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Background: Radiotherapy is a valuable treatment in the management algorithm of pituitary adenomas and craniopharyngiomas. However, the risk of second brain tumour following radiotherapy is a major concern. We assessed this risk using non-irradiated patients with the same primary pathology and imaging surveillance as controls., Methods: In this multicentre, retrospective cohort study, 4292 patients with pituitary adenoma or craniopharyngioma were identified from departmental registries at six adult endocrine centres (Birmingham, Oxford, Leeds, Leicester, and Bristol, UK and Ferrara, Italy). Patients with insufficient clinical data, known genetic predisposition to or history of brain tumour before study entry (n=532), and recipients of proton beam or stereotactic radiotherapy (n=81) were excluded. Data were analysed for 996 patients exposed to 2-dimensional radiotherapy, 3-dimensional conformal radiotherapy, or intensity-modulated radiotherapy, and compared with 2683 controls., Findings: Over 45 246 patient-years, second brain tumours were reported in 61 patients (seven malignant [five radiotherapy, two controls], 54 benign [25 radiotherapy, 29 controls]). Radiotherapy exposure and older age at pituitary tumour detection were associated with increased risk of second brain tumour. Rate ratio for irradiated patients was 2·18 (95% CI 1·31-3·62, p<0·0001). Cumulative probability of second brain tumour was 4% for the irradiated and 2·1% for the controls at 20 years., Interpretation: Irradiated adults with pituitary adenoma or craniopharyngioma are at increased risk of second brain tumours, although this risk is considerably lower than previously reported in studies using general population controls with no imaging surveillance. Our data clarify an important clinical question and guide clinicians when counselling patients with pituitary adenoma or craniopharyngioma on the risks and benefits of radiotherapy., Funding: Pfizer., Competing Interests: Declaration of interests AC has received a grant from Health Education England for a radiotherapy contouring analysis website tool in 2020. MCZ is a consultant for Novartis, Eli Lilly, and Genzyme. KB has received honoraria from HRA Pharma and Ipsen UK for talks and professional consultancy services; conference and travel grants from Novo Nordisk; and has completed a National Health Service service development project with Novartis. RDM has received research funding from Pfizer, Sandoz, and Ipsen; consultancy fees from Takeda, Sandoz, and Diurnal; conference grant from Recordati Rare Diseases UK; and honoraria for talks from Pfizer, Ipsen, Sandoz, and Novartis. RH has received a conference grant from Recordati Rare Diseases UK. NK has received honoraria from Pfizer, Ipsen, HRA Pharma and Recordati Rare Diseases for lectures; research funding from Pfizer, Ipsen, and Shire and has served as a member in Scientific Advisory Boards for Pfizer, Ipsen, and Recordati Rare Diseases. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Acromegaly is a rare disease characterized by a chronic exposition to growth hormone (GH) and insulin-like growth factor-1 (IGF-1), caused in most cases by a pituitary GH-secreting adenoma. Chronic GH excess induces systemic complications (metabolic, cardiovascular, respiratory, neoplastic, and musculoskeletal) and increased mortality if not appropriately treated. Recent epidemiological data report an improved life span of patients with acromegaly probably due to better acromegaly management; additionally, the number of pituitary incidentaloma in general population also increased over time due to more frequent imaging. Therefore, the number of elderly patients, newly diagnosed with acromegaly or in follow-up, is expected to grow in the coming years and clinicians will need to be aware of particularities in managing these patients., Purpose: This review aims to explore different aspects of acromegaly of the elderly patients, focusing on epidemiology, diagnosis, clinical presentation, complications, and management options., Methods: Available literature has been assessed through PubMed (data until August 2019) by specific keywords., Conclusions: Available data on acromegaly in the elderly patient are sparse, but point to important differences. Further studies are needed comparing elderly with younger patients with acromegaly to better define a tailored diagnostic and therapeutic management.

Context: Pituitary adenomas can cause specific syndromes due to hormone excess and/or determine sellar mass symptoms. Pituitary cell growth can sometimes be influenced by medical therapy, such as for somatotroph adenomas treated with somatostatin analogs or prolactinomas treated with dopaminergic drugs. However, nonfunctioning pituitary adenomas (NFAs) are still orphans of medical therapy. Everolimus (RAD001), a derivative of rapamycin, is a well-known immunosuppressant drug, which has been recently shown to have antineoplastic activity in several human cancers., Objective: The objective of the study was to investigate the possible antiproliferative effects of RAD001 in human NFAs., Design: We collected 40 NFAs that were dispersed in primary cultures, treated without or with 1 nm to 1 microm RAD001, 10 nm cabergoline, 10 nm SOM230 (a somatostatin receptor multiligand), and/or 50 nm IGF-I. Cell viability and apoptosis were evaluated after 48 h, and vascular endothelial growth factor (VEGF) secretion was assessed after an 8-h incubation. Somatostatin and dopamine subtype 2 receptor expression was investigated by quantitative PCR., Results: In 28 cultures (70%), Everolimus significantly reduced cell viability (by approximately 40%; P < 0.05 vs. control), promoted apoptosis (+30%; P < 0.05 vs. control), inhibited p70S6K activity (-20%), and blocked IGF-I proliferative and antiapoptotic effects. In selected tissues cotreatment with SOM230, but not cabergoline, exerted an additive effect. Everolimus did not affect VEGF secretion but blocked the stimulatory effects of IGF-I on this parameter., Conclusions: Everolimus reduced NFA cell viability by inducing apoptosis, with a mechanism likely involving IGF-I signaling but not VEGF secretion, suggesting that it might represent a possible medical treatment of invasive/recurrent NFAs.

Somatostatin has been discovered as a somatotroph release inhibitory factor (SRIF), and, indeed, it has been demonstrated that SRIF and its analogs can inhibit pituitary tumor hormone secretion and control neoplastic bulk. Several in vitro studies have contributed to the current knowledge of the mechanisms by which SRIF and its analogs may influence pituitary adenomas, opening the way to new possible therapeutic strategies. This review focuses on the results obtained by testing several SRIF analogs in vitro on pituitary adenomas, concerning both secretory activity and cell viability. These studies provide the basis for further investigations, both at basic and clinical level, of the application of SRIF analogs in the pituitary field.

The antisecretory effects of somatostatin (SRIH) and its analogs are widely recognized and provide the basis for treatment of hormonal hypersecretion in patients with pituitary adenomas, especially in the settings of acromegaly. Dopamine (DA) agonists have also been used for medical treatment of prolactin and/or GH hypersecretion, and recent evidence points to an even greater antisecretory effect for a chimeric molecule, having high affinity for both SRIH and DA receptors. Evidence for an antiproliferative effect of these compounds has also been provided. This review focuses on the antiproliferative effects of SRIH and its analogs, of DA and chimeric compounds on pituitary adenomas, and on the clinical consequences on tumor volume of pharmacological treatment of pituitary adenomas with these drugs.

Somatostatin (SRIF) analogs have been employed in medical therapy of non-functioning pituitary adenomas (NFA), with contrasting results. Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor (VEGF) secretion and action, and that VEGF expression may be related to pituitary tumor growth. The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on VEGF secretion and cell proliferation in human NFA primary cultures. We assessed the expression of SRIF receptors (SSTR1-5), the in vitro effects on VEGF secretion, and on cell viability of SRIF and of the stable SRIF analog pasireotide (SOM230), which activates SSTR1, 2, 3, and 5. Twenty-five NFA were examined by RT-PCR for expression of alpha-subunit, SSTR, VEGF, and VEGF receptors 1 (VEGF-R1) and 2 (VEGF-R2). Primary cultures were tested with SRIF and with pasireotide. All NFA samples expressed alpha-sub, VEGF and VEGFR-1 and 2, while SSTR expression pattern was highly variable. Two different groups were identified according to VEGF secretion inhibition by SRIF. VEGF secretion and cell viability were reduced by SRIF and pasireotide in the 'responder' group, but not in the 'non-responder' group, including NFA expressing SSTR5. SRIF and pasireotide completely blocked forskolin-induced VEGF secretion. In addition, SRIF and pasireotide completely abrogated the promoting effects of VEGF on NFA cell viability. Our data demonstrate that pasireotide can inhibit NFA cell viability by inhibiting VEGF secretion, and suggest that the multireceptor-SSTR agonist pasireotide might be useful in medical therapy of selected NFA.

The antisecretory effects of somatostatin (SRIF) and its analogs are widely recognised and provide the basis for treatment of hormonal hypersecretion in pituitary adenomas, especially in the settings of acromegaly. Evidence for an antiproliferative effect of these compounds has also been provided. This review focuses on the mechanisms transducing the antiproliferative effects of SRIF and its analogs on pituitary adenomas, and on the clinical consequences on tumor volume of pharmacological treatment of pituitary adenomas with these drugs.

Somatostatin (SRIF) analogs interacting with SRIF receptor (SSTR) subtypes SSTR2 and SSTR5 reduce hormone secretion of pituitary adenomas, but their antiproliferative effects are still controversial. We investigated the in vitro effects of SRIF and SSTR-selective agonists interacting with SSTR1 (BIM-23926), SSTR2 (BIM-23120), SSTR5 (BIM-23206), or both SSTR2 and SSTR5 (BIM-23244) on alpha-subunit and chromogranin A secretion and on cell viability of 12 nonfunctioning pituitary adenomas (NFA) expressing SSTR1, SSTR2, and SSTR5, as assessed by RT-PCR. Treatment with SRIF or BIM-23206 did not modify alpha-subunit and chromogranin A secretion, which was significantly inhibited by BIM-23926, BIM-23120, and BIM-23244. SRIF and BIM-23120 did not influence cell viability, which was significantly promoted by BIM-23206 and BIM-23244 and reduced by treatment with BIM-23926. These results demonstrate that, in the selected NFA, the SSTR1-selective agonist inhibits secretory activity and cell viability, the SSTR2-selective agonist inhibits secretion but not cell viability, and the SSTR5-selective agonist does not influence secretion but promotes cell viability. These data can explain the lack of inhibitory effects of currently used SRIF analogs and suggest that drugs acting potently and preferentially on SSTR1 might be useful for medical treatment of NFA.

Somatostatin (SRIF) analogs interacting with SRIF receptor subtype (SSTR) 2 and SSTR5 are known to reduce secretion in GH-secreting pituitary adenomas. We investigated the effects of SRIF and a SSTR1 selective agonist, BIM-23926, on GH and prolactin (PRL) secretion and cell viability in primary cultures deriving from 15 GH- and PRL-secreting adenomas expressing SSTR1. Quantitative RT-PCR showed SSTR1 mRNA mean levels of 6 +/- 2.2 x 10(4) molecules/ microg reverse-transcribed total RNA. SSTR2 and SSTR5 were frequently expressed (93.3%), on the contrary of SSTR3 (53.3%) and SSTR4 (6.7%). GH secretion was significantly reduced by SRIF and BIM-23926 (45 +/- 8.6% and 32 +/- 18.1% inhibition, respectively) as well as PRL secretion (16.1 +/- 4% and 19.7 +/- 3.5% inhibition, respectively). After treatment with SRIF and BIM-23926, cell viability was significantly reduced by 17.5 +/- 5% and 20 +/- 3.9%, respectively. SSTR1 mRNA levels correlated with the degree of GH and PRL secretion inhibition. These results demonstrate that SSTR1 selective activation inhibits hormone secretion and cell viability in GH- and PRL-secreting adenomas in vitro and suggest that SRIF analogs with affinity for SSTR1 may be useful to control hormone hypersecretion and reduce neoplastic growth of pituitary adenomas.

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

Objectives: In this study, we developed a radiomic signature for the classification of benign lipid-poor adenomas, which may potentially help clinicians limit the number of unnecessary investigations in clinical practice. Indeterminate adrenal lesions of benign and malignant nature may exhibit different values of key radiomics features. Methods: Patients who had available histopathology reports and a non-contrast-enhanced CT scan were included in the study. Radiomics feature extraction was done after the adrenal lesions were contoured. The primary feature selection and prediction performance scores were calculated using the least absolute shrinkage and selection operator (LASSO). To eliminate redundancy, the best-performing features were further examined using the Pearson correlation coefficient, and new predictive models were created. Results: This investigation covered 50 lesions in 48 patients. After LASSO-based radiomics feature selection, the test dataset's 30 iterations of logistic regression models produced an average performance of 0.72. The model with the best performance, made up of 13 radiomics features, had an AUC of 0.99 in the training phase and 1.00 in the test phase. The number of features was lowered to 5 after performing Pearson's correlation to prevent overfitting. The final radiomic signature trained a number of machine learning classifiers, with an average AUC of 0.93. Conclusions: Including more radiomics features in the identification of adenomas may improve the accuracy of NECT and reduce the need for additional imaging procedures and clinical workup, according to this and other recent radiomics studies that have clear points of contact with current clinical practice. Clinical relevance statement: The study developed a radiomic signature using unenhanced CT scans for classifying lipid-poor adenomas, potentially reducing unnecessary investigations that scored a final accuracy of 93%. Key Points: • Radiomics has potential for differentiating lipid-poor adenomas and avoiding unnecessary further investigations. • Quadratic mean, strength, maximum 3D diameter, volume density, and area density are promising predictors for adenomas. • Radiomics models reach high performance with average AUC of 0.95 in the training phase and 0.72 in the test phase. [ABSTRACT FROM AUTHOR]

Background: Controversies exist in the best surgical approach (open vs. laparoscopy) to large adrenal tumours without peri-operative evidence of primary carcinoma, mainly due to possible capsular disruption of an unsuspected malignancy. In addition, intra-operative blood loss, conversion rate, operative time, and hospital stay may be increased with laparoscopy.the Aims Of Our Study Were: (1) to compare clinical outcomes of laparoscopic adrenalectomy for large versus small adrenal tumours and (2) to identify risk factors associated with increased operative time and hospital stay in laparoscopic adrenalectomy.Methods: This is a multicentre retrospective cohort study in a large patient population (N = 200) who underwent laparoscopic adrenalectomy in 2004-2014 at three Italian academic hospitals. Patients were divided into two cohorts according to tumour size: "large" tumours were defined as ≥5 cm (N = 50) and "small" tumours as <5 cm (N = 150). Further analysis adopting a ≥8 cm (N = 15) cut-off size was performed.Results: The study groups were comparable in age and gender distribution as well as their tumour characteristics. The operative time (p = 0.671), conversion rate (p = 0.488), intra- (p = 0.876) and post-operative (p = 0.639) complications, and hospital stay (p = 0.229) were similar between groups. With a cut-off size ≥5 cm, the early study period (2004-2009), which included operators' learning curve, was associated with increased risk of longer operative time (HR 0.57; 95 % CI 0.40-0.82), while American Society of Anaesthesiology score ≥3 was associated with prolonged hospital stay (HR 0.67; 95 % CI 0.47-0.97). Tumour size ≥8 cm was associated with prolonged operative time (HR 0.47; 95 % CI 0.24-0.94).Conclusions: Surgeons skilled in advanced laparoscopy and adrenal surgery can perform laparoscopic adrenalectomy safely in patients with ≥5-cm tumours with no increase in hospital stay, or conversion rate, although operative time may be increased for ≥8-cm tumours. Surgeon' experience, size ≥8 cm, and patient comorbidities have the largest impact on operative time and length of hospital stay in laparoscopic large adrenal tumour resection. [ABSTRACT FROM AUTHOR]