Upregulation of the angiogenic factors PlGF, VEGF and their receptors (Flt-1, Flk-1/KDR) by TSH in cultured thyrocytes and in the thyroid gland of thiouracil-fed rats suggest a TSH-dependent paracrine mechanism for goiter hypervascularization.

Placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF) represent two closely related angiogenic growth factors active as homodimers or heterodimers. Since goiters of the thyroid gland are extremely hypervascular, we investigated the expression of PlGF, VEGF and their receptors, Flt-1 and Flk-1/KDR, in a small panel of human goiters from patients with Graves's disease, in an animal model of thyroid goitrogenesis and in in vitro cultured thyroid cells. Here we report that the mRNA expression of PlGF, VEGF and their receptors is markedly enhanced in biopsies of goiters resected from Graves's patients. In vivo studies demonstrated that in the thyroid gland of thiouracil-fed rats, increased mRNA and protein expression of PIGF, VEGF, Flt-1 and Flk-1/KDR occurred subsequent to the rise in the serum thyroid stimulating hormone (TSH) levels and in parallel with thyroid capillary proliferation. In vitro studies confirmed the existence of such TSH-dependent paracrine communication between thyroid epithelial cells and endothelium since the conditioned medium collected from TSH-stimulated thyrocytes acquired mitogenic activity for human umbilical vein endothelial (HUVE) cells. Altogether, these data suggest that PlGF and VEGF, released by thyrocytes in response to the chronic activation of the TSH receptor pathway, may act through a paracrine mechanism on thyroid endothelium.

Prognostic value of serum biological markers in patients with hepatocellular carcinoma.

PURPOSE: Prognosis of patients with hepatocellular carcinoma (HCC) is assessed by using indexes based on clinical and instrumental parameters. The Cancer of the Liver Italian Program (CLIP) staging system combines the Child-Pugh classification with tumor size, portal invasion, and alpha-fetoprotein and predicts the outcome of HCC patients more precisely than the Okuda staging system. Serum levels of a number of biological variables have been found to be increased in patients with HCC and are associated with different outcomes. Our aims in this study were to test the prognostic role of the serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble interleukin-2 receptor (sIL-2R), interleukin 6 (IL-6), and anti-p53 and to assess whether the addition of any of the above serum markers could further improve the predictive ability of the CLIP score. EXPERIMENTAL DESIGN: Serum levels of sICAM-1, sIL-2R, IL-6, and anti-p53 were assayed in 80 patients with HCC and correlated with their outcomes. Nonparametric procedures were applied to test correlations between serum sICAM-1, sIL-2R, IL-6, anti-p53, and other prognostic factors. For survival analyses, the product-limit method, log-rank test, and Cox proportional hazards model were applied. RESULTS: Only serum levels of sIL-2R correlated with survival, which was longer for patients with lower values (< or =950 units/ml). However, with multivariate analysis sIL-2R did not confirm its predictive role when tested with the CLIP score as a covariate, with a hazard of death of 1.51 (95% confidence interval, 0.76-3.01). CONCLUSIONS: Serum levels of sICAM-1, sIL-2R, IL-6, and anti-p53 are not useful as prognostic factors for HCC in clinical practice. They do not improve the predictive ability of the CLIP score.

Immunological and clinical effects of intramuscular rIFN alpha-2a and low dose subcutaneous rIL-2 in patients with advanced malignant melanoma.

Fifteen patients with tumour recurrence following radical surgical excision of malignant melanoma were treated with a combination of interferon alpha-2a (rIFN alpha-2a) and interleukin-2 (rIL-2). Immunological monitoring (performed prior to therapy and on days 7, 21, and 28, of each course of treatment) showed significant changes of several parameters after rIFN alpha-2a and rIL-2 administration. A significant increase in cells expressing CD16 (cells bearing Fc receptor), CD25 (cells bearing IL-2 receptor), and CD56 (NK cells, activated lymphocytes), as well in levels of soluble IL-2 receptor, beta 2-microglobulin and neopterin was observed. Immunological changes were closely related to the injection of the biological agent and were more relevant during the first than the second cycle of treatment. rIFN alpha-2a and rIL-2 exerted a clear synergistic activity on the same immunological parameters. No major response was seen with the present approach: four subjects showed rapid progression of decrease during the first month of therapy, while of 11 patients who completed two courses of treatment, only five were considered in stable disease. In conclusion, our results suggest that a combination of rIFN alpha-2a and rIL-2, at dosages and schedules, used in this trial, was well-tolerated and immunologically active, but was clinically ineffective in the management of advanced melanoma.

Oestradiol and testosterone blood levels in patients with viral cirrhosis and hepatocellular carcinoma.

BACKGROUND: Patients with alcoholic cirrhosis show hypogonadism and feminization associated with sex hormone imbalance due to enhanced aromatization of testosterone and subsequent reduced testosterone and increased oestradiol blood levels. Because oestrogens modulate hepatocyte proliferation and oestrogen receptors are present in liver cirrhosis and hepatocellular carcinoma, it has been proposed that sex hormone imbalance can play a role in liver carcinogenesis. Trials with the oestrogen receptor antagonist tamoxifen have been performed with conflicting results. OBJECTIVES: To investigate oestradiol and testosterone blood levels in men with viral cirrhosis and hepatocellular carcinoma and also to investigate changes in sex hormone circulating levels induced by tamoxifen treatment. PATIENTS AND METHODS: Oestradiol and testosterone blood levels were evaluated in 32 male patients with postviral cirrhosis and hepatocellular carcinoma at the time of diagnosis and during the follow-up, and in 20 healthy controls. In eight patients, hormone levels were also assayed during treatment with tamoxifen (40 mg/day). No patient had a history of high alcohol intake. RESULTS: Oestradiol values observed at the time of diagnosis were 56.1 +/- 54.5 pmol/l, while testosterone values were 13.6 +/- 8.0 pmol/l. There was no relationship between oestrogen values and age, while higher oestradiol values were observed in patients with advanced cirrhosis (Child B and C); conversely, testosterone levels progressively and significantly decreased from cirrhosis Child A (15.1 +/- 9.7) to C (7.7 +/- 7.1) (P < 0.05). Tamoxifen treatment (40mg/day) for 1 month in eight patients increased oestradiol values (62.2 +/- 77.0 vs. 156.4 +/- 83 pmol/l, P < 0.05), while testosterone levels decreased (15.1 +/- 6.8 vs. 8.5 +/- 10.6 pmol/l). However, these changes were not associated with clinical signs or symptoms of feminization. Oestrogen levels decreased after 6 months of tamoxifen treatment. No significant change in hormone levels was observed in patients not treated with tamoxifen. Unlike patients with alcoholic cirrhosis, in male patients with viral cirrhosis and hepatocellular carcinoma there were no significant alterations in blood oestradiol and testosterone levels, although a certain degree of sex hormone imbalance was observed in those with advanced cirrhosis. Treatment with tamoxifen (40 mg/day) did not induce clinical manifestations of sex hormone imbalance.

Final height and body disproportion in thalassaemic boys and girls with spontaneous or induced puberty.

UNLABELLED: The aim of the study was to evaluate whether sex hormone replacement therapy adversely affected final height and body disproportion in thalassaemic boys and girls. Thirty-six patients with spontaneous (SP) or induced puberty (IP) were studied in order to define the pattern of height growth through three observations: the first (A) at the age of 7-9; the second (B) at onset of spontaneous or induced puberty; and the third (C) when final height was reached. We examined 14 females with SP (f-SP) and 8 with IP (f-IP); 7 males with SP (m-SP) and 7 with IP (m-IP). Girls with IP reached the same final height of girls with SP (f-IP 153.8 (4.3) versus f-SP 154.4 (5.5) cm); p > 0.05) close to target height (f-IP 155.9 (5.2) cm versus f-SP 155.5 (3.6) cm). Girls with IP reached the final height at older chronological age (CA) (17.0 (0.6) y) than girls with SP (CA of 15.3 (0.7) y), but at the same bone age (BA) (f-IP 15.1 (0.9) y versus f-SP 14.8 (0.6) y). There was no difference between the two groups for pubertal growth (f-SP 16.2 (7.7) cm versus f-IP 12.2 (7.4) cm (p > 0.05)) that was negatively correlated with both prepubertal growth and BA at onset of puberty in both groups. Values of sitting height (sds) with respect to BA (SHsdsBA) were not significantly different between the two groups, and showed a worsening from the first observation to final height, reaching values around -2 SD, in both groups. Values of subischial leg length (sds) with respect to BA (SLLsdsBA) were in the normal range at both observations in all girls. High serum ferritin levels were observed in both groups (f-SP 3189 (2296) ng/ml and f-IP 3998 (2545) ng/ml; p > 0.05). Also boys with induced puberty reached the same final height of those with spontaneous one (m-IP 160.9 (5.5) cm versus m-SP 161.8 (2.4) cm; p > 0.05), but it was lower than target height in both groups (m-IP 168.1 (4.1) cm versus m-SP 169.6 (3.2) cm). Boys with IP reached final height at CA of 18.6 (1.1) y slightly older than boys with SP (CA 17.2 (0.9) y), but at the same BA (m-IP 15.9 (1.5) y versus m-SP 16.3 (0.8) y). Pubertal growth values were significantly different between boys with SP 18.9 (5.3) cm and those with IP 13.8 (4.9) cm (p < 0.05), but they were negatively correlated with prepubertal growth values in both groups (m-SP r = -0.91; p < 0.002 and m-IP r = -0.51; p < 0.05). SHsdsBA showed a worsening from the first observation to final height, reaching values around -3 SD in both groups, while SLLsdsBA were always in the normal range in all patients. Serum ferritin levels were higher in boys with IP (3400 (1179) ng/ml) than in those with SP (2020 (496) ng/ml). CONCLUSIONS: Our data showed that: (a) patients of both sexes with induced puberty reached the same final height of patients with spontaneous puberty; (b) all patients showed a body disproportion with truncal shortening and normal leg length that was more severe in boys of both groups at final height; (c) body disproportion was independent of pubertal or prepubertal period of greater height gain, suggesting that sexual steroids replacement therapy did not adversely affect either final height or body disproportion. Further studies, focused on the pathogenesis of the truncal shortening, are necessary in order to acquire more insight into the causes of this impairment.

Mucosal expression of carcinoembryonic antigen and carbohydrate antigen 19-9 in patients with gastritis and gastric cancer.

Sixty-eight patients (45 males, 23 females) were studied in order to assess the usefulness of mucosal tissue concentrations of both carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in detecting patients at high risk for gastric cancer. CEA and CA19-9 were assayed on cytosol obtained from multiple endoscopic biopsies of 41 patients with chronic superficial gastritis, 18 with chronic atrophic gastritis, and 9 with gastric cancer. Mucosal tissue concentrations of both CEA and CA19-9 increased from chronic superficial gastritis to chronic atrophic gastritis and to gastric cancer (p = 0.005 and p = 0.002, respectively). Mucosal CEA levels in patients with intestinal metaplasia (IM) were significantly higher than in nonmetaplastic mucosa (p = 0.04). Epithelial dysplasia was associated with higher, though not significant, tissue concentrations of both CEA and CA19-9 when compared with IM. Finally, a correlation between serum levels and tissue concentrations was observed only for CA19-9 (Pearson's correlation coefficient = 0.7). In conclusion, these data indicate that gastric mucosa of patients with chronic atrophic gastritis and intestinal metaplasia express high levels of both CA19-9 and CEA.