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https://www.readbyqxmd.com/read/29784193/adjuvant-vascular-endothelial-growth-factor-targeted-therapy-in-renal-cell-carcinoma-a-systematic-review-and-pooled-analysis
#1
REVIEW
Maxine Sun, Lorenzo Marconi, Tim Eisen, Bernard Escudier, Rachel H Giles, Naomi B Haas, Lauren C Harshman, David I Quinn, James Larkin, Sumanta K Pal, Thomas Powles, Christopher W Ryan, Cora N Sternberg, Robert Uzzo, Toni K Choueiri, Axel Bex
CONTEXT: Contradictory data exist with regard to adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapy in surgically managed patients for localized renal cell carcinoma (RCC). OBJECTIVE: To systematically evaluate the current evidence regarding the therapeutic benefit (disease-free survival [DFS] and overall survival [OS]) and grade 3-4 adverse events (AEs) for adjuvant VEGFR-targeted therapy for resected localized RCC. EVIDENCE ACQUISITION: A critical review of PubMed/Medline, Embase, and the Cochrane Library in January 2018 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement was performed...
May 18, 2018: European Urology
https://www.readbyqxmd.com/read/29783863/phase-1-randomized-parallel-group-double-blind-placebo-controlled-trial-to-evaluate-the-effects-of-erenumab-amg-334-and-concomitant-sumatriptan-on-blood-pressure-in-healthy-volunteers
#2
Jan de Hoon, Anne Van Hecken, Corinne Vandermeulen, Marissa Herbots, Yumi Kubo, Ed Lee, Osa Eisele, Gabriel Vargas, Kristin Gabriel
Objectives The aim of this study was to assess the effects of concomitant administration of erenumab and sumatriptan on resting blood pressure, pharmacokinetics, safety, and tolerability in healthy subjects. Methods In this phase 1, parallel-group, one-way crossover, double-blind, placebo-controlled study, healthy adult subjects were randomized (1:2) to receive either intravenous placebo and subcutaneous sumatriptan 12 mg (i.e. two 6-mg injections separated by 1 hour) or intravenous erenumab 140 mg and subcutaneous sumatriptan 12 mg...
January 1, 2018: Cephalalgia: An International Journal of Headache
https://www.readbyqxmd.com/read/29783736/revisiting-cd28-superagonist-tgn1412-as-potential-therapeutic-for-pediatric-b-cell-leukemia-a-review
#3
REVIEW
Katelyn E Brown
Pediatric acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer diagnosis, with numbers rising gradually every year. This paper proposes a novel therapeutic agent for pediatric ALL on the basis of a failed clinical drug trial in 2006. TGN1412 was a promising therapeutic agent that yielded outstanding results in both in vitro studies and animal trials. It is a CD28 superagonist monoclonal antibody that activates T regulatory (TReg ) cells in the absence of costimulation of the T cell receptor (TCR) by an antigen-presenting cell...
May 19, 2018: Diseases (Basel)
https://www.readbyqxmd.com/read/29782049/use-of-most-bothersome-symptom-as-a-coprimary-endpoint-in-migraine-clinical-trials-a-post-hoc-analysis-of-the-pivotal-zotrip-randomized-controlled-trial
#4
David W Dodick, Stewart J Tepper, Deborah I Friedman, Amy A Gelfand, Donald J Kellerman, Peter C Schmidt
OBJECTIVE: To better understand the utility of using pain freedom and most bothersome headache-associated symptom (MBS) freedom as co-primary endpoints in clinical trials of acute migraine interventions. BACKGROUND: Adhesive dermally applied microarray (ADAM) is an investigational system for intracutaneous drug administration. The recently completed pivotal Phase 2b/3 study (ZOTRIP), evaluating ADAM zolmitriptan for the treatment of acute moderate to severe migraine, was one of the first large studies to incorporate MBS freedom and pain freedom as co-primary endpoints per recently issued guidance by the US Food and Drug Administration...
May 21, 2018: Headache
https://www.readbyqxmd.com/read/29780848/controlled-human-hookworm-infection-accelerating-human-hookworm-vaccine-development
#5
David Diemert, Doreen Campbell, Jill Brelsford, Caitlyn Leasure, Guangzhao Li, Jin Peng, Maria Zumer, Naji Younes, Maria Elena Bottazzi, Rojelio Mejia, David I Pritchard, John M Hawdon, Jeffrey M Bethony
Background: Controlled human hookworm infection (CHHI) is a central component of a proposed hookworm vaccination-challenge model (HVCM) to test the efficacy of candidate vaccines. Critical to CHHI is the manufacture of Necator americanus infective larvae ( Na L3) according to current Good Manufacturing Practice (cGMP) and the determination of an inoculum of Na L3 that is safe and reliably induces patent infection. Methods: cGMP-grade Na L3 were produced for a phase 1 trial in 20 healthy, hookworm-naïve adults in the United States, who received either 25 or 50 Na L3...
May 2018: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/29779976/the-discovery-and-preclinical-evaluation-of-bms-707035-a-potent-hiv-1-integrase-strand-transfer-inhibitor
#6
B Narasimhulu Naidu, Michael A Walker, Margaret E Sorenson, Yasutsugu Ueda, John D Matiskella, Timothy P Connolly, Ira B Dicker, Zeyu Lin, Sagarika Bollini, Brian J Terry, Helen Higley, Ming Zheng, Dawn D Parker, Dedong Wu, Stephen Adams, Mark R Krystal, Nicholas A Meanwell
BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13...
May 14, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29779485/tgn-1412-and-bia-2474-trials-with-tragic-end-lessons-learnt-to-make-clinical-trials-safer
#7
Rimple Jeet Kaur, Surjit Singh, Preeti Sidhu, Pramod Kumar Sharma
BACKGROUND: Globally, there have been tremendous efforts by regulatory authorities to make clinical trials safer by making stringent clinical trial regulations. Despite this, we witnessed several tragic events. TGN1412 and BIA 10-2474 phase I trials are infamous trails in which healthy volunteers either succumbed to severe adverse effects or faced irreversible impairments of the test drug. Such afflictions in clinical trials are not only turbulent to the image of pharmaceutical industry but it also conveys dispiriting message for clinical trial participants...
May 20, 2018: Reviews on Recent Clinical Trials
https://www.readbyqxmd.com/read/29779418/modeling-adverse-event-counts-in-phase-i-clinical-trials-of-a-cytotoxic-agent
#8
Daniel G Muenz, Thomas M Braun, Jeremy Mg Taylor
Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose...
May 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
https://www.readbyqxmd.com/read/29778738/risk-adapted-therapy-for-young-children-with-medulloblastoma-sjyc07-therapeutic-and-molecular-outcomes-from-a-multicentre-phase-2-trial
#9
Giles W Robinson, Vasilisa A Rudneva, Ivo Buchhalter, Catherine A Billups, Sebastian M Waszak, Kyle S Smith, Daniel C Bowers, Anne Bendel, Paul G Fisher, Sonia Partap, John R Crawford, Tim Hassall, Daniel J Indelicato, Frederick Boop, Paul Klimo, Noah D Sabin, Zoltan Patay, Thomas E Merchant, Clinton F Stewart, Brent A Orr, Jan O Korbel, David T W Jones, Tanvi Sharma, Peter Lichter, Marcel Kool, Andrey Korshunov, Stefan M Pfister, Richard J Gilbertson, Robert P Sanders, Arzu Onar-Thomas, David W Ellison, Amar Gajjar, Paul A Northcott
BACKGROUND: Young children with medulloblastoma have a poor overall survival compared with older children, due to use of radiation-sparing therapy in young children. Radiotherapy is omitted or reduced in these young patients to spare them from debilitating long-term side-effects. We aimed to estimate event-free survival and define the molecular characteristics associated with progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure...
May 16, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29778505/novel-peptide-nanoparticle-biased-antagonist-of-ccr3-blocks-eosinophil-recruitment-and-airway-hyperresponsiveness
#10
Milica Grozdanovic, Kimberly G Laffey, Hazem Abdelkarim, Ben Hitchinson, Anantha Harijith, Hyung-Geon Moon, Gye Young Park, Lee K Rousslang, Joanne C Masterson, Glenn T Furuta, Nadya I Tarasova, Vadim Gaponenko, Steven J Ackerman
BACKGROUND: Chemokine signaling through CCR3 is a key regulatory pathway for eosinophil recruitment into tissues associated with allergic inflammation and asthma. To date, none of the CCR3 antagonists have shown efficacy in clinical trials. One reason may be their unbiased mode of inhibition that prevents receptor internalization, leading to drug tolerance. OBJECTIVE: We sought to develop a novel peptide nanoparticle CCR3 inhibitor (R321) with a biased mode of inhibition that would block G-protein signaling, but enable or promote receptor internalization...
May 17, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29776750/safety-and-immunogenicity-of-a-vi-dt-typhoid-conjugate-vaccine-phase-i-trial-in-healthy-filipino-adults-and-children
#11
Maria Rosario Capeding, Samuel Teshome, Tarun Saluja, Khalid Ali Syed, Deok Ryun Kim, Ju Yeon Park, Jae Seung Yang, Yang Hee Kim, Jiwook Park, Sue-Kyoung Jo, Yun Chon, Sudeep Kothari, Seon-Young Yang, Dong Soo Ham, Ji Hwa Ryu, Hee-Seong Hwang, Ju-Hwan Mun, Julia Lynch, Jerome Kim, Hun Kim, Jean-Louis Excler, Sushant Sahastrabuddhe
BACKGROUND: Typhoid fever remains a major public health problem in low- and middle-income countries where children aged 2-14 years bear the greatest burden. Vi polysaccharide is poorly immunogenic in children <2 years of age, and protection in adults is modest. The limitations of Vi polysaccharide vaccines can be overcome by conjugation of the Vi to a carrier protein. A typhoid conjugate vaccine composed of Vi polysaccharide conjugated to diphtheria toxoid (Vi-DT) has been developed...
May 15, 2018: Vaccine
https://www.readbyqxmd.com/read/29775768/canine-pet-dog-tumor-microsurgery-and-intratumoral-concentration-and-safety-of-metronomic-chlorambucil-for-spontaneous-glioma-a-phase-i-clinical-trial
#12
R Timothy Bentley, Stephanie A Thomovsky, Margaret A Miller, Deborah W Knapp, Aaron A Cohen-Gadol
INTRODUCTION: Metronomic (daily low-dose) chlorambucil requires further study before implementation in human glioma. OBJECTIVE: Investigate the distribution and safety of metronomic chlorambucil in naturally occurring canine glioma. METHODS: Eight client-owned (pet) dogs with newly diagnosed spontaneous glioma were prospectively enrolled. Chlorambucil was administered preoperatively at 4 mg/m2 q 24hr for ≥ 3 days, and continued postoperatively until death or dose-limiting adverse events...
May 15, 2018: World Neurosurgery
https://www.readbyqxmd.com/read/29775153/feasibility-safety-and-changes-in-systolic-blood-pressure-associated-with-endovascular-revascularization-of-symptomatic-and-chronically-occluded-cervical-internal-carotid-artery-using-a-newly-suggested-radiographic-classification-of-chronically-occluded-cervical
#13
David Hasan, Mario Zanaty, Robert M Starke, Elias Atallah, Nohra Chalouhi, Pascal Jabbour, Amit Singla, Waldo R Guerrero, Daichi Nakagawa, Edgar A Samaniego, Nnenna Mbabuike, Rabih G Tawk, Adnan H Siddiqui, Elad I Levy, Roberta L Novakovic, Jonathan White, Clemens M Schirmer, Thomas G Brott, Hussain Shallwani, L Nelson Hopkins
OBJECTIVE The overall risk of ischemic stroke from a chronically occluded internal carotid artery (COICA) is around 5%-7% per year despite receiving the best available medical therapy. Here, authors propose a radiographic classification of COICA that can be used as a guide to determine the technical success and safety of endovascular recanalization for symptomatic COICA and to assess the changes in systemic blood pressure following successful revascularization. METHODS The radiographic images of 100 consecutive subjects with COICA were analyzed...
May 18, 2018: Journal of Neurosurgery
https://www.readbyqxmd.com/read/29774061/immunotherapy-in-non-metastatic-non-small-cell-lung-cancer-can-the-benefits-of-stage-iv-therapy-be-translated-into-earlier-stages
#14
REVIEW
Griet Deslypere, Dorothée Gullentops, Els Wauters, Johan Vansteenkiste
Over the last decade, several steps forward in the treatment of patients with stage IV non-small cell lung cancer (NCSLC) were made. Examples are the use of pemetrexed, pemetrexed maintenance therapy, or bevacizumab for patients with nonsquamous NSCLC. A big leap forward was the use of tyrosine kinase inhibitors in patients selected on the basis of an activating oncogene, such as epidermal growth factor receptor ( EGFR ) activating mutations or anaplastic lymphoma kinase ( ALK ) translocations. However, all of these achievements could not be translated into survival benefits when studied in randomized controlled trials in patients with nonmetastatic NSCLC...
2018: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/29774057/ocrelizumab-a-new-milestone-in-multiple-sclerosis-therapy
#15
REVIEW
Patricia Mulero, Luciana Midaglia, Xavier Montalban
B cells play a central role in the pathogenesis of multiple sclerosis (MS): they are involved in the activation of pro-inflammatory T cells, secretion of pro-inflammatory cytokines and production of autoantibodies directed against myelin. Hence, the use of B cell-depleting monoclonal antibodies as therapy for autoimmune diseases, including MS, has increased in recent years. Previous results with rituximab, the first therapeutic B cell-depleting chimeric monoclonal antibody that showed efficacy in MS clinical trials, encouraged researchers to evaluate the efficacy of a humanized anti-CD20 antibody, ocrelizumab, in MS...
2018: Therapeutic Advances in Neurological Disorders
https://www.readbyqxmd.com/read/29773775/case-study-in-international-cooperation-cuba-s-molecular-immunology-center-and-roswell-park-cancer-institute
#16
Rachel Evans, Mary Reid, Brahm Segal, Scott I Abrams, Kelvin Lee
In 1961, the USA severed diplomatic relations with Cuba, and in 1962 an embargo was imposed on trade and financial relations with that country. It was not until five decades later that the USA and Cuba would reestablish relations. This opened the way for the New York State Trade Mission to Cuba in April 2015, during which Cuba's Molecular Immunology Center and Buffalo, New York's Roswell Park Cancer Institute signed a formal agreement that would set in motion biotechnology research collaboration to address one of the most important causes of death in both countries...
April 2018: MEDICC Review
https://www.readbyqxmd.com/read/29773717/stk11-lkb1-mutations-and-pd-1-inhibitor-resistance-in-kras-mutant-lung-adenocarcinoma
#17
Ferdinandos Skoulidis, Michael E Goldberg, Danielle M Greenawalt, Matthew D Hellmann, Mark M Awad, Justin F Gainor, Alexa B Schrock, Ryan J Hartmaier, Sally E Trabucco, Laurie Gay, Siraj M Ali, Julia A Elvin, Gaurav Singal, Jeffrey S Ross, David Fabrizio, Peter M Szabo, Han Chang, Ariella Sasson, Sujaya Srinivasan, Stefan Kirov, Joseph Szustakowski, Patrik Vitazka, Robin Edwards, Jose A Bufill, Neelesh Sharma, Sai-Hong I Ou, Nir Peled, David R Spigel, Hira Rizvi, Elizabeth Jimenez Aguilar, Brett W Carter, Jeremy Erasmus, Darragh F Halpenny, Andrew J Plodkowski, Niamh M Long, Mizuki Nishino, Warren L Denning, Ana Galan-Cobo, Haifa Hamdi, Taghreed Hirz, Pan Tong, Jing Wang, Jaime Rodriguez-Canales, Pamela A Villalobos, Edwin R Parra, Neda Kalhor, Lynette M Sholl, Jennifer L Sauter, Achim A Jungbluth, Mari Mino-Kenudson, Roxana Azimi, Yasir Y Elamin, Jianjun Zhang, Giulia C Leonardi, Fei Jiang, Kwok-Kin Wong, J Jack Lee, Vassiliki A Papadimitrakopoulou, Ignacio I Wistuba, Vincent A Miller, Garrett M Frampton, Jedd D Wolchok, Alice T Shaw, Pasi A Jänne, Philip J Stephens, Charles M Rudin, William J Geese, Lee A Albacker, John V Heymach
KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) co-mutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P<0.001) in the SU2C cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase 3 trial (0% vs 57...
May 17, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29773662/validation-of-the-16-gene-recurrence-score-in-patients-with-locoregional-high-risk-renal-cell-carcinoma-from-a-phase-3-trial-of-adjuvant-sunitinib
#18
Brian I Rini, Bernard Escudier, Jean-Francois Martini, Ahmed Magheli, Christer Svedman, Margarita Lopatin, Dejan Knezevic, Audrey D Goddard, Phillip G Febbo, Rachel Li, Xun Lin, Olga Valota, Michael Staehler, Robert J Motzer, Alain Ravaud
PURPOSE: Adjuvant sunitinib prolonged disease-free survival (DFS) (hazard ratio [HR] 0.76) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov NCT00375674). The 16-gene Recurrence Score (RS) assay was previously developed and validated to estimate risk for disease recurrence in patients with RCC post-nephrectomy. This analysis further validated the prognostic value of RS assay in patients from S-TRAC and explored association of RS results with prediction of sunitinib benefit...
May 17, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29773602/clofarabine-high-dose-cytarabine-and-liposomal-daunorubicin-in-pediatric-relapsed-refractory-acute-myeloid-leukemia-a-phase-ib-study
#19
Natasha K A van Eijkelenburg, Mareike Rasche, Essam Ghazaly, Michael N Dworzak, Thomas Klingebiel, Claudia Rossig, Guy Leverger, Jan Stary, Eveline S J M de Bont, Dana A Chitu, Yves Bertrand, Benoit Brethon, Brigitte Strahm, Inge M van der Sluis, Gertjan J L Kaspers, Dirk Reinhardt, C Michel Zwaan
Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase 2 dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose-levels of clofarabine (20-40mg/m2/day x5days) and liposomal daunorubicin (40-0mg/m2/day) were administered with cytarabine (2g/m2/day x5days)...
May 17, 2018: Haematologica
https://www.readbyqxmd.com/read/29773601/combinatorial-targeting-of-xpo1-and-flt3-exerts-synergistic-anti-leukemia-effects-through-induction-of-differentiation-and-apoptosis-in-flt3-mutated-acute-myeloid-leukemias-from-concept-to-clinical-trial
#20
Weiguo Zhang, Charlie Ly, Jo Ishizawa, Hong Mu, Vivian Ruvolo, Sharon Shacham, Naval Daver, Michael Andreeff
Targeted therapies against FLT3-mutated acute myeloid leukemia have shown limited clinical efficacy primarily because of the acquisition of secondary mutations in FLT3 and persistent activation of downstream pro-survival pathways such as MEK/ERK, PI3K/AKT, and STAT5. Activation of these additional kinases may also result in phosphorylation of tumor suppressor proteins promoting their nuclear export. Thus, co-targeting nuclear export proteins (i.e., XPO1) and FLT3 concomitantly may be therapeutically effective...
May 17, 2018: Haematologica
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