Treatment options for oncological diseases have been enhanced by the advent of targeted therapies. The point mutation of the BRAF gene at codon 600 (BRAF V600E) is found in several tumor entities and can be approached with selective inhibitory antibodies. The BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases and in other cancer diseases. Therefore the BRAF V600E mutation is a highly interesting oncological target in brain tumors. This study assesses the BRAF V600E mutation status in 969 intracranial neoplasms using a tissue microarray method and immunohistochemical staining with the mutation-specific VE-1 antibody, followed by sequencing of positively stained cases. Out of 784 primary brain tumors seven cases with a BRAF V600E mutation were detected (7/784, 1 %). Six of these cases were neuroepithelial tumors (6/667, 1 %) encompassing 2 astrocytomas WHO grade II (2/42, 5 %), 1 gliosarcoma WHO grade IV (1/75, 1 %) and 3 glioblastomas WHO grade IV (3/312, 1 %). Interestingly, all three mutant glioblastomas showed epithelioid histopathological features. Patients with V600E mutated astrocytic tumors were significantly younger (mean age 15.3 years) than wildtype cases (58.2 years). Among three rhabdoid meningiomas, one case was mutated (1/3) while all other grade I-III meningiomas (1/116, 1 %) and all fifty vestibular schwannomas analyzed were of wildtype status. The vast majority of the BRAF V600E mutations were found in cerebral metastases of malignant melanomas and carcinomas (29/135, 22 %), with false-positive staining found in four breast cancer cases and two non-small-cell lung carcinoma (NSCLC) samples. Our data suggest routine screening for BRAF V600E mutations for glioblastomas WHO grade IV below the age of 30, especially in glioblastomas with epithelioid features and in all rhabdoid meningiomas WHO grade III. For colorectal carcinoma, thyroid cancer, malignant melanoma and gliomas BRAF V600E immunostaining is sufficient for screening purposes. We also recommend routine immunohistochemical staining followed by sequencing validation in rare CNS metastases or metastases of unknown primary. Immunohistochemical analysis using mutation-specific antibodies on tissue microarrays is a feasible, time- and cost-efficient approach to high-throughput screening for specific mutations in large tumor series but sequencing validation is necessary in unexpected cases.

Kv10.1, a voltage-gated potassium channel only detected in the healthy brain, was found to be aberrantly expressed in extracerebral cancers. Investigations of Kv10.1 in brain metastasis and glioblastoma multiforme (GBM) are lacking. We analyzed the expression of Kv10.1 by immunohistochemistry in these brain tumors (75 metastasis from different primary tumors, 71 GBM patients) and the influence of a therapy with tricyclic antidepressants (which are Kv10.1 blockers) on survival. We also investigated Kv10.1 expression in the corresponding primary carcinomas of metastases patients. We observed positive Kv10.1 expression in 85.3 % of the brain metastases and in 77.5 % of GBMs. Patients with brain metastases, showing low Kv10.1 expression, had a significantly longer overall survival compared to those patients with high Kv10.1 expression. Metastases patients displaying low Kv10.1 expression and also receiving tricyclic antidepressants showed a significantly longer median overall survival as compared to untreated patients. Our data show that Kv10.1 is not only highly expressed in malignant tumors outside CNS, but also in the most frequent cerebral cancer entities, metastasis and GBM, which remain incurable in spite of aggressive multimodal therapies. Our results extend the correlation between dismal prognosis and Kv10.1 expression to patients with brain metastases or GBMs and, moreover, they strongly suggest a role of tricyclic antidepressants for personalized therapy of brain malignancies.

In occlusive hydrocephalus, cysts and some ventricular tumours, neuroendoscopy has replaced shunt operations and microsurgery. There is an ongoing discussion if neuronavigation should routinely accompany neuroendoscopy or if its use should be limited to selected cases. In this prospective clinical series, the role of neuronavigation during intracranial endoscopic procedures was investigated. In 126 consecutive endoscopic procedures (endoscopic third ventriculostomy, ETV, n = 65; tumour biopsy/resection, n = 36; non-tumourous cyst fenestration, n = 23; abscess aspiration and hematoma removal, n = 1 each), performed in 121 patients, neuronavigation was made available. After operation and videotape review, the surgeon had to categorize the role of neuronavigation: not beneficial; beneficial, but not essential; essential. Overall, neuronavigation was of value in more than 50% of the operations, but its value depended on the type of the procedure. Neuronavigation was beneficial, but not essential in 16 ETVs (24.6%), 19 tumour biopsies/resections (52.7%) and 14 cyst fenestrations (60.9%). Neuronavigation was essential in 1 ETV (2%), 11 tumour biopsies/resections (30.6%) and 8 cyst fenestrations (34.8%). Neuronavigation was not needed/not used in 48 ETVs (73.9%), 6 endoscopic tumour operations (16.7%) and 1 cyst fenestration (4.3%). For ETV, neuronavigation mostly is not required. In the majority of the remaining endoscopic procedures, however, neuronavigation is at least beneficial. This finding suggests integrating neuronavigation into the operative routine in endoscopic tumour operations and cyst fenestrations.

Hematoma puncture, fibrinolysis, and aspiration of the liquefied clot is a promising new treatment strategy for large intracerebral hemorrhages (ICH). Characteristics of the cellular injury and neuronal and glial cell death associated with ICH and the administration of fibrinolytic agents still need to be defined. We developed a porcine model to study the histopathological effects of recombinant tissue-Plasminogen-Activator (rt-PA) on perihematomatous cell integrity. In 20 pigs, lobar hematomas were induced by intracranial pressure (ICP)-controlled injections of 7.6 +/- 1.6 ml of autologous blood into the white matter of the right frontal hemisphere. In nine animals, the clots were lysed with rt-PA, thereby facilitating aspiration 2 h after hematoma induction. In 11 control pigs, the hematoma resorption followed its natural course. The rate of hematoma reduction and edema formation over 10 days was evaluated on planimetry of the MRI data and correlated to the histopathological changes found at autopsy. Although rt-PA significantly accelerated clot resolution compared to controls (p < 0.02), the increase of perihematomatous edema volume within 10 days was not significantly ameliorated in rt-PA-treated animals compared to controls on MRI. The extent of inflammatory infiltrates on histology was more pronounced in animals treated with rt-PA. In conclusion, despite significant reduction in the size of the hematoma clot liquefication with rt-PA and aspiration invokes a substantial inflammatory response when studied after 10 days and does not result in a reduction of the perihematomatous edema.

Object: The goal of this report was to describe the authors' initial experiences with an adjustable gravity-assisted valve (GAV) called the ProGAV in treating childhood hydrocephalus. Methods: The ProGAV was implanted in 53 children (29 boys and 24 girls, median age 7.3 years) with hydrocephalus of various origins. The ProGAV consists of a differential-pressure unit with adjustable opening pressures and a gravitational unit with a fixed opening pressure. Results: The mean follow-up period was 15.2 months (range 6–44 months). The authors did not observe any valve-related complications. Four infections (7.5%) occurred, warranting the removal of the shunt. In 19 children, the opening pressure was changed at least once during the follow-up period, for underdrainage in 10, overdrainage in 8, and shunt weaning in 1, with substantial clinical improvement in 18 children. Overall, good clinical results were obtained in 47 (88.7%) of the 53 valve placements. Conclusions: With an overall success rate of 88.7%, the first experiences with the ProGAV in childhood hydrocephalus are promising and justify its further use in the pediatric population.

To evaluate if the unruptured intracranial aneurysm treatment score (UIATS) is a sensitive tool to detect aneurysms at risk of rupture, we conducted an a posteriori retrospective study on ruptured intracranial aneurysms. We performed a retrospective analysis of adult patients admitted to our center from January 2010 to April 2016 with aneurysmal subarachnoid hemorrhage. The UIATS was applied to all ruptured aneurysms. Patients for whom the UIATS recommended treatment were labeled as “true positives,” whereas patients for whom the UIATS recommended observation were labeled as “false negatives.” Patients for whom the UIATS was inconclusive were excluded from the final analysis. Based on the UIATS recommendation, a sensitivity analysis was performed. A total of 262 patients with aneurysmal subarachnoid hemorrhage were screened. Of these, 212 were included in our analysis. Median age was 53 years (23–90). Most patients were females (n = 134, 63%), with an equal distribution between low-grade and high-grade hemorrhages (Hunt & Hess ≥ 3 n = 107, 50%). UIATS recommended treatment in n = 52, 25% cases (TP), was inconclusive in n = 93, 44% (excluded), and recommended observation in n = 67, 32% (FN). Based on these data, the UIATS showed a sensitivity of 44% (CI 35–53%). The UIATS exhibits rather low sensitivity for detecting aneurysms at risk of rupture.