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.

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.

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.

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.

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.

Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide.

BACKGROUND: Optimal treatment and precise classification for anaplastic glioma are needed. METHODS: The objective for long-term follow-up of NOA-04 is to optimize the treatment sequence for patients with anaplastic gliomas. Patients were randomized 2:1:1 to receive the standard radiotherapy (RT) (arm A), procarbazine, lomustine and vincristine (PCV) (arm B1), or temozolomide (TMZ) (arm B2). RESULTS: Primary endpoint was time-to-treatment-failure (TTF), defined as progression after 2 lines of therapy or any time before if no further therapy was administered. Exploratory analyses examined associations of molecular marker status with TTF, progression-free survival (PFS), and overall survival (OS). At 9.5 (95% CI: 8.6-10.2) years, no difference between arms (A vs B1/B2) was observed: median TTF (4.6 [3.4-5.1] y vs 4.4 [3.3-5.3) y), PFS (2.5 [1.3-3.5] y vs 2.7 [1.9-3.2] y), and OS (8 [5.5-10.3] y vs 6.5 [5.4-8.3] y). Oligodendroglial versus astrocytic histology-but more so the subgroups according to CpG island methylator phenotype (CIMP) and 1p/19q co-deletion status-revealed a strong prognostic value of CIMPpos with (CIMPcodel) versus without 1p/19 co-deletion (CIMPnon-codel) versus CIMPneg. but no differential efficacy of RT versus chemotherapy for any of the endpoints. PFS was better for PCV- than for TMZ-treated patients with CIMPcodel tumors (HR B1 vs B2 0.39 [0.17-0.92], P = .031). In CIMPneg. tumors, hypermethylation of the O6-methyl-guanyl-DNA methyltransferase promoter (MGMT) provided a risk reduction for PFS with chemotherapy. CONCLUSIONS: There is no differential activity of primary chemotherapy versus RT in any subgroup of anaplastic glioma. Molecular diagnosis is superior to histology. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00717210.

Nationwide Incidence of Normal Pressure Hydrocephalus (NPH) Assessed by Insurance Claim Data in Germany.

BACKGROUND: The purpose of this study is to investigate the epidemiology of the idiopathic normal pressure hydrocephalus (iNPH) in Germany. METHODS: The database of the nationwide Barmer Health Insurance was queried for specific combinations of corresponding International Classification of Diseases, Ninth Revision (ICD-9) codes and OPS codes (German modification of the ICPM and official classification of surgical procedures) in order to assess the number of patients treated for iNPH and the number surgical procedures associated with the disease in a 10 years period between 2003 and 2012. RESULTS: Between 2003 and 2012, the incidence of iNPH increased from zero to 1.36/100.000/year. CONCLUSION: This is the first population-based epidemiologic study on iNPH in Germany covering a ten year period.

Frequency of BRAF V600E mutations in 969 central nervous system neoplasms.

BACKGROUND: Treatment options for oncological diseases have been enhanced by the advent of targeted therapies. The point mutation of the BRAF gene at codon 600 (BRAF V600E) is found in several tumor entities and can be approached with selective inhibitory antibodies. The BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases and in other cancer diseases. Therefore the BRAF V600E mutation is a highly interesting oncological target in brain tumors. METHODS: This study assesses the BRAF V600E mutation status in 969 intracranial neoplasms using a tissue microarray method and immunohistochemical staining with the mutation-specific VE-1 antibody, followed by sequencing of positively stained cases. RESULTS: Out of 784 primary brain tumors seven cases with a BRAF V600E mutation were detected (7/784, 1 %). Six of these cases were neuroepithelial tumors (6/667, 1 %) encompassing 2 astrocytomas WHO grade II (2/42, 5 %), 1 gliosarcoma WHO grade IV (1/75, 1 %) and 3 glioblastomas WHO grade IV (3/312, 1 %). Interestingly, all three mutant glioblastomas showed epithelioid histopathological features. Patients with V600E mutated astrocytic tumors were significantly younger (mean age 15.3 years) than wildtype cases (58.2 years). Among three rhabdoid meningiomas, one case was mutated (1/3) while all other grade I-III meningiomas (1/116, 1 %) and all fifty vestibular schwannomas analyzed were of wildtype status. The vast majority of the BRAF V600E mutations were found in cerebral metastases of malignant melanomas and carcinomas (29/135, 22 %), with false-positive staining found in four breast cancer cases and two non-small-cell lung carcinoma (NSCLC) samples. CONCLUSIONS: Our data suggest routine screening for BRAF V600E mutations for glioblastomas WHO grade IV below the age of 30, especially in glioblastomas with epithelioid features and in all rhabdoid meningiomas WHO grade III. For colorectal carcinoma, thyroid cancer, malignant melanoma and gliomas BRAF V600E immunostaining is sufficient for screening purposes. We also recommend routine immunohistochemical staining followed by sequencing validation in rare CNS metastases or metastases of unknown primary. Immunohistochemical analysis using mutation-specific antibodies on tissue microarrays is a feasible, time- and cost-efficient approach to high-throughput screening for specific mutations in large tumor series but sequencing validation is necessary in unexpected cases.

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.

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.

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.

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.

Treatment of glioblastoma in elderly patients.

Although glioblastoma occurs mostly in elderly patients, there is a paucity of trials addressing patients older than 70 years of age. Age, by itself, constitutes an unfavorable prognostic factor, which is probably due to unpropitious genetic features, but also due to iatrogenic defeatism. However, many retrospective studies report a survival benefit achieved by aggressive surgical resection seeking gross total removal of contrast-enhancing tumor according to preoperative MRI. Combined radiochemotherapy with concomitant and adjuvant temozolomide has not been investigated in prospective trials. Numerous retrospective studies and a meta-analysis suggest benefit from combined treatment. Prospective randomized trials only evaluated either temozolomide or radiotherapy. Single-treatment hypofractionated radiotherapy performed superior to conventional fractionation. In patients with methylated MGMT promoter, first-line dose-dense temozolomide facilitates prolonged survival. However, there is no comparison with combined radiochemotherapy as the standard-of-care in adult patients. Comorbidity is more frequent in elderly patients, but does not correlate with preterm termination of temozolomide treatment. This review article compiles data proposing a straightforward glioblastoma treatment, irrespective of age.

Catheter placement for lysis of spontaneous intracerebral hematomas: is a navigated stylet better than pointer-guided frameless stereotaxy for intrahematomal catheter positioning?

The optimal management of spontaneous intracerebral hemorrhage (ICH), especially if deep-seated, remains a matter of discussion. Lysis of the blood clot applying recombinant tissue-type plasminogen activator (rtPA) by an intrahematomal catheter is a minimally invasive treatment option, currently being under investigation in a randomized trial. The center position of the catheter in the hematoma is believed to be crucial for an optimal clot lysis. To achieve this objective, frame-based stereotaxy and frameless stereotaxy with guidance of an articulated arm were used. Recently, a preregistered stylet for direct navigation, alleviating the need of guidance, became available. In this study, we evaluated the relative error (RE) describing the deviation of the catheter from the ideal center position in the clot and compared the accuracy of catheter placement using frameless stereotaxy or the novel preregistered stylet. The intrahematomal catheter position was evaluated in three dimensions in 89 patients with spontaneous supratentorial ICH. Frameless stereotaxy with guidance of an articulated arm was performed in 50 patients. The preregistered stylet was used in 39 patients. The catheter position was evaluated using a RE calculating the distance perpendicular to the center of the catheter in relation to the hematoma's diameter. The mean hematoma volume was 51.4 ml. Forty-four out of 89 hematomas were deep-seated. Intraventricular blood was found in 59 patients. The RE of the catheter position was lower in the stylet group in comparison to the frameless stereotaxy group (mean 0.57 vs. 0.90; p = 0.0018). There was no difference between deep-seated and lobar hematomas with regard to the accuracy of catheter placement (p = 0.62). The RE is a robust measure for describing intrahematomal catheter position. The preregistered stylet facilitates a satisfactory catheter placement and is a viable alternative to frameless stereotaxy and guidance with the articulated arm.

A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07).

BACKGROUND: Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing. METHODS: This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules. RESULTS: Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4-41.4 mo) and a median OS of 46.9 months (range, 21.2-49.2 mo) for this subgroup. c-KIT expression in vascular endothelial cells (n = 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity. CONCLUSION: Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS. ClinicalTrials.gov Identifier: NCT00535379.

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.

Concomitant and adjuvant temozolomide of newly diagnosed glioblastoma in elderly patients.

OBJECTIVE: The effect of concomitant and adjuvant temozolomide in glioblastoma patients above the age of 65 years lacks evidence. However, after combined treatment became standard at our center all patients were considered for combined therapy. We retrospectively analyzed the effect of temozolomide focused on elderly patients. METHODS: 293 patients with newly diagnosed glioblastoma treated single-centered between 1998 and 2010, by radiation alone or concomitant and adjuvant radiochemotherapy, were included. Treatment groups were analyzed by multi- and univariate analysis. Matched pairs for age, by a 5-year-caliper, extent of resection and general state was generated for all patients and elderly subgroups. RESULTS: 103 patients received radiation only and 190 combined treatment. Multivariate and matched pair analysis revealed a benefit due to combined temozolomide (HR 1.895 and 1.752, respectively). For patients older than 65 years median survival was 3.6 (95% CI 3.2-4.7) and 8.7 months (6.3-11.8) for radiotherapy only and combined treatment (HR 3.097, p<0.0001, n=90). Over the age of 70 and 75 years median survival was 3.2 (2.3-4.2) vs. 7.5 (5.1-10.9, HR 4.453, p<0.0001, n=62) and 3.2 (1.4-3.9) vs. 9.2 months (4.7-13.5; HR 9.037, p<0.0001, n=24), respectively. In 8/56 (14%) patients over the age of 70 years temozolomide was terminated due to toxicity. CONCLUSION: Retrospective matched pair analysis gives class 2b evidence for prolonged survival due to concomitant and adjuvant temozolomide in elderly glioblastoma patients. Until prospective data for combined radiochemotherapy in elderly patients will be available concomitant and adjuvant temozolomide therapy should not be withheld.

Establishment and characterization of primary glioblastoma cell lines from fresh and frozen material: a detailed comparison.

BACKGROUND: Development of clinically relevant tumor model systems for glioblastoma multiforme (GBM) is important for advancement of basic and translational biology. High molecular heterogeneity of GBM tumors is well recognized, forming the rationale for molecular tests required before administration of several of the novel therapeutics rapidly entering the clinics. One model that has gained wide acceptance is the primary cell culture model. The laborious and time consuming process is rewarded with a relative high success rate (about 60%). We here describe and evaluate a very simple cryopreservation procedure for GBM tissue prior to model establishment that will considerably reduce the logistic complexity. METHODS: Twenty-seven GBM samples collected ad hoc were prepared for primary cell culture freshly from surgery (#1) and after cryopreservation (#2). RESULTS: Take rates after cryopreservation (59%) were as satisfactory as from fresh tissue (63%; p = 1.000). We did not observe any relevant molecular or phenotypic differences between cell lines established from fresh or vitally frozen tissue. Further, sensitivity both towards standard chemotherapeutic agents (Temozolomide, BCNU and Vincristine) and novel agents like the receptor tyrosine kinase inhibitor Imatinib did not differ. CONCLUSIONS: Our simple cryopreservation procedure facilitates collection, long-time storage and propagation (modeling) of clinical GBM specimens (potentially also from distant centers) for basic research, (pre-) clinical studies of novel therapies and individual response prediction.

D-dimer elevation and paresis predict thromboembolic events during bevacizumab therapy for recurrent malignant glioma.

BACKGROUND: The major side-effects of bevacizumab in glioma treatment are venous thromboembolic events (VTE). We retrospectively evaluated factors potentially predictive of thromboembolic events. PATIENTS AND METHODS: Bevacizumab, alone or in combination with chemotherapy was used as salvage therapy for recurrence in malignant glioma every two weeks. None but one patient received anti-coagulants. Before each bevacizumab cycle differential blood cell count, kidney and liver parameters, D-dimers, neurological status, body-mass index, vital signs and signs of venous thrombosis were assessed. RESULTS: Thirty-eight patients received 428 cycles of bevacizumab. In five patients (13%), six VTE were observed. These complications were preceded four weeks before the onset of symptoms by D-dimer elevation above 0.865 mg/l [p<0.0001; sensitivity=89% (95% confidence interval=83-93%); specificity=89% (95% CI=52-100%)]. An existing hemiparesis constituted a 27-fold risk elevation for thrombotic complication (p<0.0001, χ(2)-test). CONCLUSION: D-Dimer elevation or hemiparesis predict VTE under bevacizumab and chemotherapy, four weeks before the event becomes clinically apparent. Future investigations should determine if prophylactic anti-coagulants for patients at risk may reduce the risk of VTE.