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Currarino syndrome (CS) is an autosomal dominant syndrome caused by mutations in MNX1 and characterized by anorectal abnormalities, partial sacral agenesis, and presacral masses. The presacral masses are typically benign; however, malignant degeneration can occur, and presacral neuroendocrine tumors (NETs) have been reported in six cases. We report three individuals from two families affected by CS in which multiple individuals developed presacral NETs. The first family, 491, had six members with features of CS, including two siblings who presented with presacral, Grade 2 NETs, one of which had metastasized to bone and lymph nodes. A germline c.874C>T (p.Arg292Trp) mutation was found in a highly conserved region of MNX1 in three affected members who underwent sequencing. A second somatic variant/deletion in MNX1 was not detected in either patient's tumor. In the second family, 342, the proband presented with an incidentally discovered presacral NET. The proband's father had previously undergone resection of a presacral NET, and so genetic testing was performed, which did not reveal an MNX1 mutation or copy number variants. The lack of a second, somatic mutation in the tumors from family 491 argues against MNX1 acting as a tumor suppressor, and the absence of a germline MNX1 mutation in family 342 suggests that other genetic and anatomic factors contribute to the development of presacral NETs. These cases highlight the variable presentation of CS, and the potential for malignancy in these patients.

BACKGROUND. The small bowel and pancreas are the most common primary sites of neuroendocrine tumors (NETs) giving rise to metastatic disease. Some patients with small bowel NETs (SBNETs) present with synchronous or metachronous pancreatic NETs (PNETs), and it is unclear whether these are separate primaries or metastases from one site to the other. METHODS. A surgical NET database including patients undergoing operations for SBNETs or PNETs was reviewed. Patients with synchronous or metachronous tumors in both the small bowel and pancreas were identified, and available tissues from primary tumors and metastases were examined using a 4-gene quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) panel developed for evaluating NETs of unknown primary. RESULTS. Of 338 patients undergoing exploration, 11 had NETs in both the small bowel and pancreas. Tissues from 11 small bowel tumors, 9 pancreatic tumors, and 10 metastases were analyzed. qPCR and IHC data revealed that three patients had separate SBNET and PNET primaries, and five patients had SBNETs that metastasized to the pancreas. Pancreatic tissue was unavailable in two patients, and qPCR and IHC gave discrepant results in one patient. CONCLUSIONS. NETs in both the small bowel and pancreas were found in 3% of our patients. In nearly two-thirds of evaluable patients, the pancreatic tumor was a metastasis from the SBNET primary, while in the remaining one-third of patients it represented a separate primary. Determining the origin of these tumors can help guide the choice of systemic therapy and surgical management.

Carcinoid syndrome (CS), characterized by diarrhea and flushing, is present in 20% of patients with neuroendocrine tumors at diagnosis and becomes more frequent with progression. The diarrhea of CS is caused mainly by tumoral secretion of serotonin. It may not be fully controlled by somatostatin analogs, the currently indicated drugs for symptomatic relief. Telotristat ethyl is a novel inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis. Administration of the drug decreases diarrhea in patients with CS. Telotristat ethyl was approved in February 2017 (USA) and September 2017 (European Commission) for the treatment of CS diarrhea in adults inadequately controlled by somatostatin analog alone. This drug is expected to greatly improve the health and quality of life of patients with CS diarrhea.

Time to Sustained Improvement in Bowel Movement Frequency With Telotristat Ethyl : Analysis of the Phase 3 TELESTAR Study

To characterize the cell surface receptor for dehydroepiandrosterone (DHEA), we synthesized a DHEA analog containing biotin and benzophenone groups (DHEA–BP–Bt). DHEA–BP–Bt was equipotent with DHEA in competing with [ 3 H]DHEA for binding to solubilized plasma membranes of bovine aortic endothelial cells (BAEC). Additionally, DHEA–BP–Bt pre-conjugated to avidin and immobilized on agarose, also inhibited plasma membrane binding of [ 3 H]DHEA. Furthermore, DHEA–BP–Bt activated endothelial nitric oxide synthase, similar to DHEA. Confocal micrographs showed that, upon photoirradiation, DHEA–BP–Bt bound to sites on the cell surface of BAEC in a DHEA inhibitable manner. Finally, DHEA–BP–Bt bound specifically to proteins of approximately 55 kDa and 80 kDa, either when live cells were UV irradiated with the analog and plasma membrane proteins separated by SDS-PAGE or in a ligand blot analysis. These data confirm the successful synthesis of a photoactive, biotinylated DHEA analog which is capable of cross-linking to and identifying plasma membrane DHEA binding sites and which will allow us to further purify this receptor.

The glucagon-like peptide-1 (GLP-1) receptor is expressed on alpha-cells, though its functional significance is unknown. The endogenous beta-cell GLP-1 receptor is coupled to adenylyl cyclase, cell depolarization, activation of voltage-dependent Ca2+ channels (VDCC) and extracellular Ca2+ influx (Lu et al., 1993 b). In contrast, the signaling pathways of the GLP-1 receptor in alpha-cells are poorly understood. To determine the signaling mechanisms of the alpha-cell GLP-1 receptor, we established a stable pancreatic islet alpha-cell line expressing the recombinant rat GLP-1 receptor (INR1-SF2), using INRl-G9 cells. These INRl-G9 cells do not express endogenous GLP-1 receptor. In INR1-SF2 cells, GLP-1 bound to the recombinant receptor (Kd = 0.9 nM) and increased cAMP (ED50 = 0.6 nM). GLP-1 increased the free cytosolic Ca2+ ([Ca2+]i) (ED50 = 50 nM) by release from intracellular stores, but did not affect INR1-SF2 cell phosphoinositol turnover. Despite expressing VDCC, the INR1-SF2 cells were not depolarized by GLP-1, even in the presence of glucose. This contrasts with the depolarizing action of GLP-1 in beta-cells in the presence of glucose (Lu et al., 1993 b). This study establishes that a single GLP-1 receptor species can mediate the effects of GLP-1 through multiple signaling pathways, including the adenylyl cyclase system and intracellular Ca2+ release, in an alpha-cell type. Furthermore, since GLP-1 is unable to cause cellular depolarization or activate VDCC in INR1-SF2 cells, these data suggest that glucose-induced membrane depolarization may be crucial for GLP-1 to further activate VDCC and potentiate glucose-stimulated insulin release in beta-cells. Finally this study describes a cell line that can be used as a model system for evaluation of GLP-1 signaling in alpha-cells.

It remains unknown whether dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) have a physiological role other than serving as metabolic intermediates in androgen synthesis. Apart from intracellular metabolism, there is no convincing cellular mechanism of action for physiological concentrations of DHEA(S). Unlike other major steroids, a receptor for DHEA(S) has not been definitively isolated. This article will review the evidence supporting a receptor-dependent basis for the direct physiological effects of DHEA(S). The data supporting an intracellular receptor for DHEA(S) are relatively weak and do not allow us to determine whether DHEA(S) directly, or a metabolite of DHEA(S), acts as a direct receptor ligand. Recent data strongly support a plasma membrane receptor for DHEA, but this potential receptor is yet to be isolated. Definitive characterization of the molecular mechanism (receptor or otherwise) of DHEA(S) action is necessary before we can determine whether DHEA(S) has a biological role other than as an androgen precursor.

Many women with diabetes notice changes in glucose control perimenstrually. To describe the pattern of changes in glucose control throughout the complete menstrual cycle, and the reproducibility of these changes, we performed a pilot study evaluating glycemic profiles continuously for three cycles in four women with type 1 diabetes. All participants had hemoglobin A1c

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are metabolic intermediates in the production of potent androgens, estrogens and other less well-characterized steroids. DHEA(S) and closely related steroid hormones have a variety of immunological effects both in vitro and in vivo in experimental animals and humans. Many of these effects have been demonstrated in animal models where there is little circulating DHEA(S), and the demonstrated effects are generally seen at concentrations of DHEA(S) which are supra-physiological in man. The physiological role of DHEA(S) in the immunological system is unknown. Furthermore, the molecular mechanism of action of DHEA(S) is unclear. In this review, I focus on studies of the immunological effects of DHEA(S) and closely related steroid metabolites and analogs, mainly derived from literature published in the last five years. My purpose is to describe the demonstrated effects and to highlight some of the remaining major research issues in this field. These issues include defining the molecular mechanism of DHEA(S) action; determining whether the effect of DHEA(S) is related to the steroid itself or to a metabolic product of DHEA; determining the relationship of physiological function to the pharmacological effects; and determining the molecular basis for species-specific differences in effects.