Biomedical subjects
Publications and source records attributed to H Ahlman.
The prevalence of the 985A>G mutation in the medium-chain acyl-CoA dehydrogenase gene was determined in the Swedish population. A heterozygote frequency of 1:127 was observed. Morbidity data indicate that most of the homozygotes with this mutation are not diagnosed and probably remain asymptomatic.
OBJECTIVE: To characterise the cholecystokinin (CCK) receptor subtypes in medullary thyroid cancer by measuring the expression of CCK-A and CCK-B/gastrin receptor mRNA. DESIGN: Open study. SETTING: Teaching hospital, Sweden. SUBJECTS: 6 patients with medullary thyroid cancer. INTERVENTION: Pentagastrin stimulation test and measurement of calcitonin concentration. Biopsy specimens were analysed using reverse transcription polymerase chain reaction (RT-PCR). MAIN OUTCOME MEASURE: Presence of CCK-A and CCK-B/gastrin receptors. RESULTS: All 6 patients with medullary thyroid cancer had positive pentagastrin tests preoperatively. CCK-B/gastrin receptors but not CCK-A receptors were detected by RT-PCR in all six biopsy specimens. By contrast, no CCK receptors were found in normal thyroid tissues or in other thyroid tumours (follicular adenoma, papillary carcinoma, or anaplastic carcinoma). CONCLUSION: The presence of CCK-B/gastrin receptors in medullary thyroid tumours may have important clinical implications.
Gastric carcinoid tumours can be divided into subtypes with a different pathogenesis and biological behaviour. Individualized surgical treatment of these tumour types is discussed. Liver metastases imply a major problem in patients with carcinoid tumours. Patients with distant metastases can undergo resection for potential cure, or for symptom palliation, due to the slow growth rate of many carcinoid tumours. In patients with the midgut carcinoid syndrome and bilobar liver metastases, interventional treatment by tumour removal and liver embolization followed by medical therapy (octreotide and/or interferon) seem to prolong survival and reduce hormonal symptoms. Patients with the foregut carcinoid syndrome may present special problems with life-threatening release of histamine during interventional treatment.
UNLABELLED: Attempts to detect tumors with intraoperative scintillation using tumor-binding radiopharmaceuticals have intensified recently. In some cases previously unknown lesions were found, but in most cases no additional lesions were detected. In this study the physical characteristics of three detector systems and their ability to detect tumors through accumulation of an 111In-labeled radiopharmaceutical were investigated. The first was a sodium iodide (NaI[TI]) detector; the second, a cesium iodide (CsI[TI]) detector; and the third, a cadmium telluride (CdTe) detector. METHODS: A body phantom and tumor phantoms (diameter 5-20 mm) made of water, agarose gel or epoxy with a density and attenuation coefficient similar to those of soft tissue were used to simulate a clinical situation. The activity concentration in the body phantom was based on reported values of 111In-octreotide in normal tissue in humans. The 111In activity concentration in the tumor phantoms varied from 3 to 80 times the 111In activity concentration in the body phantom. Data were processed to determine tumor detection levels. RESULTS: The NaI(TI) detector showed the lowest values for full width at half maximum because this detector had the best collimation, leading to a high ratio between counts from tumor and counts from background, i.e., small tumors could be detected. Because of high efficiency, the CsI(TI) detector sometimes required a somewhat shorter acquisition time to produce a statistically significant difference between tumor phantom and background. For deep-lying tumors the NaI(TI) detector was superior, whereas the CdTe detector was best suited for superficial tumors with a high activity concentration in the underlying tissue. CONCLUSION: At a maximum acquisition time of 30 s, almost all superficial tumors with a diameter of 10 mm or larger were detected if the ratio between the 111In concentration in the tumor and the 111In concentration in the background exceeded 3. However, in clinical situations, biologic variations in the uptake of 111In-octreotide in tumors and in normal tissue makes difficult the determination of a distinct detection level. For such clinical conditions, the NaI(TI) detector is the best choice because it has good resolution despite a lower efficiency. Documentation of detector characteristics is important so that clinicians can make an adequate device in relation to tumor location and receptor expression.
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Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. It has been difficult to establish a strict treatment program for ACC, and better treatment alternatives and diagnostic tools must be sought. Even though surgery is the treatment of choice, the role of surgery in advanced disease has been questioned. Eighteen consecutive patients were treated at our unit over a 22-year period (1975-1997). All patients underwent surgery and were followed by our protocol, which includes urinary steroid profiles, clinical examinations, analysis of steroid hormones, and radiologic investigations. Twelve patients received mitotane with drug concentration measurements to deliver an effective, nontoxic dose. The median duration of mitotane treatment was 12 months. Few side effects were observed. Four patients with low-stage tumors underwent second-look operations with no pathologic findings. Five patients were subjected to repeat operations, and the mean duration of the disease-free interval before repeat surgery for these patients was 59 months. There was a significant positive correlation between the disease-free interval and the observed survival after repeat surgery. Eleven patients with intentionally curative surgery had their urinary steroid profiles tested several times postoperatively. For five patients preoperative urine samples were also available. Steroid profiles indicated recurrent disease despite normal radiologic findings in two of these five patients. The follow-up ranged from 6 weeks to 24 years. The predicted 5-year survival was 58% according to the Kaplan-Meier method. We conclude that monitoring serum concentrations of mitotane makes long-term treatment possible with few side effects; steroid profile analysis can be used for early detection of tumor recurrence; and repeat surgery for recurrence is of value for patients with long disease-free intervals.
Several types of neuroendocrine tumor express high numbers of somatostatin receptors (sstr). We have compared the expression of sstr subtypes with the outcome of octreotide scintigraphy in patients with carcinoids and medullary thyroid carcinoma (MTC) in comparison with Hürthle cell tumors. The effect of sstr activation (octreotide treatment) on tumor markers was also studied in patients with disseminated carcinoid tumors. Six patients with carcinoid tumors (four midgut and two foregut), and three patients with thyroid tumors (one MTC, one Hürthle cell carcinoma, and one Hürthle cell adenoma) were studied. Octreotide scintigraphy visualized tumor sites in all nine patients. Macroscopic tumor was verified at these sites at subsequent surgical exploration. Using Northern blotting and subtype-specific riboprobes, sstr could be detected in all tumors examined. All five sstr subtypes were detected in most of the carcinoid tumors. All six carcinoids expressed sstr2. This was in contrast to the findings for the thyroid tumors analyzed, which also expressed several sstr subtypes but in some cases lacked expression of sstr2. This was also the case for normal thyroid tissue. Clinically, octreotide treatment of the patients with midgut carcinoid tumors resulted in palliation of hormonal symptoms accompanied by a significant reduction of urinary 5-HIAA levels (28-71%). These results indicate that carcinoid tumors frequently express all five sstr subtypes. The thyroid tumors also expressed multiple sstr but could lack expression of sstr2. Nevertheless, these tumors were visualized by octreotide scintigraphy, indicating that sstr2 expression is not a prerequisite for tumor imaging.
We have compared the expression of somatostatin receptor (sstr) subtypes with the outcome of somatostatin receptor scintigraphy and the effect of somatostatin receptor activation in patients with disseminated carcinoid tumours. Tumour tissues from nine patients with midgut carcinoids (ileal) and three patients with foregut carcinoids (gastric, thymic) were analysed using Northern blotting. Expression of somatostatin receptors was demonstrated in all tumours (12 out of 12), with all five receptor subtypes present in 9 out of 12 tumours. Somatostatin receptor scintigraphy using [111In]DTPA-D-Phe1-octreotide visualized tumours in all patients (12 out of 12). The 111In activity concentrations in tumour tissue (T) and blood (B) were determined in three tumours 1-7 days after injection of the radionuclide. The T/B 111In activity concentration ratios ranged between 32 and 651. Clinically, treatment with the long-acting somatostatin analogue octreotide resulted in marked symptom relief accompanied by a significant reduction in tumour markers, for example urinary-5-HIAA levels (28-71% reduction). Incubation of midgut carcinoid tumours in primary culture with octreotide (10 microM) resulted in a reduction in spontaneously secreted serotonin (45-71% reduction) and 5-HIAA (41-94% reduction). The results demonstrate that carcinoid tumours possess multiple somatostatin receptor subtypes and that somatostatin analogues such as octreotide, which preferentially bind to somatostatin receptor subtype 2 and 5, can be used in the diagnosis and medical treatment of these tumours. In the future, novel somatostatin analogues with subtype specific receptor profiles may prove to be of value for individualizing the treatment of disseminated carcinoid tumour disease.
A 50-year-old male presented with diabetes mellitus and Cushing's syndrome associated with a large mediastinal mass. The levels of serum cortisol were high (1500-1800 nmol/l) without diurnal variation. Plasma ACTH levels (200-250 ng/l) and urinary excretion of cortisol were also increased. The levels of these hormones did not change in response to stimulation with corticotrophin releasing hormone (CRH) or suppression with high doses of dexamethasone. The patient had an elevated baseline GH level (7.3 mU/l), and the levels of immunoreactive GH-releasing hormone (GHRH) in eight plasma samples were markedly increased (600-1500 ng/l). Circulating levels of IGF-1, chromogranin A and neuropeptide Y (NPY) were also increased. Computer-assisted tomography and octreotide scintigraphy revealed a large mediastinal tumour and metastases in the left supraclavicular fossa. During treatment with octreotide, the baseline GH level was decreased (to 4.4 mU/l), while the GH pulse height was unchanged. Surgical removal of most of the tumour tissue resulted in a further decrease in the baseline serum GH level to a value (1.6 mU/l) about 20% of that before treatment, while the pulse height and mean GH were affected to a lesser extent. Postoperatively, circulating levels of cortisol and IGF-1 decreased, and the patient exhibited clinical improvement. Histological examination showed a neuroendocrine tumour with characteristics consistent with a foregut carcinoid of thymic origin. Immunoreactive GHRH, ACTH and NPY, but not immunoreactive GH, were detected in 80-90% of the tumour cells and the three peptides appeared to be co-localized. In primary culture, cells from this tumour displayed calcium influx in response to GHRH or GH releasing peptide-6 (GHRP-6), while there were not such responses by cells from another carcinoid not producing GHRH, ACTH or NPY. These results demonstrate a rare case of ectopic production of GHRH, ACTH and NPY, and indicate that the tumour cells were responsive to GHRH and GHRP-6 as well as octreotide.
A case of sporadic, histamine-producing gastric carcinoid with liver metastases is reported. The patient was treated with somatostatin analogue (octreotide) combined with cortisone and blockade of histamine receptors prior to surgery, which included subtotal gastrectomy, excision of lymph node metastases and superficial liver metastases. Residual liver metastases were injected with ethanol. These interventions markedly reduced the urinary excretion of the main histamine metabolite (MelmAA). Eighteen months later combined immuno- and chemotherapy was initiated due to tumour progression and recurrent hormonal symptoms with good clinical results over 12 months. Scintigraphy, using 111In-DTPA-D-Phe1-octreotide, visualized somatostatin receptors (sstr) in primary tumour, lymph node metastases and liver metastases. The tissue/blood 111In concentration ratios of tumour biopsies were very high. Northern analyses confirmed expression of all subtypes of sstr1-5. Immunocytochemically, tumour cells were strongly positive for chromogranin A, histamine and vesicular monoamine transporter (VMAT) 2 (histamine transporter), but negative for VMAT 1, suggesting an origin from gastric enterochromaffin-like cells. In primary tumour cell cultures, histamine, 5-HTP and 5-HIAA, but not 5-HT, could be detected in conditioned culture medium, indicating a defective decarboxylation of the tryptamine precursor. This rare case of histamine-producing gastric carcinoid demonstrates that excellent symptom relief can be achieved despite disseminated disease, if active, multimodal treatment strategy is instituted. The presence of high numbers of sstr in tumour tissue also raises the possibility of receptor-guided radiotherapy.
Verification of the presence of somatostatin receptors on neuroendocrine tumour cells opened up unique diagnostic and therapeutic possibilities. Long-acting somatostatin analogues are currently used to alleviate symptoms of excessive hormone synthesis in patients with such tumours. Radiolabelled somatostatin analogues can be used both for high specificity and high sensitivity scintigraphic localisation of such tumours and for intraoperative scintillation detection. Detailed studies in patients and in tumour cells in vitro have shown 111In-octreotide uptake to be high and retention times long in tumour tissue, and have yielded evidence of intracellular localisation of the radionuclide. These findings thus showed somatostatin receptor-mediated radiotherapy to be a possible treatment alternative after close characterisation of the individual tumour. In the future, it may be possible to use other peptide receptors (e g, growth factor receptors) according to the same principles as applied in the case of somatostatin receptors.
The effects of bilateral adrenalectomy on the serotonin-, somatostatin-, and gastrin-immunoreactive cells in the rat gastrointestinal tract were studied four weeks after surgery. Body weight was reduced and the small intestine shorter in adrenalectomized animals compared with controls, while no changes were found in the histology of the mucosa. In the adrenalectomized animals the number of serotonin-immunoreactive cells was increased in the cecum and large intestine, while the somatostatin-immunoreactive cells were decreased in number in the antrum and increased in the corpus, cecum, and large intestine. The gastrin-immunoreactive cells in the antrum were not affected in number, but their nuclear size was enlarged, possibly indicating increased cellular activity.
A rat model of colitis [dextran sulfate (DSS)] was used to study the permeation of Evans blue (EB) from the lumen into the wall of proximal and distal colonic loops after exposure to the dye for 2 hr. Topical application of drugs used in human ulcerative colitis (lidocaine, mesalazine, prednisolone, or sucralfate) was given daily during induction of colitis to protect the mucosa. The mucosal changes were evaluated with special regard to peptidergic innervation [substance P (SP) and neuropeptide Y (NPY)], invasion of antigen-presenting polydendritic cells, and mucin-containing goblet cells. DSS-treatment caused a significantly increased permeation of EB. In the proximal loops a significant inhibition was obtained after treatment with lidocaine, prednisolone, or sucralfate. In the distal loops only treatment with lidocaine had a preventive effect. Immunocytochemically there was a clear hyperplasia of both mucosal SP- and NPY-immunoreactive nerve fibers in regions with crypt abnormalities. In these regions also most of the goblet cells were devoid of mucus. Like the changes in permeation, these morphological changes were most prominent in the distal loops. With induction of colitis, the mucosa and lamina propria were invaded by polydendritic cells; the visual score was markedly decreased in the proximal loops treated with lidocaine, prednisolone, or sucralfate. In the distal loops similar effects were obtained after treatment with lidocaine or prednisolone. Prevention of the influx of antigens in both loops after lidocaine treatment with reduced recruitment of polydendritic cells into the lamina propria is suggested. The nerve hyperplasia may thus be secondary to luminal challenge with antigens during induction of colitis. The discrepancy between increased permeation and absence of polydendritic cell response in the distal loops after prednisolone may reflect separate actions of steroids on the intestinal epithelium and the immune cells.
Hormonal overproduction is a significant problem in patients with disseminated midgut carcinoid tumors. Serotonin (5-HT) is one major product secreted from such tumors and the urinary excretion of its metabolite (5-hydroxyindoleacetic acid, 5-HIAA) serves as an important tumor marker. The present study aimed at elucidating mechanisms of tryptophan metabolite secretion to facilitate the treatment of the carcinoid syndrome. When midgut carcinoid tumors were studied in primary cell cultures, several similarities with adrenergic neurons could be demonstrated. A marked dose-dependent depletion of intracellular 5-HT could be induced by reserpine, and monoamine oxidase-activity was revealed both in functional studies and by immunocytochemistry. Differences between tumors in the ratios of tryptophan metabolites released indicated that enzymes for synthesis and degradation of 5-HT were individually expressed. Treatment with the somatostatin analogue octreotide or with dexamethasone decreased the extracellular levels of tryptophan metabolites, but the mechanisms were partly different. In some tumors octreotide also decreased the synthesis of 5-HT, while dexamethasone markedly increased the intracellular 5-HIAA levels. It is of clinical interest to further elucidate these mechanisms, since the two drugs may have complementary actions in carotid crisis reactions.
Most intestinal secretagogues, including cholera toxin, evoke fluid secretion in part by activating the enteric nervous system (ENS). The enterotoxins that, due to size, cannot pass the intestinal epithelial lining have been proposed to activate the ENS via the release of amines/peptides from the intestinal endocrine cells. It has been shown that calcium channel blockers of the L-type attenuate intestinal fluid secretion. This study was performed on rat jejunal segments to elucidate where calcium channel antagonists interact with the secretory nervous reflex(es) of the ENS. In vivo, net fluid transport, transmural potential difference (PD) and luminal release of serotonin from the enterochromaffin cells were monitored before and after exposing the intestinal mucosa to cholera toxin (20 microg/mL) or the calcium ionophore A23187 (0.5 mM). In vitro, the effects of transmural electrical field stimulation (EFS) on short circuit current (SCC) was investigated using the Ussing chamber method. Cholera toxin and A23187 evoked a net fluid secretion, an increased PD and an augmented luminal release of 5-HT. These effects were markedly attenuated by giving the calcium channel blocker nifedipine i.v. (5.75 micromol kg(-1) body wt). On the other hand, nifedipine (0.02 mM) had no significant effect on the increased SCC caused by EFS in vitro. The results obtained in the in vivo experiments suggest that the nifedipine markedly attenuates the initial event in cholera toxin- and A23187-induced secretion, the release of amines and probably also of peptides from the intestinal endocrine cells. The in vitro experiments seem to exclude an effect of the calcium channel blockade on the efferent part of the secretory nervous reflex.
The expression of somatostatin receptors in neuroendocrine tumors has facilitated the diagnosis and surgical treatment of patients with these tumors. After injection of a radiolabeled long-acting somatostatin analog, (111)In-octreotide, scintigraphic tumor imaging can ben performed as well as intraoperative tumor localization. During localization studies very high (111)In concentration values were found in tumor tissues versus normal tissues, especially in carcinoid tumors and endocrine pancreatic tumors. Studies on such tumors in cell culture further indicated internalization of (111)In into tumor cells, which is a prerequisite for a radiobiological effect from short range Auger and conversion electrons. Attempts to systemic radionuclide therapy via somatostatin receptors in patients with neuroendocrine tumors have been initiated.
BACKGROUND: 111In-radiolabelled (DTPA-D-Phe1)-octreotide scintigraphy can be used to localize neuroendocrine tumours expressing somatostatin receptors (SSTRs). The aim of this paper was to analyse the importance of tumour volume and growth for the visualization by SSTR scintigraphy of metastases from medullary thyroid carcinoma (MTC). METHODS: Serum calcitonin concentrations were used to estimate volume and growth rate of MTC. Twenty-two patients who had persistent hypercalcitoninaemia after total thyroidectomy for MTC, indicating the presence of metastases, were studied. RESULTS: SSTR scintigraphy visualized 15 tumours in 11 patients. Patients with scintigraphically visualized tumours had higher serum calcitonin and carcinoembryonic antigen concentrations and larger tumours, and the serum calcitonin concentration increased more rapidly with time. Tumour-associated symptoms and death from MTC occurred only in patients with scintigraphically visualized tumours. CONCLUSION: Scintigraphically visualized tumours grow more rapidly and are more aggressive than nonvisualized lesions. SSTR scintigraphy can be helpful in the planning of palliative surgery for MTC and for diagnosing distant metastases, but cannot localize microscopic metastases.
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