Key Points• Treatment with vemurafenib induced a dramatic response in 3 patients with histiocytosis harboring BRAF V600E mutations.• Tumor response was observed in both Erdheim-Chester disease and Langerhans cell histiocytosis. IntroductionErdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by the infiltration of tissues by foamy CD68 ϩ CD1a Ϫ histiocytes. 1 It is a systemic disease with diverse manifestations: the clinical course mainly depends on the extent and distribution of the disease, and ranges from asymptomatic bone lesions to life-threatening manifestations. 2 Rare cases of ECD associated with Langerhans cell histiocytosis (LCH) have been reported. 3 Unlike ECD, LCH histiocytes are CD1a ϩ and frequently infiltrate the epidermis in skin lesions. 4 Interferon ␣ (IFN) is generally the first choice for ECD therapy and improves survival. It should be prescribed at high dose if there is central nervous system and/or cardiovascular involvement. 2 However, long-term IFN treatment can lead to severe side effects and some patients are refractory to treatment. Moreover some patients with CNS and/or cardiovascular infiltrations develop secondary resistance to high-dose of IFN. Alternative treatments include recombinant human interleukin-1 receptor antagonist, cladribine, thyrosine kinase inhibitors, autologous hematopoietic stem cell transplantation. 2 However, the optimal second line therapeutic strategy remains to be defined, mostly because these treatments have been evaluated in only small numbers of patients. Despite recent therapeutic progress the overall mortality remains high (18% of the 84 ECD patients seen at our institution). BRAF V600E mutations have been observed in 38% to 69% of cases of LCH. [5][6][7] We recently reported BRAF V600E mutations in 54% of 24 patients with ECD. 8 Vemurafenib, an inhibitor of mutant BRAF, has shown some efficacy against 2 diseases (melanoma and hairy-cell leukemia) associated with the BRAF V600E mutation. 9,10

Vemurafenib has an objective and sustained efficacy in BRAF(V600E)-mutated ECD as second-line therapy. In contrast to melanoma, no resistance has emerged to date after 6 to 16 months.

Lesions of the brain, meninges, facial bones, and orbits are frequently observed and should be systematically sought on the brain MR and CT images obtained in patients with ECD, even if these patients are asymptomatic. Careful attention should be directed to the periarterial environment.

OBJECTIVE The main limitation to the efficacy of chemotherapy for brain tumors is the restricted access to the brain because of the limited permeability of the blood-brain barrier (BBB). Previous animal studies have shown that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue. Although many previous studies have been performed with external focused US transducers, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness. This method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring. The purpose of the present study was to determine if the BBB can be safely and repeatedly disrupted using such an implantable unfocused US device in a primate model. METHODS An 11.5-mm-diameter, 1-MHz, planar US device was implanted via a bur hole into the skull of 3 primates (2 Papio anubis [olive] baboons and 1 Macaca fascicularis [macaque]) for 4 months. Pulsed US sonications were applied together with the simultaneous intravenous injection of sulfur hexafluoride microbubbles (SonoVue) every 2 weeks to temporarily disrupt the BBB. In each primate, a total of 7 sonications were performed with a 23.2-msec burst length (25,000 cycles) and a 1-Hz pulse repetition frequency at acoustic pressure levels of 0.6-0.8 MPa. Potential toxicity induced by repeated BBB opening was analyzed using MRI, PET, electroencephalography (EEG), somatosensory evoked potential (SSEP) monitoring, behavioral scales, and histopathological analysis. RESULTS The T1-weighted contrast-enhanced MR images acquired after each sonication exhibited a zone of hypersignal underneath the transducer that persisted for more than 4 hours, indicating a broad region of BBB opening in the acoustic field of the implant. Positron emission tomography images with fluorine-18-labeled fluorodeoxyglucose (FDG) did not indicate any changes in the cerebral metabolism of glucose. Neither epileptic signs nor pathological central nerve conduction was observed on EEG and SSEP recordings, respectively. Behavior in all animals remained normal. Histological analysis showed no hemorrhagic processes, no petechia, and extravasation of only a few erythrocytes. CONCLUSIONS The studies performed confirm that an implantable, 1-MHz US device can be used to repeatedly open the BBB broadly in a large-animal model without inducing any acute, subacute, or chronic lesions.