Cardiotoxicity of anthracycline in young breast cancer female patients: the possibility of detection of early cardiotoxicity by TDI.

Tissue Doppler imaging (TDI) was investigated for its applicability for detecting cardiac function and early cardiotoxicity in breast cancer patients treated with anthracyclines. A total of 40 women (age range 18 to 65 years) were enrolled, who had not received anthracyclines previously and had normal systolic and diastolic cardiac function. All healthy patients in the control group were of the same age. Each patient underwent not only standard echocardiographic measurements (ventricular dimensions and wall thickness, ejection fraction, E-wave deceleration time (DT), E/A ratio), but also specific imagings (E-septum separation, pulmonary venous flow), and in addition the myocardial velocity of many segments of mitral anulus obtained with pulsed wave tissue Doppler imaging were performed during the one year of observation period. Based on the results we found that systolic left ventricular function did not change significantly - neither in the study nor in the control group. Diastolic left ventricular function was impaired in 39 patients (97.5%), and 30 (75%) of these showed clear changes by means of both the traditional E/A ratio and TDI. Diastolic dysfunction in 9 patients (22.5%), however, could be detected only with TDI. The analysis of myocardial velocity in different segments showed that diastolic dysfunction does not develop in a homogeneous way but in a different way in segments. Diastolic function was intact in the control group during the study. The detectable myocardial damage occurred in the study group of young female patients without risk factors as a result of one year anthracycline therapy was so severe that the possible outcome might be serious congestive heart failure or death. Our results confirmed our assumptions that TDI is a more precise and useful examination method than traditional ones (E/A ratio or deceleration time) to demonstrate isolated diastolic dysfunction as a result of chemotherapy. Relevant extra information might be given by TDI compared to parameters describing diastolic functions depending on several changing values. TDI may become a regularly and more widely used noninvasive method to detect subclinical cardiotoxicity emerging after chemotherapy.

Patterns of expression and secretion of vascular endothelial growth factor in malignant soft-tissue tumours.

Vascular endothelial growth factor (VEGF) is an important cytokine especially in the process of tumour angiogenesis. A total of 46 soft-tissue sarcomas were analysed for the expression and possible secretion of VEGF by immunohistochemistry, in-situ hybridisation, and enzyme-linked immunosorbent assays (ELISA). VEGF was demonstrated immunohistochemically in tumour tissue in 45 of 46 cases. The detection of mRNA transcripts yielded evidence of synthesis of VEGF in these sarcomas. ELISA could be performed in 21 cases. Higher concentrations of VEGF were found in tumour-related intraoperatively sampled venous blood in 16 out of 21 patients (76%) than in systemic concentrations taken preoperatively. The results indicated the secretion of VEGF by tumour cells although these raised concentrations were not statistically significant. In 12 out of these 16 patients (75%) a concurrent moderate to strong immunoexpression of VEGF was detected. The relevance of VEGF blood concentrations as a potential "progress parameter" for the course of disease remains questionable. This is mainly due to the lack of statistical significance in the difference between systemic VEGF concentrations in patients and those of a control group. Further long-term follow-up studies are needed, which should include patients with tumour recurrences.

Expression of type IV collagenase correlates with the expression of vascular endothelial growth factor in primary non-small cell lung cancer.

Tumor growth and metastasis are angiogenesis-dependent processes initiated and regulated by a number of cytokines. Vascular endothelial growth factor (VEGF) is a potent angiogenic protein with a selective mitogenic effect on vascular endothelial cells, known to be involved in physiological (embryogenesis) and pathophysiological (rheumatoid arthritis, tumor) angiogenesis. An increased expression of matrix metalloproteinase type IV collagenase has been reported in invading endothelial cells in vitro and in malignant cells, degrading structures of the basement membranes in various human malignancies. In the present study we investigated the expression of the genes for type IV collagenase and vascular endothelial growth factor (VEGF) in 40 cases of primary non-small-cell lung cancer (NSCLC). Specimens were immunostained by an antibody directed against VEGF and mRNA transcripts of VEGF and type IV collagenase were localized by non-radioactive in situ hybridization. VEGF mRNA was detected in 33 neoplasms, while in 23 cases transcripts of the type IV collagenase gene were visualized by digoxigenin-labeled cDNA probes. Transcripts of both mRNAs were detected in malignant cells. Furthermore, anti-VEGF immunostaining was present in newly formed microvessels close to the atypical cells, and mRNA of type IV collagenase was present in stromal cells adjacent to the tumor. A statistically significant correlation was found between the expression of type IV collagenase and VEGF (P = 0.0061). These data suggest a double role for type IV collagenase in the metastatic process of NSCLC: (1) facilitating the invasion of tumor cells by the proteolytic cleavage of the basement membrane and (2) similarly supporting the endothelial cell invasion essential for tumor angiogenesis. Furthermore, our findings sustain the hypothesis that metastatic spread and angiogenesis are associated with a clonal expansion of highly angiogenic and invasive tumor cell clones.

Hepatocyte growth factor/scatter factor and its receptor c-Met are overexpressed and associated with an increased microvessel density in malignant pleural mesothelioma.

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates cell proliferation, motility and invasiveness via its receptor c-Met during embryogenesis and repair processes. It induces angiogenesis, promoting endothelial cell migration and capillary-tube formation in vivo. Co-expression of HGF/SF and c-Met receptor results in enhanced tumour growth, invasiveness and a mesenchymal-epithelial transition in some experimental tumours. Since mesothelioma cells have been reported to express c-Met receptor and to migrate in response to HGF/SF, we investigated human malignant pleural mesotheliomas for the demonstration of possible co-expression of the growth factor and its receptor. The microvessel density of the tumours was also analysed in order to assess the influence of HGF/SF expression on tumour angiogenesis. Thirty-nine paraffin-embedded specimens of malignant pleural mesotheliomas were immunostained by anti-HGF/SF and anti-c-Met antibodies and semiquantitatively evaluated. c-Met mRNA expression was visualised in ten tumour samples by a fluorescent in situ hybridisation method. Microvessel density was calculated by counting microvessels with a high-power field (200x) on von-Willebrand-factor-stained slides. We found an increased production of HGF/SF in 33/39 tumours and a corresponding overexpression of c-Met receptor in 29/39 specimens. The FISH method detected increased transcription of c-Met mRNA in malignant cells and in neighbouring vascular endothelial cells. HGF/SF-positive mesotheliomas had significantly higher microvessel densities compared to their HGF/SF-negative counterparts. The observed co-expression of HGF/SF and c-Met in malignant pleural mesotheliomas suggests a possible self-stimulation (autocrine loop) of tumour cells. On the basis of the significantly higher microvessel density values of malignant mesotheliomas overexpressing HGF/SF, we postulate, that HGF/SF may be an additional relevant factor in tumour angiogenesis in malignant pleural mesotheliomas.

Expression and localization of thrombomodulin in preneoplastic bronchial lesions and in lung cancer.

Thrombomodulin (TM) is an endothelial surface glycoprotein that acts as a natural anticoagulant. It inhibits thrombin and accelerates the activation of the anticoagulant protein C. TM has been detected in dermal keratinocytes, where it is associated with terminal differentiation. It can also be detected in various types of squamous malignant neoplasms and in malignancies of endothelial and mesothelial origin, such as Kaposi's sarcoma or malignant mesothelioma, but is absent in pulmonary adenocarcinomas (AC). Seventy-two lung tumour specimens [33 squamous cell carcinomas (SQCC), 23 AC, 1 large cell carcinoma, 8 small cell lung cancers (SCLC) and 7 multidifferentiated tumours (MT)] were analysed immunohistochemically by staining with an anti-TM antibody in order to assess TM expression. All of the SQCC stained positively for TM. In contrast, only 9 AC and 4 MT and none of the SCLC showed positive anti-TM staining. Seven hyperplastic bronchial epithelial specimens and eight preneoplastic bronchial lesions (five cases of moderate dysplasia, two cases of severe dysplasia and one case of carcinoma in situ) were used as controls. Normal or hyperplastic areas of bronchial epithelium revealed no positive reaction. However, a distinct positive anti-TM staining pattern related to the degree of keratiniziation of dysplastic lesions was seen. The present results suggest that anti-TM immunostaining is a useful marker for squamous cell carcinoma in the differential diagnosis of pulmonary carcinoma, also indicating keratinocyte differentiation in dysplastic bronchial epithelium.

Expression and localization of vascular endothelial growth factor and its receptor flt in pulmonary sarcoidosis.

Vascular endothelial growth factor (VEGF) is a multifunctional cytokine, which has recently been reported to enhance the activation and migration of monocytes through the flt receptor in vitro, which are key events in granuloma formation of granulomatous disorders and in sarcoidosis. Since activated macrophages and monocytes are known to be involved in sarcoid granuloma formation in sarcoidosis, we investigated the expression of VEGF and its receptor flt in 33 paraffin-embedded lung tissue biopsies of patients with pulmonary sarcoidosis. VEGF-mRNA was localized by nonradioactive in situ hybridization, VEGF and flt expression were visualized immunohistochemically. We found an increased transcription and protein production of VEGF and an overexpression of flt in activated alveolar macrophages, in epitheloid cells, and in multinuclear giant cells of pulmonary sarcoid granulomas.

Expression of vascular endothelial growth factor in diffuse malignant pleural mesothelioma.

Angiogenesis is an important part of normal and pathological processes, including tumour growth, metastasis, inflammation and wound healing. VEGF is the best known angiogenic factor, implicated in tumour-associated microvascular hyperpermeability and carcinogenesis. We investigated 103 malignant pleural mesotheliomas, analysing the expression of vascular endothelial growth factor using immunohistochemistry and in situ hybridization. The grade of microvessel density was assessed with the aid of anti-factor-VIII antibodies. An increased expression of VEGF was found in biphasic and epithelioid mesotheliomas, correlating in a statistically significant manner (P<0.042). In situ hybridization confirmed the specificity of VEGF mRNA expression. There was a robust correlation between VEGF expression and increased microvessel density (P<0.001), and positive mesotheliomas had significantly higher microvessel densities than negative specimens. There was also a significant correlation between microvessel density and histological pattern. As growth pattern tended towards biphasic and sarcomatoid mesotheliomas the density of micovessels decreased (P<0.05).

Expression of c-Met receptor and hepatocyte growth factor/scatter factor in synovial sarcoma and epithelioid sarcoma.

Overexpression of c-Met receptor/hepatocyte growth factor (scatter factor) system (c-Met/HGF/SF) as a physiologically paracrine cellular signaling system is thought to be involved in the progression of malignant tumours. In 26 synovial sarcomas and epithelioid sarcomas, c-Met and HGF/SF expression was analysed immunohistochemically. There were 10 biphasic synovial sarcomas, 7 of which showed moderate to strong c-Met expression in epithelial areas compared with the fibrous component, with corresponding expression of HGF/SF. Six of 9 monophasic fibrous synovial sarcomas showed only very faint c-Met and corresponding HGF/SF expression. In 7 epithelioid sarcomas strong expression of c-Met and HGF/SF was observed within epithelioid tumour cells. Non-radioactive in situ hybridization demonstrated the synthesis of c-Met receptor in tumor cells by detecting c-met-mRNA. This analysis shows that in synovial sarcomas and epithelioid sarcomas, tumour entities with epithelial and mesenchymal structures, c-Met and HGF/SF overexpression can be detected, indicating a role of this signaling system in these subtypes of sarcoma, and especially in the more epithelioid tumour phenotype. An autocrine interaction between overexpressed c-Met receptor and HGF/SF may be hypothesized.

[Experience with hydrogen (H2) breath test]. / Hidrogén (H2) kilégzési vizsgálattal szerzett tapasztalataink.

The authors applied regularly the hydrogen (H2) breath test during the medical investigations in patients with gastrointestinal symptoms. On the basis of the repeated examinations the hydrogen (H2) breath test is a sensitive, well repeatable method. After analysing of 108 examinations the authors have observed in 51.8% lactose intolerance, in 17.8% small intestinal bacterial overgrowth syndrome, in 46.4% motility disorders. The proportion of "low hydrogen producers" was 14.3%. Only 1/5 of patients with new diagnosed lactose intolerance had knowledge about the intolerance, and 10% was asymptomatic. In case of small intestinal bacterial overgrowth syndrome the repeated hydrogen (H2) test may indicate the effectivity of applied antibiotic therapy. The mean orocaecal transit time was 99 minutes and the normal range was 66-132 minutes, counted on the basis of mean +/- 2 SD. The authors suggest that the results support the important role of hydrogen (H2) breath test in the modern gastroenterological diagnostics.

[Eosinophil activation markers in status asthmaticus]. / Eosinophil aktivációs markerek status asthmaticusban.

Eosinophil activation markers-eosinophil cationic protein, eosinophil protein-X-were investigated in acute severe asthma. The elevation of the eosinophil activity markers were found in every cases at the time of admission. The measurements were repeated eight days later. The eosinophil cationic protein and eosinophil protein-X levels were increased at the time of the admission, and a decreasing tendency was detected eight days later. The peak expiratory flow rates were monitored during the period of the hospital staying. It is important to note that, the size of the bronchial obstruction did not show any similarity in all cases comparing to the elevation or decrease of eosinophil activity markers. The authors proved the eosinophil activation in vivo in acute severe asthma. The continuous monitor of the eosinophil activity markers might have a practical value in searching of the optimal therapeutic modalities in the asthmatic patients.

Co-expression of vascular endothelial growth factor and its receptor flt-1 in malignant pleural mesothelioma.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic protein with a selective mitogenic effect on endothelial cells known to be involved in many normal and pathological processes. Coexpression of VEGF and its receptor flt-1 has been reported in different types of malignant tumors. OBJECTIVE: In the present study we investigated the expression of VEGF and flt-1 in 90 cases of diffuse malignant pleural mesotheliomas. METHODS: VEGF and flt-1 expression was analyzed by immunohistochemistry and non-radioactive in situ hybridization. RESULTS: VEGF expression was visualized immunohistochemically in tumor cells. flt-1 expression correlated with histological differentiation (p < 0.013). Furthermore, expression of flt-1 was detected in tumor cells, macrophages and microvessels adjacent to tumor cells. VEGF and flt-1 expression were confirmed by in situ hybridization. CONCLUSION: There was a statistically significant correlation between VEGF and flt-1 expression (p < 0.001). The observed coexpression of VEGF and flt-1 possibly suggests a potential autocrine loop for malignant pleural mesothelioma cells.