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https://www.readbyqxmd.com/read/27900363/integration-of-genomics-and-histology-revises-diagnosis-and-enables-effective-therapy-of-refractory-cancer-of-unknown-primary-with-pdl1-amplification
#1
Stefan Gröschel, Martin Bommer, Barbara Hutter, Jan Budczies, David Bonekamp, Christoph Heining, Peter Horak, Martina Fröhlich, Sebastian Uhrig, Daniel Hübschmann, Christina Geörg, Daniela Richter, Nicole Pfarr, Katrin Pfütze, Stephan Wolf, Peter Schirmacher, Dirk Jäger, Christof von Kalle, Benedikt Brors, Hanno Glimm, Wilko Weichert, Albrecht Stenzinger, Stefan Fröhling
Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision-making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multiagent chemotherapy...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27896938/population-pharmacokinetic-pharmacodynamic-modeling-of-tumor-size-dynamics-in-pembrolizumab-treated-advanced-melanoma
#2
M S Chatterjee, J Elassaiss-Schaap, A Lindauer, D C Turner, A Sostelly, T Freshwater, K Mayawala, M Ahamadi, J A Stone, R de Greef, A G Kondic, D P de Alwis
Pembrolizumab is a potent immune-modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE-001, -002, and -006 studies. Longitudinal tumor size modeling was pursued to quantify exposure-response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE-001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy...
November 29, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27896216/recent-advances-in-immunotherapy-in-metastatic-nsclc
#3
REVIEW
Pranshu Bansal, Diaa Osman, Gregory N Gan, George R Simon, Yanis Boumber
Non-small cell lung cancer (NSCLC) is one of most common malignancies and the leading cause of cancer deaths worldwide. Despite advances in targeted therapies, majority of NSCLC patients do not have targetable genomic alterations. Nevertheless, recent discovery that NSCLC is an immunogenic tumor type, and several breakthroughs in immunotherapies have led to rapid expansion of this new treatment modality in NSCLC with recent FDA approvals of programed death receptor-1 inhibitors, such as nivolumab and pembrolizumab...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27895920/pd1-pd-l1-inhibition-as-a-potential-radiosensitizer-in-head-and-neck-squamous-cell-carcinoma-a-case-report
#4
Misako Nagasaka, Mark Zaki, Harold Kim, S Naweed Raza, George Yoo, Ho-Sheng Lin, Ammar Sukari
BACKGROUND: Immunotherapy targeting the checkpoint PD1 (programmed cell death protein 1) or PDL1 (programmed death ligand 1) has led to advances in the treatment of melanoma and non-small cell lung cancer (NSCLC). The use of such therapies has also been introduced into the treatment of other malignancies, including head and neck cancer. The combined effects of checkpoint inhibitors and anti-PD1(L1) antibodies and radiation therapy have not yet been sufficiently investigated. CASE PRESENTATION: We report a case of locally relapsed non-resectable oral cavity squamous cell carcinoma, with excellent local control after pembrolizumab (MK3475) followed by radiotherapy...
2016: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/27894673/treatment-related-death-in-cancer-patients-treated-with-immune-checkpoint-inhibitors-a-systematic-review-and-meta-analysis
#5
O Abdel-Rahman, D Helbling, J Schmidt, U Petrausch, A Giryes, A Mehrabi, O Schöb, M Mannhart, H Oweira
AIMS: We carried out a meta-analysis to determine the risk of treatment-related death associated with immune checkpoint inhibitor use in cancer patients. MATERIALS AND METHODS: We examined data from the Medline and Google Scholar databases. We also examined original studies and review articles for cross-references. Eligible studies included randomised phase II and phase III trials of patients with cancer treated with ipilimumab, pembrolizumab; nivolumab; tremelimumab and atezolizumab...
November 25, 2016: Clinical Oncology: a Journal of the Royal College of Radiologists
https://www.readbyqxmd.com/read/27892986/new-yellow-plaques-in-a-patient-taking-pembrolizumab
#6
Paul R Massey, Krystal M Jones, Matthew C Fox
No abstract text is available yet for this article.
November 17, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27892744/evaluation-of-efficacy-and-safety-of-different-pembrolizumab-dose-schedules-in-treatment-of-non-small-cell-lung-cancer-and-melanoma-a-systematic-review
#7
Omar Abdel-Rahman
AIM: Pembrolizumab is a fully humanized anti-PD-1 agent currently approved for the treatment of advanced melanoma and pretreated non-small-cell lung cancer (NSCLC). OBJECTIVE: To assess the efficacy and safety of different dose schedules of pembrolizumab in the treatment of patients with advanced NSCLC and melanoma. Search method: MEDLINE database has been searched. Reference lists of original studies and review articles were checked for other related articles. SELECTION CRITERIA: Prospective clinical trials reporting the outcomes of more than one dose schedule of pembrolizumab in the treatment of advanced NSCLC and melanoma...
November 28, 2016: Immunotherapy
https://www.readbyqxmd.com/read/27892653/low-baseline-levels-of-nk-cells-may-predict-a-positive-response-to-ipilimumab-in-melanoma-therapy
#8
Julia K Tietze, Daniela Angelova, Markus V Heppt, Thomas Ruzicka, Carola Berking
The introduction of immune checkpoint blockade (ICB) has been a breakthrough in the therapy of metastatic melanoma. The influence of ICB on T cell populations has been studied extensively but little is known about the effect on NK cells. In this study, we analysed the relative and absolute amounts of NK cells and of the subpopulations of CD56(dim) and CD56(bright) NK cells among the peripheral blood mononuclear cells (PBMCs) of 32 patients with metastatic melanoma before and under treatment with ipilimumab or pembrolizumab by flow cytometry...
November 28, 2016: Experimental Dermatology
https://www.readbyqxmd.com/read/27884973/the-emerging-role-of-immune-checkpoint-inhibition-in-malignant-lymphoma
#9
Ida Hude, Stephanie Sasse, Andreas Engert, Paul J Bröckelmann
To evade elimination by the host immune system, tumor cells commonly exploit physiological immune checkpoint pathways, restraining efficient anti-tumor immune cell function. Growing understanding of the complex dialog between tumor cells and their microenvironment contributed to the development of immune checkpoint inhibitors. This innovative strategy has demonstrated paradigm-shifting clinical activity in various malignancies. Antibodies targeting programmed death 1 and cytotoxic T-lymphocyte-associated protein-4 are also being investigated in lymphoid malignancies with varying levels of activity and a favorable toxicity profile...
November 24, 2016: Haematologica
https://www.readbyqxmd.com/read/27881588/glucocorticoids-did-not-reverse-type-1-diabetes-mellitus-secondary-to-pembrolizumab-in-a-patient-with-metastatic-melanoma
#10
Jasna Aleksova, Peter K H Lau, Georgia Soldatos, Grant McArthur
Immune checkpoint inhibitors offer patients with advanced melanoma substantial improvements in survival. Unlike chemotherapy, immune checkpoint inhibitors such as ipilimumab and pembrolizumab cause unique immune-related adverse events (irAEs), including the development of endocrinopathies. We report a case of a man aged 60 years who developed diabetic ketoacidosis (DKA) following the use of pembrolizumab for the treatment of metastatic melanoma. He received four cycles of ipilimumab, before proceeding to pembrolizumab...
November 23, 2016: BMJ Case Reports
https://www.readbyqxmd.com/read/27870733/cutaneous-metastatic-melanoma-resembling-a-halo-nevus-in-the-setting-of-pd-1-inhibition
#11
Nathan Tobias Harvey, Michael Millward, Kirstie Macgregor, Robert Paul Bucat, Benjamin Andrew Wood
Malignant melanoma is a common source of cutaneous metastases and can occasionally adopt a histological appearance which mimics a primary melanocytic lesion, either benign or malignant. The authors describe a case of new cutaneous deposits of metastatic melanoma in a 70-year-old woman with a prominent admixed lymphocytic infiltrate, imparting a striking resemblance to a halo nevus. The authors believe this appearance was a direct reflection of treatment with pembrolizumab, a humanized antibody against the immune checkpoint inhibitor programmed death-1...
December 2016: American Journal of Dermatopathology
https://www.readbyqxmd.com/read/27864214/vasculitic-neuropathy-induced-by-pembrolizumab
#12
F Aya, V Ruiz-Esquide, M Viladot, C Font, S Prieto-González, A Prat, A Arance
No abstract text is available yet for this article.
November 17, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27863197/programmed-death-ligand-1-expression-and-response-to-the-anti-programmed-death-1-antibody-pembrolizumab-in-melanoma
#13
Adil I Daud, Jedd D Wolchok, Caroline Robert, Wen-Jen Hwu, Jeffrey S Weber, Antoni Ribas, F Stephen Hodi, Anthony M Joshua, Richard Kefford, Peter Hersey, Richard Joseph, Tara C Gangadhar, Roxana Dronca, Amita Patnaik, Hassane Zarour, Charlotte Roach, Grant Toland, Jared K Lunceford, Xiaoyun Nicole Li, Kenneth Emancipator, Marisa Dolled-Filhart, S Peter Kang, Scot Ebbinghaus, Omid Hamid
Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks...
December 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27863186/model-based-characterization-of-the-pharmacokinetics-of-pembrolizumab-a-humanized-anti-pd-1-monoclonal-antibody-in-advanced-solid-tumors
#14
M Ahamadi, T Freshwater, M Prohn, C H Li, D P de Alwis, R de Greef, J Elassaiss-Schaap, A Kondic, J A Stone
Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies...
November 14, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27863176/translational-pharmacokinetic-pharmacodynamic-modeling-of-tumor-growth-inhibition-supports-dose-range-selection-of-the-anti-pd-1-antibody-pembrolizumab
#15
A Lindauer, C R Valiathan, K Mehta, V Sriram, R de Greef, J Elassaiss-Schaap, D P de Alwis
Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has a manageable safety profile and robust clinical activity against advanced malignancies. The lowest effective dose for evaluation in further dose-ranging studies was identified by developing a translational model from preclinical mouse experiments. A compartmental pharmacokinetic model was combined with a published physiologically based tissue compartment, linked to receptor occupancy as the driver of observed tumor growth inhibition...
November 8, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27863143/using-model-based-learn-and-confirm-to-reveal-the-pharmacokinetics-pharmacodynamics-relationship-of-pembrolizumab-in-the-keynote-001-trial
#16
J Elassaiss-Schaap, S Rossenu, A Lindauer, S P Kang, R de Greef, J R Sachs, D P de Alwis
Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) properties played an important role in the early clinical development of pembrolizumab. Because analysis of data from a traditional 3 + 3 dose-escalation design revealed several critical uncertainties, a model-based approach was implemented to better understand these properties. Based on anticipated scenarios for potency and PK nonlinearity, a follow-up study was designed and thoroughly evaluated. Execution of 14,000 virtual trials led to the selection and implementation of a robust design that extended the low-dose range by 200-fold...
November 8, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27857838/hyponatraemia-secondary-to-nivolumab-induced-primary-adrenal-failure
#17
Harris Trainer, Paul Hulse, Claire E Higham, Peter Trainer, Paul Lorigan
: Checkpoint inhibitors, such as ipilimumab and pembrolizumab, have transformed the prognosis for patients with advanced malignant melanoma and squamous non-small-cell lung cancer, and their use will only expand as experience is gained in a variety of other malignancies, for instance, renal and lymphoma. As the use of checkpoint inhibitors increases, so too will the incidence of their unique side effects, termed immune-related adverse events (irAEs), which can affect dermatological, gastrointestinal, hepatic, endocrine and other systems...
2016: Endocrinology, Diabetes & Metabolism Case Reports
https://www.readbyqxmd.com/read/27852042/toxicity-profile-of-approved-anti-pd-1-monoclonal-antibodies-in-solid-tumors-a-systematic-review-and-meta-analysis-of-randomized-clinical-trials
#18
REVIEW
Ricardo Costa, Benedito A Carneiro, Mark Agulnik, Alfred W Rademaker, Sachin G Pai, Victoria M Villaflor, Massimo Cristofanilli, Jeffrey A Sosman, Francis J Giles
PURPOSE: Nivolumab and pembrolizumab are antibodies against the programmed-death-receptor- 1 (PD-1) which are associated with distinct immune related adverse effects (AEs). This meta-analysis of randomized clinical trials aims to summarize current knowledge regarding the toxicity profile of these agents. METHODS: PubMed search was conducted in February of 2016. The randomized trials needed to have at least one of the study arms consisting of nivolumab or pembrolizumab monotherapy and a control arm containing no anti-PD-1 therapy...
November 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27849399/new-chemical-treatment-options-in-second-line-hepatocellular-carcinoma-what-to-do-when-sorafenib-fails
#19
Hyun Young Woo, So Young Yoo, Jeong Heo
There have been no therapies available for patients who experience disease progression after sorafenib treatment. Regorafenib inhibits multiple kinases involved in tumor proliferation and neoangiogenesis, which has produced a survival benefit in hepatocellular carcinoma (HCC) after sorafenib failure. Other active candidate agents are c-Met inhibitors and immune checkpoint inhibitors. Areas covered: This paper presents an updated summary of the preclinical and clinical experience with regorafenib, c-Met inhibitors (tivantinib, cabozantinib and tepotinib), and a checkpoint inhibitor (nivolumab, pembrolizumab) in HCC...
November 28, 2016: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27845904/the-evaluation-of-immunotherapy-and-chemotherapy-treatment-on-melanoma-a-network-meta-analysis
#20
BaSang CiRen, Xinhua Wang, Ziwen Long
BACKGROUND: Melanoma is a highly malignant tumor that develops from a neural crest derivative called melanocytes. Chemotherapy is recommended for patients with stage III/IV melanoma. Immunomodulation has also been shown to effectively improve the survival rate of such patients. In the current study, we aimed to perform a network meta-analysis on the therapeutic value of chemotherapy and immunotherapy on melanoma. RESULTS: Twenty randomized controlled trials (RCTs) were enrolled in the study...
November 10, 2016: Oncotarget
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