Paramita Das

Occurrence and Prognostic Significance of Cervical Pseudodissection Phenomenon Associated with Acute Intracranial Internal Carotid Artery Occlusion

Acute stroke from intracranial internal carotid artery (ICA) occlusion can occasionally resemble angiographic cervical ICA dissection which may cause delays in endovascular acute ischemic stroke treatment.

Treating Pediatric Brain Tumors by Inhibiting the RAS-ERK Signaling Pathway: A Review.

Many pediatric brain tumors fail standard therapies for a variety of reasons. There is a need for novel targeted therapeutics in treating these tumors. The RAS-RAF-MEK-ERK signaling pathway transmits signals from cell surface receptors leading to cell proliferation and survival. Components of this pathway are often mutated in different cancers. Several activating RAF mutations have been identified as critical drivers of a variety of malignancies including many pediatric brain tumors, specifically BRAF V600E, which is mutated in many melanomas, and specific pediatric brain tumors. Knowledge regarding mutated portions of the ERK signaling pathway has prompted the development of small-molecule inhibitors that target components of this pathway. Most inhibitors have been developed and approved for use in treating metastatic melanoma and some are now being tested in pediatric patients with brain tumors, particularly those harboring the BRAF V600E mutations, with encouraging results. Unfortunately, clinical responses to inhibitors of RAF, MEK and combinations are temporary, with resistance to BRAF inhibitors seen in most patients, on average between 6 and 9 months after initiation of therapy. The combination of RAF and MEK inhibitors may show improved efficacy. Better understanding of the properties of the small-molecule inhibitors, as well as mechanisms of resistance will be essential in further improvement of these agents in treating children with tumors dependent on ERK signaling.

Improving Outcomes With Subspecialization and Regionalization

Abstract Hospital and surgeon performance is being more closely scrutinized due to rising costs, increasing patient expectations, demands for greater transparency, and concerns over quality, efficiency, and safety. As neurosurgeons, we can directly improve the quality metrics being examined and also the safety and quality of care delivered. Neurosurgery has moved toward expertise and experience of both surgeons and care teams, and evidence exists that both can improve quality of care and patient satisfaction. Many studies suggest that high-volume surgeons and medical centers deliver higher quality care for patients and procedures. Experience is recognized as a key driver of individual surgical performance, giving rise to a learning curve. Since there are fewer training hours available, methods are being developed to accelerate the neurosurgical learning curve via such things as simulation training. Provider volume has been shown to have an impact on postoperative mortality, complications, and costs in neurosurgery particularly for craniotomy, transsphenoidal surgery, ventriculoperitoneal shunt operations, and carotid endarterectomy. At the hospital level, increased case volume is even more strongly associated with improved outcomes. Lastly, there is evidence that patients are more satisfied and have a favorable hospital care experience if they believe they are being cared for in a center of excellence by providers and hospitals with extensive training and experience in their particular problem area. Thus, the best available evidence would suggest that quality and safety of neurosurgical care can be improved when surgeons and hospitals focus and outcomes are improved when care is delivered by experienced high-volume providers and care teams.

Intrathoracic meningocele associated with neurofibromatosis Type 1 and a novel technique for surgical repair: case report

Neurofibromatosis Type 1 (NF1) is a neurocutaneous disorder that can have associated spinal abnormalities related to both bone and dural dysplasia. Thoracic meningoceles are one spine anomaly associated with NF1, although they are a fairly uncommon pathology. Surgical techniques to treat these meningoceles, usually undertaken only when the patient is symptomatic, are targeted at decreasing the size of the protrusion and improving lung capacity. Surgical interventions discussed in the literature include shunting the pseudomeningocele, primary repair with laminectomy, thoracoscopic plication, and reinforcement of the closure with cement, muscle, or fascia. Authors here report the case of a 43-year-old woman with NF1 with worsening pulmonary function tests and in whom shunting of the pseudomeningocele failed. Subsequently, a posterolateral thoracotomy was performed. The dura mater was reconstructed and primarily closed. On this closure a Gore-Tex soft-tissue patch was placed along with polypropylene mesh and Evicel fibrin sealant, followed by titanium mesh. At the end of the procedure, a chest tube was left in place and therapeutic pneumoperitoneum was performed to decrease the dead space as the lung did not fully expand with positive-pressure ventilation. The patients pulmonary function tests improved after the procedure. Thoracic meningoceles are uncommon and difficult pathologies to treat surgically. Although shunting is arguably the least invasive surgical option, it can fail in some patients. When it does fail, there are other options that require a multidisciplinary approach and careful attention to the dural closure and reinforcing layers.

Abstract 1121: Validation of FOXR2 and ARHGAP36 as oncogenes in medulloblastoma

We are working to validate two putative oncogenes in medulloblastoma (MB), ARHGAP36 and FOXR2. These genes were identified as MB drivers using a Sleeping Beauty mutagenesis screen in mice and are overexpressed in subsets of human MB. We are using gain (GOF) and loss of function (LOF) studies both in vitro and in vivo to understand the roles of FOXR2 and ARHGAP36 in MB genesis. In GOF studies, both genes individually drove anchorage independent growth in a mouse cerebellar progenitor cell line (C17.2) and a human MB cell line (ONS76). When overexpressed individually in C17.2 cells, both FOXR2 and ARHGAP36 drove tumor formation in the flank of NU/J mice. We are also using an orthotopic injection model with C17.2 cells overexpressing either ARHGAP36 or FOXR2 individually to determine if these genes drive tumor formation in a more relevant setting. RNA sequencing and reverse-phase protein array analyses were also performed on WT and C17 cells overexpressing each oncogene to identify their effects in an unbiased manner. We are working to validate those effects using RT-PCR and Western analysis. In LOF studies, the CRISPR/Cas system is being used to create mutations in either the ARHGAP36 or FOXR2 locus in human MB cell lines (ONS76, MED8A, Daoy). This has been accomplished with ARHGAP36 in ONS76 cells, and we are currently characterizing those cells using proliferation, soft agar colony formation, and tumor formation assays. Lastly, we are working to create GOF and LOF mouse models of both FOXR2 and ARHGAP36 to characterize their oncogenic potential in vivo. We identified ARHGAP36 and FOXR2 as putative oncogenes in MB and our findings may elucidate novel targets for therapeutic efforts aimed at treating patients with MB. Citation Format: Pauline Jackson, Alex Larsson, Paramita Das, David Largaespada. Validation of FOXR2 and ARHGAP36 as oncogenes in medulloblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1121.

Where are we with Targeted Therapies for Medulloblastoma

Medulloblastoma, the most common pediatric brain cancer, is no longer thought of as a single disease. It is now known to be is a heterogeneous tumor with four distinct molecular subgroups [1] which include wingless (WNT), sonic hedgehog (SHH), group 3 (V-myc avian myelocytomatosis viral oncogene homolog [MYC] amplified), and group 4. Histological characteristics, patient demographics, copy number aberrations, and prognosis differ between the groups. Current risk stratification, based solely on clinical features, defines high risk disease as tumors with dissemination, residual disease greater than 1.5 cm2, and age less than 3 years with the remainder being termed average risk. Five year overall survival rates with high risk medulloblastoma are up to 65%and can be greater than 80% in patients in those with average risk disease [2] using current standard-of-care multimodal therapy that includes surgery, craniospinal radiation and chemotherapy. Those with recurrent/relapsed disease do not have effective salvage treatment options and the prognosis for these patients is poor [3,4].