Transarterial chemoembolization of advanced liver metastases of neuroendocrine tumors--a retrospective single-center analysis.

BACKGROUND: In neuroendocrine tumors, metastases are a negative prognostic factor for survival and quality of life. Transcatheter arterial chemoembolization (TACE) is thought to be an effective symptomatic and antiproliferative treatment in patients with otherwise progressive disease. METHODS: 62 chemoembolization procedures in 26 patients with progressive neuroendocrine tumors were reviewed. The underlying disease was carcinoid syndrome in 10, non-functional midgut tumor in 2, non-functional pancreatic tumor in 7, malignant insulinoma in 2 patients, non-functional tumor of the stomach in 1 and of unknown origin in 4 patients. Tumor burden of the liver was <25% in 3, 25-50% in 11, 50-75% in 6 and >75% in 6 patients. RESULTS: TACE was technically successful in 57 cases. Four patients developed minor and 5 major complications. The 30-day mortality rate was 7.7%. According to WHO criteria, 14 patients had no change in tumor burden, 2 had regression and 5 progress after chemoembolization. Patients with a tumor burden >75% of the liver did not benefit from TACE due to the development of major complications, whereas patients with low (<50%) tumor burden and high (>50%) lipiodol uptake showed a trend towards longer survival. Five-year survival time after diagnosis was 48%. Patients treated with octreotide and/or alpha-interferon had no benefit from chemoembolization with regard to their carcinoid syndrome. CONCLUSIONS: In this retrospective study, patients with low (<50%) tumor burden and high (>50%) lipiodol uptake responded better to TACE than end-stage patients.

Somatostatin analogues in the treatment of endocrine tumors of the gastrointestinal tract.

Somatostatin and its long-acting analogues have been introduced for the treatment of endocrine tumours of the gastrointestinal tract as they have been shown to effectively control symptoms resulting from excessive hormone release in patients with carcinoid, Verner-Morrison and glucagonoma syndromes. This beneficial effect is due to the presence of somatostatin receptors in high densities on the majority of endocrine tumours. The symptomatic effect is less pronounced in insulinomas, since 30 - 50% of these tumours lack or express only a few somatostatin receptors. With respect to symptomatic control, somatostatin receptor subtypes 2 and 5 are the most important and the currently available long-acting analogues octreotide and lanreotide bind preferentially to these receptor subtypes. Long-term studies have shown that somatostatin analogues are safe and that the most important adverse advent is the development of gallstones. The antiproliferative potency of somatostatin and its analogues in vitro and in experimental tumour models prompted a number of studies in patients with metastatic endocrine tumours that are generally unresponsive to conventional chemotherapeutic protocols. Stabilisation of tumour growth lasting for months to a few years was the most favourable result, occurring in 30 - 70% of patients. However, definite proof of antiproliferative potency in man is still pending since placebo-controlled studies are not available. Radioligand therapy based on 111Indium, 90Yttrium and 177Lutetium coupled to somatostatin analogues via bifunctional chelators is currently under investigation with promising data concerning long-lasting control of symptoms and tumour growth from Phase I trials.

Affective pictures processing, attention, and pain tolerance.

Two experiments were conducted to determine whether attention mediates the effects of affective distractors on cold pressor pain, or whether the cognitive processes of priming and appraisal best account for the effects. In Experiment I, 65 male respondents were exposed to either pleasant, neutral or unpleasant pictures selected from the International Affective Pictures System (IAPS). The cold-pressor test was administered simultaneously. Consistent with predictions based on priming and appraisal hypotheses, results revealed a linear trend across conditions, such that pain tolerance scores were higher as a function of picture pleasantness. A second study was conducted to examine the role of pain cues in the effects of negative affect on cold pressor pain. Thirty-nine male respondents were exposed to unpleasant pictures that either did or did not include pain-related material. Respondents who viewed pictures without pain cues tolerated the cold water for a longer period of time than respondents who viewed pictures that contained pain-related information. Priming and appraisal processes that might underlie the observed differences, and the type of affective distractors that could be meaningful for enhancing pain tolerance, are discussed.

Prognostic value of heart rate variability analysis in patients with carcinoid syndrome.

BACKGROUND/AIMS: Recently, a decrease in heart rate variability measures was found in patients with carcinoid syndrome suffering from carcinoid heart disease compared to those without cardiac involvement of carcinoid syndrome. The prognostic relevance of this finding, however, was not clear. PATIENTS AND METHODS: Therefore, 35 patients with carcinoid syndrome (21 men, age 56 +/- 11 years), all of them suffering from metastatic carcinoid tumors, were followed prospectively at our institution. Digital 24-hour Holter monitoring, echocardiography, and serum serotonin and urine 5-hydroxyindole acetic acid (5-HIAA) samplings were performed in all study patients at baseline. Indices of time domain heart rate variability obtained from Holter recordings included the standard deviation of all normal RR intervals (SDNN) representing overall variability, the square root of the mean of the squared differences between adjacent normal RR intervals (rMSSD), and the percentage of the number of pairs of adjacent normal RR intervals differing by >50 ms (pNN50), both indices reflecting predominantly vagal influences on heart rate. RESULTS: During a mean follow-up of 18 +/- 7 months, 15 of 35 patients with carcinoid syndrome (43%) died. Patients with cardiac manifestation of the carcinoid syndrome showed a tendency towards an increased mortality in comparison to patients without cardiac involvement (p = 0.09). Patients with the combination of decreased heart rate variability (SDNN <100 ms) and presence of carcinoid heart disease had a significant worse prognosis (p = 0.04) compared to patients without carcinoid heart disease and preserved heart rate variability (SDNN > or =100 ms). CONCLUSIONS: The presence of carcinoid heart disease in combination with decreased heart rate variability is associated with the most adverse prognosis in the setting of carcinoid syndrome.

The biocompound method in coronary artery bypass operations: surgical technique and 3-year patency.

BACKGROUND: Complete arterial revascularization may be unsafe in patients with a high operative risk. In patients with varicose ectatic veins, the biocompound technique, which uses unsuitable autologous veins, enables the surgeon to influence the bypass graft wall stress levels and diameter. This report summarizes the 3-year patency of 53 patients, the survival rate of 200 patients, and operative technical considerations. METHODS: Biocompound grafts were used for aortocoronary bypass in 200 patients who were considered inappropriate subjects for complete arterial revascularization and who had unsuitable saphenous veins. RESULTS: The mortality rate (30 days) of 200 patients was 3.5%. The 3-year survival rate was 88.5%. The patency rate of the left internal thoracic artery (LITA) after 3 years was 97.3%, of the native vein was 68.7%, and of the biocompound graft was 68.3%. The LITA showed a superior patency rate (p = < 0.05). CONCLUSIONS: The LITA is the first choice in coronary bypass operation. The biocompound technique is a reliable method to achieve complete revascularization in patients with a lack of suitable saphenous veins.

mRNA expression patterns of insulin-like growth factor system components in human neuroendocrine tumours.

BACKGROUND: Insulin-like growth factors (IGF) and their corresponding receptors and binding proteins are important in carcinogenesis for several tumours, but their expression pattern in the functionally and biologically heterogeneous human neuroendocrine tumours of the gastroenteropancreatic tract is largely unknown. MATERIALS AND METHODS: This study searched for the mRNA expression patterns of components of the IGF system: IGF-1 and IGF-2, IGF receptors 1 and 2 (IGF-1R, IGF-2R), IGF-binding proteins 1-6 (IGFBP1-6)) in the most frequent human gastroenteropancreatic neuroendocrine tumours (gastrinomas, insulinomas, tumours associated with carcinoid syndrome and functionally inactive tumours) employing reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: In the 37 tumour samples analysed (nine gastrinomas, 10 insulinomas, nine tumours associated with carcinoid syndrome and nine functionally inactive tumours) IGFBP-2 was found in all tumour samples while the IGFBP-1 was expressed only at low frequency (10-22%) among the four tumour types. The IGF-2R was predominantly expressed in gastrinomas. Among the four tumour types the expression of IGF-1R, IGF-2R and IGFBP-6 varied significantly. In addition, 12 pairs of significantly coexpressed IGF system components were detected (IGF-1 <--> IGF-1R, IGF-1 <--> IGF-2R, IGF-1 <--> IGFBP-3, IGF-1 <--> IGFBP-6, IGFBP-3 <--> IGF-1R, IGFBP-6 <--> IGF-1R, IGFBP-1 <--> IGF-2R, IGFBP-3 <--> IGF-2R, IGFBP-5 <--> IGF-2R, IGFBP-3 <--> IGFBP-5, IGFBP-3 <--> IGFBP-6, IGFBP-5 <--> IGFBP-6). CONCLUSIONS: The described differences of the expression patterns of the IGF system components in neuroendocrine tumour subtypes suggest tumour type-dependent different pathways in tumour growth control by IGF system components.

Treatment of neuroendocrine GEP tumours with somatostatin analogues: a review.

BACKGROUND: Somatostatin and its long-acting analogues are effective in symptom control in patients with functionally active neuroendocrine GEP tumours. Several in vitro and in vivo reports suggest that they are also able to control tumour growth. METHODS: Critical review of published data on the effect of long-acting somatostatin analogues on symptom and growth control in patients with metastatic neuroendocrine GEP tumours. RESULTS: With the exception of insulinoma and gastrinoma, octreotide acetate and other long-acting somatostatin formulations are currently the therapeutic principle of first choice to control hormone-mediated symptoms. The consequences of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome are best controlled by proton pump inhibitors. Available data on growth control indicate that stabilization of tumour growth seems to be the most beneficial antiproliferative effect occurring in up to 50% of patients. This effect is limited. However, it is unknown which tumour entity responds best to long- acting somatostatin analogues. CONCLUSION: Additional studies in patients with known spontaneous tumour growth and avoiding a mix-up of different entities of neuroendocrine malignancies are necessary to identify subpopulations of neuroendocrine tumours which respond to long-acting somatostatin analogues in terms of longer lasting growth inhibition.

Reduction of intimal and medial thickening in sheathed vein grafts.

BACKGROUND: Arterial pressures are described as an important factor in the development of graft degeneration and in reduced patency rate in vein bypass grafts. Sheathing of the graft with a pressure resistant mesh tubing might slow down this development. METHODS: Saphenous vein grafts were implanted into the carotid arteries of five pigs in order to evaluate the influence on myointimal hyperplasia of a compliant Phynox mesh tubing (a wrought Cobalt-Chromium-Nickel-Molybdenum-Iron Alloy), which surrounded autologous vein grafts that were exposed to arterial pressure. Each pig was operated on using a sheathed vein graft (biocompound-graft, a hybrid vascular prosthesis) on one side and an untreated saphenous vein on the other. RESULTS: After 4 weeks intimal hyperplastic changes were found in all histological sections. The wall thickness (medial and intimal layer) varied from 351 microm to 432 microm in the biocompound-graft and from 391 microm to 1196 microm in the native vein grafts (p < 0.05, n = 5). Severe myocytial and fibroblast proliferation was only found in the control grafts. Cellularity of the medial layer differed at sites of maximal cellular density and ranged from 11 to 12 cells in the biocompound-graft and from 17 to 18 cells per counting field in the native vein grafts (p < 0.05, n = 5). CONCLUSIONS: External support of vein grafts reduces intimal and medial layer proliferation. The findings of this study are in accordance with the results reported by other research groups.

Combination therapy with octreotide and alpha-interferon: effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors.

OBJECTIVE: We investigated the antiproliferative efficacy of the addition of alpha-interferon to the somatostatin analogue octreotide in patients with metastasized gastroenteropancreatic tumors unresponsive to octreotide monotherapy. METHODS: In an open prospective trial, 21 patients with metastasized neuroendocrine gastroenteropancreatic tumors (nine patients with carcinoid syndrome, eight with nonfunctioning tumors, four with gastrinoma) were treated with 5 x 10(6) IU alpha-interferon tiw in addition to 200 microg of octreotide tid. All patients, including 16 patients with preceding monotherapy with 200 microg of octreotide tid, had tumor progression documented by computed tomography before entering the study. Growth response (computed tomography documented) and biochemical response were assessed at 3-month intervals. RESULTS: Inhibition of tumor growth was observed in 14 patients (67%), 11 of whom had preceding octreotide monotherapy; complete regression was observed in one patient lasting for 49 months and stable disease (stand-still) in 13 patients lasting for 3 to 52 months (median, 12 months). Seven patients failing this combination therapy exhibited a significantly shorter overall survival (median, 23 months; range, 5 to 42 months) than the 14 patients responding to this regimen (median, 68 months; range, 12 to 112 months; p = 0.007). Two patients are still alive. Biochemical response was achieved in 69% of patients with functioning tumors: in three of four patients with gastrinoma and in six of nine patients with carcinoid syndrome. CONCLUSIONS: These data suggest that the addition of alpha-interferon to octreotide has antiproliferative efficacy in a subgroup of patients with advanced metastatic disease unresponsive to octreotide monotherapy. Prolonged survival was seen in the responder group.

Heart rate variability in carcinoid heart disease.

Time domain heart rate variability measurements and echocardiographic studies were performed in 35 patients with carcinoid syndrome. Carcinoid heart disease was present in 18 patients (51%). Heart rate variability parameters (standard deviation of all normal RR intervals, percentage of the number of pairs of adjacent normal RR intervals differing by >50 ms) were significantly reduced in patients with than in those without carcinoid heart disease.

Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours.

BACKGROUND: Human gastroenteropancreatic neuroendocrine tumours are functionally and biologically heterogeneous, but their exact growth factor receptor expression pattern, important for onco- and carcinogenesis, remains unknown. METHODS: This study searched for the mRNA expression pattern of six tyrosine- and serine/threonine kinase receptors [hepatocyte growth factor (HGFR), fibroblast growth factor (FGFR), epidermal growth factor (EGFR), insulin-like growth factor (IGF)-1R, transforming growth factor (TGF)-betaR1, TGF-betaR2] together with the five somatostatin receptors in human gastroenteropancreatic neuroendocrine tumours (gastrinomas, insulinomas, tumours with carcinoid syndrome, functionally inactive neuroendocrine tumours) using reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: EGF receptor was expressed almost exclusively in gastrinomas. Among the four tumour subtypes, expression frequencies of the somatostatin receptors 1 and 5, HGF-, IGF-1-, TGF-betaR1, TGF-betaR2 and the EGF-receptor varied significantly. CONCLUSIONS: In spite of the common cellular origin of these tumours, differences in growth factor receptor expression suggest the existence of different pathways during tumour subtype development.

Drama-induced affect and pain sensitivity.

This study was conducted to examine the pain-ameliorating and pain-sensitizing effects of exposure to emotionally engaging drama. Specifically, the consequences for pain sensitivity of exposure to dramatic expositions differing in both excitatory and hedonic qualities were determined. Hedonically negative, neutral, and positive affective states were induced in male respondents by exposure to excerpts from cinematic drama. Pain sensitivity was assessed by the cuff-pressure procedure before and after exposure and by the cold pressor test after exposure only. When compared against the control condition, pain sensitivity diminished under conditions of hedonically positive affect. An inverse effect was suggested for hedonically negative conditions, but proved tentative and statistically unreliable. The findings are consistent with earlier demonstrations of mood effects on pain sensitivity. Unlike inconclusive earlier findings concerning the magnitude of directional effects, however, they suggest an asymmetry that emphasizes the pain-ameliorating effect of positive affects while lending little, if any, support to the proposal of a pain-sensitizing effect of negative affects. The investigation did not accomplish the intended creation of conditions necessary to test the proposal that heightened sympathetic activity diminishes pain sensitivity. The utility of a rigorous determination of this hypothesized relationship is emphasized, and procedures for a viable test of the proposal are suggested.