Neoadjuvant stereotactic radiosurgery for brain metastases: a new paradigm.

OBJECTIVE: For patients with surgically accessible solitary metastases or oligometastatic disease, treatment often involves resection followed by postoperative stereotactic radiosurgery (SRS). This strategy has several potential drawbacks, including irregular target delineation for SRS and potential tumor "seeding" away from the resection cavity during surgery. A neoadjuvant (preoperative) approach to radiation therapy avoids these limitations and offers improved patient convenience. This study assessed the efficacy of neoadjuvant SRS as a new treatment paradigm for patients with brain metastases. METHODS: A retrospective review was performed at a single institution to identify patients who had undergone neoadjuvant SRS (specifically, Gamma Knife radiosurgery) followed by resection of a brain metastasis. Kaplan-Meier survival and log-rank analyses were used to evaluate risks of progression and death. Assessments were made of local recurrence and leptomeningeal spread. Additionally, an analysis of the contemporary literature of postoperative and neoadjuvant SRS for metastatic disease was performed. RESULTS: Twenty-four patients who had undergone neoadjuvant SRS followed by resection of a brain metastasis were identified in the single-institution cohort. The median age was 64 years (range 32-84 years), and the median follow-up time was 16.5 months (range 1 month to 5.7 years). The median radiation dose was 17 Gy prescribed to the 50% isodose. Rates of local disease control were 100% at 6 months, 87.6% at 12 months, and 73.5% at 24 months. In 4 patients who had local treatment failure, salvage therapy included repeat resection, laser interstitial thermal therapy, or repeat SRS. One hundred thirty patients (including the current cohort) were identified in the literature who had been treated with neoadjuvant SRS prior to resection. Overall rates of local control at 1 year after neoadjuvant SRS treatment ranged from 49% to 91%, and rates of leptomeningeal dissemination from 0% to 16%. In comparison, rates of local control 1 year after postoperative SRS ranged from 27% to 91%, with 7% to 28% developing leptomeningeal disease. CONCLUSIONS: Neoadjuvant SRS for the treatment of brain metastases is a novel approach that mitigates the shortcomings of postoperative SRS. While additional prospective studies are needed, the current study of 130 patients including the summary of 106 previously published cases supports the safety and potential efficacy of preoperative SRS with potential for improved outcomes compared with postoperative SRS.

Targeting CD133 improves chemotherapeutic efficacy of recurrent pediatric pilocytic astrocytoma following prolonged chemotherapy.

BACKGROUND: Pilocytic astrocytomas (PAs) are the most common pediatric central nervous system neoplasms. In the majority of cases these tumors are benign and receive favorable prognosis following gross total surgical resection. In patients with progressive or symptomatic tumors, aggressive surgical resection is generally not feasible, thus radiation or chemotherapy are accepted initial or adjuvant interventions. Due to serious long-lasting side-effects, radiation is limited in young children; therefore, chemotherapy is widely practiced as an adjuvant treatment for these patients. However, chemotherapy can promote the emergence of multidrug resistant tumor cells that are more malignant than those of the original tumor. CD133, a putative stem cell marker in normal tissue and malignant brain tumors, enhances multidrug resistant gene 1 (MDR1) expression following chemotherapy in adult malignant glioblastomas. This study examines the relationship between CD133 and MDR1 in pediatric PAs exposed to chemotherapy, with the goal of identifying therapeutic targets that manifest as a result of chemotherapy. METHODS: Slides were obtained for 15 recurrent PAs, seven of which had received chemotherapy prior to surgical treatment for the recurrent tumor. These samples, as well as primary tumor tissue slides from the same patients were used to investigate CD133 and MDR1 expression via immunofluorescence. Archived frozen tissue samples from the same patients were used to examine CD133, MDR1 and PI3K-Akt-NF-κB signaling mediators, via western blot. Two drug resistant pediatric PA cell lines Res186 and Res199 were also used to evaluate the role of CD133 on cell response to cytotoxic therapy. RESULTS: CD133 and MDR1 were co-expressed and their expression was elevated in recurrent PAs from patients that had received chemotherapy, compared to patients that had not received chemotherapy. PI3K-Akt-NF-κB signaling mediator expression was also elevated in recurrent, chemotherapy-treated PA. Suppressing CD133 expression with siCD133 decreased levels of PI3K-Akt-NF-κB signaling mediators and MDR1, while increasing cell chemosensitivity, as indicated by quantification of apoptotic cells following chemotherapy. CONCLUSIONS: CD133 contributes to multidrug resistance by regulating MDR1 levels via the PI3K-Akt-NF-κB signal pathway not only in adult glioblastomas, but also in pediatric PAs. Targeting CD133, adjuvant to conventional chemotherapy may improve outcomes for children with recurrent PA.

Multifocal primary central nervous system Ewing sarcoma presenting with intracranial hemorrhage and leptomeningeal dissemination: illustrative case.

BACKGROUND: Ewing sarcoma is a neoplasm within the family of small round blue cell tumors and most frequently arises from skeletal bone. Primary involvement of the central nervous system in these lesions is extremely rare, with an incidence of 1%. OBSERVATIONS: A case is presented of a 34-year-old man who presented with left facial numbness, multiple intracranial lesions, a lumbar intradural lesion, and diffuse spinal leptomeningeal involvement. A lumbar laminectomy and biopsy were performed, which revealed the diagnosis of extraskeletal Ewing sarcoma/primitive neuroectodermal tumor. The patient had a rapidly progressive clinical decline despite total neuroaxis radiation and multiple lines of chemotherapeutic treatments, eventually dying from his disease and its sequelae 6 months after diagnosis. LESSONS: The authors' review of 40 cases in the literature revealed only 2 patients with isolated intraaxial cranial lesions, 4 patients with cranial and spine involvement, and an additional 34 patients with spine lesions. The unique characteristics of this patient's case, including his presentation with diffuse disease and pathology that included a rare V600E BRAF mutation, are discussed in the context of the available literature.

A Conserved Tyrosine Residue in Slitrk3 Carboxyl-Terminus Is Critical for GABAergic Synapse Development.

Single-passing transmembrane protein, Slitrk3 (Slit and Trk-like family member 3, ST3), is a synaptic cell adhesion molecule highly expressed at inhibitory synapses. Recent studies have shown that ST3, through its extracellular domain, selectively regulates inhibitory synapse development via the trans-synaptic interaction with presynaptic cell adhesion molecule, receptor protein tyrosine phosphatase δ (PTPδ) and the cis-interaction with postsynaptic cell adhesion molecule, Neuroligin 2 (NL2). However, little is known about the physiological function of ST3 intracellular, carboxyl (C)-terminal region. Here we report that in heterologous cells, ST3 C-terminus is not required for ST3 homo-dimerization and trafficking to the cell surface. In contrast, in hippocampal neurons, ST3 C-terminus, more specifically, the conserved tyrosine Y969 (in mice), is critical for GABAergic synapse development. Indeed, overexpression of ST3 Y969A mutant markedly reduced the gephyrin puncta density and GABAergic transmission in hippocampal neurons. In addition, single-cell genetic deletion of ST3 strongly impaired GABAergic transmission. Importantly, wild-type (WT) ST3, but not the ST3 Y969A mutant, could fully rescue GABAergic transmission deficits in neurons lacking endogenous ST3, confirming a critical role of Y969 in the regulation of inhibitory synapses. Taken together, our data identify a single critical residue in ST3 C-terminus that is important for GABAergic synapse development and function.