Treatment outcome of IDH1/2 wildtype CNS WHO grade 4 glioma histologically diagnosed as WHO grade II or III astrocytomas.

BACKGROUND: Isocitrate dehydrogenase (IDH)1/2 wildtype (wt) astrocytomas formerly classified as WHO grade II or III have significantly shorter PFS and OS than IDH mutated WHO grade 2 and 3 gliomas leading to a classification as CNS WHO grade 4. It is the aim of this study to evaluate differences in the treatment-related clinical course of these tumors as they are largely unknown. METHODS: Patients undergoing surgery (between 2016-2019 in six neurosurgical departments) for a histologically diagnosed WHO grade 2-3 IDH1/2-wt astrocytoma were retrospectively reviewed to assess progression free survival (PFS), overall survival (OS), and prognostic factors. RESULTS: This multi-center study included 157 patients (mean age 58 years (20-87 years); with 36.9% females). The predominant histology was anaplastic astrocytoma WHO grade 3 (78.3%), followed by diffuse astrocytoma WHO grade 2 (21.7%). Gross total resection (GTR) was achieved in 37.6%, subtotal resection (STR) in 28.7%, and biopsy was performed in 33.8%. The median PFS (12.5 months) and OS (27.0 months) did not differ between WHO grades. Both, GTR and STR significantly increased PFS (P < 0.01) and OS (P < 0.001) compared to biopsy. Treatment according to Stupp protocol was not associated with longer OS or PFS compared to chemotherapy or radiotherapy alone. EGFR amplification (P = 0.014) and TERT-promotor mutation (P = 0.042) were associated with shortened OS. MGMT-promoter methylation had no influence on treatment response. CONCLUSIONS: WHO grade 2 and 3 IDH1/2 wt astrocytomas, treated according to the same treatment protocols, have a similar OS. Age, extent of resection, and strong EGFR expression were the most important treatment related prognostic factors.

Targeted Epidural Blood Patch Injection Through a Mini-Open Approach for Treatment of Spontaneous Intracranial Hypotension.

BACKGROUND AND OBJECTIVES: Spontaneous intracranial hypotension is recognized as a cause for refractory headache. Treatment can range from blind blood patch injection to microsurgical repair of the cerebrospinal fluid (CSF) leak. The objective of the study was to investigate the safety and efficacy of the targeted blood patch injection (TBPI) technique through a mini-open approach in treatment of refractory intracranial hypotension. METHODS: We retrospectively reviewed cases of 20 patients who were treated for spontaneous intracranial hypotension at our institute between 2011 and 2022. Head and spine MRI and whole-spine myelography were performed in an attempt to localize the CSF leak. All patients underwent implantation of two epidural drains above and beneath the index level through a minimally invasive interlaminar microsurgical approach under general anesthesia. Then, blood patch was injected under clinical surveillance. Treatment success and surgical complications were evaluated postoperatively and at follow-up. RESULTS: Patients presented with orthostatic headache, vertigo, sensory deficits, and hypacusis (95%, 15%, 15%, and 10%, respectively). Subdural effusions were present in 65% of the cases. A CSF leak was identified in all patients. The exact site of the CSF leak could be identified in 80% of cases. TBPI was performed with an average blood amount of 37.5 mL. A significant improvement of symptoms was reported in 90% of the cases. A total of 15% of the patients showed recurrent symptoms and underwent a second TBPI, resulting in symptom relief. No therapy-related complications were reported. CONCLUSION: TBPI is a safe and efficient treatment for spontaneous intracranial hypotension. It is performed in a minimally invasive procedure and can be repeated, if necessary, with a very low-risk profile.

Endoscope-enhanced fluorescence-guided microsurgery increases survival in patients with glioblastoma.

PURPOSE: Extent of resection (EOR) predicts progression-free survival (PFS) and may impact overall survival (OS) in patients with glioblastoma. We recently demonstrated that 5-aminolevulinic acid-(5-ALA)-fluorescence-enhanced endoscopic surgery increase the rate of gross total resection. However, it is hitherto unknown whether fluorescence-enhanced endoscopic resection affects survival. METHODS: We conducted a retrospective single-center analysis of a consecutive series of patients who underwent surgery for non-eloquently located glioblastoma between 2011 and 2018. All patients underwent fluorescence-guided microscopic or fluorescence-guided combined microscopic and endoscopic resection. PFS, OS, EOR as well as clinical and demographic parameters, adjuvant treatment modalities, and molecular characteristics were compared between microscopy-only vs. endoscopy-assisted microsurgical resection. RESULTS: Out of 114 patients, 73 (65%) were male, and 57 (50%) were older than 65 years. Twenty patients (18%) were operated on using additional endoscopic assistance. Both cohorts were equally distributed in terms of age, performance status, lesion location, adjuvant treatment modalities, and molecular status. Gross total resection was achieved in all endoscopy-assisted patients compared to about three-quarters of microscope-only patients (100% vs. 75.9%, p=0.003). The PFS in the endoscope-assisted cohort was 19.3 months (CI95% 10.8-27.7) vs. 10.8 months (CI95% 8.2-13.4; p=0.012) in the microscope-only cohort. OS in the endoscope-assisted group was 28.9 months (CI95% 20.4-34.1) compared to 16.8 months (CI95% 14.0-20.9), in the microscope-only group (p=0.001). CONCLUSION: Endoscope-assisted fluorescence-guided resection of glioblastoma appears to substantially enhance gross total resection and OS. The strong effect size observed herein is contrasted by the limitations in study design. Therefore, prospective validation is required before we can generalize our findings.

Surgical timing and indications for decompressive craniectomy in malignant stroke: results from a single-center retrospective analysis.

PURPOSE: Acute ischemic stroke induces rapid neuronal death and time is a key factor in its treatment. Despite timely recanalization, malignant cerebral infarction can ensue, requiring decompressive surgery (DC). The ideal timing of surgery is still a matter of debate; in this study, we attempt to establish the ideal time to perform surgery in this population. METHODS: We conducted a retrospective study of patients undergoing DC for stroke at our department. The indication for DC was based on drop in level of consciousness and standard imaging parameters. Patients were stratified according to the timing of DC in four groups: (a) "ultra-early" ≤12 h, (b) "early" >12≤24 h, (c) "timely" >24≤48 h, and (d) "late" >48 h. The primary endpoint of this study was in-house mortality, as a dependent variable from surgical timing. Secondary endpoint was modified Rankin scale at discharge. RESULTS: In a cohort of 110 patients, the timing of surgery did not influence mortality or functional outcome (p=0.060). Patients undergoing late DC were however significantly older (p=0.008), and those undergoing ultra-early DC showed a trend towards a lower GCS at admission. CONCLUSIONS: Our results add to the evidence supporting an extension of the time window for DC in stroke beyond 48 h. Further criteria beyond clinical and imaging signs of herniation should be considered when selecting patients for DC after stroke to identify patients who would benefit from the procedure.

Intraoperative MRI-Guided Resection Is Not Superior to 5-Aminolevulinic Acid Guidance in Newly Diagnosed Glioblastoma: A Prospective Controlled Multicenter Clinical Trial.

PURPOSE: Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma. METHODS: This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary end point was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of preoperative and postoperative MRI with 1-mm slices. Secondary end points included progression-free survival (PFS) and overall survival (OS), patient-reported quality of life, and clinical parameters. RESULTS: We recruited 314 patients with newly diagnosed glioblastomas at 11 German centers. A total of 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as-treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm³, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm (P = .79). Incision-suture times (P < .001) were significantly longer in the iMRI arm (316 v 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0 cm³) was a significant favorable prognostic factor for PFS (P < .001) and OS (P = .048), especially in methylguanine-DNA-methyltransferase unmethylated tumors (P = .006). CONCLUSION: We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm³ contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.

Robot-assisted spinal augmentation procedures: is it worth the increased effort?

PURPOSE: Spinal augmentation procedures (SAP) are standard procedures for vertebral compression fractures. Often, SAPs are carried out in a minimally invasive, percutaneous way. Certain anatomic conditions such as small pedicles or kyphotic deformities resulting from a significant collapse of the vertebral body might render the operation more difficult and increase the risk of complications. Thus, robot assistance might be useful to optimize the trajectory and to reduce procedure-associated complications. In this study robot-assisted percutaneous SAPs are compared with conventional fluoroscopy-guided percutaneous SAP. METHODS: A retrospective observational analysis was carried out. Standard demographic parameters were analyzed. Procedural data including radiation dosage records were screened. Biomechanical data were recorded. Cement volumes were analyzed. The precision of the pedicular trajectory was reviewed, and misplaced trajectories were categorized. Procedure-associated complications were analyzed and evaluated for their clinical significance. RESULTS: A total of 130 procedures were reviewed, and 94 patients were finally included. Osteoporotic fractures (OF) were the main indication (60.7%; OF 2-44%, OF 4-33%). Demographic parameters and clinically relevant complications were equally distributed between the two groups. Duration of surgery was significantly longer in robot-assisted procedures (p < 0.001). Intraoperative radiation exposure was equally distributed. Injected cement volume was similar in both groups. There was no significant difference in pedicle trajectory deviation. CONCLUSION: The use of robot assistance in SAP seems not to be superior with regard to accuracy, radiation exposure and the rate of complications when compared to fluoroscopy-guided SAP.

Resilience in Lower Grade Glioma Patients.

Current data show that resilience is an important factor in cancer patients' well-being. We aim to explore the resilience of patients with lower grade glioma (LGG) and the potentially influencing factors. We performed a cross-sectional assessment of adult patients with LGG who were enrolled in the LoG-Glio registry. By phone interview, we administered the following measures: Resilience Scale (RS-13), distress thermometer, Montreal Cognitive Assessment Test for visually impaired patients (MoCA-Blind), internalized stigmatization by brain tumor (ISBI), Eastern Cooperative Oncological Group performance status (ECOG), patients' perspective questionnaire (PPQ) and typical clinical parameters. We calculated correlations and multivariate regression models. Of 74 patients who were assessed, 38% of those showed a low level of resilience. Our results revealed significant correlations of resilience with distress (p < 0.001, −0.49), MOCA (p = 0.003, 0.342), ECOG (p < 0.001, −0.602), stigmatization (p < 0.001, −0.558), pain (p < 0.001, −0.524), and occupation (p = 0.007, 0.329). In multivariate analyses, resilience was negatively associated with elevated ECOG (p = 0.020, ß = −0.383) and stigmatization levels (p = 0.008, ß = −0.350). Occupation showed a tendency towards a significant association with resilience (p = 0.088, ß = −0.254). Overall, low resilience affected more than one third of our cohort. Low functional status is a specific risk factor for low resilience. The relevant influence of stigmatization on resilience is a novel finding for patients suffering from a glioma and should be routinely identified and targeted in clinical routine.

Long-term outcomes of pediatric epilepsy surgery: Individual participant data and study level meta-analyses.

OBJECTIVE: Long-term seizure outcomes of pediatric epilepsy surgery are understudied. A systematic review and independent patient data meta-analysis was performed to study seizure outcomes ≥ 10 years following pediatric resective epilepsy surgery. METHODS: Electronic literature searches of PubMed, Web of Science, and CINAHL were conducted for relevant articles from inception to April 2020. The following search terms were used in various combinations: "pediatric", "child", "adolescent", "epilepsy", "resective", "surgery", "long-term", "longitudinal", "10 year". Two reviewers (W.B.H., T.B.C.) performed title, abstract, and full-text screening. All relevant perioperative factors reported that may be associated with long-term seizure outcomes were recorded at a study or individual participant level. The primary outcome was long-term (≥ 10 year) seizure freedom measured by the Engel Classification scale, and available data on functional outcomes were also reviewed. RESULTS: Twenty-five articles met criteria for inclusion in the study, which were analyzed for proportions of 10-year seizure freedom ranging from 57.6% at the study level to 64.8% at the individual patient level. At the study level, the proportion of patients remaining seizure free at least 10 years postoperatively (61.2%; 95% CI 52.5-69.3) was significantly less than at 1 year (74.2%; 95% CI 69.3-78.6; p = 0.008) but not at 2 years (67.9%; 95% CI 58.6-76.0) or 5 years (63.7%; 95% CI 55.4-71.2). No differences in long-term seizure freedom were detected by etiology or surgery type. At the individual patient level, univariate logistic regression analyses of all variables putatively associated with seizure freedom demonstrated that lobectomy (OR 0.280, 95% CI 0.117-0.651, p = 0.003) was associated with decreased long-term seizure freedom (41.9%) compared to lesionectomy (75.7%) and hemispherectomy (69.4%), which achieved similar results. CONCLUSION: Resective surgery is a durable and potentially curative treatment option for select pediatric patients with refractory epilepsy. On a group level, two-thirds of children have long-term seizure freedom ≥ 10 years after resective epilepsy surgery. Given the greatest rate of change occurs in the first 2 years, this may serve as the best short-term follow-up period to predict long-term outcome. Although lobectomy appears to be a strong predictor for lower likelihood of long-term seizure freedom, long-term prognostication on an individual patient level is still not possible. Uniform data reporting and prospective, multicenter studies collecting high quality, stratified (e.g., by etiology, surgery type) data over an extended postoperative interval are recommended to further examine the durability of resective surgery as a treatment for pediatric epilepsy.

Regorafenib for recurrent high-grade glioma: a unicentric retrospective analysis of feasibility, efficacy, and toxicity.

We describe here 11 consecutive patients with recurrence of high-grade glioma treated with regorafenib at our university medical center. The majority of patients had MGMT promoter methylation (9/11 cases). Regorafenib was given as 2nd line systemic treatment in 6/11 patients and 3rd or higher line treatment in 5/11 patients. The median number of applied cycles was 2 with dosage reductions in 5/11. Response to treatment was observed in 4/11 (PR in 1/11, and SD in 3/11). Median overall survival for the cohort was 16.1 months, median progression-free survival 9.0 months, and median time to treatment failure 3.3 months. Side effects of any CTCAE grade were noted in all patients, hereby 6/11 with CTCAE °III-IV reactions. High-grade side effects were of dermatologic, cardiovascular, and hematologic nature. A mean treatment delay of 57.5 days (range 23-119) was noted between tumor board recommendation and treatment initiation due to the application process for off-label use in this indication. In conclusion, treatment with regorafenib in relapsed high-grade glioma is a feasible treatment option but has to be considered carefully due to the significant side effect profile.

High Periventricular T1 Relaxation Times Predict Gait Improvement After Spinal Tap in Patients with Idiopathic Normal Pressure Hydrocephalus.

PURPOSE: The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) can be challenging. Aim of this study was to use a novel T1 mapping method to enrich the diagnostic work-up of patients with suspected iNPH. METHODS: Using 3T magnetic resonance imaging (MRI) we prospectively evaluated rapid high-resolution T1 mapping at 0.5 mm resolution and 4 s acquisition time in 15 patients with suspected iNPH and 8 age-matched, healthy controls. T1 mapping in axial sections of the cerebrum, clinical and neuropsychological testing were performed prior to and after cerebrospinal fluid tap test (CSF-TT). T1 relaxation times were measured in 5 predefined periventricular regions. RESULTS: All 15 patients with suspected iNPH showed gait impairment, 13 (86.6%) showed signs of cognitive impairment and 8 (53.3%) patients had urinary incontinence. Gait improvement was noted in 12 patients (80%) after CSF-TT. T1 relaxation times in all periventricular regions were elevated in patients with iNPH compared to controls with the most pronounced differences in the anterior (1006 ± 93 ms vs. 911 ± 77 ms; p = 0.023) and posterior horns (983 ± 103 ms vs. 893 ± 68 ms; p = 0.037) of the lateral ventricles. Montreal cognitive assessment (MoCA) scores at baseline were negatively correlated with T1 relaxation times (r < -0.5, p < 0.02). Higher T1 relaxation times were significantly correlated with an improvement of the 3­m timed up and go test (r > 0.6 and p < 0.03) after CSF-TT. CONCLUSION: In iNPH-patients, periventricular T1 relaxation times are increased compared to age-matched controls and predict gait improvement after CSF-TT. T1 mapping might enrich iNPH work-up and might be useful to indicate permanent shunting.

Eloquent Lower Grade Gliomas, a Highly Vulnerable Cohort: Assessment of Patients' Functional Outcome After Surgery Based on the LoG-Glio Registry.

Majority of lower grade glioma (LGG) are located eloquently rendering surgical resection challenging. Aim of our study was to assess rate of permanent deficits and its predisposing risk factors. We retrieved 83 patients harboring an eloquently located LGGs from the prospective LoG-Glio Database. Patients without surgery or incomplete postoperative data were excluded. Sign rank test, explorative correlations by Spearman ρ and multivariable regression for new postoperative deficits were calculated. Eloquent region involved predominantly motor (45%) and language (40%). At first follow up after 3 months permanent neuro-logical deficits (NDs) were noted in 39%. Mild deficits remained in 29% and severe deficits in 10%. Complete tumor removal (CTR) was successfully in 62% of intended cases. Postoperative and 3-month follow up National Institute of Health Stroke Score (NIHSS) showed significantly lower values than preoperatively (p<0.001). 38% cases showed a decreased NIHSS at 3-month, while occurrence was only 14% at 9-12-month follow up. 6/7 patients with mild aphasia recovered after 9-12 months, while motor deficits present at 3-month follow up were persistent in majority of patients. Eastern oncology group functional status (ECOG) significantly decreased by surgery (p < 0.001) in 31% of cases. Between 3-month and 9-12-months follow up no significant improvement was seen. In the multivariable model CTR (p=0.019, OR 31.9), and ECOG>0 (p=0.021, OR 8.5) were independent predictors for permanent postoperative deficit according to NIHSS at 3-month according to multivariable regression model. Patients harboring eloquently located LGG are highly vulnerable for permanent deficits. Almost one third of patients have a permanent reduction of their functional status based on ECOG. Risk of an extended resection has to be balanced with the respective oncological benefit. Especially, patients with impaired pre-operative status are at risk for new permanent deficits. There is a relevant improvement of neurological symptoms in the first year after surgery, especially for patients with slight aphasia.

In vitro testing of explanted shunt valves in hydrocephalic patients with suspected valve malfunction.

Diagnosis of symptomatic valve malfunction in hydrocephalic patients treated with VP-Shunt (VPS) might be difficult. Clinical symptoms such as headache or nausea are nonspecific, hence cerebrospinal fluid (CSF) over- or underdrainage can only be suspected but not proven. Knowledge concerning valve malfunction is still limited. We aim to provide data on the flow characteristics of explanted shunt valves in patients with suspected valve malfunction. An in vitro shunt laboratory setup was used to analyze the explanted valves under conditions similar to those in an implanted VPS. The differential pressure (DP) of the valve was adjusted stepwise to 20, 10, 6, and 4 cmH2O. The flow rate of the explanted and the regular flow rate of an identical reference valve were evaluated at the respective DPs. Twelve valves of different types (Codman CertasPlus valve n = 3, Miethke Shuntassistant valve n = 4, Codman Hakim programmable valve n = 3, DP component of Miethke proGAV 2.0 valve n = 2) from eight hydrocephalic patients (four male), in whom valve malfunction was assumed between 2016 and 2017, were replaced with a new valve. Four patients suffered from idiopathic normal pressure (iNPH), three patients from malresorptive and one patient from obstructive hydrocephalus. Post-hoc analysis revealed a significant difference (p < 0.001) of the flow rate between each explanted valve and their corresponding reference valve, at each DP. In all patients, significant alterations of flow rates were demonstrated, verifying a valve malfunction, which could not be objectified by the diagnostic tools used in the clinical routine. In cases with obscure clinical VPS insufficiency, valve deficiency should be considered.

A matter of frailty: the modified Subdural Hematoma in the Elderly (mSHE) score.

The Subdural Hematoma in the Elderly (SHE) score was developed as a model to predict 30-day mortality from acute, chronic, and mixed subdural hematoma in the elderly population after minor or no trauma. Emerging evidence suggests frailty to be predictive of mortality and morbidity in the elderly. In this study, we aim to externally validate the SHE for chronic subdural hematoma (CSDH) alone, and we hypothesize that the incorporation of frailty into the SHE may increase its predictive power. A retrospective cohort of elderly patients with CSDH after minor or no trauma being treated at our institution was evaluated with the SHE. Thirty-day mortality and outcome were documented. Patients were assessed with the Clinical Frailty Scale (CFS), which was incorporated into a modified SHE (mSHE). Both the SHE and the mSHE were then assessed in their predictive powers through receiver operating characteristic statistics. We included 168 patients. Most (n = 124, 74%) had a favorable outcome at 30 days. Mortality was low at n = 7, 4%. The SHE failed to predict mortality (AUC = .564, p = .565). Contrarily, the mSHE performed well in both mortality (AUC = .749, p = .026) and outcome (AUC = .862, p < .001). A threshold of mSHE = 3 is predictive of mortality with a sensitivity of 50% and a specificity of 75% and of poor outcome with a sensitivity of 88% and a specificity of 64%. Frailty should be routinely evaluated in elderly individuals, as it can predict outcome and mortality, providing the possibility for medical, surgical, nutritional, cognitive, and physical exercise interventions.

The Efficacy of Local Flaps in the Treatment of Traumatic Scalp Defects.

BACKGROUND: Scalp defects represent a therapeutic challenge. The aim of this study is to present our experience with local and regional flaps in the treatment of trauma-induced scalp defects. Furthermore, a comparison with other surgical techniques was performed. METHODS: A retrospective evaluation of patient records was performed. Only patients who underwent surgery using local flaps between January 2010 and September 2020 due to traumatic scalp defects were included in the study. RESULTS: In all, 10 cases were identified (3 females, 7 males, average age at surgery of 46.5 years [range: 18-82 years]). Six patients underwent surgery due to tissue defects and four due to scar keloids. Three patients experienced minor postoperative complications, one of which required additional surgery. The mean defect size was 35.75 cm2 (range: 4-79 cm2) among the four patients where the defect size could be determined retrospectively. The mean inpatient follow-up was 12.4 days (range: 2-34 days). CONCLUSIONS: Local flaps can be widely used. In carefully selected cases, they have the fewest disadvantages of all surgical techniques. In our experience, large angiosomes of the main scalp arteries allow the treatment of defects larger than 30 cm2 with local flaps. Our experience also suggests that the dimensions of flap length to flap width can exceed a ratio of 2:1 in the scalp.

WNT11/ROR2 signaling is associated with tumor invasion and poor survival in breast cancer.

BACKGROUND: Breast cancer has been associated with activation of the WNT signaling pathway, although no driver mutations in WNT genes have been found yet. Instead, a high expression of the alternative WNT receptor ROR2 was observed, in particular in breast cancer brain metastases. However, its respective ligand and downstream signaling in this context remained unknown. METHODS: We modulated the expression of ROR2 in human breast cancer cells and characterized their gene and protein expression by RNA-Seq, qRT-PCR, immunoblots and reverse phase protein array (RPPA) combined with network analyses to understand the molecular basis of ROR2 signaling in breast cancer. Using co-immunoprecipitations, we verified the interaction of ROR2 with the identified ligand, WNT11. The functional consequences of WNT11/ROR2 signaling for tumor cell aggressiveness were assessed by microscopy, impedance sensing as well as viability and invasion assays. To evaluate the translational significance of our findings, we performed gene set enrichment, expression and survival analyses on human breast cancer brain metastases. RESULTS: We found ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. ROR2 overexpression induced a BRCAness-like phenotype in a cell-context specific manner and rendered cells resistant to PARP inhibition. High levels of ROR2 were furthermore associated with defects in cell morphology and cell-cell-contacts leading to increased tumor invasiveness. On a molecular level, ROR2 overexpression upregulated several non-canonical WNT ligands, in particular WNT11. Co-immunoprecipitation confirmed that WNT11 indeed interacts with the cysteine-rich domain of ROR2 and triggers its invasion-promoting signaling via RHO/ROCK. Knockdown of WNT11 reversed the pro-invasive phenotype and the cellular changes in ROR2-overexpressing cells. CONCLUSIONS: Taken together, our study revealed a novel auto-stimulatory loop in which ROR2 triggers the expression of its own ligand, WNT11, resulting in enhanced tumor invasion associated with breast cancer metastasis.

Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport.

BACKGROUND: Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood-brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. METHODS: Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. RESULTS: Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy. CONCLUSIONS: Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching therapeutic implications for CNS malignancies.

Safety aspects of opioid-naïve patients with high-grade glioma treated with D,L-Methadone: an observational case series.

It was suggested that D, L-Methadone might improve the clinical course of glioma patients. Owing to massive press coverage, patients demand the prescription of D, L-Methadone, but regarding its adjunctive use in glioma therapy there is no standard medication plan. Furthermore, it is not known which side effects the administration of D, L-Methadone might harbor, especially if the patients are opioid-naïve and if D, L-Methadone therapy was managed by the patients themselves or their general practitioners. Opioid-naïve patients with high-grade glioma (new diagnosis or recurrent) receiving D, L-Methadone were included in this retrospective observational analysis. Side effects were assigned if the condition deteriorated in conjunction with the initiation of D, L-Methadone and resolved/ ameliorated after cessation of the intake/reduction of the dosage. Side effects were categorized according to the common toxicity criteria (CTC). Twenty-four patients were included. All patients were opioid-naïve and received D, L-Methadone from their general practitioners. Sixteen patients experienced side effects. The median dosage when side effects began to occur was 15.8 mg/ 24 h. Fatigue and mood changes were reported most frequently (14 of 24 patients). Five patients had severe side effects related to relatively high doses. In all cases, symptoms resolved after cessation or dose reduction. Our results show that D/L M intake lead to frequent occurrence of side effects in opioid-naïve patients especially when not handled with caution and close supervision. Patients, their relatives, their GPs and neuro-oncologists need to be informed about the broad spectrum of side effects in order to thoroughly counsel glioma patients.

Invasive Monitoring of Intracranial Pressure After Decompressive Craniectomy in Malignant Stroke.

BACKGROUND AND PURPOSE: The role of decompressive hemicraniectomy (DC) in malignant cerebral infarction (MCI) has clearly been established, but little is known about the course of intracranial pressure (ICP) in patients undergoing this surgical measure. In this study, we investigated the role of invasive ICP monitoring in patients after DC for MCI, postulating that postoperative ICP predicts mortality. METHODS: In this retrospective observational study of MCI patients undergoing DC, ICP were recorded continuously in hourly intervals for the first 72 hours after DC. For every hour, mean ICP was calculated, pooling ICP of every patient. A receiver operating characteristic analysis was performed for hourly mean ICP. A subgroup analysis by age (≥60 years and <60 years) was also performed. RESULTS: A total of 111 patients were analyzed, with 29% mortality rate in patients <60 years, and 41% in patients ≥60 years. A threshold of 10 mm Hg within the first 72 postoperative hours was a reliable predictor of mortality in MCI, with an acceptable sensitivity of 70% and high specificity of 97%. Established predictors of mortality failed to predict mortality. CONCLUSIONS: Our study suggests the need to reevaluate postoperative ICP after DC in MCI and calls for a redefinition of ICP thresholds in these patients to indicate further therapy.

Mechanical Ventilation, Sedation and Neuromonitoring of Patients with Aneurysmal Subarachnoid Hemorrhage in Germany: Results of a Nationwide Survey.

OBJECTIVE: Current evidence-based guidelines for the management of aneurysmal subarachnoid hemorrhage (aSAH) focus primarily on timing, modality and technique of aneurysm occlusion, and on prevention and treatment of delayed cerebral ischemia. Significant aspects of management in the intensive care unit (ICU) during the later course of aSAH such as ventilation and sedation (VST) remain unaddressed. aSAH patients present unique challenges not accounted for in general ICU recommendations and guidelines, which is why we attempted to further characterize ICU practices in aSAH patients in Germany. METHODS: We conducted a nationwide survey on ICU practices in aSAH in Germany. Secondarily, we assessed the existence of and compliance with current guidelines regarding ICU practices. The questionnaire was designed in interdisciplinary fashion and distributed online through the kwiksurvey® platform (Bristol, UK). RESULTS: A total of 50 responses were received, accounting for a response rate of 49%. Twenty-one were university hospitals (UH), 23 high-volume centers (HVC), 6 low-volume centers (LVC). Half of the participating centers do not take into consideration WFNS at presentation to indicate ventilation. While 42% of centers rely on the P/F ratio to indicate ventilation, 62% of them have a cutoff value of < 200, and 38% of < 100. While most UH and HVC used propofol for the first phase of sedation (95%), LVC employed benzodiazepines (100%). Sedation deepening was done with ketamine in UH (75%) and HVC (60%), whereas LVC used predominantly clonidine (100%). CONCLUSIONS: Our study clearly demonstrates that attitudes and practices pertaining to ICU management in aSAH are enormously heterogeneous, reflecting the lack of good quality evidence and differing interpretations thereof.