Mediastinitis after cardiac surgery

Mediastinitis as a complication after cardiac surgery is rare but disastrous increasing the hospital stay, hospital costs, morbidity and mortality. It occurs in 1-3 % of patients after median sternotomy. The purpose of this study was to find out the risk factors and also to investigate new ways to prevent mediastinitis. First, we assessed operating room air contamination monitoring by comparing the bacteriological technique with continuous particle counting in low level contamination achieved by ultra clean garment options in 66 coronary artery bypass grafting operations. Second, we examined surgical glove perforations and the changes in bacterial flora of surgeons' fingertips in 116 open-heart operations. Third, the effect of gentamicin-collagen sponge on preventing surgical site infections (SSI) was studied in randomized controlled study with 557 participants. Finally, incidence, outcome, and risk factors of mediastinitis were studied in over 10,000 patients. With the alternative garment and textile system (cotton group and clean air suit group), the air counts fell from 25 to 7 colony-forming units/m3 (P<0.01). The contamination of the sternal wound was reduced by 46% and that of the leg wound by >90%. In only 17% operations both gloves were found unpunctured. Frequency of glove perforations and bacteria counts of hands were found to increase with operation time. With local gentamicin prophylaxis slightly less SSIs (4.0 vs. 5.9%) and mediastinitis (1.1 vs. 1.9%) occurred. We identified 120/10713 cases of postoperative mediastinitis (1.1%). During the study period, the patient population grew significantly older, the proportion of women and patients with ASA score >3 increased significantly. In multivariate logistic regression analysis, the only significant predictor for mediastinitis was obesity. Continuous particle monitoring is a good intraoperative method to control the air contamination related to the theatre staff behavior during individual operation. When a glove puncture is detected, both gloves are to be changed. Before donning a new pair of gloves, the renewed disinfection of hands will help to keep their bacterial counts lower even towards the end of long operation. Gentamicin-collagen sponge may have beneficial effects on the prevention of SSI, but further research is needed. Mediastinitis is not diminishing. Larger populations at risk, for example proportions of overweight patients, reinforce the importance of surveillance and pose a challenge in focusing preventive measures.

Identification of molecules relevant for the invasiveness of fibrosarcomas and melanomas

Cancer is becoming the leading cause of deaths in the world. As 90% of all deaths from cancer are caused by metastasis, discovery of the mechanisms behind cancer cell invasion and metastasis is of utmost importance. Only new effective therapies targeting cancer progression can reduce cancer mortality rates. The aim of this study was to identify molecules that are relevant for tumor cell invasion and spreading in fibrosarcomas and melanomas, and to analyze their potential for cancer biomarkers or therapeutic targets. First, the gene expression changes of normal cells and transformed cells showing high invasiveness, S-adenosylmethionine decarboxylase (AdoMetDC)-transfected murine fibroblasts and human melanoma cells, were studied by microarray analyses. The function of the identified candidate molecules were then studied in detail in these cell lines. Finally, the physiological relevance of the identified changes was studied by immunohistochemical analyses of human sarcoma and melanoma specimens or by a mouse xenograft model. In fibrosarcoma cells, the most remarkable change detected was a dramatic up-regulation of the actin-sequestering molecule thymosin beta 4 (TB4), which was shown to be important for the transformed phenotype of the AdoMetDC-transfected cells (Amdc-s and -as). A sponge toxin latrunculin A, inhibiting the binding of TB4 to actin, was found to selectively inhibit the migration and invasion of these cells. Further, Amdc-s-induced mouse tumors and human high-grade sarcomas were found to show intense TB4 immunostaining. In addition to TB4, integrin subunits alfa 6 and beta 7 (ItgA6 and ItgB7) were found to be up-regulated in Amdc-s and -as cells. ItgA6 was shown to dimerize mainly with ItgB1 in Amdc-s. Inhibition of ItgA6 or ItgB1 function with neutralizing antibodies fully blocked the invasiveness of Amdc-s cells, and importantly also human HT-1080 fibrosarcoma cells, in three-dimensional (3D)-Matrigel mimicking tumor extracellular matrix (ECM). By immunohistochemical analyses, strong staining for ITGA6 was detected in human high-grade fibrosarcomas and other sarcomas, especially at the invasion fronts of the tumors. In the studied melanoma cell lines, the expression levels of the adhesion-related ECM proteins tenascin-C (TN-C), fibronectin (FN), and transforming growth factor beta-induced (TGFBI) were found to be highly up-regulated. By immunohistochemistry, intense TN-C and FN staining was detected in invasive and metastatic melanoma tumors, showing co-localization (together with procollagen-I) in tubular meshworks and channels around the invading melanoma cells. In vitro, TN-C and FN were further found to directly stimulate the migration of melanoma cells in 3D-collagen-I matrix. The third candidate protein, TGFBI, was found to be an anti-adhesive molecule for melanoma cells, and knockdown of its expression in metastatic melanoma cells (TGFBI-KD cells) led to dramatically impaired tumor growth in immunocompromized mice. Interestingly, the control tumors showed intense TGFBI immunostaining in the invasion fronts, showing partial co-localization with the fibrillar FN staining, whereas the small TGFBI-KD cell-induced tumors displayed amorphous, non-fibrillar FN staining. These data suggest an important role for TGFBI in FN fibrillogenesis and melanoma progression. In conclusion, we have identified several invasion-related molecules, which show potential for cancer diagnostic or prognostic markers, or therapeutic targets. Based on our previous and present fibrosarcoma studies, we propose the possibility of using ITGA6 antagonists (affecting tumor cell adhesion) in combination with TB4 inhibitors (affecting tumor cell migration) and cathepsin L inhibitors (affecting the degradation of basement membrane and ECM proteins) for the treatment of fibrosarcomas and other tumors overexpressing these molecules. With melanoma cells, in turn, we point to the importance of three secreted ECM proteins, TN-C, FN, and TGFBI, in melanoma progression. Of these, especially the potential of TN-C as a prognostic melanoma biomarker and TGFBI as a promising therapeutic target molecule are clearly worth additional studies.