Nuclear EGFR characterize still controlled proliferation retained in better differentiated clear cell RCC.

Renal cell carcinoma (RCC) is the most common solid kidney tumor representing 2-3% of all cancers, with the highest frequency occurring in Western countries. There was a worldwide and European annual increase in incidence of approximately 2% although incidence has been stabilized in last few years. One third of the patients already have metastases in the time of the diagnosis with poor prognosis because RCC are radio and chemoresistant. The prognostic value of EGFR over-expression in RCC is a controversial issue that could be explained by different histological types of study tumors and non-standardized criteria for evaluation of expression. Recent evidences points to a new mode of EGFR signaling pathway in which activated EGFR undergoes nuclear translocalization and then, as transcription factor, mediates gene expression and other cellular events required for highly proliferating activities. According to our observations, the membranous expression of EGFR associates with high nuclear grade and poor differentiated tumors. On the other hand, nuclear EGFR expression was high in low nuclear graded and well differentiated tumors with good prognosis. We hypothesize that this mode of EGFR signaling characterizes still controlled proliferation retained in well differentiated RCC with Furhman nuclear grade I or II.

Corticosteroids provoke acute endothelial injury -- an ideal ground for thrombosis in multiple sclerosis.

Despite the effect corticosteroids exert on blood clotting and the irrefutable impact of intracranial sure decreasing shortly after lumbar puncture, a certain number of intracranial thromboses remain unexplained. Corticosteroids are useful in reducing the severity and duration of relapses of multiple sclerosis. Several questions emerge concerning the reasons behind thrombosis occurring so sporadically, not pertaining to any rule, the most important of which regard the location and timing. We developed this hypothesis as an obverse to chronic endothelial injury theory which, only partially explains atherosclerosis development. We followed Virchows classical triad of conditions which are believed to be connected to the development of thrombosis. Although corticosteroids affect more than vessel wall injury, component of Virchows triad that has been our narrowest interest is exactly vessel wall injury.

Apoptotic cell death and rupture of abdominal aortic aneurysm.

The abdominal aortic aneurysm (AAA) development and expansion is characterized by an extracellular matrix degradation and widespread inflammation. In contrast, the processes that characterize the AAA rupture are not completely understood. The results obtained in animal and clinical studies have shown the importance of inflammation, proteolysis, and antioxidant mechanisms in the aortic degeneration and formation of AAA. We hypothesize that the rupture of the AAA could have a similar pathway like an atherosclerotic plaque rupture, and in both the cases the apoptotic cell death of smooth muscle cells could play a significant role. If the apoptotic cell death significantly contributes to the expansion and rupture of aneurysm, the hypothesis is that aggressive medical antiapoptotic treatment with high doses of appropriate drugs could decrease the apoptotic index of smooth muscle cells, reduce the aneurysm expansion and prevent rupture.

Correlation of serum IL-6, IL-8 and IL-10 levels with clinicopathological features and prognosis in patients with diffuse large B-cell lymphoma.

Cytokines play important roles in the pathogenesis of lymphomas. This study aimed to determine the relationship(s) between serum levels of interleukin (IL)-6, IL-8 and IL-10, measured by enzyme-immunoassay, and the clinical characteristics and outcomes in 46 untreated patients with diffuse large B-cell lymphoma (DLBCL). Serum IL-6, IL-8 and IL-10 levels were higher in DLBCL patients than in control subjects. Elevated levels of IL-6, IL-8 and IL-10 correlated with more adverse disease features. Consequently, patients with elevated IL-6, IL-8 and IL-10 levels prior to treatment had a lower response to therapy. Furthermore, those with elevated IL-6 and IL-10 levels had poor median, 3-year and 5-year survival, while elevated serum IL-8 level did not correlate with overall survival. Worse survival was also confirmed in patients with combined elevated pretreatment serum levels of IL-6, IL-8 and IL-10 (none, one, two or three elevated). Multivariate analysis identified elevated values of IL-6 and IL-10 and response to therapy as significant predictors for overall survival. Serum levels of IL-6, IL-8 and IL-10 before treatment of patients with newly diagnosed DLBCL may give some insight into the possible prognosis and thus facilitate the decisions regarding therapeutic approaches for individual patients.

Morphometry and digital AgNOR analysis in cytological imprints of benign, borderline and malignant serous ovarian tumours.

AIM: The aim of the study was to determine values of a quantitative morphometry analysis of nuclear characteristics and argyrophilic nucleolar organizer regions (AgNORs) in differential cytodiagnosis of benign, atypically proliferating (borderline) and malignant serous ovarian tumours. METHODS: Cytological imprints of benign (n = 20), borderline (n = 19) and malignant (n = 20) ovarian serous tumours were analysed. A computerized, digital analysis was used to determine morphometric nuclear features, the number and characteristics of single AgNORs, cluster AgNORs, total AgNOR and AgNOR area/nucleus (relative area) ratio. According to their size AgNORs were classified in three categories. A one-way variance analysis and post hoc test (Scheffé) were used for statistical analysis. RESULTS: The morphometric nuclear analysis showed that benign, borderline and malignant serous ovarian tumours are statistically different (P < 0.001) according to the area and outline, the values being highest in malignant tumours and lowest in the borderline group. Digital analysis of AgNORs in benign, borderline and malignant groups showed that the total AgNOR number increases with progression of the lesion (meaning tumour malignancy) significantly (P < 0.001) between benign and malignant as well as between borderline and malignant serous ovarian tumours (P < 0.001). The progression of the lesion malignancy was accompanied by a significant (P < 0.001) progressive increase of the total and relative AgNOR area per nucleus. The AgNOR size increases from benign to malignant tumours and a statistically significant difference (P < 0.001) was observed in all three groups regarding small and large AgNORs. CONCLUSION: Combining different markers of morphometric nuclear characteristics and AgNOR values could improve differential cytodiagnosis of benign, borderline and malignant serous ovarian tumours.

Macrophage level is not affected by monocyte chemotactic protein-1 in invasive ductal breast carcinoma.

PURPOSE AND METHOD: Monocyte chemotactic protein-1 (MCP-1) is a chemokine involved in the macrophage infiltration of tumor tissue. Tumor-associated macrophages (TAMs) are a population of mononuclear phagocytic cells that can have a complex function in tumor biology. The aim of this study was to determine the possible correlation between parenchymal MCP-1 expression and TAM level by immunohistochemical analysis of 97 invasive ductal breast carcinomas, not otherwise specified (NOS), and to investigate their relation with tumor size, histological grade, mitotic activity index (MAI) and lymph node status. Secondly, the MCP-1 mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) in eight samples of normal breast tissue and 27 samples of invasive breast carcinomas and compared with TAMs. RESULTS: MCP-1 immunoreactivity was present in tumor cells (17/97), but also in TAMs, fibroblasts and endothelial cells. The statistical analysis did not show a significant correlation between MCP-1 expression in tumoral epithelium and tumor size, histological grade, MAI, lymph node status or TAMs. The results of RT-PCR showed that, in all cases of breast carcinomas (27/27) and the majority of normal breast tissues (7/8), the number of detected MCP-1 cDNA copies was above the detection limit. However, carcinomas showed higher levels of MCP-1 mRNA than normal breast tissue. Nevertheless, the statistical analysis did not find a significant correlation between MCP-1 expression and macrophage infiltrations. CONCLUSION: These results indicate that MCP-1 is probably not the only and/or crucial factor involved in macrophage attraction to tumor locus in breast carcinoma.

Primary non-Hodgkin lymphoma of the humerus following traumatic injury: case report.

A case of primary non-Hodgkin lymphoma of the right humerus which occurred in a 21-year-old male patient after an impact to the right shoulder in a car accident in July 1983 is described. Seventeen years after the injury, due to a civil lawsuit, the biopsy material was revised. Immunohistochemical analysis showed CD20 and CD79a positivity on large pleomorphic cells, while small reactive lymphocytes were CD3, Bcl-2 and CD20 positive. Molecular analysis carried out with PCR revealed a monoclonal B-lymphocyte population. The diagnosis of diffuse large peripheral B cell lymphoma of the bone was confirmed. The present case concurs with the literature on primary bone lymphoma, in which the diagnostic problem, trauma-related presentation and an excellent prognosis of malignant tumour are emphasized.

Cytomorphological variations, proliferation and angiogenesis in the prognosis of cutaneous melanoma.

Depth of invasion and stage of the disease are well known prognostic indicators in cutaneous melanoma (CM). However, the role of other parameters, such as the variations in cytomorphology of melanocyte tumours, mitotic activity and angiogenesis is still open to question. The aim of this study was to analyse proliferation by mitotic activity index (MAI) and immunostaining of proliferating cell nuclear antigen (PCNA), and the intensity of neovascularization (microvessel density; MVD) in CM clinical stage I in relation to epithelioid, spindle and nevoid cell type, histological type (superficial spreading melanoma and nodular melanoma), Clark's level and Breslow thickness. Finally, the role of all parameters in the prognosis of CM was evaluated. Statistical analysis demonstrated that cytological characteristics of CM correlate only with Clark's level, while histological types correlate with MAI, PCNA and MVD. MAI and PCNA also showed correlation between groups according to Clark's level and Breslow thickness. Finally, tumour cell PCNA was found to correlate with MVD. Survival of patients with CM correlated significantly with MAI. These results suggest that cytological variation, histological type, PCNA and MVD alone are not independent prognostic parameters, whereas MAI is a potentially important prognostic marker in CM.

The influence of the incision length on the early postoperative intraocular pressure following cataract surgery.

In a prospective study we recorded the early postoperative intraocular pressure of 60 eyes following phacoemulsification and posterior chamber lens implantation. In 30 patients each the implantation either of a folded polyHema intraocular lens through a 3.5 mm incision or of a polymethylmetacrylate intraocular lens through a 7 mm incision was performed. Healon was used in all eyes and thoroughly evacuated from the capsular bag behind the implanted lens and the anterior chamber. For intraoperative miosis 0.5 ml acetylcholine chloride was injected into the anterior chamber after wound closure. Intraocular pressure was measured preoperatively as well as six hours, 18 hours, one week and two months postoperatively without the influence of antiglaucomatous medication. We found no statistically significant change of intraocular pressure at any measurement time in the 3.5 mm group (Student's t-test, p > 0.1). In the 7 mm group only the rise of intraocular pressure at 18 hours was statistically significant (p < 0.05, student's t-test). The comparison of the changes of intraocular pressure from preoperative values between both groups revealed a statistically significant difference at 18 hours (p < 0.05, student's t-test) but not at any other time recorded. Intraocular pressure exceeding 22 mmHg was found at 6 hours in 4 (13.3%) patients of both groups and at 18 hours in 3 (10%) eyes of the 3.5 mm group and 5 (16%) eyes of the 7 mm group (p > 0.1, Fisher's Exact Test). From these results we conclude that 1) regardless of the wound size the pressure rising effect of Healon is successfully counteracted by the aspiration technique described, and 2) with small-incision cataract surgery statistically significant less changes of intraocular pressure are observed in the early postoperative period.

Effects of dichloroacetate on exercise performance in healthy volunteers.

Dichloroacetate (DCA), a stimulator of the pyruvate dehydrogenase complex, decreases lactate levels and peripheral resistance and increases cardiac output. This study was performed to examine the effects of DCA on exercise performance in humans. Eight healthy male volunteers (age 20-28 years) were tested by bicycle spiro-ergometry using a microprocessor-controlled gas analysis system after infusion of DCA (50 mg/kg body weight) or saline. Prior infusion of DCA significantly reduced the increase of lactate levels during exercise when compared with infusion of saline (1.40 +/- 0.21 vs 2.10 +/- 0.09 mmol.l-1 at 50% of the expected maximal working capacity, P < 0.05; 8.53 +/- 0.45 vs 9.92 +/- 0.59 mmol.l-1 at maximal working capacity, P < 0.05). Oxygen uptake increased significantly after DCA when compared with saline from 7.5 +/- 0.4 vs 7.4 +/- 0.5 to 27.2 +/- 1.5 vs 23.7 +/- 1.7 (P < 0.05) at anaerobic threshold and to 35.6 +/- 1.7 vs 30.5 +/- 1.0 ml.kg-1 min-1 (P < 0.05) at maximal exercise capacity. Following DCA infusion the workload at which the anaerobic threshold was reached was significantly higher (160 +/- 7 vs 120 +/- 5 W, P < 0.05) and the maximal working capacity was significantly increased (230 +/- 9 vs 209 +/- 8 W, P < 0.05). In summary, DCA reduced the increase of lactate levels during exercise and increased oxygen uptake at the anaerobic threshold and at maximal working capacity, which was significantly increased. These results warrant further studies on a potential therapeutic application of DCA in patients with reduced exercise capacity.

Effects of dichloroacetate and bicarbonate on haemodynamic parameters in healthy volunteers.

1. It has been shown that sodium bicarbonate has no effect or could even be detrimental in various forms of metabolic acidosis. Dichloroacetate, a stimulator of the pyruvate dehydrogenase complex, might offer an alternative treatment. The present study therefore examines the metabolic and haemodynamic effects of dichloroacetate and sodium bicarbonate in healthy volunteers. 2. On 2 different days, sodium dichloroacetate (50 mg/kg body weight) or sodium bicarbonate (1.5 mmol/kg body weight) was given intravenously as a single bolus in 10 healthy volunteers. Haemodynamic parameters were measured using a microprocessor-controlled system. Measurements were performed before and 30 and 60 min after infusion. 3. After administration of dichloroacetate, cardiac index increased from 2.3 +/- 0.03 to 2.7 +/- 0.1 1 min-1 m-2 (P less than 0.05), peripheral vascular resistance decreased from 266 +/- 9.7 to 240 +/- 1.7 kPa s l-1 (2662 +/- 97 to 2398 +/- 169 dyn s cm-5, P less than 0.05), oxygen availability increased from 442 +/- 16 to 535 +/- 30 ml min-1 m-2 (P less than 0.05) and serum lactate concentration fell from 1.4 +/- 0.14 to 0.6 +/- 0.1 mmol/l (P less than 0.05). With infusion of sodium bicarbonate there were no significant effects on any of these variables. 4. Our results show that dichloroacetate administered intravenously reduces the serum lactate concentration. The main effects of dichloroacetate itself are on the haemodynamic variables. Dichloroacetate increases cardiac index and oxygen availability and decreases peripheral vascular resistance, whereas sodium bicarbonate has no effect on haemodynamic or metabolic parameters. These data give some further insights in the actions of dichloroacetate and support the use of dichloroacetate as alternative therapy in various forms of metabolic acidosis.