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SCLC is the most common BP-NET, while LCNEC is rare, %10% and 1%, respectively, of all lung cancers. Both SCLC and LCNEC progress rapidly, are aggressively metastatic, and exhibit a poor prognosis. The incidence of BP-carcinoids (TC and AC) in the US was 1.57 of 100,000 in 2003 (an unexplained and substantial increase over the last 30 years, %6% per year). No curative treatment except for radical surgery (almost never feasible) exists. The slow-growing TC exhibit a fairly good prognosis (%88%, 5-year survival), whereas AC demonstrate a 5-year survival of %50%, and the highly malignant LCNEC and SCLC 5-year survival of 15% to 57% and <5%, respectively. This review provides a broad overview on BPNETs and focuses on the evolution of the disease, general features, and current diagnostic and therapeutic options.

CgA is currently the best available biomarker for the diagnosis of NETs. It is critical to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy. Measurement of plasma CgA is mandatory for the effective diagnosis and management of NET disease.

Summary Background  The discovery of somatostatin (SST) and the synthesis of a variety of analogues constituted a major therapeutic advance in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours (GEP‐NETs). They currently provide the most efficient treatment to achieve symptomatic relief and have recently been demonstrated to inhibit tumour growth. Aim  To review 35 years of experience regarding the clinical application and efficacy of SST analogues. Methods  The PubMed database (1972–2009) was searched using somatostatin as a search term with combinations of terms including ‘treatment’; ‘neuroendocrine’; ‘carcinoid’; ‘tumor’; ‘octreotide’; ‘lanreotide’ and ‘pasireotide’. Results  In a review of 15 studies including 481 patients, the slow‐release formulations Sandostatin LAR and Somatuline SR/Autogel achieved symptomatic relief in 74.2% (61.9–92.8%) and 67.5% (40.0–100%), biochemical response in 51.4% (31.5–100%) and 39.0% (17.9–58%), and tumour response in 69.8% (47.0–87.5%) and 64.4% (48.0–87.0%) respectively. Novel SST analogues like SOM230 (pasireotide) that exhibit pan SST receptor activity and analogues with high affinity to specific somatostatin receptor (sstr) subtypes may further advance the field, but efficacy studies are lacking. Conclusion  As more precise understanding of NET cell biology evolves and molecular biological tools advance, more accurate identification of individual tumours sstr profile will probably facilitate a more precise delineation of SST analogue treatment. Aliment Pharmacol Ther 31, 169–188

BACKGROUND. The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program has proven to be a significant resource in US neuroendocrine tumor (NET) epidemiology. Norway also holds a robust and detailed cancer registry: the Norwegian Registry of Cancer (NRC). METHODS. SEER NET data were compared with corresponding NRC data in the time period 1993 to 2004 to determine whether there are differences in NET epidemiology between Norway and the United States. RESULTS. The SEER and NRC reported 17,312 and 2030 NETs, respectively. The overall Caucasian SEER NET incidence was 4.44, compared with 3.24 in the NRC. In the SEER white subset, bronchopulmonary NETs were the most common (incidence = 1.42; 32% of all NETs), compared with small intestinal NETs in the NRC (0.81; 26%). A marked increase in SEER NET incidence (37%‐40%) was observed in the period 2000 to 2004, compared with 1993 to 1997; an even more pronounced increase (72%) was seen in the NRC. African Americans exhibited a remarkably high overall NET incidence of 6.50; furthermore, among African Americans, rectal NETs were most common (1.65; 27%). Small intestinal NET incidence was ∼30% higher in men compared with women in all populations. The highest 5‐year survival rates were for rectal NETs (74%‐88%) in both databases, whereas prostatic NETs had the worst outcome (0%‐23%). At diagnosis, NETs were localized in 27% to 46% of patients. CONCLUSIONS. NET incidence in the US Caucasian population and in Norway is similar, but considerably higher (∼50%) among African Americans. NETs have been regarded as indolent tumors; however, the 5‐year survival is only ∼55%. Cancer 2008. © 2008 American Cancer Society.

Mechanisms by which gut luminal content regulates secretion and motility are ill understood. We evaluated whether neuroendocrine enterochromaffin (EC) cells act as luminal sensors for a wide variety of nutrients and defined the secretory mechanisms of this process. Pure (98-99%) FACS-sorted human EC cells and neoplastic EC cells (KRJ-I) were studied. RT-PCR identified transcripts for T2R1 (bitter), OR1G1 (class II olfactory) and trace amine (TAR1) G protein-coupled receptors (GPCRs) and transporters for glutamine (SNAT1/2), glucose (GLUT1/3/SGLT1), and bile salts (ABST). Glutamine and sodium deoxycholate stimulated 5-HT release (EC(50) = 0.002-0.2 microM; 2-fold release) but were 10-100 times more potent in neoplastic EC cells, which also secreted 6-13 times more 5-HT. Tastants (caffeine, tyramine, octopamine) and olfactants (thymol and eugenol) also stimulated normal and neoplastic EC cell 5-HT secretion (EC(50) = 1.2 nM to 2.1 microM and 0.05 nM to 0.1 microM release, respectively); 2-deoxyglucose and the artificial sweetener sucralose also stimulated (EC(50) = 9.2 and 0.38 nM). 5-HT release was associated with ERK phosphorylation (1.5-fold, P < 0.02) and could be inhibited by a somatostatin analog (IC(50) = 1 pM). Eleven secretory associated genes including the vesicle docking inhibitor STXBP3 were upregulated in response to glutamine and bile salt stimulation in neoplastic EC cells. Targeting STXBP3 expression by use of antisense knockdown significantly (P < 0.05) reduced 5-HT secretion. In conclusion, EC cells express GPCRs and transporters for luminal tastants, olfactants, glutamine, glucose, and bile salts. Activation includes a panel of secretory genes, ERK phosphorylation, and 5-HT secretion. Luminal EC cell regulation is likely to be as important as G cell regulation in gastric acid secretion; development of agents to target EC cell function is therefore a critical therapeutic goal.

Background-The purpose of this study was to investigate whether rats dosed with serotonin develop changes similar to those seen in human carcinoid heart disease. Methods and Results-Ten Sprague-Dawley rats were given serotonin injections subcutaneously once daily for 3 months; controls were given saline. A long-lasting hyperserotoninemia with a Ͼ10-fold increase in both platelet-poor plasma and dialysate from the femoral muscles appeared. The animals developed clinical signs such as flushing and loose stools. After 3 months, 6 of 10 rats given serotonin had pathological echocardiographs. Two animals had a combination of aortic and pulmonary valve insufficiency, 1 had isolated aortic valve insufficiency, and 3 had isolated pulmonary valve insufficiency. Histopathological examination revealed shortened and thickened aortic cusps and carcinoidlike plaques characterized by a collection of myofibroblasts within an extracellular matrix of collagen ground substance.Immunostaining for Ki-67 demonstrated an increased number of proliferating subendocardial cells. In the control group, no pathological changes were seen. With the use of reverse-transcription polymerase chain reaction, normal rat aortic cusps were shown to express mRNA for serotonin receptors 5-HT 1A , 5-HT 2A , and 5-HT 2B and the serotonin transporter 5-HTT. Conclusions-For the first time, long-term serotonin administration was performed in rats. Morphological and echocardiographic changes similar to those seen in human carcinoid heart disease developed. This study demonstrates that serotonin most likely is involved in the pathogenesis of carcinoid heart disease.

Complementary imaging modalities provide more information than either method alone can yield and we have developed a dual-mode imaging probe for combined magnetic resonance (MR) and positron emission tomography (PET) imaging. We have developed dual-mode PET/MRI active probes targeted to vascular inflammation and present synthesis of (1) an aliphatic amine polystyrene bead and (2) a novel superparamagnetic iron oxide nanoparticle targeted to macrophages that were both coupled to positron-emitting copper-64 isotopes. The amine groups of the polystyrene beads were directly conjugated with an amine-reactive form (isothiocyanate) of aza-macrocycle 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA). Iron oxide nanoparticles are dextran sulfate coated, and the surface was modified to contain aldehyde groups to conjugate to an amine-activated DOTA. Incorporation of chelated Cu-64 to nanoparticles under these conditions, which is routinely used to couple DOTA to macromolecules, was unexpectedly difficult and illustrates that traditional conjugation methods do not always work in a nanoparticle environment. Therefore, we developed new methods to couple Cu-64 to nanoparticles and demonstrate successful labeling to a range of nanoparticle types. We obtained labeling yields of 24% for the amine polystyrene beads and 21% radiolabeling yield for the anionic dextran sulfate iron oxide nanoparticles. The new coupling chemistry can be generalized for attaching chelated metals to other nanoparticle platforms.