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PFS6 and PFS12 depending of the in intention-to-treat or per protocole analyses as investigator or central review analyses.

Table S1: Patient characteristics T : Tumor ; IK : Karnofski index; NA : Not available, SST2 : SST2 receptor expression (IRS Immunoreactivity score ) ; Conv: Convexity; RT: Radiotherapy; RS: Radiosurgery; CT chemotherapy * : for the NF2 genomic alterations, deletion and mutation of the gene were researched according to the quality of the available tumoral fragment(cf Table S4)

Study of correlation between SSTR2A receptor expression and growth rate (GR) before and under treatment as with progression. No significant correlation was observed. Immunohistochemical detection of SSTR2A protein was performed on 5 µm thick formalin fixed paraffin embedded (FFPE) tissue sections with Ventana Benchmark XT. The monoclonal SSTR2A antibody (clone UMB1, Abcam) was used at 1/4000 dilution.

Purpose:Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas.Patients and Methods:Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety.Results:A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003).Conclusions:The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.

Meningioma genes analyses The coding exons and exon-intron boundaries of 13 genes (NF2, AKT1, SMO, KLF4, TRAF7, PIK3CA, SUFU, SMARCB1, SMARCE1, CDKN2A, CDKN2B, PTEN and TERT was sequenced using the Custom QIAseq targeted DNA Panel (Qiagen, Germany) following the manufacturer's instructions. These genes were chosen according the most recent publication on whole genome sequencing or exome sequencing of meningiomas5. TheQIAseq targeted DNA panel utilizes Unique Molecular Indices (UMI)

Genes tested in molecular analysis and references

Study flow chart

Surface (2D area) growth rate before inclusion expressed in %/3months. Patients with a very high growth rate related to an initial very small tumor were not included in the pretreatement growth rate analysis.

Volume curves for all patients integrating pre and under treatment 3D volume data by central review. *patients with drugs intake < 2 months ** pre/post operative MRI non-available

Objective The aim of this study was to describe progestin-associated meningiomas’ characteristics, outcome and management. Material and methods We included 53 patients operated on and/or followed in the department for meningioma with progestin intake longer than one year and with recent drug discontinuation. Results Cyproterone acetate (CPA), nomegestrol acetate (NomA), and chlormadinone acetate (ChlA) were involved in most cases. Mean duration of progestin drugs intake was 17.5 years. Tumors were multiple in 66% of cases and were located in the anterior and the medial skull base in 71% of cases. Transitional subtype represented 16/25 tumors; 19 meningiomas were WHO grade I and 6 were grade II. The rate of transitional subtype and skull base location was significantly higher compared to matched operated meningioma general population. No difference was observed given WHO classification. But Ki67 proliferation index tends to be lower and 5/6 of the WHO grade II meningiomas were classified as WHO grade II because of brain invasion. Strong progesterone receptors expression was observed in most cases. After progestin discontinuation, a spontaneous visual recovery was observed in 6/10 patients. Under CPA (n = 24) and ChlA/NomA (n = 11), tumor volume decreased in 71% and 18% of patients, was stabilized in 25% and 64% of patients, and increased in 4% and 18% of patients, respectively. Volume outcome was related to meningioma location. Conclusions Outcome at progestins discontinuation is favorable but different comparing CPA versus ChlA-NomA and comparing tumor location. Long-term follow-up is required. In most cases, simple observation is recommended and surgery should be avoided.

Background We aimed to improve the assessment of the drug activity in meningioma clinical trials based on the study of the 3D volume growth rate (3DVGR) in a series of aggressive meningiomas. We secondarily aimed to correlate 3DVGR study with patient outcome. Methods We performed a post hoc analysis based on volume data and 3DVGR extracted from CEVOREM study including 18 patients with 32 recurrent high-grade meningiomas and treated with everolimus and octreotide. The joint latent class model was used to classify tumor 3DVGR undertreatment. Results Class 1 includes lesions responding to treatment with decrease in volume in the first 3 months, and then a stabilization thereafter (9.5% of tumors) (mean pretreatment 3DVGR = 6.13%/month; mean undertreatment 3DVGR = −18.7%/month within 3 first months and −0.14%/month after the 3 first months). Class 2 includes lesions considered as stable or with a slight increase in volume undertreatment (65.5%) (mean pretreatment 3DVGR = 6.09%/month; undertreatment 3DVGR = −0.09% within the first 3 months). Class 3 includes lesions without 3DVGR decrease (25%) (mean pretreatment 3DVGR = 46.9%/month; mean undertreatment 3DVGR = 19.2%/month within the first 3 months). Patients with class 3 lesions had a significantly worse progression-free survival (PFS) rate than class 1 and 2 ones. Conclusions Tumor 3DVGR could be helpful to detect early signal of drugs antitumoral activity or nonactivity. This volume response classification could help in the assessment of drug activity in tumors with mostly volume stabilization and rare response as aggressive meningiomas even with a low number of patients in complement to 6 months PFS.

BACKGROUND Post-operative complications do occur in all neurosurgical departments, but the way they are defined, and their true incidence vary a lot. The aim of the present study is to objectively assess the morbidity and mortality related to all neurosurgical procedures performed in our department and provide insight on their main causes and identify key factors to reduce their incidence. METHODS Data were retrieved from a prospectively-maintained database regarding all patients undergoing a cranial or spinal neurosurgical procedure between November 2016 and April 2016 in the neurosurgical department in Timone University Hospital (APHMMarseille). Patients undergoing a functional, pediatric or interventional neuroradiological procedures were not included. RESULTS The medical records of a total number of 963 patients were analyzed. A postoperative complication occurred in 208 patients (21.6%) including 115 (26.6%) in the cranial surgery group and 93 (17.5%) in the spinal surgery group. A complication occurred 1.5 more frequently in the cranial than in the spinal surgery group. Cranial surgery is 1.5 times more at risk of complications than spinal surgery (p=0.007). Preoperative comorbidities (ASA score > 3 to 4) were significantly associated with the occurrence of complications (p

Resume Objectif Rapporter les resultats chirurgicaux apres prise en charge de 5 luxations atlanto2 axoidienne post-traumatique par fracture d’une facette articulaire de C2 dans une population adulte. Materiel et methodes Les dossiers de 5 patients pris en charge depuis 2009 pour une luxation atlanto-axoidienne par fracture d’une facette de C2 ont ete analyses retrospectivement. Trois femmes et 2 hommes avec un âge moyen de 60ans (27–82) etaient inclus, dont un avec des troubles neurologiques initiaux. La strategie operatoire comportait systematiquement une fixation posterieure, de type Harms dans 4 cas et trans-articulaire associee a des crochets dans cas. Resultats Ces luxations par fracture du massif articulaire de C2 sont rares chez l’adulte et differentes strategies ont ete decrites. Dans notre experience, la fixation posterieure par vis apporte des resultats satisfaisants cliniques et radiologiques. La realisation d’une arthrodese ne semble pas necessaire car la luxation est liee a une fracture asymetrique sans lesions ligamentaires. Conclusion La realisation d’une fixation posterieure permet une reduction satisfaisante de ces lesions et permet d’obtenir une consolidation osseuse satisfaisante. Cette prise en charge chirurgicale peut etre realisee rapidement apres le traumatisme et constitue une alternative interessante a la prise en charge par traitement orthopedique.

International audience; PURPOSE: Report the results of surgical treatment of post-traumatic atlantoaxial rotatory fixation (AARF) due to C2 articular facet fracture in adults.ăMATERIAL AND METHODS: The records of five patients treated since 2009 for AARF due to a C2 articular facet fracture were analyzed retrospectively. Three women and two men with an average age of 60 years (27-82) were included, one of whom initially had neurological deficits. In all cases, the surgical strategy consisted of posterior fixation: Harms-type in four cases and trans-articular with hooks in one case.ăRESULTS: Dislocations due to fracture of the C2 articular facet are rare in adults; various treatment strategies have been described. In our experience, posterior screw fixation leads to satisfactory clinical and radiological outcomes. Fusion is not necessary in these cases because the dislocation is related to an asymmetric fracture without ligament damage.ăCONCLUSION: Posterior fixation provides satisfactory reduction of these injuries and leads to satisfactory bone union. This surgical treatment can be performed early on after the trauma and is an interesting alternative to conservative treatment.

BACKGROUND Meningioma therapy efficiency is used to being assessed by 6 months progression survival rate (PFS6), which remains the most consensual criterion. Nevertheless, different patterns of meningiomas intrinsic aggressiveness and growth rates directly impact the PFS6 leading to unreliability of drug effect assessment. Moreover, therapeutic response remains rare in meningiomas. These points lead to consider classical and updated RANO criteria as not fully adapted to meningiomas. Based on phase II CEVOREM trial experience, we aim to improve the assessment of drugs efficiency in meningiomas via the determination of growth rate before and under treatment. MATERIAL AND METHODS Twenty patients were included in Cevorem trial which tested the combination of octreotide and everolimus as previously described. MRI assessment was performed in the 3 to 6 preinclusion months, at inclusion then every 3 months. Progression was assessed by investigators according to RANO criteria. An independent central review was performed with 2 reviewers and 1 adjudicator: largest diameter, 2D maximal area as 3D volume were assessed by autosegmentation software (Brainlab). Results from central review were correlated to investigators assessment. 3D volume growth rate (3DVGR) was calculated using 2 different processes (one simple and one complex). Comparison of 3DVGR before vs. under treatment was performed. Meningioma growth under treatment was compared to theoretical meningioma growth based on preinclusion data using a model of meningioma growth. RESULTS PFS6 assessed via the independent central review was in accordance with PFS6 assessed by investigators following RANO criteria. Then, we analyzed 3DVGR before and during therapy. Standard deviation was higher using the complex 3DVGR calculation process. A decrease of more than 50% of the 3DVGR was observed in 30/36 tumors at 3 months with the both calculation modes and could be considered as a threshold of drugs activity. Median volume growth rate decreased from 88.3 or 17.2%/3 months before inclusion to -2.2 or à -0.6 %/3mo at 3 months depending of the calculation mode (p CONCLUSION 3DVGR measurement during versus before seems as a sensitive and reliable tool which provides valuable comparison in a phase 2 study to assess drugs activity in meningioma in complement to PFS6. 3DVGR assessment should be considered in future clinical trials.

Purpose: Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas. Patients and Methods: Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety. Results: A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003). Conclusions: The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.

Introduction Pyogenic spondylodiscitis is a rare disease, but incidence is increasing. Reported failure rates following conservative management range from 12% to 18%. The purpose of this study was to determine the safety and efficacy of posterior percutaneous pedicle screw fixation combined with anterior debridement and fusion (ADF) for infective spondylodiscitis in the thoracic and/or lumbar spine. Methods The retrospective study cohort comprised all patients without neurological deficit who underwent minimally invasive posterior and anterior surgery between April 2008 and April 2016 for thoracic and/or lumbar spondylodiscitis. Results Forty patients were eligible (16 female: 40%). The lumbar region was affected in 31 cases (77.5%). Source of infection was identified in only 22 cases (55%) and bacteriological identification was obtained in 32 cases (80%). Mean hospital stay was 14.8 days (range, 6–39 days). Complete recovery was achieved in 39 patients (97.5%) at 3 months’ follow-up. Mean preoperative local kyphosis angle was 16.1o, versus 14o at 1-year (P > 0.05). 36 patients (90%) had at least 1 year's follow-up, and fusion was obtained for all these cases. Conclusion Two-stage minimally invasive surgery is effective and safe for the treatment of single or two-level thoracolumbar spondylodiscitis. It could be an alternative to conventional open surgery or conservative treatment.

2011 Background: After iterative surgeries and radiotherapy (RT)/radiosurgery (RS) failure, aggressive meningiomas remain an unmet medical need. We have shown in vitro that everolimus (EVE) combined to octreotide (OCT) is active in meningiomas. Methods: Prospective multicentric single arm phase II study (NCT02333565) including pts with recurrent meningioma with documented progression ( > 10% increase of tumor surface over 6 months) after surgery and RT/RS. EVE was orally administrated at 10mg/day and OCT by IM injection 30 mg/28 days. MRI was performed every 3 months with planned central review of imaging including volumetric progression at inclusion and during treatment. The primary endpoint was PFS6. The criteria for success was defined as a PFS6 > 40%. Results: 20 pts were included, aged 30-75 years (median 55) with 37 progressive intra cranial meningiomas (WHO: 2 grade I, 27 grade II, 8 grade III) including 4 NF2 pts. Median KPS was 70%. All pts previously underwent at least one surgery and more than 1 in 18/20 patients. 19/20 pts were treated with radiotherapy or radiosurgery and 5 pts with prior chemotherapy. 1 pt was not evaluable at 3 months. With a median f/u of 12.3 months (2-24 months), PFS6 was 58.2% (95% CI 33.5-76.5%) and PFS12 was 38% (95% CI 16-60%). Volumetric analysis at 3 months demonstrated a decrease in tumor volume superior to 10% in 8 tumors (4 pts). Pre therapeutic growth rate was decreased of more than 50% in 29/35 tumors (18/20 pts) during the first 3 months. Inclusion (I)-to-3 months tumor growth rate (mean at 1.9%/month) was significantly lower than pre inclusion (Pre-I)-to-I growth rate (mean at 18.5%/month) (p = 0.0003). 3 highly aggressive tumors (3 pts) were separately assessed: Pre-I-to-I growth rate superior to 1000%/month was decreased to 3%, 15% and 44%/month in the first 3 months. Toxicity included 7 grade III AE (stomatitis, 3; pneumopathy, 1). AE of special interest included stomatitis (10, 50%), rash (8, 40%), abdominal pain and diarrhea (11, 55%) and nausea and vomiting (4, 20%). Conclusions: Everolimus and octreotide combination appears active in refractory aggressive and progressive meningiomas with acceptable and manageable toxicity and should request further evaluation. Clinical trial information: NCT02333565.

Meckel’s cave (MC) is a meningeal cleft lying in the middle fossa laterally to the cavernous sinus. Tumours that develop inside the MC may require a surgical resection. The authors describe the surgical technique of the intracranial epidural approach to the MC. Based upon anatomical dissection showing the relevant surgical anatomy, and illustrated by the video of an operated case, the authors detail the surgical procedure. The key point is to shave the floor of the middle fossa and skeletonize the superior orbital fissure, rotundum and ovale foramen in order to delineate the plane of dural elevation and expose the lateral wall of the MC. The rules of exposure and resection of the tumour are then shown. Variations and limitations of the approach are discussed. Conducted in a stepwise manner and following relevant landmarks, the epidural anterolateral approach offers a safe and reliable exposure to the diseases that develop within the MC.

Introduction Les spondylodiscites restent des pathologies graves pouvant entrainer une impotence fonctionnelle et une destruction vertebrale. Une prise en charge mini-invasive par osteosynthese percutanee associe a une discectomie ou corporectomie pourrait ameliorer les suites operatoires de ces patients fragiles. Patients et methode Entre 2008 et 2015, 28 cas de spondylodiscite (20 hommes et 8 femmes, âge moyen 60 ans) sans deficit neurologique ont ete inclus dans ce travail. Le niveau concerne etait lombaire (78 %) au niveau de la charniere thoracolombaire (7 %) ou thoracique (14 %). La technique chirurgicale comportait systematiquement une osteosynthese percutanee associee a une discectomie (86 %) ou une corporectomie (14 %) par une voie anterieure associee. La reconstruction anterieure utilisait une cage avec de la BMP2 (19 %), un greffon osseux (77 %), ou un corps prothetique expansible (4 %). Resultats L’EVA moyenne preoperatoire etait de 9 10 avec une evolution moyenne des symptomes de 3 mois. La realisation de l’osteosynthese percutanee etait toujours possible dans un premier temps et les 2 temps chirurgicaux etaient realises conjointement dans 63 % des cas. Un lever precoce etait possible dans 80 % des cas a j3 avec une duree moyenne d’hospitalisation de 10 jours [4–29]. Lors de la sortie l’EVA moyenne etait de 4 10. La realisation de prelevements bacteriologiques permettait une identification du germe dans 67 % des cas (76 % dans le groupe vierge d’antibiotherapie preoperatoire) avant instauration d’une antibiotherapie postoperatoire au long cours (3 mois). Dans les suites operatoires, aucune aggravation neurologique n’etait notee, un patient presentait une infection superficielle de cicatrice traitee medicalement et un patient etait repris pour une fracture sus-jacente a l’osteosynthese. Au recul de 3 mois postoperatoires (2 perdus de vue), aucun cas de debricolage n’etait rapporte et le traitement antibiotique etait systematiquement arrete devant la bonne evolution. Le taux de fusion intervertebrale etait de 100 % chez les patients revus a 1 an (53 % des patients). Discussion La prise en charge chirurgicale des spondylodiscites est indiquee en cas de douleurs invalidantes ou de destruction vertebrale. L’association d’une osteosynthese percutanee et discectomie corporectomie par voie anterieure permet une diminution rapide et significative des douleurs ainsi qu’une remise en charge precoce. La morbidite operatoire et perioperatoire est faible avec une guerison systematique de l’infection dans cette serie, associee a un taux de fusion satisfaisant. Chez ces patients fragiles, la realisation d’une strategie mini-invasive constitue donc une alternative interessante.