Florian Ringel

Contribution of anion transporters to the acidosis-induced swelling and intracellular acidification of glial cells.

Abstract : This study examines the contribution of anion transporters to the swelling and intracellular acidification of glial cells from an extracellular lactacidosis, a condition well‐known to accompany cerebral ischemia and traumatic brain injury. Suspended C6 glioma cells were exposed to lactacidosis in physiological or anion‐depleted media, and different anion transport inhibitors were applied. Changes in cell volume and intracellular pH (pHi) were simultaneously quantified by flow cytometry. Extracellular lactacidosis (pH 6.2) led to an increase in cell volume to 125.1 ± 2.5% of baseline within 60 min, whereas the pHi dropped from the physiological value of 7.13 ± 0.05 to 6.32 ± 0.03. Suspension in Cl‐‐free or HCO3‐/CO2‐free media or application of anion transport inhibitors [0.1 mM bumetanide or 0.5 mM 4,4′‐diisothio‐cyanatostilbene‐2,2′‐disulfonic acid (DIDS)] did not affect cell volume during baseline conditions but significantly reduced cell swelling from lactacidosis. In addition, the Cl‐‐free or HCO3‐/CO2‐free media and DIDS attenuated intracellular acidosis on extracellular acidification. From these findings it is concluded that besides the known activation of the Na+/H+ exchanger, activation of the Na+‐independent Cl‐/HCO3‐ exchanger and the Na+‐K+‐Cl‐ cotransporter contributes to acidosis‐induced glial swelling and the intracellular acidification. Inhibition of these processes may be of interest for future strategies in the treatment of cytotoxic brain edema from cerebral ischemia or traumatic brain injury.

Factors associated with supportive care needs in glioma patients in the neuro-oncological outpatient setting

Objective of this study aimed at assessing glioma patients’ supportive care needs in a neurosurgical outpatient setting and identifying factors that are associated with needs for support. In three neuro-oncological outpatient departments, glioma patients were assessed for their psychosocial needs using the Supportive Care Needs Survey short-form (SCNS-SF34-G). Associations between clinical, sociodemographic, treatment related factors as well as distress (measured with the distress thermometer) and supportive care needs were explored using multivariable general linear models. One-hundred and seventy three of 244 eligible glioma patients participated, most of them with primary diagnoses of a high-grade glioma (81%). Highest need for support was observed in ‘psychological needs’ (median 17.5, range 5–45) followed by ‘physical and daily living needs’ (median 12.5, range 0–25) and ‘health system and information needs’ (median 11.3, range 0–36). Needs in the psychological area were associated with distress (R2 = 0.36) but not with age, sex, Karnofsky performance status (KPS), extend of resection, currently undergoing chemotherapy and whether guidance during assessment was offered. Regarding ‘health system and information needs’, we observed associations with distress, age, currently undergoing chemotherapy and guidance (R2 = 0.31). In the domain ‘physical and daily living needs’ we found associations with KPS, residual tumor, as well as with distress (R2 = 0.37). Glioma patients in neuro-oncological departments report unmet supportive care needs, especially in the psychological domain. Distress is the factor most consistently associated with unmet needs requiring support and could serve as indicator for clinical neuro-oncologists to initiate support.

Combination of ultrasound and rtPA enhances fibrinolysis in an In Vitro clot system

Background Catheter-based lysis with recombinant tissue plasminogen activator (rtPA) is a well-established therapy for spontaneous intracerebral hemorrhage (ICH). The effectiveness of this therapy can be increased with ultrasound, but the optimal conditions are not yet clearly established. Using a novel in vitro system of blood clots previously developed by our group, we investigated various parameters of intralesional sonothrombolysis using an endosonography catheter in combination with rtPA. Methods Standardized human blood clots were equipped with a drainage catheter and weighed before and after 4 treatments: control (drainage only), rtPA only, ultrasound only and the combination of rtPA+ultrasound. The effectiveness of ultrasound was further analysed in terms of optimal frequency, duration and distance to the probe. Temperature and acoustic peak rarefaction pressure (APRP) were assessed to analyse potential adverse effects and quantify lysis. Histo-morphological analysis of the treated clots was performed by H&E staining and confocal laser scanning microscopy using fluorescent fibrinogen. Results The combined treatment rtPA+ultrasound achieved the highest lysis rates with a relative weight of 30.3%±5.5% (p≤0.0001) compared to all other groups. Similar results were observed when treating aged clots. Confocal fluorescent microscopy of the treated clots revealed a rarefied fibrin mesh without cavitations. No relevant temperature increase occurred (0.53±0.75°C). The optimal insonation treatment time was 1 hour. APRP measurements showed a lysis threshold of 515.5±113.4 kPa. Application of 10 MHz achieved optimal lysis and lysis radius, while simultaneously proving to be the best frequency for morphologic imaging of the clot and surrounding tissue. Conclusions These promising data provide the basis for an individualized minimal invasive ICH therapy by rtPA and sonothrombolysis independent of ICH age.

Revision Rate of Misplaced Pedicle Screws of the Thoracolumbar Spine–Comparison of Three-Dimensional Fluoroscopy Navigation with Freehand Placement: A Systematic Analysis and Review of the Literature

BACKGROUND Recent studies have shown higher accuracy rates of image-guided pedicle screw placement compared to freehand (FH) placement. However, data focusing on the impact of spinal navigation on the rate of revision surgeries caused by misplaced pedicle screws (PS) are scarce. OBJECTIVE This study is aimed at identifying the rate of revision surgeries for misplaced PS comparing three-dimensional (3D) fluoroscopy navigation (3DFL) with FH PS placement. METHODS A retrospective analysis was conducted of 2232 patients (mean age, 65.3 ± 13.5 years) with 13,703 implanted PS who underwent instrumentation of the thoracolumbar spine between 2007 and 2015. Group 1 received surgery with use of 3DFL (January 2011 to December 2015), group 2 received surgery in the FH technique (April 2007 to December 2015). Because the use of 3DFL was initiated in January 2011, the examined period for 3DFL-navigated surgeries is shorter. Patients routinely received postoperative computed tomography scans and/or intraoperative control 3D scans. RESULTS There was an overall rate of revision surgeries for malpositioned PS of 2.9%. In the 3DFL group, the rate of secondary revision surgeries was significantly lower with 1.35% (15/1112 patients) compared to 4.38% (49/1120 patients) in the FH group, respectively (odds ratio, 3.35; P < 0.01). Of all PS in the 3DFL group (30/7548 PS), 0.40% needed revision surgery (P < 0.01) compared to 1.14% in the FH group (70/6155 PS). CONCLUSIONS We were able to show that the use of 3DFL-navigated PS placement significantly reduces the rate of revision surgeries after posterior spinal instrumentation compared to freehand PS placement.

Spinal ependymoma in adults: a multicenter investigation of surgical outcome and progression-free survival

OBJECTIVE Spinal ependymomas are rare glial neoplasms. Because their incidence is low, only a few larger studies have investigated this condition. There are no clear data concerning prognosis and therapy. The aim of the study was to describe the natural history, perioperative clinical course, and local tumor control of adult patients with spinal ependymomas who were surgically treated under modern treatment standards. METHODS The authors performed a multicenter retrospective study. They identified 158 adult patients with spinal ependymomas who had received surgical treatment between January 2006 and June 2013. The authors analyzed the clinical and histological aspects of these cases to identify the predictive factors for postoperative morbidity, tumor resectability, and recurrence. RESULTS Gross-total resection (GTR) was achieved in 80% of cases. At discharge, 37% of the patients showed a neurological decline. During follow-up the majority recovered, whereas 76% showed at least preoperative status. Permanent functional deterioration remained in 2% of the patients. Transient deficits were more frequent in patients with cervically located ependymomas (p = 0.004) and in older patients (p = 0.002). Permanent deficits were independently predicted only by older age (p = 0.026). Tumor progression was observed in 15 cases. The 5-year progression-free survival (PFS) rate was 80%, and GTR (p = 0.037), WHO grade II (p = 0.009), and low Ki-67 index (p = 0.005) were independent prognostic factors for PFS. Adjuvant radiation therapy was performed in 15 cases. No statistically relevant effects of radiation therapy were observed among patients with incompletely resected ependymomas (p = 0.079). CONCLUSIONS Due to its beneficial value for PFS, GTR is important in the treatment of spinal ependymoma. Gross-total resection is feasible in the majority of cases, with acceptable rates of permanent deficits. Also, Ki-67 appears to be an important prognostic factor and should be included in a grading scheme for spinal ependymomas.

Evaluation of surgical decision making and resulting outcome in patients with highly eloquent glioblastoma: Results of a multicenter assessment

INTRODUCTION Treatment of glioblastoma(GB) patients amenable only for a subtotal resection(STR) is controversial. Since outcome of patients is affected by surgical management, our aim was to assess surgical decision making and resulting outcome in patients with highly eloquent GBs. PATIENTS AND METHODS We retrospectively assessed GB patients with intended sub-total resection (STR) or stereotactic biopsy (STX) of 3 neurooncological centers operated between 2008 and 2013. A volumetric assessment of overall extent of resection(oEoR), presence of complications, new permanent neurological deficits(nPNDs) was performed. A central reviewer reassessed all cases blinded and gave recommendation on surgical management and on a potential EoR(pEoR) based on imaging data. We compared outcome data using Mann-Whitney-U-test and Sign-Rank-Test. Survival was assessed based on Kaplan-Meier-estimates. RESULTS 97 patients were included. In 17 patients received STX, 70 patients a STR and 10 patients a near total resection (NTR, EoR>95%). Median OS was significantly different from STX patients only if NTR was reached (16 vs. 7 months, p=0.042). The central reviewer recommended a more aggressive strategy(NTR or STR resp.) in 41 patients and a less aggressive strategy in 13 patients. Overall, management recommendation was significantly different to clinical treatment (p<0.001). Mean pEoR was significantly higher than oEoR (85.7% vs. 71.3%, p=0.001). Regarding the different OR subgroups, no significant differences were found in the NTR group(12/13 ties, p=1) and in STX group (14/17 ties, p=0.125). In STR group, a significant difference was found (p=0.001). In 38/69 patients a NTR and in 13/77 patients a STX was recommended. CONCLUSION Surgery in GB patients with intended STR requires precise preoperative planning since potential EoR is mainly underestimated. Especially, patients with lesions amenable for a NTR should not be missed.

Can Early Postoperative O-(2-18FFluoroethyl)-l-Tyrosine Positron Emission Tomography After Resection of Glioblastoma Predict the Location of Later Tumor Recurrence?

OBJECTIVE Glioblastoma inevitably recurs despite aggressive therapy. Therefore, it would be helpful to predict the location of tumor recurrence from postoperative imaging to customize further treatment. O-(2-18Ffluoroethyl)-l-tyrosine (FET) positron emission tomography (PET) might be a helpful technique, because tumor tissue can be differentiated from normal brain tissue with high specificity. METHODS Thirty-two consecutive patients with perioperative and follow-up imaging data available were included. On postoperative FET-PET, the tumor/normal brain (TTB) ratio around the resection cavity borders was measured. Increased TTB ratios were recorded and anatomically correlated with the site of later tumor recurrence. On postoperative magnetic resonance imaging (MRI), residual contrast-enhancing tumor correlated with the site of later tumor recurrence. RESULTS Location of progression was predictable using MRI alone in 42% of patients by residual tumor on postoperative MRI. FET-PET was predictive in 25 patients by a clear hot spot at the site of later tumor recurrence. In 3 patients, it was partially predictive and in 4 was not predictive of the tumor recurrence location. One patient without any tracer uptake was recurrence free at the last follow-up examination. In contrast to the postoperative MRI results, tumor recurrence was found in 79% at a site of elevated TTB ratio on postoperative FET-PET. Therefore, the predictability of the tumor recurrence location using postoperative FET-PET was greater than that with MRI, and all cases predictable using MRI could have been predicted using FET-PET. CONCLUSIONS Postoperative FET-PET can be helpful for planning subsequent therapy, such as repeat resection or radiotherapy, because tumor recurrence can be predicted with relatively greater sensitivity than with MRI alone.

Risk Stratification by nrTMS Language Mapping

Resecting language-eloquent brain lesions is a major challenge in neurosurgery since we need to weight the risks of worsening the patients’ functional integrity and achieving a maximum safe resection. Although relevant functional brain structures can be identified intraoperatively by direct cortical mapping during awake surgery, a preoperative identification of functional anatomy is recommended in order to gauge surgical risks, evaluate resectability, plan the surgical approach, and identify potential starting points for intraoperative stimulation mapping.

Classification of orbital exenteration and reconstruction

Orbital exenteration (OE) is considered to be a mutilating surgical procedure reserved for relentlessly progressive neoplastic disorders or extensive facial trauma with unfavourable eye involvement. Malignant tumours, accounting for the majority of ablative orbital surgeries, may be caused by primary orbital tumours or secondarily by neoplasias from the surrounding skin, the maxillary sinus or intracranial malignomas. Orbital exenteration following trauma is mostly caused by penetrating globe defects or extended infections with the danger of intracranial effects. Thoughtful resection planning, the exploitation of reconstructive possibilities as well as the consideration of adjuvant therapy are essential to provide the patient with the best available treatment. As a multitude of reconstructive procedures exist, it is of crucial importance to offer a disease-tailored treatment to achieve a successful patient outcome. After retrospective analysis of 45 orbital exenteration cases within the last decade, we developed a defect-driven classification for ablative orbital therapy followed by a guideline for reconstructive procedures. The classification as well as the reconstruction guideline will help the surgeon to restore anatomic boundaries and to promote physiological and psychological recovery for the patient.

Decreased Secondary Lesion Growth and Attenuated Immune Response after Traumatic Brain Injury in Tlr2/4(-/-) Mice

Danger-associated molecular patterns are released by damaged cells and trigger neuroinflammation through activation of non-specific pattern recognition receptors, e.g., toll-like receptors (TLRs). Since the role of TLR2 and 4 after traumatic brain injury (TBI) is still unclear, we examined the outcome and the expression of pro-inflammatory mediators after experimental TBI in Tlr2/4−/− and wild-type (WT) mice. Tlr2/4−/− and WT mice were subjected to controlled cortical injury and contusion volume and brain edema formation were assessed 24 h thereafter. Expression of inflammatory markers in brain tissue was measured by quantitative PCR 15 min, 3 h, 6 h, 12 h, and 24 h after controlled cortical impact (CCI). Contusion volume was significantly attenuated in Tlr2/4−/− mice (29.7 ± 0.7 mm3 as compared to 33.5 ± 0.8 mm3 in WT; p < 0.05) after CCI while brain edema was not affected. Only interleukin (IL)-1β gene expression was increased after CCI in the Tlr2/4−/− relative to WT mice. Inducible nitric oxide synthetase, TNF, IL-6, and COX-2 were similar in injured WT and Tlr2/4−/− mice, while the increase in high-mobility group box 1 was attenuated at 6 h. TLR2 and 4 are consequently shown to potentially promote secondary brain injury after experimental CCI via neuroinflammation and may therefore represent a novel therapeutic target for the treatment of TBI.