tbuckley/cabot-search huggingface dataset:
Molecular predictors of long-term response to crizotinib in ALK+ advanced non-small cell lung cancer (NSCLC) patients.
Authors: Mathilde Couetoux du Tertre, Maud Marques, Lise Tremblay, Nicole Bouchard, Razvan Diaconescu, Normand Blais, Cyrla Hoffert, Archana Srivastava, Luisa Izzi, Suzan McNamara, Gerald Batist, Victor Cohen, Jason Scott Agulnik
Journal: Journal of Clinical Oncology (2018)

e21038 Background: While most ALK+ NSCLC patients (pts) initially respond to crizotinib, resistance ultimately develops. The identification of fusion partners and mutations in ALK has led to the development of subsequent generations of TKIs designed to more efficiently bind and inhibit ALK. Although a 60% response rate1 is observed with these newer generation TKIs, pts inevitably relapse. Together these data suggest that factors other than the molecular status of ALK determine the rate and duration of response. 1 Rosenbaum et al. Genomic heterogeneity of ALK fusion breakpoints in non-small-cell lung cancer. Mod Pathol. (2018) 00, 1-18 Methods: Exome sequencing on primary and metastatic tissue was performed to identify genomic aberrations and ALK fusions. RNA sequencing was performed on select samples to confirm fusions. Baseline blood samples were analyzed by mass spectrometry to identify proteomic profiles. Pts were grouped by response and defined as long-term responders (LR) with a PFS ≥24 mos (n=8), responders (R) with a PFS between 3 and 24 mos (n=10), and non-responders (NR) with a PFS <3 mos (n=6). Results: Twenty-four pts with stage III-IV ALK+ NSCLC received crizotinib either as first or second-line treatment. Median duration of therapy was 11.1 mos (range 1-40.3 mos) and median PFS was 13.6 mos at data cut-off. The median PFS in LR, R and NR was 32.6 vs. 11.7 vs. 1.6 mos, respectively. EML4-ALK variant 3, involved in ALK resistance1, was identified at baseline and relapse in 3 NR pts. While we could not confirm their predictive value due to our small cohort, we identified novel ALK gene fusions in both NR and LR. Proteomic analysis revealed that baseline expression levels of TSP1, LUM, SODE and CO6A1 were significantly higher while FRIL and MMP9 were lower in LR versus N or NR. 1 Woo CG et al: Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer. Ann Oncol 2017 Apr 1, 28 (4): 791-797 Conclusions: By comparing the different response subgroup profiles, we identified molecular determinants that may help predict which pts will likely derive a durable response with ALK+ inhibitors. Clinical trial information: NCT02041468.
Demethylation and epigenetic modification with 5-azacytidine reduces IDH1 mutant glioma growth in combination with temozolomide
Authors: Alex Shimura Yamashita, Marina da Costa Rosa, Alexandra Borodovsky, William T Festuccia, Timothy Chan, Gregory J Riggins
Journal: Neuro-Oncology (2018)

Isocitrate deyhydrogenase (IDH) mutant glioma comprises the majority of grades II-III gliomas and nearly all secondary glioblastomas. These progressive gliomas arise from mutations in IDH1 or IDH2 that pathologically produce D-2-hydroxyglutarate (2HG), which interferes with cell reactions using alpha ketoglutarate, leading to a hypermethylated genome and epigenetic dysregulation of gene expression initiating tumorigenesis.Human IDH1 wild type (wt) and IDH1 R132H cell lines and patient-derived xenografts (PDXs) were used to evaluate the FDA-approved DNA demethylating agent 5-azacytidine (5-aza). Cell growth, protein and gene expression, chromatin immunoprecipitation, and nucleosome position assays were performed in 5-aza treated cells. To evaluate antitumor activity in vivo, 5-aza was administered alone and in combination with temozolomide (TMZ) in a PDX glioma model harboring IDH1 R132H mutation.5-Aza treatment has been found to reduce cell growth and increase expression of glial fibrillary acid protein (GFAP). Chromatin immunoprecipitation and nucleosome position assay showed that the mechanism of increased GFAP expression induction is associated with histone modification and nucleosome repositioning of the GFAP promoter, respectively. In vivo, 5-aza treatment extended survival in IDH1 R132H mutant but not in an IDH1 wt glioma model. Additionally, 5-aza enhances the therapeutic effect of the DNA damaging agent TMZ in both subcutaneous and orthotopic PDX models of IDH1 R132H mutant glioma.5-Aza provided a survival benefit as a single agent but worked best in combination with TMZ in 2 different IDH1 R132H mutant glioma models.
Role of diffusion weighted magnetic resonance imaging in evaluation of response to chemotherapy in gall bladder carcinoma.
Authors: Lavdeep Singh, Raju Sharma, Devasenathipathy Kandasamy, Madhusudhan KS, Shivanand Gamanagatti, Ranjit Sahoo, Atul Sharma, Surendra Pal Chaudhary, Pramod Kumar Garg, Peush Sahni, Sreenivas Vishnu
Journal: Journal of Clinical Oncology (2016)

e15590 Background: Response evaluation to chemotherapy in gall bladder carcinoma (Ca GB) is conventionally done after completion of 3-4 cycles of chemotherapy according to size criteria based on Response Evaluation Criteria in Solid Tumors (RECIST).We hypothesized that diffusion weighted MRI and apparent diffusion coefficient (ADC) values can be used as early markers of response to chemotherapy in Ca GB. Methods: In this ethically approved study 42 patients were prospectively enrolled (31 females, 11 males; mean age 48 years) after obtaining informed consent. Total 23 patients completed the treatment and were evaluated for response assessment. MR imaging was done at baseline, after 1st (early time point), 2nd(middle time point) and 3rd(last time point) cycle of chemotherapy.Percentage change in size after 3 cycles of chemotherapy was taken as the gold standard to assess response based on RECIST criteria.Total 22 primary masses, 32 lymph nodes and 18 liver metastases were evaluated. BaselineADC was compared between responders and non-responders. To assess response to chemotherapy percentage size and ADC change at early time point were compared between responders and non-responders. Results: Mean percentage increase in ADC at early time point for primary mass, lymph nodes and liver metastases was significantly higher in responders (24.8%, 29.6%, 15.9%) than non-responders (11.5%, 6.9%, 0.8%) respectively (p = 0.02, 0.0001, 0.04). There was no significant difference between baseline ADC of responders and non-responders in primary mass (p = 0.46). Area under curve (AUC) for percentage change in ADC and size for differentiating responders at early time point was (0.79, 0.86)for primary mass, (0.89, 0.95) for lymph nodes and (0.79, 0.92) for liver metastases respectively. Conclusions: Early increase in ADC can be used to evaluate response to chemotherapy in Ca GB. However baseline ADC cannot predict response to chemotherapy.
Geographic and ethnic heterogeneity in the <i>BRCA1/2</i> pre-screening population for the randomized phase III POLO study of olaparib maintenance in metastatic pancreatic cancer (mPC).
Authors: Talia Golan, Hedy L. Kindler, Joon Oh Park, Michele Reni, Teresa Macarulla Mercade, Pascal Hammel, Eric Van Cutsem, Dirk Arnold, Daniel Hochhauser, Gershon Y. Locker, Michael J. Hall
Journal: Journal of Clinical Oncology (2018)

4115 Background: Germ-line mutations in BRCA1/2 (gBRCAm) can cause defective repair of double-strand DNA breaks and are a risk factor for mPC. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib exploits homologous recombination repair deficiency in BRCAm tumors to produce synthetic lethality. Its efficacy is being evaluated in the POLO trial (NCT02184195). It is unknown how geography and ethnicity impact uptake of gBRCAm pre-screening in mPC. Methods: POLO is an international, ongoing, placebo-controlled trial to determine efficacy of olaparib (tablet formulation) maintenance monotherapy in gBRCAm pts with mPC. Mandatory pre-screening involves gBRCA testing by Integrated BRACAnalysis (Myriad Genetic Laboratories/MGL). The current analysis includes pts with gBRCAm previously identified by MGL or via pre-screening. Demographic/clinical history data were collected at enrollment. Results: 2206 pts from 12 countries were tested between 10/14 and 12/17. Pre-screening identified 130/2179 (6.0%) with a new gBRCAm; 27 additional pts had a previously known gBRCAm that were confirmed by Myriad testing; total 159/2206 (7.2%). Pre-screened pts were 57.2% male; 21% had early-onset mPC (Age in yrs: < 33: 0.6%; 33-49: 20.3%; 50-64: 49.4%; 65-88: 29.7%). gBRCAm pts were younger (57.9 vs. 61.1 yrs).The countries with the highest rates of new gBRCAm by pre-screening were: USA 37/288 (12.8%), Israel 26/230 (11.3%), France 24/293 (8.1%), Germany 17/262 (6.4%), Italy 15/250 (6%), Spain 14/344 (4%), and Korea 10/196 (5.1%). Outside US and Israel (populations enriched in Ashkenazi Jews), gBRCAm was newly identified in 96/1668 (5.75%). All pts with a known gBRCAm were White; all gBRCAm in African American/Asian/Hispanic pts (n = 19) were first identified by pre-screening. Conclusions: 6-7% unselected mPC have gBRCAm, with substantial geographic variability. Pts with gBRCAm were diagnosed at younger ages. Non-White pts were universally unaware of familial gBRCAm before pre-screening, highlighting potential disparities in uptake of genetic testing in minority populations and emphasizing the need to improve access to testing. Clinical trial information: NCT02184195.
TCT-641 Transcatheter Aortic Valve Replacement Outcomes In Patients With End-Stage Renal Disease: Systematic Review and Meta-analysis
Authors: Mohinder Vindhyal, Sinan Khayyat, Sachin Srinivasan, Tabitha Muutu, Sumaya Hammami, Paul Ndunda, Zaher Fanari
Journal: Journal of the American College of Cardiology (2018)
Randomised study of 2 low doses of sunitinib to modulate tumor microvasculature prior to chemotherapy in nasopharyngeal carcinoma (NPC).
Authors: Chee Seng Tan, Ting Ting Wang, Chwee-Ming Lim, Thomas Kwok Seng Loh, Si Yin Chin, Raghav Sundar, Wan Qin Chong, Samuel Guan Wei Ow, Ross A. Soo, Soo-Chin Lee, Boon C. Goh
Journal: Journal of Clinical Oncology (2016)

6034 Background: NPC is chemo- and radiosensitive but relapse rate is high and progression free survival (PFS) short for stage 4 disease. Almost all NPCs overexpress VEGF that promotes immature vasculature and poor tumor perfusion. We conducted a randomised phase 2 study of 2 low doses of sunitinib to promote maturity of tumor microvasculature prior to standard cisplatin-gemcitabine therapy in stage 4 NPC patients with the primary objectives to determine safety, tolerability and response rate (RR), and secondary objectives to determine PFS and effects on microvasculature. Methods: Eligible patients were randomised to receive sunitinib 12.5mg (ARM A) or 25mg (ARM B) daily for 7 days prior to each 3 weekly cycle of D1 cisplatin 75mg/m2 + D1, D8 gemcitabine 1000mg/m2, for 3 cycles followed by concurrent chemoradiotherapy in stage 4A/B (locally advanced) patients, and for 6 cycles in stage 4C (metastatic) patients. Enumeration of endothelial cell (CD34 antibody) and pericyte (SMA antibody) counts at 200x magnification by immunohistochemistry was performed by a blinded pathologist on tumor biopsies at baseline and cycle 1 day 7 sunitinib treatment to evaluate vascular normalization. Results: 33 patients were recruited (15 Arm A; 18 Arm B). The overall RR to induction chemotherapy was 82% (27/33) with 3 complete responses; 13/15 Arm A and 14/18 Arm B; 2 were non evaluable. At a median follow up of 23 months in stage 4A/B patients, 7/26 (27%) patients had progressed; median PFS was 9 months for stage 4C. G3/4 neutropenia without fever and thrombocytopenia without bleeding occurred in 67% and 40% in both Arms, respectively; resulting in dose delay of a week in 47% patients in Arm A and 50% in Arm B. Sunitinib alone induced early rise in plasma EBV DNA titre in 14/17 patients with detectable titres. 3/4 patients with detectable EBV DNA after induction chemotherapy relapsed within 12 months. Increase in vascular maturation reflected by increased SMA/CD34 score was seen in 75% of patients after 1 week of sunitinib in both arms. Conclusions: Sunitinib prior to chemotherapy is tolerable and active in stage 4 NPC, and induces early evidence of microvascular maturation, warranting further clinical studies. Clinical trial information: NCT01309633.
Efficacy and cost-effectiveness of antiviral therapy in patients with advanced hepatitis B virus-related hepatocellular carcinoma treated with sorafenib.
Authors: Qiu Li, Pengfei Zhang, Yu Yang, Feng Wen, Jack Wheeler
Journal: Journal of Clinical Oncology (2016)

e15622 Background: The incidence of hepatocellular carcinoma (HCC) in China accounts for 55% of cases worldwide; 85% of Chinese HCC cases are hepatitis B virus (HBV)-related. The aim of this study was to investigate the efficacy and the cost-effectiveness of antiviral therapy in patients with advanced HBV-related HCC treated with Sorafenib. Methods: Patients with HBV-related HCC who received Sorafenib as first-line treatment in West China Hospital were enrolled into this retrospective study. All patients were histologically or clinically diagnosed with HCC, according to the American Association for the Study of Liver Diseases standard, and positive for serum hepatitis B surface antigen. Data on the patients’ treatment, survival, and cost were recorded. A Markov model was created comprising three health states (progression-free survival (PFS), progressive disease and death). One-way sensitivity analyses and probabilistic sensitivity analyses were performed to explore model uncertainties. The protocol was approved by the Ethics Committee of West China Hospital, Sichuan University, China. Results: Between June 2009 and May 2013,92 patients were recruited?.41 patients received antiviral therapy while 51 did not. The median overall survival (OS) and PFS were 12.2 and 6.0 months, respectively, in patients with Sorafenib plus antiviral therapy. For those patients with Sorafenib alone, the OS and PFS were 8.0 and 4.5 months, respectively. The incremental cost-effectiveness ratio was $18442.27 per quality-adjusted life years (QALY) for the antiviral therapy combined with Sorafenib versus Sorafenib alone. Conclusions: Antiviral therapy significantly improved the survival in patients with advanced HBV-related HCC treated with first-line Sorafenib. Furthermore, based on the commonly accepted willingness to pay (a threshold of $20,301 per QALY in China),as estimated according to the World Health Organization guidelines, the addition of antiviral therapy to Sorafenib should be considered a cost-effective option in patients with advanced HBV-related HCC in China.
TCT-860 LAMPOON to Facilitate Tendyne Transcatheter Mitral Valve Replacement: From Animal Model to First-in-Human
Authors: Jaffar Khan, Robert Lederman, Robert Guyton, Chandan Devireddy, Norihiko Kamioka, Altayyeb Yousef, Patrick Gleason, Vasilis Babaliaros
Journal: Journal of the American College of Cardiology (2018)
Evaluation of baseline asymptomatic dysimmunity prevalence in cancer patients receiving monoclonal anti-PD1 antibodies.
Authors: Jennifer ARRONDEAU, Pascaline Boudou-Rouquette, Claire Goulvestre, Olivier Huillard, Nora Kramkimel, Jeanne Chapron, Camille Tlemsani, Anne Jouinot, Marco Alifano, Audrey Mansuet-Lupo, Diane Damotte, Jerome Alexandre, Francois Goldwasser, Frédéric Batteux
Journal: Journal of Clinical Oncology (2016)

e14551 Background: Monoclonal anti-PD1 antibodies are usually well tolerated but have dysimmune toxicities as specific adverse events. We hypothesized that pretherapeutic biological dysimmunity might favor the occurrence of acute toxicity. Therefore we measured the prevalence of biological dysimmunity. Methods: All cancer patients (pts) treated with immunotherapy from July 2015 to December 2015 were included in this prospective cohort study. Eighteen plasma autoantibodies (pAB) were assessed before initiation of immunotherapy and at each cycle of treatment during 4 cycles. Toxicity outcomes were evaluated using CTCAEv4. Results: Forty-nine pts (median age: 66.3 (41-83)) were treated with nivolumab (n = 41) or pembrolizumab (n = 8), including 31 non-small cell lung cancers, 11 melanomas and 4 renal cell carcinomas. No pt had known dysimmune disorder at baseline. Median follow-up and cycle number were 70 days (0-193) and 4 (1-13), respectively. Twenty-eight pts (57%) are still under treatment. Forty-four pts (90%) have at least one positive pAB at baseline. More frequent positive pAB at baseline were anti-nuclear pAB (positive threshold > 1/160: 33%), which 14 had speckled pattern and 10 had no specific subtype, antineutrophil cytoplasmic pAB (ANCA) ( > 1/20: 27%), antiphospholipid IgG and/or IgM pAB ( > 1/10: 20% / 35%). Under treatment 20 pts (41%) became positive and 13 pts (27%) became negative at least for one pAB. More frequent toxicities were asthenia (27%), diarrhea (14%) and arthralgia (8%). At this time, no thrombosis event was reported in pts with positive antiphospholipid pAB. The only pt with positive antinuclear anti-Jo1 pAB developed grade 3 myositis after 2 pembrolizumab injections. Conclusions: Ninety percent of pts have positive biological dysimmunity before immunotherapy initiation. Some specific pAB might be associated with specific acute toxicity.
The DNA repair transcriptome in severe COPD
Authors: Maor Sauler, Maxime Lamontagne, Eric Finnemore, Jose D. Herazo-Maya, John Tedrow, Xuchen Zhang, Julia E. Morneau, Frank Sciurba, Wim Timens, Peter D. Paré, Patty J. Lee, Naftali Kaminski, Yohan Bossé, Jose L. Gomez
Journal: European Respiratory Journal (2018)

Inadequate DNA repair is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the mechanisms that underlie inadequate DNA repair in COPD are poorly understood. We applied an integrative genomic approach to identify DNA repair genes and pathways associated with COPD severity. We measured the transcriptomic changes of 419 genes involved in DNA repair and DNA damage tolerance that occur with severe COPD in three independent cohorts (n=1129). Differentially expressed genes were confirmed with RNA sequencing and used for patient clustering. Clinical and genome-wide transcriptomic differences were assessed following cluster identification. We complemented this analysis by performing gene set enrichment analysis, Z-score and weighted gene correlation network analysis to identify transcriptomic patterns of DNA repair pathways associated with clinical measurements of COPD severity. We found 15 genes involved in DNA repair and DNA damage tolerance to be differentially expressed in severe COPD. K-means clustering of COPD cases based on this 15-gene signature identified three patient clusters with significant differences in clinical characteristics and global transcriptomic profiles. Increasing COPD severity was associated with downregulation of the nucleotide excision repair pathway. Systematic analysis of the lung tissue transcriptome of individuals with severe COPD identified DNA repair responses associated with disease severity that may underlie COPD pathogenesis.
MicroRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-κB-TNFα pathway
Authors: Tianpeng Zhang, Junjie Hu, Xiaomei Wang, Xiaoling Zhao, Zhuoyu Li, Junqi Niu, Clifford J. Steer, Guohua Zheng, Guisheng Song
Journal: Journal of Hepatology (2018)
CircRNA microarray profiling identifies a novel circulating biomarker for detection of gastric cancer
Authors: Weiwei Tang, Kai Fu, Handong Sun, Dawei Rong, Hanjin Wang, Hongyong Cao
Journal: Molecular Cancer (2018)

CircRNA expression profiles for gastric cancer (GC) were screened using plasma samples from 10 GC patients with different TNM stages and 5 healthy individuals as controls. Results showed lower expression of circ-KIAA1244 in GC tissues, plasmas, and cells compare to normal controls. Further clinical data analysis demonstrated that a decreased expression of circ-KIAA1244 in plasmas was negatively correlated with TNM stage and lymphatic metastasis, and a shorter overall survival time of GC patients. Moreover, we found that circ-KIAA1244 could be detected in GC plasma exosomes and showed no obvious significance compared to the expression level in the corresponding plasmas. This study revealed a GC-tissues-derived circ-KIAA1244 could serve a novel circulating biomarker for detection of GC.
Evaluation and Optimization of Pharmacokinetic Models for<i>in Vitro</i>to<i>in Vivo</i>Extrapolation of Estrogenic Activity for Environmental Chemicals
Authors: Warren M. Casey, Xiaoqing Chang, David G. Allen, Patricia C. Ceger, Neepa Y. Choksi, Jui-Hua Hsieh, Barbara A. Wetmore, Stephen S. Ferguson, Michael J. DeVito, Catherine S. Sprankle, Nicole C. Kleinstreuer
Journal: Environmental Health Perspectives (2018)

To effectively incorporate in vitro data into regulatory use, confidence must be established in the quantitative extrapolation of in vitro activity to relevant end points in animals or humans.Our goal was to evaluate and optimize in vitro to in vivo extrapolation (IVIVE) approaches using in vitro estrogen receptor (ER) activity to predict estrogenic effects measured in rodent uterotrophic studies.We evaluated three pharmacokinetic (PK) models with varying complexities to extrapolate in vitro to in vivo dosimetry for a group of 29 ER agonists, using data from validated in vitro [U.S. Environmental Protection Agency (U.S. EPA) ToxCast™ ER model] and in vivo (uterotrophic) methods. In vitro activity values were adjusted using mass-balance equations to estimate intracellular exposure via an enrichment factor (EF), and steady-state model calculations were adjusted using fraction of unbound chemical in the plasma ([Formula: see text]) to approximate bioavailability. Accuracy of each model-adjustment combination was assessed by comparing model predictions with lowest effect levels (LELs) from guideline uterotrophic studies.We found little difference in model predictive performance based on complexity or route-specific modifications. Simple adjustments, applied to account for in vitro intracellular exposure (EF) or chemical bioavailability ([Formula: see text]), resulted in significant improvements in the predictive performance of all models.Computational IVIVE approaches accurately estimate chemical exposure levels that elicit positive responses in the rodent uterotrophic bioassay. The simplest model had the best overall performance for predicting both oral (PPK_EF) and injection (PPK_[Formula: see text]) LELs from guideline uterotrophic studies, is freely available, and can be parameterized entirely using freely available in silico tools. https://doi.org/10.1289/EHP1655.
Added Value of 3- Versus 2-Dimensional Echocardiography Left Ventricular Ejection Fraction to Predict Arrhythmic Risk in Patients With Left Ventricular Dysfunction
Authors: Hugo Rodríguez-Zanella, Denisa Muraru, Eleonora Secco, Francesca Boccalini, Danila Azzolina, Patrizia Aruta, Elena Surkova, Davide Genovese, Giacomo Cavalli, Giuseppe Sammarco, Niccolò Ruozi, Rosaria M Tenaglia, Oscar Calvillo-Argüelles, Chiara Palermo, Sabino Iliceto, Luigi P Badano
Journal: JACC. Cardiovascular imaging (2018)
TCT-855 Optical coherence tomography appraisal of residual thrombus burden in patients with ST-segment elevation myocardial infarction undergoing high versus low bivalirudin infusion. The MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and angioX) OCT study
Authors: Hector Garcia-Garcia, Andrea Picchi, Gennaro Sardella, Marianna Adamo, Enrico Frigoli, Ugo Limbruno, Roberto Diletti, Giacomo Boccuzzi, Marco Zimarino, Marco Contarini, None Filippo Russo, Paolo Calabro', Giuseppe Ando, Stefano Garducci, Cataldo Palmieri, Carlo Briguori, Kayode Kuku, Martina Rothenbuehler, Alexios Karagiannis, Marco Valgimigli
Journal: Journal of the American College of Cardiology (2018)