Impact de la prise d’agonistes progestatifs sur les mécanismes de l’initiation et de la croissance tumorale des méningiomes

Meningioma are the most frequent tumors in the central nervous system. However, the cell of origin, the timing of initiating events, or the initiation mechanisms in the 20% of meningiomas without known driver mutations are still unknown. Progestin agonists (PA) like cyproterone acetate lead to a significant increase of meningioma development, with patients presenting multiple meningiomas generally located at the skull base. These lesions can stop growing or even decrease when PA are stopped. In this work, we provide new insights in meningioma initiation mechanism through the description of the mutational landscape of normal meninges. Thanks to ultradeep targeted exome sequencing of normal samples of dura mater and arachnoid, we describe that mutations of NF2 and TRAF7 genes, the two main driver genes of meningiomas, are present at very low frequency in normal meninges. Our results suggest that mutant clones are present physiologically in the meninges without any micro or macroscopic signs of meningioma formation. In the second part, we present a multi-omic analysis (WES, RNA seq and methylation study) of multiple meningiomas in patients under PA or not. We report that PA have a fundamental role in meningioma initiation: they induce the apparition of MM belonging to the non-NF2 mutational subgroups (TRAF7 and PIK3). Moreover, MM have a monoclonal origin while they harbor different driver mutations, suggesting a non-mutational initiating event. Transcriptional study reveal that PA are associated with the expression of both endometrial markers and genes described in endometrial response to progesterone. This modified response to progesterone reflects the morphological changes of hormonal induced meningiomas, that show a pseudo-microcystic aspect with edematous extra cellular matrix and dilated blood vessels. Taken together, these results suggest that PA affect the cellular and tissular architecture rather than increase proliferation, leading to reversible changes when PA are stopped.Les méningiomes sont les tumeurs primitives les plus fréquentes du système nerveux central. Cependant, certaines questions restent toujours non résolues. Ainsi, la cellule d’origine des méningiomes n’est toujours pas formellement identifiée, le timing des évènements biologiques menant à l’apparition de méningiomes n’est pas connu, et le mécanisme de genèse des méningiomes sans mutation driver retrouvée (20% des cas) est inconnu. Les agonistes progestatifs sont associés à un sur-risque de développer des méningiomes multiples (MM) à la base du crâne. Dans la première partie de cette thèse, nous présentons les premières données de caractérisation mutationnelle de la méninge « normale ». Nous rapportons que des mutations intéressant les deux gènes driver principaux des méningiomes (NF2 et TRAF7) étaient présents chez 4 sujets sur 5. Nos données sont en faveur de la présence de clones mutés au sein de la méninge, dont la transition vers le développement de méningiomes serait conditionnée à la survenue d’autres mécanismes (co- mutations, dérégulation épigénétique, influence de facteurs exogènes…). Dans une deuxième partie, nous avons caractérisé par séquençage d’exome, d’ARN, et étude de méthylation une cohorte de MM développés avec ou sans agonistes progestatifs (AP). La prise d’AP a un effet très important dans l’initiation de la tumorigenèse, puisqu’elle oriente les méningiomes vers des sous-types mutationnels spécifiques, et promeut le développement de MM ayant une origine monoclonale malgré des mutations initiatrices différentes. L’étude du profil transcriptionnel des méningiomes montre que la prise d’AP est associée à l’expression de marqueurs endométriaux, et à un profil de réponse à la progestérone habituellement décrit dans les cellules endométriales. Enfin nous montrons que la prise d’AP oriente les méningiomes vers des modifications morphologiques, avec un aspect « pseudo-micro kystique », marqué par un œdème de la matrice extracellulaire et la présence de vaisseaux sanguins béant. Cet aspect, potentiellement réversible à l’arrêt des AP, pourrait expliquer en partie la possibilité de régression des méningiomes à l’arrêt des AP

Impact de la prise d’agonistes progestatifs sur les mécanismes de l’initiation et de la croissance tumorale des méningiomes

Meningioma are the most frequent tumors in the central nervous system. However, the cell of origin, the timing of initiating events, or the initiation mechanisms in the 20% of meningiomas without known driver mutations are still unknown. Progestin agonists (PA) like cyproterone acetate lead to a significant increase of meningioma development, with patients presenting multiple meningiomas generally located at the skull base. These lesions can stop growing or even decrease when PA are stopped. In this work, we provide new insights in meningioma initiation mechanism through the description of the mutational landscape of normal meninges. Thanks to ultradeep targeted exome sequencing of normal samples of dura mater and arachnoid, we describe that mutations of NF2 and TRAF7 genes, the two main driver genes of meningiomas, are present at very low frequency in normal meninges. Our results suggest that mutant clones are present physiologically in the meninges without any micro or macroscopic signs of meningioma formation. In the second part, we present a multi-omic analysis (WES, RNA seq and methylation study) of multiple meningiomas in patients under PA or not. We report that PA have a fundamental role in meningioma initiation: they induce the apparition of MM belonging to the non-NF2 mutational subgroups (TRAF7 and PIK3). Moreover, MM have a monoclonal origin while they harbor different driver mutations, suggesting a non-mutational initiating event. Transcriptional study reveal that PA are associated with the expression of both endometrial markers and genes described in endometrial response to progesterone. This modified response to progesterone reflects the morphological changes of hormonal induced meningiomas, that show a pseudo-microcystic aspect with edematous extra cellular matrix and dilated blood vessels. Taken together, these results suggest that PA affect the cellular and tissular architecture rather than increase proliferation, leading to reversible changes when PA are stopped.Les méningiomes sont les tumeurs primitives les plus fréquentes du système nerveux central. Cependant, certaines questions restent toujours non résolues. Ainsi, la cellule d’origine des méningiomes n’est toujours pas formellement identifiée, le timing des évènements biologiques menant à l’apparition de méningiomes n’est pas connu, et le mécanisme de genèse des méningiomes sans mutation driver retrouvée (20% des cas) est inconnu. Les agonistes progestatifs sont associés à un sur-risque de développer des méningiomes multiples (MM) à la base du crâne. Dans la première partie de cette thèse, nous présentons les premières données de caractérisation mutationnelle de la méninge « normale ». Nous rapportons que des mutations intéressant les deux gènes driver principaux des méningiomes (NF2 et TRAF7) étaient présents chez 4 sujets sur 5. Nos données sont en faveur de la présence de clones mutés au sein de la méninge, dont la transition vers le développement de méningiomes serait conditionnée à la survenue d’autres mécanismes (co- mutations, dérégulation épigénétique, influence de facteurs exogènes…). Dans une deuxième partie, nous avons caractérisé par séquençage d’exome, d’ARN, et étude de méthylation une cohorte de MM développés avec ou sans agonistes progestatifs (AP). La prise d’AP a un effet très important dans l’initiation de la tumorigenèse, puisqu’elle oriente les méningiomes vers des sous-types mutationnels spécifiques, et promeut le développement de MM ayant une origine monoclonale malgré des mutations initiatrices différentes. L’étude du profil transcriptionnel des méningiomes montre que la prise d’AP est associée à l’expression de marqueurs endométriaux, et à un profil de réponse à la progestérone habituellement décrit dans les cellules endométriales. Enfin nous montrons que la prise d’AP oriente les méningiomes vers des modifications morphologiques, avec un aspect « pseudo-micro kystique », marqué par un œdème de la matrice extracellulaire et la présence de vaisseaux sanguins béant. Cet aspect, potentiellement réversible à l’arrêt des AP, pourrait expliquer en partie la possibilité de régression des méningiomes à l’arrêt des AP

Tumoral initiation mechanisms and biologic effects of progestin agonists on meningiomas

Les méningiomes sont les tumeurs primitives les plus fréquentes du système nerveux central. Cependant, certaines questions restent toujours non résolues. Ainsi, la cellule d’origine des méningiomes n’est toujours pas formellement identifiée, le timing des évènements biologiques menant à l’apparition de méningiomes n’est pas connu, et le mécanisme de genèse des méningiomes sans mutation driver retrouvée (20% des cas) est inconnu. Les agonistes progestatifs sont associés à un sur-risque de développer des méningiomes multiples (MM) à la base du crâne. Dans la première partie de cette thèse, nous présentons les premières données de caractérisation mutationnelle de la méninge « normale ». Nous rapportons que des mutations intéressant les deux gènes driver principaux des méningiomes (NF2 et TRAF7) étaient présents chez 4 sujets sur 5. Nos données sont en faveur de la présence de clones mutés au sein de la méninge, dont la transition vers le développement de méningiomes serait conditionnée à la survenue d’autres mécanismes (co- mutations, dérégulation épigénétique, influence de facteurs exogènes…). Dans une deuxième partie, nous avons caractérisé par séquençage d’exome, d’ARN, et étude de méthylation une cohorte de MM développés avec ou sans agonistes progestatifs (AP). La prise d’AP a un effet très important dans l’initiation de la tumorigenèse, puisqu’elle oriente les méningiomes vers des sous-types mutationnels spécifiques, et promeut le développement de MM ayant une origine monoclonale malgré des mutations initiatrices différentes. L’étude du profil transcriptionnel des méningiomes montre que la prise d’AP est associée à l’expression de marqueurs endométriaux, et à un profil de réponse à la progestérone habituellement décrit dans les cellules endométriales. Enfin nous montrons que la prise d’AP oriente les méningiomes vers des modifications morphologiques, avec un aspect « pseudo-micro kystique », marqué par un œdème de la matrice extracellulaire et la présence de vaisseaux sanguins béant. Cet aspect, potentiellement réversible à l’arrêt des AP, pourrait expliquer en partie la possibilité de régression des méningiomes à l’arrêt des AP.Meningioma are the most frequent tumors in the central nervous system. However, the cell of origin, the timing of initiating events, or the initiation mechanisms in the 20% of meningiomas without known driver mutations are still unknown. Progestin agonists (PA) like cyproterone acetate lead to a significant increase of meningioma development, with patients presenting multiple meningiomas generally located at the skull base. These lesions can stop growing or even decrease when PA are stopped. In this work, we provide new insights in meningioma initiation mechanism through the description of the mutational landscape of normal meninges. Thanks to ultradeep targeted exome sequencing of normal samples of dura mater and arachnoid, we describe that mutations of NF2 and TRAF7 genes, the two main driver genes of meningiomas, are present at very low frequency in normal meninges. Our results suggest that mutant clones are present physiologically in the meninges without any micro or macroscopic signs of meningioma formation. In the second part, we present a multi-omic analysis (WES, RNA seq and methylation study) of multiple meningiomas in patients under PA or not. We report that PA have a fundamental role in meningioma initiation: they induce the apparition of MM belonging to the non-NF2 mutational subgroups (TRAF7 and PIK3). Moreover, MM have a monoclonal origin while they harbor different driver mutations, suggesting a non-mutational initiating event. Transcriptional study reveal that PA are associated with the expression of both endometrial markers and genes described in endometrial response to progesterone. This modified response to progesterone reflects the morphological changes of hormonal induced meningiomas, that show a pseudo-microcystic aspect with edematous extra cellular matrix and dilated blood vessels. Taken together, these results suggest that PA affect the cellular and tissular architecture rather than increase proliferation, leading to reversible changes when PA are stopped

Predictive Evolution Factors of Incidentally Discovered Suspected Low-Grade Gliomas: Results From a Consecutive Series of 101 Patients

International audienceBackground: Incidentally discovered suspected diffuse low-grade gliomas (LGGs) on brain imaging pose a challenge to neurosurgeons. Modern surgical series of LGGs favor early prophylactic surgery with a maximal extent of resection. However, some nonevolutive lesions may mimic LGGs on magnetic resonance imaging (MRI).Objective: To determine objective criteria to advocate surgical resection of an incidentally discovered suspected LGG based upon MRI findings.Methods: The prospective cohort of patients referred to our institution for an incidental finding suggestive of LGG was retrospectively reviewed. Stable lesions underwent systematic serial MRI follow-up, while evolutive lesions underwent prophylactic surgery under awake conditions. Initial clinico-radiological features were compared between stable and evolutive lesions in order to determine predictive criteria of further evolution.Results: Among 101 patients referred for surgical resection of incidentally discovered suspected LGG in our center, 19 patients (18.8%) had nonevolutive MRI lesions after a mean follow-up of 46.9 ± 34.9 mo. Insular topography (P = .003), higher mean volume at discovery (19.2 vs 5.2 cm3, P < .001), and adjacent sulcal effacement (P = .001) were associated with evolutive lesions. Histopathological diagnosis of LGG was confirmed in all surgical cases.Conclusion: Increasing volume is an effective predictor of LGG diagnosis in incidental MRI findings, as all patients who subsequently underwent surgery had confirmed histopathological diagnosis of diffuse glioma. Approximately 18.8% of incidental findings were stable over time. Insular topography, adjacent sulcal effacement, and volume greater than 4.5 cm3 were predictive of further radiological progression. These significant elements will help neurosurgeons to define personalized strategies in this complex setting of incidental discovery

Mouse Models in Meningioma Research: A Systematic Review

International audienceMeningiomas are the most frequent primitive central nervous system tumors found in adults. Mouse models of cancer have been instrumental in understanding disease mechanisms and establishing preclinical drug testing. Various mouse models of meningioma have been developed over time, evolving in light of new discoveries in our comprehension of meningioma biology and with improvements in genetic engineering techniques. We reviewed all mouse models of meningioma described in the literature, including xenograft models (orthotopic or heterotopic) with human cell lines or patient derived tumors, and genetically engineered mouse models (GEMMs). Xenograft models provided useful tools for preclinical testing of a huge range of innovative drugs and therapeutic options, which are summarized in this review. GEMMs offer the possibility of mimicking human meningiomas at the histological, anatomical, and genetic level and have been invaluable in enabling tumorigenesis mechanisms, including initiation and progression, to be dissected. Currently, researchers have a range of different mouse models that can be used depending on the scientific question to be answered

Bow Hunter's Syndrome: Surgical Vertebral Artery Decompression Guided by Dynamic Intraoperative Angiography

International audienceBACKGROUND: Bow hunter's syndrome is a symptomatic vertebrobasilar insufficiency resulting from a rotational stenosis or occlusion of a dominant vertebral artery (VA). The VA is dynamically compressed by cervical osteoarthritis (discovertebral structure or osteophytes) during head rotation or neck extension. Diagnosis is based on dynamic computed tomography angiography and confirmed with dynamic catheter angiography. Surgery tends to be the best treatment option in most cases. Dynamic intraoperative assessment of VA decompression seems to improve surgical results but remains poorly evaluated in the literature. CASE DESCRIPTION: A 70-year-old man with bow hunter's syndrome related to left VA compression by C3-4 osteophyte protrusion presented with syncopal episodes during left head rotation. Bow hunter's syndrome was successfully managed with an anterior transuncal surgical decompression of the left VA and C3-4 fusion. Surgical decompression was guided by dynamic intraoperative catheter angiography and secured with an intra-arterial remodeling balloon placed just before surgery. The patient was symptom-free after surgery. CONCLUSIONS: Surgical decompression guided by dynamic intraoperative catheter angiography leads to selective VA release and allows real-time assessment of the efficacy of the decompression. This multidisciplinary treatment involving neurosurgical and neuroradiologic teams is a simple and effective treatment. Dynamic intraoperative catheter angiography is an essential guide to perform selective decompression of the VA, and implementation of an intra-arterial remodeling balloon can improve the safety of surgery making this method valuable compared with other intraoperative assessment techniques, such as Doppler ultrasound and indocyanine green fluorescent videography

Electrocorticography Is Not Necessary During Awake Brain Surgery for Gliomas

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Low Rate of Intraoperative Seizures During Awake Craniotomy in a Prospective Cohort with 374 Supratentorial Brain Lesions: Electrocorticography Is Not Mandatory

International audienceOBJECTIVE:Awake craniotomy (AC) in brain lesions has allowed an improvement of both oncologic and functional results. However, intraoperative seizures (IOSs) were reported as a cause of failure of AC. Here, we analyze the incidence, risk factors, and consequences of IOSs in a prospective cohort of 374 ACs without electrocorticography (ECoG).METHODS:We performed a prospective study including all patients who underwent AC for an intra-axial supratentorial cerebral lesion from 2009-2014 in our department. Occurrence of IOS was analyzed with respect to medical and epilepsy history, tumor characteristics, operative technique, and postoperative outcomes.RESULTS:The study comprised 374 patients with a major incidence of low-grade glioma (86%). Most of the patients (83%) had epilepsy history before surgery (20% had intractable seizures). Preoperative mean Karnofsky performance scale (KPS) score was 91. IOSs occurred in 13 patients (3.4%). All IOSs were partial seizures, which quickly resolved by irrigation with cold Ringer lactate. No procedure failed because of IOS, and the rate of aborted AC whatever the cause was nil. Mean stimulation current intensity for cortical and subcortical mapping was 2.25 ± 0.6 mA. Presurgical refractory epilepsy was not associated with a higher incidence of IOS. Three months after surgery, no patients had severe or disabling permanent worsening, even within the IOS group (mean KPS score of 93.7).CONCLUSIONS:AC for intra-axial brain lesion can be safely and reproducibly achieved without ECoG, with a low rate of IOS and excellent functional results, even in patients with preoperative intractable epilepsy

Is hospital information system relevant to detect surgical site infection? Findings from a prospective surveillance study in posterior instrumented spinal surgery

International audienceOBJECT:Spinal instrumentation has a high rate of surgical site infection (SSI), but results greatly vary depending on surveillance methodology, surgical procedures, or quality of follow-up. Our aim was to study true incidence of SSI in spinal surgery by significant data collection, and to compare it with the results obtained through the hospital information system.METHODS:This work is a single center prospective cohort study that included all patients consecutively operated on for spinal instrumentation by posterior approach over a six-month period regardless the etiology. For all patients, a "high definition" prospective method of surveillance was performed by the infection control (IC) department during at least 12 months after surgery. Results were then compared with findings from automatic surveillance though the hospital information system (HIS).RESULTS:One hundred and fifty-four patients were included. We found no hardly difference between "high definition" and automatic surveillance through the HIS, even if HIS tended to under-estimate the infection rate: rate of surgical site infection was 2.60% and gross SSI incidence rate via the hospital information system was 1.95%. Smoking and alcohol consumption were significantly related to a SSI.CONCLUSION:Our SSI rates to reflect the true incidence of infectious complications in posterior instrumented adult spinal surgery in our hospital and these results were consistent with the lower levels of published infection rate. In-house surveillance by surgeons only is insufficiently sensitive. Further studies with more patients and a longer inclusion time are needed to conclude if SSI case detection through the HIS could be a relevant and effective alternative method

Robot-assisted spine surgery: feasibility study through a prospective case-matched analysis

International audiencePURPOSE:While image guidance and neuronavigation have enabled a more accurate placement of pedicle implants, they can inconvenience the surgeon. Robot-assisted placement of pedicle screws appears to overcome these disadvantages. However, recent data concerning the superiority of currently available robots in assisting spinal surgeons are conflicting. The aim of our study was to evaluate the percentage of accurately placed pedicle screws, inserted using a new robotic-guidance system.METHOD:20 Patients were operated on successively by the same surgeon using robotic assistance (ROSA™, Medtech) (Rosa group 10 patients, n = 40 screws) or by the freehand conventional technique (Freehand group 10 patients, n = 50 screws). Patient characteristics as well as the duration of the operation and of exposure to X rays were recorded.RESULTS:The mean age of patients in each group (RG and FHG) was 63 years. Mean BMI and operating time among the RG and FHG were, respectively, 26 and 27 kg/m(2), and 187 and 119 min. Accurate placement of the implant (score A and B of the Gertzbein Robbins classification) was achieved in 97.3% of patients in the RG (n = 36) and in 92% of those in the FHG (n = 50). Four implants in the RG were placed manually following failed robotic assistance.CONCLUSION:We report a higher rate of precision with robotic as compared to the FH technique. Providing assistance by permanently monitoring the patient's movements, this image-guided tool helps more accurately pinpoint the pedicle entry point and control the trajectory. Limitations of the study include its small sized and non-randomized sample. Nevertheless, these preliminary results are encouraging for the development of new robotic techniques for spinal surgery