Valproic acid for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results.

in Expert Opinion on Investigational Drugs (2012), 21(9), 1391-415

INTRODUCTION: Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to ... [more ▼]

INTRODUCTION: Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to inhibit the proliferation of various cancers including glioblastoma multiforme. AREAS COVERED: We provide a comprehensive review of the mechanisms of action of valproate in gliomas, of its potential side effects and of the published clinical results obtained with this drug in glioblastomas. Valproate inhibits a subset of histone deacetylases and cellular kinases, and affects gene transcription through histone hyperacetylation, DNA hypomethylation and the modulation of several transcription factors. As a result, VPA induces differentiation of glioma cells, can prevent their invasion in surrounding tissues and may inhibit tumor angiogenesis. VPA can also inhibit DNA repair, thereby potentiating cytotoxic treatments such as chemotherapies or radiation therapy. Based on these mechanisms and case reports of glioblastoma remissions following VPA treatment, several clinical studies currently assess the therapeutic potential of VPA in glioma therapy. EXPERT OPINION: The combination of VPA treatment with chemotherapy and radiotherapy in glioblastoma appears a rational option that deserves well-designed prospective clinical trials that assess the efficacy and the molecular characteristics of the responding tumors in these patients. [less ▲]

Human glioblastoma-initiating cells invade specifically the subventricular zones and olfactory bulbs of mice after striatal injection.

in International Journal of Cancer = Journal International du Cancer (2011), 129(3), 574-585

This study reports the subsequent isolation of human glioblatoma cells able to initiate experimental brain tumors, specifically and repeatedly found in the subventricular zones and olfactory bulbs ... [more ▼]

This study reports the subsequent isolation of human glioblatoma cells able to initiate experimental brain tumors, specifically and repeatedly found in the subventricular zones and olfactory bulbs following xenograft in the caudate putamen of immunodeficient mice.In patients with glioblastoma multiforme, recurrence is the rule despite continuous advances in surgery, radiotherapy and chemotherapy. Within these malignant gliomas, glioblastoma stem cells or initiating cells have been recently described and they were shown to be specifically involved in experimental tumorigenesis. In this study, we show that some human glioblastoma cells injected into the striatum of immunodeficient nude mice exhibit a tropism for the subventricular zones. There and similarily to neurogenic stem cells, these subventricular glioblastoma cells were then able to migrate towards the olfactory bulbs. Finally, the glioblastoma cells isolated from the adult mouse subventricular zones and olfactory bulbs display high tumorigenicity when secondary injected in a new mouse brain. Together, these data suggest that neurogenic zones could be a reservoir for particular cancer-initiating cells. [less ▲]

Does radiation treatment delay affect survival in glioblastoma

in Surgical Neurology (2009), 72(5), 519

Does radiation treatment delay affect survival in glioblastoma ?

Conference (2009, March 21)

Monosomy of chromosome 10 associated with dysregulation of epidermal growth factor signaling in glioblastomas.

in JAMA : Journal of the American Medical Association (2009), 302(3), 276-89

CONTEXT: Glioblastomas--uniformly fatal brain tumors--often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7, an association for ... [more ▼]

CONTEXT: Glioblastomas--uniformly fatal brain tumors--often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7, an association for which the mechanism is poorly understood. OBJECTIVES: To assess whether coselection of EGFR gains on 7p12 and monosomy 10 in glioblastomas promotes tumorigenic epidermal growth factor (EGF) signaling through loss of the annexin A7 (ANXA7) gene on 10q21.1-q21.2 and whether ANXA7 acts as a tumor suppressor gene by regulating EGFR in glioblastomas. DESIGN, SETTING, AND PATIENTS: Multidimensional analysis of gene, coding sequence, promoter methylation, messenger RNA (mRNA) transcript, protein data for ANXA7 (and EGFR), and clinical patient data profiles of 543 high-grade gliomas from US medical centers and The Cancer Genome Atlas pilot project (made public 2006-2008; and unpublished, tumors collected 2001-2008). Functional analyses using LN229 and U87 glioblastoma cells. MAIN OUTCOME MEASURES: Associations among ANXA7 gene dosage, coding sequence, promoter methylation, mRNA transcript, and protein expression. Effect of ANXA7 haploinsufficiency on EGFR signaling and patient survival. Joint effects of loss of ANXA7 and gain of EGFR expression on tumorigenesis. RESULTS: Heterozygous ANXA7 gene deletion is associated with significant loss of ANXA7 mRNA transcript expression (P = 1 x 10(-15); linear regression) and a reduction (mean [SEM]) of 91.5% (2.3%) of ANXA7 protein expression compared with ANXA7 wild-type glioblastomas (P = .004; unpaired t test). ANXA7 loss of function stabilizes the EGFR protein (72%-744% increase in EGFR protein abundance) and augments EGFR transforming signaling in glioblastoma cells. ANXA7 haploinsufficiency doubles tumorigenic potential of glioblastoma cells, and combined ANXA7 knockdown and EGFR overexpression promotes tumorigenicity synergistically. The heterozygous loss of ANXA7 in approximately 75% of glioblastomas in the The Cancer Genome Atlas plus infrequency of ANXA7 mutation (approximately 6% of tumors) indicates its role as a haploinsufficiency gene. ANXA7 mRNA transcript expression, dichotomized at the median, associates with patient survival in 191 glioblastomas (log-rank P = .008; hazard ratio [HR], 0.667; 95% confidence interval [CI], 0.493-0.902; 46.9 vs 74.8 deaths/100 person-years for high vs low ANXA7 mRNA expression) and with a separate group of 180 high-grade gliomas (log-rank P = .00003; HR, 0.476; 95% CI, 0.333-0.680; 21.8 vs 50.0 deaths/100 person-years for high vs low ANXA7 mRNA expression). Deletion of the ANXA7 gene associates with poor patient survival in 189 glioblastomas (log-rank P = .042; HR, 0.686; 95% CI, 0.476-0.989; 54.0 vs 80.1 deaths/100 person-years for wild-type ANXA7 vs ANXA7 deletion). CONCLUSION: Haploinsufficiency of the tumor suppressor ANXA7 due to monosomy of chromosome 10 provides a clinically relevant mechanism to augment EGFR signaling in glioblastomas beyond that resulting from amplification of the EGFR gene. [less ▲]

Hypopituitarisme consécutif aux atteintes cérébrales: le traumatisme cranien et l'hémorragie sous-arachnoidienne mis en cause.

in Revue Médicale de Liège (2009), 64(9), 457-463

Brain injuries namely traumatic brain injuries (TBI) and subarachnoid haemorrhage (SAH) are relevant causes of acquired adult hypopituitarism, perhaps more prevalent than ever believed. TBI represent a ... [more ▼]

Brain injuries namely traumatic brain injuries (TBI) and subarachnoid haemorrhage (SAH) are relevant causes of acquired adult hypopituitarism, perhaps more prevalent than ever believed. TBI represent a major health problem with an annual incidence of 300 cases per 100.000. SAH affects six new cases per 1.000.000 habitants in USA. In Belgium we estimate nearly 30.000 new TBI cases and 600 SAH cases per year. In the English literature, TBI secondary hypopituitarism has been well documented in 14 retrospective and prospective series accounting for 1.077 cases. In all these series the main pituitary deficits were: GH (14%), ACTH (14%), gonadotrope (18%), TSH (7%) and diabetes insipidus (4%). SAH was documented as a cause of hypopituitarism in three retrospective series accounting for 110 cases and in one prospective series. In all these series main pituitary deficits were GH (25%), ACTH (15%), gonadotrope (8.5%), TSH (6%) and diabetes insipidus (4%). In this review, we analyze recent data and discuss diagnostic and treatment features of secondary hypopituitarism due TBI and SAH. [less ▲]

Preliminary observations after discectomy plus fusion with the use of bioresorbable cages

Poster (2008, March 08)

Surgical management of anterior cranial base fractures with cerebrospinal fluid fistulae: a single-institution experience.

in Neurosurgery (2008), 62(2), 463-9469-71

OBJECTIVE: The management of cerebrospinal fluid (CSF) fistulae after anterior cranial base fracture remains a surgical challenge. We reviewed our results in the repair of CSF fistulae complicating ... [more ▼]

OBJECTIVE: The management of cerebrospinal fluid (CSF) fistulae after anterior cranial base fracture remains a surgical challenge. We reviewed our results in the repair of CSF fistulae complicating multiple anterior cranial base fractures via a combined intracranial extradural and intradural approach and describe a treatment algorithm derived from this experience. METHODS: We retrospectively reviewed the files of 209 patients with an anterior cranial base fracture complicated by a CSF fistula who were admitted between 1980 and 2003 to Liege State University Hospital. Among those patients, 109 had a persistent CSF leak or radiological signs of an unhealed dural tear. All underwent the same surgical procedure, with combined extradural and intradural closure of the dural tear. RESULTS: Of the 109 patients, 98 patients (90%) were cured after the first operation. Persistent postoperative CSF rhinorrhea occurred in 11 patients (10%), necessitating an early complementary surgery via a transsphenoidal approach (7 patients) or a second-look intracranial approach (4 patients). No postoperative neurological deterioration attributable to increasing frontocerebral edema occurred. During the mean follow-up period of 36 months, recurrence of CSF fistula was observed in five patients and required an additional surgical repair procedure. CONCLUSION: The closure of CSF fistulae after an anterior cranial base fracture via a combined intracranial extradural and intradural approach, which allows the visualization and repair of the entire anterior base, is safe and effective. It is essentially indicated for patients with extensive bone defects in the cranial base, multiple fractures of the ethmoid bone and the posterior wall of the frontal sinus, cranial nerve involvement, associated lesions necessitating surgery such as intracranial hematomas, and post-traumatic intracranial infection. Rhinorrhea caused by a precisely located small tear may be treated with endoscopy. [less ▲]

Actualites neurochirurgicales dans le traitement des tumeurs cerebrales

in Revue Médicale de Liège (2007), 62(5-6, May-Jun), 405-409

Neuronavigation is a tool for image guidance surgery. Based on the principle of the GPS, it is notably used for the ablation of brain tumors. Because of their millimetre precision, neuronavigation devices ... [more ▼]

Neuronavigation is a tool for image guidance surgery. Based on the principle of the GPS, it is notably used for the ablation of brain tumors. Because of their millimetre precision, neuronavigation devices bring more safety and effectiveness due to the ever increasing performances of medical imaging. However, neuronavigation presents a major pitfall as it uses a static support (the images acquired preoperatively) to perform a dynamic process (the surgical ablation). To preserve the performance of neuronavigation, it is mandatory to update the images during surgery. This is now achievable by interventional MRI, intra-operative ultrasound and the incorporation of fluorescent tracers by the tumor cells. These major tools, now available at Sart Tilman University Hospital of combined with state-of-the-art chemotherapy, radiotherapy and experimental protocols (including gene therapy) will undoubtedly improve the prognosis of brain tumors. [less ▲]

Improved PRESS sequence for lactate detection in the human vitreous body

in Proceedings of the International Society for Magnetic Resonance in Medicine (2006), 14