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| 2. |
- Ekeblad, Sara, et al.
(author)
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Co-expression of ghrelin and its receptor in pancreatic endocrine tumours
- 2007
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In: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 66:1, s. 115-122
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Journal article (peer-reviewed)abstract
- Objective Expression of ghrelin has been reported in pancreatic endocrine tumours, but data on ghrelin receptor protein expression are lacking. The aim of this study was to examine the ghrelin receptor, as well as ghrelin, in a selected series of these tumours, including multiple endocrine neoplasia 1 (MEN1) associated tumours, and to correlate data with clinical features including body mass index.Design Immunohistochemical detection of ghrelin and its receptor was performed on frozen tissue from 31 tumours: 9 MEN1 and 22 sporadic. Twenty tumours were analysed by quantitative PCR. Plasma ghrelin was assessed in 26 patients.Results Twenty-one (68%) of 31 tumours showed immunoreactivity for ghrelin (8/9 MEN1) and 19/20 expressed ghrelin mRNA. Ghrelin receptor protein was detected in 21/30 (70%) tumours (4/8 MEN1), and mRNA was detected in all analysed tumours. Insulinomas had significantly higher levels of receptor mRNA than other tumours. Five patients had elevated plasma ghrelin (> 2 SD above the control group mean). No significant difference in mean plasma ghrelin levels was found between patients (908 ± 569 ng/l) and controls (952 ± 164 ng/l). Mean BMI was 24·3 kg/m2. There was no association between ghrelin or receptor expression and survival.Conclusions We report the first immunohistochemical data on expression of the ghrelin receptor in pancreatic endocrine tumours: 70% of tumours in our material. Concomitant ghrelin and receptor expression was seen in 50% of tumours, indicating an autocrine loop. Ghrelin was expressed in 68% of tumours (8/9 MEN1). Despite frequent ghrelin expression, elevated circulating ghrelin is rare in these patients.
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| 3. |
- Ekeblad, Sara, et al.
(author)
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Gastrointestinal stromal tumors express the orexigen ghrelin
- 2006
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In: Endocrine-related cancer. - : Bioscientifica. - 1351-0088 .- 1479-6821. ; 13:3, s. 963-70
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Journal article (peer-reviewed)abstract
- Expression of the neuroendocrine marker synaptic vesicle protein 2 (SV2) has been reported in a few cases of gastrointestinal stromal tumors (GISTs). The goal of the present study was to assess the relevance of this finding and identify a possible hormone production in these tumors. We chose to study the orexigen ghrelin and its receptor, since these patients are seldom cachexic, even in advanced disease stages. We investigated ghrelin expression by means of immunohistochemistry on frozen or paraffin-embedded sections from 22 GISTs from a well-characterized patient material. Expression of the growth hormone secretagogue receptor, the ghrelin receptor, was investigated in a subset of lesions. In six tumors, mRNA levels of ghrelin, the ghrelin receptor, and SV2 were analyzed by real-time quantitative PCR. Totally 17 out of 22 tumors showed immunoreactivity for ghrelin. Five out of ten tumors were immunoreactive for the ghrelin receptor, and all of these co-expressed ghrelin. All tumors expressed ghrelin, ghrelin receptor, and SV2 mRNA. GISTs frequently express SV2, ghrelin, and its receptor, indicating the presence of autocrine/paracrine loops.
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| 4. |
- Ekeblad, Sara, 1980-
(author)
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Pancreatic Endocrine Tumors and GIST - Clinical Markers, Epidemiology and Treatment
- 2007
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Doctoral thesis (other academic/artistic)abstract
- Pancreatic endocrine tumors and gastrointestinal stromal tumors are rare. Evidence regarding prognostic factors, and in the former also treatment, is scarce. We evaluated the survival and prognostic factors in a consecutive series of 324 patients with pancreatic endocrine tumors treated at a single institution. Radical surgery, WHO classification, TNM stage, age and Ki67 ≥2% emerged as independent prognostic factors. Having a non-functioning tumor was not an independent prognostic marker, and neither was hereditary tumor disease. We present the first evaluation of the newly proposed TNM staging system for these patients. A separate analysis of well-differentiated neuroendocrine carcinomas is reported, suggesting tumor size ≥5cm and Ki67 ≥2% as negative prognostic markers in this group. The first 36 patients with advanced neuroendocrine tumors treated with temozolomide at our clinic were evaluated. The median time to progression was seven months. Fourteen percent showed partial regression and 53% stabilization of disease. Side effects were generally mild. Investigation of O6-methylguanine DNA methyltransferase revealed a low expression in a subset of tumors. Four out of five patients responding to treatment had tumors with low expression. Concomitant expression of the orexigen ghrelin and its receptor in pancreatic endocrine tumors is demonstrated. No significant difference in mean plasma ghrelin between patients and controls were found, but elevated plasma ghrelin was seen in five patients. We provide the first report of expression of ghrelin and its receptor in gastrointestinal stromal tumors. Concomitant expression was frequent, indicating the presence of an autocrine loop. The tumors also expressed the neuroendocrine marker synaptic vesicle protein 2. Together, these findings are suggestive of neuroendocrine features.
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| 5. |
- Ekeblad, Sara, et al.
(author)
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Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution
- 2008
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 14:23, s. 7798-7803
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Journal article (peer-reviewed)abstract
- PURPOSE: Unequivocal pathologic markers for the prognosis of pancreatic endocrine tumors are often lacking. Suggestions for prognostic guidance include the WHO classification. Recently, a tumor-node-metastasis (TNM) staging system was proposed. We evaluate this system, as well as assess other potential prognostic factors such as tumor Ki67, size, endocrine syndrome, heredity, body mass index (BMI), and plasma chromogranin A, in a large patient material treated at a single institution. EXPERIMENTAL DESIGN: A total of 324 patients with pancreatic endocrine tumor, consecutively diagnosed and treated at a tertiary referral center, were retrospectively evaluated. Median follow-up was 54 months (range, 1-423 months). Patient and tumor data were extracted from medical records. Univariate and multivariate analyses were done to recognize factors of prognostic value. RESULTS: The median overall survival was 99 months (95% confidence interval, 81-117). Five- and 10-year survival rates were 64% and 44%, respectively. In univariate analysis, TNM stage, radical surgery, WHO classification, nonfunctioning tumor, Ki67 ≥2%, chromogranin A ≥3 times the upper normal limit, BMI <20 kg/m2, sporadic tumor, tumor size, and referral from our primary uptake area had a significant prognostic effect. In multivariate analysis, TNM stage, WHO classification, radical surgery, and Ki67 ≥2% retained their significance. Having a nonfunctioning tumor was not an independent marker of poor prognosis and neither was heredity. CONCLUSIONS: The recently suggested TNM staging system emerged as a useful clinical tool.
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| 6. |
- Ekeblad, Sara, et al.
(author)
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Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors
- 2007
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:10, s. 2986-2991
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Journal article (peer-reviewed)abstract
- Purpose: A retrospective analysis of the toxicity and efficacy of temozolomide in advanced neuroendocrine tumors. Experimental Design: Thirty-six patients with advanced stages of neuroendocrine tumor (1 gastric, 7 thymic and 13 bronchial carcinoids, 12 pancreatic endocrine tumors, 1 paraganglioma, 1 neuroendocrine foregut, and 1 neuroendocrine cecal cancer) were treated with temozolomide (200 mg/m2) for 5 days every 4 weeks. Patients had previously received a mean of 2.4 antitumoral medical regimens. Tumor response was evaluated radiologically according to the Response Evaluation Criteria in Solid Tumors every 3 months on an intent-to-treat basis. The circulating tumor marker plasma chromogranin A was also assessed. The expression of 06-methylguanine DNA methyltransferase, an enzyme implicated in chemotherapy resistance, was studied by immunohistochemistry (n = 23) and compared with response to temozolomide. Results: Median overall time to progression was 7 months (95% confidence interval, 3-10). Radiologic response was seen in 14% of patients and stable disease in 53%. Side effects were mainly hematologic; 14% experienced grade 3 or 4 thrombocytopenia (National Cancer Institute toxicity criteria). Ten patients had tumors with 06-methylguanine DNA methyltransferase immunoreactivity in <10% of nuclei, whereas four patients showed radiologic responses. Conclusions: Temozolomide as monotherapy had acceptable toxicity and antitumoral effects in a small series of patients with advanced malignant neuroendocrine tumors and four of these showed radiologic responses.
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| 7. |
- Eriksson, John, et al.
(author)
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Surgery and radiofrequency ablation for treatment of liver metastases from midgut and foregut carcinoids and endocrine pancreatic tumors
- 2008
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In: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 32:5, s. 930-938
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Journal article (peer-reviewed)abstract
- BACKGROUND:Many neuroendocrine tumors (NETs) have a tendency to metastasize to the liver. In case of limited number of metastases, liver surgery or radiofrequency ablation (RFA) may result in apparently total clearance of metastases. However, it is not clear whether such therapy will provide symptom reduction or increased survival.METHODS: Seventy-three patients with foregut (n=6) or midgut carcinoids (n=37) or endocrine pancreatic tumors (n=28), and two patients with NETs without discernable origin were studied. Symptoms were evaluated using a Symptom Severity Score. Liver surgery was performed in 42 operations and RFA on 205 lesions.RESULTS:Apparently total clearance of liver metastases was attained in 1 of 6 patients with foregut carcinoids, 15 of 37 with midgut carcinoids, and 13 of 28 with EPT. Symptom improvement was noted in 12 of 17 (70.6%) patients with carcinoid syndrome, and 75% also reduced their 5-HIAA and P-CgA by at least 50%. Patients with nonfunctioning EPT generally had no improvement of symptoms after surgical/RFA liver treatment, but eight patients had functioning EPT, and four of these reduced their biochemical markers by at least 50%. NETs with higher Ki67 index tended to recur more often. Complications occurred in 9 of 45 open surgery procedures, and in 8 of 203 RFA procedures.CONCLUSIONS:Treatment of liver metastases is successful in midgut carcinoid patients with limited liver metastases. Patients with foregut carcinoid and EPTs recur more often, possibly related to higher Ki67 index, and treatment of liver lesions less often reduces symptoms. Liver resections and RFA may be safely performed, and RFA is associated with few complications.
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| 8. |
- Granberg, Dan, et al.
(author)
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Gastrin-releasing-peptide in neuroendorine tumours
- 2006
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In: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 45:1, s. 23-27
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Journal article (peer-reviewed)abstract
- In a substantial proportion of cases with endocrine malignant disease the primary lesion cannot be localised and the pathologist hesitates upon the origin of the tumour. Well differentiated neuroendocrine carcinomas of the small bowel can usually be identified by the strong serotonin immunoreactivity, but foregut carcinoids may also stain positive for serotonin and the differential diagnosis between the various foregut tumours may be difficult. We examined if immunostaining for gastrin-releasing-peptide (GRP) may aid in establishing the origin of an unknown neuroendocrine tumour. Tumour tissue from 79 patients (27 lung carcinoids, 4 thymic carcinoids, 4 gastric neuroendocrine tumours, 17 pancreatic well differentiated neuroendocrine carcinomas, 1 duodenal well differentiated neuroendocrine tumour and 26 well differentiated neuroendocrine carcinomas of the small bowel) were immunostained with antibodies against GRP and serotonin. Positive staining for GRP was found in 12/27 lung carcinoids. All other tumour types were consistently GRP-negative (p?
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| 9. |
- Granberg, Dan, et al.
(author)
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Liver embolization with trisacryl gelatin microspheres (embosphere) in patients with neuroendocrine tumors
- 2007
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In: Acta Radiologica. - : SAGE Publications. - 0284-1851 .- 1600-0455. ; 48:2, s. 180-185
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Journal article (peer-reviewed)abstract
- PURPOSE: To report our experience of liver embolization with trisacryl gelatin microspheres (Embospheretrade mark) in patients with metastatic neuroendocrine tumors. MATERIAL AND METHODS: Fifteen patients underwent selective embolization of the right or left hepatic artery with Embosphere. One lobe was embolized in seven patients and both lobes, on separate occasions, in eight patients. Seven patients had midgut carcinoids, two had lung carcinoids, one suffered from a thymic carcinoid, and five had endocrine pancreatic tumors. Eight patients suffered from endocrine symptoms, seven of whom had carcinoid syndrome and one WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome. RESULTS: Partial radiological response was seen after eight embolizations (in six different patients), stable disease was observed after 13 embolizations (after three of these, necroses occurred), while radiological progression was noted after only two embolizations. Only two patients experienced a biochemical response. Clinical improvement of carcinoid syndrome was observed after five embolizations. There were no major complications. Fever >38 degrees C was seen after all but four embolizations, and urinary tract infections were diagnosed after eight embolizations. CONCLUSION: Selective hepatic artery embolization with Embosphere particles is a safe treatment for patients with metastatic neuroendocrine tumors and may lead to partial radiological response as well as symptomatic improvement of disabling endocrine symptoms.
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