Breast cancer metastasis to the brain develops after a clinical latency of years to even decades, suggesting that colonization of the brain is the most challenging step of the metastatic cascade. However, the underlying mechanisms used by breast cancer cells to successfully colonize the brain's microenvironment remain elusive. Reelin is an archetypal extracellular glycoprotein that regulates migration, proliferation, and lamination of neurons. It is epigenetically silenced in various cancers, and its expression in multiple myelomas is linked to poor patient survival. We found that Reelin expression was low in primary breast cancer tissue. However, its expression was significantly higher in Her2 breast cancers metastasizing to the brain. In particular, Reelin was highly expressed in the tumor periphery adjacent to surrounding astrocytes. This augmented Reelin expression was seen in Her2 metastases, but not in triple negative (TN) primary tumors or in TN breast to brain metastasis cells co-cultured with astrocytes. Furthermore, the elevated expression was sustained in Her2 cells grown in the presence of the DNA methyltransferase inhibitor 5-azacytidine, indicating epigenetic regulation of Reelin expression. The relative growth and rate of spheroids formation derived from Her2 primary and BBM cells co-cultured with astrocytes were higher than those of TN primary and BBM cells, and knockdown of both Reelin and Her2 suppressed the astrocyte-induced growth and spheroid forming ability of Her2 cells. Collectively, our results indicate that within the neural niche, astrocytes epigenetically regulate Reelin expression and its interaction with Her2 leading to increased proliferation and survival fitness.

Introduction: Surgical simulation is valuable in neurovascular surgery given the progressive rarity of these cases and their technical complexity, but its use has not been well described for pediatric vascular pathologies. We herein review the use of surgical simulation at our institution for complex pediatric aneurysmal malformations. Methods: A retrospective review of patients treated for middle cerebral artery aneurysmal malformations with surgical simulation assistance (SuRgical Planner [SRP]; Surgical Theater, Mayfield Village, OH) during a 2-year period at Rady Children's Hospital of San Diego was performed. Results: In 5 pediatric patients with complex MCA aneurysmal malformations (mean age = 33.2 ± 49.9 months), preoperative 3-dimensional (3D) interactive modeling informed treatment planning and enhanced surgeon understanding of the vascular pathology. Availability of intraoperative simulation also aided real-time anatomical understanding during surgery. Specific benefits of simulation for these cases included characterization of involved perforating vessels, as well as an enhanced understanding of flow patterns within associated complex arteriovenous fistulas and feeding vessel/daughter branch anatomy. Despite the complexity of the lesions treated, use of simulation qualitatively enhanced surgeon confidence. There were no perioperative complications for patients treated with open surgery. Conclusions: Surgical simulation may aid in the treatment of complex pediatric aneurysmal malformations.

Pediatric cerebellopontine angle (CPA) meningiomas are extremely rare and are usually treated with a retrosigmoid surgical approach or radiation. The authors present the use of a middle fossa approach for the treatment of a symptomatic CPA meningioma in a 22-month-old female. The patient initially presented at 17 months with isolated progressive, long-standing right-sided facial weakness. MRI demonstrated a 5.0 × 5.0–mm right CPA lesion just superior to the cisternal segment of cranial nerve (CN) VII, which demonstrated growth on interval imaging. At 22 months of age she underwent a successful middle fossa craniotomy, including wide exposure of the porus acusticus, allowing for a gross-total resection with preservation of CNs VII and VIII. Pathological analysis revealed a WHO grade I meningioma. The patient remained neurologically stable on follow-up. The middle fossa approach can be used to safely access the CPA in properly selected pediatric patients.

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