ES and NM participated in the design of the study. lung. For this reason, she was enrolled into another clinical trial with the GSK2118436 BRAF inhibitor, dabrafenib, as a second line of therapy. She had a partial response that was maintained until 13 weeks of treatment. In January 2011 she developed symptoms typical for brain metastases and received a diagnosis of leptomeningeal involvement of melanoma cells after an examination of her cerebral spinal fluid; magnetic resonance imaging was negative for meningitis or brain metastases. Analysis of her cerebral spinal fluid sample confirmed that the melanoma cells still carried the V600EBRAF mutation. After a few days, our patient went into a coma and died. Conclusion Starting with a clinical case, we discuss the pathogenesis of leptomeningeal metastases and whether the leptomeninges may represent a sanctuary where melanoma cells may generate resistance and/or BRAF inhibitors cannot reach an adequate concentration for significant activity. We assess whether treatment with BRAF inhibitors in melanoma patients should be interrupted as soon as disease progression appears or continued beyond progression, through the administration of additional compounds. Introduction The incidence of leptomeningeal metastases (LM) in cancer patients has increased, probably due to the achievement of prolonged survival. Both solid tumors (including 6-FAM SE breast, lung and gastrointestinal carcinomas 6-FAM SE as well as melanoma) and hematopoietic tumors (including lymphoma and leukemia) may induce LM formation [1]. The prognosis is poor and less than 10% of patients survive to 12 months [1,2]. The base of the brain and the cauda equina are the most prevalent sites of metastasis. Standard treatment, which includes radiotherapy to symptomatic sites and intrathecal chemotherapy, is mostly ineffective [3]. Recently, two 6-FAM SE important compounds changed the history of treatment for advanced melanoma: the anti- cytotoxic T-lymphocyte antigen 4 (CTLA4) monoclonal antibody 6-FAM SE [4,5] among unselected patients and the BRAF inhibitors (BRAFi) [6] among patients carrying a mutation at the valine 6-FAM SE 600 codon in the gene (V600EBRAF mutation). Although both seem to act on melanoma brain metastases [4,7], the BRAFi (vemurafenib, GSK2118436, dabrafenib) seem to be particularly effective on melanoma brain metastases harboring the V600EBRAF mutation – which represents the most prevalent oncogenic variant in such a gene [7-9]. Moreover, a high concordance for V600EBRAF mutation frequency between primary melanomas and correspondent brain metastases from the same patients has been recently reported by our group [10]. To date, two important studies are focusing on the treatment of melanoma brain metastases with BRAFi [11,12]. Here, we report the clinical case of a woman who developed LM disease during BRAFi treatment and discuss more general considerations about melanoma brain involvement. Case presentation A 39-year-old Italian woman, who received the diagnosis of cutaneous melanoma in 2005, was enrolled into the BRIM3 trial (vemurafenib versus dacarbazine [6]) in August 2010 after disease progression was ascertained with the detection of metastases in both her lung and peritoneum. Despite being positive for the V600EBRAF mutation, she was randomized to receive dacarbazine. After two cycles, disease progression was registered, with the appearance of new peritoneal lesions associated with ascites and lung lesions associated with pleural effusion. Therefore, our patient was enrolled into another clinical trial with GSK2118436 BRAF inhibitor, dabrafenib, as a second line of therapy. After two weeks of treatment, the ascites and pleural effusion disappeared and her visceral lesions also reduced dramatically (Figure ?(Figure1);1); this partial response was maintained over 13 weeks of treatment until the beginning of January 2011 (Figure ?(Figure2),2), when a diagnosis of leptomeningeal involvement of the melanoma cells was inferred by Rabbit Polyclonal to DQX1 a cerebral spinal fluid (CSF) examination – with magnetic resonance imaging negative for meningitis or brain metastases (Figure ?(Figure3).3). Analysis of her CSF sample confirmed.