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Reviews in Endocrine and Metabolic Disorders

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01-12-2020 | Carcinoid Tumor

Serotonin pathway in carcinoid syndrome: Clinical, diagnostic, prognostic and therapeutic implications

Authors: Giuseppe Fanciulli, Rosaria M. Ruggeri, Erika Grossrubatscher, Fabio Lo Calzo, Troy D. Wood, Antongiulio Faggiano, Andrea Isidori, Annamaria Colao, on behalf of NIKE

Published in: Reviews in Endocrine and Metabolic Disorders | Issue 4/2020

Abstract

Carcinoid syndrome represents the most common functional syndrome that affects patients with neuroendocrine neoplasms. Its clinical presentation is really heterogeneous, ranging from mild and often misdiagnosed symptoms to severe manifestations, that significantly worsen the patient’s quality of life, such as difficult-to-control diarrhoea and fibrotic complications. Serotonin pathway alteration plays a central role in the pathophysiology of carcinoid syndrome, accounting for most clinical manifestations and providing diagnostic tools. Serotonin pathway is complex, resulting in production of biologically active molecules such as serotonin and melatonin, as well as of different intermediate molecules and final metabolites. These activities require site- and tissue-specific catalytic enzymes. Variable expression and activities of these enzymes result in different clinical pictures, according to primary site of origin of the tumour. At the same time, the biochemical diagnosis of carcinoid syndrome could be difficult even in case of typical symptoms. Therefore, the accuracy of the diagnostic methods of assessment should be improved, also attenuating the impact of confounding factors and maybe considering new serotonin precursors or metabolites as diagnostic markers. Finally, the prognostic role of serotonin markers has been only evaluated for its metabolite 5-hydroxyindole acetic acid but, due to heterogeneous and biased study designs, no definitive conclusions have been achieved. The most recent progress is represented by the new therapeutic agent telotristat, an inhibitor of the enzyme tryptophan hydroxylase, which blocks the conversion of tryptophan in 5-hydroxy-tryptophan. The present review investigates the clinical significance of serotonin pathway in carcinoid syndrome, considering its role in the pathogenesis, diagnosis, prognosis and therapy.

Thorson A, Biorck G, Bjorkman G, Waldenstrom J. Malignant carcinoid of the small intestine with metastases to the liver, valvular disease of the right side of the heart (pulmonary stenosis and tricuspid regurgitation without septal defects), peripheral vasomotor symptoms, bronchoconstriction, and an unusual type of cyanosis; a clinical and pathologic syndrome. Am Heart J. 1954;47(5):795–817.CrossRef

Kronenberg HWR. Williams textbook of endocrinology, vol. IXI. 11th ed; 2008.

Levine RJ, Elsas LJ, Duvall CP, Rice JS. Malignant carcinoid tumors with and without Flushing. JAMA. 1963;186:905–7.PubMed

Feldman JM. Carcinoid tumors and syndrome. Semin Oncol. 1987;14(3):237–46.PubMed

Beri N, Farid A, Galkin M, Lewis W, Amsterdam E. Diagnostic Dilemma: Carcinoid Syndrome. Am J Med. 2018;131(10):e405–e7. https://doi.org/10.1016/j.amjmed.2018.05.026.CrossRefPubMed

Halperin DM, Shen C, Dasari A, Xu Y, Chu Y, Zhou S, et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol. 2017;18(4):525–34. https://doi.org/10.1016/S1470-2045(17)30110-9.CrossRefPubMedPubMedCentral

Pandit S, Bhusal K. Carcinoid syndrome. Treasure Island: StatPearls; 2019.

Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012;26(6):737–53. https://doi.org/10.1016/j.bpg.2012.12.003.CrossRefPubMedPubMedCentral

Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128(6):1717–51.CrossRef

10.

Walther DJ, Bader M. A unique central tryptophan hydroxylase isoform. Biochem Pharmacol. 2003;66(9):1673–80.CrossRef

11.

Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science. 2003;299(5603):76. https://doi.org/10.1126/science.1078197.CrossRefPubMed

12.

Lesurtel M, Soll C, Graf R, Clavien PA. Role of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives. Cell Mol Life Sci. 2008;65(6):940–52. https://doi.org/10.1007/s00018-007-7377-3.CrossRefPubMed

13.

Suominen T, Uutela P, Ketola RA, Bergquist J, Hillered L, Finel M, et al. Determination of serotonin and dopamine metabolites in human brain microdialysis and cerebrospinal fluid samples by UPLC-MS/MS: discovery of intact Glucuronide and sulfate conjugates. PLoS One. 2013;8(6):e68007. https://doi.org/10.1371/journal.pone.0068007.CrossRefPubMedPubMedCentral

14.

Kvols LK. Metastatic carcinoid tumors and the malignant carcinoid syndrome. Ann N Y Acad Sci. 1994;733:464–70.CrossRef

15.

Bender DA. Biochemistry of tryptophan in health and disease. Mol Asp Med. 1983;6(2):101–97.CrossRef

16.

Feldman JM. Serotonin metabolism in patients with carcinoid tumors: incidence of 5-hydroxytryptophan-secreting tumors. Gastroenterology. 1978;75(6):1109–14.CrossRef

17.

Kang H, O'Connell JB, Leonardi MJ, Maggard MA, McGory ML, Ko CY. Rare tumors of the colon and rectum: a national review. Int J Color Dis. 2007;22(2):183–9. https://doi.org/10.1007/s00384-006-0145-2.CrossRef

18.

Cunningham JL, Janson ET, Agarwal S, Grimelius L, Stridsberg M. Tachykinins in endocrine tumors and the carcinoid syndrome. Eur J Endocrinol. 2008;159(3):275–82. https://doi.org/10.1530/EJE-08-0196.CrossRefPubMed

19.

Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063–72. https://doi.org/10.1200/JCO.2007.15.4377.CrossRefPubMed

20.

Sherman SK, Maxwell JE, O'Dorisio MS, O'Dorisio TM, Howe JR. Pancreastatin predicts survival in neuroendocrine tumors. Ann Surg Oncol. 2014;21(9):2971–80. https://doi.org/10.1245/s10434-014-3728-0.CrossRefPubMedPubMedCentral

21.

von der Ohe MR, Camilleri M, Kvols LK, Thomforde GM. Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea. N Engl J Med. 1993;329(15):1073–8. https://doi.org/10.1056/NEJM199310073291503.CrossRefPubMed

22.

Boutzios G, Kaltsas G. Clinical syndromes related to gastrointestinal neuroendocrine neoplasms. Front Horm Res. 2015;44:40–57. https://doi.org/10.1159/000382053.CrossRefPubMed

23.

Oberg K, Theodorsson-Norheim E, Norheim I. Motilin in plasma and tumor tissues from patients with the carcinoid syndrome. Possible involvement in the increased frequency of bowel movements. Scand J Gastroenterol. 1987;22(9):1041–8.CrossRef

24.

Hannah-Shmouni F, Stratakis CA, Koch CA. Flushing in (neuro)endocrinology. Rev Endocr Metab Disord. 2016;17(3):373–80. https://doi.org/10.1007/s11154-016-9394-8.CrossRefPubMedPubMedCentral

25.

Connolly HM, Pellikka PA. Carcinoid heart disease. Curr Cardiol Rep. 2006;8(2):96–101.CrossRef

26.

Modlin IM, Shapiro MD, Kidd M. Carcinoid tumors and fibrosis: an association with no explanation. Am J Gastroenterol. 2004;99(12):2466–78. https://doi.org/10.1111/j.1572-0241.2004.40507.x.CrossRefPubMed

27.

Oberg K, Casanovas O, Castano JP, Chung D, Delle Fave G, Denefle P, et al. Molecular pathogenesis of neuroendocrine tumors: implications for current and future therapeutic approaches. Clin Cancer Res. 2013;19(11):2842–9. https://doi.org/10.1158/1078-0432.CCR-12-3458.CrossRefPubMed

28.

Ito T, Lee L, Jensen RT. Carcinoid-syndrome: recent advances, current status and controversies. Curr Opin Endocrinol Diabetes Obes. 2018;25(1):22–35. https://doi.org/10.1097/MED.0000000000000376.CrossRefPubMedPubMedCentral

29.

Aluri V, Dillon JS. Biochemical testing in neuroendocrine tumors. Endocrinol Metab Clin N Am. 2017;46(3):669–77. https://doi.org/10.1016/j.ecl.2017.04.004.CrossRef

30.

Meijer WG, Kema IP, Volmer M, Willemse PH, de Vries EG. Discriminating capacity of indole markers in the diagnosis of carcinoid tumors. Clin Chem. 2000;46(10):1588–96.CrossRef

31.

Kema IP, Meijer WG, Meiborg G, Ooms B, Willemse PH, de Vries EG. Profiling of tryptophan-related plasma indoles in patients with carcinoid tumors by automated, on-line, solid-phase extraction and HPLC with fluorescence detection. Clin Chem. 2001;47(10):1811–20.CrossRef

32.

Oberg K, Modlin IM, De Herder W, Pavel M, Klimstra D, Frilling A, et al. Consensus on biomarkers for neuroendocrine tumour disease. Lancet Oncol. 2015;16(9):e435–e46. https://doi.org/10.1016/S1470-2045(15)00186-2.CrossRefPubMedPubMedCentral

33.

Oberg K, Couvelard A, Delle Fave G, Gross D, Grossman A, Jensen RT, et al. ENETS consensus guidelines for standard of Care in Neuroendocrine Tumours: biochemical markers. Neuroendocrinology. 2017;105(3):201–11. https://doi.org/10.1159/000472254.CrossRefPubMed

34.

Kuo TR, Chen JS, Chiu YC, Tsai CY, Hu CC, Chen CC. Quantitative analysis of multiple urinary biomarkers of carcinoid tumors through gold-nanoparticle-assisted laser desorption/ionization time-of-flight mass spectrometry. Anal Chim Acta. 2011;699(1):81–6. https://doi.org/10.1016/j.aca.2011.05.012.CrossRefPubMed

35.

Tellez MR, Mamikunian G, O'Dorisio TM, Vinik AI, Woltering EA. A single fasting plasma 5-HIAA value correlates with 24-hour urinary 5-HIAA values and other biomarkers in midgut neuroendocrine tumors (NETs). Pancreas. 2013;42(3):405–10. https://doi.org/10.1097/MPA.0b013e318271c0d5.CrossRefPubMed

36.

Adaway JE, Dobson R, Walsh J, Cuthbertson DJ, Monaghan PJ, Trainer PJ, et al. Serum and plasma 5-hydroxyindoleacetic acid as an alternative to 24-h urine 5-hydroxyindoleacetic acid measurement. Ann Clin Biochem. 2016;53(Pt 5):554–60. https://doi.org/10.1177/0004563215613109.CrossRefPubMed

37.

O'Toole D, Grossman A, Gross D, Delle Fave G, Barkmanova J, O'Connor J, et al. ENETS consensus guidelines for the standards of Care in Neuroendocrine Tumors: biochemical markers. Neuroendocrinology. 2009;90(2):194–202. https://doi.org/10.1159/000225948.CrossRefPubMed

38.

Rubin de Celis Ferrari AC, Glasberg J, Riechelmann RP. Carcinoid syndrome: update on the pathophysiology and treatment. Clinics (Sao Paulo). 2018;73(suppl 1):e490s. https://doi.org/10.6061/clinics/2018/e490s.CrossRef

39.

Corcuff JB, Chardon L, El Hajji RI, Brossaud J. Urinary sampling for 5HIAA and metanephrines determination: revisiting the recommendations. Endocr Connect. 2017;6(6):R87–98. https://doi.org/10.1530/EC-17-0071.CrossRefPubMedPubMedCentral

40.

Gallo M, Muscogiuri G, Pizza G, Ruggeri RM, Barrea L, Faggiano A, et al. The management of neuroendocrine tumours: a nutritional viewpoint. Crit Rev Food Sci Nutr. 2019;59(7):1046–57. https://doi.org/10.1080/10408398.2017.1390729.CrossRefPubMed

41.

Swami T, Weber HC. Updates on the biology of serotonin and tryptophan hydroxylase. Curr Opin Endocrinol Diabetes Obes. 2018;25(1):12–21. https://doi.org/10.1097/MED.0000000000000383.CrossRefPubMed

42.

Kanakis G, Kaltsas G. Biochemical markers for gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Best Pract Res Clin Gastroenterol. 2012;26(6):791–802. https://doi.org/10.1016/j.bpg.2012.12.006.CrossRefPubMed

43.

Kyriacou A, Stepien KM, Issa B. Urinary steroid metabolites in a case of florid Ectopic Cushing's syndrome and clinical correlations. Hormones (Athens). 2016;15(4):540–7. https://doi.org/10.14310/horm.2002.1695.CrossRef

44.

Gill GV, Yong A, Power E, Ramage J. Carcinoid-associated ectopic ACTH syndrome with variable response to octreotide. Postgrad Med J. 1999;75(880):98–100. https://doi.org/10.1136/pgmj.75.880.98.CrossRefPubMedPubMedCentral

45.

Isidori AM, Venneri MA, Graziadio C, Simeoli C, Fiore D, Hasenmajer V, et al. Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(3):173–85. https://doi.org/10.1016/S2213-8587(17)30398-4.CrossRefPubMed

46.

Pozza C, Graziadio C, Giannetta E, Lenzi A, Isidori AM. Management strategies for aggressive Cushing's syndrome: from macroadenomas to Ectopics. J Oncol. 2012;2012:685213. https://doi.org/10.1155/2012/685213.CrossRefPubMedPubMedCentral

47.

Kema IP, de Vries EG, Slooff MJ, Biesma B, Muskiet FA. Serotonin, catecholamines, histamine, and their metabolites in urine, platelets, and tumor tissue of patients with carcinoid tumors. Clin Chem. 1994;40(1):86–95.CrossRef

48.

Psychogios N, Hau DD, Peng J, Guo AC, Mandal R, Bouatra S, et al. The human serum metabolome. PLoS One. 2011;6(2):e16957. https://doi.org/10.1371/journal.pone.0016957.CrossRefPubMedPubMedCentral

49.

Bouatra S, Aziat F, Mandal R, Guo AC, Wilson MR, Knox C, et al. The human urine metabolome. PLoS One. 2013;8(9):e73076. https://doi.org/10.1371/journal.pone.0073076.CrossRefPubMedPubMedCentral

50.

Gijsman HJ, van Gerven JM, de Kam ML, Schoemaker RC, Pieters MS, Weemaes M, et al. Placebo-controlled comparison of three dose-regimens of 5-hydroxytryptophan challenge test in healthy volunteers. J Clin Psychopharmacol. 2002;22(2):183–9.CrossRef

51.

Guo K, Li L. Differential 12C-/13C-isotope dansylation labeling and fast liquid chromatography/mass spectrometry for absolute and relative quantification of the metabolome. Anal Chem. 2009;81(10):3919–32. https://doi.org/10.1021/ac900166a.CrossRefPubMed

52.

Trabado S, Al-Salameh A, Croixmarie V, Masson P, Corruble E, Feve B, et al. The human plasma-metabolome: reference values in 800 French healthy volunteers; impact of cholesterol, gender and age. PLoS One. 2017;12(3):e0173615. https://doi.org/10.1371/journal.pone.0173615.CrossRefPubMedPubMedCentral

53.

Alfredsson G, Wiesel FA. Monoamine metabolites and amino acids in serum from schizophrenic patients before and during sulpiride treatment. Psychopharmacology. 1989;99(3):322–7.CrossRef

54.

Yao JK, Dougherty GG Jr, Reddy RD, Keshavan MS, Montrose DM, Matson WR, et al. Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia. Mol Psychiatry. 2010;15(9):938–53. https://doi.org/10.1038/mp.2009.33.CrossRefPubMed

55.

Lentner C. Geigy Scientific Tables. 8th Rev ed. Switzerland c; 1981–1992. p. 165–77.

56.

Beck O, Borg S, Jonsson G, Lundman A, Valverius P. Measurement of 5-hydroxytryptophol and 5-hydroxyindoleacetic acid in human and rat brain and plasma. J Neural Transm. 1984;59(1):57–67.CrossRef

57.

Fuertig R, Ceci A, Camus SM, Bezard E, Luippold AH, Hengerer B. LC-MS/MS-based quantification of kynurenine metabolites, tryptophan, monoamines and neopterin in plasma, cerebrospinal fluid and brain. Bioanalysis. 2016;8(18):1903–17. https://doi.org/10.4155/bio-2016-0111.CrossRefPubMed

58.

Sakaguchi Y, Ikenaga J, Yoshida H, Hayama T, Itoyama M, Todoroki K, et al. Selective and sensitive liquid chromatographic determination method of 5-hydroxyindoles with fluorous and fluorogenic derivatization. J Pharm Biomed Anal. 2015;114:348–54. https://doi.org/10.1016/j.jpba.2015.06.003.CrossRefPubMed

59.

Boulet L, Faure P, Flore P, Monteremal J, Ducros V. Simultaneous determination of tryptophan and 8 metabolites in human plasma by liquid chromatography/tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2017;1054:36–43. https://doi.org/10.1016/j.jchromb.2017.04.010.CrossRef

60.

Tekes K. HPLC determination of serotonin and its metabolites from human platelet-rich plasma; shift to 5-hydroxytryptophol formation following alcohol consumption. J Chromatogr Sci. 2008;46(2):169–73. https://doi.org/10.1093/chromsci/46.2.169.CrossRefPubMed

61.

Miller AG, Brown H, Degg T, Allen K, Keevil BG. Measurement of plasma 5-hydroxyindole acetic acid by liquid chromatography tandem mass spectrometry--comparison with HPLC methodology. J Chromatogr B Anal Technol Biomed Life Sci. 2010;878(7–8):695–9. https://doi.org/10.1016/j.jchromb.2010.01.010.CrossRef

62.

Stephanson N, Helander A, Beck O. Alcohol biomarker analysis: simultaneous determination of 5-hydroxytryptophol glucuronide and 5-hydroxyindoleacetic acid by direct injection of urine using ultra-performance liquid chromatography-tandem mass spectrometry. J Mass Spectrom. 2007;42(7):940–9. https://doi.org/10.1002/jms.1231.CrossRefPubMed

63.

Carter MD, Calcutt MW, Malow BA, Rose KL, Hachey DL. Quantitation of melatonin and n-acetylserotonin in human plasma by nanoflow LC-MS/MS and electrospray LC-MS/MS. J Mass Spectrom. 2012;47(3):277–85. https://doi.org/10.1002/jms.2051.CrossRefPubMedPubMedCentral

64.

Wolrab D, Fruhauf P, Gerner C. Quantification of the neurotransmitters melatonin and N-acetyl-serotonin in human serum by supercritical fluid chromatography coupled with tandem mass spectrometry. Anal Chim Acta. 2016;937:168–74. https://doi.org/10.1016/j.aca.2016.08.012.CrossRefPubMed

65.

Yang S, Zheng X, Xu Y, Zhou X. Rapid determination of serum melatonin by ESI-MS-MS with direct sample injection. J Pharm Biomed Anal. 2002;30(3):781–90.CrossRef

66.

Borucki K, Schreiner R, Dierkes J, Jachau K, Krause D, Westphal S, et al. Detection of recent ethanol intake with new markers: comparison of fatty acid ethyl esters in serum and of ethyl glucuronide and the ratio of 5-hydroxytryptophol to 5-hydroxyindole acetic acid in urine. Alcohol Clin Exp Res. 2005;29(5):781–7.CrossRef

67.

Stephanson N, Dahl H, Helander A, Beck O. Determination of urinary 5-hydroxytryptophol glucuronide by liquid chromatography-mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2005;816(1–2):107–12. https://doi.org/10.1016/j.jchromb.2004.11.026.CrossRef

68.

Wiseman JM, Puolitaival SM, Takats Z, Cooks RG, Caprioli RM. Mass spectrometric profiling of intact biological tissue by using desorption electrospray ionization. Angew Chem Int Ed Eng. 2005;44(43):7094–7. https://doi.org/10.1002/anie.200502362.CrossRef

69.

Gerbig S, Golf O, Balog J, Denes J, Baranyai Z, Zarand A, et al. Analysis of colorectal adenocarcinoma tissue by desorption electrospray ionization mass spectrometric imaging. Anal Bioanal Chem. 2012;403(8):2315–25. https://doi.org/10.1007/s00216-012-5841-x.CrossRefPubMed

70.

Phelps DL, Balog J, Gildea LF, Bodai Z, Savage A, El-Bahrawy MA, et al. The surgical intelligent knife distinguishes normal, borderline and malignant gynaecological tissues using rapid evaporative ionisation mass spectrometry (REIMS). Br J Cancer. 2018;118(10):1349–58. https://doi.org/10.1038/s41416-018-0048-3.CrossRefPubMedPubMedCentral

71.

Davis Z, Moertel CG, McIlrath DC. The malignant carcinoid syndrome. Surg Gynecol Obstet. 1973;137(4):637–44.PubMed

72.

Agranovich AL, Anderson GH, Manji M, Acker BD, Macdonald WC, Threlfall WJ. Carcinoid tumour of the gastrointestinal tract: prognostic factors and disease outcome. J Surg Oncol. 1991;47(1):45–52.CrossRef

73.

Wangberg B, Westberg G, Tylen U, Tisell L, Jansson S, Nilsson O, et al. Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction. World J Surg. 1996;20(7):892–9 discussion 9.CrossRef

74.

Onaitis MW, Kirshbom PM, Hayward TZ, Quayle FJ, Feldman JM, Seigler HF, et al. Gastrointestinal carcinoids: characterization by site of origin and hormone production. Ann Surg. 2000;232(4):549–56.CrossRef

75.

Hellman P, Lundstrom T, Ohrvall U, Eriksson B, Skogseid B, Oberg K, et al. Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases. World J Surg. 2002;26(8):991–7. https://doi.org/10.1007/s00268-002-6630-z.CrossRefPubMed

76.

van der Horst-Schrivers AN, Post WJ, Kema IP, Links TP, Willemse PH, Wymenga AN, et al. Persistent low urinary excretion of 5-HIAA is a marker for favourable survival during follow-up in patients with disseminated midgut carcinoid tumours. Eur J Cancer. 2007;43(18):2651–7. https://doi.org/10.1016/j.ejca.2007.07.025.CrossRefPubMed

77.

Formica V, Wotherspoon A, Cunningham D, Norman AR, Sirohi B, Oates J, et al. The prognostic role of WHO classification, urinary 5-hydroxyindoleacetic acid and liver function tests in metastatic neuroendocrine carcinomas of the gastroenteropancreatic tract. Br J Cancer. 2007;96(8):1178–82. https://doi.org/10.1038/sj.bjc.6603699.CrossRefPubMedPubMedCentral

78.

Janson ET, Holmberg L, Stridsberg M, Eriksson B, Theodorsson E, Wilander E, et al. Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol. 1997;8(7):685–90.CrossRef

79.

Turner GB, Johnston BT, McCance DR, McGinty A, Watson RG, Patterson CC, et al. Circulating markers of prognosis and response to treatment in patients with midgut carcinoid tumours. Gut. 2006;55(11):1586–91. https://doi.org/10.1136/gut.2006.092320.CrossRefPubMedPubMedCentral

80.

Bergestuen DS, Aabakken L, Holm K, Vatn M, Thiis-Evensen E. Small intestinal neuroendocrine tumors: prognostic factors and survival. Scand J Gastroenterol. 2009;44(9):1084–91. https://doi.org/10.1080/00365520903082432.CrossRefPubMed

81.

Zandee WT, Kamp K, van Adrichem RC, Feelders RA, de Herder WW. Limited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours. Eur J Endocrinol. 2016;175(5):361–6. https://doi.org/10.1530/EJE-16-0392.CrossRefPubMed

82.

Zandee WT, van Adrichem RC, Kamp K, Feelders RA, van Velthuysen MF, de Herder WW. Incidence and prognostic value of serotonin secretion in pancreatic neuroendocrine tumours. Clin Endocrinol. 2017;87(2):165–70. https://doi.org/10.1111/cen.13364.CrossRef

83.

Ghia JE, Li N, Wang H, Collins M, Deng Y, El-Sharkawy RT, et al. Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology. 2009;137(5):1649–60. https://doi.org/10.1053/j.gastro.2009.08.041.CrossRefPubMed

84.

Manocha M, Khan WI. Serotonin and GI disorders: an update on clinical and experimental studies. Clin Transl Gastroenterol. 2012;3:e13. https://doi.org/10.1038/ctg.2012.8.CrossRefPubMedPubMedCentral

85.

Margolis KG, Stevanovic K, Li Z, Yang QM, Oravecz T, Zambrowicz B, et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut. 2014;63(6):928–37. https://doi.org/10.1136/gutjnl-2013-304901.CrossRefPubMed

86.

Kim JJ, Wang H, Terc JD, Zambrowicz B, Yang QM, Khan WI. Blocking peripheral serotonin synthesis by telotristat etiprate (LX1032/LX1606) reduces severity of both chemical- and infection-induced intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2015;309(6):G455–65. https://doi.org/10.1152/ajpgi.00299.2014.CrossRefPubMed

87.

Kulke MH, O'Dorisio T, Phan A, Bergsland E, Law L, Banks P, et al. Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer. 2014;21(5):705–14. https://doi.org/10.1530/ERC-14-0173.CrossRefPubMedPubMedCentral

88.

Pavel M, Horsch D, Caplin M, Ramage J, Seufferlein T, Valle J, et al. Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial. J Clin Endocrinol Metab. 2015;100(4):1511–9. https://doi.org/10.1210/jc.2014-2247.CrossRefPubMed

89.

Kulke MH, Horsch D, Caplin M, Anthony L, Bergsland E, Oberg K, et al. 37LBA Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy (the phase 3 TELESTAR clinical trial). 2015.

90.

Pavel M, Gross DJ, Benavent M, Perros P, Srirajaskanthan R, Warner RRP, et al. Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial. Endocr Relat Cancer. 2018;25(3):309–22. https://doi.org/10.1530/ERC-17-0455.CrossRefPubMedPubMedCentral

Title: Serotonin pathway in carcinoid syndrome: Clinical, diagnostic, prognostic and therapeutic implications
Authors: Giuseppe Fanciulli
Rosaria M. Ruggeri
Erika Grossrubatscher
Fabio Lo Calzo
Troy D. Wood
Antongiulio Faggiano
Andrea Isidori
Annamaria Colao
on behalf of NIKE
Publication date: 01-12-2020
Publisher: Springer US
Keyword: Carcinoid Tumor
Published in: Reviews in Endocrine and Metabolic Disorders / Issue 4/2020
Print ISSN: 1389-9155
Electronic ISSN: 1573-2606
DOI: https://doi.org/10.1007/s11154-020-09547-8

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Clinical manifestations and management of fatty acid oxidation disorders

Review of the veteran affairs diabetes trial: Lessons learned

Endocrine and metabolic aspects of the COVID-19 pandemic

Hypothalamus-pituitary-adrenal Axis in Glucolipid metabolic disorders

COVID-19 and diabetes mellitus: how one pandemic worsens the other

Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials