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In many species, spatial navigation is supported by a network of place cells that exhibit increased firing whenever an animal is in a certain region of an environment. Does this neural representation of location form part of the spatiotemporal context into which episodic memories are encoded? We recorded medial temporal lobe neuronal activity as epilepsy patients performed a hybrid spatial and episodic memory task. We identified place-responsive cells active during virtual navigation and then asked whether the same cells activated during the subsequent recall of navigation-related memories without actual navigation. Place-responsive cell activity was reinstated during episodic memory retrieval. Neuronal firing during the retrieval of each memory was similar to the activity that represented the locations in the environment where the memory was initially encoded.

Background The prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU), one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare. Methods We performed a retrospective analysis of 35 patients with recurrent or progressive glioblastoma treated with 80 mg/m 2 BCNU on days 1 on 3 intravenously at our department for efficacy, toxicity and prognostic factors. Progression free survival and overall survival were estimated by the Kaplan-Meier method. The influence of age, Karnofsky performance status (KPS), tumor burden, pretreatment with temozolomide (TMZ), type of surgery for initial diagnosis and number of previous relapses on outcome was analyzed in a proportional hazards regression model. Results The median age of the group was 53 years, median KPS was 70. Median progression free survival was 11 weeks (95% confidence interval [CI]: 8-15), median overall survival 22 weeks (95% CI: 18-27). The rate of adverse events, especially hematological toxicity, is relatively high, and in 3 patients treatment had to be terminated due to adverse events (one pulmonary embolism, one pulmonary fibrosis, and one severe bone marrow suppression). No influence of age, KPS, tumor burden, pre-treatment with TMZ and number of previous relapses on outcome could be demonstrated, while gross total resection prior to recurrence showed a borderline statistically significant negative impact on PFS and OS. These data compare well with historical survival figures. However prospective randomized studies are needed to evaluate BCNU efficacy against newer drugs like bevacizumab or the intensified temozolomide regime (one week on/one week off). Conclusion In summary, BCNU treatment appears to be a valuable therapeutic option for recurrent glioblastomas, where no other validated radio- and/or chemotherapy are available.

Magnetic resonance imaging (MRI) is the standard neuroimaging method to diagnose neoplastic brain lesions, as well as to perform stereotactic biopsy surgical planning. MRI has the advantage of providing structural anatomical details with high sensitivity, though histological specificity is limited. Although combining MRI with other imaging modalities, such as positron-emission tomography (PET), has proven to increment specificity, exact correlation between PET threshold uptake ratios (URs) and histological diagnosis and grading has not yet been described.Objectives: The aim of this study was to correlate exactly the histopathological criteria of the biopsy site to its PET uptake value with high spatial resolution (mm3), and to analyze the diagnostic value of PET using the amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET in patients with newly diagnosed brain lesions in comparison to histological findings obtained from stereotactic serial biopsy.Patients and methods: A total of 23 adult patients with newly diagnosed brain tumors on MRI were enrolled in this study. Subsequently to diagnoses, all patients underwent a 18F-FET PET-guided stereotactic biopsy, using an original newly developed software module, which is presented here. Conventional MRI, stereotactic computed tomography series, and 18F-FET PET images were semiautomatically fused, and hot-spot detection was performed for target planning. UR was determined using the uptake value from the biopsy sites in relation to the contralateral frontal white matter. UR values ≥1.6 were considered positive for glioma. High-grade glioma (HGG) was suspected with URs ≥3.0, while low-grade glioma (LGG) was suspected with URs between 1.6 and 3.0. Stereotactic serial biopsies along the trajectory at multiple sites were performed in millimeter steps, and the FET URs for each site were correlated exactly with a panel of 27 different histopathological markers. Comparisons between FET URs along the biopsy trajectories and the histological diagnoses were made with Pearson product-moment correlation coefficients. Analysis of variance was performed to test for significant differences in maximum UR between different tumor grades.Results: A total of 363 biopsy specimens were taken from 23 patients by stereotactic serial biopsies. Histological examination revealed eight patients (35%) with an LGG: one with a World Health Organization (WHO)-I lesion and seven with a WHO-II lesion. Thirteen (57%) patients revealed an HGG (two with a WHO-III and three with a WHO-IV tumor), and two patients (9%) showed a process that was neither HGG nor LGG (group X or no-grade group). The correlation matrix between histological findings and the UR revealed five strong correlations. Low cell density in tissue samples was found to have a significant negative correlation with the measured cortical uptake rate (r=-0.43, P=0.02), as well as moderate cell density (r=-0.48, P=0.02). Pathological patterns of proliferation (r=0.37, P=0.04), GFAP (r=0.37, P=0.04), and Olig2 (r=0.36, P=0.05) showed a significant positive correlation with cortical URs. Analysis of variance tests showed a significant difference between the LGG and the HGG groups (F=8.27, P<0.002), but no significant differences when differentiating between the X group and the HGG (P=0.2)/LGG (P=0.8) groups, nor between the no-grade group and the WHO-I group.Conclusion: 18F-FET PET is a valuable tool, as it allows the differentiation of HGGs from LGGs. Its use is not limited to preoperative evaluation; it may also refine biopsy targeting and improve tumor delimitation for radiotherapy. Histology is still necessary, and remains the gold standard for definitive diagnosis of brain lesions.

We have conducted the first in-vivo experiments in pencilbeam irradiation, a new synchrotron radiation technique based on the principle of microbeam irradiation, a concept of spatially fractionated high-dose irradiation. In an animal model of adult C57 BL/6J mice we have determined technical and physiological limitations with the present technical setup of the technique. Fifty-eight animals were distributed in eleven experimental groups, ten groups receiving whole brain radiotherapy with arrays of 50 µm wide beams. We have tested peak doses ranging between 172 Gy and 2,298 Gy at 3 mm depth. Animals in five groups received whole brain radiotherapy with a center-to-center (ctc) distance of 200 µm and a peak-to-valley ratio (PVDR) of ∼ 100, in the other five groups the ctc was 400 µm (PVDR ∼ 400). Motor and memory abilities were assessed during a six months observation period following irradiation. The lower dose limit, determined by the technical equipment, was at 172 Gy. The LD50 was about 1,164 Gy for a ctc of 200 µm and higher than 2,298 Gy for a ctc of 400 µm. Age-dependent loss in motor and memory performance was seen in all groups. Better overall performance (close to that of healthy controls) was seen in the groups irradiated with a ctc of 400 µm.

Background Adult brainstem gliomas are rare primary brain tumors (<2% of gliomas). The goal of this study was to analyze clinical, prognostic and therapeutic factors in a large series of histologically proven brainstem gliomas. Methods Between 1997 and 2007, 104 patients with a histologically proven brainstem glioma were retrospectively analyzed. Data about clinical course of disease, neuropathological findings and therapeutic approaches were analyzed. Results The median age at diagnosis was 41 years (range 18-89 years), median KPS before any operative procedure was 80 (range 20-100) and median survival for the whole cohort was 18.8 months. Histopathological examinations revealed 16 grade I, 31 grade II, 42 grade III and 14 grade IV gliomas. Grading was not possible in 1 patient. Therapeutic concepts differed according to the histopathology of the disease. Median overall survival for grade II tumors was 26.4 months, for grade III tumors 12.9 months and for grade IV tumors 9.8 months. On multivariate analysis the relative risk to die increased with a KPS ≤ 70 by factor 6.7, with grade III/IV gliomas by the factor 1.8 and for age ≥ 40 by the factor 1.7. External beam radiation reduced the risk to die by factor 0.4. Conclusion Adult brainstem gliomas present with a wide variety of neurological symptoms and postoperative radiation remains the cornerstone of therapy with no proven benefit of adding chemotherapy. Low KPS, age ≥ 40 and higher tumor grade have a negative impact on overall survival.

Abstract BACKGROUND: Intracranial in vivo recordings of individual neurons in humans are increasingly performed for a better understanding of the mechanisms of epileptogenesis and of the neurobiological basis of cognition. So far, information about the safety of stereotactic implantations and of magnetic resonance imaging (MRI) with hybrid depth electrodes is scarce. OBJECTIVE: The aim of this study was to assess neurosurgical safety of implantations, recordings, and imaging using hybrid electrodes in humans. METHODS: Perioperative and long-term safety of implantation of a total of 88 hybrid depth electrodes with integrated microwires was assessed retrospectively in 25 consecutive epilepsy patients who underwent implantation of electrodes from 2007 to 2011 based on electronically stored charts. Safety aspects of MRI are reported from both in vitro and in vivo investigations. Precision of electrode implantation is evaluated based on intraoperative computed tomography and pre- and postoperative MRI. RESULTS: There was no clinically relevant morbidity associated with the use of hybrid electrodes in any of the patients. Precision of recordings from the targets aimed at was similar to that of standard depth electrodes. In vitro studies demonstrated the absence of relevant heating of hybrid electrodes with newly designed connectors with MRI at 1.5 T, corresponding to well-tolerated clinical MRI in patients. CONCLUSION: Given the technical approach described here, precise targeting and safe use are possible with hybrid electrodes containing microwires for in vivo recording of human neuronal units.

•The stereotactic suboccipital-transcerebellar approach is a reliable and safe approach.•Performance is simple using standard stereotactic frame systems without modification.•It is a favorable stereotactic approach with a high success rate and no permanent morbidity. The stereotactic suboccipital-transcerebellar approach is widely regarded as technically demanding requiring substantial modifications of the standard stereotactic methods thus often making a transfrontal approach preferable. In this comprehensive series we aim to present our experience with the stereotactic suboccipital-transcerebellar approach to lesions of the brainstem or cerebellum using two standard stereotactic systems. In the period of 2000–2015 overall 80 patients (mean age 43.95 ± 23.76 years) with lesions of the brainstem or cerebellum underwent stereotactic surgery for diagnostic or therapeutic purposes via a suboccipital approach. In 59 patients stereotactic surgery was performed using the Riechert-Mundinger Stereotactic Frame, the Leksell Stereotactic Frame was used in 21 patients. For both frames standard systems were used without modification. Retrospective analysis of intraoperative stereotactic technique, achievement of the predefined surgical objectives and perioperative complications was carried out. In this series, the stereotactic suboccipital-transcerebellar approach proved to be feasible with two standard stereotactic systems. Using either frame the predefined surgical objective was achieved in 90.0%. A verified neuropathological diagnosis was obtained in 89.6%. Minor transient perioperative complications occurred in 8.75%. There was no surgery-related permanent morbidity or mortality. In this comprehensive series the stereotactic suboccipital-transcerebellar approach using a standard stereotactic system proved to be a favorable stereotactic approach with a high diagnostic success rate and no surgery-related permanent morbidity.

To report on iodine-125 (I125) interstitial irradiation in the treatment of low grade brain stem gliomas in adults. Ten patients with well-circumscribed lesions of the brainstem and histological confirmation of low grade glioma treated with stereotactically implanted I-125 seed in our department between 1995 and 2012 were retrospectively analyzed. In 9 patients the lesion was treated with one I-125 seed and in one patient, 2 spatial separated lesions were implanted, therefore a total of 11 I-125 seeds were implanted. The mean volume of the 11 lesions was 2.76ml (range: 0.5–7.2ml), mean activity of the seeds was 6.23mCi (range: 1.5–11.1mCi), mean duration of irradiation was 28.5 days (range: 21–41 days) and mean effective dose rate was 9.16cGy/h (range: 6.2–12cGy/h). The 30 days perioperative morbidity and mortality rate was 0%. Median follow up was 72.5 month (range 5–168 months). Six of ten patients were free of progression until last follow up. In our experience at the University Clinic in Freiburg Germany, interstitial radiosurgery based on MRI is a safe and effective method to diagnose and treat low grade gliomas of the brain stem. Furthermore randomized studies are needed to confirm the therapeutic impact of this method in comparison to external beam radiation of brain stem gliomas.

•The use of stereotactic frame in young children remains controversial in the literature.•99 frame-based surgeries in patients younger than seven years-old were analyzed.•The overall complication rate related to frame fixation was 5%. No neurological deficit.•Frame-based stereotactic neurosurgery is a safe technique also in the youngest patients.•Experience in the adjustment of the frame in children is crucial to reducing complications. Stereotactic frame-based procedures proved to be precise, safe and are of widespread use among adult patients. Regarding pediatric patients few data is available, therefore the use of the stereotactic frame remains controversial in this population. This motivated us to report our experience in stereotactic procedures in the youngest patients and review the literature concerning this subject. All frame-based procedures performed in patients younger than seven years in the University of Freiburg during the last 10 years were retrospectively analyzed and discussed under the light of the current literature. The studied population was composed of 72 patients under the age of seven (mean 3.4±2.1 years-old), in whom 99 stereotactic procedures were performed. Brain tumor was present in 60 patients, hydrocephalus in five, cystic lesions in three, intracranial abscess in three and epilepsy in one patient. Stereotactic surgery was performed in 36 cases for brachytherapy, in 29 for biopsy, in 20 cases for cyst puncture, in eight for stereotactically guided endoscopic ventriculostomy, in five for catheter placement and in one case for depth electrode insertion. The overall complication rate was 5%. There were three cases of pin penetration through the skull, one case of frame dislocation after extensive cyst drainage and two skull fractures. Neurologic deficit related to frame fixation was observed in none of the cases. In disagreement with other authors, no case of pin related infection, air embolism, hematoma or CSF leak was observed. Frame-based stereotactic neurosurgery is a safe technique also in the youngest patients. Rather than the simple use of torque-limiting devices training and experience in the manual adjustment of the stereotactic frame in children have been proven to be crucial factors that contribute to reducing pin related complications.