Current Status of Gastrointestinal Carcinoids

Modlin, Irvin M.; Kidd, Mark; Latich, Igor; Zikusoka, Michelle N.; Shapiro, Michael D.

doi:10.1053/j.gastro.2005.03.038

Cited by 723 publications

(707 citation statements)

References 262 publications

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“…Many tumours grow slowly, although some can grow very rapidly (Modlin et al, 2003(Modlin et al, , 2005. They express neuroendocrine differentiation markers, have secretory characteristics and may present with hypersecretory syndromes (Plockinger et al, 2004;Ramage et al, 2005).…”

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confidence: 99%

Assessment of the efficacy and toxicity of 131I-metaiodobenzylguanidine therapy for metastatic neuroendocrine tumours

et al. 2008

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131 I-metaiodobenzylguanidine ( 131 I-MIBG) is a licensed palliative treatment for patients with metastatic neuroendocrine tumours. We have retrospectively assessed the consequences of 131 I-MIBG therapy in 48 patients (30 gastroenteropancreatic, 6 pulmonary, 12 unknown primary site) with metastatic neuroendocrine tumours attending Royal Liverpool University Hospital between 1996 and 2006. Mean age at diagnosis was 57.6 years (range 34 -81). 131 I-MIBG was administered on 88 occasions (mean 1.8 treatments, range 1 -4). Twenty-nine patients had biochemical markers measured before and after 131 I-MIBG, of whom 11 (36.7%) showed 450% reduction in levels post-therapy. Forty patients had radiological investigations performed after 131 I-MIBG, of whom 11(27.5%) showed reduction in tumour size post-therapy. Twenty-seven (56.3%) patients reported improved symptoms after 131 I-MIBG therapy. Kaplan -Meier analysis showed significantly increased survival (P ¼ 0.01) from the date of first 131 I-MIBG in patients who reported symptomatic benefit from therapy. Patients with biochemical and radiological responses did not show any statistically significant alteration in survival compared to non-responders. Eleven (22.9%) patients required hospitalisation as a consequence of complications, mostly due to mild bone marrow suppression. 131 I-MIBG therefore improved symptoms in more than half of the patients with metastatic neuroendocrine tumours and survival was increased in those patients who reported a symptomatic response to therapy.

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confidence: 99%

Assessment of the efficacy and toxicity of 131I-metaiodobenzylguanidine therapy for metastatic neuroendocrine tumours

et al. 2008

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“…As a consequence, biochemical markers of early disease have not been identified, the mechanisms responsible for the growth or metastasis of these tumors are for the most part unknown, and no molecular tools exist to predict malignant progression. 3 In contrast to the small intestinal carcinoids (EC cell-derived), gastric carcinoids (EC-like cell-derived) have been well characterized and, therefore, early diagnosis is possible, the mechanistic basis of disease is established, and a rational therapeutic strategy thus exists with excellent outcome. 3 Gastric carcinoids are derived from the ECL cells that proliferate in response to elevated levels of gastrin caused by decreased acid secretion.…”

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confidence: 99%

“…3 In contrast to the small intestinal carcinoids (EC cell-derived), gastric carcinoids (EC-like cell-derived) have been well characterized and, therefore, early diagnosis is possible, the mechanistic basis of disease is established, and a rational therapeutic strategy thus exists with excellent outcome. 3 Gastric carcinoids are derived from the ECL cells that proliferate in response to elevated levels of gastrin caused by decreased acid secretion. 4,5 In contrast, the mechanisms of neoplastic transformation of the small intestinal EC cell are unknown and uncharacterized.…”

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confidence: 99%

“…4,5 In contrast, the mechanisms of neoplastic transformation of the small intestinal EC cell are unknown and uncharacterized. 3 Examining the molecular alterations that characterize malignancy and metastases have identified that EC cell carcinoids exhibit a microsatellite stable phenotype with retention of mismatch repair function, 6,7 but often display chromosomal alterations, particularly loss of chromosome 18, which occurs in 50% to 67% of cases. 8 This arises early in small intestinal carcinoid development and is present in both primary tumors and metastases.…”

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confidence: 99%

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Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor–β1‐mediated regulatory abnormalities including up‐regulation of C‐Myc and MTA1

Kidd

Modlin

Pfragner

et al. 2007

Cancer

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Objective To examine whether and to what extent the intracellular trafficking features of HLA–B*2705, which is associated with the development of spondylarthritis (SpA), differ from those of HLA–B*2709 and HLA–B*0702, which are not associated with SpA. Methods HeLa cells were transfected with complementary DNA encoding for HLA–B proteins fused to Renilla luciferase or yellow fluorescent protein. The subcellular distribution of properly folded and unfolded/misfolded HLA–B proteins was examined by flow cytometry and confocal microscopy of cells labeled with ME1 and HC‐10 antibodies, respectively. HLA–B/HLA–B interactions were monitored in endoplasmic reticulum (ER)– and plasma membrane–enriched subcellular fractions, by bioluminescence resonance energy transfer (BRET). Results All 3 HLA–B alleles displayed a similar distribution pattern (properly folded heavy chain at the cell surface, unfolded/misfolded proteins only in the cytoplasm). By means of BRET, we provided evidence that both HLA–B*2705 and HLA–B*2709 formed more oligomers in the ER and the plasma membrane than did HLA–B*0702. The propensity of HLA–B*2705 to form oligomers in the ER was partly attributable to residue Cys67 of the molecule. For all 3 alleles, increased expression of HLA–B proteins was associated with intracytoplasmic accumulation of unfolded/misfolded proteins and intracellular vesicles, probably corresponding to expanded ER–Golgi intermediate compartments, in which these proteins accumulated together with the stress sensor BiP. Conclusion Our results suggest that the difference in disease susceptibility conferred by HLA–B*2705 and HLA–B*2709 cannot be explained by their different propensity to form dimers or misfolded proteins, thus presumably implicating other, still unknown factors.

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“…From a pathophysiologic point of view, the tumor secretion of various substances into systemic circulation, including serotonin as the most predominant released vasoactive peptide, and also histamine, prostaglandins, tachykinins, and kallikrein, causes the carcinoid syndrome [8].…”

Section: Carcinoid Syndromementioning

confidence: 99%

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

et al. 2016

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The carcinoid syndrome represents a set of signs and symptoms associated with neuroendocrine tumors (NETs) that occur primarily when metastases are developed in the liver, resulting in the worsening of quality of life. Serotonin plays a central role in the physiology of carcinoid syndrome by promoting intestinal motility. Somatostatin analogs (SSAs) have widely demonstrated their efficacy as symptomatic relievers of carcinoid syndrome, but this control is ephemeral, being reduced by approximately 50% within the first year. The exact mechanisms of resistance to SSAs are not fully understood, but it is believed that serotonin might be involved. Patients with carcinoid syndrome present with a significant increase in serotonin plasma levels and, consequently, in the soluble urinary metabolite 5‐hydroxyindole acetic acid. Telotristat etiprate is a potent inhibitor of tryptophan hydroxylase, a rate‐limiting enzyme in the synthesis of serotonin, that has demonstrated in the phase III TELESTAR clinical trial a significant improvement in the control of bowel movements in patients with NETs who have carcinoid syndrome and who have progressed to an SSA. Based on these results, telotristat etiprate has emerged as a potential new option in the treatment algorithm of symptomatic control of functioning NETs. However, some issues need to be clarified, such as the safety profile of the drug outside clinical trials, the benefit in quality of life, and the possible impact on tumor growth, as well as its role within sequencing or combination treatment strategies with pre‐existing drugs effective in NET treatment. Implications for Practice: This article reviews the literature about carcinoid syndrome, which affects patients diagnosed with neuroendocrine tumors. Few articles have been published about this syndrome and its pathophysiology. Somatostatin analogs provide symptomatic relief; however, patients may become refractory to this strategy, usually within the first year of treatment. In this context, as an agent with an innovative mechanism of action, telotristat etiprate has demonstrated activity in a phase III trial, and findings may offer a path to an improve quality of life and prolonged survival for certain patients.

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Current Status of Gastrointestinal Carcinoids

Cited by 723 publications

References 262 publications

Assessment of the efficacy and toxicity of 131I-metaiodobenzylguanidine therapy for metastatic neuroendocrine tumours

Assessment of the efficacy and toxicity of 131I-metaiodobenzylguanidine therapy for metastatic neuroendocrine tumours

Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor–β1‐mediated regulatory abnormalities including up‐regulation of C‐Myc and MTA1

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

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