IDH1 mutation is associated with improved resection rates, progression-free survival and overall survival in patients with anaplastic astrocytomas.

PURPOSE: The introduction of molecular markers in to the diagnosis of gliomas has changed the therapeutic approach to this tumors. The aim of this study was to examine the impact of surgery on anaplastic astrocytomas (AA), which has not previously been fully elucidated. METHODS: This was a retrospective study involving a total of 143 patients who underwent surgery for primary AA in our department between 1995 and 2020. RESULTS: Total tumor resection was achieved more often in patients with IDH-mutant tumors (41.09%) than in patients with IDH-wildtype tumors (30.76%). The median PFS was 1876 days for patients with IDH1 mutations and 238 days for patients with IDH-wildtype tumors. The 1-, 3-, 5- and 10-year PFS were longer in patients with total tumor resection and IDH-mutant AA (86.2%, 69%, 65.5% and 44.8%, respectively) than in patients with subtotal tumor resection and IDH-mutant AA (83.3%, 55.6%, 41.7% and 25%, respectively) and even longer compared to all IDH-wildtype tumors. The median OS was 2472 days for patients with IDH1 mutations and 434 days for patients with IDH-wildtype tumors. The 3-, 5- and 10-year OS times were longer in patients with total tumor resection and IDH-mutant AA (89.2%, 85.2% and 72.6%, respectively) than in patients with subtotal tumor resection and IDH-mutant AA (85.9%, 73.7% and 52.6%, respectively) and were even longer compared to all IDH-wildtype tumors. CONCLUSION: Total tumor resection is more common with IDH-mutant AA than with IDH-wildtype tumors. Patients with IDH-mutant AA had significantly better PFS and OS after total tumor resection than after subtotal tumor resection and biopsy.

Surgical approach for convexity meningiomas: An analysis of the preoperative clinical signs, radiological features and surgical outcomes of these tumors.

BACKGROUND: Convexity meningiomas (CM) can be successfully treated with neurosurgery. However, clinical complications due to CM have been reported. Moreover, systematic investigations of CM with respect to all relevant clinical factors are currently lacking. METHODS: We performed a systematic investigation in 210 patients with supratentorial CM considering all relevant clinical and radiological factors, with a follow-up time of 19.5 years. RESULTS: Among 812 patients with intracranial meningiomas treated in our department (2003-2020), 28.2 % of intracranial meningiomas were located over the supratentorial convexity, and the patients had a median age of 62 years (95 % CI:59-64). The median follow-up was 30.4 months (95 % CI:21.6-37.1). Tumor-related symptoms were observed in 88.1 % of patients. The most common preoperative symptom was headache (28.1 %), followed by seizure (19.5 %). Symptomatic patients had significantly higher tumor volumes than asymptomatic patients (p = 0.0003; 24.5 cm3 and 6.98 cm3, respectively). Complete tumor resection was achieved in 92.9 % of patients. The most common postoperative complication was bleeding (7.1 %) in the approach area. Of all bleedings, only three were intracerebral hemorrhages and did not require surgical intervention. The second most common complication was postoperative seizure (4.7 %). The multiple logistic regression analyses showed that tumor volume (OR:1.007; 95 % CI:1.001-1.013; p = 0.02) and brain infiltration by the tumor (OR:1.961; 95 % CI:1.028-3.741; p = 0.04) had a significant impact on postoperative complications. The postoperative and final KPS scores significantly improved (p < 0.001). The tumor recurrence rate was 6.2 %, with a median time of 38 months. No surgery-related deaths occurred. CONCLUSION: A large tumor volume and brain infiltration by the tumor were significant factors for postoperative complications. The clinical conditions significantly improved postoperatively and further during the follow-up period.

Impact of peritumoral brain edema on pre- and postoperative clinical conditions and on long-term outcomes in patients with intracranial meningiomas.

BACKGROUND: Peritumoral brain edema (PTBE) is a common complication related to intracranial meningiomas. In several studies, researchers have investigated the pathogenesis of PTBE, and the factors involved in its development in patients with intracranial meningiomas have been reported. However, very little is known about the clinical effect of PTBE on patients with intracranial meningiomas; therefore, a systematic examination of this matter is necessary. METHODS: In this study, we performed a systematic examination of 696 patients with primary intracranial meningiomas to assess the effect of preoperative PTBE on preoperative symptoms, neurological deficits and postoperative complications, and long-term outcomes with a follow-up period of 16.8 years. We performed a univariate analysis and multiple regression for specific outcomes and adjusted for other relevant clinical factors. RESULTS: A total of 627 (90.1%) patients were symptomatic preoperatively. One hundred eighty-eight (90.8%) patients with small to moderate PTBE and 125 (98.4%) patients with severe PTBE presented with symptoms significantly more often than the 314 (86.7%) patients without PTBE (p < 0.001, univariate analysis). Cognitive deficits, palsy and seizure were significantly more present, preoperatively, in patients with PTBE than in patients without PTBE (p < 0.001, univariate analysis). Two hundred fifty-five (36.6%) patients experienced surgical and systemic complications postoperatively. The complication rate was significantly higher in patients with PTBE; 41.5% for patients with small to moderate PTBE and 52.8% for patients with severe PTBE, compared to 28.2% of patients without PTBE (p < 0.001, univariate analysis). Furthermore, pre- and postoperative KPS scores were significantly lower in patients with PTBE (p < 0.001). Patients with PTBE required additional medical support significantly more often (p < 0.001) and had a significantly longer hospital stay (p < 0.001). The mortality rate was higher in patients with PTBE immediately after surgery and in the follow-up period; however, the difference was not significant. The neurological condition of all patients improved in the follow-up and did not show significant differences between patients with and without preoperative PTBE (p = 0.6361). Multiple logistic regression analyses revealed a significant association between PTBE and the presence of preoperative cognitive deficits, the incidences of seizure and postoperative complications, and low pre- and postoperative KPS scores. CONCLUSIONS: Preoperative PTBE significantly increased the incidences of specific preoperative symptoms, neurological deficits and postoperative complications in patients with intracranial meningiomas. After surgery, patients with preoperative PTBE required medical support significantly more often than patients without PTBE. However, all patients had favorable outcomes after surgery.

Risks and neurological benefits of meningioma surgery in elderly patients compared to young patients.

INTRODUCTION: While surgery is the primary treatment choice for intracranial meningiomas in young patients, surgery in elderly patients, especially those with pre-existing comorbidities, has been the subject of repeated discussion. This study investigated the postoperative risks and neurological benefits of meningioma surgery in elderly patients compared to young patients. METHODS: In total, 768 patients were included and divided into two main groups: group I (age: ≤ 64 years; 484 young patients) and group II (age: ≥ 65 years; 284 elderly patients). Group II was subdivided into: IIa (age: 65-69 years), IIb (age: 70-79 years); and IIc (age: ≥ 80 years). RESULTS: The total tumor resection rate was higher in the elderly cohort than in the young cohort (84.5 and 76.2%, respectively). 154 young patients (31.8%) and 132 elderly patients (46.5%) developed postoperative morbidities, with the three most common being bleeding (12.9%), cranial nerve disorder (10%) and CSF fistula (8.1%). Postoperative bleeding, palsy, speech disorder, pneumonia and renal insufficiency were dependent on age (r = 0.123, p = 0.001; r = 0.089, p = 0.014; r = 0.100, p = 0.006; r = 0.098, p = 0.007 and r = 0.084, p = 0.020) and presented more often in elderly patients. 6 young and 15 elderly patients died during the 17.4-year observation period. Most patients showed a significant improvement in postoperative KPS (p < 0.001), except those over 80 years old (p = 0.753). The KPS at the last follow-up was significantly improved in all patients (p < 0.001). CONCLUSION: Meningioma surgery is associated with a higher rate of postoperative complications in elderly patients than in young patients. Most elderly patients, similar to young patients, show a significant improvement in neurological status postoperatively.

Towards the targeted assessment of relevant problems: Optimization of the distress Thermometer for adult neuro-oncological patients.

OBJECTIVE: Generic psychosocial screening tools may not reflect the unique symptom profile of brain tumour patients (BTPs). The aim was to adapt the problem list of the distress thermometer (DT) for BTPs. METHODS: First, items of low relevance for BTPs were identified on basis of retrospective analyses. Second, relevant yet missing problems were identified via an extensive literature search, qualitative interviews with BTPs and experts, as well as an online expert survey. The resulting raw version of the adapted problem list in BTPs was subsequently pretested. RESULTS: In the first part, data of n = 657 BTPs were analysed. Twelve items (20%) were excluded in this step as they proved to be less relevant for BTPs (i.e., items were endorsed by less than 10% and without significant correlations to patients' DT score). In the second part, qualitative interviews and the online survey with 102 professionals led to the addition of 21 new and the modification and condensation of 17 relevant problems specific for BTPs. This adapted list was than successfully pretested in n = 19 patients, leading to the 'distress thermometer brain tumour problem list' (DT-BT), consisting of 42 relevant problems. CONCLUSION: The adapted problem list for the DT particularly reflects the neurological and psychosocial burden of an intracranial tumour and allows for the targeted assessment of the specific burdens and needs of BTPs. Our revised version of the DTs problem list (DT-BT) should in the next step be widely validated in multinational samples.

Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial.

BACKGROUND: Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge when counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinson's disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone. METHODS: We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinson's disease who were disabled by early motor complications. Participants were randomly allocated (1:1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinson's Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only. FINDINGS: Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (-363·3 mg/day [SE 41·8]) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245·8 mg/day [40·4]) in those assigned medical therapy alone (p<0·0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change -0·65 points [SE 0·15]) and did not change with medical therapy alone (-0·02 points [0·15]); the between-group difference in change from baseline was significant (p=0·0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change -1·26 points [SE 0·35]) and had increased with medical therapy alone (1·12 points [0·35]); the between-group difference was significant (p<0·0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide. INTERPRETATION: In a large cohort with Parkinson's disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications. FUNDING: German Federal Ministry of Education and Research, French Programme Hospitalier de Recherche Clinique National, and Medtronic.

Movement-Related Activity of Human Subthalamic Neurons during a Reach-to-Grasp Task.

The aim of the study was to record movement-related single unit activity (SUA) in the human subthalamic nucleus (STN) during a standardized motor task of the upper limb. We performed microrecordings from the motor region of the human STN and registered kinematic data in 12 patients with Parkinson's disease (PD) undergoing deep brain stimulation surgery (seven women, mean age 62.0 ± 4.7 years) while they intraoperatively performed visually cued reach-to-grasp movements using a grip device. SUA was analyzed offline in relation to different aspects of the movement (attention, start of the movement, movement velocity, button press) in terms of firing frequency, firing pattern, and oscillation. During the reach-to-grasp movement, 75/114 isolated subthalamic neurons exhibited movement-related activity changes. The largest proportion of single units showed modulation of firing frequency during several phases of the reach and grasp (polymodal neurons, 45/114), particularly an increase of firing rate during the reaching phase of the movement, which often correlated with movement velocity. The firing pattern (bursting, irregular, or tonic) remained unchanged during movement compared to rest. Oscillatory single unit firing activity (predominantly in the theta and beta frequency) decreased with movement onset, irrespective of oscillation frequency. This study shows for the first time specific, task-related, SUA changes during the reach-to-grasp movement in humans.

Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma.

We characterized health-related quality of life (HRQoL), cognitive, and functional status in newly diagnosed glioblastoma (GBM) patients receiving Tumor treating fields (TTFields) with temozolomide (TMZ) versus TMZ alone in a planned interim analysis of a randomized phase III trial [NCT00916409], which showed significant improvement in progression-free and overall survival with TTFields/TMZ. After radiotherapy with concomitant TMZ, newly diagnosed GBM patients were randomized (2:1) to TTFields/TMZ (n = 210) or TMZ (n = 105). Interim analysis was performed in 315 patients with ≥18 months of follow-up. HRQoL, a secondary endpoint, was evaluated in per-protocol patient population and expressed as change from baseline (CFB) at 3, 6, and 9 months for each subscale in the EORTC QLQ-C30/BN20. Karnofsky performance scores (KPS) and Mini-Mental State Examination scores (MMSE) were assessed. CFB in HRQoL was balanced in treatment groups at the 12-month time point. Initially, HRQoL improved in patients treated with TTFields/TMZ (CFB3: 24% and CFB6: 13%) versus TMZ (CFB3: -7% and CFB6: -17%), though this difference was no longer evident at the 9-month point. General scales, including physical and social functioning, showed no difference at 9 and 12 months. TTFields/TMZ group reported higher concerns of "itchy skin". KPS over 12 months was just below 90 in both groups. Cognitive status (MMSE) was stable over time. HRQoL, KPS, and MMSE were balanced in both groups over time. There was no preliminary evidence that HRQoL, cognitive, and functional status is adversely affected by the continuous use of TTFields.

Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine-DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial.

PURPOSE: In patients with newly diagnosed glioblastoma that harbors a nonmethylated O(6)-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. PATIENTS AND METHODS: In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150-200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). RESULTS: In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. CONCLUSION: BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

Low-grade Glioma Surgery in Intraoperative Magnetic Resonance Imaging: Results of a Multicenter Retrospective Assessment of the German Study Group for Intraoperative Magnetic Resonance Imaging.

BACKGROUND: The ideal treatment strategy for low-grade gliomas (LGGs) is a controversial topic. Additionally, only smaller single-center series dealing with the concept of intraoperative magnetic resonance imaging (iMRI) have been published. OBJECTIVE: To investigate determinants for patient outcome and progression-free-survival (PFS) after iMRI-guided surgery for LGGs in a multicenter retrospective study initiated by the German Study Group for Intraoperative Magnetic Resonance Imaging. METHODS: A retrospective consecutive assessment of patients treated for LGGs (World Health Organization grade II) with iMRI-guided resection at 6 neurosurgical centers was performed. Eloquent location, extent of resection, first-line adjuvant treatment, neurophysiological monitoring, awake brain surgery, intraoperative ultrasound, and field-strength of iMRI were analyzed, as well as progression-free survival (PFS), new permanent neurological deficits, and complications. Multivariate binary logistic and Cox regression models were calculated to evaluate determinants of PFS, gross total resection (GTR), and adjuvant treatment. RESULTS: A total of 288 patients met the inclusion criteria. On multivariate analysis, GTR significantly increased PFS (hazard ratio, 0.44; P < .01), whereas "failed" GTR did not differ significantly from intended subtotal-resection. Combined radiochemotherapy as adjuvant therapy was a negative prognostic factor (hazard ratio: 2.84, P < .01). Field strength of iMRI was not associated with PFS. In the binary logistic regression model, use of high-field iMRI (odds ratio: 0.51, P < .01) was positively and eloquent location (odds ratio: 1.99, P < .01) was negatively associated with GTR. GTR was not associated with increased rates of new permanent neurological deficits. CONCLUSION: GTR was an independent positive prognostic factor for PFS in LGG surgery. Patients with accidentally left tumor remnants showed a similar prognosis compared with patients harboring only partially resectable tumors. Use of high-field iMRI was significantly associated with GTR. However, the field strength of iMRI did not affect PFS. ABBREVIATIONS: EoR, extent of resectionFLAIR, fluid-attenuated inversion recoveryGTR, gross total resectionIDH1, isocitrate dehydrogenase 1iMRI, intraoperative magnetic resonance imagingLGG, low-grade gliomaMGMT, methylguanine-deoxyribonucleic acid methyltransferasenPND, new permanent neurological deficitOS, overall survivalPFS, progression-free survivalSTR, subtotal resectionWHO, World Health Organization.

The medical treatment of patients with Parkinson's disease receiving subthalamic neurostimulation.

INTRODUCTION: Deep brain stimulation of subthalamic nucleus (STN-DBS) for Parkinson's disease allows for a reduction in medication dosage. Changes in total levodopa equivalent daily dose (LEDD) have been frequently reported, there is little information about changes within the drug classes. METHODS: We retrospectively assessed the changes in antiparkinsonian drugs dosages in 150 patients from one center who had preoperative and postoperative evaluations at 6 months and 3 years. Two long term subgroups with postoperative follow-up till the 5th-6th year (n = 58) and 10th year (n = 15) were included. RESULTS: The major modifications in medication dosage occurred during the initial postoperative period. LEDD was reduced by 53.4% compared to baseline at 6 months and 47.9% at 3 years. Fifty six percent and 41.3% of the patients were on monotherapy, 9.3% on no medication at 6 months and 6.7% at 3 years post surgery. Patients on levodopa, or dopamine agonists showed similar reductions. At the 3rd year the oldest group of patients showed a significant decrease in dopamine agonists. The number of patients treated with amantadine was significantly reduced; however the number of patients treated with antidepressants was significantly increased over the first 3 years. Annual medication costs per patient were decreased after the DBS-STN implantation by 61.3% at 6 months and 55.4% at 3 years. CONCLUSION: STN-DBS allows for a reduction in the dosage of medication and the costs are similarly reduced. In this cohort different medication groups were reduced to a similar extent. Patients' demographic factors did not play a major role in the selection of treatment.

A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma.

PURPOSE: A randomised, open label phase III trial was conducted to evaluate efficacy of nimotuzumab, a monoclonal antibody against epidermal growth factor receptor (EGF-R) added to standard therapy for newly diagnosed glioblastoma. PATIENTS AND METHODS: 149 glioblastoma patients stratified as with or without residual tumour were randomly assigned to receive either intravenous nimotuzumab 400mg weekly added to standard radiochemotherapy followed by 400mg biweekly after twelve weeks or standard radiochemotherapy. Progression status after 52 weeks (12moPFS) and progression-free survival (PFS) based on Macdonald criteria were co-primary and overall survival (OS), toxicity and quality of life secondary end-points. RESULTS: 142 patients were evaluated for efficacy (per protocol cohort). 12 moPFS was 25.6% in the experimental arm and 20.3% in the control group. In residual tumour patients (n=81) median PFS was 5.6 versus 4.0 months, (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.55-1.37), for patients without residual tumour (n=61) it was 10.6 versus 9.9 months, (HR, 1.01; 95% CI, 0.57-1.77). Median OS in patients with residual tumour was 19.5 versus 16.7 months, (HR, 0.90; 95% CI, 0.52-1.57; P=0.7061), for patients without 23.3 versus 21.0 months (HR, 0.77; 95% CI, 0.41-1.44; P=0.4068). A small cohort of MGMT non-methylated patients with residual tumour showed PFS of 6.2 versus 4.0 months (HR, 0.77; 95% CI, 0.35-1.67; P=0.4997) and OS of 19.0 versus 13.8 months (HR, 0.66; 95% CI, 0.27-1.64; P=0.3648). EGF-R amplification did not correlate with clinical efficacy of nimotuzumab. Nimotuzumab was well tolerated. CONCLUSION: This study, albeit negative, contains hypothesis generating signals supporting evaluation of correlative, efficacy-predicting tumour parameters for nimotuzumab in the treatment of glioblastoma.

A multicentre, prospective, randomized, controlled study to evaluate the use of a fibrin sealant as an adjunct to sutured dural repair.

BACKGROUND: Obtaining intra-operative watertight closure of the dura is considered important in reducing post-operative cerebrospinal fluid (CSF) leak. The purpose of this study was to evaluate a fibrin sealant as an adjunct to sutured dural repair to obtain intra-operative watertight closure in cranial neurosurgery. METHODS: This randomized, controlled multicenter study compared a fibrin sealant (EVICEL® Fibrin Sealant [Human]) to sutured dural closure (Control). Subjects underwent supratentorial or posterior fossa procedures. Following primary dural repair by sutures, the closure was evaluated for intra-operative CSF leak by moderately increasing the intracranial pressure. If present, subjects were randomized to EVICEL® or additional sutures (2:1 ratio), stratified by surgical approach. Following treatment, subjects were successful if no CSF leaks were present during provocative challenge. Safety was assessed to 30 days post-surgery, including incidence of CSF leakage. RESULTS: One hundred and thirty-nine subjects were randomized: 89 to EVICEL® and 50 to Control. Intra-operative watertight closure was achieved in 92.1% EVICEL®-treated subjects versus 38.0% controls; a treatment difference of 54.1% (p < 0.001). The treatment differences in the supratentorial and posterior fossa strata were 49.1% and 75.7%, respectively (p < 0.001). The incidence of adverse events was similar between treatment groups. No deaths or unexpected serious adverse drug reactions were reported. CSF leakage within 30 days post-operatively was 2.2% and 2.0% in EVICEL® and control groups, respectively. In addition, 2 cases of CSF rhinorrhoea were observed in the EVICEL® group. Although not associated with the suture line where EVICEL® was applied, when combined with the other CSF leaks, the observed leak rate in the EVICEL® group was 4.5%. CONCLUSIONS: These results indicate that EVICEL® is effective as an adjunct to dural sutures to provide watertight closure of the dura mater in cranial surgery. The study confirmed the safety profile of EVICEL®.

Neuroendoscopy and high-field intraoperative MRI: first experience.

BACKGROUND: To date, information about the use of intraoperative MRI (iMRI) in patients undergoing neuroendoscopic procedures is sparse. The benefit may be (re)definition of neuronavigation, confirmation of fenestrations and biopsies, detection of complications, and redefinition of anatomical changes during the operation. MATERIAL AND METHODS: Our setting consists of a fully integrated high-field 1.5-T MRI into the operating room. The operating room can be functionally divided into (1) the MRI scanner and (2) the operating table outside the 5 Gauss line where ferromagnetic surgical instruments can be used. We included a consecutive series of 11 adult patients who underwent 11 endoscopic operations in the iMRI setting between January 2007 and September 2011. RESULTS: The median age of patients was 54 years (range: 40-69 years). The male-to-female ratio was 4.5:1. Diagnoses leading to endoscopic treatment were aqueductal stenosis (n = 8; caused by tumors in three cases), pineal cyst (n = 1), tumor of the third ventricle (n = 1), and brain abscess with ventriculitis (n = 1). Endoscopic procedures were endoscopic third ventriculostomy with or without tumor biopsy (n = 5), aqueductoplasty (n = 4), tumor biopsy and septostomy (n = 1), and tumor resection (n = 1). All patients were scanned at least once, seven patients twice during surgery. The mean scan time per procedure was 19 minutes. The following sequences were regarded as most useful: T2 axial (placement of catheter, ruling out of complications), T2 sagittal (flow void signal), and true fast imaging (TRUFI) (fenestration defect). CONCLUSIONS: iMRI enables high-resolution imaging immediately after endoscopic operation. The combined use is technically feasible and of potential value in selected cases with complex hydrocephalus. In most of these cases, scanning can be limited to T2 axial, T2 sagittal, and TRUFI MR images.

The impact of age and disease duration on the long term outcome of neurostimulation of the subthalamic nucleus.

BACKGROUND: Selection of patients with Parkinson's disease for neurostimulation of subthalamic nucleus (STN-DBS) is still poorly studied. AIM: To identify the impact of age and disease duration on the outcome of bilateral STN-DBS. METHODS: 110 operated patients in a single center covering a large range of age and disease duration were retrospectively included and followed for up-to 5 years. Standardized UPDRS assessments were obtained at 0.5-1 and 3-5 years. Patients were stratified into three age groups (≤ 55, 56-64 and ≥ 65 years) and the middle age group was further stratified into 2 disease duration subgroups (<15 years, ≥ 15 years). RESULTS: The age groups had comparable baseline data except for the predefined differences. Compared to baseline early and late intra-group "Med Off-Stim On" motor scores were significantly improved for all groups (p < 0.001). Mood/cognition were significantly improved in younger two groups (p = 0.008, 0.019) at 0.5-1 year. Inter-group comparisons showed significantly worse early and late axial scores for older patients (p < 0.05). All groups had comparable postoperative improvement except for the older group which had significantly less improvement of early UPDRS-II, late UPDRS-I, and early and late PIGD/axial scores. Different disease durations had no effect on the outcome except for worse Schwab and England Off-score in longer duration group (p = 0.02). Side effects of surgery and long-term management were similar. CONCLUSION: STN-DBS is an efficient treatment of advanced PD for all treated age-groups. Provided strict inclusion criteria are respected, older age and longer disease duration are associated with slightly worse effects mainly on L-dopa-resistant symptoms.

Incomplete tumour control following DNA vaccination against rat gliomas expressing a model antigen.

BACKGROUND: Vaccination against tumour-associated antigens is one approach to elicit anti-tumour responses. We investigated the effect of polynucleotide (DNA) vaccination using a model antigen (E. coli lacZ) in a syngeneic gliosarcoma model (9L). METHODS: Fisher 344 rats were vaccinated thrice by intramuscular injection of a lacZ-encoding or a control plasmid in weekly intervals. One week after the last vaccination, lacZ-expressing 9L cells were implanted into the striatum. RESULTS: After 3 weeks, in lacZ-vaccinated animals the tumours were significantly smaller than in control-vaccinated animals. In cytotoxic T cell assays lysis rates of >50 % could only be observed in a few of the lacZ-vaccinated animals. This response was directed against lacZ-expressing and parental 9L cells but not against syngeneic MADB 106 adenocarcinoma cells. In Elispot assays interferon-γ production was observed upon stimulation with 9LlacZ and 9L wild-type but not MADB 106 cells. This response was higher for lacZ-immunized animals. All animals revealed dense infiltrates with CD8+ lymphocytes and, to a lesser extent, with NK cells. CD25-staining indicated cells possibly associated with the maintenance of peripheral tolerance to self-antigens. All tumours were densely infiltrated by microglia consisting mostly of ramified cells. Only focal accumulation of macrophage-like cells expressing ED1, a marker for phagocytic activity, was observed. CONCLUSION: Prophylactic DNA vaccination resulted in effective but incomplete suppression of brain tumour formation. Mechanisms other than cytotoxic T cell responses as measured in the generally used in vitro assays appear to play a role in tumour suppression.

NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality.

PURPOSE: NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. METHODS: Phase III trial of chemotherapy-free treatment of NovoTTF (20-24h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. RESULTS: Patients (median age 54 years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n=120) or active chemotherapy control (n=117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0 months (hazard ratio 0.86 [95% CI 0.66-1.12]; p=0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6 months was 21.4% and 15.1% (p=0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p=0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p=0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. CONCLUSIONS: This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF.

Camptocormia in idiopathic Parkinson's disease: a focal myopathy of the paravertebral muscles.

The objective of our study was to describe the clinical features of camptocormia, an involuntary, marked flexion of the thoracolumbar spine in idiopathic Parkinson's disease (PD) and to understand its etiology. In a prospective, cross-sectional study, we examined 15 patients with PD and camptocormia using laboratory parameters, EMG, muscle magnetic resonance imaging, and biopsy of the paravertebral muscles. The clinical data were compared with a matched control group of PD patients without camptocormia, and the biopsies were compared with muscles from age-matched autopsies. Almost all the patients (median age, 68.0 years; 7 women) with camptocormia suffered from advanced PD. Camptocormia occurred at a median of 9.0 years after the PD diagnosis. Compared with our clinical control group, back pain was more frequent and less dopa-sensitive in the patients with camptocormia who suffered more often from additional diseases of the back. On EMG, we found mainly a myopathic pattern. The MRI of the paravertebral muscles showed localized changes ranging from edema with contrast enhancement, which are considered to be early signs, to atrophy and/or fatty degeneration, interpreted as late degenerative changes. Early signs were seen mainly during the first year and degenerative changes after 1.5 years. Biopsies revealed consistently myopathic changes and in some cases fatty degeneration. Clinical or electromyographic features favoring dystonia were absent. Camptocormia is a major disabling, non-fluctuating and levodopa-resistant complication of advanced PD. The cause of camptocormia in idiopathic PD is a focal myopathy. Our findings suggest that the myopathy has a progressive course, which finally leads to degeneration of the paravertebral muscles.

Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide.

A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0-2 who had completed previous treatment comprising surgical resection, irradiation therapy, and first-line chemotherapy (preferably temozolomide (TMZ) containing regimen) and who have progressed despite treatment. If first-line chemotherapy did not contain TMZ, a second completed chemotherapy was acceptable. The primary efficacy parameter was progression-free survival (PFS). The primary comparison of combination therapy versus monotherapy for PFS was not significant (adjusted P = 0.56). The hazard ratio (HR) (adjusted HR = 0.93) was not clinically relevant. The median PFS for the combination arm was low at 6 weeks and similar to the median PFS in the monotherapy arm (6 weeks). The 6-month PFS for the two treatment groups was very similar (5% in the combination arm vs. 7% in the monotherapy arm). No clinically meaningful differences were found between the two treatment arms, and the primary study end point was not met. Among the patients receiving imatinib, no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease.

Perioperative intensity-modulated brachytherapy for refractory orbital rhabdomyosarcomas in children.

PURPOSE: To evaluate the feasibility and toxicity of perioperative intensity-modulated brachytherapy (IMBT) as well as functional outcome in children with therapy-refractory orbital rhabdomyosarcomas (RMS). PATIENTS AND METHODS: Since 1993, children with therapy-refractory orbital RMS have been treated by a multidisciplinary approach combining function-preserving, mostly R1 tumor resection and perioperative IMBT at the University Hospital of Schleswig-Holstein, Germany. All children with orbital RMS, who were enrolled in this multidisciplinary treatment protocol between 1993 and 2002, were prospectively assessed with respect to evaluation of side effects and functional outcome. RESULTS: Ten children (six boys, four girls) were included. Median age was 6.5 years (range, 1-19 years) at the beginning of our treatment and 6.0 years (range 1-17 years) at diagnosis. All children were in Intergroup Rhabdomyosarcoma Study Group (IRSG) group III and had embryonal subtype. Estimated 5-year survival was 62% +/- 18%. There was no radiation-related toxicity grade 3 or 4 observed. The eyes were primarily preserved in all cases. One child underwent secondary orbital exenteration 10 months after completion of IMBT. Visual acuity could be preserved apart from one child developing significant visual deterioration due to radiation cataract grade 2. The cosmetic results were good or very good in eight and moderate in two children. Four children died of their disease. CONCLUSION: This interdisciplinary, individually tailored and function-preserving treatment procedure has proven to be a well-tolerated therapeutic option in cases with refractory orbital RMS. It provides both improvement of local tumor control and quality of life.