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Journal of Clinical Oncology
2011 Background: Melanoma is a growing clinical health concern where the incidence has doubled over the last 30 years. A major driver of melanoma associated deaths is the development of brain metastases (MBM). It is estimated that 40-60% of patients with metastatic melanoma will develop MBM. Current treatment strategies have a great local control rate, but do not prevent recurrent disease, with a distant intracranial failure rate of 50% at 1 year. Novel treatments and an improved understanding of the MBM tumor microenvironment are needed. Toll-like receptor signaling is activated in cutaneous melanoma, triggering innate inflammatory activation downstream through the adapter proteins MyD88 and interleukin (IL)-1 receptor-associated kinase (IRAK-1 and -4). Increased expression of IRAK-4 stimulates transcription of multiple cellular kinases and transcription factors, and production of inflammatory chemokines and cytokines. This places IRAK-4 as a central driver of both intrinsic tumori...
2012 •
Toll-like receptors (TLR) are expressed by a variety of cancers, including melanoma, but their functional contributions in cancer cells are uncertain. To approach this question, we evaluated the effects of stimulating or inhibiting the TLR/IL-1 receptor-associated kinases IRAK-1 and IRAK-4 in melanoma cells where their functions are largely unexplored. TLRs and TLR-related proteins were variably expressed in melanoma cell lines, with 42% expressing activated phospho-IRAK-1 constitutively and 85% expressing high levels of phospho-IRAK-4 in the absence of TLR stimulation. Immunohistochemical evaluation of melanoma tumor biopsies (n = 242) revealed two distinct patient populations, one that expressed p-IRAK-4 levels similar to normal skin (55%) and one with significantly higher levels than normal skin (45%). Levels of p-IRAK-4 levels did not correlate with clinical stage, gender, or age, but attenuated IRAK-1,-4 signaling with pharmacologic inhibitors or siRNA-enhanced cell death in vi...
Neuro-Oncology Advances
Targeted therapy strategies for melanoma brain metastasisMelanoma is the most aggressive of the common forms of skin cancer. Metastasis to the central nervous system is one of the most common and deadly complications of this disease. Historically, melanoma patients with brain metastases had a median survival of less than 6 months. However, outcomes of melanoma patients have markedly improved over the last decade due to new therapeutic approaches, including immune and targeted therapies. Targeted therapies leverage the high rate of driver mutations in this disease, which result in the activation of multiple key signaling pathways. The RAS-RAF-MEK-ERK pathway is activated in the majority of cutaneous melanomas, most commonly by point mutations in the Braf serine-threonine kinase. While most early targeted therapy studies excluded melanoma patients with brain metastases, subsequent studies have shown that BRAF inhibitors, now generally given concurrently with MEK inhibitors, achieve high rates of tumor response and disease control in Braf-mu...
Expert Review of Neurotherapeutics
Melanoma brain metastasis: overview of current management and emerging targeted therapies2012 •
International Journal of Molecular Sciences
In Vitro Treatment of Melanoma Brain Metastasis by Simultaneously Targeting the MAPK and PI3K Signaling Pathways2014 •
Clinical Cancer Research
Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases2023 •
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
New Era in the Management of Melanoma Brain Metastases2018 •
The remarkable advances in the systemic therapy of metastatic melanoma have now extended the 1-year overall survival rate from 25% to nearing 85%. Systemic treatment in the form of BRAF-targeted therapy and immunotherapy is slowly but surely proving its efficacy in the treatment of metatstatic brain metastases (MBM). Single-agent BRAF inhibitors provide an intracranial response rate of 25% to 40%, whereas the combination of BRAFi/MEKi leads to responses in up to 58%. However, the durability of responses induced by BRAFi/MEKi seems to be even shorter than in extracranial disease. On the other hand, single-agent ipilimumab provides comparable clinical benefit in MBMs as it does in extracranial metastases. Single-agent PD-1 anitbodies induce response rates of approximately 20%, and those responses appear durable. Similarly the combination of CTLA-4+ PD-1 antibodies induces durable responses at an impressive rate of 55% and is safe to administer. Although the local treatment approaches ...
Journal of Clinical Oncology
Phase II Trial of a Toll-Like Receptor 9-Activating Oligonucleotide in Patients With Metastatic Melanoma2006 •
Purpose The recent identification of toll-like receptors (TLRs) and respective ligands allows the evaluation of novel dendritic cell (DC) –activating strategies. Stimulation of TLR9 directly activates human plasmacytoid DCs (PDCs) and indirectly induces potent innate immune responses in preclinical tumor models. We performed an open-label, multicenter, single-arm, phase II pilot trial with a TLR9-stimulating oligodeoxynucleotide in melanoma patients. Patients and Methods Patients with unresectable stage IIIb/c or stage IV melanoma received 6 mg PF-3512676 weekly by subcutaneous injection for 24 weeks or until disease progression to evaluate safety as well as clinical and immunologic activity. Clinical and laboratory safety assessments were performed weekly; blood samples for immunological measurements were taken every 8 weeks. Tumor measurements were performed according to Response Evaluation Criteria in Solid Tumors. Results Twenty patients received PF-3512676 for a mean of 10.9 we...
2016 •
Oncology & Hematology Review (US)
Time for a New Paradigm in the Treatment of Metastatic MelanomaMetastatic melanoma is a very common disease with an increasing incidence worldwide and is notoriously difficult to treat. The long-established treatments including dacarbazine and interleukin-2 have shown limited response rates and are associated with significant toxicities. More recently, treatments have been developed that decrease inhibition of T-cell action against melanomas. Among these, ipilimumab was recently approved for use in metastatic melanoma and has shown improved overall survival (OS) and progression-free survival rates (PFS). Another such treatment currently in development is the monoclonal antibody, anti-PD-1. This blocks PD-1 inhibition of T-cells and has shown promising response rates in early clinical trials. Another treatment approach is to use targeted therapies in patients with mutations in BRAF or CKIT signaling pathways and it is vital that the mutational status of these genes be determined in patients with metastatic melanoma to best determine effective th...
Journal of the American Academy of Religion
Healing burns with fire: The facilitations of experience in Tibetan Buddhism1999 •
Mahalle, oda, komşu, misafir?
Mahalle, oda, komşu, misafir? Oda Projesi, 2005.2005 •
BÁO CÁO KHOA HỌC VỀ NGHIÊN CỨU VÀ GIẢNG DẠY SINH HỌC Ở VIỆT NAM - PROCEEDING OF THE 4TH NATIONAL SCIENTIFIC CONFERENCE ON BIOLOGICAL RESEARCH AND TEACHING IN VIETNAM
Vận Dụng Chu Trình Dạy Học Trải Nghiệm Tổ Chức Dạy Học Dự Án Cho Sinh Viên Ngành Sư Phạm Sinh Học2020 •
XI Coloquio Internacional Educação e Conteiporaneadade
A Utilização Das Tdic No Desenvolvimento Da Aprendizagem Infantil Na Escola: Apontamentos Iniciais e Exploratórios Sobre O Uso Das Tdic Por Crianças2018 •
2020 •
European Heart Journal - Cardiovascular Imaging
P361 Assessment of accuracy and reproducibility of coronary flow reserve measured by SPECT in patients with known or suspected coronary artery disease2020 •
American Journal of Clinical Pathology
Myometrial Inflammation in Human Delivery and Its Association With Labor and Infection2003 •
DOAJ (DOAJ: Directory of Open Access Journals)
A criação do curso superior em Administração na UFRGS em 1963: Uma análise histórica2018 •
Comunicação e Cidadania. Actas do 5º …
Responsabilidade Social E Inovação Tecnológica No Mundo Automóvelpresente E Futuro2008 •