Type 1 plasminogen activator inhibitor (PAI-1) in clear cell renal cell carcinoma (CCRCC) and its impact on angiogenesis, progression and patient survival after radical nephrectomy.

BACKGROUND: To examine the expression of type 1 plasminogen inhibitor (PAI-1) in clear cell renal cell carcinoma (CCRCC), and its possible association with microvessel density (MVD), the expression of thrombospondin-1 (TSP-1), nuclear grade, tumour stage, continuously coded tumour size (CCTS) and to assess the value of PAI as a prognostic marker in 162 patients with CCRCC treated with radical nephrectomy. METHODS: A total of 172 consecutive patients with CCRCC treated with radical nephrectomy were enrolled in the study. The expression of PAI-1, TSP-1 and factor VIII were analysed on formalin-fixed, paraffin-embedded tissues without knowledge of the clinical outcome. Ten cases, where PAI-1 immunohistochemistry was not possible due to technical problems and lack of material, were excluded. Sixty-nine patients (43%) died of RCC, while 47 patients (29%) died of other diseases. Median follow-up was 13.8 years for the surviving 46 patients (28%). RESULTS: Nine percent of the tumours showed PAI-1 positivity. High expression of PAI-1 was significantly inversely correlated with TSP-1 (p = 0.046) and directly with advanced stage (p = 0.008), high NG (3+4) (p = 0.002), tumour size (p = 0.011), microvessel density (p = 0.049) and disease progression (p = 0.002). In univariate analysis PAI-1 was a significant prognosticator of cancer-specific survival (CSS) (p < 0.001). Multivariate analysis revealed that TNM stage (p < 0.001), PAI-1 (p = 0.020), TSP-1 (p < 0.001) and MVD (p = 0.007) were independent predictors of CSS. CONCLUSIONS: PAI-1 was found to be an independently significant prognosticator of CSS and a promoter of tumour angiogenesis, aggressiveness and progression in CCRCC.

The expression of thrombospondin-1 and p53 in clear cell renal cell carcinoma: its relationship to angiogenesis, cell proliferation and cancer specific survival.

PURPOSE: We evaluated possible associations among thrombospondin-1, p53 expression, microvessel density, cell proliferation index, nuclear grade, tumor stage and continuously coded tumor size in clear cell renal cell carcinoma. The value of thrombospondin-1 as a prognostic marker in clear cell renal cell carcinoma was examined. MATERIALS AND METHODS: A total of 172 consecutive patients with clear cell renal cell carcinoma treated with radical nephrectomy were initially enrolled in the study. However, due to technical problems and lack of material 12 cases were excluded from analysis. A total of 68 patients (43%) died of renal cell carcinoma and 46 (29%) died of other diseases. Median followup for the surviving 42 patients (29%) was 13.8 years. The expression of thrombospondin-1, Ki-67 (proliferation index), p53 and microvessel density were analyzed without knowledge of the clinical outcome on formalin fixed, paraffin embedded tissues. RESULTS: Low expression of thrombospondin-1 was significantly associated with advanced stage (p <0.001), high nuclear grade (p = 0.001), positive p53 status (p <0.001), high proliferation index (p = 0.001), high microvessel density (p = 0.036) and tumor progression (p = 0.006). On univariate analysis thrombospondin-1, microvessel density, proliferation index, p53 over expression, TNM stage, Fuhrman nuclear grade (p <0.001) and continuously coded tumor size (p = 0.002) had a significant impact on survival. Multivariate analysis revealed TNM stage, thrombospondin-1, p53, Ki-67 (proliferation index) and microvessel density were independent predictors of cancer specific survival. CONCLUSIONS: Thrombospondin-1 expression is strongly associated with prognostic tumor features in clear cell renal cell carcinoma and is an independent prognostic factor for cancer specific survival. Our findings revealed a significant correlation among p53, proliferation index, microvessel density and thrombospondin-1 expression, and indicate that thrombospondin-1 may have an impact on angiogenesis, proliferation and tumor aggressiveness in clear cell renal cell carcinoma.

The prognostic relevance of interactions between venous invasion, lymph node involvement and distant metastases in renal cell carcinoma after radical nephrectomy.

BACKGROUND: To investigate a possible prognostic significance of interactions between lymph node invasion (LNI), synchronous distant metastases (SDM), and venous invasion (VI) adjusted for mode of detection, Eastern Cooperative Oncology Group performance status (ECOG PS), erythrocyte sedimentation rate (ESR) and tumour size (TS) in 196 patients with renal cell carcinoma treated with radical nephrectomy. METHODS: Median follow-up was 5.5 years (mean 6.9 years; range 0.01-19.4). The mode of detection, ECOG PS, ESR and TS were obtained from the patients' records. Vena cava invasion and distant metastases were detected by preoperative imaging. The surgical specimens were examined for pathological stage, LNI and VI. RESULTS: The univariate analyses showed significant impact of VI, LNI, SDM, ESR and TS (p < 0.001), as well as mode of detection (p = 0.003) and ECOG PS (p = 0.002) on cancer specific survival. In multivariate analyses LNI was significantly associated with survival only in patients without SDM or VI (p < 0.001) with a hazard ratio of 9.0. LNI lost its prognostic significance when SDM or VI was present. CONCLUSION: Our findings underline the prognostic importance of the status of the lymph nodes. LNI, SDM, ESR, and VI were independently associated with cancer specific survival after radical nephrectomy. LNI provided the strongest prognostic information for patients without SDM or VI whereas SDM and VI had strongest impact on survival when there was no nodal involvement.

Renal cell carcinoma: a clinicopathological follow-up study after radical nephrectomy.

OBJECTIVE: To examine the prognostic significance of performance status, tumour stage, histological subtype, nuclear grade and histological tumour necrosis (HTN) in a population of consecutive patients subjected to radical nephrectomy for renal cell carcinoma (RCC). MATERIAL AND METHODS: The cohort consisted of 110 males and 86 females with a mean age of 66 years (range 39-88 years). The Eastern Cooperative Oncology Group performance status (ECOG PS) was determined in all cases. The tumours were staged according to the 2002 TNM classification of the American Joint Committee on Cancer. Histological subtype was diagnosed using the Heidelberg classification. Nuclear grading was performed by means of Fuhrman's method. The median follow-up period was 65 months (mean 83 months; range 1-232 months). RESULTS: Median overall survival (OS) was 65 months and median cancer-specific survival (CSS) was 171 months. CSS was correlated with TNM classification, with the longest survival occurring for stage I and II tumours, shorter survival for stage III tumours and shortest survival for stage IV tumours (p<0.001). A significant difference in CSS was found between T1N0M0 and T2N0M0 tumours (p<0.01). A 15-year CSS of 100% was revealed in patients with tumours

Histological and nonhistological criteria in the evaluation of liver involvement in chronic hepatitis C.

The treatment of chronic viral hepatitis is based mainly on interferon therapy. This therapy has many drawbacks, among which potentially dangerous side-effects. Moreover, the majority of the patients are asymptomatic at the time of diagnosis, and most of them will never develop cirrhosis, liver failure or hepatocellular carcinoma, making the decision to treat a difficult one. Currently, the best method of selection is liver biopsy, considered "the gold standard" for recommending antiviral treatment. The histological aspect can vary in different hepatic areas and the smaller the bioptic fragment, the more probable is the histopathologist's error in correctly defining the hepatitis. There has been made important progress in defining the degree of liver involvement using serological tests, with the purpose of avoiding liver biopsy, but this approach has not yet proven to be superior. At present, the benefits of the pretreatment liver biopsy outbalance the risks. The future developments in the domain of antiviral drugs or nonhistological tests for evaluating the liver injury (circulating cytokines, subtypes of collagen) will show if the liver biopsy could be abandoned.

Portal hypertensive gastropathy.

Portal hypertensive gastropathy (PHG) is the term used to describe the endoscopic appearance of gastric mucosa seen in patients with cirrhotic or non-cirrhotic portal hypertension with a characteristic mosaic-like pattern with or without red spots. The prevalence of PHG varies from 50% to 98%, this variation of the prevalence being perhaps related to patient selection, inter- and intra-observer variation and absence of uniform criteria and classification. About 8% of the upper digestive hemorrhages in the cirrhotic patients are secondary to PHG. There is no general consensus on the endoscopic classification of PHG (the most New Italian Endoscopy Club). The exact pathogenesis of PHG is not completely understood, but the portal hypertension is the main factor involved in its development and not the severity of the hepatic disease. Gastric Antral Vascular Ectasia (GAVE) is a term used for the typical endoscopic findings of red stripes, separated by normal mucosa, most frequently seen in the gastric antrum or proximal stomach. Current therapy of PHG includes beta blockers, somatostatin and derivates, endoscopic and surgical methods including hepatic transplantation.

Protective efficacy of IgA monoclonal antibodies to O and H antigens in a mouse model of intranasal challenge with Salmonella enterica serotype Enteritidis.

Protective properties of immunoglobulin A (IgA) monoclonal antibodies (MAbs) directed against O and H antigens of Salmonella enterica serotype Enteritidis (S. enteritidis) were evaluated in a model of generalized infection after intranasal (i.n.) inoculation of BALB/c mice. Passive i.n. instillation of antibodies 1 h before i.n. challenge did not prevent infection, and mice developed rapid inflammatory response in the lower respiratory tract. The passive systemic immunization was partially protective and a single intravenous (i.v.) injection of both O and H antigen specific IgA antibodies prolonged survival period of the infected animals. Permanent secretion of O:9 specific IgA MAb 177E6 into the respiratory tract in a "backpack" tumor model protected 50% of animals infected i.n. with a high dose of virulent S. enteritidis strain. Thus, secretory IgA (S-IgA) directed against O:9 antigen alone can prevent bacterial invasion in the respiratory epithelium.

The effects of carvedilol a nonselective beta-blocker on portal hemodynamics in cirrhosis.

UNLABELLED: Portal hypertension is the result of increased hepatic resistance and portal influx. AIM: To assess the effects of Carvedilol, a 3rd-generation nonselective beta blocker with alpha1-adrenergic activity on portal and systemic homodynamic in patients with cirrhosis and portal hypertension. METHODS: Fifty patients with cirrhosis and portal hypertension were divided into two groups and statistically compared as follows: group I - 25 patients received Carvedilol, 12.5 mg/day and group II - 25 patients received placebo for six days. All the patients had hemodynamic, endocrine and renal measurements before and after administration of Carvedilol or placebo. They underwent creatinine clearance, lithium clearance, plasma renin activity, concentration of plasma aldosteron and urinary sodium excretion. Hemodynamic effects were assessed by portal flow volume and velocity, cardiac output and medium blood pressure. RESULTS: Carvedilol significantly increased the portal blood flow and velocity (p<0.05). Carvedilol reduced the medium blood pressure (p<0.001) with statistically insignificant alterations in creatinine clearance and 24-hours urinary sodium excretion. Carvedilol also reduced the concentration of plasma aldosteron (p < 0.002). CONCLUSIONS: Carvedilol can be used as an alternative drug for the prophylactic treatment of portal hypertension with careful monitoring of blood pressure regarding its hypotensive effects.

Monoclonal antibody of IgG isotype against a cross-reactive lipopolysaccharide epitope of Chlamydia and Salmonella Re chemotype enhances infectivity in L-929 fibroblast cells.

A murine monoclonal antibody (MAb) 202D7 of IgG3 isotype recognizes a lipopolysaccharide (LPS) epitope of Chlamydia spp. and cross-reacts with the Re chemotype LPS of Salmonella and Escherichia coli. The antibody exhibits strong complement activating properties and stimulates phagocytosis of Salmonella enterica serovar Minnesota Re mutant by murine macrophages. Salmonella Re mutants are non-invasive for cell monolayers but still can enter and replicate in L-929 murine fibroblast cells. The entry of bacteria within the cells increases five-fold in the presence of MAb 202D7. The antibody mediates attachment and enhances five-fold the infectivity of Chlamydia pneumoniae into L-929 cells, which suggests a possible IgG-mediated mechanism of entry and survival of the pathogen in fibroblast cells.

Production and characterization of monoclonal immunoglobulin A antibodies directed against Salmonella H:g,m flagellar antigen.

Hybridomas were generated after intragastral immunization of BALB/c mice with live Salmonella suberu and subsequent fusion between isolated spleen lymphoblasts and myeloma cells. Three monoclonal antibodies (MAbs) of immunoglobulin A (IgA) isotype were selected and characterized. All of them were found to recognize the H:g epitope in enzyme-linked immunosorbent assay and immunoblotting but did not react with all H:g-expressing strains in slide agglutination test. All MAbs strongly agglutinated Salmonella enteritidis type strain and a large number of S. enteritidis clinical isolates. They were not bactericidal in the presence of complement. All hybridoma clones produced secretory IgA forms, which were found in the gastrointestinal tract of mice bearing hybridoma as a subcutaneous 'backpack' tumor or after intravenous application of purified MAbs. The IgA MAbs stability demonstrated in different tests together with their antigen specificity and strong agglutination ability make them a useful diagnostic tool for serotyping of Salmonella strains.

Neoductular progenitor cells regenerate hepatocytes in severely damaged liver: a comparative ultrastructural study.

In severely injured liver, stem cells give rise to progeny that tend to replace lost hepatocytes. Neoductular reaction appears as an inherent stage of liver reconstruction following severe damage caused by different pathological mechanisms. Few ultrastructural types of progenitor cells have been described, and some molecular phenotypes of progenitor stages have been characterized, but the details of the differentiation process are largely unknown. We prepared for light and electron microscopy examination human liver from biopsies of patients with chronic active hepatitis, and rat liver with allyl alcohol-induced periportal necrosis. We found that progenitor neoductular cells acquire the hepatocytic polarity pattern during a multi-step process apparently involving cell migration and dissolution of neoductular basement membrane. An intermediate stage with "mixed" ductular and hepatocytic polarity was described.

Lipopolysaccharide-specific but not anti-flagellar immunoglobulin A monoclonal antibodies prevent Salmonella enterica serotype enteritidis invasion and replication within HEp-2 cell monolayers.

The protective potential of immunoglobulin A (IgA) monoclonal antibodies (MAbs) directed against O and H antigens of Salmonella enterica serotype Enteritidis to prevent bacterial adhesion to and invasion of HEp-2 cells was evaluated. Although anti-flagellar IgA MAbs showed strong agglutinating capacities, they did not protect cell monolayers. In contrast, IgA MAbs specific for the O:9 epitope of Salmonella lipopolysaccharide antigen alone prevented S. enterica serotype Enteritidis entry and replication within HEp-2 cells, and the protection was not mediated by direct binding of antibodies to bacterial adhesins or by agglutination of microorganisms.

Interferon prophylaxis of hepatic carcinoma.

The present article reveals the importance of hepatic carcinoma among the other diseases in digestive oncology, and also the importance of a correct designation of these cases. Epidemiology and actual hypothesis on the mechanisms of oncogenesis are discussed. There are reviewed some studies in the literature concerning infection with hepatitis B virus, hepatitis C virus, coinfection (B and C viruses, B and D viruses), the role of interferon prophylaxis in such cases. Also there is present a statistics on chronic viral hepatits, cirrhosis of viral etiology and hepatic carcinoma, diagnosed in patients in "N.Gh.Lupu" Hospital, over two decades.

Gastro-intestinal lesions induced by non-steroidal anti-inflammatory drugs.

Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with serious and sometimes fatal side effects as gastrointestinal ulcers, bleeding and less frequently kidney and liver damage. These side effects are caused primarily by the reduction of prostaglandin synthesis, which in turn deprives the stomach's self-protection mechanism. NSAIDs prevent prostaglandin formation by inhibiting the enzyme cyclooxygenase. Recent research has shown that there are two types of cyclooxygenase, one that produces the form of prostaglandin involved in the gastric protection and the other that produces the form of prostaglandin involved in inflammation. Current NSAIDs inhibit both forms of cyclooxygenase. Gastrointestinal lesions associated with NSAIDs are predominantly observed in the stomach and are defined under the term of "NSAID gastropathy". Intestinal lesions secondary to the ingestion of NSAIDs were only recently described. Rectocolic lesions induced by NSAID are frequent and severe. The noxious effect of NSAID on preexisting low pathologies can be differentiated from "de novo" induced acute and chronic lesions.

Treatment with alpha-interferon in chronic hepatitis.

The treatment of chronic viral hepatitis with Interferon has been introduced in clinical practice over the past decade an represents an important step in the management of those diseases. The data existing in literature are conflicting about the dose and period of treatment with Interferon, many treatment schedules being proposed. There are also a lot of markers used or proposed to be used to determine the response to treatment, their predicting efficacy being largely studied. The response to alpha-Interferon in a standard 6 month regimen in chronic hepatitis B, chronic hepatitis C and chronic hepatitis B and C is studied; alanine-aminotransferase (ALAT) and aspartate-aminotransferase (ASAT) are the markers used to determine the response to treatment.