Clinical Impact of Bevacizumab in Patients with Relapsed Glioblastoma: Focus on a Real-Life Monocentric SurVey (SV1 Study).

OBJECTIVES: Glioblastoma is one of the most frequent primitive brain tumors. Patients who experience tumor relapse after surgery and concomitant radiochemotherapy have a dismal prognosis. The objective of this study is to analyze efficacy data in terms of overall survival (OS) and progression- free survival (PFS) following combination therapy with bevacizumab (BVZ) and irinotecan among patients with relapsed glioblastoma. Safety data will also be reviewed and all results will be compared with data of the literature. METHODS: In this single-center retrospective study, all records of patients treated with BVZ and irinotecan for a relapsed glioblastoma were analyzed. Each chemotherapy cycle was repeated every 15 days until progression. Magnetic resonance imaging and neurologic examination were repeated every 6 weeks during treatment. RESULTS: Forty-five patients were analyzed. The median number of BVZ-irinotecan cycles was 8 (range 1-38). Median PFS was 26 weeks and median OS was 28 weeks. Eighteen of the 45 patients (40% of cases) had an objective response 6 months after initiation of treatment. Two patients had to discontinue treatment due to toxicity. CONCLUSIONS: The results of the SV1 study are consistent with those found in phase II studies evaluating the same treatment. The irinotecan-BVZ combination is effective in relapsed glioblastoma with acceptable toxicity. Biomarkers predictive of response to BVZ should help in the selection of patients who could benefit from treatment.

Ex vivo confocal microscopy imaging to identify tumor tissue on freshly removed brain sample.

Confocal microscopy is a technique able to realize "optic sections" of a tissue with increasing applications. We wondered if we could apply an ex vivo confocal microscope designed for dermatological purpose in a routine use for the most frequent brain tumors. The aim of this work was to identify tumor tissue and its histopathological hallmarks, and to assess grading criteria used in neuropathological practice without tissue loss on freshly removed brain tissue. Seven infiltrating gliomas, nine meningiomas and three metastases of carcinomas were included. We compared imaging results obtained with the confocal microscope to frozen sections, smears and tissue sections of formalin-fixed tissue. Our results show that ex vivo confocal microscopy imaging can be applied to brain tumors in order to quickly identify tumor tissue without tissue loss. It can differentiate tumors and can assess most of grading criteria. Confocal microscopy could represent a new tool to identify tumor tissue on freshly removed sample and could help in selecting areas for biobanking of tumor tissue.

New insights into the functional significance of the frontal aslant tract: an anatomo-functional study using intraoperative electrical stimulations combined with diffusion tensor imaging-based fiber tracking.

We used the method of direct electrostimulation combined with navigated tractography to map the frontal "aslant" tract, enabling us to perform reliable anatomo-functional correlation in a patient undergoing awake surgery to remove a left frontal glioma. The findings enhanced our understanding of the organization of language within the human brain.

Intraoperative visualisation of language fascicles by diffusion tensor imaging-based tractography in glioma surgery.

BACKGROUND: For gliomas, the goal of surgery is to maximise the extent of resection (EOR) while minimising the postoperative morbidity. The purpose of this study was to evaluate the benefits of a protocol developed for the surgical management of gliomas located in language areas, where tractography-integrated navigation was used in conjunction with direct electrical stimulations (DES). METHODS AND MATERIALS: The authors included ten patients suffering of gliomas located in language areas. The preoperative planning for multimodal navigation was done by integrating anatomical magnetic resonance images and subcortical pathway volumes generated by diffusion tensor imaging. Six white matter fascicles implicated in language functions were reconstructed in each patient, including fibres for phonological processing (i.e. the arcuate fasciculus), fibres for lexical-semantic processing (i.e. the inferior frontooccipital fasciculus, inferior longitudinal fasciculus and uncinate fasciculus), and two premotor fasciculi involved in the preparation of speech movements (the subcallosal medialis fasciculus and cortical fibres originating from the medial and lateral premotor areas). During surgery, language fascicles were identified by direct visualisation on tractography-integrated navigation images and by observing transient language inhibition after subcortical DES. Language deficits were evaluated preoperatively and postoperatively, and compared with the EOR. RESULTS: Tractography was successfully performed in all patients, preoperatively demonstrating the relationships between the tumours to resect and the language fascicles to preserve from injury. With the use of the tractography-integrated navigation system and intraoperative DES, language functions were preserved in all patients. The mean volumetric resection was 93.0 ± 10.4 % of the preoperative tumour volume, with a gross total resection in 60 % of patients. CONCLUSION: The intraoperative combination of tractography and DES contributed to maximum safe resection of gliomas located in language areas.

[Intracranial hemorrhages: epidemiology and implication of antithrombotic therapy]. / Hémorragies intracrâniennes : épidémiologie et implication des traitements antithrombotiques.

OBJECTIVE: Intracranial hemorrhage (ICH) is an antithrombotic treatment complication. Our study's goal is to assess the proportion of ICH occurring while the patient is on antithrombotic treatment. The secondary goal is to assess the proportion of "avoidable" ICH (anticoagulant overdosage, debatables indications). METHODS: We conducted a descriptive epidemiological single-center study of ICH during 2 years. We analyzed the type of ICH, the type of antithrombotic treatment, the level of anticoagulation and the relevance of antithrombotic treatment indication. RESULTS: Of the 400 patients admitted for an ICH, 131 (33%) were treated by antithrombotic therapy: oral anti-vitamin K anticoagulants (VKA) in 14.1% of cases and antiplatelet agents in 15.1%. Of VKA patients, overdosage rate was 30.2%. The indication of antithrombotic therapy was debatable in 18.3% of cases. CONCLUSION: Our study highlights the frequency of ICH occurring on antithrombotic therapy and the significant proportion of "avoidable" ICH.

Prolonged temozolomide for treatment of glioblastoma: preliminary clinical results and prognostic value of p53 overexpression.

We report retrospective data on the feasibility and efficacy of prolonging adjuvant temozolomide (TMZ) more than 6 months after chemoradiotherapy completion in patients with glioblastoma (GBM). Molecular prognostic factors were assessed. Data from 46 patients were reviewed. Patients received postoperative irradiation, 60 Gy in 30 fractions, combined with concurrent TMZ, 75 mg/m(2). Four weeks later, adjuvant TMZ was prescribed, 150-200 mg/m(2) for a total of 24 cycles unless there was progression or toxicity. Tumor samples were tested for the following prognostic factors: EGFR overexpression, 1p19q deletion, p53 overexpression and proliferation index. Overall survival (OS) was 84.8% at 6 months, 54.3% at 12 months, 26.1% at 18 months, and 21.7% at 24 months. Progression-free survival (PFS) was 73.9% at 6 months, 34.8% at 12 months, 15.2% at 18 months and 10.4% at 24 months. In the adjuvant phase, no treatment disruption for toxicity was necessary but eight patients required dose adaptation because of side effects. No significant molecular prognostic factor was evidenced for OS. We found that p53 overexpression was the only significant prognostic factor for PFS, with a median PFS of 9.3 months versus 7 months for patients without p53 overexpression (P = 0.031). This study suggests that delivering adjuvant TMZ therapy for more than 6 months is feasible in patients with GBM. Efficacy data warrant further prospective assessment with the focus on molecular prognostic factors, such as p53 overexpression, which was found to be the only significant molecular prognostic factor for outcome.

Improved dexterity after chronic electrical stimulation of the motor cortex for central pain: a special relevance for thalamic syndrome.

OBJECTIVES: To demonstrate that motor cortex stimulation (MCS) could improve motor function in patients with neuropathic pain. METHODS: In this prospective clinical study of 38 patients referred for MCS as treatment for their neuropathic pain, we collected any declaration of improvement in motor performance that could be attributed to MCS. RESULTS: Ten patients (26%) declared a benefit in their motor function. Eight presented objective evidence of recovered dexterity for rapid alternating movements. A minor proportion had improvement in dystonic posture (n = 2), but none had detectable increased motor strength or tonus changes. Overall, 73% of the patients with limb ataxia declared a benefit after MCS. In 6 out of 10 patients (60%), the anatomic lesion responsible for pain was restricted to the lateral aspect of the thalamus. All of them had either clinical or electrophysiological evidence of lemniscal dysfunction (proprioceptive ataxia). No correlation was found between the scores of pain relief and the modification of motor status. The correlation between thalamic lesions and benefits in motor performance was significant (Fisher's exact test, two-tailed, p = 0.0017). CONCLUSIONS: Up to 26% of patients estimated that MCS improved their motor outcome through recovered dexterity and in cases of lateral thalamic lesions.

Margin-free, en bloc resection of a multilevel cervical chordoma with C-2 involvement: case report with 2-year follow-up and description of operative technique.

The purpose of this technical/case report is to demonstrate that the appropriate oncological principle of margin-free, tumour en bloc removal can be successfully achieved in a large multilevel chordoma with C-2 involvement, with limited morbidity. Although technically challenging, such an approach offers the patient's best chance for cure.

Solitary fibrous tumors of the central nervous system: report of five cases with unusual clinicopathological and outcome patterns.

BACKGROUND: This is a retrospective study of 11 patients harboring a solitary fibrous tumor (SFT) of the central nervous system (CNS), with special emphasis on unusual clinicopathological and outcomes patterns. METHOD: Between 2000 and 2008, 11 patients harboring CNS SFTs were treated at our institution. Patient charts were retrospectively reviewed and tumor location, clinical presentation, imaging characteristics, extent of resection, dural origin, pathological features, adjuvant treatment, and follow-up data were collected, focusing on five atypical cases (four intracranial and one within the spine). FINDINGS: One intracranial SFT arose from the sella turcica and relapsed threefold during the 6 years following partial removal. Disease progressed as successive isolated local recurrences treated by subsequent surgical interventions and gamma-knife radiosurgery. The MiB-1 labeling index analysis showed a steady increase in these sequential recurrences (ranging from less than 3% up to 6%) without obvious malignant transformation. The second SFT occurred in the cerebellopontine angle and exhibited a high MiB-1 index (10%) without noticeable features of malignancy. It relapsed twice during the 5 years following gross total resection without demonstrating a more aggressive histological pattern. The third SFT arose from the cerebellar tentorium, widely invaded the lateral sinus and adjacent bone, had a low MiB-1 index, and has not recurred within the 2 years after incomplete resection. The two remaining SFTs presented with unusual clinicoradiological features. We described a extremely rare case of intraventricular SFT, and a case of extradural SFT of the thoracic spine (T8-T9) radiologically consistent with a schwannoma. Immunohistochemistry confirmed that all tumors were SFTs. CONCLUSIONS: These atypical presentations gave us the opportunity to provide further information about the variability of the clinicoradiological patterns and natural histological course of CNS SFTs.

Positional cluster-like headache. A case report of a neurovascular compression between the third cervical root and the vertebral artery.

Symptomatic cluster-like headaches have been described with lesions of the trigeminal and parasympathetic systems. Here, we report the case of a 44-year-old woman with continuous auricular pain and a positional cluster-like headache associated with red ear syndrome. Clinical data and morphological investigations raised the hypothesis of a neurovascular compression between the C3 root and vertebral artery. Neurosurgical exploration found a fibrosis surrounding both the C3 root and the vertebral artery. The excellent outcome after microvascular cervical decompression suggests a causal relationship between the cluster-like headache and the vertebral constraint on the C3 root.

Is the analgesic effect of motor cortex stimulation somatotopically driven or not?

OBJECTIVES: Mechanisms of analgesic efficacy related to motor cortex stimulation (MCS) remain poorly understood. Specifically, it is unclear whether pain relief is somatotopically driven or not. We present three illustrative case-reports of MCS in which unintentional stimulation setting errors occurred, leading to differential (and reversible) pain relief outcomes across the hemi-body. METHODS: After successful preoperative rTMS trials, three patients suffering from post-stroke pain were selected for MCS. Stimulation was set with the aim of activating two epidural electrodes over the somatotopic representation of the lower and upper limbs. Data regarding pain relief were prospectively collected. RESULTS: At the first follow-up, all three patients complained of a lack of pain relief in the lower limb, contrasting with good outcome in the upper limb. In fact, for each of them we diagnosed the same stimulation setting error, to which they were "blinded", i.e., the parasagittal electrode over the somatotopic representation of the lower limb was inadvertently turned off. Subsequently, six months after having the electrode turned on (still in a "blinded" fashion), all three patients described substantial pain relief in the lower limb, with a median improvement of 50% (range: 40-70%). DISCUSSION: These incidental case reports argue in favor of a genuine and at least partly somatotopically-driven analgesic efficacy of MCS. Therefore, the parasagittal electrode seems crucial when treating lower limb pain with MCS.

Contact position analysis of deep brain stimulation electrodes on post-operative CT images.

PURPOSE: Groups performing deep brain stimulation advocate post-operative imaging [magnetic resonance imaging (MRI) or computer tomography (CT)] to analyse the position of each electrode contact. The artefact of the Activa 3389 electrode had been described for MRI but not for CT. We undertook an electrode artefact analysis for CT imaging to obtain information on the artefact dimensions and related electrode contact positions. METHODS: The electrode was fixed on a phantom in a set position and six acquisitions were run (in-vitro study). The artefacts were compared with the real electrode position. Ten post-operative acquisitions were analysed (in-vivo analysis). We measured: H (height of the lateral black artefact), D (distance between the beginning of the white and the lateral black artefacts) and W (maximal artefact width), representing respectively the lengths of the four contacts and the electrode tip and width of the contact zone. A Student t-test compared the results: in vivo vs in vitro and coronal vs sagittal reconstructions along the electrode. RESULTS: The limits of the lateral black artefact around the electrode contacts corresponded to the final electrode position. There was no significant difference for D (in vivo, 1.1 +/- 0.1 mm; in vitro, 1.2 +/- 0.2 mm; p = 0.213), while W and H differed slightly (in vivo, W = 3.3 +/- 0.2 mm, H = 7.7 +/- 0.2 mm; in vitro, W = 3.1 +/- 0.1 mm, H = 7.5 +/- 0.2 mm). Results obtained with sagittal and coronal reconstructions were similar (p > 0.6). CONCLUSIONS: Precise three-dimensional (3D) localisation of the four-contact zone of the electrode can be obtained by CT identification of the limits of the lateral black artefact. The relative position of the four contacts is deduced from the size of the contacts and the inter-contact distance. Sagittal and coronal reconstructions along the electrode direction should be considered for the identification of the four electrode contacts. CT offers a useful alternative to post-operative MRI.

Added value of multiple versus single sessions of repetitive transcranial magnetic stimulation in predicting motor cortex stimulation efficacy for refractory neuropathic pain.

OBJECTIVESelection criteria for offering patients motor cortex stimulation (MCS) for refractory neuropathic pain are a critical topic of research. A single session of repetitive transcranial magnetic stimulation (rTMS) has been advocated for selecting MCS candidates, but it has a low negative predictive value. Here the authors investigated whether multiple rTMS sessions would more accurately predict MCS efficacy.METHODSPatients included in this longitudinal study could access MCS after at least four rTMS sessions performed 3-4 weeks apart. The positive (PPV) and negative (NPV) predictive values of the four rTMS sessions and the correlation between the analgesic effects of the two treatments were assessed.RESULTSTwelve MCS patients underwent an average of 15.9 rTMS sessions prior to surgery; nine of the patients were rTMS responders. Postoperative follow-up was 57.8 ± 15.6 months (mean ± standard deviation). Mean percentage of pain relief (%R) was 21% and 40% after the first and fourth rTMS sessions, respectively. The corresponding mean durations of pain relief were respectively 2.4 and 12.9 days. A cumulative effect of the rTMS sessions was observed on both %R and duration of pain relief (p < 0.01). The %R value obtained with MCS was 35% after 6 months and 43% at the last follow-up. Both the PPV and NPV of rTMS were 100% after the fourth rTMS session (p = 0.0045). A significant correlation was found between %R or duration of pain relief after the fourth rTMS session and %R at the last MCS follow-up (R2 = 0.83, p = 0.0003).CONCLUSIONSFour rTMS sessions predicted MCS efficacy better than a single session in neuropathic pain patients. Taking into account the cumulative effects of rTMS, the authors found a high-level correlation between the analgesic effects of rTMS and MCS.

Motor cortex stimulation for refractory neuropathic pain: four year outcome and predictors of efficacy.

Thirty-one patients with medically refractory neuropathic pain were included in a prospective evaluation of motor cortex stimulation. The long-term outcome was evaluated using five variables: (a) rate (percentage) of pain relief, (b) pain scores as assessed on VAS, (c) postoperative decrease in VAS scores, (d) reduction in analgesic drug intake, (e) a dichotomic (yes/no) response to the question whether the patient would accept, under similar circumstances, to be operated on again. Pain relief was rated as excellent (>70 % pain relief) in 10 % of cases, good (40-69 %) in 42 %, poor (10-39 %) in 35 % and negligible (0-9 %) in 13 %. Intake of analgesic drugs was decreased in 52 % of patients and unchanged in 45 % (unavailable data in 3 %), with complete withdrawal of analgesic drugs in 36 % of patients. Twenty-one patients (70 %) declared themselves favourable to re-intervention if the same beneficial outcome could be guaranteed. Neither preoperative motor status, pain characteristics, type or localisation of lesions, quantitative sensory testing, Somatosensory Evoked Potentials, nor the interval between pain and surgery were found to predict the efficacy of MCS. The level of pain relief, as evaluated in the first month following implantation was a strong predictor of long-term relief (regression analysis, R=0.744; p<0.0001). These results confirm that MCS can be a satisfactory and durable alternative to medical treatments in patients with refractory pain, and suggest that the efficacy of MCS may be predicted in the first month of therapy.

Cerebral relapsing meningioma: a surgical series with lack of reliability of standard parameters establishing prognosis.

BACKGROUND/AIM: Meningioma is the most frequent meningeal neoplasm, usually without relapse or metastasis. Patient follow-up is challenging, not standardized and is decided in multidisciplinary case discussion. Our aim was to determine the clinical and histological factors influencing the time to relapse. PATIENTS AND METHODS: We conducted a single-Center retrospective study on 38 patients with surgically-excised relapsing meningiomas and collected clinical and pathological data. RESULTS: Our results show that none of the histological factors included in the WHO classification, nor those not included are related to a shorter time to relapse. CONCLUSION: In our study, none of the histological, immunohistochemical and clinical parameters evaluated seem to be able to predict the time to relapse in meningioma.

Direct stereotactic targeting of the ventrointermediate nucleus of the thalamus based on anatomic 1.5-T MRI mapping with a white matter attenuated inversion recovery (WAIR) sequence.

BACKGROUND: The ventrointermediate nucleus (Vim) of the thalamus is still considered "invisible" on current magnetic resonance imaging (MRI), requiring indirect methods based on stereotactic atlases for estimation of its location. Direct visualization of Vim is desirable to improve targeting. OBJECTIVE: To evaluate the ability of Inversion-Recovery 1.5-T MR images to produce high-resolution, anatomical depiction of the thalamus suitable for direct Vim targeting. METHODS: Twenty patients with essential tremor or tremor associated with Parkinson's disease received Vim deep brain stimulation (DBS). Fahn-Tolosa-Marin and Unified Parkinson's Disease Rating Scale (UPDRS) tremor scores were assessed pre- and postoperatively. Preoperative stereotactic 1.5-T MR images of the thalamus were acquired using a White Matter Attenuated Inversion Recovery (WAIR) sequence. Thalamic nuclei were manually contoured on the basis of spontaneous MRI contrasts; labeling relied on 3D identification from stereotactic books and in-house ex vivo 4.7-T microscopic MRI atlas. Vim was then directly probed for electrophysiological confirmation and determination of the optimal site for electrode placement. RESULTS: The shape, spatial orientation, and signal contrast of Vim as depicted on our WAIR images were similar to those observed on the Schaltenbrand and Bailey atlas, as well as in our high-field MRI atlas. These images were successfully used for pure direct Vim targeting: at the last follow-up (median = 46.3 months), the average tremor score improved from 3.80 preoperatively to 0.50 postoperatively (on stimulation; P < 0.01). CONCLUSION: 1.5-T MRI with WAIR sequence provides high-quality images of Vim suitable in DBS surgery, for accurate preoperative planning, direct targeting and anatomic analysis.