Patients with metastatic or unresectable (advanced) pheochromocytoma and paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity 131 I-meta-iodobenzylguanidine (HSA 131 I-MIBG) in patients with advanced PPGL. Methods: In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA 131 I-MIBG. Of these patients, 68 received at least 1 therapeutic dose (∼18.5 GBq) of HSA 131 I-MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 mo. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0, biochemical tumor marker response, overall survival, and safety. Results: Of the 68 patients who received at least 1 therapeutic dose of HSA 131 I-MIBG, 17 (25%; 95% confidence interval, 16%–37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 mo. Decreases in elevated (≥1.5 times the upper limit of normal at baseline) serum chromogranin levels were observed, with confirmed complete and partial responses 12 mo after treatment in 19 of 28 patients (68%). The median overall survival was 36.7 mo (95% confidence interval, 29.9–49.1 mo). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA 131 I-MIBG. Conclusion: HSA 131 I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.

There have been significant developments in diagnostic and therapeutic options for patients with neuroendocrine tumors. Key phase III studies include the CLARINET trial which evaluated lanreotide in patients with non-functioning enteropancreatic NETs, the RADIANT 2 and RADIANT 4 studies, which evaluated everolimus in functioning and non-functioning NETs of the GI tract and lungs, the TELESTAR study which evaluated telotristat ethyl in patients with refractory carcinoid syndrome, and the NETTER-1 trial which evaluated 177Lutetium-dotatate in NETs of the small intestine and proximal colon (midgut). Based on these and other advances, the North American Neuroendocrine Tumor Society (NANETS) convened a multidisciplinary panel of experts with the goal of updating consensus-based guidelines for evaluation and treatment of midgut NETs. The medical aspects of these guidelines (focusing on systemic treatment, nonsurgical liver-directed therapy, and post-operative surveillance) are summarized in this manuscript. Surgical guidelines are described in a companion manuscript.

The adrenal steroid dehydroepiandrosterone (DHEA) has no known cellular receptor or unifying mechanism of action, despite evidence suggesting beneficial vascular effects in humans. Based on previous data from our laboratory, we hypothesized that DHEA binds to specific cell-surface receptors to activate intracellular Gproteins and endothelial nitric-oxide synthase (eNOS). We now pharmacologically characterize a putative plasma membrane DHEA receptor and define its associated G-proteins. The physiological role of the adrenal steroid dehydroepiandrosterone (DHEA) 1 is not known. There are widespread data suggesting a beneficial effect of DHEA on vascular function. Extensive epidemiologic evidence shows an inverse correlation between circulating DHEA levels and the prevalence of atherosclerotic and cardiovascular diseases (1-5). There are few human intervention studies focused on vascular outcomes of DHEA administration, and these are not of a size or duration to define whether DHEA therapy has an effect on cardiovascular morbidity or mortality. Available studies do suggest a beneficial effect on atherosclerosis (6). Studies of the short term effect of DHEA on human vascular function, using sophisticated assays of vascular function, are beginning to emerge. Williams et al. (7) showed a significant increase in flow-mediated dilatation and systemic arterial compliance in postmenopausal women taking DHEA for 3 months. DHEA reduces atherosclerosis, decreases the accumulation of cholesterol in aortic and coronary arteries (8, 9), and inhibits platelet aggregation (10) in various animal models. DHEA also affects growth factor-induced mitogenesis and proliferation of vascular smooth muscle cells (11-13). However, the molecular mechanisms by which DHEA acts to protect from atherosclerotic and cardiovascular diseases are still unknown. Furthermore, it is unclear whether the effect on vascular tissues is related to DHEA or to its metabolites, which include estradiol.Steroid hormones are known to bind specific intracellular receptors, which function as ligand-dependent gene transcription factors (14). However, previous efforts to isolate an intracellular receptor for DHEA have failed (15-18). In contrast to this classical pathway of steroid hormone action, there are also rapid, plasma membrane-dependent, non-genomic effects of steroids in various tissues, which lead to important physiological responses (19 -24). Plasma membrane-associated receptors are postulated to mediate these non-genomic actions of steroids. Functional plasma membrane binding sites have been identified for several steroids, including estrogen, vitamin D, and progesterone (25-28). However, besides the receptor for estrogen, no plasma membrane steroid receptor has yet been unequivocally identified and characterized.We have found that DHEA stimulates nitric oxide (NO) generation within minutes from bovine aortic endothelial cells (BAEC).2 Furthermore, DHEA conjugated to bovine serum albumin (BSA) had similar effects. These cellular responses to DHEA were spe...

Genistein may improve vascular function, but the mechanism of this effect is unclear. We tested the hypothesis that genistein directly regulates vascular function through stimulation of endothelial nitric oxide synthesis. Genistein activated endothelial nitric oxide synthase (eNOS) in intact bovine aortic endothelial cells and human umbilical vein endothelial cells over an incubation period of 10 min. The maximal eNOS activity was at 1 M genistein. Consistent with this activation pattern, 1 M genistein maximally stimulated the phosphorylation of eNOS at serine 1179 at 10 min of incubation. The rapid activation of eNOS by genistein was not dependent on RNA transcription or new protein synthesis and was not blocked by a specific estrogen receptor antagonist. In addition, inhibition of MAPK or phosphatidylinositol 3-OH kinase/Akt kinase had no affect on eNOS activation by genistein. Furthermore, the genistein effect on eNOS was also independent of tyrosine kinase inhibition. However, inhibition of cAMP-dependent kinase [protein kinase A (PKA)] by H89 completely abolished the genistein-stimulated eNOS activation and phosphorylation, suggesting that genistein acted through a PKA-dependent pathway. These findings demonstrated that genistein had direct nongenomic effects on eNOS activity in vascular endothelial cells, leading to eNOS activation and nitric oxide synthesis. These effects were mediated by PKA and were unrelated to an estrogenic effect. This cellular mechanism may underlie some of the cardiovascular protective effects proposed for soy phytoestrogens. (Endocrinology 145: 5532-5539, 2004)

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.