The Cytokinome Profile in Patients with Hepatocellular Carcinoma and Type 2 Diabetes.

Understanding the dynamics of the complex interaction network of cytokines, defined as ''cytokinome'', can be useful to follow progression and evolution of hepatocellular carcinoma (HCC) from its early stages as well as to define therapeutic strategies. Recently we have evaluated the cytokinome profile in patients with type 2 diabetes (T2D) and/or chronic hepatitis C (CHC) infection and/or cirrhosis suggesting specific markers for the different stages of the diseases. Since T2D has been identified as one of the contributory cause of HCC, in this paper we examined the serum levels of cytokines, growth factors, chemokines, as well as of other cancer and diabetes biomarkers in a discovery cohort of patients with T2D, chronic hepatitis C (CHC) and/or CHC-related HCC comparing them with a healthy control group to define a profile of proteins able to characterize these patients, and to recognize the association between diabetes and HCC. The results have evidenced that the serum levels of some proteins are significantly and differently up-regulated in all the patients but they increased still more when HCC develops on the background of T2D. Our results were verified also using a separate validation cohort. Furthermore, significant correlations between clinical and laboratory data characterizing the various stages of this complex disease, have been found. In overall, our results highlighted that a large and simple omics approach, such as that of the cytokinome analysis, supplemented by common biochemical and clinical data, can give a complete picture able to improve the prognosis of the various stages of the disease progression. We have also demonstrated by means of interactomic analysis that our experimental results correlate positively with the general metabolic picture that is emerging in the literature for this complex multifactorial disease.

Cytokinome profile evaluation in patients with hepatitis C virus infection.

The ''omics sciences'' (genomics, transcriptomics, proteomics) are often used to study living organisms as a whole system by evaluating the complex expression patterns of genes, miRNA, proteins, and metabolites. This study aimed, through bioinformatics and systems biology, to decipher the cytokinome profile in the evolution of inflammatory processes leading to cancer. The cytokinome was defined as the totality of cytokines and their interactions in and around biological cells. The system biology approach would provide a better understanding of the complex interaction network of cytokines, especially in cancer patients. Acquired knowledge would enable health providers with tools to evaluate disease onset through progression as well as identifying innovative therapeutic strategies. Understanding the role each cytokine plays in the metabolic network is of great importance. This paper reviews our group's ''omics'' work. In particular, it addresses the role cytokines play in liver disease in six different scenarios. The first is the role the cytokines play in chronic inflammatory diseases and cancers. The second is the significance of the cytokinome profile. The third is the role of liver cirrhosis as an inflammatory disease. The fourth is the comparison of cytokine levels evaluated in patients with chronic hepatitis C virus (HCV) or with HCV-related cirrhosis. The fifth is the comparison of cytokine levels evaluated in patients with HCV-related cirrhosis in the presence and absence of type 2 diabetes. And lastly, we present a comparison of cytokine levels evaluated in patients with HCV-related cirrhosis in the presence and absence of hepatocellular carcinoma.

Role of IL28B gene polymorphism and cell-mediated immunity in spontaneous resolution of acute hepatitis C.

BACKGROUND: A single-nucleotide polymorphism (SNP; rs12979860) near the IL28B gene has been associated with spontaneous and treatment-induced hepatitis C virus clearance. We investigated predictors of spontaneous disease resolution in a cohort of patients with acute hepatitis C (AHC), analyzing epidemiological, clinical and virological parameters together with IL28B.rs12979860 genotypes and cell-mediated immunity (CMI). METHODS: Fifty-six symptomatic AHC patients were enrolled and followed prospectively. CMI was measured in 31 patients at multiple time points by interferon-γ enzyme-linked immunospot assay and was correlated to the IL28B.rs12979860 SNP. RESULTS: Eighteen patients had a self-limiting AHC that was associated with female sex (P = .028), older age (P = .018), alanine aminotransferase level >1000 U/L (P = .027), total bilirubin level >7 mg/dL (P = .036), and IL28B.rs12979860 genotype CC (P = .030). In multivariate analysis, only CC genotype was independently associated with self-limiting AHC (odds ratio, 5.3; 95% confidence interval, 1.1-26.5). Patients with the CC genotype with self-limiting AHC had a stronger (P = .02) and broader (P = .013) CMI than patients with the CT genotype with chronically evolving AHC. In patients with chronically evolving disease, CC genotype was associated with a broader CMI compared to CT genotype (P = .028). A negative CMI was more frequently associated with CT genotype among persistently infected patients (P = .043) and with persistent infection among CT patients (P = .033). CONCLUSIONS: . Self-limiting AHC was independently associated with CC genotype. The correlation between IL28B.rs12979860 genotypes and CMI is suggestive of a possible important role of CMI in favoring hepatitis C virus clearance in CC patients.

Cancer biomarker profiling in patients with chronic hepatitis C virus, liver cirrhosis and hepatocellular carcinoma.

The detection and diagnosis of hepatocellular carcinoma (HCC) at an early stage may significantly affect the prognosis of HCC patients. Thus, it is necessary to always identify novel putative markers for improving diagnosis. Hepatocarcinogenesis correlates with pathological hepatic angiogenesis. However, each tumor-induced angio-genetic process is influenced by the microenvironment through several pro- and anti-angiogenic factors released from tumor cells, tumor-associated inflammatory cells and/or from the extracellular matrix, and modulated by various signal pathways. In this study, we evaluated the profiling of angiogenic factors using Bio-Plex Pro™ Human Cancer Biomarker Panel 1, a 16-plex magnetic bead-based assay, in sera of patients with chronic hepatitis C (CHC) virus, liver cirrhosis (LC) and HCC. Our results demonstrated: i) high levels of hepatocyte growth factor (HGF) and prolactin only in LC and HCC patients, ii) high levels of soluble human epidermal growth factor receptor­2 (sHER-2/neu; ErbB-2), sIL-6Ra, leptin (LEP) and platelet endothelial cell adhesion molecule­1 (PECAM-1) in CHC, LC and HCC patients and iii) that sIL-6R correlated with the fibrosis stage in CHC patients, with Child­Pugh score in those patients with LC and with tumor size in those patients with HCC, confirming that this protein may be used as a predictor of liver damage and of inflammatory process leading to fibrosis, cirrhosis, and subsequently to cancer. Moreover, an interactomic study conducted using the Ingenuity Pathway Analysis (IPA) software proved the existence of a correlation between 5 significant proteins [ErbB-2, sIL-6Ra, prolactin (PRL), HGF and LEP] which are involved in the same metabolic pathways.

Treatment optimization and prediction of HCV clearance in patients with acute HCV infection.

BACKGROUND & AIMS: The lack of consensus on the optimal timing, regimen, and duration of treatment, in patients with acute HCV infection, stimulates the research on both favourable outcome predictors and individualized treatment regimens. This study aimed at investigating the impact of IL28B SNP rs12979860 alone or in combination with HLA class II alleles in both predicting spontaneous viral clearance and individualizing treatment strategies for patients with HCV persistence, after acute HCV exposure. METHODS: 178 patients with AHC, consecutively treated with interferon alone or in combination with ribavirin, starting within or after 48 weeks from the diagnosis of AHC, were tested for IL28B SNPs and HLA class II alleles. RESULTS: Spontaneous viral clearance was achieved in 28% of 169 patients available for genetic testing. Factors associated with HCV elimination were jaundice (OR 2.75, 95% CI 1.31-5.77) and IL28B CC (OR 3.87, CI 1.71-8.51), but not HLA alleles. In CT/TT patients without jaundice, NPV for virus persistence was 98%. In patients with IL28B CT/TT, starting treatment 48 weeks after the onset was significantly associated with lower rates of response (28% vs. 100%, p=0.027). By contrast, no significant differences in the rate of SVR were observed for CC carriers who started treatment later (65% vs. 85%, p=1.0). CONCLUSIONS: In patients with acute HCV hepatitis, lack of viral clearance may be predicted by absence of jaundice and IL28B CT/TT genotype; in patients with these characteristics, treatment needs to be started immediately.

[Abdominal tuberculosis in a young immigrant patient: a clinical case]. / Tubercolosi addominale in un giovane paziente extracomunitario: descrizione di un caso clinico.

In developing countries, tuberculosis (TBC) is commonly associated with inadequate socio-economic and sanitary conditions. Currently, in Western countries, TBC is often linked with HIV infection, an ageing population or trans-global migration. Approximately two out of ten TB cases worldwide are extra-pulmonary, of which abdominal tuberculosis accounts for 11%-16%. The Mycobacterium tuberculosis complex involves the abdomen as primary or secondary localization (hematogenous spread or from pulmonary foci or infected neighbouring organs). Abdominal TBC can infect the gastrointestinal tract, peritoneum, mesentery, abdominal lymph nodes, liver, spleen, and pancreas. Diagnosis of abdominal tuberculosis is difficult because of vague and non-specific clinical features and due to the differential diagnosis with other granulomatous diseases such as Crohn's Disease. It is of great importance for clinicians to pay great attention to tubercular aetiology as a possible cause of gastrointestinal symptoms. Here we describe the clinical case of a young immigrant patient with intestinal TB for whom the wrong initial diagnosis led to a delay in the correct diagnosis and a worsening of the already serious general conditions.

Cytokinome profile of patients with type 2 diabetes and/or chronic hepatitis C infection.

Both type 2 diabetes (T2D) and chronic hepatitis C (CHC) infection are associated with increased risk of developing hepatocellular carcinoma (HCC). Cytokines are known to play an important role not only in the mechanisms of insulin resistance and glucose disposal defects but also in the pathological processes occurring in the liver during viral infection. We evaluated the serum levels of many cytokines, chemokines, adipokines and growth factors in patients with type 2 diabetes, CHC, CHC-related cirrhosis, CHC and type 2 diabetes and CHC-related cirrhosis and type 2 diabetes by BioPlex assay. The obtained data evidenced that the serum levels of some proteins are significantly up-regulated in all the patients or in those with only one disease and are often higher, even if in different amounts, when both diseases are associated. In particular, our results can be useful for the clinical monitoring of patients because they give specific information in regard to the progression from CHC to LC and CHD to LCD. Moreover, some molecules have shown significant correlations with clinical/biochemical data, suggesting the possibility to define mini-panels that can be used as specific markers for the different disease staging. However, our observations demonstrate that an integrated approach is much more powerful than isolated measurements to evaluate specific stages of these two complex pathologies (type 2 diabetes and chronic CHC hepatitis) alone or when they are concomitant in a patient. In fact it has emerged as an accurate, simple, specific, noninvasive, reproducible and less expensive method that, in future, could be included in routine clinical practice to monitor the association of type 2 diabetes and/or CHC to liver cirrhosis and, possibly, to cancer, and to improve the prognosis of these diseases.

Serum cytokine levels as putative prognostic markers in the progression of chronic HCV hepatitis to cirrhosis.

Hepatitis C virus (HCV) infection can present as an acute manifestation, and can lead to severe complications such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). It represents a global health problem because there is no vaccine currently available. Cytokines play an important role in viral clearance, infection control, inflammation, regeneration and fibrosis, and also are implicated in the pathological processes occurring in the liver during viral infection. Immunological markers of chronic HCV hepatitis progression as compared to cirrhosis and HCC would be extremely useful, particularly for distinguishing between the molecules produced during HCV-induced chronic inflammation and those secreted during cirrhosis and HCC. In this work, we evaluated the serum levels of several cytokines, chemokines and growth factors in 30 patients affected by chronic HCV (HC), 30 patients affected by HCV-related cirrhosis (LC) and 20 healthy, control subjects. We used a multiplex biometric ELISA-based immunoassay in order to identify molecules that might be useful for monitoring the progression of HCV to liver cirrhosis and, possibly, to cancer. Our results show that some pro-inflammatory molecules are significantly up-regulated, and play a role as immunological markers in the intermediate steps towards liver cancer, and that hepatocyte growth factor (HGF) is a specific marker of liver cirrhosis. Finally, these data will be used to define a cytokinome profile, which might prove useful for studies involving the transition of chronic inflammation to neoplastic processes.

Visceral leishmaniasis in a patient with common variable immunodeficiency and evans syndrome: clinical remarks.

Visceral Leishmaniasis (VL) is a vector-borne zoonosis endemic in Southern Italy whose usual clinical features include fever, splenomegaly, pancytopenia and hypergammaglobulinemia. The clinical and biochemical picture may be misleading in patients with immunodeficiency diseases hampering the diagnosis. We describe a VL case in a patient whose spleen had been removed and who had Common Variable Immunodeficiency and Evans syndrome.

Impact of viral selected mutations on T cell mediated immunity in chronically evolving and self limiting acute HCV infection.

The ability of HCV to mutate in response to cytotoxic T lymphocyte (CTL) pressure is increasingly recognized, but the influence of such a mechanism in viral persistence and final disease outcome has not been ascertained. In this study, we performed a detailed longitudinal analysis of cell mediated immunity and HCV evolution in two self limiting and two chronically evolving HCV acutely infected patients, one of whom transiently controlled viremia. Amino acid mutations in immunodominant regions of viruses were observed in all patients, although they conferred viral escape from CTL responses only in chronically infected individuals. Resurgence of viremia coincided with the replacement of the original virus quasispecies with mutant viruses that had escaped recognition by primary CD8(+) T cell responses and infection persisted in the presence of variant viruses which were less efficiently recognized by preexisting and de novo induced T cell responses.

Mycobacterium xenopi pulmonary infection resulting in self-limited immune reconstitution inflammatory syndrome in an HIV-1 infected patient.

Highly active antiretroviral therapy (HAART) has been shown to induce a major and durable viral load reduction accompanied by a stable CD4 increase. This process may evolve with adverse clinical phenomena, known as the immune reconstitution inflammatory syndrome (IRIS). In the HIV population, non-tuberculous mycobacteria are a common cause of IRIS. However, only a few cases of Mycobacterium xenopi associated IRIS have been described. This paper concerns a case of M. xenopi pulmonary infection resulting in self-limited immune reconstitution inflammatory syndrome in an HIV-1 infected patient.

Infected atrial myxoma: case report and literature review.

Myxoma is the most common type of cardiac tumour in all age groups. It may simulate infective endocarditis but is rarely infected. We describe one case of infected left atrial myxoma caused by Enterococcus faecalis. Combined therapy, consisting of surgical management and antimicrobial therapy, was used. Histological examination of the excised tumour revealed a typical myxoma with infiltrates of neutrophils. Few cases of infected atrial myxomas have been reported in the literature.

[Pathways for surgical antibiotic prophylaxis]. / Percorsi in antibiotico-profilassi chirurgica.

Surgical site infections (SSIs) are a notable cause of hospital morbidity and mortality. Antibiotic prophylaxis has demonstrated a significant reduction in infection rate in clean-contaminated surgery and in clean surgery to a limited extent. To make antibiotic prophylaxis effective it is necessary to choose the right antibiotic, to administer it preoperatively and maintain sufficient serum and tissue levels through the operation. Open issues remain: antibiotic prophylaxis duration in prosthetic surgery, its use in hernia repair, breast surgery and mini-invasive surgery.

[Multicentre survey of post-surgical infections in Campania (Italy)]. / Multicentre survey of post-surgical infections in Campania (Italy).

The aim of the study was to evaluate the incidence of post-surgical infections and to assess the way of managing antibiotic surgical prophylaxis. The survey was carried out by means of a questionnaire in order to obtain diverse information such as demographics, length of pre- and post-operative hospitalization, type of surgery, intervention duration, possible antibiotic prophylaxis and onset of post-surgical infections also monitored by post-discharge ambulatory controls. Four General Surgery and five Obstetrics and Gynaecology Departments in Campania (southern Italy) participated in the study, which was carried out in the period December 2001-January 2002. Overall, 410 questionnaires were collected referring to as many patients; antibiotic prophylaxis was performed in 385 (93.9%) patients. Antibiotic prophylaxis was generally managed not according to the general principles suggested by the international guidelines either for timing or for its duration or for the route of administration. Substantial differences were also noted in patient selection and antibiotic choice. Surgical site infections were recorded in 0.6% of patients undergoing clean surgery, in 5.3% of patients undergoing clean-contaminated surgery and in 3.2% of those undergoing contaminated surgery. Distant infections occurred in 1.8% and 6.5% in clean-contaminated and contaminated surgery, respectively. The results of the present study suggest the need of a continuous and accurate monitoring of post-surgical infections and the need to adopt appropriate guidelines to improve the management of surgical prophylaxis.