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Introduction: Diarrhea associated with carcinoid syndrome (CS) has been attributed to excess serotonin. Telotristat etiprate is an oral serotonin synthesis inhibitor that decreases peripheral serotonin production. Aim(s): This randomized study assessed safety, tolerability, and efficacy of telotristat etiprate in CS-associated diarrhea. Materials and methods: Carcinoid patients with octreotide-refractory diarrhea (>4 bowel movements (BM)/ day on stable-dose octreotide) were randomly assigned 3:1 to receive telotristat etiprate or placebo. Patients were dosed in sequential, escalating dose cohorts of 150, 250, 350, or 500mg tid, with an expansion cohort (500 mg tid). Endpoints included safety, reduction in BMs, 24-hour urinary 5-HIAA (uS-HIAA), and self-reported clinical improvement. Results: Of 23 patients enrolled, 18 received telotristat etiprate. Median age was 62 yrs, mean 6.2 BMs/day, and mean u5-HIAA of 64.2 mg. Most observed AEs were GI-related. Among evaluable telotristat etiprate-treated patients, 5/18 (28%) experienced a clinical (BM) response, 9/16 (56%) experienced a biochemical (uS-HIAA) response, and 6/12 (50%) reported subjective relief of CS bowel complaints at Wk 4. No evaluable placebo patients experienced a BM response (0/5), u5-HIAA response, (0/4) or subjective relief of bowel symptoms at Wk 4 (0/4). Conclusion: Treatment with telotristat etiprate was well-tolerated and associated with decreases in BM frequency, 24-hour u5-HIAA, and improvements in subjective relief of CS symptoms. [ABSTRACT FROM AUTHOR]

Background: Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors.Methods: We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here.Results: At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame.Conclusions: Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .). [ABSTRACT FROM AUTHOR]

We hypothesized that non-proliferating (quiescent) human vascular endothelial cells would not express somatostatin receptor subtype 2 (sst 2) and that this receptor would be expressed when the endothelial cells begin to grow. To test this hypothesis, placental veins were harvested from 6 human placentas and 2 mm vein disks were cultured in 0.3% fibrin gels. Morphometric analysis confirmed that 50-75% of cultured vein disks developed radial capillary growth within 15 days. Sst 2 gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) analysis of the RNA from veins before culture and from tissue-matched vein disks that exhibited an angiogenic response. The sst 2 gene was expressed in the proliferating angiogenic sprouts of human vascular endothelium. The presence of sst 2 receptors on proliferating angiogenic vessels was confirmed by immunohistochemical staining and in vivo scintigraphy. These results suggest that sst 2 may be a unique target for antiangiogenic therapy with sst 2 preferring somatostatin analogues conjugated to radioisotopes or cytotoxic agents. [ABSTRACT FROM AUTHOR]

The effect of a synthetic somatostatin analog was studied in a patient with severe secretory diarrhea due to pancreatic cholera syndrome. Basal intestinal perfusion studies indicated an absence of water and sodium absorption, and active chloride secretion in the small bowel. Intravenous administration of the somatostatin analog (1 microgram/kg.h) changed zero net water movement to absorption (122 mL/30 cm of the jejunum per hour). Chloride secretion changed to absorption (5.0 to 7.9 meq/30 cm.h), and plasma vasoactive intestinal polypeptide concentration was reduced from 330 to 45 pmol/L (normal, less than 51). When the analog was given subcutaneously, 100 micrograms twice daily, stool weight decreased, and plasma vasoactive intestinal polypeptide concentration fell toward the normal range (67 pmol/L). Plasma concentration of pancreatic polypeptide was initially elevated and dropped during intravenous infusion of somatostatin analog but returned to baseline on maintenance therapy with the analog delivered subcutaneously. The patient has not had further diarrhea during 9 months of therapy. [ABSTRACT FROM AUTHOR]

A correction to the article "The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours" that was published in the December 28, 2013 is presented.

Introduction: CgA and PcSt are widely used in assessing response to treatment in mNETs. Aim(s): To study the role of pre PRRT levels of CgA and PcSt on overall survival (OS) and median time to progression (mTTP). Materials and methods: One-hundred and thirty-five cases from the University of Iowa NET database were analyzed and survival calculated. Results: Pre PRRT CgA and PcSt levels were elevated in 70% and 72 % of cases, respectively. In patients (pts) with elevated Pre PRRT CgA, those with CgA level 3-10 times and >10 times the normal value had decreased OS after 1st PRRT [Hazard ratio (HR) of 2.805 (p=0.04) and 4.421 (p=0.002) resp]. In pts with elevated Pre PRRT PcSt, those with levels >10 times the normal value had decreased OS after 1st PRRT [HR 2.913 (p=0.018)]. HR was adjusted for age. mTTP was 20 months v. 29 months in pts with elevated pre PRRT CgA levels v. normal pre PRRT CgA levels (p=0.87) and 25 months v. 35.5 months in pts with elevated pre PRRT PcSt levels v. normal pre PRRT PcSt levels (p=0.87). Conclusion: Elevated pre PRRT CgA and PcSt seem to predict inferior OS after PRRT. Shorter mTTP was seen in pts with elevated pre-PRRT markers; however, it was not statistically significant. [ABSTRACT FROM AUTHOR]

Introduction: cNEC is a rare and aggressive cancer; the best treatment is unknown. Aim(s): To report cNEC cases seen at the University of Iowa (UI) in 1977-2010. Materials and methods: Thirty-six cases from the UI database were analyzed. Results: Median age at diagnosis was 49 yrs (26-77). FIGO staging: IB1:39%; IB2: 8%; II:19%; ≥III:34%. Seventeen pts (47.2%) had resection; 20 (56%) radiation therapy (RT); 27 (82%) chemotherapy (CT). Median overall survival (MS) was 20.7 mos, 5-OS: 23%. Pts with stage ≤IB1 had longer MS and 5-OS than pts with higher stage (MS 42 v. 11.1 mos, p=0.008, 5-OS 47 v. 6%). Resection predicted outcome (MS: 50 v. 9.3 mos, p=0.0004, 5-OS: 50 v. 0%). Seven of 17 pts recurred after resection in a median of 19.4 mos (7.5 - 43 mos); all but one died. RT did not improve survival (MS 16 mo for RT v. 23 mo for no RT, p=0.6). After resection, MS was 43.8 mos with RT v. 128.5 mos without (p=0.76). Pts with no resection had MS of 11.8 mos with v. 10.5 mos without RT (p=0.8). Pts with unresectable nNEC receiving CT fared better (MS 10.8 mos v. 2.7 ms (p=0.006). Platinum and etoposide were used in 73%. Partial response or stable disease were seen in 50%; mean duration of response 9.1 mos. 2nd line CT was used in 44.4%. CT in resectable disease did not impact survival (MS 45 mos on CT v. 156.5 mos with no CT (p=0.37). Conclusion: Surgery in early stages resulted in the best outcome. RT was not associated with survival. CT seemed beneficial in unresectable cNEC; effect of second line CT is undefined. [ABSTRACT FROM AUTHOR]

Introduction: PRRT is an accepted treatment in Europe for patients (pts) with mNETs, but considered investigational in the USA. Aim(s): To describe the University of Iowa (UI) experience with PRRT. Materials and methods: One-hundred and thirty-five cases from the UI NET database were analyzed and survival calculated. Results: Sixt-four percent were men; median age at diagnosis (Dx) was 51 years (18 - 78). The primary tumor was in the small bowel (SBNET) in 37.8%; pancreas (PNET) - 26.0%; lung - 13.3%; unknown primary - 9.6%; other sites - 13.3 %. PRRT was performed at the University of Basel in 68.8%; UI, USA - 25.2%; elsewhere - 6%. 90Y used in 83.2%, 177Lu - 15.3%. PRRT #2 was given to 114 pts. Radiographic responses at 1-6 mo after PRRT found in 65.8%, 11.1% - mixed response, 15.4% - progression. Median overall survival (OS) from Dx (all pts) - 10.4 yrs (7.5 - 12.3); 16.8 yrs for SBNET; 5.7 yrs for PNETS; 12.1 yrs for lung; 5.4 yrs for unknown primary (p<0.0001). OS from PRRT #1 (all pts) - 40.6 mo (32.9 - 58.1); 79.9 mo for SBNET; 37.8 mo for PNET; 32.9 mo for lung; 20.7 mo for unknown primary (p=0.1). The median time to progression after PRRT #1 (all pts) - 31.7 mo (20.9-71.9); 35.5 mo for SBNET; 19.9 mo for PNET; 38.8 mo for lung (P<0.0001). Conclusion: North American pts with mNETs have a relatively long survival. PRRT was used late in the disease course. PRRT appears to be a valuable treatment option for mNETs, especially SBNETS. Its role earlier in the disease course needs further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Transarterial LDT can ameliorate symptoms and improve time to tumor progression (TTP) in mNETs. Aim(s): To compare clinical outcomes of hepatic artery embolization (HAE)/chemoembolization (HACE) and hepatic radioembolization (HRE) in mNETs in a single institution. Materials and methods: Forty-two cases from the University of Iowa NET database treated with transarterial LDT from 2001 to 2011 were analyzed. Results: The primary tumor was in the small bowel in 21 patients (pts) (50%), pancreas eight (19%), lung two (5%), other locations 11 (26%). Ten pts (24%) had extra-hepatic metastases. Thirteen pts had HAE, 17 HACE, 12 HRE. There was no significant difference in initial radiographic response rate among the three treatment groups (p=0.082). TTP was similar after HRE (15.1 mos) and HAE or HACE (19.6 mos) (p=0.968). There was a trend towards an increased TTP after HACE (33.4 mos), compared to HAE (12.1 mos) or HRE (15.1 mos) (p=0.512). The overall survival for all pts from the first intervention was 41.9 mos. Among symptomatic pts, there was no significant difference in symptom improvement among the treatment groups (p=0.265). Conclusion: There was no significant difference in TTP after HRE compared to HAE or HACE in this cohort. Pts appear to have a prolonged survival after all three therapies. No single therapy was better than another in reducing symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Most patients (pts) with cNEC are treated with chemotherapy regimens used for SCLC due to both tumors' histological similarity and aggressive behavior. Aim(s): To explore if differences exist in the expression of DNA replication and damage repair processes between cNEC and SCLC. Materials and methods: Expression of thymidine kinase (TK), thymidylate synthetase (TS), proliferating cell nuclear antigen (PCNA), replication protein A (RPA), Ki-67, and DNA excision repair protein (ERCC-1) in tumor specimens from 20 pts with cNEC and 15 pts with SCLC was determined by immunohistochemistry. Results: RPA and Ki-67 were expressed at higher levels in SCLC than in cNEC (P=0.04 and 0.002, respectively). There was no difference in the expression of TK, TS, PCNA or ERCC-1. The mean % of positive (+) cells and standard error of the mean for SCLC v. cNEC were 74.7% (9.4) and 48.3% (7.7) for RPA; 49.9% (8.4) and 16.9% (5.3) for Ki-67; 49.7% (10.8) and 58.4% (6.4) for TK; 45.0% (11.3) and 25.3% (6.7) for TS; 56.6% (7.9) and 64.5% (5.9) for PCNA; and 43.5% (9.3) and 29.9% (7.8) for ERCC-1, respectively. Eight SCLC pts (53.3%) had very high levels of RPA (>80% cells +), v. only two cNEC pts (10%). Very high levels of Ki-67 (>80% cells +) found in 4 SCLC pts (26.6%) and in none of cNEC pts. Conclusion: RPA and Ki-67 are expressed at significantly higher levels in SCLC than in cNEC. The mean expression rate was higher in SCLC than in cNEC for all markers but PCNA. [ABSTRACT FROM AUTHOR]