Female gender predisposes for cerebrospinal fluid overdrainage in ventriculoperitoneal shunting.

BACKGROUND: Gravitational valves (GVs) prevent overdrainage in ventriculoperitoneal shunting (VPS). However, there are no data available on the appropriate opening pressure in the shunt system when implementing a GV. We performed a retrospective analysis of hydrocephalic patients who were successfully treated with VPS which included one or more GV. METHOD: In this retrospective study in adult VPS patients with GVs, we analysed all available data, including the most recent computed tomography (CT) scans, to determine the best adjustments for alleviating any symptoms of overdrainage and underdrainage. Vertical effective opening pressure (VEOP) of the entire shunt system, including the differential pressure valve, was determined. RESULTS: One hundred and twenty-two patients were eligible for the study. Of these, female patients revealed a higher VEOP compared with males (mean, 35.6 cmH2O [SD ± 2.46] vs 28.9 cmH2O [SD ± 0.87], respectively, p = 0.0072, t-test). In patients older than 60 years, lower VEOPs, by a mean of 6.76 cmH2O ± 2.37 (p = 0.0051), were necessary. Mean VEOP was found to be high in idiopathic intracranial hypertension (IIH; 41.6 cmH2O) and malresorptive and congenital HC (35.9 and 36.3), but low in normal pressure HC (27.5, p = 0.0229; one-way ANOVA). In the total cohort, body mass index (BMI) and height did not correlate with VEOP. Twelve patients required a VEOP of more than 40 cmH2O, and in eight of these patients this was accomplished by using multiple GVs. All but one of these eight patients were of female gender, and none of the latter were treated for normal pressure hydrocephalus (NPH) (p = 0.0044 and p = 0.0032, Fisher's exact test). CONCLUSIONS: In adult VPS patients, female gender increases the risk of overdrainage requiring higher VEOPs. Initial implantation of adjustable GV should be considered in female patients treated with VP shunts for pathology other than NPH.

The intra- and postoperative management of accidental durotomy in lumbar spine surgery: results of a German survey.

BACKGROUND: The intra- and postoperative management of accidental durotomy in operations of the lumbar spine is not standardized. It is the aim of our survey to obtain an overview on the current practice in neurosurgical departments in Germany. METHODS: The used questionnaire consisted of three questions and could be answered within a few minutes by checking boxes. In September 2012, the questionnaire was sent to 149 German neurosurgical departments. In the following 4 weeks 109 replies (73.2 %) were received. RESULTS: Seventy-one neurosurgical departments (65.1 %) treat dural tears by a combination of methods, 28 (25.7 %) with suture alone, 7 (6.4 %) with fibrin-coated fleeces alone, 2 (1.8 %) with muscle patch alone and 1 (0.9 %) with fibrin glue alone. Sixty-six neurosurgical departments (60.5 %) decide on postoperative bed rest depending on the quality of the dural closure. Forty-three (39.5 %) neurosurgical departments do not rely on the quality of the dural closure for their postoperative management. In total, 72.5 % of the neurosurgical departments prescribe bed rest for 1-3 days, 1.8 % for more than 3 days, whereas 25.7 % allow immediate mobilization. CONCLUSIONS: Among German neurosurgeons, no consensus exists concerning the intra- and postoperative management of accidental durotomies in lumbar spine surgery. Despite not being proved to reduce the rate of cerebrospinal fluid fistulas, bed rest is frequently used. As bed rest prolongs the hospital stay with additional costs and has the potential of a higher rate of medical complications, a prospective multicenter trial is warranted.

Unskilled unawareness and the learning curve in robotic spine surgery.

BACKGROUND: Robotic assistance for the placement of pedicle screws has been established as a safe technique. Nonetheless rare instances of screw misplacement have been reported.The aim of the present retrospective study is to assess whether experience and time affect the accuracy of screws placed with the help of the SpineAssist™ robot system. METHODS: Postoperative computed tomography (CT) scans of 258 patients requiring thoracolumbar pedicle screw instrumentation from 2008 to 2013 were reviewed. Overall, 13 surgeons performed the surgeries. A pedicle breach of >3 mm was graded as a misplacement. Surgeons were dichotomised into an early and experienced period in increments of five surgeries. RESULTS: In 258 surgeries, 1,265 pedicle screws were placed with the aid of the robot system. Overall, 1,217 screws (96.2 %) were graded as acceptable. When displayed by surgeon, the development of percent misplacement rates peaked between 5 and 25 surgeries in 12 of 13 surgeons. The overall misplacement rate in the first five surgeries was 2.4 % (6/245). The misplacement rate rose to 6.3 % between 11 and 15 surgeries (10/158; p = 0.20), and reached a significant peak between 16 and 20 surgeries with a rate of 7.1 % (8/112; p = 0.03). Afterwards, misplacement rates declined. CONCLUSIONS: A major peak in screw inaccuracies occurred between cases 10 and 20, and a second, smaller one at about 40 surgeries. One potential explanation could be a transition from decreased supervision (unskilled but aware) to increased confidence of a surgeon (unskilled but unaware) who adopts this new technique prior to mastering it (skilled). We therefore advocate ensuring competent supervision for new surgeons at least during the first 25 procedures of robotic spine surgery to optimise the accuracy of robot-assisted pedicle screws.

Flow-related noise in patients with ventriculoperitoneal shunt using gravitational adjustable valves.

BACKGROUND: Noise disturbance arising from the valve is a rare event of ventriculoperitoneal shunts. We queried and investigated shunt patients for occurrence and evaluated the possible factors related to noise development. METHODS: Fifty ambulatory patients with implanted proGAV valve were investigated consecutively. Patients were asked for any noise arising from the shunt. In all cases, the valve was auscultated in sitting and upright position. The position of the gravitational unit (GU) was determined in respect to the Frankfurt horizontal plane (FHP) and in head reclination. Ten valves were perfused in vitro at different settings. One valve was opened for video documentation, and a frequency analysis of the noise was performed in nine valves. RESULTS: Eight percent (4/50) of the patients reported a noise arising from the valve only in upright position in combination with maximum head reclination, and immediately stopped when performing Vasalva's maneuver. In three out of four of these patients, the noise was also audible for the investigator (FS) with a prepared stethoscope. Patients complaining about a noise had a larger GU deviation from vertical during head reclination (median: -80 vs -43°, p = 0.0007, t-test). A deviations threshold of less than -58.4° excluding audible noise by a negative predictive value of 1 (95 % confidence interval [CI] 0.9 to 1.0). In an experimental setting, the noise came from vibrations of the ball in the cone of the adjustable unit and was restricted to a flow of at least 220 ml/h. The noise frequencies tended to be higher at higher opening pressures. CONCLUSIONS: Valve-related noise development may occur in patients with proGAV valves. This event could be prevented during shunt placement by avoiding posterior tilt of the gravitational unit, especially in patients with a good cervical mobility. The noise might indicate transient peak flows and was not associated with clinical or radiological signs of overdrainage.

In vitro performance and principles of anti-siphoning devices.

BACKGROUND: Anti-siphon devices (ASDs) of various working principles were developed to overcome overdrainage-related complications associated with ventriculoperitoneal shunting. OBJECTIVE: We aimed to provide comparative data on the pressure and flow characteristics of six different types of ASDs (gravity-assisted, membrane-controlled, and flow-regulated) in order to achieve a better understanding of these devices and their potential clinical application. METHODS: We analyzed three gravity-dependent ASDs (ShuntAssistant [SA], Miethke; Gravity Compensating Accessory [GCA], Integra; SiphonX [SX], Sophysa), two membrane-controlled ASDs (Anti-Siphon Device [IASD], Integra; Delta Chamber [DC], Medtronic), and one flow-regulated ASD (SiphonGuard [SG], Codman). Defined pressure conditions within a simulated shunt system were generated (differential pressure 10-80 cmH2O), and the specific flow and pressure characteristics were measured. In addition, the gravity-dependent ASDs were measured in defined spatial positions (0-90°). RESULTS: The flow characteristics of the three gravity-assisted ASDs were largely dependent upon differential pressure and on their spatial position. All three devices were able to reduce the siphoning effect, but each to a different extent (flow at inflow pressure: 10 cmH2O, siphoning -20 cmH2O at 0°/90°: SA, 7.1 ± 1.2*/2.3 ± 0.5* ml/min; GCA, 10.5 ± 0.8/3.4 ± 0.4* ml/min; SX, 9.5 ± 1.2*/4.7 ± 1.9* ml/min, compared to control, 11.1 ± 0.4 ml/min [*p < 0.05]). The flow characteristics of the remaining ASDs were primarily dependent upon the inflow pressure effect (flow at 10 cmH2O, siphoning 0 cmH2O/ siphoning -20cmH2O: DC, 2.6 ± 0.1/ 4 ± 0.3* ml/min; IASD, 2.5 ± 0.2/ 0.8 ± 0.4* ml/min; SG, 0.8 ± 0.2*/ 0.2 ± 0.1* ml/min [*p < 0.05 vs. control, respectively]). CONCLUSION: The tested ASDs were able to control the siphoning effect within a simulated shunt system to differing degrees. Future comparative trials are needed to determine the type of device that is superior for clinical application.

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.

No prognostic value of IDH1 mutations in a series of 100 WHO grade II astrocytomas.

Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) have been identified in approximately 70-80 % of astrocytomas and oligodendrogliomas of WHO grades II and III, and in secondary glioblastomas. In addition, a low incidence of IDH2 mutations has been detected in these tumors, and the occurence of IDH1 and IDH2 mutations is mutually exclusive. For patients with anaplastic gliomas and glioblastomas with IDH1 mutations, overall survival was significantly longer than for patients with wild-type tumours. However, the prognostic value of IDH1 in low-grade gliomas remains ambiguous. IDH1 codon 132 and IDH2 codon 172 mutation status were determined by direct sequencing for a retrospective series of 100 patients with histologically diagnosed Astrocytomas WHO Grad II (A II), and investigated for association with patient outcome. For the patient cohort analysed, median progression-free survival (PFS) was 44.6 months (95 %-CI 1.0-267.0), time to progression (median time to malignant progression (TtMP) was 74.9 months (95 %-CI 1.6-236.2), and median overall survival (OS) was 81.4 months (95 %-CI 5.5-274.8). IDH1 mutations were identified in 79 % of the patients. IDH2 mutations were not observed. Univariate and multivariate analysis revealed no association between IDH1 mutation status and PFS, TtMP, and OS. Furthermore, there were no significant differences regarding PFS, TtMP, and OS between patients with and without IDH1 mutations who did not receive adjuvant treatment. The prognostic value of IDH1 mutations in low-grade astrocytomas is rather low compared with that in high-grade gliomas.

Cellular-based immunotherapies for patients with glioblastoma multiforme.

Treatment of patients with glioblastoma multiforme (GBM) remains to be a challenge with a median survival of 14.6 months following diagnosis. Standard treatment options include surgery, radiation therapy, and systemic chemotherapy with temozolomide. Despite the fact that the brain constitutes an immunoprivileged site, recent observations after immunotherapies with lysate from autologous tumor cells pulsed on dendritic cells (DCs), peptides, protein, messenger RNA, and cytokines suggest an immunological and even clinical response from immunotherapies. Given this plethora of immunomodulatory therapies, this paper gives a structure overview of the state-of-the art in the field. Particular emphasis was also put on immunogenic antigens as potential targets for a more specific stimulation of the immune system against GBM.

Favorable outcome in the elderly cohort treated by concomitant temozolomide radiochemotherapy in a multicentric phase II safety study of 5-ALA.

The primary objective of this augmental, prospective, uncontrolled phase II multicentre trial was to assess adverse events (AE) associated with malignant glioma resection using 5-aminolevulinic (5-ALA). During accrual, the standard of adjuvant therapy changed to concomitant radiochemotherapy with adjuvant temozolomide (RT/TMZ). Thus, this study also provided a platform for investigating the influence of RT/TMZ on survival in patients with fluorescence-guided resections. Malignant glioma patients, aged 18-75 years and with a Karnofsky performance score (KPS) ≥70%, were eligible. Data were collected on adverse events, KPS, survival and adjuvant therapies. In 243 patients evaluable for safety, 6-week AE incidence was 51.9% (nervous system disorders: 30.0%). Three patients experienced four possibly drug-related AEs. Grade III/IV incidence was 18.9% (nervous system disorders: 10.7%). About 48 h after surgery, AE incidence was 26.3% (9.9% grade III/IV), which was related to overall survival. A total of 219 patients (glioblastoma 206; anaplastic astrocytoma: 13) qualified for efficacy analysis. Median overall survival was 14.1 months (95% CI: 12.0-16.6), but 16.3 (13-19.2) months in 122 glioblastoma patients receiving RT/TMZ compared to 11.9 (9.6-14.1) months in the remaining 84 patients (P = 0.0194). Older patients (≥60 years) had less adjuvant therapies than younger patients. Median survival of older glioblastoma patients with RT/TMZ was also significantly prolonged (16.3; 12.0-17.2 months vs. 11.2; 7.4-14.1, hazard ratio = 0.55; 0.32-0.92). Risks of surgery were similar to past experiences with 5-ALA. Ancillary analyses demonstrated surgical glioblastoma patients, including the elderly, to have derived benefit from RT/TMZ. Thus, older patients should not generally be excluded from accepted therapies (fluorescence-guided resection plus RT/TMZ).

Identification of diagnostic serum protein profiles of glioblastoma patients.

Diagnosis of a glioblastoma (GBM) is triggered by the onset of symptoms and is based on cerebral imaging and histological examination. Serum-based biomarkers may support detection of GBM. Here, we explored serum protein concentrations of GBM patients and used data mining to explore profiles of biomarkers and determine whether these are associated with the clinical status of the patients. Gene and protein expression data for astrocytoma and GBM were used to identify secreted proteins differently expressed in tumors and in normal brain tissues. Tumor expression and serum concentrations of 14 candidate proteins were analyzed for 23 GBM patients and nine healthy subjects. Data-mining methods involving all 14 proteins were used as an initial evaluation step to find clinically informative profiles. Data mining identified a serum protein profile formed by BMP2, HSP70, and CXCL10 that enabled correct assignment to the GBM group with specificity and sensitivity of 89 and 96%, respectively (p < 0.0001, Fischer's exact test). Survival for more than 15 months after tumor resection was associated with a profile formed by TSP1, HSP70, and IGFBP3, enabling correct assignment in all cases (p < 0.0001, Fischer's exact test). No correlation was found with tumor size or age of the patient. This study shows that robust serum profiles for GBM may be identified by data mining on the basis of a relatively small study cohort. Profiles of more than one biomarker enable more specific assignment to the GBM and survival group than those based on single proteins, confirming earlier attempts to correlate single markers with cancer. These conceptual findings will be a basis for validation in a larger sample size.

Continuous low-dose temozolomide and celecoxib in recurrent glioblastoma.

Even after gross tumor resection and combined radiochemotherapy, glioblastomas recur within a few months. Salvage therapy often consists of rechallenging with temozolomide in a dose-intensified schedule. Previously, low-dose metronomic temozolomide in combination with cyclo-oxigenase 2 inhibitors has had a beneficial effect as first-line treatment for glioblastoma. We report our experience with this procedure in recurrent glioblastomas after standard treatment. From June 2007 to April 2009, 28 patients with recurrent glioblastoma received continuous low-dose temozolomide of 10 mg/m(2) twice daily and 200 mg celecoxib. Before therapy the recurrent tumor was resected in 19 of 28 patients. Microvessel density (MVD) was determined by immunohistochemistry in 19 patients, and MGMT promoter methylation status, using the pyrosequencing method, was determined in 17 patients. In 14/28 patients, positron emission tomography with [F-18]-fluoroethyl)-L-tyrosine (FET-PET) was performed. Tumor progression was defined by the Macdonald criteria on MRI every 8-12 weeks or by clinical deterioration. The median time to progression was 4.2 months. Progression-free survival (PFS) after 6 months was 43%. Except for a lymphopenia in one patient, there was no grade 3 or 4 toxicity. PFS did not correlate with MVD or MGMT status. A high FET uptake correlated with tumor control after 6 months under therapy (P = 0.041, t-test). Low-dose continuous temozolomide in combination with celecoxib seems to have activity in recurrent glioblastoma without relevant toxicity. High FET uptake correlated with a better outcome under metronomic therapy.

5-Aminolevulinic Acid Fluorescence Indicates Perilesional Brain Infiltration in Brain Metastases.

BACKGROUND: In glioma surgery, 5-aminolevulinic acid (5-ALA) fluorescence reflects tumor infiltration, and fluorescence-assisted resection correlates with higher removal rates and improved progression-free survival. Recent studies report that a sizable proportion of brain metastases exhibit peritumoral infiltration on the cellular level. There is little information regarding whether 5-ALA is useful to guide surgery in the peritumoral zone in metastases. The aim of this study was to assess histologically whether 5-ALA fluorescence accurately reflects metastatic brain infiltration. METHODS AND MATERIALS: Fluorescence-assisted tumor resection was performed in 27 patients with brain metastases. Patients received 20 mg/kg 5-ALA 3 hours before anesthesia. After resection, biopsy specimens of the surrounding parenchyma were analyzed for 5-ALA fluorescence and histologic evidence of infiltrating tumor cells. The correlation between 5-ALA positivity and immunohistochemical evidence of tumor in the peritumoral zone was also assessed. RESULTS: Of 27 metastases, 23 (85%) were 5-ALA positive. For qualitative tissue analysis, 110 of 125 samples were collected. Metastatic infiltration was present in 49 samples with faint or red fluorescence; 33 samples without fluorescence were tumor-free. The presence of metastatic infiltration correlated with fluorescence (P < 0.001). Tumor infiltration correlated with fluorescence (blue fluorescence 0.09% ± 0.04% and red or faint fluorescence 3.26%; P = 0.003). CONCLUSIONS: Infiltration of surrounding brain tissue is a common finding in brain metastases in selected primary tumors. 5-ALA fluorescence correlates with tumor cell infiltration and might guide more radical resection.

Expression of Olig2, Nestin, NogoA and AQP4 have no impact on overall survival in IDH-wildtype glioblastoma.

Despite many years of research efforts and clinical trials the prognosis of patients diagnosed with glioblastoma remains very poor. The oligodendrocyte transcription factor 2 (Olig2) was identified as a marker for glioma stem cells, which are believed to be responsible for glioma recurrence and therapy resistance. In this retrospective analysis we assessed the prognostic value of oligodendroglial and glioma stem cell markers in 113 IDH-wildtype glioblastomas. Immunohistochemical staining for Olig2, NogoA, AQP4 and Nestin was performed in combination with sequencing of IDH1 and IDH2 as well as promotor methylation analysis of the MGMT gene. Even though differences in overall survival according to Olig2 expression were observed, univariate and multivariate survival analysis did not reveal a firm significant prognostic impact of Olig2, NogoA, AQP4 or Nestin expression. Additionally, no differences in the expression of these markers depending on clinical status, age or gender were found. The established independent prognostic factors age<65, Karnofsky Performance Status> = 70 and methylated MGMT gene promoter were significant in the multivariate analysis. In conclusion expression of oligodendroglial and glioma stem cell markers do not have an independent prognostic effect in IDH-wildtype glioblastoma.

Decreased expression of the active subunit of the cystine/glutamate antiporter xCT is associated with loss of heterozygosity of 1p in oligodendroglial tumours WHO grade II.

AIMS: Oligodendroglial tumours with loss of heterozygosity on 1p (LOH1p) respond better to treatment than oligodendrogliomas without LOH. Previous reports have assigned a crucial role of glutamate metabolism to glioma growth and invasion. The aim was to study the protein expression of different glutamate transporters in relation to LOH1p in low-grade oligodendroglial tumours. METHODS AND RESULTS: Seventeen oligodendrogliomas World Health Organization (WHO) grade II, 16 oligoastrocytomas WHO grade II and seven astrocytomas WHO grade II were examined. Eleven oligodendrogliomas and five oligoastrocytomas exhibited LOH1p. Immunoreactivity scores (IRS) for glutamate transporters excitatory amino acid transporter (EAAT)-1, -2 and -3 as well as the active cystine/glutamate antiporter subunit xCT were semiquantitatively rated by percentage of positive cells and intensity of immunoreactivity. Reactivity for xCT was lower in tumours with LOH1p than in those without (P = 0.03, Mann-Whitney U-test). No association was found between LOH status and IRS for EAAT-1, -2 or -3. High xCT immunoreactivity was associated with high expression of EAAT-1, -2 or -3. CONCLUSIONS: Expression of xCT is significantly reduced in low-grade oligodendroglial tumours harbouring LOH1p. Further studies should investigate a potential beneficial effect by inhibiting xCT in low-grade gliomas.

Neurophysiological intraoperative monitoring in neurosurgery: aid or handicap? An international survey.

OBJECT: Neurophysiological intraoperative monitoring (IOM) is regarded as a useful tool to provide information about physiological changes during surgery in eloquent areas of the nervous system, to increase safety and reduce morbidity. Nevertheless, numerous older studies report that very few patients benefit from IOM, and that there are high rates of false-positive and false-negative changes of neurophysiological parameters during surgery. There is an ongoing discussion about the effectiveness of neurophysiological IOM. This questionnaire study was performed to evaluate the attitude of neurosurgeons toward neurophysiological IOM and the availability of this tool. METHODS: One hundred fifty neurosurgeons from 60 institutions in 16 countries were asked to answer anonymously a questionnaire with 11 questions. The questionnaire covered aspects of personal experience, the neurosurgical institution, and availability of neurophysiological IOM as well as asking the surgeon's opinion of the procedure. RESULTS: One hundred nine questionnaires were returned (73%). Seven questionnaires were excluded because of failure to complete the form correctly or completely, leaving 102 respondents from 44 institutions in 16 countries in the study; 79.5% of the included institutions provided neurophysiological IOM. Young neurosurgeons did not put more trust in IOM than experienced neurosurgeons. With growing IOM experience, surgeons seem to allow less influence of the findings on the course of their operation. At large institutions in which > 1500 operations per year are done, IOM is performed by the neurosurgeons themselves in most cases. In institutions with fewer operations, the IOM team consists mostly of nonneurosurgeons. Regardless of the availability of neurophysiological IOM, all surgeons stated that IOM is gaining increasing importance. CONCLUSIONS: Neurophysiological IOM represents an established tool in neurosurgery. Although the importance of IOM is emphasized by the majority of neurosurgeons, the relevance of this tool to the course of the operation changes with increasing neurophysiological IOM experience.

Association of F18-fluoro-ethyl-tyrosin uptake and 5-aminolevulinic acid-induced fluorescence in gliomas.

PURPOSE: Malignant gliomas are highly infiltrative tumours with a fatal prognosis. F18-fluoroethyl-tyrosine (FET)-positron emission tomography (PET) often reveals a broader extension of these tumours compared with contrast-enhanced magnetic resonance imaging (MRI). Complete resection of the contrast-enhancing lesion is aspired. Fluorescence-guided resection using 5-aminolevulinic acid (5-ALA) improved the extent of resection. In this study, we investigated whether the FET uptake correlates with the extent of resection using 5-ALA-induced fluorescence. METHODS: Thirteen patients who underwent preoperative and postoperative MRI, FET-PET and fluorescence-guided neuronavigated resection were included in this study. The areas in which intraoperative fluorescence terminated the resection were marked. After fusion of PET and MRI, the standardized uptake value (SUV) of FET related to normal brain (SUV(R)) was measured in regions of interest corresponding to resected and remaining tissue, respectively. Receiver-operating characteristic (ROC) curve analysis determined the optimal threshold of the relative SUV anticipating 5-ALA-induced fluorescence. RESULTS: During resection a vivid fluorescence was present in all patients. Histology revealed glioblastomas in 11 cases, an anaplastic astrocytoma in one case and a low-grade astrocytoma in one case. The median FET SUV(R) was higher in areas corresponding to the fluorescent tumour compared with the non-fluorescent normal brain (2.321 vs 1.142, p < 0.0001, t-test). A SUV(R) greater than 1.374 predicted the fluorescence with a sensitivity of 0.87 [95% confidence interval (CI): 0.74-0.94] and a specificity of 0.94 (CI: 0.84-0.99). The area under the ROC curve was 0.9656 (CI: 0.9364-0.9948). CONCLUSIONS: FET uptake predicts the 5-ALA-induced fluorescence in glioma patients. Thus, FET-PET provides useful information for planning glioma resection.

The prognostic role of IDH mutations in homogeneously treated patients with anaplastic astrocytomas and glioblastomas.

The detection of IDH mutations in patients with diffusely infiltrating malignant astrocytomas resulted in substantial modifications in the concept of WHO classification of these tumors. An important underlying observation was that patients with anaplastic astrocytomas (AA) without IDH mutation had a clinical course similar to that of patients with glioblastomas (GBM). The underlying observations of the German Glioma Network and NOA-04, however, were based on mixed patient cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually had radiotherapy or chemotherapy only. This intrinsic shortcoming of the study raised the question of whether patients with AA, IDH wildtype, WHO grade III, might have better prognosis if treated with combined radiochemotherapy than patients with GBM receiving the same combination therapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of an IDH mutation are still important if neither vascular proliferation nor necrosis are detectable. All patients in the cohort investigated here with the diagnosis of AA or GBM were subjected to a combined radiochemotherapy according to the Stupp protocol independently of the histopathological diagnosis. Thus, the analysis of these patients allows to clarify whether patients with AA, IDH wildtype, WHO grade III have a prognosis similar to that of GBM, IDH wildtype, WHO grade IV, even under equivalent therapeutic conditions. We determined the IDH1 and IDH2 status by sequencing, the MGMT status by pyrosequencing after bisulfite treatment and the EGFR status of the patients by FISH. In fact, the patients with the histopathological diagnosis of an AA IDH wild-type under similar aggressive therapy showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a GBM (mOS 13 months). Instead, patients with an AA and an IDH mutation receiving the same therapy had a mOS of 54 months. Thus, it can be concluded that in the absence of an IDH mutation, the established histopathological grading criteria 'necrosis' and 'vascular proliferation' actually lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and an IDH mutation are examined, there is still a difference between patients with necrosis and/or vascular proliferation and those whose tumors do not show such characteristics. Accordingly, in patients with malignant astrocytomas with IDH mutation it can be concluded that a histological differentiation between AA IDH mutated and GBM IDH mutated remains beneficial from a prognostic perspective.

Expression of glucose transporter 1 is associated with loss of heterozygosity of chromosome 1p in oligodendroglial tumors WHO grade II.

Objective Oligodendroglial tumors with a loss of heterozygosity of 1p (LOH1p) appear to have a better prognosis than oligodendrogliomas without LOH. Previously, we reported glucose uptake in low-grade oligodendroglial tumors to be related to LOH 1p status. Here, we performed an immunohistochemical study of the common glucose transporters (GLUT) in relation to LOH1p. Material and methods We examined 17 oligodendrogliomas (O II, 11 with LOH1p), 16 oligoastrocytomas (OA II, 5 with LOH1p) and 7 astrocytomas (A II, none with LOH1p). Confocal microscopy was performed for p53, GLUT-1, -3 and -12. Immunoreaction was rated semiquantitatively by percentage of positive cells and staining intensity on immunohistological stainings. Results Confocal microscopy depicted immunoreaction for GLUT-1, -3 and -12 in the cytoplasm of the tumor cells. Oligodendrogliomas revealed a lower immunoreactivity for GLUT-1 than oligoastrocytomas and astrocytomas (P = 0.0263). No differences in immunoreactivity were found for GLUT-3 and GLUT-12. GLUT-1 expression in tumors with LOH 1p was significantly lower than in tumors with wild type 1p status (P = 0.0017). GLUT-3 and GLUT-12 immunoreactivity was not correlated with LOH 1p. Conclusion Expression of GLUT-1 is significantly reduced in low-grade oligodendroglial tumors harboring LOH 1p. Further studies should address the functional role of GLUT-1 in regard to chemosensitivity of oligodendrogliomas.

GAVCA Study: Randomized, Multicenter Trial to Evaluate the Quality of Ventricular Catheter Placement with a Mobile Health Assisted Guidance Technique.

BACKGROUND: Freehand ventricular catheter placement may represent limited accuracy for the surgeon's intent to achieve primary optimal catheter position. OBJECTIVE: To investigate the accuracy of a ventricular catheter guide assisted by a simple mobile health application (mhealth app) in a multicenter, randomized, controlled, simple blinded study (GAVCA study). METHODS: In total, 139 eligible patients were enrolled in 9 centers. Catheter placement was evaluated by 3 different components: number of ventricular cannulation attempts, a grading scale, and the anatomical position of the catheter tip. The primary endpoint was the rate of primary cannulation of grade I catheter position in the ipsilateral ventricle. The secondary endpoints were rate of intraventricular position of the catheter's perforations, early ventricular catheter failure, and complications. RESULTS: The primary endpoint was reached in 70% of the guided group vs 56.5% (freehand group; odds ratio 1.79, 95% confidence interval 0.89-3.61). The primary successful puncture rate was 100% vs 91.3% (P = .012). Catheter perforations were located completely inside the ventricle in 81.4% (guided group) and 65.2% (freehand group; odds ratio 2.34, 95% confidence interval 1.07-5.1). No differences occurred in early ventricular catheter failure, complication rate, duration of surgery, or hospital stay. CONCLUSION: The guided ventricular catheter application proved to be a safe and simple method. The primary endpoint revealed a nonsignificant improvement of optimal catheter placement among the groups. Long-term follow-up is necessary in order to evaluate differences in catheter survival among shunted patients.