tbuckley/cabot-search huggingface dataset:
Run-in-phase results from a multicenter phase II trial to evaluate pembrolizumab (P) and gemcitabine (Gem) in patients (pts) with HER2-negative advanced breast cancer (ABC): GEICAM/2015-04 PANGEA-Breast
Authors: V. Quiroga, E. Holgado, J.L. Alonso, R. Andres, F. Moreno Anton, M.D.C. Alamo De La Gala, F. Henao, B. Cirauqui Cirauqui, M. Margeli, J. Cortes Castan, M. Gion Cortes, A. Soto, S. Benito, M.J. Escudero, M. Chiesa, R. Caballero, S. Bezares Montes, E.M. Carrasco, L. De La Cruz Merino
Journal: Annals of Oncology (2018)

Background: This trial is based on a combination strategy with two immunostimulatory agents in the search of synergism that may induce responses with long term clinical benefit in ABC pts. Here, we report the results from the run-in-phase of the study (ClinicalTrials.gov Identifier: NCT03025880). Methods: HER2-negative ABC pts previously treated with anthracyclines and taxanes (unless contraindicated) and ≥ 2 lines of hormone therapy, if hormone receptor (HR)-positive disease, were eligible. Treatment consisted of 21-day cycles (cy) of P 200mg on day 1 and Gem on days 1 and 8. A 6 + 6 design was used with 2 dose levels (DL) of Gem: 1250mg/m2 (DL0) and 1000mg/m2 (DL1). The primary objective was to define the Recommended Phase II Dose (RP2D) based on dose limiting toxicities (DLT) during the first cy (<33% of pts with a DLT); secondary objectives included evaluation of safety and efficacy. Pts were treated until progression, or unacceptable toxicity whatever occurs first. Results: Fourteen pts were included in DL0; 3 pts were replaced due to early progressive disease (PD). DL1 was not explored as DL0 was considered the RP2D . Median age was 48 years (range 32-61), and 9 pts had triple negative disease. The majority of pts had an ECOG performance status ≤ 1 (n = 13) and visceral involvement (n = 12); 8 pts had ≤2 involved sites. Median number of prior lines (any therapy) for metastatic disease was 3 (range 1-7). Pts received a median of 4.5 cy of Gem (range 1-11) and 3 cy of P (range 1-11). One DLT was observed, Gem dose omission on day 8 due to grade (G) 2 thrombocytopenia. G ≥ 3 adverse events (AEs) related to the treatment were reported on 5 pts; G4 AEs included thrombocytopenia and lymphopenia (7.1% each); G3 AEs included neutropenia (14.3%), anemia, leukopenia, thrombocytopenia, diarrhea and transaminases increase (7.1% each). The best overall tumor response was stable disease on 3 pts at the time of this analysis; 9 pts discontinued treatment due to PD, 1 pt due to respiratory failure, and 2 pts died of breast cancer. Twenty-two pts have been included on the ongoing phase II part. Conclusions: P can be safely combined with Gem. P 200mg and Gem 1250mg/m2 was declared as the RP2D. Clinical trial identification: NCT03025880. Legal entity responsible for the study: GEICAM, Spanish Breast Cancer Group. Funding: Merck Sharp & Dohme Corp (MSD). Disclosure: J. Cortes Castan: Honoraria: Roche, Novartis, Eisai, Celgene, Pfizer. Consulting/advisor: Roche, Celgene, AstraZeneca, Cellestia Biotech, Biothera, Merus, Seattle Genetics. E.M. Carrasco: Husband: Honoraria: Pfizer. All other authors have declared no conflicts of interest.
Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis
Authors: Dongqing Yan, Anthony D. Pomicter, Srinivas Tantravahi, Clinton C. Mason, Anna V. Senina, Jonathan M. Ahmann, Qiang Wang, Hein Than, Ami B. Patel, William L. Heaton, Anna M. Eiring, Phillip M. Clair, Kevin C. Gantz, Hannah M. Redwine, Sabina I. Swierczek, Brayden J. Halverson, Erkan Baloglu, Sharon Shacham, Jamshid S. Khorashad, Todd W. Kelley, Mohamed E. Salama, Rodney R. Miles, Kenneth M. Boucher, Josef T. Prchal, Thomas O'Hare, Michael W. Deininger
Journal: Clinical Cancer Research (2018)

Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive activation of JAK/STAT signaling through mutations in JAK2, CALR, or MPL is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better therapeutic targets in myelofibrosis.A short hairpin RNA library screening was performed on JAK2V617F-mutant HEL cells. Nuclear-cytoplasmic transport (NCT) genes including RAN and RANBP2 were among top candidates. JAK2V617F-mutant cell lines, human primary myelofibrosis CD34+ cells, and a retroviral JAK2V617F-driven myeloproliferative neoplasms mouse model were used to determine the effects of inhibiting NCT with selective inhibitors of nuclear export compounds KPT-330 (selinexor) or KPT-8602 (eltanexor).JAK2V617F-mutant HEL, SET-2, and HEL cells resistant to JAK inhibition are exquisitely sensitive to RAN knockdown or pharmacologic inhibition by KPT-330 or KPT-8602. Inhibition of NCT selectively decreased viable cells and colony formation by myelofibrosis compared with cord blood CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and apoptosis, both in newly diagnosed and ruxolitinib-exposed myelofibrosis cells. Inhibition of NCT in myelofibrosis CD34+ cells led to nuclear accumulation of p53. KPT-330 in combination with ruxolitinib-normalized white blood cells, hematocrit, spleen size, and architecture, and selectively reduced JAK2V617F-mutant cells in vivo.Our data implicate NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis.
Comparative analysis of different maintenance regimens after first-line induction in patients with metastatic colorectal cancer.
Authors: AMR Mohamed, Nadine Abdallah, Hibah Ismail, Wei Chen, Hyejeong Jang, Daryn W. Smith, Alaa Akhras, Anteneh A. Tesfaye, Philip Agop Philip, Anthony Frank Shields
Journal: Journal of Clinical Oncology (2018)

789 Background: Although, previous trials have demonstrated the benefits of maintenance chemotherapy for unresectable metastatic colorectal cancer (MCRC), the optimal maintenance regimen with acceptable safety profile is still undetermined. The primary objective of this meta-analysis was to compare the effectiveness of the most common clinically used maintenance regimens after first line therapy in MCRC. Methods: Among 52 prospective studies published 2009-2017, 14 were qualified for inclusion. Random-effect model was used for pooled effects within different categories include those with no maintenance treatment versus different maintenance regimens (Bevacizumab, capecitabine, bevacizumab plus capecitabine, bevacizumab plus erlotinib, and cetuximab). Primary endpoint was median progression free survival (PFS), and secondary endpoint was median overall survival (OS). All statistical tests were two-sided and p values &lt; 0.05 were considered significant. Results: 14 studies with 3553 patients (57% males) were included in final analysis. Induction treatment was 5-FU or capecitabine - based chemotherapy with either oxaliplatin or irinotecan with or without bevacizumab. After stratifying for induction status, patients who did not receive treatment had worse PFS compared to maintenance treatment [pooled median PFS 3.52 months, 95% CI (2.97- 4.07) Vs 5.08 months, 95% CI (4.59- 5.57), z-test adjusted p-value 0.0005]. Among different maintenance regimens, capecitabine /bevacizumab combination showed better PFS [pooled median PFS 6.87 month, 95% CI (5.17- 8.57)], however the results were not significant (z test adjusted p-value 0.1383). No statistical significant difference in median OS between maintenance regimens. Conclusions: MCRC patients who did not receive maintenance treatment had shorter PFS. Although the superiority of bevacizumab plus capecitabine maintenance cannot be confirmed, there was a trend towards better PFS. This study suggests that bevacizumab plus capecitabine may be an appropriate maintenance option after first induction therapy depending on the tolerability and compliance with oral capecitabine.
On Mediation Models in Clinical Neurology Studies
Authors: Hugo Cogo-Moreira, Walter Swardfager
Journal: JAMA Neurology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Annual flu vaccination reduces risk of death in patients with heart failure, study finds
Authors: Susan Mayor
Journal: BMJ (2018)

The risk of all-cause and cardiovascular death in patients with heart failure is reduced by almost one fifth in those having annual flu vaccinations compared with non-vaccinated patients, a Danish cohort study1 has found.

“Recent studies have shown that the influenza vaccination coverage of patients with heart failure is inadequate,” said the lead author of the study, Daniel Modin, from the University of Copenhagen, Denmark. He added, “I hope that our study can help make physicians and cardiologists who …
Phase I/II Study of Ruxolitinib for Minimal Residual Disease in Chronic Myeloid Leukemia
Authors: Abhishek Maiti, Hagop M. Kantarjian, Elias J. Jabbour, Rebecca Poku, Brittany A Yearby, Stephanie Breakefield, Farhad Ravandi, Jorge E. Cortes
Journal: Blood (2018)
Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer
Authors: Sarah P. Blagden, Anne L. Hamilton, Linda Mileshkin, Shirley Wong, Agnieszka Michael, Marcia Hall, Jeffrey C. Goh, Alla S. Lisyanskaya, Michelle DeSilvio, Eleni Frangou, Euan A. Stronach, Prashanth Gopalakrishna, Tarek M. Meniawy, Hani Gabra
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors. Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum-refractory ovarian cancer (PPROC). Patients and Methods: Part I was a combination 3+3 dose escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50–150 mg/day with intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) every 3 weeks for six cycles followed by maintenance afuresertib at 125 mg/day until progression or toxicity. Part II was a single-arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the MTD defined in Part I in combination with PC for six cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose escalation), and investigator-assessed overall response rate (ORR) as per RECIST version 1.1 (Part II). Results: Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities of grade 3 rash were observed, one at 125 mg and two at 150 mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. The most common (≥50%) drug-related adverse events observed in Part I of the study were nausea, diarrhea, vomiting, alopecia, fatigue, and neutropenia and, in Part II, were diarrhea, fatigue, nausea, and alopecia. The Part II ORR in the intention to treat patients was 32% [95% confidence interval (CI), 15.9–52.4] by RECIST 1.1 and 52% (95% CI, 31.3–72.2) by GCIG CA125 criteria. Median progression-free survival was 7.1 months (95% CI, 6.3–9.0 months). Conclusions: Afuresertib plus PC demonstrated efficacy in recurrent PROC with the MTD of afuresertib defined as 125 mg/day.
Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome
Authors: Arnau Vich Vila, Floris Imhann, Valerie Collij, Soesma A. Jankipersadsing, Thomas Gurry, Zlatan Mujagic, Alexander Kurilshikov, Marc Jan Bonder, Xiaofang Jiang, Ettje F. Tigchelaar, Jackie Dekens, Vera Peters, Michiel D. Voskuil, Marijn C. Visschedijk, Hendrik M. van Dullemen, Daniel Keszthelyi, Morris A. Swertz, Lude Franke, Rudi Alberts, Eleonora A. M. Festen, Gerard Dijkstra, Ad A. M. Masclee, Marten H. Hofker, Ramnik J. Xavier, Eric J. Alm, Jingyuan Fu, Cisca Wijmenga, Daisy M. A. E. Jonkers, Alexandra Zhernakova, Rinse K. Weersma
Journal: Science Translational Medicine (2018)

Differences in gut microbiota composition and function were observed between patients with inflammatory bowel disease or irritable bowel syndrome.
Abstract 17548: Cardiac Rehabilitation in Young Adults Following Myocardial Infarction is Associated With Better 1 Year Outcomes
Authors: David Biery, Avinainder Singh, Bradley Collins, Mary Cawley, Monica Eng, Roxanna Rajabi, Julio Baez, Arman Qamar, Amber Fatima, Ankur Gupta, Khurram Nasir, Donna M Polk, Hicham Skali, Marcelo F Di Carli, Deepak L Bhatt, Ron Blankstein
Journal: Circulation (2017)

Introduction: The utilization of cardiac rehabilitation (CR) among patients, who experience a myocardial infarction (MI) at a young age, and its prognostic implications have not been well studied. ...
Abstract 17209: Family History of CHD Predicts a More Diffuse CAC Distribution in the CAC Consortium
Authors: Jaideep Patel, Zeina Dardari, Daniel S Berman, Matthew J Budoff, Michael D Miedema, Khurram Nasir, Leslee J Shaw, John A Rumberger, Alan Rozanski, Roger S Blumenthal, Michael J Blaha
Journal: Circulation (2017)

Introduction: A family history of coronary heart disease (FH) is associated with risk of CHD, however the mechanism underlying this relationship remains unclear. Hypothesis: FH is significantly ass...
Clinical Characterization of Immunotherapy-Related Pruritus Among Patients Seen in 2 Oncodermatology Clinics
Authors: Gregory S. Phillips, Azael Freites-Martinez, Jennifer Wu, Donald Chan, Gabriella Fabbrocini, Matthew D. Hellmann, Mario E. Lacouture
Journal: JAMA Dermatology (2018)

Immunotherapies are landmark disease-modifying agents in cancer but have the potential to cause adverse events that can lead to treatment interruptions, decreased quality of life (QOL), or morbidity. 1Immunotherapy agents include monoclonal antibodies that target downregulators or checkpoints of the immune response, including cytotoxic T-lymphocyteassociated protein 4 (CTLA-4), programmed cell death 1 (PD1), and programmed death ligand 1 (PD-L1), activating the immune system against tumor cells.Pruritus occurs in 14% to 47% of patients treated with immune checkpoint inhibitors and can range in severity from mild and localized to debilitating and widespread in 1% to 3% of patients. 2Pruritus in various dermatologic conditions is associated with lower QOL, 3 but to our knowledge the repercussions of immunotherapy-related pruritus among patients with cancer have not been reported. Methods | Patients referred to the oncodermatology clinics atMemorial Sloan Kettering Cancer Center in New York City and the University of Naples Federico II in Naples, Italy, for pruritus attributed to immunotherapy between December 1, 2014, and November 30, 2017, were given the ItchyQoL pruritus assessment, visual analog scale, and body distribution diagram.This study was approved by Memorial Sloan Kettering Cancer Center's Institutional Review Board, and written informed consent was obtained from all participants.ItchyQoL is validated to assess QOL regarding pruritus symptoms, functional status, and emotional wellbeing.Each ItchyQoL item is scored from 1 to 5, with higher scores indicating greater burden on QOL. 4 ItchyQoL is reported as a single score consisting of the mean of the responses to all the items.In the visual analog scale, participants rate their degree of itch on a 100-mm horizontal visual analog scale; possible scores range from 0 to 100, with a score of 0 indicating no itch and 100, extreme itch.Relevant clinical and demographic data were abstracted from electronic medical records.
Best Practices for QSAR Model Reporting: Physical and Chemical Properties, Ecotoxicity, Environmental Fate, Human Health, and Toxicokinetics Endpoints
Authors: Geven Piir, Iiris Kahn, Alfonso T. García-Sosa, Sulev Sild, Priit Ahte, Uko Maran
Journal: Environmental Health Perspectives (2018)

Background: Quantitative and qualitative structure–activity relationships (QSARs) have been used to understand chemical behavior for almost a century. The main source of QSAR models is the scientific literature, but the open question is how well these models are documented. Objectives: The main aim of this study was to critically analyze the publication practices of QSARs with regard to transparency, potential reproducibility, and independent verification. The focus was on the level of technical completeness of the published QSARs. Methods: A total of 1,533 QSAR articles reporting 79 individual endpoints, mostly in environmental and health science, were reviewed. The QSAR parameters required for technical completeness were grouped into five categories: chemical structures, experimental endpoint values, descriptor values, mathematical representation of the model, and predicted endpoint values. The data were summarized and discussed using Circos plots. Results: Altogether, 42.5% of the reviewed articles were found to be potentially reproducible. The potential reproducibility for different endpoint groups varied; the respective rates were 39% for physical and chemical properties, 52% for ecotoxicity, 56% for environmental fate, 30% for human health, and 32% for toxicokinetics. The reproducibility of QSARs is discussed and placed in the context of the reproducibility of the experimental methods. Included are 65 references to open QSAR datasets as examples of models restored from scientific articles. Discussion: Strikingly poor documentation of QSARs was observed, which reduces the transparency, availability, and consequently, the application of research results in scientific, industrial, and regulatory areas. A list of the components needed to ensure the best practices for QSAR reporting is provided, allowing long-term use and preservation of the models. This list also allows an assessment of the reproducibility of models by interested parties such as journal editors, reviewers, regulators, evaluators, and potential users. https://doi.org/10.1289/EHP3264
First-in-Human Use of Coronary Sinus Reducer in Patients With Refractory Angina
Authors: Parth Parikh, Parloop Bhatt, Deepa Shah, Piyush Thakar, Ajay Naik, Hemang Baxi, Shmuel Banai, Keyur Parikh
Journal: Journal of the American College of Cardiology (2018)
Evolution of the Yeast Recombination Landscape
Authors: Haoxuan Liu, Calum J Maclean, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2018)

Abstract Meiotic recombination comprises crossovers and noncrossovers. Recombination, crossover in particular, shuffles mutations and impacts both the level of genetic polymorphism and the speed of adaptation. In many species, the recombination rate varies across the genome with hot and cold spots. The hotspot paradox hypothesis asserts that recombination hotspots are evolutionarily unstable due to self-destruction. However, the genomic landscape of double-strand breaks (DSBs), which initiate recombination, is evolutionarily conserved among divergent yeast species, casting doubt on the hotspot paradox hypothesis. Nonetheless, because only a subset of DSBs are associated with crossovers, the evolutionary conservation of the crossover landscape could differ from that of DSBs. Here, we investigate this possibility by generating a high-resolution recombination map of the budding yeast Saccharomyces paradoxus through whole-genome sequencing of 50 meiotic tetrads and by comparing this recombination map with that of S. cerevisiae. We observe a 40% lower recombination rate in S. paradoxus than in S. cerevisiae. Compared with the DSB landscape, the crossover landscape is even more conserved. Further analyses indicate that the elevated conservation of the crossover landscape is explained by a near-subtelomeric crossover preference in both yeasts, which we find to be attributable at least in part to crossover interference. We conclude that the yeast crossover landscape is highly conserved and that the evolutionary conservation of this landscape can differ from that of the DSB landscape.
Abstract 12912: Impact of Graft Configuration of The Right Internal Mammary Artery in Coronary Artery Bypass Grafting: In-situ Versus Y Composite versus Aorto-coronary Bypass
Authors: Jiro Sakai, Tatsuhiko Komiya, Hiroshi Tsuneyoshi, Takeshi Shimamoto
Journal: Circulation (2015)

Background: Right internal mammary artery (RIMA) has been used as second graft with various configurations. The aim of this study was to compare the patency of RIMA with using either aorto-coronary bypass (AC) or Y composite grafting proximally anastomosing to left internal mammary artery (LIMA) or in-situ grafting. Methods: Between January 1996 and June 2013, 324 patients underwent isolated coronary artery bypass grafting (CABG) using RIMA in addition to LIMA-left anterior descending artery (LAD) bypass. Target vessel of RIMA was either diagonal or circumflex branch with significant stenosis. Those patients were divided into 3 groups according to the proximal anastomosis site of RIMA. Group I contained 247 cases with in-situ RIMA grafting. Group A contained 33 cases with AC bypass with proximal anastomosis of RIMA to ascending aorta. Group Y contained 43 cases with Y composite grafting with proximal anastomosis to LIMA. Patients were evaluated by coronary angiography or CT scan postoperatively at discharge and during follow up. Graft patency and risk factors influencing IMA patency were statistically investigated. Results: RIMA patency at discharge were 97.6% in group I and 97.0% in group A, 93.0% in group Y, respectively (p=0.695). RIMA patency in 5 years were 90.5% in Group I, 100% in group A, 88.4% in group Y, respectively (Logrank P=0.309). LIMA patency at discharge were 99.2% in group I and 97.0% in group A, 97.7% in group Y, respectively (p=0.438). LIMA patency in 5 years were 100% in group A, 96.0% in group I, 76.2% in group Y (Logrank P= 0.009). Survival rate in 5 years were 89.7% in group I, 86.6% in group A, 60.7% in group Y (Logrank P= 0.011). Multivariate analysis showed Y composite grafting as risk factor in late LIMA occlusion (p=0.024, Hazard ratio (HR) 6.867, 95% Confidence Interval (CI) 1.29-36.5) and late death (p&lt;0.001 HR 2.99, 95% CI 1.70-5.27). Conclusion: In our study, the patency of RIMA was not significantly different between the groups, but LIMA patency was inferior when used as the inflow of Y composite grafting with RIMA. Y composite grafting may impact on the patency of LIMA and furthermore late survival.