Endoluminal vacuum therapy for the treatment of anastomotic leakage after anterior rectal resection.

Anastomotic leakage is the most important complication after (deep) anterior rectal resection, and is the main cause for the high level of patient mortality and morbidity. It can lead to generalized peritonitis, with a severe septic progression involving multiple organ failure and potentially culminating in the death of the patient. Despite numerous improvements in the surgical technique, it has so far not been possible to reduce the leakage rate significantly. An innovative endoscopic method for treating anastomotic leakage has now been developed and established clinically at the Department of Surgery, University of Munich-Grosshadern. Working together with B. Braun, we have been able to develop the technique of endoluminal vacuum therapy further into the Endo-SPONGE treatment, and prepare it as an autonomous therapeutic method. In the following report we present our experiences to date in the area of endoluminal vacuum therapy.

Development of a cost-effective system for digital off-line analysis of transrectal ultrasound.

BACKGROUND: Transrectal ultrasound (TRUS) is the most sensitive and accurate technique for preoperative staging and follow-up of rectal cancer. One of the most relevant problems of this technique is that the assessment of TRUS is possible only during real-time examination. Furthermore, interpretation of the ultrasound findings is difficult and requires long experience. We show the development of a new, cost-effective software solution for off-line examination and documentation of transrectal ultrasound. METHODS: The ultrasound device is connected to a frame-grabber card in a standard PC. Video capturing is done using a freeware software solution and various video codecs. The whole examination course is recorded. The examiner only has to concentrate on producing an artifact-free realization of the examination. RESULTS: The software solution offers a flexible review of each individual "frame" of the investigation on the personal computer, very similar to CT and MRI scans. Infiltration depth and lymph node status can be assessed at any time, independently of the investigation and the investigator. The picture quality is excellent even if a lossy codec is used. It is not necessary to do definitive assessment of the TRUS during the examination. CONCLUSIONS: This new technique gives a cost-effective possibility for high-quality off-line staging, re-examination, re-evaluation, and documentation of rectal cancer. TRUS becomes an examiner-independent objective examination technique for staging and follow-up of rectal cancer.

c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems.

PURPOSE: The c-erbB-2 gene (encoding the protein p185) is overexpressed in diverse human cancers and has been implicated to be of prognostic value in gastric cancer. Recent studies suggest a role of p185 in tumor progression by specifically promoting the invasive capacity of tumor cells. Therefore, the present study was conducted with the following three objectives: (1) to support the prognostic value of c-erbB-2 in gastric cancer in a large prospective series using a monoclonal antibody and a highly sensitive immunohistochemical method; (2) to determine the association of c-erbB-2 expression with the expression of invasion-related genes; and (3) to perform the first overall multivariate analysis including c-erbB-2 and the invasion-related tumor-associated protease systems. PATIENTS AND METHODS: In a consecutive prospective series of 203 gastric cancer patients (median follow-up, 42 months), expression of c-erbB-2 and a panel of tumor-associated proteases and inhibitors by tumor cells were evaluated semiquantitatively (score 0 to 3) and analyzed for correlation (chi(2) test, Bonferroni-corrected). Kaplan-Meier survival analysis and multivariate Cox analysis were performed to determine the relative prognostic impact of c-erbB-2 and the invasion-related parameters. RESULTS: Kaplan-Meier analysis (log-rank statistics) revealed a significant association of increasing expression of c-erbB-2 with shorter disease-free (P =. 0023) and overall survival (P =.0160). High amounts of p185 were significantly associated with a high expression of urokinase-type plasminogen activator (uPA) (P <.010), uPA-receptor (P =.030), type-1 plasminogen activator inhibitor (PAI) (P <.010), type-2 PAI (P =.021), cathepsin D (P =.036), matrix metalloproteinase-2 (P =. 024), alpha-1-antichymotrypsin (P =.025), and alpha-2-macroglobulin (P =.017). Multivariate analysis considering these proteases/protease inhibitors, in addition to alpha-1-antitrypsin, tissue plasminogen activator, plasminogen, alpha-2-antiplasmin, and antithrombin III, and established prognostic parameters revealed that, in addition to surgical curability, pT stage, pN stage, and PAI-1, c-erbB-2 is an independent prognostic factor for overall survival of curatively resected patients (n = 139; P =.049; relative risk, 1.54; 95% confidence interval, 1.08 to 1.67) and all patients (P =.028; relative risk 1.33; 95% CI, 1.28 to 1.38). CONCLUSION: c-erbB-2 is confirmed as a new independent, functional prognostic parameter for overall survival in gastric cancer, even when a panel of invasion-related factors, including the strong prognostic parameter PAI-1, are considered. The significant correlation of p185 with several tumor-associated proteases supports the hypothesis that c-erbB-2 is a promoter of invasion and metastasis. This strongly suggests that c-erbB-2 may be a promising target for anti-invasive therapy in gastric cancer.

Clinical value of extended biologic staging by bone marrow micrometastases and tumor-associated proteases in gastric cancer.

OBJECTIVE: To investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional prognostic information on patients with curatively resected gastric cancer. BACKGROUND: Tumor-associated proteolytic mechanisms have been shown to be essential for invasion and metastasis. The urokinase-type plasminogen activator (uPA) system is of major biologic impact, but different interactive proteases and inhibitors with modulating effects also must be considered. The detection of early tumor cell dissemination indicates the systemic character of a primarily local gastric cancer. The confrontation of the organism with these cells determines the often unpredictable course of an individual tumor after presumed curative primary treatment. METHODS: In a prospective study of 247 consecutive patients with gastric cancer, detection of disseminated tumor cells in bone marrow aspirates was immunocytochemically performed in 180 patients. The expression of uPA, activators of uPA (cathepsin D, antithrombin III), uPA substrates (plasminogen, matrix-metalloproteinase 2 [collagenase IV, 72 kD; MMP-2]), uPA/plasmin inhibitors (plasminogen activator inhibitor type 1 and 2 [PAI-1, PAI-2], alpha1-antitrypsin, alpha2-antiplasmin), uPA receptor (uPA-R), and parameters of the uPA-R cycle (alpha2-macroglobulin, alpha1-antichymotrypsin) could be determined immunohistochemically and were scored semiquantitatively in 203 patients. Kaplan-Meier statistical techniques and multivariate Cox regression models were used for prognostic analyses. RESULTS: In multivariate analysis considering all the established risk factors, disease-free survival was independently predicted by PAI-1 (relative risk 2.21, 1.32-3.73) and cathepsin D (relative risk 2.98, 1.28-6.91) besides pT, pN, and extended resection. Tumor cell dissemination was found to be an additional prognostic factor in early tumor stages (pT1, T2) and lymphnode-negative patients. Stepwise regression analysis revealed an extended staging system with new risk groups. Node-positive, curatively resected pT1/2 patients with low expression of PAI-1 had a favorable prognosis (mean recurrence-free survival [MRT] 54.84 months), similar to that of node-negative patients (MRT 54.76 months). In node-negative, curatively resected pT1/2 patients, detection of bone marrow tumor cells and high expression of PAI-1 defined a subgroup with a steep decrease of prognosis (MRT 36.60 months), which was worse than that of node-positive patients (MRT 45.81). CONCLUSION: This new staging model gives better prognostic differentiation of subgroups, which should be considered in future adjuvant therapy protocols. In addition, it indicates that the uPA system might be a future therapeutic target.

Prognostic influence of blood transfusion on minimal residual disease in resected gastric cancer patients.

BACKGROUND: The effect of blood transfusion on prognosis of resected cancer patients has been debated controversially. Therefore, we raised the hypothesis that transfusion-associated immunomodulation affects minimal residual disease after curative tumour resection, an unknown and uncontrolled phenomenon in all former studies which might significantly influence long-term prognosis. PATIENTS AND METHODS: 104 patients of a prospective study with curatively resected gastric cancer were stratified according to the immunocytochemical detection of disseminated tumour cells in bone marrow and the prognostic impact of allogeneic blood transfusion was tested. Multiple sequential bone marrow aspirations during follow-up were performed in 74 patients to investigate the blood transfusion effect on long-term development of this systemic disease component. RESULTS: Whereas in patients with tumour cell detection in bone marrow a significant association of blood transfusion and survival was seen (P = 0.048; relative risk 2.91; 95% CI 1.51-5.61), this was not found in patients without disseminated tumour cells (P = 0.129). Quantitative development of tumour cells in bone marrow during follow-up demonstrated a significant quantitative increase of tumour cells in transfused patients only (P = 0.028). CONCLUSION: These findings might explain the contradictory results of recent studies and suggest that the prognostic effect of transfusion is mediated through an impact on minimal residual disease in resected cancer patients.

The prognostic impact of the urokinase-type plasminogen activator system is associated with tumour differentiation in gastric cancer.

The prognostic value of tumour-associated proteolysis, especially the urokinase plasminogen activator (uPA) system, has been proposed in gastric cancer. In a prospective series of 203 resected patients, the expression of immunohistochemically assessed uPA, uPA-receptors and PAI-1 was strongly associated with survival. Multivariate analysis revealed PAI-1 as a new independent prognostic factor (overall survival: P = 0.005, relative risk 1.47, 95% CI 1.31-1.64). Gastric cancer is assumed to consist of two biologically different tumour types according to the histomorphological Lauren's classification. Consideration of this classification revealed strong prognostic impact of the uPA system in diffuse type cancers (overall survival: uPA, P = 0.028, relative risk 1.58, 95% CI 1.30-1.91; uPA-receptor, P = 0.001, relative risk 1.42, 95% CI 1.25-1.61) which are by definition low-differentiated (G3). For intestinal type cancers only in low-differentiated (G3) tumours a prognostic value was obtained (overall survival: PAI-1, P = 0.050, relative risk 2.16, 95% CI 1.17-3.96) while the association of grading and survival was not significant. This implies that the clinically relevant impact of the uPA system is associated with tumour differentiation.

Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer.

It is unclear whether disseminated tumour cells detected in bone marrow in early stages of solid cancers indicate a subclinical systemic disease component determining the patient's fate or simply represent mainly irrelevant shed cells. Moreover, characteristics differentiating high and low metastatic potential of disseminated tumour cells are not defined. We performed repeated serial bone marrow biopsies during follow-up in operated gastric cancer patients. Most patients with later tumour relapse revealed either an increase or a constantly high number of tumour cells. In contrast, in patients without recurrence, either clearance of tumour cells or negative or low cell counts were seen. Urokinase plasminogen activator (uPA)-receptor expression on disseminated tumour cells was significantly correlated with increasing tumour cell counts and clinical prognosis. These results demonstrate a systemic component in early solid cancer, indicated by early systemically disseminated tumour cells, which may predict individual disease development.

Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system.

PURPOSE: The significance of tumor-associated proteolysis as reflected by parameters of the urokinase-type plasminogen activator (uPA) system for prognosis in cancer patients has been proposed because of evidence for its central role in basic mechanisms of invasion and metastasis. The aim of the present study was to evaluate whether the expression of the uPA parameters might be of clinical value in gastric cancer as a tumor/biologically defined risk factor. PATIENTS AND METHODS: In a consecutive series of 203 patients resected for primary gastric cancer, the expression of uPA, uPA-receptor (uPA-R), plasminogen activator inhibitor (PAI)-1, and PAI-2 was determined immunohistochemically. The results were classified semiquantitatively (0 to 3). Patients were followed-up prospectively for a median of 31 months (range, 9 to 56 months). Disease-free and overall survival were analyzed according to Kaplan-Meier and with univariate and multivariate Cox analyses in relation to conventional prognostic factors. RESULTS: Univariate analyses revealed a highly significant inverse correlation of uPA, uPA-R, and PAI-1 expression with survival time (P = .0008, P = .0002, and P = .0002, respectively), whereas PAI-2 demonstrated only a weak correlation. In multivariate analyses, PAI-1 was an independent and strong prognostic factor (P = .005; relative risk, 1.47 per staining degree; 95% confidence interval [CI], 1.31 to 1.64). In pT1/2 tumors and in Laurén's diffuse and mixed types, uPA, uPA-R, and PAI-1 added significant prognostic information. PAI-1 was also associated with survival in the subgroup of lymph node-positive patients. CONCLUSION: PAI-1, uPA, and uPA-R are new functional risk factors reflecting clinical prognosis. In particular, PAI-1 is a new independent variable for the identification of patients at high risk after tumor resection. Our results support the hypothesis that the uPA system probably is of general importance for prognosis of patients with malignant disease, indicating an individual tumor's capacity for invasion and metastasis.