SST Analogs Research Articles

Successful Management of Recurrent Neuroendocrine Carcinoma of the Sphenoid Sinus Using Octreotide LAR: A Case Report

Overexpression of somatostatin (SST) receptors detected in most neuroendocrine carcinomas (NECs) appears to play an important role in the pathogenesis of NECs. Inhibition of SST receptors with SST analogues has been proved to be effective in various types of neuroendocrine tumors. We present here a case report of a 59-year-old female with recurrent sphenoidal NEC treated with SST analogues Octreotide and Octreotide long-acting release (LAR) as a salvage therapy. Improvement of optic nerve compression and quality of life (QOL) were observed along with a 77 months of progression free survival. This result suggests that OCT/OCT LAR may be a new approach to treating advanced NECs of the paranasal sinuses.

Paget’s Disease Mimicking Bone Metastasis in a Patient with Neuroendocrine Tumor on 68Ga-DOTANOC PET/CT

Somatostatin (SST) is a neuropeptide present in neurons, endocrine cells, and a wide range of neuroendocrine tumors (NETs). 68Ga-DOTATOC, 68Ga-DOTANOC, and 68Ga-DOTATATE are current SST analogues used for PET/CT which bind to SST receptors expressed in NETs. These SST analogues have been used successfully for diagnosis of SST-expressing tumors with a more sensitive detection technique than conventional scintigraphy. However, there is a lack of clinical data on the differentiation between NETs and other malignant tumors or benign pathological conditions. Here, we report a case of Paget’s disease mimicking bone metastasis of NET on PET/CT due to increased 68Ga-DOTANOC uptake and review examples of similar cases in the literature.

Current knowledge on the sensitivity of the (68)Ga-somatostatin receptor positron emission tomography and the SUVmax reference range for management of pancreatic neuroendocrine tumours.

Physiologically increased pancreatic uptake at the head/uncinate process is observed in more than one-third of patients after injection of one of the three 68Ga-labelled octreotide-based peptides used for somatostatin (sst) receptor (r) imaging. There are minor differences between these 68Ga-sstr-binding peptides in the imaging setting. On 68Ga-sstr-imaging the physiological uptake can be diffuse or focal and usually remains stable over time. Differences in the maximal standardised uptake values (SUVmax) reported for the normal pancreas as well as for pancreatic neuroendocrine tumour (PNET) lesions may be related to several factors, including (a) differences in the peptide binding affinities as well as differences in sstr subtype expression of pancreatic α- and β-cells, and heterogeneity / density of tumour cells, (b) differences in scanner resolution, image reconstruction techniques and acquisition protocols, (c) mostly retrospective study designs, (d) mixed patient populations, or (e) interference with medications such as treatment with long-acting sst analogues. The major limitation in most of the studies lies in the lack of histopathological confirmation of abnormal findings. There is a significant overlap between the calculated SUVmax-values for physiological pancreas and PNET-lesions of the head/uncinate process that do not favour the use of quantitative parameters in the clinical setting. Anecdotal long-term follow-up studies have even indicated that increased uptake in the head/uncinate process still can turn out to be malignant over years of follow up. SUVmax-data for the pancreatic body and tail are limited. Therefore, any visible focal tracer uptake in the pancreas must be considered as suspicious for malignancy irrespective of quantitative parameters. In general, sstr-PET/CT has significant implications for the management of NET patients leading to a change in treatment decision in about one-third of patients. Therefore, follow-up with 68Ga-sstr-PET/CT is mandatory in the clinical setting if uptake in the head/uncinate process is observed.

Effect of Octreotide on Hepatic Steatosis in Diet-Induced Obesity in Rats.

BackgroundNon-alcoholic fatty liver disease (NAFLD) caused by liver lipid dysregulation is linked to obesity. Somatostatin (SST) and its analogs have been used to treat pediatric hypothalamic obesity. However, the application of such drugs for the treatment of NAFLD has not been evaluated.ObjectiveThis study aimed to investigate the expression levels of important regulators of hepatic lipid metabolism and the possible effect of the SST analog octreotide on these regulators.MethodsSD rats were assigned to a control group and a high-fat diet group. Obese rats from the high-fat diet group were further divided into the obese and octreotide-treated groups. The body weight, plasma SST, fasting plasma glucose (FPG), insulin, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) levels were measured. Hepatic steatosis was evaluated based on the liver TG content, HE staining and oil red O staining. The SREBP-1c, ACC1, FAS, MTP, apoB and ADRP expression levels in the liver were also determined by RT-PCR, qRT-PCR, western blot or ELISA.ResultsThe obese rats induced by high-fat diet expressed more SREBP-1c, FAS and ADRP but less MTP protein in the liver than those of control rats, whereas octreotide intervention reversed these changes and increased the level of apoB protein. Compared to the control group, obese rats showed increased liver ACC1, SREBP-1c and apoB mRNA levels, whereas octreotide-treated rats showed decreased mRNA levels of apoB and SREBP-1c. This was accompanied by increased body weight, liver TG contents, FPG, TG, TC, LDL-C, FFA, insulin and derived homeostatic model assessment (HOMA) values. Octreotide intervention significantly decreased these parameters. Compared to the control group, the obese group showed a decreasing trend on plasma SST levels, which were significantly increased by the octreotide intervention.ConclusionOctreotide can ameliorate hepatic steatosis in obese rats, possibly by decreasing hepatic lipogenesis and increasing TG export from hepatocytes.

Somatostatin and its Analogs

Somatostatin (SST) is a cyclic hormone-release inhibitory peptide that has high binding affinity to all of its five SST receptors (SSTRs). SST negatively regulates cell proliferation and the release of multiple hormones via activation of its cognate receptors. A variety of SST analogs, some with high affinity and selectivity of receptor subtypes, have been synthesized and developed. Certain long-acting SST analogs such as octreotide, lanreotide and pasireotide have been clinically applied to the treatment of human diseases such as those caused by excessive release of growth hormone (acromegaly), or adrenocorticotropic hormone (Cushing's syndrome), and for the treatment of carcinoid syndrome. Investigations into new biological activities of these long-acting SSTs and their possible clinical applications are also still ongoing. Also, novel SST analogs are being designed and developed to target different receptor subtype(s) or mimic natural SST's multiple biological properties. Additionally, since SSTRs, especially SSTR2, are aberrantly expressed in many cancer cells and tumor blood vessels, internalizing SST analogs is currently being used as drug-delivery vehicle for the application of receptor-targeted therapeutics. This review will discuss recent advances in the development and applications of SST and its analogs.

THE USAGE OF "OCTREOTIDE-DEPOT" FOR THE PREVENTION OF POSTOPERATIVE PANCREATITIS AFTER EXTENDED SURGERY OF MALIGNANT TUMORS OF THE STOMACH, ESOPHAGUS AND THE CARDIA

Surgical treatment of patients with gastric cancer with extended lymph node dissection often leads to the primary (intra-operative injury) and secondary (inflammatory processes in the postoperative period) damage to the parenchyma of the pancreas. The incidence of pancreatitis in the postoperative period, according to various authors, reaches 20% or more. Synthetic analogues of somatostatin occupy the special place among the pharmacological methods of prophylaxis. Earlier studies have shown a significantly lower rate of complications, including the formation of pancreatic fistula after operations on the pancreas when using somatostatin analogues. Usage of prolonged SST analogues for the prevention of postoperative pancreatitis remains a matter of research. The article presents a review of existing literature and own experience with prophylactic use of «Оctreotide depot » in patients with malignant tumors of the stomach, esophagus and the cardia

Optimization of combined temozolomide and peptide receptor radionuclide therapy (PRRT) in mice after multimodality molecular imaging studies

BackgroundSuccessful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine tumours (NET) comprise somatostatin-analogue lutetium-177-labelled octreotate (177Lu-TATE) treatment, also referred to as peptide receptor radionuclide therapy (PRRT), and temozolomide (TMZ) treatment. Their combination might result in additive effects. Using MRI and SPECT/CT, we studied tumour characteristics and therapeutic responses after different (combined) administration schemes in a murine tumour model in order to identify the optimal treatment schedule for PRRT plus TMZ.MethodsWe performed molecular imaging studies in mice bearing SSTR-expressing H69 (humane small cell lung cancer) tumours after single intravenous (i.v.) administration of 30 MBq 177Lu-TATE or TMZ (oral 50 mg/kg daily for 14 days). Tumour perfusion was evaluated weekly by dynamic contrast-enhanced MRI (DCE-MRI), whereas tumour uptake of 111In-octreotide was quantified using SPECT/CT until day 39 after treatment. Based on these results, seven different 177Lu-octreotate and TMZ combination schemes were evaluated for therapy response, varying the order and time interval of the two therapies and compared with single treatments.ResultsPRRT and TMZ both resulted in tumour size reduction, accompanied by significant changes in MRI characteristics such as an enhanced tumour perfusion. Moreover, TMZ treatment also resulted in increased uptake of the SST analogue 111In-octreotide until day 13. In the subsequent therapy study, 90 % of animals receiving 177Lu-TATE at day 14 after TMZ treatment showed complete response, being the best anti-tumour results among groups.ConclusionsMolecular imaging studies indicated that PRRT after TMZ treatment could induce optimal therapeutic effects because of enhanced tumour uptake of radioactivity after TMZ, which was confirmed by therapy responses. Therefore, clinical translation of TMZ treatment prior to PRRT might increase tumour responses in NET patients as well.

Lanreotide and its Potential Applications in Polycystic Kidney and Liver Diseases

Multiple Gαi protein-coupled somatostatin receptors (SSTRs) are expressed in human kidney and liver tissues. Also, aberrant cAMP signaling has been shown to play a critical role in cysto-genesis and enlargement of the human kidney and liver. Thus, somatostatin (SST) analogs become potential and promising alternatives in treating human polycystic kidney disease (PKD) and polycystic liver disease (PLD) via interacting with Gαi protein-coupled SSTRs and further blocking cAMP production. Lanreotide is a synthetic, long-acting SST analog with high binding affinity to SSTR2, and has been clinically approved for the treatment of acromegaly due to excessive growth hormone. Recently, this SST analog has been applied in the treatment of PKD and PLD, and has shown an effective reduction of liver and kidney volume compared to placebo. This review will discuss the discovery of this peptide and its clinical applications in the treatment of PKD/PLD patients.

Lutetium-177 DOTATATE Production with an Automated Radiopharmaceutical Synthesis System.

Peptide Receptor Radionuclide Therapy (PRRT) with yttrium-90 ((90)Y) and lutetium-177 ((177)Lu)-labelled SST analogues are now therapy option for patients who have failed to respond to conventional medical therapy. In-house production with automated PRRT synthesis systems have clear advantages over manual methods resulting in increasing use in hospital-based radiopharmacies. We report on our one year experience with an automated radiopharmaceutical synthesis system. All syntheses were carried out using the Eckert & Ziegler Eurotope's Modular-Lab Pharm Tracer® automated synthesis system. All materials and methods used were followed as instructed by the manufacturer of the system (Eckert & Ziegler Eurotope, Berlin, Germany). Sterile, GMP-certified, no-carrier added (NCA) (177)Lu was used with GMP-certified peptide. An audit trail was also produced and saved by the system. The quality of the final product was assessed after each synthesis by ITLC-SG and HPLC methods. A total of 17 [(177)Lu]-DOTATATE syntheses were performed between August 2013 and December 2014. The amount of radioactive [(177)Lu]-DOTATATE produced by each synthesis varied between 10-40 GBq and was dependant on the number of patients being treated on a given day. Thirteen individuals received a total of 37 individual treatment administrations in this period. There were no issues and failures with the system or the synthesis cassettes. The average radiochemical purity as determined by ITLC was above 99% (99.8 ± 0.05%) and the average radiochemical purity as determined by HPLC technique was above 97% (97.3 ± 1.5%) for this period. The automated synthesis of [(177)Lu]-DOTATATE using Eckert & Ziegler Eurotope's Modular-Lab Pharm Tracer® system is a robust, convenient and high yield approach to the radiolabelling of DOTATATE peptide benefiting from the use of NCA (177)Lu and almost negligible radiation exposure of the operators.

Human somatostatin receptor-3 distinctively induces apoptosis in MCF-7 and cell cycle arrest in MDA-MB-231 breast cancer cells

Somatostatin (SST) mediates cytostatic and pro-apoptotic effects through five somatostatin receptors (SSTR1-5). The modest clinical benefits of SST analogs in cancers of different origin such as breast cancer are attributed to diminished SSTRs expression at tumor sites. In the present study, SSTR3 was overexpressed in MCF-7 and MDA-MB-231, and analyzed for downstream signaling molecules associated with cytostatic and cytotoxic effect. Cells overexpressing SSTR3 displayed inhibition of EGF induced proliferation and enhanced antiproliferative effect of SSTR3-specific agonist in comparison to non-transfected cells. SSTR3 overexpression in MCF-7 cells (R3-MCF-7) constitutively enhanced TUNEL staining, PARP-1 and p27Kip1 expression suggesting apoptosis and cell-cycle arrest. Conversely, R3-MB-231 cells with SSTR3 overexpression exerted cytostatic and were devoid of any cytotoxic effects. The expression of PTP-1C and the status of ERK1/2, p38 and PI3K phosphorylation was modulated in a cell-specific manner. These findings provide new insights in understanding the antiproliferative role of SSTR3 in breast tumor biology.

60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years.

At the time of the publication of Geoffrey Harris's monograph on 'Neural control of the pituitary gland' 60 years ago, the pituitary was recognised to produce a growth factor, and extracts administered to children with hypopituitarism could accelerate growth. Since then our understanding of the neuroendocrinology of the GH axis has included identification of the key central components of the GH axis: GH-releasing hormone and somatostatin (SST) in the 1970s and 1980s and ghrelin in the 1990s. Characterisation of the physiological control of the axis was significantly advanced by frequent blood sampling studies in the 1980s and 1990s; the pulsatile pattern of GH secretion and the factors that influenced the frequency and amplitude of the pulses have been defined. Over the same time, spontaneously occurring and targeted mutations in the GH axis in rodents combined with the recognition of genetic causes of familial hypopituitarism demonstrated the key factors controlling pituitary development. As the understanding of the control of GH secretion advanced, developments of treatments for GH axis disorders have evolved. Administration of pituitary-derived human GH was followed by the introduction of recombinant human GH in the 1980s, and, more recently, by long-acting GH preparations. For GH excess disorders, dopamine agonists were used first followed by SST analogues, and in 2005 the GH receptor blocker pegvisomant was introduced. This review will cover the evolution of these discoveries and build a picture of our current understanding of the hypothalamo-GH axis.

Clinical use of pasireotide for Cushing's disease in adults

Cushing’s diseaseExcessive corticotroph hormone levels sustained by an adrenocorticotropic hormone-secreting pituitary adenoma lead to a severe clinical condition caused by excess cortisol secretion, called Cushing’s disease (CD). Neurosurgery and radiotherapy are used to treat the pituitary adenoma directly, but new medical treatments targeting the corticotroph cells have recently become available.PasireotideThis is a novel multireceptor ligand somatostatin (SST) analog with a high binding affinity for SST receptor 5, the predominant receptor in human corticotroph adenomas that is not downregulated by high cortisol levels (as SST receptor 2 is). Pasireotide has been recently approved by the European Medical Agency and the US Food and Drug Administration for treating adults with CD with recurrent hypercortisolism after surgery, or for whom surgery is not an option. A dose of 600–1,200 μg twice a day can normalize urinary free cortisol levels after 3 months of treatment in up to 28% of patients, reducing their blood pressure and improving their weight, lipid profile, and quality of life. Combining pasireotide with cabergoline to achieve a greater hormone response can normalize cortisol secretion in 50% of patients, and adding ketoconazole induces biochemical control in most patients with CD.Safety and hyperglycemiaThe adverse effects of pasireotide are similar to those of other SST analogs, including diarrhea, nausea, and biliary sludge or gallstones. Hyperglycemia is common during pasireotide treatment, which affects the secretion of pancreatic insulin and intestinal glucagon-like peptide 1. Self-monitoring is essential to achieve good metabolic control, and endocrinologists should first administer metformin if insulin resistance is evident and then add dipeptidyl peptidase 4 inhibitors/glucagon-like peptide 1 receptor agonists or insulin.ConclusionIn recent years, medical treatment with pasireotide has been proposed as monotherapy for adults with CD characterized by mild to moderate hypercortisolemia, as well as in combination with other available therapies. It is generally well-tolerated, but endocrinologists need to monitor glucose levels to ensure prompt treatment.

Promoter hypermethylation-related reduced somatostatin production promotes uncontrolled cell proliferation in colorectal cancer.

BackgroundSomatostatin (SST) has anti-proliferative and pro-apoptotic effects. Our aims were to analyze and compare the SST expression during normal aging and colorectal carcinogenesis at mRNA and protein levels. Furthermore, we tested the methylation status of SST in biopsy samples, and the cell growth inhibitory effect of the SST analogue octreotide in human colorectal adenocarcinoma cell line.MethodsColonic samples were collected from healthy children (n1 = 6), healthy adults (n2 = 41) and colorectal cancer patients (CRCs) (n3 = 34) for SST mRNA expression analysis, using HGU133 Plus2.0 microarrays. Results were validated both on original (n1 = 6; n2 = 6; n3 = 6) and independent samples ((n1 = 6; n2 = 6; n3 = 6) by real-time PCR. SST expressing cells were detected by immunohistochemistry on colonic biopsy samples (n1 = 14; n2 = 20; n3 = 23). The effect of octreotide on cell growth was tested on Caco-2 cell line. SST methylation percentage in biopsy samples (n1 = 5; n2 = 5; n3 = 9) was defined using methylation-sensitive restriction enzyme digestion.ResultsIn case of normal aging SST mRNA expression did not alter, but decreased in cancer (p<0.05). The ratio of SST immunoreactive cells was significantly higher in children (0.70%±0.79%) compared to CRC (0%±0%) (p<0.05). Octreotide significantly increased the proportion of apoptotic Caco-2 cells. SST showed significantly higher methylation level in tumor samples (30.2%±11.6%) compared to healthy young individuals (3.5%±1.9%) (p<0.05).ConclusionsIn cancerous colonic mucosa the reduced SST production may contribute to the uncontrolled cell proliferation. Our observation that in colon cancer cells octreotide significantly enhanced cell death and attenuated cell proliferation suggests that SST may act as a regulator of epithelial cell kinetics. The inhibition of SST expression in CRC can be epigenetically regulated by promoter hypermethylation.

Inhibitory effect of somatostatin on insulin secretion is not mediated via the CNS.

The inhibitory effect of somatostatin (SST) on insulin secretion in vivo is attributed to a direct effect on pancreatic beta cells, but this is inconsistent with some in vitro results in which exogenous SST is ineffective in inhibiting secretion from isolated islets. We therefore investigated whether insulin secretion from the pancreatic islets may partly be regulated by an indirect effect of SST mediated via the CNS. Islet hormone secretion was assessed in vitro by perifusion and static incubations of isolated islets and in vivo by i.v. or i.c.v. administration of the SST analogue BIM23014C with an i.v. glucose challenge to conscious, chronically catheterised rats. Hormone content of samples was assessed by ELISA or RIA and blood glucose levels using a glucose meter. Exogenous SST14/SST28 or BIM23014C did not inhibit the release of insulin from isolated rodent islets in vitro, whereas peripheral i.v. administration of BIM23014C (7.5 μg) with glucose (1 g/kg) led to decreased plasma insulin content (2.3±0.5 ng insulin/ml versus 4.5±0.5 ng/ml at t=5 min, P<0.001) and elevated blood glucose levels compared with those of the controls (29.19±1.3 mmol/l versus 23.5±1.7 mmol/l, P<0.05). In contrast, central i.c.v. injection of BIM23014C (0.75 μg) had no significant effect on either plasma insulin (3.3±0.4 ng/ml, P>0.05) or blood glucose levels (23.5±1.7 mmol/l, P>0.05) although i.v. administration of this dose increased blood glucose concentrations (32.3±0.7 mmol/l, P<0.01). BIM23014C did not measurably alter plasma glucagon, SST, GLP1 or catecholamine levels whether injected i.v. or i.c.v. These results indicate that SST does not suppress insulin secretion by a centrally mediated effect but acts peripherally on islet cells.

Octreotide Protects the Mouse Retina against Ischemic Reperfusion Injury through Regulation of Antioxidation and Activation of NF-κB.

Somatostatin (SST), an endogenous peptide, may exert anti-inflammatory and neuroprotective effects on retinal injury induced by ischemia. Retinal ischemic reperfusion (I/R) injury always produces many reactive oxygen species (ROS), which can aggravate the tissue damage. The effects of octreotide (OCT), a SST analogue, on retinal I/R injury and ROS formation, are not very clear. In this study, we observed the effects of OCT on morphological changes, oxidative stress, and cell death, induced by retinal I/R injury. The activation of nuclear factor κB (NF-κB) and intercellular adhesion molecule-1 (ICAM-1) were further evaluated in I/R retina treated with or without OCT. The retinal layer thickness was increased at 1 day after I/R and decreased at 7 days after I/R (P < 0.05). This effect was associated with increase in MDA and ROS levels (P < 0.05). The Tunel-positive cells increased and the number of ganglion cell layer (GCL) neurons decreased significantly after I/R injury. The expression of p-p65 and ICAM-1 increased significantly in I/R retinas (P < 0.05). Each effect was markedly attenuated by application of OCT. These data indicate that OCT protects the retina against retinal I/R damage, which could be through inhibition of oxidative stress and downregulation of NF-κB and ICAM-1 expression.

Somatostatin receptor based imaging and radionuclide therapy.

Somatostatin (SST) receptors (SSTRs) belong to the typical 7-transmembrane domain family of G-protein-coupled receptors. Five distinct subtypes (termed SSTR1-5) have been identified, with SSTR2 showing the highest affinity for natural SST and synthetic SST analogs. Most neuroendocrine tumors (NETs) have high expression levels of SSTRs, which opens the possibility for tumor imaging and therapy with radiolabeled SST analogs. A number of tracers have been developed for the diagnosis, staging, and treatment of NETs with impressive results, which facilitates the applications of human SSTR subtype 2 (hSSTr2) reporter gene based imaging and therapy in SSTR negative or weakly positive tumors to provide a novel approach for the management of tumors. The hSSTr2 gene can act as not only a reporter gene for in vivo imaging, but also a therapeutic gene for local radionuclide therapy. Even a second therapeutic gene can be transfected into the same tumor cells together with hSSTr2 reporter gene to obtain a synergistic therapeutic effect. However, additional preclinical and especially translational and clinical researches are needed to confirm the value of hSSTr2 reporter gene based imaging and therapy in tumors.

Somatostatin and diabetic retinopathy: current concepts and new therapeutic perspectives

Somatostatin (SST) is abundantly produced by the human retina, and the main source is the retinal pigment epithelium (RPE). SST exerts relevant functions in the retina (neuromodulation, angiostatic, and anti-permeability actions) by interacting with SST receptors (SSTR) that are also expressed in the retina. In the diabetic retina, a downregulation of SST production does exist. In this article, we give an overview of the mechanisms by which this deficit of SST participates in the main pathogenic mechanisms involved in diabetic retinopathy (DR): neurodegeneration, neovascularization, and vascular leakage. In view of the relevant SST functions in the retina and the reduction of SST production in the diabetic eye, SST replacement has been proposed as a new target for treatment of DR. This could be implemented by intravitreous injections of SST analogs or gene therapy, but this is an aggressive route for the early stages of DR. Since topical administration of SST has been effective in preventing retinal neurodegeneration in STZ-induced diabetic rats, it seems reasonable to test this new approach in humans. In this regard, the results of the ongoing clinical trial EUROCONDOR will provide useful information. In conclusion, SST is a natural neuroprotective and antiangiogenic factor synthesized by the retina which is downregulated in the diabetic eye and, therefore, its replacement seems a rational approach for treating DR. However, clinical trials will be needed to establish the exact position of targeting SST in the treatment of this disabling complication of diabetes.

Gastrointestinal neuroendocrine tumors (NETs): new diagnostic and therapeutic challenges

This paper summarizes the current understanding of the biology of somatostatin receptor (sst), role of immunotherapy in neuroendocrine tumor (NET), new agents for PPRT, and methods to assess response and clinical benefit in NET. One of the most interesting aspects of sst biology is the recent discovery of truncated variants of the sst5 receptor subtype with unique tissue distribution and response to somatostatin (SST). These truncated receptors are associated with bad patient prognosis, decreased response to SST analogs, and may be new targets for diagnoses and treatment. IFN remains a cost-effective agent, particularly in classic mid gut carcinoids, and there is interest to continue examining immunotherapy's in this disease. PRRT remains a key strategy for treatment and imaging. In addition to the classic agents, there are a series of new agents targeting other receptors such as the incretin receptors (GLP-1R; GIPR) and other G-protein coupled receptors with great potential. With regards to therapy monitoring, the most commonly used criteria are Response Criteria Evaluation in Solid Tumors (RECIST). However, for different reasons, these criteria are not very useful in NET. Incorporation of other criteria such as Choi as well as functional imaging assessment with PET would be of great interest in this area.

Does Somatostatin Have a Role in the Regulation of Cortisol Secretion in Primary Pigmented Nodular Adrenocortical Disease (PPNAD)? A Clinical and in Vitro Investigation

Somatostatin (SST) receptors (SSTRs) are expressed in a number of tissues, including the adrenal cortex, but their role in cortisol secretion has not been well characterized. The objective of the study was to investigate the expression of SSTRs in the adrenal cortex and cultured adrenocortical cells from primary pigmented nodular adrenocortical disease (PPNAD) tissues and to test the effect of a single injection of 100 μg of the SST analog octreotide on cortisol secretion in patients with PPNAD. The study was conducted at an academic research laboratory and clinical research center. Expression of SSTRs was examined in 26 PPNAD tissues and the immortalized PPNAD cell line CAR47. Ten subjects with PPNAD underwent a randomized, single-blind, crossover study of their cortisol secretion every 30 minutes over 12 hours (6:00 pm to 6:00 am) before and after the midnight administration of octreotide 100 μg sc. SSTRs expression was investigated by quantitative PCR and immunohistochemistry. The CAR47 and primary cell lines were studied in vitro. The data of the 10 patients were analyzed before and after the administration of octreotide. All SSTRs, especially SSTR1-3, were expressed in PPNAD at significantly higher levels than in normal adrenal. SST was found to differentially regulate expression of its own receptors in the CAR47 cell line. However, the administration of octreotide to patients with PPNAD did not significantly affect cortisol secretion. SSTRs are overexpressed in PPNAD tissues in comparison with normal adrenal cortex. Octreotide did not exert any significant effect on cortisol secretion in a short clinical pilot study in a small number of patients with PPNAD, but long-acting SST analogs targeting multiple SSTRs may be worth investigating in this condition.

Octreotide: A Drug Often Used in the Critical Care Setting but Not Well Understood

While the canonical function of somatostatin (SST) is to inhibit the secretion of growth hormone, it has a number of other physiologic effects that are less widely appreciated. Octreotide, an analog of SST, is not uncommonly used in the critical care setting, particularly for the treatment of variceal hemorrhage. Herein, we discuss the biology and pharmacology of SST, octreotide, and other SST analogs. We also review the evidence behind their use in esophageal variceal bleeds, hepatorenal syndrome, hypoglycemia due to sulfonylurea poisoning, and chylous pleural effusions.