Laparoscopic live donor nephrectomy: Are ten cases per year enough to reach the quality standards? A report from a single small-volume transplant center.

BACKGROUND: Laparoscopic live donor nephrectomy is the preferred method of kidney donation in high-volume US transplant centers, but for small transplant programs the question of the minimal case load per year necessary to reach the quality standards is open. PATIENTS AND METHODS: From 1996 to 2007 we performed 130 live kidney donations including 93 laparoscopic donor nephrectomies followed by transplantation in a community hospital with an average case load of 10 laparoscopic cases per year. We compared the results after 37 open and 93 laparoscopic live donor operations with respect to operating time, conversion rate, complications, and recipients' outcome. RESULTS: There were no significant differences in terms of safe outcome of donor patients after open or laparoscopic donor nephrectomy. The mean operating time was significantly shorter (p < 0.001) in the open group (125 min, OG) than in the laparoscopic group (150 min, LG). Mean hospital stay was significantly shorter (p < 0.001) in LG (6.8 days) versus OG (9.7 days). The conversion rate was 3.2% in the LG. Postoperative complication of donors consisted of temporary nerve irritation (two patients) and retroperitoneal hematoma (one patient) in the LG, and wound infection followed by hernia formation (one patient) and ileus 1 year after organ donation (one patient) in the OG. Safe outcome of the recipients after open (RaOD) or laparoscopic donation (RaLD) was similar. Uneventful transplantation occurred in 94.6% of the RaOD and in 92.5% of the RaLD. One kidney was lost due to renal vein thrombosis (RaLD). Mean postoperative creatinine after 4 weeks showed no difference between RaOD (1.6 mg/dl) and RaLD (1.7 mg/dl). CONCLUSION: Approximately ten cases per year may be enough to ensure safety and quality of laparoscopic live donor nephrectomy.

Simultaneous pancreas-kidney transplantation: analysis of rejection.

UNLABELLED: The 3-year data concerning the occurrence of rejection episodes (RE) are reported herein. PATIENTS AND METHODS: Two hundred five simultaneous pancreas-kidney (SPK) transplantations were performed from May 1998 to September 2000, including 103 patients randomly assigned to tacrolimus (Tac) and 102 to cyclosporine microemulsion (CsA-ME). All patients received concomitant rATG induction therapy, mycophenolate mofetil (MMF), and short-term corticosteroids. RESULTS: After a follow-up of 3 years, acute rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving CsA ME. The majority of first rejection episodes in both groups occurred during the first 6 months (93% and 90%, respectively) and in most cases were treated with corticosteroids (88% and 90%). Actuarial rejection-free graft survival was not significantly different between the two groups (54% and 44% at 3 years posttransplant). In a multivariate analysis, HLA compatibility (P = .003) and graft vessel extension (P = .0005) had a significant influence on rejection-free survival. Rejection influenced pancreatic graft survival (P = .01) and pancreatic graft loss owing to rejection influenced patient survival (P = .02). In the intent-to-treat analysis of early rejection, first moderate-to-severe episodes (1 of 40 versus 12 of 47; P = .004) and refractory episodes (2 of 40 versus 10 of 47; P = .03) were significantly lower with tacrolimus than with CsA ME. Pancreatic graft survival was worse among late rejectors (53%) than nonrejectors (86%; P = .002). In addition, serum creatinine was highest in late rejectors. In conclusion, Tac-based immunosuppressive therapy shows advantages over CsA ME in terms of the severity of acute rejection episodes among patients undergoing SPK transplantation.

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.

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.

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.

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.

Influence of autologous blood transfusion on natural killer and lymphokine-activated killer cell activities in cancer surgery.

BACKGROUND AND OBJECTIVES: Immunosuppression associated with blood transfusion may influence postoperative infection rates. It may also affect the prognosis of patients treated surgically for colorectal cancer. To control this effect, study protocols have applied autologous blood donation programs, which are thought to be immunologically neutral. However, evidence has emerged that blood donation itself might have suppressive effects on natural killer (NK) cell activities. At present, there are no data available on the effects of autologous blood transfusion on NK or lymphokine-activated killer (LAK) cells. This might be of interest as LAK cells may be active in tumor control. MATERIALS AND METHODS: 26 patients who underwent surgical resection for colorectal cancer, were assigned at random into two groups: (1) autologous blood donation and transfusion, or (2) allogeneic blood transfusion. NK and LAK activities were determined before blood donation, at surgery, and on the 3rd and 8th postoperative day. RESULTS: Blood donation induced a small decrease in NK and LAK activities. The postoperative courses of the two groups differed. In the allogeneic group, NK activity (-50%, p = 0.018) and LAK activity decreased (-60.7%, p = 0.043), whereas in the autologous group the decline in LAK was less pronounced (-33.7%, p = 0.091), and their NK activity even increased (+17.4%, p = 0.315). NK activity was modulated differently in the two study groups (0.0036). Differences in LAK activities were found between the 3rd and 8th day postoperatively (p = 0.354). CONCLUSIONS: In patients receiving autologous blood transfusion, postoperative suppressed NK and LAK activities were modulated. This implies that autologous blood transfusion is not immunologically neutral, but has an intrinsic immunomodulatory potential.

Modulation of immune response by blood transfusion: evidence for a differential effect of allogeneic and autologous blood in colorectal cancer surgery.

Even though blood transfusion-associated immunomodulatory effects have been reported, the basic immune mechanism is still not understood. Data from studies on the clinical effects of allogeneic blood-induced immunosuppression are contradictory. However, there are indications that autologous blood transfusion is not immunologically neutral but has intrinsic immunomodulatory potential. Therefore we investigated in vivo different immunological mediators in 56 randomized patients of a study comparing autologous and allogeneic blood transfusion in colorectal cancer surgery. Soluble IL-2 receptor, which is an indicator of general immune activation and the following immunologic refractory phase, indicated immunosuppression was more elevated at the seventh postoperative day in patients with allogeneic transfusions (p = .013) and autologous transfusions (p = .0003). The immunologic determination of TNF-alpha showed a significant postoperative increase in patients with autologous transfusions only (p = .0031). However, postoperative increase of soluble TNF-receptors p55 and p75 was also significant in patients transfused with allogenic blood (p = .022; p = .0014). The response to tetanus toxoid vaccination, an indicator of humoral immunity, was higher in patients transfused with allogeneic rather than autologous blood (p = .082), whereas responses of patients with autologous transfusions were even lower than in nontransfused patients. The reciprocal was already found for cell-mediated immunity determined by epicutaneously tested delayed-type hypersensitivity-reactions. IL-10 levels, an indicator of cellular immunosuppression, were determined in 27 additional patients before operation, immediately postoperative, and at the seventh postoperative day. IL-10 was found elevated immediately postoperative in allogeneic (p = .011) and nontransfused patients only (p = .042). The data from this study substantiate recent findings of a different immunomodulatory potential of allogeneic and autologous blood transfusion. They furthermore support the hypothesis that autologous blood transfusion does not contain immunologically neutral effects of allogeneic blood, but itself exerts an immunomodulatory effect.

Perisurgical erythropoietin application in anemic patients with colorectal cancer: A double-blind randomized study.

BACKGROUND: Blood transfusions are associated with higher postoperative morbidity and tumor recurrence rates in colorectal cancer surgery, To reduce the need for transfusions in patients with tumor-induced anemia who are not suitable for autologous blood donation, it was tested whether perisurgical erythropoietin application would be able to stimulate hematopoiesis adequately. METHODS: In a double-blind randomized study 150 IU/kg body weight erythropoietin was given subcutaneously every 2 days beginning 10 days before operation and continuing until postoperative day 2. Twenty patients were randomized into the erythropoietin group with three observed dropouts and 10 patients into the placebo group. RESULTS: In the erythropoietin group two episodes of hypertension and one deep venous thrombosis were observed. Preoperative hemoglobin response in the erythropoietin group (p = 0.069) was paralleled by a highly significant reticulocyte increase (p = 0.0004). However, frequency of blood transfusion was not different between both study groups (erythropoietin, 1.82 +/- 0.80 units/ patient; placebo, 1.80 +/- 0.97 units/patient). If iron availability was analyzed, a strong correlation between ferritin blood levels and transferrin iron saturation with hemoglobin response was observed in regression analysis (p < 0.001). CONCLUSIONS: These results indicate that hematopoiesis in anemic patients with colorectal cancer can be stimulated by erythropoietin; however, clinical efficacy is to be expected only in selected patients with high iron availability, which calls for further studies combining erythropoietin and parenteral iron application.