tbuckley/cabot-search huggingface dataset:
Association of mutant EGFR concentration in circulating cell-free DNA (cfDNA) by ddPCR with tumor burden and prognosis in NSCLC patients treated with EGFR-TKIs.
Authors: Yan-juan Zhu, Hai-bo Zhang, Yi-hong Liu, Fu-li Zhang, Ya-zhen Zhu, Guang-juan Zheng, Jun Chen, Yong Li, Jian-ping Bai, Li-rong Liu, Yan-chun Qu, Xin Qu, Xian Chen, Yan Li
Journal: Journal of Clinical Oncology (2016)

e23063 Background: To determine the clinical significance of plasma EGFR mutation by droplet digital PCR (ddPCR). Methods: Plasma DNA from 103 consecutive NSCLC patients, including 54 with mutated and 49 with wild EGFR in tumor tissues, were tested for L858R, exon 19 deletion (ex19del) and T790M mutation by ddPCR. The Plasma EGFR was compared with the matched tumors to determine the concordance. Second, we analyzed the correlation of plasma mutant EGFR concentrations with tumor burden and prognosis of patients taking EGFR-TKIs. Results: The sensitivity and specificity of ddPCR were 72.22% (26/36) and 98.51% (66/67) for mutant L858R, and 83.33% (15/18) and 100% (85/85) for ex19del, respectively. No T790M mutation in tumor tissue or plasma at baseline was detected. Plasma mutant EGFR concentrations were significantly higher in patients with extensive tumor burden (lg(L858R) 2.44±0.20 vs. 0.66±0.26, p<0.0001; lg(ex19del) 2.68±0.41 vs. 1.05 ±0.39, p=0.012). Median PFS of patients taking EGFR-TKIs with high and low baseline mutant L858R was 11.47 vs. 14.63 months (p=0.6434), while that of ex19del was 8.43 vs. 13.07 months, respectively (p=0.8269). In the 13 progressed patients whose plasma EGFR were also tested at progression, 10 were with the same plasma mutation as baseline, while 7 were with mutant T790M. Conclusions: Plasma EGFR mutation concentration by ddPCR, with significant correlation with tumor burden, displayed satisfactory monitoring value and concordance with tumor tissues. However, we failed to find correlation of baseline mutant EGFR concentration with PFS in patients taking EGFR-TKIs. Plasma EGFR, tumor burden, and PFS. Concentration in Plasma (copies/ml, median(25% ~75% percentile)) L858R (36 patients) ex19del (18 patients) Total 222.1(0~ 494.25) 211.65 (3.8~780) Tumor burden p<0.0001 p=0.0127 Extensivea 380(244.2~872.7) 693.55(123.3~4720) Non-extensive 0(0~21.1) 5.4(0~187.5) Median PFS (months, 49 patients) Concentration group p=0.6434 p=0.8269 High groupb 11.47 8.43 Low group 14.63 13.07 a Diffuse involvement of one organ or ≥3 distinct organs involved; b Plasma mutant EGFR concentration was more than median.
TCT-781 Patients With Von Willebrand Factor Abnormalities Bleed Less Frequently After Transcatheter Than Surgical Aortic Valve Replacement
Authors: Kajetan Grodecki, Karol Zbroński, Bartosz Rymuza, Anna Olasińska-Wiśniewska, Piotr Scisło, Radosław Wilimski, Marek Grygier, Krzysztof Filipiak, Grzegorz Opolski, None Zenon Huczek
Journal: Journal of the American College of Cardiology (2018)
Metastatic breast cancer (MBC) patients′ perspective in the valuation of health states for QALY calculation.
Authors: Francisco Ayala, Jorge Eduardo Martinez Perez, Maria Benitez Urrea, Elisa Garcia-Garre, Fernando Ignacio Sanchez Martinez, Rosa Castelllano, Pilar de la Morena, Jose Maria Abellan, Vicente Vicente
Journal: Journal of Clinical Oncology (2016)

e18131 Background: Cost-utility analysis is the preferred method for oncology drug evaluation. For QALY calculation, utilities are usually assigned to each health state (HS) by healthy individuals using standard-gamble or time-trade-off (TTO) methods. However, those values might differ from MBC patient’s preferences due to adaptation processes, gender differences or a limited knowledge of the impact of the disease by healthy persons. The aim of this work was to determine whether differences exist between utilities directly obtained from MBC patients (TTO) and those assigned by healthy individuals. Methods: MBC patients with ECOG 0-2 and active treatment were included. Health states were obtained with EQ-5D-5L and SF-6D questionnaires. MBC patients valued their own HS with TTO methods. A control group of women matched by age also valued the most frequent MBC patients’ HS by TTO. Patients’ values for HS were compared with societal-derived values and with those provided by the control group. Mean utilities were compared between groups using Mann-Whitney or T-test. Results: 55 MBC patients were included; median age: 56 (21-86); ECOG 0-1: 89.1%; visceral disease: 54.5%; active chemotherapy: 76.4%. Mean societal values for EQ-5D and SF-6D health states were significantly lower than those directly provided by MBC patients using TTO methods (EQ-5D: 0.64 vs 0.76, p = 0.02; SF6D: 0.61 vs 0.76, p = 0.003). These differences were larger in those patients with visceral disease, without response or under treatment with chemotherapy. HS valuation also differed between patients and the control group (n = 55). A regression model showed that age, disease-free interval, chemotherapy and antidepressant treatment were the main determinants of utilities provided by MBC patients. Conclusions: MBC patients assign higher values to their health states than those provided by healthy individuals. The calculation of QALYs in pharmacoeconomic studies according only to societal values might lose the patient’s perspective, potentially leading to inadequate quantification of treatment benefits.
TCT-14 Final 5-Year Outcomes of the REPRISE II Study: Long-term Outcomes With the Fully Repositionable and Retrievable Lotus Transcatheter Aortic Valve
Authors: Nicolas Dumonteil, Darren Walters, Stephen G. Worthley, Didier Tchetche, Ganesh Manoharan, Daniel Blackman, Gilles Rioufol, David Hildick-Smith, Robert Whitbourn, Thierry Lefevre, Ruediger Lange, Ralf Mueller, Simon Redwood, Dominic J. Allocco, Ian Meredith
Journal: Journal of the American College of Cardiology (2018)
MASTER KEY project: A basket/umbrella trial for rare cancers in Japan.
Authors: Hitomi Sumiyoshi Okuma, Kan Yonemori, Toshio Shimizu, Yasushi Goto, Yoshitaka Honma, Chigusa Morizane, Emi Noguchi, Kazuki Sudo, Wataru Munakata, Kuniko Sunami, Nobuyoshi Hiraoka, Takashi Kohno, Akihiro Hirakawa, Taro Shibata, Tamie Sukigara, Akira Kawai, Noboru Yamamoto, Kenichi Nakamura, Toshirou Nishida, Yasuhiro Fujiwara
Journal: Journal of Clinical Oncology (2018)

TPS2598 Background: Establishment of standard therapies for patients with rare cancers have been poor compared to those of major cancers, due to lack of basis for clinical studies and investigations. The MASTER KEY Project is a biomarker driven basket/umbrella trial using a “master protocol”, aiming to find more efficient ways to evaluate treatments for rare cancers and to build a treatment development infrastructure by collaborating with industries. Similar studies including NCI–MATCH trial are ongoing; however, MASTER KEY Project is the first to be reported for such large scale trials that proceeds concurrently with a quality assured registry study focused only on rare cancers. Methods: The project is a two–stage structured study: the prospective registry study part and the multiple clinical trials (sub–study) part. Patients with advanced rare cancers/cancers of unknown primary/rare pathological subtypes of major cancers, who have priorly been evaluated by a molecular diagnostic testing, such as a validated next generation sequencing assay, are enrolled into the registry study. Rare cancer is defined as “annual incidence less than 6 cases per 100,000 population”. The primary objective of the registry study part is to collect consecutive data on biomarker, clinicopathological background, and prognosis of rare cancers to build a large–scale database that is highly reliable as historical control data for future use in clinical trials of rare cancers. In the sub–studies, drugs are provided by various industries, who are collaborators, and could be approved or investigational agents. Sub–studies are placed under a “master protocol”, allowing new sub–studies to be added at any time. Each sub–study is ordinarily a single arm study and will enroll 5–20 patients with the appropriate biomarker of interest, regardless of histopathologic tumor type. Typically, the primary endpoint is response rate (set according to each sub–study), and Bayesian method will be used. A biomarker–negative sub–study will also be available so that all patients have a chance to be enrolled in a sub–study. The project opened in May 2017. As of Jan 2018, 154 of a planned 100 patients/year have been enrolled. There is one ongoing sub–study and three sub–studies will open in April 2018. Clinical trial information: UMIN000027552.
The dual SYK/JAK inhibitor cerdulatinib demonstrates rapid tumor responses in a phase 2 study in patients with relapsed/refractory B- and T-cell non-Hodgkin lymphoma (NHL).
Authors: Paul A. Hamlin, Bruce D. Cheson, Charles Michael Farber, Tatyana Feldman, Timothy S Fenske, Brian T. Hess, James L. Khatcheressian, Carole Brennan Miller, Javier Munoz, Manish R. Patel, Sonali M. Smith, Stephen Douglas Smith, Don A. Stevens, Jing Christine Ye, Andrew Steele, Anjali Pandey, Matt Birrell, Janet Leeds, Greg Coffey, John T Curnutte
Journal: Journal of Clinical Oncology (2018)

7511 Background: Cerdulatinib is a selective, potent inhibitor of SYK, JAK1, JAK3, and TYK2. Preclinical and clinical data suggest that combined SYK/JAK inhibition may have activity in B- and T-cell NHL. SYK is a key regulator of BCR signalling (upstream of BTK and PI3K), and is also expressed in T-cell lymphomas. Preclinical studies suggest it may be an oncogenic driver in PTCL. Frequent activating JAK/STAT mutations are observed in B and T cell NHL. A phase 1 dose escalation study of cerdulatinib in 43 patients with r/r CLL and NHL was completed in 2016. Complete inhibition of SYK and JAK was well tolerated and consistent antitumor activity was seen in CLL and FL. Methods: This phase 2a study intended to confirm the safety and efficacy of cerdulatinib dosed 30 mg orally BID in patients with r/r B- and T-cell lymphoma. Dose reductions were permitted to a minimum of 15mg BID. Response was assessed by Lugano Classification criteria. Results: 99 patients enrolled (FL: 36, CLL/SLL: 28, PTCL: 18, marginal zone lymphoma: 8, aggressive: 5, Waldenstrom’s macroglobulinemia: 4). Median age is 68 (42-93) and median # of prior therapies is 3 (1–13). 30 patients had prior BTK, PI3K or BCL-2 inhibitor therapy. The most common AEs of any grade are diarrhea (42%), fatigue (36%), and nausea (32%). Grade 3+ AEs occurring in ≥5% patients are neutropenia (18%), lipase increase (15%), pneumonia (12%), diarrhea (10%), and fatigue (7%). 5 patients have had Grade 5 infections considered related to study drug (3 of 5 in the CLL cohort). The target PK range has been achieved with an average SSCmin of ~0.8 µM. Broad activity seen: 61% ORR in CLL/SLL, 50% in FL, and 43% in PTCL (4 CRs, 2 PRs in 14 patients). The first PTCL patient achieved a CR and is on drug at 11 months. Responses typically occurred after 2 cycles of treatment. Durable PRs have occurred in patients who relapsed on BTK inhibitor (CLL, 5+ months, WM, 7+ months, FL, 12 months), venetoclax (SLL, 18+ months), and tenalisib (PTCL, 3+ months) therapy. Updated PK/PD, safety and efficacy will be presented. Conclusions: The cerdulatinib phase 2 dose of 30 mg BID demonstrates good tolerability and efficacy in heavily pre-treated r/r B and T cell NHL. Clinical trial information: NCT01994382.
A phase I study of enadenotucirev (EnAd), an oncolytic Ad11/Ad3 chimeric group B adenovirus, in combination with nivolumab in tumors of epithelial origin.
Authors: Wael A. Harb, Lee S. Rosen, Ding Wang, Marwan Fakih, Daruka Mahadevan, Wendy Clemens, Giovanni Selvaggi, Suzanne Bosque, Richard Brown, Simon Alvis, Brian Champion, Hilary McElwaine-Johnn
Journal: Journal of Clinical Oncology (2017)

TPS3115 Background: EnAd is a tumor-selective chimeric Ad11/Ad3 group B oncolytic adenovirus developed using directed evolution. Phase I clinical studies have identified a well-tolerated systemic dose and regimen for EnAd monotherapy. EnAd shows a high level of selective replication and cell killing for a broad range of carcinoma cell lines with little replication in normal and non-carcinoma cells. Previous studies have shown that after systemic administration there is significant uptake and replication of EnAd in various carcinomas associated with improved CD8+ T-cell tumor infiltration. These data provide the rationale for combination of EnAd with the checkpoint inhibitor (CPI), nivolumab (anti-PD-1 antibody) to potentially enhance the response to nivolumab. This is a phase I study in subjects with metastatic or advanced carcinoma. The study design has a dose escalation stage, followed by a dose expansion stage which will evaluate the ability to improve responses in tumors normally non-responsive to CPI and also to evaluate the ability to detect meaningful responses in PDL1 negative tumors that are less responsive to CPI. Methods: The dose escalation phase consists of 5 cohorts of patients with metastatic or advanced epithelial tumors in a standard "3 + 3" design. Subjects will receive increasing dose levels and/or cycles of EnAd followed by a q3w regimen of nivolumab (360mg). EnAd treatment cycles comprise 3 intravenous (IV) infusions on Days 1, 3 and 5. Nivolumab is administered as an IV infusion given every 3 weeks starting on Day 15 and continuing for up to 8 treatment cycles. The Dose Expansion phase will investigate the combination of EnAd and nivolumab in expanded cohorts of colorectal cancer, urothelial cell carcinoma, squamous cell carcinoma of the head &amp; neck, and non-small cell lung cancer patients. The primary objectives are to establish the MTD of EnAd and nivolumab combination, to evaluate the safety and to recommend doses for future studies. Secondary endpoints include overall response, duration of response and progression free survival, assessed according to RECIST Version 1.1 and irRECIST Version 1. Enrollment to cohorts 3 &amp; 4 began in January 2017. Clinical trial information: NCT02636036.
Progression-free survival as surrogate endpoint for overall survival in NSCLC trials of anti PD-1 and anti PD-L1 agents and the impact of line of treatment.
Authors: Anandaroop Dasgupta, Nidhi Dhingra, Tom Stinchcombe, Jaideep V Thottassery
Journal: Journal of Clinical Oncology (2018)

e21135 Background: Post progression interventions and their impact on survival, which can be different among lines of treatment (LOTs) can influence the association between progression-free survival (PFS) and overall survival (OS), thereby differentially affecting the strength of surrogacy of PFS to OS. To explore the potential benefit of PFS as a surrogate for OS we evaluated the correlation between PFS and OS among anti-PD-1/PD-L1 agents in NSCLC between sets of LOT1+ versus LOT2+ trials. Methods: Trial-level analyses were performed using the SMARTImmuno-Oncology (SMART-IO) repository of completed and ongoing trials evaluating IO treatments in NSCLC. Weighted (by trial size) mixed regression models were used to determine the correlation between mPFS and mOS from trial data of anti-PD-1/PD-L1 agents and the strength of association was estimated vis-à-vis LOT. Results: A majority of the NSCLC IO trials (n = 268) had single agent anti-PD-1 (22%) as the intervention regimen of which nivolumab trials (n = 31) were most common, followed by pembrolizumab (n = 27). Anti-PD-L1 agents accounted for 12% of the trials with atezolizumab being most common (n = 18). Among all trials with a comparator group (n = 49), docetaxel was the most commonly used (n = 7) control regimen. Overall PD1/L1 agents showed higher correlation in LOT2+ (r = 0.48) compared to LOT1+ (r = 0.38) trials. Also, mPFS correlated better with mOS in anti-PD-1 trials (range: 0.82-0.84) as opposed to trials where the intervention arm was an anti-PD-L1 agent, wherein no correlation was found (range: 0.08-0.1). Among PD-1/L1 agents, correlation was best for nivolumab (r = 0.84) followed by pembrolizumab (r = 0.82), whereas there was no correlation in atezolizumab (r = 0.10) and durvalumab (r = 0.08) trials. Pembrolizumab showed higher correlation in LOT2+ (r = 0.87) compared to LOT1+ (r = 0.79) trials. Conclusions: PFS acts as a reliable surrogate for OS in LOT2+ versus LOT1+. Whereas PFS is a strong surrogate for OS in anti PD-1 agent trials, it is currently unclear whether this also extends to anti PD-L1 agents. Future LOT2+ trials of anti PD-1 agents should further validate if PFS can be treated as a primary endpoint instead of OS.
Abstract 20287: Cardiac MIBG Imaging Predicts Cardiac Death in Patients With Chronic Heart Failure , Irrespective of Hyperuricemia
Authors: Satoshi Takahashi, Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Takumi Kondo, Tsutomu Kawai, Masashi Ishimi, Hideyuki Hakui, Tatsuhisa Ozaki, Yoshihiro Sato, Masahiro Seo, Masatake Fukunami
Journal: Circulation (2014)

Background: Elevated uric acid level is associated with an increased risk of adverse outcome in patients with chronic heart failure (CHF). On the other hand, cardiac metaiodobenzylguanidine (MIBG) imaging provides prognostic information in patients with CHF. However, there is no information available on the prognostic value of cardiac MIBG imaging in CHF patients, relating to hyperuricemia. Methods: We enrolled 113 CHF outpatients (NYHA2.0±0.6, ischemic origin 48%) with radionuclide LVEF &lt;40%(30±8%). The cardiac MIBG washout rate (WR) was calculated from the chest anterior view images obtained at 20 and 200 min after isotope injection. Abnormal WR was defined as &gt;27% as reported previously. At the entry, we measured serum uric acid level and hyperuricemia was define as &gt;7.0mg/dl. The primary end point was cardiac death. Reults: At the entry, 59 and 51 of 113 patients had abnormal WR and hyperuricemia, respectively. Serum uric acid level was significantly higher in patients with than without abnormal WR (7.3±1.8 vs 6.3±2.0 mg/dl, p=0.007). During the follow up period of 7.6±4.3 years, 35 patients had cardiac death. Cardiac death was significantly more often observed in patients with than without abnormal WR (47% vs 13%, p&lt;0.001) and hyperuricemia (42% vs 23%, p=0.034). At multivariate Cox analysis, abnormal WR and hyperuricemia were significantly independently associated with cardiac death (p=0.02 and p=0.03, respectively). Patients with abnormal WR had a significantly greater risk of cardiac death than those with normal WR in group with hyperuricemia (p=0.004, harard ratio: 6.5, 95%CI 1.8 to 23.4) and without hyperuricemia(p=0.001, hazard ratio: 4.4, 95%CI 1.5 to 13.2). Conclusion: Cardiac MIBG imaging provides the additional information to hyperuricemia in CHF.
TCT-846 Multicenter Study of the Efficacy and Safety of Distal Radial Approach in Coronary Angiography and Intervention
Authors: Yukio Mizuguchi, Takuya Izumikawa, Akihiko Takahashi, Takeshi Yamada, Norimasa Taniguchi, Shunsuke Nakajima, Tetsuya Hata
Journal: Journal of the American College of Cardiology (2018)
HeteroMeth: A Database of Cell-to-Cell Heterogeneity in DNA Methylation
Authors: Qing Huan, Yuliang Zhang, Shaohuan Wu, Wenfeng Qian
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract DNA methylation is an important epigenetic mark that plays a vital role in gene expression and cell differentiation. The average DNA methylation level among a group of cells has been extensively documented. However, the cell-to-cell heterogeneity in DNA methylation, which reflects the differentiation of epigenetic status among cells, remains less investigated. Here we established a gold standard of the cell-to-cell heterogeneity in DNA methylation based on single-cell bisulfite sequencing (BS-seq) data. With that, we optimized a computational pipeline for estimating the heterogeneity in DNA methylation from bulk BS-seq data. We further built HeteroMeth, a database for searching, browsing, visualizing, and downloading the data for heterogeneity in DNA methylation for a total of 141 samples in humans, mice, Arabidopsis, and rice. Three genes are used as examples to illustrate the power of HeteroMeth in the identification of unique features in DNA methylation. The optimization of the computational strategy and the construction of the database in this study complement the recent experimental attempts on single-cell DNA methylomes and will facilitate the understanding of epigenetic mechanisms underlying cell differentiation and embryonic development. HeteroMeth is publicly available at http://qianlab.genetics.ac.cn/HeteroMeth.
Assessing performance status and clinical outcomes with wearable activity monitors.
Authors: Gillian K. Gresham, Elad Neeman, Andrew Eugene Hendifar, Quanlin Li, Richard Tuli, Bj Rimel, Christine S. Walsh, Brennan Spiegel, Robert A. Figlin, Steven Piantadosi, Arvind Manohar Shinde
Journal: Journal of Clinical Oncology (2017)

6571 Background: Performance status (PS) is assessed to inform treatment decisions and predict outcomes in cancer. PS is often evaluated using ECOG or KPS scales, limited by their subjective and static nature. Wearable activity monitors provide oncologists with the opportunity to obtain continuous objective data on patients’ daily activity including steps, stairs climbed, and sleep. We evaluated the association between wearable activity monitor data, PS, and clinical outcomes. Methods: Patients with advanced cancer were enrolled in a prospective, observational study conducted at Cedars-Sinai Medical Center. Patients wore a Fitbit Charge HR for 3 consecutive clinic visits. ECOG/KPS were rated by treating physicians and serious adverse events (AE, clinically relevant grade 3+ by CTCAE v4), hospitalizations, and 6-month survival were collected. Correlations between PS and activity metrics were calculated. Multivariable regression models were fit to predict AEs and hospitalizations with activity data. The association between activity metrics and time to death was evaluated using survival analysis. Results: 35 patients (median age 62 years, 53% male) were evaluated. Most had gastrointestinal cancers (82%). Patients had ECOG PS of 0 (20%), 1 (40%), 2 (23%), and 3(17%). There were 10 (29%) pts with serious AEs, 14 (40%) hospitalizations, and 11 (31%) deaths. Average daily steps were significantly correlated with ECOG PS and KPS (r=0.73 and 0.70, respectively). Relationships between activity metrics, AEs, hospitalizations, and overall survival (OS) are displayed in the table below. Conclusions: We found a significant association between wearable activity monitor data and the risk of AEs, hospitalization and death. There is a strong correlation between step counts and KPS/ECOG PS. The potential of wearable activity data to predict outcomes and supplement PS assessment should be explored in future studies. Clinical trial information: NCT02659358. [Table: see text]