Publications by authors named "Stephane Goutagny"

27 Publications

  • Page 1 of 1

Security and reliability of CUSTOMBONE cranioplasties: a prospective multicentric study.

Neurochirurgie 2021 Mar 2. Epub 2021 Mar 2.

Neurosurgery department, Hôpital de Lariboisière, APHP, Paris, France.

Background: Repairing bone defects generated by craniectomy is a major therapeutic challenge in terms of bone consolidation as well as functional and cognitive recovery. Furthermore, these surgical procedures are often grafted with complications such as infections, breaches, displacements and rejections leading to failure and thus explantation of the prosthesis.

Objective: To evaluate cumulative explantation and infection rates following the implantation of a tailored cranioplasty CUSTOMBONE prosthesis made of porous hydroxyapatite. One hundred and ten consecutive patients requiring cranial reconstruction for a bone defect were prospectively included in a multicenter study constituted of 21 centres between December 2012 and July 2014. Follow-up lasted 2 years.

Results: Mean age of patients included in the study was 42 ± 15 years old (y.o), composed mainly by men (57.27%). Explantations of the CUSTOMBONE prosthesis were performed in 13/110 (11.8%) patients, significantly due to infections: 9/13 (69.2%) (p<0.0001), with 2 (15.4%) implant fracture, 1 (7.7%) skin defect and 1 (7.7%) following the mobilization of the implant. Cumulative explantation rates were successively 4.6% (SD 2.0), 7.4% (SD 2.5), 9.4% (SD 2.8) and 11.8% (SD 2.9%) at 2, 6, 12 and 24 months. Infections were identified in 16/110 (14.5%): 8/16 (50%) superficial and 8/16 (50%) deep. None of the following elements, whether demographic characteristics, indications, size, location of the implant, redo surgery, co-morbidities or medical history, were statistically identified as risk factors for prosthesis explantation or infection.

Conclusion: Our study provides relevant clinical evidence on the performance and safety of CUSTOMBONE prosthesis in cranial procedures. Complications that are difficulty incompressible mainly occur during the first 6 months, but can appear at a later stage (> 1 year). Thus assiduous, regular and long-term surveillances are necessary.
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http://dx.doi.org/10.1016/j.neuchi.2021.02.007DOI Listing
March 2021

Validation of a scoring system to evaluate the risk of rapid growth of intracranial meningiomas in neurofibromatosis type 2 patients.

J Neurosurg 2020 May 22:1-9. Epub 2020 May 22.

1Department of Neurosurgery and.

Objective: Intracranial meningiomas occur in about half of neurofibromatosis type 2 (NF2) patients and are very frequently multiple. Thus, estimating individual meningiomas' growth rates is of great interest to tailor therapeutic interventions. The Asan Intracranial Meningioma Scoring System (AIMSS) has recently been published to estimate the risk of tumor growth in sporadic meningiomas. The current study aimed to determine predictors of rapid meningioma growth in NF2 patients and to evaluate the AIMSS score in a specific NF2 cohort.

Methods: The authors performed a retrospective analysis of 92 NF2 patients with 358 measured intracranial meningiomas that had been observed prospectively between 2012 and 2018. Tumor volumes were measured at diagnosis and at each follow-up visit. The growth rates were determined and evaluated with respect to the clinicoradiological parameters. Predictors of rapid tumor growth (defined as growth ≥ 2 cm3/yr) were analyzed using univariate followed by multivariate logistic regression to build a dedicated predicting model. Receiver operating characteristic (ROC) curves to predict the risk of rapid tumor growth with the AIMSS versus the authors' multivariate model were compared.

Results: Sixty tumors (16.76%) showed rapid growth. After multivariate analysis, a larger tumor volume at diagnosis (p < 0.0001), presence of peritumoral edema (p = 0.022), absence of calcifications (p < 0.0001), and hyperintense or isointense signal on T2-weighted MRI (p < 0.005) were statistically significantly associated with rapid tumor growth. It is particularly notable that the genetic severity score did not seem to influence the growth rate of NF2 meningiomas. In comparison with the AIMSS, the authors' multivariate model's prediction did not show a statistically significant difference (area under the curve [AUC] 0.82 [95% CI 0.76-0.88] for the AIMSS vs AUC 0.86 [95% CI 0.81-0.91] for the authors' model, p = 0.1).

Conclusions: The AIMSS score is valid in the authors' cohort of NF2-related meningiomas. It adequately predicted risk of rapid meningioma growth and could aid in decision-making in NF2 patients.
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http://dx.doi.org/10.3171/2020.3.JNS192382DOI Listing
May 2020

Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis.

J Neurol Neurosurg Psychiatry 2020 04 10;91(4):378-387. Epub 2020 Feb 10.

Department of Neurosurgery, Copenhagen, Copenhagen University Hospital, Denmark.

Background: gene alterations (-alt) have been linked to increased risk of recurrence in meningiomas, whereas the association to mortality largely remain incompletely investigated. As incongruence between clinical course and WHO grade exists, reliable biomarkers have been sought.

Methods: We applied the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data Statement. We compiled data from eight studies and allocated patients to -alt (n=59) or promoter wild-type (p-wt; n=618). We compared the two groups stratified for WHO grades as: incidence rates, survival probabilities and cumulative recurrences. We estimated the effects of WHO grade, age at diagnosis and sex as HRs.

Results: -alt occurred in 4.7%, 7.9% and 15.4% of WHO-I/WHO-II/WHO-III meningiomas, respectively. The median recurrence-free survival was 14 months for all alt patients versus 101 months for all p-wt patients. The HR for -alt was 3.74 in reference to p-wt. For all -alt patients versus all p-wt patients, the median overall survival was 58 months and 160 months, respectively. The HR for -alt was 2.77 compared with p-wt. -alt affected prognosis independent of WHO grades. Particularly, the recurrence rate was 4.8 times higher in WHO-I/-II -alt patients compared with WHO-III p-wt patients. The mortality rate was 2.7 times higher in the WHO-I and WHO-II -alt patients compared with WHO-III p-wt patients.

Conclusions: -alt is an important biomarker for significantly higher risk of recurrence and death in meningiomas. -alt should be managed and surveilled aggressively. We propose that -alt analysis should be implemented as a routine diagnostic test in meningioma and integrated into the WHO classification.

Trial Registration Number: PROSPERO: CRD42018110566.
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http://dx.doi.org/10.1136/jnnp-2019-322257DOI Listing
April 2020

Surface reconstruction from routine CT-scan shows large anatomical variations of falx cerebri and tentorium cerebelli.

Acta Neurochir (Wien) 2021 Mar 7;163(3):607-613. Epub 2020 Feb 7.

Neurosurgery, Assistance Publique Hôpitaux de Paris, Hôpital Beaujon, 100 boulevard du Général Leclerc, 92110, Clichy, France.

Background: Finite element modeling of the human head offers an alternative to experimental methods in understanding the biomechanical response of the head in trauma brain injuries. Falx, tentorium, and their notches are important structures surrounding the brain, and data about their anatomical variations are sparse.

Objective: To describe and quantify anatomical variations of falx cerebri, tentorium cerebelli, and their notches.

Methods: 3D reconstruction of falx and tentorium was performed by points identification on 40 brain CT-scans in a tailored Matlab program. A scatter plot was obtained for each subject, and 8 anatomical landmarks were selected. A reference frame was defined to determine the coordinates of landmarks. Segments and areas were computed. A reproducibility study was done.

Results: The height of falx was 34.9 ± 3.9 mm and its surface area 56.5 ± 7.7 cm. The width of tentorium was 99.64 ± 4.79 mm and its surface area 57.6 ± 5.8 cm. The mean length, height, and surface area of falx notch were respectively 96.9 ± 8 mm, 41.8 ± 5.9 mm, and 28.8 ± 5.8 cm (range 15.8-40.5 cm). The anterior and maximal widths of tentorial notch were 25.5 ± 3.5 mm and 30.9 ± 2.5 mm; its length 54.9 ± 5.2 mm and its surface area 13.26 ± 1.6 cm. The length of falx notch correlated with the length of tentorial notch (r = 0.62, P < 0.05).

Conclusion: We observe large anatomical variations of falx, tentorium, and notches, crucial to better understand the biomechanics of brain injury, in personalized finite element models.
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http://dx.doi.org/10.1007/s00701-020-04256-2DOI Listing
March 2021

More complications in cervical than in non-cervical spine tuberculosis.

Infect Dis (Lond) 2020 03 13;52(3):170-176. Epub 2019 Nov 13.

Service de Médecine Interne, Hôpital Beaujon, Assistance Publique Hôpitaux Paris Nord, Clichy, France.

Cervical spine tuberculosis (CST) is a rare disease that may lead to severe neurological complications. The goal of the study was to compare the characteristics of patients with CST with those of patients with non-cervical spine tuberculosis (NCST). Between 1997 and 2016, we reviewed all cases of proven tuberculosis from a cohort of spine infections in a tertiary care hospital. Clinical, biological, and imaging data were collected at baseline and after treatment. Fifty-one cases of spine tuberculosis were included: 14 with CST on imaging (27%) and 37 with no cervical localization. Median age was 39 y. Demographic characteristics, duration of symptoms and neurological findings of spine compression were similarly present at presentation in CST and NCST patients. On imaging, lesions were more often multifocal in CST than in NCST patients (9/14 [64%] versus 10/37 [27%],  = .014). Spinal surgery was required in 32/51 (63%) patients. At the end of follow-up (median: 20 months), cure rates were similar in CST and NCST patients but motor and/or sensitive functional sequel were more frequent in CST than NCST patients (6/14 [43%] versus 2/37 [5%],  = .003). Cervical involvement is present in more than a quarter of patients with spinal tuberculosis. Patients with CST had more frequent neurological sequelae than patients with NCST. This was mainly due to a more multifocal disease at presentation. Screening for cervical localization should be systematic in patients with spinal tuberculosis even in the absence of cervical symptoms.
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http://dx.doi.org/10.1080/23744235.2019.1690675DOI Listing
March 2020

[Biomarkers of Alzheimer's disease in older and oldest old patients].

Geriatr Psychol Neuropsychiatr Vieil 2019 03;17(1):65-72

Centre de neurologie cognitive Paris-Nord, Hôpital Lariboisière-Fernand Widal, AP-HP, Paris, France, Inserm U942 BioCanVas, Hôpital Lariboisière, Paris, France.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in older patients, leading to progressive cognitive impairment. Brain amyloid and tau deposits are the main pathological features of the disease and may appear several decades before the onset of clinical symptoms. The biomarkers of AD, measured in the plasma or in the cerebrospinal fluid, reflect the brain accumulation of beta-amyloid and tau. Therefore, they enable early and more accurate etiological diagnosis when combined with brain neuroimaging and neuropsychological assessment. The new definition of AD brings biomarkers forward, shifting the focus from symptoms to brain changes in living patients. The growing body of evidence from longitudinal studies has established their ability to improve the accuracy of AD diagnosis but also to predict the progression of cognitive impairment. The biomarkers of AD are also important for recruiting participants who are at increased risk of developing AD dementia in drug trials. Beyond their role in clinical research, these tools have been increasingly used for several years in clinical practice in secondary and tertiary-referral memory clinics. However, interpreting the results of AD biomarkers may be delicate in the oldest old patients with comorbidity. A tailored, patient-centered decision is mandatory in these situations. Complicated ethical issues may also arise in using these biomarkers in asymptomatic subjects. In the absence of clear guidelines for their utilization, we hereby discuss their potential interests and limitations in older adults.
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http://dx.doi.org/10.1684/pnv.2019.0779DOI Listing
March 2019

The molecular landscape of glioma in patients with Neurofibromatosis 1.

Nat Med 2019 01 10;25(1):176-187. Epub 2018 Dec 10.

Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.
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http://dx.doi.org/10.1038/s41591-018-0263-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857804PMC
January 2019

Distribution of Cerebrospinal Fluid Biomarker Profiles in Patients Explored for Cognitive Disorders.

J Alzheimers Dis 2018 ;64(3):889-897

Background: CSF Alzheimer's disease (AD) biomarkers allow classifying individuals based on their levels of amyloid and neurodegeneration pathologies.

Objective: To investigate the distribution of AD biomarker profiles from patients suffering from cognitive disorders.

Methods: We analyzed 3001 patients with cognitive disorders and referred by 18 French memory clinics located in and around Paris. Patients were classified as normal, amyloidosis (A+/N-), amyloidosis and neurodegeneration (A+/N+) or suspected non-AD pathophysiology (SNAP), according to their CSF levels of biomarkers. Analysis were performed for the overall population and stratified by gender, age quintiles, and Mini-Mental State Examination (MMSE) score quintiles. Results were compared to previous findings in cohorts of healthy elderly adults.

Results: 37% of the sample were classified as A+/N+, 22% were classified A+/N-, and 15% as SNAP. The A+/N+ profile was associated with female gender, advanced age, and lower MMSE score, while the A+/N-profile was observed more frequently in men and the distribution was stable across age and MMSE. The SNAP profile showed no association with gender or age, was less frequent in patients with lower MMSE, and had a lower repartition than the one previously reported in asymptomatic populations.

Conclusions: While A+/N+ patients had the clinical characteristics typically observed in AD, A+/N-patients had a different epidemiological pattern (higher frequency in men, no association with advanced age or lower MMSE). The SNAP profile was less frequent than previously reported in the general elderly population, suggesting that this profile is not a frequent cause of memory impairment in this population.
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http://dx.doi.org/10.3233/JAD-180240DOI Listing
July 2019

Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis.

Neuro Oncol 2018 06;20(7):917-929

Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: Clinical overlap between neurofibromatosis type 2 (NF2), schwannomatosis, and meningiomatosis can make clinical diagnosis difficult. Hence, molecular investigation of germline and tumor tissues may improve the diagnosis.

Methods: We present the targeted next-generation sequencing (NGS) of NF2, SMARCB1, LZTR1, SMARCE1, and SUFU tumor suppressor genes, using an amplicon-based approach. We analyzed blood DNA from a cohort of 196 patients, including patients with NF2 (N = 79), schwannomatosis (N = 40), meningiomatosis (N = 12), and no clearly established diagnosis (N = 65). Matched tumor DNA was analyzed when available. Forty-seven NF2-/SMARCB1-negative schwannomatosis patients and 27 NF2-negative meningiomatosis patients were also evaluated.

Results: A NF2 variant was found in 41/79 (52%) NF2 patients. SMARCB1 or LZTR1 variants were identified in 5/40 (12.5%) and 13/40 (∼32%) patients in the schwannomatosis cohort. Potentially pathogenic variants were found in 12/65 (18.5%) patients with no clearly established diagnosis. A LZTR1 variant was identified in 16/47 (34%) NF2/SMARCB1-negative schwannomatosis patients. A SMARCE1 variant was found in 3/39 (∼8%) meningiomatosis patients. No SUFU variant was found in the cohort. NGS was an effective and sensitive method to detect mutant alleles in blood or tumor DNA of mosaic NF2 patients. Interestingly, we identified a 4-hit mechanism resulting in the complete NF2 loss-of-function combined with SMARCB1 and LZTR1 haploinsufficiency in two-thirds of tumors from NF2 patients.

Conclusions: Simultaneous investigation of NF2, SMARCB1, LZTR1, and SMARCE1 is a key element in the differential diagnosis of NF2, schwannomatosis, and meningiomatosis. The targeted NGS strategy is suitable for the identification of NF2 mosaicism in blood and for the investigation of tumors from these patients.
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http://dx.doi.org/10.1093/neuonc/noy009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007397PMC
June 2018

A 4-year phase II study of everolimus in NF2 patients with growing vestibular schwannomas.

J Neurooncol 2017 Jun 22;133(2):443-445. Epub 2017 Apr 22.

Neurochirurgie, Hôpital Pitié Salpêtrière, Assistance Publique Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75013, Paris, France.

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http://dx.doi.org/10.1007/s11060-017-2447-3DOI Listing
June 2017

A 19-year-old male with a well-demarcated parieto-occipital mass.

Brain Pathol 2017 05;27(3):401-402

Department of Neurosurgery, Assistance Publique Hôpitaux de Paris, Hôpital Beaujon, Clichy, France.

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http://dx.doi.org/10.1111/bpa.12509DOI Listing
May 2017

Mechanism-based modeling of the clinical effects of bevacizumab and everolimus on vestibular schwannomas of patients with neurofibromatosis type 2.

Cancer Chemother Pharmacol 2016 06 4;77(6):1263-73. Epub 2016 May 4.

Inria, Project Team NuMed, Ecole Normale Supérieure de Lyon, Lyon, France.

Purpose: To describe the natural growth of vestibular schwannoma in patients with neurofibromatosis type 2 and to predict tumor volume evolution in patients treated with bevacizumab and everolimus.

Methods: Clinical data, including longitudinal tumor volumes in patients treated by bevacizumab (n = 13), everolimus (n = 7) or both (n = 2), were analyzed by means of mathematical modeling techniques. Together with clinical data, data from the literature were also integrated to account for drugs mechanisms of action.

Results: We developed a model of vestibular schwannoma growth that takes into account the effect of vascular endothelial growth factors and mammalian target of rapamycin complex 1 on tumor growth. Behaviors, such as tumor growth rebound following everolimus treatment stops, was correctly described with the model. Preliminary results indicate that the model can be used to predict, based on early tumor volume dynamic, tumor response to variation in treatment dose and regimen.

Conclusion: The developed model successfully describes tumor volume growth before and during bevacizumab and/or everolimus treatment. It might constitute a rational tool to predict patients' response to these drugs, thus potentially improving management of this disease.
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http://dx.doi.org/10.1007/s00280-016-3046-2DOI Listing
June 2016

PDGF activation in PGDS-positive arachnoid cells induces meningioma formation in mice promoting tumor progression in combination with Nf2 and Cdkn2ab loss.

Oncotarget 2015 Oct;6(32):32713-22

Department of Neurosurgery, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.

The role of PDGF-B and its receptor in meningeal tumorigenesis is not clear. We investigated the role of PDGF-B in mouse meningioma development by generating autocrine stimulation of the arachnoid through the platelet-derived growth factor receptor (PDGFR) using the RCAStv-a system. To specifically target arachnoid cells, the cells of origin of meningioma, we generated the PGDStv-a mouse (Prostaglandin D synthase). Forced expression of PDGF-B in arachnoid cells in vivo induced the formation of Grade I meningiomas in 27% of mice by 8 months of age. In vitro, PDGF-B overexpression in PGDS-positive arachnoid cells lead to increased proliferation.We found a correlation of PDGFR-B expression and NF2 inactivation in a cohort of human meningiomas, and we showed that, in mice, Nf2 loss and PDGF over-expression in arachnoid cells induced meningioma malignant transformation, with 40% of Grade II meningiomas. In these mice, additional loss of Cdkn2ab resulted in a higher incidence of malignant meningiomas with 60% of Grade II and 30% of Grade III meningiomas. These data suggest that chronic autocrine PDGF signaling can promote proliferation of arachnoid cells and is potentially sufficient to induce meningiomagenesis. Loss of Nf2 and Cdkn2ab have synergistic effects with PDGF-B overexpression promoting meningioma malignant transformation.
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http://dx.doi.org/10.18632/oncotarget.5296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741724PMC
October 2015

Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas.

J Neurooncol 2015 Apr 8;122(2):313-20. Epub 2015 Jan 8.

Neurochirurgie, Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, 100 boulevard du General Leclerc, 92100, Clichy, France.

Neurofibromatosis type 2 (NF2) is a genetic disorder with bilateral vestibular schwannomas (VS) as the most frequent manifestation. Merlin, the NF2 tumor suppressor, was identified as a negative regulator of mammalian target of rapamycin complex 1. Pre-clinical data in mice showed that mTORC1 inhibition delayed growth of NF2-schwannomas. We conducted a prospective single-institution open-label phase II study to evaluate the effects of everolimus in ten NF2 patients with progressive VS. Drug activity was monitored every 3 months. Everolimus was administered orally for 12 months and, if the decrease in tumor volume was >20 % from baseline, treatment was continued for 12 additional months. Other patients stopped when completed 12 months of everolimus but were allowed to resume treatment when VS volume was >20 % during 1 year follow-up. Nine patients were evaluable. Safety was evaluated using CTCAE 3.0 criteria. After 12 months of everolimus, no reduction in volume ≥20 % was observed. Four patients had progressive disease, and five patients had stable disease with a median annual growth rate decreasing from 67 %/year before treatment to 0.5 %/year during treatment. In these patients, tumor growth resumed within 3-6 months after treatment discontinuation. Everolimus was then reintroduced and VS decreased by a median 6.8 % at 24 months. Time to tumor progression increased threefold from 4.2 months before treatment to > 12 months. Hearing was stable under treatment. The safety of everolimus was manageable. Although the primary endpoint was not reached, further studies are required to confirm the potential for stabilization of everolimus.
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http://dx.doi.org/10.1007/s11060-014-1710-0DOI Listing
April 2015

Forestier's disease presenting with dysphagia and disphonia.

Pan Afr Med J 2014 6;17:168. Epub 2014 Mar 6.

Service de Neurochirurgie, CHU Beaujon, Paris, France.

Forestier's disease, also known as diffuse idiopathic skeletal hyperostosis (DISH), is a pathology of vertebral bodies characterised by exuberant osteophytis formation. Forestier's disease is usually managed conservatively. Surgical resection of the osteophytes is reported to be an effective treatment for severe cases and/ or cases with airway obstruction. We report a 55-year-old man presenting with 6 months' progressive dysphagia and dysphonia. He was managed successfully with an anterior cervical osteophytectomy without fusion. A literature review is included.
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http://dx.doi.org/10.11604/pamj.2014.17.168.2453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119450PMC
April 2015

mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma.

Neuro Oncol 2014 Apr 10;16(4):493-504. Epub 2014 Jan 10.

House Research Institute, Center for Neural Tumor Research, Los Angeles, CA, USA (M.G., N.-X.B., J.V., F.C., K.T., R.A., L.M.F.); Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles, California (M.G.); Département de Dermatologie, Centre de référence des neurofibromatoses, Hôpital Henri-Mondor, AP-HP and EA 4393 LIC, Université Paris Est Créteil, Créteil, France (L.V.-A., P.W.); Department of Neurosurgery, AP-HP, Hopital Beaujon, Clichy, France (S.G); Department of Neurosurgery, AP-HP, Hôpital Pitié Salpêtrière, Paris Cedex 13, France (M.K.); Université Pierre et Marie Curie, Faculté de Médecine, Paris Cedex 13, France (M.K.); Unité Inserm U674, Fondation Jean Dausset, Paris, France (S.G., M.K.).

Background: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant genetic disorder, resulting in a variety of neural tumors, with bilateral vestibular schwannomas as the most frequent manifestation. Recently, merlin, the NF2 tumor suppressor, has been identified as a novel negative regulator of mammalian target of rapamycin complex 1 (mTORC1); functional loss of merlin was shown to result in elevated mTORC1 signaling in NF2-related tumors. Thus, mTORC1 pathway inhibition may be a useful targeted therapeutic approach.

Methods: We studied in vitro cell models, cohorts of mice allografted with Nf2(-/-) Schwann cells, and a genetically modified mouse model of NF2 schwannoma in order to evaluate the efficacy of the proposed targeted therapy for NF2.

Results: We found that treatment with the mTORC1 inhibitor rapamycin reduced the severity of NF2-related Schwann cell tumorigenesis without significant toxicity. Consistent with these results, in an NF2 patient with growing vestibular schwannomas, the rapalog sirolimus induced tumor growth arrest.

Conclusions: Taken together, these results constitute definitive evidence that justifies proceeding with clinical trials using mTORC1-targeted agents in selected patients with NF2 and in patients with NF2-related sporadic tumors.
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http://dx.doi.org/10.1093/neuonc/not242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956353PMC
April 2014

Recommendations for imaging tumor response in neurofibromatosis clinical trials.

Neurology 2013 Nov;81(21 Suppl 1):S33-40

From the Pediatric Oncology Branch (E.D., B.C.W.), National Cancer Institute, Bethesda, MD; Department of Neurology (S.L.A.-H.), The Children's Hospital at Westmead, Sydney, Australia; Department of Medical Genetics (D. B.-V.), Mayo Clinic, Rochester, MN; Neurosurgical Service (F.G.B.), Department of Radiology (G.J.H.), and Department of Neurology and Cancer Center (S.R.P.), Massachusetts General Hospital, Boston, MA; Department of Neuroradiology (S.C.), King's College Hospital, London, UK; Department of Genetic Medicine (D.G.E.), MAHSC, St Mary's Hospital, Manchester, UK; Division of Oncology (M.J.F.) and Department of Radiology (D.J.), The Children's Hospital of Philadelphia; Department of Pediatrics (M.J.F.), The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Department of Neurosurgery (S.G.), Hôpital Beaujon, Clichy, France; Division of Pediatric Hematology/Oncology and NYU Cancer Institute (M.A.K.), NYU Langone Medical Center, New York, NY; Department of Genetics (B.R.K.), University of Alabama at Birmingham, Birmingham, AL; Department of Neurology (V.M.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Radiology (T.Y.P.), Boston Children's Hospital, Boston, MA; and Department of Pediatrics (K.R., C.-S.S.), Riley Hospital for Children, Indianapolis, IN.

Objective: Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors.

Methods: Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members.

Results: MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies.

Conclusions: The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors.
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http://dx.doi.org/10.1212/01.wnl.0000435744.57038.afDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908340PMC
November 2013

High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression.

Brain Pathol 2014 Mar 23;24(2):184-9. Epub 2013 Dec 23.

Assistance Publique-Hôpitaux de Paris, Department of Neurosurgery, Hôpital Beaujon, Clichy, France; INSERM, Génomique Fonctionnelle des Tumeurs Solides, IUH, Paris, France.

Meningiomas are common central nervous system tumors. The World Health Organization (WHO) defines three grades, predictive of the risk of recurrence. These tumors can relapse frequently and sometimes undergo malignant transformation. Maintenance of telomere length is a key process in malignant progression, and mutations in TERT promoter have recently been identified in various types of cancer. We sequenced the TERT promoter in 85 meningiomas from 73 patients. We found a high incidence of TERT promoter mutations in patients with meningiomas undergoing malignant histological progression (28%, n = 5/18 patients). In this subset of patients with histological progression, TERT promoter mutations were found in both the lowest and the highest grade tumors, and in both NF2-mutated and nonmutated samples. In contrast, one mutation was identified in 35 meningiomas without recurrence or progression, belonging to various histological grades. This sample was an aggressive meningioma in a patient who died shortly after surgery. Interestingly, tumors showing relapse without histological progression were not mutated for TERT promoter (n = 20). Finally, TERT promoter mutations were associated with a marked increase in TERT expression. Thus, TERT promoter mutations are pivotal genetic alterations involved in malignant progression of meningiomas and could be used as a biomarker to identify meningiomas at risk of malignant transformation.
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http://dx.doi.org/10.1111/bpa.12110DOI Listing
March 2014

Conservative management of bilateral vestibular schwannomas in neurofibromatosis type 2 patients: hearing and tumor growth results.

Neurosurgery 2013 Jun;72(6):907-13; discussion 914; quiz 914

AP-HP, Hôpital Beaujon, Department of Neurosurgery, Clichy, France.

Background: As new treatment modalities develop for the management of vestibular schwannomas (VS) in patients with neurofibromatosis type 2, it remains crucial to ascertain the natural history of the disease.

Objective: To determine the relationship between hearing and tumor growth in patients undergoing conservative VS management.

Methods: Patients harboring bilateral VS with at least 1 year of radiological follow-up were selected. Conservative management was proposed based on the small tumor size and/or serviceable hearing at presentation. Tumor size was calculated by using the 2-component box model and reported as mean tumor diameter. Hearing was evaluated by using pure-tone average and the American Academy of Otololaryngologists and Head and Neck Surgery classification.

Results: Forty-six patients harboring 92 VS were included. The mean clinical and radiological follow-up times were 6.0 and 4.2 years, respectively. The mean tumor diameter was 13 mm at presentation and 20 mm at the end of follow-up. Mean tumor growth rate was 1.8 mm/year. During follow-up, 17 patients (37%) underwent surgery for VS. Surgery-free rate for VS was 88% at 5 years. The number of patients with at least 1 serviceable ear was 39 (85%) at presentation and 34 (74%) at the end of follow-up, including 22 (66%) with binaural serviceable hearing maintained. There was no statistical correlation between tumor growth rate and preservation of serviceable hearing. Tumor growth rates and age at presentation were inversely correlated.

Conclusion: This study illustrates the high variability among neurofibromatosis type 2 patients regarding hearing status and VS growth rate and justifies the choice of initial conservative management in selected cases.

Abbreviations: : AAO-HNS, American Academy of Otololaryngologists and Head and Neck Surgery classificationMTD, mean tumor diameterNF2, neurofibromatosis type 2PTA, pure-tone averageSDS, speech discrimination scoreVS, vestibular schwannomas.
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http://dx.doi.org/10.1227/NEU.0b013e31828bae28DOI Listing
June 2013

Neurofibromatosis type 2 in the elderly population: clinical and molecular features.

Am J Med Genet A 2013 Apr 15;161A(4):667-70. Epub 2013 Jan 15.

Department of Neurosurgery, NF2 Clinic, APHP, Hôpital Beaujon, Clichy, France.

Neurofibromatosis type 2 (NF2) is rare genetic disorder characterized by the development of multiple benign tumors of the nervous system. The majority of people with NF2 are diagnosed in the second or third decade of life with bilateral vestibular schwannomas. Among NF2 patients followed up in our NF2 clinic, seven patients have been diagnosed with NF2 after the age of 70 years. Bilateral vestibular schwannomas were present in 4/7 patients. No NF2 mutation was identified by blood screening, suggesting a high prevalence of NF2 somatic mosaicism. During a mean follow-up of 96 months, 8/11 vestibular schwannomas demonstrated no tumor growth, and only one patient required treatment. Other tumors, including meningiomas and other schwannomas, remained stable. One patient required shunting for secondary normal-pressure hydrocephalus. Thus, NF2 can occasionally be diagnosed in people aged 70 and older, and is characterized by a high prevalence of atypical forms and a low growth potential of tumors, arguing in favor of a wait-and-scan policy as initial management.
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http://dx.doi.org/10.1002/ajmg.a.35851DOI Listing
April 2013

Penetrating craniocerebral injury caused by a rubber bullet questions the relative harmlessness of these weapons.

Am J Emerg Med 2013 Mar 4;31(3):636.e5-7. Epub 2012 Dec 4.

Department of Neurosurgery, Hopital Beaujon, APHP, Paris, France; University Sorbonne Paris Cité, Paris, France.

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http://dx.doi.org/10.1016/j.ajem.2012.10.026DOI Listing
March 2013

Increased growth rate of a WHO grade I ganglioglioma during pregnancy.

Br J Neurosurg 2013 Feb 31;27(1):119-21. Epub 2012 Jul 31.

Service de Neurochirurgie, Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris, France.

We report the case of a 32-year-old woman with a left frontal ganglioglioma (WHO grade I). Quantitative analysis based on three dimensional magnetic resonance images revealed a threefold increase of growth rate during pregnancy as compared to pre-pregnancy, causing neurological deterioration and leading to prompt surgical treatment 3 months after delivery.
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http://dx.doi.org/10.3109/02688697.2012.703356DOI Listing
February 2013

Long-term follow-up of 287 meningiomas in neurofibromatosis type 2 patients: clinical, radiological, and molecular features.

Neuro Oncol 2012 Aug 18;14(8):1090-6. Epub 2012 Jun 18.

Department of Neurosurgery, Neurofibromatosis type 2 clinic, Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, Clichy, France.

Decision-making criteria for optimal management of meningiomas in neurofibromatosis type 2 (NF2) patients is hampered by lack of robust data, particularly long-term natural history. Seventy-four NF2 patients harboring 287 cranial meningiomas followed up for a mean period of 110.2 months were studied retrospectively. The median number of meningiomas per patient was 3. The mean maximum diameter of meningiomas at diagnosis was 14.3 mm, with a mean annual growth rate of 1.5 mm. Sixty-six percent of tumors showed no or minimal growth. In a subgroup of patients with 3D MRI, 7.3% of meningiomas (28% of patients) had a volumetric growth rate 20% or more per year. Twenty-five de novo meningiomas appeared during the follow-up (8.7%) and demonstrated a higher growth rate than other meningiomas (6.6 mm/year). Fifty-six meningiomas (23%) in 34 NF2 patients (45.9%) were operated on during the follow-up period. Among symptomatic resected meningiomas, grades II and III tumors were found in 29% and 6% of cases, respectively, with a remarkable intratumor histological heterogeneity. Single nucleotide polymorphism array analysis of 22 meningioma samples in 14 NF2 patients showed increasing chromosome instability with increasing grade, the most frequent losses being on 22q, 1p, 18q, and 6p. This study provides clues to improve tailored treatment of meningiomas: de novo and brain edema-associated meningiomas require active treatment. Future clinical trials in NF2 need to focus specifically on meningiomas as the primary endpoint and should include patients with meningiomas growing 20% or more per year in order to assess new treatments.
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http://dx.doi.org/10.1093/neuonc/nos129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408259PMC
August 2012

Increased growth rate of vestibular schwannoma after resection of contralateral tumor in neurofibromatosis type 2.

Neuro Oncol 2011 Oct 28;13(10):1125-32. Epub 2011 Jul 28.

Service de Neurochirurgie, Assistance Publique–Hôpitaux de Paris, Hôpital Beaujon, Clichy, France.

Surgical management of bilateral vestibular schwannomas (VS) in neurofibromatosis type 2 (NF2) is often difficult, especially when both tumors threaten the brainstem. When the largest tumor has been removed, the management of the contralateral VS may become puzzling. To give new insights into the growth pattern of these tumors and to determine the best time point for treatment (surgery or medical treatment), we studied radiological growth in 11 VS (11 patients with NF2) over a long period (mean duration, 7.6 years), before and after removal of the contralateral tumor while both were threatening the brainstem. We used a quantitative approach of the radiological velocity of diametric expansion (VDE) on consecutive magnetic resonance images. Before first surgery, growth patterns of both tumors were similar in 9 of 11 cases. After the first surgery, VDE of the remaining VS was significantly elevated, compared with the preoperative period (2.5 ± 2.2 vs 4.4 ± 3.4 mm/year; P = .01, by Wilcoxon test). Decrease in hearing function was associated with increased postoperative growth in 3 cases. Growth pattern of coexisting intracranial meningiomas was not modified by VS surgery on the first side. In conclusion, removal of a large VS in a patient with NF2 might induce an increase in the growth rate of the contralateral medium or large VS. This possibility should be integrated in NF2 patient management to adequately treat the second VS.
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http://dx.doi.org/10.1093/neuonc/nor101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177662PMC
October 2011

Meningiomas and neurofibromatosis.

J Neurooncol 2010 Sep 17;99(3):341-7. Epub 2010 Aug 17.

INSERM, U674, Paris, France.

Neurofibromatosis type 2 (NF2) is a rare genetic disorder predisposing to multiple benign tumors of the nervous system. Meningiomas occur in about half of NF2 patients, and are often multiple. Patients harboring seemingly isolated multiple meningiomas should be investigated to diagnose NF2 by careful familial history collection, detailed clinical examination (skin lesions and slit lamp examination of the lens), audiovestibular testing, and fine cranio-spinal Magnetic Resonance Imaging. Somatic mosaicism is frequent in NF2 and may explain a mild phenotype as, e.g. isolated multiple meningiomas. Neurofibromatosis type 1 is not associated with an increased risk of meningioma. Whether meningiomas are part of the schwannomatosis tumor phenotype or not remains debated. Meningiomas in NF2 patients are associated with a higher risk of mortality, and their treatment is challenging, but data about natural history of meningiomas in NF2 patients in the literature are sparse. Thus, knowledge of tumor behavior is essential in slow growing tumors like meningiomas, to balance the risk of treatment against the natural history of the disease, and to evaluate the efficiency of alternative therapeutics (radiation therapy or new drugs).
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http://dx.doi.org/10.1007/s11060-010-0339-xDOI Listing
September 2010

Genomic profiling reveals alternative genetic pathways of meningioma malignant progression dependent on the underlying NF2 status.

Clin Cancer Res 2010 Aug 3;16(16):4155-64. Epub 2010 Aug 3.

Université Paris 5-Descartes, Paris, France.

Purpose: Meningiomas are the most common central nervous system tumors in the population of age 35 and older. WHO defines three grades predictive of the risk of recurrence. Clinical data supporting histologic malignant progression of meningiomas are sparse and underlying molecular mechanisms are not clearly depicted.

Experimental Design: We identified genetic alterations associated with histologic progression of 36 paired meningioma samples in 18 patients using 500K SNP genotyping arrays and NF2 gene sequencing.

Results: The most frequent chromosome alterations observed in progressing meningioma samples are early alterations (i.e., present both in lower- and higher-grade samples of a single patient). In our series, NF2 gene inactivation was an early and frequent event in progressing meningioma samples (73%). Chromosome alterations acquired during progression from grade I to grade II meningioma were not recurrent. Progression to grade III was characterized by recurrent genomic alterations, the most frequent being CDKN2A/CDKN2B locus loss on 9p.

Conclusion: Meningiomas displayed different patterns of genetic alterations during progression according to their NF2 status: NF2-mutated meningiomas showed higher chromosome instability during progression than NF2-nonmutated meningiomas, which had very few imbalanced chromosome segments. This pattern of alterations could thus be used as markers in clinical practice to identify tumors prone to progress among grade I meningiomas.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-0891DOI Listing
August 2010

[Meningiomas].

Rev Prat 2006 Oct;56(16):1792-8

Service de neurochirurgie, hôpital Beaujon, 92110 Clichy.

Meningiomas account for approximately one-fourth of all primary central nervous system tumour, arising from arachnoidal cells surrounding brain and spinal cord. They usually affect older adults, particularly women. Ninety percent of meningiomas are slow growing benign tumours. Meningiomas are revealed by various symptoms including neurologic deficits and epileptic seizures. Surgery remains the treatment of choice. Fractionated radiotherapy or stereotactic radiosurgery are used for meningiomas that are recurrent, surgically inacessible, partially excised and either atypical or malignant. Most meningiomas have good long-term prognosis after treatment, some dysplay aggressive clinical behaviour leading to increased patient morbidity and mortality.
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October 2006