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Biomedical subjects

H Ahlman

Publications and source records attributed to H Ahlman.

At least 73 records · Page 4Linked to original sources
PubMed1996

[Glucagonoma. A tumor disease with multiple clinical manifestations].

Glucagon-producing neoplasms are rare pancreatic tumours that may give rise to a characteristic syndrome including, diabetes and typical skin manifestations (necrolytic migrating erythema). Dermatological problems are often the first signs of the disease and the diagnosis is easily overlooked. In most series reported to date, glucagonomas had already metastasized at diagnosis, which means that curative surgery was possible to perform in less than half of the patients. To increase awareness of glucagonoma symptomatology a review of the syndrome is presented together with the clinical histories of three patients, recently treated. These cases illustrate aspects of modern diagnosis and treatment.

Adult↗
PubMed1996

The effect of vagotomy on enterochromaffin-like cells in Mastomys natalensis.

The effect of vagotomy on the development of ECL cell tumours was analyzed during drug-induced hypergastrinemia in Mastomys natalensis, a rodent prone to develop ECL cell tumours. Untreated animals were compared with animals receiving the histamine2-receptor blocker loxtidine (LOX) and with animals subjected to unilateral subdiaphragmatic vagotomy prior to loxtidine treatment (VAG+LOX). Loxtidine (2g/l) was administered in drinking water for 48 weeks to allow multiple ECL cell carcinoids to develop. Plasma gastrin levels were increased in LOX animals (94 +/- 31 pmol/l) and in VAG+LOX animals (181 +/- 59 pmol/l) compared to controls (45 +/- 4 pmol/l). Corpus weight and oxyntic mucosal thickness was almost doubled in all loxtidine-treated animals and the density of mucosal endocrine cells was increased by 65% in the LOX group and by 135% in VAG+LOX animals. No significant differences in mucosal thickness and endocrine cell density were seen when denervated and intact parts of the stomach were compared. In the VAG+LOX animals endocrine cell neoplasia was seen in 60% and dysplasia in 40% of animals compared to 40% neoplasia, 45% dysplasia and 15% hyperplasia in LOX animals. The frequency of neoplastic and dysplastic lesions did not differ between denervated and intact parts of the stomach. Untreated animals showed no neoplastic or dysplastic lesions. It is concluded that unilateral vagotomy has no protective effect on the development of ECL-cell tumours in Mastomys during hypergastrinemia, as opposed to previous studies in the rat.

Animals↗
PubMed1996

Treatment of liver metastases of carcinoid tumors.

Liver metastases imply a major problem in patients with carcinoid tumors. Patients with localized disease should always undergo resection for cure. Patients with distant metastatic disease can also undergo resection for potential cure or symptom palliation because of the slow growth rate of many carcinoid tumors. In patients with the midgut carcinoid syndrome and bilobar hepatic disease we have performed primary surgery to relieve such symptoms as intestinal obstruction and ischemia, followed by successive embolizations of the hepatic arteries to reduce functional tumor burden in the liver. For optimal palliation, all patients with residual tumor were treated by octreotide. In a consecutive series of 64 patients with the midgut carcinoid syndrome we thus attained a 5-year survival rate of 70%. Fourteen of the patients underwent intentionally curative surgery (e.g., primary surgery followed by liver surgery). Of these patients, none died from their tumor disease during the period of study. The value of adjunctive interferon therapy is currently under evaluation.

Antineoplastic Agents, Hormonal↗
PubMed1996

Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction.

Sixty-four consecutive patients with disseminated midgut carcinoids were treated during an 8-year period according to a single clinical protocol aimed at aggressive tumor reduction by surgery alone or with subsequent hepatic artery embolization. All patients had markedly elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) levels (581 +/- 79 micromol/24 h) and hormonal symptoms. Fourteen patients (22%) reached anatomic and biochemical cure by surgery alone. At follow-up, the mean 5-HIAA levels were still normal after 69.0 +/- 6. 2 months; two patients had died from unrelated causes. With the introduction of somatostatin receptor scintigraphy, subclinical disease was diagnosed in 7 of these 14 patients. Forty patients with bilobar hepatic disease underwent embolization in combination with octreotide. In this group, 5-HIAA levels were still reduced by 55% after 71 +/- 11 months of follow-up, and the 5-year survival was 56%, estimated from the total death hazard function. After embolization, two subgroups could be identified with marked differences in their long-term response to treatment. Ten patients were not embolized owing to complicating diseases. The 5-year survival for the entire series was 58%. A significantly increased risk of cardiovascular deaths was seen, which underlines the importance of total survival analysis in a disease with multiple hormonal effects. It is concluded that an active surgical approach must be recommended to patients with the midgut carcinoid syndrome. In patients with bilobar hepatic disease, embolization combined with octreotide treatment markedly reduced the 5-HIAA excretion and suggested a prolonged 5-year survival.

Adult↗
PubMed1996

Neuroendocrine insights from the laboratory to the clinic.

BACKGROUND: The interaction between adrenergic nerves and enterochromaffin (EC) cells was studied in health and disease using animal models and patients with the midgut carcinoid syndrome. METHODS: The methods included morphological techniques (fluorescence microscopy/cytofluorimetry, electronmicroscopy), experimental models (in vivo/in vitro nerve stimulation, pharmacological analyses, axonal transport, tumor transplantation, tumor cell cultures) and clinical tests (pentagastrin provocation, octreotide scintigraphy). RESULTS: From vagal nerve stimulation studies it was clear that activation of adrenergic fibers could release serotonin (5-HT) from EC cells, which led to the mapping of a vagal adrenergic pathway. Ultrastructurally a direct innervation of EC cells was demonstrated. It was confirmed in vitro that adrenoceptors controlled the release of 5-HT; it was maintained in neoplasia as studied in the tumor models. The tumor cells shared several functional and morphological characteristics with adrenergic neurons and exerted trophic actions on neurons grown in co-culture. CONCLUSIONS: Pentagastrin provocation of 5-HT release in carcinoid patients may be mediated via release of catecholamines from the adrenals in turn activating adrenoceptors on tumor cells. Pretreatment with a somatostatin analog can reduce these reactions and thus minimize the risk for carcinoid crisis during surgery.

Adrenergic Fibers↗
PubMed1996

Intraoperative detection of somatostatin-receptor-positive neuroendocrine tumours using indium-111-labelled DTPA-D-Phe1-octreotide.

After injection of 111In-labelled DTPA-D-Phe1-octreotide, intraoperative tumour localisation was performed using a scintillation detector in 23 patients with neuroendocrine tumours. Count rates from suspect tumour lesions and adjacent normal tissue were expressed as a ratio before (Rin situ) and after (Rex vivo) excision. 111In activity concentration ratios of tumour tissue to blood (T/B) were determined in a gamma counter. In patients with midgut carcinoids, (all scintigraphy positive), false Rin situ recordings were found in 4/29 macroscopically identified tumours. T/B ratios were all high (27-650). In patients with medullary thyroid carcinomas (eight out of ten scintigraphy positive), misleading Rin situ results were found in 4/37 macroscopically identified tumours. T/B ratios were lower (3-39) than those seen in midgut carcinoids. Two out of four patients with endocrine pancreatic tumours had positive scintigraphy, reliable intraoperative measurements and very high T/B ratios (910-1500). One patient with a gastric carcinoid had correct measurements in situ and ex vivo with high T/B ratios (71-210). In situ measurements added little information to preoperative scintigraphy and surgical findings using the present detection system. Rex vivo measurements were more reliable. The very high T/B ratios seen in midgut carcinoids and some endocrine pancreatic tumours would be favourable for future radiation therapy via somatostatin receptors.

Carcinoid Tumor↗
PubMed1996

The role of surgery in patients with advanced midgut carcinoid tumours.

64 consecutive patients with disseminated midgut carcinoids were treated over 8 years by active intervention. Their 5-year survival was 57.5%. 14(22%) attained anatomical and biochemical cure by surgery alone. Their mean 5-hydroxindoleacetic acid (5-HIAA) levels were still normal after 69 +/- 6.2 months of follow-up. Subclinical disease was diagnosed in 7/14 patients using somatostatin receptor scintigraphy; subsequent re-exploration of 6 led to scintigraphically proven cure in 5.40 patients with bilobar hepatic disease underwent embolisation in combination with octreotide; their 5-HIAA levels were still reduced by 55% after 71 +/- 10 months of follow-up and their estimated 5-year survival was 56%. More specifically, those with good radiological response on computerised tomography (> 50%) had a pronounced reduction of 5-HIAA levels (81%) and low mortality, while those with poor radiological volume reduction had a limited reduction of 5-HIAA levels (28%) and a much higher mortality (death by tumour or cardiovascular disease). 10 patients were not embolised due to complicating diseases and had a very poor 5-year survival. The increased risk of cardiovascular death underlines the importance of total survival analysis in patients suffering from a disease with multiple hormonal effects.

Adult↗
PubMed1996

Radioisotope-guided surgery in patients with neuroendocrine tumours.

We evaluated a hand-held scintillation detector for intra-operative localisation of somatostatin-receptor-positive tumours in situ, and after excision, as an addition to preoperative scintigraphy with [111In-DTPA-Phe1]octreotide. Using the hand-held detector, the suspect tumour/normal tissue ratio R(in situ) between measurements was calculated for 23 patients with neuroendocrine tumours. The count rates of excised tumour and normal tissue were also measured ex vivo and their ratio R(ex vivo) was calculated. In midgut carcinoid (MC) patients (all scintigraphy positive), 4/29 macroscopically identified tumours gave false R(in situ). Tumour/blood 111In activity (T/B) ratios measured in a gamma counter were all high (27-650). In patients with medullary thyroid carcinoma (8/10 scintigraphy positive), misleading R(in situ) were found in 4/37 macroscopically identified tumours. T/B ratios were lower (3-39) than those seen in MC patients. 2/4 patients with endocrine pancreatic tumours (EPTs) had positive scintigraphy, reliable intra-operative measurements, and very high T/B ratios (910-1,500). 1 patient with a gastric carcinoid had correct R(in situ) and R(ex vivo), with high T/B ratios (71-210). 1 patient with sporadic insulinoma had negative scintigraphy and 1 patient with neuroendocrine carcinoma of the uterus also had low T/B ratios. In most cases, in situ measurements added little information to preoperative scintigraphy and surgical findings. The very high T/B ratios seen in MC tumours and some EPTs seem promising for future radiotherapy via somatostatin receptors.

Carcinoid Tumor↗
PubMed1996

Histidine decarboxylase expression and histamine metabolism in gastric oxyntic mucosa during hypergastrinemia and carcinoid tumor formation.

Histamine is an important stimulator of gastric acid secretion. In experimental animals, inhibition of acid secretion by long term histamine2 receptor blockade causes hypergastrinemia, proliferation of enterochromaffin-like (ECL) cells, and formation of histamine-producing gastric carcinoids. The aim of this study was to examine the role of gastrin in histamine synthesis and metabolism of the oxyntic mucosa of normal, hyperplastic, and carcinoid-bearing Mastomys natalensis. Administration of exogenous gastrin to normal animals increased histidine decarboxylase (HDC) messenger RNA (mRNA) expression in the oxyntic mucosa within 30 min, indicating that gastrin stimulates histamine synthesis by regulating HDC mRNA abundance. Endogenous hypergastrinemia, induced by short term histamine2 receptor blockade (loxtidine) for 3-29 days, did not induce tumors, but enhanced the expression of HDC mRNA (2- to 4-fold elevated) and histamine contents (2-fold elevated) in the oxyntic mucosa. Long term histamine2 receptor blockade (7-21 months) resulted in sustained hypergastrinemia and ECL tumor formation. Tumor-bearing animals had a 4-fold increase in HDC mRNA expression and histamine contents of the oxyntic mucosa. Urinary excretion of the histamine metabolite methyl-imidazole-acetic acid was 2-fold elevated. Tumor-bearing animals recovering from histamine2 receptor blockade were normogastrinemic and had normal levels of HDC mRNA and histamine in the oxyntic mucosa as well as normal excretion of methyl-imidazole-acetic acid. The results indicate that ECL cell carcinoids developing during hypergastrinemia are well differentiated tumors that respond to high gastrin levels with increased histamine synthesis and secretion.

Animals↗
PubMed1996

Systemic radionuclide therapy using indium-111-DTPA-D-Phe1-octreotide in midgut carcinoid syndrome.

A 55-yr-old woman with a midgut carcinoid syndrome due to metastatic spread of an ileal tumor to the liver, paraortic and mediastinal lymph nodes and to the skeleton was given systemic radionuclide therapy with 111In-DTPA-D-Phe1-octreotide. Before therapy, dosimetric calculations were performed on whole-body scintigraphs and 111In retention was shown to be long-lasting. Excretion was mainly seen during the first 24 hr after injection; thereafter whole-body retention remained stationary at 30%. Indium-111 activity in tumor biopsies and blood was measured using a gamma counter. Very high tumor-to-blood ratios were obtained: 150 for the primary tumor and 400-650 for liver metastases, which further justified radiation therapy. Indium-111-DTPA-D-Phe1-octreotide treatment was given on three separate occasions (3.0, 3.5 and 3.1 GBq) 8 and 4 wk apart. After each therapy, the patient experienced facial flush and pain over the skeletal lesions followed by symptomatic relief, even though no objective tumor regression was found radiologically after 5 mo. After initiation of octreotide treatment, there was a 14% reduction of the main tumor marker, urinary 5-HIAA. After three subsequent radionuclide therapies, there was a further 31% reduction of 5-HIAA levels. No adverse reactions, other than a slight decrease in leukocyte counts, were seen. The mean absorbed radiation dose after the three treatments was estimated to be about 10-12 Gy in liver metastases and 3-6 Gy in other tumors, depending on the size and location of the metastases. Assuming internalization of 111In into tumor cells and a radiobiological effect from short range Auger and conversion electrons, there might be a therapeutic effect on the tumor.

Female↗
PubMed1996

Internalization of indium-111 into human neuroendocrine tumor cells after incubation with indium-111-DTPA-D-Phe1-octreotide.

UNLABELLED: Neuroendocrine tumor cells frequently overexpress somatostatin receptors at their cell surfaces. To evaluate the possibility of using the somatostatin analog 111In-DTPA-D-Phe1-octreotide for radiation therapy, we studied the binding and subsequent internalization of 111In into three types of cultured human neuroendocrine tumor cells. METHODS: Primary cultures of gastric carcinoid, midgut carcinoid and glucagonoma cells were incubated with 111In-DTPA-D-Phe1-octreotide and cell-surface bound, internalized and released 111In activity was measured. Electron microscopic autoradiography was also performed. RESULTS: All three cell types specifically (80%-95%) bound 111In-DTPA-D-Phe1-octreotide and internalized 111In. After 1 hr pulse incubation with 111In-DTPA-D-Phe1-octreotide, there was an initial decrease in intracellular 111In to about 50% during the subsequent 6-hr incubation. Almost no further release was observed during the remaining 18-42 hr studied. Autoradiography showed that the internalized 111In was found in the cytoplasm and nucleus in the midgut carcinoid cells. CONCLUSION: Indium-111 DTPA-D-Phe1-octreotide might be useful for radiation therapy of patients with surgically incurable tumors having high somatostatin receptor densities.

Autoradiography↗
PubMed1995

Are enterochromaffinlike cell tumours reversible? An experimental study on gastric carcinoids induced in Mastomys by histamine2-receptor blockade.

A rapid induction of enterochromaffinlike (ECL) cell tumours has been shown in Praomys (Mastomys) natalensis subjected to histamine2-receptor blockade. In the present study the reversibility of ECL cell proliferation induced by acid inhibition was investigated. Short-term treatment (8 weeks) with the histamine2-receptor antagonist loxtidine caused a moderate hypergastrinemia, accompanied by a minor increase in histamine contents and a 2-fold increased volume density of the endocrine cells in gastric oxyntic mucosa. Eight weeks after withdrawal of treatment the volume density of endocrine cells was normalised as were the tissue levels of histamine, indicating a total reversibility of ECL cell hyperplasia. Long-term treatment (24 weeks) caused severe changes in the endocrine cell population of the oxyntic mucosa with neoplasia (5/21), dysplasia (11/21) and nodular hyperplasia (5/21). The endocrine cell density increased twofold and tissue histamine levels fourfold. 24 weeks after cessation of treatment, the endocrine cell density had decreased to 136% of controls, while histamine concentrations were normalised. The frequency of invasive carcinoids after recovery (4/23) differed only slightly from that seen after treatment for 24 weeks (5/21). Dysplastic lesions were only seen in 1/23 and hyperplastic lesions were of less severe type after recovery. The results demonstrate that ECL cell hyperplasia and dysplasia, induced by acid inhibition, are reversible after cessation of treatment. However, ECL cell tumours did not disappear, within the given observation period. One may therefore speculate that ECL cell proliferation is no longer reversible once the neoplastic (transformed) phenotype has developed.

Animals↗
PubMed1995

Expression of transforming growth factor alpha and its receptor in human neuroendocrine tumours.

Transforming growth-factor-alpha (TGF-alpha) is a 50-amino-acid polypeptide that binds to the epidermal growth factor (EGF) receptor and stimulates cell growth. It has been suggested that enhanced production of TGF-alpha and EGF receptors by tumour cells promote tumour-cell growth by autocrine mechanisms. In the present study we have investigated the expression of TGF-alpha and EGF receptors in human neuroendocrine tumours, including midgut carcinoid tumours, phaeochromocytomas and medullary thyroid carcinomas. TGF-alpha expression was demonstrated in biopsies of all tumours examined (n = 30) and EGF receptors in a majority of tumours by Northern analysis and/or immunocytochemistry. Expression of TGF-alpha and EGF receptors was also demonstrated in primary cultures of tumour cells. Carcinoid tumours and phaeochromocytomas in culture secreted detectable amounts of TGF-alpha into the culture medium (400-700 pM). The amount of secreted TGF-alpha could be suppressed by octreotide treatment in individual tumours. Administration of exogenous TGF-alpha stimulated carcinoid tumour growth in vitro as determined by the DNA contents of cell cultures. The growth-stimulatory effect of TGF-alpha could be partially blocked by the use of neutralizing anti-EGF receptor monoclonal antibodies (MAbs). In conclusion, several human neuroendocrine tumours express both TGF-alpha and EGF receptors in in vivo and in vitro, suggesting that TGF-alpha may regulate tumour-cell growth by autocrine mechanisms.

Adrenal Gland Neoplasms↗
PubMed1995

Accumulation of natural killer cells after hepatic artery embolisation in the midgut carcinoid syndrome.

Eleven patients with disseminated midgut carcinoid tumour disease were subjected to hepatic artery embolisation. In six patients, lymphocytosis with a predominance of NK cells occurred and the cytotoxic activity of isolated lymphocytes increased. A relation between NK cell accumulation and subsequent radiological and biochemical response was observed, and it is suggested that anti-tumour mechanisms other than ischaemia may contribute to the therapeutic response in these patients.

Cytotoxicity, Immunologic↗
PubMed1995

Indium-111 activity concentration in tissue samples after intravenous injection of indium-111-DTPA-D-Phe-1-octreotide.

METHODS: Indium-111 activity concentrations in human tumor and normal tissue samples were determined at 24, 48 and 120 hr after i.v. injection of 111In-DTPA-D-Phe-1-octreotide. Fourteen patients were included in the study. Seven patients had medullary thyroid carcinoma, four had midgut carcinoid tumors, two had endocrine pancreatic tumors and one had chronic pancreatitis. RESULTS: For midgut carcinoids, the tumor-to-blood ratio was 51:220, for medullary thyroid carcinoma 4:39, and for two endocrine pancreatic tumors 6 and 1500. Tumor-to-muscle ratios varied between 1 and 1200 and tumor-to-fat between 2 and 1500 depending on tumor type. CONCLUSION: The sometimes extremely high tumor-to-normal tissue ratios present the possibility for use of radiolabeled octreotide for radiation therapy of somatostatin receptor positive tumors.

Abdominal Neoplasms↗
PubMed1994

Oddi: the paradox of the man and the sphincter.

Ruggero Oddi was born of a modest family in the small town of Perugia, Italy, in 1866. While still a young medical student, he identified the sphincter and in addition characterized its physiological properties. At the early age of 29 years, he was appointed as the director of the Physiological Institute at Genoa, but a dalliance with drugs and fiscal improprieties resulted in his being relieved of this eminent position in Italian Physiology. He subsequently sought employment as a physician in the Belgian colonial medical service and briefly spent time in the Congo. The deterioration of his physical status and his use of Vitaline, a homeopathic preparation, led to the demise of his medical career. For reasons that are unclear, he then traveled to Africa where he died in Tunisia. In the last 50 years, the use of sophisticated methodology has allowed delineation of aspects of the neural and hormonal regulatory mechanisms of the sphincter. Its exact role in disease has not been determined, although its relationship to the putative entity of biliary dyskinesia has been suggested. The paradox of both the sphincter and its original discoverer remain to be resolved.

History, 19th Century↗