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Biomedical subjects

Nicolas de Tribolet

Publications and source records attributed to Nicolas de Tribolet.

At least 19 recordsLinked to original sources
PubMed2006

HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity.

Cancer stem cells are rare tumor cells characterized by their ability to self-renew and to induce tumorigenesis. They are present in gliomas and may be responsible for the lethality of these incurable brain tumors. In the most aggressive and invasive type, glioblastoma multiforme (GBM), an average of about one year spans the period between detection and death [1]. The resistence of gliomas to current therapies may be related to the existence of cancer stem cells [2-6]. We find that human gliomas display a stemness signature and demonstrate that HEDGEHOG (HH)-GLI signaling regulates the expression of stemness genes in and the self-renewal of CD133(+) glioma cancer stem cells. HH-GLI signaling is also required for sustained glioma growth and survival. It displays additive and synergistic effects with temozolomide (TMZ), the current chemotherapeutic agent of choice. TMZ, however, does not block glioma stem cell self-renewal. Finally, interference of HH-GLI signaling with cyclopamine or through lentiviral-mediated silencing demonstrates that the tumorigenicity of human gliomas in mice requires an active pathway. Our results reveal the essential role of HH-GLI signaling in controlling the behavior of human glioma cancer stem cells and offer new therapeutic possibilities.

Animals↗
PubMed2006

Orthostatic mesodiencephalic dysfunction after decompressive craniectomy.

An extreme syndrome of the trephined after decompressive craniectomy is reported here. The most extensive clinical syndrome observed was established over 4 weeks and consisted of bradypsychia, dysartria, and limb rigidity with equine varus feet predominating on the right. The syndrome was aggravated when the patient was sitting with the sequential appearance over minutes of a typical parkinsonian levodopa-resistant tremor starting on the right side, extending to all four limbs, followed by diplopia resulting from a left abducens nerve palsy followed by a left-sided mydriasis. All signs recovered within 1-2 h after horizontalisation. It was correlated with an orthostatic progressive sinking of the skin flap, MRI and CT scan mesodiencephalic distortion without evidence of parenchymal lesion. Brain stem auditory evoked potential wave III latency increases were observed on the right side on verticalisation of the patient. EEG exploration excluded any epileptic activity. Symptoms were fully recovered within 2 days after cranioplasty was performed. The cranioplasty had to be removed twice due to infection. Bradypsychia, speech fluency, limb rigidity and tremor reappeared within a week after removal of the prosthesis. While waiting for sterilisation of the operative site, the symptoms were successfully prevented by a custom-made transparent suction-cup helmet before completion of cranioplasty.

Adult↗
PubMed2006

Intracranial aneurysm stenting: follow-up with MR angiography.

Intracranial stenting is increasingly being used to treat intracranial aneurysms and stenoses. We wanted to assess the utility of magnetic resonance angiography (MRA) in the follow-up of patients treated with various types of intracranial stents and to assess the utility of performing gadolinium-enhanced MRA. A total of 19 patients having undergone intracranial stenting for aneurysms were imaged by MRI at 1.5T. A total of 20 stents were placed in 19 patients. In addition to conventional T2- and diffusion-weighted MRI, 3D time-of-flight MRA was performed before and after contrast administration. In the case of metallic INX stents (N = 7), there was a signal drop at the level of the vessel. which did not allow to evaluating the parent vessel, whereas this was visible in Nitinol stents (N = 8). Additionally a stent with a wire had a small artifact (N = 3). Contrast administration also improved vessel lumen visualization. In the case of Nitinol stents, MRA can be used to reliably demonstrate the vessel lumen after intracranial stenting. The use of postcontrast 3D time-of-flight imaging helps improve the intraluminal definition.

Adult↗
PubMed2005

B7-homolog 1 expression by human glioma: a new mechanism of immune evasion.

Immunosuppressive soluble factors such as transforming growth factor beta and cell surface molecules such as FasL may contribute to the immune evasion of malignant glioma. B7 homolog 1 is a member of the B7 family of costimulatory molecules implicated in the negative regulation of T cell immune responses. Here, we show that human glioma cell lines express B7 homolog 1 protein that reduces interferon-gamma production by activated T cells. The expression of B7 homolog 1 in vivo was demonstrated in a large series of human glioma samples, with a significant correlation between the level of B7 homolog 1 expression and the tumor grade. Overall, our data suggest that B7 homolog 1 may be involved in the immune evasion of glioma and encourage the blockade of this pathway in future immunotherapies.

Adolescent↗
PubMed2005

MGMT gene silencing and benefit from temozolomide in glioblastoma.

BACKGROUND: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. RESULTS: The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. CONCLUSIONS: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

Antineoplastic Agents, Alkylating↗
PubMed2005

Frontobasal interhemispheric trans-lamina terminalis approach for suprasellar lesions.

The frontobasal interhemispheric approach for suprasellar tumors currently incorporates technological advancements and refinements in patient selection, operative technique, and postoperative care. This technique is a valid choice for the removal of suprasellar lesions with extension into the third ventricle without major sequelae related to the surgical approach. The method described here reflects the combination of the frontal interhemispheric and trans-lamina terminalis approaches.

Adult↗
PubMed2004

Highly efficient DNA incorporation of intratumourally injected [125I]iododeoxyuridine under thymidine synthesis blocking in human glioblastoma xenografts.

Intratumoural (i.t.) injection of radio-iododeoxyuridine (IdUrd), a thymidine (dThd) analogue, is envisaged for targeted Auger electron- or beta-radiation therapy of glioblastoma. Here, biodistribution of [(125)I]IdUrd was evaluated 5 hr after i.t. injection in subcutaneous human glioblastoma xenografts LN229 after different intravenous (i.v.) pretreatments with fluorodeoxyuridine (FdUrd). FdUrd is known to block de novo dThd synthesis, thus favouring DNA incorporation of radio-IdUrd. Results showed that pretreatment with 2 mg/kg FdUrd i.v. in 2 fractions 0.5 hr and 1 hr before injection of radio-IdUrd resulted in a mean tumour uptake of 19.8% of injected dose (% ID), representing 65.3% ID/g for tumours of approx. 0.35 g. Tumour uptake of radio-IdUrd in non-pretreated mice was only 4.1% ID. Very low uptake was observed in normal nondividing and dividing tissues with a maximum concentration of 2.9% ID/g measured in spleen. Pretreatment with a higher dose of FdUrd of 10 mg/kg prolonged the increased tumour uptake of radio-IdUrd up to 5 hr. A competition experiment was performed in FdUrd pretreated mice using i.t. co-injection of excess dThd that resulted in very low tumour retention of [(125)I]IdUrd. DNA isolation experiments showed that in the mean >95% of tumour (125)I activity was incorporated in DNA. In conclusion, these results show that close to 20% ID of radio-IdUrd injected i.t. was incorporated in tumour DNA after i.v. pretreatment with clinically relevant doses of FdUrd and that this approach may be further exploited for diffusion and therapy studies with Auger electron- and/or beta-radiation-emitting radio-IdUrd.

Animals↗
PubMed2004

Transient crossed aphasia evidenced by functional brain imagery.

Crossed aphasia refers to language deficits induced by unilateral right hemisphere injuries in right-handed people who had no previous history of brain damage. One of the intriguing questions concerning crossed aphasia is the atypical language representation in the brain. In this respect, fMRI is a valuable tool for understanding the neural basis of crossed aphasia. Here, we used neuropsychological and fMRI language tasks in a right-handed subject who presented a crossed aphasia due to a right frontal meningioma. fMRI maps from two language tasks showed bilateral patterns of activation. In the light of previous studies reporting much frequent bilateral than exclusive right hemisphere representations, we hypothesise that some crossed aphasia cases could occur in subjects with bilateral language representation.

Aphasia↗
PubMed2004

Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide.

PURPOSE: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. EXPERIMENTAL DESIGN: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. RESULTS: Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (P = 0.002; Fisher's exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor (P = 0.017; Cox regression). CONCLUSIONS: This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.

Adult↗
PubMed2004

Arachidonylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1.

The anti-tumor properties of cannabinoids have recently been evidenced, mainly with delta9-tetrahydrocannabinol (THC). However, the clinical application of this drug is limited by possible undesirable side effects due to a broad expression of cannabinoid receptors (CB1 and CB2). An attractive field of research therefore is to identify molecules with more selective tumor targeting. This is particularly important for malignant gliomas, considering their poor prognosis and their location in the brain. Here we investigated whether the most potent endogenous cannabinoid, arachidonylethanolamide (AEA), could be a candidate. We observed that AEA induced apoptosis in long-term and recently established glioma cell lines via aberrantly expressed vanilloid receptor-1 (VR1). In contrast with their role in THC-mediated death, both CB1 and CB2 partially protected glioma against AEA-induced apoptosis. These data show that the selective targeting of VR1 by AEA or more stable analogues is an attractive research area for the treatment of glioma.

Antineoplastic Agents↗
PubMed2004

Far-lateral lumbar disc herniation: the microsurgical transmuscular approach.

Intra- and extraforaminal disc herniations can be treated via a lateral approach. The far-lateral approach is a muscle-splitting approach that allows surgeons to reach the disc herniation without any facet bone removal. The target of the surgical exposure is the isthmus. Good knowledge of the anatomic features of the intervertebral foramen and intertransverse space is mandatory. The transmuscular approach is discussed. We provide illustrations and a video to emphasize some operative aspects.

Aged↗
PubMed2004

Shunt-dependent hydrocephalus after rupture of intracranial aneurysms: a prospective study of the influence of treatment modality.

OBJECT: This study was designed to determine whether the frequency of shunt-dependent hydrocephalus in patients suffering from aneurysmal subarachnoid hemorrhage (SAH) differs when comparing surgical clip application with endovascular obliteration of ruptured aneurysms. METHODS: In this prospective nonrandomized study, 245 patients with aneurysmal SAH treated using either surgical clip application or endovascular coil embolization were studied at our institution between September 1997 and March 2003. One hundred eighty patients underwent clip application and 65 had coil embolization. In those patients who underwent clip application of anterior circulation aneurysms, the lamina terminalis was systematically fenestrated. The occurrence of acute, asymptomatic, and shunt-dependent hydrocephalus was analyzed in both treatment groups. A subgroup analysis of patients with good clinical grade (World Federation of Neurosurgical Societies [WFNS] Grades I-III) and better Fisher Grade (1-3) and of patients with Fisher Grade 4 hemorrhage was performed. Acute hydrocephalus was observed in 19% of surgical cases and 46% of endovascular ones. The occurrence of asymptomatic hydrocephalus was similar in both treatment groups (p = 0.4). Shunt-dependent hydrocephalus occurred in 14% of surgical cases and 19% of endovascular cases. This difference did not reach statistical significance (p = 0.53). Logistic regression models controlling for patient age, WFNS grade, Fisher grade, and acute hydrocephalus in patients with good clinical grade and better Fisher grade revealed no significant difference in the rate of shunt-dependent hydrocephalus in both therapy groups (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.2-2.65). Results of similar models indicated that among patients with intraventricular hemorrhage (IVH), surgical clip application carried a lower risk of shunt-dependent hydrocephalus (OR 0.32, 95% CI 0.14-0.75) compared with that for endovascular embolization. CONCLUSIONS: Shunt-dependent hydrocephalus was comparable in the two treatment groups, even in patients with better clinical and radiological grades on admission. Only patients in the endovascular therapy group who had experienced IVH showed a higher likelihood of shunt-dependent hydrocephalus.

Adolescent↗
PubMed2003

Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes.

The development of targeted treatment strategies adapted to individual patients requires identification of the different tumor classes according to their biology and prognosis. We focus here on the molecular aspects underlying these differences, in terms of sets of genes that control pathogenesis of the different subtypes of astrocytic glioma. By performing cDNA-array analysis of 53 patient biopsies, comprising low-grade astrocytoma, secondary glioblastoma (respective recurrent high-grade tumors), and newly diagnosed primary glioblastoma, we demonstrate that human gliomas can be differentiated according to their gene expression. We found that low-grade astrocytoma have the most specific and similar expression profiles, whereas primary glioblastoma exhibit much larger variation between tumors. Secondary glioblastoma display features of both other groups. We identified several sets of genes with relatively highly correlated expression within groups that: (a). can be associated with specific biological functions; and (b). effectively differentiate tumor class. One prominent gene cluster discriminating primary versus nonprimary glioblastoma comprises mostly genes involved in angiogenesis, including VEGF fms-related tyrosine kinase 1 but also IGFBP2, that has not yet been directly linked to angiogenesis. In situ hybridization demonstrating coexpression of IGFBP2 and VEGF in pseudopalisading cells surrounding tumor necrosis provided further evidence for a possible involvement of IGFBP2 in angiogenesis. The separating groups of genes were found by the unsupervised coupled two-way clustering method, and their classification power was validated by a supervised construction of a nearly perfect glioma classifier.

Adolescent↗
PubMed2003

Does treatment modality of intracranial ruptured aneurysms influence the incidence of cerebral vasospasm and clinical outcome?

BACKGROUND: Cerebral vasospasm is the most common cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). This study is designed to determine whether the incidence of symptomatic vasospasm and the overall clinical outcome differ between patients treated with surgical clipping compared with endovascular obliteration of aneurysms. METHODS: In this prospective study, 98 patients with aneurysmal SAH were treated. Seventy-two patients underwent surgery and clipping and 26 had coil embolization. The incidence of symptomatic vasospasm, permanent neurologic deficit due to vasospasm and clinical outcome were analyzed. Patients with better clinical and radiological grades (World Federation of Neurological Surgeons grades I-III and Fisher grades I-III) were analyzed separately. RESULTS: Symptomatic vasospasm occurred in 22% of the patients; 25% in the surgical group and 15% in the endovascular group. Nine percent of the patients in the surgical group and 7% in the endovascular group suffered ischemic infarction with permanent neurological deficit. These differences did not reach statistical significance (p = 0.42). For patients with better clinical and radiological grades, no significant difference was found for the rate of symptomatic vasospasm; 23% in the surgical and 12% in the endovascular group (p = 0.49). The overall clinical outcome was comparable in both groups, with no difference in the likelihood of a Glasgow Outcome Scale score of 3 or less (15% in the surgical and 16% in the endovascular group; p = 0.87). The same results for outcome were obtained for the subgroup of patients with better clinical grades on admission. CONCLUSION: Symptomatic vasospasm and ischemic infarction rate seem comparable in both groups, even for patients with better clinical and radiological admission grades. There is no significant difference in the overall clinical outcome at the long-term follow-up between both groups.

Adult↗
PubMed2003

Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain.

The number and localization of effector cells to the tumor site are crucial elements for immune rejection of solid tumors. However, for cerebral malignancies, antitumor responses need to be finely tuned to avoid neuropathologic consequences. In this study, we determine factors that regulate CTL localization and tumoricidal function after intracerebral implantation of tumors expressing model Ag. H-2(bxd) mice implanted with a CW3(+) murine glioma lacking H-2K(d) molecules necessary to present the CW3(170-179) epitope demonstrate cross-priming of H-2K(d)-restricted CTL, and moreover, Ag-dependent accumulation of functional H-2K(d)/CW3(170-179)-specific CTL within the tumor bed. This implicates a role for cross-presentation not only in priming, but also in retention of fully differentiated CTL in the tumor stroma at the effector stage of the response. Modulating cross-presentation of Ag may be the key in regulating specific immune responses in the brain: either by augmenting protective responses or by down-modulating destructive autoimmune reactions.

Animals↗