What is the current clinical practice in pituitary adenoma surgery in Europe? European Pituitary Adenoma Surgery Survey (EU-PASS) results-technical part.

Pituitary adenoma surgery has evolved rapidly in recent decades, changing clinical practice markedly and raising new challenges. There is no current consensus or guidelines for perioperative care that includes possible complication management. This study aims to determine current practice across European neurosurgical centres. We created a list of eligible departments performing pituitary adenoma surgery based on cooperation with EANS, national neurosurgical societies, and personal communication with local neurosurgeons. We contacted the chairpersons from each department and asked them (or another responsible neurosurgeon) to fill out the survey. The survey consisted of 58 questions. For further analysis, departments were divided into subgroups: "academic"/ "non-academic centre", "high-volume"/"low-volume", "mainly endoscopic"/ "mainly microscopic"/ "mixed practise", and by geographical regions. Data from 254 departments from 34 countries were obtained. The average time to complete the survey was 18 min. Notably, the endoscopic approach is the predominant surgical approach in Europe, used in 56.8% of the centres. In routine cases without intraoperative cerebrospinal fluid leak, high-volume centres are less pedantic with sellar closure when compared with low-volume centres (p < 0.001). On the other hand, when a postoperative cerebrospinal fluid leak occurs, high-volume centres are more active and indicate early reoperation (p = 0.013). Less than 15% of the participating centres perform early postoperative MRI scans. Marked variation was noted among different groups of respondents and some contentious issues are discussed. Such information can encourage useful debate about the reasons for the variations seen and perhaps help develop standardised protocols to improve patient outcomes. A future research focus is to compare European results with other regions.

High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML.

Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade.

Should neurosurgeons continue to work in the absence of personal protective equipment during the COVID-19 era?

The COVID-19 pandemic has resulted in a widespread shortage of personal protective equipment (PPE). Many healthcare workers, including neurosurgeons, have expressed concern about how to safely and adequately perform their medical responsibilities in these challenging circumstances. One of these concerns revolves around the pressing question: should providers continue to work in the absence of adequate PPE? Although the first peak of the COVID-19 crisis seems to have subsided and supply of PPE has increased, concerns about insufficient PPE availability remain. Inconsistent supply, limited efficacy, and continued high demand for PPE, combined with the continued threat of a second COVID-19 wave, mean that the issues surrounding PPE availability remain unresolved, including a duty to work. This paper offers an ethical investigation of whether neurosurgeons should perform their professional responsibilities with limited availability of PPE. We evaluate ethical considerations and conflicting duties and thereby hope to facilitate providers in making a well-considered personal and moral decision about this challenging issue.

Ethical triage during the COVID-19 pandemic: a toolkit for neurosurgical resource allocation.

BACKGROUND: The COVID-19 pandemic confronts healthcare workers, including neurosurgeons, with difficult choices regarding which patients to treat. METHODS: In order to assist ethical triage, this article gives an overview of the main considerations and ethical principles relevant when allocating resources in times of scarcity. RESULTS: We discuss a framework employing four principles: prioritizing the worst off, maximizing benefits, treating patients equally, and promoting instrumental value. We furthermore discuss the role of age and comorbidity in triage and highlight some principles that may seem intuitive but should not form a basis for triage. CONCLUSIONS: This overview is presented on behalf of the European Association of Neurosurgical Societies and can be used as a toolkit for neurosurgeons faced with ethical dilemmas when triaging patients in times of scarcity.

Neurosurgical procedures performed during residency in Europe-preliminary numbers and time trends.

BACKGROUND: Differences in the postgraduate training programs of neurosurgical residents are suspected throughout Europe. The influence of working hour restrictions by the European Working Time Directive (WTD) 2003/88/EC on the number of surgical procedures remains unclear. We designed a survey to collect information on the number of surgical procedures, performed by European neurosurgical trainees during residency. This article reports preliminary data. METHODS: An electronic survey was distributed among the European Association of Neurosurgical Societies (EANS) member countries by national delegates of the training committee, as well as by members of the Young Neurosurgeons' committee. The EANS mailing list of individual members was also used for distribution. All responses received between 04/2018 and 12/2018 were considered. RESULTS: From n = 180 responses received, 42 were omitted as responders were still in residency and for 58 relevant information was missing. The final sample was n = 80, with a mean responder's age of 43.0 years (SD 8.6) and 88.8% being male. Responses came from 16 European countries; board certification was received between the years of 1976-2018. The numbers of surgical procedures performed independently were 511 (mean, 95% confidence interval (CI) 413-610), supervised were 514 (95%CI 360-668) and assisted were 752 (95%CI 485-1019) throughout residency. More detailed numbers for specific procedure types are reported in the article. Independently performed cranial procedures outnumbered spinal procedures (p < 0.006), and adult procedures outnumbered pediatric procedures (p < 0.001). There was a strong decrease in caseload between 1976 and 2018, with trainees performing on average 65 cases less throughout residency for each calendar year increase in board certification (95% CI - 116 to - 15, p = 0.012). Trainees graduating residency before introduction of the European WTD 2003/88/EC participated in more procedures than those graduating afterwards (mean 2797 vs. 1418, p = 0.005). CONCLUSIONS: The preliminary analysis of the first 80 responses now provides a first reference frame for caseload that can be used by current and future European residents to critically compare their own operative numbers to. There was a strong decline in surgical cases over time, and trainees graduating after introduction of the European WTD 2003/88/EC had less surgical exposure. The survey remains open, and we invite further European neurosurgeons to provide their data in order to get even more robust estimates.

Congenital Spinal Malformation and Stroke: Aneurysmal Dilatations and Bilateral Rotational Vertebral Artery Occlusion.

A 30-year-old woman suffered from acute vertebrobasilar stroke. Cranial tomography (CT) scans showed multiple vertebral abnormalities suggestive of congenital spine malformation, and angiographic CT revealed aneurysmal dilatations (ADs) at segment V2 of both vertebral arteries (VAs). Dynamic neuroimaging tests including angiography and angio-CT were performed and showed occlusion of both VAs at the point of the ADs with contralateral rotation of the neck. The presence of a bony structure causing the artery compression was excluded and embolic phenomena originating at the AD was proposed as the likely source of stroke. Even if infrequent, the presence of craniocervical anomalies should be considered in vertebrobasilar stroke of indeterminate etiology.

[Treatment of giant acoustic neuromas]. / Tratamiento del neurinoma acústico gigante.

INTRODUCTION AND OBJECTIVES: To analyze the treatment modality and outcome of a series of patients with giant acoustic neuromas, a particular type of tumour characterised by their size (extracanalicular diameter of 4cm or more) and high morbidity and mortality. MATERIALS AND METHODS: This was a retrospective unicentre study of patients with acoustic neuromas treated in a period of 12 years. In our institutional series of 108 acoustic neuromas operated on during that period, we found 13 (12%) cases of giant acoustic neuromas. We reviewed the available data of these cases, including presentation and several clinical, anatomical, and microsurgical aspects. RESULTS: All patients were operated on by the same neurosurgeon and senior author (EU) using the suboccipital retrosigmoid approach and complete microsurgical removal was achieved in 10 cases. In one case, near total removal was deliberately performed, in another case a CSF shunt was placed as the sole treatment measure, and in the remaining case no direct treatment was given. One patient died in the immediate postoperative period. One year after surgery, 4 patients showed facial nerve function of iii or more in the House-Brackman scale. CONCLUSIONS: The 4 most important prognostic characteristics of giant acoustic neuromas are size, adhesion to surrounding structures, consistency and vascularity. Only the first of these is evident in neuroimaging. Giant acoustic neuromas are characterised by high morbidity at presentation as well as after treatment. Nevertheless, the objective of complete microsurgical removal with preservation of cranial nerve function is attainable in some cases through the suboccipital retrosigmoid approach.

[Frameless stereotactic biopsy: diagnostic yield and complications]. / Biopsia cerebral estereotáctica sin marco: capacidad diagnóstica y complicaciones.

OBJECTIVE: The aim of this study was to evaluate the variables that could modify the diagnostic yield of frameless stereotactic biopsy, as well as its complications. MATERIALS AND METHOD: This was a retrospective study of frameless stereotactic biopsies carried out between July 2008 and December 2011 at Donostia University Hospital. The variables studied were size, distance to the cortex, contrast uptake and location. RESULTS: A total of 70 patients were included (75 biopsies); 39 males and 31 females with an age range between 39 and 83 years. The total diagnostic yield in our series was 97.1%. For lesions >19mm, the technique offered a sensitivity of 95.2% (95% CI: 86.9-98.4) and specificity of 57.1% (95% CI: 25.0-84.2). The yield was lower for lesions within 17mm of the cortex: sensitivity of 74.6% (95% CI: 62.1-84.7) and specificity of 71.4% (95% CI: 29.0-96.3). Seven (10%) patients developed complications after the first biopsy and none after the second. CONCLUSIONS: The diagnostic yield was lower for lesions less than 2cm in size and located superficially. In this series we did not observe an increased rate of complications after a second biopsy.

Semisitting position for cerebello-pontine angle surgery: Analysis of complications and how to avoid it.

OBJECTIVE: To analyze the primary complications related to semisitting position in patients undergoing cerebelo-pontine angle surgery. METHODS: Retrospective data analysis from patients undergoing elective tumoral cerebelo-pontine angle surgery in a semisitting position. The incidence, severity, occurrence moment, treatment, duration, and outcomes of venous air embolism (VAE), pneumocephalus, postural hypotension, and other complications were recorded. Neurointensive care unit (NICU), length of stay (LOS), hospital LOS, and modified Rankin scale scores were calculated six months after surgery. RESULTS: Fifty patients were operated on. Eleven (22%) presented VAE (mean duration 8±4.5min): five (10%) during tumor resection, and four (8%) during dural opening. Ten (20%) were resolved by covering the surgical bed, air bubbles aspiration, jugular compression, and one (2%) tilted to a steep Trendelenburg position. One (2%) had intraoperative hemodynamic instability. The only variable associated with VAE was meningioma at histopathology OR=4.58, p=0.001. NICU was higher in patients with VAE (5.5±1.06 vs. 1.9±0.20 days, p=0.01). There were no differences in the Rankin scale. All patients presented postoperative pneumocephalus with a good level of consciousness, except one (2%) who required evacuation. Seven patients (14%) showed postural hypotension, three (6%) after positioning, and one (2%) after developing a VAE; all were reversed with usual vasoactive drugs. No other position-related complications or mortality were registered in this series. CONCLUSIONS: The semisitting position is a safe option with the knowledge, prevention, detection, and early solution of all the possible complications. The development of VAE rarely implies hemodynamic instability or greater disability after surgery. Postoperative pneumocephalus is very common and rarely requires evacuation. Excellent cooperation between anesthesia, nursing, neurophysiology, and neurosurgery teams is essential to manage complications.

Current advances in temozolomide encapsulation for the enhancement of glioblastoma treatment.

Glioblastoma is the most common and lethal brain tumor in adults. The incorporation of temozolomide (TMZ) into the standard treatment has increased the overall survival rate of glioblastoma patients. Since then, significant advances have been made in understanding the benefits and limitations of TMZ. Among the latter, the unspecific toxicity of TMZ, poor solubility, and hydrolyzation are intrinsic characteristics, whereas the presence of the blood-brain barrier and some tumor properties, such as molecular and cellular heterogeneity and therapy resistance, have limited the therapeutic effects of TMZ in treating glioblastoma. Several reports have revealed that different strategies for TMZ encapsulation in nanocarriers overcome those limitations and have shown that they increase TMZ stability, half-life, biodistribution, and efficacy, offering the promise for future nanomedicine therapies in handling glioblastoma. In this review, we analyze the different nanomaterials used for the encapsulation of TMZ to improve its stability, blood half-life and efficacy, paying special attention to polymer- and lipid-based nanosystems. To improve TMZ drug resistance, present in up to 50% of patients, we detail TMZ combined therapeutic with i) other chemotherapies, ii) inhibitors, iii) nucleic acids, iv) photosensitizers and other nanomaterials for photodynamic therapy, photothermal therapy, and magnetic hyperthermia, v) immunotherapy, and vi) other less explored molecules. Moreover, we describe targeting strategies, such as passive targeting, active targeting to BBB endothelial cells, glioma cells, and glioma cancer stem cells, and local delivery, where TMZ has demonstrated an improved outcome. To finish our study, we include possible future research directions that could help decrease the time needed to move from bench to bedside.

[Functions and organisation of a neuro-oncology committee in hospitals with a neurosurgery service]. / Funciones y organización de un comité de neurooncología en un hospital con servicio de neurocirugía.

The Neuro-Oncology Study Group (NOSG) at SENEC has commissioned the elaboration of the present document to the Neuro-Oncology Committee at Donostia University Hospital. It is intended to serve as a NOSG Consensus Guide and a proposed recommendation for the management of this pathological condition at all Spanish Hospitals, both public and private. Neuro-Oncology Committees must be established and active at all centres with a Neurosurgery Service, taking into account the specific diagnostic and therapeutic capacity available. The work presents an example of the constitution, functioning and experience of such a Committee, drawing on 8 years of multidisciplinary work with brain tumour patients.

Ethico-legal regional differences in European neurosurgical practice: Part 1-pre-COVID-19 era.

Introduction: Professionalism entails expert knowledge, self-regulation, accountability, and professional ethics. These factors are influenced by culture, political observance, professional maturity, education, and occupation; ethical practices may thus vary between countries and affect how neurosurgery is practiced. Research question: This paper aims to conduct a survey that addresses whether ethico-legal practices differ in European countries and whether existing ethical guidelines have been implemented. Material and methods: A questionnaire survey was used to examine the ethico-legal situation in 29 European countries or regions. The reports were validated by representatives of each nation. Results: Existing guidelines had been implemented to a minimal extent. Major regional and national differences were found in attitudes toward life and death, prioritization, and issues related to professional conduct. Discussion and conclusion: The results of this survey reveal inadequacies and weaknesses of policies and resources, which should spark national discussions to improve the conditions that influence professional ethics. Unfortunately, only a minority of neurosurgeons know the neurosurgical ethics guidelines and apply them in their decision making. Our findings highlight the importance of values and professional ethics in decision making.

Atypical facial pain after cranioplasty: A too perfect design?: Dolor facial atípico asociado a craneoplastia: ¿un encaje demasiado perfecto?

Cranioplasty is a procedure routinely performed in neurosurgery. It is associated with significant morbidity and several types of postsurgical complications. The most common are infections, bone flap resorption and hematomas. Atypical facial pain has not been documented yet as a potential postoperative complication. We present a case of atypical facial pain reported at inmediate postoperative period after cranioplasty. The pain was refractory to medical treatment and sphenopalatine ganglion block. Eventually, the pain totally disappeared after surgical revision of the cranial implant.

Pituitary Adenoma Surgery Survey: Neurosurgical Centers and Pituitary Adenomas.

Objective: Pituitary adenoma surgery has evolved rapidly in recent decades. This study aims to determine current practice across a wide range of European neurosurgical centers. Methods: A list of eligible departments performing pituitary adenoma surgery was created. The survey consisted of 58 questions. For analysis, the departments were divided into four subgroups: academic/nonacademic, high-volume/low-volume, "mainly endoscopic/mainly microscopic practice," and geographical regions. Results: Data from 254 departments from 34 countries were obtained. In 108 centers (42.5%), <30 pituitary adenomas were operated per year. Twenty (7.9%) centers performed >100 adenoma surgeries per year. Number of neurosurgeons performing endonasal surgeries are as follows: 1 in 24.9% of centers and 2 in 49.8% of centers. All residents assisted endonasal surgeries in 126 centers (49.8%). In 28 centers (21.1%), all residents performed endonasal surgery under supervision during residency. In 141 centers (56.8%), the endoscopic approach was used in >90% of the surgeries. Regular pituitary board (either weekly or once a month) meetings were held in 147 centers (56.3%). Nonfunctioning adenomas represent >70% of pituitary caseload in 149 centers (58.7%). Conclusions: In our survey, most centers perform less than 100 surgeries for pituitary adenomas. In most centers, pituitary surgeries are performed by one or two neurosurgeons. Residents have a limited exposure to this type of surgery, and the formal pituitary board is not a standard. Nonfunctioning adenomas make up most of surgically treated adenomas. This study can serve as a benchmark for further analyses of pituitary adenoma centers in Europe.

Endocrinological aspects of pituitary adenoma surgery in Europe.

Hormone-secreting adenomas are treated in many neurosurgical centers within Europe. The goal of the survey is to understand variance in practice management of pituitary tumors amongst neurosurgical centers. A list of departments performing pituitary surgery was created. The survey consisted of 58 questions. This study focuses on neurosurgical care of hormone-secreting adenomas. For analysis, the departments were divided into four subgroups: academic/non-academic, high-volume/low-volume, "mainly endoscopic/mainly microscopic practice" and geographical regions. Data from 254 departments from 34 countries were obtained. Most centers surgically treat 1-5 hormone-secreting adenomas per year. In prolactinomas this is the case in 194 centers, (76.4%), in GH-secreting adenomas: 133 centers, (52.4%), ACTH-secreting adenomas: 172 centers, (69.8%). Surgery as a primary treatment of prolactinomas is considered in 64 centers (25.2%). In 47 centers (18.8%), GH-secreting microadenomas are often treated pharmacologically first. Debulking surgery for an invasive GH-secreting adenoma in which hormonal remission is not a realistic goal of the surgery and the patient has no visual deficit surgery is always or mostly indicated in 156 centers (62.9%). Routine postoperative hydrocortisone replacement therapy is administered in 147 centers (58.6%). Our survey shows that in most centers, few hormone-secreting adenomas are treated per year. In about 25% of the centers, prolactinoma surgery may be regarded as first-line treatment; in about 20% of the centers, medical treatment is the first-line treatment for GH-secreting adenomas. Pretreatment for ACTH-secreting adenomas is routinely used in 21% of centers. This survey may serve as plea for neurosurgical care centralization of hormone-secreting adenomas.

Chaperone-Mediated Autophagy Controls Proteomic and Transcriptomic Pathways to Maintain Glioma Stem Cell Activity.

Chaperone-mediated autophagy (CMA) is a homeostatic process essential for the lysosomal degradation of a selected subset of the proteome. CMA activity directly depends on the levels of LAMP2A, a critical receptor for CMA substrate proteins at the lysosomal membrane. In glioblastoma (GBM), the most common and aggressive brain cancer in adulthood, high levels of LAMP2A in the tumor and tumor-associated pericytes have been linked to temozolomide resistance and tumor progression. However, the role of LAMP2A, and hence CMA, in any cancer stem cell type or in glioblastoma stem cells (GSC) remains unknown. In this work, we show that LAMP2A expression is enriched in patient-derived GSCs, and its depletion diminishes GSC-mediated tumorigenic activities. Conversely, overexpression of LAMP2A facilitates the acquisition of GSC properties. Proteomic and transcriptomic analysis of LAMP2A-depleted GSCs revealed reduced extracellular matrix interaction effectors in both analyses. Moreover, pathways related to mitochondrial metabolism and the immune system were differentially deregulated at the proteome level. Furthermore, clinical samples of GBM tissue presented overexpression of LAMP2, which correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA in directly regulating GSCs activity via multiple pathways at the proteome and transcriptome levels. SIGNIFICANCE: A receptor of chaperone-mediated autophagy regulates glioblastoma stem cells and may serve as a potential biomarker for advanced tumor grade and poor survival in this disease.

Frailty is associated with mortality in brain tumor patients.

Frailty represents a state of vulnerability that increases the risk of adverse health outcomes. In the last years, frailty has emerged as a good indicator of patient's functional reserve and it seems to be a predictor of negative outcomes in oncological patients. In this work, we analyzed the clinical utility of frailty as preoperative risk assessment tool in a brain tumor cohort from Donostia University Hospital (Spain). For that, we used several frailty tools consisting of questionnaires based on frailty phenotype (FRAIL scale), evaluating functional performance (Gait Speed) and a self-report questionnaire that includes variables related to the physical, cognitive and psychosocial domains of frailty (Tilburg Frailty Indicator). We identified a higher percentage of patients in vulnerable situation prior to surgery when using frailty tools compared to routine scales such as Karnosfky score and Barthel Index. Remarkably, patients diagnosed with malignant tumors were frailer and presented significant less six-month survival than patients with benign tumors by all the frailty scales abovementioned. In line with this, the vast majority of patients that became pre-frail or frail after neurosurgery (by FRAIL scale) harbored a malignant tumor. Moreover, frailty status significantly correlated with patient's mortality and autonomy, but not with the presence of postoperative outcomes in our cohort. Taken together, our results show that frailty measurement, mainly by FRAIL scale, is a useful tool to evaluate preoperative risk in brain tumor patients as well as patient's prognosis after neurosurgery.

Identification of a Dexamethasone Mediated Radioprotection Mechanism Reveals New Therapeutic Vulnerabilities in Glioblastoma.

(1) Background: Despite the indisputable effectiveness of dexamethasone (DEXA) to reduce inflammation in glioblastoma (GBM) patients, its influence on tumour progression and radiotherapy response remains controversial. (2) Methods: We analysed patient data and used expression and cell biological analyses to assess effects of DEXA on GBM cells. We tested the efficacy of tyrosine kinase inhibitors in vitro and in vivo. (3) Results: We confirm in our patient cohort that administration of DEXA correlates with worse overall survival and shorter time to relapse. In GBM cells and glioma stem-like cells (GSCs) DEXA down-regulates genes controlling G2/M and mitotic-spindle checkpoints, and it enables cells to override the spindle assembly checkpoint (SAC). Concurrently, DEXA up-regulates Platelet Derived Growth Factor Receptor (PDGFR) signalling, which stimulates expression of anti-apoptotic regulators BCL2L1 and MCL1, required for survival during extended mitosis. Importantly, the protective potential of DEXA is dependent on intact tyrosine kinase signalling and ponatinib, sunitinib and dasatinib, all effectively overcome the radio-protective and pro-proliferative activity of DEXA. Moreover, we discovered that DEXA-induced signalling creates a therapeutic vulnerability for sunitinib in GSCs and GBM cells in vitro and in vivo. (4) Conclusions: Our results reveal a novel DEXA-induced mechanism in GBM cells and provide a rationale for revisiting the use of tyrosine kinase inhibitors for the treatment of GBM.