Discontinuation of Drug Treatment in Cushing's Disease Not Cured by Pituitary Surgery.

OBJECTIVE: When transsphenoidal surgery (TSS) does not cure Cushing's disease (CD), 4 treatments are available: drug treatment (DT), second TSS (2nd TSS), bilateral adrenalectomy (BA), and pituitary radiotherapy (PR). DT is attractive but supposes long-term continuation, which we aimed to evaluate. DESIGN AND METHODS: Retrospective study, in a center prioritizing 2nd TSS, of 36 patients, including 19 with TSS failure and 17 with recurrence, out of 119 patients with CD treated by a first TSS, average follow-up 6.1 years (95% confidence interval 5.27-6.91). Control was defined as normalization of urinary free cortisol (UFC) and final treatment (FT) as the treatment allowing control at last follow-up. We also analyzed discontinuation rates of DT in published CD prospective clinical trials. RESULTS: Control was achieved in 33/36 patients (92%). DT was initiated in 29/36 patients (81%), allowing at least 1 normal UFC in 23/29 patients (79%) but was discontinued before last follow-up in 18/29 patients (62%). DT was FT in 11/29 patients (38%), all treated with cortisol synthesis inhibitors. Second TSS was FT in 8/16 (50%), BA in 14/14 (100%), and PR in 0/5. In published trials, discontinuation of DT was 11% to 51% at 1 year and 32% to 74% before 5 years. CONCLUSION: DT allowed at least 1 normal UFC in 23/29 patients (79%) but obtained long-term control in only 11/29 (38%), as discontinuation rate was high, although similar to published data. Interestingly, a successful 2nd TSS was the cause for discontinuing efficient and well-tolerated DT in 5 patients. Further studies will show whether different strategies with cortisol synthesis inhibitors may allow for a lower discontinuation rate in patients not candidates for a 2nd TSS so that BA may be avoided in these patients.

Functional Graphene for Peritumoral Brain Microenvironment Modulation Therapy in Glioblastoma.

Peritumoral brain invasion is the main target to cure glioblastoma. Chemoradiotherapy and targeted therapies fail to combat peritumoral relapse. Brain inaccessibility and tumor heterogeneity explain this failure, combined with overlooking the peritumor microenvironment. Reduce graphene oxide (rGO) provides a unique opportunity to modulate the local brain microenvironment. Multimodal graphene impacts are reported on glioblastoma cells in vitro but fail when translated in vivo because of low diffusion. This issue is solved by developing a new rGO formulation involving ultramixing during the functionalization with polyethyleneimine (PEI) leading to the formation of highly water-stable rGO-PEI. Wide mice brain diffusion and biocompatibility are demonstrated. Using an invasive GL261 model, an anti-invasive effect is observed. A major unexpected modification of the peritumoral area is also observed with the neutralization of gliosis. In vitro, mechanistic investigations are performed using primary astrocytes and cytokine array. The result suggests that direct contact of rGO-PEIUT neutralizes astrogliosis, decreasing several proinflammatory cytokines that would explain a bystander tumor anti-invasive effect. rGO also significantly downregulates several proinvasive/protumoral cytokines at the tumor cell level. The results open the way to a new microenvironment anti-invasive nanotherapy using a new graphene nanomaterial that is optimized for in vivo brain delivery.

Long-term surgical oncological and functional outcome of large petroclival and cerebellopontine angle epidermoid cysts: a multicenter study.

Cranial nerve (CN) disorders are the foremost symptoms in cerebellopontine angle (CPA) and petroclival area (PCA) epidermoid cysts (EC).The aim of this work was to  assess the long-term surgical results on CN function and tumor control in these patients. We performed a retrospective cohort study about 56 consecutive patients operated on for a CPA or PCA EC between January 2001 and July 2019 in six participating French cranial base referral centers. Sixteen patients (29%) presented a PCA EC and 40 a CPA EC (71%). The median clinical and radiological follow-up was 46 months (range 0-409). Preoperative CN disorders were present in 84% of patients (n = 47), 72% of them experienced CN deficits improvement at the last follow-up consultation (n = 34): 60% of cochlear and vestibular deficits (n = 9/15 in both groups), 67% of trigeminal neuralgia (n = 10/15), 53% of trigeminal hypoesthesia (n = 8/15), 44% of lower cranial nerve disorders (n = 4/9), 38% of facial nerve deficits (n = 5/8) and 43% of oculomotor deficits (n = 3/7) improved or were cured after surgery. New postoperative CN deficits occurred in 48% of patients (n = 27). Most of them resolved at the last follow-up, except for cochlear deficits which improved in only 14% of cases (n = 1/7). Twenty-six patients (46%) showed evidence of tumor progression after a median duration of 63 months (range 7-210). The extent of resection, tumor location, and tumor size was not associated with the occurrence of new postoperative CN deficit or tumor progression. A functional nerve-sparing resection of posterior fossa EC is an effective strategy to optimize the results on preexisting CN deficits and reduce the risk of permanent de novo deficits.

Rate of Rebleed and Retreatment of Previously Treated Intracranial Aneurysms.

BACKGROUND: Intracranial aneurysms (IAs) can be treated through endovascular treatment (EVT) or microsurgery (MS). Treated IAs can recanalize, which can lead to rupture or retreatment. OBJECTIVE: The aim of our study was to evaluate the natural history of previously treated IA, by evaluating the risk of rupture and the risk of retreatment. METHODS: All patients treated for an IA between 2007 and 2017 in 4 hospitals were included. The rate of (recurrent) hemorrhage and the rate of prophylactic retreatment were retrospectively evaluated. Kaplan-Meier survival analysis with log-rank tests was used to compare the rates of rupture or retreatment. Patients with ruptured and unruptured aneurysms were separated, and we compared the risk of retreatment between EVT and the surgical treatment. RESULTS: A total of 4997 IAs were included in the study, corresponding to 20,489 patient-years. Overall, 28 (0.6%) aneurysms that had been previously treated demonstrated hemorrhage. Moreover, 237 (4.7%) aneurysms were retreated for recanalization without hemorrhage. The rate of retreatment was higher in the EVT-treated IAs as compared with the MS-treated IAs (LogRank: P < 0.0001) and higher in the previously ruptured IAs versus unruptured IAs (LogRank: P < 0.0001). However, the rate of posttreatment hemorrhage/IA rupture was similar for both groups. CONCLUSIONS: The rate of IA retreatment is low; however, the rate of hemorrhage/rupture from treated IAs is even lower. A higher rate of retreatment was noted in EVT-treated IAs versus MS-treated IAs and in ruptured IAs versus unruptured IAs; however, the rate of hemorrhage or rerupture was comparable between the groups.

Personal and psychosocial factors of burnout: A survey within the French neurosurgical community.

OBJECT: The neurosurgical community is particularly exposed to burnout. The objectives of this study were to report the prevalence and associated factors of burnout within the French neurosurgical community using validated academic and psychologic scales. METHODS: A national survey was sent to 141 French residents and 432 neurosurgeons between April and July 2019. Burnout was surveyed using the Maslach burnout inventory. The survey included demographic data and several academic psychologic scales. A stepwise multiple regression was used to determine factors that are associated with burnout scores. RESULTS: The response rate was 100% and 23.6% for residents and neurosurgeons, respectively. Prevalence of burnout within the French neurosurgical community was 49%. There were no significant differences between residents and neurosurgeons. Two categories of factors were associated with the main dimensions of burnout during the stepwise multiple regression: personality and factors related with neurosurgical practice. Personality types such as neuroticism were negatively associated with burnout while agreeableness was protective. Work addictive profile with excessive work and absorption at work were negatively associated. Factors associated with neurosurgical practice such as conflict of work into family life, unbalanced effort to reward ratio, work duration were negatively associated. Pleasure at work was protective. CONCLUSION: Prevalence of burnout is high among French neurosurgeons. Predictive models can be used to identify and prevent burnout among profiles at risk.

Why We Should Still Treat by Neurosurgery Patients With Cushing Disease and a Normal or Inconclusive Pituitary MRI.

CONTEXT: In patients with Cushing disease (CD) and a typical image of adenoma at MRI, transsphenoidal surgery is consensual. However, when MRI is inconclusive or normal, some authors now advocate medical treatment instead. The implicit assumption is that modern MRI should miss only very small microadenomas that are too difficult to visualize at surgery. OBJECTIVE: To analyze the evolution with time of the performances of MRI and the outcomes of surgery in patients with CD with a typical image of adenoma vs an inconclusive or normal MRI. DESIGN AND PATIENTS: Retrospective single center study of 195 patients with CD treated by transsphenoidal surgery between 1992 and 2018, using first a translabial microscopic and then a transnasal endoscopic approach. Patients with inconclusive or normal MRI were explored by bilateral inferior petrosal sinus sampling. Four MRI groups were defined: microadenomas (n = 89), macroadenomas (n = 18), or MRI either inconclusive (n = 44) or normal (n = 44). RESULTS: The proportion of inconclusive/normal MRI decreased with time, from 60% (21/35) in 1992 to 1996 to 27% (14/51) in 2012 to 2018 (P = 0.037). In the four MRI groups, the per-operatory adenoma visualization rate was only slightly lower when MRI was normal (95%, 100%, 86%, 79%; P = 0.012) and postoperative remission rates were not different (85%, 94%, 73%, 75%; P = 0.11). CONCLUSION: The diagnostic performances of MRI have improved but remain inferior to the eye of an expert neurosurgeon, best assisted by endoscopy. We propose that patients with CD and an inconclusive/normal MRI be addressed by an expert neurosurgeon for transsphenoidal surgery rather than being treated medically.

Strategic proposal for a national trauma system in France.

In this road map for trauma in France, we focus on the main challenges for system implementation, surgical and radiology training and upon innovative training techniques. Regarding system organisation: procedures for triage, designation and certification of trauma centres are mandatory to implement trauma networks on a national scale. Data collection with registries must be created, with a core dataset defined and applied through all registries. Regarding surgical and radiology training, diagnostic-imaging processes should be standardised and the role of the interventional radiologist within the trauma team and the trauma network should be clearly defined. Education in surgery for trauma is crucial and recent changes in medical training in France will promote trauma surgery as a specific sub-specialty. Innovative training techniques should be implemented and be based on common objectives, scenarios and evaluation, so as to improve individual and team performances. The group formulated 14 proposals that should help to structure and improve major trauma management in France over the next 10 years.

Bilateral adrenalectomy in Cushing's disease: Altered long-term quality of life compared to other treatment options.

OBJECTIVE: Bilateral adrenalectomy (BADX) has become an important treatment of Cushing's disease (CD), especially when other treatment options have failed. The aim of this study was to evaluate the long-term quality of life (QoL) of patients having undergone BADX for CD, in comparison to other therapeutic options. METHODS: Thirty-four patients with CD were identified in two French centers: 17 underwent BADX and the remaining 17 one or more of the following treatments: surgery, medical therapy or radiotherapy. Three questionnaires were filled in by each patient in order to evaluate their QoL: Short Form-36 Health Survey (SF-36), Cushing QoL questionnaire and Beck depression inventory (BDI). RESULTS: The mean age of patients was 49.3±15.2 years. Average time lapse between diagnosis and BADX was 6.1 years. Results from each questionnaire adjusted to age showed a lower QoL among patients who underwent BADX. These were significant in most aspects of the SF-36 questionnaire (bodily pain P<0.01, general health P<0.01, vitality P≤0.05, social functioning P≤0.05), as well as in the Cushing QoL questionnaire (P<0.05) and BDI (P≤0.05). Adrenal insufficiency appeared to be the major predictor of poor QoL whatever their initial treatment. CONCLUSIONS: Despite their clinical remission, patients who undergo BADX appear to be at a greater risk of suffering an impaired QoL due to more prolonged period of time with imperfectly controlled hypercortisolism combined with definitive adrenal insufficiency.

Strategies to reduce external ventricular drain-related infections: a multicenter retrospective study.

OBJECTIVEVarious strategies have been proposed to reduce the incidence of external ventricular drain (EVD)-related infections. The authors retrospectively studied the impact of EVD care management on EVD-related infections at 3 French university hospital intensive care units.METHODSBetween 2010 and 2014, 462 consecutive adult patients with no evidence of a preexisting CSF infection received EVDs as part of their care at one of the following sites: Grenoble (221 patients), Saint-Etienne (130 patients), and Marseille (111 patients). Written protocols describing the EVD placement procedure, management, and removal were implemented at the 3 sites. Daily CSF sampling and intraventricular administration of antibiotics prior to EVD removal were performed at the Grenoble site only. EVD-related infection was considered for any confirmed ventriculostomy-related infection (VRI) and ventriculitis. VRI was defined as one or more positive CSF cultures or Gram stain with CSF pleocytosis and biochemical abnormalities. Ventriculitis was defined as CSF pleocytosis and biochemical abnormalities with degradation of neurological status and fever.RESULTSA total of 6945 EVD days were observed in the entire population. In the Grenoble cohort, the mean cumulative incidence of EVD-related infections was significantly lower than that in the 2 other cohorts: 1.4% (95% CI 0.0%-2.9%) versus 9.2% (95% CI 4.2%-14.2%) and 7.2% (95% CI 2.4%-12.0%) at Saint-Etienne and Marseille, respectively (p < 0.01). Accounting for the duration of external ventricular drainage at each site, the risk for EVD-related CSF infections was significantly higher at Saint-Etienne and Marseille than at Grenoble, with ORs of 15.9 (95% CI 3.6-71.4, p < 0.001) and 10.0 (95% CI 2.2-45.5, p = 0.003), respectively.CONCLUSIONSThese findings indicate that it is possible to attain a low incidence of EVD-related infections, provided that an EVD care bundle, which can include routine daily CSF sampling, is implemented and strongly adhered to.

Greater occipital nerve cryoneurolysis in the management of intractable occipital neuralgia.

OBJECTIVE: To assess technical feasibility of cryoneurolysis of the greater occipital nerve in the management of occipital neuralgia. METHODS: Six patients suffering from unilateral refractory greater occipital neuralgia and who underwent 7 GON cryoneurolysis were assessed between October 2015 and January 2017. All procedures were performed under CT guidance and local anesthesia. A planning CT was performed with contrast enhancement to plan needle target and identify surrounding major vascular structures. A 12G coaxial needle (Inomed) was then inserted and targeted the first bend of the GON under and lateral to the obliquus capitis inferior muscle. A 2.0mm cryoprobe was then inserted in the coaxial and sensitive stimulation at 100Hz was performed. One to three freezing cycles were performed in one session. RESULTS: Technical feasibility was 100% as cryoneurolysis could be performed in all 7 cases with accurate sensitive nerve stimulation prior to freezing cycle. One patient benefited from a second session after failure of the first session. More than 50% pain reduction was achieved at day 7 in all cases, and 5 of 6 cases at one and three months follow-up. CONCLUSION: Cryoneurolysis of the GON in the management of refractory GON neuralgia is feasible. Initial results are promising as 5/7 cases benefited from a 3-month pain alleviation period.

AFM mapping of the elastic properties of brain tissue reveals kPa µm(-1) gradients of rigidity.

It is now well established that the mechanical environment of the cells in tissues deeply impacts cellular fate, including life cycle, differentiation and tumor progression. Designs of biomaterials already include the control of mechanical parameters, and in general, their main focus is to control the rheological properties of the biomaterials at a macroscopic scale. However, recent studies have demonstrated that cells can stress their environment below the micron scale, and therefore could possibly respond to the rheological properties of their environment at this micron scale. In this context, probing the mechanical properties of physiological cellular environments at subcellular scales is becoming critical. To this aim, we performed in vitro indentation measurements using AFM on sliced human pituitary gland tissues. A robust methodology was implemented using elasto-adhesive models, which shows that accounting for the adhesion of the probe on the tissue is critical for the reliability of the measurement. In addition to quantifying for the first time the rigidity of normal pituitary gland tissue, with a geometric mean of 9.5 kPa, our measurements demonstrated that the mechanical properties of this tissue are far from uniform at subcellular scales. Gradients of rigidity as large as 12 kPa µm(-1) were observed. This observation suggests that physiological rigidity can be highly non-uniform at the micron-scale.

OP-1 Compared with Iliac Crest Autograft in Instrumented Posterolateral Fusion: A Randomized, Multicenter Non-Inferiority Trial.

BACKGROUND: Spinal fusion with the use of autograft is a commonly performed procedure. However, harvesting of bone from the iliac crest is associated with complications. Bone morphogenetic proteins (BMPs) are extensively used as alternatives, often without sufficient evidence of safety and efficacy. The purpose of this study was to investigate non-inferiority of osteogenic protein-1 (OP-1, also known as BMP-7) in comparison with iliac crest bone graft in posterolateral fusions. METHODS: This study was a randomized, controlled multicenter trial. Patients who underwent a single-level instrumented posterolateral fusion of the lumbar spine for degenerative or isthmic spondylolisthesis with symptoms of neurological compression were randomized to receive OP-1 combined with local bone (OP-1 group) or autologous bone graft from the iliac crest combined with local bone (autograft group). The primary outcome was overall success, defined as a combination of clinical success and evidence of fusion on computed tomography (CT) scans, at one year postoperatively. RESULTS: One hundred and nineteen patients were included in the study, and analysis of the overall outcome was performed for 113. Non-inferiority of OP-1 compared with iliac crest autograft was not found at one year, with a success rate of 40% in the OP-1 group versus 54% in the autograft group (risk difference = -13.3%, 90% confidence interval [CI] = -28.6% to +2.10%). This was due to the lower rate of fusion (the primary aim of OP-1 application) seen on the CT scans in the OP-1 group (54% versus 74% in the autograft group, p = 0.03). There were no adverse events that could be directly related to the use of OP-1. CONCLUSIONS: OP-1 with a collagen carrier was not as effective as autologous iliac crest bone for achieving fusion and cannot be recommended in instrumented posterolateral lumbar fusion procedures. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects.

Mammals have three HP1 protein isotypes HP1 beta (CBX1), HP1 alpha (CBX3) and HP1 alpha (CBX5) that are encoded by the corresponding genes Cbx1, Cbx3 and Cbx5. Recent work has shown that reduction of CBX3 protein in homozygotes for a hypomorphic allele (Cbx3hypo) causes a severe postnatal mortality with around 99 percent of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3hypo/hypo conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3hypo/hypo placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3hypo/hypo placental labyrinth are narrower than wild-type. Newborn Cbx3hypo/hypo pups are hypoglycemic, the livers are depleted of glycogen reserves and there is almost complete loss of stored lipid in brown adipose tissue (BAT). There is a 10-fold reduction in expression of the BAT-specific Ucp1 gene, whose product is responsible for nonshivering themogenesis. We suggest that it is the small size of the Cbx3hypo/hypo neonates, a likely consequence of placental growth and transport defects, combined with a possible inability to thermoregulate that causes the severe postnatal mortality.

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

OBJECTIVE: Predicting the outcome of patients operated on for Cushing's 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. DESIGN AND PATIENTS: Sixty-seven patients with initial remission and a minimal postsurgical follow-up greater than 18 months were included in this retrospective bicentre study. MEASUREMENTS: Follow-up included 3-6 months followed by yearly 24-h urinary-free cortisol, ACTH and cortisol plasmatic levels, a 1-mg overnight dexamethasone suppression test (1-mg DST), desmopressin test and the CDDT. ROC curves were performed to define the optimal threshold of immediate postsurgical cortisol level and 3- to 6-month desmopressin test and CDDT, as predictors of final outcome in comparison with classical biological markers of recurrence. RESULTS: Eleven patients presented recurrence. The patient's median follow-up was 52 months (range, 18-180). As early predictors of outcome, immediate postsurgical plasma cortisol level <35 nmol/l predicted the lack of recurrence with 93% negative predictive value (NPV), whereas predictive positive value (PPV) was 25%. During the follow-up, the CDDT was more precise than the desmopressin test in predicting the lack of recurrence (100% NPV) when performed in the first 3 years after surgery. Positivity of the CDDT was defined based on ROC curves by ACTH and cortisol increments >50%. The CDDT was highly reproducible, as the same response was observed every year in 91% of the patients. CONCLUSIONS: Adding the CDDT the first 3 years after surgery to immediate postsurgical cortisol evaluation should allow obtaining an optimal follow-up management of patients operated for Cushing's disease.

Trigeminal nerve deficit in large and compressive acoustic neuromas and its correlation with MRI findings.

OBJECTIVES: Evaluate the prevalence of preoperative trigeminal nerve deficit in large/compressive acoustic neuromas and try to find a correlation between pre/postoperative magnetic resonance imaging (MRI) findings and pre/postoperative trigeminal nerve deficit. STUDY DESIGN: Case series with chart review. SETTING: University medical center. SUBJECTS AND METHODS: Retrospective study (1994-2009) including patients with stage 4 or 5 acoustic neuromas (Zini-Magnan classification). All patients underwent surgical resection. Pre- and postoperative trigeminal symptoms were sought. Imaging criteria were sought on pre- and 3-month postoperative MRI scans. Pearson χ(2) statistical test was used. RESULTS: Fifty-three patients (27 females, mean 51 years) were operated on. Preoperatively, 3 patients (5.7%) had trigeminal neuralgia, 1 (1.9%) trigeminal anesthesia, and 28 (52.8%) trigeminal hypoesthesia. Sixteen patients (30.2%) had no corneal reflex (ophthalmic branch); keratitis occurred in 1 patient (1.9%). Postoperatively, 2 patients (3.8%) had trigeminal neuralgia, 1 (1.9%) trigeminal anesthesia, and 24 (45.3%) trigeminal hypoesthesia. Twenty-six patients (49%) had no corneal reflex; keratitis occurred in 11 patients (20.7%). Preoperative trigeminal hypoesthesia was statistically correlated with impaction of the tumor on cerebellar peduncles on preoperative MRI. Postoperative trigeminal hypoesthesia was statistically correlated with nonvisibility of the trigeminal nerve on postoperative MRI. CONCLUSION: In large/compressive acoustic neuromas, trigeminal nerve deficit has to be sought to avoid corneal complications in particular. Trigeminal hypoesthesia occurs preoperatively in about half of the cases. It remains relatively stable after tumor removal, but there appears to be an increased rate of absent corneal reflex and keratitis postoperatively. We were able to correlate pre/postoperative trigeminal hypoesthesia with pre/postoperative MRI findings.

Comprehensive gas chromatography-electron ionisation mass spectrometric analysis of fatty acids and sterols using sequential one-pot silylation: quantification and isotopologue analysis.

RATIONALE: Fatty acids and sterol lipids play crucial roles in several biological processes and several biological facts underline the interconnection between these lipid classes. Therefore, it is of interest to develop a comprehensive method analysing both classes in the form of their most favourable derivatives suitable for quantification and isotopologue analysis. METHODS: Lipids were derivatised by a sequential one-pot procedure using N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MtBSTFA) and N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA). No clean-up or concentration steps were necessary. The prepared samples were directly available for gas chromatography-electron ionisation mass spectrometric (GC-EI-MS) analysis on a standard column. For quantification, the SIM mode was used and for isotopologue analysis scheduled scan mode was applied. RESULTS: Development of a sequential one-pot derivatisation for GC-EI-MS allowing comprehensive analysis of fatty acids and sterols as their most favourable derivatives. Validation carried out using human plasma, comparison with certified NIST plasma. LLOQ of usually 3.3 ng/mL achieved. Isotopologue analysis of 2-[(13)C]-acetate incorporation in HL-60 cells proving feasibility of method. CONCLUSIONS: The presented method successfully combines two consecutive silylation reactions in one pot, enabling the analysis of both fatty acids and sterols in a comprehensive analytical method. The method has great potential for the quantification of lipids as well as the comprehensive study of both biochemical pathways, using [(13)C]-flux analysis.