Antiproliferative treatment of patients with metastatic endocrine gastroenteropancreatic tumours (GEP) is based mainly on chemotherapeutic protocols whereby drug toxicity is a major handicap. Octreotide is the first choice in the control of hormone mediated symptoms. From retrospective and a few prospective studies it has been suggested that octreotide exhibits antiproliferative properties. The prospective German Sandostatin multicentre phase II trial investigated the effects of 200 micrograms octreotide thrice daily for one year on tumour growth and endocrine abnormalities in 103 patients. Octreotide treatment was continued in those patients responding to the drug until tumour progression occurred. In 28 of those with tumour progression during 200 micrograms thrice daily octreotide dose was increased to 500 micrograms thrice daily. The study sample consisted of 52 patients with computed tomography confirmed tumour progression and 13 patients with stable disease before octreotide treatment, whereas no preobservation period was available in 38 patients. Nineteen patients (36.5%) with computed tomography confirmed tumour progression experienced stabilisation of tumour growth lasting for at least three months. Median duration of stable disease was 18 months. At month 12, stable disease continued in 12 patients, declined after 24 months to nine patients, and after 36 months to five patients. Tumour regression has not been seen in this or other subgroups. In the subgroup with stable disease before octreotide, stable disease continued in 53.8% of patients over 12 months. Increase of octreotide dose to 500 micrograms thrice daily did not influence progression seen during the lower dose with the exception of one patient in whom tumour progression changed to stable disease. No association of tumour size response and patients' characteristics could be detected. The results suggest that octreotide inhibits tumour growth in patients with metastasised endocrine GEP tumours. The antiproliferative effect is, at least in some patients, longlasting. Currently, octreotide can only be recommended as an antiproliferative drug if patients with clearly progressive disease show stabilisation after treatment for three to six months.

The differentiating agent sodium butyrate inhibits proliferation and stimulates cell-specific hormone expression in rat insulinoma cells. In this study, we investigated the effect of sodium butyrate on neuroendocrine cytodifferentiation in the rat insulinoma subclone, RINm5F. The cells were cultured with 0.5, 1, or 1.5 mM sodium butyrate for up to 72 h. Ultrastructurally, cells cultured with 1 mM sodium butyrate revealed a more differentiated appearance with an induction of cellular compartments involved in regulated insulin secretion. Morphometric analysis showed a significant elevation of neuroendocrine granule density. The total area of the specific granules was increased after incubation with 1 mM sodium butyrate for 48 and 72 h. Proliferation of RINm5F cells was inhibited by sodium butyrate in a dose-dependent manner. DNA production ceased completely within 24 h at 1.5 mM sodium butyrate. This concentration of sodium butyrate increased the cellular insulin content 8.9-fold and the insulin production 2-fold after 72 h. The insulin release was reduced from 79 +/- 3.5% in controls to 37 +/- 5.6% of total in a 24-h incubation period after 3 days of culture with 1.5 mM sodium butyrate. Insulin mRNA levels increased to a maximum of 324% compared with controls after 48 h of culture with 1.5 mM sodium butyrate. Chromogranin A mRNA levels increased to a similar extent (368 +/- 26%), whereas sodium butyrate did not stimulate the expression of synaptophysin, a major membrane component of small neuroendocrine vesicles. In conclusion, our data suggest the selective induction of neuroendocrine cytodifferentiation by sodium butyrate in RINm5F cells.(ABSTRACT TRUNCATED AT 250 WORDS)

In the serum of patients with malignant endocrine gastroenteropancreatic (GEP) tumours, both alpha-subunit (alpha-SU), common to all glycoprotein hormones, as well as free beta-subunit of human chorionic gonadotropin (hCG-beta) have been reported to be elevated in a substantial fraction. Both have been discussed as markers of malignancy in these neoplasms. In the present study we evaluated the diagnostic significance of alpha-SU and hCG-beta as serum markers in patients with malignant endocrine gastroenteropancreatic tumours.The study group consisted of 52 patients with endocrine GEP-malignancies (24 nonfunctioning, 23 carcinoid syndromes, four gastrinoma, one glucagonoma), located in the small intestine (n = 29), pancreas (n = 17), colon or rectum (n = 3), retroperitoneum (n = 2) and stomach (n = 1). alpha-SU and hCG-beta immunoreactivity was also assessed in the serum of patients with benign GEP-tumors (five insulinoma, and three gastrinoma).Concentrations of alpha-SU and hCG-beta were determined using two highly sensitive and specific immunoradiometric assays employing two monoclonal antibodies each. In 19 of 52 patients (37%), either alpha-SU (n = 9), hCG-beta (n = 7) or both subunits (n = 3) were elevated. In the subgroup of 24 patients with nonfunctioning GEP-tumours, increased concentrations of either alpha-SU (n = 6) or hCG-beta(n = 3) or both subunits (n = 1) were found in 10 of 24 patients (42%). In four of 23 patients with carcinoid syndrome (17%), either alpha-SU (n = 2), hCG-beta(n = 1) or both subunits (n = 1) were above the normal range. Of five patients with functionally active endocrine pancreatic islet cell tumours, all had an elevation of at least one of the two substances. In contrast, in the serum of all eight patients with benign GEP-tumours, alpha-SU and hCG-beta were within normal limits. In summary, our data show a high frequency of elevated alpha-SU or hCG-beta immunoreactivity in the serum of patients with malignant endocrine gastroenteropancreatic tumours. Since immunoreactivity is mostly discordantly elevated, the two markers are well suited to supplement each other. Absolute values had a similar range in the subgroups analysed. The prevalence was highest for functionally active endocrine pancreatic islet cell cancers, but nonfunctioning endocrine GEP-malignancies also exhibited a high frequency of predominantly alpha-SU immunoreactivity. This is important since this subgroup of endocrine GEP-tumours usually lacks hormonal markers. In patients with carcinoid syndrome, however, increased serum levels of alpha-SU or hCG-beta appear to be rare and of no diagnostic value.

OBJECTIVE:The purpose of this study was to determine the value of somatostatin-receptor scintigraphy (SRS) in the preoperative localization of gastrointestinal endocrine tumors. The authors report their preliminary experiences with this new technique as compared to conventional imaging studies like computed tomography (CT) and ultrasonography (US).SUMMARY BACKGROUND DATA:Most endocrine tumors possess high-affinity somatostatin-receptors. Using the stable, 111Indium labelled somatostatin analogue pentatreotid, which binds to these receptors, it is possible to detect somatostatin-receptor-positive tumors scintigraphically.METHODS:In nine patients with various gastrointestinal endocrine tumors, SRS, CT, and US were performed before surgical exploration. The preoperative imaging studies and intraoperative ultrasound (IOUS) were then compared to findings on surgical exploration.RESULTS:Twelve primary tumors were found in 8 patients at surgical exploration. These primary tumors were correctly identified with SRS in five patients, with US in four patients, and with CT in three patients. In one patient with the Zollinger-Ellison syndrome, scintigraphy suggested a tumor in the area of the hepatoduodenal ligament, while CT and US had negative results. The underlying gastrinoma could not be identified despite extensive surgical exploration. Scintigraphy, CT, and US showed comparable results in the detection of metastases in four patients.CONCLUSIONS:The data from this small series suggest that SRS is helpful in the preoperative localization of gastrointestinal endocrine tumors.

Receptor scintigraphy with In-111-pentetreotide is a complementary imaging technique with a sensitivity of 88% for the localization of the primary tumor and its metastases in patients presenting with the clinical and biochemical symptoms of an endocrine tumor of the gastrointestinal tract or the pancreas. As a whole-body scintigraphic technique it covers all body regions and is also able to reveal small tumors which can only be detected with difficulty or not at all by the usual imaging methods. In 104 patients with GEP tumors or after operative removal of such tumors, receptor scintigraphy proved to be superior to ultrasound and computed tomography in 34%, equal in 52% and inferior in 14% of the cases.

Receptor scintigraphy with In-111-pentetreotide is a simple method with a sensitivity of 86 % for the localization of the primary tumor and its metastases in patients presenting with the clinical and biochemical symptoms of an endocrine tumor of the gastrointestinal tract or the pancreas. As a whole-body scintigraphic technique it covers all body regions and is also able to reveal small tumors which either cannot be detected or can only be detected with difficulty by the usual imaging methods. In 85 patients with GEP tumors or after operative removal of such tumors, receptor scintigraphy proved to be superior to ultrasound and computed tomography in 34 %, equal in 52 %, and inferior in 14 % of the cases.

The value of silver staining of nucleolar organizer regions (AgNORs) and human chorionic gonadotropin α‐chain reaction (HCG‐α) as markers of malignancy was investigated in 60 primary pancreatic endocrine tumours, 37 of which had metastasized at the time of surgery, and in one of which metastases developed 4 years after surgery. Assessment of AgNORs by digital image analysis revealed few but large AgNORs (mean number 2.5 ± 1.1; mean area ± in the 22 benign tumours and many but small AgNORs (mean number 5.1 ± 1.9, P<0.05; mean ± 9 μm2. P<0.01) in the malignant tumours. Quantification of the number of AgNORs per tumour cell AgNOR distribution score) showed that 96% (26/27) of tumours exhibiting at least 5% of cells with more six AgNORs per nucleolus showed metastases either at the time of diagnosis or up to 4 years after surgery. HCG‐α immunoreactive cells were present in 25/38 (66%) malignant tumours and in 4/22 (18%) benign tumours. Combined evaluation of AgNOR distribution and HCG‐α scores showed a high positive predictive value of 96% in cases with a raised AgNOR distribution score irrespective of the HCG‐α status. A good negative predictive value (81%) was, however, only obtained if both parameters, AgNOR distribution and HCG‐α scores, were negative. Thus, investigation of AgNORs HCG‐α is helpful in predicting malignancy in a high percentage of pancreatic endocrine tumours.

Amylin was isolated from human insulinomas, but there has been only preliminary data regarding whether this peptide can also be detected in other types of gastroenteropancreatic endocrine tumors. In the present study, immunohistochemical staining of 87 gastroenteropancreatic endocrine tumors demonstrated amylin immunoreactivity in 21.8% of the neoplasmas. Thirteen of 15 insulinomas, three of 21 gastrinomas, two of 29 nonfunctioning tumors, and one of 18 carcinoids were amylin-immunoreactive. Seventeen of the 19 amylin-immunoreactive tumors were primarily located in the pancreas, but two tumors were found in the intestine. Measurements of amylin messenger RNA expression in a few tumors revealed amylin synthesis in these tumors. Amylin immunoreactivity did not correlate with invasion and metastasis. However, the rate of curative resections was significantly higher in amylin-immunoreactive tumors. These results demonstrate for the first time that amylin immunoreactivity is not restricted to insulinomas and can also occur rarely in endocrine tumors of the intestine.

RINm5F cells, an insulin-secreting subclone of a rat insulinoma cell line, were incubated in serum-free medium up to 24 hours in the presence or absence of glucagonlike peptide-1(7-36)amide in various concentrations, 3-isobutyl-1 methylxanthine (1 mM), choleratoxin (10 nM), carbachol (1 mM), and potassium (40 mM). Insulin release and biosynthesis were measured by the immunoreactive insulin content of the cells and the medium. Steady-state levels of insulin-specific mRNA were determined by Northern and slot blot analysis. Short-term insulin release is significantly stimulated by all secretagogues tested. A significant increase of insulin biosynthesis by any of the various secretagogues was not detectable on the peptide and mRNA level. Sodium butyrate (1 mM), a differentiating agent, increased insulin-specific mRNA levels in RINm5F cells after 72 hours. In conclusion, substances known to stimulate short-term insulin release in RINm5F cells do not stimulate insulin biosynthesis, indicating an uncoupling of insulin secretion and biosynthesis in these transformed beta cells.