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Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease. [ABSTRACT FROM AUTHOR]

Purpose: Highlight and characterize manifestations, diagnostic/management approaches and outcomes in a contemporary cohort of patients with pituitary metastases (PM) from a large European pituitary center—over 10 years. Methods: Retrospective review of PM cases between 1/2009 and 12/2018. Clinical, laboratory, imaging data at PM detection and during follow-up were analysed. Results: 18 cases were identified (14 females; median age at diagnosis 61.5 years). Most common primary malignancies were lung (39%) and breast (32%). Most frequent presenting manifestation was visual dysfunction (50%). Gonadotrophin, ACTH, TSH deficiency were diagnosed in 85%, 67%, 46% of cases, respectively; diabetes insipidus (DI) was present in 17%. 33% of cases were detected during investigation for symptoms unrelated to PM. PM management included radiotherapy (44%), transsphenoidal surgery (17%), transsphenoidal surgery and radiotherapy (6%) or monitoring only (33%). One-year survival was 49% with median survival from PM detection 11 months (range 2–47). Conclusions: In our contemporary series, clinical presentation of PM has evolved; we found increased prevalence of anterior hypopituitarism, decreased rates of DI and longer survival compared with older literature. Increased availability of diagnostic imaging, improvements in screening and recognition of pituitary disease and longer survival of patients with metastatic cancer may be contributing factors. [ABSTRACT FROM AUTHOR]

Summary: High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. Introduction: High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. Methods: Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. Results: Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m, p < 0.001). Conclusion: Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass. [ABSTRACT FROM AUTHOR]

The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by inhibition of cell proliferation. Two isozymes of 11?-hydroxysteroid dehydrogenase (11?-HSD) interconvert cortisol (F) and inactive cortisone (E), and are thus able to modulate GC action at an autocrine level. Previously, we have demonstrated absent expression of 11?-HSD2 in normal pituitaries; however, in a small number of pituitary tumors analysed, 11?-HSD2 was readily demonstrable. Here we have used real-time RT-PCR to quantify expression of mRNA for 11 ?-HSD1 and 2 in 105 human pituitary tumors and have performed enzyme expression and activity studies in primary pituitary cultures. Overall, pituitary tumors expressed lower levels of 11?-HSDl mRNA compared with normals (0.2-fold, P<0.05). In contrast, expression of 11?-HSD2 mRNA was 9.8-fold greater in tumors than in normals (P<0.001). Enzyme assays showed significant 11?-HSD2 activity (71.9±22.3?pmol/h/mg protein (mean±s.d.)) but no detectable 11?-HSDl activity. Proliferation assays showed that addition of glycyrrhetinic acid (an 11?-HSD2 inhibitor) resulted in a 30.3±7.7% inhibition of cell proliferation. In summary, we describe a switch in expression from 11?-HSDl to 11?-HSD2 in neoplastic pituitary tissue. We propose that abnormal expression of 11?-HSD2 acts as a proproliferative prereceptor determinant of pituitary cell growth, and may provide a novel target for future tumor therapy.Oncogene (2003) 22, 1663-1667. doi:10.1038/sj.onc.1206293 [ABSTRACT FROM AUTHOR]