Les glioblastomes, un exemple de recherche translationnelle?
Kroonen, Jérôme ; Nguyen-Khac, Minh-Tuan ; Deprez, Manuel et al
in Revue Médicale de Liège (2008), 63(5-6), 251-6
Among patients which develop glioblastoma multiform (GBM), recurrence is the rule despite continuous progress in surgery, radiotherapy and chemotherapy. In the adult, GBM is the most frequent and most ... [more ▼]
Among patients which develop glioblastoma multiform (GBM), recurrence is the rule despite continuous progress in surgery, radiotherapy and chemotherapy. In the adult, GBM is the most frequent and most aggressive tumour of the Central Nervous System. A better understanding of the mechanisms by which these tumours relapse could promote the use of preventive therapy and could increase patients' survival. GBM stem cells have been recently described and it was demonstrated that they are specifically implied in the experimental tumorigenesis. It is thus very attractive to speculate on a possible relationship between these GBM stem cells and the neural stem cells which are persisting in the neurogenic zones of the adult brain. In this review, we formulate and discuss the hypothesis by which, in a patient with GBM, malignant stem cells might be present in the neurogenic zones, away from the tumour mass. This hypothesis could explain the tumour relapse observed after the first treatments. [less ▲]Detailed reference viewed: 143 (49 ULg)
Surgical management of anterior cranial base fractures with cerebrospinal fluid fistulae: a single-institution experience.
; Scholtes, Félix ; et al
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 ▲]Detailed reference viewed: 52 (1 ULg)
3D FEM/XFEM-based Biomechanical Brain Modeling for Preoperative Image Update
; Boman, Romain ; Robe, Pierre et al
in Miller, Karol; Paulsen, Keith D.; Young, Alistair A. (Eds.) et al MICCAI 2007 Workshop Proceedings : Computational Biomechanics for Medicine II (2007, November)
We present an end-to-end system for updating 3D preoperative images in the presence of brain shift and successive resections. The tissue discontinuities due to resections are handled via the eXtented ... [more ▼]
We present an end-to-end system for updating 3D preoperative images in the presence of brain shift and successive resections. The tissue discontinuities due to resections are handled via the eXtented Finite Element Method (XFEM), which has the appealing feature of handle arbitrarily-shaped discontinuity without any remeshing. The main novelty of the paper lies in the use of XFEM in 3D. [less ▲]Detailed reference viewed: 53 (11 ULg)
Sufasalazine unveils a contact-independent HSV-TK/ganciclovir gene therapy bystander effect in malignant gliomas
Robe, Pierre ; Nguyen-Khac, Minh-Tuan ; Lambert, Frédéric et al
in International Journal of Oncology (2007), 30(1), 283-290
The efficacy of HSV-TK/ganciclovir-based gene therapy on malignant gliomas largely relies on the amplitude of the bystander effect. In these experiments, the anti-inflammatory drug Sulfasalazine increased ... [more ▼]
The efficacy of HSV-TK/ganciclovir-based gene therapy on malignant gliomas largely relies on the amplitude of the bystander effect. In these experiments, the anti-inflammatory drug Sulfasalazine increased the HSV-TK/ganciclovir bystander effect in C6, 9L and LN18 cells but not in U87 glioma cells. Using bi-compartmental culture devices and conditioned medium transfer experiments, we showed that in C6, 9L and LN18 cells but not in U87 cells, Sulfasalazine also unveiled a new, contact-independent mechanism of HSV-TK/ganciclovir bystander effect. Upon treatment with ganciclovir, human LN18-TK but not U87-TK cells synthetized and released TNF-alpha in the culture medium. Sulfasalazine sensitized glioma cells to the toxic effect of TNF-alpha. and enhanced its secretion in LN18-TK cells in response to GCV treatment. The caspase-8 inhibitor Z-IETD-FMK and a blocking antibody to TNF-alpha both inhibited the contact-independent bystander effect in LN18 cells. Taken together, these results suggest that TNF-alpha mediates the contact-independent bystander effect in LN18 cells. The treatment with GCV and/or Sulfasalazine of tumor xenografts consisting of a mix of 98% C6 and 2% C6-TK cells shows that Sulfasalazine is also a potent adjunct to the in vivo treatment of gliomas. [less ▲]Detailed reference viewed: 57 (5 ULg)
A STAT3 Gene Expression Signature in Gliomas is Associated with a Poor Prognosis.
; ; et al
in Translational Oncogenomics (2007), 2
Gliomas frequently display constitutive activation of the transcription factor STAT3, a protein that is known to be able to mediate neoplastic transformation. STAT3 regulates genes that play a central ... [more ▼]
Gliomas frequently display constitutive activation of the transcription factor STAT3, a protein that is known to be able to mediate neoplastic transformation. STAT3 regulates genes that play a central role in cellular survival, proliferation, self-renewal, and invasion, and a cohort of STAT3 target genes have been found that are commonly coexpressed in human cancers. Thus, these genes likely subserve the transforming ability of constitutively activated STAT3. To determine whether the coordinated expression of STAT3 target genes is present in a subset of human gliomas, and whether this changes the biology of these tumors in patients, gene expression analysis was performed in four distinct human glioma data sets for which patient survival information was available. Coordinate expression of STAT3 targets was significantly associated with poor patient outcome in each data set. Specifically, patients with tumors displaying high expression of STAT3 targets had a shorter median survival time compared to patients whose tumors had low expression of STAT3 targets. These data suggest that constitutively activated STAT3 in gliomas can alter the biology of these tumors, and that development of targeted STAT3 inhibitors would likely be of particular benefit in treatment of this disease. [less ▲]Detailed reference viewed: 9 (1 ULg)
Actualites neurochirurgicales dans le traitement des tumeurs cerebrales
Robe, Pierre ; Martin, Didier
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 ▲]Detailed reference viewed: 50 (7 ULg)
Radiation enhances the invasive potential of primary glioblastoma cells via activation of the Rho signaling pathway.
; ; et al
in Journal of neuro-oncology (2006), 76(3), 227-37
Glioblastoma multiforme (GBM) is among the most treatment-refractory of all human tumors. Radiation is effective at prolonging survival of GBM patients; however, the vast majority of GBM patients ... [more ▼]
Glioblastoma multiforme (GBM) is among the most treatment-refractory of all human tumors. Radiation is effective at prolonging survival of GBM patients; however, the vast majority of GBM patients demonstrate progression at or near the site of original treatment. We have identified primary GBM cell lines that demonstrate increased invasive potential upon radiation exposure. As this represents a novel mechanism by which radiation-treated GBMs can fail therapy, we further investigated the identity of downstream signaling molecules that enhance the invasive phenotype of irradiated GBMs. Matrigel matrices were used to compare the extent of invasion of irradiated vs. non-irradiated GBM cell lines UN3 and GM2. The in vitro invasive potential of these irradiated cells were characterized in the presence of both pharmacologic and dominant negative inhibitors of extracellular matrix and cell signaling molecules including MMP, uPA, IGFR, EGFR, PI-3K, AKT, and Rho kinase. The effect of radiation on the expression of these signaling molecules was determined with Western blot assays. Ultimately, the in vitro tumor invasion results were confirmed using an in vivo 9L GBM model in rats. Using the primary GBM cell lines UN3 and GM2, we found that radiation enhances the invasive potential of these cells via activation of EGFR and IGFR1. Our findings suggest that activation of Rho signaling via PI-3K is required for radiation-induced invasion, although not required for invasion under physiologic conditions. This report clearly demonstrates that radiation-mediated invasion is fundamentally distinct from invasion under normal cellular physiology and identifies potential therapeutic targets to overcome this phenomenon. [less ▲]Detailed reference viewed: 22 (0 ULg)
Can NF-kappaB be a target for novel and efficient anti-cancer agents?
Olivier, Sabine ; Robe, Pierre ; Bours, Vincent
in Biochemical Pharmacology (2006), 72(9), 1054-1068
Since the discovery of the NF-kappaB transcription factor in 1986 and the cloning of the genes coding for NF-kappaB and IkappaB proteins, many studies demonstrated that this transcription factor can, in ... [more ▼]
Since the discovery of the NF-kappaB transcription factor in 1986 and the cloning of the genes coding for NF-kappaB and IkappaB proteins, many studies demonstrated that this transcription factor can, in most cases, protect transformed cells from apoptosis and therefore participate in the onset or progression of many human cancers. Molecular studies demonstrated that ancient widely used drugs, known for their chemopreventive or therapeutic activities against human cancers, inhibit NF-kappaB, usually among other biological effects. It is therefore considered that the anti-cancer activities of NSAIDs (non-steroidal anti-inflammatory drugs) or glucocorticoids are probably partially related to the inhibition of NF-kappaB and new clinical trials are being initiated with old compounds such as sulfasalazine. In parallel, many companies have developed novel agents acting on the NF-kappaB pathway: some of these agents are supposed to be NF-kappaB specific (i.e. IKK inhibitors) while others have wide-range biological activities (i.e. proteasome inhibitors). Today, the most significant clinical data have been obtained with bortezomib, a proteasome inhibitor, for the treatment of multiple myeloma. This review discusses the preclinical and clinical data obtained with these various drugs and their putative future developments. [less ▲]Detailed reference viewed: 69 (7 ULg)
Improved PRESS sequence for lactate detection in the human vitreous body
Balteau, Evelyne ; COLLIGNON, Nathalie ; Robe, Pierre et al
in Proceedings of the International Society for Magnetic Resonance in Medicine (2006), 14Detailed reference viewed: 45 (8 ULg)
A phase 1-2, prospective, double blind, randomized study of the safety and efficacy of Sulfasalazine for the treatment of progressing malignant gliomas: study protocol of [ISRCTN45828668].
Robe, Pierre ; Martin, Didier ; Albert, Adelin et al
in BMC Cancer (2006), 6
BACKGROUND: The prognosis of patients suffering from WHO grade 3 and 4 astrocytic glioma remains poor despite surgery, radiation therapy and the use of current chemotherapy regimen. Indeed, the median ... [more ▼]
BACKGROUND: The prognosis of patients suffering from WHO grade 3 and 4 astrocytic glioma remains poor despite surgery, radiation therapy and the use of current chemotherapy regimen. Indeed, the median survival of glioblastoma multiforme (WHO grade 4) patients is at best 14.6 month with only 26.5 percent of the patients still alive after 2 years and the median survival of anaplastic astrocytomas (WHO grade 3) is 19.2 month. Recent evidence suggests that the transcription factor NF-kappaB is constitutively expressed in malignant gliomas and that its inhibition by drugs like Sulfasalazine may block the growth of astrocytic tumors in vitro and in experimental models of malignant gliomas. DESIGN: ULg_GBM_04/1 is a prospective, randomized, double blind single-center phase 1-2 study. A total of twenty patients with progressive malignant glioma despite surgery, radiation therapy and a first line of chemotherapy will be recruited and assigned to four dosage regimen of Sulfasalazine. This medication will be taken orally t.i.d. at a daily dose of 1.5-3-4 or 6 g, continuously until complete remission, evidence of progression or drug intolerance. Primary endpoints are drug safety in the setting of malignant gliomas and tumor response as measured according to MacDonald's criteria. An interim analysis of drug safety will be conducted after the inclusion of ten patients. The complete evaluation of primary endpoints will be conducted two years after the enrollment of the last patient or after the death of the last patient should this occur prematurely. DISCUSSION: The aim of this study is to evaluate the safety and efficacy of Sulfasalazine as a treatment for recurring malignant gliomas. The safety and efficacy of this drug are analyzed as primary endpoints. Overall survival and progression-free survival are secondary endpoint. [less ▲]Detailed reference viewed: 76 (19 ULg)
Transsphenoidal surgery for Cushing’s disease. Early and long-term results in 106 patients
Stevenaert, Achille ; Robe, Pierre ; Martin, Didier et al
Conference (2005, October 07)Detailed reference viewed: 10 (0 ULg)
Peripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression
Hans, Grégory ; Wislet, Sabine ; et al
in Biochemical Pharmacology (2005), 69(5), 819-830
Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising ... [more ▼]
Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising chemotherapeutic candidates. However, conflicting results were reported regarding the actual effect of these drugs on cellular survival ranging from protection to toxicity. Moreover, the concentrations needed to observe such a toxicity were usually high, far above the affinity range for their receptor, hence questioning its specificity. In the present study, we have shown that micromolar concentrations of FGIN-1-27 And Ro 5-4864, two chemically unrelated PBR ligands are toxic for both PBR-expressing SK-N-BE neuroblastoma cells and PBR-deficient Jurkat lymphoma cells. We have thereby demonstrated that the cytotoxicity of these drugs is unrelated to their PBR-binding activity. Moreover, Ro 54864-induced cell death differed strikingly between both cell types, being apoptotic in Jurkat cells while necrotic in SK-N-BE cells. Again, this did not seem to be related to PBR expression since Ro 5-4864-induced death of PBR-transfected Jurkat cells remained apoptotic. Taken together, our results show that PBR is unlikely to mediate all the effects of these PBR ligands. They however confirm that some of these ligands are very effective cytotoxic drugs towards various cancer cells, even for reputed chemoresistant tumors such as neuroblastoma, and, surprisingly, also for PBR-lacking tumor cells. (C) 2004 Elsevier Inc. All rights reserved. [less ▲]Detailed reference viewed: 69 (8 ULg)
Connexin 30 expression in high grade gliomas : correlation with survival and resistance to ionizing radiation.
Robe, Pierre ; Nguyen Khac, Minh-Tuan ; Deprez, Manuel et al
Conference (2005, March)Detailed reference viewed: 32 (1 ULg)
Two stages total vertebrectomy : about a series of 16 patients.
Lenelle, Jacques ; ; Dubuisson, Annie et al
Conference (2005, March)Detailed reference viewed: 7 (0 ULg)
beta-carbolines induce apoptosis in cultured cerebellar granule neurons via the mitochondrial pathway
Hans, Grégory ; Malgrange, Brigitte ; et al
in Neuropharmacology (2005), 48(1), 105-117
N-Butyl-beta-carboline-3-carboxylate (betaCCB) is, together with 2-methyl-norharmanium and 2,9-dimethylnorharmanium ions, an endogenously occurring beta-carboline. Due to their structural similarities ... [more ▼]
N-Butyl-beta-carboline-3-carboxylate (betaCCB) is, together with 2-methyl-norharmanium and 2,9-dimethylnorharmanium ions, an endogenously occurring beta-carboline. Due to their structural similarities with the synthetic neurotoxin 1-methy14-phenyl-1,2,3,6-tetrahydropyridine (MPTP), harman and norharman compounds have been proposed to be involved in the pathogenesis of Parkinson's disease. While also structurally related, betaCCB has received much less interest in that respect although we had previously demonstrated that it induces the apoptotic cell death of cultured cerebellar granule neurons (CGNs). Herein, we have investigated the molecular events leading to CGN apoptosis upon betaCCB treatment. We first demonstrated that betaCCB-induced apoptosis occurs in neurons only, most likely as a consequence of a specific neuronal uptake as shown using binding/uptake experiments. Then we observed that, in betaCCB-treated CGNs, caspases 9, 3 and 8 were successively activated, suegesing an activation of the mitochondrial pathway. Consistently, betaCCB also induced the release from the mitochondrial intermembrane space of two pro-apoptotic factors. i.e. cytochrome c and apotptosis inducing factor (AIF). Interestingly, no mitochondrial membrane depolarisation was associated with this release. suggesting a mitochondrial permeability transition pore-independent mechanism. The absence of any neuroprotective effect provided by two mPTP inhibitors. i.e. cyclosporine A and bongkrekic acid. further supported this hypothesis. Together. these results show that betaCCB is specifically taken up by neuronal cells where it triggers a specific permeabilization of the outer mitochondrial membrane and a subsequent apoptotic cell death. (C) 2004 Elsevier Ltd. All rights reserved. [less ▲]Detailed reference viewed: 57 (14 ULg)
Dexamethasone inhibits the HSV-tk/ ganciclovir bystander effect in malignant glioma cells.
Robe, Pierre ; Nguyen-Khac, Minh-Tuan ; Jolois, Olivier et al
in BMC Cancer (2005), 5
BACKGROUND: HSV-tk/ ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate ... [more ▼]
BACKGROUND: HSV-tk/ ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy in the treatment of human brain tumors. Since dexamethasone is a frequently used symptomatic treatment for malignant gliomas, its interaction with the bystander effect and the overall efficacy of HSV-TK gene therapy ought to be assessed. METHODS: Stable clones of TK-expressing U87, C6 and LN18 cells were generated and their bystander effect on wild type cells was assessed. The effects of dexamethasone on cell proliferation and sensitivity to ganciclovir were assessed with a thymidine incorporation assay and a MTT test. Gap junction mediated intercellular communication was assessed with microinjections and FACS analysis of calcein transfer. The effect of dexamethasone treatment on the sensitivity of TK-expressing to FAS-dependent apoptosis in the presence or absence of ganciclovir was assessed with an MTT test. Western blot was used to evidence the effect of dexamethasone on the expression of Cx43, CD95, CIAP2 and BclXL. RESULTS: Dexamethasone significantly reduced the bystander effect in TK-expressing C6, LN18 and U87 cells. This inhibition results from a reduction of the gap junction mediated intercellular communication of these cells (GJIC), from an inhibition of their growth and thymidine incorporation and from a modulation of the apoptotic cascade. CONCLUSION: The overall efficacy of HSV-TK gene therapy is adversely affected by dexamethasone co-treatment in vitro. Future HSV-tk/ GCV gene therapy clinical protocols for gliomas should address this interference of corticosteroid treatment. [less ▲]Detailed reference viewed: 29 (4 ULg)
Endovascular aneurysm treatment: angiographic and clinical follow-up in a series of 114 consecutive lesions
Robe, Pierre ; ; Lenelle, Jacques et al
Conference (2004, April 27)Detailed reference viewed: 8 (0 ULg)
Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms.
; ; et al
in Oncogene (2004), 23(45), 7494-506
The observed radioresistance of human glioblastoma multiforme (GBM) poses a major challenge, which, if overcome, may lead to significant advances in the management of this patient population. There is ... [more ▼]
The observed radioresistance of human glioblastoma multiforme (GBM) poses a major challenge, which, if overcome, may lead to significant advances in the management of this patient population. There is accumulating evidence from correlative studies that Survivin expression is associated with increased malignant potential of human gliomas. The purpose of this study was to investigate whether Survivin plays a direct role in mediating radiation resistance in primary human glioma cell lines, and, if so, investigating the underlying mechanisms. Our panel of GBM cell lines included two that were relatively radiation resistant (GM20 and GM21) and two that were more radiation sensitive (GM22 and GM23), which demonstrated differential levels of Survivin expression between the two groups. Through the use of adenoviral vectors containing either dominant-negative (pAd-S(T34A)) or wild-type Suvrivin (pAd-S(WT)), we were able to inactivate or overexpress Survivin, respectively. Our findings suggest that Survivin plays a critical role in mediating radiation resistance in primary GBM cells, in part through suppression of apoptotic cell death via a caspase-independent manner. We have identified novel mechanisms by which Survivin may enhance tumor cell survival upon radiation exposure such as regulation of double-strand DNA break repair and tumor cell metabolism, which were most evident in the radiation-resistant cell lines. These differences in Survivin function both in radiation-resistant vs radiation-sensitive cell lines and in the presence vs absence of radiation exposure warrant further investigation and highlight potentially important mechanisms of radiation resistance in these tumors. [less ▲]Detailed reference viewed: 14 (0 ULg)
Sodium bromide encephalopathy with decreased serum Cl- level and increased anion gap: report of one case.
Robe, Pierre ; Sadzot, Bernard ;
in European Neurology (2004), 51(4), 246-7Detailed reference viewed: 17 (0 ULg)