[Role of vacuum therapy in the management of the septic abdomen]. / Einsatzmöglichkeiten der Vakuumtherapie zur Therapie des septischen Abdomens.

Progress in intensive care medicine contributed substantially in lowering the mortality rate of patients suffering from diffuse secondary peritonitis. In the medical care of patients presenting a septic abdomen the persisting septic focus is one of the greatest problems. This is associated with other problems like temporary closure of the abdomen, complications due to re-laparotomies, healing of the abdominal wall after soft tissue infection, loss of abdominal wall musculature, or persisting enteral fistulas. The vacuum therapy is used with increasing frequency for the treatment of septic complications in different areas of the body. The excellent drainage characteristics of the vacuum therapy appear to be a therapeutic option for the control of surgically untreatable septic processes in the abdominal cavity. More and more experience is gathered with the successful treatment of enterocutaneous fistulas, small intestine and pancreatic fistulas as well as anastomotic leakage after rectal surgery. There exist hardly any evidence-based recommendations for the application of vacuum therapy for treatment of the septic abdomen. But the good results of temporary closure of open abdomen of trauma patients by the vacuum therapy arises hope that the results can be transferred to the treatment modalities of persisting peritonitis. Additionally, these patients could profit from the drainage characteristics of the vacuum therapy.

Prognostic relevance of MMP-2 (72-kD collagenase IV) in gastric cancer.

The association of MMP-2 (matrix metalloproteinase 2, 72-kD collagenase IV) with invasive and metastatic capacity of tumor cells has implicated a potential role in the prognosis for cancer patients. However, no larger study has been done to prove this hypothesis. The present study was therefore designed to investigate the prognostic impact of MMP-2 in a prospective series of 203 gastric cancer patients. MMP-2 expression was measured immunohistochemically and scored semiquantitatively (score 0-3) in carcinoma cells, and results were correlated with clinicopathological tumor parameters and parameters of the urokinase-type plasminogen activator (uPA) system. Survival analyses were done using the Kaplan-Meier method (log-rank statistics) and multivariate Cox analysis. Significant correlations were found for MMP-2 and Laurén's classification, M stage and proteases/inhibitors of the uPA system in the primary tumor. Kaplan-Meier analysis revealed an association of increasing MMP-2 expression with worse prognosis. This was especially seen in patients with a parallel high expression of uPA receptor. However, differences in survival probabilities between low and high MMP-2 levels were not significant. In a separate analysis of diffuse-type cancers, MMP-2 was significantly associated with disease-free (p = 0.0056) and overall survival (p = 0.0426). Multivariately, MMP-2 was not an independent parameter. Our results demonstrate that there is an association of immunohistochemical detection of MMP-2 with prognosis of cancer patients. For diffuse gastric cancers, it is a significant prognostic parameter, however, not of independent impact. The study further suggests that consideration of interrelated tumor-associated proteases like uPA receptor in combination with MMP-2 may improve its prognostic power.

Tumor-associated proteases and inhibitors in gastric cancer: analysis of prognostic impact and individual risk protease patterns.

Expression of proteolytic parameters of the urokinase-type plasminogen activator (uPA) system [uPA receptor (uPA-R), plasminogen activator inhibitor (PAI)-1] has been proven to be an independent prognostic parameter in cancer. However, it has not been considered that the uPA system is interacting with several other protease/inhibitor systems, neither has a comparable prognostic role of these factors been investigated. Moreover, studies evaluating specific protease patterns indicating high individual risk are missing completely. Therefore, in a consecutive prospective series of 203 gastric cancer patients, the expression of activators (plasminogen, tPA, MMP-2, cathepsin D, antithrombin 3) and inhibitors (alpha-2-antiplasmin, alpha-2-macroglobulin, alpha-1-antitrypsin, alpha-1-antichymotrypsin) of proteolysis was studied immunohistochemically in the tumor epithelium semiquantitatively (score 0-3) in addition to the uPA system. Kaplan-Meier analysis (median time of follow-up 31 months) revealed a significant association of cathepsin D (P=0.0042), alpha-2-macroglobulin (P=0.0281) and antitrypsin (P=0.0372) with disease-free survival and of cathepsin D (P=0.0018), antitrypsin (P=0.0112) and antichymotrypsin (P=0.0002) with overall survival. Multivariate Cox analysis performed to correct these results for relative impact of the uPA system and established prognostic factors showed PAI-1 (disease-free survival: P=0.002, relative risk 1.86; overall survival: P=0.005, relative risk 1.39), pT and pN as independent parameters. Cathepsin D was shown to have an independent impact on disease-free survival (P=0.020, relative risk 2.98). Comparative chi-square analysis of cases with poor and good prognoses revealed that in patients with good clinical outcome, inhibitors of proteolysis are correlated significantly, whereas in patients with poor prognosis activators of proteolysis are significantly associated preferentially and significant correlations with the uPA-R are dominant. For detailed pattern analysis, stepwise overall Kaplan-Meier analyses were performed in subgroups of high uPA-R-, uPA-, PAI1- and cathepsin D expression for two additional proteases each. From these analyses, the combination of high (score 2/3) expression of uPA-R, PAI-1, antichymotrypsin and alpha-2-macroglobulin was identified as a high-risk pattern, representing parameters known to be essential for uPA-R internalization and recycling. This suggests some of the uPA-associated proteases and inhibitors investigated as univariate prognostic parameters in gastric cancer. Cathepsin D is a new independent parameter for disease-free survival. The study further demonstrates that a protease pattern promoting uPA-R recycling in tumor cells especially indicates high individual risk tumors in gastric cancer.

An immunohistochemical assessment of cathepsin D in gastric carcinoma: its impact on clinical prognosis.

BACKGROUND: In the context of tumor-associated proteolysis, the prognostic value of cathepsin D in breast carcinoma has been studied but its role is controversial in relation to gastrointestinal carcinoma. The aim of the current study was to determine whether cathepsin D is a prognostic parameter for gastric carcinoma, and also to consider interaction with the urokinase-plasminogen activator (uPA) system as an established risk factor for tumor-associated proteolysis. METHODS: In a consecutive prospective series of 203 gastric carcinoma patients, expression of cathepsin D in tumor cells was semiquantitatively analyzed with immunohistochemistry (scored 0-3). Median follow-up time was 31 months (range, 9-56 months). Kaplan-Meier (log rank) and multivariate Cox analyses were used to analyze survival. RESULTS: Kaplan-Meier analysis (log rank statistics) revealed significant association of increasing cathepsin D detection with poorer disease free survival (P = 0.0042) and poorer overall survival (P = 0.0018) of curatively resected patients. Overall survival of all patients was not significantly correlated. Multivariate analysis of established risk factors for gastric carcinoma, including the uPA system, identified cathepsin D as a new and independent prognostic parameter for disease free survival (P = 0.020; relative risk, 2.98; 95% confidence interval, 1.28-6.91). Plasminogen activator inhibitor type-1 as a representative of the uPA system was confirmed as a strong independent factor for disease free and overall survival. Chi-square analysis showed significant correlation of higher cathepsin D levels with Laurén's diffuse-type carcinomas and strong evidence of uPA receptor in tumor cells. However, a subgroup analysis performed according to Laurén's classification revealed a univariate prognostic impact of cathepsin D on both diffuse and intestinal types without independent value. For patients with high levels of uPA receptor (scores of 2 and 3, n = 132), a highly significant association of increasing evidence of cathepsin D with disease free survival (P < 0.0001) and overall survival (P < 0.0001) was observed for curatively resected patients. Significant association with survival was also observed for all patients (P = 0.0407). CONCLUSIONS: Cathepsin D is a new functional prognostic parameter for gastric carcinoma patients with independent value for disease free survival. Moreover, this study indicates that consideration of more than one tumor-associated protease could lead to a more individualized estimation of risk for carcinoma patients.

Urokinase plasminogen activator receptor (uPA-R): one potential characteristic of metastatic phenotypes in minimal residual tumor disease.

Evidence of dynamic development of cytokeratin (CK) 18-positive disseminated tumor cells in bone marrow of curatively resected cancer patients has implicated a subclinical minimal residual disease as a biologically relevant component in solid cancer. However, differentiation between irrelevant shed cells and those cells potentially capable of causing later recurrence has not yet been made. In parallel, accumulating data show functional association of the urokinase plasminogen activator (uPA) system and the membranous uPA receptor (uPA-R) with the capacity of a tumor cell for invasion and metastasis. The present study was designed to find descriptive evidence in vivo concerning whether uPA-R could be one potential characteristic for metastatically relevant phenotypes of disseminated tumor cells. An immunocytochemical double staining for uPA-R and CK18 (immunogold/alkaline phosphatase anti-alkaline phosphatase) was performed on perioperative and follow-up bone marrow aspirations of 78 curatively resected gastric cancer patients, if positive tumor cell status had been shown previously with the single alkaline phosphatase anti-alkaline phosphatase method. Bone marrow cells (10(6)) were examined in each assay. Postoperative qualitative and quantitative development of uPA-R-expressing disseminated tumor cells was followed in relation to uPA-R-negative cells and correlated with later clinical relapse. Double staining could be performed perioperatively or in follow-up, or both, in 58 of 78 patients. Expression of uPA-R on perioperatively disseminated tumor cells significantly correlated with later quantitative increases of tumor cells (P = 0.0009). Overall median tumor cell numbers with uPA-R expression significantly increased during follow-up from a median value of 5.5 to 10.0 in 10(6) cells (P = 0.008), and the mean relative percentage of uPA-R-positive, compared with uPA-R-negative, disseminated tumor cells also increased, from 47.9% at surgery to 68.6% in follow-up (P < 0.001). This was mainly due to patients with later tumor relapse (increase from 63.9 to 80.7%, P = 0.001). Patients without relapse showed slight increases at lower percentage levels (5.7% at surgery, 7.4% in follow-up). Differences for relapsing patients were significant (surgery, P = 0.006; follow-up, P < 0.001). Our results suggest from an in vivo model that uPA-R may be one antigen that enables identification and follow-up observations of metastatically relevant phenotypes of disseminated tumor cells, differentiating their individual potential for causing relapse.