Islet Cell Carcinoma Research Articles

Pancreatic cholera: beneficial effects of treatment with streptozotocin.

Two patients with pancreatic cholera and islet-cell carcinoma were treated with intra-arterial streptozotocin. Before therapy, they had stool volumes from 2 to 8 liters per day and required 200 to 800 mEq per day of supplemental potassium. After three to five doses of streptozotocin (1.5 per square meter), both stool volume and number and size of hepatic metastases decreased markedly. One patient has had normally formed stools for 12 months; the other had a 90 per cent reduction in stool volume for 13 months with additional therapy. Both patients' serum potassium returned to normal without need for supplementation. Jejunal adenylate cyclase activity was normal in both, and plasma vasoactive intestinal peptide was detectable in only one. After chemotherapy, these findings showed no consistent change. Pharmacologic studies suggest that arterial administration increased either tumor or hepatic extraction (or both) of streptozotocin by two times and decreased renal exposure to this nephrotoxic drug by one third.

Multiple hormone producing islet cell carcinomas of the pancreas: A morphological and biochemical investigation

Biochemical, light, and electron microscopic studies of two multiple hormone producing metastatic islet cell carcinomas of the pancreas are presented. Both tumors initially produced symptoms referable to a single hormone and over a period of years produced two other endocrine active polypeptides. The tumor in case 1 had been studied electron microscopically six years previously and had demonstrated no significant ultrastructural changes since then. The tumor in case 2 contained secretory granules of markedly varying size and density, suggesting a formation of packaged precursor molecules of possibly all three hormones. The pathogenesis of these tumors is discussed in light of recent evidence concerning the origin of endocrine cells.

Immunochemical Heterogeneity of Calcitonin in Plasma

Calcitonin was measured in the plasma of 13 patients with medullary throid carcinoma and one patient with a calcitonin-producing islet cell carcinoma of the pancreas. The hormone was measured by the simultaneous application of two calcitonin antisera which had differing specificity. Calcitonin measurements were also made of gel filtration (Bio Gel P30) fractions of plasma samples. Although the two antisera were of comparable sensitivity for the measurement of human calcitonin standards, they reacted differently with the calcitonin in the plasma samples. One antiserum (LD-1) gave consistently higher estimations of hormone concentration in the plasma of patients with medullary thyroid carcinoma than the other (LD-26). By contrast, the concentration of calcitonin from the islet cell carcinoma of the pancreas was higher in the LD-26 assay. Multiple gel filtration peaks of immunoreactive calcitonin activity were present in both thyroidal and nonthyroidal calcitonin. Furthermore, the two different antisera identified differing immunochemical peaks of calcitonin activity for agiven plasma sample. These findings demonstrate the presence of immunochemical heterogeneity in plasma calcitonin and suggest the presence of immunological differences between thyroidal and nonthyroidal calcitonin.

Uncontrolled diabetes mellitus and hyperglucagonemia associated with an islet cell carcinoma

A 53 year old woman presented with diabetes mellitus, hyperglucagonemia (600 to 1,500 pg/ml), clinical hyperparathyroidism and an abdominal mass diagnosed on biopsy as an islet cell carcinoma. Glucagon content of the tumor was 0.78 μg/g wet weight. Hourly blood samples during a 24 hour period revealed a direct correlation between plasma glucose and glucagon. The oral administration of glucose paradoxically increased whereas the intravenous administration decreased plasma glucagon. Circulating glucagon levels were markedly increased with arginine and epinephrine infusion. Both short- and long-term administration of alpha adrenergic blockade depressed the glucagon response to epinephrine infusion. In contrast, long-term alpha adrenergic blockade increased glucagon secretion despite improved glucose tolerance during a second 24 hour study. Although the patient demonstrated overt clinical and chemical findings of hyperparathyroidism, parathyroid hormone (PTH) was not detected in her plasma. The pattern of tumor growth was consistent with an origin from pancreatic islets. We conclude that (1) the tumor was responsive to physiologic stimuli known to affect glucagon secretion; (2) elevations of plasma glucagon levels with oral and dietary glucose suggest regulation of secretion by intestinal factors; and (3) improvement of glucose tolerance with alpha adrenergic blockade may be related to increased insulin secretion.

Das vasoaktive intestinale Polypeptid beim Verner-Morrison-Syndrom

A 40-year-old man with the Verner-Morrison syndrome (refractory watery diarrhoea and hypokalaemia in islet-cell tumour of the pancreas) had an islet-cell carcinoma of the non-B-cell type with metastases to liver and mesenteric lymph nodes. High concentrations of a vasoactive intestinal polypeptide (VIP) were demonstrated in tumour tissue and plasma by radioimmunological tests. After surgical removal of the tumour the plasma VIP concentration fell to normal. Immunohistochemical tests of the tumour for gastrointestinal hormones demonstrated marked fluorescence only for vaso-active intestinal polypeptide. It is assumed that this polypeptide is largely responsible for the clinical signs. In the described case the severe watery diarrhoea ceased after glucocorticoid administration.

Pancreatic Islet Cell Carcinoma Metastatic to the Eyes

Pancreatic Islet Cell Carcinoma Metastatic to the Eyes

Effects of secretin on guanyl cyclase of various tissues.

Secretin (4 µg'ml) activated guanyl cyclase in 30,000 × g supernatant preparations from rat liver, lung, skeletal muscle, pancreas, stomach, brain cortex, fat cells, isolated pancreatic islets and one human islet cell carcinoma, but not in supernatants from rat heart, small intestine and two other human islet cell carcinomas. Both islet cell carcinomas displayed high basal activities. Guanyl cyclase of the rat iris was inhibited by secretin. These studies suggest that guanyl cyclase has receptors for secretin in “nontarget” as well as “target” tissues. (Endocrinology 94: 276, 1974)

Effects of streptozotocin on an islet cell carcinoma with hypercalcemia

A 57 year old man had an inoperable pancreatic islet cell carcinoma with liver metastases. Biochemical studies indicated the possibility of a circulating parathyroid hormone-like substance; exploration of the neck revealed normal parathyroid glands. Biochemical studies of family members revealed no evidence of familial endocrine adenomatosis. The patient's hypercalcemia could not be controlled with the usual calcium lowering measures. He was treated with streptozotocin, with temporary increases in his hypercalcemia after each of the first three treatments. After four doses of streptozotocin, the size of the tumor decreased and the serum calcium fell to hypocalcemic levels. The serum calcium subsequently stabilized at low normal levels, and the tumor has remained in partial remission for 14 months after administration of the last dose of streptozotocin.

Insulin and ACTH production by a streptozotocin responsive islet cell carcinoma

We describe a patient with insulin and ACTH production by an islet cell carcinoma with hepatic metastases and cite three previously reported cases of this bihormonal production. The patient was treated with multiple instillations of streptozotocin, a drug with specific beta cell toxicity. After therapy, insulin and ACTH levels declined. These responses after the administration of a drug with beta cell specificity are evidence that both insulin and ACTH were produced by beta cells rather than by multiple cell types.

Pancreatic islet cell carcinoma. II. Results of therapy with streptozotocin in 52 patients.

The clinical experience with streptozotocin (NSC-85998) in 52 patients with metastatic islet cell carcinoma was analyzed. The drug was given intravenously in 44 patients and intra-arterially in 8 patients, most often on a weekly schedule of administration of 0.6 to 1.0 g/m2 body surface area. Biochemical responses were seen in 64% of evaluable functional cases, and measurable disease responses were seen in 50% of these cases. Insulin responses occurred 2 to 3 weeks after drug administration at a total dose of about 2 to 4 g/m2 body surface area. A significant increase in 1-year survival rate and a doubling of median survival were shown for the responders as compared with the nonresponders. Acute toxicity, consisting of nausea and vomiting, was observed in 98% of the cases, whereas renal or hepatic toxicity was seen in 65% and 67% of the cases, respectively. Hematological toxicity, observed in 20% of the cases, was mild. Renal and hepatic toxicity were usually reversible, but five patients died in renal failure.

Pancreatic islet cell carcinoma. I. Clinical features of 52 patients.

The clinical features of 52 patients with metastatic pancreatic islet cell carcinoma treated with streptozotocin (NSC-85998) were analyzed. Seventy-nine percent of the patients had functioning tumors, with the majority secreting insulin; 21% of the patients had nonfunctioning tumors. The tumors were found primarily in the tail of the pancreas and were noted with equal frequency in men and women, at a median age of 52 years. Metastases were mainly to the liver and by local extension; distant metastases were rarely noted. The most frequently reported presenting symptom was hypoglycemia, occurring in 90% of the functioning-tumor patients. Gastrointestinal ulceration and diarrhea were less frequently observed. An overall median survival of 908 days, from diagnosis to last follow-up, was noted. There was no significant difference in survival rates between the sexes or between the functioning- as compared to the nonfunctioning-tumor patients.

Control of hypoglycemia with L-asparaginase in a patient with islet cell cancer.

l-asparaginase, an anti-leukemic drug with diabetogenic properties, was administered to a patient with functioning islet cell carcinoma who had become less responsive to streptozotocin. Hypoglycemic symptoms were controlled and serum insulin levels decreased. Serial liver scans remained unchanged. Drug associated toxicity included slight azotemia, anemia, hypoalbuminemia, moderate intermittent vomiting, and episodic tearing and feelings of sadness. Toxicity was mostly reversible with lowering of dose to maintenance levels. l-asparaginase is a useful drug in the control of hypoglycemic symptoms in malignant hypoglycemic states.

Cross‐classification and survival characteristics of 5,000 cases of cancer of the pancreas

AbstractOver 5,000 histologically confirmed cases of cancer of the pancreas from the End Results Group of cancer registries have been examined for differences in behavior by epidemiologic and pathologic variables. Thirteen percent had a specific histologic diagnosis other than “adenocarcinoma,” “carcinoma,” or “cancer.” The 92 cases of islet cell carcinoma were unique, having a much younger age at diagnosis (two‐thirds instead of one‐third diagnosed under the age of 60), a locational preference for the body and/or tail (only 40% instead of 70% occurring in the head of the pancreas), and a very favorable survival experience (15 year relative survival of 14%). Of cancers of the exocrine pancreas, the 64 cases with papillary histology were most distinct, two‐thirds being found in women, 18% instead of 10% being localized, and having relatively favorable survival (30% one‐year survival, 5% three‐year survival). Patients whose tumors revealed squamous metaplasia occurred in general at older ages and had unusually poor survival. Analysis by anatomic location showed an increasing percentage of carcinomas occurring in the head of the pancreas with increasing age. Analysis of “adenocarcinomas” by histologic grade indicated that grade may carry some prognostic information not explained by difference in stage. A striking gradient of decreasing survival with increasing age did not explain, and was not explained by survival gradients in other variables.

“Big” insulin and the treatment of an islet cell carcinoma with streptozotocin

Total plasma immunoreactive insulin (IRI) and percentage “big” insulin (proinsulinlike material) were measured in a patient with an inoperable islet cell carcinoma who did not improve clinically after streptozotocin administration. Prior to the streptozotocin, the total IRI rose with administration of tolbutamide, and the percentage of “big” insulin remained constant. After intravenous glucose there was little change in plasma IRI, but a substantial rise in the percentage of “big” insulin occurred. The administration of streptozotocin was acutely associated with hypoglycemia, a slight increase in total IRI, and no change in the percentage “big” insulin. With chronic administration and extension of the disease, the total IRI and percentage “big” insulin rose progressively. It is concluded that the percentage “big” insulin rises as loss of tumor differentiation occurs and that changes in the percentage of “big” insulin after streptozotocin may give an early indication of likely response to streptozotocin.

Biologically active circulating proinsulin-like materials from an islet cell carcinoma patient.

Circulating immunoreactive insulin (IRI) material was obtained from a hypoglycemic patient with a pancreatic islet cell carcinoma. On gel filtration, 85% of this material eluted as a homogeneous proinsulin peak (PLM) and 15% as insulin. On polyacrylamide gel electrophoresis, in addition to a small amount of insulin, two peaks were obtained. One had the migration of intact human proinsulin. The second electrophoresed as an intermediate species compatible with desdipeptide proinsulin. Trypsin treatment of PLM resulted in IRI material eluting as insulin on gel filtration. When comparable amounts of IRI material were tested, PLM showed about one half of the biological activity of porcine insulin in the rat hemidiaphragm system. No evidence of conversion to insulin was found after PLM had exerted its biological activity. In addition to large amounts of proinsulin, islet cell tumors may secrete significant amounts of intermediate species into the circulation.

Familial nesidioblastosis as the predominant manifestation of multiple endocrine adenomatosis

The incidence of endocrine abnormalities in eight members of a family with multiple endocrine adenomatosis was compared with that in five nonrelated subjects with islet cell tumors and in seven normal control subjects. Three members of the family had documented islet cell hyperplasia, adenoma and/or carcinoma associated with hypoglycemia or the Zollinger-Ellison syndrome, and all but one member of the family was found to have hypersecretion of insulin, often associated with elevated blood glucagon and/or gastrin levels. Five members had hyper-insulinism but were asymptomatic, although several demonstrated glucose intolerance. Asymptomatic hypercalcemia and abnormal adrenal function were noted in some subjects. There was no evidence of primary abnormalities in pituitary function or of catecholamine and 5-hydroxyindoleacetic acid levels in the family subjects. The nonfamily subjects with insulinoma had no other endocrine abnormalities. In one nonfamily subject, who may also have multiple endocrine adenomatosis, the Zollinger-Ellison syndrome was associated with high blood gastrin and insulin levels with glucose intolerance. It is proposed that the basic genetic defect in the family with multiple endocrine adenomatosis involves hyperplasia of the primordial cell of the islets of Langerhans (nesidioblastosis) with chronic oversecretion of one or more islet cell hormones. Secondary changes in other endocrine glands may then evolve as a consequence of the islet cell hormone excess(es). A high incidence of asymptomatic endocrine abnormalities was found in this and other studies. It is suggested that when abnormal growth or function of one endocrine gland is detected, a careful search for asymptomatic involvement of other glands should be made in the patient and his immediate relatives.

A unique form of circulating insulin in human islet cell carcinoma.

ABSTRACT We have partially characterized the circulating insulin components from a patient with islet cell carcinoma. The proinsulin-like component is larger in size, less reactive by radioimmunoassay, and more reactive by bioassay than identical preparations from a non-tumor patient. The insulin component is less reactive by radioimmunoassay but otherwise indistinguishable from the non-tumor component. These unique circulating insulin components either represent a specific mutation in an individual patient or a more general heterogeneity of the insulin components in disease states.

Further studies on streptozotocin therapy for a multiple-hormone-producing islet cell carcinoma.

A patient with a multiple-hormone-producing islet cell carcinoma, who had previously been successfully treated with streptozotocin, was given three further infusions of this drug because of the redevelopment of gastric hypersecretion. Although some evidence of damage to the gastrinsecreting cells was obtained, the fasting plasma gastrin was not significantly altered and the patient died from a perforated duodenal ulcer. Serum insulin levels were considerably reduced and the patient became mildly diabetic but the main complication of treatment was a severe though reversible renal tubular defect. At necropsy considerable quantities of gastrin, but low levels of insulin and glucagon were extracted from a tumour metastasis.

Carcinoid of the pancreas

A patient is presented with carcinoid syndrome due to a pancreatic tumor. Histologically the tumor resembled a carcinoid, adenocarcinoma and islet cell carcinoma, depending upon the area examined. A review of the literature uncovered similar instances of confusion. By correlating the clinical, biochemical, histochemical and pathological findings, we conclude that our patient's tumor was a primary pancreatic carcinoid.

Streptozotocin Therapy for Metastatic Insulinoma

Streptozotocin, an antibiotic derived from<b>Streptomyces achromogenes</b>, was selected for treatment of a previously diabetic patient with incapacitating hypoglycemia caused by an islet cell carcinoma that had metastasized to the liver. Complete control of all symptoms, together with normalization of biochemical measurements, disappearance of evidence of hepatic metastases as shown on liver scan, and return to his pretumor diabetic state, have been accomplished without the development of a serious toxic reaction. This antibiotic appears to be useful in the control of insulinomas not amenable to surgery. Significant laboratory observations over an 80-day period of treatment are presented.