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Two patients suffering from benign and one patient suffering from malignant insulinoma experienced frequent incapacitating hypoglycemic attacks which did not respond to treatment with streptozotocin, diazoxide and/or diphenylhydantoin. Dl-propranolol, in dosages ranging from 30-240 mg/day, successfully abolished the symptoms of hypoglycemia, prevented recurrent hypoglycemic attacks, and normalized blood glucose levels concomitant with a reduction in pulse rate to 60/min. The main mechanism of the drug's effect seems to be the suppression of insulin release. However, other mechanisms may be involved such as increased peripheral insulin resistance. No side effects of treatment with dl-propranolol were noted. In patients suffering from insulinoma who are refractory to other forms of treatment, and for those who need symptomatic relief before surgery, dl-propranolol may play an important therapeutic role.

A 62-year-old man had necrolytic migratory erythema in association with hyperglucagonemia and multiple hepatic tumors. A diagnosis of metastatic glucagonoma was made. He was treated with human lymphoblastoid interferon given subcutaneously in the dose of 2.8 to 7.1 X 10(6) IU/day. This produced a considerable fall in plasma glucagon and resolution of the associated rash. The treatment was continued for 10 weeks over a 4-month period. Computed tomography demonstrated a reduction in hepatic tumor mass.

The tumor-forming endocrine cells of the pancreas belong to the APUD system. These cells are of neuroectodermal origin. The tumor can be diagnosed in most cases by a distinct clinical picture, and the diagnosis can be veryfied by direct hormone determination or/and by the biochemical disorders caused by the hormones. For localisation angiography, szintigrams, endoscopic pancreatography, and sonograms were used up to now without convincing results in many cases; computerized tomography promises to be the decisive examination in the future. Three hormones can, up to now, not yet be correlated with a distinct clinical picture specific for a pancreatic tumor. On the other hand, four tumors are responsible for a very typical clinical entity, the insulinoma, the glucagonoma, the gastrinoma, and the vipoma, as illustrated by our own cases. The surgical therapy consists mainly in enucleation of an adenoma or in partial pancreatic resection. Total pancreatectomy is indicated only in few cases. The Zollinger-Ellison syndrome is treated best by total gastrectomy. Malignant tumors are sensible to streptozotozin.

The results of combination chemotherapy with intermittent courses of 5-fluorouracil and streptozotocin in ten patients with metastatic carcinoid tumors and in eight patients with islet cell carcinoma are reported. Objective responses occurred in two of ten and in two of seven evaluable patients respectively. Biochemical responses occurred in an additional two patients with carcinoid. No improvement over single-agent chemotherapy and no effects on survival were noted.

A patients with metastatic insulin-producing islet-cell carcinoma has been treated with Streptozotocin intravenously and studied by selective celiac angiography during treatment. A 50% decrease of the tumor's size has been demonstrated by this technique after a total dose of 19 grams of the drug together with return to normal of the serum-insulin and blood-glucose values. The usefulness of angiography in evaluating the tumor response to Streptozotocin and in managing chemotherapy is discussed.

A woman with a multiple-hormone-producing pancreatic islet cell tumor with hepatic metastases and with recurrent hypoglycemic attacks, was treated with streptozotocin. After this treatment, the elevated serum levels of insulin, C-peptide, glucagon and serotonin fell markedly and the low level of fasting blood glucose returned to normal. In accordance with these hormonal changes, scintiscan and CT scan revealed marked regression of the metastatic tumors in the liver. She is alive at this writing, five years after the streptozotocin treatment. Streptozotocin should thus be considered for treatment of malignant islet cell carcinoma with liver metastases and which is not amenable to surgery.

Four patients with metastatic glucagonoma and one patient with metastatic diarrheogenic islet cell carcinoma of the pancreas were treated with dimethyltriazenoimidazole carboxamide (DTIC), 250 mg/M2 daily for five days repeated every four weeks. All patients responded clinically and chemically in one or more ways by a reduction in plasma glucagon levels, improved glucose tolerance, decreased measureable tumor, weight gain, and resolution of necrolytic migratory erythema and diarrhea. This experience and other cases from the literature call for the investigation of DTIC as the initial therapy in metastatic islet cell carcinoma of the pancreas and as being of possible benefit in other tumors of neuroendocrine origin.

The effects of somatostatin on diarrhea and on small intestinal flow of water and electrolytes (slow-marker perfusion technique) in a patient with pancreatic cholera are reported. Continuous intravenous infusion of somatostatin (8 micrograms/kg/hr) suppressed the diarrhea, but a rebound was observed after somatostatin. Infusion of somatostatin at the same dosage decreased the ileal fluid flow rate to within control values. This effect was mainly due to a sharp reduction in the rate fluid entered the jejunum, but was also due to a suppression of the abnormal water and electrolyte secretion in the proximal jejunum. Secretion in the rest of the small bowel remained unchanged. Somatostatin did not noticeably alter the high preinfusion plasma level of prostaglandin E1, but decreased the initially high plasma concentration of vasoactive intestinal peptide to normal values. These results suggest that long-acting somatostatin analogs could be of value in the symptomatic treatment of diarrhea in pancreatic cholera.

To define the course of malignant pancreatic islet cell tumors, 20 patients seen over 14 years with these neoplasms were reviewed. The 12 men and 8 women ranged in age from 22 to 76 years, with a mean of 52. Seven functional tumors included three insulinomas, two glucagonomas, one gastrinoma, and one somatostatinoma. One insulinoma was associated with a multiple endocrine neoplasia type I (MEN-I) syndrome. The 13 patients with nonfunctioning tumors had abdominal pain (3), jaundice (2), and steatorrhea (2). Seven had a palpable abdominal mass. Diagnosis of malignancy was based on local invasion (4), distant metastases (15), or both (1). One patient had percutaneous biopsy of a hepatic metastasis. All others had laparotomy for diagnosis and/or treatment. Each patient had a single tumor except the patient with MEN-I syndromes, who had multiple tumors throughout the pancreas. The head was involved in seven patients, the body in seven, and the tail in five. Operations included six curative and three palliative resections, five biliary diversions (two with concomitant enteric bypass), and five biopsies. Palliative resections were done for hormonal or local symptoms such as gastrointestinal (GI) bleeding and pain. Multiple chemotherapeutic agents were used, but the best results were obtained with DTIC (50% response). Four patients had radiation for liver, brain, or bone metastasis, with some improvement. Of five patients who had curative resections, four are alive 15 to 144 months, with a mean of 75 months. One died six years after diagnosis. Of the remaining 15 patients who had liver metastasis, seven patients are alive 8 to 168 months later, with a mean of 87 months.(ABSTRACT TRUNCATED AT 250 WORDS)

As streptozocin has a toxic effect on gastrin producing cells in some patients with gastrinomas, the action of the drug upon normal gastrin release was evaluated in patients with carcinoid tumours (n=6) and malignant insulinomas (n=2). No acute effects were recorded in 22 instances where gastrin levels were followed during the first 24 hours after infusion of streptozocin. When gastrin levels were compared throughout a course of repeated infusions during months a significant increase was noted. Concentrations were doubled after 6 g streptozocin given during a four months period, and tripled after 10 g in nine months period. One patients developed bleeding duodenal ulcer after a total dose of 6 g. It is concluded that streptozocin does not damage normal G cells, but by some action seems to stimulate gastrin relase. Peptic ulceration may be an important side effect during a long term treatment.

Three patients with the Verner-Morrison syndrome due to pancreatic tumours are reported; all had an overproduction of calcitonin and hypercalcemia. In two cases the hypercalcitoninaemia was due to an ectopic secretion from the pancreatic tumour, but in one the source could not be determined with certainty. Hypercalcemia in the Verner-Morrison syndrome might be due to simultaneous hyper-parathyroidism (MEA I) or secretion from the tumour of a substance or substances with calcium-elevating properties. Streptozotocin was of beneficial value in treating these patients. None of the patients became diabetic or had any other side effects of the therapy except for nausea and vomiting.

Pentamidine can cause hypoglycemia followed by hyperglycemia. The mechanism of this biphasic response is not known but has been reported to be similar to that of streptozotocin and N-3-pyridyl-N-p- nitrourea (Vacor). Pentamidine (4 mg/kg per day for 12 days) was used in a patient with malignant insulinoma after several unsuccessful debulking procedures and chlorozotocin therapy. Mean glucose and immunoreactive insulin levels (+/- SEM) before and after therapy were 80 +/- 40 mg/dl versus 70 +/- 50 mg/dl and 216 +/- 12 microU/ml versus 198 +/- 22 microU/ml, respectively. These were not significantly different. The patient's five-month-old malignant insulinoma monolayer cell culture was incubated with pentamidine (60 micrograms/ml) in the presence or absence of supplemented stimulatory medium consisting of glucose (300 mg/dl) and theophylline (20 micrograms/ml). Chloroquine (60 micrograms/ml) was added to inhibit lysosomal degradation of immunoreactive insulin. Aliquots of media for immunoreactive insulin determination were obtained at 30 minutes, 20 hours, 72 hours, and three weeks. The cells were examined by high-power light microscopy at each time interval. At 30 minutes, pentamidine alone caused passive release of immunoreactive insulin, 23 percent higher than control (p less than 0.01). Stimulatory medium increased immunoreactive insulin 45 percent greater than control (p less than 0.01). Pentamidine plus stimulatory medium had no additive effect on immunoreactive insulin released within 30 minutes. At the end of 20 hours, immunoreactive insulin was no different with pentamidine and/or stimulatory medium. However, the addition of chloroquine increased immunoreactive insulin by 35 percent above the medium with pentamidine and stimulatory medium (p less than 0.01). At 72 hours, pentamidine suppressed immunoreactive insulin by 100 percent in all the media, irrespective of the presence or absence of stimulatory medium and/or chloroquine. At the end of three weeks, there was 50 percent suppression of immunoreactive insulin in the control medium, but pentamidine again completely suppressed immunoreactive insulin. High-power microscopy demonstrated intact cells in the control medium, whereas no cell structure could be detected in the media containing pentamidine at three weeks. In summary, pentamidine had no acute in vivo effect in a patient with malignant insulinoma. However, when used in an in vitro monolayer system, pentamidine caused (1) acute immunoreactive insulin release followed by inhibition of immunoreactive insulin secretion and (2) cytolysis of human malignant insulinoma cells in vitro.

Over a period of 21 years 39 patients with gastrinoma were surgically treated. Thirty-three patients had total gastrectomy with two postoperative deaths, and 6 patients had a lesser procedure. The postoperative fasting gastrin levels remained elevated and did not always indicate the extent of tumor involvement. Further mobilization of tumor gastrin by provocative infusion of calcium gluceptate, 15 mg/kg of body weight, should be carried out routinely. A hepatic angiogram should be considered when the gastrin levels exceed 1,000 picograms per ml. Chemotherapy consisting of Tubercidin, Streptozotocin and 5-Fluorouracil was given to 5 patients with extensive gastrinoma. All patients felt better and gained from three to 35 pounds in weight. Since 60% of the patients died or have definite evidence of tumor activity it is assumed that the tumor growth was not inhibited and that it is malignant. Approximately 40% of the patients seem to do well despite modest elevations in gastrin levels suggesting that the retained tumor could be considered benign.

Two patients with metastatic islet-cell carcinoma underwent multiple hepatic artery catheterizations for streptozotocin infusion. An intimal flap was raised during one of the initial arteriographic procedures and a false aneurysm developed. The progression of the aneurysm was documented on sequential studies. False aneurysm formation appears to be a relatively unappreciated complication of intimal dissection, and these 2 cases permitted observation of their natural history.

A patient with metastatic insulinoma who suffered from severe hypoglycaemic attacks was treated with 7-5 g of streptozotocin (Upjohn). Shortly after the start of treatment, the hypoglycaemic attacks ceased; fasting blood glucose levels and serum immunoreactive insulin values returned to normal upon completion of the treatment. Two years after treatment, the patient is well and active and has not had any attacks. The oral glucose tolerance test and tolbutamide stimulation test now show serum immunoreactive insulin excretion patterns similar to those seen in diabetics.

The possibilities of treating different types of pancreatic islet cell cancer with the active drug streptozotocin have been studied in reports of 21 patients published during the last 8 years. The unusual features of the symptomatology, dosage and injection methods, side-effects after different infusion schedules and complications of streptozotocin therapy, are compared. A new case with pancreatic carcinoma and liver metastases was treated with a total dose of 14 g streptozotocin, divided into 7 injections with an increasing interval between them. This patient underwent a marked amelioration of the disease, without serious side-effects of the streptozotocin treatment. She has been apparently well for the 22 months which have now elapsed since the beginning of treatment. This seems to be one of the longest remission periods yet published in the insulinoma literature.

Malignant intra-abdominal neuroendocrine tumors are rare; consequently, a standard chemotherapeutic protocol for patients with unresectable disease has not been established. This prompted a review of our experience with dimethyltriazeno imidazole carboxamide (dacarbazine) (DTIC) treatment for these tumors. From 1976 to 1986, 14 patients were treated with DTIC for metastatic neuroendocrine tumors. There were seven men and seven women whose ages ranged from 19 to 76 years. Diagnoses included eight nonfunctioning islet-cell carcinomas, three retroperitoneal neuroendocrine tumors, two glucagonomas, and one ileal carcinoid. Before DTIC chemotherapy, four patients were treated with streptozotocin and 5-FU, and one was treated with cytoxan and methotrexate without response. Two patients who were initially treated with DTIC with no response were subsequently treated with streptozotocin and 5-FU without benefit. Standard treatment with DTIC consisted of monthly cycles of 250 mg/m2/day administered intravenously for 5 days. Seven patients had an objective response to DTIC with both improvement in quality of life and a decrease of more than 50% in tumor size on computerized tomography (CT) or liver scanning. Response duration ranged from 1 to 10 years. One patient with a glucagonoma was treated for two years and had no evidence of disease at laparotomy 7 years later. Four patients with nonfunctioning islet cell carcinoma had a positive response to DTIC, but three of these patients had tumor recurrence 3 to 6 years after treatment. Two patients with retroperitoneal neuroendocrine tumors had a positive response to DTIC treatment. One patient with a glucagonoma and one with a nonfunctioning islet-cell tumor had equivocal responses with transient clinical improvement but no objective changes in tumor size. Five patients did not respond; two were given DTIC therapy as a last resort and died 1 and 12 days later. Of the other three patients, two died 6 months and one 2 years after treatment. DTIC chemotherapy was effective in 50% of patients with intra-abdominal neuroendocrine tumors. Although DTIC therapy was associated with nausea, no major gastrointestinal, hematologic, or renal complications were noted. This favorable experience with DTIC chemotherapy for nonresectable intra-abdominal neuroendocrine tumors indicates that further clinical evaluation and use are warranted.

A case of a 65-year-old woman with a pancreatic tumor secreting insulin, glucagon, and associated with high PTH levels and hypercalcemia is reported. The patient underwent two Streptozotocin (STZ) treatments (1 g iv/week for 10 weeks) after liver metastases were found. Hormonal and metabolic parameters were monitorized . Before the first STZ treatment insulin levels ranged between 78 and 132 microU/ml. After STZ administration insulin decreased and then remained lower (8-48 microU/ml) until the death of the patient. Pre-treatment glucagon levels ranged between 1.3 and 3.9 ng/ml. STZ induced a decrease of glucagon to 0.5 ng/ml. Glucagon chromatography revealed the prevalence of high molecular weight (greater than 6,000 mol wt) immunoreactive glucagon (0.9 ng/ml) drastically reduced by STZ treatment (0.15 ng/ml). Hypoaminoacidemia was observed before STZ administration, but at the end of the therapy plasma amino acid concentrations were normal. Hypercalcemia too was sensitive to STZ, but not PTH value, which remained high. The second STZ treatment performed a year later was less effective and so a chemotherapeutic protocol was started. Our findings suggest a cytolitic effect of STZ on malignant A-cell, with reduction of glucagon levels and restoration of amino acid metabolism. This effect would be useful for medical treatment of non-operable glucagon secreting tumors.

Seventeen patients with islet cell carcinoma received chlorozotocin (CTZ). Nine received 200 mg/m2 IV every 6 weeks and 8 received 100 mg/m2. Responses were seen in eight (2 complete, 5 partial, 1 minor) of 13 patients who had received no prior chemotherapy, and in zero of four who had received prior chemotherapy. Toxicity was mild in most patients and consisted predominantly in myelosuppressions; however, in one patient severe renal failure developed. CTZ may have activity comparable to streptozotocin in this group of patients.

A review is given of the early 1976 situation in somatostatin research: the effects on pituitary hormones and the effects outside the pituitary gland, the production of somatostatin outside the hypothalamus, the artificial analogues, the problem of "side effects", and the mode of action. The possible clinical applications of somatostatin and somatostatin analogues are discussed.

We measured human chorionic gonadotropin (hCG) and its subunits in 76 patients with islet-cell tumors. Seventeen of 27 patients with functioning islet-cell carcinomas had elevated plasma levels of hCG or one of its subunits (hCG-alpha and hCG-beta). Secretion was often discordant; the most frequent finding was an elevated level of hCG-alpha alone. In one patient responding to streptozocin, changes in hCG-alpha correlated with the clinical course. Studies of tumor extracts suggested that the markers observed in the circulation were being produced in the tumor itself. In contrast, none of the 43 patients with benign disease or the six patients with nonfunctioning malignant tumors had elevated levels of hCG, hCG-alpha or hCG-beta. These data show that hCG and its subunits are prevalent and specific markers for islet-cell carcinoma, and suggest that ectopic secretion results from malignant derepression of the genome rather than overproduction by an aberrant "cell rest."

The use of diazoxide in patients with insulinoma has been evaluated using the euglycaemic clamp technique. There was significantly reduced mean tissue sensitivity to insulin, expressed as the ratio of glucose disposal rate to serum insulin concentration (M/I), in untreated patients compared to the control group. The metabolic clearance rate of insulin (MCRI) was reduced in the patients before treatment in comparison with the controls. The administration of diazoxide (Proglicem1) for three days (3 mg.kg-1 per day) caused a fall in serum insulin concentrations, together with an increase in the metabolic clearance rate of insulin and increased tissue sensitivity to insulin.

Three cases of pancreatic islet cell tumors, 1 malignant and 2 benign, producing predominantly pancreatic polypeptide (PP) are described. All 3 patients exhibited elevated plasma PP concentrations, either basal or protein-meal-stimulated, during the period of observation. Immunocytochemical study revealed that while PP cells predominated in the tumor, A, B, and D cells were also present. A comparison of the hormone content of the tumor tissue, adjacent pancreatic tissue, and normal pancreas was made by radioimmunoassay of tissue extracts. The PP content of tumors clearly exceeded that of normal pancreas. The insulin, glucagon, and somatostatin (SRIF) content was more variable, but in one case the glucagon content of the tumor was higher than in normal pancreas, and two of the tumors exhibited an elevated SRIF content. Gel filtration of a tumor extract showed that insulin, glucagon, and PP immunoreactivity was of expected molecular dimensions but immunoreactive SRIF in this extract was composed of two species. The PP in gel fractions reacted equally well with antibody directed toward different parts of the PP molecule.

Various chemotherapeutic modalities have been tried in the treatment of patients with malignant glucagonomas. Promising results have been reported after drug treatment with dimethyltriazenoimidazole carboxamide (DTIC). We present a patient with a metastasizing pancreatic glucagonoma, in whom treatment with neither DTIC nor with the combination of streptozotocin and 5-fluorouracil resulted in any noticeable improvement.

We report 1 patient with a necrolytic migratory erythema, a high plasma glucagon concentration and a metastatic pancreatic endocrine tumor who has now been treated effectively for 33 months with the somatostatin analogue octreotide (SMS 201-995) (400 micrograms/day). The results of SMS 201-995 in the treatment of glucagonoma syndrome are reviewed.