The volume-outcome relationship for endoscopic transsphenoidal pituitary surgery for benign neoplasm: analysis of an administrative dataset for England.

BACKGROUND: Setting minimum annual volume thresholds for pituitary surgery in England is seen as one way of improving outcomes for patients and service efficiency. However, there are few recent studies from the UK on whether a volume-outcome effect exists, particularly in the era of endoscopic surgery. Such data are needed to allow evidence-based decision making. The aim of this study was to use administrative data to investigate volume-outcome effects for endoscopic transsphenoidal pituitary surgery in England. METHODS: Data from the Hospital Episodes Statistics database for adult endoscopic transsphenoidal pituitary surgery for benign neoplasm conducted in England from April 2013 to March 2019 (inclusive) were extracted. Annual surgeon and trust volume was defined as the number of procedures conducted in the 12 months prior to the index procedure. Volume was categorised as < 10, 10-19, 20-29, 30-39 and ≥40 procedures for surgeon volume and < 20, 20-39, 40-59, 60-79 and ≥80 procedures for trust volume. The primary outcome was repeat ETSPS during the index procedure or during a hospital admission within one-year of discharge from the index procedure. RESULTS: Data were available for 4590 endoscopic transsphenoidal pituitary procedures. After adjustment for covariates, higher surgeon volume was significantly associated with reduced risk of repeat surgery within one year (odds ratio (OR) 0.991 (95% confidence interval (CI) 0.982-1.000)), post-procedural haemorrhage (OR 0.977 (95% CI 0.967-0.987)) and length of stay greater than the median (0.716 (0.597-0.859)). A higher trust volume was associated with reduced risk of post-procedural haemorrhage (OR 0.992 (95% CI 0.985-0.999)), but with none of the other patient outcomes studied. CONCLUSIONS: A surgeon volume-outcome relationship exists for endoscopic transsphenoidal pituitary surgery in England.

A career in neurosurgery: perceptions and the impact of a national SBNS/NANSIG neurosurgery careers day.

OBJECTIVE: Entrance to neurosurgical training is highly competitive. Without proper advice, information and opportunities, talented individuals may be dissuaded from applying. The Neurology and Neurosurgery Interest Group (NANSIG) organises a Careers Day in Neurosurgery every year. Our objective was to assess the overall utility of a neurosurgery careers day and the perceived factors that attract and detract from the specialty, from attendees of the ninth annual neurosurgery careers day. METHODS: Eighteen-item pre-conference and 19-item post-conference questionnaires were disseminated electronically to conference attendees. Questions aimed to capture: (i) baseline demographics; (ii) previous experience and exposure in neurosurgery; (iii) interest in neurosurgery; (iv) understanding training and a career in neurosurgery; (v) perceived factors of attraction and dissuasion of neurosurgery; and (vi) perceived value, quality and educational purpose of the conference. RESULTS: In total, 77 delegates attended the careers day. Most did not have a formal neurosurgical rotation during medical school (24.7%, n = 19), but almost half had gained neurosurgical experience and presented research work. The careers day increased knowledge of the neurosurgical application process (median Likert score 3/5 to 4/5, p < 0.01), duration of training (72.7-88.3%), and desire to pursue a career in neurosurgery (75.3-81.8%). The most commonly reported factors attracting delegates to neurosurgery were interest in neuroanatomy (80.5%, n = 62), practical skills (64.9%, n = 50), and impact on patients (62.3%, n = 48). The most common dissuasive factors were competition to entry (64.9%, n = 50), long working hours (40.3%, n = 31), and other career interests (35.1%, n = 27). Almost all would recommend the event to a colleague (94.9%, n = 73). CONCLUSIONS: Formal undergraduate exposure to neurosurgery is limited. Neurosurgery careers days increase awareness and understanding of the application process and improve interest in a selected cohort. The factors attracting applicants to neurosurgery remain practical links to neuroanatomy, opportunities in neurosurgery for innovation and research, and direct impact on patients.

The use of augmented reality in transsphenoidal surgery: A systematic review.

BACKGROUND: Augmented reality (AR) has become a promising tool in neurosurgery. It can minimise the anatomical challenges faced by conventional endoscopic or microscopic transsphenoidal reoperations and can assist in intraoperative guidance, preoperative planning, and surgical training. OBJECTIVES: The aims of this systematic review are to describe, compare, and evaluate the use of AR in endoscopic and microscopic transsphenoidal surgery, incorporating the latest primary research. METHODS: A systematic review was performed to explore and evaluate existing primary evidence for using AR in transsphenoidal surgery. A comprehensive search of MEDLINE and EMBASE was conducted from database inception to 11th August 2021 for primary data on the use of AR in microscopic and endoscopic endonasal skull base surgery. Additional articles were identified through searches on PubMed, Google Scholar, JSTOR, SCOPUS, Web of Science, Engineering Village, IEEE transactions, and HDAS. A synthesis without meta-analysis (SWiM) analysis was employed quantitatively and qualitatively on the impact of AR on landmark identification, intraoperative navigation, accuracy, time, surgeon experience, and patient outcomes. RESULTS: In this systematic review, 17 studies were included in the final analysis. The main findings were that AR provides a convincing improvement to landmark identification, intraoperative navigation, and surgeon experience in transsphenoidal surgery, with a further positive effect on accuracy and time. It did not demonstrate a convincing positive effect on patient outcomes. No studies reported comparative mortalities, morbidities, or cost-benefit indications. CONCLUSION: AR-guided transsphenoidal surgery, both endoscopic and microscopic, is associated with an overall improvement in the areas of intraoperative guidance and surgeon experience as compared with their conventional counterparts. However, literature on this area, particularly comparative data and evidence, is very limited. More studies with similar methodologies and quantitative outcomes are required to perform appropriate meta-analyses and to draw significant conclusions.

Temporal trends in craniopharyngioma management and long-term endocrine outcomes: A multicentre cross-sectional study.

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.

CSF rhinorrhoea after endonasal intervention to the anterior skull base (CRANIAL): proposal for a prospective multicentre observational cohort study.

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.

The evolution of an SBNS-accredited NANSIG simulated skills workshop for aspiring neurosurgical trainees: an analysis of qualitative and quantitative data.

BACKGROUND: The Neurology and Neurosurgery Interest Group (NANSIG) neurosurgical skills workshop is novel in teaching neurosurgical skills solely to medical students and foundation trainees in the UK. The aim is to offer an affordable option for a high-fidelity simulation course enabling students to learn and practise specific neurosurgical skills in a safe, supervised environment. METHODS: A 10-delegate cohort was quantitatively assessed at the NANSIG neurosurgical skills workshop. Two assessors used a novel modified Objective Structured Assessment of Technical Skills (mOSATS) assessment tool, comprising 5 domains ranked according to a 5-point scale to rate delegates' ability to create a burr hole. Qualitative data from previous workshops were collected, consisting of open-ended, closed-ended and 5-point Likert scale responses to pre- and post-workshop questionnaires. Data were analysed using SPSS® software. RESULTS: Delegates scored a mean total of 62.1% (21.75/35) and 85.1% (29.8/35) in pre- and post-workshop assessments respectively revealing a statistically significant improvement. Regarding percentage of improvement, no significant difference was shown amongst candidates when comparing the number of neurosurgical cases observed and/or assisted in the past. There was no significant difference in the overall rating between the last two workshops (4.89 and 4.8 out of 5, respectively). One hundred percent of the attendees reported feeling more confident in assisting in theatre after the last two workshops. CONCLUSION: We show that a simulation workshop cannot only objectively quantify the improvement of surgical skill acquisition but can also be beneficial regardless of the extent of prior experience.

Obesity and posterior spinal fat content: impact on complications in non-complex lumbar spine surgery.

AIM: Obesity is increasing in prevalence across the world with a potentially very significant impact in spine surgery. This study aimed to characterise this in the setting of neurosurgical spine practise at a single centre in UK. Uniquely, we assess the contribution of posterior spinal fat content to intraoperative complications. MATERIALS AND METHODS: All cases of lumbar spine surgery in 1 year were investigated. Case note review was carried out documenting patient demographics, comorbidities, operative details, complications and length of stay. Ninety-four complete datasets were compiled from 128 cases. The posterior spinal fat content was recorded from T2-weighted MRI. Body mass index (BMI) was correlated with each measure using logistic multiple regression and contingency table analysis. RESULTS: Mean BMI was 28.3 (SD: 5.2) comprising one underweight (BMI <18.5), 26 normal weight (BMI: 18.5-24.9), 32 overweight (BMI ≥25), 33 obese (BMI ≥30) and two morbidly obese patients (BMI ≥40). BMI (coefficient: 0.03, SE: 0.01, p = 0.005) and posterior spinal fat content (coefficient: 0.01, SE: 0.005, p = 0.042) correlated significantly with increasing length of stay. Procedure (p = 0.006) and complication rate (p = 0.010) also correlated with length of stay. Neither BMI nor posterior spinal fat content had a significant effect on the incidence of perioperative complications (p = 0.932, p = 0.742), operating time (p = 0.454, p = 0.748) or blood loss (p = 0.127, p = 0.692). There were three non-operative complications in the obese and overweight groups compared with none in the normal weight group, but this was not significant. Overall complication rate was 15%. CONCLUSION: Obesity and posterior spinal fat content correlate with the length of stay in simple spine surgery. There is a non-significant trend towards increased non-operative complications in overweight and obese patients, which could reach significance with larger numbers and prospective data. Excess posterior spinal fat is not associated with increased operative complications, operating time or blood loss.

Clinical outcomes in patients with nonfunctioning pituitary adenomas managed conservatively.

CONTEXT: The natural history and the optimum management of patients with nonfunctioning pituitary adenomas (NFPAs) are unclear. OBJECTIVE: Our objective was to characterize the natural history of patients with NFPAs managed conservatively. DESIGN AND PATIENTS: We conducted a retrospective analysis of patients presenting to a tertiary referral centre between 1986 and 2009. Patients with pituitary adenomas and no clinical or biochemical evidence of hormonal hypersecretion were included. Those presenting with apoplexy or a radiological follow-up period of less than 1 year were excluded. The pituitary imaging for all patients was re-examined by two neuroradiologists in consensus. OUTCOME MEASURES: The outcome measures were change in tumour size and pituitary hormone function. RESULTS: Sixty-six patients were managed conservatively for a mean follow-up period of 4·3 years (range: 1-14·7). Forty-seven (71%) had a macroadenoma, and nineteen (29%) had a microadenoma. Tumour size decreased or remained stable in 40% of macroadenomas and 47% of microadenomas. The median annual growth rate of enlarging macroadenomas and microadenomas was 1·0 mm/year and 0·4 mm/year, respectively. The median annual growth rate of macroadenomas was significantly higher than that of microadenomas (P < 0·01). Sixty-eight percentage of patients with a macroadenoma had pituitary hormone deficiency in one or more axes, compared to 42% of those with a microadenoma. CONCLUSION: Patients with NFPAs without optic chiasm compression can be managed conservatively. All patients need pituitary function assessment, irrespective of tumour size. These findings provide clinically relevant data for the management of patients with NFPAs.

Examining Introduction of E-consent in the Neurosurgical Caseload: Understanding the Barriers to Implementation.

OBJECTIVE: To evaluate current usage and barriers of electronic consent (e-consent) implementation in neurosurgical practice. E-consent forms provide an alternative method for conducting the informed consent (IC) procedure. IC requires an ability to understand, retain, weigh up, and communicate decisions regarding the proposed procedure. Currently, e-consent has shown promise as a method of improving IC, yet barriers to implementation exist. METHODS: A comparative analysis regarding procedural and consent data was collected over six months in 2 neurosurgical centers with elective and emergency caseloads. These were evaluated for changes over time following e-consent introduction. Clinicians were surveyed for their experience using of e-consenting to understand the barriers to implementation. RESULTS: Over one half (55.6%) of neurosurgical procedures made use of e-consent for IC. Lower rates of e-consent were used in trauma related procedures (38.38%) as compared to elective procedures. This did not increase significantly over the study period. Positive clinician survey feedback indicated e-consenting reduces the time required to perform IC, with 50% of respondents strongly agreeing. Barriers to implementation were reported on free-text entry pertaining largely to difficulties in emergency situations due to form complexity. The inability to create and edit templates for personalized e-consent delivery was a further limitation. CONCLUSIONS: Despite the advantages conferred by e-consent for the administration of IC in neurosurgical procedures, reflected in our survey data, there remains limited use of the technology. Limitations remain relating to ease of access and complexity of use in trauma scenarios.

Evaluation of corticospinal excitability in cervical myelopathy, before and after surgery, with transcranial magnetic stimulation: a pilot study.

PURPOSE: A pilot study to examine the impact of cervical myelopathy on corticospinal excitability, using transcranial magnetic stimulation, and to investigate whether motor evoked potential (MEP) and silent period (SP) recruitment curve (RC) parameters can detect changes in corticospinal function pre- and post-surgery. METHODS: We studied six cervical myelopathy patients undergoing surgery and six healthy controls. Clinical and functional scores and neurophysiological parameters were examined prior to and 3 months following the surgery. RESULTS: MEP latencies for abductor pollicis brevis (APB) and tibialis anterior (TA) muscles and central motor conduction time were prolonged pre- and post-surgery; SP durations were differentially altered. There were significant differences in parameters of RCs for (1) MEP area in APB (max values, S50) and TA (slope) between controls and patients pre- and post-surgery and (2) SP duration in APB (max values) between patients pre-surgery and controls. CONCLUSIONS: The findings of this pilot study suggest an uncoupling of excitatory and inhibitory pathways, which persists at 3 months following cord decompression. RCs for MEP and SP at 3 months provide more information on the functional status of the cord and prompts for a longer term follow-up.

Spinal extradural solitary fibrous tumor with retiform and papillary features.

We report a 66-year-old man with a spinal, extradural solitary fibrous tumor showing unique retiform and papillary architecture. The patient presented in May 2008 with worsening right-sided lower back pain and urinary frequency. Magnetic resonance imaging of the spine documented a heterogeneously enhancing dumbbell-shaped extradural lesion causing cord compression at T11/12 level. The tumor extended to the paravertebral soft tissue and invaded the right adjacent vertebral pedicles and laminae. An angiogram showed prominent vascular supply mainly from the right T11 radicular artery. The patient underwent surgery to relieve cord compression in May 2008 and a second operation following embolization with coils in October 2009. No recurrence was observed at the last neuroimaging follow-up in June 2012. The tumor was composed of vimentin, CD34, Bcl-2, and CD99-positive rounded or slightly elongated cells with scant cytoplasm and oval to spindle nuclei. Several pseudovascular spaces reminiscent of the rete testis were present, and several of them contained papillary projections. Cytologic atypia was minimal, and mitotic activity was low. Focal infiltration of the paraspinal adipose tissue was seen at microscopic level. To our knowledge, retiform and papillary features have never been reported in a solitary fibrous tumor.

The expression of neural cell adhesion molecule and the microenvironment of pituitary neuroendocrine tumours.

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.

A 5-year retrospective study assessing the association between seasonal and meteorological change and incidence of aneurysmal subarachnoid haemorrhage.

OBJECTIVE: Seasonal variation in incidence of spontaneous subarachnoid haemorrhage (SAH) is well recognised. This retrospective single-centre study aimed to characterise seasonality of SAH in the temperate climate of London, UK and to determine associations of incidence with meteorological variables. We further investigated whether associations vary according to location of aneurysm. METHODS: Admission data on 647 patients admitted with spontaneous SAH from December 2003 to August 2008 was analysed using our neurosurgical referrals database. Average monthly incidence of SAH was correlated with local temperature, atmospheric pressure and humidity data. In a subset of 467 patients, impact of aneurysm location on seasonal variation was evaluated. RESULTS: A non-significant bi-annual peak incidence was observed in Spring and Autumn with a trough in Summer (chi(2) = 1.5, p = 0.47). This trend was particularly marked with middle cerebral and posterior communicating artery aneurysms. However, anterior communicating artery aneurysmal SAH peaked in Summer only. SAH incidence correlated significantly with average humidity (coefficient 0.213, CI (0.02-0.404), p = 0.035) and peak humidity (coefficient 0.128, CI (0.008-0.248), p = 0.041). Temperature and atmospheric pressure did not correlate with incidence. CONCLUSIONS: This study illustrates a pattern of variation in SAH incidence similar to that seen in other populations and climates. However, our data suggests that this pattern differs according to aneurysm location. Unusually, we also find that humidity, and not temperature or atmospheric pressure, correlates with SAH incidence. Seasonal variability in aneurysm rupture is likely to be multifactorial, but meteorological factors may play an important role.

Neurosurgery specialty training in the UK: What you need to know to be shortlisted for an interview.

Neurosurgery is one of the most competitive specialties in the UK. In 2019, securing an ST1 post in neurosurgery corresponds to competition ration of 6.54 whereas a CST1 post 2.93. Further, at ST3 level, neurosurgery is the most competitive. In addition, the number of neurosurgical training posts are likely to be reduced in the coming years. A number of very specific shortlisting criteria, aiming to filter and select the best candidates for interview exist. In the context of the high competition ratios and the specific shortlisting criteria, developing an interest in the neurosciences early on will allow individuals more time to meet the necessary standards for neurosurgery. Here, we aim to outline the shortlisting criteria and offer advice on how to achieve maximum scores, increasing the likelihood to be shortlisted for an interview.

The role of the tumour microenvironment in the angiogenesis of pituitary tumours.

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.

A Case Series of Patients with Isolated IgG4-related Hypophysitis Treated with Rituximab.

CONTEXT: The acute presentation of immunoglobulin G4 (IgG4)-related hypophysitis can be indistinguishable from other forms of acute hypophysitis, and histology remains the diagnostic gold standard. The high recurrence rate necessitates long-term immunosuppressive therapy. Rituximab (RTX) has been shown to be effective in systemic IgG4-related disease (IgG4-RD), but experience with isolated pituitary involvement remains limited. CASE DESCRIPTION: We report 3 female patients with MRI findings suggestive of hypophysitis. All patients underwent transsphenoidal biopsy and fulfilled diagnostic criteria for IgG4-related hypophysitis. Treatment with glucocorticoids (GCs) resulted in good therapeutic response in Patients 1 and 2, but the disease recurred on tapering doses of GCs. GC treatment led to emotional lability in Patient 3, necessitating a dose reduction. All 3 patients received RTX and Patients 2 and 3 received further courses of treatment when symptoms returned and B-cells repopulated. Patient 3 did not receive RTX until 12 months from the onset of symptoms. Patient 1 was not able to have further RTX treatments due to an allergic reaction when receiving the second dose. Rituximab treatment resulted in sustained remission and full recovery of anterior pituitary function in Patients 1 and 2, with complete resolution of pituitary enlargement. By contrast, Patient 3 only showed a symptomatic response following RTX treatment, but pituitary enlargement and hypofunction persisted. CONCLUSION: Rituximab treatment for IgG4-related hypophysitis resulted in sustained remission in 2 patients treated early in the disease process but only achieved partial response in a patient with chronic disease, suggesting that early therapeutic intervention may be crucial in order to avoid irreversible changes.

Day 5 morning serum cortisol predicts hypothalamic-pituitary-adrenal function after transsphenoidal surgery for pituitary tumors.

BACKGROUND: Adrenal insufficiency is a complication of transsphenoidal surgery (TSS) for pituitary adenoma, and correct identification of patients requiring glucocorticoid replacement is important. Controversy exists over which early postoperative 9 AM cortisol concentration reliably predicts hypothalamic-pituitary-adrenal (HPA) axis reserve, as defined by the insulin tolerance test (ITT). METHODS: Data were reviewed for 36 patients undergoing TSS followed by day 5 postoperative 9 AM cortisol measurement and ITT 6 weeks postsurgery. All patients received postoperative glucocorticoid replacement, which was discontinued if the 9 AM serum cortisol was >300 nmol/L. RESULTS: Of 23 patients who failed the ITT (peak cortisol <500 nmol/L), 20 also had a day 5, 9 AM serum cortisol <300 nmol/L. Nine of 13 patients who passed the ITT had a day 5, 9 AM cortisol >300 nmol/L. The cutoff cortisol concentration of 300 nmol/L had 86.9% (66.4%-97.2%) diagnostic sensitivity, 69.2% (38.6%-90.9%) diagnostic specificity, and 83.3% (61.8%-94.5%) positive predictive value (PPV) for detecting secondary adrenal insufficiency. Increasing the cutoff to 392 nmol/L resulted in 100% (85.2%-100%) sensitivity, 46.1% (19.2%-74.9%) specificity, and 76.6% (57.3%-89.4%) PPV. Decreasing the cutoff to 111 nmol/L resulted in 100% (75.3%-100%) specificity and 100% (67.9%-100%) PPV, although sensitivity was 47.8% (26.8%-69.4%). CONCLUSIONS: A day 5 post-TSS 9 AM serum cortisol <111 nmol/L reliably detects secondary adrenal insufficiency, and concentrations >392 nmol/L support intact HPA function. Because concentrations of 111-392 nmol/L are poorly predictive of HPA function, glucocorticoid replacement should continue in such cases until definitive testing is performed using an ITT.

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours.

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 < 0.001), with a 3-fold increased CD163:HLA-DR macrophage ratio. PitNETs contained more CD4+ T-lymphocytes (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 < 0.001). GH3 cell-CM increased macrophage chemotaxis, while macrophage-CM changed morphology, invasion, epithelial-to-mesenchymal transition and secreted cytokines of GH3 cells. PitNETs are characterised by increased CD163:HLA-DR macrophage and reduced CD8:CD4 and CD8:FOXP3 T cell ratios. PitNET-derived chemokines facilitate macrophage, neutrophil and T cell recruitment into the tumours which can determine aggressive behaviour.

Pituitary tumour fibroblast-derived cytokines influence tumour aggressiveness.

Tumour-associated fibroblasts (TAFs) are key elements of the tumour microenvironment, but their role in pituitary neuroendocrine tumours (PitNETs) has been little explored. We hypothesised that TAF-derived cytokines may play a role in tumour aggressiveness and that their release can be inhibited by somatostatin analogues. TAFs were isolated and cultured from 16 PitNETs (11 clinically non-functioning tumours and 5 somatotropinomas). The fibroblast secretome was assessed with a 42-plex cytokine array before and after multiligand somatostatin receptor agonist pasireotide treatment. Angiogenesis and epithelial-to-mesenchymal transition pathway assessment included CD31, E-cadherin and ZEB1 expression. GH3 cells treated with TAF- or skin fibroblast-conditioned medium were assessed for migration, invasion and cell morphology changes. PitNET TAFs secreted significant amounts of cytokines including CCL2, CCL11, VEGF-A, CCL22, IL-6, FGF-2 and IL-8. TAFs from PitNETs with cavernous sinus invasion secreted higher IL-6 levels compared to fibroblasts from non-invasive tumours (P = 0.027). Higher CCL2 release from TAFs correlated with more capillaries (r = 0.672, P = 0.004), and TAFs from PitNETs with a higher Ki-67 tended to secrete more CCL2 (P = 0.058). SST1 is the predominant somatostatin receptor in TAFs, and pasireotide decreased TAF-derived IL-6 by 80% (P < 0.001) and CCL2 by 35% (P = 0.038). GH3 cells treated with TAF-conditioned medium showed increased migration and invasion compared to cells treated with skin fibroblast-conditioned medium, with morphological and E-cadherin and ZEB1 expression changes suggesting epithelial-to-mesenchymal transition. TAF-derived cytokines may increase PitNET aggressiveness, alter angiogenesis and induce epithelial-to-mesenchymal transition changes. Pasireotide's inhibitory effect on TAF-derived cytokines suggest that this effect may play a role in its anti-tumour effects.