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The course of hepatitis C virus (HCV) infection carriers with normal/near-normal aminotransferases (NALT) is usually mild; however, in a few, fibrosis progression occurs. We aimed to verify whether monitoring by liver biopsy might be replaced by noninvasive methods and to identify factors associated with fibrosis progression in patients with persistently normal alanine aminotransferases. We studied 40 untreated HCV-RNA-positive subjects (22 male; median age, 44 years), who underwent two liver biopsies, with a median interval of 78.5 months, during which alanine aminotransferase concentrations (median number of determinations: 12) never exceeded 1.2 times the upper normal limit. Within 9 months from the second biopsy, they were tested by the shear elasticity probe (Fibroscan) and the artificial intelligence algorithm FibroTest. METAVIR fibrosis scores were analyzed in relationship to demographic, clinical, and viral parameters. Weighted kappa analysis was used to verify whether the results of noninvasive methods agreed with histology. Significant fibrosis (> or = F2), present at the first biopsy in only one patient (2.5%), was observed at the second biopsy in 14 patients (35%). At multivariate analysis, excess alcohol consumption in the past (>20 g/d; P = .017) and viral load (>8.0 x 10(6) copies/mL; P = .021) were independent predictors of progression. In identifying patients with significant fibrosis, inter-rater agreement was excellent for Fibroscan (weighted kappa = 1.0), and poor for FibroTest (weighted kappa = -0.041). In conclusion, among HCV carriers with NALT, Fibroscan is superior to the FibroTest in the noninvasive identification of fibrosis, for which excess alcohol consumption in the past and high viral load represent risk factors.

Background: Subjects who carry the D allele of the angiotensin-converting enzyme (ACE) gene have higher plasma and tissue angiotensin II levels, possibly concurrent with the development of obesity. In transplant recipients, treatment with calcineurin antagonists would magnify these effects. The present study verifies whether the allelic variants of ACE are a factor involved in excess weight gain after liver transplantation., Methods: A consecutive series of 108 liver transplant recipients (73 males) were studied. Recipient ACE genotypes, determined by a polymerase chain reaction-based method, were related to body mass changes 1 year after transplant., Results: Body mass index (BMI) increased from the pretransplant value of 25.1+/-3.3 kg/m2 to 25.9+/-3.5 kg/m2 (P<0.005). The difference was mainly attributable to recipients carrying 1 D allele or more (N=88) in whom the BMI increased from 25.3+/-3.1 kg/m2 to 26.3+/-3.3 kg/m2 (P<0.005). A BMI of 25 kg/m or greater was measured in 30 of 45 deletion/deletion homozygotes and 25 of 43 insertion/deletion heterozygotes; in contrast, 14 of 20 insertion/insertion homozygotes had a normal body mass (P<0.01). Among patients with normal body mass pretransplant (N=56), none of 13 insertion/insertion homozygotes reached a BMI value 25 kg/m or greater posttransplant (P<0.005). At multivariate analysis, pretransplant body mass and carriage of 1 D allele or more were independent predictors of body mass gain greater than 2 kg/m., Conclusions: Carriage of the D allele of the ACE gene is a strong, independent risk factor for excess weight gain after liver transplantation.

Recently we observed that pancreatic carcinoma cell lines constitutively express Interleukin-18 (IL-18). Bioactive IL-18 induces Interferon (IFN)-gamma production, Fas Ligand (FasL) expression, and inhibits angiogenesis, raising the issue of anti-tumor effects of a tumor-derived cytokine and motivating a more detailed analysis of IL-18 production in pancreatic carcinoma cells. This analysis included the study of effects of chemotherapeutic drugs (5-fluorouracil [5-FU], gemcitabine, cisplatin) commonly used in the treatment of pancreatic cancer patients on IL-18 production and processing. IL-18 expression and post-translational processing were determined using RT-PCR, immunoblot and ELISA in pancreatic carcinoma cell lines and in tumor tissue and serum samples from pancreatic carcinoma patients in the presence and absence of chemotherapeutic drugs. We describe expression of IL-18 in pancreatic carcinoma cells and tissues associated with significantly elevated IL-18 levels in patients sera. Specifically, Capan-2 pancreatic tumor cells produced and secreted precursor IL-18 with no apparent biological activity. However, the chemotherapeutic agent 5-FU, by inducing Caspase-1 and Caspase-3 activation, induced secretion of proteolytically processed mature and degraded IL-18 species, respectively, in Capan-2 cells. Conditioned medium from 5-FU-treated but not control Capan-2 cells induced IFN-gamma production by activated T cells in an IL-18-dependent manner. Furthermore, adjuvant polychemotherapy including 5-FU significantly increased serum levels of mature, bioactive IL-18 in pancreatic carcinoma patients. Treatment of pancreatic cancer cells with 5-FU induced Caspase-dependent processing of pro-IL18 leading to the secretion of biologically active IL-18. These findings delineate a novel mechanism by which chemotherapeutic agents may modulate local anti-tumor cell-mediated immune responses.

Aim: The aim of this study was to determine the prevalence in the Turin area of the pathogens most implicated in pelvic inflammatory disease (PID), with particular regard to which risk factors the population taken into consideration is exposed to., Methods: From January 1st 1997 to December 31(st) 2001, 13809 women, aged between 14-54, all subjects being fertile and sexually active, were examined for the first time at St. Anna Hospital in Turin for the diagnosis of sexually transmitted diseases (STDs). A total of 5559 unselected patients were divided into 2 groups according to the presence (1721) or absence (3838) of subjective symptoms related to PID. Both groups underwent a cervico-vaginal bacteriological test for common pathogens, Candida spp., T. vaginalis, bacterial vaginosis, C. trachomatis, Mycoplasma spp., N. gonorrhoeae. The prevalence of each micro-organism was coupled with the anamnestic data collected from a pre-determined questionnaire submitted to all patients. The questionnaire collected personal data: age at the time of first sexual intercourse; the number of partners in the last 6 months; the type of contraceptives used. Statistical analysis was performed using a chi squared test., Results: In our analysis 2 factors proved to be decisive for a correct PID diagnosis: a subjective symptomatology and an anamnesis mainly focused on risk factor evaluation. This result is in accordance with what has been emphasized many times in the literature, i.e. many of these infections have only a few or no symptoms at all., Conclusion: Greater attention to the anamnestic data collection would therefore be the key to focusing the clinical investigations on those who are at a major risk to contracting STDs.

Multiple genetic aberrations contribute to the development of biologically aggressive, clinically malignant colorectal carcinomas (CRCs). Some of these have been linked to inappropriate signaling through the tyrosine kinase moieties of growth factor receptors. We have described previously (G. Bellone et al., J. Cell. Physiol., 172: 1-11, 1997) that human CRCs overexpress both the receptor tyrosine kinase c-kit and its ligand, stem cell factor (SCF), relative to normal mucosa cells, thus establishing an autocrine c-kit-mediated loop. In addition, we noted that exogenous SCF contributes to anchorage-independent growth of HT-29 colon carcinoma cells in semisolid medium. Here, we investigated possible roles of the c-kit/SCF autocrine/paracrine system in survival and invasive capacity of DLD-1 colon carcinoma cells. We report that SCF was required for migration and invasion of DLD-1 cells through reconstituted basement membranes (Matrigel) and up-regulated gelatinase (matrix metalloproteinase-9) activity in DLD-1 cells. Furthermore, we describe that SCF supported survival of DLD-1 cells in growth factor-deprived conditions. These results suggest multiple roles of c-kit activation in support of the malignant phenotype of DLD-1 cells related to growth, survival, migration, and invasive potential.

We report here that the progression of pancreatic carcinomas in tumor patients is associated with increased serum levels of both the soluble forms of CD95 ligand (CD95L/FasL) and its receptor, CD95 (Fas). Shedding of proteolytically processed soluble CD95L was also observed in pancreatic carcinoma cells in vitro, thus identifying one possible source of CD95L in patients' sera. Because the secreted forms of both CD95 and CD95L have been implicated previously in protection of cells from CD95-mediated cell death, we assessed the effect of soluble CD95L in supernatants of pancreatic carcinoma cells on viability of Jurkat T lymphocytes. We describe that (a) supernatants derived from cultured pancreatic carcinoma cells caused apoptosis of Jurkat cells; (b) soluble tumor-derived CD95L contributed significantly to this effect; and (c) in comparison to Jurkat cells, pancreatic carcinoma cells themselves revealed increased resistance to apoptosis induction by autocrine soluble CD95L. These results are consistent with the notion that in the microenvironment of pancreatic tumors, tumor-derived shed CD95L exerts paracrine pro-apoptotic effects. In addition, because it is released at high levels into the bloodstream, soluble CD95L may have systemic effects in tumor patients that reach beyond the microenvironment of the tumor site.

Background: After the liver, the lungs represent the most frequent site of metastasis from primary tumours. Surgical treatment of lung secondary neoplasms leads to a significant improvement in survival., Methods: Between 1960-1997, 178 patients with lung metastases underwent surgery at the Thoracic Surgery Department of Turin University in a total of 193 operations. A retrospective study was made in order to identify the prognostic factors which influenced final survival in this population., Results: Overall survival was 47% after 2 years and 20% after five years. Prognosis was not influenced by the size of metastases, the type of surgery, adjuvant therapy and the number of operations on the same patient. On the other hand, useful prognostic factors were found to be the histological type of the primary tumour, the original site of the neoplasm, the number of metastases and, above all, the disease-free interval (DFI)., Conclusions: Lung metastasectomy is an important therapeutic aid in selected patients, whereas the preoperative evaluation of the above prognostic factors enables a reasonably precise prognosis to be made in most patients.

Background: Pancreatic adenocarcinomas are among the most aggressive types of cancer with an extremely poor diagnosis. Since this type of cancer is not well amenable to chemo- and radiotherapy or immunotherapy, surgical resection remains the only feasible treatment to date. Transforming Growth Factor (TGF)-beta and Interleukin (IL)-10 are potent immunomodulators that have been shown to suppress several aspects of the immune response. Vascular Endothelial Growth Factor (VEGF) is a powerful angiogenic factor, recently thought to be involved in neoangiogenesis and metastasis spreading. Therefore the three cytokines may contribute, by different pathways, to immune escape and growth of tumor. This study was conducted to determine the possible significance of TGF-beta1, IL-10 and VEGF as markers for monitoring the clinical course of pancreatic adenocarcinoma patients., Methods: Cytokine serum levels were measured in 30 pancreatic cancer patients and in 30 age and sex-matched healthy subjects., Results: In comparison to serum concentrations in controls, TGF-beta1, IL-10 and VEGF levels were significantly elevated in all patients. Where the patients were divided by groups on the basis of the clinical stage of the disease, no differences were observed in TGF-beta1 levels among the groups. On the contrary, IL-10 and VEGF were more represented in stage IV patients than in stage II and III patients. In addition, the 14 patients who underwent surgical resection had postoperative cytokine serum levels markedly lower than those observed at diagnosis., Conclusions: Overall, the results suggest the importance of these markers in predicting the biological activity of the disease and suggest new targets for future rational therapies.

There is increasing evidence to support the concept that growth and metastasis of solid tumors, including those of gastrointestinal tract, is facilitated by neoangiogenesis. Vascular Endothelial Growth Factor (VEGF) is one of the most powerful known inducer of endothelial cell growth. Therefore, VEGF is likely to contribute to tumor growth by promoting angiogenesis and stroma formation both directly, through its neovascularization inducing activity, and indirectly, by increasing vascular permeability. In addition, VEGF facilitates tumor diffusion favouring metastatic spread of cancer cells. In view of these implications, it is important to understand the physiopathological role played by this factor. In this review the authors present the accumulating body of data on the biological and functional properties of VEGF, paying special reference to new evidence on its contribution in tumor immune escape, through a marked inhibition of differentiation and activity of the professional antigen presenting cells (APC), namely dendritic cells (DC). As the molecular and cellular events that underlie the functional role of VEGF in tumor angiogenesis and immune suppression become better defined, rational pharmacological and/or gene therapies can be derived in order to treat those neoplasms, such as pancreatic adenocarcinoma, not well amenable to chemo- and radiotherapy or immunotherapy.