tbuckley/cabot-search huggingface dataset:
Phase I trial of veliparib, (ABT-888), a poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with doxorubicin and cyclophosphamide in breast cancer and other solid tumors.
Authors: A. R. Tan, D. Toppmeyer, M. N. Stein, R. A. Moss, M. Gounder, D. C. Lindquist, J. J. Ji, A. P. Chen, M. J. Egorin, B. Kiesel, J. H. Beumer, R. S. DiPaola
Journal: Journal of Clinical Oncology (2011)

3041 Background: Veliparib is a potent, oral inhibitor of PARP-1 and PARP-2. We previously reported phase I results of veliparib and cyclophosphamide (C). Evaluation of veliparib and C with doxorubicin (A) was conducted given activity of anthracyclines in breast cancer treatment. Main objectives were to determine maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib with AC and PAR levels in peripheral blood mononuclear cells (PBMCs). Methods: Veliparib doses ranged from 50 to 150 mg every 12 h on days 1 - 4 with fixed dosing of AC (60/600 mg/m2) on day 3 every 21 days. Prior A ≤ 300 mg/m2 was permitted. Further A was omitted after a cumulative dose of 420 mg/m2. PKs of veliparib and PAR levels were collected. Results: 18 pts (17F:1M; median age 53 yrs) treated with veliparib (mg) every 12 h at 50 (n= 3), 100 (n= 9), and 150 (n= 6) on days 1 - 4 every 21 days. Tumor types were breast (14; 5 BRCA mutation carriers), ovarian (1), and other (3). Mean cycles were 5 (2-18). Two instances of gr 3 febrile neutropenia were considered dose-limiting at the 150 mg veliparib dose level. MTD of veliparib was 100 mg every 12 h with AC. Drug-related toxicities included fatigue and myelosuppression. PK analysis suggests dose-linearity of veliparib Cmax and AUC with no significant effect of AC on Tmax (1.7 h; SD 0.7) or t1/2 (4.7 h; SD 0.5) of veliparib. In presence of AC on day 3, a 15% decrease in apparent clearance (Cl/F) (90%CI 8-22%) of veliparib relative to Cl/F of veliparib alone on day 1 (21.9 L/h; SD 5.0) was observed. Within-subject variability of veliparib Cmax and Cl/F were 34% and 28%, respectively. PARP in PBMCs was inhibited >50% in 14 pts and >90% in 4 pts. PRs were observed in 3/5 BRCA mutation carriers (2 pts too early to evaluate) with triple-negative breast tumors; 8 breast cancer pts had stable disease > 12 weeks. Conclusions: MTD of veliparib is 100 mg every 12 h with AC every 21 days. Veliparib inhibits PARP in PBMCs at all dose levels. Objective antitumor activity was seen in BRCA mutation carriers. Enrollment continues in the breast cancer dose expansion cohort. This work is supported by NCI U01-CA132194 (NJ) and NCI U01-CA099168 (PA).
PTU-061 Use of faecal calprotectin in primary care to distinguish irritable bowel syndrome from inflammatory bowel disease: Abstract PTU-061 Table 1
Authors: JO Rouke, A Dhaliwal, V Sagar, J Davies, A Milestone
Journal: Gut (2015)

<h3>Introduction</h3> Faecal Calprotectin (FC) is a simple, non-invasive test which can differentiate Irritable Bowel Syndrome (IBS) from Inflammatory Bowel Disease (IBD). High negative predictive values suggest potential cost-effective benefits in Primary Care, reducing unnecessary referrals to secondary care and expensive/invasive diagnostic tests eg. colonoscopy. FC is well established in secondary care, but the literature for FC in primary care is extremely limited. <h3>Aim</h3> Evaluation of a pilot study of a defined FC pathway in Primary Care. <h3>Method</h3> A primary care referral pathway was devised to guide appropriate use of FC in Primary Care to exclude IBD in appropriate patients, particularly if secondary care referral was being considered. This was based on IBS guidelines (BSG), FC literature and recent NHS Centre for Evidence-Based Purchasing report (2010), consisting of a pathway proforma with initial screening tests (FBC, LFTs, TTG, CRP, TSH and stool microbiology). <b>Inclusion/Exclusion criteria</b>: 16–45 yrs age, IBS-compatible symptoms for ≥6 weeks/recurrent, no red flags. FC results (Quantum Blue) classified as normal, intermediate or high and supplied with appropriate action guidance (Table 1). Subsequent clinic attendances, investigations, diagnostic outcomes and associated costs were evaluated. <h3>Results</h3> Nineteen GP surgeries (19/22) referred 277 patients via FC pathway over 24 months (Jan 2013–Jan 2015). Forty-five samples rejected as inappropriate. Diagnosis outcomes were available on 175/232 patients at the time of presented data analysis: Elevated 13.7% (24), Indeterminate 19.4% (34) and Normal 66.8% (117). In Elevated FC clinic attenders, IBD was detected in 50% (11/22). Indeterminates were repeated in only 68%: normal repeat 52.2% (12/23), 2 IBD cases detected. After a normal FC, 12.8% were referred to secondary care anyway, but no IBD detected. In the normal FC group alone, assuming a normal FCP avoided a secondary care referral in 87.2% (102/117), the potential cost savings = £73,468 (assuming new patient clinic + 1 colonoscopy = £741.68). <h3>Conclusion</h3> Preliminary data suggests a structured FC pathway is effective in distinguishing IBD and IBS in Primary Care with significant cost savings. Age ranges and FC cut-off points need further refinement. Based on this pilot data and latest NICE Diagnostic Appraisal 11, the Herefordshire Clinical Commission Group have commissioned a secondary care supervised FC service for primary care. <h3>Disclosure of interest</h3> None Declared.
Treat-to-target (T2T) recommendations for gout
Authors: U Kiltz, J Smolen, T Bardin, A Cohen Solal, N Dalbeth, M Doherty, B Engel, C Flader, J Kay, M Matsuoka, F Perez-Ruiz, G da Rocha Castelar-Pinheiro, K Saag, A So, J Vazquez Mellado, M Weisman, T H Westhoff, H Yamanaka, J Braun
Journal: Annals of the Rheumatic Diseases (2016)

Objectives The treat-to-target (T2T) concept has been applied successfully in several inflammatory rheumatic diseases. Gout is a chronic disease with a high burden of pain and inflammation. Because the pathogenesis of gout is strongly related to serum urate levels, gout may be an ideal disease in which to apply a T2T approach. Our aim was to develop international T2T recommendations for patients with gout. Methods A committee of experts with experience in gout agreed upon potential targets and outcomes, which was the basis for the systematic literature search. Eleven rheumatologists, one cardiologist, one nephrologist, one general practitioner and one patient met in October 2015 to develop T2T recommendations based on the available scientific evidence. Levels of evidence, strength of recommendations and levels of agreement were derived. Results Although no randomised trial was identified in which a comparison with standard treatment or an evaluation of a T2T approach had been performed in patients with gout, indirect evidence was provided to focus on targets such as normalisation of serum urate levels. The expert group developed four overarching principles and nine T2T recommendations. They considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications and monitoring of serum urate levels were also considered to be of major importance. Conclusions This is the first application of the T2T approach developed for gout. Since no publication reports a trial comparing treatment strategies for gout, highly credible overarching principles and level D expert recommendations were created and agreed upon.
MGD011, A CD19 x CD3 Dual-Affinity Retargeting Bi-specific Molecule Incorporating Extended Circulating Half-life for the Treatment of B-Cell Malignancies
Authors: Liqin Liu, Chia-Ying K. Lam, Vatana Long, Lusiana Widjaja, Yinhua Yang, Hua Li, Linda Jin, Steve Burke, Sergey Gorlatov, Jennifer Brown, Ralph Alderson, Margaret D. Lewis, Jeffrey L. Nordstrom, Scott Koenig, Paul A. Moore, Syd Johnson, Ezio Bonvini
Journal: Clinical Cancer Research (2016)

Purpose: CD19, a B-cell lineage-specific marker, is highly represented in B-cell malignancies and an attractive target for therapeutic interventions. MGD011 is a CD19 x CD3 DART bispecific protein designed to redirect T lymphocytes to eliminate CD19-expressing cells. MGD011 has been engineered with a modified human Fc domain for improved pharmacokinetic (PK) properties and designed to cross-react with the corresponding antigens in cynomolgus monkeys. Here, we report on the preclinical activity, safety and PK properties of MGD011.Experimental Design: The activity of MGD011 was evaluated in several in vitro and in vivo models. PK, safety and pharmacodynamic activity was also assessed in dose-escalation and repeat-dose studies of MGD011 administered once weekly in cynomolgus monkeys.Results: MGD011 mediated killing of human B-cell lymphoma lines by human or cynomolgus monkey PBMCs as well as autologous B-cell depletion in PBMCs from both species. MGD011-mediated killing was accompanied by target-dependent T-cell activation and expansion, cytokine release and upregulation of perforin and granzyme B. MGD011 demonstrated antitumor activity against localized and disseminated lymphoma xenografts reconstituted with human PBMCs. In cynomolgus monkeys, MGD011 displayed a terminal half-life of 6.7 days; once weekly intravenous infusion of MGD011 at doses up to 100 μg/kg, the highest dose tested, was well tolerated and resulted in dose-dependent, durable decreases in circulating B cells accompanied by profound reductions of B lymphocytes in lymphoid organs.Conclusions: The preclinical activity, safety and PK profile support clinical investigation of MGD011 as a therapeutic candidate for the treatment of B-cell malignancies. Clin Cancer Res; 23(6); 1506-18. ©2016 AACR.
Prognosticating after Variceal Bleed in Cryptogenic Cirrhosis: Non Cirrhotic Portal Hypertension can be a Confounder
Authors: A. Goel, B. Ramakrishna, U. Zachariah, K.G. Sajith, G. Chandy, G. Kurian, C.E. Eapen
Journal: Journal of Hepatology (2016)
Subsets of CD34+ and Engraftment Kinetics in Allogeneic Peripheral Stem Cell Transplantation.
Authors: Domenico Pastore, Anna Mestice, Paola Carluccio, Tommasina Perrone, Manuela Leo, Silvia Sibilla, Anna M. Mazzone, Margherita Casanova, Vincenzo Liso, Giorgina Specchia
Journal: Blood (2006)
A Novel SAHA-Bendamustine Hybrid Induces Apoptosis of Leukemia Cells
Authors: Jing Yu, Shaowei Qiu, Qiufu Ge, Ying Wang, Hui Wei, Dianwu Guo, Shuying Chen, Shuang Liu, Qing Rao, Jianxiang Wang, Min Wang
Journal: Blood (2014)
Asthma hospitalisations and air pollution
Authors: B Barratt, J K Quint
Journal: Thorax (2016)

There has been significant interest in recent years on the effect of the environment on respiratory health and fairly consistent evidence that air pollution and temperature are somehow associated with asthma symptoms. However, studies have varied in the relationships found, with some suggesting high and others low temperature associations with asthma morbidity.1–3 Several air pollutants, such as particulate matter, NO2 and O3, have been inconsistently associated with asthma and inevitably temperature confounds associations between asthma and pollutants.2 ,4 In addition, ambient temperature, particularly in temperate climates, may affect dry powder inhaler drug stability, and this may inadvertently confound worsening asthma control in areas of high humidity and high temperature, such as Hong Kong.5 ,6

So while assessing the liaison between meteorological factors and asthma hospitalisations is not new, few studies have had sufficient statistical power to differentiate the effect of exposures on differing populations; that is children, adults and the elderly in a subtropical climate and in a city such as Hong Kong. With climate change an evolving phenomenon that will not go away, and increasing interest in disease ‘splitting’ as opposed …
Long-Term Follow-Up of Patients with Chronic HCV Infection following Treatment with Direct Acting Antiviral Regimens: Maintenance of SVR, Persistence of Resistance Mutations and Clinical Outcomes
Authors: E.J. Lawitz, P. Ruane, C. Stedman, G. Foster, R.H. Hyland, S. Coogan, S. Moody, H. Dvory-Sobol, S.J. Knox, D.M. Brainard, A. Abergel, K. Agarwal, Z. Younes, C. Schwabe
Journal: Journal of Hepatology (2016)
Pediatric osteosarcoma pneumonectomy for pulmonary metastases: Is it justified?
Authors: N. Jaffe
Journal: Journal of Clinical Oncology (2004)

8565 Background:Over the past 25 years, 95 of 210 patients (pts) under 20 years of age were subjected to surgical procedures for resection of pulmonary metastases (PM). This included completion pneumonectomy (CPN) in five pts and removal of the RML and RLL in another pt. Interval from diagnosis to detection of PM ranged from 1.5 to 2 yrs. Interval from removal of the last PM to CPN ranged from 1.7 to 3 yrs. Pts were considered candidates for CPN provided the following criteria were met: 1) Despite responses, all PM could not be eradicated with chemotherapy; 2) PM were always confined to one lung; 3) Primary tumor was extirpated; 4) No evidence of extra PM; 5) Existing PM could not be extirpated by wedge resection or lobectomy; 6) Pulmonary function would be adequate after CPN. Methods:Pulmonary function tests obtained. CPN performed. After CPN additional chemotherapy administered. Four pts were also treated with radiation therapy (45–50 Gy) to sites of suspected residual microscopic disease with methotrexate to potentiate radiotherapeutic effect. Results:No significant post operative complications. Four of six pts are alive and disease free (10.5, 4.5, 1, and 0.3 yrs) post CPN. Cause of death: One pt: inoperable left paraspinal mass with the remaining lung clear. Second pt: tumor invasion into hilar lymph nodes and pericardium. Conclusions:Long term survival following CPN appears attainable in some pts who meet the criteria described above. Important indications appear to be inability to eradicate PM by chemotherapy and inability to perform wedge resection or lobectomy. However, the long surveillance period with continual absence of disease in the contralateral lung, i.e. 3.2–5 yrs from diagnosis, was probably the major eligibility criterion. No significant financial relationships to disclose.
Control of Hepatic Cells Growth by Topologically Modulated Substrates
Authors: M. Lunova, V. Zablotskii, N. Dempsey, D. Givord, T. Devillers, M. Jirsa, E. Syková, Š. Kubinová, O. Lunov, A. Dejneka
Journal: Journal of Hepatology (2016)
Efficacy and Patient-Reported Outcomes in Decompensated Cirrhotic with Chronic Hepatitis C Treated with Sofosbuvir and Velpatasvir with or without Ribavirin: Results from Astral-4 Clinical Trial
Authors: Z.M. Younossi, M. Stepanova, M. Charlton, J.G. O’Leary, M.P. Curry, R.S. Brown, S. Hunt
Journal: Journal of Hepatology (2016)
Demographic, Systemic, and Ocular Factors Associated with Nonarteritic Anterior Ischemic Optic Neuropathy
Authors: Dean M. Cestari, Eric D. Gaier, Peggy Bouzika, Taylor S. Blachley, Lindsey B. De Lott, Joseph F. Rizzo, Janey L. Wiggs, Jae H. Kang, Louis R. Pasquale, Joshua D. Stein
Journal: Ophthalmology (2016)
Regular aspirin (ASA) use and survival in patients with PIK3CA-mutated metastatic colorectal cancer (CRC).
Authors: Nishi Kothari, Richard D. Kim, Peter Gibbs, Timothy Joseph Yeatman, Michael J. Schell, Jayesh Desai, Jeanne Tie, Lara Rachel Lipton, Robert N. Jorissen, Hui-Li Wong, Oliver Sieber, Fiona Day, Ian Faragher, Ian Jones, Ben Tran
Journal: Journal of Clinical Oncology (2014)

386 Background: Recent data has demonstrated that regular ASA use improves overall and cancer-specific survival in the subset of CRC patients harboring PIK3CA mutations. However, as this series only analyzed 15 PIK3CA mutant CRC patients with metastatic disease at diagnosis, it remains uncertain whether the survival benefit associated with regular ASA use extends to patients with metastatic disease. We combined data from two large academic institutions to explore the association between regular ASA use and survival in metastatic CRC. Methods: Patients with PIK3CA mutated CRC were identified at Moffitt Cancer Center (MCC) in Tampa, FL and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data (including age, sex, site of disease) and survival data were available. At MCC, PIK3CA mutations were identified by exome sequencing using an Illumina Next Generation Sequencing platform with 50-100X coverage. At RMH, Sanger sequencing was used to identify PIK3CA mutations. Survival analyses were conducted using Cox regression. Results: We identified 187 CRC patients who harbored a PIK3CA mutation. Median age was 72 years and median follow up was 48 months. 49 (26%) patients used ASA regularly. 47 (25%) patients had metastatic disease at diagnosis. In univariate analyses, regular ASA use was not associated with improved overall survival (HR 0.87, p = 0.60), although there was a trend towards improved cancer-specific survival (HR 0.48, p = 0.06). In patients with stage-II or stage-III disease, regular ASA use did not improve overall, cancer-specific or recurrence-free survival. However, in stage-IV patients, regular ASA use was significantly associated with improved overall (HR 0.35, p = 0.04) and cancer-specific (HR 0.28, p = 0.02) survival in a univariate analysis. Conclusions: Our study demonstrates that in patients with metastatic CRC harboring a PIK3CA mutation, regular ASA use is associated with a significant overall and cancer-specific survival advantage. However, we were not able to confirm the survival advantage across all stages. To our knowledge, our study is the largest to examine ASA use in PIK3CA mutated CRC.
Ledipasvir/Sofosbuvir ± Ribavirin in HCV Post-Transplant Patients: Real-World Heterogeneous Population from the Trio Network
Authors: S. Flamm, B. Bacon, M. Curry, D. Dieterich, L. Guest, K. Kowdley, Y. Lee, N. Tsai, Z. Younossi, N. Afdhal
Journal: Journal of Hepatology (2016)
O-021 Tailored strategy for locally-advanced rectal carcinoma: preliminary results of a phase II multicenter trial (GRECCAR 4)
Authors: P. Rouanet, E. Rullier, B. Lelong, P. Maingon, J. Tuech Jean, D. Pezet, M. Rivoire, B. Meunier, S. Nougaret, F. Castan, C. Lemanski, S. Gourgou, M. Ychou
Journal: Annals of Oncology (2016)
Optimization of Survival Prediction in Patients under Sorafenib Treatment: Usefulness of Carbonic Anhydrase IX Baseline and Baseline and Evolutive Angiopoyetin 2
Authors: M. Reig, B. Loreto, F. Torres, J.M. Lopez-Oliva, J. Rimola, A. Darnell, A. Forner, Á. Díaz, A. Ribeiro, N. LLarch, C. Ayuso, J. Bruix
Journal: Journal of Hepatology (2016)
CRM1 Is Highly Expressed in Myeloma Plasma Cells and Its Inhibition by KPT-SINE Induces Cytotoxicity by Increasing p53 in the Nucleus of Multiple Myeloma (MM) Cells
Authors: Malathi Kandarpa, Stephanie J Kraftson, Sean P Maxwell, Dilara McCauley, Sharon Shacham, Michael Kauffman, Andrzej J Jakubowiak
Journal: Blood (2011)
MICRORNA-150 Downregulation is Involved in Pathogenesis of HBV associated Hepatocellular Carcinoma through HBX-Mir150-CXCR4 Signaling Pathway
Authors: S.B. Dar, M.C. Choudhary, C. Bihari, N. Trehanpati, G. Ramakrishna, S.K. Sarin
Journal: Journal of Hepatology (2016)
Phosphoproteomic Analysis of Intracellular Signaling in the Human Hepatic Tissue of Patients with Non-Alcoholic Fatty Liver Disease and Fibrosis
Authors: Z.M. Younossi, A. Karrar, M. Pierobon, M. Stepanova, K. Jeiran, K. Reeder, T. Jeffers, Z. Younoszai, Z. Goodman, E.F. Petricoin
Journal: Journal of Hepatology (2016)
PKC412 Inhibits In Vitro Growth of Neoplastic Mast Cells Expressing the D816V-Mutated Variant of KIT: Comparison with AMN107 and Imatinib, and Evaluation of Drug-Interactions.
Authors: Karoline V. Gleixner, Matthias Mayerhofer, Karl J. Aichberger, Sophia Derdak, Karoline Sonneck, Alexandra Boehm, Puchit Samorapoompichit, Alexander Gruze, Winfried Pickl, Paul Manley, Doriano Fabbro, Christian Sillaber, Peter Valent
Journal: Blood (2005)
Tumor treating fields (TTFields): A novel treatment modality added to standard chemo- and radiotherapy in newly diagnosed glioblastoma—First report of the full dataset of the EF14 randomized phase III trial.
Authors: Roger Stupp, Sophie Taillibert, Andrew Kanner, Santosh Kesari, Steven A Toms, Gene H. Barnett, Karen L. Fink, Antonio Silvani, Frank S. Lieberman, Jay-Jiguang Zhu, Lynne Patricia Taylor, Jerôme Honnorat, Andreas Hottinger, Thomas Chen, David Dinh Tran, Chae-yong Kim, Hal W. Hirte, Monika E. Hegi, Yoram Palti, Zvi Ram
Journal: Journal of Clinical Oncology (2015)

2000 Background: TTFields is an established antimitotic treatment modality delivered to patients by a portable, home use, medical device. Here we evaluate whether this antimitotic effect can be translated into improved survival in a clinical setting. Based on a pre-specified interim analysis on 315 patients, the IDMC recommended early trial closure; we here report the first analysis of the full dataset of 700 randomized patients. Methods: This prospective phase 3 trial randomized patients with newly diagnosed glioblastoma, after completion of concomitant chemoradiotherapy, to receive either adjuvant temozolomide (TMZ) chemotherapy alone, or TMZ with TTFields (TTF/TMZ). The primary endpoint was progression-free survival, with overall survival, safety, cognitive function and quality of life as secondary endpoints. Results: (ITT) From 2009 to 2014, 700 Grade IV astrocytoma (glioblastoma) patients (68% male) were randomized 2:1. Patient characteristics were well balanced: median age was 56 and 57 years in the TMZ and TTF/TMZ arms, respectively. Tumor was resected in 87% of patients. MGMT was centrally assessed in 77% of patients, 35% and 39% of the tumors had a methylated promoter; 10% and 8% of the results were invalid. Median time from diagnosis to randomization was 3.8 and 3.7 months. Progression-free survival was 7.1 for TTF/TMZ vs 4.2 months for TMZ alone, hazard ratio (HR) 0.694 (95% CI 0.558-0.863) log rank p = 0.0010; overall survival 19.4 vs 16.6 months, HR 0.754 (0.595-0.955), p = 0.0222. This translates into 2-year survival rates of 43% (CI 36-50%) vs. 29% (CI 21-38%). No significant added toxicity was seen in the TMZ/TTF arm. Quality of life and gross cognitive function were comparable in the 2 arms. Conclusions: This is the first randomized trial demonstrating improved progression-free and overall survival of patients treated with Tumor Treating Fields. It sets a new standard of care for patients with glioblastoma, and warrants further investigation in other clinical indications. Clinical trial information: NCT00916409.
Unexpected Very Early Atherosclerotic and Cardiac Damage in Patients Undergoing Liver Transplantation
Authors: G. Pisano, R. Lombardi, M. Orlandi, M.F. Donato, S. Zannoni, C.G. Bertelli, G. Oberti, L. Caccamo, M. Colombo, S. Fargion, A.L. Fracanzani
Journal: Journal of Hepatology (2016)
Mast cell desensitization inhibits calcium flux and aberrantly remodels actin
Authors: W.X. Gladys Ang, Alison M. Church, Mike Kulis, Hae Woong Choi, A. Wesley Burks, Soman N. Abraham
Journal: Journal of Clinical Investigation (2016)

Rush desensitization (DS) is a widely used and effective clinical strategy for the rapid inhibition of IgE-mediated anaphylactic responses. However, the cellular targets and underlying mechanisms behind this process remain unclear. Recent studies have implicated mast cells (MCs) as the primary target cells for DS. Here, we developed a murine model of passive anaphylaxis with demonstrated MC involvement and an in vitro assay to evaluate the effect of DS on MCs. In contrast with previous reports, we determined that functional IgE remains on the cell surface of desensitized MCs following DS. Despite notable reductions in MC degranulation following DS, the high-affinity IgE receptor FcεRI was still capable of transducing signals in desensitized MCs. Additionally, we found that displacement of the actin cytoskeleton and its continued association with FcεRI impede the capacity of desensitized MCs to evoke the calcium response that is essential for MC degranulation. Together, these findings suggest that reduced degranulation responses in desensitized MCs arise from aberrant actin remodeling, providing insights that may lead to improvement of DS treatments for anaphylactic responses.