Efficacy of cabergoline in non-irradiated patients with acromegaly: a multi-centre cohort study.

OBJECTIVE: Elucidate the efficacy (as per current biochemical criteria) of cabergoline monotherapy or as addition to long-acting somatostatin receptor ligand (SRL) in patients with acromegaly and no previous pituitary radiotherapy. DESIGN: Multi-centre, retrospective, cohort study (four UK Pituitary centres: Birmingham, Bristol, Leicester, Oxford). METHODS: Clinical, laboratory, imaging data were analysed. RESULTS: Sixty-nine patients on cabergoline monotherapy were included [median IGF-1 xUpper Limit of Normal (ULN) pre-cabergoline 2.13 (1.02-8.54), median treatment duration 23 months, median latest weekly dose 3 mg]. 31.9% achieved normal IGF-1 (25% GH-secreting, 60% GH+prolactin co-secreting tumours); median weekly cabergoline dose was similar between responders and non-responders. IGF-1 normalisation was related with GH+prolactin co-secreting adenoma (B 1.50, p=0.02) and lower pre-cabergoline IGF-1 xULN levels (B -0.70, p=0.02). Both normal IGF-1 and GH<1 mcg/L were detected in 12.9% of cases and tumour shrinkage in 29.4% of GH-secreting adenomas.Twenty-six patients on SRL+cabergoline were included [median IGF-1 xULN pre-cabergoline 1.7 (1.03-2.92), median treatment duration 36 months, median latest weekly dose 2.5 mg]. 23.1% achieved normal IGF-1 (15.8% GH-secreting, 33.3% GH+prolactin co-secreting tumours). Normal IGF-1 and GH<1 mcg/L were detected in 17.4%. CONCLUSIONS: In non-irradiated patients, cabergoline normalises IGF-1 in around one-third and achieves both IGF-1 and GH targets in approximately one out of ten cases. SRL+cabergoline is less efficient than previously reported possibly due to differences in studies methodology and impact of confounding factors.

Natural history of non-functioning pituitary microadenomas: results from the UK non-functioning pituitary adenoma consortium.

OBJECTIVE: The optimal approach to the surveillance of non-functioning pituitary microadenomas (micro-NFPAs) is not clearly established. Our aim was to generate evidence on the natural history of micro-NFPAs to support patient care. DESIGN: Multi-centre, retrospective, cohort study involving 23 endocrine departments (UK NFPA consortium). METHODS: Clinical, imaging, and hormonal data of micro-NFPA cases between January, 1, 2008 and December, 21, 2021 were analysed. RESULTS: Data for 459 patients were retrieved [median age at detection 44 years (IQR 31-57)-152 males/307 females]. Four hundred and nineteen patients had more than two magnetic resonance imagings (MRIs) [median imaging monitoring 3.5 years (IQR 1.71-6.1)]. One case developed apoplexy. Cumulative probability of micro-NFPA growth was 7.8% (95% CI, 4.9%-8.1%) and 14.5% (95% CI, 10.2%-18.8%) at 3 and 5 years, respectively, and of reduction 14.1% (95% CI, 10.4%-17.8%) and 21.3% (95% CI, 16.4%-26.2%) at 3 and 5 years, respectively. Median tumour enlargement was 2 mm (IQR 1-3) and 49% of micro-NFPAs that grew became macroadenomas (nearly all >5 mm at detection). Eight (1.9%) patients received surgery (only one had visual compromise with surgery required >3 years after micro-NFPA detection). Sex, age, and size at baseline were not predictors of enlargement/reduction. At the time of detection, 7.2%, 1.7%, and 1.5% patients had secondary hypogonadism, hypothyroidism, and hypoadrenalism, respectively. Two (0.6%) developed hypopituitarism during follow-up (after progression to macroadenoma). CONCLUSIONS: Probability of micro-NFPA growth is low, and the development of new hypopituitarism is rare. Delaying the first follow-up MRI to 3 years and avoiding hormonal re-evaluation in the absence of tumour growth or clinical manifestations is a safe approach for micro-NFPA surveillance.

Risk of second brain tumour after radiotherapy for pituitary adenoma or craniopharyngioma: a retrospective, multicentre, cohort study of 3679 patients with long-term imaging surveillance.

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.

Surgical resection of giant extrasellar thyrotropinoma: Use of orbitozygomatic and endoscopic endonasal approach.

Background: Thyrotropinomas (TSHoma) are rare pituitary adenomas. Case Description: A 34-year-old female presented with mild bitemporal field defect in third trimester with intact pituitary function. MRI demonstrated an enhancing lesion from the posterior planum to suprasellar, interpeduncular and prepontine cisterns with chiasmal compression and right fetal posterior communicating artery encasement. With no sellar expansion, the differentials included meningioma or craniopharyngioma. She underwent a postpartum expanded endoscopic endonasal transtuberculum transchiasmatic sulcus approach [Video 1]. The lesion was debulked in the chiasmatic cistern to decompress the chiasm with preservation of superior hypophyseal perforators. Pituitary transposition and midclival approach to access the retrosellar component was not undertaken pending formal histology as the lesion encased the perforators and was atypical for the outlined differentials. In addition, the diaphragm was intact. Postoperatively, visual field normalized and the patient developed mild diabetes insipidus. Following the diagnosis of TSHoma (with an abnormal thyroid function test [TFT]) and due to patient preference and slightly increased risk of CSF leak with revisional endoscopic procedure, she underwent an orbitozygomatic craniotomy (pretemporal and transsylvian approach) without tentorial division to resect the disease in the interpeduncular and prepontine cisterns [Video 1]. The anatomical triangles and tumor characteristics facilitated this. A residual cuff was left along the base of the stalk and the floor of the third ventricle to preserve the superior hypophyseal and thalamoperforators. Postoperatively, the patient had normal TFT without any neurological deficit. Conclusion: Operative treatment strategy is presented for a rare large challenging multicompartmental extrasellar TSHoma using endoscopic endonasal and open skull base approaches.

A decade of the sharing economy: Concepts, users, business and governance perspectives.

Sharing economy platforms have been transforming production and consumption systems in cities around the world. While the sharing economy may contribute to addressing sustainability issues, its actual economic, social and environmental impacts remain poorly understood. Advancing more sustainably promising forms of sharing and leveraging its benefits, while circumventing its pitfalls, is becoming increasingly important in the era of Covid-19 and climate crisis, economic downturn and uncertainty, and loss of social connectedness, particularly in anonymous urban environments. The ways to capitalise on strengths of the sharing economy are still poorly understood. In particular, the roles and perspectives of users, businesses and municipal governments in institutionalising the sharing economy in various geographical contexts are essential to examine. This volume seeks to advance the research field by focusing on four research areas: 1) understanding the sharing economy conceptually; 2) user perspectives on the sharing economy; 3) business perspective on the sharing economy; and 4) urban governance perspective on the sharing economy. The twenty articles in this volume discuss sustainability implications of the sharing economy from different perspectives, in various geographical contexts, and drawing on a range of disciplines. The volume makes a significant contribution by bringing in empirical findings from emerging and developing economies, including Brazil, China, Indonesia, Poland, the Philippines, South Korea, Thailand and Vietnam, thereby supplementing more frequently discussed perspectives from high-income countries. The volume also outlines the course for future research.

Identifying Cardiovascular Risk in Survivors of Childhood Leukaemia Treated with Haematopoietic Stem Cell Transplantation and Total Body Irradiation
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BACKGROUND: Survivors of childhood with haematopoietic stem cell transplantation and total body irradiation (HSCT/TBI) have an increased cardiometabolic risk without overt obesity. AIM: To describe cardiometabolic risk in HSCT/TBI survivors and identify anthropometric measurements of adiposity representative of cardiometabolic risks in HSCT/TBI survivors. METHOD: Childhood leukaemia survivors treated with HSCT/TBI (n = 21, 11 males) were compared with chemotherapy-only (n = 31) and obese non-leukaemic controls (n = 30). All subjects (16-26 years) had blood pressure and auxological measurements (body mass index, waist and hip circumferences) and blood tests (triglycerides, high-density lipoprotein [HDL], and oral glucose tolerance tests). Central adiposity was defined as either increased waist circumference (WC), waist-to-height ratio (WHtR) (>0.5), or waist-to-hip ratio (WHR) (males >0.9, females >0.85). RESULTS: HSCT/TBI survivors showed higher prevalence of hypertriglyceridaemia than both comparison groups and higher prevalence of reduced HDL compared to the chemotherapy-only group. The WHR reported a higher prevalence of increased adiposity in HSCT/TBI survivors compared with WC and WHtR, but such differences were not observed in the other groups. In the HSCT survivors, WHR had the highest number of significant associations with metabolic risk factors, and metabolic risks worsen with time elapsed since primary treatment. CONCLUSIONS: HSCT/TBI survivors have high cardiometabolic risk that is not sufficiently reflected by WC alone. WHR is a useful surrogate marker for increased cardiometabolic risk in HSCT/TBI survivors.
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Reduced beta-cell reserve and pancreatic volume in survivors of childhood acute lymphoblastic leukaemia treated with bone marrow transplantation and total body irradiation.

BACKGROUND: Impaired glucose tolerance (IGT) and diabetes mellitus (DM) occur more frequently after bone marrow transplantation and total body irradiation (BMT/TBI), but the mechanism is unclear. This study investigates insulin sensitivity, ß-cell reserve and pancreatic volume in adult survivors of childhood acute lymphoblastic leukaemia (ALL). METHOD: Survivors (aged 16-26 years) of ALL treated with BMT/TBI (10-14·4 Gy) Group 1 (n = 20, 10 m) were compared with a chemotherapy-only Group 2 (n = 28, 11 m). Participants underwent assessments of insulin sensitivity by whole body composite-insulin-sensitivity-index (ISIcomp ) from oral glucose tolerance tests (OGTTs); first (AIRarg , AIRg , AUCin10 ) and second (AUC in second phase ) phase insulin responses from arginine-intravenous glucose tolerance tests; and pancreatic volume by abdominal magnetic resonance imaging (MRI). Data were analysed by odds ratio, Chi-square or Fisher's exact tests, Student's t-tests, analysis of covariance (ancova) and Pearson's or partial correlations (5% significance). RESULTS: Abnormal OGTTs were documented in Group 1 (DM = 2, IGT = 7). Insulin secretion adjusted for insulin sensitivity was lower in Group 1 than Group 2 as a whole [LogAIRarg (P = 0·008), logAIRg (P = 0·013) and logAUCin10 (P = 0·014)] and after exclusion of those with abnormal glucose tolerance [logAIRarg (P = 0·011), logAIRg (P = 0·007) and logAUCin10 (P = 0·006)]. Group 1 had lower pancreatic volume than Group 2 [52·0 (14·2) vs 72·8 (23·5), P = 0·001] cm(3) , and results were consistent after adjustment for size by body surface area (P = 0·019). Pancreatic volume correlated with logAIRarg adjusted log ISIcomp (partial correlation = 0·34, P = 0·025). CONCLUSIONS: Adult survivors of childhood BMT/TBI for ALL demonstrated reduced ß-cell reserve and smaller pancreatic volume, both likely additional aetiological factors, with reduced insulin sensitivity, in their increased risk of diabetes.

Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene.

The hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the occurrence of parathyroid tumors and ossifying jaw fibromas. The gene causing HPT-JT, HRPT2, is located on chromosome 1q31.2 and consists of 17 exons that encode a 531-amino acid protein, designated parafibromin. We recently identified six Roma families in Portugal with 56 members (11 affected and 45 asymptomatic), who had the HPT-JT syndrome. We postulated that they may have a common ancestor and that the HPT-JT syndrome may be due to a mutation of the HRPT2 gene. Haplotype analysis using 14 chromosome 1q24-q32 polymorphic markers showed that the 11 affected individuals shared a common haplotype defined by seven markers that spanned an approximately 12.5-cM region, flanked centromerically by D1S202 and telomerically by D1S306. DNA sequence analysis identified a 2-bp (TG or GT) frameshift deletion in exon 8, which predicts a truncated parafibromin protein, in all 11 affected individuals. This mutation was also found in 19 unaffected individuals (age range, 12-74 yr) who shared the affected haplotype, suggesting a low age-related penetrance for HPT-JT in these families. Thus, the HPT-JT syndrome in six Roma families from Portugal is due to a novel founder mutation in the HRPT2 gene.