Health-related quality of life in patients with untreated cavernous malformations of the central nervous system.

BACKGROUND AND PURPOSE: To estimate health-related quality of life (HRQOL) in patients with untreated cavernous malformation of the CNS [cavernous cerebral malformations (CCMs)]. METHODS: We performed a cross-sectional observational study on patients with CCMs admitted to our department from 1 November 2017 to 10 January 2020 using standardized interviews [short-form-36 questionnaire, hospital anxiety and depression score (HADS-A/D), CCM perception questionnaire]. Included criteria were diagnosis of an untreated CCM and information about the diagnosis in a specialized CCM consultation. Health-related quality of life (HRQOL) data were analyzed and compared to the German normal population. Uni- and multivariate analyses were carried out to identify variables with impact on outcome. RESULTS: Two hundred nineteen (93%) of 229 eligible patients were included. Mean age was 46.3 ± 14.7 (18-86) years; 136 (62%) were female. Ninety-eight (45%) patients presented with symptomatic hemorrhage (SH), and 17 (8%) with repetitive SH. Ninety-two (42%) patients were asymptomatic. Thirty-seven patients (17%) suffered from cavernoma-related epilepsy. Twenty-eight patients (13%) suffered from familial CCMs. Patients showed significantly decreased component scores and subdomain scores compared to the normal population, with effects ranging from small to large. This accounted largely also for asymptomatic patients (except for physical component score and main physical subdomains). Multivariate regression analysis confirmed impact of functional impairment on physical component score. HADS-A was significantly increased. HADS-A/D strongly correlated with mental component score and individual perception of the CCM. CONCLUSIONS: Patients with the diagnosis of a CCM showed decreased HRQOL compared to the normal population even when not suffering functional impairment or neurological symptoms. Our data may function as benchmarks in evaluation of different (future) management strategies.

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

Does the expression of glial fibrillary acid protein (GFAP) stain in glioblastoma tissue have a prognostic impact on survival?

OBJECTIVE: Several parameters are known to predict the survival of glioblastoma (GB), including extent of resection and MGMT promotor methylation. Staining for glial fibrillary acidic protein (GFAP) is a common component of routine histological work-up, but its clinical utility in GB is unclear. The aim of the present study was to analyze the predictive value of quantitative GFAP measurements for survival of patients with GB. METHODS: All subjects in our institutional database of patients with primary GB who underwent surgery between 2011 and 2014 with examination of immunohistochemical staining of GFAP were included. Percentage GFAP staining was measured in 5% increments (5-100%). Univariate and multivariate analyses were performed between GFAP values and survival data. Clinically relevant cut-offs for GFAP staining were identified by receiver operating characteristic (ROC) curves. RESULTS: The final cohort consisted of 272GB patients with available quantitative GFAP measurements (mean age, 62 (±11.1) years, 117 females [43%]). Overall survival was 11.4 months (±8.6). Median GFAP value was 70% (range, 5-100%). The ROC curve showed the clinically relevant cut-off for GFAP at 75% (area under the curve: 0.691). Accordingly, GB patients with GFAP≥75% presented poorer survival on Kaplan-Meier survival estimation (P=0.021). Multivariate analysis adjusted for age, extent of resection, preoperative Karnofsky performance status scale, IDH1 mutation and MGMT methylation status confirmed the independent predictive value of GFAP≥75% for overall survival (P=0.032). Finally, patients with GFAP≥75% showed significantly poorer long-term survival than those with GFAP<75%: 5.8% vs. 15.2% (P=0.0183) and 0.8% vs. 8% (P=0.0076) for 2- and 3-year survival, respectively. CONCLUSION: Quantitative immunohistochemical assessment of GFAP staining could provide a novel biomarker for overall and especially long-term survival of patients with GB. Prospective multi-center validation of the prognostic value of GFAP for GB survival is needed.

Wall Contrast Enhancement of Thrombosed Intracranial Aneurysms at 7T MRI.

BACKGROUND AND PURPOSE: The pathophysiology of wall contrast enhancement in thrombosed intracranial aneurysms is incompletely understood. This in vivo study aimed to investigate wall microstructures with gadolinium-enhanced 7T MR imaging. MATERIALS AND METHODS: Thirteen patients with 14 thrombosed intracranial aneurysms were evaluated using a 7T whole-body MR imaging system with nonenhanced and gadolinium-enhanced high-resolution MPRAGE. Tissue samples were available in 5 cases, and histopathologic findings were correlated with 7T MR imaging to identify the gadolinium-enhancing microstructures. RESULTS: Partial or complete inner wall enhancement correlated with neovascularization of the inner wall layer and the adjacent thrombus. Additional partial or complete outer wall enhancement can be explained by formation of vasa vasorum in the outer aneurysm wall layer. The double-rim enhancement correlated with perifocal edema and wall histologic findings suggestive of instability. CONCLUSIONS: Two distinct aneurysm wall microstructures responsible for gadolinium enhancement not depictable at lower spatial resolutions can be visualized in vivo using high-resolution gadolinium-enhanced 7T MR imaging.

Xenografting for disease modeling of intramedullary spinal cord tumors: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: The overall incidence of intramedullary spinal cord tumors (IMSCT) remains low and clinical trials or standardized treatment strategies are missing. Therefore, multiple animal-based xenograft models (AXM) have been developed to foster preclinical research efforts on IMSCT. We constructed a systematic literature review to summarize and compare all AXM for IMSCT, published until April 16, 2018. METHODS: The review was conducted using 4 independent research databases following the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Studies were included, if they reported on surgical transplantation of tumor cells or tumor tissue to the spinal cord. Methodological study quality was assessed according to the SYRCLE (systematic review center for laboratory animal experimentation) risk of Bias tool. RESULTS: Systematic search yielded 20 publications dealing with AXM for IMSCT. In summary, 4 tumor entities were analyzed in 23 experiments using ~337 animals, mainly investigating glioblastoma or gliosarcoma biology. Studies varied regarding the use of engrafted animals, surgical techniques and tumor burden. Most commonly authors used heterotopic, transdural injection of immortalized brain tumor cell lines (1 × 105 in 5 µl) into the thoracic spinal cord of immunocompromised rats. Quality assessment demonstrated an unclear risk of bias in most cases. CONCLUSION: Although different AXM for IMSCT have been described so far, one rat model is technically feasible, enables robust experiments and demonstrates reproducible results. However, there is a need for new AXM using orthotopic engraftment of patient-derived tumor cells and for genetically engineered animal models.

Visualization and Classification of Deeply Seated Collateral Networks in Moyamoya Angiopathy with 7T MRI.

BACKGROUND AND PURPOSE: Collateral networks in Moyamoya angiopathy have a complex angioarchitecture difficult to comprehend on conventional examinations. This study aimed to evaluate morphologic patterns and the delineation of deeply seated collateral networks using ultra-high-field MRA in comparison with conventional DSA. MATERIALS AND METHODS: Fifteen white patients with Moyamoya angiopathy were investigated in this prospective trial. Sequences acquired at 7T were TOF-MRA with 0.22 × 0.22 × 0.41 mm3 resolution and MPRAGE with 0.7 × 0.7 × 0.7 mm3 resolution. Four raters evaluated the presence of deeply seated collateral networks and image quality in a consensus reading of DSA, TOF-MRA, and MPRAGE using a 5-point scale in axial source images and maximum intensity projections. Delineation of deeply seated collateral networks by different imaging modalities was compared by means of the McNemar test, whereas image quality was compared using the Wilcoxon signed-rank test. RESULTS: The relevant deeply seated collateral networks were classified into 2 categories and 6 pathways. A total of 100 collateral networks were detected on DSA; 106, on TOF-MRA; and 73, on MPRAGE. Delineation of deeply seated collateral networks was comparable between TOF-MRA and DSA (P = .25); however, both were better than MPRAGE (P < .001). CONCLUSIONS: This study demonstrates excellent delineation of 6 distinct deeply seated collateral network pathways in Moyamoya angiopathy in white adults using 7T TOF-MRA, comparable to DSA.

The CHESS score: a simple tool for early prediction of shunt dependency after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Acute hydrocephalus is an early and common complication of aneurysmal subarachnoid hemorrhage (SAH). However, considerably fewer patients develop chronic hydrocephalus requiring shunt placement. Our aim was to develop a risk score for early identification of patients with shunt dependency after SAH. METHODS: Two hundred and forty-two SAH individuals who were treated in our institution between January 2008 and December 2013 and survived the initial impact were retrospectively analyzed. Clinical parameters within 72 h after the ictus were correlated with shunt dependency. Independent predictors were summarized into a new risk score which was validated in a subsequent SAH cohort treated between January and December 2014. RESULTS: Seventy-five patients (31%) underwent shunt placement. Of 23 evaluated variables, only the following five showed independent associations with shunt dependency and were subsequently used to establish the Chronic Hydrocephalus Ensuing from SAH Score (CHESS, 0-8 points): Hunt and Hess grade ≥IV (1 point), location of the ruptured aneurysm in the posterior circulation (1 point), acute hydrocephalus (4 points), the presence of intraventricular hemorrhage (1 point) and early cerebral infarction on follow-up computed tomography scan (1 point). The CHESS showed strong correlation with shunt dependency (P = 0.0007) and could be successfully validated in both internal SAH cohorts tested. Patients scoring ≥6 CHESS points had significantly higher risk of shunt dependency (P < 0.0001) than other patients. CONCLUSION: The CHESS may become a valuable diagnostic tool for early estimation of shunt dependency after SAH. Further evaluation and external validation will be required in prospective studies.

Predictors and impact of early cerebral infarction after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Cerebral infarction is a frequent and serious complication of aneurysmal subarachnoid hemorrhage (SAH). This study aimed to identify independent predictors of the timing of cerebral infarction and clarify its impact on disease course and patients' outcome. METHODS: All consecutive patients with SAH admitted to our institution from January 2005 to December 2012 were analyzed. Serial computed tomography (CT) scans were evaluated for cerebral infarctions. Demographic, clinical, laboratory and radiological data of patients during hospitalization as well as clinical follow-ups 6 months after SAH were recorded. RESULTS: Of the 632 analyzed patients, 320 (51%) developed cerebral infarction on CT scans. 136 patients (21.5%) with early cerebral infarction (occurring within 3 days after SAH) had a significantly higher risk of unfavorable outcome than patients with late infarction [odds ratio (OR) 2.94; P = 0.008], a higher in-hospital mortality (OR 3.14; P = 0.0002) and poorer clinical outcome after 6 months (OR 0.54; P < 0.0001). The rates of decompressive craniectomy (OR 1.96, P = 0.0265), tracheostomy (OR 1.87, P = 0.0446), the duration of intensive care unit stay and mechanical ventilation were significantly higher in patients with early infarction. In multivariate analysis, Hunt and Hess grades 4 and 5 (OR 2.06, P = 0.008), Fisher grades 3 and 4 (OR 3.99, P = 0.014), sustained elevations of intracranial pressure >20 mmHg (OR 5.95, P < 0.0001) and early vasospasm on diagnostic angiograms (OR 3.01, P = 0.008) were predictors of early cerebral infarction. CONCLUSION: Early cerebral infarction after SAH is associated with severe clinical course and unfavorable outcome and can be reliably predicted by poor initial clinical condition, thick subarachnoid clot, early angiographic vasospasm and sustained elevations of intracranial pressure.