National Institute for Digestive Diseases

Castellana Sicula, Italy

National Institute for Digestive Diseases

Castellana Sicula, Italy
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Guerra V.,National Institute for Digestive Diseases
European Journal of Gastroenterology and Hepatology | Year: 2014

Background: Massive hepatocellular carcinomas (HCCs) are uncommon and poorly characterized. Aim: To characterize a large cohort of HCC patients with massive tumors, with documented baseline characteristics and survival data. Methods: Records were examined of a cohort of 344 biopsy-proven and randomly presenting unresectable HCC patients with tumors of at least 10 cm diameter (massive), which were analyzed for their clinical characteristics and survival. Results: Massive HCC patients were significantly different from others, in having less severe cirrhosis and higher blood platelet counts, α-fetoprotein (AFP), alkaline phosphatase (ALKP), and γ-glutamyl transpeptidase (GGTP) levels. Platelets, ALKP, and GGTP correlated with tumor size. Within massive HCCs, ALKP levels related to tumor number, whereas platelet counts related to tumor size. AFP and GGTP related to neither. All four parameters related to survival. A multivariate Cox proportional hazard model showed that ALKP and AFP were significant for overall survival. Survival of massive tumors was not significantly worse than for other larger tumors. Conclusion: Massive HCCs were characterized by high blood platelets, AFP, ALKP, and GGTP levels. AFP levels were important for survival, but did not directly relate to tumor size or number, suggesting that AFP represents some other property of massive HCC biology. Patients with massive HCC should thus be considered for active therapeutic intervention, just as for other sizes of HCC. Copyright ©2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Bonamassa B.,Laboratory of Lipid Metabolism and Cancer | Moschetta A.,Laboratory of Lipid Metabolism and Cancer | Moschetta A.,University of Bari | Moschetta A.,Italian National Cancer Institute | Moschetta A.,National Institute for Digestive Diseases
Trends in Endocrinology and Metabolism | Year: 2013

Modulation of the cholesterol-sensing liver X receptors (LXRs) and their downstream targets has emerged as promising therapeutic avenues in atherosclerosis. The intestine is important for its unique capabilities to act as a gatekeeper for cholesterol absorption and to participate in the process of cholesterol elimination in the feces and reverse cholesterol transport (RCT). Pharmacological and genetic intestine-specific LXR activation have been shown to protect against atherosclerosis. In this review we discuss the LXR-targeted molecular players in the enterocytes as well as the intestine-driven pathways contributing to cholesterol homeostasis with therapeutic potential as targets in the prevention and treatment of atherosclerosis. © 2012 Elsevier Ltd.


Carr B.I.,Tel Aviv Sourasky Medical Center | Guerra V.,National Institute for Digestive Diseases | Steel J.L.,University of Pittsburgh | Lu S.-N.,Chang Gung University
Seminars in Oncology | Year: 2015

Hepatocellular carcinoma (HCC) is a leading cause of cancer death and has characteristic causes, epidemiology and clinical features. The leading causes include hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholism, and aflatoxin B1 dietary exposure, as well as combinations of these factors. Few cancers offer the opportunity to study the clinical and cancer phenotype that results from different causes, quite like HCC. Advantage was taken of a large cohort of advanced, unresectable and untransplantable HCCs to compare the phenotypes resulting from HBV-based compared with HCV-based HCC. The main findings were that HBV-based HCC patients were statistically significantly younger, had a higher percent of males, had larger maximum tumor sizes, and had higher blood alpha-fetoprotein (AFP) and albumin levels and platelet counts than HCV-based HCC patients. These differences partly reflect an earlier age of HBV infection and a lesser degree of cirrhosis-associated liver damage, as a result of the different biological consequences of chronic HBV compared with chronic HCV infection. © 2015 Elsevier Inc. All rights reserved.


Carr B.I.,National Institute for Digestive Diseases | Carr B.I.,Thomas Jefferson University
Seminars in Oncology | Year: 2012

A concordance of multiple advances is changing the management of hepatocellular carcinoma (HCC). These include: (1) identification of preventable and treatable causal factors, including hepatitis B and obesity (non-alcoholic steatotic hepatitis [NASH]); (2) description of molecular and proteomic profiles for HCC prognosis, disease subtyping, and drug selection; (3) identification of circulating tumor cells for non-invasive molecular typing; (4) identification of tumor stem cells, for HCC subtyping and as treatment targets; (5) large numbers of multi-kinase inhibitors that are currently undergoing clinical trial assessment and comparison; (6) an array of newer therapies of different drug classes, aimed at a wide range of targets in cell growth, apoptosis, autophagy, and tumor invasion pathways; (7) newer regional chemotherapy and radiotherapy regimens and delivery systems; (8) the extension of liver transplantation to larger HCCs and its wider availability through use of living-related organ donors; (9) new radiological techniques to assess the changes in HCC vascularity associated with angiogenic drug actions; (10) re-evaluation of the importance of tumor biopsy to obtain molecular signatures; (11) recognition of the importance of non-tumor liver parenchyma for tumor growth control and as a source of prognostic profiling in HCC patients; (12) the evaluation of kinase- and other inhibitors in neo-adjuvant and adjuvant therapy associated with resection and liver transplant and minimization of transplant waiting list drop-out; (13) re-evaluation of the role or limitation of tumor responses, since kinase inhibitors can enhance survival without HCC size responses; and (14) the development of combination therapies to enhance tumor control rates, either using drugs targeting differing pathways, or kinase-inhibitors combined with either chemotherapy drugs or yttrium 90. © 2012 Elsevier Inc.


Russo F.,National Institute for Digestive Diseases | Linsalata M.,National Institute for Digestive Diseases | Orlando A.,National Institute for Digestive Diseases
World Journal of Gastroenterology | Year: 2014

Gastric cancer is still the second leading cause of cancer death worldwide, accounting for about 10% of newly diagnosed neoplasms. In the last decades, an emerging role has been attributed to the relations between the intestinal microbiota and the onset of both gastrointestinal and non-gastrointestinal neoplasms. Thus, exogenous microbial administration of peculiar bacterial strains (probiotics) has been suggested as having a profound influence on multiple processes associated with a change in cancer risk. The internationally accepted definition of probiotics is live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. The possible effects on the gastrointestinal tract following probiotic administration have been investigated in vitro and in animal models, as well as in healthy volunteers and in patients suffering from different human gastrointestinal diseases. Although several evidences are available on the use of probiotics against the carcinogen Helicobacter pylori, little is still known about the potential cross-interactions among probiotics, the composition and quality of intestinal flora and the neoplastic transformation of gastric mucosa. In this connection, a significant role in cell proliferation is played by polyamines (putrescine, spermidine, and spermine). These small amines are required in both pre-neoplastic and neoplastic tissue to sustain the cell growth and the evidences here provided suggest that probiotics may act as antineoplastic agents in the stomach by affecting also the polyamine content and functions. This review will summarize data on the most widely recognized effects of probiotics against neoplastic transformation of gastric mucosa and in particular on their ability in modulating cell proliferation, paying attention to the polyamine metabolism. © 2014 Baishideng Publishing Group Inc. All rights reserved.


Pancoska P.,University of Pittsburgh | Carr B.I.,National Institute for Digestive Diseases
Seminars in Oncology | Year: 2014

We previously developed a network phenotyping strategy (NPS), a graph theory-based transformation of clinical practice data, for recognition of two primary subgroups of hepatocellular cancer (HCC), called S and L, which differed significantly in their tumor masses. In the current study, we have independently validated this result on 641 HCC patients from another continent. We identified the same HCC subgroups with mean tumor masses 9 cm x n (S) and 22 cm x n (L), P<10-14. The means of survival distribution (not available previously) for this new cohort were also significantly different (S was 12 months, L was 7 months, P<10-5). We characterized nine unique reference patterns of interactions between tumor and clinical environment factors, identifying four subtypes for S and five subtypes for L phenotypes, respectively. In L phenotype, all reference patterns were portal vein thrombosis (PVT)-positive, all platelet/alpha fetoprotein (AFP) levels were high, and all were chronic alcohol consumers. L had phenotype landmarks with worst survival. S phenotype interaction patterns were PVT-negative, with low platelet/AFP levels. We demonstrated that tumor-clinical environment interaction patterns explained how a given parameter level can have a different significance within a different overall context. Thus, baseline bilirubin is low in S1 and S 4, but high in S2 and S3, yet all are S subtype patterns, with better prognosis than in L. Gender and age, representing macro-environmental factors, and bilirubin, prothrombin time, and AST levels representing micro-environmental factors, had a major impact on subtype characterization. Clinically important HCC phenotypes are therefore represented by complete parameter relationship patterns and cannot be replaced by individual parameter levels. © 2014 Elsevier Inc.


Orlando A.,National Institute for Digestive Diseases | Russo F.,National Institute for Digestive Diseases
Journal of Gastrointestinal Cancer | Year: 2013

Introduction Cancers of the gastrointestinal tract account for 25 % of all cancers and for 9 % of all causes of cancer death in the world, so gastrointestinal cancers represent a major health problem. In the past decades, an emerging role has been attributed to the interactions between the gastrointestinal content and the onset of neoplasia. Methods Thus, exogenous microbial administration of peculiar bacterial strains (probiotics) has been suggested as having a profound influence on multiple processes associated with a change in cancer risk. Probiotics are mono or mixed cultures of live microorganisms that might beneficially affect the host by improving the characteristics of indigenous microflora. Although the effects of probiotic administration has been intensively investigated in vitro, in animal models, in healthy volunteers, and in some human gastrointestinal diseases, very little is still known about the possible cross-interactions among probiotic administration, changes of intestinal flora, and the neoplastic transformation of gastrointestinal mucosa. Results Theoretically, probiotics are able to reduce cancer risk by a number of mechanisms: (a) binding and degradation of potential carcinogens; (b) quantitative, qualitative and metabolic alterations of the intestinal microflora; (c) production of anti-tumorigenic or anti-mutagenic compounds; (d) competitive action towards pathogenic bacteria; (e) enhancement of the host's immune response; (f) direct effects on cell proliferation. Conclusion This review will attempt to highlight the literature on the most widely recognized effects of probiotics against neoplastic transformation of gastrointestinal mucosa and in particular on their effects on cell proliferation. © Springer Science+Business Media New York 2012.


Carr B.I.,National Institute for Digestive Diseases | Guerra V.,National Institute for Digestive Diseases
Hepato-Gastroenterology | Year: 2013

Background/Aims: Thrombocytopenia has been reported to be a surrogate for cirrhosis, but the HCC phenotypes associated with and without cirrhosis are not well studied. To compare characteristics of HCC patients with and without associated thrombocytosis. Methodology: Records were examined of a cohort of 668 biopsy-proven and randomly presenting unresectable HCC patients, who were dichotomized for presence (platelets <125 × 109/L) or absence (platelets 125-400 × 109/L) of thrombocytopenia. Results: Patients with normal platelets had larger tumors, more tumor nodules and longer survival than in the thrombocytopenia group. They also had more normal total plasma bilirubin, albumin and prothrombin times, yet had higher GGTP, ALKP and AFP levels. Conclusions: Thrombocytopenia in association with HCC occurs in patients with smaller tumor sizes, worse liver function and poorer survival, supporting the importance of host factors and liver micro-environment in HCC patients and the likelihood of two pathways for HCC development. © H.G.E. Update Medical Publishing S.A.


Carr B.I.,National Institute for Digestive Diseases | Guerra V.,National Institute for Digestive Diseases
Digestive Diseases and Sciences | Year: 2013

Background: Thrombocytopenia has been reported to be both a risk factor for hepatocellular carcinoma (HCC) development as well as a prognostic factor. Many HCCs also occur in presence of normal platelets. Aim: To examine a cohort of HCC patients with associated thrombocytosis. Methods: Records were examined of a cohort of 634 biopsy-proven and randomly presenting HCC patients without thrombocytopenia. Results: In the total cohort, 52 patients were identified with thrombocytosis (platelet levels >400 × 109/L) and compared with 582 patients with normal platelet values. The average tumor sizes were 13.1 versus 8.8 cm (p < 0.0001), and their total average bilirubin levels were 0.9 versus 1.5 (p = 0.02), comparing thrombocytosis patients versus normal platelet count HCC patients. These differences were even more pronounced in patients with HCC sizes >5 cm. Thrombocytosis patients were younger and had less cirrhosis, but similar percent with hepatitis B or C or alcohol consumption. Conclusion: Thrombocytosis in association with HCC occurs in patients with larger tumor sizes and better liver function. © 2013 Springer Science+Business Media New York.


Notarnicola M.,National Institute for Digestive Diseases | Tutino V.,National Institute for Digestive Diseases | Caruso M.G.,National Institute for Digestive Diseases
Current Medicinal Chemistry | Year: 2014

Alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Cancer cells esterify fatty acids predominantly to phospholipids, an essential component of cell membranes. The main pathway along which proliferating cells gain lipids for membrane synthesis is the endogenous mevalonate pathway. Increased synthesis of mevalonate and mevalonate-derived isoprenoids supports increased cell proliferation through activating growthregulatory proteins and oncoproteins and promoting DNA synthesis. The importance of a better knowledge of metabolic changes in lipogenic enzymes pathways, as well as of the role of each biochemical pathway in carcinogenesis, provides the rationale for in-depth study of the oncogenic signaling important for the initiation and progression of tumors. The dependence of tumor cells on a dysregulated lipid metabolism suggests that the proteins involved in this process may be excellent chemotherapeutic targets for cancer treatment. Here, we confirm the vital link between lipogenesis and cell proliferation, and our recent findings suggest that nutritional intervention is an effective and safe way to reduce cell proliferation in experimental models of carcinogenesis. The olive oil diet significantly reduces the protein activities of lipogenic enzymes associated with cell growth. The use of natural dietary components could potentially assist in the management of subjects with metabolic disorders-related tumors. © 2014 Bentham Science Publishers.

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