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Funder: Wellcome Trust, PurposeSurgical workflow analysis seeks to systematically break down operations into hierarchal components. It facilitates education, training, and understanding of surgical variations. There are known educational demands and variations in surgical practice in endoscopic transsphenoidal approaches to pituitary adenomas. Through an iterative consensus process, we generated a surgical workflow reflective of contemporary surgical practice.MethodsA mixed-methods consensus process composed of a literature review and iterative Delphi surveys was carried out within the Pituitary Society. Each round of the survey was repeated until data saturation and > 90% consensus was reached.ResultsThere was a 100% response rate and no attrition across both Delphi rounds. Eighteen international expert panel members participated. An extensive workflow of 4 phases (nasal, sphenoid, sellar and closure) and 40 steps, with associated technical errors and adverse events, were agreed upon by 100% of panel members across rounds. Both core and case-specific or surgeon-specific variations in operative steps were captured.ConclusionsThrough an international expert panel consensus, a workflow for the performance of endoscopic transsphenoidal pituitary adenoma resection has been generated. This workflow captures a wide range of contemporary operative practice. The agreed "core" steps will serve as a foundation for education, training, assessment and technological development (e.g. models and simulators). The "optional" steps highlight areas of heterogeneity of practice that will benefit from further research (e.g. methods of skull base repair). Further adjustments could be made to increase applicability around the world.

Funder: Wellcome Trust, PURPOSE: Pituitary adenomas affect patients' quality-of-life (QoL) across several domains, with long-term implications even following gross-total resection or disease remission. While clinical outcomes can assess treatment efficacy, they do not capture variations in QoL. We present the development and validation of a patient reported outcome measure (PROM) for patients with pituitary adenomas undergoing transsphenoidal surgery. METHODS: The COSMIN checklist informed the development of the pituitary outcome score (POS). Consecutive patients undergoing surgical treatment for suspected pituitary adenoma at a single centre were included prospectively. An expert focus group and patient interviews informed item generation. Item reduction was conducted through exploratory factor analysis and expert consensus, followed by assessment of the tool's validity, reliability, responsiveness, and interpretability. RESULTS: 96 patients with a median age of 50 years validated the POS. The final questionnaire included 25 questions with four subscales: EQ-5D-5L-QoL, Visual Symptoms, Endocrine Symptoms and Nasal Symptoms. CONCLUSION: The POS is the first validated PROM for patients undergoing transsphenoidal surgery for a pituitary adenoma. This PROM could be integrated into contemporary practice to provide patient-centred outcomes assessment for this patient group, aligning more closely with patient objectives.

Clinically non-functioning pituitary adenomas (NFPAs) represent the second most common subtype of pituitary tumours, representing 15-43% of all pituitary adenomas. NFPAs are usually benign tumours with no clinical evidence of hormonal hypersecretion. In most of the cases the tumours are arising from the gonadotroph linage, but silent corticotroph, somatotroph, thyrotroph and rarely lactotroph cell characteristics can be discovered with immunostaining. As a result of lack of hormonal hyper-secretion, the diagnosis of NFPAs is made most often when the patient presents with mass effects due to a macroadenoma. NFPAs are most common tumour types in surgical series, and their primary treatment is indeed surgery. However, complete resection is achieved only in about 66% of the cases, and 20% of gross total resected tumours recur after 10 years. Over the past few decades, remarkable progress has been achieved regarding medical treatment options for pituitary tumours. However, NFPAs remain the only subtype with no widely accepted pharmacological treatment. Dopamine receptor type 2 (DRD2) and somatostatin receptor (SST) expression have been demonstrated in NFPAs, prompting the investigation of dopamine agonists and somatostatin analogues as potential treatment strategies. The DRD2 agonist cabergoline is already used as first-line treatment of prolactinomas to induce tumour shrinkage and reduce prolactin secretion. Here we aim to investigate the efficacy of cabergoline on human NFPA tissue. We assessed DRD2 expression levels via immunohistochemistry and qPCR in a large cohort of NFPAs (n=40) and in few prolactinomas (n=10). D2DR has two different isoforms, long (D2RL) and short (D2RS), which are differently expressed and can induce different effects on cell viability. In cabergoline-sensitive prolactinomas D2RS is the predominant isoform. NFPAs shown 10-fold and 5-fold decrease expression of D2RS and D2RL compared to prolactinomas, respectively. Additionally, in NFPAs we observed a significant decrease of cAMP production after cabergoline treatment (45% ±7; p We have also seen in NFPAs downregulation of Ga i2 protein expression levels, highlighting the general decrease of expression levels in the dopamine pathway (50% less, p Our data suggest that the difference in cabergoline responses between NFPAs and prolactinomas may be due to their distinct expression of D2DR isoforms, which differ by 29 amino acids in the third cytoplasmic loop, essential for G-protein binding. It has been shown that D2RL, but not D2RS, requires Gai2. The difference in D2R isoform expression could translate to distinct G-protein activation, ultimately leading to the contrasting viability results after cabergoline treatment. Taken together, these data will help inform future treatment strategies for patients with NFPAs. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Background:Non-functioning pituitary macroadenomas (NFPMs) may present with hypopituitarism. Pituitary surgery and radiotherapy pose an additional risk to pituitary function.ObjectivesTo assess the incidence of hypopituitarism at presentation, the impact of treatment, and the likelihood of endocrine recovery during follow-up.MethodsAll patients treated surgically with and without radiotherapy for NFPMs between 1987 and 2018 who had longer than 6 months follow-up were identified. Demographics, presentation, investigation, treatment, and outcomes were collected.ResultsIn total, 383 patients were identified. The median age was 57 years with a median follow-up of 8 years. Preoperatively, 235 patients (235/377; 62%) had evidence of at least one pituitary deficiency. Anterior panhypopituitarism was more common in men (p =0.001), older patients (p =0.005), and in those with adenomas extending beyond the sella turcica (p =0.05). Patients treated with surgery and radiotherapy had a higher incidence of all individual pituitary hormone deficiency and anterior panhypopituitarism as well as significantly lower GH, ACTH, and TSH deficiencies free survival probability than those treated with surgery alone. Recovery of central hypogonadism, hypothyroidism, and anterior panhypopituitarism was also less likely to be reported in those treated with surgery and radiotherapy.ConclusionNFPMs are associated with significant degree of hypopituitarism at time of diagnosis and post therapy. The combination of surgery and radiotherapy is associated with higher risk of pituitary dysfunction. Recovery of pituitary hormone deficit may occur after surgical treatment. Patients should have regular ongoing endocrine evaluation post-treatment to assess changes in pituitary function and the need for long-term replacement therapy.

Purpose Angiogenesis has been studied in pituitary neuroendocrine tumours (PitNETs), but the role of the tumour microenvironment (TME) in regulating PitNET angiogenesis remains unknown. We aimed to characterise the role of TME components in determining the angiogenetic PitNET profile, focusing on immune cells and tumour-derived cytokines. Methods Immune cells were studied by immunohistochemistry in 24 human PitNETs (16 non-functioning-PitNETs (NF-PitNETs) and 8 somatotrophinomas): macrophages (CD68, CD163, HLA-DR), cytotoxic (CD8) and T helper (CD4) lymphocytes, regulatory T cells (FOXP3), B cells (CD20) and neutrophils (neutrophil elastase); endothelial cells were assessed with CD31. Five normal pituitaries (NP) were included for comparison. Microvessel density and vascular morphology were estimated with ImageJ. The cytokine secretome from these PitNETs were assessed on culture supernatants using a multiplex immunoassay panel. Results Microvessel density/area was higher in NP than PitNETs, which also had rounder and more regular vessels. NF-PitNETs had vessels of increased calibre compared to somatotrophinomas. The M2:M1 macrophage ratio correlated with microvessel area. PitNETs with more CD4+ T cells had higher microvessel area, while tumours with more FOXP3+ cells were associated with lower microvessel density. PitNETs with more B cells had rounder vessels. Of the 42 PitNET-derived cytokines studied, CCL2, CXCL10 and CX3CL1 correlated with microvessel density and vessel architecture parameters. Conclusions M2 macrophages appear to play a role in PitNET neovascularisation, while B, CD4+ and FOXP3+ lymphocytes, as well as non-cellular TME elements such as CCL2, CXCL10 and CX3CL1, may also modulate the angiogenesis of PitNETs.

Objective To evaluate and understand the clinical behavior and radiologic correlates of tumors originating from the posterior pituitary gland. To review the management strategy for these rare tumors and add to the limited existing literature. Methods Retrospective review of 8 cases (5 pituicytomas, 2 spindle cell oncocytomas, and 1 granular cell tumor) managed at our institution between 2004 and 2019. The patients' clinical course, histologic features, and radiologic findings were reviewed. Their management and long-term follow-up is presented and compared with the literature. Results Long-term follow-up ranged from 1 to 9 years. There was 1 recurrence in a patient with spindle cell oncocytoma, and this was treated with radiotherapy. The endoscopically managed cases resulted in complete tumor excision with no recurrence. Conclusions Epidemiologic data on primary tumors of the neurohypophysis is limited because of the rarity of these tumors. This study adds to the literature that these tumors behave as World Health Organization grade I tumors, although close follow-up is recommended as a few cases have shown recurrence. The endoscopic approach resulted in better gross total tumor resection rate in this series.

Background In patients with symptomatic Rathke’s cleft cyst, transsphenoidal surgery is highly effective at preventing further visual loss and usually allows for some recovery of vision. However, cyst recurrence and the need for re-operation are well recognized. To this end, the aim of this study was to investigate patterns of recurrence and long-term outcomes and to use this information to develop an optimal follow-up strategy. Method A prospectively maintained database was searched over a 10-year period between 1 January 2008 and the 1 January 2018 to identify all adults that underwent transsphenoidal surgery with a new diagnosis of Rathke’s cleft cyst. A retrospective case note review was performed for each patient to extract data on their presentation, investigation, treatment, and outcome. Results In all, 61 eligible patients were identified. The median follow-up was 34 months (range 2–112 months). In the 22 patients with pre-operative visual loss, the outcomes at 6 months were as follows: normal vision (2/22; 9.1%), improved but not normal (7/22; 31.8%), stable (12/22; 54.5%), worse but not blind (1/22; 4.5%), and blind (0/22; 0%). The overall rate of regrowth and re-operation in our study was 19.7 and 11.5%, respectively. The only factor that was significantly associated with recurrence was the presence of residual cystic disease on the post-operative MRI (p Conclusions We propose a follow-up strategy that stratifies patients at “low risk” if there is no residual cyst, with increasing interval scans, or “high risk” if there is residual cyst, with annual visual assessment and scans.

Neuro-oncology surgery would benefit from detailed intraoperative tissue characterization provided by noncontact, contrast-agent-free, noninvasive optical imaging methods. In-depth knowledge of target tissue optical properties across a wide-wavelength spectrum could inform the design of optical imaging and computational methods to enable robust tissue analysis during surgery. We adapted a dual-beam integrating sphere to analyse small tissue samples and investigated ex vivo optical properties of five types of human brain tumour (meningioma, pituitary adenoma, schwannoma, low- and high-grade glioma) and nine different types of healthy brain tissue across a wavelength spectrum of 400 to 1800 nm. Fresh and frozen tissue samples were analysed. All tissue types demonstrated similar absorption spectra, but the reduced scattering coefficients of tumours show visible differences in the obtained optical spectrum compared to those of surrounding normal tissue. These results underline the potential of optical imaging technologies for intraoperative tissue characterization. ispartof: JOURNAL OF BIOPHOTONICS vol:15 issue:4 ispartof: location:Germany status: published

The neural cell adhesion molecule (NCAM) has previously been studied in pituitary neuroendocrine tumours (PitNETs), but its role in tumour biology and aggressiveness remains controversial, and its relationship with the tumour microenvironment remains unknown. We aimed to characterise NCAM expression in PitNETs, to correlate this with clinico-pathological features, and to assess the role of various microenvironment components on NCAM expression. NCAM and immune cells were investigated by immunohistochemistry in 16 human non-functioning-PitNETs (NF-PitNETs) and eight somatotrophinomas, including macrophages (CD68, CD163, HLA-DR), cytotoxic (CD8) and T helper (CD4) lymphocytes, regulatory T cells (FOXP3), B cells (CD20), and neutrophils (neutrophil elastase). Five normal pituitaries were included for comparison. The cytokine secretome from these PitNETs and from PitNET-derived tumour-associated fibroblasts (TAFs) were assessed on culture supernatants using a multiplex immunoassay panel. There were no significant NCAM expression differences between PitNETs and normal pituitary, and no difference between types of pituitary tumours (NF-PitNETs vs. somatotrophinomas). There was no association between NCAM expression and different clinico-pathological features, including cavernous sinus invasion and Ki-67, nor with serum hormone levels. NCAM immunoreactivity correlated negatively with PitNET-derived CXCL10 (rho = -0.417; p = .042) and CX3CL1 (rho = -0.423; p = .040) levels. NCAM immunoreactivity was negatively correlated with TAF-derived fibroblast growth factor (FGF)-2 (rho = -0.632; p = .009), but not with other TAF-derived cytokines. Within the PitNET cohort, there were no correlations between NCAM immunoreactivity and immune infiltrates or ratios, although, within NF-PitNETs, NCAM expression was higher in tumours with more FOXP3+ cells. NCAM expression does not differ between PitNETs and normal pituitary, and does not appear to relate to tumour invasiveness or proliferation. However, our data suggest a possible role for cytokines in the modulation of NCAM expression in PitNETs, particularly CXCL10, CX3CL1 and FGF-2, but not for immune cell infiltrates.

Background. Ultrasound has been explored as an alternative, less bulky, less time-consuming and less expensive means of intraoperative imaging in pituitary surgery. However, its use has been limited by the size of its probes relative to the transsphenoidal corridor. We developed a novel prototype that is more slender than previously reported forward-viewing probes and, in this report, we assess its feasibility and safety in an initial patient cohort. Method. The probe was integrated into the transsphenoidal approach in patients with pituitary adenoma, following a single-centre prospective proof of concept study design, as defined by the Innovation, Development, Exploration, Assessment and Long-Term Study (IDEAL) guidelines for assessing innovation in surgery (IDEAL stage 1 – Idea phase). Results. The probe was employed in 5 cases, and its ability to be used alongside the standard surgical equipment was demonstrated in each case. No adverse events were encountered. The average surgical time was 20 minutes longer than that of 30 contemporaneous cases operated without intraoperative ultrasound. Conclusion. We demonstrate the safety and feasibility of our novel ultrasound probe during transsphenoidal procedures to the pituitary fossa, and, as a next step, plan to integrate the device into a surgical navigation system (IDEAL Stage 2a – Development phase).

Non-tumoural cells within the tumour microenvironment (TME) influence tumour proliferation, invasiveness and angiogenesis. Little is known about TME in pituitary neuroendocrine tumours (PitNETs). We aimed to characterise the role of TME in the aggressive behaviour of PitNETs, focusing on immune cells and cytokines. The cytokine secretome of 16 clinically non-functioning PitNETs (NF-PitNETs) and 8 somatotropinomas was assessed in primary culture using an immunoassay panel with 42 cytokines. This was correlated with macrophage (CD68, HLA-DR, CD163), T-lymphocyte (CD8, CD4, FOXP3), B-lymphocyte (CD20), neutrophil (neutrophil elastase) and endothelial cells (CD31) content, compared to normal pituitaries (NPs, n = 5). In vitro tumour–macrophage interactions were assessed by conditioned medium (CM) of GH3 (pituitary tumour) and RAW264.7 (macrophage) cell lines on morphology, migration/invasion, epithelial-to-mesenchymal transition and cytokine secretion. IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 are the main PitNET-derived cytokines. PitNETs with increased macrophage and neutrophil content had higher IL-8, CCL2, CCL3, CCL4 and CXCL1 levels. CD8+ T-lymphocytes were associated to higher CCL2, CCL4 and VEGF-A levels. PitNETs had more macrophages than NPs (p p = 0.005), but fewer neutrophils (p = 0.047) with a 2-fold decreased CD8:CD4 ratio. NF-PitNETs secreted more cytokines and had 9 times more neutrophils than somatotropinomas (p = 0.002). PitNETs with higher Ki-67 had more FOXP3+ T cells, as well as lower CD68:FOXP3, CD8:CD4 and CD8:FOXP3 ratios. PitNETs with “deleterious immune phenotype” (CD68hiCD4hiFOXP3hiCD20hi) had a Ki-67 ≥ 3%. CD163:HLA-DR macrophage ratio was positively correlated with microvessel density (p = 0.015) and area (p

Background: Endoscopic skull base surgery (ESBS) is a new subspecialty area that has become more popular over the past 20 years. It is fast evolving and the indications are getting increasi...

Purpose The expanded endoscopic endonasal approach, a representative example of keyhole brain surgery, allows access to the pituitary gland and surrounding areas through the nasal and sphenoid cavities. Manipulating rigid instruments through these constrained spaces makes this approach technically challenging, and thus, a handheld robotic instrument could expand the surgeon’s capabilities. In this study, we present an intuitive handle prototype for such a robotic instrument. Methods We have designed and fabricated a surgical instrument handle prototype that maps the surgeon’s wrist directly to the robot joints. To alleviate the surgeon’s wrist of any excessive strain and fatigue, the tool is mounted on the surgeon’s forearm, making it parallel with the instrument’s shaft. To evaluate the handle’s performance and limitations, we constructed a surgical task simulator and compared our novel handle with a standard neurosurgical tool, with the tasks being performed by a consultant neurosurgeon. Results While using the proposed handle, the surgeon’s average success rate was $$80\%$$ 80 % , compared to $$41\%$$ 41 % when using a conventional tool. Additionally, the surgeon’s body posture while using the suggested prototype was deemed acceptable by the Rapid Upper Limb Assessment ergonomic survey, while early results indicate the absence of a learning curve. Conclusions Based on these preliminary results, the proposed handle prototype could offer an improvement over current neurosurgical tools and procedural ergonomics. By redirecting forces applied during the procedure to the forearm of the surgeon, and allowing for intuitive surgeon wrist to robot-joints movement mapping without compromising the robotic end effector’s expanded workspace, we believe that this handle could prove a substantial step toward improved neurosurgical instrumentation.

Purpose Postoperative cerebrospinal fluid rhinorrhoea (CSFR) remains a frequent complication of endonasal approaches to pituitary and skull base tumours. Watertight skull base reconstruction is important in preventing CSFR. We sought to systematically review the current literature of available skull base repair techniques. Methods Pubmed and Embase databases were searched for studies (2000–2020) that (a) reported on the endonasal resection of pituitary and skull base tumours, (b) focussed on skull base repair techniques and/or postoperative CSFR risk factors, and (c) included CSFR data. Roles, advantages and disadvantages of each repair method were detailed. Random-effects meta-analyses were performed where possible. Results 193 studies were included. Repair methods were categorised based on function and anatomical level. There was absolute heterogeneity in repair methods used, with no independent studies sharing the same repair protocol. Techniques most commonly used for low CSFR risk cases were fat grafts, fascia lata grafts and synthetic grafts. For cases with higher CSFR risk, multilayer regimes were utilized with vascularized flaps, gasket sealing and lumbar drains. Lumbar drain use for high CSFR risk cases was supported by a randomised study (Oxford CEBM: Grade B recommendation), but otherwise there was limited high-level evidence. Pooled CSFR incidence by approach was 3.7% (CI 3–4.5%) for transsphenoidal, 9% (CI 7.2–11.3%) for expanded endonasal, and 5.3% (CI 3.4–7%) for studies describing both. Further meaningful meta-analyses of repair methods were not performed due to significant repair protocol heterogeneity. Conclusions Modern reconstructive protocols are heterogeneous and there is limited evidence to suggest the optimal repair technique after pituitary and skull base tumour resection. Further studies are needed to guide practice.

Introduction The extended endoscopic approach (EEA) provides direct access for resection of tuberculum sellae (TSM) and olfactory groove meningiomas (OGM) but is associated with cerebrospinal fluid (CSF) leak in up to 25% of patients. To evaluate the impact of improved skull base reconstructive techniques, we assessed published CSF leak percentages in EEA over the last two decades. Method Random-effects meta-analyses were performed for studies published between 2004-2020. Outcomes assessed were CSF leak, gross total resection, visual improvement, intraoperative arterial injury and 30-day mortality. For the main analyses, publications were pragmatically grouped based on publication year in three categories: 2004-2010, 2011-2015, and 2016-2020. Results We included 29 studies describing 540 TSM and 115 OGM patients. CSF leak incidence dropped over time from 22% (95% CI: 6-43%) in studies published between 2004 and 2010, to 16% (95% CI: 11-23%) between 2011 and 2015, and 4% (95% CI: 1-9%) between 2016 and 2020. Outcomes of gross total resection, visual improvement, intraoperative arterial injury, and 30-day mortality remained stable over time Conclusions We report a noticeable decrease in CSF leak over time, which might be attributed to the development of reconstructive techniques (e.g., hadad bassagasteguy flap, and gasket seal), refined multilayer repair protocols, and selected lumbar drain usage.

Background CRANIAL (CSF Rhinorrhoea After Endonasal Intervention to the Skull Base) is a prospective multicenter observational study seeking to determine 1) the scope of skull base repair methods used and 2) corresponding rates of postoperative cerebrospinal fluid (CSF) rhinorrhea in the endonasal transsphenoidal approach (TSA) and the expanded endonasal approach (EEA) for skull base tumors. We sought to pilot the project, assessing the feasibility and acceptability by gathering preliminary data. Methods A prospective observational cohort study was piloted at 12 tertiary neurosurgical units in the United Kingdom. Feedback regarding project positives and challenges were qualitatively analyzed. Results A total of 187 cases were included: 159 TSA (85%) and 28 EEA (15%). The most common diseases included pituitary adenomas (n = 142/187), craniopharyngiomas (n = 13/187). and skull base meningiomas (n = 4/187). The most common skull base repair techniques used were tissue glues (n = 132/187, most commonly Tisseel), grafts (n = 94/187, most commonly fat autograft or Spongostan) and vascularized flaps (n = 51/187, most commonly nasoseptal). These repairs were most frequently supported by nasal packs (n = 125/187) and lumbar drains (n = 20/187). Biochemically confirmed CSF rhinorrhea occurred in 6/159 patients undergoing TSA (3.8%) and 2/28 patients undergoing EEA (7.1%). Four patients undergoing TSA (2.5%) and 2 patients undergoing EEA (7.1%) required operative management for CSF rhinorrhea (CSF diversion or direct repair). Qualitative feedback was largely positive (themes included user-friendly and efficient data collection and strong support from senior team members), demonstrating acceptability. Conclusions Our pilot experience highlights the acceptability and feasibility of CRANIAL. There is a precedent for multicenter dissemination of this project, to establish a benchmark of contemporary practice in skull base neurosurgery, particularly with respect to patients undergoing EEA.

Objective The extended endoscopic approach provides unimpaired visualization and direct access to ventral skull base pathology, but is associated with cerebrospinal fluid (CSF) leak in up to 25% of patients. To evaluate the impact of improved surgical techniques and devices to better repair skull base defects, we assessed published surgical outcomes of the extended endoscopic endonasal approach in the last two decades for a well-defined homogenous group of tuberculum sellae and olfactory groove meningioma patients. Methods Random-effects meta-analyses were performed for studies published between 2004 (first publications) and April 2020. We evaluated CSF leak as primary outcome. Secondary outcomes were gross total resection, improvement in visual outcomes in those presenting with a deficit, intraoperative arterial injury, and 30-day mortality. For the main analyses, publications were pragmatically grouped based on publication year in three categories: 2004–2010, 2011–2015, and 2016–2020. Results We included 29 studies describing 540 patients with tuberculum sellae and 115 with olfactory groove meningioma. The percentage patients with CSF leak dropped over time from 22% (95% CI: 6–43%) in studies published between 2004 and 2010, to 16% (95% CI: 11–23%) between 2011 and 2015, and 4% (95% CI: 1–9%) between 2016 and 2020. Outcomes of gross total resection, visual improvement, intraoperative arterial injury, and 30-day mortality remained stable over time Conclusions We report a noticeable decrease in CSF leak over time, which might be attributed to the development and improvement of new closure techniques (e.g., Hadad-Bassagasteguy flap, and gasket seal), refined multilayer repair protocols, and lumbar drain usage.

Background Transsphenoidal surgery is the gold standard for pituitary adenoma resection. Although rare, a serious complication of surgery is worsened vision post-operatively. Objective To determine whether, in patients undergoing transsphenoidal surgery for pituitary adenoma, intraoperative monitoring of visual evoked potentials (VEP) is a safe, reproducible, and effective technological adjunct in predicting postoperative visual function. Methods The PubMed and OVID platforms were searched between January 1993 and December 2020 to identify publications that (1) featured patients undergoing transsphenoidal surgery for pituitary adenoma, (2) used intraoperative optic nerve monitoring with VEP and (3) reported on safety or effectiveness. Reference lists were cross-checked and expert opinion sought to identify further publications. Results Eleven studies were included comprising ten case series and one prospective cohort study. All employed techniques to improve reliability. No safety issues were reported. The only comparative study included described a statistically significant improvement in post-operative visual field testing when VEP monitoring was used. The remaining case-series varied in conclusion. In nine studies, surgical manipulation was halted in the event of a VEP amplitude decrease suggesting a widespread consensus that this is a warning sign of injury to the anterior optic apparatus. Conclusions Despite limited and low-quality published evidence regarding intra-operative VEP monitoring, our review suggests that it is a safe, reproducible, and increasingly effective technique of predicting postoperative visual deficits. Further studies specific to transsphenoidal surgery are required to determine its utility in protecting visual function in the resection of complex pituitary tumours.

Background: The endonasal transsphenoidal approach (TSA) has emerged as the preferred approach in order to treat pituitary adenoma and related sellar pathologies. The recently adopted expanded endonasal approach (EEA) has improved access to the ventral skull base whilst retaining the principles of minimally invasive surgery. Despite the advantages these approaches offer, cerebrospinal fluid (CSF) rhinorrhoea remains a common complication. There is currently a lack of comparative evidence to guide the best choice of skull base reconstruction, resulting in considerable heterogeneity of current practice. This study aims to determine: (1) the scope of the methods of skull base repair; and (2) the corresponding rates of postoperative CSF rhinorrhoea in contemporary neurosurgical practice in the UK and Ireland. Methods: We will adopt a multicentre, prospective, observational cohort design. All neurosurgical units in the UK and Ireland performing the relevant surgeries (TSA and EEA) will be eligible to participate. Eligible cases will be prospectively recruited over 6 months with 6 months of postoperative follow-up. Data points collected will include: demographics, tumour characteristics, operative data), and postoperative outcomes. Primary outcomes include skull base repair technique and CSF rhinorrhoea (biochemically confirmed and/or requiring intervention) rates. Pooled data will be analysed using descriptive statistics. All skull base repair methods used and CSF leak rates for TSA and EEA will be compared against rates listed in the literature. Ethics and dissemination: Formal institutional ethical board review was not required owing to the nature of the study–this was confirmed with the Health Research Authority, UK. Conclusions: The need for this multicentre, prospective, observational study is highlighted by the relative paucity of literature and the resultant lack of consensus on the topic. It is hoped that the results will give insight into contemporary practice in the UK and Ireland and will inform future studies.

Background: The optimal management of craniopharyngiomas remains controversial. Objectives: To examine temporal trends in the management of craniopharyngioma with a focus on endocrine outcomes. Methods: This was a cross‐sectional, multicentre study. Patients treated between 1951 and 2015 were identified and divided into four quartiles. Demographics, presentation, treatment and outcomes were collected. Results: In total, 142 patients with childhood‐onset craniopharyngioma (48/142; 34%) and adult‐onset disease (94/142; 66%) were included. The median follow‐up was 15 years (IQR 5‐23 years). Across quartiles, there was a significant trend towards using transsphenoidal surgery (P < .0001). The overall use of radiotherapy was not different among the four quartiles (P = .33). At the latest clinical review, the incidence of GH, ACTH, gonadotrophin deficiencies and anterior panhypopituitarism fell significantly across the duration of the study. Anterior panhypopituitarism was not affected by treatment modality (surgery vs surgery and radiotherapy) (P = .23). There was no difference in the incidence of high BMI (≥25 kg/m2) among the four quartiles (P = .14). BMI was higher in patients who treated with surgery and radiotherapy than those treated with surgery only (P = .006). Tumour regrowth occurred in 51 patients (51/142; 36%) with no difference in regrowth among quartiles over the time course of the study (P = .15). Conclusion: We demonstrate a significant reduction in panhypopituitarism in craniopharyngioma patients over time, most likely because of a trend towards more transsphenoidal surgery. However, long‐term endocrine sequelae remain common and lifelong follow‐up is required.

Emerging optical imaging techniques such as hyperspectral imaging (HSI) provide a promising non-invasive solution for intraoperative tissue characterisation with the potential to provide rich tissue-differentiation information over the entire surgical field. Neuro-oncology surgery would especially benefit from detailed real-time in vivo tissue characterisation, improving the accuracy with which boundaries of safe surgical resection are delineated and thereby improving patient outcomes. Current systems are limited by challenges with processing the HSI data because of incomplete characterisation of the optical properties of tissue across the complete visible and near-infrared wavelength spectrum. In this study, we characterised the optical properties of various freshly-excised brain tumours and normal cadaveric human brain tissue using a dual-beam integrating sphere spectrophotometer and the inverse adding-doubling technique. We adapted an integrating sphere to analyse 2 mm-thick tissue samples measuring 4 – 7 mm in diameter and validated the experimental setup with a tissue-mimicking optical phantom. We investigated the different spectral signatures of freshly-excised tumour tissues including pituitary adenoma, meningioma and vestibular schwannoma and compared these to normal grey and white matter, pons, pituitary, dura and cranial nerve tissues across the wavelength range of 400 – 1800 nm. It was found that brain and tumour tissues could be differentiated by their optical properties but the freezing process did alter the tissues’ relative absorption and reduced scattering coefficients. In this work, we have demonstrated a method to characterise the optical properties of small human brain and tumour specimens that may be used as a reference dataset for developing optical imaging techniques.

Background: The endonasal approach is the gold standard for the resection of pituitary tumours, with either microscopic endonasal transsphenoidal (MET) or endoscopic endonasal transsphenoidal (EET)...

Introduction: Cytokines are important elements of the tumor microenvironment (TME) coordinating host responses against the tumor, promoting growth, invasion, angiogenesis and regulating non-tumoral cells in TME. Little is known regarding the cytokine network in pituitary adenomas (PAs) and its role in the TME. We aimed to characterise PA-derived cytokines to study their role in the TME of PAs. Methods: The cytokine secretome of culture supernatants from 27 human PAs (16 NFPAs, 9 GHomas, 1 TSHoma, 1 ACTHoma) was assessed using Millipore MILLIPLEX cytokine/chemokine 42-plex. IL-8 and CCL2 expression was further studied by RNAscope. Angiogenesis, macrophages and epithelial-to-mesenchymal transition were evaluated by immunohistochemistry for CD31, CD68, CD163, HLA-DR, E-cadherin and ZEB1. Macrophage infiltration in PAs and its phenotype was further assessed with the gene-signature based method xCELL. We have developed an in vitro model of pituitary cells (GH3) and macrophages (RAW264.7) and studied their interaction via assessing the effect of conditioned media. We documented cell morphology (ImageJ), migration and invasion (Boyden chambers), epithelial-to-mesenchymal transition pathway (RT-qPCR and immunocytochemistry) and secretome changes (cytokine array). Results: IL-8, CCL2, CCL3 and CCL4 are the main PA-derived cytokines, with CXCL1, CXCL10, CCL22 and CX3CL1 also secreted by most of these tumors. RNAscope data showed that CCL2 and IL-8 are mainly synthesised in the pituitary tumour cells. NFPAs secreted more cytokines than somatotropinomas, especially CCL2 (16x more), IL-8 (25x more) and CCL4 (27x more). PAs contained more macrophages than normal pituitary (4.9±0.7 vs 1.2±0.2%, p=0.007). Macrophage infiltration was associated with higher chemokine levels (CCL2, CCL3, CCL4, CXCL1 and IL-8). Macrophages in PAs belong to the CD163+ M2-subtype, while in normal pituitary M1-macrophages predominate, resulting in 3-fold increased M2:M1 ratio in PAs (p

Introduction: Tumour-associated fibroblasts (TAFs) are important elements of the tumour microenvironment (TME) well-studied in several cancers, but their role in pituitary adenomas (PAs) has never been shown. We aimed to study the role of TAFs in PAs and its response to somatostatin analogues (SSA). Methods: TAFs were isolated from 11 freshly-cultured NFPAs and 5 GHomas as confirmed by vimentin and αSMA immunostaining. TAF presence in PAs was confirmed by immunohistochemistry, and further assessed with the gene-signature based method xCELL on a different set of samples. Macrophage infiltration, angiogenesis and epithelial-to-mesenchymal pathways were evaluated by immunohistochemistry for CD68, CD163, HLA-DR, E-cadherin, ZEB1 and CD31. TAFs secretome was assessed in vitro on culture supernatants, at baseline and after treatment with pasireotide (10-7M) using Millipore MILLIPLEX human cytokine 42-plex. GH3 cells were treated with TAF-conditioned media (CM) and normal skin fibroblasts-CM (F-CM). Cell morphology (analysed by ImageJ), invasion and epithelial-to-mesenchymal pathways were assessed. Results: CCL2 and eotaxin-1 were identified as the top secreted cytokines in TAF supernatants, followed by VEGF-A, CCL22, IL-6, FGF-2 and IL-8. TAF secretomes from NFPAs and GHomas did not differ significantly. PAs with cavernous sinus invasion had higher TAF-derived IL-6 levels compared to non-invasive PAs (72.7±10.7 vs 43.9±6.3pg/mL; p=0.027), while there was a trend for TAFs from PAs with higher Ki67 to secrete more CCL2 (p=0.058). Correlation between macrophages and TAF-derived FGF-2 was found (r=0.499, p=0.049), and increased FGF-2 and CXCL1 levels were seen in PAs with a macrophage M2:M1 ratio≥2. CCL2 levels were correlated with microvessel area (r=0.672, p=0.004), whereas PDGF-AA was negatively correlated with E-cadherin immunoreactivity (r=-0.564, p=0.023). RT-qPCR analyses indicated that the sst1 receptor is the predominant somatostatin receptor expressed in TAFs, while sst2 and sst5 receptors are poorly expressed. Pasireotide treatment decreased TAF-derived IL-6 by 80% (p

OBJECTIVEThe management of children with craniopharyngioma has evolved over time, with a trend toward less invasive neurosurgical approaches as surgeons have sought to balance oncological control and treatment-related morbidity. To this end, the aim of this study was to evaluate the safety and effectiveness of the current management of children with craniopharyngioma compared to the previous management methods used at the authors’ treatment center.METHODSA prospectively maintained database was searched over a 14-year period between January 1, 2005, and December 31, 2018, to identify all children 17 years of age or younger with a new diagnosis of craniopharyngioma. A retrospective case note review was performed for each child to extract data on the presentation, investigation, treatment, and outcome of their illness. Morbidity was assessed in the same fashion as in previous cohorts, according to the following categories: visual loss, pituitary dysfunction, hypothalamic dysfunction, neurological deficits, and cognitive impairment.RESULTSIn total, 59 children were identified with craniopharyngioma during the study period. A total of 92 operations were performed, including cyst drainage (35/92; 38.0%), craniotomy and resection (30/92; 32.6%), and transsphenoidal resection (16/92; 17.4%). Approximately two-thirds of all operations were performed using image guidance (66/92; 71.7%) and one-third were performed using endoscopy (27/92; 29.3%). The majority of children had adjuvant therapy comprising proton beam therapy (18/59; 30.5%) or conventional radiotherapy (16/59; 27.1%). The median follow-up duration was 44 months (range 1–142 months), and approximately one-half of the children had no evidence of residual disease on MRI studies (28/59; 47.5%). Of the remaining 31 children, there was a reduction in the volume of residual disease in 8 patients (8/59; 13.6%), stable residual disease in 18 (18/59; 30.5%), and tumor growth in 5 patients (5/59; 8.5%). There was significantly reduced morbidity (p < 0.05) in all categories in the current cohort compared with our last cohort (1996–2004).CONCLUSIONSThe authors’ institutional experience of pediatric craniopharyngioma confirms a trend toward less invasive neurosurgical procedures, most of which are now performed with the benefit of image guidance or endoscopy. Moreover, the authors have identified an expanding role for more targeted radiotherapy for children with residual disease. These advances have allowed for tumor control comparable to that achieved in previous cohorts, but with significantly reduced morbidity and mortality.

Background: Cushing’s disease is a challenging endocrine disorder caused by non-physiological cortisol excess from adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. Inferior petrosal venous sampling (IPSS) is considered the gold standard investigation to differentiate Cushing’s disease from ectopic ACTH syndrome. Methods: This retrospective study included all patients who underwent IPSS between January 2011 and October 2020 at The National Hospital for Neurology and Neurosurgery in London. Patients demographics, radiological, surgical, endocrinological and, histological data were retrieved. We assessed the accuracy of IPSS in localizing ACTH secreting pituitary adenoma and its concordance with neuroimaging and surgical findings at the time of tumor resection. Results: In total 68 patients underwent IPSS, 22 males and 46 females. The median age was 42 years. IPSS was performed prior to primary surgery in 61 patients (90%) and before secondary surgery in 4 patients (6%). Three patients (4%) are awaiting surgery at the time of our study. Fifty-two patients (80%) had positive histology of ACTH expressing adenoma. Four patients (8%) had ectopic ACTH syndrome. The sensitivity of IPSS in predicting Cushing’s disease prior to corticotropin-releasing hormone (CRH) stimulation was 91% (95% CI [83% to 97%]) and accuracy of 88% (95% CI [77% to 95%]). The sensitivity of IPSS post CRH administration was 96% (95% CI [87% to 100%]) with accuracy of 86% (95% CI [75% to 93%]). Data on lateralization of pituitary adenoma were available for 63 patients. Prior to CRH stimulation, lateralization was right sided in 35 patients (56%), left sided in 15 (24%), and 13 patients (20%) did not have adequate interpetrosal sinus ACTH ratio. Lateralization post CRH stimulation was right sided in 40 patients (64%), left sided in 20 (32%), and 3 patients (4%) did not achieve adequate ACTH gradient ratio between two sides. Eighteen patients (30%) switched adenoma lateralization between pre and post CRH stimulation. Post CRH IPSS was consistent with neuroradiology in localizing pituitary adenomas in 59% (29 out of 49 patients) and concordant with surgical findings in 41% (25 out of 61 patients). Patients with ectopic ACTH syndrome had negative IPSS at all stages. IPSS procedure failed in 2 patients (3%). No post procedure complications were reported. Conclusion: IPSS has high sensitivity in diagnosing pituitary driven Cushing’s disease with good safety profile. However, the reliability in lateralizing pituitary adenoma is debated. One third of patients in this cohort switched lateralization before and after CRH administration. Studies on monkeys and rats showed that CRH induces coronary vasodilation and reduction in systemic vascular resistance. This suggest that CRH might have vasoactive effect on pituitary blood vessels with subsequent influence on IPS:P ACTH gradient ratio between the two sides.

The endonasal transsphenoidal approach allows surgeons to access the pituitary gland through the natural orifice of the nose. Recently, surgeons have also described an Expanded Endoscopic Endonasal Approach (EEEA) for the treatment of other tumours around the base of the brain. However, operating in this way with nonarticulated tools is technically very difficult and not widely adopted. The goal of this study is to develop an articulated end-effector for a novel handheld robotic tool for the EEEA. We present a design and implementation of a 3.6[Formula: see text]mm diameter, three degrees-of-freedom, tendon-driven robotic end-effector that, contrary to rigid instruments which operate under fulcrum, will give the surgeon the ability to reach areas on the surface of the brain that were previously inaccessible. We model the end-effector kinematics in simulation to study the theoretical workspace it can achieve prior to implementing a test-bench device to validate the efficacy of the end-effector. We find promising repeatability of the proposed robotic end-effector of 0.42[Formula: see text]mm with an effective workspace with limits of [Formula: see text], which is greater than conventional neurosurgical tools. Additionally, although the tool’s end-effector has a small enough diameter to operate through the narrow nasal access path and the constrained workspace of EEEA, it showcased promising structural integrity and was able to support approximately a 6N load, despite a large deflection angle the limiting of which is scope of future work. These preliminary results indicate the end-effector is a promising first step towards developing appropriate handheld robotic instrumentation to drive EEEA adoption.

OBJECTIVE: The results of recent high-profile delict and medical negligence cases now require doctors to take "reasonable care to ensure that the patient is aware of any material risks involved in any recommended treatment, and of any reasonable alternative or variant treatments." Thus, we report the development and evaluation of a procedure-specific online educational resource to support the informed consent process for patients undergoing transsphenoidal excision of pituitary adenomas. METHODS: An interactive educational multimedia website was developed using a combination of text, images, and videos. A telephone questionnaire was devised to evaluate patients' understanding that included 15 true/false questions. The questionnaire was administered to separate cohorts of patients on the waiting list for transsphenoidal excision of a pituitary adenoma before and after introduction of the website. The patients were also asked to rate the extent to which they found the website easy to understand and useful on a 10-point Likert scale. Data were compared using the χ2 and Mann-Whitney U test, with P < 0.05 considered to indicate statistical significance. RESULTS: Ten consecutive patients completed the questionnaire before the introduction of the website and nine afterward. The median questionnaire scores were significantly greater after the introduction of the website (14 of 15 vs. 12 of 15; P = 0.002), and all patients subjectively found the website easy to understand and useful (10 of 10 in both groups). CONCLUSIONS: An interactive educational multimedia website appears to be a helpful adjunct to the informed consent process for patients undergoing transsphenoidal excision of a pituitary adenoma.

Elastography measures tissue strain, which can be interpreted under certain simplifying assumptions to be representative of the underlying stiffness distribution. This is useful in cancer diagnosis where tumors tend to have a different stiffness to healthy tissue and has also shown potential to provide indication of the degree of bonding at tumor–tissue boundaries, which is clinically useful because of its dependence on tumor pathology. We consider the changes in axial strain for the case of a symmetrical model undergoing uniaxial compression, studied by characterizing changes in tumor contrast transfer efficiency (CTE), inclusion to background strain contrast and strain contrast generated by slip motion, as a function of Young’s modulus contrast and applied strain. We present results from a finite element simulation and an evaluation of these results using tissue-mimicking phantoms. The simulation results show that a discontinuity in displacement data at the tumor boundary, caused by the surrounding tissue slipping past the tumor, creates a halo of “pseudostrain” across the tumor boundary. Mobile tumors also appear stiffer on elastograms than adhered tumors, to the extent that tumors that have the same Young’s modulus as the background may in fact be visible as low-strain regions, or those that are softer than the background may appear to be stiffer than the background. Tumor mobility also causes characteristic strain heterogeneity within the tumor, which exhibits low strain close to the slippery boundary and increasing strain toward the center of the tumor. These results were reproduced in phantom experiments. In addition, phantom experiments demonstrated that when fluid lubrication is present at the boundary, these effects become applied strain-dependent as well as modulus-dependent, in a systematic and characteristic manner. The knowledge generated by this study is expected to aid interpretation of clinical strain elastograms by helping to avoid misinterpretation as well as provide additional diagnostic criteria stated in the paper and stimulate further research into the application of elastography to tumor mobility assessment.

Background Transsphenoidal surgery is the gold standard for pituitary adenoma resection. However, despite advances in microsurgical and endoscopic techniques, some pituitary adenomas can be challenging to cure. Objective We sought to determine whether, in patients undergoing transsphenoidal surgery for pituitary adenoma, intraoperative ultrasound is a safe and effective technologic adjunct. Methods The PubMed database was searched between January 1996 and January 2016 to identify relevant publications that 1) featured patients undergoing transsphenoidal surgery for pituitary adenoma, 2) used intraoperative ultrasound, and 3) reported on safety or effectiveness. Reference lists were also checked, and expert opinions were sought to identify further publications. Results Ultimately, 10 studies were included, comprising 1 cohort study, 7 case series, and 2 case reports. One study reported their prototype probe malfunctioned, leading to false-positive results in 2 cases, and another study' prototype probe was too large to safely enter the sphenoid sinus in 2 cases. Otherwise, no safety issues directly related to use of intraoperative ultrasound were reported. In the only comparative study, remission occurred in 89.7% (61/68) of patients with Cushing disease in whom intraoperative ultrasound was used, compared with 83.8% (57/68) in whom it was not. All studies reported that surgeons anecdotally found intraoperative ultrasound helpful. Conclusions Although there is limited and low-quality evidence available, the use of intraoperative ultrasound appears to be a safe and effective technologic adjunct to transsphenoidal surgery for pituitary adenoma. Advances in ultrasound technology may allow for more widespread use of such devices.

Focal symptomatic epilepsy is the most common form of epilepsy that can often be cured with surgery. A small proportion of patients with focal symptomatic epilepsy do not have identifiable lesions on magnetic resonance imaging (MRI). The most common pathology in this group is type II focal cortical dysplasia (FCD), which is a subtype of malformative brain lesion associated with medication-resistant epilepsy. We present a patient with MRI-negative focal symptomatic epilepsy who underwent invasive electrode recordings. At the time of surgery, a novel ultrasound-based technique called ShearWave Elastography (SWE) was performed. A 0.5 cc lesion was demonstrated on SWE but was absent on B-mode ultrasound and 3-T MRI. Electroencephalography (EEG), positron emission tomography (PET), and magnetoencephalography (MEG) scans demonstrated an abnormality in the right frontal region. On the basis of this finding, a depth electrode was implanted into the lesion. Surgical resection and histology confirmed the lesion to be type IIb FCD. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Study Design Case report. Objective We present the first reported case of spontaneous spinal epidural hematoma secondary to calcium pyrophosphate crystal deposition disease (pseudogout) in a 75-year-old woman. Methods A retrospective review of the patient's case notes was undertaken and the limited literature on this subject reviewed. Results This patient presented with sudden-onset lower limb paresis, sensory loss, urinary retention, and back pain. Magnetic resonance imaging showed an epidural hematoma, which was evacuated. Histologic specimens of the clot showed calcium pyrophosphate dihydrate crystal deposits (pseudogout). Conclusion The importance of histopathologic review of surgical specimens is highlighted when considering the differential diagnosis of apparently spontaneous spinal epidural hematoma.

Introduction Differentiation of brain tumours from normal brain, during surgical resection is, in part, based on their differing mechanical properties. Brain tumours have variable stiffness characteristics. Surgical evaluations on stiffness are, at best, subjective. Ultrasound elastography is a non-invasive method for imaging mechanical properties of tissues such as stiffness at depth. It is hypothesized that this technique may assist in differentiating tumour from the brain in an intraoperative setting. Methods This study evaluated the feasibility of the intraoperative use of ultrasound elastography during brain tumour resection. A total of 24 patients were recruited for the study. Surgical findings on tumour stiffness were compared with the elastogram findings. Furthermore, visibility of the brain-tumour interface on ultrasound echography compared with ultrasound elastography was analysed. Results Ultrasound elastography was found to have a sensitivity of 100% and specificity of 75% at detecting that tumour had a different stiffness to the brain when compared with surgical findings. The technique was also found to have a 100% sensitivity and specificity at the detection of intratumoral stiffness heterogeneity compared with surgical findings. The presence of fluid-filled cysts limited the quality of the elastograms. Ultrasound elastography did not detect the brain-tumour interface as accurately as conventional echography. Conclusion These findings suggest that ultrasound elastography in combination with conventional B-mode ultrasound may be a useful adjunct to differentiate tumour from the brain.

This article presents a new method for acquiring three-dimensional (3-D) volumes of ultrasonic axial strain data. The method uses a mechanically-swept probe to sweep out a single volume while applying a continuously varying axial compression. Acquisition of a volume takes 15-20 s. A strain volume is then calculated by comparing frame pairs throughout the sequence. The method uses strain quality estimates to automatically pick out high quality frame pairs, and so does not require careful control of the axial compression. In a series of in vitro and in vivo experiments, we quantify the image quality of the new method and also assess its ease of use. Results are compared with those for the current best alternative, which calculates strain between two complete volumes. The volume pair approach can produce high quality data, but skillful scanning is required to acquire two volumes with appropriate relative strain. In the new method, the automatic quality-weighted selection of image pairs overcomes this difficulty and the method produces superior quality images with a relatively relaxed scanning technique.

The recent move of the neurosurgical services from The Royal Free London NHS Foundation Trust in Hampstead to The National Hospital for Neurology and Neurosurgery at Queen Square signified the end of an era of neurosurgery in North London. It also represents also another chapter in the history of the remarkable North London hospital that is The Royal Free Hospital. This short article looks at the history of the Department of Neurosurgery at The Royal Free Hospital and the factors contributing to the reorganisation of neurosurgical services in North London.