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See detailEnhanced FEM-based Modeling of Brain Shift Deformation in Image-Guided Neurosurgery
Vigneron, Lara M.; Boman, Romain ULg; Ponthot, Jean-Philippe ULg et al

in Journal of Computational & Applied Mathematics (2010), 234

We consider the problem of improving outcomes for neurosurgery patients by enhancing intraoperative navigation and guidance. Current navigation systems do not accurately account for intraoperative brain ... [more ▼]

We consider the problem of improving outcomes for neurosurgery patients by enhancing intraoperative navigation and guidance. Current navigation systems do not accurately account for intraoperative brain deformation. We focus on the brain shift deformation that occurs just after the opening of the skull and dura. The heart of our system is a nonrigid registration technique using a biomechanical model. We specifically work on two axes: the representation of the structures in the biomechanical model and the evaluation of the surface landmark displacement fields between intraoperative MR images. Using the modified Hausdorff distance as an image similarity measure, we demonstrate that our approach significantly improves the alignment of the intraoperative images. ' 2009 Elsevier B.V. All rights reserved. [less ▲]

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See detailIntraoperative electrical stimulation in awake craniotomy: methodological aspects of current practice.
Szelenyi, Andrea; Bello, Lorenzo; Duffau, Hugues et al

in Neurosurgical focus (2010), 28(2), 7

There is increasing evidence that the extent of tumor removal in low-grade glioma surgery is related to patient survival time. Thus, the goal of resecting the largest amount of tumor possible without ... [more ▼]

There is increasing evidence that the extent of tumor removal in low-grade glioma surgery is related to patient survival time. Thus, the goal of resecting the largest amount of tumor possible without leading to permanent neurological sequelae is a challenge for the neurosurgeon. Electrical stimulation of the brain to detect cortical and axonal areas involved in motor, language, and cognitive function and located within the tumor or along its boundaries has become an essential tool in combination with awake craniotomy. Based on a literature review, discussions within the European Low-Grade Glioma Group, and illustrative clinical experience, the authors of this paper provide an overview for neurosurgeons, neurophysiologists, linguists, and anesthesiologists as well as those new to the field about the stimulation techniques currently being used for mapping sensorimotor, language, and cognitive function in awake surgery for low-grade glioma. The paper is intended to help the understanding of these techniques and facilitate a comparison of results between users. [less ▲]

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See detailDoes radiation treatment delay affect survival in glioblastoma
Robe, Pierre ULg; Nguyen-Khac, Minh-Tuan ULg; Lenelle, Jacques ULg et al

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

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See detailDoes radiation treatment delay affect survival in glioblastoma ?
Robe, Pierre ULg; Nguyen Khac, Minh-Tuan ULg; Lenelle, Jacques ULg et al

Conference (2009, March 21)

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See detailMonosomy of chromosome 10 associated with dysregulation of epidermal growth factor signaling in glioblastomas.
Yadav, Ajay K; Renfrow, Jaclyn J; Scholtens, Denise M et al

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 ▲]

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See detail2D XFEM-based modeling of retraction and successive resections for preoperative image update.
Vigneron, Lara M.; Duflot, Marc P.; Robe, Pierre ULg et al

in Computer aided surgery : official journal of the International Society for Computer Aided Surgery (2009), 14(1-3), 1-20

This paper considers an approach to improving outcomes for neurosurgery patients by enhancing intraoperative navigation and guidance. Currently, intraoperative navigation systems do not accurately account ... [more ▼]

This paper considers an approach to improving outcomes for neurosurgery patients by enhancing intraoperative navigation and guidance. Currently, intraoperative navigation systems do not accurately account for brain shift or tissue resection. We describe how preoperative images can be incrementally updated to take into account any type of brain tissue deformation that may occur during surgery, and thus to improve the accuracy of image-guided navigation systems. For this purpose, we have developed a non-rigid image registration technique using a biomechanical model, which deforms based on the Finite Element Method (FEM). While the FEM has been used successfully for dealing with deformations such as brain shift, it has difficulty with tissue discontinuities. Here, we describe a novel application of the eXtended Finite Element Method (XFEM) in the field of image-guided surgery in order to model brain deformations that imply tissue discontinuities. In particular, this paper presents a detailed account of the use of XFEM for dealing with retraction and successive resections, and demonstrates the feasibility of the approach by considering 2D examples based on intraoperative MR images. To evaluate our results, we compute the modified Hausdorff distance between Canny edges extracted from images before and after registration. We show that this distance decreases after registration, and thus demonstrate that our approach improves alignment of intraoperative images. [less ▲]

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See detailEarly termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults.
Robe, Pierre ULg; Martin, Didier ULg; Nguyen-Khac, Minh-Tuan ULg et al

in BMC Cancer (2009), 9

BACKGROUND: Sulfasalazine, a NF-kappaB and x(c)-cystine/glutamate antiport inhibitor, has demonstrated a strong antitumoral potential in preclinical models of malignant gliomas. As it presents an ... [more ▼]

BACKGROUND: Sulfasalazine, a NF-kappaB and x(c)-cystine/glutamate antiport inhibitor, has demonstrated a strong antitumoral potential in preclinical models of malignant gliomas. As it presents an excellent safety profile, we initiated a phase 1/2 clinical study of this anti-inflammatory drug for the treatment of recurrent WHO grade 3 and 4 astrocytic gliomas in adults. METHODS: 10 patients with advanced recurrent anaplastic astrocytoma (n = 2) or glioblastoma (n = 8) aged 32-62 years were recruited prior to the planned interim analysis of the study. Subjects were randomly assigned to daily doses of 1.5, 3, 4.5, or 6 grams of oral sulfasalazine, and treated until clinical or radiological evidence of disease progression or the development of serious or unbearable side effects. Primary endpoints were the evaluation of toxicities according to the CTCAE v.3.0, and the observation of radiological tumor responses based on MacDonald criteria. RESULTS: No clinical response was observed. One tumor remained stable for 2 months with sulfasalazine treatment, at the lowest daily dose of the drug. The median progression-free survival was 32 days. Side effects were common, as all patients developed grade 1-3 adverse events (mean: 7.2/patient), four patients developed grade 4 toxicity. Two patients died while on treatment or shortly after its discontinuation. CONCLUSION: Although the proper influence of sulfasalazine treatment on patient outcome was difficult to ascertain in these debilitated patients with a large tumor burden (median KPS = 50), ISRCTN45828668 was terminated after its interim analysis. This study urges to exert cautiousness in future trials of Sulfasalazine for the treatment of malignant gliomas. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45828668. [less ▲]

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See detailHypopituitarisme consécutif aux atteintes cérébrales: le traumatisme cranien et l'hémorragie sous-arachnoidienne mis en cause.
Valdes Socin, Hernan Gonzalo ULg; Vroonen, Laurent ULg; Robe, Pierre ULg et al

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 ▲]

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See detailIssues in FEM-based Modeling of Brain Shift in Neurosurgery
Vigneron, Lara M.; Boman, Romain ULg; Ponthot, Jean-Philippe ULg et al

in Hogge, Michel; Van Keer, R.; Noels, Ludovic (Eds.) et al Proceedings of ACOMEN’2008, Advanced Computational Methods in Engineering (2008, May)

We consider the problem of improving outcomes for neurosurgery patients by enhancing intraoperative navigation and guidance. Current navigation systems do not accurately account for intraoperative brain ... [more ▼]

We consider the problem of improving outcomes for neurosurgery patients by enhancing intraoperative navigation and guidance. Current navigation systems do not accurately account for intraoperative brain deformation. In this work, we focus on the brain shift deformation that occurs just after the opening of the skull and dura, before any cut and subsequent deformation has happened. We test several algorithms and parameters in order to evaluate their impact on the modeling of the brain shift. [less ▲]

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See detailLes glioblastomes, un exemple de recherche translationnelle?
Kroonen, Jérôme ULg; Nguyen-Khac, Minh-Tuan ULg; Deprez, Manuel ULg 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 ▲]

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See detailSurgical management of anterior cranial base fractures with cerebrospinal fluid fistulae: a single-institution experience.
Scholsem, Martin; Scholtes, Félix ULg; Collignon, Frederick 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 ▲]

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See detail3D FEM/XFEM-based Biomechanical Brain Modeling for Preoperative Image Update
Vigneron, Lara; Boman, Romain ULg; Robe, Pierre ULg 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 ▲]

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See detailSufasalazine unveils a contact-independent HSV-TK/ganciclovir gene therapy bystander effect in malignant gliomas
Robe, Pierre ULg; Nguyen-Khac, Minh-Tuan ULg; Lambert, Frédéric ULg 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 ▲]

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See detailA STAT3 Gene Expression Signature in Gliomas is Associated with a Poor Prognosis.
Alvarez, James V.; Mukherjee, Neelanjan; Chakravarti, Arnab 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 ▲]

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See detailActualites neurochirurgicales dans le traitement des tumeurs cerebrales
Robe, Pierre ULg; Martin, Didier ULg

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 ▲]

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See detailRadiation enhances the invasive potential of primary glioblastoma cells via activation of the Rho signaling pathway.
Zhai, Gary G; Malhotra, Rajeev; Delaney, Meaghan 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 ▲]

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See detailCan NF-kappaB be a target for novel and efficient anti-cancer agents?
Olivier, Sabine ULg; Robe, Pierre ULg; Bours, Vincent ULg

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 ▲]

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See detailImproved PRESS sequence for lactate detection in the human vitreous body
Balteau, Evelyne ULg; COLLIGNON, Nathalie ULg; Robe, Pierre ULg et al

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

Detailed reference viewed: 58 (8 ULg)