Melanoma BRAF Inhibitors Review
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Molecular ‘safety-net’ stops tumour cell DNA being torn apart

Molecular ‘safety-net’ stops tumour cell DNA being torn apart | Melanoma BRAF Inhibitors Review | Scoop.it
Seat belts, emergency exits and upright tray tables – you’re probably familiar with the roll call of safety checks that accompany a plane journey.
Krishan Maggon 's insight:
Brownlow, N., et al. (2014). Mitotic catenation is monitored and resolved by a PKCε-regulated pathway Nature Communications, 5 DOI: 10.1038/ncomms6685

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Cancer cell image courtesy of Dr Nicola Brownlow and Professor Peter Parker from the Cancer Research UK London Research Institute

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Melanoma BRAF Inhibitors Review
Zelboraf (vemurafenib, Roche) and Tafinlar (dabrafenib, GSK) get FDA and EMA approval for advanced metastatic melanoma. Several follow up BRAF inhibitors are in clinical development by rival pharma  companies  (Novartis, BMS, J&J, Teva) to get a share of expanding melanoma market and improve complete response rates and overcome resistance. Nexavar (sorafenib, Bayer) for for liver (HCC) and renal (RCC) cancer was the first approved and marketed BRAF inhibitor.
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Vemurafenib (PLX 4032, Roche) Melanoma: FDA Review & Approval - un knol de Krishan Maggon

Vemurafenib (PLX 4032, Roche) Melanoma: FDA Review & Approval - un knol de Krishan Maggon | Melanoma BRAF Inhibitors Review | Scoop.it
Only a single new investigation drug has produced a 81% response rate and extended overall survival by 7 months (range 2-18...
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EMA Refuses a Change to the Marketing Authorisations for Nivolumab and Ipilimumab | ESMO

EMA Refuses a Change to the Marketing Authorisations for Nivolumab and Ipilimumab | ESMO | Melanoma BRAF Inhibitors Review | Scoop.it
Intended change concerned both medicines in combination for first-line treatment of advanced renal cell carcinoma...
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Paolo Antonio Ascierto, MD - Society for Immunotherapy of Cancer (SITC)

Paolo Antonio Ascierto, MD - Society for Immunotherapy of Cancer (SITC) | Melanoma BRAF Inhibitors Review | Scoop.it
Biography Dr. Paolo A. Ascierto is Director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy at the National Tumor Institute Fondazione G. Pascale in Naples (Italy). He earned his medical degree from the University of Naples where he earned board certification in oncology. Before the present position at the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy of the National Tumor Institute, he previously served there as a postdoctoral fellow and then vice-director of the Department of Clinical Immunology. Major research interests have included genetics and proteomics research of melanoma, assessment of new molecular markers for tumor progression in patients with malignant melanoma, targeted therapies for melanoma, biochemical and immunological monitoring, immunotherapy and vaccination treatments. He has served as principal investigator in numerous clinical trials and has been well-published in peer-reviewed journals on topics related to his interests. Dr. Ascierto serves on the editorial boards of the Journal of Translational Medicine, the Journal of Immunotherapy of Cancer (JITC), Combination Products in Therapy, the Journal of Skin Cancer and the Dataset Papers in Immunology. He is the Editor in Chief of the Combination Strategies section of the Journal of Translational Medicine. He has been an invited speaker at more than 350 national and international meetings and maintains active memberships in several medical societies in Italy and abroad. Platform Questions WHAT ARE THE TWO OR THREE CRITICAL ISSUES FACING THE FIELD OF CANCER IMMUNOTHERAPY? Clinical evidence emerging from the treatment of patients with cancer applying new immunotherapeutic agents clearly indicates the need to identify biomarkers predictive of clinical effectiveness that could help in patients selection. Moreover, the plurality of immunotherapeutic modalities targeting immune stimulating, as well as, the immune suppressive mechanisms opens the way to extensive testing of combinatorial approaches. Finally, deeper understanding of patients and their cancer biology, together with refined understanding of the mechanism of action of therapeutics, will be the basis for the personalized immunotherapy. WHAT IS YOUR VISION FOR SITC? As Medical Oncologist involved in translational research I would like to create a permanent bridge between clinicians and basic researchers in order to increase the knowledge in the field of immunotherapy. I feel that the Society for the Immunotherapy of Cancer (SITC) is the paramount venue to exert this goal particularly because it represents a hub for interactions among the leaders in the field at the global level and provides a platform for networking and the development of high profile, large research and clinical collaborations.
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Inflammatory colitis after treatment of melanoma with talimogene laherparepvec (T-VEC) Gardner J, Hyun T, Steinbach G, Thompson J - J Immunother Precis Oncol

Inflammatory colitis after treatment of melanoma with talimogene laherparepvec (T-VEC) Gardner J, Hyun T, Steinbach G, Thompson J - J Immunother Precis Oncol | Melanoma BRAF Inhibitors Review | Scoop.it
Abstract  

Talimogene laherparepvec (T-VEC) is an intralesional oncolytic viral therapy for the treatment of recurrent, unresectable cutaneous, subcutaneous, and nodal melanoma. It is thought to work through direct tumor oncolysis and by eliciting a tumor-specific systemic immune response. Immune-related adverse events have been reported only rarely with this therapy. We report a case of culture-negative, biopsy-proven colitis following pathologic complete response of recurrent, and intransit cutaneous melanoma to T-VEC. To the best of our knowledge, this is the first report of immune-related colitis following T-VEC.

Keywords: Colitis, immune-related adverse event, immunotherapy, melanoma, talimogene laherparepvec
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Reputed Oncogene May Act as a Tumor Suppressor

Reputed Oncogene May Act as a Tumor Suppressor | Melanoma BRAF Inhibitors Review | Scoop.it
Tumor suppressor activity attributed to the PLK1 gene, which has long been considered an oncogene because of its high expression in many tumors.
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Selumetinib-based therapy in uveal melanoma (UM) patient-derived xenografts (PDXs)

Selumetinib-based therapy in uveal melanoma (UM) patient-derived xenografts (PDXs) | Melanoma BRAF Inhibitors Review | Scoop.it
Selumetinib-based therapy in uveal melanoma (UM) patient-derived xenografts (PDXs)   Currently, there are no viable therapeutic options for the majority of metastatic uveal melanoma patients. Uveal melanoma is characterized by mutations in GNAQ or GNA11 - alterations in proteins normally present in cells that lead to tumour growth. Therapies that target proteins associated with GNAQ and GNA11 (their “downstream effectors”), aiming to inactivate tumour proliferation, are being evaluated. One of these targeted therapies (treatments that block a specific molecule in a pathway) is selumetinib, responsible for blocking a molecule that increases in quantity after disease-causing changes in GNAQ and GNA11 occur. Due to the potential side-effects of this types of treatment, preclinical studies – where drugs are tested in animals and cell culture – are crucial for establishing the safety of new therapies. Patient-Derived Xenografts are models where human cancer cells are transferred to animals whose genetic profiles (types of mutations) are known. They allow for continuous monitoring of the growth of cancer and to test specific therapies in a known full organism.       In this study, two chemotherapy agents (dacarbazine and docetaxel), and three different targeted therapy agents (selumetinib, AZ6197 and AZD2014) were used in PDX models. Differently from targeted therapy, chemotherapy works by being toxic to cancer cells, stopping their division. Additional studies were performed with both selumetinib and dacarbazine directly on UM cells in a laboratory dish. The authors found consistent results with those from the SUMIT trial, confirming the low efficacity of a combination of selumetinib with dacarbazine.  New therapeutic approaches are, therefore, required to achieve significant improvements in outcome in patients with metastatic disease. Some synergy between selumetinib and darcabazine´s combination had been observed in UM cell lines in the laboratory dish. Unfortunately, when using the same combination in a whole organism, the PDX model, the efficacy of combination therapy vs single agent therapy was not improved. In summary, the preclinical study showed that selumetinib only had weak efficacy in vivo (in an animal model) when used alone, with an overall response rate of 18% and no tumor shrinkage or complete remission. In vivo efficacy of several selumetinib-based combinations is required to improve the clinical benefit of its effects in the cell. As stated before, in the in vitro (laboratory dish) preclinical assays, the authors have observed a trend towards a synergistic activity between selumetinib and darcabazine in uveal melanoma cell lines; in contrast, these results did not translate to the in vivo experiments using UM. This comes to show that drug efficacity may vary upon the used model to test it and ultimately can differ from its final clinical use.   “Given the small number of UM PDXs treated, it was not possible to demonstrate a correlation between response and the genetic background of the models. Thus, all the preclinical and clinical results suggest that, despite the presence of GNAQ or GNA11 mutations, targeting MEK activity is not sufficient for the effective treatment of metastatic UM. New combination strategies are required and should be evaluated.”   To this end, new selumetinib-based combinations were tested in UM PDXs: selumetinib + docetaxel, selumetinib + AZ6197, and selumetinib + AZD2014. The investigators used a group of PDX mice under monotherapy (with only one of the drugs that were also used in combination regimens) to assess if using the drugs in combination therapy is useful or not. Encouraging results were observed with docetaxel, AZ6197 and AZD2014 in monotherapy. Additionally, combination treatments resulted in an even slight increase in the overall response rate with selumetinib + docetaxel and specially using selumetinib + AZ6197 or selumetinib + AZD2014. In conclusion, approaches that block multiples points of the UM disease pathway in cells, related to changes in GNAQ or GNA11, are promising for the treatment of metastatic UM. You can access the full paper here.
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Cancer cell membrane-coated magnetic nanoparticles for MR/NIR fluorescence dual-modal imaging and photodynamic therapy - Biomaterials Science (RSC Publishing)

Cancer cell membrane-coated magnetic nanoparticles for MR/NIR fluorescence dual-modal imaging and photodynamic therapy - Biomaterials Science (RSC Publishing) | Melanoma BRAF Inhibitors Review | Scoop.it
Theranostic nanoprobes integrated with dual-modal imaging and therapeutic functions, such as photodynamic therapy (PDT), have exhibited significant potency in cancer treatments due to their high imaging accuracy and non-invasive advantages for cancer elimination.
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Reporting of immune checkpoint inhibitor-associated myocarditis

Reporting of immune checkpoint inhibitor-associated myocarditis | Melanoma BRAF Inhibitors Review | Scoop.it
CORRESPONDENCE| VOLUME 392, ISSUE 10145, P382-383, AUGUST 04, 2018 Reporting of immune checkpoint inhibitor-associated myocarditis DOI:https://doi.org/10.1016/S0140-6736(18)31542-3 Linked Article We read with interest the Correspondence by Javid J Moslehi and colleagues (March 10, p 933),1 in which they reported an increase in reporting incidence of myocarditis associated with immune checkpoint inhibitors in WHO's VigiBase database and shed insight on patient outcomes. We used the US Food and Drug Administration (FDA) Adverse Events Reporting System2 (a program designed to track post-marketing drug safety) to find all reported cases of myocarditis between 2012 and 2017 that were associated with immune checkpoint inhibitors that are ap-proved in the USA (ie, ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab). We then used the χ2 test to compare the proportion of myocarditis of all immune checkpoint inhibitor-associated adverse events by year, and myocarditis-related mortality by year, patient characteristics, and treatment drug. We identified 250 cases of myocarditis, of which 124 (50%) resulted in death. The number of cases of myocarditis increased from 18 in 2012–15, to 70 in 2016, and 162 in 2017 (figure). The proportion of cases of myocarditis to all reported adverse events associated with immune checkpoint inhibitors also increased over time, from 0·12% in 2012–15, to 0·76% in 2017 (p<0·0001). Of the 250 cases, we found no difference in mortality by age group (<65 years 33 [47%] of 70 vs ≥65 years 67 [52%]of 128; p=0·55), sex (men 73 [53%] of 137 vs women 36 [43%] of 84; p=0·17), year (eight [44%] of 18 in 2012–15 vs 37 [53%] of 70 in 2016 vs 79 [49%] of 162 in 2017; p=0·77), or treatment regimen (anti-programmed cell death protein-1/programmed cell death ligand-1 90 [48%] of 188 vs anti-cytotoxic T-lymphocyte protein-4 34 [55%] of 62; p=0·38). Using the FDA database, we found a similar mortality risk of 50% in the USA as that found by Moslehi and colleagues in the global WHO database. However, we found a larger number of reported cases of immune checkpoint inhibitor-associated myocarditis in the USA than in the population surveyed in the WHO database. Our analysis was restricted by a paucity of details on concomitant therapies and patient comorbidities. Further studies are needed to identify mechanisms and predictors of myocarditis associated with immune checkpoint inhibitors. We declare no competing interests. References Moslehi, JJSalem, J-ESosman, JALebrun-Vignes, BJohnson, DB Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018; 391: 933 US Food and Drug Administration FDA adverse event reporting system (FAERS) public dashboard. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillance/adversedrugeffects/ucm070093.htm Date accessed: July 12, 2018 Article Info Publication History Published: 04 August 2018 IDENTIFICATION DOI: 10.1016/S0140-6736(18)31542-3 Copyright © 2018 Elsevier Ltd. All rights reserved. ScienceDirect Access this article on ScienceDirect
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Adjuvant Nivolumab Gains European Approval for Melanoma

Adjuvant Nivolumab Gains European Approval for Melanoma | Melanoma BRAF Inhibitors Review | Scoop.it
Adjuvant nivolumab has been approved by the European Commission as a treatment for adult patients with&nbsp;completely resected melanoma with lymph node involvement or metastatic disease, regardless of <em>BRAF</em> mutation status,&nbsp;based on findings from the randomized phase III...
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Neddylation Blockade Diminishes Hepatic Metastasis by Dampening Cancer Stem-Like Cells and Angiogenesis in Uveal Melanoma

Neddylation Blockade Diminishes Hepatic Metastasis by Dampening Cancer Stem-Like Cells and Angiogenesis in Uveal Melanoma | Melanoma BRAF Inhibitors Review | Scoop.it
Purpose: Liver metastasis is the major and direct cause of death in patients with uveal melanoma (UM). There is no effective therapy for patients with metastatic UM. Improved treatments of hepatic metastatic patients with UM were urgently needed.
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Regulation of the adaptation to ER stress by KLF4 facilitates melanoma cell metastasis via upregulating NUCB2 expression | Journal of Experimental & Clinical Cancer Research | Full Text

Regulation of the adaptation to ER stress by KLF4 facilitates melanoma cell metastasis via upregulating NUCB2 expression | Journal of Experimental & Clinical Cancer Research | Full Text | Melanoma BRAF Inhibitors Review | Scoop.it
Adaptation to ER stress has been indicated to play an important role in resistance to therapy in human melanoma. However, the relationship between adaptation to ER stress and cell metastasis in human melanoma remains unclear. The relationship of adaptation to ER stress and cell metastasis was investigated using transwell and mouse metastasis assays. The potential molecular mechanism of KLF4 in regulating the adaptation to ER stress and cell metastasis was investigated using RNA sequencing analysis, q-RT-PCR and western blot assays. The transcriptional regulation of nucleobindin 2 (NUCB2) by KLF4 was identified using bioinformatic analysis, luciferase assay, and chromatin immunoprecipitation (ChIP). The clinical significance of KLF4 and NUCB2 was based on human tissue microarray (TMA) analysis. Here, we demonstrated that KLF4 was induced by ER stress in melanoma cells, and increased KLF4 inhibited cell apoptosis and promoted cell metastasis. Further mechanistic studies revealed that KLF4 directly bound to the promoter of NUCB2, facilitating its transcription. Additionally, an increase in KLF4 promoted melanoma ER stress resistance, tumour growth and cell metastasis by regulating NCUB2 expression in vitro and in vivo. Elevated KLF4 was found in human melanoma tissues, which was associated with NUCB2 expression. Our data revealed that the promotion of ER stress resistance via the KLF4-NUCB2 axis is essential for melanoma cell metastasis, and KLF4 may be a promising specific target for melanoma therapy.
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Vaccines | Improved Induction of Anti-Melanoma T Cells by Adenovirus-5/3 Fiber Modification to Target Human DCs

Vaccines | Improved Induction of Anti-Melanoma T Cells by Adenovirus-5/3 Fiber Modification to Target Human DCs | Melanoma BRAF Inhibitors Review | Scoop.it
Abstract
To mount a strong anti-tumor immune response, non T cell inflamed (cold) tumors may require combination treatment encompassing vaccine strategies preceding checkpoint inhibition. In vivo targeted delivery of tumor-associated antigens (TAA) to dendritic cells (DCs), relying on the natural functions of primary DCs in situ, represents an attractive vaccination strategy. In this study we made use of a full-length MART-1 expressing C/B-chimeric adenoviral vector, consisting of the Ad5 capsid and the Ad3 knob (Ad5/3), which we previously showed to selectively transduce DCs in human skin and lymph nodes. Our data demonstrate that chimeric Ad5/3 vectors encoding TAA, and able to target human DCs in situ, can be used to efficiently induce expansion of functional tumor-specific CD8+ effector T cells, either from a naïve T cell pool or from previously primed T cells residing in the melanoma-draining sentinel lymph nodes (SLN). These data support the use of Ad3-knob containing viruses as vaccine vehicles for in vivo delivery. “Off-the-shelf” DC-targeted Ad vaccines encoding TAA could clearly benefit future immunotherapeutic approaches. View Full-Text
Keywords: melanoma; adenovirus (Ad)5/3; dendritic cell targeting; melanoma-specific T cells; MART-1; sentinel lymph node
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Patient-derived organoids: Are PDOs the new PDX?

Patient-derived organoids: Are PDOs the new PDX? | Melanoma BRAF Inhibitors Review | Scoop.it
Patient-derived organoids in pancreatic cancer maintain genotypic, transcriptomic, and potentially phenotypic responses to chemotherapy of the primary tumor.
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HTG EdgeSeq EGFR, KRAS, and BRAF Mutation Assay

HTG EdgeSeq EGFR, KRAS, and BRAF Mutation Assay | Melanoma BRAF Inhibitors Review | Scoop.it
The HTG EdgeSeq EGFR, KRAS, and BRAF Mutation Assay is a research use only (RUO) service offering available exclusively from our VERI/O Laboratory Services.
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Researchers artificially generate immune cells integral to creating cancer vaccines

Researchers artificially generate immune cells integral to creating cancer vaccines | Melanoma BRAF Inhibitors Review | Scoop.it
For the first time, Mount Sinai researchers have identified a way to make large numbers of immune cells that can help prevent cancer reoccurrence, according to a study published in August in Cell Reports.
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Researchers create specialized delivery methods to help treat cancer, other disorders

Researchers create specialized delivery methods to help treat cancer, other disorders | Melanoma BRAF Inhibitors Review | Scoop.it
More than 100 years ago, German Nobel laureate Paul Ehrlich popularized the "magic bullet" concept—a method that clinicians might one day use to target invading microbes without harming other parts of the body.
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New study views cancer treatment as a game to find strategies that improve patient outcomes

New study views cancer treatment as a game to find strategies that improve patient outcomes | Melanoma BRAF Inhibitors Review | Scoop.it
Game theory can be utilized to identify potential flaws in current cancer treatment approaches and suggest new strategies to improve outcomes in patients with metastatic cancer, according to a new article published online ...
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Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response

Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response | Melanoma BRAF Inhibitors Review | Scoop.it
Melanoma cells release programmed death-ligand 1 (PD-L1) on the surface of circulating exosomes, suggesting a mechanism by which tumours could evade the immunesystem, and the&nbsp;potential application of exosomal PD-L1 to monitor patient response to checkpoint therapies.
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Tessa Therapeutics Immunotherapy Science

Tessa Therapeutics Immunotherapy Science | Melanoma BRAF Inhibitors Review | Scoop.it
A comprehensive approach to cancer immunotherapy. Successful cancer immunotherapy treatments mimic core aspects of the body's anti-viral immune response.
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Immunoregulatory protein B7-H3 regulates cancer stem cell enrichment and drug resistance through MVP-mediated MEK activation

Immunoregulatory protein B7-H3 regulates cancer stem cell enrichment and drug resistance through MVP-mediated MEK activation | Melanoma BRAF Inhibitors Review | Scoop.it
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Human papillomavirus infection mediates response and outcome of vulvar squamous cell carcinomas treated with radiation therapy

Human papillomavirus infection mediates response and outcome of vulvar squamous cell carcinomas treated with radiation therapy | Melanoma BRAF Inhibitors Review | Scoop.it
Human papillomavirus (HPV) is implicated as a causative factor in vulvar squamous
cell carcinoma (VSCC). This study evaluates if p16-positivity, a surrogate for HPV,
predicts for better response rates to chemoradiation therapy and survival.
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Melanoma Field Continues to Shift With Targeted Therapy, Immunotherapy Approvals

Melanoma Field Continues to Shift With Targeted Therapy, Immunotherapy Approvals | Melanoma BRAF Inhibitors Review | Scoop.it
Joseph Stilwill, MD, addresses recent advances in melanoma and the focus of research moving forward.
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Novartis combination Tafinlar® + Mekinist® receives positive CHMP opinion for adjuvant treatment of BRAF V600 mutation-positive melanoma

Novartis combination Tafinlar® + Mekinist® receives positive CHMP opinion for adjuvant treatment of BRAF V600 mutation-positive melanoma | Melanoma BRAF Inhibitors Review | Scoop.it

Novartis today announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) for the adjuvant treatment of adult patients with stage III melanoma with a BRAF V600 mutation, following complete resection. The CHMP recommendation is based on findings from the COMBI-AD study, which was published in The New England Journal of Medicine (NEJM).      

 

 

  • Phase III trial showed a 53% reduction in risk of recurrence or death with the combination of a BRAF and MEK inhibitor as adjuvant therapy versus placebo[1]
     
  • Relapse-free survival benefit with Tafinlar + Mekinist combination was observed across all patient subgroups, including stage III A, B and C
     
  • If approved, expected to be the first targeted combination therapy in the EU for adjuvant treatment of melanoma
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Characterizing parathyroid carcinomas and atypical neoplasms based on the expression of programmed death-ligand 1 expression and the presence of tumor-infiltrating lymphocytes and macrophages

Characterizing parathyroid carcinomas and atypical neoplasms based on the expression of programmed death-ligand 1 expression and the presence of tumor-infiltrating lymphocytes and macrophages | Melanoma BRAF Inhibitors Review | Scoop.it
Four distinct tumor microenvironments have been proposed based on the expression of programmed death-ligand 1 and the presence of tumor-infiltrating lymphocytes: immunotype I (adaptive resistance, tumor-infiltrating lymphocytes+ and programmed death-ligand 1+); immunotype II (immunologic...
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Challenging PD-L1 expressing cytotoxic T cells as a predictor for response to immunotherapy in melanoma

Challenging PD-L1 expressing cytotoxic T cells as a predictor for response to immunotherapy in melanoma | Melanoma BRAF Inhibitors Review | Scoop.it
We would like to report our observation that PD-L1 expressing cytotoxic T cells are associated with an altered immune climate and a negative impact on disease outcome in melanoma patients independent of treatment. It therefore meets the criteria of a prognostic biomarker2. Whether this biomarker is also predictive for response to immunotherapy—meaning that the effect of immunotherapy is different in biomarker positive and negative patients—cannot be deduced from the retrospective single-arm (only treated patients) data in the study by Jacquelot et al. In fact this would require at least a two-arm design preferably in a randomized study, and known PD-L1+ cytotoxic T levels in all patients. The only way to permit solid conclusions on its predictive value would be to demonstrate that the treatment-by-biomarker interaction is statistically significant, meaning that the levels of PD-L1 cytotoxic T cells are not only associated with worse disease outcome (prognostic), but are also associated with different response reactions to immunotherapy (predictive).
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Histidine metabolism boosts cancer therapy

Histidine metabolism boosts cancer therapy | Melanoma BRAF Inhibitors Review | Scoop.it
Clinical use of the anticancer drug methotrexate can be limited by its high toxicity. It emerges that a diet rich in the amino acid histidine increases the effectiveness of methotrexate treatment and lowers toxicity in mice.
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