Prognostic relevance of survivin in pancreatic endocrine tumors.

BACKGROUND: Better prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in several tumor types. Contradictory data exist, especially regarding the significance of a nuclear versus cytoplasmic location of survivin. The prognostic relevance of nuclear and cytoplasmic survivin expression in pancreatic endocrine tumors-controlled for the tumor Ki-67 index, World Health Organization classification, and TNM stage-was investigated. METHODS: A total of 111 patients treated at a tertiary referral center were retrospectively evaluated. Clinical data were gathered from medical records. Immunohistochemistry for survivin and Ki-67 was performed on paraffin-embedded tissue. Univariate and multivariate Cox analyses were performed. RESULTS: Patients with tumors that had <5% survivin-positive nuclei had a mean survival of 225 months [95% confidence interval (CI) 168-281]. The corresponding figure for patients with 5 to 50% survivin-positive tumor cell nuclei was 101 months [95% CI 61-140; hazard ratio (HR) 2.4; P < 0.01) and with >50% survivin-positive nuclei 47 months (95% CI 24-71; HR 4.9; P < 0.001). Nuclear survivin expression in >50% of the tumor cells was an independent marker of a poor prognosis (HR 5.7; P < 0.01). Cytoplasmic survivin was not a significant prognostic factor in the multivariate analysis (HR 0.94; P = 0.90). CONCLUSIONS: High expression of nuclear survivin is a significant marker of a poor prognosis in patients with a pancreatic endocrine tumor.

Islet cell tumours.

Pancreatic endocrine tumours can cause hormonal symptoms by over-secretion of hormones. They are less aggressive than exocrine pancreatic cancer, but carry a variable prognosis. The tumours are either sporadic or hereditary, as part of the multiple endocrine neoplasia type 1 syndrome. Despite the rarity of these tumours, they evoke significant interest in the research community and important advances have been made over the past years. This chapter provides an overview of the tumours and recent advances in the field. Hereditary forms of pancreatic endocrine tumours are caused by mutations in the MEN1 gene. Menin, the protein encoded by this gene, has been shown to interact with numerous transcription factors and proteins involved in cell-cycle control, shedding some light on the importance of the protein. Several genes have been shown to be up- or down-regulated, suggesting candidates to be further evaluated for a role in tumourigenesis. Several advances have been made in prognostication; a tumour-node-metastasis system has been evaluated and seems to have prognostic value, and several new molecular prognostic markers are under evaluation. It is hoped that the tumour-node-metastasis system and other prognostic markers will be adopted in clinical routine and improve prognostication and treatment choices. Surgery is still the only cure, but several new palliative drugs and interventions are in use or under investigation. Radiofrequency ablation is increasingly used for liver metastases, and a number of new chemotherapy drugs are being tested. Despite improvements in treatment, no clear improvement in survival has been demonstrated.

Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution.

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 > or = 2%, chromogranin A > or = 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 > or = 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.

Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors.

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/m(2)) 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 O(6)-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 O(6)-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.

Co-expression of ghrelin and its receptor in pancreatic endocrine tumours.

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/m(2). 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.

Recognizing genes differentially regulated in vitro by the multiple endocrine neoplasia type 1 (MEN1) gene, using RNA interference and oligonucleotide microarrays.

BACKGROUND: Data on downstream effects of MEN1 gene inactivation is scarce. In an effort to identify genes regulated by MEN1, we designed a silencing experiment in a human endocrine pancreatic tumor cell line (BON1). METHODS: By using RNA interference, MEN1 mRNA expression was knocked-down by >85%. Gene expression was assessed by oligonucleotide microarrays and compared to expression in nonsilenced controls. We also investigated if genes were differentially expressed in 6 malignant endocrine pancreatic tumors (EPTs) with homozygous MEN1 inactivation compared to 2 without MEN1 gene alterations. RESULTS: Using a cut-off of > or =2 times, 66 genes were found to be upregulated, and 22 were downregulated in the MEN1-silenced clones. We corroborated the microarray findings by performing quantitative-PCR on the RNA from the silencing experiments for 7 of the 88 differentially regulated genes. Genes involved in endocrine cell fate determination, as well as genes known to be involved in NFkappaB, Notch, and Wnt signaling pathways, were among genes verified as differentially regulated in vitro. CONCLUSIONS: The demonstration of pathways affected by silencing of MEN1 in vitro provides novel insight into neoplastic processes of potential importance in vivo, which warrants further study.

Gastrointestinal stromal tumors express the orexigen ghrelin.

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.