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https://www.readbyqxmd.com/read/28817755/measuring-toxic-effects-and-time-to-treatment-failure-for-nivolumab-plus-ipilimumab-in-melanoma
#1
Alexander N Shoushtari, Claire F Friedman, Pedram Navid-Azarbaijani, Michael A Postow, Margaret K Callahan, Parisa Momtaz, Katherine S Panageas, Jedd D Wolchok, Paul B Chapman
Importance: Nivolumab plus ipilimumab (nivo + ipi) is a standard treatment of advanced melanoma. Two randomized trials describe high objective response rates by Response Evaluation Criteria in Solid Tumors. The trials assessed toxic effects using the Common Terminology Criteria for Adverse Events (CTCAE), which may underestimate incidence of clinically significant immune-related adverse events (AEs). Objective: To describe detailed toxic effects and time to treatment failure of patients with melanoma treated with nivo + ipi in a prospective cohort...
August 17, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28817386/cxcr4-blockade-with-amd3100-enhances-taxol-chemotherapy-to-limit-ovarian-cancer-cell-growth
#2
Patrick M Reeves, Mojgan A Abbaslou, Farah R W Kools, Mark C Poznansky
The standard of care for ovarian cancer includes initial treatment with chemotherapy. Despite initial efficacy, over 70% of patients develop recurrence; thus, there is a need to identify novel approaches that can improve therapeutic outcomes. We evaluated AMD3100 (Plerixafor), an FDA-approved CXCR4 inhibitor, as a potential adjunctive therapy for low-dose Taxol (Paclitaxel) by assessing the impact on in-vitro ovarian cancer cell proliferation. Proliferation was a measure for both human TOV-112D and murine ID8 ovarian cancer cells incubated with AMD3100 and Taxol, either individually or in combination...
August 16, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28817371/phase-i-ii-trial-of-labetuzumab-govitecan-anti-ceacam5-sn-38-antibody-drug-conjugate-in-patients-with-refractory-or-relapsing-metastatic-colorectal-cancer
#3
Efrat Dotan, Steven J Cohen, Alexander N Starodub, Christopher H Lieu, Wells A Messersmith, Pamela S Simpson, Michael J Guarino, John L Marshall, Richard M Goldberg, J Randolph Hecht, William A Wegener, Robert M Sharkey, Serengulam V Govindan, David M Goldenberg, Jordan D Berlin
Purpose The objectives were to evaluate dosing schedules of labetuzumab govitecan, an antibody-drug conjugate targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) for tumor delivery of 7-ethyl-10-hydroxycamptothecin (SN-38), in an expanded phase II trial of patients with relapsed or refractory metastatic colorectal cancer. Patients and Methods Eligible patients with at least one prior irinotecan-containing therapy received labetuzumab govitecan once weekly at 8 and 10 mg/kg, or two times per week at 4 and 6 mg/km on weeks 1 and 2 of 3-week repeated cycles...
August 17, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28817277/discovery-and-characterization-of-r-6-neopentyl-2-pyridin-2-ylmethoxy-6-7-dihydropyrimido-2-1-c-1-4-oxazin-4-9h-one-pf-06462894-an-alkyne-lacking-metabotropic-glutamate-receptor-5-negative-allosteric-modulator-profiled-in-both-rat-and-non-human-primates
#4
Antonia F Stepan, Michelle M Claffey, Matthew R Reese, Gayatri Balan, Gabriela Barreiro, Jason Barricklow, Michael J Bohanon, Brian P Boscoe, Gregg D Cappon, Lois K Chenard, Julie Cianfrogna, Laigao Chen, Karen J Coffman, Susan E Drozda, Joshua R Dunetz, Somraj Ghosh, Xinjun Hou, Christopher Houle, Kapil Karki, John T Lazzaro, Jessica Y Mancuso, John M Marcek, Emily L Miller, Mark A Moen, Steven V O'Neil, Isao Sakurada, Marc Skaddan, Vinod Parikh, Deborah L Smith, Patrick E Trapa, Jamison B Tuttle, Patrick R Verhoest, Daniel P Walker, Annie C Won, Ann S Wright, Jessica Whritenour, Kenneth Zasadny, Margaret M Zaleska, Lei Zhang, Christopher L Shaffer
We previously observed a cutaneous type IV immune response in non-human primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp(3) character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily)...
August 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28817190/a-phase-1-and-2-study-of-filanesib-alone-and-in-combination-with-low-dose-dexamethasone-in-relapsed-refractory-multiple-myeloma
#5
Jatin J Shah, Jonathan L Kaufman, Jeffrey A Zonder, Adam D Cohen, William I Bensinger, Brandi W Hilder, Selena A Rush, Duncan H Walker, Brian J Tunquist, Kevin S Litwiler, Mieke Ptaszynski, Robert Z Orlowski, Sagar Lonial
BACKGROUND: Filanesib (ARRY-520) is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity. METHODS: This open-label Phase 1/2 study determined the maximum tolerated dose of Filanesib administered on Days 1 and 2 of 14-Day Cycles in patients with multiple myeloma (MM) and included expansion cohorts with and without dexamethasone (40 mg/week). Patients in the dose-escalation (N = 31) and Phase 2 single-agent (N = 32) cohorts had received prior bortezomib as well as prior thalidomide and/or lenalidomide...
August 17, 2017: Cancer
https://www.readbyqxmd.com/read/28816644/cyp2b6-haplotype-predicts-efavirenz-plasma-concentration-in-black-south-african-hiv-1-infected-children-a-longitudinal-pediatric-pharmacogenomic-study
#6
Riaan Reay, Collet Dandara, Michelle Viljoen, Malie Rheeders
South Africa has the highest burden of the human immunodeficiency virus (HIV) infection globally. Efavirenz (EFV), a frequently used drug against HIV infection, displays a relationship between drug concentration and pharmacodynamics effects clinically. However, haplotype-based genetic variation in drug metabolism in a pediatric sample has been little considered in a longitudinal long-term context. CYP2B6 plays a key role in variation of EFV plasma concentration through altered drug metabolism. We report here on a prospective clinical pharmacogenomics/pharmacokinetic study of Bantu-speaking children, importantly, over a period of 24 months post-initiation of EFV-based treatment in South Africa...
August 2017: Omics: a Journal of Integrative Biology
https://www.readbyqxmd.com/read/28816536/optimizing-lenvatinib-therapy-in-patients-with-metastatic-radioactive-iodine-resistant-differentiated-thyroid-cancers
#7
Sina Jasim, Nicole M Iniguez-Ariza, Crystal R Hilger, Ashish V Chintakuntlawar, Mabel M Ryder, John C Morris, Keith C Bible
BACKGROUND AND OBJECTIVES: Lenvatinib is approved for use in advanced radioactive iodine resistant differentiated thyroid cancers (RAIR-DTCs); its efficacy is indisputable, but toxicities are great, creating daunting challenges for patients and providers. Few data regarding early adverse events and impact on quality of life (QOL) exist; we sought to add clarity to these issues by analyzing our initial post-approval lenvatinib experience. METHODS: Standardized patient education was implemented, providing detailed instructions and expert provider contacts to facilitate timely reporting of toxicities and guide responsive actions...
August 17, 2017: Endocrine Practice
https://www.readbyqxmd.com/read/28816367/the-in-vitro-and-in-vivo-antiangiogenic-effects-of-flavokawain-b
#8
Mariana C Rossette, Débora C Moraes, Erika K Sacramento, Marco Aurélio Romano-Silva, Juliana L Carvalho, Dawidson A Gomes, Hanna Caldas, Eitan Friedman, Luciana Bastos-Rodrigues, Luiz De Marco
Angiogenesis is implicated in the development of a variety of pathological processes, most commonly cancer. It is essential for tumor growth and metastasis, making it an important cancer therapeutic target. Naturally occurring substances have led to the discovery of anticancer agents. Flavokawain B (FKB), a chalcone isolated from the root extracts of kava-kava plant, inhibits proliferation and causes apoptosis in vitro and in vivo of various cancer cell lines. The antimetastatic potential of FKB has also been suggested...
August 17, 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28816170/role-of-consolidative-radiation-therapy-after-autologous-hematopoietic-cell-transplantation-for-the-treatment-of-relapsed-or-refractory-hodgkin-lymphoma
#9
Christopher Wilke, Qing Cao, Kathryn E Dusenbery, Veronika Bachanova, Aleksandr Lazaryan, Chung K Lee, Jianling Yuan
PURPOSE: To evaluate the role of the addition of consolidative radiation therapy after high-dose chemotherapy and autologous hematopoietic cell transplantation (AHCT) for relapsed or refractory Hodgkin lymphoma (HL). METHODS AND MATERIALS: Medical records were reviewed from a total of 80 consecutive patients who underwent high-dose chemotherapy with AHCT treated under a single protocol at University of Minnesota between November 2005 and January 2014. Of these, 32 patients received radiation therapy after AHCT as planned consolidation...
September 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28816165/incidence-and-predictors-of-pericardial-effusion-after-chemoradiation-therapy-for-locally-advanced-non-small-cell-lung-cancer
#10
Matthew S Ning, Linglong Tang, Daniel R Gomez, Ting Xu, Yangkun Luo, Jinhai Huo, Elie Mouhayar, Zhongxing Liao
PURPOSE: Findings from Radiation Therapy Oncology Group (RTOG) 0617 suggested that collateral radiation to the heart may contribute to early death in patients receiving chemoradiation therapy for non-small cell lung cancer (NSCLC); however, reports of cardiac toxicity after thoracic radiation therapy (RT) remain limited. Because pericardial disease is the most common cardiac complication of thoracic RT, we investigated the incidence of and risk factors for pericardial effusion (PCE) in patients enrolled in a phase 2 prospective randomized study of intensity modulated RT versus proton therapy for locally advanced NSCLC...
September 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28816162/heart-dosimetry-is-correlated-with-risk-of-radiation-pneumonitis-after-lung-sparing-hemithoracic-pleural-intensity-modulated-radiation-therapy-for-malignant-pleural-mesothelioma
#11
Ellen D Yorke, Andrew Jackson, Li Cheng Kuo, Anthonia Ojo, Kelly Panchoo, Prasad Adusumilli, Marjorie G Zauderer, Valerie W Rusch, Annemarie Shepherd, Andreas Rimner
PURPOSE: To determine clinically helpful dose-volume and clinical metrics correlating with symptomatic radiation pneumonitis (RP) in malignant pleural mesothelioma (MPM) patients with 2 lungs treated with hemithoracic intensity modulated pleural radiation therapy (IMPRINT). METHODS AND MATERIALS: Treatment plans and resulting normal organ dose-volume histograms of 103 consecutive MPM patients treated with IMPRINT (February 2005 to January 2015) to the highest dose ≤50...
September 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28816159/consensus-guidelines-for-implementing-pencil-beam-scanning-proton-therapy-for-thoracic-malignancies-on-behalf-of-the-ptcog-thoracic-and-lymphoma-subcommittee
#12
REVIEW
Joe Y Chang, Xiaodong Zhang, Antje Knopf, Heng Li, Shinichiro Mori, Lei Dong, Hsiao-Ming Lu, Wei Liu, Shahed N Badiyan, Stephen Both, Arturs Meijers, Liyong Lin, Stella Flampouri, Zuofeng Li, Kikuo Umegaki, Charles B Simone, Xiaorong R Zhu
Pencil-beam scanning (PBS) proton therapy (PT), particularly intensity modulated PT, represents the latest advanced PT technology for treating cancers, including thoracic malignancies. On the basis of virtual clinical studies, PBS-PT appears to have great potential in its ability to tightly tailor the dose to the target while sparing critical structures, thereby reducing treatment-related toxicities, particularly for tumors in areas with complicated anatomy. However, implementing PBS-PT for moving targets has several additional technical challenges compared with intensity modulated photon radiation therapy or passive scattering PT...
September 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28816150/phase-1-study-of-ipilimumab-combined-with-whole-brain-radiation-therapy-or-radiosurgery-for-melanoma-patients-with-brain-metastases
#13
Noelle L Williams, Evan J Wuthrick, Hyun Kim, Joshua D Palmer, Shivank Garg, Harriet Eldredge-Hindy, Constantine Daskalakis, Kendra J Feeney, Michael J Mastrangelo, Lyndon J Kim, Takami Sato, Kari L Kendra, Thomas Olencki, David A Liebner, Christopher J Farrell, James J Evans, Kevin D Judy, David W Andrews, Adam P Dicker, Maria Werner-Wasik, Wenyin Shi
PURPOSE: We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. METHODS AND MATERIALS: Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design...
September 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28816142/vorinostat-and-concurrent-stereotactic-radiosurgery-for-non-small-cell-lung-cancer-brain-metastases-a-phase-1-dose-escalation-trial
#14
Clara Y H Choi, Heather A Wakelee, Joel W Neal, Mary C Pinder-Schenck, Hsiang-Hsuan Michael Yu, Steven D Chang, John R Adler, Leslie A Modlin, Griffith R Harsh, Scott G Soltys
PURPOSE: To determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates. MATERIALS AND METHODS: In this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial...
September 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28816137/high-dose-rate-brachytherapy-in-the-management-of-operable-rectal-cancer-a-systematic-review
#15
Hannah Buckley, Charles Wilson, Thankamma Ajithkumar
PURPOSE: To evaluate the role of high-dose-rate endorectal brachytherapy (HDREBT) in the preoperative and definitive management of operable rectal cancer in terms of clinical outcomes and toxicities using a systematic review. METHODS AND MATERIALS: A review of published articles from January 1990 to December 2016 was conducted using the PubMed, Embase, and Scopus databases using the search terms "rectal" or "rectum" in combination with "brachytherapy," "high dose rate," "HDR," and "endorectal...
September 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28816065/improved-hematopoietic-gene-therapy-in-a-mouse-model-of-fanconi-anemia-mediated-by-mesenchymal-stromal-cells
#16
Maria Fernandez-Garcia, Maria Lamana Luzuriaga, Miriam Hernando-Rodriguez, Rebeca Sanchez-Dominguez, Juan Bueren, Rosa Yañez
In this study we propose a novel approach based on the use of mesenchymal stromal cells (MSC) aiming at limiting risks of graft failure in gene therapy protocols associated with low conditioning regimens. Because the engraftment of corrected hematopoietic stem cells (HSCs) is particularly challenging in Fanconi anemia (FA), we have investigated the relevance of MSCs in an experimental model of FA gene therapy. Our results firstly showed that risks of graft failure in recipients conditioned with a moderate dose of 5Gy and infused with limited numbers of WT HSCs are significantly higher in Fanca-/- recipients as compared to WT recipients...
August 17, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28815861/radiation-and-chemotherapy-with-no-excessive-toxicity-in-a-patient-with-human-papillomavirus-related-tonsillar-cancer-and-porphyria-cutanea-tarda-case-report-and-literature-review
#17
James K Russo, Annie Braseth
BACKGROUND: Porphyria is a condition of cutaneous photosensitivity. It is unclear if radiotherapy (RT) is safe in patients with porphyria. METHODS: We report a patient case with uncontrolled porphyria cutanea tarda treated with chemoradiation for p16-positive oropharyngeal cancer. Given the scarcity of data on this subject, we also conducted a literature review on the topic of radiation in patients with porphyria. RESULTS: The patient in our study did not experience any unusual acute or late toxicity, despite receiving a high dose of cutaneous radiation...
August 16, 2017: Head & Neck
https://www.readbyqxmd.com/read/28815646/a-novel-endpoint-for-the-assessment-of-chemotherapy-induced-peripheral-neuropathy-in-rodents-biomechanical-properties-of-peripheral-nerve
#18
Chang-Ning Liu, Edwin Berryman, David Zakur, Ahmed M Shoieb, Ingrid D Pardo, Magalie Boucher, Chris J Somps, Chedo M Bagi, Jon C Cook
Chemotherapy-induced peripheral neuropathy (CiPN) is a frequent adverse effect in patients and a leading safety consideration in oncology drug development. Although behavioral assessment and microscopic examination of the nerves and dorsal root ganglia can be incorporated into toxicity studies to assess CiPN risk, more sensitive and less labor-intensive endpoints are often lacking. In this study, rats and mice administered vincristine (75 μg kg(-1)  day(-1) , i.p., for 10 days in rats and 100 μg kg(-1)  day(-1) , i...
August 16, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/28815642/nox4-and-nrf2-mediated-oxidative-stress-induced-by-silver-nanoparticles-in-vascular-endothelial-cells
#19
Xia Sun, Yi Yang, Junpeng Shi, Chengcheng Wang, Zhenfeng Yu, Hongwu Zhang
It has been widely reported that silver nanoparticles (AgNPs) induce oxidative stress in various cell lines. However, the mechanism for this effect and its consequences for cellular signaling are poorly understood. In this study, human umbilical vein endothelial cells (HUVECs) were used to assess the toxicity and investigate the associated molecular mechanisms caused by exposure to AgNPs. We demonstrated that AgNP exposure significantly and dose-dependently decreased the cell viability, induced reactive oxygen species (ROS) generation and led to early apoptosis in HUVECs...
August 16, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/28815320/inhibitory-growth-evaluation-and-apoptosis-induction-in-mcf-7-cancer-cells-by-new-5-aryl-2-butylthio-1-3-4-oxadiazole-derivatives
#20
Rashmin Khanam, Kamal Ahmad, Iram I Hejazi, Ibrar A Siddique, Vikash Kumar, Abdul Roouf Bhat, Amir Azam, Fareeda Athar
BACKGROUND: Cancer has become one of the global health issues and it is the life-threatening disease characterized by unrestrained growth of cells. Despite various advances being adopted by chemotherapeutic management, the use of the current anticancer drugs such as Doxorubicin, Asparginase, Methotrexate, Vincristine remains limited due to high toxicity, side effects and developing drug resistance. Apoptosis is a crucial cellular process and improper regulation of apoptotic signaling pathways may lead to cancer formation...
August 16, 2017: Cancer Chemotherapy and Pharmacology
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