tbuckley/cabot-search huggingface dataset:
Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis
Authors: Dongxue Su, Shuai Ma, Lin Shan, Yue Wang, Yuejiao Wang, Cheng Cao, Beibei Liu, Chao Yang, Liyong Wang, Shanshan Tian, Xiang Ding, Xinhua Liu, Na Yu, Nan Song, Ling Liu, Shangda Yang, Qi Zhang, Fuquan Yang, Kai Zhang, Lei Shi
Journal: Journal of Clinical Investigation (2018)

Central to the recognition, signaling, and repair of DNA double-strand breaks (DSBs) are the MRE11-RAD50-NBS1 (MRN) complex and mediator of DNA damage checkpoint protein 1 (MDC1), the interplay of which is essential for initiation and amplification of the DNA damage response (DDR). The intrinsic rule governing the regulation of the function of this molecular machinery remains to be investigated. We report here that the ubiquitin-specific protease USP7 was physically associated with the MRN-MDC1 complex and that the MRN-MDC1 complex acted as a platform for USP7 to efficiently deubiquitinate and stabilize MDC1, thereby sustaining the DDR. Accordingly, depletion of USP7 impaired the engagement of the MRN-MDC1 complex and the consequent recruitment of the downstream factors p53-binding protein 1 (53BP1) and breast cancer protein 1 (BRCA1) at DNA lesions. Significantly, USP7 was overexpressed in cervical cancer, and the level of its expression positively correlated with that of MDC1 and worse survival rates for patients with cervical cancer. We demonstrate that USP7-mediated MDC1 stabilization promoted cervical cancer cell survival and conferred cellular resistance to genotoxic insults. Together, our study reveals a role for USP7 in regulating the function of the MRN-MDC1 complex and activity of the DDR, supporting the pursuit of USP7 as a potential therapeutic target for MDC1-proficient cancers.
TCT-523 RVOT/Ao Ratio on Computed Tomography Better Predicts RV Dysfunction and Invasive Hemodynamic Abnormalities as Compared to RV/LV Ratio in Patients with Pulmonary Embolism
Authors: Alexandru Marginean, Andrew Putnam, Atman Shah, Sandeep Nathan, John Blair, Jonathan Chung, Jonathan Paul
Journal: Journal of the American College of Cardiology (2018)
Impact of simultaneous radiotherapy in melanoma patients treated with pembrolizumab in the French early access program.
Authors: Philippe Saiag, Laurent Mortier, Caroline Dutriaux, Lynda Benmahammed, Ouzna Morsli, Abir Tadmouri, Catherine Hunault, Marie Thérèse Leccia, Nicolas Meyer
Journal: Journal of Clinical Oncology (2018)

9555 Background: Information on the use of radiotherapy in anti-PD-1 monoclonal antibody-treated melanoma pts is limited although some data support a synergistic effect. Methods: We investigated the influence of simultaneous radiotherapy in a multicenter ambispective cohort of advanced melanoma patients initiating pembrolizumab between May 2014-sept 2015 (CCTIRS, #15.640). Palliative or curative intent of radiotherapy was recorded. Overall (OS) and progression-free (PFS) survivals were analyzed using Kaplan-Meier survival analysis and Log rank tests were used to compare curves. Results: 663 pts (151 pts with brain metastases) were included in 40 French centers, with 125 pts (19%) receiving simultaneous radiotherapy (43 pts with ≥1 brain metastasis, 82 without). No significant difference in baseline LDH level, ECOG performance status, N of metastatic sites, previous treatment lines or post-progression therapies was observed between pts who did or did not receive radiation. As compared to pts without brain metastases, radiotherapy was performed in brain metastases pts closer to initiation of pembrolizumab (median 1.1 m vs 3.7 m, p = 0.009) and more frequently with a curative intent (72% vs 37%, p < 0.001). Globally, OS was longer in radiated vs non-radiated pts (median 18.9 m vs 12.5 m, HR:0.78, 95%CI: 0.57-0.96). This benefit was mainly driven by the pts with brain metastases (OS: median 26.0 m vs 6.0 m, HR:0.35, 95%CI:0.22-0.56, p < 0.001)(PFS: 6.4 m vs 2.5 m, HR:0.54, 95%CI:0.36-0.81, p < 0.002). No significant difference was seen for OS in radiated pts without brain metastasis, who were mainly radiated later and for palliative reasons and had shorter PFS (2.8 vs 3.4 m, HR 1.32, P < 0.03). Conclusions: Simultaneous radiotherapy may enhance efficacy of anti-PD1 therapy, particularly when initiated early and in brain metastases pts. Controlled studies are needed. Clinical trial information: 15.640.
Demographic analysis of the 2013 National Cancer Database (NCDB) of colon cancer in Hispanics.
Authors: Nicholas B George, Carlos J Silva, Lakshmi Manogna Chintalacheruvu, Mridula Krishnan, Ryan W Walters, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2016)

e15157 Background: Hispanics represent approximately 17.4% of the US population. A recent analysis of cancer in Hispanics was performed using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program that estimated 11,700 new cases of colorectal cancer (CRC) in Hispanics in 2015. Methods: We analyzed 608,192 patients using the National Cancer Database (NCDB) Participant User File (PUF) of colon cancer from 2004 to 2013, of which 31,102 were Hispanic (5.1%). Continuous variables were compared using independent-samples t-tests; categorical variables were compared using chi-square tests; p < 0.05 was used to indicate statistical significance. Results: Our data showed that when compared to non-Hispanics with CRC, Hispanics with CRC were an average of 5 years younger, more likely to be uninsured (10% vs 3%), on Medicaid (12% vs 4%), have a lower income (27% vs 18%), live in a metro area (74% vs 52%) and are three times less likely to have a high school diploma. A slightly higher proportion of Hispanics with CRC were male. Distribution of stage within the Hispanic population was minimally skewed toward higher stages when compared to non-Hispanics. Of 70,419 patients receiving multi-agent chemotherapy in Stage III CRC, Hispanics and Non-Hispanics showed similar percentages of 46.7% and 45.1% respectively, suggesting similar intensity of therapy. Conclusions: 5.1% of the database were Hispanic while the US population of Hispanics is 17.4%. This could be due to lower cancer rates as showed by SEER, lower capturing of Hispanic patients, or Hispanics seeking less care due to younger age, economic factors or lack of health insurance. Our data suggests that lower screening rates had only a small effect on the incidence of CRC due to similar percentages within stage groups. Further studies should be performed to analyze survival. Hispanic (n = 31,102) Non- Hispanic (n = 577,090) Mean Age* 64 69 Charlson/Deyo Score* 0.35 0.39 n (%) Stage* 0 7% 7% I 19% 22% II 26% 26% III 28% 26% IV 21% 20% Male* 51% 49% Insurance Status* Uninsured 10% 3% Medicaid 12% 4% Medicare 41% 58% Income < $38,000* 27% 18% Live where >21% have not earned a high school diploma* 48% 16% Reside in a Metropolitan Area (≥1,000,000)* 74% 52% * p<0.05
Outcomes of immunomodulatory radiation strategies in combination with nivolumab compared with single agent nivolumab in lung cancer patients.
Authors: Aparna Madhukeshwar Hegde, Cynthia R. Cherry, Chipman Robert Geoffrey Stroud, Ramya Pinnamaneni, Sulochana Devi Cherukuri, Nitika Sharma, Mark Bowling, Andrew Wenhua Ju, Hyder Husain Arastu, Paul R. Walker
Journal: Journal of Clinical Oncology (2018)

e21134 Background: In advanced non- small cell lung cancer, when compared with Docetaxel, the absolute improvement in one- year overall survival (OS) with nivolumab monotherapy (Checkmate 017 and 057) is a modest 12- 18%. Preclinical studies have demonstrated improved response rates with combined PD- 1 blockade and ablative radiation. Hence, it has been our programmatic approach to combine nivolumab with stereotactic ablative radiotherapy to symptomatic metastatic sites. However, the optimal fractionation and timing of radiation with nivolumab are unclear. Here we examine the OS, incidence of toxicities and the timing of radiation in lung cancer patients who received nivolumab and external beam radiotherapy (iEBRT), nivolumab and stereotactic ablative radiotherapy (iSABR) and nivolumab monotherapy. Methods: All lung cancer patients who started nivolumab between April 2015 and May 2017 were identified by retrospective chart review. Patients who received EBRT or SABR 3 months before initiating nivolumab or during nivolumab therapy were identified. Follow up cut off date was 31 December, 2017. Kaplan Meier analysis was used to estimate OS. Results: Out of 109 advanced lung cancer patients who received nivolumab, 30 received iSABR and 13 received iEBRT. Seventeen patients received SABR in the 3 months preceding initiation of nivolumab (Before) and 13 received SABR during nivolumab therapy (Sandwich). All 13 patients who received EBRT did so in the 3 months preceding the initiation of nivolumab. Median follow up time was 18.5 months. No statistically significant difference was found in the incidence of grade 3-4 adverse events between different groups (χ2(2) = 4.2, p = 0.25). There were no grade 5 adverse events. Survival estimates are as follows- Conclusions: This review of our programmatic approach, demonstrates a 29% absolute improvement in 18- month OS with iSABR Sandwich when compared to nivolumab monotherapy and no OS improvement with EBRT given prior to initiation of nivolumab. Group 18-month OS (%) mOS (95% CI) (months) Log rank p = 0.02 iSABR Sandwich 41.6 16.4 (8.8- 22.0) iSABR Before 18.5 8.6 (5.1- 15.0) iEBRT 7.7 3.9 (1.4- 11.4) Nivolumab monotherapy 12.5 5.4 (2.8- 7.8)
Learning from failure
Authors: Elizabeth Loder
Journal: BMJ (2018)

This weekThe BMJ is filled with tales of failure, but many would say this is something to celebrate.Failure, and figuring out how to learn from it, is an important part of success, or so the thinking goes.What can be learnt from the failure of high dose folic acid to prevent pre-eclampsia in women at high risk?Results of the FACT trial (doi:10.1136/bmj.k3478)showed no difference in the risk of pre-eclampsia between women who received daily supplements of 4 mg of folic acid and those who received placebo.Our editorialists (doi:10.1136/bmj.k3536)suggest that these negative results teach us that "the concept of a one size fits all prophylactic against pre-eclampsia is unlikely."They call for better phenotyping of the disorder and implementation of proven treatments.These include aspirin prophylaxis, magnesium sulfate, treatment of hypertension, and prompt delivery.
Prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs
Authors: Giuseppe Patti, Ilaria Cavallari, Felicita Andreotti, Paolo Calabrò, Plinio Cirillo, Gentian Denas, Mattia Galli, Enrica Golia, Ernesto Maddaloni, Rossella Marcucci, Vito Maurizio Parato, Vittorio Pengo, Domenico Prisco, Elisabetta Ricottini, Giulia Renda, Francesca Santilli, Paola Simeone, Raffaele De Caterina
Journal: Nature Reviews Cardiology (2018)

Abstract Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease.
The anti-tumour immune response after radiofrequency ablation of colorectal cancer.
Authors: Katia Lemdani, Claude Capron, Johanne Seguin, Nathalie Mignet, Vincent Boudy, Frederique Peschaud, Jean Francois Emile, Robert Malafosse
Journal: Journal of Clinical Oncology (2017)

e14540 Background: Results of radiofrequency ablation (RFA), increasingly used to treat liver tumors, are compromised by local and systemic relapse. Hyperthermia related cancer cells death, release of tumor antigens and expression of danger signals activate a tumor-specific T-cells response. This effect remains ineffective to avoid recurrence. Therefore we propose to combine RFA with an activation of a solid immune antitumor response as curative treatment of a colorectal (CRC) metastatic disease in immunocompetent mouse. Methods: RFA was used to treat a CT26- luc tumor. In two distinct clinical situations, distant macroscopic or microscopic tumors were established as metastases before or at the time of RFA. Immune response was modulated by an injection in situof a thermo-reversible hydrogel loaded by GM-CSF and BCG, targeting dendritic cells. In the group of mice with large far lesions this strategy was combined with immune checkpoint inhibition. The efficiency was assessed on survival, evolution of distant lesions, characterization of lymphocyte infiltration in tumors and systemic immunity through specific TNF- α and IFN-y expression in spleen and draining lymph nodes. Results: The in situ immunogel injection after RFA resulted in a prolonged survival of mice. Regression of distant lesions was related to a strong systemic antitumor immune response and a great improvement of tumor infiltration by specific cytotoxic lymphocytes. In adjuvant situation, the use of immunogel induced a complete cure of microscopic secondary lesions without any treatment. Immune escape of large secondary lesions was reversed by association of RFA-immunogel vaccination with a systemic check point blockade, separately ineffective. Conclusions: Validation of this strategy, combining RFA of liver metastases and activation of a strong immune response controlling the residual disease, could result in a clinical assay including this approach within the standard treatment of CRC. Furthermorethe powerful synergy between RFA-in situ immunomodulation as a starter treatment and checkpoint blockade ineffective alone in CRC or after single RFA, allows reconsidering the use of immune checkpoint inhibitors in metastatic microsatellite stable CRC.
Prognostic factors of cervical cancer recurrence.
Authors: Ekaterina Guskova, Oleg Ivanovich Kit, Galina Andreevna Nerodo, Nailya Guskova, Natalia V. Chernikova, Yuriy A. Poryvaev, Vera Nikitina, Ekaterina V. Verenikina
Journal: Journal of Clinical Oncology (2016)

e17025 Background: The purpose of the study was to analyze the frequency and time of recurrence development in patients with cervical cancer (CC) after primary treatment. Methods: Clinical data of 1048 patients with histologically verified stage I-IV cervical cancer were studied retrospectively. 236 (22.5%) of 1048 patients developed recurrences. Frequency and time of recurrences were compared with patients’ age, disease stage, morphological structure and type of growth of primary tumor; DFS was analyzed. Results: Age of patients with newly diagnosed cervical cancer was 20-75 years, mean age 50.5±1.3; almost a third of cases (27.8%) were women under 40 years of age. Recurrences were more frequent in patients of 50-59 (25.2%) and 40-49 (24.8%) y.o. Recurrence rate in stage I was 8.3%, stage II – 21.3%, stage III – 29.1%, and stage IV – 43.5%. A significant proportion of women with recurrences (44.9%) had stage III disease. Recurrence rate in patients with squamous cell CC was 20.6%, adenocarcinoma – 33.6%, adenosquamous carcinoma – 28.6%, and poorly differentiated cancer – 42.8%. High recurrence rate was observed in patients with prognostically unfavorable types of primary tumor growth: crateriform – 44.6%, endophytic – 26.5%, mixed type – 28.9%. 62.3% of patients developed recurrences during the first 1.5 years after primary treatment, 20.3% - in 1.5-2 years. Conclusions: The majority of CC patients prior to the primary treatment already had clinical signs that determine aggressive course of the disease with a tendency to early recurrence development. Recurrence rate was highly determined by the disease stage, morphological structure and the type of primary tumor growth.
TCT-36 The Impact of Guideline-Directed Medical Therapy after Revascularization in Patients With Left Main Coronary Artery Disease: Analysis From the EXCEL Trial
Authors: R. Jay Widmer, Bernard Gersh, Patrick Serruys, John Puskas, Ori Ben-Yehuda, David Taggart, Marie-Claude Morice, Nicholas Lembo, William Brown, Adrian Banning, Yiran Zhang, Ovidiu Dressler, A. Pieter Kappetein, Joseph Sabik, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
Prognostic factors in early stage lung cancer patients: Retrospective single center data.
Authors: Ozkan Alan, Ozlem Ercelep, Tugba Akin Telli, Rahib Hasanov, Tugba basoglu Tuylu, Eda Tanrikulu Simsek, Tunc Lacin, Emine Bozkurtlar, Nalan Babacan, Serap Kaya, Faysal Dane, Fulden Perran Yumuk
Journal: Journal of Clinical Oncology (2018)

e20500 Background: Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In this study, we retrospectively evaluated the prognostic factors and outcomes of operated NSCLC cases. Methods: Retrospective analysis of data from 208 patients with early stage NSCLC who presented after surgery and treated and followed in our clinic between 2006-2017 was performed. Stage, histology,lymphatic, vascular, perineural and pleural invasion were investigated as prognostic factor.The findings were analyzed using SPSS. Results: At the time of diagnosis, median age was 62 (39-82) and 84% of the patients were male. Eightynine percent of our patients were smokers and in male patients it was 98%. Most common pathologic subtype was adenocarcinoma.Mean follow-up duration was 36 months (2-135 months). Fifteen patients with microscopic surgical margin positive had re-resection and all patients had negative surgical margin. Adjuvant therapy were given to 135 (65%) patients who had stage 3, stage 2, stage 1 with poor prognostic factors and wedge resection. During the follow-up 40% of the patients recurred. Five-year progression-free survival (PFS) rate was 44% and overall survival (OS) was 56%.In univariate analysis stage, lymphatic, vascular and perineural invasion were statistically significant for OS (p < 0.05). In multivariate analysis, presence of lymphatic and perineural invasion was found to be independent prognostic factors (p 0.049 and 0.027, respectively). Conclusions: Approximately 30% of NSCLC patients are diagnosed at early stage. Although surgery is curative treatment in early stage, recurrences are common. Stage, lymphovascular invasion and perineural invasion are the most important prognostic factors reported in the literature. We have also found presence of lymphatic and perineural invasion to be independent prognostic factors in early stage NSCLC in our retrospective study.
A first-in-human phase 1 study of proxalutamide (GT0918), a dual MOA androgen receptor blocker in patients with advanced CRPC.
Authors: Tie Zhou, Wei-Dong Xu, Chuang-Liang Xu, Xu Gao, Jian-Guo Hou, Shancheng Ren, Bo Yang, Guolan Wei, Ye Sun, Chunyun Chen, Chuangxing Guo, Youzhi Tong, Karl Zhou, Ying-Hao Sun
Journal: Journal of Clinical Oncology (2017)

e16511 Background: Proxaluatmide is a novel dual MOA androgen receptor (AR) blocker with potent AR antagonist activity and capability to down-regulate AR level. We conducted a first-in-human phase 1 study to investigate safety, tolerability, and pharmacokinetics of GT0918 in patients with advanced CRPC. Methods: All participating patients must be confirmed with advanced CRPC progressed on SoC, PS 0-1, went through 2 periods of time of both single-dose and repeated-dose PK. Patients received GT0918 once orally followed by PK in first 7 days, and then once daily continuously for 28 days for DLT evaluation and repeated-dose PK. PK of drug elimination was done at the end of first cycle (7 days off-treatment). By the end of first 28-day cycle, DLT was evaluated and dose escalation was determined by modified Fibonacci's rule of 3+3 design. If patient tolerated GT0918 well and had no sign of tumor progression, he continued on the study medication thereafter. Results: Ninteen patients were enrolled and 16 patients were treated with GT0918 at five dose levels: 50 mg (n = 2), 100 mg (n = 4), 200 mg (n = 3), 300 mg (n = 3) and 400 mg (n = 4). No DLT was observed. MTD was not reached. GT0918-related adverse events were relatively mild (CTCAE grade 1 or 2), including hypercholesterolemia, peripheral edma, fatigue, flush, constipation and anorexia. PK study showed plasma drug concentrations increased as dose increased from 50mg to 300mg and saturation observed between 300mg and 400mg. Compared single dose (D1) with repeated dose (D35), the elimination half-life (T 1/2 ) were shown 14-35h and 28-51h, respectively. With consideration of overly drug exposure and saturation of oral absorption, 100-400mg were recommended to be the dose range for Phase 2 for further clinical evaluations and dose selection. Clinical activities have been observed in numbers of patients in 100/200/300/400mg dose cohorts. Conclusions: Proxalutamide (GT0918) dosed orally once a day continuously for 12 weeks was generally well tolerated. GT0918 showed promising preliminary anti-tumor activity. Dose range of 100-400mg was recommended for Phase 2 trial and for 24 weeks of treatment.