tbuckley/cabot-search huggingface dataset:
A phase I study of TAS-102 in combination with oxaliplatin (TAS-OX) for refractory metastatic colorectal cancer (mCRC).
Authors: Michael Cecchini, Jeremy S. Kortmansky, Jill Lacy, Neal A. Fischbach, Jaykumar Ranchodbhai Thumar, Kert D. Sabbath, Christina M. Gomez, Jonathan Sporn, Stacey Stein, Howard S. Hochster
Journal: Journal of Clinical Oncology (2019)

630 Background: TAS-102 is an oral combination of the anti-metabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI), preventing the degradation of FTD. It is approved as mCRC monotherapy with improved survival. Oxaliplatin is often reintroduced in mCRC after progressive disease (PD) on maintenance 5-FU although response is poor. The decreased efficacy may be related to acquired 5-FU resistance. We therefore explored the safety and efficacy of oxaliplatin in combination with an alternative and non cross-resistant anti-metabolite, TAS-102. Methods: Phase 1 of TAS-OX is a 3+3 dose-escalating study at a starting dose of TAS-102 25 mg/m 2 and oxaliplatin 85 mg/m 2 with three dose levels (table). TAS-102 is administered days 1-5 and oxaliplatin day 1, every 2 weeks. Eligible patients previously received 5FU, oxaliplatin, irinotecan, appropriate biologics, had measurable disease, usual laboratory parameters, and ECOG PS 0-1. The primary objective was to determine the recommended phase II dose (RP2D). Results: Twelve patients were evaluable for dose limiting toxicity (DLT). No DLTs were observed. Treatment related grade ≥ 3 AEs were neutropenia (n = 4) and thrombocytopenia (n = 1). No AEs resulted in treatment discontinuation. Two patients (dose levels 2 and 3) required dose reductions for prolonged neutropenia. Median number of cycles for all treated patients was 6 ± 4. The disease control rate (DCR) at 8 weeks was 67%. Best response in all evaluable patients was 1 PR (8%) 7 (59%) SD and 4 (33%) PD. Conclusions: The RP2D of TAS-102 is 35 mg/m 2 in combination with oxaliplatin 85 mg/m 2 . No DLTs were observed and no unexpected AEs were seen. The DCR in this heavily pretreated patient population is encouraging. Phase II is now enrolling at this dose (NCT 02848079). Clinical trial information: NCT02848079. [Table: see text]
Trends in Gender of Speakers at the American Academy of Dermatology Annual Meeting, 2010-2018
Authors: Nisma Mujahid, Hannah Song, David G. Li, Cara Joyce, Arash Mostaghimi
Journal: JAMA Dermatology (2019)

This retrospective review of American Academy of Dermatology Annual Meeting data for even years between 2010 and 2018 was performed to identify the number of female speakers and associated presentation times.
Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation
Authors: Nico Gagelmann, Markus Ditschkowski, Rashit Bogdanov, Swann Bredin, Marie Robin, Bruno Cassinat, Rabia Shahswar, Felicitas Thol, Michael Heuser, Gerard Socié, Dietrich Beelen, Ioanna Triviai, Anita Badbaran, Nicolaus Kröger
Journal: Blood (2019)
Midostaurin in Adults with Newly Diagnosed FLT3-Mutation-Positive Acute Myeloid Leukemia Eligible for Standard Chemotherapy: Update from the Radius-X Midostaurin Expanded Access Program
Authors: Alexander E. Perl, Kendra L. Sweet, Gail J. Roboz, Stephen A. Strickland, Mark R. Litzow, Gaetano J Bonifacio, Kelly Haines, Alysha Barbera, Das Purkayastha, Andrew Dalovisio
Journal: Blood (2018)
The RANO Leptomeningeal Metastasis Group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal
Authors: Emilie Le Rhun, Patrick Devos, Thomas Boulanger, Marion Smits, Dieta Brandsma, Roberta Rudà, Julia Furtner, Johann-Martin Hempel, Tjeerd J Postma, Patrick Roth, Tom J Snijders, Frank Winkler, Sebastian Winklhofer, Antonella Castellano, Elke Hattingen, Jaume Capellades, Thierry Gorlia, Martin Van den Bent, Patrick Y Wen, Martin Bendszus, Michael Weller
Journal: Neuro-Oncology (2019)

A scorecard to evaluate magnetic resonance imaging (MRI) findings during the course of leptomeningeal metastases (LM) has been proposed by the Response Assessment in Neuro-Oncology (RANO) group.To explore the feasibility of the Leptomeningeal Assessment in Neuro-Oncology (LANO) scorecard, cerebrospinal MRIs of 22 patients with LM from solid tumors were scored by 10 neuro-oncologists and 9 neuroradiologists at baseline and at follow-up after treatment. Raters were blinded for clinical data including treatment. Agreement between raters of single items was evaluated using a Krippendorff alpha coefficient. Agreement between numerical parameters such as scores for changes between baseline and follow-up and total scores was evaluated by determining the intraclass coefficient of correlation.Most raters experienced problems with the instructions of the scorecard. No acceptable alpha concordance coefficient was obtained for the rating of single items at baseline or follow-up. The most concordant ratings were obtained for spinal nodules. The concordances were worst for brain linear leptomeningeal enhancement and cranial nerve enhancement. Discordance was less prominent among neuroradiologists than among neuro-oncologists. High variability was also observed for evaluating changes between baseline and follow-up and for total scores.Assessing response of LM by MRI remains challenging. Central imaging review is therefore indispensable for clinical trials. Based on the present results, we propose a new, simplified scorecard that will require validation using a similar approach as pursued here. The main challenges are to define measurable versus nonmeasurable (target) lesions and measures of change that allow assessment of response.
BRCA1 promoter methylation in breast cancer cell lines and primary tumors
Authors: Jinhua Xu, Cindy Collins, Dezheng Hou, Chika Nwachukwu, Judy Dering, Dennis Slamon, Olufunmilayo Olopade
Journal: Cancer Research (2007)

1043  Using primary tumors and the breast cancer cell line UACC3199, we have demonstrated that inactivation of BRCA1 by promoter methylation is associated with decreased BRCA1 gene copy number, reduced transcripts and chromosome 17 aneusomy, as observed in tumors from BRCA1 mutant carriers (Wei M et al. 2005). BRCA1 promoter methylation has been observed in 11 to 31% of sporadic primary tumors . To understand the mechanism of transcriptional down-regulation of BRCA1 bypromoter methylation, we screened DNA from 51 cultured breast cancer cell lines by methylation-specific PCR, and identified HCC38 as another BRCA1-promoter methylated cell line. There was low mRNA and protein expression in HCC38 and UACC3199 cells compared with the promoter unmethylated MCF-7 cells. After transient treatment with 5-aza-2’-deoxycytidine (5-aza-CdR)/trichostatin A (TSA) or Zebularine/TSA, re-expression of BRCA1 mRNA and BRCA1 protein were detected by quantitative RT-PCR and Western blot. Bisulfite DNA sequencing of the BRCA1 promoter region revealed that the proportion of methylated CpG dinucleotides located at positions -533, -355, -173, -21 decreased dramatically in demethylated UACC3199. To test the hypothesis that methylation of those CpG cites may affect binding of transcription factors to the BRCA1 promoter and consequently cause down-regulation of BRCA1, we systematically analyzed the binding of four transcription factors (CTCF, Sp1, CREB and E2F) to the BRCA1 promoter using a chromatin immunoprecipitation assay (ChIP). The four transcription factors bind to the unmethylated BRCA1 promoter in MCF-7 cells. In contrast, the four transcription factors failed to bind to the methylated BRCA1 promoter in UACC3199 cells. Following treatment with 5-aza-CdR and TSA, three of the four transcription factors were able to bind to BRCA1 promoterin the demethylated UACC3199 cells. This indicated that reduced accessibility of transcription factors to the methylated promoter is one of the mechanisms for down-regulation of BRCA1 in heavily methylated UACC3199 cancer cells. Future work will investigate if a similar mechanism affects transcription factors binding in HCC38 cells. Our results demonstrated that down-regulation of BRCA1 by methylation is reversible, and methods to reverse this process may be clinically relevant in the treatment and/or prevention of breast cancer.
Identification of reactive oxygen production site in Siglec-8 induced eosinophil death
Authors: Toshihiro Tomii, Gen Kano
Journal: Journal of Allergy and Clinical Immunology (2019)

Siglec-8 is expressed on the surface of eosinophils and induces cell death. This function is paradoxically enhanced by co-stimulation with IL-5, an activation/survival factor for eosinophils. We previously reported that this cell death was dependent on intracellular reactive oxygen species (ROS) unlike ETosis, which require extracellular ROS. Here we conducted functional analysis of NAPDH oxidase (NOX) and mitochondria to identify the source of intracellular ROS production in Siglec-8 induced cell death. Human peripheral blood eosinophils were purified and stimulated by anti-Siglec-8 monoclonal antibodies (as ligand) simultaneously with IL-5, or by Ca++ionophore A23187 as ETosis inducer. Then we evaluated (1) phosphorylation of p40phox/ p47phox(NOX cytosolic subunits) by Western Blotting and phospho-flow, (2) cell surface expression of gp91phox(a NOX membrane subunit) by flow cytometry, (3) mitochondrial membrane depolarization and its ROS production using fluorescent indicators JC-1 and MitoSOX Red, respectively. Phosphorylation of p40phoxwas observed with both Siglec-8 and A23187 stimulation, with the latter showed more prominent change. p47phoxactivation were found to be similar with both stimulations. Interestingly, cell surface expression of gp91phoxwas not changed by Siglec-8, contrary to the significant increase by A23187. In mitochondrial analysis, mild depolarization but no ROS production was detected in Siglec-8 stimulated cells. NOX was turned out to be the predominant source of intracellular ROS in Siglec-8 mediated cell death. The difference in surface expression of gp91phoxmay explain the difference in ROS production by Siglec-8 and ETosis stimuli, proposing previously unrecognized property of eosinophil NOX.
Association of Diabetes and Glycated Hemoglobin With the Risk of Intracerebral Hemorrhage: A Population-Based Cohort Study
Authors: Walid Saliba, Ofra Barnett-Griness, Naomi Gronich, Jeremy Molad, Jonathan Naftali, Gad Rennert, Eitan Auriel
Journal: Diabetes Care (2019)

OBJECTIVE To examine the association of diabetes and glycated hemoglobin (HbA1c) with the risk of intracerebral hemorrhage (ICH) in a large population-based cohort. RESEARCH DESIGN AND METHODS The computerized database of the largest health care provider in Israel was used to identify adult members aged 40 years or older and alive at 1 January 2010 (297,486 with diabetes and 1,167,585 without diabetes). The cohort was followed until 31 December 2017 for incidence of ICH. Multivariable Cox proportional hazards regression models, adjusted for baseline disease risk score, were applied to estimate the hazard ratio (HR) of ICH. RESULTS Overall 4,170 ICH cases occurred during 10,730,915 person-years of follow-up. Diabetes was independently associated with increased ICH risk, with hazard ratio (HR) 1.36 (95% CI 1.27–1.45), and increased with longer diabetes duration: 1.23 (1.12–1.35) and 1.44 (1.34–1.56) for diabetes duration ≤5 years and &amp;gt;5 years, respectively. The increased ICH risk associated with diabetes was more pronounced in patients ≤60 years old (Pinteraction &amp;lt;0.001). Among patients with diabetes, HbA1c had a nonlinear J-shaped relationship with ICH (P for nonlinearity = 0.0186). Compared to the fourth HbA1c decile, 6.5–6.7% (48–50 mmol/mol), the HR for ICH was 1.27 (1.01–1.59) and 2.19 (1.75–2.73) in the lowest HbA1c decile, ≤6.0% (≤42 mmol/mol), and highest HbA1c decile, &amp;gt;9.3% (&amp;gt;78 mmol/mol), respectively. CONCLUSIONS Diabetes is associated with increased risk of ICH that is directly associated with diabetes duration. ICH and HbA1c appear to have a J-shaped relationship, suggesting that both poor control as well as extreme intensive diabetes control might be associated with increased risk.
SAMD9 and SAMD9L Germline Disorders in Patients Enrolled in Studies of the European Working Group of MDS in Childhood (EWOG-MDS): Prevalence, Outcome, Phenotype and Functional Characterisation
Authors: Sushree Sangita Sahoo, Victor Pastor Loyola, Pritam Kumar Panda, Enikoe Amina Szvetnik, Emilia J. Kozyra, Rebecca K Voss, Dirk Lebrecht, Shlomit Barzilai, Jochen Büchner, Albert Catala, Barbara De Moerloose, Michael Dworzak, Oksana Fabri, Henrik Hasle, Kirsi Jahnukainen, Krisztián Kállay, Franco Locatelli, Riccardo Masetti, Sophia Polychronopoulou, Markus Schmugge, Jan Stary, Owen P Smith, Dominik Turkiewicz, Marek Ussowicz, Marry M. van den Heuvel-Eibrink, Peter Noellke, Gudrun Göhring, Miriam Erlacher, Christian Flotho, Brigitte Strahm, Charlotte Niemeyer, Marcin W. Wlodarski
Journal: Blood (2018)
Abstract 19220: Longitudinal Myocardial Strain is Associated With Incident Heart Failure and Mortality in Older Adults: The Cardiovascular Health Study
Authors: Harnish H Patel, Jeanette Cheng, Shyam Patnaik, Axi Patel, M Cristina Abduch, Jorge Kizer, John Gottdiener, Bruce Psaty, Sanjiv J Shah
Journal: Circulation (2017)

Introduction: Longitudinal myocardial strain, which can be measured by speckle-tracking echo, provides a window into cardiomyocyte Ca2+ homeostasis and is a sensitive measure of subendocardial func...
Comparison of radiation treatment volumes for borderline resectable pancreatic cancer.
Authors: Trevor Scott Bluemel, Jordan Kharofa
Journal: Journal of Clinical Oncology (2019)

440 Background: Optimal radiation target volumes for downstaging and local control in patients with borderline resectable pancreatic cancer (BRPCa) are undefined. Most local recurrences are near the celiac axis (CA) and superior mesenteric artery (SMA), as demonstrated by pattern of failure mapping (Dholakia et al IJROBP 2013). Methods for generating target volumes include symmetric margins around the tumor or a customized approach. We investigated three current prospective trials’ coverage of vascular regions at risk of recurrence. Methods: CT simulation scans of 14 patients with BRPCa from an institutional prospective trial were used to create treatment volumes for comparison. Treatment volumes from three current prospective trials (PREOPANC, Alliance A021101, and Alliance A021501) were generated for each patient based upon their respective protocols. The trials’ volumes were compared to two reference volumes created for coverage evaluation. A customized vasculature (CustVasc) CTV was based on the CA, SMA, and vessels abutting the tumor. The Hopkins PTV reference volume was based upon the proximal 1 cm of the CA and 3 cm of the SMA, and expanded according to the study’s protocol. Boolean operators located regions the three prospective trials would not provide treatment when compared to reference volumes. Results: Table outlines the target volumes and the proportion of the CustVascPTV and Hopkins PTV covered by each trial definition. Conclusions: Symmetric expansion from the primary tumor to generate target volumes may not adequately cover the mesenteric vasculature which is at high risk of local recurrence and varies based on patient/tumor anatomy. An approach utilizing a customized target volume that specifically includes the SMA and CA will improve coverage to this region at high risk of local recurrence.[Table: see text]
Comparable Survival Outcomes of Haploidentical Stem Cell Transplantation and Unrelated Bone Marrow Transplantation
Authors: Junichi Sugita, Yoshiko Atsuta, Mio Kurata, Hirohisa Nakamae, Naoki Kurita, Ken Ishiyama, Souichi Shiratori, Takahiro Fukuda, Kazuteru Ohashi, Yukiyasu Ozawa, Junya Kanda, Tatsuo Ichinohe, Takanori Teshima
Journal: Blood (2018)
Abstract B038: Convergent hormone therapy resistance mediated by stress/dormancy-like pathways in prostate cancer
Authors: Kathryn E. Ware, Santosh Gupta, Jared Eng, Wen-Chi Foo, Lorin Crawford, Garland Austin, Bhairavy Puviindran, Jennifer Freedman, Steven R. Patierno, Tian Zhang, David Corcoran, Mariaelena Pierobon, Emanuel Petricoin, Jason A. Somarelli, Andrew J. Armstong
Journal: Cancer Research (2018)

Abstract Background: Novel agents that inhibit the androgen receptor (AR), including abiraterone acetate and enzalutamide, have significantly prolonged life in many men with metastatic castration-resistant prostate cancer (mCRPC). However, after 1-2 years of therapy acquired resistance to these drugs is nearly universal. Therefore, identifying mechanisms of resistance and innovative therapies to treat enzalutamide-resistant disease represents a major unmet clinical need. Methods: In this study, we developed four enzalutamide-resistant cell lines and analyzed each cell line by RNA-seq and phospho-proteomics to identify common pathways deregulated during disease progression to enzalutamide resistance. We manipulated p38 levels and activity in order to determine its mechanistic relationship to resistance. We measured p38 activity in metastatic biopsies from men with both hormone-sensitive and metastatic prostate cancer. Results: At the nexus of acquired enzalutamide resistance in four independently derived prostate cancer model systems, we identified a convergent mechanism of resistance through activation of the p38 stress response/dormancy pathway. Enzalutamide-resistant cells are sensitized to p38 inhibition, and enzalutamide- sensitive cells developed resistance to enzalutamide with constitutive activation of p38 signaling. Enzalutamide-resistant cells have sustained AR activity, which is blocked with genetic or small-molecule p38 inhibition, indicating that p38 promotes AR activity in the absence of ligand binding. Finally, we found common activation of p38 in lymph node, visceral, and bone metastases from men with mCRPC. Conclusions: We have identified the stress response/dormancy p38-signaling pathway as a common mechanism driving enzalutamide resistance. Most importantly, p38 is a targetable pathway activated in tumors from men with mCRPC, suggesting that novel therapeutic strategies could be applied to prolong the lives of men with metastatic, drug-resistant prostate cancer. Citation Format: Kathryn E. Ware, Santosh Gupta, Jared Eng, Wen-Chi Foo, Lorin Crawford, Garland Austin, Bhairavy Puviindran, Jennifer Freedman, Steven R. Patierno, Tian Zhang, David Corcoran, Mariaelena Pierobon, Emanuel Petricoin, Jason A. Somarelli, Andrew J. Armstong. Convergent hormone therapy resistance mediated by stress/dormancy-like pathways in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B038.
Impact of adjuvant hepatic arterial chemoinfusion using high-dose 5-fluorouracil with systemic gemcitabine for pancreatic cancer: A propensity score–matched analysis.
Authors: Kota Nakamura, Masayuki Sho, Takahiro Akahori, Minako Nagai, Kenji Nakagawa, Tadataka Takagi, Naoya Ikeda, Toshihiro Tanaka, Hideyuki Nishiofuku, Kimihiko Kichikawa
Journal: Journal of Clinical Oncology (2019)

402 Background: The aim of this retrospective study was to evaluate the efficacy of adjuvant hepatic arterial infusion chemotherapy (HAI) using high-dose 5-fluorouracil with systemic gemcitabine on prognosis of resected pancreatic cancer. Methods: Between January 2006 and April 2016, 298 patients underwent elective pancreatic resection for resectable or borderline resectable pancreatic cancer at Nara Medical University Hospital. Patients who received adjuvant HAI plus systemic gemcitabine after surgery (HAI group) were compared with those who received systemic chemotherapy alone (control group). Patients were propensity score matched for age, sex, ASA score, CA19-9, NCCN resectability status, neoadjuvant treatment, surgical procedure, portal vein invasion, T stage, N stage, and margin status. Results: 224 patients with resectable or borderline resectable pancreatic cancer were enrolled in this study. 151 patients in the HAI group and 73 patients in the control group were included. Propensity score matching analysis was used to identify 63 well-balanced patients in each group for overall survival comparison. The estimate overall survival (OS) for patients treated with HAI was longer than patients without HAI in both the whole cohort (median OS, 54 vs. 24 months, respectively; P &lt; 0.001) or matched cohort (median OS, 58 vs. 26 months, respectively; P = 0.003). The liver was only recurrence site in which significant decrease was observed in the HAI group compared to the control group ( P = 0.031). In the multivariate analysis, adjuvant chemotherapy without HAI were independently associated with worse outcome in the whole cohort. A total of 127 patients in the HAI group (84%) had completed the planned dose of HAI. The remaining 24 patients stopped treatment before the end of the planned cycle due to catheter-associated complications in 9 (6.0%) and development of liver abscess in 2 (1.3%). No treatment-related deaths occurred. Conclusions: The efficacy of hepatic arterial chemoinfusion as adjuvant treatment for resectable pancreatic cancer should be revisited.
Biofabrication of a vascularized islet organ for type 1 diabetes
Authors: Antonio Citro, Philipp T. Moser, Erica Dugnani, Taufiek K. Rajab, Xi Ren, Daniele Evangelista-Leite, Jonathan M. Charest, Andrea Peloso, Bruno K. Podesser, Fabio Manenti, Silvia Pellegrini, Lorenzo Piemonti, Harald C. Ott
Journal: Biomaterials (2019)
Abstract 14906: The Effect of Shunt Type on Non-invasive Pressure-Volume Loop Measures of Cardiac Mechanics After Stage 2 Palliation: Insights From the Pediatric Heart Network Single Ventricle Reconstruction Trial Public Use Dataset
Authors: Shahryar M Chowdhury, Andrew M Atz, Carolyn L Taylor, Sinai C Zyblewski, Scott M Bradley, Minoo N Kavarana, Eric M Graham
Journal: Circulation (2016)

Introduction: The early survival benefit of the RV to pulmonary artery shunt (RVPAs) over the modified Blalock-Taussig shunt (mBTs) dissipates over time in children with single RV after the Norwood...
Relationship Between Operator Volume and Long-Term Outcomes After Percutaneous Coronary Intervention
Authors: Alexander C. Fanaroff, Pearl Zakroysky, Daniel Wojdyla, Lisa A. Kaltenbach, Matthew W. Sherwood, Matthew T. Roe, Tracy Y. Wang, Eric D. Peterson, Hitinder S. Gurm, Mauricio G. Cohen, John C. Messenger, Sunil V. Rao
Journal: Circulation (2019)

Although many studies show an inverse association between operator procedural volume and short-term adverse outcomes after percutaneous coronary intervention (PCI), the association between procedural volume and longer-term outcomes is unknown.