Abstract Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.
Adrenal insufficiency is managed by hormone replacement therapy, which is far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for a curative approach to restoring the complex feedback regulation of the hypothalamic-pituitary-adrenal axis. Here, we generated human induced steroidogenic cells (hiSCs) from fibroblasts, blood-, and urine-derived cells through forced expression of steroidogenic factor-1 and activation of the PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells, expressed steroidogenic enzymes, and secreted steroid hormones in response to stimuli. hiSCs were viable when transplanted into the mouse kidney capsule and intra-adrenal. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia was rescued by expressing the wild-type version of the defective disease-causing enzymes. Our study provides an effective tool with many potential applications for studying adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies.
Abstract Background: Neuroendocrine tumours (NETs) are a wide-ranging group of neoplasms originating from neuroendocrine cells. In 2014 NETs incidence was 7 per 100000 people annually. The purpose of this systematic review is to evaluate the safety and efficacy of various types of chemotherapeutic agents on gastroenteropancreatic NETs (GEP NETs) and to determine which type of chemotherapy is the most effective for different tumour types, with minimum adverse events. To our knowledge, this study is the first systematic review that compares several types of chemotherapy and evaluates their safety and efficacy on GEP NETs. Methods: The study followed recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines on reporting systematic reviews. The literature search for this systematic review was conducted using the following databases and search engines: Cochrane library, EMBASE, Google Scholar, PubMed, and Web of Science, from 1963 to 2020. Results: The review comprised 26 observational studies, and 5 randomized controlled trials (RCTs). The total number of subjects included in this study was 1783. Our study showed that the most effective treatment for Grade 3 NETs and Grade 3 neuroendocrine carcinomas was cisplatin/etoposide. Furthermore, capecitabin/temozolomide therapy has been shown to be most effective in Grade 1 and Grade 2 NETs. Conclusion: Therapy with two chemotherapeutic agents has been shown to be more effective than monotherapy and therapy with three chemotherapeutic agents. Unfortunately, our study has limitations and we urgently need RCTs or larger observational studies that will contain all the necessary efficacy and safety tools, and thus provide answers to our clinical questions.
131I-meta-iodobenzylguanidine (131I-MIBG) has been in therapeutic use since 1980s. Newer treatment modalities are emerging for neuroendocrine tumours (NETs) and chromaffin cell tumours (CCTs), but many of these do not yet have adequate long-term follow-up to determine their longer term efficacy and sequelae. Fifty-eight patients with metastatic NETs and CCTs who had received 131I-MIBG therapy between 2000 and 2011 were analysed. Survival and any long-term haematological or renal sequelae were investigated. In the NET group, the overall median survival and median survival following the diagnosis of metastatic disease was 124 months. The median survival following the commencement of 131I-MIBG was 66 months. For the CCT group, median survival had not been reached. The 5-year survival from diagnosis and following the diagnosis of metastatic disease was 67% and 67.5% for NETs and CCTs, respectively. The 5-year survival following the commencement of 131I-MIBG therapy was 68%. Thirty-two patients had long-term haematological sequelae: 5 of these 32 patients developed haematological malignancies. Two patients developed a mild deterioration in renal function. Long follow up of 131I-MIBG therapy reveals a noteable rate of bone marrow toxicities and malignancy and long term review of all patients receiving radionuclide therapies is recommended.
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