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OBJECTIVE Current guidelines primarily suggest resection of brain metastases (BMs) in patients with limited lesions. With a growing number of highly effective local and systemic treatment options, this view may be challenged. The purpose of this study was to evaluate the role of metastasectomy, disregarding BM count, in a comprehensive treatment setting. METHODS In this monocentric retrospective analysis, the authors included patients who underwent resection for at least 1 BM and collected demographic, clinical, and tumor-associated parameters. Prognostic factors for local control and overall survival (OS) were analyzed with the log-rank test and Cox proportional hazards analysis. RESULTS The authors analyzed 216 patients. One hundred twenty-nine (59.7%) patients were diagnosed with a single/solitary BM, whereas 64 (29.6%) patients had 2–3 BMs and the remaining 23 (10.6%) had more than 3 BMs. With resection of symptomatic BMs, a significant improvement in Karnofsky Performance Scale (KPS) was achieved (p < 0.001), thereby enabling adjuvant radiotherapy for 199 (92.1%) patients and systemic treatment for 119 (55.1%) patients. During follow-up, 83 (38.4%) patients experienced local recurrence. BM count did not significantly influence local control rates. By the time of analysis, 120 (55.6%) patients had died; the leading cause of death was systemic tumor progression. The mean (range) OS after surgery was 12.7 (0–88) months. In univariate analysis, the BM count did not influence OS (p = 0.844), but age < 65 years (p = 0.007), preoperative and postoperative KPS ≥ 70 (p = 0.002 and p = 0.005, respectively), systemic metastases other than BM (p = 0.004), adjuvant radiation therapy (p < 0.001), and adjuvant systemic treatment (p < 0.001) were prognostic factors. In regression analysis, the presence of extracranial metastases (HR 2.30, 95% CI 1.53–3.48, p < 0.001), adjuvant radiation therapy (HR 0.97, 95% CI 0.23–0.86, p = 0.016), and adjuvant systemic treatment (HR 0.37, 95% CI 0.25–0.55, p < 0.001) remained as independent factors for survival. CONCLUSIONS Surgery for symptomatic BM from non–small cell lung cancer may be indicated even for patients with multiple lesions in order to alleviate their neurological symptoms and to consequently facilitate further treatment.

Background Meningioma is the most common primary brain tumor in adults. In recent years, several non-neurofibromin 2 mutations, i.e., AKT1, SMO, TRAF7, and KLF4 mutations, specific for meningioma have been identified. This study aims to analyze the clinical impact and imaging characteristics of the KLF4K409Q mutation in meningioma. Methods Clinical, neuropathologic, and imaging data of 170 patients who underwent meningioma resection between 2013 and 2018 were retrospectively collected and tumors were analyzed for the presence of the KLF4K409Q mutation. We collected imaging characteristics, performed volumetric analysis of tumor size and peritumoral edema (PTBE), and calculated the edema index (EI, i.e., ratio of PTBE to tumor volume). Receiver operating characteristic curve analysis was performed to identify cut-off EI values to predict the mutational status of KLF4. Results Eighteen (10.6%) of the meningiomas carried the KLF4K409Q mutation; these were significantly associated with a secretory subtype (P Conclusions The KLF4K409Q mutation is associated with a distinct small tumor subtype, prone to substantial PTBE. EI is a reliable parameter to predict the KLF4K409Q mutation in meningioma, thus providing a tool for improvement of pre- and perioperative medical management.

Repetitive TMS (rTMS) with a frequency of 5–10 Hz is widely used for language mapping. However, it may be accompanied by discomfort and is limited in the number and reliability of evoked language errors. We, here, systematically tested the influence of different stimulation frequencies (i.e., 10, 30, and 50 Hz) on tolerability, number, reliability, and cortical distribution of language errors aiming at improved language mapping. 15 right‐handed, healthy subjects (m = 8, median age: 29 yrs) were investigated in two sessions, separated by 2–5 days. In each session, 10, 30, and 50 Hz rTMS were applied over the left hemisphere in a randomized order during a picture naming task. Overall, 30 Hz rTMS evoked significantly more errors (20 ± 12%) compared to 50 Hz (12 ± 8%; p, The use of repetitive transcranial magnetic stimulation (rTMS) for language mapping is still hampered by a limited sensitivity and specificity, by an overall poor reliability and by stimulation‐associated discomfort. We, here, found that increasing the stimulation intensity up to 30 and 50 Hz can improve language mapping results as compared to the most commonly used protocol of 10 Hz rTMS.

Objective Although intracranial aneurysms are increasingly treated endovascularly, microsurgical clipping has been the standard approach for middle cerebral artery (MCA) aneurysms. We compared microsurgical clipping and state-of-the-art endovascular treatment of unruptured MCA bifurcation aneurysms treated at a neurovascular center following a “coil-first” policy. Methods This single-center study included 148 patients treated for 160 unruptured MCA bifurcation aneurysms. Technical success, complications, clinical outcome, and angiographic results were retrospectively compared. Results Microsurgical clipping was performed for 120 MCA aneurysms (75%) and endovascular treatment for 40 (25%; conventional coiling: 8, stent-assisted coiling: 16, balloon-assisted coiling: 3, and flow-disruption: 13). Technical treatment success was higher in the clipping group (100%) than in the endovascular group (92.5%, P = 0.015). Overall, complications occurred in 16.7% for clipping and in 20.0% for endovascular treatment (P = 0.631). Major ischemic stroke rates were 4.2% in the clipping group and 7.5% in the endovascular group (P = 0.414). At 6 months, a favorable outcome was obtained by 99.2% after clipping and 95.0% after endovascular treatment (P = 0.154). The 6-month complete aneurysm occlusion rates were by trend higher in the clipping group (89.2%) than in the endovascular group (75.9%, P = 0.078). Conclusions Microsurgical clipping was associated with a higher technical success rate and tendentially higher complete occlusion than endovascular treatment, with no additional morbidity and similar clinical outcome. On the basis of these results, clipping proves to be the standard treatment option for MCA bifurcation aneurysms. However, endovascular treatment represents a safe and efficient alternative treatment option for patients.

Purpose The introduction of hypofractionated stereotactic radiosurgery (hSRS) extended the treatment modalities beyond the well-established single-fraction stereotactic radiosurgery and fractionated radiotherapy. Here, we report the efficacy and side effects of hSRS using Cyberknife® (CK-hSRS) for the treatment of patients with critical brain metastases (BM) and a very poor prognosis. We discuss our experience in light of current literature. Methods All patients who underwent CK-hSRS over 3 years were retrospectively included. We applied a surface dose of 27 Gy in 3 fractions. Rates of local control (LC), systemic progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan–Meier method. Treatment-related complications were rated using the Common Terminology Criteria for Adverse Events (CTCAE). Results We analyzed 34 patients with 75 BM. 53% of the patients had a large tumor, tumor location was eloquent in 32%, and deep seated in 15%. 36% of tumors were recurrent after previous irradiation. The median Karnofsky Performance Status was 65%. The actuarial rates of LC at 3, 6, and 12 months were 98%, 98%, and 78.6%, respectively. Three, 6, and 12 months PFS was 38%, 32%, and 15%, and OS was 65%, 47%, and 28%, respectively. Median OS was significantly associated with higher KPS, which was the only significant factor for survival. Complications CTCAE grade 1–3 were observed in 12%. Conclusion Our radiation schedule showed a reasonable treatment effectiveness and tolerance. Representing an optimal salvage treatment for critical BM in patients with a very poor prognosis and clinical performance state, CK-hSRS may close the gap between surgery, stereotactic radiosurgery, conventional radiotherapy, and palliative care.

Die Inzidenz, Behandlung und Prognose von Patienten mit Hirnmetastasen haben sich in den letzten Jahrzehnten grundlegend geandert. Wahrend die Uberlebenszeit zerebral metastasierter Patienten noch vor 10 Jahren durchschnittlich 3 bis maximal 6 Monate betrug, konnte diese aufgrund neuer Methoden in der operativen, strahlentherapeutischen und systemischen Behandlung deutlich verlangert werden. Noch vor wenigen Jahren fuhrte das Auftreten von Hirnmetastasen zu einem Ruckzug aus der systemisch-onkologischen Behandlung und dem Ausschluss aus medikamentosen Therapiestudien und zu einer rein palliativ orientierten Behandlung im Sinne einer Ganzhirnbestrahlung (WBRT) mit oder ohne Operation. Die zunehmende Verfugbarkeit zielgerichteter und immunmodulatorischer Medikamente sowie adaptierte radioonkologischer Verfahren erlauben immer mehr individualisierte Therapieansatze. Im Rahmen dieser Ubersichtsarbeit soll der Fortschritt und die Komplexitat der Behandlung von Hirnmetastasen im Kontext moderner fachubergreifender Konzepte dargelegt werden.

Background The importance of the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status as a predictive factor for the response to chemotherapy with temozolomide is well established. Its significance though at stratifying glioblastoma (GBM) patients in regard to their prognostic factors and the impact of surgical approach on them has not been identified. Objective To reveal possible differences in the prognostic factors and the impact of surgery between GBM patients stratified according to their MGMT status. Methods The authors retrospectively analyzed 186 patients with a newly diagnosed primary supratentorial GBM treated with surgical resection followed by standard radiation and chemotherapy. A prospective quantitative volumetric analysis of tumor characteristics identified on magnetic resonance imaging was performed. Results For the 109 patients with unmethylated MGMT promoter, extent of resection (EOR) represented independent predictor of survival, whereas residual tumor volume (RTV), Karnofsky Performance Score, and age were found to be independent prognostic factors of survival for the 77 patients with methylated MGMT promoter. For the group of patients with unmethylated and the group with methylated MGMT promoter, an EOR threshold of 70% and 98% and an RTV threshold of 1.5 and 1 cm3 were identified, respectively. Conclusion The selection of patients according to the MGMT promoter methylation status resulted in different prognostic factors and different resection thresholds for each patient population. A survival benefit seen from 70% EOR threshold in patients with MGMT unmethylated GBM supports the doctrine of maximum safe resection rather than the "all-or-nothing" approach.

BACKGROUND Intrasaccular flow-disruption represents a new paradigm in endovascular treatment of wide-necked bifurcation aneurysms. OBJECTIVE To retrospectively compare Woven Endobridge (WEB) embolization with microsurgical clipping for unruptured anterior circulation aneurysms using propensity score adjustment. METHODS A total of 63 patients treated with WEB and 103 patients treated with clipping were compared based on the intention-to-treat principle. The primary outcome measures were immediate technical treatment success, major adverse events, and 6-mo complete aneurysm occlusion. RESULTS The technical success rates were 83% for WEB and 100% for clipping. Procedure-related complications occurred more often in the clipping group (13%) than the WEB group (6%, adjusted P

Background Percutaneous pedicle screw fixation in obese patients remains a surgical challenge. We aimed to compare patient-reported outcomes and complication rates between obese and nonobese patients who were treated by minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). Methods The authors retrospectively reviewed patients who underwent MIS-TLIF at a single institution between 2011 and 2014. Patients were classified as obese (body mass index [BMI] ≥30 kg/m2) or nonobese (BMI Results The final study group consisted of 71 patients, 24 obese (33.8%, 34.8 ± 3.8 kg/m2) and 47 nonobese (66.2%, 25.4 ± 2.9 kg/m2). Instrumentation failures (13.6 vs. 17.0%), dural tears (17.2 vs. 4.0%), and revision rates (16.7 vs. 19.1%) were similar between both groups (p > 0.05). Perioperative improvements in back pain (4.3 vs. 5.4, p = 0.07), leg pain (3.8 vs. 4.2, p = 0.6), and ODI (13.3 vs. 22.5, p = 0.5) were comparable among the groups and persisted at long-term follow-up. Obese patients had worse postoperative physical component SF-36 scores than nonobese patients (36.4 vs. 42.7, p = 0.03), while the mental component scores were not statistically different (p = 0.09). Conclusion Obese patients can achieve similar improvement of the pain intensity and functional status even at long-term follow-up. In patients with appropriate surgical indications, obesity should not be considered a contraindication for MIS-TLIF surgery.

The CeTeG/NOA-09 trial showed a survival benefit for combined CCNU/TMZ therapy in MGMT-promoter-methylated glioblastoma patients (quantitative methylation-specific PCR [qMSP] ratio > 2). Here, we report on the prognostic value of the MGMT promoter methylation ratio determined by qMSP and evaluate the concordance of MGMT methylation results obtained by qMSP, pyrosequencing (PSQ) or DNA methylation arrays (MGMT-STP27). A potential association of qMSP ratio with survival was analyzed in the CeTeG/NOA-09 trial population (n = 129; log-rank tests, Cox regression analyses). The concordance of MGMT methylation assays (qMSP, PSQ and MGMT-STP27) was evaluated in 76 screened patients. Patients with tumors of qMSP ratio > 4 showed superior survival compared to those with ratios 2-4 (P = .0251, log-rank test). In multivariate analysis, the qMSP ratio was not prognostic across the study cohort (hazard ratio [HR] = 0.88; 95% CI: 0.72-1.08). With different cutoffs for qMSP ratio (4, 9, 12 or 25), the CCNU/TMZ benefit tended to be larger in subgroups with lower ratios (eg, for cutoff 9: HR 0.32 for lower subgroup, 0.73 for higher subgroup). The concordance rates with qMSP were 94.4% (PSQ) and 90.2% (MGMT-STP27). Discordant results were restricted to tumors with qMSP ratios ≤4 and PSQ mean methylation rate ≤25%. Despite a shorter survival in MGMT-promoter-methylated patients with lower methylation according to qMSP, these patients had a benefit from combined CCNU/TMZ therapy, which even tended to be stronger than in patients with higher methylation rates. With acceptable concordance rates, decisions on CCNU/TMZ therapy may also be based on PSQ or MGMT-STP27.

Background Brain metastases (BM) frequently cause focal neurological deficits leading to a reduced Karnofsky performance score (KPS). Since KPS is routinely used to guide the choice of adjuvant therapy, we hypothesized that improving KPS by surgical resection may improve the chance for adjuvant treatment and ultimately result in better survival. We therefore analyzed the course of a large cohort undergoing resection of symptomatic brain metastases in the context of further treatment and clinical outcome. Patients and methods In a bi‐centric retrospective analysis we retrieved baseline, clinical, and treatment‐related parameters of patients operated on BM between 2010 and 2019. Survival was calculated using Kaplan‐Meier estimates; prognostic factors for survival were analyzed by Log‐rank test and Cox proportional hazards. Results We included 750 patients with a median age of 61 (19‐87) years. The functional status was significantly improved by surgical resection, with a median preoperative (KPS) of 80 (10‐100) increasing to 90 (0‐100) after surgery (P, In patients with symptomatic brain metastases systemic oncological treatment is the strongest factor for further survival. Resection of a symptomatic brain metastasis results in an improved clinical status which facilitates further treatment.

Background Cerebral infarction because of parent artery stenosis represents a potential complication of microsurgical aneurysm clipping. Case Description We report a case of a 60-year-old woman that developed left-sided hemiparesis and aphasia 9 hours after clipping of an unruptured middle cerebral artery aneurysm with heavy calcification of the aneurysm neck. Angiographic workup revealed a marked parent artery stenosis, which occurred presumably because of thrombus generation at the reconstructed aneurysm neck. Revision surgery with relocation of the aneurysm clip was ultimately performed 19 hours after symptom onset. Although follow-up computed tomography scan showed a small cerebral infarction, the patient recovered fully from surgery. Conclusions This case shows that relocation of the aneurysm clip in case of vessel stenosis can lead to penumbral salvage, even when performed more than 6 hours after symptom onset.

OBJECTIVECerebral infarction is a significant cause of morbidity and mortality related to microsurgical clipping of intracranial aneurysms. The objective of this study was to determine the impact of aneurysm shape and neck configuration on cerebral infarction after aneurysm surgery.METHODSThe authors retrospectively reviewed consecutive cases of ruptured and unruptured aneurysms treated with microsurgical clipping at their institution between 2010 and 2018. Three-dimensional reconstructions from preoperative computed tomography and digital subtraction angiography were used to determine aneurysm shape (regular/complex) and neck configuration (regular/irregular). Morphological and procedure-related risk factors for cerebral infarction were identified using univariate and multivariate statistical analyses.RESULTSAmong 243 patients with 252 aneurysms (148 ruptured, 104 unruptured), the overall cerebral infarction rate was 17.1%. Infarction tended to occur more often in aneurysms with complex shape (p = 0.084). Likewise, aneurysms with an irregular neck had a significantly higher rate of infarction (37.5%) than aneurysms with regular neck configuration (10.1%, p < 0.001). Aneurysms with an irregular neck were associated with a higher rate of intraoperative rupture (p = 0.003) and temporary parent artery occlusion (p = 0.037). In the multivariate analysis, irregular neck configuration was identified as an independent risk factor for infarction (OR 4.2, 95% CI 1.9–9.4, p < 0.001), whereas the association between aneurysm shape and infarction was not significant (p = 0.966).CONCLUSIONSIrregular aneurysm neck configuration represents an independent risk factor for cerebral infarction during microsurgical clipping of both ruptured and unruptured aneurysms.

Background and Purpose— EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods— Subjects were World Federation of Neurological Surgeons grades 2–4, modified Fisher grades 2–4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6–8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results— The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83–1.22], P =0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P =0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3–4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94–1.58], P =0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions— There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02790632.

MuT Homolog1 (MTH1) is an enzyme involved in DNA repair in normal cells and is often up-regulated in cancer cells. The enzyme catalyses the hydrolysis of oxidised dNTPs, to prevent their incorporation into DNA or RNA, resulting in mutations or cell damage/death. Cancer cells can have a high concentration of ROS, due to defective redox regulation. This results in the damage of DNA and oxidises free dNTPS, which in turn leads to mutations in DNA replication or cell death. The quantification of MTH1 expression was done by Western Blot analysis. 16 tumours were obtained during neurosurgery, 8 metastatic and 8 recurrent tumours of the same patient, and immediately frozen using liquid nitrogen. The proteins were extracted using RIPA lysis buffer. Western Blot was performed and detection followed via peroxidase linked secondary antibodies. MTH1 expression was shown to be up-regulated in brain metastases (1,442+/-0,6374) versus normal brain tissue (0,4133+/-0,277). However, in the recurrent tumour of the brain metastases, MTH1 was not expressed in a significantly higher amount compared the control tissue and less than in the brain metastases (0,6941+/-0,4146). The high expression of MTH1 in cerebral metastases presents a therapeutic target for MTH1-inhibitors, provided these are able to cross the blood brain barrier. Comparison to the primary melanoma tumour would be useful in showing significant differences of the metastases. Lower levels of MTH1 in recurrent brain metastases may suggest dedifferentiation from the original metastases. It may present a target for specific treatment of brain metastases of melanoma.

BACKGROUND The BRAF V600E mutation is present in approximately 50% of patients with melanoma and is an important prerequisite for a response to targeted therapies such as BRAF inhibitors. In the majority of patients, the BRAF mutational status is based on the analysis of tissue samples from the extracranial primary tumor only. Since the extracranial and intracranial BRAF mutational status may be discrepant, the additional information on the BRAF mutational status of melanoma brain metastases would be of clinical value, e.g., for the prediction of response to targeted therapies. Here, we evaluated the potential of MRI radiomics for the determination of the intracranial BRAF mutational status in patients with melanoma brain metastases. PATIENTS AND METHODS Fifty-nine patients with melanoma brain metastases from two university hospitals (group 1, 45 patients; group 2, 14 patients) were operated with subsequent genetic analysis of the intracranial BRAF mutational status. All patients underwent structural MRI preoperatively. Areas of contrast enhancement were manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After image preprocessing and radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data. Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses. RESULTS Twenty-two patients (49%) in group 1, and 6 patients (43%) in group 2 had an intrametastatic BRAF V600E mutation. Using the best performing six parameter radiomics signature, a linear support vector machine classifier yielded an area under the ROC curve (AUC) of 0.92 (sensitivity, 83%; specificity, 88%) in the test data. CONCLUSION The developed radiomics classifier allows a non-invasive prediction of the intracranial BRAF V600E mutational status in patients with melanoma brain metastases and may be of value for treatment decisions.

BACKGROUND Glioblastoma (GBM) is an aggressive primary tumor of the central nervous system. Current interdisciplinary treatment strategies outside clinical trials include maximal safe resection, followed by treatment with radiation and an alkylating chemotherapy. Based on the results of the positive phase III trial EF-14, the addition of Tumor Treating Fields (TTFields) to temozolomide (TMZ) maintenance therapy brought an additional treatment method to clinical routine. The prospective non-interventional study TIGER (TTFields In GErmany in Routine Clinical Care) documents the use of TTFields in routine clinical care with a particular focus on health-related quality of life (HRQoL) within 4 months after starting therapy, treatment compliance and duration. MATERIAL AND METHODS This multi-center prospective non-interventional study in Germany (NCT03258021) included ndGBM patients eligible for TTFields therapy. Following their consent to participate in the study, patients received a comprehensive introduction to the therapy and their baseline demographic data were collected. Information on TTFields therapy decision is evaluated based on a dedicated TTFields questionnaire at baseline in both arms, follow-up information on how patients cope with the therapy is collected two months after TTFields treatment start, if applicable. HRQoL was assessed in patients deciding for TTFields therapy at baseline as well as at 2 months and 4 months thereafter using the EORTC-QLQ-C30/BN-20 questionnaires. RESULTS Between August 2017 and November 2019, 710 patients (259 female/451 male) were enrolled at 81 participating centers. The mean age was 58.5 years (range: 19.0–85.0; Cut-off: August 31, 2020). The overall baseline characteristics of the study group reflects a typical GBM population. Of these, 582 (82%) decided to start TTFields and 128 (18%) refused TTFields treatment. Health-related QoL did not decline during TTFields therapy except for itchy skin, comparable to the results of the EF-14 phase 3 trial. A detailed analysis of the cohort as well as their reported QoL will be presented. CONCLUSION The TIGER study is the largest non-interventional trial on the use of TTFields in routine clinical care. The use of TTFields in patients with ndGBM did not impair HRQoL during the follow-up period, except for more itchy skin.

Glioblastoma (GBM) is a non-T-cell–inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T-cell cytotoxicity. Proangiogenic cytokines such as VEGF and angiopoietin-2 (Ang-2) have high expression in glioblastoma in a cell-specific manner and not only drive tumor angiogenesis and vascular permeability but also negatively regulate T-lymphocyte and innate immune cell responses. Consequently, the alleviation of immunosuppression might be a prerequisite for successful immune checkpoint therapy in GBM. We here combined antiangiogenic and immune checkpoint therapy and demonstrated improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of VEGF, Ang-2, and programmed cell death protein-1 (PD-1) significantly extended survival compared with vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of CTLs, which inversely correlated with myeloid-derived suppressor cells and regulatory T cells. Transcriptome analysis of GBM microvessels indicated a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome tumor immunosuppression and the current limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity through a normalized vasculature.

To compare flow-regulated (FR) and differential pressure (DP) valves for treatment of patients with idiopathic normal hydrocephalus (iNPH) focusing on overdrainage and neurological outcome. This is a retrospective study of patients with iNPH treated with FR and DP valves at a single institution between 2008 and 2018. The neurological status was evaluated retrospectively with the Kiefer scale at baseline, after shunt placement and at the 6-month follow-up. Groups were compared using inverse probability of treatment weighting based on propensity scores. The study cohort consisted of 38 patients treated with FR valves and 49 with DP valves. The mean patient age was 72.0 ± 7.6 years. Based on the Kiefer scale score, neurological improvement at the 6-month follow-up was recorded in 79.6% in the DP group and 89.5% in the FR group (p = 0.252). The overdrainage rates were higher among DP valves (10.2%) than among FR valves (2.6%, adjusted p = 0.002). Valve malfunction occurred in 2.0% in the DP group and 5.3% in the FR group (adjusted p = 0.667). The current study demonstrates a comparable neurological improvement between DP and FR valves, with potentially lower overdrainage rates among FR valves. Long-term studies will be necessary to draw a definite conclusion on FR valves for treatment of iNPH patients.

Previous studies have indicated that lobulated aneurysms are more susceptible to rupture than are single-sac aneurysms. We aimed to determine the angiographic characteristics related to the lobulated shape of unruptured intracranial aneurysms (UIAs) and ruptured (RIAs) intracranial aneurysms.This is a retrospective analysis of consecutive patients with UIAs (n = 143) and RIAs (n = 190) who underwent digital subtraction angiography at our institution between 2010 and 2017. Patient and aneurysm characteristics were compared between lobulated and regular single-sac aneurysms.Patients with lobulated UIAs were significantly older than were patients with regular aneurysms (56.5 ± 10.7 years vs. 49.3 ± 13.0 years; P = 0.003). In the multivariate analysis, lobulated morphology was significantly related to bifurcation location (69.5% vs. 27.3%; odds ratio [OR], 3.0, 95% confidence interval [CI], 1.2-7.5; P = 0.019), aneurysm size (8.1 ± 3.2 mm vs. 4.9 ± 3.0 mm; OR, 5.4; 95% CI, 1.7-17.8; P = 0.005), and inflow angle (145 ± 27° vs. 114 ± 27°; OR, 2.8; 95% CI, 1.1-7.2; P = 0.031). Bifurcation location (P = 0.031) and larger aneurysm size (P0.001) were confirmed as independent characteristics for lobulation in the RIA group. Compared with regular aneurysms, lobulated UIAs were more often allocated to treatment (86.6% vs. 60.3%; P0.001) and treated by microsurgical clipping (39.4% vs. 16.4%; P = 0.002).Bifurcation location, an increased aneurysm size, and a straighter aneurysm inflow angle are independently associated with lobulated aneurysms.

Objective Indocyanine green (ICG) videoangiography (VAG) is an established method for assessment of cerebral blood flow during microsurgical clipping of intracranial aneurysms. FLOW 800 is a surgical microscope-integrated software program that shows the cerebral blood flow in color-coded maps, thus providing semi-quantitative and real-time analysis of ICG data. We aimed to establish reference values for FLOW 800 parameters before and after microsurgical clipping of intracranial aneurysms and to evaluate the potential of FLOW 800 to guide intraoperative decisions. Methods We retrospectively reviewed 54 patients (mean age, 53.6 ± 11.6 years) who underwent microsurgical clipping for 60 aneurysms and intraoperative evaluation of ICG fluorescence dynamics using FLOW 800 color-coded maps. FLOW 800 data were correlated with patient characteristics, clinical outcomes, and intraoperative decision making. Results There were no significant differences in FLOW 800 data between ruptured and unruptured aneurysms (P > 0.05). Likewise, the hemodynamic parameters were not significantly different before and after definite clip placement (P > 0.05). However, in 2 cases, analysis of transit times by FLOW 800 analysis showed a hemodynamically significant clip stenosis that might have been missed by conventional ICG-VAG and resulted in adjustment of the clip position. Overall, there was 1 cerebral infarction, which was not related to clip placement. Conclusions FLOW 800 is a useful adjunct to ICG-VAG for intraoperative assessment of cerebral perfusion and may help to identify hemodynamically relevant clip stenosis. The beneficial impact of FLOW 800 on clinical outcome after microsurgical clipping needs to be confirmed by comparative studies.

Background Functional magnetic resonance imaging (fMRI) is a useful method for noninvasive presurgical functional mapping. However, the scanner environment is inherently unsuitable for the examination of auditory and language functions, due to the loud acoustic noise produced by the scanner. Interleaved acquisition methods alleviate this problem by providing a silent period for stimulus presentation and/or response control (sparse sampling) but at the expense of a diminished amount of data collected. There are possible improvements to these sparse acquisition methods that increase the amount of data by acquiring several images per event (clustered sampling). We tested accelerated clustered fMRI acquisition in comparison with conventional sparse sampling in a pilot study. Methods The clustered and sparse acquisition techniques (7.4 minutes scanning time per protocol) were directly compared in 15 healthy subjects (8 men; mean age: 24 ± 3 years) using both a motor (tongue movement) and a language (overt picture-naming) task. Functional imaging data were analyzed using Statistical Parametric Mapping software (SPM12 Wellcome Department of Imaging Neuroscience, London, UK). For both tasks, activation levels were compared and Euclidean distances (EDs) between cluster centers (i.e., local activation maxima and centers of gravity) were calculated. Overlaps and laterality indices were computed for the picture-naming task. In addition, the feasibility of the clustered acquisition protocol in a clinical setting was assessed in one pilot patient. Results For both tasks, activation levels were higher using the clustered acquisition protocol, reflected by bigger cluster sizes (p Conclusion Despite some drawbacks inherent to the acquisition technique, the clustered sparse sampling protocol showed increased sensitivity for activation in language-related cortical regions with short scanning times. Such scanning techniques may be particularly advantageous for investigating patients with contraindications for long scans (e.g., reduced attention span).

To provide detailed long-term data after initial observation for patients after histological confirmation of low grade (WHO II) gliomas according to molecular stratification. A series of 110 patients with watchful waiting strategy after initial surgery for LGG and re-surgery at tumor progression were analyzed. Progression-free survival, time to malignant transformation, post-recurrence survival, and overall survival were estimated with the Kaplan–Meier method. Prognostic factors were identified by the Log Rank test and Cox multivariate proportional hazards model. The cohort comprised 18 IDH wild type (IDHwt) and 53 IDH mutated (IDHmut) astrocytomas, and 39 IDH mutated and 1p 19q co-deleted (IDHmut/codel) patients. The median follow-up was 126 (95% CI 109–143) months. Surgery was gross total resection in 58, subtotal resection in 28, and biopsy in 24 patients. Progression-free survival rates at 5, 10 and 15 years was 38% 18% and 1%. The corresponding malignant transformation rates were 17%, 39% and 71%. The initial extent of resection influenced progression-free survival, time to malignant transformation and overall survival. Molecular subtype IDHmut/codel was the strongest prognostic factor for overall survival and for time to malignant transformation. The strongest determinant of the patients’ course after initial watchful waiting was the molecular tumor status. Extensive resection may increase time to progression and malignant transformation. Observation may be justified in selected patients.

OBJECTIVEData on the survival effects of supportive care compared to second-line multimodal treatment for glioblastoma progression are scarce. Thus, the authors assessed survival in two population-based, similar cohorts from two European university hospitals with different treatment strategies at first progression.METHODSThe authors retrospectively identified patients with newly diagnosed glioblastoma treated at two neurooncological centers. After diagnosis, patients from both centers received identical treatments, but at tumor progression each center used a different approach. In the majority of cases, at center A (Greece), supportive care or a single therapeutic modality was offered at progression, whereas center B (Germany) provided multimodal second-line therapy. The main outcome measure was survival after progression (SaP). The influence of the treatment strategy on SaP was assessed by multivariate analysis.RESULTSOne hundred three patients from center A and 156 from center B were included. Tumor progression was observed in 86 patients (center A) and 136 patients (center B). At center A, 53 patients (72.6%) received supportive care alone, while at center B, 91 patients (80.5%) received second-line treatment. Progression-free survival at both centers was similar (9.4 months [center A] vs 9.0 months [center B]; p = 0.97), but SaP was significantly improved in the patients treated with multimodal second-line therapy at center B (7 months, 95% CI 5.3–8.7 months) compared to those treated with supportive care or a single therapeutic modality at center A (4.5 months, 95% CI 3.5–5.5 months; p = 0.003). In the multivariate analysis, the treatment center was an independent prognostic factor for overall survival (HR 1.59, 95% CI 0.17–2.15; p = 0.002).CONCLUSIONSTreatment strategy favoring multimodal second-line treatment over minimal treatment or supportive care at glioblastoma progression is associated with significantly better overall survival.

BACKGROUND/AIM Death receptor 6 (DR6) is a member of the tumor necrosis factor receptor superfamily. The expression of DR6 is elevated in different kinds of tumors including ovarian, breast cancer and adult sarcoma. In these tumors, the receptor may be handled as a new diagnostic and prognostic marker. Thus, we investigated the expression of DR6 in gliomas. MATERIALS AND METHODS Tumor and control tissues were extracted during neurosurgery and grouped according to the WHO classification. DR6 expression was investigated in low- and high-grade gliomas PCR (n=70), immunofluorescence staining (n=33) and western blot (n=58). Additional analysis of TCGA-data was performed to assess the general alteration of DR6 in cancer and influence of IDH-mutation on DR6 expression in gliomas. RESULTS The expression of DR6 was significantly enhanced in gliomas (p

Inevitable tumor recurrence and a poor median survival are frustrating reminders of the inefficacy of our current standard of care for patients with newly diagnosed glioblastoma (GBM), which includes surgery followed by radiotherapy and chemotherapy with the DNA alkylating agent temozolomide. Because resistance to genotoxic damage is achieved mainly through execution of the DNA damage response (DDR) and DNA repair pathways, knowledge of the changes in DNA repair and cell-cycle gene expression that occur during tumor development might help identify new targets and improve treatment. Here, we performed a gene expression analysis targeting components of the DNA repair and cell-cycle machineries in cohorts of paired tumor samples (i.e., biopsies from the same patient obtained at the time of primary tumor operation and at recurrence) from patients treated with radiotherapy or radiotherapy plus temozolomide. We identified and validated a 27-gene signature that resulted in the classification of GBM specimens into three groups, two of which displayed inverse expression profiles. Each group contained primary and recurrent samples, and the tumor at relapse frequently displayed a gene expression profile different from that of the matched primary biopsy. Within the groups that exhibited opposing gene expression profiles, the expression pattern of the gene signature at relapse was linked to progression-free survival. We provide experimental evidence that our signature exposes group-specific vulnerabilities against genotoxicants and inhibitors of the cell cycle and DDR, with the prospect of personalized therapeutic strategies. Significance: These findings suggest that classification of GBM tumors based on a DNA repair and cell-cycle gene expression signature exposes vulnerabilities to standard-of-care therapies and offers the potential for personalized therapeutic strategies.

Objective Computer-aided design and manufacturing (CAD/CAM) implants are fabricated based on volumetric analysis of computed tomography (CT) scans and are routinely used for the reconstruction of orbital fractures. We present three cases of patients with sphenoorbital meningiomas that underwent tumor resection, orbital decompression, and orbital reconstruction with patient specific porous titanium or acrylic implants in a single procedure. Methods The extent of bone resection of the sphenoorbital meningiomas was planned in a virtual three-dimensional (3D) environment using preoperative thin-layer CT data. The anatomy of the orbital wall in the resection area was reconstructed by superimposing the contralateral unaffected orbit and by using the information of the neighboring bony structures. The customized implants and a corresponding craniotomy template were designed in the desired size and shape by the manufacturer. Results All patients presented with a sphenoorbital meningioma and exophthalmos. After osteoclastic craniotomy with the drilling template, orbital decompression was performed. Implant fitting was tight in two cases and could be easily fixated with miniplates and screws. In the third patient, a reoperation was necessary for additional bone resection, as well as drilling and repositioning of the implant. The postoperative CT scans showed an accurate reconstruction of the orbital wall. After surgery, exophthalmos was substantially reduced and a satisfying cosmetic result could be finally achieved in all patients. Conclusions The concept of preoperative 3D virtual treatment planning and single-step orbital reconstruction with CAD/CAM implants after tumor resection involving the orbit is well feasible and can lead to good cosmetic results.

Summary Background There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial. Methods In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18–70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m 2 per day concomitant to radiotherapy [59–60 Gy] followed by six courses of temozolomide 150–200 mg/m 2 per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m 2 on day 1) plus temozolomide (100–200 mg/m 2 per day on days 2–6 of the 6-week course) in addition to radiotherapy (59–60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109. Findings Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7–47·1) with temozolomide to 48·1 months (32·6 months–not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35–1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35–1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths. Interpretation Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial. Funding German Federal Ministry of Education and Research.

Modulatory effects of transcranial magnetic stimulation (TMS) strongly depend on the stimulation parameters. Here, we compared the immediate, task-locked inhibitory effects on speech-related muscles and the tolerability of different TMS protocols during a language production task. Repetitive TMS (rTMS) and paired-pulse TMS (PP) were applied in 13 healthy subjects over the primary motor cortex (M1) during a finger-tapping/tongue-twisting tasks. The lowest subject-specific TMS intensity leading to movement disruptions was used for TMS over left-sided speech-related areas during picture naming. Here, time-locked PP and rTMS (10/30/50 Hz; randomized sequence) were applied. Cortical silent periods (cSPs) were analyzed from electromyography obtained from various face muscles. 30 Hz- and 50 Hz-rTMS reliably evoked tongue movement disruption (ICC = 0.65) at lower rTMS intensities compared to 10 Hz-rTMS or PP. CSPs were elicited from the left hemisphere by all TMS protocols, most reliably by PP (p

Meningiomas are the most common intracranial tumors. Yet, only few controlled clinical trials have been conducted to guide clinical decision making, resulting in variations of management approaches across countries and centers. However, recent advances in molecular genetics and clinical trial results help to refine the diagnostic and therapeutic approach to meningioma. Accordingly, the European Association of Neuro-Oncology (EANO) updated its recommendations for the diagnosis and treatment of meningiomas. A provisional diagnosis of meningioma is typically made by neuroimaging, mostly magnetic resonance imaging. Such provisional diagnoses may be made incidentally. Accordingly, a significant proportion of meningiomas, notably in patients that are asymptomatic or elderly or both, may be managed by a watch-and-scan strategy. A surgical intervention with tissue, commonly with the goal of gross total resection, is required for the definitive diagnosis according to the WHO classification. A role for molecular profiling including gene panel sequencing and genomic methylation profiling is emerging. A gross total surgical resection including the involved dura is often curative. Inoperable or recurrent tumors requiring treatment can be treated with radiosurgery, if the size or the vicinity of critical structures allows that, or with fractionated radiotherapy (RT). Treatment concepts combining surgery and radiosurgery or fractionated RT are increasingly used, although there remain controversies regard timing, type, and dosing of the various RT approaches. Radionuclide therapy targeting somatostatin receptors is an experimental approach, as are all approaches of systemic pharmacotherapy. The best albeit modest results with pharmacotherapy have been obtained with bevacizumab or multikinase inhibitors targeting vascular endothelial growth factor receptor, but no standard of care systemic treatment has been yet defined.

Background and Purpose: The value of gross-total surgical resection remains debatable in patients with brain metastases (BMs) as most patients succumb to systemic disease progression. In this study, we evaluated the impact of the extent of resection of singular/solitary BM on in-brain recurrence (iBR), focusing on local recurrence (LR) and overall survival (OS) in an interdisciplinary adjuvant treatment setting. Patients and Methods: In this monocentric retrospective analysis, we included patients receiving surgery of one BM and subsequent adjuvant treatment. A radiologist and a neurosurgeon determined in consensus the extent of resection based on magnetic resonance imaging. The OS was calculated using Kaplan–Meier estimates, prognostic factors for LR and OS were analysed by Log rank test and Cox proportional hazards. Results: We analyzed 197 patients. Gross-total resection was achieved in 123 (62.4%) patients. All patients were treated with adjuvant radiotherapy, and 130 (66.0%) received systemic treatment. Ninety-six (48.7%) patients showed iBR with an LR rate of 23.4%. LR was not significantly influenced by the extent of resection (p = 0.139) or any other parameter. The median OS after surgery was 18 (95%CI 12.5–23.5) months. In univariate analysis, the extent of resection did not influence OS (p = 0.6759), as opposed to adjuvant systemic treatment (p &lt, 0.0001) and controlled systemic disease (p = 0.039). Systemic treatment and controlled disease status remained independent factors for OS (p &lt, 0.0001 and p = 0.009, respectively). Conclusions: In this study, the extent of resection of BMs neither influenced the LR nor the OS of patients receiving interdisciplinary adjuvant treatment.

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity. The objective was to evaluate, whether specific morphological aneurysm characteristics could serve as predictive values for aSAH severity, disease-related complications and clinical outcome.A total of 453 aSAH patients (mean age: 54.9 ± 13.8 years, mean aneurysm size: 7.5 ± 3.6 mm) treated at a single center were retrospectively included. A morphometric analysis was performed based on angiographic image sets, determining aneurysm location, aneurysm size, neck width, aneurysm size ratios, aneurysm morphology and vessel size. The following outcome measures were defined: World Federation of Neurosurgical Societies (WFNS) grade 4 and 5, Fisher grade 4, vasospasm, cerebral infarction and unfavorable functional outcome.Regarding morphology parameters, aneurysm neck width was an independent predictor for Fisher 4 hemorrhage (OR: 1.1, 95%CI: 1.0-1.3, p = 0.048), while dome width (OR: 0.92, 95%CI: 0.86-0.97, p = 0.005) and internal carotid artery location (OR: 2.1, 95%CI: 1.1-4.2, p = 0.028) predicted vasospasm. None of the analyzed morphological characteristics prognosticated functional outcome. Patient age (OR: 0.95, 95%CI: 0.93-0.96, p 0.001), WFNS score (OR: 4.8, 95%CI: 2.9-8.0, p 0.001), Fisher score (OR: 2.3, 95%CI: 1.4-3.7, p 0.001) and cerebral infarction (OR: 4.5, 95%CI: 2.7-7.8, p 0.001) were independently associated with unfavorable outcome.The findings indicate a correlation between aneurysm morphology, Fisher grade and vasospasm. Further studies will be required to reveal an independent association of aneurysm morphology with cerebral infarction and functional outcome.

OBJECTIVE Glioblastoma (GBM) is widely treated with surgery, chemoradiation and TTFields in combination with chemotherapy. Since the introduction of TTFields to first-line GBM treatment, prescribing physicians in Germany are interested to gain additional knowledge on the use in clinical practice. The TIGER study was designed to assess the therapy decision making process, safety and efficacy of TTFields in clinical routine, as well as evaluating quality of life (QoL) within 4 months after start of therapy, treatment compliance and duration. METHODS This multi-center prospective non-interventional study in Germany (NCT03258021) included newly diagnosed GBM patients eligible for TTFields therapy. Within the study, after receiving introduction to TTFields therapy, patients could decide for or against receiving TTFields. The study was designed to recruit 500 patients for each group, with and without TTFields. Demographic data, QoL and reasons for therapy decision 2–4 months after treatment start are assessed using the EORTC-QLQ-C30/BN-20 and a TTFields questionnaire, respectively, with 18 months follow-up. RESULTS At the last data cut-off (31st March, 2020), the median follow-up was 11 months (range: 0–28 months) and 581 (82%) of the 710 recruited patients in the trial had decided for TTFields therapy. According to preliminary analysis, this patient population represents a typical GBM population regarding median age (59 years, range: 19.0–85.0), gender (37 % female), median KPS (90, range: 40–100) and MGMT promoter methylation status (44% methylated). In this population 49 % received complete resection, 33 % partial resection and 19 % biopsy. CONCLUSION The TIGER study allows prospective and systematic analysis of TTFields treatment decision making and use of typical GBM patient population in routine clinical care. In addition, the study allows the evaluation of compliance and treatment duration. Here, we will present an updated analysis of the TIGER study.

OBJECTIVE Timely aneurysm occlusion and neurointensive care treatment are key principles in the management of aneurysmal subarachnoid hemorrhage (aSAH) to prevent secondary brain injury. Patients with early (EHA) and delayed hospital admission (DHA) were compared in terms of clinical presentation, treatment strategies, aSAH-related complications, and outcome. METHODS In this retrospective study, consecutive aSAH patients were treated at a single neurovascular center between 2009 and 2019. Propensity score matching was performed to account for divergent baseline characteristics. RESULTS Among 509 included patients, 55 were admitted more than 48 hours after ictus (DHA group). DHA patients were significantly younger (52 ± 11 vs 56 ± 14 years, p = 0.03) and had lower World Federation of Neurosurgical Societies scores (p < 0.01) than EHA patients. In 54.5% of the cases, DHA patients presented with neurological deterioration or aggravated symptoms. Propensity score matching revealed a higher vasospastic infarction rate in the DHA group (41.5%) than in the EHA group (22.6%) (p = 0.04). A similar portion of patients in both groups achieved favorable outcome at midterm follow-up (77.3% vs 73.6%, p = 0.87). DHA patients (62.3%) received conventional coiling more often than EHA patients (41.5%) (p = 0.03). CONCLUSIONS DHA patients are at an increased risk of cerebral infarction. Nevertheless, state-of-the-art neurointensive care treatment can result in a good clinical outcome.

PET using O-(2-F-18-fluoroethyl)-L-tyrosine (F-18-FET) is useful to detect residual tumor tissue after glioma resection. Recent animal experiments detected reactive changes in F-18-FET uptake at the rim of the resection cavity within the first 2 wk after resection of gliomas. In the present study, we evaluated pre- and postoperative F-18-FET PET scans of glioma patients with particular emphasis on the identification of reactive changes after surgery. Methods: Forty-three patients with cerebral gliomas (9 low-grade, 34 high-grade; 9 primary tumors, 34 recurrent tumors) who had preoperative (time before surgery: median, 23 d; range, 6-44 d) and postoperative F-18-FET PET (time after surgery: median, 14 d; range, 5-28 d) were included. PET scans (20-40 min after injection) were evaluated visually for complete or incomplete resection and compared with MRI. Changes in F-18-FET uptake were evaluated by tumor-to-brain ratios in residual tumor and by maximum lesion-to-brain ratios near the resection cavity. Results: Visual analysis of F-18-FET PET scans revealed complete resection in 16 of 43 patients and incomplete resection in the remaining patients. PET results were concordant with MRI in 69% of the patients. The maximum lesion-to-brain ratio for F-18-FET uptake near the resection cavity was significantly higher than preoperative values (1.59 +/- 0.36 vs. 1.14 +/- 0.17; n = 43; P

Precise and comprehensive mapping of somatotopic representations in the motor cortex is clinically essential to achieve maximum resection of brain tumours whilst preserving motor function, especially since the current gold standard, that is, intraoperative direct cortical stimulation (DCS), holds limitations linked to the intraoperative setting such as time constraints or anatomical restrictions. Non‐invasive techniques are increasingly relevant with regard to pre‐operative risk‐assessment. Here, we assessed the congruency of neuronavigated transcranial magnetic stimulation (nTMS) and functional magnetic resonance imaging (fMRI) with DCS. The motor representations of the hand, the foot and the tongue regions of 36 patients with intracranial tumours were mapped pre‐operatively using nTMS and fMRI and by intraoperative DCS. Euclidean distances (ED) between hotspots/centres of gravity and (relative) overlaps of the maps were compared. We found significantly smaller EDs (11.4 ± 8.3 vs. 16.8 ± 7.0 mm) and better spatial overlaps (64 ± 38% vs. 37 ± 37%) between DCS and nTMS compared with DCS and fMRI. In contrast to DCS, fMRI and nTMS mappings were feasible for all regions and patients without complications. In summary, nTMS seems to be the more promising non‐invasive motor cortex mapping technique to approximate the gold standard DCS results., The motor representations of the hand, the foot and the tongue regions were mapped pre‐operatively using neuronavigated transcranial magnetic stimulation (nTMS) and functional magnetic resonance imaging (fMRI) in thirty six patients with intracranial tumours and were compared with intraoperative direct cortex stimulation (DCS). We found significantly smaller Euclidean distances and better spatial overlaps between DCS and nTMS compared with DCS and fMRI. In summary, nTMS seems to be the more promising non‐invasive motor cortex mapping technique to approximate the gold standard DCS results.

Objective Microsurgical clipping of aneurysms demands precise spatial understanding of aneurysm morphology and vascular geometry. We analyzed the impact of preoperative three-dimensional (3D) angiographic imaging on clinical and angiographic outcome after clipping of ruptured intracranial aneurysms. Methods This is a retrospective analysis of consecutive patients who underwent microsurgical clipping during the acute phase of subarachnoid hemorrhage between 2010 and 2017. Surgical planning was made based on two-dimensional (2D) or 3D angiographic images. We retrospectively compared complication rates, morbidity, and angiographic outcome between these 2 groups. Results A total of 157 patients (mean age: 54.8 ± 13.1 years) were included in the study. Preoperative 3D angiographic imaging was available for 117 cases. The rate of procedure-related ischemia was significantly lower in the 3D group (16.2%) than in the 2D group (35.0%; P = 0.013). In the multivariate analysis, 2D imaging alone remained as independent factor for subsequent brain ischemia (odds ratio: 2.8, 95% confidence interval 1.2–6.6; P = 0.018). Favorable outcome (modified Rankin scale ≤2) was more often attained in the 3D group (70.0%) than in the 2D group (41.9%; P = 0.002). The rate of complete aneurysm occlusion was not significantly different between the 2 groups (P = 0.967). Conclusions In our study, accurate operation planning using 3D angiography was associated with a lower ischemic complication rate after clipping of ruptured intracranial aneurysms, which may potentially influence clinical outcome.

Overdrainage and frequent reprogramming are common issues with programmable valves after ventriculoperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (iNPH). Flow-regulated valves may address these limitations, but data on their efficacy are sparse. We present our single-center experience with flow-regulated valves focusing on overdrainage and efficiency.Thirty-two patients with iNPH treated with the Integra® NPH Low Flow Valve were prospectively enrolled. Clinical evaluation was performed at baseline, postoperatively as well as 3 and 6 months after surgery. The outcome was assessed by employing the iNPH grading scale and the Mini Mental Status Examination (MMSE). Overdrainage was assessed clinically and radiologically by computed tomography.The mean patient age was 71 years. All patients presented with gait disturbance, 29 had cognitive impairment and 25 had urinary incontinence. The mean duration of symptoms was 22.9 months. At 3-month follow-up, 25/31 patients (80.6%) improved on the total iNPH score by at least 5 points (p 0.001). The mean MMSE score increased from 24.5 to 26.1 points (p = 0.013). After 6 months, the improvement rates of the iNPH (82.1%) and the MMSE scores (26.8 points) were stable. The rate of clinically significant overdrainage was 3.2%. One patient presented with subdural hygromas that necessitated evacuation. In the remaining patients, clinical and radiological signs of overdrainage were absent.The use of the Integra® NPH Low Flow Valve leads to a good neurological outcome and has low overdrainage rates without the need for reprogramming. These results are encouraging and justify further investigation of this valve.

The authors present a novel biological nonliving epineurial nerve coaptation training model, which allows cost-efficient practicing on organic mammal nerves and offers an objective performance control on the basis of successful suturing and respecting the 3R model.Anatomic dissection of 40 rat cadavers was performed. Four residents without prior microneurosurgical experience were included. Each trainee performed 20 epineurial nerve coaptations. The number of successful sutures served as qualitative variable and operation time as a quantitative variable for efficiency control.The rate for successful sutures was 51.9% in the first half of trials and improved to 94.4% in the second half. Whereas, the trainees needed a mean time of 34 minutes for the first 10 coaptations, the last 10 coaptations were performed within 24.5 minutes.The authors' presented model is an easily accessible, low-cost microneurosurgical simulation model, allowing a realistic and instructive performance of epineurial nerve coaptation. Because cadaveric nerves are used, an approval of the local ethics committee is not needed. Furthermore, anatomic knowledge about the topography related to the harvest of the sciatic nerve of rats is provided in this study.

Evaluation of postoperative fractionated local 3D-conformal radiotherapy (3DRT) of the resection cavity in brain metastases. Between 2011 and 2016, 57 patients underwent resection of a single, previously untreated (37/57, 65%) or recurrent (20/57, 35%) brain metastasis (median maximal diameter 3.5 cm [1.1–6.5 cm]) followed by 3DRT. For definition of the gross tumor volume (GTV), the resection cavity was used and for the clinical target volume (CTV), margins of 1.0–1.5 cm were added. Median dose was 48.0 Gy (30.0–50.4 Gy) in 25 (10–28) fractions; most patients had 36.0–42.0 Gy in 3.0 Gy fractions (n = 16, EQD210Gy 39.0–45.5 Gy) or 40.0–50.4 Gy in 1.8–2.0 Gy fractions (n = 37, EQD210Gy 39.3–50.0 Gy). Median follow-up was 18 months. Local control rates were 83% at 1 year and 78% at 2 years and were significantly influenced by histology (breast cancer 100%, non-small lung cancer 87%, melanoma 80%, colorectal cancer 26% at 2 years, p = 0.006) and resection status (p

In consideration of the 3-R-rule (Refine-Replace-Reduce) as a guideline for promoting ethical use of animals for surgical training, we present a novel training model for microvessel anastomosis. In a rat cadaveric study, we evaluated the surgical anatomy of the common carotid artery (CCA), external jugular vein (EJV) and femoral vessels (FV) which were then used as templates for the present investigation. Anatomical dissection of 30 rat cadavers was performed. Two residents without prior microsurgical experience were included in the study and performed 5 CCA, 5 femoral artery, 5 EJV and 5 femoral vein anastomoses. Patency and leakage served as qualitative variables and operation time as a quantitative variable for efficiency control. The average time improved for arterial and venous anastomoses (45 min–22 and 60 to 32 min, respectively) for both surgeons. While both surgeons experienced patency failure or leakage within the first half of performed arterial and venous anastomoses, they could improve to a 100% patency rate without the occurrence of leakage for the last half of trials. The rat head & neck anatomy presents various characteristics related to the harvest of the vessels of interest. We provide anatomical knowledge about the topography related to the harvest of the CCA, EJV, and FV. Our model is an easily accessible, low-cost microsurgical simulation model, allowing a realistic and instructive performance of anastomoses. Since cadaveric vessels are used, an approval of the local ethics committee is not needed.

We evaluated patterns of tumor growth in patients with newly diagnosed MGMT-non-methylated glioblastoma who were assigned to undergo radiotherapy in conjunction with bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ) within the randomized phase II GLARIUS trial. In 142 patients (94 BEV/IRI, 48 TMZ), we reviewed magnetic resonance imaging scans at baseline and first tumor recurrence. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery images, we assessed tumor growth patterns and tumor invasiveness. Tumor growth patterns were classified as either multifocal or local at baseline and recurrence; at first recurrence, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations with treatment arms were calculated using Fisher's exact test. At baseline, 115 of 142 evaluable patients (81%) had a locally confined tumor. Between treatment arms, there was no significant difference in the fraction of tumors that changed from an initially local tumor growth pattern to a multifocal pattern (12 and 13%, p = 0.55). Distant lesions appeared in 17% (BEV/IRI) and 13% (TMZ) of patients (p = 0.69). 15% of patients in the BEV/IRI arm and 8% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p = 0.42). The tumor growth and invasiveness patterns do not differ between BEV/IRI and TMZ-treated MGMT-non-methylated glioblastoma patients in the GLARIUS trial. BEV/IRI was not associated with an increased rate of multifocal, distant, or highly invasive tumors at the time of recurrence.

BACKGROUND The CeTeG/NOA-09 trial showed that lomustine/temozolomide chemotherapy prolongs survival for newly diagnosed MGMT-methylated glioblastoma patients. Previous reports on temozolomide monotherapy suggested, that the survival benefit of temozolomide in MGMT-methylated tumors may be restricted to the RTK II methylation subgroup and absent in RTK I and MES subgroups. To identify patients with a particularly strong benefit from CCNU/TMZ, we explored the association of methylation subgroups with outcome after lomustine/temozolomide therapy. METHODS All patients from the CeTeG/NOA-09 trial with sufficiently available tumor tissue (n = 98) underwent 850K methylation array analysis of their tumor and methylation subgroup annotation (Heidelberg brain tumor methylation classifier v11b4; calibrated score > 0.5 required). Overall survival (OS) was compared between a pooled cohort of tumors of the RTK I/MES subgroups and RTK II tumors. RESULTS In the CCNU/TMZ arm of CeTeG/NOA-09, OS was prolonged in RTK I/MES (n = 16; median not reached, 4-year OS 69%) as compared to RTK II patients (n = 14; median 20.6 months, 4-year OS 23%; p = 0.004 logrank test). In the standard temozolomide arm of CeTeG/NOA-09, OS tended to be shorter in RTK I/MES (n = 7; median 23.7 months, 4-year OS 17%) as compared to RTK II patients (n = 17; median 35.2 months; 4-year OS 38%, p = 0.15). CONCLUSION The CCNU/TMZ-dependent survival prolongation in patients with RTK I/MES tumors as opposed to RTK II seen in CeTeG/NOA-09 suggests that methylation-based subgrouping could be predictive for CCNU/TMZ efficacy in newly diagnosed MGMT-methylated glioblastoma.

Objective To assess the impact of driver mutations in non-small cell lung cancer (NSCLC) on the formation and treatment outcome of brain metastases (BM). Patients and methods We retrospectively analyzed patients with BM from NSCLC with respect to driver mutations and assessed timing and pattern of BM development as well as local cerebral control and survival after BM treatment. Results We included 253 patients. Histology was adenocarcinoma in 223, squamous cell carcinoma in 25 and not otherwise specified (NOS) in five patients. All tumors were analyzed for known alterations in NSCLC by panel sequencing and fluorescence in situ hybridization (FISH). An activating KRAS mutation (n=85) was the most prevalent mutation, followed by activating EGFR mutation (n=31) and MET amplification (n=29). Other mutations were detected in 27 patients. No alterations were found in 102 patients. Time to BM development did not differ between the molecular groups (p=.22), nor did the number (p=.72) or location (supra- vs. infratentorial; p=.76) of the BM. Patients underwent multimodal cerebral treatment comprising surgery followed by radiotherapy and/or stereotactic radiosurgery (n=138), whole brain radiotherapy (n=13) or stereotactic radiosurgery alone (n=102). Systemic treatment was initiated or continued after BM therapy in 169 patients and its frequency did not differ significantly between genotypes (p=.08) while the modality of medical treatment depended on genotype (p Conclusion The actual known driver mutations do not influence BM formation. Specific genotypes show a better oncological course, presumably due to available molecular treatment.

Background and Purpose While data reporting the number of brain metastasis as a prognostic factor for patients with NSCLC, we analyzed whether the prognostic importance of the mere count of brain metastasis in a modern, multimodal treatment setting. Patients and Methods We retrospectively analyzed patients treated for BM from non-small lung cancer between 2010 and 2020. Demographics, baseline characteristics, and tumor-associated parameters were retrieved from an electronic database. Prognostic factors for local cerebral control and survival were identified using the log-rank test and Cox regression analysis. Results We included 343 consecutive patients (male n=187, female n=156; median age 61 years). Histological subtypes were adenocarcinoma (n=283), squamous-cell carcinoma (n=42) and neuroendocrine carcinoma (n=18). The median number of BM was one (range 1–20). Single (n = 189), oligo (n=110) and multiple BM (n=44) showed in total a median follow up of 10 months (minimum 1, maximum 142). Treatment comprised surgical resection (n=218) with radiotherapy, stereotactic radiosurgery (n=125) and adjuvant systemic therapy (n=203). The median local cerebral control was 11 months (95%CI 8.5 – 13.5) and the median overall survival was 16 months (95%CI 12.8 – 19.2). The number of BM did not influence local control and overall survival rates (p = 0.234 and p = 0.210, respectively). Controlled systemic disease (HR 0.42; 95% CI 0.2284–0.633; p 70; HR 0.41; 95% CI 0.265–0.661; p Conclusions The mere number of brain metastases is not a prognostic factor for survival and local cerebral control in a multimodal treatment setting.

Details of the human facial parotid plexus (PP) are not readily accessible during ordinary anatomical teaching because of insufficient time and difficulties encountered in the preparation. For parotid and facial nerve surgery however, precise knowledge of PP is of crucial importance. The aim of this study was therefore to provide more details of PP in anatomic specimens. Following anatomical dissection, its location, syntopy and morphology were analyzed in 158 cervico-facial halves of 95 cadavers. The facial nerve (FN) divides into a larger temporo-facial and a smaller cervico-facial trunk. Both trunks branch, form PP, and thus form connections along six distinctive anastomotic types. These anastomoses may explain why accidental or essential severance of a supposed terminal facial branch fails to result in the expected muscle weakness. However, whereas earlier anatomical and clinical studies report connections between both trunks in 67-90% of the cases, our data indicate the presence of anastomoses only in 44%. One reason for this difference may be found in our microscope-assisted dissection in infratemporal regions from which the parotid gland has been removed. Thereby we tracked both FN-trunks in both directions - distally and proximally - and determined the exact origin of all terminal FN branches. This lower rate of occurrence of connections between both trunks reduces the chances of luckily preserved muscle innervation and enhances the risk of facial palsy after transection of a terminal branch. Accordingly, precise anatomical knowledge on PP should be renewed and transection of facial nerve branches avoided.

Objective Chronic subdural hematoma (CSDH), a common condition in elderly patients, presents a therapeutic challenge with recurrence rates of 33%. We aimed to identify specific prognostic factors for recurrence using quantitative analysis of hematoma volume and density. Methods We retrospectively reviewed radiographic and clinical data of 227 CSDHs in 195 consecutive patients who underwent evacuation of the hematoma through a single burr hole, 2 burr holes, or a mini-craniotomy. To examine the relationship between hematoma recurrence and various clinical, radiologic, and surgical factors, we used quantitative image-based analysis to measure the hematoma and trapped air volumes and the hematoma densities. Results Recurrence of CSDH occurred in 35 patients (17.9%). Multivariate logistic regression analysis revealed that the percentage of hematoma drained and postoperative CSDH density were independent risk factors for recurrence. All 3 evacuation methods were equally effective in draining the hematoma (71.7% vs. 73.7% vs. 71.9%) without observable differences in postoperative air volume captured in the subdural space. Conclusions Quantitative image analysis provided evidence that percentage of hematoma drained and postoperative CSDH density are independent prognostic factors for subdural hematoma recurrence.

Recently, several Non-NF2 driver mutations (KLF4, TRAF7, SMO, AKT1E17K) in meningioma have been identified. While they have been shown to correlate with certain pathological subtypes and locations, the clinical impact and repercussions on cellular pathways have largely remained elusive. Through analysis of clinical, pathological and preoperative imaging data of 96 patients and sequencing of the corresponding 96 tumor samples for the Krueppel like factor 4-K409Q mutation (KLF4K409Q) we present evidence that the KLF4K409Q tumors harbour an increased risk for peritumoral brain edema (PTBE) and can be predicted with the edema-index, a simple tool based on preoperative imaging. Further analysis involving RNA-sequencing of a matched subset of 7 KLF4K409Q and 10 KLF4-wildtype (wt) tumors revealed a significant shift of gene expression and the upregulation of hypoxia driven pathways, including VEGF levels, in KLF4K409Q tumors. On the cellular level, we go on to show that the KLF4K409Q mutation results in an increased KLF-4 stability as well as the inhibition of hydroxylation dependent degradation of HIF1-α and a significant increase of VEGF expression under hypoxic conditions. Finally, we demonstrate that this upregulation of VEGF in KLF4K409Q cells can be inhibited by targeting the mammalian target of rapamycin (mTor) with Temsirolimus. In summary we show that the KLF4K409Q mutation in meningioma has highly relevant repercussions in both, the biological and clinical context and can be harnessed for targeted therapy.

OBJECTIVES The aim of the study was to investigate the association between meningioma volume and the occurrence of clinic-radiologic signs of tumor aggressiveness. For volumetric approximation, the authors evaluated the method of semiautomatic image segmentation at hand of high-resolution MRI-image sequences. METHODS ITK-SNAP was utilized for semiautomatic image segmentation of 58 gadolinium-contrast enhanced T1-weighted thin-slice MRI datasets for volumetric analysis. Furthermore, multimodal imaging datasets (including T2, FLAIR, T1) were evaluated for radiological biomarkers of aggressiveness and growth potential. Thereby generated data was checked for association with retrospectively collected data points. RESULTS Location (P = 0.001), clinical disease manifestation (P = 0.033), peritumoral edema (P = 0.038), tumor intrinsic cystic degeneration (P = 0.007), three-dimensional complexity (P = 0.022), and the presence of meningioma mass effect (P = 0.001) were statistically associated with higher tumor volumes. There was no association between higher tumor volumes and histopathological tumor grade. CONCLUSION The size of a meningioma does not seem to reliably predict tumor grade. Growth potential seems to be influenced by tumor location. Higher tumor volumes were significantly associated with the occurrence of clinical symptoms.