Lanreotide versus placebo for tumour reduction in patients with a 68Ga-DOTATATE PET-positive, clinically non-functioning pituitary macroadenoma (GALANT study): a randomised, multicentre, phase 3 trial with blinded outcome assessment.

Background: No established medical treatment options currently exist for patients with non-functioning pituitary macroadenoma (NFPMA). Somatostatin analogues may prevent tumour growth, but randomised controlled trials are lacking. In vivo somatostatin receptor assessment with 68Ga-DOTATATE PET could help in selecting patients for treatment. We aimed to determine the effect of the somatostatin analogue lanreotide on tumour size in patients with a 68Ga-DOTATATE PET-positive NFPMA. Methods: The GALANT study was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial with recruitment at three academic hospitals in the Netherlands. Adult patients with a suprasellar extending NFPMA, either surgery-naïve or postoperative remnant ≥10 mm, were eligible for inclusion. Important exclusion criteria were previous sellar radiotherapy and use of dopamine receptor agonists. Somatostatin receptor expression in the NFPMA was determined through 68Ga-DOTATATE PET/CT, co-registered with MRI. A predefined sample of 44 patients with PET-positive NFPMA were randomly assigned (1:1) to lanreotide acetate 120 mg or placebo, both administered as deep subcutaneous injections every 28 days for 72 weeks. Primary outcome was the change in cranio-caudal tumour diameter measured on pituitary MRI from baseline to end-of-treatment in the intention-to-treat population. Participants, investigators and outcome assessors were masked to treatment allocation. The trial is registered with the Netherlands Trial Registry, NL5136, and EudraCT, 2015-001234-22. Findings: Between Nov 3, 2015, and Dec 10, 2019, 49 patients were included in the study. Forty-four patients with a 68Ga-DOTATATE PET-positive NFPMA were randomly assigned to lanreotide (22 [50%]) or placebo (22 [50%]). Study treatment was completed in 13 (59%) lanreotide and 19 (86%) placebo participants. The mean (SD) change from baseline in cranio-caudal tumour diameter after treatment was +1·2 (2·5) mm with lanreotide and +1·3 (1·5) mm with placebo; adjusted mean difference versus placebo -0·1 mm (95% CI -1·3 to 1·2, p = 0·93). Adverse events occurred in 22 (100%, 147 events) lanreotide and 21 (95%, 94 events) placebo participants. Gastrointestinal complaints were most common, reported by 18 (82%) lanreotide and 8 (36%) placebo participants. There were no treatment-related serious adverse events. Interpretation: Compared with placebo, lanreotide treatment did not reduce tumour size or growth in patients with 68Ga-DOTATATE PET-positive NFPMA. Funding: Ipsen Farmaceutica BV.

Basal cortisol in relation to metyrapone confirmation in predicting adrenal insufficiency after pituitary surgery.

PURPOSE: Pituitary surgery can lead to post-surgical adrenal insufficiency with the need for glucocorticoid replacement and significant disease related burden. In patients who do not receive hydrocortisone replacement before surgery, at our center, an early morning plasma cortisol concentration using a cut-off value of 450 nmol/L 3 days after surgery (POD3) is used to guide the need for hydrocortisone replacement until dynamic confirmatory testing using metyrapone. The aim of this study was to critically assess the currently used diagnostic and treatment algorithm in patients undergoing pituitary surgery in our pituitary reference center. METHODS: Retrospective analysis of all patients with a POD3 plasma cortisol concentration < 450 nmol/L who received hydrocortisone replacement and a metyrapone test after 3 months. Plasma cortisol concentration was measured using an electrochemiluminescence immunoassay (Roche). All patients who underwent postoperative testing using metyrapone at Amsterdam UMC between January 2018 and February 2022 were included. Patients with Cushing's disease or those with hydrocortisone replacement prior to surgery were excluded. RESULTS: Ninety-five patients were included in the analysis. The postoperative cortisol concentration above which no patient had adrenal insufficiency (i.e. 11-deoxycortisol > 200 nmol/L) was 357 nmol/L (Sensitivity 100%, Specificity 31%, PPV:32%, NPV:100%). This translates into a 28% reduction in the need for hydrocortisone replacement compared with the presently used cortisol cut-off value of 450 nmol/L. CONCLUSION: Early morning plasma cortisol cut-off values lower than 450 nmol/L can safely be used to guide the need for hydrocortisone replacement after pituitary surgery.

High prevalence of venous thrombotic events in Cushing's syndrome: data from ERCUSYN and details in relation to surgery.

OBJECTIVE: The aim of this study was to evaluate the prevalence of venous thromboembolism (VTE) in patients included in the European Registry on Cushing's syndrome (ERCUSYN), compare their clinical characteristics with those who did not develop VTE and identify risk factors for VTE. DESIGN: A retrospective observational cohort study. METHODS: Data extraction from the registry was taken on February, 7, 2022. At the time there were 2174 patients diagnosed with Cushing's syndrome (CS) and 95 VTEs were reported in the database. RESULTS: Of 95 VTE events 70 (74%) were in pituitary-dependent CS patients, 12 (12.5%) in adrenal-dependant CS, 10 (10.5%) in ectopic CS, and 3 (3%) in CS due to other causes. Sex, 24-hour urinary free cortisol (UFC) value at diagnosis, as well as the number of operations remained statistically significant predictors of VTE. Of patients who were treated with at least one surgery, 12 (13%) VTE occurred before and 80 (87%) after the surgery. Nearly half of these VTEs occurred within six months since the operation (36; 45%). Over half of the centers that reported VTE did not routinely anticoagulate CS patients. Anticoagulation schemes varied widely. CONCLUSION: Patients with CS have an elevated risk of developing VTE for an extended period of time. From ERCUSYN cohort patients have higher risk for VTE if they need multiple surgeries to treat CS, are males and have high UFC values at the diagnosis of CS. Since there is no agreement on thromboprohpylaxis, a protocol for VTE prevention that is widely adopted appears to be necessary for patients with CS.

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.

Continuing Challenges in the Definitive Diagnosis of Cushing's Disease: A Structured Review Focusing on Molecular Imaging and a Proposal for Diagnostic Work-Up.

The definitive diagnosis of Cushing's disease (CD) in the presence of pituitary microadenoma remains a continuous challenge. Novel available pituitary imaging techniques are emerging. This study aimed to provide a structured analysis of the diagnostic accuracy as well as the clinical use of molecular imaging in patients with ACTH-dependent Cushing's syndrome (CS). We also discuss the role of multidisciplinary counseling in decision making. Additionally, we propose a complementary diagnostic algorithm for both de novo and recurrent or persistent CD. A structured literature search was conducted and two illustrative CD cases discussed at our Pituitary Center are presented. A total of 14 CD (n = 201) and 30 ectopic CS (n = 301) articles were included. MRI was negative or inconclusive in a quarter of CD patients. 11C-Met showed higher pituitary adenoma detection than 18F-FDG PET-CT (87% versus 49%). Up to 100% detection rates were found for 18F-FET, 68Ga-DOTA-TATE, and 68Ga-DOTA-CRH, but were based on single studies. The use of molecular imaging modalities in the detection of pituitary microadenoma in ACTH-dependent CS is of added and complementary value, serving as one of the available tools in the diagnostic work-up. In selected CD cases, it seems justified to even refrain from IPSS.

Starting point for benchmarking outcomes and reporting of pituitary adenoma surgery within the European Reference Network on Rare Endocrine Conditions (Endo-ERN): results from a meta-analysis and survey study.

Objective: The European Reference Network on Rare Endocrine Conditions (Endo-ERN) aims to organize high-quality healthcare throughout Europe, including care for pituitary adenoma patients. As surgery is the mainstay of treatment, we aimed to describe the current surgical practice and published surgical outcomes of pituitary adenoma within Endo-ERN. Design and Methods: Systematic review and meta-analysis of studies reporting surgical outcomes of pituitary adenoma patients within Endo-ERN MTG6 pituitary reference centers between 2010 and 2019. A survey was completed by reference centers on their current surgical practice. Results: A total of 18 out of 43 (42%) reference centers located in 7 of the 20 (35%) MTG6-represented countries published 48 articles. Remission rates were 50% (95% CI: 42-59) for patients with acromegaly, 68% (95% CI: 60-75) for Cushing's disease, and 53% (95% CI: 39-66%) for prolactinoma. Gross total resection was achieved in 49% (95% CI: 37-61%) of patients and visual improvement in 78% (95% CI: 68-87). Mortality, hemorrhage, and carotid injury occurred in less than 1% of patients. New-onset hypopituitarism occurred in 16% (95% CI: 11-23), transient diabetes insipidus in 12% (95% CI: 6-21), permanent diabetes insipidus in 4% (95% CI: 3-6), syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in 9% (95% CI: 5-14), severe epistaxis in 2% (95% CI: 0-4), and cerebrospinal fluid leak in 4% (95% CI: 2-6). Thirty-five (81%) centers completed the survey: 54% were operated endoscopically and 57% were together with an ENT surgeon. Conclusion: The results of this study could be used as a first benchmark for the outcomes of pituitary adenoma surgery within Endo-ERN. However, the heterogeneity between studies in the reporting of outcomes hampers comparability and warrants outcome collection through registries.

Costs and Its Determinants in Pituitary Tumour Surgery.

Purpose: Value-based healthcare (VBHC) provides a framework to improve care by improving patient outcomes and reducing healthcare costs. To support value-based decision making in clinical practice we evaluated healthcare costs and cost drivers in perioperative care for pituitary tumour patients. Methods: We retrospectively assessed financial and clinical data for surgical treatment up to the first year after surgery of pituitary tumour patients treated between 2015 and 2018 in a Dutch tertiary referral centre. Multivariable regression analyses were performed to identify determinants of higher costs. Results: 271 patients who underwent surgery were included. Mean total costs (SD) were €16339 (13573) per patient, with the following cost determinants: surgery time (€62 per minute; 95% CI: 50, 74), length of stay (€1331 per day; 95% CI 1139, 1523), admission to higher care unit (€12154 in total; 95% CI 6413, 17895), emergency surgery (€10363 higher than elective surgery; 95% CI: 1422, 19305) and postoperative cerebrospinal fluid leak (€14232; 95% CI 9667, 18797). Intradural (€7128; 95% CI 10421, 23836) and combined transsphenoidal/transcranial surgery (B: 38494; 95% CI 29191, 47797) were associated with higher costs than standard. Further, higher costs were found in these baseline conditions: Rathke's cleft cyst (€9201 higher than non-functioning adenoma; 95% CI 1173, 17230), giant adenoma (€19106 higher than microadenoma; 95% CI 12336, 25877), third ventricle invasion (€14613; 95% CI 7613, 21613) and dependent functional status (€12231; 95% CI 3985, 20477). In patients with uncomplicated course, costs were €8879 (3210) and with complications €17551 (14250). Conclusions: Length of hospital stay, and complications are the main drivers of costs in perioperative pituitary tumour healthcare as were some baseline features, e.g. larger tumors, cysts and dependent functional status. Costs analysis may correspond with healthcare resource utilization and guide further individualized care path development and capacity planning.

Implementation of functional imaging using 11C-methionine PET-CT co-registered with MRI for advanced surgical planning and decision making in prolactinoma surgery.

PURPOSE: To report the first experience of our multidisciplinary team with functional imaging using 11C-methionine positron emission tomography-computed tomography (11C-methionine PET-CT) co-registered with MRI (Met-PET/MRICR) in clinical decision making and surgical planning of patients with difficult to treat prolactinoma. METHODS: In eighteen patients with prolactinoma, referred to our tertiary referral centre because of intolerance or resistance for dopamine agonists (DA), Met-PET/MRICR was used to aid decision-making regarding therapy. RESULTS: Met-PET/MRICR was positive in 94% of the patients. MRI and Met-PET/MRICR findings were completely concordant in five patients, partially concordant in nine patients, and non-concordant in four patients. In five patients Met-PET/MRICR identified lesion(s) that were retrospectively also visible on MRI. Met-PET/MRICR was false negative in one patient, with a cystic adenoma on conventional MRI. Thirteen patients underwent transsphenoidal surgery, with nine achieving full biochemical remission, two clinical improvement and near normalized prolactin levels, and one patient clinical improvement with significant tumour reduction. Hence, nearly all patients (94%) were considered to have a positive outcome. Permanent complication rate was low. Three patients continued DA, two patients have a wait and scan policy. CONCLUSION: Met-PET/MRICR can provide additional information to guide multidisciplinary preoperative and intraoperative decision making in selected cases of prolactinoma. This approach resulted in a high remission rate with a low rate of complications in our expert centre.

Impact of patient-reported nasal symptoms on quality of life after endoscopic pituitary surgery: a prospective cohort study.

PURPOSE: Endoscopic transsphenoidal surgery causes nasal morbidity and negatively affects health-related quality of life (HRQoL). Knowledge on actionable symptoms that could improve postoperative HRQoL is therefore important. This study assessed the impact of nasal symptoms on postoperative HRQoL. METHODS: This perioperative cohort study included 103 adult patients undergoing endoscopic pituitary adenoma resection (August 2016-December 2018), with measurements preoperatively, and 5 days, 6 weeks and 6 months after surgery. Nasal symptoms were measured with the Anterior Skull base nasal inventory-12, and HRQoL with the Short Form-36 (SF-36) physical (PCS) and mental component scores (MCS). Linear regression analysis was used to assess (1) determinants of postoperative nasal morbidity, (2) associations between number of symptoms or (3) individual symptoms and HRQoL, and (4) the percentage of variance of HRQoL explained by nasal symptoms. RESULTS: The number of nasal symptoms transiently increased after surgery. No significant treatment- or disease-related determinants of nasal morbidity were identified. The number of nasal symptoms was significantly associated with a lower PCS (ß = - 1.0; 95%CI - 1.5, - 0.4), but not with MCS at 6 weeks. Similar results were observed at 6 months. Headaches (42.2%), problems with smell (42.0%), and taste (36.0%) were the most prevalent symptoms, while sense of smell and taste, and nasal discharge showed the strongest associations with HRQoL. CONCLUSIONS: Postoperative nasal symptoms, in particular problems with smell and taste, significantly affect pituitary patients' physical HRQoL. Monitoring of these symptoms may aid in determining which patients may benefit from intensified follow-up and treatment, aiming to optimize HRQoL.

Consensus on diagnosis and management of Cushing's disease: a guideline update.

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.

The PRolaCT studies - a study protocol for a combined randomised clinical trial and observational cohort study design in prolactinoma.

BACKGROUND: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size. METHODS: We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naïve patients; PRolaCT-2: patients with limited duration of DA treatment (4-6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months. DISCUSSION: Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine. TRIAL REGISTRATION: US National Library of Medicine registry (ClinicalTrials.gov) NCT04107480 . Registered on 27 September 2019, registered retrospectively (by 2 months).

Safety of therapy with and withdrawal from denosumab in fibrous dysplasia and McCune-Albright syndrome: an observational study.

Denosumab (Dmab) treatment can benefit patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) by suppressing the receptor activator of nuclear factor κB ligand (RANKL)-mediated increased bone resorption. However, limited data of two pediatric cases indicate that a rebound phenomenon may occur after withdrawal. Therefore we studied the safety of Dmab discontinuation in FD/MAS. Thirty-seven patients using Dmab, mostly after unsuccessful bisphosphonate (BP) treatment, were included. Health records were screened for pain scores, side effects, and bone turnover markers (BTMs) (calcium, alkaline phosphatase [ALP], procollagen 1 N-terminal propeptide [P1NP], and ß-crosslaps [B-CTX, also termed ß-C-terminal telopeptide]) during treatment, and for BTMs and clinical rebound effects after withdrawal. BTM levels after withdrawal were compared to pretreatment values. Data were calculated as median (interquartile range [IQR]). BTMs normalized in two-thirds of patients and pain scores decreased significantly during treatment (p = 0.002). One patient (2.7%) developed osteonecrosis of the jaw. Sixteen patients discontinued Dmab treatment after a median of 1.6 years (IQR 1.0 years) because of insufficient effect on pain (n = 10, 63%), side effects (n = 4, 25%), or other reasons (n = 4, 25%). Follow-up posttreatment was 3.2 (2.8) years, wherein no fractures, pain flares, or lesion progression occurred. Calcium remained normal in all but one patient, who had a mild asymptomatic hypercalcemia (2.73 mmol/L) 5 months after discontinuation. ALP passed pretreatment levels in five of 11 patients (46%), increased most after 6 months by 18 (43) U/L, and returned to baseline levels thereafter. P1NP exceeded pretreatment levels in four of nine patients (44%), CTX in eight of nine patients (89%). P1NP rose most after 3 months and stabilized thereafter. CTX showed the highest relative elevation. Patients with high pretreatment levels responding well to Dmab seemed to have the highest rebound. These results suggest beneficial effects of Dmab on pain and BTMs, and show a biochemical but asymptomatic rebound phenomenon after withdrawal in adults with FD/MAS, mainly in case of high pretreatment levels, good response, and multiple injections. Further studies on the safety of Dmab and withdrawal are needed and ongoing. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Serum Inflammation-based Scores in Endocrine Tumors.

CONTEXT: Serum inflammation-based scores reflect systemic inflammatory response and/or patients' nutritional status, and may predict clinical outcomes in cancer. While these are well-described and increasingly used in different cancers, their clinical usefulness in the management of patients with endocrine tumors is less known. EVIDENCE ACQUISITION: A comprehensive PubMed search was performed using the terms "endocrine tumor," "inflammation," "serum inflammation-based score," "inflammatory-based score," "inflammatory response-related scoring," "systemic inflammatory response markers," "neutrophil-to-lymphocyte ratio," "neutrophil-to-platelet ratio," "lymphocyte-to-monocyte ratio," "Glasgow prognostic score," "neutrophil-platelet score," "Systemic Immune-Inflammation Index," and "Prognostic Nutrition Index" in clinical studies. EVIDENCE SYNTHESIS: The neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio are the ones most extensively investigated in patients with endocrine tumors. Other scores have also been considered in some studies. Several studies focused in finding whether serum inflammatory biomarkers may stratify the endocrine tumor patients' risk and detect those at risk for developing more aggressive and/or refractory disease, particularly after endocrine surgery. CONCLUSIONS: In this review, we summarize the current knowledge on the different serum inflammation-based scores and their usefulness in predicting the phenotype, clinical aggressiveness, and disease outcomes and prognosis in patients with endocrine tumors. The value of such serum inflammation-based scores in the management of patients with endocrine tumors has been emerging over the last decade. However, further research is necessary to establish useful markers and their cut-offs for routine clinical practice for individual diseases.

Outcome Squares Integrating Efficacy and Safety, as Applied to Functioning Pituitary Adenoma Surgery.

CONTEXT: Transsphenoidal surgery is standard care in the treatment of hormone-secreting pituitary adenomas. Current clinician-reported surgical outcome measures are one-dimensional, typically focusing primarily on complete or partial resection, and secondarily on complication rates. However, outcomes are best reflected by the delicate balance of efficacy and complications at patient level. OBJECTIVE: This study proposes a novel way to classify and report outcomes, integrating efficacy and safety at the patient level. METHODS: Retrospective chart review of all pure endoscopic transsphenoidal surgical procedures for acromegaly, Cushing's disease, and prolactinoma between 2010 and 2018 in a single tertiary referral center. We present our results in a classic (remission and complications separate) and in a novel outcome square integrating both outcomes, focusing on intended and adverse effects (long-term complications). This resulted in 4 outcome groups, ranging from good to poor. We use this approach to present these outcomes for several subgroups. RESULTS: A total of 198 surgical procedures were included (44 reoperations). Remission was achieved in 127 operations (64%). Good outcome was observed after 121 (61%), and poor outcome after 6 (3%) operations. When intended effect of surgery was applied (instead of remission), good outcome as intended was achieved after 148 of 198 surgeries (75%) and poor outcome after 4 (2%). CONCLUSION: Quality of a surgical intervention can be presented in 4 simple categories, integrating both efficacy and safety with flexibility to adapt to the individualized situation at patient, disease, and surgical strategy and to the outcome of interest.

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.

The DEXA-CORT trial: study protocol of a randomised placebo-controlled trial of hydrocortisone in patients with brain tumour on the prevention of neuropsychiatric adverse effects caused by perioperative dexamethasone.

INTRODUCTION: The synthetic glucocorticoid dexamethasone can induce serious neuropsychiatric adverse effects. Dexamethasone activates the glucocorticoid receptor (GR) but, unlike endogenous cortisol, not the mineralocorticoid receptor (MR). Moreover, dexamethasone suppresses cortisol production, thereby eliminating its MR binding. Consequently, GR overactivation combined with MR underactivation may contribute to the neuropsychiatric adverse effects of dexamethasone. The DEXA-CORT trial aims to reactivate the MR using cortisol to reduce neuropsychiatric adverse effects of dexamethasone treatment. METHODS AND ANALYSIS: The DEXA-CORT study is a multicentre, randomised, double-blind, placebo-controlled trial in adult patients who undergo elective brain tumour resection treated perioperatively with high doses of dexamethasone to minimise cerebral oedema. 180 patients are randomised between treatment with either two times per day 10 mg hydrocortisone or placebo during dexamethasone treatment. The primary study outcome is the difference in proportion of patients scoring ≥3 points on at least one of the Brief Psychiatric Rating Scale (BPRS) questions 5 days postoperatively or earlier at discharge. Secondary outcomes are neuropsychiatric symptoms, quality of sleep, health-related quality of life and neurocognitive functioning at several time points postoperatively. Furthermore, neuropsychiatric history, serious adverse events, prescribed (psychiatric) medication and referrals or evaluations of psychiatrist/psychologist and laboratory measurements are assessed. ETHICS AND DISSEMINATION: The study protocol has been approved by the Medical Research Ethics Committee of the Leiden University Medical Center, and by the Dutch competent authority, and by the Institutional Review Boards of the participating sites. It is an investigator-initiated study with financial support by The Netherlands Organisation for Health Research and Development (ZonMw) and the Dutch Brain Foundation. Results of the study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NL6726 (Netherlands Trial Register); open for patient inclusion. EudraCT number 2017-003705-17.

Healthcare utilization and costs among prolactinoma patients: a cross-sectional study and analysis of determinants.

PURPOSE: Prolactinomas are the most prevalent functioning pituitary adenomas. They affect gonadal function as well as health-related quality of life (HRQoL). This study aimed to report healthcare utilization and costs, including their determinants, for prolactinoma patients. METHODS: Cross-sectional study of 116 adult prolactinoma patients in chronic care in a Dutch tertiary referral center. Patients completed four validated questionnaires, assessing healthcare utilization and costs over the previous 12 months (Medical Consumption Questionnaire), disease bother and needs (Leiden Bother and Needs Questionnaire Pituitary), HRQoL (Short Form-36), and self-reported health status (EuroQol 5D). Regression analyses were used to assess associations between disease-related characteristics and healthcare utilization and costs. RESULTS: Mean age was 52.0 years (SD 13.7) and median follow-up was 15.0 years (IQR 7.6-26.1). Patients visited the endocrinologist (86.2%), general practitioner (37.9%), and ophthalmologist (25.0%) most frequently. Psychological care was used by 12.9% of patients and 5% were admitted to hospital. Mean annual healthcare costs were €1928 (SD 3319), mainly for pituitary-specific medication (37.6% of total costs), hospitalization (19.4%) and specialist care (16.1%). Determinants for higher healthcare utilization and costs were greater disease bother and needs for support, lower HRQoL, elevated prolactin, and longer disease duration, while tumor size, hypopituitarism and adrenal insufficiency were not significantly associated with healthcare utilization and costs. CONCLUSION: Healthcare utilization and costs of prolactinoma patients are related to patient-reported HRQoL, bother by disease and needs for support. Therefore, addressing patients' HRQoL and needs is a way forward to improve efficiency of care and patients' health status.

Postoperative diabetes insipidus: how to define and grade this complication?

PURPOSE: Although transient diabetes insipidus (DI) is the most common complication of pituitary surgery, there is no consensus on its definition. Polyuria is the most overt symptoms of DI, but can also reflect several physiological adaptive mechanisms in the postoperative phase. These may be difficult to distinguish from and might coincide with DI. The difficulty to distinguish DI from other causes of postoperative polyuria might explain the high variation in incidence rates. This limits interpretation of outcomes, in particular complication rates between centers, and may lead to unnecessary treatment. Aim of this review is to determine a pathophysiologically sound and practical definition of DI for uniform outcome evaluations and treatment recommendations. METHODS: This study incorporates actual data and the experience of our center and combines this with a review of literature on pathophysiological mechanisms and definitions used in clinical studies reporting of postoperative DI. RESULTS: The occurrence of excessive thirst and/or hyperosmolality or hypernatremia are the best indicators to discriminate between pathophysiological symptoms and signs of DI and other causes. Urine osmolality distinguishes DI from osmotic diuresis. CONCLUSIONS: To improve reliability and comparability we propose the following definition for postoperative DI: polyuria (urine production > 300 ml/hour for 3 h) accompanied by a urine specific gravity (USG) < 1.005, and at least one of the following symptoms: excessive thirst, serum osmolality > 300 mosmol/kg, or serum sodium > 145 mmol/L. To prevent unnecessary treatment with desmopressin, we present an algorithm for the diagnosis and treatment of postoperative DI.

Improvement in Symptoms and Health-Related Quality of Life in Acromegaly Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Whereas biochemical response is often used as a primary study outcome, improvement in symptoms and health-related quality of life (HRQoL) is the relevant goal for patients to consider treatment successful. We performed a systematic review and meta-analysis to assess the effect of treatment on symptoms and HRQoL in acromegaly. METHODS: Seven electronic databases were searched for longitudinal studies assessing patient-reported symptoms or HRQoL in acromegaly. Meta-analyses were performed to assess differences during treatment for the Acromegaly Quality of Life Questionnaire (AcroQoL) and Patient-Assessed Acromegaly Symptom Questionnaire (PASQ), and standardized mean difference (SMD) for individual symptoms (interpretation: 0.2 small, 0.5 moderate, and 0.8 large effect). Treatment-naive and previously treated patients were assessed separately. RESULTS: Forty-six studies with 3301 patients were included; 24 contributed to quantitative analyses. Thirty-six studies used medication as main treatment, 1 transsphenoidal adenomectomy, and 9 various treatments. Symptoms and HRQoL both improved: AcroQoL increased 2.9 points (95% CI, 0.5 to 5.3 points), PASQ decreased -2.3 points (95% CI, -1.3 to -3.3 points), and individual symptom scores decreased for paresthesia -0.9 (95% CI, -0.6 to -1.2), hyperhidrosis -0.4 (95% CI, -0.1 to -0.6), fatigue -0.3 (95% CI, -0.1 to -0.6), arthralgia -0.3 (95% CI, -0.1 to -0.5), headache -0.3 (95% CI, 0.0 to -0.6), and soft-tissue swelling -0.2 (95% CI, 0.0 to -0.4). CONCLUSION: Symptoms and HRQoL improved during acromegaly treatment. Consensus is needed on which symptoms should be included in a potential core outcome set, taking into account symptom frequency, severity, and sensitivity to change, which can be used in clinical practice and as outcome in trials.