CRISPRi-based radiation modifier screen identifies long non-coding RNA therapeutic targets in glioma.

BackgroundLong non-coding RNAs (lncRNAs) exhibit highly cell type-specific expression and function, making this class of transcript attractive for targeted cancer therapy. However, the vast majority of lncRNAs have not been tested as potential therapeutic targets, particularly in the context of currently used cancer treatments. Malignant glioma is rapidly fatal, and ionizing radiation is part of the current standard-of-care used to slow tumor growth in both adult and pediatric patients.ResultsWe use CRISPR interference (CRISPRi) to screen 5689 lncRNA loci in human glioblastoma (GBM) cells, identifying 467 hits that modify cell growth in the presence of clinically relevant doses of fractionated radiation. Thirty-three of these lncRNA hits sensitize cells to radiation, and based on their expression in adult and pediatric gliomas, nine of these hits are prioritized as lncRNA Glioma Radiation Sensitizers (lncGRS). Knockdown of lncGRS-1, a primate-conserved, nuclear-enriched lncRNA, inhibits the growth and proliferation of primary adult and pediatric glioma cells, but not the viability of normal brain cells. Using human brain organoids comprised of mature neural cell types as a three-dimensional tissue substrate to model the invasive growth of glioma, we find that antisense oligonucleotides targeting lncGRS-1 selectively decrease tumor growth and sensitize glioma cells to radiation therapy.ConclusionsThese studies identify lncGRS-1 as a glioma-specific therapeutic target and establish a generalizable approach to rapidly identify novel therapeutic targets in the vast non-coding genome to enhance radiation therapy

Seizure outcomes in nonresective epilepsy surgery: an update.

In approximately 30 % of patients with epilepsy, seizures are refractory to medical therapy, leading to significant morbidity and increased mortality. Substantial evidence has demonstrated the benefit of surgical resection in patients with drug-resistant focal epilepsy, and in the present journal, we recently reviewed seizure outcomes in resective epilepsy surgery. However, not all patients are candidates for or amenable to open surgical resection for epilepsy. Fortunately, several nonresective surgical options are now available at various epilepsy centers, including novel therapies which have been pioneered in recent years. Ablative procedures such as stereotactic laser ablation and stereotactic radiosurgery offer minimally invasive alternatives to open surgery with relatively favorable seizure outcomes, particularly in patients with mesial temporal lobe epilepsy. For certain individuals who are not candidates for ablation or resection, palliative neuromodulation procedures such as vagus nerve stimulation, deep brain stimulation, or responsive neurostimulation may result in a significant decrease in seizure frequency and improved quality of life. Finally, disconnection procedures such as multiple subpial transections and corpus callosotomy continue to play a role in select patients with an eloquent epileptogenic zone or intractable atonic seizures, respectively. Overall, open surgical resection remains the gold standard treatment for drug-resistant epilepsy, although it is significantly underutilized. While nonresective epilepsy procedures have not replaced the need for resection, there is hope that these additional surgical options will increase the number of patients who receive treatment for this devastating disorder-particularly individuals who are not candidates for or who have failed resection

The Superior Cerebellar Artery Aneurysm: A Posterior Circulation Aneurysm with Favorable Microsurgical Outcomes

BACKGROUND: Superior cerebellar artery (SCA) aneurysms are usually grouped with aneurysms that arise from the upper basilar artery or more broadly, the posterior circulation. However, the SCA aneurysm has distinctive anatomy that facilitates safe surgical management, notably few associated perforating arteries, and excellent exposure in the carotid-oculomotor triangle. OBJECTIVE: To demonstrate the outcomes of patients treated with microsurgery in a continuous surgical series. METHODS: Sixty-two patients harboring 63 SCA aneurysms were retrospectively reviewed from a prospectively maintained database, focusing on clinical characteristics, surgical techniques, and clinical outcomes. RESULTS: Of 31 patients (49%) presenting with subarachnoid hemorrhage, the SCA aneurysm was the source in 16 (25%). Thirty-three aneurysms were complex (52%) and 43 patients (59%) had multiple aneurysms. Fifty-seven SCA aneurysms (90.5%) were clipped and 5 were bypassed/trapped or wrapped. Complete angiographic occlusion was achieved in 91.7%. Permanent neurological morbidity occurred in 3 patients and 3 patients that presented in coma after subarachnoid hemorrhage died. All patients with simple aneurysms and without subarachnoid hemorrhage had improved or unchanged modified Rankin scale scores. Overall, outcomes were stable or improved in 82.5% of patients. CONCLUSION: SCA aneurysms are favorable for microsurgical clipping with low rates of permanent morbidity and mortality. Microsurgery should be considered alongside endovascular techniques as a treatment option in many patients

Neurosurgical Management of a Thoracic Dorsal Arachnoid Web: Case Illustration

Dorsal thoracic arachnoid webs are rare clinical entities caused by a thickened intradural extramedullary band of arachnoid tissue that compresses the spinal cord, and often present with progressive back pain, paresthesias, and lower extremity weakness. In this report, we review the radiographic features of the "Scalpel Sign" and describe the case of a 47-year-old male that failed conservative therapy and was found to have dorsal thoracic arachnoid web. The patient underwent laminectomy and microsurgical release of the compressing arachnoid band. Postoperatively, the patient had complete resolution of his pain. Intraoperatively, the somatosensory evoked potentials were improved once the band was released. The prompt diagnosis of dorsal arachnoid webs remains critical because surgical treatment arrests and potentially reverses the pathology

The Current State of Rural Neurosurgical Practice: An International Perspective

Introduction: Rural and low-resource areas have diminished capacity to care for neurosurgical patients due to lack of infrastructure, healthcare investment, and training programs. This review summarizes the range of rural neurosurgical procedures, novel mechanisms for delivering care, rapid training programs, and outcome differences across international rural neurosurgical practice. Methods: A comprehensive literature search was performed for English language manuscripts with keywords “rural” and “neurosurgery” using the National Library of Medicine PubMed database (01/1971–06/2017). Twenty-four articles focusing on rural non-neurosurgical practice were included. Results: Time to care and/or surgery and shortage of trained personnel remain the strongest risk factors for mortality and poor outcome. Telemedicine consults to regional centers with neurosurgery housestaff have potential for increased timeliness of diagnosis/triage, improved time to surgery, and reductions in unnecessary transfers in remote areas. Mobile neurosurgery teams have been deployed with success in nations with large transport distances precluding initial transfers. Common neurosurgical procedures involve trauma mechanisms; accordingly, training programs for nonneurosurgery medical personnel on basic assessment and operative techniques have been successful in resource-deficient settings where neurosurgeons are unavailable. Conclusions: Protracted transport times, lack of resources/training, and difficulty retaining specialists are barriers to successful outcomes. Advances in telemedicine, mobile neurosurgery, and training programs for urgent operative techniques have been implemented efficaciously. Development of guidelines for paired partnerships between rural centers and academic hospitals, supplying surplus technology to rural areas, and rapid training of qualified local surgical personnel can create sustainable feed-forward programs for trainees and infrastructural solutions to address challenges in rural neurosurgery

Bilateral External Ventricular Drain Placement and Intraventricular Irrigation Combined with Concomitant Serial Prone Patient Positioning: A Novel Treatment for Gravity-Dependent Layering in Bacterial Ventriculitis.

A feared complication of ventricular access for drainage or shunting is ventriculitis. Early diagnosis and treatment is vital to prevent morbidity and mortality. Efficacy of directed antibiotic therapy in ventriculitis is limited by increasing multidrug resistant microorganisms and insufficient systemic antibiotic absorption into the cerebrospinal fluid. Treatment may involve intravenous and/or intrathecal antibiotics as well as external ventricular drainage. We present the first case report suggesting a potential role of a novel technique - direct ventricular catheter-mediated continuous saline irrigation and serial prone patient positioning - to treat a fulminant bacterial ventriculitis. This novel technique promotes egress of purulence from the ventricles and may result in more rapid control of intraventricular infectious burden

Metastatic clival chordoma: a case report of multiple extraneural metastases following resection and proton beam radiotherapy in a 5-year old boy.

The authors report the case of a 5-year-old boy in whom extraneural metastases developed 5 years after he underwent an occipitocervical fusion and transoral approach to treat a clival chordoma without local recurrence. Following primary resection, the patient's postoperative course was complicated by recurrent meningitis secondary to CSF leak, which responded to antibiotics, and communicating hydrocephalus, for which a ventriculoperitoneal shunt was placed. The patient then underwent postoperative proton beam radiotherapy. Five years following his initial presentation, surveillance imaging revealed a new asymptomatic lung mass for which the patient underwent thoracotomy and resection of the mass. Histological examination of the lung mass revealed findings consistent with a de-differentiated chordoma, confirming extraneural metastasis from the original tumor without evidence of local recurrence. Chest wall and scalp metastases subsequently developed, and the patient was started on an adjuvant chemotherapy regimen that included imatinib and rapamycin followed by subsequent nivolumab and an EZH2 inhibitor for recurrent, disseminated disease. Despite this patient's remote and distant metastases, primary gross-total resection for chordoma remains a critical treatment objective, followed by proton beam radiotherapy. This case illustrates the importance of interval posttreatment imaging and the emerging potential to treat chordoma with molecularly targeted therapies

Stability of Programmable Shunt Valve Settings with Simultaneous Use of the Optune Transducer Array: A Case Report.

The Optune® transducer array (Novocure Ltd., Haifa, Israel) is an FDA-approved noninvasive regional therapy that aims to inhibit the growth of glioblastoma multiforme (GBM) cells via utilization of alternating electric fields. Some patients with GBM may develop hydrocephalus and benefit from subsequent shunt placement, but special attention must be paid to patients in whom programmable valves are utilized, given the potential effect of the magnetic fields on valve settings. We present the first case report illustrating the stability of programmable shunt valve settings in a neurosurgical patient undergoing therapy with the Optune device. In this study, shunt valve settings were stable over a period of five days despite Optune therapy. This is reassuring for patients with GBM who require simultaneous treatment with both the Optune device and a programmable shunt system

Stability of Programmable Shunt Valve Settings with Simultaneous Use of the Optune Transducer Array: A Case Report.

The Optune® transducer array (Novocure Ltd., Haifa, Israel) is an FDA-approved noninvasive regional therapy that aims to inhibit the growth of glioblastoma multiforme (GBM) cells via utilization of alternating electric fields. Some patients with GBM may develop hydrocephalus and benefit from subsequent shunt placement, but special attention must be paid to patients in whom programmable valves are utilized, given the potential effect of the magnetic fields on valve settings. We present the first case report illustrating the stability of programmable shunt valve settings in a neurosurgical patient undergoing therapy with the Optune device. In this study, shunt valve settings were stable over a period of five days despite Optune therapy. This is reassuring for patients with GBM who require simultaneous treatment with both the Optune device and a programmable shunt system