Hyperthermic liver perfusion chemotherapy in the foregut carcinoid syndrome.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
H Ahlman
Publications and source records attributed to H Ahlman.
[All patients in Sweden with metastazing carcinoid tumors in the small intestine will be studied].
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Carcinoid Tumor↗
The effect of a somatostatin analogue on the release of hormones from human midgut carcinoid tumour cells.
The use of a somatostatin analogue (SMS 201-995) has greatly facilitated the treatment of patients with the midgut carcinoid syndrome. Clinical studies have shown that SMS reduces the peripheral levels of tumour-produced serotonin (5-HT) and tachykinins, e.g. neuropeptide K (NPK), basally and after pentagastrin provocation. Some studies have indicated an inhibitory effect of SMS on tumour cell growth as well. In the present study we have investigated the effects of SMS on four different human midgut carcinoid tumours maintained in long term culture. Media levels of 5-HT and NPK-LI in tumour cell cultures decreased rapidly during incubation with SMS (10(-8)-10(-10) M) in all four tumours studied without evidence for tachyphylaxis (up to 6 weeks observation period). SMS treatment (10(-8) M) during 4 days reduced the media concentrations of 5-HT by 56%, while the intracellular contents of 5-HT were decreased by 27% indicating dual inhibitory effects on synthesis and secretion of 5-HT from tumour cells. The DNA contents of cultures were not affected by SMS (10(-8) M or 10(-10) M) treatment for 4 or 14 days. When tumour cell cultures were challenged with isoprenaline (IP) (10(-6) M) no reduction of the IP induced release of 5-HT could be detected after pretreatment of tumour cell cultures with SMS (10(-8) M) for 1 h, 4 h or 4 days. These studies provide evidence for a direct action of the somatostatin analogue on midgut carcinoid tumour cells, reducing both synthesis and secretion of hormones from tumour cells. This effect appears not to be related to inhibition of tumour cell growth. The inhibition of 5-HT secretion from tumour cells by SMS seems to operate via a second messenger system different from the one mediating the beta-adrenoceptor stimulated release of 5-HT.
Aged↗
Production of transferable neuronotrophic factor(s) by human midgut carcinoid tumour cells; studies using cultures of rat fetal cholinergic neurons.
A co-culture system was established between human midgut carcinoid tumour cells and rat fetal cholinergic neurons. In monocultures in serum-free media, only tumour cells survived, while neurons deteriorated. In serum-free co-cultures, neurons displayed outgrowth of neuritic processes. Neurons of neuronal serum-free monocultures thrived if supplemented with conditioned media from tumour cell cultures grown serum-free. This indicates that tumour cells produce transferable growth factor(s) with potent neuronotrophic actions. Immunocytochemical studies indicate that this growth factor resembles nerve growth factor immunologically, since tumour cells were strongly immunoreactive after incubation with a rabbit anti-nerve growth factor antiserum, and furthermore expressed immunoreactive nerve growth factor receptors.
Animals↗
Management of disseminated midgut carcinoid tumours.
Forty-one patients with disseminated midgut carcinoid tumours were treated over a 6-year period according to a strict programme including primary surgical treatment. In 10 patients, a total remission of the disease was obtained. Patients with bilobar hepatic disease had ischaemic treatment of their liver metastases by hepatic arterial embolisation after primary surgical and medical treatment (low dose octreotide). Thus, by combining surgical, radiological and medical treatment modalities, we wanted to offer these patients optimal palliation. This treatment programme resulted in good symptomatic relief in all patients accompanied by a marked reduction in 5-hydroxyindoleacetic acid (5-HIAA) levels. At recurrence of symptoms in combination with rising 5-HIAA levels, embolisation was repeated. Ten of the treated patients have deceased during the observation period, but only 5 from their carcinoid disease.
Adult↗
Somatostatin analogue and tissue cultures in the study of a human malignant glucagonoma.
A patient with metastasizing glucagonoma producing multiple molecular forms of glucagon is reported. The patient responded to symptomatic treatment with a somatostatin analogue (SMS 201-995). Glucagonoma tumour cells were studied in two tissue culture systems: intraocular transplants of immunosuppressed rats and long-term cell cultures. In both systems, several region-specific glucagon antisera gave a positive immunoreaction with tumour cells indicating synthesis of multiple molecular species. Intraocular tumour transplants released glucagon into the chamber fluid. In animals with unilateral transplants, glucagon was also detected in the contralateral eye chamber, indicating passage from the transplants via unknown mechanisms. Treatment of tumour cells during culture with SMS 201-995 inhibited rapidly the spontaneous release of glucagon without evident cytotoxic effects. The inhibitory effect decreased with time.
Adenoma, Islet Cell↗
Is the CCK-8 induced relaxation of the feline sphincter of Oddi mediated by VIP neurons?
The regional, intraarterial, injection of CCK-8 elicits reciprocal effects on the motility of the extrahepatic biliary tree in the cat: the contraction of the gallbladder and a relaxation of the sphincter of Oddi as well as of the duodenal wall. After neural blockade with tetrodotoxin the responses of the sphincter to CCK-8 were blocked, and the responses of the gallbladder were markedly reduced. After the regional administration of a VIP antiserum the sphincter relaxation in response to CCK-8 was blocked. Immunocytochemically it was demonstrated that the feline sphincter contains a rich VIP-ergic innervation, while CCK-like immunoreactivity was found only in mucosal endocrine cells. The results indicate that CCK-8 selectively activates inhibitory VIP neurons innervating the sphincter. After the administration of a nonpeptide CCK-receptor antagonist, the CCK-8 induced motor responses of both the sphincter and the gallbladder were markedly reduced. This indicates that blockade of CCK-8 receptors involves muscular as well as neural CCK-receptors.
Animals↗
Transport of serotonin from the rat jejunal lumen into mesenteric veins in vivo.
The transport of labelled (hot) and non-labelled (cold) serotonin (5-HT) into the mesenteric venous circulation was studied after instillation of test solutions into an isolated jejunal loop of anaesthetized rats. After instillation of [3H]H2O and [14C]5-HT there was an almost parallel appearance of the isotopes in mesenteric venous blood. After instillation of 5-HT a marked early increase of the total amounts of cold 5-HT was observed in mesenteric veins compared with animals instilled with saline only. In a third type of experiment the label was detected in mesenteric venous whole blood after instillation of [3H]5-HT into the gut lumen. After hydrolysis of blood cells and protein precipitation the samples were fractionated and determined for 5-HT and metabolites. Only 5-HT was detected in these fractions. The label was present within 5-HT peaks in three out of eight animals. The experiments indicate rapid transport of 5-HT (or metabolites) across the rat jejunal mucosa. These substances may be bound to a binding protein in platelets since the isotope was detected in whole blood but more seldom in supernatants after hydrolysis and precipitation.
Animals↗
The role of gastric resection in the management of multicentric argyrophil gastric carcinoids.
A patient with pernicious anemia, atrophic non-antral gastritis, hypergastrinemia, and widespread hyperplasia of enterochromaffin-like cells and manifest enterochromaffin-like cell carcinoma was followed up during 39 months, including 15 months after gastric resection. In this case normalization of gastrin levels did not prevent the development of multiple gastric carcinoids in the fundic mucosa, suggesting that factors other than gastrin are of importance in the pathogenesis.
Anemia, Pernicious↗
Coexistence of delta sleep-inducing peptide and serotonin in midgut carcinoid tumour cells in vivo and in vitro.
By immunocytochemistry, delta sleep-inducing peptide (DSIP) was demonstrated to coexist with serotonin (5-HT) in a majority of midgut carcinoid tumour cells studied in biopsies and long-term cell cultures. Tumour cell colonies were characterized ultrastructurally and by confocal laser microscopy. The cultures produced several DSIP-like peptides chromatographically separated from culture media. DSIP has not yet proved to be a useful tumour marker clinically. Provocation with pentagastrin in patients with midgut carcinoid syndrome resulted in increased peripheral levels of 5HT, but not of DSIP.
Biopsy↗
Presence of nerve growth factor-like immunoreactivity in carcinoid tumour cells and induction of a neuronal phenotype in long-term culture.
Mid-gut carcinoid tumour cells expressed a neuronal phenotype, observed and characterized immunocytochemically in long-term culture. Initially the culture contained a main population of spherical tumour cells with granules immunopositive for serotonin (5-HT) and tachykinins (TK). Production and secretion of these substances into media was verified biochemically. Cytoplasmic granules with 5-HT-like immunoreactivity (5-HT-LI) were markedly reduced during culture, while granules with TK-LI were unchanged in number, corresponding to the biochemical findings. After a few days in culture, tumour cells were flattened and fine neurite-like processes extended. After 2-3 weeks many endocrine tumour cells had converted to neuron-like cells with slender cell processes containing granules with TK-LI. Varicose enlargements and apparent growth cones were observed. When neurites were extended, 50-80% of the neuron-like cells were positive with antisera against the neurofilament triplet. Cells of both endocrine and neuronal phenotypes were positive with antisera against tetanustoxin, Thy 1-antigen, neuron-specific enolase, synapsin and a synaptic vesicle protein (p 38) supporting the concept of these tumour cells as para-neurons. Intermediate filaments, studied with monoclonal anti-vimentin, were found in all cells. Filaments were also observed ultrastructurally. Initially, nerve growth factor (NGF)-LI was found in granules of all spherical tumour cells. When neuritic processes were extended, the cells appeared to lose these granules. After 40 days in culture, NGF-LI was absent or very sparse. The studies indicate autocrine secretion of a growth factor, reacting with the NGF antiserum, by cultured mid-gut carcinoid tumour cells inducing a neuronal phenotype with enhanced NF and TK synthesis and suppressed 5-HT synthesis. In bioassay systems the culture media caused a delayed neurite reaction on PC12 cells, but no reaction on chick ciliary ganglion cells, indicating that the factor is not authentic NGF.
Carcinoid Tumor↗
Concomitant occurrence of an adrenal ganglioneuroma and a contralateral pheochromocytoma in a patient with von Recklinghausen's neurofibromatosis. An immunocytochemical study.
This report presents concomitant occurrence of an adrenal ganglioneuroma and a contralateral pheochromocytoma in a patient with von Recklinghausen's disease. The patient's daughter also has cutaneous neurofibromatosis and an adrenal medullary tumor indicating that the observed "three component disease" may represent an inherited neurocristopathy. Immunocytochemically the ganglioneuroma showed a positive reaction with a tyrosinhydroxylase antiserum, but a negative reaction with a dopamine-beta-hydroxylase antiserum, suggesting the capacity of dopamine synthesis. Frequent ganglion cells were immunopositive against neuropeptide Y, but occasional ganglion cells were also positive against enkephalin and substance P. Adrenergic nerve fibers were abundant in the Schwann cell portion of the tumor, but peptide containing nerve cell processes were also demonstrated.
Adrenal Gland Neoplasms↗
Clinical and experimental studies on a midgut carcinoid tumor.
This study reports on a patient with a midgut carcinoid discovered due to the occurrence of a subcutaneous metastasis that caused symptoms. The histopathologic diagnosis of a carcinoid was confirmed by light and electron microscopic and immunocytochemical examination of the metastasis. The primary ileal tumors were only localized after the determination of serotonin in platelet-poor plasma/whole blood sampled at selective mesenteric vein catheterization. Tumor cells from lymph node metastases were studied in vitro, in intraocular heterotransplants, and in cell culture.
Animals↗
Adrenergic and VIP-ergic relaxatory mechanisms of the feline extrahepatic biliary tree.
Relaxatory mechanisms of the extrahepatic biliary tree were investigated in anesthetized cats allowing separate recordings of the sphincter of Oddi, gallbladder and duodenal wall. Regional intra-arterial administration of vasoactive intestinal peptide (VIP) elicited dose-dependent relaxatory motor responses, which were not influenced by blockade of cholino- or beta-adrenoceptors, but were most probably due to activation of VIP receptors at the smooth muscle membrane. Efferent electrical vagal nerve stimulation unmasked relaxatory motor responses after previous blockade of muscarinic cholinoceptors. The neural transmission did not involve beta-adrenoceptors but was effectively antagonized after additional blockade with hexamethonium. Since both nerve terminals and ganglion cells with VIP-like immunoreactivity were abundant in the feline sphincter of Oddi, VIP is one possible transmitter candidate of the postganglionic inhibitory neurons. Non-selective activation of beta-adrenoceptors by isoprenaline or selective activation of beta 2-adrenoceptors by terbutaline also induced a dose-dependent relaxation of these regions. On a molar basis, relaxation via beta-adrenoceptors was 40-50 times less potent than via VIP. Both types of beta-adrenergic relaxation were antagonized by propranolol. The terbutaline-induced responses were selectively antagonized by beta 2-adrenoceptor blockade. To evaluate the role of beta 1-adrenoceptors, non-selective stimulation with isoprenaline was given; this relaxation was little influenced by blockade of beta 2-adrenoceptors but was completely antagonized by propranolol. In all experiments using beta-adrenoceptor antagonists these drugs each increased the basal tone of the preparation suggesting release of tonic inhibition exerted via beta-adrenoceptors.
Animals↗
Intraocular transplants of a human gastrinoma in immuno-suppressed rats: morphological, chromatographic and functional studies.
Tissue pieces of a metastatic human gastrinoma (ultrastructural Type II) were successfully transplanted to the anterior eye-chamber of rats immunosuppressed with Cyclosporin A. Immunocytochemical investigation of the transplants showed evidence for preserved endocrine activity of tumour cells with immunoreactivity towards the C-terminal of the gastrin/cholecystokinin molecule. Studies of gastric acid secretion in tumour-bearing rats and sham-operated controls with chronic gastric fistulas showed that the basal acid output did not differ between the groups during 3 weeks of study. However, the stimulated gastric acid secretion decreased after 5 days in both groups to remain significantly depressed throughout the study, an effect probably due to Cyclosporin A treatment of the groups. The concentration of immunoreactive gastrin in plasma from rats with tumours in oculo was 5 times higher than in sham-operated rats. Gastrin-34 was the major immunoreactive component in both patient serum and rat plasma. An immunoreactive fraction corresponding to component I was found in the patient serum, but not in the rat plasma, although present in the chamber fluid. Components corresponding to gastrin-17 were found both in the patient serum and in the rat plasma. The chromatographic pattern of the tumour was similar to that in rat chamber fluid. The dominating component corresponded to gastrin-17, while gastrin-34 represented the quantitatively smaller component. Gastrin-34 was, however, relatively more abundant in the tumour extract than in the chamber fluid. The study also indicates that a gastrin-producing tumour transplanted in oculo in immunosuppressed rats may increase the rat plasma concentration of the same molecular forms of gastrin as seen in the clinical situation.
Adolescent↗
Survival of rat fetal cholinergic neurons co-cultured with human carcinoid tumour cells.
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Animals↗
VIP antisera inhibit the relaxatory motor responses of the feline sphincter of Oddi and gall-bladder induced by VIP or vagal nerve stimulation.
Regional administration of VIP elicited a dose-dependent relaxation of the feline sphincter of Oddi and gall-bladder. Relaxatory motor responses of these regions at efferent electrical stimulation of the vagal nerves were unmasked after atropine (resistant to propranolol but sensitive to hexamethonium). These findings in combination with the presence of a rich VIP-ergic innervation, including intrinsic VIP neurons, have made VIP a tentative post-ganglionic non-adrenergic, non-cholinergic neurotransmitter to these regions. The relaxatory motor responses elicited by VIP or vagal activation were selectively antagonized using regional administration of specific VIP antisera in support of this hypothesis.
Ampulla of Vater↗
The effects of octreotide on basal and stimulated hormone levels in patients with carcinoid syndrome.
The carcinoid syndrome, a common feature of small intestinal carcinoid tumors with liver metastases, includes flushing, diarrhea, bronchoconstriction, and right heart failure. The etiology of the carcinoid syndrome is not well understood, but serotonin seems to be involved in the diarrhea, whereas tachykinins may play a role in the flush reaction. In a double blind placebo-controlled study, we studied the effect of octreotide in 20 patients with midgut carcinoid tumors and liver metastases. A sc injection of 50 micrograms octreotide caused a significant (P less than 0.001) decrease in median plasma tachykinins and serum pancreatic polypeptide, GH, and insulin for up to 4 h. Administration of octreotide (50 micrograms, twice daily, sc) caused a 26% decrease in urinary 5-hydroxyindoleacetia acid excretion, but the number of flushing attacks or bowel movements did not change significantly. A typical flush was provoked by pentagastrin, and plasma tachykinin and serotonin levels were measured. The flush reaction was graded on a 10-point visual analog scale. Octreotide (50 micrograms, sc) given 45 min before flush stimulation prevented tachykinin release completely and significantly reduced the median flushing score from 8.5 to 2. Placebo administered in the same way did not prevent tachykinin release after pentagastrin administration. Thus, octreotide prevents pentagastrin-induced flushing and the related hormonal changes in patients with the carcinoid syndrome.
Aged↗