Effects of Dendrimer-microRNA Nanoformulations against Glioblastoma Stem Cells.

Glioblastoma is a rapidly progressing tumor quite resistant to conventional treatment. These features are currently assigned to a self-sustaining population of glioblastoma stem cells. Anti-tumor stem cell therapy calls for a new means of treatment. In particular, microRNA-based treatment is a solution, which in turn requires specific carriers for intracellular delivery of functional oligonucleotides. Herein, we report a preclinical in vitro validation of antitumor activity of nanoformulations containing antitumor microRNA miR-34a and microRNA-21 synthetic inhibitor and polycationic phosphorus and carbosilane dendrimers. The testing was carried out in a panel of glioblastoma and glioma cell lines, glioblastoma stem-like cells and induced pluripotent stem cells. We have shown dendrimer-microRNA nanoformulations to induce cell death in a controllable manner, with cytotoxic effects being more pronounced in tumor cells than in non-tumor stem cells. Furthermore, nanoformulations affected the expression of proteins responsible for interactions between the tumor and its immune microenvironment: surface markers (PD-L1, TIM3, CD47) and IL-10. Our findings evidence the potential of dendrimer-based therapeutic constructions for the anti-tumor stem cell therapy worth further investigation.

Treatment of Unique Bilateral Distal Fusiform Superior Cerebellar Artery Aneurysms with Mini-Flow Diverter Device Implantation: Case Report.

Currently, surgical revascularization procedures using intracranial-intracranial (IC-IC) or extracranial-intracranial (EC-IC) bypass and distal clipping or trapping are the valid and rescue treatment modality for extremely rare unilateral distal fusiform superior cerebellar artery (SCA) aneurysms. Yet, in case of bilateral fusiform SCA aneurysms, surgical therapy reaches its limit. Mini-flow diverter devices (FDDs) have only recently become available for treating fusiform aneurysms of such small vessels. We report the unique case of bilateral distal fusiform SCA aneurysms in a 43-year-old man with subarachnoid hemorrhage (Fisher grade IV and World Federation of Neurosurgical Societies [WFNS] grade II) treated with endovascular implantation of bilateral mini-FDDs with excellent outcome and no radiographic signs of infarction. Yet, occlusion of one of the FDDs was found in the follow-up, which again shows the eminent danger of occlusion in case of an implantation of FDDs in such small-caliber vessels, which leaves the discussion about the optimal therapy method open.

The impact of preoperative MRI-based apparent diffusion coefficients on local recurrence and outcome in patients with cerebral metastases.

BACKGROUND: Surgery of single cerebral metastases is standard but frequently fails to achieve local tumour control. Reliable predictors for local tumour progression and overall survival are unknown. MRI-based apparent diffusion coefficients (ADC) correlate with tumour cellularity and invasion. The present study analysed a potential relation between the MRI based apparent diffusion coefficients local recurrence and outcome in patients with brain metastases. METHODS: A retrospective analysis was performed for patients with cerebral metastases and complete surgical resection evaluated by an early postoperative MRI < 72h. Minimal ADC and mean ADC were assessed in preoperative 1,5T-MRI scans by placing regions of interests in the tumour and the peritumoural tissue. RESULTS: Analysis of the relation between ADC values, local progression and outcome was performed in 86 patients with a mean age of 59 years (range 33-83 years). Primary site was NSCLC in 37.2% of all cases. Despite complete resection 33.7% of all patients suffered from local in-brain-progression. There were no significant differences in ADC values in groups based on histology. In the present cohort, the mean ADCmin and the mean ADCmean within the metastasis did not differ significantly between patients with and without a later local in-brain progression (634 × 10-6 vs. 661 × 10-6 mm2/s and 1324 × 10-6 vs. 1361 × 10-6 mm2/s; 1100 × 10-6 vs. 1054 × 10-6 mm2/s; each p > 0.05). Mean ADC values did not correlate significantly with PFS and OAS. CONCLUSION: In the present study analysed ADC values had no significant impact on local in brain progression and survival parameters.

Defining activities in neurovascular microsurgery training: entrustable professional activities for vascular neurosurgery.

BACKGROUND: Entrustable professional activities (EPAs) represent an assessment framework with an increased focus on competency-based assessment. Originally developed and adopted for undergraduate medical education, concerns over resident ability to practice effectively after graduation have led to its implementation in residency training but yet not in vascular neurosurgery. Subjective assessment of resident or fellow performance can be problematic, and thus, we aim to define core EPAs for neurosurgical vascular training. METHODS: We used a nominal group technique in a multistep interaction between a team of experienced neurovascular specialists and a medical educator to identify relevant EPAs. Panel members provided feedback on the EPAs until they reached consent. RESULTS: The process produced seven core procedural EPAs for vascular residency and fellowship training, non-complex aneurysm surgery, complex aneurysm surgery, bypass surgery, arteriovenous malformation resection, spinal dural fistula surgery, perioperative management, and clinical decision-making. CONCLUSION: These seven EPAs for vascular neurosurgical training may support and guide the neurosurgical society in the development and implementation of EPAs as an evaluation tool and incorporate entrustment decisions in their training programs.

Second-look surgery after pediatric brain tumor resection - Single center analysis of morbidity and volumetric efficacy.

Introduction: Postoperative residual tumor can occur for intentional or unintentional reasons. Decision-making regarding second-look surgery has to weigh molecular biology, probability of total resection and prognostic relevance against potential additional morbidity. In interdisciplinary tumor boards the neurosurgeon has to estimate risk and efficacy of second-look surgery in individual cases, based on precise data. Research question: Aim of this study was to provide such data by analyzing morbidity and volumetric efficacy of second-look surgery at a designated pediatric neuro-oncology unit. Material and methods: Children who received second-look surgery in 2007-2018 after incomplete resections were analyzed retrospectively. Measurements were performed on early postoperative magnetic resonance imaging, comparing axial diameter-based measurement as well as computer-assisted volumetric analysis. Results: 59 patients (37% of the overall cohort; 21 female; mean age: 8 â€‹± â€‹5 years) received a subtotal (n â€‹= â€‹35) or near total (n â€‹= â€‹24) resection. After interdisciplinary case review, 12 of these patients received second-look surgery mainly for residual ependymoma. This led to further tumor volume reduction in all cases (new degrees of resection: subtotal â€‹= â€‹2, near total â€‹= â€‹6, gross total â€‹= â€‹4). No new permanent morbidity or perioperative mortality was observed. Discussion and conclusion: Second-look surgery did not increase mortality and permanent morbidity, had an 8% rate of transient morbidity and achieved tumor volume reduction above 95% in 75% of selected cases, with 4 additional gross total resections. Second-look surgery is safe and effective with regard to volumetric outcome parameters even in cases with good initial resections, although the role of second-look surgery regarding oncological outcome has to be further investigated in times of personalized molecular medicine.

Janus Faced HMGB1 and Post-Aneurysmal Subarachnoid Hemorrhage (aSAH) Inflammation.

Aneurysmal subarachnoid hemorrhage (aSAH), resulting majorly from the rupture of intracranial aneurysms, is a potentially devastating disease with high morbidity and mortality. The bleeding aneurysms can be successfully secured; however, the toxic and mechanical impact of the blood extravasation into the subarachnoid space damages the brain cells leading to the release of different damage-associated molecular pattern molecules (DAMPs). DAMPs upregulate the inflammation after binding their cognate receptors on the immune cells and underlies the early and delayed brain injury after aSAH. Moreover, these molecules are also associated with different post-aSAH complications, which lead to poor clinical outcomes. Among these DAMPs, HMGB1 represents a prototypical protein DAMP that has been well characterized for its proinflammatory role after aSAH and during different post-aSAH complications. However, recent investigations have uncovered yet another face of HMGB1, which is involved in the promotion of brain tissue remodeling, neurovascular repair, and anti-inflammatory effects after SAH. These different faces rely on different redox states of HMGB1 over the course of time after SAH. Elucidation of the dynamics of these redox states of HMGB1 has high biomarker as well as therapeutic potential. This review mainly highlights these recent findings along with the conventionally described normal role of HMGB1 as a nuclear protein and as a proinflammatory molecule during disease (aSAH).

In-Vitro Use of Verteporfin for Photodynamic Therapy in Glioblastoma.

BACKGROUND: Stummer et al. established fluorescence-guided surgery (FGS) for glioblastoma (GBM) using 5-aminolevulinic acid (5-ALA). Its metabolite, protoporphyrin IX (PPIX), is also a photosensitizer and can be used for photodynamic therapy (PDT) using a laser beam of 635 nm. The porphyrin derivate verteporfin (VP) was discovered to have properties to penetrate the brain, pharmacologically target glioma cells, and is approved for PDT of choroidal neovascularization in wet age-related macular degeneration at 689 nm. OBJECTIVE: To elucidate whether GBM cell lines are susceptible to PDT with second-generation photosensitizer VP. METHODS: Human glioma cell lines LN229, HSR-GBM1, and a low-passage patient-derived GBM cell line P1 were treated with variable concentrations of VP for 24 h, followed by PDT at 689 nm using a diode laser light. Cell viability was measured using the MTT assay and VP uptake was measured using a desktop cytometer. RESULTS: Significantly higher cell death following PDT with VP compared to VP treatment alone or no treatment was detected in all cell models (LN229, HSR-GBM1, P1). Flowcytometric measurements revealed a concentration-dependent cellular uptake of VP after 24 h incubation up to 99% at 10 µM (HSR-GBM1). CONCLUSION: This study demonstrates that PDT with VP causes cell death in GBM cells at marginal concentrations. Additionally, red spectrum fluorescence was detected at therapeutic concentrations in all cell lines, validating the cellular uptake of VP in GBM cells. VP, therefore, is not only a potential drug for targeting GBM pharmacologically but can be used as an optical imaging dye in surgery and photosensitizer to make GBM susceptible to PDT.

Stereotactic Radiosurgery for Benign Cavernous Sinus Meningiomas: A Multicentre Study and Review of the Literature.

Cavernous sinus meningiomas (CSMs) remain a surgical challenge due to the intimate involvement of their contained nerves and blood vessels. Stereotactic radiosurgery (SRS) is a safe and effective minimally invasive alternative for the treatment of small- to medium-sized CSMs. Objective: To assess the medium- to long-term outcomes of SRS for CSMs with respect to tumour growth, prevention of further neurological deterioration and improvement of existing neurological deficits. This multicentric study included data from 15 European institutions. We performed a retrospective observational analysis of 1222 consecutive patients harbouring 1272 benign CSMs. All were treated with Gamma Knife stereotactic radiosurgery (SRS). Clinical and imaging data were retrieved from each centre and entered into a common database. All tumours with imaging follow-up of less than 24 months were excluded. Detailed results from 945 meningiomas (86%) were then analysed. Clinical neurological outcomes were available for 1042 patients (85%). Median imaging follow-up was 67 months (mean 73.4, range 24-233). Median tumour volume was 6.2 cc (+/-7), and the median marginal dose was 14 Gy (+/-3). The post-treatment tumour volume decreased in 549 (58.1%), remained stable in 336 (35.6%) and increased in only 60 lesions (6.3%), yielding a local tumour control rate of 93.7%. Only 27 (2.8%) of the 60 enlarging tumours required further treatment. Five- and ten-year actuarial progression-free survival (PFS) rates were 96.7% and 90.1%, respectively. Tumour control rates were higher for women than men (p = 0.0031), and also for solitary sporadic meningiomas (p = 0.0201). There was no statistically significant difference in outcome for imaging-defined meningiomas when compared with histologically proven WHO Grade-I meningiomas (p = 0.1212). Median clinical follow up was 61 months (mean 64, range 6-233). Permanent morbidity occurred in 5.9% of cases at last follow-up. Stereotactic radiosurgery is a safe and effective method for treating benign CSM in the medium term to long term.

WNT/ß-Catenin-Mediated Resistance to Glucose Deprivation in Glioblastoma Stem-like Cells.

Isocitrate dehydrogenase (IDH)-wildtype glioblastoma is the most common primary malignant brain tumor. It is associated with a particularly poor prognosis, as reflected by an overall median survival of only 15 months in patients who undergo a supramarginal surgical reduction of the tumor mass followed by combined chemoradiotherapy. The highly malignant nature of IDH-wildtype glioblastoma is thought to be driven by glioblastoma stem-like cells (GSCs) that harbor the ability of self-renewal, survival, and adaptability to challenging environmental conditions. The wingless (WNT) signaling pathway is a phylogenetically highly conserved stemness pathway, which promotes metabolic plasticity and adaptation to a nutrient-limited tumor microenvironment. To unravel the reciprocal regulation of the WNT pathway and the nutrient-limited microenvironment, glioblastoma cancer stem-like cells were cultured in a medium with either standard or reduced glucose concentrations for various time points (24, 48, and 72 h). Glucose depletion reduced cell viability and facilitated the survival of a small population of starvation-resistant tumor cells. The surviving cells demonstrated increased clonogenic and invasive properties as well as enhanced chemosensitivity to pharmacological inhibitors of the WNT pathway (LGK974, berberine). Glucose depletion partially led to the upregulation of WNT target genes such as CTNNB1, ZEB1, and AXIN2 at the mRNA and corresponding protein levels. LGK974 treatment alone or in combination with glucose depletion also altered the metabolite concentration in intracellular compartments, suggesting WNT-mediated metabolic regulation. Taken together, our findings suggest that WNT-mediated metabolic plasticity modulates the survival of GSCs under nutrient-restricted environmental conditions.

Crosstalk between ß-Catenin and CCL2 Drives Migration of Monocytes towards Glioblastoma Cells.

Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) is a fast growing and highly heterogeneous tumor, often characterized by the presence of glioblastoma stem cells (GSCs). The plasticity of GSCs results in therapy resistance and impairs anti-tumor immune response by influencing immune cells in the tumor microenvironment (TME). Previously, ß-catenin was associated with stemness in GBM as well as with immune escape mechanisms. Here, we investigated the effect of ß-catenin on attracting monocytes towards GBM cells. In addition, we evaluated whether CCL2 is involved in ß-catenin crosstalk between monocytes and tumor cells. Our analysis revealed that shRNA targeting ß-catenin in GBMs reduces monocytes attraction and impacts CCL2 secretion. The addition of recombinant CCL2 restores peripheral blood mononuclear cells (PBMC) migration towards medium (TCM) conditioned by shß-catenin GBM cells. CCL2 knockdown in GBM cells shows similar effects and reduces monocyte migration to a similar extent as ß-catenin knockdown. When investigating the effect of CCL2 on ß-catenin activity, we found that CCL2 modulates components of the Wnt/ß-catenin pathway and alters the clonogenicity of GBM cells. In addition, the pharmacological ß-catenin inhibitor MSAB reduces active ß-catenin, downregulates the expression of associated genes and alters CCL2 secretion. Taken together, we showed that ß-catenin plays an important role in attracting monocytes towards GBM cells in vitro. We hypothesize that the interactions between ß-catenin and CCL2 contribute to maintenance of GSCs via modulating immune cell interaction and promoting GBM growth and recurrence.

Structural damage burden and hypertrophic olivary degeneration in pediatric postoperative cerebellar mutism syndrome.

Cerebellar mutism syndrome (CMS) occurs in one out of four children after posterior fossa tumor surgery, with open questions regarding risk factors, pathophysiology, and prevention strategies. Because of similarities between several cerebellar syndromes, a common pathophysiology with damage to the dentato-thalamo-cortical and dentato-rubro-olivary pathways has been proposed. Hypertrophic olivary degeneration (HOD) is an imaging correlate of cerebellar injury observed for instance in stroke patients. Aim of this study was to investigate whether the occurrence and severity of CMS correlates with the extent of damage to the relevant anatomical structures and whether HOD is a time-dependent postoperative neuroimaging correlate of CMS. We performed a retrospective single center study of CMS patients compared with matched non-CMS controls. CMS occurred in 10 children (13% of the overall cohort) with a median age of 8 years. Dentate nucleus (DN) injury significantly correlated with CMS, and superior cerebellar peduncle (SCP) injury was associated by tendency. HOD was observed as a dynamic neuroimaging phenomenon in the postoperative course and its presence significantly correlated with CMS and DN injury. Children who later developed HOD had an earlier onset and tended to have longer persistence of CMS. These findings can guide surgical measures to protect the DN and SCP during posterior fossa tumor resections and to avoid a high damage burden (i.e., bilateral damage). Development of intraoperative neuromonitoring of the cerebellar efferent pathways as well as improved preoperative risk stratification could help to establish a patient-specific strategy with optimal balance between degree of resection and functional integrity.

Development and external validation of a clinical prediction model for survival in patients with IDH wild-type glioblastoma.

OBJECTIVE: Prognostication of glioblastoma survival has become more refined due to the molecular reclassification of these tumors into isocitrate dehydrogenase (IDH) wild-type and IDH mutant. Since this molecular stratification, however, robust clinical prediction models relevant to the entire IDH wild-type glioblastoma patient population are lacking. This study aimed to provide an updated model that predicts individual survival prognosis in patients with IDH wild-type glioblastoma. METHODS: Databases from Germany and the Netherlands provided data on 1036 newly diagnosed glioblastoma patients treated between 2012 and 2018. A clinical prediction model for all-cause mortality was developed with Cox proportional hazards regression. This model included recent glioblastoma-associated molecular markers in addition to well-known classic prognostic variables, which were updated and refined with additional categories. Model performance was evaluated according to calibration (using calibration plots and calibration slope) and discrimination (using a C-statistic) in a cross-validation procedure by country to assess external validity. RESULTS: The German and Dutch patient cohorts consisted of 710 and 326 patients, respectively, of whom 511 (72%) and 308 (95%) had died. Three models were developed, each with increasing complexity. The final model considering age, sex, preoperative Karnofsky Performance Status, extent of resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and adjuvant therapeutic regimen showed an optimism-corrected C-statistic of 0.73 (95% confidence interval 0.71-0.75). Cross-validation between the national cohorts yielded comparable results. CONCLUSIONS: This prediction model reliably predicts individual survival prognosis in patients with newly diagnosed IDH wild-type glioblastoma, although additional validation, especially for long-term survival, may be desired. The nomogram and web application of this model may support shared decision-making if used properly.

Would they do it again? Final treatment decisions in malignant brain tumour patients-a caregiver's perspective.

PURPOSE: Overall survival of malignant brain tumour patients has significantly been increased over the last years. However, therapy remains palliative, and side effects should be balanced. Once terminal phase is entered, both patients and caregivers may find it hard to accept, and further therapies are demanded. But little is known about this highly sensitive period. Therefore, we analysed the last therapy decisions from the family caregiver's perspective. Would they support their beloved ones in the same way or would they now recommend a different therapy decision? METHODS: Caregivers of deceased malignant brain tumour patients, treated at our neurooncological centre between 2011 and 2017, were included. We designed a questionnaire to analyse the impact of the last therapy decision (resection, chemotherapy, radiotherapy), focusing on probable repeat of the choice taken and general therapy satisfaction. Independent variables, for example "satisfaction with therapy", were analysed using linear regression analysis, the coefficient of determination R2 and the standardized regression coefficient ß. The binary logistic regression analyses were taken to illustrate relationships with the dichotomously scaled outcome parameter "re-choice of therapy". Odds ratio analyses were used to determine the strength of a relationship between two characteristics. RESULTS: Data from 102 caregivers (life partners (70.6%)) were analysed retrospectively. Each 40% of patients died in a hospice or at home (20% in a hospital). In 67.6% the last therapy was chemotherapy followed by radiotherapy (16.7%) and surgery (15.7%). A positive evaluation of the last therapy was significantly correlated to re-choosing of respective therapy (chemo-/radiotherapy: p = 0.000) and satisfaction with informed consent (p = 0.000). Satisfaction regarding interpersonal contact was significantly correlated to satisfaction with resection (p = 0.000) and chemotherapy (p = 0.000 27 caregivers (28.7%) felt overburdened with this situation). CONCLUSION: This analysis demonstrates a significant correlation between a positive relation of patient/caregiver/physician and the subjective perception of the latest therapy. It underlines the central role of caregivers, who should be involved in therapy discussions. Neurooncologists should be specially trained in communication and psycho-oncology.

Molecular features of glioblastomas in long-term survivors compared to short-term survivors-a matched-pair analysis.

BACKGROUND: Although glioblastoma (GB) is associated with a devastating prognosis, a small proportion of patients achieve long-term survival rates. We herein present a matched-pair analysis of molecular factors found in long- and short-term survivors (LTS, STS). METHODS: We performed a cross-institutional analysis of 262 patient records and matched a group of 91 LTS (≥ 3 years) with two groups of STS (STS-1, n = 91; STS-2, n = 80). Matching was performed according to age, Karnofsky Performance Status, initial therapy and adjuvant therapy. Molecular factors were compared between LTS (total of 91 patients) v. STS-1, and LTS (subgroup of 80 patients) v. STS-2. We included glial fibrillary acidic protein (GFAP), O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, isocitrate dehydrogenase 1 (IDH-1); furthermore, the proliferation index was analyzed (Ki-67/MIB-1). RESULTS: IDH-1 and decreased Ki-67 were numerically associated with LTS but the difference was only significant compared to STS-1 (n.s. v. STS-2). LTS was associated with MGMT promoter hypermethylation (p = 0.013 and p = 0.022) and GFAP expression (p < 0.001 and p = 0.001). Positivity for both factors combined compared to negativity for one factor occurred more often in the LTS group (p = 0.002 and p = 0.006); negativity for both factors combined did not occur in the LTS group. CONCLUSION: In this retrospective analysis, GFAP expression and MGMT promoter methylation were associated with LTS. Given the hypothesis-generating nature of our study, these observations should be confirmed in prospective clinical trials.

Canonical WNT pathway inhibition reduces ATP synthesis rates in glioblastoma stem cells.

BACKGROUND: The conserved stem cell signaling network canonical Wingless (WNT) plays important roles in development and disease. Aberrant activation of this pathway has been linked to tumor progression and resistance to therapy. Industry and academia have substantially invested in developing substances, which can efficiently and specifically block the WNT signaling pathway. However, a clear clinical proof of the efficacy of this approach is still missing. Studies on the metabolomics dysregulation of cancer cells have led to innovations in oncological diagnostics. In addition, modulation of cancer cell metabolome is at the base of promising clinical oncology trials currently underway. While onco-protein activation can have profound metabolic outcomes, the involvement of stem cell signals, such as the WNT pathway, in tumor cell metabolomics is yet insufficiently characterized. MATERIAL AND METHODS: We determined live cell metabolism and bioenergetics in pathophysiological relevant, WNT-dependent glioblastoma stem cell (GSC) models. We quantified those parameters in cells with canonical WNT activity and in isogenic cells where WNT activity had been inhibited by short hairpin RNA against ß-catenin. Furthermore, we applied computational analysis of RNA sequencing to verify our functional findings in independent GSCs cohorts. RESULTS: The investigated collection of disease models allows the separation in tumors with low, moderate and high base line metabolic activity. Suppression of canonical WNT signaling led to significant reduction of total, mitochondrial, and glycolytic ATP production rates. Elevated canonical WNT transcription signature in GSCs positively correlated with transcription levels of mitochondrial ATP synthesis, whereas non-canonical WNT gene expression signature did not. CONCLUSION: The applied disease modeling technology allows the recapitulation of inter-tumoral heterogeneous metabolic properties of glioblastoma. Our data show for the first time that inhibition of canonical WNT signaling in alive GSCs functionally correlates with energy inhibition and glucose homeostasis. As this correlation occurs in GSCs from different transcriptional or epigenetic transcriptional subtypes, our results suggest that developing therapies directed against glycolysis/ATP-synthesis may be a promising strategy to overcome therapy resistance due to inter-tumoral heterogeneity and offers starting point to impair downstream signal WNT.

Synthetic vascular grafts as a new treatment option for space-occupying tumor bed cysts.

INTRODUCTION: Several authors have reported the formation of slit valves as the underlying pathomechanism of space-occupying tumor bed cysts. Iatrogenic slit valves following the resection of high-grade gliomas have been linked to certain risk factors such as intraoperative opening of the ventricles and attempts to seal these. The best therapeutic management of such cystic lesions remains elusive. Several treatment options such as cyst fenestration or cystoperitoneal shunting have been employed but remain associated with high rates of recurrence. With the given complications of the above-described treatment options, the objective was to devise a new therapy option that is safe and effective and treats the slit valve itself rather than its symptoms. METHODS: Between the years of 2010 and 2020, we successfully treated four patients with high-pressure tumor bed cysts following glioma resection by implantation of synthetic ringed vascular grafts into the slit valve. RESULTS: Postoperatively, the tumor bed cysts were regressive in all patients. Moreover, none of the treatment patients developed any complications associated with the implanted vascular grafts. Revision-free survival was 10, 12, 53, and 126 months, respectively. CONCLUSION: The use of synthetic vascular grafts as a means of stenting slit valves is a safe and effective novel treatment option for high-pressure tumor bed cysts.

Profile and Prognosis of Spontaneous Lobar Intracerebral Hemorrhage: Comparison of 6-month Survival with STICH II and the MISTIE III Lobar Hemorrhage Subset.

BACKGROUND: Randomized trials on spontaneous lobar intracerebral hemorrhage (ICH) provided no convincing evidence of the superiority of surgical treatment. Since recruitment in the trials was under the premise of equipoise, a selection bias toward patients who did not need surgery or were in hopeless condition must be suspected. The aim of the actual analysis was to compare outcome and patient profile of an unselected hospital series with recent randomized trials and to develop a prognostic model. METHODS: Of 821 patients with spontaneous ICH managed at the neurosurgical department of the University Hospital Düsseldorf between 2013 and 2018, 159 had lobar bleedings. Patient characteristics, hematoma volume, treatment modality, and 6-month survival were compared with STICH II and the subset of lobar hemorrhage in the MISTIE III trial. In addition, a prognostic model for 6-month survival in our patients was developed using a random forest classifier. RESULTS: One hundred and seven patients were managed by surgical evacuation of the hematoma and 52 without surgical evacuation. Median hemorrhage volume in our surgical cohort was 66 and 42 mL in the conservative cohort, compared with 38 and 36 mL in the STICH II trial, and 46 and 47 mL in the surgical and conservative MISTIE III lobar hemorrhage subset. Median initial Glasgow Coma Scale (GCS) score was 12 in our surgical group and 11 in the conservative group, compared with 13 in the STICH II cohorts and 12 in the MISTIE III lobar hemorrhage subset. Median age in our surgical and conservative cohorts was 73 and 74 years, respectively, compared with 65 years in both STICH II cohorts and 68 years in the MISTIE II subsets. Twenty-nine percent of our surgical cohort and 55% of our conservatively managed patients deceased within the first 6 months, compared with 18 and 24%, respectively, in STICH II and 17 and 24% in the MISTIE III subset. Our prognostic model identified large hemorrhage volumes and low admission GCS score as main unfavorable prognostic factors for 6-month survival. The random forest classifier achieved a predictive accuracy of 78% and an area under curve (AUC)- value of 88% regarding survival at 6 months, on a test set independent of the training set. CONCLUSIONS: In comparison with our surgical group, the STICH II and MISTIE III cohorts, recruited under the premise of physician equipoise, underrepresented patients with large ICHs. The cohorts in the randomized trials were therefore biased toward patients with a favorable perspective under conservative management. Initial hematoma volume and admission GCS were the main prognostic factors in our patients.

Psychooncological distress in low-grade glioma patients-a monocentric study.

BACKGROUND: Patients diagnosed with low-grade glioma (LGG) must live with constant knowledge of an upcoming malignant tumor transformation which may lead to increased anxiety and reduced quality of life. Here, we (1) analyzed the prevalence and risk factors for distress in LGG patients using (2) different screening tools to subsequently (3) evaluate their need for psychological support. METHOD: Patients with LGG-suspicious findings in MRI studies as well as patients with histopathological confirmed LGG were screened using three established self-assessment instruments (Hospital Anxiety and Depression Scale, Distress Thermometer, EORTC-QLQ-C30-BN20). Screening results were correlated with sociodemographic factors. RESULTS: One hundred forty-nine patients (74 men and 75 women) were prospectively included. Patients were further divided into different subgroups regarding the time of screening and diagnosis. An increased level of distress was observed in 20.8% (mean score 1.21, 95% CI 1.15-1.28) of all patients screened by HADS. Significant associated factors were pre-existing psychiatric disorders (p = 0.003) and psychotropic medication (p = 0.029). HRQoL (p = 0.022) and global health item (p = 0.015), as well as future uncertainty (p = 0.047), assessed by the EORTC-QLQ-C30-BN20 were significantly higher in those patients without histopathological diagnosis. Increased distress was significantly correlated with results in chosen sub-items of the HRQoL questionnaire (p < 0.001). CONCLUSIONS: Our results demonstrate the need for frequent distress screening. If specific tools are not available, HRQoL questionnaires can also be used. Patients with pre-existing psychological stress should be offered additional psychooncological support, irrespectively of the time of screening or tumor diagnosis. CLINICAL TRIAL REGISTRATION NUMBER: 4087.

Optimized Intraoperative Imaging for Stereotactic Planning with a Multiaxial Robotic C-arm System: Technical Note and Case Series.

BACKGROUND: The preoperative preparation of the planning dataset for frame-based stereotactic brain biopsy is often associated with logistical effort and burden on the patient. Intraoperative imaging modalities need to be investigated to overcome these limitations. OBJECTIVE: The objective of the study was to develop and apply a new method for the intraoperative acquisition of the planning dataset with the multiaxial robotic C-arm system Artis zeego. METHODS: An indication-customized dose-reduced protocol for Artis zeego was developed and implemented into the workflow. A sample of 14 patients who had undergone intraoperative imaging with Artis zeego was analyzed. A sample of 10 patients with conventional preoperative imaging by cranial computed tomography (CT) was used as a control group. Outcomes were compared with regard to target deviation, diagnostic value of the biopsies, complications, and procedure time. RESULTS: In all patients, a suitable intraoperative planning dataset could be acquired with Artis zeego. Total procedure time was shorter for the Artis zeego group (p = 0.01), whereas time in the operating room area was longer in the Artis zeego group (p = 0.04). Biopsy results were diagnostic in 12 patients (86%) in the Artis zeego group and in 8 patients (80%) in the control group. There were no significant differences in target size, trajectory length, or target deviation. CONCLUSION: Intraoperative imaging for frame-based stereotactic brain biopsy with Artis zeego is an easy and feasible method. Accuracy is comparable to conventional CT, whereas radiation exposure could be additionally reduced. It allows a significant reduction of the total procedure length and improves the comfort for the patient and staff.