Endoscopic endonasal pituitary surgery: How we do it. Consensus statement on behalf of the EANS skull base section.

Introduction and research question: The use of an endoscope in skull base surgery provides a panoramic close-up view over the intracranial structures from multiple angles with excellent illumination, thus permitting greater extent of resection of tumors arising at sellar area, mostly represented by PitNet - Pituitary neuroendocrine tumors, with higher likelihood of preserving vital/intact gland tissue. For this refined specialty of neurosurgery, unique skills need to be acquired along a steep learning curve. Material and methods: EANS (European Association of Neurosurgical Societies) skull base section panelists were enrolled and 11 completed the survey: the goal was to provide a consensus statement of the endoscopic endonasal approach for pituitary adenoma surgery. Results: The survey consisted of 44 questions covering demographics data (i.e., academic/non-academic center, case load, years of experience), surgical techniques (i.e., use of neuronavigation, preoperative imaging), and follow-up management. Discussion and conclusions: In this paper we identified a series of tips and tricks at different phases of an endoscopic endonasal pituitary surgery procedure to underline the crucial steps to perform successful surgery and reduce complications: we took in consideration the principles of the surgical technique, the knowledge of the anatomy and its variations, and finally the importance of adjoining specialties experts.

Differences in intraoperative sampling during meningioma surgery regarding CNS invasion - Results of a survey on behalf of the EANS skull base section.

Introduction: and Research Question: Invasive growth of meningiomas into CNS tissue is rare but of prognostic significance. While it has entered the WHO classification as a stand-alone criterion for atypia, its true prognostic impact remains controversial. Retrospective analyses, on which the current evidence is based, show conflicting results. Discordant findings might be explained by different intraoperative sampling methodologies. Material and methods: To assess the applied sampling methods in the light of the novel prognostic impact of CNS invasion, an anonymous survey was designed and distributed via the EANS website and newsletter. The survey was open from June 5th until July 15th, 2022. Results: After exclusion of 13 incomplete responses, 142 (91.6%) datasets were used for statistical analysis. Only 47.2% of participants' institutions utilize a standardized sampling method, and 54.9% pursue a complete sampling of the area of contact between the meningioma surface and CNS tissue. Most respondents (77.5%) did not change their sampling practice after introduction of the new grading criteria to the WHO classification of 2016. Intraoperative suspicion of CNS invasion changes the sampling for half of the participants (49.3%). Additional sampling of suspicious areas of interest is reported in 53.5%. Dural attachment and adjacent bone are more readily sampled separately if tumor invasion is suspected (72.5% and 74.6%, respectively), compared to meningioma tissue with signs of CNS invasion (59.9%). Discussion and conclusions: Intraoperative sampling methods during meningioma resection vary among neurosurgical departments. There is need for a structured sampling to optimize the diagnostic yield of CNS invasion.

Update in Cushing disease: What the neurosurgeon has to KNOW, on behalf of the EANS skull base section.

Introduction: Cushing's disease is a state of chronic and excessive cortisol levels caused by a pituitary adenoma. Research question: CD is a complex entity and often entails difficulties in its diagnosis and management. For that reason, there are still controversial points to that respect. The aim of this consensus paper of the skull base section of the EANS is to review the main aspects of the disease a neurosurgeon has to know and also to offer updated recommendations on the controversial aspects of its management. Material and methods: PUBMED database was used to search the most pertinent articles published on the last 5 years related with the management of CD. A summary of literature evidence was proposed for discussion within the EANS skull base section and other international experts. Results: This article represents the consensual opinion of the task force regarding optimal management and surgical strategy in CD. Discussion and conclusion: After discussion in the group several recommendations and suggestions were elaborated. Patients should be treated by an experienced multidisciplinary team. Accurate clinical, biochemical and radiological diagnosis is mandatory. The goal of treatment is the complete adenoma resection to achieve permanent remission. If this is not possible, the treatment aims to achieving eucortisolism. Radiation therapy is recommended to patients with CD when surgical options have been exhausted. All patients in remission should be tested all life-long.

Surgical management of giant pituitary neuroendocrine tumors: Meta-analysis and consensus statement on behalf of the EANS skull base section.

Introduction: The optimal surgical treatment for giant pituitary neuroendocrine tumors(GPitNETs) is debated. Research question: The aim of this paper is to optimize the surgical management of these patients and to provide a consensus statement on behalf of the EANS Skull Base Section. Material and methods: We constituted a task force belonging to the EANS skull base committee to define some principles for the management of GPitNETs. A systematic review was performed according to PRISMA guidelines to perform a meta-analysis on surgical series of GPitNETs. Weighted summary rates were obtained for the pooled extent of resection and according to the surgical technique. These data were discussed to obtain recommendations after evaluation of the selected articles and discussion among the experts. Results: 20articles were included in our meta-analysis, for a total of 1263 patients. The endoscopic endonasal technique was used in 40.3% of cases, the microscopic endonasal approach in 34% of cases, transcranial approaches in 18.7% and combined approaches in 7% of cases. No difference in terms of gross total resection (GTR) rate was observed among the different techniques. Pooled GTR rate was 36.6%, while a near total resection (NTR) was possible in 45.2% of cases. Cavernous sinus invasion was associated with a lower GTR rate (OR: 0.061). After surgery, 35% of patients had endocrinological improvement and 75.6% had visual improvement. Recurrent tumors were reported in 10% of cases. Discussion and conclusion: After formal discussion in the working group, we recommend the treatment of G-PitNETs tumors with a more complex and multilobular structure in tertiary care centers. The endoscopic endonasal approach is the first option of treatment and extended approaches should be planned according to extension, morphology and consistency of the lesion. Transcranial approaches play a role in selected cases, with a multicompartmental morphology, subarachnoid invasion and extension lateral to the internal carotid artery and in the management of residual tumor apoplexy.

Management of non-vestibular schwannomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section Part II: Trigeminal and facial nerve schwannomas (CN V, VII).

BACKGROUND: Non-vestibular schwannomas are relatively rare, with trigeminal and jugular foramen schwannomas being the most common. This is a heterogenous group which requires detailed investigation and careful consideration to management strategy. The optimal management for these tumours remains unclear and there are several controversies. The aim of this paper is to provide insight into the main principles defining management and surgical strategy, in order to formulate a series of recommendations. METHODS: A task force was created by the EANS skull base section committee along with its members and other renowned experts in the field to generate recommendations for the surgical management of these tumours on a European perspective. To achieve this, the task force performed an extensive systematic review in this field and had discussions within the group. This article is the second of a three-part series describing non-vestibular schwannomas (V, VII). RESULTS: A summary of literature evidence was proposed after discussion within the EANS skull base section. The constituted task force dealt with the practice patterns that exist with respect to pre-operative radiological investigations, ophthalmological assessments, optimal surgical and radiotherapy strategies, and follow-up management. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the treatment of trigeminal and facial schwannoma. The aim of treatment is maximal safe resection with preservation of function. Careful thought is required to select the appropriate surgical approach. Most middle fossa trigeminal schwannoma tumours can be safely accessed by a subtemporal extradural middle fossa approach. The treatment of facial nerve schwannoma remains controversial.

Management of non-vestibular schwannomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section Part III: Lower cranial nerve schwannomas, jugular foramen (CN IX, X, XI) and hypoglossal schwannoma (XII).

BACKGROUND: Non-vestibular schwannomas are relatively rare, with trigeminal and jugular foramen schwannomas being the most common. This is a heterogenous group which requires detailed investigation and careful consideration to management strategy. The optimal management for these tumours remains unclear, and there are several controversies. The aim of this paper is to provide insight into the main principles defining management and surgical strategy, in order to formulate a series of recommendations. METHODS: A task force was created by the EANS skull base section committee along with its members and other renowned experts in the field to generate recommendations for the surgical management of these tumours on a European perspective. To achieve this, the task force performed an extensive systematic review in this field and had discussions within the group. This article is the third of a three-part series describing non-vestibular schwannomas (IX, X, XI, XII). RESULTS: A summary of literature evidence was proposed after discussion within the EANS skull base section. The constituted task force dealt with the practice patterns that exist with respect to preoperative radiological investigations, ophthalmological assessments, optimal surgical and radiotherapy strategies and follow-up management. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the treatment of non-vestibular schwannomas. For each of these tumours, the management paradigm is shifting towards the compromise between function preservation and progression free survival.

Olfactory Groove Meningiomas: Comprehensive assessment between the different microsurgical transcranial approaches and the Endoscopic Endonasal Approaches, systematic review and metanalysis on behalf of the EANS skull base section.

•OGM surgery is much more complex than a simple debate of "from above or from below" (transcranial vs endoscopic).•Lateral Sub-frontal and Superior Interhemispheric seem the most effective, superior and versatile approaches for OGM.•Minimally Invasive Transcranial approaches showed no inferiority in OGM sized <4 â€‹cm.•Endoscopic Endonasal Approaches showed inferior results in surgical and in functional outcomes for OGM.

Management of non-vestibular schwannomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section. Part I: oculomotor and other rare non-vestibular schwannomas (I, II, III, IV, VI).

BACKGROUND: Non-vestibular schwannomas are relatively rare, with trigeminal and jugular foramen schwannomas being the most common. This is a heterogeneous group which requires detailed investigation and careful consideration to management strategy. The optimal management for these tumours remains unclear, and there are several controversies. The aim of this paper is to provide insight into the main principles defining management and surgical strategy, in order to formulate a series of recommendations. METHODS: A task force was created by the EANS skull base section along with its members and other renowned experts in the field to generate recommendations for the surgical management of these tumours on a European perspective. To achieve this, the task force performed an extensive systematic review in this field and had discussions within the group. This article is the first of a three-part series describing non-vestibular schwannomas (I, II, III, IV, VI). RESULTS: A summary of literature evidence was proposed after discussion within the EANS skull base section. The constituted task force dealt with the practice patterns that exist with respect to pre-operative radiological investigations, ophthalmological assessments, optimal surgical and radiotherapy strategies and follow-up management. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the treatment of non-vestibular schwannomas. For each of these tumours, the management of these patients is complex, and for those which are symptomatic tumours, the paradigm is shifting towards the compromise between function preservation and progression-free survival.

Aggressive pituitary neuroendocrine tumors: current practices, controversies, and perspectives, on behalf of the EANS skull base section.

Aggressive pituitary neuroendocrine tumors (APT) account for 10% of pituitary tumors. Their management is a rapidly evolving field of clinical research and has led pituitary teams to shift toward a neuro-oncological-like approach. The new terminology "Pituitary neuroendocrine tumors" (PitNet) that was recently proposed to replace "pituitary adenomas" reflects this change of paradigm. In this narrative review, we aim to provide a state of the art of actual knowledge, controversies, and recommendations in the management of APT. We propose an overview of current prognostic markers, including the recent five-tiered clinicopathological classification. We further establish and discuss the following recommendations from a neurosurgical perspective: (i) surgery and multi-staged surgeries (without or with parasellar resection in symptomatic patients) should be discussed at each stage of the disease, because it may potentialize adjuvant medical therapies; (ii) temozolomide is effective in most patients, although 30% of patients are non-responders and the optimal timeline to initiate and interrupt this treatment remains questionable; (iii) some patients with selected clinicopathological profiles may benefit from an earlier local radiotherapy and/or chemotherapy; (iv) novel therapies such as VEGF-targeted therapies and anti-CTLA-4/anti-PD1 immunotherapies are promising and should be discussed as 2nd or 3rd line of treatment. Finally, whether neurosurgeons have to operate on "pituitary adenomas" or "PitNets," their role and expertise remain crucial at each stage of the disease, prompting our community to deal with evolving concepts and therapeutic resources.

Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines.

Glioblastoma multiforme, the most common type of malignant brain tumor as well as the most aggressive one, lacks an effective therapy. Glioblastoma presents overexpression of mesenchymal markers Snail, Slug, and N-Cadherin and of the autophagic marker p62. Glioblastoma cell lines also present increased autophagy, overexpression of mesenchymal markers, Shh pathway activation, and lack of primary cilia. In this study, we aimed to evaluate the role of HDAC6 in the pathogenesis of glioblastoma, as HDAC6 is the most overexpressed of all HDACs isoforms in this tumor. We treated glioblastoma cell lines with siHDAC6. HDAC6 silencing inhibited proliferation, migration, and clonogenicity of glioblastoma cell lines. They also reversed the mesenchymal phenotype, decreased autophagy, inhibited Shh pathway, and recovered the expression of primary cilia in glioblastoma cell lines. These results demonstrate that HDAC6 might be a good target for glioblastoma treatment.

APR-246 combined with 3-deazaneplanocin A, panobinostat or temozolomide reduces clonogenicity and induces apoptosis in glioblastoma cells.

Glioblastoma is the most malignant brain tumor and presents high resistance to chemotherapy and radiotherapy. Surgery, radiotherapy and chemotherapy with temozolomide are the only treatments against this tumor. New targeted therapies, including epigenetic modulators such as 3­deazaneplanocin A (DZ­Nep; an EZH2 inhibitor) and panobinostat (a histone deacetylase inhibitor) are being tested in vitro, together with temozolomide. The present study combined APR­246 with DZ­Nep, panobinostat and teomozolomide in order to explore the possibility of restoring p53 function in mutated cases of glioblastoma. Following the Chou­Talalay method it was demonstrated that APR­246 acts in an additive manner together with the other compounds, reducing clonogenicity and inducing apoptosis in glioblastoma cells independently of p53 status.

Surgical management for large vestibular schwannomas: a systematic review, meta-analysis, and consensus statement on behalf of the EANS skull base section.

BACKGROUND AND OBJECTIVE: The optimal management of large vestibular schwannomas continues to be debated. We constituted a task force comprising the members of the EANS skull base committee along with international experts to derive recommendations for the management of this problem from a European perspective. MATERIAL AND METHODS: A systematic review of MEDLINE database, in compliance with the PRISMA guidelines, was performed. A subgroup analysis screening all surgical series published within the last 20 years (January 2000 to March 2020) was performed. Weighted summary rates for tumor resection, oncological control, and facial nerve preservation were determined using meta-analysis models. This data along with contemporary practice patterns were discussed within the task force to generate consensual recommendations regarding preoperative evaluations, optimal surgical strategy, and follow-up management. RESULTS: Tumor classification grades should be systematically used in the perioperative management of patients, with large vestibular schwannomas (VS) defined as > 30 mm in the largest extrameatal diameter. Grading scales for pre- and postoperative hearing (AAO-HNS or GR) and facial nerve function (HB) are to be used for reporting functional outcome. There is a lack of consensus to support the superiority of any surgical strategy with respect to extent of resection and use of adjuvant radiosurgery. Intraoperative neuromonitoring needs to be routinely used to preserve neural function. Recommendations for postoperative clinico-radiological evaluations have been elucidated based on the surgical strategy employed. CONCLUSION: The main goal of management of large vestibular schwannomas should focus on maintaining/improving quality of life (QoL), making every attempt at facial/cochlear nerve functional preservation while ensuring optimal oncological control, thereby allowing to meet patient expectations. Despite the fact that this analysis yielded only a few Class B evidences and mostly expert opinions, it will guide practitioners to manage these patients and form the basis for future clinical trials.

The synergistic effect of DZ­NEP, panobinostat and temozolomide reduces clonogenicity and induces apoptosis in glioblastoma cells.

Current treatment against glioblastoma consists of surgical resection followed by temozolomide, with or without combined radiotherapy. Glioblastoma frequently acquires resistance to chemotherapy and/or radiotherapy. Novel therapeutic approaches are thus required. The inhibition of enhancer of zeste homolog 2 (EZH2; a histone methylase) and histone deacetylases (HDACs) are possible epigenetic treatments. Temozolomide, 3­deazaneplanocin A (DZ­Nep; an EZH2 inhibitor) and panobinostat (an HDAC inhibitor) were tested in regular and temozolomide­resistant glioblastoma cells to confirm whether the compounds could behave in a synergistic, additive or antagonistic manner. A total of six commercial cell lines, two temozolomide­induced resistant cell lines and two primary cultures derived from glioblastoma samples were used. Cell lines were exposed to single treatments of the drugs in addition to all possible two­ and three­drug combinations. Colony formation assays, synergistic assays and reverse transcription­quantitative PCR analysis of apoptosis­associated genes were performed. The highest synergistic combination was DZ­Nep + panobinostat. Triple treatment was also synergistic. Reduced clonogenicity and increased apoptosis were both induced. It was concluded that the therapeutic potential of the combination of these three drugs in glioblastoma was evident and should be further explored.

[Ectopic pituitary adenoma associated with empty sella turcica]. / Adenoma hipofisario ectópico asociado a silla turca vacía.

Ectopic pituitary adenoma is a rare entity that is most commonly located in the sphenoid sinus. We report a case of a patient with ectopic pituitary adenoma with no functional expression associated with empty sella turcica, which gives rise to a broad differential diagnosis. Although it is a benign neoplasm, necrosis is encountered in a proportion of cases. Magnetic resonance imaging is the diagnostic method of choice for hypothalamic-pituitary-related endocrine diseases with endoscopic biopsy for histological confirmation. It is important to include pituitary markers in the immunohistochemical diagnostic panel.

Dumbbell malignant dorsal schwannoma embolized and operated by single posterior approach. / Schwannoma maligno dorsal en reloj de arena embolizado e intervenido por abordaje posterior único.

We report a case of a 41 years old patient complaining of chronic dorsalgia. MRI showed a well defined intradural extramedular dumbbell-shaped lesion, associated to a left paravertebral tumor at D5-D6 level. The tumor was embolizated prior to surgery. Following she underwent a D4-D6 laminotomy, left D5-D6 costotransversectomy and resection of the intracanal extradural part of the lesion with section of the left D5 nerve. Posteriorly, complete resection of the extracanal portion of the tumor was performed by a postero-lateral approach. The anatomopathologic diagnosis was a malignant schwannoma. After the surgery, the patient required adyuvant radiotherapic treatment. Malignant schwannoma is a very uncommon tumor which belongs to the malignant peripheral nerve sheath tumors (MPNST). It develops from Schwann cells. It is frequently associated with type 1 neurofibromatosis. MPNST usually present local recurrence and can metastatize.

Retroclival epidural haematoma: a diagnosis to suspect. Report of three cases and review of the literature.

Retroclival epidural haematoma (REDH) has been reported infrequently. It is a rare entity which is probably underdiagnosed. It is most commonly seen in the paediatric population and is generally associated with high-velocity injuries. We report three cases of paediatric patients diagnosed with REDHs: two of them secondary to high-energy trauma related to a motor-vehicle accident and the other a low-energy trauma after a slip while playing football. All three patients were managed conservatively by cervical immobilisation with favourable outcome. REDH is probably underdiagnosed by computed tomography scan. When the suspicion is high, sagittal reconstructions or magnetic resonance imaging should be considered to confirm the diagnosis. Usually, it is related to hyperflexion or hyperextension cervical injuries secondary to motor vehicle accident. However, it can also be observed in milder injuries.

[Comparison of intracranial meningioma outcome scales in operated patients older than 65 years old. Our experience between 2002-2012 and a literature review]. / Comparación de escalas pronósticas en pacientes mayores de 65 años intervenidos de meningioma intracraneal. Nuestra experiencia entre 2002-2012 y revisión de la literatura.

OBJECTIVE: Meningioma is the most common intracranial tumor in the elderly. Its incidence rate increases with age; so as life expectancy increases, meningiomas are diagnosed more frequently. A comparison is made between 4 outcome scales in this study: Clinical-Radiological Grading System, Geriatric Scoring Scale, SKALE (Sex, Karnofsky, ASA, localization and edema), and the Charlson score, to analyze which patients could benefit from surgery. MATERIALS AND METHODS: A total of 52 patients of 65 years and older operated in our hospital between 2002 and 2012 were identified, and a retrospective analysis was performed. All individual variables were collected and applied the scales to see their relationship with 3 month and annual mortality. The critical values of each scale were applied and their positive and negative predictive values were calculated. RESULTS: From the four scales, only the Clinical-Radiological Grading System and the SKALE had a significant statistical result when annual mortality was analyzed. None of them were associated with 3 month mortality. There was no statistically significant association between mortality and sex, edema, previous clinical history, and tumor location. But there was an association with age, tumor size and previous Karnofsky. CONCLUSION: The SKALE and the Clinical-Radiological Grading System are easy tools that can give an insight as regards patients who can benefit from a surgical treatment. Nevertheless, individualized patient analysis and neurosurgeon experience still have great importance.

Epigenetic regulation of human hedgehog interacting protein in glioma cell lines and primary tumor samples.

Glioma constitutes one of the most common groups of brain tumors, and its prognosis is influenced by different genetic and epigenetic modulations. In this study, we demonstrated low or no expression of hedgehog interacting protein (HHIP) in most of the cell lines and primary glioma tumor samples. We further proceeded to promoter methylation study of this gene in the same cell lines and primary tumor samples and found 87 % (7/8) HHIP methylation in glioblastoma cell lines and 75 % (33/44) in primary tumor samples. These methylation pattern correlates with low or unexpressed HHIP in both cell lines and primary tumor samples. Our results suggest the possibility of epigenetic regulation of this gene in glioma, similarly to medulloblastoma, gastric, hepatic, and pancreatic cancers. Also, HHIP might be a diagnostic or prognostic marker in glioma and help to the detection of these tumors in early stages of disease.

A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool.

BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults, and its prognosis remains dismal despite intensive research and therapeutic advances. Diagnostic biomarkers would be clinically meaningful to allow for early detection of the tumor and for those cases in which surgery is contraindicated or biopsy results are inconclusive. Recent findings show that GBM cells release microvesicles that contain a select subset of cellular proteins and RNA. The aim of this hypothesis-generating study was to assess the diagnostic potential of miRNAs found in microvesicles isolated from the serum of GBM patients. METHODS: To control disease heterogeneity, we used patients with newly diagnosed GBM. In the discovery stage, PCR-based TaqMan Low Density Arrays followed by individual quantitative reverse transcriptase polymerase chain reaction were used to test the differences in the miRNA expression levels of serum microvesicles among 25 GBM patients and healthy controls paired by age and sex. The detected noncoding RNAs were then validated in another 50 GBM patients. RESULTS: We found that the expression levels of 1 small noncoding RNA (RNU6-1) and 2 microRNAs (miR-320 and miR-574-3p) were significantly associated with a GBM diagnosis. In addition, RNU6-1 was consistently an independent predictor of a GBM diagnosis. CONCLUSIONS: Altogether our results uncovered a small noncoding RNA signature in microvesicles isolated from GBM patient serum that could be used as a fast and reliable differential diagnostic biomarker.

Promoter Methylation of RASSF1A Associates to Adult Secondary Glioblastomas and Pediatric Glioblastomas.

While allelic losses and mutations of tumor suppressor genes implicated in the etiology of astrocytoma have been widely assessed, the role of epigenetics is still a matter of study. We analyzed the frequency of promoter hypermethylation by methylation-specific PCR (MSP) in five tumor suppressor genes (PTEN, MGMT, RASSF1A, p14(ARF), and p16(INK4A)), in astrocytoma samples and cell lines. RASSF1A was the most frequently hypermethylated gene in all grades of astrocytoma samples, in cell lines, and in adult secondary GBM. It was followed by MGMT. PTEN showed a slight methylation signal in only one GBM and one pilocytic astrocytoma, and in two cell lines; while p14(ARF) and p16(INK4A) did not show any evidence of methylation in primary tumors or cell lines. In pediatric GBM, RASSF1A was again the most frequently altered gene, followed by MGMT; PTEN, p14 and p16 showed no alterations. Lack or reduced expression of RASSF1A in cell lines was correlated with the presence of methylation. RASSF1A promoter hypermethylation might be used as a diagnostic marker for secondary GBM and pediatric GBM. Promoter hypermethylation might not be an important inactivation mechanism in other genes like PTEN, p14(ARF) and p16(INK4A), in which other alterations (mutations, homozygous deletions) are prevalent.