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Cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), and tumor necrosis factor-α (TNF-α) are mediators of inflammation and angiogenesis; all of them are produced in liver cirrhosis (LC) and in hepatocellular carcinoma (HCC). It was proposed that there is an association between single nucleotide polymorphisms (SNPs) and HCC. These allelic variants influence the transcriptional activity of these genes, and therefore the proteins levels. The VEGF-A pathway is a potential therapeutic target in HCC, and several antiangiogenic agents have entered clinical trials in HCC. We evaluated the frequency of SNPs of COX-2, TNF-α, and VEGF-A genes in patients with HCC versus LC patients and a control group. The aim of this article was to verify the correlation between the allelic variations and the risk of developing HCC. The study included 96 HCC, 79 LC patients, and 162 healthy subjects. The evaluation of SNPs was performed by the restriction fragment length polymorphism (RFLP-PCR) method. The SNPs analyzed were: -1195 GA of the COX-2 gene, -308 GA of the TNF-α gene, and +936 CT of the VEGF-A gene. Chi-square and Fisher exact tests were used for statistical analysis. Our results confirm that carriers with the C allele in the VEGF-A gene are more frequent in HCC versus LC (p=0.039), suggesting that this SNP may predispose to the development of HCC.

Many cytokine polymorphisms have been studied for associations with susceptibility to breast, gastric, liver, lung, prostate, and ovarian cancer without conclusive results. The cytokine network, indeed, is characterized by complex interactions, and the final biological effect of a single genetic variation depends on the balance among different molecular signals. As is well known, Th1/Th2 cytokine unbalanced production might predispose to different pathologies, cancer included. In general, a prolonged type 1 inflammatory response might allow that cells accumulating enough "genetic hits" are promoted to neoplastic transformation. On the other hand, IL-13-producing cells through the IL-13/IL-4 receptor-alpha (R-alpha) pathway might facilitate escape from tumor immunosurveillance. Here are reported data on the evaluation of the influence of some type 2 and type 1 cytokine genetic polymorphisms as risk factors for pancreatic cancer. There was no overall association between pancreatic cancer risk and single cytokine SNPs. On the other hand, in evaluating the influence of combined cytokine genotypes we found that the combined IL-10-1082GA heterozygous and IL-4 Ralpha-1902AA homozygous genotype is underrepresented in the pancreatic cancer subject group. As is well known, the IL-10-1082GA genotype is associated with an intermediate production of this regulatory cytokine, whereas the IL-10-1902AA genotype of the IL-4Ralpha gene is associated with a reduced efficiency in signal transduction when the receptor is engaged by IL-13 or IL-4. These results strongly suggest that a genetic background associated to a mild downregulation of type 1 and type 2 inflammatory signals might be protective against pancreatic cancer.

Background and Aims: Hepatic enzyme CYP2E1 is involved in the metabolism of a number of exogenous and endogenous substances (i.e. ethanol, drugs and chemical carcinogens). Being polymorphic, CYP2E1 gene can give different xeno-metabolic capabilities in a population and it is well known that inadequate or no enzymatic deactivation of xenobiotics could induce an increased susceptibility to disease and cancer. In particular, one of the 5 -flanking region polymorphisms, able to differentiate CYP2E1 gene transcriptional activity, is caused by the appearance/disappearance of RsaI and PstI restriction sites, which generates two different alleles, namely *C1(Rsa+/Pst−) and *C2(Rsa−/Pst+) respectively, reported to be in complete linkage disequilibrium. Methods: To confirm the existence of a correlation between some particular CYP2E1 genotypes/haplotypes and hepatocarcinoma, we determined CYP2E1 PstI/RsaI genotypes/haplotypes by RFLP-PCR in a cohort of central western Sicily hepatocarcinoma patients and in a population of healthy students from the same geographic area. Results: In hepatocarcinoma patients, modal genotype association was Rsa++/Pst−−, corresponding to CYP2E1 *C1/*C1 haplotype, whereas the Rsa+−/Pst−+ association, equivalent to CYP2E1 *C1/*C2 haplotype, resulted to have the lowest frequency both in patients and in controls. Moreover, both in patients and in controls, noncanonical genotype associations were frequent and arose from a no-linkage disequilibrium between the two polymorphic sites. Other authors reported this finding as a rare occurrence. Thus, from analysis of only one restriction site, Rsa++ genotype was approximately 1.5-fold more frequent in patients than in controls, and the non-canonical Rsa+− genotype was found relatively frequent in patients. Moreover, HuH7 and HA22T transformed hepatocarcinoma cell lines also showed the Rsa+− genotype. Conclusions: These results suggest that the presence in CYP2E1 genotype of at least one allele with an Rsa I restriction site is correlated with hepatocarcinoma. As this site is known a consensus sequence for some specific CYP gene transcription factors, like HNF-1, it may be supposed that a single nucleotide polymorphism can alter the possibility of HNF-1 to bind CYP2E1 promoter. This could determine a marked change in the transcriptional activity of the gene, incompetence in xenobiotic metabolism or in toxic substance deactivation and an increased susceptibility to neoplastic diseases, such as hepatocarcinoma.

Objectives: High levels of soluble E-selectin have been reported in acute and chronic inflammatory disorders. Moreover, in some types of tumor elevated values have been found while in other types reduced levels have been reported. Our aims were to determine whether soluble E-selectin levels might be useful in monitoring the progression of chronic liver disease, including hepatocellular carcinoma. Methods: Circulating soluble E-selectin was measured by an enzyme-linked immunosorbent assay in the sera of 18 patients with chronic hepatitis, 44 with liver cirrhosis, and 38 with hepatocellular-carcinoma-associated liver cirrhosis. Immunohistochemical localization of E-selectin was also performed on liver tissue specimens of patients with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Results: Serum levels of soluble E-selectin were higher in the chronic hepatitis and liver cirrhosis patients than in the hepatocellular carcinoma patients and healthy controls. Levels in the hepatocellular carcinoma patients and controls were not significantly different. In the liver cirrhosis group, divided according to the Child-Pugh classification, soluble E-selectin decreased with disease severity. Similarly, in patients with liver cirrhosis who developed hepatocellular carcinoma, soluble E-selectin decreased as the disease progressed. Immunohistochemical localization showed strong membrane staining on endothelial cells in areas rich in inflammatory cells in severe chronic hepatitis. In some hepatocellular carcinoma tissues a marked E-selectin staining was observed on endothelial cells of tumor-associated small vessels. Conclusions: The results obtained suggest that high serum levels of soluble E-selectin are associated with chronic hepatitis and liver cirrhosis, and that levels decrease in liver cirrhosis patients as the disease progresses. Patients with hepatocellular carcinoma have different types of soluble E-selectin behaviour the significance of which requires further investigation.

Actinomycosis is a bacterial infection due to Gram positive bacteria of Actinomyces genus. Actinomyces israelii is the most common in human infection.The authors described a case occurred in a 43 aged woman with a clinical presentation of a right submandibular indurative mass.After surgery, histological examination showed a granulomatous tissue with many actinomycetes. Patient was submitted to treatment with i.v penicillin. On the 11th day antibiotic therapy was replaced with ceftriaxone and teicoplanina. Patient did not present intercurrence during this period and presented improvement of the lesion.Actinomycosis is an uncommon disease. Establishment of the definite diagnosis requires a high index of suspicion in all cases of relapsing cervical lesions. Penicillin is effective and it can be replaced by third-generation cephalosporins.

Urinary tract schistosomiasis is a parasitic disease caused by S. haematobium with a wide range of clinical manifestations related to the mucosal and submucosal granulomatous lesions of the bladder. It affects about 80 million people in Africa, Middle-East and India, while in Italy it is rarely seen among immigrants from endemic areas and returning travellers. The authors describe a case occurred in a 26 year old man, recently emigrated from a rural area of Ghana. He had the symptoms of a haemorrhagic cystitis. Cystoscopy and biopsy showed granulomatous lesions of bladder with calcified eggs. Microscopic examination of urine was positive for Schistosoma haematobium eggs. The therapy with Praziquantel (40 mg/Kg una tantum) was effective. The authors emphatized the risk of introduction of schistosomiasis in some regions of our country, in consideration of the presence of the intermediate host as well as of an appropriate climate.

Multivesicular, pulmonary and cardiac hydatidosis are rarely observed and can give rise to serious complications. Cysts can remain asymptomatic for a long time, until they reveal themselves perforating into cardiac chambers and/or pulmonary arteries or the systemic circulation. A rare case of multivesicular interatrial septum hydatid cyst with multiple pulmonary involvement in a native Italian farm labourer is reported. Clinical, radiological, serological and histological findings are described. MR imaging showed the exact anatomic location and the multivesicular nature of the cardiac cyst and was useful in planning surgical treatment. A successful outcome was achieved with a combination of pre- and post-operative albendazole therapy and a three-step surgery procedure. The patient made a rapid recovery and his post-operative period was totally uneventful. This case highlights the importance of an early multidisciplinary surgical approach and long-term chemotherapy treatment of this serious and rare disease. MR Imaging was crucial in the pre-surgical and follow-up observations.

The association of Helicobacter pylori (Hp) infection with gastric cancer is well known and might be considered a paradigmatic example of the role that interaction among environmental factors and individual background might play in inducing age-associated disease. To evaluate the role of interaction of Hp infection with genetic background, gastric cancer and chronic gastritis patients as well as random selected controls were typed for five inflammation-related polymorphisms of IL-1 and IL-10 cytokine genes. No association among IL-10 or IL-1 variants with an increased risk of gastric cancer was found, whereas an Hp-independent association of IL-1beta -511T positive genotypes to an increased risk of chronic gastritis was found (Hp-/511T+ OR 1.89, 95% CI: 1.01-3.54; Hp+/-511T+ OR 1.83, 95% CI: 1.05-3.19). Stratification of gastric cancer group according to Hp infection does not allow finding a statistically significant association of Hp+ to the higher histological grading (G3) of gastric cancer (OR 1.54, 95% CI: 0.46-5.11). Our findings seem to confirm that cytokine genetic variants might contribute to determining the background for inflammaging in which H. pylori infection might facilitate cancer development.

Since PAP is a stress protein expressed in human pancreas during pancreatitis but also constitutively synthesized in the small intestine, we looked whether its expression would be altered in patients with celiac disease. Serum PAP concentrations were determined consecutively in 54 patients with celiac disease on a free diet (group A), in 47 patients with celiac disease on a gluten-free diet (group B), in 22 patients with other intestinal pathologies but with normal intestinal mucosa (group C), in 14 patients with retarded growth, no gastrointestinal disease and normal intestinal mucosa (group D), and in 17 controls (group E). Serum PAP levels (ng/ml) were significantly higher in group A (127.3 +/- 56.8) than in the other groups (B: 47.2 +/- 20.5; C: 51.5 +/- 32.2; D: 47 +/- 22.8; E: 27.6 +/- 9.0), which were not different from each other. In group A, a positive correlation was observed between serum PAP values and antigluten antibody levels (vs. AGA IgG r = 0.58, p0.001; vs. AGA IgA r = 0.66, p0.001). Furthermore, 12 patients from group A were evaluated after 10-12 months of gluten-free diet and in all of them PAP serum concentration had decreased (mean +/- SE before the diet 122.5 +/- 36.4, after the diet 48.7 +/- 13.7, p0.0001). In addition, we performed an immunocytochemical study to localize PAP in the intestinal mucosa of patients from all groups except E. PAP was localized to the Paneth cells and to some globet cells, in patients with mucosal atrophy as well as in those with normal mucosa with no obvious quantitative difference. We concluded that in patients with celiac disease the active phase of the disease was accompanied by an increased serum concentration of PAP. Further studies are necessary to understand the mechanism leading to PAP elevation in the serum of patients with celiac disease.

Intercellular adhesion molecule-1 (ICAM-1) is thought to play an important role in cellular immunological reactions. Expression can be induced by inflammatory cytokines in a wide variety of cells, including hepatocytes.To compare the behaviour of ICAM-1 in liver diseases.We assayed serum ICAM-1 (sICAM-1) in patients with hepatocellular carcinoma-associated liver cirrhosis, and compared them with a group of cirrhotic patients and controls. sICAM-1 values were also correlated with some biochemical parameters of liver function. Moreover, immunohistochemical localization of ICAM-1 was performed on liver tissue sections of patients with hepatocellular carcinoma, liver cirrhosis and a sample of normal liver.sICAM-1 levels were significantly higher in the hepatocellular carcinoma patients than in controls (P0.0001) and the cirrhosis group (P0.001). sICAM-1 values directly correlated with alanine aminotransferase, total bilirubin, alkaline phosphatase and gamma-glutamyltranspeptidase serum values (P0.05), with an inverse correlation with albuminaemia values (P0.05). There was no correlation with alpha-fetoprotein values, but sICAM-1 values were higher in hepatocellular carcinoma patients with large tumours (3 cm) than in those with small tumours (3 cm) (P0.04). Immunohistochemical localization of ICAM-1 was negative in normal liver tissue; positive staining for endothelial cells was found in chronic liver disease, while in hepatocellular carcinoma tissues, positive membrane staining was observed in hepatocytes and, to a lesser extent, at the cytoplasmic level.These results suggest that high serum levels of sICAM-1 are associated with severe liver disease, such as liver cirrhosis and hepatocellular carcinoma, and that they tend to increase with deteriorating hepatic function and tumour size.

BACKGROUND: Aiming to deepen the understanding of the factors involved in the genesis of groin hernia, this study is focused on identifying the histological changes within the muscle fibers of the internal inguinal ring in patients having indirect inguinal hernia. METHODS: In eight patients with primary or recurrent bilateral indirect inguinal hernia who underwent a Stoppa open posterior inguinal hernia repair, a tissue specimen from the edge of the internal inguinal ring was biopsied and histologically examined. RESULTS: In all of the tissue samples, remarkable degenerative changes such as fibrohyaline degeneration of the muscle fibers, vascular congestion, and phlogistic infiltration through lymphohistiocytary elements was constantly detected. Also, in the patients with recurrent hernia, the key characteristic of the muscular change was that of fibrohyaline and, occasionally, myxoid degeneration of the myocytes. Nerve endings were frequently detected within the muscular structures of the internal inguinal ring. CONCLUSION: The degenerative fibrohyaline alteration, as well as the evidence of phlogistic elements within the examined structures, could represent a reason for a contractile incompetence of the internal inguinal ring. Consequently, the described findings lead the authors to depict this inflammatory degenerative structural weakness of the internal inguinal ring as a possible culprit of indirect inguinal hernia formation.

Background The involvement of Heat Shock Proteins (HSP) in cancer development and progression is a widely debated topic. The objective of the present study was to evaluate the presence and expression of HSP60 and HSP10 in a series of large bowel carcinomas and locoregional lymph nodes with and without metastases. Methods 82 Astler and Coller's stage C2 colorectal cancers, of which 48 well-differentiated and 34 poorly-differentiated, were selected along with 661 lymph nodes, including 372 with metastases and 289 with reactive hyperplasia only, from the same tumours. Primitive tumours and both metastatic and reactive lymph nodes were studied; specifically, three different compartments of the lymph nodes, secondary follicle, paracortex and medullary sinus, were also analysed. An immunohistochemical research for HSP60 and HSP10 was performed and the semiquantitative results were analysed by statistical analysis to determine the correlation between HSPs expression and 1) tumour grading; 2) degree of inflammation; 3) number of lymph nodes involved; 4) lymph node compartment hyperplasia. Moreover, western blotting was performed on a smaller group of samples to confirm the immunohistochemical results. Results Our data show that the expression of HSP60, in both primary tumour and lymph node metastasis, is correlated with the tumoral grade, while the HSP10 expression is not. Nevertheless, the levels of HSP10 are commonly higher than the levels of HSP60. In addition, statistical analyses do not show any correlation between the degree of inflammation and the immunopositivity for both HSP60 and HSP10. Moreover, we find a significant correlation between the presence of lymph node metastases and the positivity for both HSP60 and HSP10. In particular, metastatic lymph nodes show a higher percentage of cells positive for both HSP60 and HSP10 in the secondary follicles, and for HSP10 in the medullary sinuses, when compared with hyperplastic lymph nodes. Conclusion HSP60 and HSP10 may have diagnostic and prognostic significance in the management of this tumour and their overexpression in tumoral cells may be functionally related to tumoral progression. We hypothesise that their expression in follicular and medullary cells of lymph nodes may be induced by formation of metastases. Further studies based on these observations could lead to a better understanding of the HSPs involvement in colorectal cancer progression, as well as other neoplasms.