Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice.

B cells can serve dual roles in modulating T cell immunity through their potent capacity to present Ag and induce regulatory tolerance. Although B cells are necessary components for the initiation of spontaneous T cell autoimmunity to beta cell Ags in nonobese diabetic (NOD) mice, the role of activated B cells in the autoimmune process is poorly understood. In this study, we show that LPS-activated B cells, but not control B cells, express Fas ligand and secrete TGF-beta. Coincubation of diabetogenic T cells with activated B cells in vitro leads to the apoptosis of both T and B lymphocytes. Transfusion of activated B cells, but not control B cells, into prediabetic NOD mice inhibited spontaneous Th1 autoimmunity, but did not promote Th2 responses to beta cell autoantigens. Furthermore, this treatment induced mononuclear cell apoptosis predominantly in the spleen and temporarily impaired the activity of APCs. Cotransfer of activated B cells with diabetogenic splenic T cells prevented the adoptive transfer of type I diabetes mellitus (T1DM) to NOD/scid mice. Importantly, whereas 90% of NOD mice treated with control B cells developed T1DM within 27 wk, <20% of the NOD mice treated with activated B cells became hyperglycemic up to 1 year of age. Our data suggest that activated B cells can down-regulate pathogenic Th1 immunity through triggering the apoptosis of Th1 cells and/or inhibition of APC activity by the secretion of TGF-beta. These findings provide new insights into T-B cell interactions and may aid in the design of new therapies for human T1DM.

Interferon-alpha 2b, with or without prior hepatic artery embolization: clinical response and survival in mid-gut carcinoid patients. The Norwegian carcinoid study.

BACKGROUND: Mid-gut carcinoid tumours often present with liver metastases, and survival has then been less than 2 years in earlier reports. We have evaluated the effects of interferon therapy on clinical response and survival, with or without hepatic artery embolization in these patients. METHODS: In a prospective study 30 female and 12 male patients, aged 23 to 75 years, with mid-gut carcinoid tumours and liver metastases underwent surgery with removal of as much as possible of their primary tumour. If technically feasible, embolization of hepatic arteries was performed in the absence of contraindications. Seventeen patients were embolized, and all patients received interferon-alpha 2b treatment for 1 year. Response factors were computer tomography (CT) measurement of the largest liver metastasis and the 24-h urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA). After 12 months patients with objective response or stable disease either continued or withdrew from interferon therapy. Survival was estimated when all patients had been observed for at least 36 months. RESULTS: Nine patients reduced the dose, and five withdrew from interferon treatment owing to side-effects the 1st year. Three patients died. Fifteen patients (39%) showed objective response 12 months after inclusion. Cumulative 5-year survival estimated from inclusion was 37.5% in all 42 patients but 71.4% in those who continued interferon therapy. The difference in survival between the interferon-treated and those who withdrew from interferon therapy at 12 months was significant when embolization was corrected for in a Cox model (p < 0.0125). The seemingly increased survival in embolized versus non-embolized patients did not reach statistical significance (p = 0.07). CONCLUSION: Interferon induced an objective response in mid-gut carcinoid patients as judged by the 24-h urinary 5-HIAA excretion. Patients receiving continuous interferon therapy showed improved response and survival compared with patients who stopped the treatment. Regardless of medical therapy, more survivors and more responders, as evaluated from CT measurements, were found among the embolized patients than among the non-embolized. Embolization could, however, not be shown to have a significant effect on survival.

Clinical effects of octreotide compared to placebo in patients with gastrointestinal neuroendocrine tumours. Report on a double-blind, randomized trial.

OBJECTIVES: To compare the effect of octreotide with f placebo on symptoms, tumour marker and quality of life in patients with gastrointestinal neuroendocrine tumours and liver metastases. DESIGN: A blinded, placebo-controlled, cross-over study was performed. The number of flushing epidodes and diarrhoea episodes were registered for 1 week prior to the study and for the 8-week duration of the study. Quality of life and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion were measured before the start, and at 4 and 8 weeks. Quality of life was registered with the Psychosocial Adjustment to Illness Scale (PAIS) and 5-HIAA measured by high-performance chromatography with electrochemical detection. 5-HIAA values exceeding 45 mumol 24 h-1 were considered to be elevated. SETTING: The study was performed in a tertiary referral centre. SUBJECTS: Twelve patients were approached; eleven patients were included, with a mean age of 56.5 (range 30-72) years. The primary tumour originated from the small intestine in nine and from the pancreas in two patients. The main symptoms were diarrhoea, flushing and nausea. The 24-h excretion of 5-HIAA was increased in all patients. INTERVENTIONS: Patients were treated for 4 weeks with octreotide (100 micrograms) subcutaneously, twice daily, and for 4 weeks on placebo (octreotide vehicle) in random starting order. MAIN OUTCOME MEASURES: The main outcome measures were the number of episodes of the main clinical symptom(s) and 24-h 5-HIAA excretion. RESULTS: Octreotide lowered diarrhoea and flushing frequency significantly compared to placebo. 5-HIAA excretion was reduced during treatment with the active drug. Two domains of the PAIS were significantly improved, indicating that the reduction of tumour marker and symptoms were clinically important. CONCLUSIONS: The clinical effect of octreotide on symptoms in patients with neuroendocrine tumours was demonstrated in a controlled, prospective trial.

Cardiac manifestations in mid-gut carcinoid disease.

The extent of heart disease and its relationship to the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), was studied with M-mode, 2D and Doppler echocardiography in 42 consecutive patients, 30 females and 12 males, median age 63 (range 23-75) years with histologically verified mid-gut tumour, liver metastases and 24-h urinary 5-HIAA excretion above 47 mumol.24 h-1. All patients had normal left ventricular ejection fractions, median 65% (interquartile range (IQR) 54-74%). Moderate to severe tricuspid regurgitation (TR) was diagnosed in 22 patients (59%); mitral or aortic regurgitation was found in nine (24%) and six (16%) patients, respectively. The mitral flow peak early (E) on late (A) velocity ratio was significantly decreased compared to age-matched normal subjects. The group of patients with 5-HIAA excretion exceeding 1000 mumol.24h-1 contained significantly more patients with severe TR than those with a lower excretion. The decrease in the E/A ratio may indicate reduced left ventricular compliance, possibly secondary to fibrous changes similar to those seen intra-abdominally and in the right side of the heart. As serotonin is degraded in the lung circulation, other mediators such as tachykinins and cytokines (PDGF) may be involved.

Interferon-alpha-2b alone and combined with octreotide in primary carcinoid cell-cultures.

Interferon and octreotide are two main therapeutic options in metastatic carcinoid disease. In primary cell cultures prepared from 26 previously untreated carcinoid patients interferon-alpha 2b (alpha-INF), alone and combined with octreotide, significantly reduced medium serotonin (5-HT). The amines were measured with reversed phase HPLC and electrochemical detection, total DNA with a photometric method. Interferon lowered the medium concentration of serotonin to 53% (range 42-79%), octreotide alone to 44% (range 23-48%). Neither interferon, octreotide nor the combined treatment decreased DNA content. Octreotide had no effect on intracellular 5-HT. Both interferon alone and combined with octreotide lowered intracellular 5-HT concentrations significantly. This may represent a direct biochemical effect of interferon on tryptophan metabolism.

Influence of interferon and radiation on serotonin content in primary carcinoid cell cultures.

Carcinoids are in general thought to be radioresistent, and have not been subjected to radiation therapy, except for palliative purposes. Clinical experience has indicated that interferons might enhance radiation effect and toxicity. In order to examine the effect of radiation, the combination of radiation and interferon, and the usefulness of the main metabolic product of primary cell cultures--serotonin--as a response indicator, we exposed primary carcinoid cell cultures with and without interferon pretreatment to radiation (2 Gy and 8 Gy). Irradiation alone had no effect on the serotonin content of the medium at the low dose (2 Gy) and even at the high dose (8 gy) the effect was not significant. When cells were preincubated with 1,000 IU/ml alpha-interferon, however, irradiation with 8 Gy induced a significant reduction of the hormone concentration in the medium on day 12 to 54.9 +/- 8.0% of the control value (p = 0.026). We think our model may provide a useful tool for further exploration of these mechanisms.

The effect of somatostatin analogue SMS 201-995 on serotonin levels in the medium of primary carcinoid cell cultures.

Carcinoid cell cultures were established from primary tumours and liver and mesenteric metastases. The cells continued to produce serotonin for up to 6 months. Cells from different tumours showed different properties. In most wells carcinoid cells grew on a layer of fibroblasts. The tendency to co-culture seemed to be less marked in cells from liver biopsy specimens. The amount of serotonin decreased to 63% 300 min after addition of the somatostatin analogue SMS 201-995 (SMS) to the culture, compared with controls (p < 0.05; n = 10). This decrease was observed up until 12 days, when SMS was added at each change of medium (p < 0.005; n = 8). In the first 10 min, however, SMS induced an increase in serotonin concentration (p < 0.005; n = 11). This effect may be related to other, immediate stimulatory effects of SMS seen in other cell lines originating from neural ridge-derived tissue. We believe it is important to elucidate the properties of individual tumours, as choice of therapy may vary between patients with the same diagnosis. We have described a method to obtain such information within a couple of days, before a definite treatment is selected.

Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors.

Seventy-five patients with advanced abdominal carcinoid tumors (65 midgut, 10 others) have been examined retrospectively to evaluate the role of surgical treatment as a principle, irrespective of stage of disease. Eighteen of 52 patients (35%) exhibited the carcinoid syndrome. Two or more primaries were found in 39% of patients with midgut lesion, 81% of these patients had regional metastases, 5% of these patients had distant lymph node metastases, and 74% of the patients had liver secondaries. All patients underwent operation, an additional 34% of the patients had a further reoperation, 9% of the patients had a second reoperation, 3% of the patients had a third reoperation, and one patient (2%) had a fourth reoperation. Intraoperative debulking (liver excluded) was performed in 33% of the patients, and 48% of the patients had treatment (resection, hepatic artery ligation, embolization) directed at the liver. The postoperative mortality rate was 2% after the primary operation for midgut lesions. The median survival for midgut tumors was 92 months, compared to 40 months for other lesions (not significant). A significantly higher survival rate was revealed for those patients with midgut lesion who were undergoing intraabdominal debulking procedures (liver excluded); median survival was 139 months versus 69 months without debulking. For those patients with liver metastases, median survival after intervention was 216 months and 48 months without such treatment (p less than 0.001). It is concluded that resection of intraabdominal carcinoid tumor masses can be performed in a high proportion of patients. Despite the retrospective, uncontrolled nature of this study, the difference in survival probabilities in favor of aggressive surgical therapy is so marked that it is not unreasonable to conclude that surgery has played a role in prolonging life in these patients.

Psoriasis induced by interferon-alpha.

Recombinant human interferon-alpha has been used in the treatment of several cancers, but there have been several reports that it may exacerbate psoriasis or trigger off its onset. We report four patients, three of whom first developed psoriasis and one who had an aggravation of the condition during treatment with interferon-alpha. Three of the patients had the carcinoid syndrome and one a renal carcinoma, and all were treated with interferon-alpha 2b or 2a (IFN-alpha 2b, 2a) with doses ranging from 1.5 x 10(6) U daily to 18 x 10(6) U three times weekly. In two of the patients there appeared to be a correlation between the severity of the psoriasis and the dosage of interferon.

Increased lymphatic flow from the liver in different intra- and extrahepatic diseases demonstrated by CT.

Increase in the production of hepatic lymph is a compensatory mechanism known to occur in cirrhosis, neoplasia of the liver, biliary obstruction, and right-sided cardiac decompensation with elevated hepatic venous pressure. In hepatic lymphostasis, dilated hepatic lymphatics are reflected on CT as low attenuation rims--perivascular lucencies (PVLs)--surrounding the portal veins and the intrahepatic vena cava. In this study, CT scans of the livers of normal controls and patients in each of the four disease categories mentioned above were evaluated for the presence of PVLs; the presence/absence of PVLs was correlated with other CT findings and various biochemical and pathophysiologic parameters. The PVLs were seen with some frequency in patients in each of the four disease categories (12-52%) but in none of the normal controls. In patients with tricuspid incompetence, the presence of PVLs correlated perfectly with the presence of mottled enhancement of the hepatic parenchyma (evidence of sinusoidal stasis). The presence of PVLs was associated with elevation of certain biochemical parameters, but no common biochemical marker was observed across the disease categories. Perivascular lucencies on CT reflect altered hepatic lymphatic dynamics; in the absence of impaired efferent lymph drainage, they reflect increased lymphatic flow. However, the sensitivity of the finding--the relationship of the presence/absence of PVLs on CT to the degree of alteration of the lymphatic dynamics--has yet to be assessed.

Side effects and complications after hepatic artery embolization in the carcinoid syndrome.

Twenty patients with histologically verified carcinoid liver metastases underwent a total of 24 liver artery embolizations by means of interventional radiologic techniques. There were no deaths. The postembolization syndrome, consisting of fever, abdominal pain, nausea, and vomiting, occurred in all the patients. Severe complications were rare, the most serious being multiple hepatic abscesses with septicemia in one patient, septicemia in another, and mild acute pancreatitis in a third. All these three patients recovered without any sequels from the embolization, and none required surgical intervention. The hepatic abscesses were drained percutaneously, guided by ultrasound. Hepatic artery embolization seems justified in patients with disabling symptoms from the carcinoid syndrome, as long as alternative therapy with the same benefit but fewer complications is not available.

Extended experience with recombinant alpha-2b interferon with or without hepatic artery embolization in the treatment of midgut carcinoid tumours. A preliminary report.

Thirty-six patients with histologically verified midgut carcinoid tumours and liver metastases were included in a prospective study with daily interferon therapy 5 x 10(6) IU s.c. for one or two years. All had the primary tumour removed at laparotomy, and whenever technically possible, an embolization of the hepatic arteries was performed prior to interferon start. Recombinant human alpha 2b interferon from Schering-Plough was employed. When interferon was given alone, 24% responded after one year, judged from a 50% reduction in excretion of 5-hydroxyindoleacetic acid in the urine. Three patients had died. Stable disease was found in 43%, while 19% progressed. Survival rate was 40% after 5 years from start of therapy. The median survival time from start of therapy was 3 years and 4 months. When embolization of the liver arteries had been performed prior to the start of interferon treatment, the response rate was 60% after one year, 20% had stable disease and 20% progressed. Survival rate was 75% up to 5 years of observation. We conclude that interferon is an effective treatment of malignant metastatic midgut carcinoid and that survival might be prolonged compared with historical controls. Embolization of the liver arteries seems to increase the response rate after one year. Kaplan-Meier plots suggest prolonged survival when interferon treatment is combined with embolization.

Treatment of malignant metastatic midgut carcinoid tumours with recombinant human alpha2b interferon with or without prior hepatic artery embolization.

Nineteen patients with histologically verified midgut carcinoid tumours and liver metastases were included in a prospective study with daily recombinant human alpha 2b interferon injections of 5 million IU subcutaneously for 1 year. All had as much as possible of the primary tumour removed at laparotomy. Whenever technically possible (in seven cases), an embolization of the hepatic arteries was performed before interferon start. The response rate of the combined embolization and interferon treatment (n = 7) was 86% after 1 year, as judged from either a 50% reduction in excretion of 5-hydroxy-3-indoleacetic acid in the urine or a 50% reduction in the area of the largest liver metastasis as evaluated by computed tomography. All patients experienced an improvement in diarrhoea and/or flushing. When interferon was given alone (n = 12), 40% responded on the basis of objective criteria (50% after 6 months), whereas an improvement in either diarrhoea or flushing was experienced by 70% (75% after 6 months). In this group one patient had died and one had decided to withdraw after 6 months, at which time both were responders. We conclude that interferon seems to be an effective treatment of malignant metastatic midgut carcinoid tumours and that embolization of the liver arteries seems to increase the response rate, as judged after 1 year.

Recombinant alpha-2 interferon with or without hepatic artery embolization in the treatment of midgut carcinoid tumours. A preliminary report.

Nineteen patients with histologically verified midgut carcinoid tumours and liver metastases were included in a prospective study with daily interferon therapy 3 mill IU x m-2 subcutaneously for one year. All had the primary tumour removed at laparotomy, and whenever technically possible, an embolization of the hepatic arteries was performed prior to interferon start. Recombinant human alpha-2b interferon from Schering was employed. When interferon was given alone for one year 40% responded, judged from either a 50% reduction in excretion of 5-hydroxy-indoleacetic acid in the urine or a 50% reduction in the area of the largest liver metastasis, as evaluated by computer tomography. One patient died later on and one withdrew from therapy of her own will; both were responders at the evaluation at 6 months. When prior embolization of the liver arteries had been performed, the response rate was 85% after one year. When diarrhoea and/or flushing was evaluated, 70% had response on interferon alone, while all patients experienced improvement after the combined procedure. We conclude that interferon is an effective treatment of malignant metastatic midgut carcinoid and that embolization of the liver arteries seems to increase the response rate.

CQP 201-403, a new dopamine agonist in the treatment of hyperprolactinemia.

Current drugs used for hyperprolactinemia may have severe side effects. Effects and side effects of a new propylergoline derivate (CQP 201-403 SANDOZ) have been evaluated. Twenty-four otherwise healthy women (21-44 years) with hyperprolactinemia (35-318 micrograms/l) without extrasellar extension of pituitary adenomas took part in a randomized, double-blind study. Fasting prolactin levels measured on day 7 was significantly decreased when compared with day 1 (P less than 0.05) in all CQP groups, to 78% with 0.005 mg daily, to 40% with 0.015 mg daily, and to 27% with 0.025 mg CQP per day for one week. The levels in the control group did not change (96%). The area under the curve of the prolactin day curve (1-8 h after drug administration) decreased significantly (P less than 0.05) at all doses when day 7 was compared with day 1, to 77% with 0.005 mg, to 51% with 0.015 mg, and to 37% with 0.025 mg CQP. No change was seen in the control group (96%). Four patients (one on 0.005 mg, one on 0.015 mg, and two on 0.025 mg) experienced orthostatic hypotension while standing blood pressure was to be measured on the first day of treatment, and they had to lie down. CQP 201-403 lowers prolactin levels in hyperprolactinemic women at all doses employed. The effect was seen after the first dose of treatment, and lasted for at least 24 h. The adverse reactions are few and tolerable, and might be less than with current bromocriptine therapy.

Effect of somatostatin on human gastric blood flow evaluated by endoscopic laser Doppler flowmetry.

The effect of somatostatin on human gastric blood flow has been evaluated by endoscopic laser Doppler flowmetry. A bolus injection of 250 micrograms somatostatin intravenously caused a transitory decrease in the gastric blood flow of 40%. After continuous infusion of somatostatin for 1 h no change in the gastric microcirculation could be demonstrated in spite of significantly elevated somatostatin-like immunoreactivity in plasma. The results do not give evidence that somatostatin has a possible beneficial effect in patients with gastric bleeding caused by a significant gastric blood flow reduction.

Diminution of postprandial release of pancreatic polypeptide in myotonic dystrophy.

The meal-stimulated release of pancreatic polypeptide (PP), gastrin, somatostatin and glucagon was studied in nine patients with myotonic dystrophy (MD) and in 11 healthy controls. PP-release was significantly reduced in MD compared to controls. This reduction may be related to the abnormal gut motility demonstrated in MD. The release of gastrin, somatostatin and glucagon was not significantly different in the two groups.

The immediate effect of human renal transplantation on basal and meal-stimulated levels of gastrointestinal hormones.

Elevated serum levels of gastrin, pancreatic polypeptide, and glucagon were found in 10 uraemic patients, whereas gastric inhibitory polypeptide and somatostatin levels were normal. After renal transplantation there was a significant reduction in serum gastrin (median, 5 pmol/l; p = 0.05, n = 9), pancreatic polypeptide (145 pmol/l; p less than 0.01, n = 9), GIP (9.5 pmol/l; p = 0.02, n = 7), and glucagon (92 pg/l; p less than 0.02, n = 9), whereas no alteration was seen in the somatostatin level. Meal stimulation produced consistent increases in serum levels of all hormones, and the response appeared to be unchanged after renal transplantation.

Gastric emptying and intestinal transit of hyperosmolar solutions in relation to indomethacin and certain gut polypeptides in the rat.

The present study in the rat demonstrates an inhibitory mechanism of gastric emptying, sensitive to the osmolality of a liquid meal. Gastric emptying and intestinal transit were studied in groups that differed with regard to the osmolality of the gastric or duodenal instillation, experimental time, and indomethacin treatment. By intragastric instillation animals were fed an aqueous solution containing the nonabsorbable marker 51CrO2-4. After certain fixed time intervals the rats were killed and the stomach and small intestine were dissected out en bloc. The distribution of the isotope along the gastrointestinal canal was then determined. Intestinal transit was evaluated in a similar manner. The marker solution was introduced into the duodenum. A hyperosmolar solution, 1200 mOsm kg-1, was emptied from the stomach significantly more slowly than was an iso-osmolar solution, 300 mOsm kg-1. Of the iso- and hyper-osmolar solutions 87% and 74%, respectively, were emptied in 1 h. The isotope distribution along the intestinal canal after intraduodenal instillation was not affected by the osmolality of the installation. The osmotic inhibition of gastric emptying was not affected by indomethacin treatment (4 mg kg-1) or related to elevated plasma levels of gastrin, neurotensin, somatostatin, or gastric inhibitory polypeptide.

The antisecretory effects of RP 40 749 in patients with previous duodenal ulcer.

Thirteen male patients with a history of duodenal ulcer were given 150 mg RP 40 749 or placebo tablets at bedtime in a double-blind crossover study. The medication was given for two periods of 10 days with an 11-day wash-out period between. pH and pepsin concentrations were determined each hour in aspirates of gastric juice for 24 h on day 1, 10, 22, 31, and a 2-h collection of gastric juice was examined in the middle of the treatment and wash-out periods. At defined hours blood samples were examined for gastrin, somatostatin, and pancreatic polypeptide (PP) by radioimmunological methods, and concentrations of RP 40 749 were determined in blood and gastric juice. Meals were served at fixed hours on days 1, 10, 22, and 31. After treatment with RP 40 749 a highly significant elevation of pH was found after the 1st day compared with placebo, most pronounced during night hours. The pepsin activity was slightly elevated. The serum concentrations of gastrin were increased and those of somatostatin and PP decreased during the first 3-4 h after medication, with a subsequent normalization. No side effects were observed.