المؤلفون: Jeannine D. Rinderknecht, Simone M. Goldinger, Sima Rozati, Jivko Kamarashev, Katrin Kerl, Lars E. French, Reinhard Dummer, Benedetta Belloni

المصدر: PLoS ONE, Vol 8, Iss 10 (2013)

مصطلحات موضوعية: Medicine, Science

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3798685Test; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/15bfa8c2504f4090bef0afbde387bbd2Test

المؤلفون: Lukas Krähenbühl, Simone M Goldinger, Joanna Mangana, Katrin Kerl, Ines Chevolet, Liève Brochez, Christine Horak, Mitch Levesque, Reinhard Dummer, Phil F Cheng

المصدر: Neoplasia: An International Journal for Oncology Research, Vol 20, Iss 2, Pp 218-225 (2018)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: A deepened understanding of the cellular and molecular processes in the tumor microenvironment is necessary for the development of precision immunotherapy (IT). We simultaneously investigated CD3, PDL1, and IDO by immunohistochemistry in paired biopsies from various organs of 43 metastatic melanoma patients treated with IT and targeted therapy (TT). Intraindividual biopsies taken after a period of weeks to months demonstrate discordant results in 30% of the cases. Overlap of IDO and PDL1 increased after therapy. IT only marginally impacted PDL1 expression over time in contrast to TT. Standardized repeated assessments of multiple immune markers in repeated biopsies will generate detailed insights in melanoma's immune evolution and adaption during therapies and might be used to support treatment decisions.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S1476558617304992Test; https://doaj.org/toc/1476-5586Test

الوصول الحر: https://doaj.org/article/737f5d8ced014c089412099c5e1cbe58Test

المؤلفون: Mitchell P. Levesque, Reinhard Dummer, John B.A.G. Haanen, Nicolas Pasqual, Pia Kvistborg, Marieke I.G. Raaijmakers, Thi Dan Linh Nguyen-Kim, Jean-François Mouret, Nadia Plantier, Solène Perez, Manuarii Manuel, Simone M. Goldinger, Nicoletta F. Jaberg-Bentele, Phil F. Cheng, Anaïs Courtier, Sabrina A. Hogan

الوصف: Figure Legends for Supplemental Figures 1-4

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::25269a334a7acee2caf869b2771c70d3Test
https://doi.org/10.1158/2326-6066.22536020Test

المؤلفون: Dirk Schadendorf, Levi A. Garraway, Gad Getz, Scott L. Carter, Stacey B. Gabriel, Jessica C. Hassel, Benjamin Weide, Carmen Loquai, Uwe Trefzer, Carola Berking, Friederike Egberts, Helen J. Gogas, Selma Ugurel, Simone M. Goldinger, Ralf Gutzmer, Uwe Hillen, Lisa Zimmer, Deborah Farlow, Kristian Cibulskis, Aaron McKenna, Mara Rosenberg, Eran Hodis, Gregory V. Kryukov, Steven Whittaker, Amaro Taylor-Weiner, Chelsea S. Place, Eva M. Goetz, Cory M. Johannessen, Daniel J. Treacy, Antje Sucker, Nikhil Wagle, Eliezer M. Van Allen

الوصف: PDF file, 12065K, Supplementary Table S4. Complete listing of all somatic mutations seen in all tumors. This table provides details on every non-synonymous mutation or short insertion/deletion observed in this cohort, with data on genomic coordinates, protein change, protein region affected, and read counts for each event. Many additional annotations are provided (e.g. cDNA change, RefSeq number)

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5506ae088ed88f5f363d9c3bc77d56e0Test
https://doi.org/10.1158/2159-8290.22530882.v1Test

المؤلفون: Mitchell P. Levesque, Reinhard Dummer, John B.A.G. Haanen, Nicolas Pasqual, Pia Kvistborg, Marieke I.G. Raaijmakers, Thi Dan Linh Nguyen-Kim, Jean-François Mouret, Nadia Plantier, Solène Perez, Manuarii Manuel, Simone M. Goldinger, Nicoletta F. Jaberg-Bentele, Phil F. Cheng, Anaïs Courtier, Sabrina A. Hogan

الوصف: Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4; however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE50, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment peripheral blood mononuclear cells from melanoma patients treated with anti-CTLA4 (n = 42) or anti-PD1 (n = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA). A receiver operating characteristic curve determined the optimal threshold for a dichotomized analysis according to objective responses as defined by RECIST1.1. Correlations between treatment outcome, clinical variables, and DE50 were assessed in multivariate regression models and confirmed with Fisher exact tests. In samples obtained prior to treatment initiation, we showed that low DE50 values were predictive of a longer progression-free survival and good responses to PD-1 blockade, but, on the other hand, predicted a poor response to CTLA4 inhibition. Multivariate logistic regression models identified DE50 as the only independent predictive factor for response to anti-CTLA4 therapy (P = 0.03) and anti-PD1 therapy (P = 0.001). Fisher exact tests confirmed the association of low DE50 with response in the anti-CTLA4 (P = 0.041) and the anti-PD1 cohort (P = 0.0016). Thus, the evaluation of basal TCR repertoire diversity in peripheral blood, using a PCR-based method, could help predict responses to anti-PD1 and anti-CTLA4 therapies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1af8cde818efcf21e10b8eaa589b0b65Test
https://doi.org/10.1158/2326-6066.c.6548021.v1Test

المؤلفون: Adil Daud, Robert H. Pierce, Edward B. Garon, Simone M. Goldinger, Jimmy Hwang, David Elashoff, Tristan R. Grogan, Reinhard Dummer, Bartosz Chmielowski, Alain P. Algazi, Pamela N. Munster, Emma J. Taylor, Peter D. Boasberg, I. Peter Shintaku, Jeremy Chang, Dan L. Nguyen-Kim, Juan C. Osorio, Nooriel Banayan, Phillip J. Sanchez, Eduardo V. Sosa, Andrew Tucker, Matthew F. Krummel, Adi Nosrati, Neharika Khurana, Nathan Handley, Janis M. Taube, Christina L. Harview, Michael Rosenblum, Matthew A. Gubens, Kimberly L. Loo, Katy K. Tsai, Omid Hamid, Matthew D. Hellmann, Paul C. Tumeh

الوصف: Quantitative CD8+ Counts in patients with Liver and skin metastases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::10d270a153ae4819fa9fb036210de719Test
https://doi.org/10.1158/2326-6066.22538122.v1Test

المؤلفون: Adil Daud, Robert H. Pierce, Edward B. Garon, Simone M. Goldinger, Jimmy Hwang, David Elashoff, Tristan R. Grogan, Reinhard Dummer, Bartosz Chmielowski, Alain P. Algazi, Pamela N. Munster, Emma J. Taylor, Peter D. Boasberg, I. Peter Shintaku, Jeremy Chang, Dan L. Nguyen-Kim, Juan C. Osorio, Nooriel Banayan, Phillip J. Sanchez, Eduardo V. Sosa, Andrew Tucker, Matthew F. Krummel, Adi Nosrati, Neharika Khurana, Nathan Handley, Janis M. Taube, Christina L. Harview, Michael Rosenblum, Matthew A. Gubens, Kimberly L. Loo, Katy K. Tsai, Omid Hamid, Matthew D. Hellmann, Paul C. Tumeh

الوصف: Univariate Analysis of Pretreatment prognostic factors in the Discovery cohort.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::39f93cf6b3d79e117aee064e87840310Test
https://doi.org/10.1158/2326-6066.22538125Test

المؤلفون: Mitchell P. Levesque, Reinhard Dummer, John B.A.G. Haanen, Nicolas Pasqual, Pia Kvistborg, Marieke I.G. Raaijmakers, Thi Dan Linh Nguyen-Kim, Jean-François Mouret, Nadia Plantier, Solène Perez, Manuarii Manuel, Simone M. Goldinger, Nicoletta F. Jaberg-Bentele, Phil F. Cheng, Anaïs Courtier, Sabrina A. Hogan

الوصف: Lymphocyte to leukocyte ratio in high and low ANC/ALC groups for anti-PD1 treated patients at baseline. (Wilcoxon test)

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4002c25ca42799ef82fdb010fd1eb11aTest
https://doi.org/10.1158/2326-6066.22536029Test

المؤلفون: Dirk Schadendorf, Levi A. Garraway, Gad Getz, Scott L. Carter, Stacey B. Gabriel, Jessica C. Hassel, Benjamin Weide, Carmen Loquai, Uwe Trefzer, Carola Berking, Friederike Egberts, Helen J. Gogas, Selma Ugurel, Simone M. Goldinger, Ralf Gutzmer, Uwe Hillen, Lisa Zimmer, Deborah Farlow, Kristian Cibulskis, Aaron McKenna, Mara Rosenberg, Eran Hodis, Gregory V. Kryukov, Steven Whittaker, Amaro Taylor-Weiner, Chelsea S. Place, Eva M. Goetz, Cory M. Johannessen, Daniel J. Treacy, Antje Sucker, Nikhil Wagle, Eliezer M. Van Allen

الوصف: PDF file 73K, This file contains legends for the five supplementary tables

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::78b6cf1ac8c8319d26e53969c1823a5aTest
https://doi.org/10.1158/2159-8290.22530894.v1Test

المؤلفون: Alexandra Valeska Matter, Simone M. Goldinger, Sara Micaletto, Ursula Urner-Bloch, Reinhard Dummer

المساهمون: University of Zurich, Dummer, Reinhard

المصدر: The Oncologist

مصطلحات موضوعية: Male, Proto-Oncogene Proteins B-raf, 0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, MAPK/ERK pathway, Cancer Research, Skin Neoplasms, medicine.medical_treatment, 610 Medicine & health, Drug resistance, GTP Phosphohydrolases, Targeted therapy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, Cell Line, Tumor, Humans, Medicine, 1306 Cancer Research, Melanoma, Protein Kinase Inhibitors, Aged, business.industry, Kinase, 10177 Dermatology Clinic, Membrane Proteins, Binimetinib, medicine.disease, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Mutation, Cancer research, 2730 Oncology, Precision Medicine Clinic: Molecular Tumor Board, Benzimidazoles, Female, business

الوصف: Melanoma can be classified based on the detection of relevant oncogenic driver mutations. These mutations partially determine a patient's treatment options. MEK inhibitors have demonstrated little efficacy in patients with NRAS‐mutated melanoma owing to primary and secondary resistance. We report two patients with NRAS‐mutant metastatic melanoma with long‐term response to intermittent MEK‐inhibitor binimetinib therapy. Intermittent dosing schedules could play a key role in preventing resistance to targeted therapy. This article highlights the efficacy of an intermittent dosing schedule, toxicities associated with binimetinib, and possible mechanisms preventing resistance in targeted therapy. Intermittent MEK‐inhibitor therapy may be considered in patients with NRAS‐mutated melanoma that have failed all standard therapies. Key Points Melanomas harbor NRAS mutations in 10%–30% of the cases. These mutations promote hyperactivation of the MAPK pathway, leading to proliferation and prolonged survival of tumor cells.Currently, drugs directly targeting NRAS are not available. Downstream inhibition of the MAPK pathway can be considered as a therapeutic option after immunotherapeutic failure.Intermittent administration of kinase inhibitors might be the way to partially overcome the development of drug resistance by (a) inducing a fitness deficit for drug‐resistant cells on treatment break, (b) increasing the immunogenicity, and (c) inducing apoptosis and cell cycle arrest. It also enhances expression of numerous immunomodulating molecules, and reduction of immunosuppressive factors, which suggests better access of the immune system to the tumor.
Case reports for two patients with NRAS‐mutant metastatic melanoma are presented, highlighting toxicities associated with binimetinib, as well as the efficacy of an intermittent dosing schedule and possible mechanisms preventing resistance in targeted therapy.

وصف الملف: 855_Matter_A._et_al._Long-Term_response_to_intermittent_binimetinib_in_patients_with_NRAS-mutant_Melanoma_the_Oncologist_2020.pdf - application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::145601bc949f4b0f83188d4b388aa2acTest
https://doi.org/10.1634/theoncologist.2019-0656Test