V. Lubrano

What makes surgical tumor resection feasible in Broca's area? Insights into intraoperative brain mapping.

OBJECTIVESurgical resection of mass lesions in Brocas area is controversial. To demonstrate that pathology may influence the localization of functional areas and language performance, we reviewed our experience of awake craniotomies in Brocas area. METHODSSixteen consecutive patients who underwent awake craniotomy and direct brain mapping for resective surgery in Brocas area were analyzed. Six patients had well-circumscribed lesions, whereas 10 patients had infiltrative gliomas. A short version of the Boston Diagnostic Aphasia Examination test was used for language assessment. RESULTSInferior frontal language sites were found in all but 4 patients. In patients with cavernomas or well-circumscribed tumors, 9 of 9 (100%) of the positive sites were located in the classic Brocas area (BA 44/45). By contrast, in those patients with gliomas, only 5 of 20 (25%) of the positive sites were located in BA 44/45. Patients with infiltrative gliomas demonstrated more deficits in the pre and postoperative periods than those with well-circumscribed mass lesions. All patients returned to their baseline abilities within 6 months. CONCLUSIONIntraoperative language maps generated in cases with well-circumscribed lesions are different from those generated in cases with infiltrative gliomas. This supports the view that interindividual language variability and displacement of critical structures by mass effect should first be considered for circumscribed lesions, whereas reshaping should largely be attributed to brain plasticity in gliomas. Surgery in Brocas area can be safely conducted using awake craniotomy and brain mapping.

Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance

Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.

Anatomical correlates for category-specific naming of objects and actions: a brain stimulation mapping study.

The production of object and action words can be dissociated in aphasics, yet their anatomical correlates have been difficult to distinguish in functional imaging studies. To investigate the extent to which the cortical neural networks underlying object‐ and action‐naming processing overlap, we performed electrostimulation mapping (ESM), which is a neurosurgical mapping technique routinely used to examine language function during brain‐tumor resections. Forty‐one right‐handed patients who had surgery for a brain tumor were asked to perform overt naming of object and action pictures under stimulation. Overall, 73 out of the 633 stimulated cortical sites (11.5%) were associated with stimulation‐induced language interferences. These interference sites were very much localized (<1 cm2), and showed substantial variability across individuals in their exact localization. Stimulation interfered with both object and action naming over 44 sites, whereas it specifically interfered with object naming over 19 sites and with action naming over 10 sites. Specific object‐naming sites were mainly identified in Brocas area (Brodmann area 44/45) and the temporal cortex, whereas action‐naming specific sites were mainly identified in the posterior midfrontal gyrus (Brodmann area 6/9) and Brocas area (P = 0.003 by the Fishers exact test). The anatomical loci we emphasized are in line with a cortical distinction between objects and actions based on conceptual/semantic features, so the prefrontal/premotor cortex would preferentially support sensorimotor contingencies associated with actions, whereas the temporal cortex would preferentially underpin (functional) properties of objects. Hum Brain Mapp 35:429–443, 2014.

αvβ3 Integrin and Fibroblast growth factor receptor 1 (FGFR1): Prognostic factors in a phase I–II clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma

BACKGROUND Based on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway. PATIENTS AND METHODS Patients were treated with 200mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvβ3, αvβ5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome. RESULTS For the phase II patients median TTP was 23.1 weeks (95%CI = [15.4; 28.2]) while the median OS was 80.3 weeks (95%CI = [57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4 w (95%CI = [47.3; 97.6]) while median TTP was 18.1 w (95%CI = [16.9; 25.6]). FGFR1 over-expression (HR = 4.65; 95%CI = [1.02; 21.21], p = 0.047) was correlated with shorter TTP while FGFR1 (HR = 4.1 (95% CI = [1.09-15.4]; p = 0.036)) and αvβ3 (HR = 10.38 (95%CI = [2.70; 39.87], p = 0.001)) over-expressions were associated with reduced OS. CONCLUSION Association of 200mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvβ3 integrin are independent bad prognostic factors of OS and TTP.

Evaluation of O-(2-[18F]-Fluoroethyl)-L-Tyrosine in the Diagnosis of Glioblastoma

OBJECTIVE To assess the feasibility of synthesis of O-(2-[(18)F]-fluoroethyl)-l-tyrosine (FET), a new positron emission tomographic (PET) tracer described in several studies but not yet considered standard in management of glioma, in routine practice and to determine FET uptake in a homogeneous group of patients with suspected high-grade glioma. DESIGN Prospective nonrandomized trial. PATIENTS Twelve patients with suspicion of high-grade glioma. RESULTS The mean (SD) FET uptake ratio was 3.15 (0.72) for the 12 patients and 3.16 (0.75) for the 11 patients with glioblastoma. CONCLUSION The initial results are promising and indicate that FET PET is a valuable and applicable tool for the imaging of high-grade glioma.

MRI with DWI helps in depicting rheumatoid meningitis.

Journal of Neuroradiology - In Press.Proof corrected by the author Available online since mardi 7 janvier 2014

fMRI study of graduated emotional charge for detection of covert activity using passive listening to narratives

Detection of awareness in patients with consciousness disorders is a challenge that can be facilitated by functional neuroimaging. We elaborated a functional magnetic resonance imaging (fMRI) protocol to detect covert activity in altered states of consciousness. We hypothesized that passive listening to narratives with graduated emotional charge triggers graduated cerebral activations. The fMRI protocol was designed in healthy subjects for further clinical applications. The emotional charge was graduated using voice familiarity and long-term declarative memory content: low emotional charge, unknown person telling general semantic memory; mean emotional charge, relative telling the same narratives; high emotional charge, same relative telling autobiographical memory. Autobiographical memory was subdivided into semantic autobiographical memory and episodic autobiographical memory. The protocol proved efficient at triggering graduated cerebral activations: low emotional charge, superior temporal gyri and sulci; mean emotional charge, same as low emotional charge plus bilateral premotor cortices and left inferior frontal gyrus; high emotional charge, cingulate, temporal, frontal, prefrontal and angular areas, thalamus and cerebellum. Semantic autobiographical memory revealed larger activations than episodic autobiographical memory. Independent ROI analysis confirmed the preponderant contribution of narratives with autobiographical memory content in triggering cerebral activation, not only in autobiographical memory-sensitive areas, but also in voice-sensitive, language-sensitive and semantic memory-sensitive areas.

OC-0615: Voxel-based perfusion normalisation in GBM patients included in a phase I-II trial of RT/Tipifarnib combination

2.7%, p= 0.041). In the Capox-RT group, 85.7% (191/223) patients received radiotherapy on schedule and 74.9% (166/223) with concurrent chemotherapy on schedule, as did 94.1% (238/253) and 92.1% (233/353) in the Cap-RT group, respectively. Grade 3-4 acute toxicity was observed in 38.1% of patients in the Capox-RT group and in 29.2% in the Cap-RT group (p = 0.041). Grade 3–4 tenesmus was more common in the Capox-RT group than in the Cap-RT group (5.4% vs. 2.0%), as were grade 3–4 nausea (2.2% vs. 0%), grade 3–4 vomiting (1.8% vs. 0%), and grade 3–4 fatigue (3.1% vs. 0.4%). Conclusions: The interim analysis revealed that inclusion of oxaliplatin into capecitabine based postoperative chemoradiotherapy was feasible and could decrease cumulative locoregional recurrence rate for patients with locally advanced rectal cancer.

Glioma di alto grado: astrocitoma anaplastico e glioblastoma

Gli astrocitomi anaplastici e i glioblastomi rappresentano i tumori maligni primitivi piu frequenti e piu aggressivi del sistema nervoso centrale. Essi colpiscono dei pazienti giovani e la loro prognosi, anche se notevolmente migliorata negli ultimi anni, resta drammatica. Il loro trattamento costituisce una sfida fondamentale per la neuro-oncologia. Sul piano della diagnostica per immagini, la risonanza magnetica (RM) morfologica resta lo standard attuale per la diagnosi e il follow-up di questi tumori. Tuttavia, numerosissimi studi insistono sull’apporto della diagnostica per immagini multimodale (sequenza di perfusione, di diffusione in RM e spettroscopia RM in particolare) per migliorare il nostro approccio diagnostico e la valutazione terapeutica. D’altronde, importanti progressi sono stati realizzati negli ultimi anni in biologia molecolare, permettendo di affinare la diagnosi e di individuare degli indicatori prognostici. Anche sul piano terapeutico, sono stati osservati importanti progressi, sia a livello delle tecniche chirurgiche che a livello di quelle mediche, che permettono di migliorare la mediana di sopravvivenza, la qualita della vita e le capacita funzionali di questi pazienti. Il trattamento postoperatorio di prima linea si basa sull’associazione chemioterapia-radioterapia nella maggioranza dei casi. Il trattamento di seconda linea e meno ben codificato: tuttavia, numerosi studi hanno dimostrato l’apporto del bevacizumab in questa indicazione. Peraltro, nuove molecole e/o strategie terapeutiche sono attualmente in corso di valutazione, permettendo di sperare in un miglioramento della prognosi e della qualita della vita in futuro.

A prospective video-based observational and analytical approach to evaluate management during brain tumour surgery at a university hospital

The operating room (OR) is a high-risk complex setting, where patient safety relies on the coordinated efforts of multiple team members. However, little attention has been paid to evaluating the strategies employed by OR practitioners to prevent and correct incidents that inevitably occur during surgery. Therefore, we were prompted to investigate human factor (HF) engineering methods that have been used in an innovative way in order to systematically observe and analyze the management of incidents in the neurosurgical OR of a French university hospital. A technical case report illustrates our approach that associates the following procedures: the recording of OR team member activities and behaviour by video cameras and direct observation of a HF researcher, with the description and the explicit demonstration of safety related procedures in self- and cross-confrontation interviews of OR team members. This technical report emphasizes complementary aspects of clinical performance related to safety skills. Moreover, individual and team performances rely on complementary abilities that associate practical knowledge, skills, and attitudes, which are engaged at various degrees to prevent and manage incidents. This report also enlightens new quality-improvement opportunities as well as further objectives for future studies.