Interventional treatment of neuroendocrine liver metastases.

Neuroendocrine gastroenteropancreatic tumours are rare with an incidence of 2-4/100.000 per year. More than 75% of the patients develop hepatic metastases, which reduce the five year survival from 70-80% to 30-40%. In addition to chemo- and biotherapy, interventional therapy of liver metastases should be considered in order to prolong survival and reduce endocrine and local symptoms. Surgical resection is the only curative treatment, but possible in less than 10% of the patients. Curative and palliative resection, which is possible in less than 20-25% of the patients, relieve endocrine and local symptoms in 90% of the patients for more than two years, and the five year survival is prolonged to 40-85%, although metastases recur or progress in almost all patients. Tumour ablation by radiofrequency therapy has a palliative effect on endocrine symptoms in 70-90% of the patients for up to two years, but should not be a substitute for surgical treatment. When metastases are not eligible for surgical treatment or ablation, embolization or chemoembolization are alternative options with a reduction in tumour burden in about 50% and a five year survival of around 60% ofthe patients. The symptomatic response rate is 90% with a mean duration of two years. Liver transplantation should be restricted to very few and highly selected patients without extrahepatic disease. Recurrence is inevitable in nearly all patients.

The effect of gastrin on basal- and glucose-stimulated insulin secretion in man.

The effect of gastrin on basal- and glucose-stimulated insulin secretion was studied in 32 normal, young subjects. The concentration of gastrin and insulin in serum was measured radioimmunochemically. Maximal physiologic limit for the concentration of gastrin in serum was of the order of 160 pmol per liter as observed during a protein-rich meal. Oral ingestion of 50 g glucose produced a small gastrin response from 28+/-3 to 39+/-5 pmol per liter (mean +/-SEM, P < 0.01). Intravenous injection or prolonged infusion of gastrin increased the concentration of insulin in peripheral venous blood to a maximum within 2 min followed by a decline to basal levels after a further 10 min. The minimum dose required to induce a significant insulin response (31.2 ng gastrin per kg) increased the gastrin level in serum above the physiologic range. Maximum effect was obtained with 500 ng gastrin per kg. When 15.6 ng (7.1 pmol) gastrin per kg body weight and 25 g glucose were injected simultaneously, the glucose-induced insulin response was potentiated (from 2.32+/-0.33 to 4.33+/-0.98 nmol per liter per 20 min, P < 0.02), even though gastrin concentrations only increased to 71.2+/-6.6 pmol per liter. No effect, however, was noted on glucose disposal. 15.6 ng gastrin per kg given i.v. 30 min before an i.v. glucose tolerance test was without significant effect on the insulin response. The results indicate that gastrin can stimulate a rapid and short-lived release of insulin. In physiologic concentrations gastrin potentiates the glucose-stimulated insulin secretion and is without effect on basal insulin secretion. A small release of gastrin during oral glucose ingestion may to a limited extent contribute to the nonglycemic insulin secretion. During protein ingestion, gastrin probably stimulates insulin secretion significantly.

Effect of atropine on gastrin and gastric acid response to peptone meal.

The action of intravenous atropine on meal-and pentagastrin-induced gastric acid secretion was studied in six duodenal ulcer patients.A test meal of 10% peptone solution adjusted to pH 5.0 was maintained in the stomach at at distention presure of 15 cm H(2)O, and a modification of the intragastric titration method of Fordtran and Walsh was used to measure gastric acid output by monitoring the rate at which a solution of 0.5 M sodium bicarbonate had to be added to keep the pH of the gastric content constant at the initial (pH 5.0) value. Serum gastrin concentrations were measured simultaneously by radioimmunoassy. The dose of 25 mug/kg-h atropine inhibited meal-induced acid secretion by about 70% and that evoked by pentagastrin by about 30%. The serum gastrin response to the test meal was not significantly altered by atropine. We conclude that atropine is a very strong inhibitor of meal-induced gastric acid secretion and does not significantly change serum gastrin response to feeding in duodenal ulcer patients when postprandial gastric acidity (pH 5.0) and intragastric pressure (15 cm H(2)O) are kept constant.

Vagal, cholinergic regulation of pancreatic polypeptide secretion.

THE EFFECT OF EFFERENT, PARASYMPATHETIC STIMULATION UPON PANCREATIC POLYPEPTIDE (PP) SECRETION WAS STUDIED IN THREE WAYS: (a) Plasma PP concentrations increased in response to insulin-induced hypoglycemia in both normal subjects, from 11 pM (9.5-12.5) to 136 pM (118-147), n = 8 (median and interquartile range) and in duodenal ulcer patients, from 33 pM (21-52) to 213 pM (157-233), n = 7. The PP response to hypoglycemia was diminished by atropine in normal subjects (P < 0.005) and completely abolished by vagotomy in the duodenal ulcer patients. (b) Electrical stimulation, 8 Hz, of the vagal nerves in anesthetized pigs induced an increase in portal PP concentrations within 30 s from 32 pM (28-39) to 285 pM (248-294), n = 12. Minimal stimulatory frequency was 0.5 Hz and maximal stimulatory frequency 8-12 Hz. Atropine inhibited the PP response to electrical stimulation. Median inhibition with 0.5 mg of atropine/kg body wt was 74%, range 31-90%, n = 6. The response was eliminated by hexamethonium. Adrenergic alpha and beta blockade did not influence the release of PP in response to vagal stimulation. (c) Acetylcholine stimulated, in a dose-dependent manner, the secretion of PP from the isolated perfused porcine pancreas, half-maximal effective dose being 0.19 muM; maximal PP output in response to 5 min stimulation was 228 pmol, range 140-342 pmol, n = 5. Atropine completely abolished this response.The results of the present study together with the previously demonstrated poor PP response to food in vagotomized patients, indicate that vagal, cholinergic stimulation is a major regulator of PP secretion.

Prevalence of endocrine abnormalities in patients with the Zollinger-Ellison syndrome and in their families.

To evalute the frequency of associated and hereditary endocrinopathies in the Zollinger-Ellison syndrome, 10 patients with the syndrome were studied. In seven of them, coexisting endocrine disease was found. In six, the Zollinger-Ellison syndrome was probably a feature of multiple endocrine adenomatosis type I, whereas Cushing's syndrome in the remaining patient may have been caused by the production of an ACTH-like substance by a mixed pancreatic tumor. A total of 109 family members, including all living first degree relatives over 15 years of age, were screened for endocrine abnormalities. All six patients with evidence of multiple endocrine adenomatosis type I had relatives with endocrinopathies. In the families of the four other patients with the Zollinger-Ellison syndrome, no endocrine abnormalities were found. During this study four new cases of pituitary tumor, 17 of hyperparathyroidism, seven of the Zollinger-Ellison syndrome and one of insulinoma were detected. Although most of the disorders were asymptomatic, this clearly indicates that patients suffering from Zollinger-Ellison syndrome and also their families should undergo detailed endocrine studies.

Activation of histidine decarboxylase by H2-receptor blockade: mechanism of action.

1 Treatment with histamine H2-receptor antagonists, which inhibit basal acid secretion was found to activate rat stomach histidine decarboxylase. At the same time the serum gastrin concentration was greatly increased. 2 In antrectomized rats neither the enzyme activity nor the serum gastrin concentration was affected by the treatment. 3 In analogy with previous observations on other inhibitors of acid secretion we suggest that the H2-receptor antagonists stimulate gastrin release through their effect on acid secretion and that the raised serum gastrin level is responsible for the enzyme activation.

Effect of histamine on immunoreactive gastrin in gastric juice and in serum.

Due to recent reports claiming that gastrin is present in the gastric juice, the method for gastrin determination has been evaluated. Separate experiments showed that gastrin added to gastric juice disappears rapidly if the juice is not boiled or neutralized. A total of 82 patients with various abdominal disorders were examined. No or only a trace amount of gastrin was found in untreated, boiled, or boiled and neutralized gastric juice in every patient, including three patients with achlorhydria. Histamine injection (0.04 mg. per kilogram, subcutaneously) did not influence this and was without effect upon serum gastrin concentrations of nine duodenal ulcer patients. Because gastrin apparently is degraded rapidly by gastric juice, this study does not necessarily disprove that gastrin is secreted into the stomach. However, the virtual absence of gastrin in all specimens examined, including some collected directly upon boiling water bath during continuous gastric aspiration lends no support to this speculation. Because gastrin does not survive even a short exposure to gastric juice without degradation, we suggest that earlier reports on the presence of gastrin within the stomach are questionable.

Case report: somatostatin producing teratoma, causing rapidly alternating extreme hyperglycemia and hypoglycemia, and ovarian somatostatinoma.

A 54-year-old woman presented with extremely fluctuating and symptomatic blood glucose levels. Very high levels of somatostatin and low levels of insulin, C-peptide, gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) in peripheral blood were constantly present. A benign somatostatinoma was localized by meta-iodobenzyl guanidine iodine 123 (MIBG-I(123)) scintigraphy and successfully removed encapsulated in an ovarian teratoma. The patient made a complete recovery. The case described is unique with regard to clinical symptomatology and anatomic localization of the tumor.

Extraction of neurotensin-like immunoreactivities from porcine ileal mucosa.

The extractability of neurotensin (NT) from porcine ileal mucosa was studied by comparison of eight extraction procedures. Tissue content of neurotensin-like immunoreactivity was quantitated and characterized by sequence-specific radioimmunoassays and gel filtration chromatography. Homogenization prior to boiling in extraction solvent produced higher levels of the intact peptide than the reverse procedure. N-terminal immunoreactivity was not influenced by the sequence of these steps. Tissue levels of intact NT were highest after extraction with 2.0 M acetic acid (mean 79.1 pmol/g, N = 6) and lowest with distilled water (mean 6.5 pmol/g, N = 6). The opposite was the case with levels of N-terminal immunoreactivity (mean 55.2 pmol/g and 105.7 pmol/g respectively, N = 6). Recovery experiments with addition of synthetic NT 1-13 and the N-terminal fragment NT 1-8 indicated that these differences could be explained by differences in recovery of intact NT and N-terminal immunoreactive components in tissue. Gel chromatography confirmed that in acetic acid almost only the intact peptide was extracted from ileal mucosa, and showed that after extraction in water or phosphate buffer several N-terminal components were present. The results suggest that a molecular heterogeneity may be present in ileal tissue. If this concept is supported by further studies differential extraction procedures may be needed in the future.

Sulfation of gastrin in Zollinger--Ellison sera: evidence for association between sulfation and proteolytic processing.

Sulfated gastrins were quantitated in sera from 15 patients with the Zollinger--Ellison syndrome (ZES) by specific radioimmunoassays. The total concentration of gastrin varied from 174 to 285 000 pmol/l. Sulfated gastrins constituted 44.8 +/- 5.5% (mean +/- S.E.M.) of the gastrins in ZES sera compared with 37.7 +/- 1.9% in sera from 100 control subjects (P greater than 0.1). There was no correlation between gastrin concentration and sulfation (r = 0.40). Gel and ion-exchange chromatography showed that up to 90% of the gastrins could be in the sulfated form. The highest degree of sulfation was found in sera where the small gastrin components dominated. Thus, the percentage of small gastrins (G-17 and G-14) correlated with the degree of sulfation (N = 15, r = 0.75, P less than 0.01). We suggest therefore that proteolytic processing of the gastrin precursor and sulfation of tyrosyl are associated.

Meal stimulated levels of pancreatic polypeptide (PP) and vasoactive intestinal polypeptide (VIP) in gastroplasty for morbid obesity.

Plasma concentrations of pancreatic polypeptide (PP) and vasoactive intestinal polypeptide (VIP) were measured after a meal consisting of 11 ml meat extract and 40 ml of 20% soya oil in 11 patients before and 3 months after gastroplasty for morbid obesity. Gastroplasty results in a small proximal pouch with a narrow stoma allowing delayed emptying into the distal pouch, and consequently postprandial distension of the proximal pouch. Postprandial plasma PP increased significantly (P less than 0.01) independent of gastroplasty. PP is therefore not involved in the early satiety after gastroplasty. Postprandial plasma VIP increased significantly from fasting levels both before and after gastroplasty (P less than 0.05). Only 10 min after a meal, the median value of VIP was significantly higher after than before gastroplasty (P less than 0.02) and may be caused by distension of the proximal pouch.

Plasma levels of neurotensin in gastroplasty for morbid obesity.

Fasting and postprandial plasma levels of the tridecapeptide neurotensin were determined in ten women before and three months after gastroplasty for morbid obesity. Measurements were by radioimmunoassay in unextracted plasma with two antisera recognizing intact neurotensin (NT1-13) or intact neurotensin together with small C-terminal fragments, which may circulate as metabolites of neurotensin. Levels of both intact neurotensin and C-terminal immunoreactivity in obese women were in the same order of magnitude as those found previously in lean persons. Fasting levels measured with both antisera were significantly reduced following gastroplasty (P less than 0.01). Meal-stimulated levels and increments were unchanged. The cause of this prolonged reduction is at present unknown, but may be a reduced luminal stimulation of the small intestine or an altered vagal tonus following gastroplasty.

Ultrasonically guided percutaneous interstitial implantation of iodine 125 seeds in cancer therapy.

A new method for ultrasonically guided percutaneous interstitial implantation of 125I seeds in abdominal tumours is described. A linear array puncture transducer mounted on a special x-y-z co-ordinate frame is used in combination with a special insertion technique. Following in vitro experiments the technique was applied in two patients with pancreatic cancer. There were no immediate complications after the implantation of 36 and 37 125I seeds.

The measurement of gastrin.

The days of the autumn 1970 when a gastrin assay was developed have been revisited, and the research conditions then and now compared. No valid conclusions seem possible from such a study, but a lot of facts suggest that the good old days were better.

Mast cells and histamine release in Crohn's disease.

To study the role of intestinal mast cells in Crohn's disease, a sensitive glass-fiber histamine assay was conducted in conjunction with mechanical dispersion of surgical specimens of 80 macroscopically actively inflamed colons, 40 non-inflamed colons, 40 actively inflamed ileums, and 16 non-inflamed ileums from patients with Crohn's disease and 96 control subjects. A strong correlation was found between the number of mast cells and the total histamine content in the controls (r = 0.682) (p < 0.05). The number of mast cells was decreased in Crohn's disease as compared with the controls (p < 0.01). Intestinal mast cells release histamine in a dose-dependent manner after challenges with anti-IgE (1.875-240.0 U/ml). A significant difference was noted in the release by anti-IgE between actively inflamed and non-inflamed colons of patients with Crohn's disease or control subjects (p < 0.01). Mast cells in actively inflamed tissue with Crohn's disease were shown to have different roles in the pathogenesis of inflammation.

[Iatrogenic biliary tract injuries]. / Iatrogene galdevejslaesioner.

From 1984 to 1986 The Medico-Legal Council was heard concerning four cases of iatrogenic lesions of the common bile duct during cholecystectomy. The Council's statements show that lesions of the common bile duct or the common hepatic duct during otherwise uncomplicated, elective cholecystectomy are considered surgical malpractice and not accidental mishaps.

Effects of omeprazole on acid secretion and acid-related symptoms in patients with Zollinger-Ellison syndrome.

In the Zollinger-Ellison syndrome, symptoms and complications are due to hypersecretion of acid, and the first therapeutic step is to suppress the acid secretion. Long-term treatment with histamine H2-receptor antagonists was compared with omeprazole treatment. A total of 30 consecutive ZES patients were treated continuously with H2-receptor antagonists. During long-term treatment, a marked tachyphylaxis was noted, more than 50% of the patients had periods of dyspepsia, recurrent ulcers were found in 10 patients and in 16 a decline in the action of the H2-receptor antagonist required a change to omeprazole after a median duration of 36 months. A total of 22 patients were treated with omeprazole. During long-term treatment, the dose could be reduced slightly. Inhibition of acid secretion was maintained in all cases, and none had dyspeptic symptoms. The median duration of treatment was 18 months, with a range of 1-120 months (H2-receptor antagonists) and 27 months with a range of 1-66 months (omeprazole). No side-effects were seen with omeprazole.

Gastrin content and gastrin release. Studies on the antral content of gastrin and its release to serum during stimulation by food.

To examine the release of gastrin by food from antral mucosa eight patients were stimulated for 30 minutes by instillation of bovril during gastroscopy. Bovril caused a steady increase in serum concentrations of gastrin and an acute fall in the antral content of gastrin to 42+/-8.4 per cent after 10 minutes. After 10 minutes the antral content increased again towards the basal values. No change in gastrin components could be detected; component III (gastrin-17) constituted more than 95 per cent of the antral gastrins throughout the 30-minute period. The serum gastrin response to a steak meal was higher in 22 duodenal ulcer patients than in nine young normal subjects and it was higher postoperatively in eight patients studied before and after truncal vagotomy. In the duodenal ulcer patients whith the highest antral content of gastrin, the serum response to food was higher only during the early phase of the feeding response. It is concluded that the gastrin content of the antral mucosa represents an acute releasable pool of gastrin-17, which contributes only to the first 10-15 minutes of the feeding response. It does not reflect the total amount of gastrin released into the circulation during feeding.

Gastrin response to food after three types of intestinal shunt operations for obesity.

In a retrospective study the basal and food-stimulated serum concentrations of gastrin and gastric secretion of acid were studied in 28 patients following three types of intestinal shunt operation for obesity. In each type 48 cm of functioning small intestine was preserved, but the ratio between functioning jejunum and ileum was different. The basal and stimulated concentrations of gastrin in serum were significantly higher in patients with the shortest jejunum in function. There was no difference in the gastric acid output. The study suggests that gastrin participates in evoking the gastric hypersecretion of acid which follows massive bowel resection or bypass. Deprivation of a hormonal inhibitory substance from the upper jejunum may be responsible for the increased serum gastrin concentration.

The clinical diagnosis of the Zollinger-Ellison syndrome.

Recent clinical experiences with 34 Z-E patients indicates that the clinical features and course of the syndrome is less dramatic than described originally. Eighty-five per cent of the patients presented stories of abdominal complaints lasting more than five years and resembling the complaints presented by duodenal ulcer patients (DU). Ulcers were present in 91 per cent of the patients. Fifty-one per cent had either ectopic or multiple ulcers. One third had a single duodenal ulcer resembling an ordinary ulcer. No patients died from complications to the ulcer diathesis. Marked hypersecretion of acid and gastrin was present in the ZE group (BAO:33.7 +/- 7.4; PAO:62.8 +/- 6.1 meq H+/h; gastrin: 5094 pmol/l), but because of great individual variation in the ZE, some overlapping with the acid and gastrin measurements of the DU was seen. The diagnostic value of provocative tests using secretin, calcium, glucagon and food stimulations demonstrated a considerable overlapping between the two groups, indicating that these tests are of little clinical value. Tumours were found in half the patients, revealing malignancy in ten. The ZE can be diagnosed in most cases by combining symptomatology, with measurements of acid and gastrin.