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Background and aims Multinodular/plexiform schwannomas and neurofibromas of major nerves are rare: before surgery, differential diagnosis among these two uncommon variants is challenging. For both forms, surgical removal is recommended in case of progressive growth and worsening of neurological symptoms. Surgery has a higher risk of neurological damage than conventional schwannomas or neurofibromas. In literature, a comparison among these rare tumors is usually limited to the pathological aspect while specific surgical and clinical management indications are lacking. Cutaneous tumors of both forms arising from terminal peripheral nerves’ branches might be treated by plastic surgeons while tumors of major nerves remain under neurosurgical competence. Here we report our recent neurosurgical experience on the matter, to furnish useful suggestions for the management of these tumors. Method We analyzed the clinical, radiological, and pathological data in a consecutive case series of plexiform/multinodular nerve tumors operated at our institution in the last five years. Results In our series, neurofibroma type of plexiform tumors was more frequent than schwannoma type: two sporadic plexiform-multinodular schwannomas (patients 1, and 5) and three multinodular/plexiform Neurofibromatosis familial (Neurofibromatosis 1 / NF-1) (patients 2, 3, and 4). Surgery was complex when major nerves were involved. The early outcome appeared mostly related to the pre-surgical neurological conditions and histological grading. Interpretation Although sharing some features, multinodular-plexiform schwannomas and neurofibromas have consistent differences from the clinical, surgical and pathological points of view.

Background Trans-sphenoidal endoscopic surgery has drawn huge benefits from advances in surgical visualization. The Ultra-HD "4K" endoscope has improved 4-fold image resolution compared with HD, but its actual advantages are unclear. Aim of the present study was to assess its usefulness in the early outcome of trans-sphenoidal surgery. Methods We analyzed a series of 199 trans-sphenoidal pituitary adenoma procedures performed by an experienced team using alternatively HD (n=102) or 4K (n=97) endoscopes. We evaluated extent of resection both subjectively, based on intraoperative surgeon's impression, and objectively based on post-operative MR scan. Results Baseline patients' characteristics were balanced. Objective near-total and total resection rates were comparable between 4K and HD groups (91.5% vs 86.3% and 64.9% vs 56.9%, respectively). 4K endoscope slightly improved resection rate in recurrent adenoma. At multivariate analysis, the only independent prognosticator of total resection was cavernous sinus invasion. Importantly, 4K endoscope enhanced the reliability of intraoperative judgement on extent of resection, significantly reducing unexpected residuals (12.8% vs 33.3% for HD). Operative features and clinical outcomes were similar. Conclusions The HD endoscope remains the standard-of-care for pituitary surgery. The 4K enhanced, "immersive" visualization significantly improved the reliability of surgeon's judgment on resection and might be useful in surgically difficult cases.

Aggressive meningiomas are prone to recur despite GTR and eventually progress: they represent a challenge and are difficult to recognize at first diagnosis. SOX2 (Sex-determining region Y-box2) is a transcription regulator whose role is crucial for cell’s fate and maintenance of progenitor’s identity during embryogenesis, and homeostasis and regeneration in adult tissue through stem cell activity preservation. We reviewed meningioma cases surgically treated at Gemelli Hospital, Rome between 2014 and 2019. We included all patients with diagnosis of grade 3 meningiomas, both progressive and de novo, grade 2 with at least one surgical recurrence after GTR and benign grade 1 and grade 2 without recurrence at 10 and 5 years long follow-up respectively. SOX2 expression was evaluated through IHC and RT-PCR. Its role in predicting progression, recurrence, OS and PFS was investigated. 87 patients were included: 16 de novo grade 3 meningioma, 7 progressive grade 1, 13 progressive grade 2, 12 recurrent grade 2, 20 benign grade 1, 19 benign grade 2. The IHC method for SOX2 was validated by correlation between IHC score and mRNA levels (Spearman R=0.0398, p=0.001, AUC 0.87). Although SOX2 expression is related to WHO grade in the series, its status doesn’t change with progression. SOX2 expression at first surgery is related to risk of progression (p< 0,0001) and represents a grade independent prognostic factor for PFS and OS (PFS 38,41 months in positive cases vs not reached in negative cases; p< 0,0001; OS 173,9 months in positive cases vs not reached in negative cases; p=0,0001) and both in grade 1 and grade 2. Histomorphological criteria, cornerstone of the current WHO classification, are inadequate to predict aggressiveness. SOX2 expression since first diagnosis is able to point out meningiomas prone to recur and progress. SOX2 status could integrate current classification as molecular biomarker of stemness and aggressiveness.

Background Pituitary melanoma metastases (PMMs) are extremely rare and only a few cases are reported in the literature. PMMs can grow rapidly and present local invasiveness, leading to acute onset of neurological symptoms such as headache, visual and oculomotion disorders or endocrinological signs such as diabetes insipidus and hypopituitarism, and can be life-threatening. For this reason, PMMs must be recognized and treated promptly. Case Description The authors present 2 cases of PMMs managed at their institution, performing a review of the dedicated literature and analyzing current therapeutic strategies.

Purpose Transsphenoidal surgery (TSS) for pituitary adenomas can be complicated by the occurrence of intraoperative cerebrospinal fluid (CSF) leakage (IOL). IOL significantly affects the course of surgery predisposing to the development of postoperative CSF leakage, a major source of morbidity and mortality in the postoperative period. The authors trained and internally validated the Random Forest (RF) prediction model to preoperatively identify patients at high risk for IOL. A locally interpretable model-agnostic explanations (LIME) algorithm is employed to elucidate the main drivers behind each machine learning (ML) model prediction. Methods The data of 210 patients who underwent TSS were collected; first, risk factors for IOL were identified via conventional statistical methods (multivariable logistic regression). Then, the authors trained, optimized, and audited a RF prediction model. Results IOL reported in 45 patients (21.5%). The recursive feature selection algorithm identified the following variables as the most significant determinants of IOL: Knosp's grade, sellar Hardy's grade, suprasellar Hardy's grade, tumor diameter (on X, Y, and Z axes), intercarotid distance, and secreting status (nonfunctioning and growth hormone [GH] secreting). Leveraging the predictive values of these variables, the RF prediction model achieved an area under the curve (AUC) of 0.83 (95% confidence interval [CI]: 0.78; 0.86), significantly outperforming the multivariable logistic regression model (AUC = 0.63). Conclusion A RF model that reliably identifies patients at risk for IOL was successfully trained and internally validated. ML-based prediction models can predict events that were previously judged nearly unpredictable; their deployment in clinical practice may result in improved patient care and reduced postoperative morbidity and healthcare costs.

Intraoperative neuromonitoring is crucial for facial nerve preservation in cerebellopontine angle (CPA) surgery. Among the available techniques, the role of intraoperative corticobulbar facial motor evoked potentials (FMEPs) is unclear.To evaluate the significance of intraoperative FMEPs as indicators for early and late postoperative facial nerve function (FNF) in CPA tumor resection and the feasibility of their integration with standard monitoring techniques.An institutional series of 83 patients who underwent surgery under intraoperative monitoring for CPA extra-axial tumor resection was reported. A pair of needle electrodes was used to record FMEP from orbicularis oculi (OOc) and orbicularis oris (OOr) muscles at baseline, at the end of surgery and minimum values recorded. From FMEP amplitudes, minimum-to-baseline amplitude ratio (MBR), final-to-baseline amplitude ratio (FBR), and recovery value, intended as FBR minus MBR, were calculated. These indices were correlated with early and late postoperative FNF.Our analysis demonstrated that higher FBR (both from OOc and OOr) and MBR (from OOr only) were associated with a good early and late FNF; a higher MBR from OOc was significantly associated with a good late FNF. The most accurate index in predicting early FNF was FBR measured from OOr with a cutoff of 35.56%, whereas the most accurate index in predicting late FNF was FBR as measured from OOc with a cutoff of 14.29%.Our study confirmed that FMEPs are reliable predictors of early and late postoperative FNF in CPA surgery and could be easily integrated with standard intraoperative neuromonitoring techniques.

Lumbosacral chordoma is a slow-growing but locally aggressive tumor, resistant to adjuvant treatments and endowed with dismal prognosis. Surgery is the mainstay of treatment but the choice of surgical approach (the posterior-only approach or the combined anterior-posterior approach) remains an open question due to the need of both pursuing a surgical radicality and preserving the neurologic function. The aim of the study was to compare the surgical and clinical outcomes of these approaches in the management of lumbosacral chordomas. A systematic review and meta-analysis in agreement with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines of papers comparing the outcomes of the two approaches was performed. Ten papers met the inclusion criteria. The combined anterior-posterior approach was more frequently performed for tumors with an upper level beyond S2 (p = 0.012). The 5-year progression-free survival was significantly higher in posterior-only approach compared with the combined anterior-posterior approach (44.7% vs 27.1%, p = 0.049). Adjuvant radiotherapy was added more frequently after a posterior-only approach (p = 0.036) and the rate of complications was significantly lower after a posterior-only approach (p = 0.040). No significant differences in sex, age, tumor diameter, entity of resection, and overall survival were observed. Posterior-only surgical approach may be a reasonable option for lumbosacral chordoma, being associated with comparable entity of surgical resection, reduced complication rate and increased 5-year progression-free survival rate as compared with combined anterior-posterior approach.

Facial nerve palsy is a highly invalidating condition, possibly complicating surgery for cerebellopontine angle lesions, other skull base tumours and trauma. In this context, hypoglossal-facial nerve anastomosis, with hypoglossal axons re-directed into the extracranial facial nerve to reinnervate the denervated facial muscles, is a reconstructive technique, which guarantees the best functional results. While several variations of this classical technique have been reported, the crucial point of this procedure is the correct identification of the facial nerve at the stylomastoid foramen. In fact, a few months after the injury, the nerve structure is transformed, with changes in external appearance as well as consistency, thereby hampering its correct identification. Standard intraoperative neuronavigation has the ability to reliably identify the stylomastoid foramen, thus providing a quick and effective recognition of the facial nerve at its exit from the skull base.We describe the technical nuances of this procedure by presenting two surgical cases who underwent hypoglossal-facial nerve anastomosis for complete facial nerve palsy occurring post removal of a giant vestibular schwannoma 6 months earlier.CT-based neuronavigation allowed a quick and reliable identification of the stylomastoid foramen and of the facial nerve at its exit from the skull. The entire procedure lasted for 3 hours. Three months after the anastomosis, the first signs of facial muscle reinnervation were visible.The use of neuronavigation during hypoglossal-facial nerve anastomosis is a simple and cost-effective strategy to decrease operative duration and increase surgical effectiveness.

Introduction Following the results from the REGOMA study, regorafenib has become the first chemotherapeutic option for recurrent glioblastoma, IDH-wildtype, in many countries. However, predictive factors for response to regorafenib are scarcely recognized. The objective of this study was to identify molecular predictive factors for response to regorafenib using a clinically available platform. METHODS We analyzed a prospective cohort of 30 patients harboring recurrent glioblastoma, IDH-wildtype, and treated with regorafenib. Next-generation sequencing (NGS) analysis was performed on DNA extracted from paraffin-embedded tissues using a rapid, cheap, and clinically validated platform. MGMT methylation was assessed using methylation-specific PCR, and EGFRvIII expression was assessed using RT-PCR. RESULTS In our series, six-month progression-free survival (PFS) was 30% and median overall survival (OS) was 7.5 months: these data are consistent with current literature. Among clinical variables, gross-total resection was endowed with a positive prognostic value for PFS (p=0.0296, log-rank test). NGS analysis revealed a mutation in the EGFR pathway (EGFR and/or PIK3CA) in 18% of cases; a mutation in the mitogen-activated protein-kinase (MAPK) pathway (RAS and/or RET) in 18% of cases; no mutations in the remaining cases. Patients carrying MAPK pathway mutation had a poor response to regorafenib treatment, with a significantly shorter PFS and a nonsignificantly shorter OS compared to EGFR-mutated patients (for PFS, 2.5 vs 4.5 months, p=0.0061; for OS, 7 vs 9 months, p=0.1076). By combining NGS analysis with RT-PCR for EGFRvIII, we identified 14 patients with EGFR pathway activation, who had a significantly longer PFS and OS after regorafenib treatment. Multivariate analysis confirmed that MAPK pathway mutations predicted a scarce response to regorafenib treatment. Conclusions Through an easy-to-use and cheap platform, we identified a mesenchymal, MAPK-altered signature in IDH-wildtype glioblastoma, predictive of scarce response to regorafenib at recurrence. We thus provide a molecular selection criterion to implement in the clinical practice.

BACKGROUND Cerebellopontine angle (CPA) surgery for extra-axial lesions in elderly patients could be hampered by concerns regarding functional outcomes. However, an overall ageing society warrants an improved approach. Intraoperative neuromonitoring is crucial for facial nerve (FN) preservation: intraoperative cortico-bulbar facial motor evoked potentials (FMEPs) can be effectively coupled to standard techniques. In a previous work, we validated the use of FMEPs as preditors of early and late post-operative FN function (FNF). Aim of this study was to re-evaluate FMEP role in patients beyond 65 years of age. METHODS An institutional series of 83 patients was reported. A pair of needle electrodes was used to record FMEP from orbicularis oculi (OOc) and orbicularis oris (OOr) muscles; baseline, final and minimum values were recorded. From FMEP amplitudes, minimum-to-baseline (MBR) and final-to-baseline (FBR) amplitude ratios, and recovery value (RV=FBR-MBR), were calculated. These indices were correlated to early (at discharge) and late (at 1-year) post-operative FNF. RESULTS 23 (27.7%) patients were older than 65 years. Among these, 52.2% and 81% had a good early and late FNF, respectively. Early and late FNF were not associated to age (p > 0.99 and p=0.72, respectively). In elderly patients, higher FBR (from OOc and OOr) and MBR (from OOc) were associated to a good early FN recovery (p=0.01, p=0.009, and p=0.03, respectively). Conversely, MBR from OOr was the only parameter significantly associated with late FN function (p=0.049). ROC analysis confirmed that, in elderly patients, the most accurate index for predicting late FN function was MBR as measured from OOr (AUC=0.869, cut-off value 12.5%). The most accurate index for predicting early FN function was FBR from OOc (AUC=0.865). CONCLUSION Cortico-bulbar FMEPs are reliable predictors of early and late post-operative FNF in elderly patients and allow a safe and feasible surgery in this important cohort.

Nerve biopsy has been widely used to investigate patients with peripheral neuropathy, and in many centers, it is still a useful diagnostic tool in this setting. In this study, we reviewed the histopathological spectrum of the nerve biopsies performed in our center in a 30-year period and we analyzed their relevance in the clinical setting. Retrospective analysis of the retrieved data was done for cases of nerve biopsies performed in our institute between 1988 and 2018. Surgical technique and histopathological analysis were done accordingly to standard protocol. Complete clinical and pathological data were available only for 717 cases. The procedure was generally safe, with only 0.3% superimposed infection. Main pathological results were “unspecific” axonal polyneuropathy (49.8%), vasculitis neuropathy (9.3%), acquired demyelinating neuropathy (8.9%), and Charcot-Marie-Tooth (8.2%). Considering clinical-neurophysiological suspicion of vasculitis, nerve biopsy confirmed the diagnosis in 60.9% of cases. In conclusion, for inherited neuropathies, we do not recommend this invasive procedure, but we strongly suggest a genetic test. Conversely, in vasculitic neuropathies or in dysimmune neuropathies not clearly confirmed by neurophysiological examination, nerve biopsy continues to represent a useful and irreplaceable tool.

Objective Different surgical set-ups for endoscopic transsphenoidal surgery (ETS) have been described, but studies on their ergonomics are limited. The aim of this article is to describe present trends in the ergonomics of ETS. Design and Participants A 33-question, web-based survey was sent to North American Skull Base Society members in 2018 and 116 responded to it (16% of all members). Most respondents were from North America (76%), in academic practice (87%), and neurosurgeons (65%); they had more than 5 years of experience in ETS (73%), had received specific training (66%), and performed at least 5 procedures/mo (55%). Results Mean reported time for standard and complex procedures were 3.7 and 6.3 hours, respectively. The patient's body is usually positioned in a straight, supine position (84%); the head is in a neutral position (46%) or rotated to the side (38%). Most surgeons perform a binostril technique, work with a partner (95%), and operate standing (94%), holding suction (89%) and dissector (83%); sometimes the endoscope is held by the primary surgeon (22–24%). The second surgeon usually holds the endoscope (72%) and irrigation (42%). During tumor removal most surgeons stand on the same side (65–66%). Many respondents report strain at the dorsolumbar (50%) or cervical (26%) level. Almost one-third of surgeons incorporate a pause during surgery to stretch, and approximately half exercise to be fit for surgery; 16% had sought medical attention for ergonomic-related symptoms. Conclusion Most respondents value ergonomics in ETS. The variability in surgical set-ups and the relatively high report of complaints underline the need for further studies to optimize ergonomics in ETS.

BACKGROUND Failure of clinical trials with targeted therapies in glioblastoma (GBM) is probably related to the enrollment of molecularly unselected patients. In this study we report the results of a precision medicine protocol in recurrent GBM. METHODS We prospectively evaluated 34 patients with recurrent GBM. We determined the expression of vascular endothelial growth factor (VEGF), epidermal growth factor receptor variant III (EGFRvIII), and phosphatase and tensin homolog (PTEN). According to the molecular pattern we administered bevacizumab alone in patients with VEGF overexpression, absence of EGFRvIII, and normal PTEN (group A; n=16); bevacizumab + erlotinib in patients with VEGF overexpression, expression of EGFRvIII, and normal PTEN (group B; n=14); and bevacizumab + sirolimus in patients with VEGF overexpression and loss of PTEN, irrespective of the EGFRvIII status (group C; n=4). We evaluated the response rate, the clinical benefit rate, the 6-month progression-free survival (PFS-6), the 12-month PFS (PFS-12) and the safety profile of the treatment. Moreover we compared our results with the ones of EORTC 26101 trial. RESULTS Response rate was 50% in the whole cohort with the highest rate in group C (75%). Clinical benefit rate was 71% with the highest rate in group C (75%). PFS-6 was 56% in the whole cohort with the highest rate in group B (64%). PFS-12 was 21% in the whole cohort with the highest rate in group B (29%). When comparing our results with those from the combination arm of the EORTC 26101 trial we found a significantly higher PFS-6 and PFS-12 in our cohort. CONCLUSIONS The precision medicine protocol for recurrent GBM is feasible and leads to improved results if compared with studies lacking molecular selection.

Objective: To study motor cortex plasticity after a period of training with a new prototype of bidirectional hand prosthesis in three left trans-radial amputees, correlating these changes with the modification of Phantom Limb Pain (PLP) in the same period., Methods: Each subject underwent a brain motor mapping with Transcranial Magnetic Stimulation (TMS) and PLP evaluation with questionnaires during a six-month training with a prototype of bidirectional hand prosthesis., Results: The baseline motor maps showed in all three amputees a smaller area of muscles representation of the amputated side compared to the intact limb. After training, there was a partial reversal of the baseline asymmetry. The two subjects affected by PLP experienced a statistically significant reduction of pain., Conclusions: Two apparently opposite findings, the invasion of the "deafferented" cortex by neighbouring areas and the "persistence" of neural structures after amputation, could vary according to different target used for measurement. Our results do not support a correlation between PLP and motor cortical changes., Significance: The selection of the target and of the task is essential for studies investigating motor brain plasticity. This study boosts against a direct and unique role of motor cortical changes on PLP genesis. (C) 2020 Published by Elsevier B.V. on behalf of International Federation of Clinical Neurophysiology.

The surgical injury of the intracranial portion of the facial nerve (FN) is a severe complication of many skull base procedures, and it represents a relevant issue in terms of patients’ discomfort, social interactions, risk for depression, and social costs. The aim of this study was to investigate the surgical and functional outcomes of the most common facial nerve rehabilitation techniques. The present study is a systematic review of the pertinent literature, according to the PRISMA guidelines. Two different online medical databases (PubMed, Scopus) were screened for studies reporting the functional outcome, measured by the House-Brackman (HB) scale, and complications, in FN early reanimation, following surgical injuries on its intracranial portion. Data on the VII-to-VII and XII-to-VII coaptation, the surgical technique, the use of a nerve graft, the duration of the deficit, and complications were collected and pooled. The XII-to-VII end-to-side coaptation seems to provide higher chances for functional restoration (HB 1–3) than the VII-to-VII (68.8% vs 60.6%), regardless of the duration of the palsy deficit, the use or not of a nerve graft, and the use of stitches or glues. However, its complication rate was as high as 28.6%, and a second procedure is then often needed. The XII-to-VII side-to-end coaptation is the most effective in providing a functional outcome (HB 1–3), even though it is associated to a higher complication rate. Further trials are needed to better investigate this relevant topic, in terms of health-related social costs and patients’ quality of life.

Background Pituitary tumors are a heterogeneous group of lesions that are usually benign. Therefore, a proper understanding of the anatomy, physiology, and pathology is mandatory to achieve favorable outcomes. Accordingly, diagnostic tests and treatment guidelines should be determined and implemented. Thus, we decided to perform a multicenter study among Italian neurosurgical centers performing pituitary surgery to provide an actual depiction from the neurosurgical standpoint. Methods On behalf of the SINch (Societa Italiana di Neurochirurgia), a survey was undertaken with the participants to explore the activities in the field of pituitary surgery within 41 public institutions. Results Of the 41 centers, 37 participated in the present study. The total number of neurosurgical procedures performed in 2016 was 1479. Most of the procedures were performed using the transsphenoidal approach (1320 transsphenoidal [1204 endoscopic, 53 microscopic, 53 endoscope-assisted microscopic] vs. 159 transcranial). A multidisciplinary tumor board is convened regularly in 32 of 37 centers, and a research laboratory is present in 18 centers. Conclusions Diagnosing pituitary/hypothalamus disorders and treating them is the result of teamwork, composed of several diverse experts. Regarding neurosurgery, our findings have confirmed the central role of the transsphenoidal approach, with preference toward the endoscopic technique. Better outcomes can be expected at centers with a multidisciplinary team and a full, or part of a, residency program, with a greater surgical caseload.

Background The use of high-definition endoscopes in extended transsphenoidal approaches to the suprasellar area has significantly improved visualization of its vascularization. Objective To systematically examine the superior hypophyseal arteries (SHAs) anatomy from an endonasal endoscopic perspective. Methods The endoscopic endonasal transsphenoidal trans-tuberculum approach was performed in 19 adult, fresh and latex injected specimens. Dissections recordings were reviewed to analyze SHAs type, number, and branches, as well as internal carotid arteries (ICA) branches that vascularized optic nerves and chiasm. Results Identification of SHAs was possible in all specimens (37/38 sides). The number of SHAs varied from 1 to 3 per side (mean: 1.7). The anterior superior hypophyseal artery was visible in almost all cases (35/37 sides) and originated at the level of the carotid cave in 18/35 specimens; number of branches ranged from 1 to 6 (mean: 3.5), directed to the optic nerve (86%), chiasm (57%), infundibulum (86%), and/or parallel to the pituitary stalk (74%). The 4 main branches and patterns, originally described by McConnell in 1953, were confirmed. The posterior superior hypophyseal artery was evident in 28/37 sides with number of branches ranging from 0 to 4 (mean: 2.1), directed to the optic chiasm (50%), optic tract (32%), infundibulum (79%), and/or pituitary stalk (36%). The surgical implications of this study, together with anatomical and clinical videos, are also briefly discussed. Conclusion SHAs constitute a complex of anterior and posterior branches that stem from the medial ICA with different patterns, vascularizing the optic apparatus and pituitary stalk.

Xanthogranulomas are rare intracranial lesions with controversial etiology. The sellar location is exceedingly rare. Here we report a clinical case and a review of the English-language literature of histologically confirmed xanthogranulomas in order to furnish useful tools in diagnosis and management of this unusual disease. We performed an English-language literature MEDLINE search for the last 18 years and analyzed the reports of the published series and the present case. The clinical, radiological, pathological features and outcome of the published cases of Xanthogranuloma have also been compared with the traits of Craniopharyngioma and Rathke Cleft Cyst. The data collection has been hindered by the lack of important details in the published series. The available clinical and radiological data have been reported in Table 1 (28 papers for a total of 59 patients reported). A clinical-radiological comparison among common pathologies of the sellar-parasellar region has been performed in Table 2 . Endocrine impairment was a common finding in the clinical presentation and it was often worsened by surgery. Natural history of Xanthogranuloma is similar to other benign pathologies of the sellar area, but some typical features might help in distinguishing it before the pathological exam.

OBJECT Only a few published studies of the surgical treatment of benign peripheral nerve sheath tumors (BPNSTs), malignant peripheral nerve sheath tumors (MPNSTs), and peripheral non–neural sheath tumors (PNNSTs) have analyzed the results and possible prognostic factors using multivariate analysis. The authors report on their surgical series of cases of BPNSTs, MPNSTs, and PNNSTs with long-term follow-up and analyze the role of selected factors with respect to the prognosis and risk of recurrence of these tumors using multivariate analysis. They also review the pertinent literature and discuss their results in its context. METHODS The authors retrospectively reviewed data from cases involving patients who underwent resection of a peripheral nerve tumor between January 1983 and December 2013 at their institution. Of a total of 200 patients, 150 patients (with 173 surgically treated tumors) had adequate follow-up data available for analysis. Pain was assessed using a visual analog scale (VAS), and motor and sensory function were assessed by means of the Louisiana State University grading system. They also analyzed the relationship between tumor recurrence and patient sex, patient age, diagnosis of neurofibromatosis (NF), tumor histopathology, tumor size, tumor location, and extent of resection (subtotal vs gross-total resection), using univariate and multivariate analyses. RESULTS There was a statistically significant improvement in the mean VAS pain score (preoperative 3.96 ± 2.41 vs postoperative 0.95 ± 1.6, p = 0.0001). Motor strength and sensory function were significantly improved after resection of tumors involving the brachial plexus (p = 0.0457 and p = 0.0043, respectively), tumors involving the upper limb (p = 0.0016 and p = 0.0016, respectively), BPNSTs (p = 0.0011 and p < 0.0001, respectively), and tumors with dimensions less than 5 cm (motor strength: p = 0.0187 and p = 0.0021 for ≤ 3 cm and 3–5 cm tumors, respectively; sensory function: p = 0.0003 and p = 0.0001 for ≤ 3 cm and 3–5 cm tumors, respectively). Sensory function showed a statistically significant improvement also in patients who had undergone resection of tumors involving the lower limb (p = 0.0118). Total resection was associated with statistically significant improvement of motor strength (p = 0.0251) and sensory function (p < 0.0001). In univariate analysis, a history of NF (p = 0.0034), a diagnosis of MPNST or PNNST (p < 0.0001), and subtotal resection (p = 0.0042) were associated with higher risk of tumor recurrence. In multivariate analysis (logistic regression analysis), a history of NF (OR 9.28%, 95% CI 1.62–52.94, p = 0.0121) and a diagnosis of MPNST (OR 0.03%, 95% CI 0.002–0.429, p = 0.0098) or PNNST (OR 0.081%, 95% CI 0.013–0.509, p = 0.0077) emerged as independent prognostic factors for tumor recurrence. CONCLUSIONS A total resection should be attempted in all cases of peripheral nervous system tumors (irrespective of the supposed diagnosis and tumor dimensions) because it is associated with better prognosis in term of functional outcome and overall survival. Moreover, a total resection predicts a lower risk of tumor recurrence. Patients with a history of NF and tumors with malignant histology remain a challenge both for neurosurgeons and oncologists due to higher recurrence rates and the lack of standardized adjuvant therapies.

Under the definition “glomus tumors” are often erroneously enclosed neoplasms that are absolutely unlike for origin, location, and behavior. Glomus tumors (GTs) are small but extremely painful skin tumors of mesenchymal origin. GTs derive from the neuromyoarterial glomus in adults of middle-age and are generally benign. Due to their small size, diagnosis is often difficult and patients harboring these tumors usually consult many physicians, including sometimes neurosurgeons. More familiar to neurosurgeons are neoplasms as glomus jugular, glomus vagale, and glomus tympanicum that instead all belong to the family of paragangliomas (PGs) and for this reason should not be confused with the aforementioned skin tumors. Here we present a brief review of these two different classes of tumors and also the clarification of any misunderstanding that may derive from an improper use of the terminology. In order to illustrate why skin tumors may interest neurosurgeons, we have reviewed our institutional series of outpatient surgical procedures. Differential diagnosis with other tumors that appear as cutaneous nodules is also discussed. From January 2012 to May 2015, seven patients harboring a GT (six male and one female) were treated. The age ranged from 34 to 71 years (mean, 54.1). The clinical suspect of GT, was validated by ultrasound (US) and, if necessary, by magnetic resonance imaging (MRI). All patients underwent surgery for total tumor removal. Immediate pain relief was obtained in all the patients, and no recurrences were observed during follow-up. Histology confirmed the diagnosis of GT. Subcutaneous painful nodules, originating from the glomus body, are properly called GTs. Unlikely from other tumors, as schwannomas or neurofibromas, GTs are the cause of pain that is disproportionate to their tiny size and that is not associated to neurological disturbances. Surgical treatment allows a complete regression of pain with significant patient satisfaction. Neoplasms originating from neuroepithelial cells, on the contrary, should not be defined as GTs.

Treatment options for recurrent glioblastoma are scarce; targeted therapy trials were disappointing, probably due to enrollment of patients without molecular selection. We treated with bevacizumab and erlotinib a 66-year-old male suffering from recurrent glioblastoma, IDH-wildtype and MGMT unmethylated, after three neurosurgeries. Treatment was tailored on molecular profile of recurrent tumor—namely, EGFRvIII positivity, VEGF overexpression, normal PTEN, low total VEGF and VEGF-121 mRNA—and resulted in complete, exceptionally durable response (51-month progression-free survival). Notably, histology of further recurrence after therapy was reminiscent of sarcoma. We suggest a thorough molecular screening for personalization of targeted therapy in recurrent glioblastoma.

Background In transsphenoidal endoscopic cranial base surgery, a precise navigational support may be crucial. This is particularly evident when tumors extend to the parasellar region or in recurrent tumors whereas normal anatomy has been altered by previous surgery/radiotherapy. Methods Previous unsatisfactory experiences with various navigation techniques in this type of surgery encouraged us to perform an endoscopic endonasal approach with an O-arm (Medtronic, Inc., Minneapolis, Minnesota, USA) assisted technique for the surgical treatment of 4 patients affected respectively by an orbital tumor and 3 cases of relapse of nonfunctioning pituitary adenoma, 1 of them localized in the infrasellar-clival region. Results The system O-arm-StealthStation allows for merging intraoperative bone 3-D acquisition with preoperative computed tomography/magnetic resonance imaging and provides the surgeon with an extremely reliable operative navigational tool. Conclusions This is the first report of an O-arm-assisted endoscopic surgery for cranial base tumors. Here we report on the feasibility and usefulness of such a new application of the O-arm: technical details, setting of the operating room, advantages, and limits of the method are also described. Our overall impression, considering the limited number of patients, is that use of the O-arm may be successfully extended to selected cases of cranial base tumors operated through an endoscopic endonasal approach.

Objective The orbital cavity is an anatomically complex region and an area of interest of many specialists, each of whom is familiar with specific surgical approaches. Methods We retrospectively reviewed clinical and outcome data of 70 patients who underwent surgery for resection of an orbital tumor with a mean follow-up of 111.9 ± 79.6 months. The clinical outcome was reported and the role of sex, age, histology, tumor location, tumor size, and surgical approach on the extent of tumor removal was assessed. Results Total removal was achieved in 74.3%, subtotal removal in 20%, and partial removal in 5.7% of patients. A fronto-orbital craniotomy was used in 57.1% of cases, frontal approach in 17.1%, fronto-orbit-zygomatic approach in 10%, and endoscopic endonasal approach in 11.4%. Complications included visual acuity decrease (4.3%), cerebrospinal fluid leak (4.3%), nerve palsy (10%; supra-orbital nerve 4.3%; frontal branches of facial nerve 2.9%, third cranial nerve 2.9%), and enophthalmos (1.4%). Lateral orbitotomy, combined fronto-orbital and maxillotomy, and trans-eyelid approaches were used in the remaining cases. The fronto-orbital, frontal, and lateral orbitotomy approaches were associated with greater rates of total resection as compared with the fronto-orbit-zygomatic approach, which was used in difficult cases in which the tumor involved several regions. Conclusions We recommend, 1) the endoscopic endonasal approach for primary orbital tumors located in the medial or inferior orbital walls without extra-orbital extension; 2) the trans-eyelid approach for tumors of the upper and upper-lateral quadrants extraconally located, and 3) the fronto-orbital approach for intraconally located tumors involving more than one quadrant.

Background Total removal of craniopharyngiomas is burdened by high morbidity. In cases of a cystic or mixed craniopharyngioma, when the symptoms are caused by the cystic component of the tumor, a less invasive surgical approach aiming at cyst drainage may be recommended. Here, we report our experience with intraventricular neuroendoscopy, describe our clear-cut surgical technique, and analyze results in the context of literature data. Methods We reviewed the clinical data of 8 consecutive adult patients affected by cystic or mixed craniopharyngioma who were treated with intraventricular neuroendoscopy at our institution in the last decade. At surgery, wide opening and emptying of the cyst was performed; a ventricular catheter with adjunctive holes was then placed to maintain a continuous cerebrospinal fluid (CSF) washout. A systematic review of the pertinent literature was performed and a pooled analysis of individual data from selected studies was made. Results Ten neuroendoscopic procedures were performed. The treatment determined immediate neurologic and radiologic improvement without significant complications in all patients. No chemical meningitis was observed. Recurrence rate was 20%, in line with literature data. Median progression-free survival was 57 months. The systematic review of the literature showed that neuroendoscopy carries a lower recurrence rate than stereotaxy (P = 0.0390). Moreover, the creation of a cyst–CSF communication is a protective factor against recurrences. Finally, adjuvant radiotherapy determined no significant differences in terms of cyst recurrence rate. Conclusions We describe a neuroendoscopic treatment of cystic craniopharyngiomas that, without adjuvant radiotherapy, is safe and effective and ensures long-term recurrence-free survival.

Chronic compression of the ulnar nerve at the elbow is the second most common entrapment neuropathy. Various surgical options have been described. Timing of surgery is also debated. In this study we report the long-term results of a consecutive surgical series of anterior subcutaneous transpositions and review the pertinent literature. Sixty consecutive patients underwent anterior subcutaneous transposition at our Institution to treat ulnar nerve compression at the elbow. McGowan scale was used in the neurological exam before surgery. Bishop rating system was used to assess outcome. Seventy-eight% of patients scored good-excellent. None of the patients worsened. No complications and no recurrences were reported. Young age and good pre-operative neurological status (McGowan grade 1) were predictive of favorable outcome both at univariate and at multivariate analysis. No differences in outcome were observed between patients with intermediate (McGowan grade 2) and severe (McGowan grade 3) neuropathy. Thirty-four studies assessing outcome of different surgical techniques were reviewed. Anterior subcutaneous transposition had the lowest recurrence rate with an excellent effectiveness and safety profile. The favorable predictive role for outcome of preoperative neurological status was confirmed. The good long-term clinical results of the present series and the results of literature analysis confirm the value of anterior subcutaneous transposition of the ulnar nerve at the elbow. This technique has a particular effectiveness in most severe compressions, where outcomes are comparable with intermediate neuropathy cases. Moreover, our results suggest an aggressive attitude towards ulnar nerve compression at the elbow, particularly in younger patients.

INTRODUCTION Failure of clinical trials with targeted therapies in glioblastoma (GBM) is probably due to the enrollment of molecularly unselected patients. In preliminary studies, we prospectively selected recurrent GBM patients on the basis of molecular pattern and administered targeted therapy accordingly. This tailored approach gave encouraging results in term of low recurrence rate (RR) and high 6-month progression free survival (PFS-6). Here, we present the long-term results of our work. METHODS On recurrent tumor samples of 34 adult patients, we assessed the expression of VEGF and PTEN through immunohistochemistry and of EGFRvIII through RT-PCR. Patients with VEGF overexpression were treated with bevacizumab (10 mg/Kg i.v. every 2 weeks in 6-week cycles). Patients with EGFRvIII expression and normal PTEN expression added erlotinib (150 mg/day orally). Patients with loss of PTEN expression, irrespective of EGFRvIII status, added sirolimus (1–10 mg/day orally). RESULTS Sixteen patients received bevacizumab alone (bev), 14 bevacizumab plus erlotinib (bev+erl) and 4 bevacizumab plus sirolimus (bev+sir). RR was 50% in the whole cohort and 37.5%, 57.1% and 75% in bev, bev+erl and bev+sir groups, respectively. PFS-6 was 55.9% in the whole cohort and 50%, 64.3% and 50% in bev, bev+erl and bev+sir groups, respectively. Our data compare favorably with those from the large EORTC 26101 trial, which showed a RR of 41.5% and a PFS-6 lower than 30%. When considering sustained response (defined as PFS ≥ 12 months), we overall observed a 20.6% rate, with the highest value in bev+erl subgroup (28.6%). Interestingly, in EORTC 26101 trial, less than 10% of patients achieved PFS ≥ 12 months. CONCLUSIONS Our results confirm that the tailored approach in recurrent GBM provides an advantage in terms of RR, PFS and, above all, of long-term responses, compared with trials without molecular selection.

Background Elbow trauma, cubitus valgus deformity, and prolonged flexion of the elbow are recognized risk factors for ulnar nerve entrapment. Case Description The 3 conditions coincided in the present case. In fact, a 36-year-old woman had a bilateral severe congenital cubitus valgus. A trauma of the right elbow caused luxation and supracondylar humeral fracture for which the joint was fixed in flexion at 90° for 1 month. The patient developed a severe ulnar nerve entrapment syndrome that did not respond to several months of physiotherapy and active mobilization of the elbow. The symptoms recovered after surgical decompression and anterior subcutaneous transposition of the nerve. Conclusions The present case illustrates how the development of a cubital tunnel syndrome should be considered as the expected outcome of a long immobilization in flexion of an elbow with a severe cubitus valgus. A simple subcutaneous anterior transposition of the ulnar nerve might be recommended before a long immobilization of a cubitus valgus elbow is performed.

Surgical treatment of traumatic nerve lesions is a matter of debate, mostly about the timing and technical aspects of the procedure. In deciding about and planning the operation, it is often necessary to repeat the electrophysiological and neuroradiological studies several times. Here we present our experience with ultrasonography taken before and after surgery: this simple and handy tool allowed clear visualization of the preoperative anatomy, thorough preparation and fast carrying out of surgery, and accurate postoperative monitoring of the graft's vitality at follow-up. Though this is a limited series, the importance of ultrasonographic evaluation in traumatic peripheral nerve lesions appears remarkable.

Acrylic hydrogels, like the polymer of 2-hydroxyethyl methacrylate, are biocompatible, mechanically stable, porous materials that can be coated with collagen or laminin acting as bioadhesive substrates. Poly-2-hydroxyethyl methacrylate sponges have been proposed for restoring the anatomical continuity of damaged neural structures. In the present work, the ability of poly-2-hydroxyethyl methacrylate sponges to provide the injured spinal cord neurons with a conductive substrate for their regenerating axons was investigated in 32 adult Wistar rats. Collagen impregnated poly-2-hydroxyethyl methacrylate sponges were implanted into suction cavities of the dorsal funiculus of the spinal cord. Two to four months after implantation, the spinal cord was removed and processed for histology, and S100 and GFAP immunohistochemistry. To study axonal regeneration into the sponge, the spinal cord or the sensorimotor cortex were injected with 0.05-0.1 microl of an 8% solution of lectin-conjugated horseradish peroxidase or 10% dextran tetramethylrhodamine. The fibroglial reaction, accumulation of mononuclear cells, and angiogenesis at the interface between the spinal cord and the sponge were minimal. Cystic cavitation in the spinal cord was virtually absent. Anterograde labeled axons were seen to penetrate and to elongate the full length of the sponge. These results demonstrate that poly-2-hydroxyethyl methacrylate sponges represent a safe supportive material for regenerating spinal cord axons.

Entrapment of the brachial plexus (BP) can be primary or secondary to either trauma or surgery. Most frequently, the BP is entrapped at the “thoracic outlet” resulting in thoracic outlet syndrome (TOS). Hyperabduction syndrome, scalenus anterior (or anticus) syndrome, costoclavicular syndrome, cervical rib syndrome, and long-C7 transverse process syndrome are all entrapment syndromes of the BP. These last terms are used either independently or as part of TOS, although “true TOS” is due to an alteration of the soft tissues at the thoracic outlet and not to bone causes. In 1956, Peet et al. [4] introduced the term TOS to describe a clinical picture with signs and symptoms due to compression of the BP and subclavian vessels at the thoracic outlet. The etiology and clinical presentation of BP entrapment syndromes, including TOS, are variable; diagnosis may be difficult, and treatment is controversial. Knowledge of the anatomy, clinical presentation, diagnostic tools and therapeutic options is very important for correct diagnosis and therapy.

The anatomic reorganization of the subnucleus that controls the stylohyoid muscle (the stylohyoid subnucleus) within the brain stem facial nucleus was studied after regeneration of the facial nerve in adult rats. Horseradish peroxidase was injected into the right stylohyoid muscle 3 to 21 months after transection and repair of the right facial nerve at the level of the stylomastoid foramen. Position, number, and soma diameter of retrogradely horseradish peroxidase-labeled motoneurons were established, as well as the rostro-caudal extension of the stylohyoid subnucleus. In experimental rats, the stylohyoid subnucleus showed either an ipsilateral (50% of the rats) or a bilateral representation. In all of the experimental rats, the motoneurons composing the stylohyoid subnucleus had a more dispersed horizontal distribution pattern when compared with controls. More than 80% of the motoneurons were located outside the borders of the normal stylohyoid subnucleus, either ventrally or, especially in the rostral sections, dorsally closer to the floor of the fourth ventricle. The mean rostro-caudal length of the stylohyoid subnucleus was 2028.6 +/- 152.7 microns. The mean motoneuron number was 481.4 +/- 109.5 (2.20-fold greater than control values), and the motoneuron diameter distribution ranged from 7 to 43 microns. This study demonstrates that after regeneration of the facial nerve in adult rats, major changes occur in both the location and number of motoneurons that make up the stylohyoid subnucleus.(ABSTRACT TRUNCATED AT 250 WORDS)

Advances in comprehension of molecular biology of glioblastoma (GBM) have led to the development of targeted therapies. The aim of the present study was to evaluate the efficacy and safety of a targeted therapeutic approach in which administration of bevacizumab and erlotinib was tailored on the molecular profile of recurrent GBM. We prospectively enrolled ten adult patients suffering from recurrent GBM who had undergone surgical resection and standard chemo-radiotherapy. Tumor tissue was assessed for the expression of EGFRvIII and MGMT promoter methylation by RT-PCR, and for PTEN and VEGF expression by immunohistochemistry. Normal PTEN status was required for inclusion. Patients with VEGF overexpressing tumors (10/10) were treated with bevacizumab (10 mg/kg iv every 2 weeks in 6-week cycles); patients whose tumor expressed EGFRvIII (4/10) added erlotinib (150 mg/day orally; 300 mg/day if on enzyme-inducing antiepileptic drugs). Therapy was continued until disease progression or unacceptable toxicity. Primary endpoints of the study were response rate (RR), 6-month progression-free survival (PFS-6), and safety profile. The RR and PFS-6 were 100 % (4/4) and 50 % (3/6) in patients treated with bevacizumab+erlotinib (n = 4) and bevacizumab (n = 6), respectively. In the whole cohort (n = 10), RR and PFS-6 were both 70 % (7/10); median PFS and overall survival (OS) were 8.0 (3.0–31.0) and 9.5 (5.0–31.0) months, respectively. No grade 3/4 adverse events were observed; three patients treated with bevacizumab+erlotinib displayed grade 1/2 rash not requiring dose reduction; one patient treated with bevacizumab developed intratumoral hemorrhage requiring treatment discontinuation. To our knowledge, this is the first study on recurrent GBM in which administration of bevacizumab and erlotinib was tailored on the molecular profile of the patient’s tumor. Although we treated a limited number of patients, we obtained significantly higher RR and PFS-6 than those reported in a previous trial lacking molecular tumor analysis.

Decompressive hemicraniectomy (DHC) is performed to treat a variety of conditions, such as traumatic brain injury, subarachnoid hemorrhage, and brain swelling following middle cerebral artery (MCA) infarction. The rationale for this treatment is to remove a portion of bone and open the dura mater in order to decrease intracranial pressure (ICP) and prevent brain shift. However, the usefulness of routine hemicraniectomy for MCA infarction is still unclear because some patients may not progress to cerebral herniation [1]. We report on a man submitted to DHC for brain swelling and midline shift following right MCA infarction, whose clinical conditions rapidly ameliorated, despite an increase of cerebral herniation on post-operative CT scan. We, also, review the pertinent literature.

Primary empty sella syndrome (ESS) shares with idiopathic intracranial hypertension (IIH) high intracranial pressure (ICP) and association with obesity. Bariatric surgery is effective in IIH treatment; no data, however, exist about ESS. We report two overweight ESS patients in whom bariatric surgery resolved obesity but failed in curing ESS, requiring cerebrospinal fluid (CSF) shunt placement.

We report on an unusual case of a patient, not affected by neurofibromatosis, harbouring two radiologically spatially contiguous tumours within the same cerebello-pontine angle. Pathological findings were consistent with the diagnosis of two spatially distinct primary tumours, namely a meningioma and a schwannoma. We proposed a classification of tumours occurring at the same location consistent with the different spatial arrangement and histological nature of these conditions. The correct classification of these nosological entities will allow further more accurate evaluations of these cases in order to clarify the pathogenesis, prognosis and best treatment of each one.

Object Communicating hydrocephalus is an uncommon complication in patients treated for glioblastoma multiforme (GBM). Its pathogenesis remains unclear. The authors evaluated the clinical and radiological factors associated with the onset of communicating hydrocephalus and the impact of ventriculoperitoneal (VP) shunt surgery on the outcome of these patients. Methods One hundred twenty-four patients harboring GBM, who had undergone craniotomy for tumor resection and adjuvant radiochemotherapy, were retrospectively assessed. Seven of them developed communicating hydrocephalus and were treated with VP shunt surgery. Clinical and radiological estimates included Karnofsky Performance Scale (KPS) score, previous surgery, overall survival (OS), CSF pressure and components, tumor location, and leptomeningeal dissemination. Results All 7 patients who developed communicating hydrocephalus had undergone at least 2 craniotomies for tumor resection before the onset of hydrocephalus (p = 0.0006; Fisher exact test). Six cases showed high levels of CSF proteins. There was a highly significant relationship between ventricular opening at surgery for tumor recurrence and onset of hydrocephalus (p = 0.0002; Fisher exact test). In these patients, VP shunt surgery was followed by a significant improvement of KPS score (p = 0.0180; Wilcoxon signed-rank test). The median OS after VP shunt insertion was 5 ± 2.9 months. Conclusions Ventricular opening after radiochemotherapy and high CSF protein levels are significant predictors of communicating hydrocephalus in patients with GBM. The VP shunt surgery improves quality of life in these patients.

The spinal cord of adult female rats was completely transected at the T8 level. Nerve growth factor (NGF) was administered at the lesion site via indwelling, implanted, osmotic minipumps. Purified NGF was supplied at doses of 100, 200, and 500 micrograms during a 30-day period. Control rats were treated with saline. At the end of the treatment, the proximal stump of corticospinal tract axons in the spinal cord was labeled with anterograde transported horseradish peroxidase (HRP) injected into the sensorimotor cortex. In control rats, the corticospinal tract axons ended abruptly, proximal to the zone of maximal damage. Sterile swellings developed at the axon tips, and no labeled axonal sprouts were apparent. On the contrary, in NGF-treated animals, the leading front of the corticospinal tract axons showed a trend of approaching the zone of maximal damage following abnormal paths through the dorsal-injured white matter. Axonal sprouts were seen more proximally, traveling toward the transection site in aberrantly located dorsal paths, completely outside the normal position of the corticospinal tract. NGF seems to partly restore the pattern of the regenerative behavior of the severed corticospinal tract axons after spinal cord transection in newborn rats, i.e., the induction of axonal sprouting in aberrantly located dorsal paths. An automated image analysis of the HRP reaction field close to the transection site demonstrated that the density of HRP-labeled axons in the corticospinal tract was significantly higher in the NGF-treated rats than in the control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Propionibacterium acnes (P. acnes) has been associated with shunt infection. The signs of infection are mild. We report on a case of P. acnes shunt infection presenting with massive ascites as the unique sign of CSF infection. Shunt removal, antibiotic therapy and drenaige of ascites were performed with a rapid clinical recovery.

A 42-year-old man with a 9-month history of right leg paresthesias was admitted because of the acute onset of numbness and weakness of the left leg with gait impairment. Neurologic examination demonstrated bilateral lower …