Nicolas-Xavier Bonne

mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma

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.

Middle fossa approach for resection of vestibular schwannoma: impact of cochlear fossa extension and auditory monitoring on hearing preservation.

Objective To analyze the impact of patient selection and auditory monitoring on hearing results after middle fossa craniotomy approach for resection of a vestibular schwannoma (VS). Study Design Retrospective case review. Setting Tertiary referral center. Patients Patients undergoing a middle fossa craniotomy for resection of VS at a single institution between 1995 and 2006 were included in the study population. Patients presenting with Neurofibromatosis Type 2 or who underwent a combined approach (middle fossa and retrosigmoid) were excluded. Main Outcome Measures Hearing preservation as measured by serial audiograms. Results Seventy-seven patients were identified. Before excluding patients with cochlear fossa enhancement and the use of auditory monitoring, 47% of the patients maintained serviceable hearing (American Academy of Otolaryngology–Head and Neck Surgery Class A or B). By selecting tumors that did not involve the cochlear fossa and using auditory monitoring, serviceable postoperative hearing was preserved in 76% of the patients. Conclusion Modification of our selection criteria for surgery and the use of auditory monitoring have improved our hearing results for patients undergoing a middle fossa approach for resection of VS from 47% to 76%.

Causes of mortality in neurofibromatosis type 2

Abstract Object. The causes of mortality in neurofibromatosis type 2 (NF2) patients are poorly studied in the literature. Our study aimed to fit this gap by analyzing the main causes of death in this population. Methods. This study is the retrospective review of prospectively collected data of 80 patients with NF2 disease followed in Lille University Hospital between 1987 and 2011. Demographical data, diagnosis criteria, and cause of death were recorded. Results. There were 45 men and 35 women, with a mean age at diagnosis of 27.2 years (range: 6–73 years; SD: ± 15.4). Sixty-eight patients met Manchester criteria and the others had an identified mutation in the NF2 gene which confirmed the diagnosis. Of all patients, we noted 7 deaths. The mean age at diagnosis of dead patients was 26 years. The mean age of death was 38.9 years. The causes of death were suicide in 1 patient, hematoma after surgical removal of grade IV vestibular schwannoma in 1 patient, aspiration pneumonia after swallowing disturbances in 3 patients, intracranial hypertension related to growth of multiple meningiomas in 1 patient, and brachial plexus sarcoma grade 3 in the last patient. Conclusion. NF2 is a serious disease that can quickly be life-threatening. The presence of lower cranial nerves schwannomas is a poor prognostic factor, and radiosurgery should be considered for their treatment, as surgical removal often worsens the swallowing disturbances. A psychological support should also be provided.

Long‐term growth rate of vestibular schwannoma in neurofibromatosis 2: A volumetric consideration

To determine the long‐term growth rate of vestibular schwannoma (VS) in neurofibromatosis type 2 (NF2) patients based on volumetric measurements.

An allograft mouse model for the study of hearing loss secondary to vestibular schwannoma growth.

Vestibular schwannoma is a benign neoplasm arising from the Schwann cell sheath of the auditory-vestibular nerve. It most commonly affects both sides in the genetic condition Neurofibromatosis type 2, causing progressive high frequency sensorineural hearing loss. Here, we describe a microsurgical technique and stereotactic coordinates for schwannoma cell grafting in the vestibular nerve region that recapitulates local tumor growth in the cerebellopontine angle and inner auditory canal with resulting hearing loss. Tumor growth was monitored by bioluminescence and MRI in vivo imaging, and hearing assessed by auditory brainstem responses. These techniques, by potentially enabling orthotopic grafting of a variety of cell lines will allow studies on the pathogenesis of tumor-related hearing loss and preclinical drug evaluation, including hearing endpoints, for NF2-related and sporadic schwannomas.

Progression of vestibular schawnnoma after GammaKnife radiosurgery: A challenge for microsurgical resection

OBJECTIVE We aimed to evaluate the outcome of patients who underwent salvage microsurgery for vestibular schwannoma (VS) that failed primary Gammaknife radiosurgery (GKS). PATIENTS AND METHODS Among the 1098 patients who received GKS for the treatment of VS in our center between January 2004 and December 2012, the follow-up was organized in our institution for 290 patients who lived in our recruitment area. Tumor progression was noted in 23 patients. A salvage microsurgical resection was performed in 11 patients, who were included in our study. Grading of facial function was done according to the House & Brackman scale. RESULTS The mean age at diagnosis was 50.2 years (19-68 years) and the mean follow-up was 9.4 years (4-13 years). The mean dose was 11.8 Gy (11-12 Gy) and the mean volume was 922 mm3 (208-2500 mm3). The mean period between GKS and diagnosis of tumor progression was 32 months (18-72 months). Concerning salvage microsurgery, complete resection was obtained in 8 patients. Small residual tumor on the facial nerve was deliberately left in 3 patients and no tumor progression was noted with a mean follow-up of 26 months. At last follow-up, facial nerve function was grade 1 in 4 patients, grade 2 in 3 patients, grade 3 in 1 patient and grade 4 in 3 patients. CONCLUSION Salvage surgery of recurrent vestibular schwannoma after failed initial GKS remains a good treatment. However, facial nerve preservation is more challenging in this case and small tumor remnant could be sometimes deliberately left.

Infrared videoangiographic assessment of cochlear nerve vasculature during middle fossa surgery.

INTRODUCTION Hearing preservation in the surgery of intracanalicular vestibular schwannomas (VS) using a middle fossa craniotomy (MFC) approach is achieved in up to 75% of attempted cases. Failure to maintain any hearing is easily explained when the cochlear nerve is injured during surgery. Injury may occur secondary to stretching, cautery, or section; it is more frequent when the interface between the tumor and the cochlear nerve is corrupted—or when the tumor extends to the cochlear aperture located at the lateral end of the fundus where the nerve fibers split to progress through the modiolus. Indeed, proper selection of patients, including a cochlear aperture free of tumor on preoperative magnetic resonance scan, could improve the outcomes. The use of a reliable intraoperative auditory monitoring is also associated with increasing the rate of preservation. However, there are remaining cases when the mechanism by which hearing loss occurs cannot be identified. For these situations, implication of the cochlear vasculature (e.g., vasospasm) has been proposed. Indocyanine green (ICG) is a fluorescent nearinfrared dye approved by the U.S. Food and Drug Administration for angiography (1956: cardiac function; 1975: ophthalmic angiography). Recently, its indication was extended to intracranial surgery (e.g., intracranial aneurysm, bypass, arteriovenous malformation, and meningioma surgeries). Indocyanine green fluorescence videoangiography is now widely used in neurosurgery for the intraoperative assessment of vessel patency. We applied the use of intraoperative ICG videoangiography to describe the common cochlear artery pattern and patency during the removal of intracanalicular VS.

Technical note for post-auricular route surgery in Mongolian gerbil.

The Mongolian gerbil (Meriones unguiculatus) is commonly used in hearing research because the hearing frequency spectrum of the gerbil is rather similar to that of the human being. However, a precise description of the surgical post-auricular route has not been reported. The aim of this technical note is to provide details on the procedure and the surgical anatomy of the post-auricular route in the Mongolian gerbil. Surgery was performed under general anesthesia on eight (2 males and 6 females) adult Mongolian gerbils. All steps of the post-auricular route were detailed. This surgery provided an access to the following structures: the semi-circular posterior and lateral canals, the external auditory meatus, the tympanic membrane, the round window, the stapes, the stapedial artery and the reliefs of the cochlea. No anatomic variation was noticed among the 8 animals. This post-auricular route in the Mongolian gerbil defines a brief and simple surgery, overall standardized as a consequence of the absence of common anatomic variation, with painless and uncomplicated post-operative stage.