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Expression of Cocaine- and Amphetamine-Regulated Transcriptis Associated with Worse Survival in Small Bowel Carcinoid Tumors
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Lund University, Department of Clinical Sciences in Malmö, Sweden.
Department of Clinical Pathology, Ryhov Hospital, Jönköping, Sweden.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
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2012 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, no 13, 3668-3676 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Cocaine- and amphetamine-regulated transcript (CART) peptide exerts several regulatory functions acting both as neurotransmitter and hormone. We recently showed that CART is expressed in various neuroendocrine tumors, including small bowel carcinoid. The main objective of the present study was to examine whether CART expression is associated with survival in small bowel carcinoid patients. Secondary aims were to assess if CART expression is associated with other tumor characteristics or clinical symptoms.

Experimental Design: Specimens from 97 patients with small bowel carcinoids were examined for CART expression using immunohistochemistry and in situ hybridization. A CART score was introduced based on the proportion of CART immunoreactive cells. On inclusion, specimens were examined by routine histopathological methods and detailed clinical patient data were retrieved. The effect of CART on cell viability was assessed in vitro using an enteroendocrine cell line.

Results: Expression of CART (P = 0.011), and increasing CART score (P = 0.033) were associated with worse disease-specific survival. Adjusting for age, disease stage and tumor grade in multivariable analysis, CART expression was still associated with worse survival (Low CART hazard ratio (HR) 5.47, 95% confidence interval (CI) 0.71 to 42.46; and High CART HR 9.44, 95% CI 1.14 to 78.14). Expression of CART correlated with higher tumor grade, but not with age or disease stage, neither with weight loss or any other symptom. Supporting our clinical data, we found that CART promoted tumor cell viability in vitro.

Conclusion: Expression of CART in small bowel carcinoid tumors is associated with worse survival.

Place, publisher, year, edition, pages
American Association for Cancer Research , 2012. Vol. 18, no 13, 3668-3676 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71887DOI: 10.1158/1078-0432.CCR-11-2513ISI: 000307502600019OAI: oai:DiVA.org:liu-71887DiVA: diva2:455188
Note

funding agencies|Futurum-Academy of Healthcare at Jonkoping County Council||Foundation for Clinical Cancer Research in Jonkoping||Swedish Research Council|522-2008-4216K2009-55X 21111-01-4K2007-55X-04499-33-3|Faculty of Medicine at Lund University||Novo Nordisk Foundation||Gyllenstiernska Krapperup Foundation||Fredrik and Ingrid Thuring Foundation||Magnus Bergwall Foundation||Crafoord Foundation||Albert Pahlsson Foundation||

Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Clinical and immunohistochemical studies of small bowel carcinoid tumours
Open this publication in new window or tab >>Clinical and immunohistochemical studies of small bowel carcinoid tumours
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Small bowel carcinoid tumours arising from enterochromaffin cells in the jejunum and ileum are neuroendocrine tumours (NETs) characterized by secretion of serotonin, tachykinins and other bioactive substances. These substances may lead to the typical carcinoid syndrome as well as pronounced fibrosis locally and in the heart. Although the most frequent histological subtype of malignancy in the small bowel, small bowel carcinoids are rare and therefore difficult to study. We found that previous studies either described selected patients at referral centres, or were based on limited data from large registries. The main objective of this thesis was to investigate small bowel carcinoid patients from a geographically defined cohort with no selection bias.

PAPERS I AND II

The aims of papers I and II were to investigate the incidence, histopathological characteristics, stage atdiagnosis, symptomatology, surgical treatment, prognostic factors and survival of small bowel carcinoid.All patients resident in Jönköping County when diagnosed with small bowel carcinoid between 1960 and2005 were eligible for inclusion. After thorough review of medical records and reexamination of availabletumour specimens, 145 patients were included.

A higher incidence of small bowel carcinoid than previously described was found: 1.12 per 100,000 persons and year. The incidence increased during the study period. Symptoms were most often uncharacteristic: the carcinoid syndrome was seen in only 13% of symptomatic patients. Many small bowel carcinoid tumours presented as surgical emergencies without preceding symptoms, often as intestinal obstruction (35%) caused by mesenteric fibrosis. The majority of small bowel carcinoid tumours had metastasized to the mesentery or the liver at diagnosis. Disease-specific survival after 5 years was 75.0% and after 10 years 63.5%. Independent prognostic factors for worse disease-specific survival were higher age at diagnosis, more advanced disease stage at diagnosis and incomplete tumour resection. Completeness of resection was of particular importance in patients with regional metastases.

PAPER III

There are previous case reports describing small bowel carcinoid in two first-degree relatives, but it is unknown whether this represents hereditary disease forms or chance. Paper III was the first article to describe metastasizing ileal carcinoid tumours in three consecutive generations − strongly suggestive of a hereditary disease form.

PAPER IV

We recently demonstrated expression of cocaine- and amphetamine-regulated transcript (CART) in several types of NETs, including small bowel carcinoid. The aim of paper IV was to investigate whether content of CART in small bowel carcinoid tumours is associated with tumour characteristics, symptoms and survival. CART expression was examined in all available tumour specimens from the patients in Papers I and II − 97 patients were included.

Presence of CART IR tumour cells was associated with histological grade, but not with stage or age. CART expression in small bowel carcinoid tumours was not associated with clinical symptoms. Increasing levels of CART IR in small bowel carcinoid tumour cells was associated with worse disease-specific survival. CART was also found to increase cell viability in an enteroendocrine cell line in vitro. The results suggest that CART could be used as a prognostic biomarker and that CART is a potential anti-tumour treatment target.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 90 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1265
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71888 (URN)978-91-7393-055-0 (ISBN)
Public defence
2011-12-03, Originalet, Qulturum, Länssjukhuset Ryhov, Jönköping, 13:00 (Swedish)
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Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2011-11-16Bibliographically approved

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Landerholm, KalleJärhult, Johannes

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