Thomas Graillon

Somatostatin receptor sst2 gene transfer in human prolactinomas in vitro: impact on sensitivity to dopamine, somatostatin and dopastatin, in the control of prolactin secretion.

OBJECTIVE As prolactinomas fail to respond to dopamine agonist (DA) in 10-20% of cases, we hypothesized that somatostatin subtype 2 receptor (sst2) overexpression in DA-resistant prolactinomas may enhance suppression of prolactine (PRL) using chimeric agonist (dopastatin) that simultaneously binds sst2 and the dopamine subtype 2 receptor (D2DR). DESIGN AND METHODS PRL suppression by octreotide, sst5 agonist, sst2-D2DR agonist (BIM-23A760 dopastatin) and cabergoline was assessed in primary cultures of seven DA-resistant prolactinomas overexpressing sst2. RESULTS sst2 was effectively overexpressed via adenoviral expression in prolactinomas (38.1±7.4 vs. 0.1±0.1 copy/copy β-Gus) and induced octreotide sst2-mediated PRL suppression that remained lower than that induced by DA. BIM-23A760 inhibited PRL similarly to cabergoline both in the control and sst2-expressing cells. Antagonist experiments confirmed predominant dopaminergic effect in dopastatin activity. CONCLUSION sst2 was successfully overexpressed in prolactinomas. However BIM-23A760 was unable to enhance PRL suppression underlining a predominant dopaminergic contribution in its action.

Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas

Abstract Treatment for recurrent and aggressive meningiomas remains an unmet medical need in neuro-oncology, and chemotherapy exhibits limited clinical activity, if any. Merlin expression, encoded by the NF2 gene, is lost in a majority of meningiomas, and merlin is a negative regulator of mTORC1. The sst2 somatostatin receptor, targeted by octreotide, is highly expressed in meningiomas. To investigate new therapeutic strategies, we evaluated the activity of everolimus (mTOR inhibitor), BKM-120 and BEZ-235 (new Pi3K/Akt/mTOR inhibitors), octreotide and a combined treatment (octreotide plus everolimus), on cell proliferation, signaling pathways, and cell cycle proteins, respectively. The in vitro study was conducted on human meningioma primary cells extracted from fresh tumors, allowing the assessment of somatostatin analogs at the concentration levels used in patients. The results were correlated to WHO grades. Further, everolimus decreased cell viability of human meningiomas, but concomitantly, induced Akt activation, reducing the antiproliferative effect of the drug. The new Pi3K inhibitors were not more active than everolimus alone, limiting their clinical relevance. In contrast, a clear cooperative inhibitory effect of octreotide and everolimus was observed on cell proliferation in all tested meningiomas, including WHO grades II–III. Octreotide not only reversed everolimus-induced Akt phosphorylation but also displayed additive and complementary effects with everolimus on downstream proteins involved in translation (4EB-P1), and controlling cell cycle (p27Kip1 and cyclin D1). We have demonstrated a co-operative action between everolimus and octreotide on cell proliferation in human meningiomas, including aggressive ones, establishing the basis for a clinical trial.

Adult symptomatic and growing arachnoid cyst successfully treated by ventriculocystostomy: A new insight on adult arachnoid cyst history

BACKGROUND Adult arachnoid cysts are known to be stable and asymptomatic but their history remains undefined. CASE DESCRIPTION The authors report the case of an 81-year-old woman with progressive hemiplegia and aphasia. CT scan revealed a voluminous left frontotemporal arachnoid cyst with a major mass effect on the midline and contralateral blocked hydrocephalus. Endoscopic ventriculocystostomy was performed with a spectacular neurological improvement. DISCUSSION AND CONCLUSIONS Symptomatic adult arachnoid cysts are extremely rare. To our knowledge, no similar clinical case of a growing arachnoid cyst in elderly patients has yet been reported in the literature. The mechanisms of cyst enlargement and decompensation still remain undefined and debated. The possibility of adult arachnoid cyst growth has to be considered in clinical practice. Endoscopic ventriculocystostomy is as effective as in paediatric cases.

Postoperative follow-up of Cushing's disease using cortisol, desmopressin and coupled dexamethasone-desmopressin tests: a head-to-head comparison.

Predicting the outcome of patients operated on for Cushings disease (CD) is a challenging task. Our objective was to assess the accuracy of immediate postsurgical plasma cortisol, desmopressin test and the coupled dexamethasone‐desmopressin test (CDDT) as predictors of outcome.

Minimally invasive transmuscular approach for the treatment of benign intradural extramedullary spinal cord tumours: Technical note and results

BACKGROUND Minimally invasive surgery has expanded over the past two decades and was initially used for the treatment of lumbar disc herniation. Later, this approach was used to treat other spine pathologies, as well as to perform spinal fusion and extended spinal decompression. In this study, we report our experience regarding the use of a minimal surgical approach in the treatment of intradural extramedullary spinal cord tumours. METHODS Between January 2008 and July 2013, 18 patients with an intradural extramedullary tumour were included in the study (13 thoracic, 4 lumbar and one cervical tumours). The mean age was 59 years. We operated on 11 meningiomas, 6 neurinomas and one ependymoma. All patients underwent minimally invasive surgery using a tubular retractor system to perform a hemilaminectomy in order to access the spinal canal. Fifteen patients had a neurological deficit and 7 suffered from radicular pain prior to surgery. RESULTS Gross completed resection was performed in all patients. Mean time of surgery was 95 min. Blood loss was less than 200 cc. Fifteen patients out of 18 were able to get up the day after surgery. Mean hospital stay was 6 days. There were no complications. CONCLUSION A minimal surgical approach using a tubular retractor permits an effective resection of intradural extramedullary tumours. This procedure may be a useful tool to decrease the risk of secondary spine instability and postoperative kyphosis, and could also be used for spinal junctions and in fragile patients.

Limited endoscopic transsphenoidal approach for cavernous sinus biopsy: Illustration of 3 cases and discussion

Advances in transsphenoidal surgery and endoscopic techniques have opened new perspectives for cavernous sinus (CS) approaches. The aim of this study was to assess the advantages and disadvantages of limited endoscopic transsphenoidal approach, as performed in pituitary adenoma surgery, for CS tumor biopsy illustrated with three clinical cases. The first case was a 46-year-old woman with a prior medical history of parotid adenocarcinoma successfully treated 10 years previously. The cavernous sinus tumor was revealed by right third and sixth nerve palsy and increased over the past three years. A tumor biopsy using a limited endoscopic transsphenoidal approach revealed an adenocarcinoma metastasis. Complementary radiosurgery was performed. The second case was a 36-year-old woman who consulted for diplopia with right sixth nerve palsy and amenorrhea with hyperprolactinemia. Dopamine agonist treatment was used to restore the patients menstrual cycle. Cerebral magnetic resonance imaging (MRI) revealed a right sided CS tumor. CS biopsy, via a limited endoscopic transsphenoidal approach, confirmed a meningothelial grade 1 meningioma. Complementary radiosurgery was performed. The third case was a 63-year-old woman with progressive installation of left third nerve palsy and visual acuity loss, revealing a left cavernous sinus tumor invading the optic canal. Surgical biopsy was performed using an enlarged endoscopic transsphenoidal approach to the decompress optic nerve. Biopsy results revealed a meningothelial grade 1 meningioma. Complementary radiotherapy was performed. In these three cases, no complications were observed. Mean hospitalization duration was 4 days. Reported anatomical studies and clinical series have shown the feasibility of reaching the cavernous sinus using an endoscopic endonasal approach. Trans-foramen ovale CS percutaneous biopsy is an interesting procedure but only provides cell analysis results, and not tissue analysis. However, radiotherapy and radiosurgery have proven effective for SC meningiomas. When histological diagnosis is required, limited endoscopic transsphenoidal approach appears as a safe, fast, and useful alternative to the classical endocranial approach. Also, a tailored enlargement of the approach could be performed if optic nerve decompression is required. The feasibility of CS endoscopic transsphenoidal biopsy has prompted us to consider CS biopsy when the diagnosis of CS meningioma is uncertain.

Trends in the surgical management of odontoid fractures in patients above 75 years of age: Retrospective study of 70 cases

BACKGROUND Odontoid fractures are the most common upper cervical spine fracture in adults over 70 years of age. Hence, treatment of these fractures has public health implications. OBJECTIVES Evaluate the early complications, bone healing and mortality in patients above 75 years of age who undergo surgical treatment of an odontoid fracture. Compare the results between patients operated with the Harms technique or anterior screw fixation. METHODS This was a retrospective study of 70 patients with an odontoid fracture who were treated surgically between 2000 and 2015 at the Hôpital de la Timone in France. The age at the time of diagnosis, comorbidities, ASA score and autonomy were evaluated. Bone healing was determined using computed tomography. RESULTS In the cohort, 22 patients underwent anterior screw fixation, 38 were treated using the Harms technique and 10 with other procedures. The average age was 85.1 years. Fifty-four percent of patients had an ASA score above 3. The average follow-up was 23.4 months. An Anderson type II fracture was present in 80.6% of patients. In the anterior screw fixation group, the operative time was significantly shorter than in the Harms group and no blood transfusions were needed. However, 13.6% of these patients had to be re-operated because the initial construct was unstable; no patients in the Harms group underwent revision surgery. There were more complications in the anterior screw fixation group than in the Harms group: 41% versus 13.2% (P<0.02). The fractures had healed in all patients reviewed after 1 year. The 3-month survival in the anterior screw fixation group was 64.7% and it was 81.3% in the Harms group. These rates were stable at 1 year with no statistical differences between groups. CONCLUSION Surgical treatment of odontoid fractures in the elderly results in an excellent union rate. The mortality rate is stable after 3 months. In our experience, the Harms technique has a lower risk of complications and better mechanical stability than anterior screw fixation. Despite the steep learning curve, we believe the Harms technique is probably the best choice for treating odontoid fractures in the elderly. LEVEL OF EVIDENCE IV.

Octreotide therapy in meningiomas: in vitro study, clinical correlation, and literature review

OBJECTIVE Meningiomas express somatostatin receptor subtype 2 (SST2), which is targeted by the somatostatin analog octreotide. However, to date, using somatostatin analog therapy for the treatment of these tumors in clinical practice has been debated. This study aims to clarify the in vitro effects of octreotide on meningiomas for precise clinical applications. METHODS The effects of octreotide were analyzed in a large series of 80 meningiomas, including 31 World Health Organization (WHO) Grade II and 4 WHO Grade III tumors, using fresh primary cell cultures to study the impact on cell viability, apoptosis, and signal transduction pathways. RESULTS SST2 mRNA was detected in 100% of the tested meningiomas at levels similar to those observed in other SST2-expressing tumors, neuroendocrine tumors, or pituitary adenomas. Octreotide significantly decreased cell proliferation in 88% of meningiomas but did not induce cell death. On average, cell proliferation was more inhibited in the meningioma group expressing a high level of SST2 than in the low-SST2 group. Moreover, octreotide response was positively correlated to the level of merlin protein and inversely correlated to the level of phosphorylated p70-S6 kinase, a downstream effector of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway. Octreotide inhibited Akt phosphorylation and activated tyrosine phosphatase without impacting the extracellular regulated kinase (ERK) pathway. CONCLUSIONS Octreotide acts exclusively as an antiproliferative agent and does not promote apoptosis in meningioma in vitro. Therefore, in vivo, octreotide is likely to limit tumor growth rather than induce tumor shrinkage. A meta-analysis of the literature reveals an interest in octreotide for the treatment of WHO Grade I tumors, particularly those in the skull base for which the 6-month progression-free survival level reached 92%. Moreover, somatostatin analogs, which are well-tolerated drugs, could be of interest for use as co-targeting therapies for aggressive meningiomas.

Corpectomy and Vertebral Body Reconstruction with Expandable Cage Placement and Osteosynthesis via the single stage Posterior Approach: a Retrospective Series of 34 Patients with Thoracic and Lumbar Spine Vertebral Body Tumors

BACKGROUND Metastatic disease of the spine requires a multidisciplinary and comprehensive approach to patient care, especially, for patients in a lot of pain with neurological deficit or spinal instability requiring surgical stabilization. OBJECTIVES The purpose of the study is to report our experience on 34 patients who underwent spinal metastasis resection. We used a single-stage posterior approach with vertebral body reconstruction by an expandable titanium cage and a posterior instrumentation. The parameters assessed were neurologic status, OMS score, angle of sagittal deformity, and morbidity. METHODS Between January 2011 and June 2014 we performed a monocentric consecutive case review of 34 patients with vertebral body tumor. All of them underwent a single-stage vertebrectomy with circumferential reconstruction and an arthrodesis by posterior approach. RESULTS 34 patients underwent a single stage surgery by posterior approach, including 30 thoracic lesions and 4 lumbar lesions. Pre operatively, sixteen patients presented a neurologic impairment. The mean follow-up was 13.7 months [1-32 m]. No neurologic impairment was observed in the 34 cases. At the last term of follow-up, neurologic status was improved in 23 cases. OMS score was improved in 23 cases (67.6 %), and worsened in one case. Before surgery, the average of visual analogic scale was 8.94/10 [7-10] and decreased to 2.62/10 [1-5] after surgery. Single posterior approach surgery significantly reduced the average sagittal deformity to 10.0° (0.01-19.96; P = 0.013, Mann-Whitney test). CONCLUSION Our outcomes suggest that it will be more efficient to perform an aggressive approach in spinal metastatic treatment in order to improve quality of life.

Rhinorrhée cérébrospinale après chirurgie hypophysaire endoscopique trans-sphénoïdale : réflexions après 337 patients

INTRODUCTION Cerebrospinal fluid (CSF) leak is a frequent complication after trans-sphenoidal pituitary surgery. We try to determine the incidence, risk factors, diagnostic procedures, and management of CSF leaks following trans-sphenoidal pituitary macroadenoma surgery. METHODS A retrospective analysis of 337 patients data. RESULTS Postoperative CSF leaks occurred in 11 patients (3,1%). Ten patients had to be reoperated. Three patients had meningitis. Intraoperative CSF leak is the only significant predictive factor of postoperative CSF leak. Revision surgery, wide opening of the sella turcica and insufficient reconstruction of the sellar floor also seem to play a role (for six cases of postoperative CSF leak, the closure material had been excluded). CONCLUSION Prevention of the postoperative CSF leak needs screening of intra-operative CSF leak. The strength of the sellar floor is essential in order to avoid the ejection of the closure material, related to the intracranial pression.