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Pamela S. Jones, Daniel P. Cahill, Priscilla K. Brastianos, Keith T. Flaherty and William T. Curry

BRAF and is effective against tumors with the BRAF V600E mutation, which is present in up to 60% of melanoma cases. After demonstration of improved progression-free and overall survival in these patients, FDA approval was granted in 2011. 7 Immune checkpoint blockade is being increasingly validated as therapy for some patients with advanced melanoma. Ipilimumab is a monoclonal antibody that binds cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), a negatively regulatory co-stimulatory molecule that is expressed highly on activated T lymphocytes. Blockade of

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Or Cohen-Inbar, Han-Hsun Shih, Zhiyuan Xu, David Schlesinger and Jason P. Sheehan

combination of surgical excision, systemic therapy, and stereotactic radiosurgery (SRS) to attain local control of brain metastases. The categorization of the CNS as an immune-privileged site has for a time dampened the hopes for development of immunotherapies for brain tumors. 6 , 41 FDA approval of cytokine-based therapy with interleukin-2 in 1998 and checkpoint blockade with ipilimumab in 2011 were major developments in melanoma treatment. 22 , 33 Checkpoint blockade–based therapy demonstrates an improved tumor control and reduced toxicity compared with cytokine

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Kevin Diao, Shelly X. Bian, David M. Routman, Cheng Yu, Paul E. Kim, Naveed A. Wagle, Michael K. Wong, Gabriel Zada and Eric L. Chang

S tereotactic radiosurgery (SRS), which delivers highly conformal radiation in a single fraction, has been increasingly used for the treatment of brain metastases. SRS has better local control rates and fewer neurocognitive side effects compared with whole-brain radiation therapy (WBRT). 1 , 2 Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), is an immune-modulating agent that was demonstrated to improve overall survival in metastatic melanoma patients during 2 Phase III randomized controlled trials. 7 , 19 In these

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Jonathan P. S. Knisely, James B. Yu, Jaclyn Flanigan, Mario Sznol, Harriet M. Kluger and Veronica L. S. Chiang

Recently, 2 large randomized studies showed that ipilimumab, a fully human antibody that binds to CTLA-4, improves survival in patients with unresectable Stage III and Stage IV melanoma. 5 , 9 One was the first randomized clinical trial to demonstrate an overall survival benefit for any systemic therapy in patients with metastatic melanoma. Survival was improved from 6.4 to ≥ 10 months for patients (p ≤ 0.003) in the 2 arms that were treated with ipilimumab. A significant proportion (22.0%) of those who received ipilimumab survived more than 2 years, as compared with 13

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Rupesh Kotecha, Jacob A. Miller, Vyshak A. Venur, Alireza M. Mohammadi, Samuel T. Chao, John H. Suh, Gene H. Barnett, Erin S. Murphy, Pauline Funchain, Jennifer S. Yu, Michael A. Vogelbaum, Lilyana Angelov and Manmeet S. Ahluwalia

P atients with metastatic melanoma have the highest predisposition for developing brain metastasis, and autopsy studies have demonstrated brain metastases in up to 55%–75% of patients with metastatic melanoma. 28 Melanoma is associated with a number of somatic mutations and aberrations, the most common of which is the BRAF mutation. 22 The BRAF inhibitors (BRAFi), including vemurafenib and dabrafenib, and immune-based therapies, including ipilimumab, have demonstrated intracranial efficacy and improved survival in Phase II studies in patients with active

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Paul Porensky and E. Antonio Chiocca

Neurosurgery adds an intriguing chapter to immune-modulating therapy in the setting of Stage IV melanoma with brain metastases. 4 The authors undertook a retrospective chart review for disease modifiers in 77 patients who had undergone SRS between 2002 and 2010. Twenty-seven patients who also received ipilimumab immunotherapy were identified, and both overall and 2-year median survivals were compared with survival in 50 patients in the unmatched control group. The SRS with ipilimumab group yielded an overall median survival of 21.3 months compared with 4.9 months in

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Xiao Zhu, Michael M. McDowell, William C. Newman, Gary E. Mason, Stephanie Greene and Mandeep S. Tamber

temozolomide failed to improve outcomes in children. 4 , 6 , 10 , 13 Researchers hypothesize that this failure may be due to tumor over-expression of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase. 4 , 6 , 10 Immunotherapy with ICIs, such as those targeting programmed cell death protein 1 (PD1), like nivolumab and pembrolizumab, or cytotoxic T-lymphocyte-associated antigen 4, like ipilimumab, hold promise as new therapeutic approaches for managing glioblastoma in pediatric patients. Nivolumab is currently FDA-approved for metastatic melanoma, non

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Daniel W. Fults, Thomas Chen and Jeffrey N. Bruce

surgery for brain metastasis while undergoing treatment with the immune checkpoint blocking agent ipilimumab. Caruso et al. review the literature on treatment approaches to metastatic melanoma, with emphasis on the role of immunotherapy of metastases to the spine. Endovascular technology is being exploited to augment surgery and chemotherapy, while those traditional treatments have continued to be applied in new and unique ways. Shah and coworkers describe preoperative embolization of meningiomas. Wang et al. report on the efficacy of convection-enhanced delivery of

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James P. Caruso, Or Cohen-Inbar, Mark H. Bilsky, Peter C. Gerszten and Jason P. Sheehan

interleukin-2 (IL-2) in 1998 and ipilimumab in 2011 were major breakthroughs in the development of immunotherapy for melanoma. 78 These treatments exemplify 2 important classifications of immunotherapy, cytokine based and checkpoint blockade based. Although checkpoint blockade–based therapy demonstrates improved tumor control and reduced toxicity compared with cytokine-based therapy, clinical trials are still being conducted to evaluate the efficacy of both treatments. Cytokine-based therapy involves administration of recombinant cytokines to potentiate the activity of

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Zhiyuan Xu, Cheng-Chia Lee, Arjun Ramesh, Adam C. Mueller, David Schlesinger, Or Cohen-Inbar, Han-Hsun Shih and Jason P. Sheehan

) have been shown to be effective in treating patients with BRAF mutation–positive cancer cells. 19 However, due to the expected short-term survival after the diagnosis of melanoma intracranial metastases, patients with melanoma BMs were generally excluded from the clinical trial of ipilimumab and BRAF i. 19 , 20 Hence, the impact of BRAF mutation status and adjuvant BRAF i on the local control of BMs treated with SRS in those patients remains elusive. In this study, we aimed to investigate the effectiveness of this combined treatment option for patients with