Irmgard Kronberger, Michael Haffner, Johannes Laimer, Christof Seifarth, Georg Schaefer, Dietmar Ofner, Matthias Zitt, Gilbert Muhlmann, Christine Sheehan, Jeffrey Ross, Andrea Brunner, Raimund Margreiter, Neil Bander
Journal: Cancer Research (2008)

2181  Background:  Prostate Specific Membrane Antigen (PSMA) is a type II transmembrane metallo-peptidase overexpressed in prostate cells. Initially thought to be highly specific for prostate and cancer, recent evidence suggest that PSMA is also expressed in endothelial cells associated with non-prostatic solid tumors. Thus far only a limited number of solid tumors have been investigated in detail for PSMA expression in the neovasculature. Because of its potential use as a vascular targeting molecule we determined the expression of PSMA in a representative collection of a variety of solid tumor entities including gastric, colo-rectal, renal-cell and urothelial carcinoma.   Experimental design:  PSMA expression was determined by immunohistochemistry in formalin-fixed paraffin-embedded tissue sections of 119 cases of primary gastric cancer, 130 cases of primary colorectal cancers, 19 cases of renal cell carcinoma (RCC), 18 cases of urothelial carcinoma of the bladder and 23 urothelial carcinoma of the renal pelvis. Immunoreactivity was scored semiquantitatively based on staining intensity and distribution. Expression data were correlated with clinicopathological information.   Results:  PSMA expression was detected in tumor-associated neo-vasculature of 79 of 119 (66.4%) of gastric and 110 of 130 (84.6%) of colorectal cancers. Interestingly, 15 (12%) colorectal cancer samples showed also a strong epithelial PSMA staining. There was a trend for high grade tumors to higher PSMA expression (Spearman r = 0.18, P = 0.046) and men generally had higher PSMA level than women (Spearman r = 0.23, P = 0.009) in colorectal cancers. 17 of 19 (89 %) samples of RCC showed strong staining for PSMA in tumor-associated endothelial cells. Non-clearcell carcinoma samples showed no PSMA expression. Thirty-six of fourty-two (88%) urothelial carcinomas exhibited detectable PSMA expression.   Conclusions:  We confirm previous reports on the tumor specific expression of PSMA in neo-vasculature in a large sample collection of solid malignancies. PSMA is frequently expressed in the tumorvasculature but expression levels vary significantly within one tumor entity and between different entities. Further studies investigating the biological significance and regulation of PSMA expression are therefore needed. Because of its highly tumor-specific expression and its unique biological characteristics PSMA represents an interesting target for anti-angiogenic therapies in solid tumors.
Microaxial Left Ventricular Assist Devices
Authors: Holger Thiele, Steffen Desch, Anne Freund
Journal: JAMA (2020)

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DMSOの拒絶: ジメチルスルホキシドはシスプラチン,カルボプラチン,および他の白金錯体を不活性化する
Authors: D Hall Matthew, A Telma Katherine, Chang Ki-Eun, D Lee Tobie, P Madigan James, R Lloyd John, S Goldlust Ian, D Hoeschele James, M Gottesman Michael
Journal: Cancer Research (2014)
Sustained, cell-intrinsic versus intermittent, cell-extrinsic checkpoint blockade in solid tumor CAR T-cell therapy.
Authors: Camille Linot, Jasmeen Saini, Prasad S. Adusumilli
Journal: Journal of Clinical Oncology (2020)

16 Background: We and others have published that antigen-stress induced functional exhaustion of chimeric antigen receptor (CAR) T cells can be rescued by addition of anti-PD1 agents. To avoid the need for multiple administrations of anti-PD1 agent, we developed CAR T-cell intrinsic PD1 dominant negative receptor (PD1 DNR). Herein, we investigated the anti-tumor efficacy of cell-extrinsic versus intrinsic anti-PD1 strategies. Methods: Human T cells transduced with CD28 costimulated mesothelin-targeted CAR T cells (M28z) with or without anti-PD1 agent, and M28zPD1DNR CAR T cells were investigated against mesothelin-expressing cancer cells with inducible or constitutive PDL1 over expression. In vitro, cytotoxicity upon single and multiple antigen stimulation and proliferation, inhibitory receptor expression (PD1, TIM3 LAG3) were tested. In vivo, tumor burden regression kinetics and median survival were determined in an orthotopic model of pleural mesothelioma. Results: Following single antigen stimulation, both CAR T cells exhibited equivalent cytotoxicity. Following multiple antigen stimulations (antigen stress test), M28z PD1DNR CARs showed sustained and relatively higher cytotoxicity and proliferation compared to M28z CAR T cells, even when combined with anti-PD1 agent. PD1, TIM3 and LAG3 expression upregulation was noticed in both CAR T cells. CAR T cell therapy combined with extrinsic PD1 blockade or intrinsic PD1 DNR demonstrated enhanced and sustained tumor regression and prolonged survival (median survival 66 and 60 days) compared to CAR T cell therapy alone (27.5 days). In mouse model with constitutive PDL1 overexpressing cancer, similar trend is observed (74, 69 versus 28 days). Conclusions: A single dose of M28z CAR T cells with cell-intrinsic PD1DNR demonstrated equal anti-tumor efficacy compared to multiple doses of extrinsic anti-PD1 agent administration in models with inducible and constitutive high-PDL1 expressing cancer with no on-target, off-tumor toxicity with either strategy. This data provides the rationale for our ongoing phase II trial of combination therapy with M28z CAR T cells and anti-PD1 agent, and upcoming M28zPD1DNR CAR T cell trial in 2020.
Substrate for the Myocardial Inflammation–Heart Failure Hypothesis Identified Using Novel USPIO Methodology
Authors: Jakub Lagan, Josephine H. Naish, Kara Simpson, Min Zi, Elizabeth J. Cartwright, Phil Foden, Julie Morris, David Clark, Lindsay Birchall, Jessica Caldwell, Andrew Trafford, Christien Fortune, Michael Cullen, Nazia Chaudhuri, James Fildes, Jaydeep Sarma, Erik B. Schelbert, Matthias Schmitt, Karen Piper Hanley, Christopher A. Miller
Journal: JACC. Cardiovascular imaging (2020)

The purpose of this study was to identify where ultrasmall superparamagnetic particles of iron oxide (USPIO) locate to in myocardium, develop a methodology that differentiates active macrophage uptake of USPIO from passive tissue distribution; and investigate myocardial inflammation in cardiovascular diseases. Myocardial inflammation is hypothesized to be a key pathophysiological mechanism of heart failure (HF), but human evidence is limited, partly because evaluation is challenging. USPIO-magnetic resonance imaging (MRI) potentially allows specific identification of myocardial inflammation but it remains unclear what the USPIO-MRI signal represents. Histological validation was performed using a murine acute myocardial infarction (MI) model. A multiparametric, multi-time-point MRI methodology was developed, which was applied in patients with acute MI (n = 12), chronic ischemic cardiomyopathy (n = 7), myocarditis (n = 6), dilated cardiomyopathy (n = 5), and chronic sarcoidosis (n = 5). USPIO were identified in myocardial macrophages and myocardial interstitium. R1 time-course reflected passive interstitial distribution whereas multi-time-point R2* was also sensitive to active macrophage uptake. R2*/R1 ratio provided a quantitative measurement of myocardial macrophage infiltration. R2* behavior and R2*/R1 ratio were higher in infarcted (p = 0.001) and remote (p = 0.033) myocardium in acute MI and in chronic ischemic cardiomyopathy (infarct: p = 0.008; remote p = 0.010), and were borderline higher in DCM (p = 0.096), in comparison to healthy controls, but were no different in myocarditis or sarcoidosis. An R2*/R1 threshold of 25 had a sensitivity and specificity of 90% and 83%, respectively, for detecting active USPIO uptake. USPIO are phagocytized by cardiac macrophages but are also passively present in myocardial interstitium. A multiparametric multi-time-point MRI methodology specifically identifies active myocardial macrophage infiltration. Persistent active macrophage infiltration is present in infarcted and remote myocardium in chronic ischemic cardiomyopathy, providing a substrate for HF.
Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab: Results of the expansion part of a phase I study in patients with metastatic colorectal cancer.
Authors: Roberto Bordonaro, Aitana Calvo, Alessandra Auriemma, Antoine Hollebecque, Gabor Rubovszky, Mark P. Saunders, Zsuzsanna Papai, Gerald W. Prager, Alexander Stein, Thierry Andre, Guillem Argiles, Antonio Cubillo, Laetitia Dahan, Julien Edeline, Catherine Leger, Nadia Amellal, Valerie Cattan, Josep Tabernero
Journal: Journal of Clinical Oncology (2020)

140 Background: Trifluridine/tipiracil (FTD/TPI) is approved for use in patients (pts) with pretreated mCRC. In vivo studies have shown an increase in anti-tumor activity when combining FTD/TPI, oxaliplatin or bevacizumab, and an increase in tumor immunogenicity after treatment with FTD/TPI and oxaliplatin (Ghiringhelli, 2018). The recommended dose for expansion had been defined as FTD/TPI 35 mg/m² bid, days 1–5 q14, together with oxaliplatin 85 mg/m² (day 1). Methods: In addition to FTD/TPI and oxaliplatin, eligible pts received bevacizumab 5 mg/kg (Cohort A) or nivolumab 3 mg/kg (Cohort B) on day 1. Eligibility criteria included measurable disease, performance status (PS) 0-1, normal organ function, progression after &gt; 1 prior anti-tumor therapy (excluding oxaliplatin), and confirmed MSS status (Cohort B). A Bayesian design was used for futility and efficacy assessments. Efficacy endpoints of objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and adverse events (AEs) were assessed for each cohort; biomarkers of immune function including PD-L1 expression for Cohort B. Results: A total of 37 and 17 pts were enrolled in Cohorts A and B respectively; with a median age of 64 years (range 33 to 83 years), 61% and 39% had an PS of 0 and 1. At baseline, no pt showed PD-L1 expression on tumor cells, and only 1 pt on immune cells (5% threshold). At data cutoff, 32 and 12 pts were evaluable for response in Cohorts A and B. In Cohort A, ORR was 13% (1 CR; 3 PR), and DCR was 91%. The mPFS was 6.9 months (95% IC, 4.3-9.3). In Cohort B, ORR was 8% (1 PR), DCR was 67%. The mPFS was 6.5 months (95% IC, 1.8-8.6). Overall, the most common treatment-related AEs (≥20% of pts) included neutropenia, nausea, diarrhoea, and fatigue; only 1 pt reported grade 3 febrile neutropenia; 5 pts discontinued due to AEs and no treatment-related death were reported. Conclusions: In this study, bevacizumab in addition to FTD/TPI and oxaliplatin showed antitumor activity. The cohort of nivolumab was prematurely discontinued due to lack of efficacy. Both cohorts showed an acceptable safety profile in pretreated mCRC pts. Clinical trial information: NCT02848443.
Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies
Authors: Rong Fu, Yi Li, Nan Jiang, Bo-Xue Ren, Chen-Zi Zang, Li-Juan Liu, Wen-Cong Lv, Hong-Mei Li, Stephen Weiss, Zheng-Yu Li, Tao Lu, Zhao-Qiu Wu
Journal: Journal of Clinical Investigation (2020)

Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium–enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-β signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti–programmed cell death protein 1 (anti–PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.
Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with mFOLFOX6 (three versus six months) in the prospective IDEA France cohort study (PRODIGE-GERCOR).
Authors: Franck Pages, Thierry Andre, Julien Taieb, Dewi Vernerey, Julie Henriques, Christophe Borg, Florence Marliot, Rim Ben Jannet, Christophe Louvet, Laurent Mineur, Jaafar Bennouna, Jérôme Desrame, Roger Faroux, Alex Duval, Pierre Laurent-Puig, Magali Svrcek, Fabienne Hermitte, Aurelie Catteau, Jerome Galon, Jean-François Emile
Journal: Journal of Clinical Oncology (2020)

10 Background: In stage III colon cancer patients treated with CAPOX, 3 months of therapy was as effective as 6 months. It was not the case for those receiving mFOLFOX6. We assessed the prognostic and predictive value of the Immunoscore (IS) in the mFOLFOX6 subgroup (90% of patients enrolled) of the IDEA France cohort study. Methods: 1200 patients randomly assigned to 3 months (n = 593) or 6 months (n = 607) of mFOLFOX6, with available tumor sample, were included. Densities of CD3+ and cytotoxic CD8+ T-cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS using the pre-defined cut-off. The IS performance to predict disease-free survival (DFS) was assessed in each arm and adjusted in multivariate Cox models. Results: In a two-category IS analysis, Low and (Int+High) IS were observed in 423 (43.5%) and 550 (56.5%) patients, respectively. Low IS identified patients with higher-risk of relapse or death (HR = 1.60; 95% CI 1.27-2.01, P &lt; 0.0001). The 3-year DFS was 66.34% (95% CI 61.54-70.69) and 77.66% (95% CI 73.86-80.97) for Low and (Int+High) IS, respectively. In multivariate analysis, IS remained independently associated with DFS (P = 0.0007) when combined with T/N stage. A statistically significant interaction was observed for the IS predictive value for treatment duration (3 vs 6 months) in term of DFS in the whole population (P = 0.0566) and TN subgroups (Low-risk T1-3, N1 vs High-risk T4 and/or N2; P = 0.0015). The 3-year DFS of patients with (Int+High) IS in the 3-month arm was 71.5% (95% CI 65.7-76.6) versus 83.8% (95% CI, 78.8-87.8) in the 6-month arm (HR = 0.528; 95% CI 0.372-0.750; log-rank P = 0.0004); the benefit retained in low-risk and high-risk patients (all P≤0.010). 6-month mFOLFOX6 showed no significant benefit for patients with Low IS (HR = 0.836, log-rank P = 0.269). Conclusions: The IS prognostic value in patients treated with mFOLFOX6 was confirmed. Its predictive value for benefit of longer duration treatment, despite a strong statistical signal, needs to be confirmed in an external validation cohort. Clinical trial information: NCT03422601.
Dupilumab 治疗 95 例特应性皮炎患者的有效性:日常实践数据
Authors: L.E.M. Wijs, A.L. Bosma, N.S. Erler, L.M. Hollestein, L.A.A. Gerbens, M.A. Middelkamp‐Hup, A.C.M. Kunkeler, T.E.C. Nijsten, P.I. Spuls, D.J. Hijnen
Journal: British Journal of Dermatology (2020)

特应性皮炎 (AD) 是一种湿疹,在儿童中非常常见,但也影响全世界 2%‐10% 的成年人。主要症状是瘙痒,其严重程度足以妨碍患者正常入睡。它可以发生在任何部位的皮肤上(包括脸部),但最常见的区域是肘部、膝盖、腕部和颈部。发病的皮肤通常是红色和干燥的,并且可能因刮擦而出血。 目前,对于患有中度至重度 AD 患者的治疗可能是有效的,但可能有局限性,例如副作用。Dupilumab 是注册用于治疗中度至重度 AD 的第一个生物制剂类别药物。大型临床试验已证明其疗效、耐受性(指患者是否能够继续接受治疗)和安全性。但是,关于 Dupilumab 的日常实践数据有限。 这项研究的目的是评估日常实践中使用 Dupilumab 治疗 AD 患者,作者纳入荷兰两家大学医院 95 例接受 Dupilumab 治疗的 AD 患者。62 例患者从一开始(基线)使用全身性免疫抑制剂治疗,在 Dupilumab 治疗期间 43 例继续使用全身性免疫抑制剂。 这项研究使用了各种系统来监测每位患者湿疹的改善情况,可由医生或患者报告。从基线到治疗的 16 周,疾病严重程度评分(湿疹面积和严重程度指数评分 (0‐72),供医生记录湿疹的严重程度)从 18.6 降低到 7.3,患者报告的评分(由患者回答问题来表明症状是否有所改善或恶化)改善了 41%‐66%。 5 例患者由于副作用或无效而停止了 Dupilumab 治疗。据报道,分别有 62% 和 8% 的患者出现眼部症状和口面(非眼)单纯疱疹病毒 (HSV) 再激活。 作者得出的结论是,在日常实践中使用 Dupilumab 治疗显示医师报告的分数和患者报告的分数均具有临床意义的改善,这与来自临床试验的疗效数据一致。除了经常报告的眼部症状和口面部(非眼部)HSV 再激活以外,没有明显的安全性问题。 本摘要涉及研究: Dupilumab 治疗 95 例特应性皮炎的有效性: 日常实践数据
Activism for health: green surgery
Authors: Amit S Gill, Thomas Hampton, Ravi Sharma
Journal: BMJ (2020)

This year has seen an unprecedented focus on our climate change emergency.1 Activist Greta Thunberg has called for adults to join the campaign, noting, “To change everything, we need everyone.”2 We recommend self-awareness around the use of equipment in surgical theatres.

Some UK estimates find the NHS responsible for 25% of public sector emissions.3 Grant and Bailey explained how …