tbuckley/cabot-search huggingface dataset:
Intergroup randomized phase III study of postoperative oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) vs mFOLFOX6 and bevacizumab (Bev) for patients (pts) with stage II/ III rectal cancer receiving pre-operative chemoradiation.
Authors: Al Bowen Benson, Fengmin Zhao, Neal J. Meropol, Paul J. Catalano, Bapsi Chakravarthy, Patrick J. Flynn, Robert B. Catalano, Bruce J. Giantonio, Edith P. Mitchell, Daniel G. Haller, Cynthia G. Leichman, Nicholas J. Petrelli, Frank A. Sinicrope, Joel E. Tepper, James D. Brierley, Elin R. Sigurdson, Richard M. Whittington, Peter J. O'Dwyer
Journal: Journal of Clinical Oncology (2016)

3616 Background: Metastatic colorectal cancer trials have shown improved outcomes when Bev was added to chemotherapy. E5204 was designed to test whether the addition of Bev to postoperative mFOLFOX6 could improve OS in pts with stage II/ III rectal cancer after preoperative chemoradiation. Methods: Eligible pts had rectal adenocarcinoma , clinical Stage T3N0M0, T4N0M0, TanyN1-2M0 before neoadjuvant therapy; had received preoperative chemoradiation (may have included oxaliplatin); had a completely resected tumor and able to begin adjuvant treatment by day 56. Pts were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 and Bev (5mg/kg) (Arm B) administered every 2 wks for 12 cycles. Results: E5204 was terminated on 4/29/09 due to poor accrual. 355 pts were registered (17% of accrual goal). Median follow-up was 72 mos. There was no significant difference in OS between arm A and arm B (one-sided stratified log rank p = 0.876, HR = 0.72, 95% CI: 0.41, 1.26). 5-yr OS was 88.3% (95% CI: 52.3, 92.4) in arm A and 83.7% (95% CI: 77.1, 88.6) in arm B. No significant difference was observed in DFS (two-sided stratified log-rank p = 0.299, HR = 1.25, 95% CI: 0.82,1.90). 5-yr DFS rate was 71.2% (95% CI: 63.4, 77.6) in arm A and 76.5% (95% CI: 69.2, 82.3) in arm B. The incidence rate of treatment-related grade ≥ 3 AEs was 68.8% (119/173, 95% CI: 61.3, 75.6) on arm A, and 70.7% (123/174, 95% CI: 63.3, 77.3) on arm B. Arm B pts had earlier discontinuation of therapy due to AEs and pt withdrawal than arm A (32.4% vs 21.5%, p = 0.029).The most common treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea w/o prior colostomy and fatigue. Conclusions: At 17% of planned accrual, the trial did not meet its primary end point. The addition of Bev to postoperative mFOLFOX6 did not significantly improve OS in pts with stage II/ III rectal cancer after preoperative chemoradiation. These results are consistent with adjuvant colon cancer trials with Bev. About two-thirds of pts developed grade 3 or higher toxicity, and in a subset, pt-reported outcome endpoints were not different between the 2 arms. Clinical trial information: E5204.
A phase I study of PT-112 in advanced solid tumors.
Authors: Daniel D. Karp, D. Ross Camidge, Alan Haruo Bryce, Jose Jimeno, Jeffrey R. Infante
Journal: Journal of Clinical Oncology (2017)

2519 Background: PT-112 is a novel platinum-pyrophosphate agent designed to avoid the toxicity and drug resistance mechanisms of conventional chemotherapy. Pre-clinical models show effects on multiple cell signaling components: p16 mediated G1/S cell cycle arrest; modulation of MDM2/p53 expression; extrinsic apoptosis initiation; and immunogenic cell death (ICD) induction. This Phase I first-in-human, multicenter, open label study assesses PT-112’s safety and pharmacokinetic (PK) profile in advanced solid tumor patients (pts), to determine the RP2D and signals of activity. Methods: Pts with advanced solid tumors and acceptable marrow / organ function received PT-112 IV over 1-hr on days 1, 8, and 15 every 4 wks in a 3+3 dose escalation design. Intra-subject escalation was allowed. PK samples from cycles 1-2 were analyzed by ICP-MS and LC-MS/MS. Results: 44 pts have been treated across dose levels (DL) from 12-300mg/m 2 . Cumulative dosing ranged from 1 to 60 infusions, and cumulative exposure from 96 to 5,244 mg/m 2 . PK parameters were dose proportional. Target C max and AUC levels were achieved, with constant V D . DLTs were observed at 150mg/m 2 (G3 pancytopenia); 250mg/m 2 (G2 renal injury in a cervical ca pt with hydro-nephrosis); and 300mg/m 2 (G3 rash). The most common treatment-related AEs were G1-2 fatigue (26% pts), nausea (23%), vomiting (14%), constipation (12%), and diarrhea (12%). Numerous signals of activity were observed at DLs ≥ 125mg/m 2 . These include a confirmed PR in a NSCLC pt with 6 prior lines of therapy and no response to TKI inhibition or PD-1 blockade; PFS &gt; 6 months (7-18 months) in 3 pts; metabolic response via PET scan in bone and liver mets (basal cell and pancreatic ca.); biomarker responses in ovarian and prostate ca.; and nodal/metastatic volumetric reduction in 3 pts. Conclusions: PT-112 is a well-tolerated novel agent with a pleiotropic mode of action and feasibility for long-term and combination treatment. Numerous signals of anti-cancer efficacy in heavily pre-treated pts suggest lack of cross-resistance with conventional agents. MTD has not yet been reached. PT-112’s profile makes it an attractive candidate for further development, including in combination with immunotherapy. Clinical trial information: NCT02266745.
IDEAL CRT: ISOTOXIC DOSE ESCALATION AND ACCELERATION IN LUNG CANCER CHEMORADIOTHERAPY - A PHASE I/II TRIAL OF CONCURRENT CHEMORADIATION WITH DOSE-ESCALATED RADIOTHERAPY IN PATIENTS WITH STAGE II OR STAGE III NON-SMALL CELL LUNG CANCER
Authors: David B. Landau, Iftekhar Khan, Yenting Ngai, Laura L. Hughes, Elizabeth Miles, Dean Wilkinson, Emma Parsons, Philip Mayles, Helen Mayles, Andrew T. Bates, Nazia Mohammed, Jonathan Hicks, Susan Harden, Marianne Illsley, Angel Garcia, Zafar Malik, Simon Hughes, James Spicer, Angela Baker, Paula Wells, Virginia Laurence, John Fenwick
Journal: Journal of Thoracic Oncology (2013)
Effect of cabozantinib treatment on circulating immune cell populations in patients with metastatic triple-negative breast cancer (TNBC).
Authors: Dan G. Duda, David R. Ziehr, Hao Guo, Mei Ng, William Thomas Barry, Michaela Jane Higgins, Steven J. Isakoff, Jane E. Brock, Elena Ivanova, Cloud Paweletz, Michelle Demeo, Nikhil H. Ramaiya, Beth Overmoyer, Rakesh K. Jain, Eric P. Winer, Sara M. Tolaney
Journal: Journal of Clinical Oncology (2016)

1093 Background: We evaluated the changes in circulating immune cell populations in patients enrolled in a phase II study of cabozantinib (cabo), an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2, for metastatic TNBC. Methods: In this single-arm, two-stage phase 2 study, patients with metastatic TNBC with measurable disease by RECIST and up to 3 lines of prior chemotherapy for metastatic disease received cabo 60 mg daily on a 21-day cycle. Patients were restaged at 6 weeks and every 9 weeks thereafter. The primary endpoint was objective response rate (ORR). Predefined secondary endpoints included progression free survival (PFS) and toxicity. Here, we examined cellular biomarkers using flow cytometry in serial blood samples collected at days 0 (baseline/pre-treatment), 8, 22, 43, and 64 of cabo treatment. Mixed effect models were used to evaluate the changes of biomarker levels over time from baseline to day 64. Wilcoxon signed rank test were used to evaluate whether the change of biomarker levels from baseline to day 8 were different by clinical benefit. Results: The analysis included all 35 patients who initiated protocol therapy. As previously reported (ASCO 2015), the ORR was 11%, the clinical benefit rate (PR+SD) at 15 weeks was 34% (95% CI 19-52%) and the median PFS was 2.0 months (95%, CI 1.3-3.3). From baseline to day 64, there were significant increases in the number of circulating CD3+ cells and CD8+ T cells, and decreases in CD14+ monocytes (all p < 0.05) at all time-points. There was a trend for increase in CD4+ cells (p = 0.08) and CD56+ NK cells (p = 0.07) but no significant changes in the fraction of CD133+ progenitor/stem cells, CD4+CD25+ Tregs, CD4+CD127+ memory T cells and CD3+CD56+ NKT cells. The changes of biomarker levels from baseline to day 8 were not significantly different between patients with and without clinical benefit. Conclusions: Analysis of circulating cell biomarkers showed that cabo induces systemic changes consistent with activation of the immune system in metastatic TNBC patients. These hypothesis-generating data support consideration of studies of cabo with immunotherapy in this patient population. Clinical trial information: NCT02260531.
Food effect studies and drug label recommendations: A review of recently approved oncology products.
Authors: Mark Farha, Eric Masson, Helen Tomkinson, Ganesh Mugundu
Journal: Journal of Clinical Oncology (2017)

2535 Background: Evaluation of the effect of food on the pharmacokinetics of orally administered oncology drugs is a critical aspect of drug development, as food can mitigate or exacerbate toxicities and can change and influence variability in systemic exposure. Our aim in this review of approved oncology products is to describe the approaches used by sponsors to assess food effect and decide on the final dosing recommendations. Methods: Data for small molecule oncology drugs approved between 2003-2016 was extracted from the clinical pharmacology review in the sponsor’s FDA submission package. Information on food-effect study design, outcomes, intersubject variability, exposure-response relationships for safety, and the label dosing recommendation regarding food was analyzed. Results: Of the 29 drugs analyzed, 19 food effect studies were conducted in healthy volunteers, and 10 were conducted in cancer patients. The ratio of population geometric means between fed and fasted treatments fell outside the 80-125 percent equivalence limit in 55% of compounds for AUC and in 69% of compounds for Cmax. 6 drugs (21%) are recommended to be given with food, 11 drugs (38%) in the fasted state, and 12 drugs (41%) can be dosed regardless of food. Label recommendations appeared to be driven by the exposure-response analysis. 80% of drugs with a fasted label recommendation despite an increase in bioavailability with food had an exposure-response relationship for safety. Conclusions: Optimizing study design by conducting early food effect studies designed to estimate food effect rather than confirming no food effect, and learning the impact of food early may eliminate unnecessary study arms and save sponsors money and time. Furthermore, understanding the potential of food to mitigate or exacerbate toxicities may improve patients’ experience with treatments and has been shown here to be a major driver of the final dosing recommendation regarding food.
Abstract 17550: PPAR-{delta} Activation Induces Angiomyogenesis Through the Potentiation of Endothelial Progenitor Cell Paracrine Network
Authors: Hack-Lyoung Kim, Jung-Ku Han, Young-Eun Choi, Ki-Hyun Jeon, Hyun-Sook Lee, Yoo-Wook Kwon, Hyun-Jai Cho, Hyun-Jae Kang, Byung-Hee Oh, Young-Bae Park, Hyo-Soo Kim
Journal: Circulation (2011)

Background Endothelial progenitor cells (EPCs) paracrine network has been known to play a key role in neovascularization. We focused on skeletal muscle regeneration as well as new vessel formation ...
VIDEO-ANALYSIS OF MODERATE AND SEVERE MATCH INJURIES IN GERMAN MEN'S PROFESSIONAL HANDBALL
Authors: Patrick Luig, Hendrik Bloch, Thomas Henke, Christian Klein
Journal: British Journal of Sports Medicine (2017)

<h3>Background</h3> There is little knowledge about the causes of injuries in men9s professional handball, in particular with a view to the specificity of regular league play. <h3>Objective</h3> To identify and describe typical injury situations, mechanisms and characteristics in German men9s professional handball. <h3>Design</h3> Prospective video-based analysis of match injuries. <h3>Setting</h3> Two highest German professional leagues in men9s handball. <h3>Participants</h3> All first and second league handball players who played at least one competitive club match (n=1,194) were included in the study and observed over a period of three consecutive seasons (2010–2013). <h3>Interventions (or Assessment of Risk Factors)</h3> Analysis of all moderate and severe match injuries (time-loss&gt;7 days) that were registered by clubs or physicians with the VBG (German statutory accident insurance for the administrative sector) as part of the occupational accident reporting. <h3>Main Outcome Measurements</h3> The video observation form contained 27 variables including data on injury location, time of injury, injury situation, injury mechanism. <h3>Results</h3> 560 moderate or severe match injuries were recorded during 2,227 competitive matches. 243 injuries (43.4%) were identified on video. 56.8% of injuries were contact injuries, 25.1% indirect contact injuries and 18.1% non-contact injuries. 63.8% of injuries occurred during attacking play. While pivots most often injured themselves in a defensive position and through contact, injuries in backcourt players were more often the result of indirect contact and in an attacking position. Injuries in field players were significantly overrepresented during the final thirds of each half, specifically in the last ten minutes of the game. Moreover, 7 typical injury situations for knee, ankle, shoulder and head injuries in were recognized. <h3>Conclusions</h3> Video-analysis of match injuries made it clear that not only sport-specific, but also position- and injury-specific aspects must be taken into account in order to derive targeted, multidisciplinary preventive measures.
Queen’s speech promises change on mental health but ignores wider NHS problems
Authors: Adrian O’Dowd
Journal: BMJ (2017)

Mental healthcare services in England will be the only part of NHS care to be changed by new legislation as part of the government’s plans for the next two years, announced in the Queen’s speech on 21 June.

Doctors’ leaders have accused the government of failing to tackle deep rooted overall problems faced by the NHS as part of measures outlined in the speech in which the Queen announced the government’s intentions for new laws over the first half of the new parliament.

Although the government is not proposing any major health reforms in legislation, it does plan to review existing mental health legislation with the intention of ensuring that mental health is prioritised in the NHS in …
Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches
Authors: Matthias Pauthner, Colin Havenar-Daughton, Devin Sok, Joseph P. Nkolola, Raiza Bastidas, Archana V. Boopathy, Diane G. Carnathan, Abishek Chandrashekar, Kimberly M. Cirelli, Christopher A. Cottrell, Alexey M. Eroshkin, Javier Guenaga, Kirti Kaushik, Daniel W. Kulp, Jinyan Liu, Laura E. McCoy, Aaron L. Oom, Gabriel Ozorowski, Kai W. Post, Shailendra K. Sharma, Jon M. Steichen, Steven W. de Taeye, Talar Tokatlian, Alba Torrents de la Peña, Salvatore T. Butera, Celia C. LaBranche, David C. Montefiori, Guido Silvestri, Ian A. Wilson, Darrell J. Irvine, Rogier W. Sanders, William R. Schief, Andrew B. Ward, Richard T. Wyatt, Dan H. Barouch, Shane Crotty, Dennis R. Burton
Journal: Immunity (2017)

Highlights•Immunization protocols for rapid and consistent generation of autologous tier 2 nAbs•Germinal center responses predict and correlate with HIV nAbs after immunization•Env protein design curtails responses to the non-neutralizing V3-loop epitope•Subcutaneous and extended immunogen delivery enhances nAb generationSummaryThe development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation.Graphical abstract
Phase 1/2a trial of intravenous BAL101553, a novel tumor checkpoint controller (TCC), in advanced solid tumors.
Authors: Juanita Lopez, T.R. Jeffry Evans, Elizabeth R. Plummer, Nikolaos Diamantis, Heather May Shaw, Ishtiaq Husain Zubairi, Noor R Md Haris, Julie MacDonald, Alastair Greystoke, Rene Lynnette Roux, Nina Tunariu, L Rhoda Molife, Alison L. Hannah, Stephanie Anderson, Heidi A Lane, Martina Maurer, Anne Schmitt-Hoffmann, Felix Bachmann, Marc Frederick Engelhardt, Rebecca Sophie Kristeleit
Journal: Journal of Clinical Oncology (2016)

2525 Background: BAL101553 (prodrug of BAL27862) is a small molecule TCC that binds microtubules and promotes tumor cell death through activation of the mitotic checkpoint. Antiproliferative effects appear driven by AUC; vascular disruption by Cmax . In a NSCLC xenograft mouse model, dose-dependent vascular disruption with reduction of tumor perfusion was observed. Methods: Patients (pts) with advanced solid tumors who failed standard therapy, received 2-h intravenous (IV) BAL101553 on days 1, 8 and 15 of each 28-day cycle. The Phase 1 (P1) part of the study used an accelerated 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). In Phase 2a (P2a), pts were randomized to assess whether MTD or sub-MTD doses provide better anti-tumor activity. Adverse events were assessed by CTCAEv4 grade (G); tumor response by RECIST 1.1 every 2 cycles. Assessments included PK, tumor biopsies, functional imaging, and analysis of circulating tumor, endothelial and endothelial progenitor cells (CTCs, CECs, CEPs). Results: 73 pts (39M/34F; median age 58 y; 29-80 y) received doses of 15-80 mg/m2 (N = 24, P1) and 30-60 mg/m2 (N = 49, P2a). DLTs in P1 at 60-80 mg/m2 were G2-3 gait disturbance (reversible) with G1-2 peripheral neuropathy. In P2a, myocardial ischemia (reversible ECG changes, troponin elevations) was observed in 3 pts (45-60 mg/m2), resulting in a recommended P2 dose (RP2D) of 30 mg/m2. Of 59 pts evaluable for efficacy to date, 39 received BAL101553 at 30 mg/m2 (as starting dose or adjustment). Of these, 1 pt (ampullary cancer) had a partial response for > 2 y; 10 pts had stable disease (3 pts > 4 cycles). Tumor biopsies showed effects on tumor cell proliferation and vascularization at ≥ 60 mg/m2, with time profiles of transient blood pressure elevations linking the vascular effect to Cmax . The CEC/CEP pattern supported vascular disruption at 60 mg/m2 and potentially increased vascular leakage at 30 mg/m2. Conclusions: BAL101553 as 2-h IV infusion showed dose-dependent vascular effects that were dose-limiting and related to Cmax . The RP2D of 30 mg/m2is well tolerated, showed signals of antitumor activity and potentially increases vascular leakage, which may be useful for combination therapy. (NCT01397929). Clinical trial information: NCT01397929.
Abstract 19023: Distinct Remodeling of Mitral Valve Leaflets in Severe Myxomatous and Ischemic Mitral Regurgitation
Authors: Tarek S Absi, Cristi L Galindo, Michael R Petracek, Daniel J Lenihan, Marzia Leacche, Douglas B Sawyer, John G Byrne, Yan Ru Su
Journal: Circulation (2012)

OBJECTIVES: The mitral valve (MV) leaflets in severe MR undergo structural remodeling associated with multiple degenerative and adaptive changes. We hypothesized that the gene expression profiles of MV leaflets from patients with severe myxomatous MR (MMR) are distinct from those with severe ischemic MR (IMR), reflecting different underlying pathophysiologic processes. METHODS: MVs were obtained from 11 MMR patients (9 m, 2 f; age= 60.5±11.9 y, LVEF=58.2±4.6%) and 6 IMR patients (3 m, 3 f, age= 66.5±6.7 y, LVEF=33.3±16.3%) undergoing surgery for severe MR. Hemodynamic abnormalities were similar in the two groups. Tissue RNA was extracted and cDNA were hybridized to the Affymetrix Gene Chip 1.1. Normalization and two-way ANOVA analysis were performed by Partek Genomics Suite. Only genes that resulted in &gt;1.5 fold difference and p &lt;0.05 were considered significantly altered. RESULTS: Of ∼29,000 genes examined, 453 (1.6%) were differentially expressed between the two groups. Hierarchical clustering of the normalized fluorescence signal values for these genes successfully differentiated all the MMR from the IMR samples (Figure 1). Based on functional analysis, the most statistically enriched biological processes were development (MYH11, ACTA2, ECM1, MMP19), cell growth (IGF1, IGFBP3, ADAMTSL2), adhesion (MCAM, PCDH10, COL4A1) and metabolic processes (ACOT7, CYP4A11) as shown in Table 1. CONCLUSIONS: MV leaflets in severe MMR and IMR exhibit distinct gene expression patterns, suggesting different pathophysiologic mechanisms are involved in the leaflet remodeling processes. Understanding such adaptive mechanisms can potentially provide therapeutic opportunities.
Abstract 2264: Long Term Effects of Bosentan Therapy on Echocardiographic Parameters in Patients With Eisenmenger Syndrome
Authors: Mehmet Kaya, Yat Yin Lam, Betul Erer, Selim Ayhan, Mehmet A Vatankulu, Zekeriya Nurkalem, Mehmet Eren, Namik K Eryol
Journal: Circulation (2009)
The liver–gut microbiota axis modulates hepatotoxicity of tacrine in the rat
Authors: Lian Yee Yip, Chiu Cheong Aw, Sze Han Lee, Yi Shuen Hong, Han Chen Ku, Winston Hecheng Xu, Jessalyn Mei Xuan Chan, Eleanor Jing Yi Cheong, Kern Rei Chng, Amanda Hui Qi Ng, Niranjan Nagarajan, Ratha Mahendran, Yuan Kun Lee, Edward R. Browne, Eric Chun Yong Chan
Journal: Hepatology (2017)

The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver-gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus, Bacteroides, and Enterobacteriaceae) and approximately 9% higher β-glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral β-glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo.This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (Hepatology 2018;67:282-295).