Anwar Tarabichi

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.

Minimal Residual Disease in Gastric Cancer: Evidence of an Independent Prognostic Relevance of Urokinase Receptor Expression by Disseminated Tumor Cells in the Bone Marrow

PURPOSE To study the invasion-related molecule urokinase-type plasminogen activator receptor (u-PAR) expressed by disseminated tumor cells as a biologic predictor of poor survival in a large prospective series of patients with gastric cancer. PATIENTS AND METHODS In 156 gastric cancer patients (prospective series), disseminated tumor cells in the bone marrow and the u-PAR expressed by these tumor cells were determined by cytokeratin (CK) 18 immunocytochemistry and u-PAR/CK18 double immunocytochemistry. RESULTS In contrast to the mere detection of disseminated tumor cells at primary surgery, the additional evidence of u-PAR on these cells correlated significantly with pathologic T stage (P =.0474) and the expression of u-PAR (P =.0093) and plasminogen-activator inhibitor 1 (P =.0145) in the primary tumor (immunohistochemistry, chi(2)). Kaplan-Meier analysis revealed no association with prognosis for the mere detection of disseminated tumor cells. In contrast, a significant association was seen between detection of u-PAR on these cells and shorter disease-free (P <.0001) and overall survival (P <.0001). Multivariate analysis revealed that u-PAR on disseminated tumor cells at the time of primary surgery is an independent prognostic factor for disease-free (95% confidence interval [CI], 1.72 to 3.21; P =.024) and overall survival (P =.0049; relative risk, 2.89; 95% CI, 1.92 to 4.30). CONCLUSION This is the first large study to show that u-PAR, detected on disseminated tumor cells in the bone marrow, is an independent prognostic parameter in gastric cancer, in contrast to the mere detection of minimal residual disease (MRD). u-PAR may be a promising marker to define a critical subpopulation of disseminated tumor cells and a target to eliminate MRD. Molecular phenotyping of MRD is critical for defining its individual clinical relevance.

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.

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 (a-2-antiplasmin, a-2-macroglobulin, a-1-antitrypsin, a-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), a-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 dominan t. For detailed pattern analysis, stepwise overall Kaplan-Meier analyses were performed in subgroups of high uPA-R-, uPA-, PAI-1-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 a-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.

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

&NA; 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‐&agr; 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.

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.

A calcineurin antagonist-free induction/maintenance strategy for immunosuppression in elderly recipients of renal allografts from elderly cadaver donors: long-term results from a prospective single centre trial.

Abstract:  Background:  With the aim to improve the inferior outcomes in elderly recipients of kidneys from elderly cadaver donors, we applied and investigated a therapeutic regimen consisting of calcineurin inhibitor (CNI)‐free, mycophenolate mofetil (MMF)‐based immunosuppressive (i.s.) induction/maintenance protocol. In this article, we report the long‐term results of this clinical trial.

Antithrombin therapy in pancreas retransplantation and pancreas-after-kidney/pancreas-transplantation-alone patients.

Fertmann JM, Arbogast HP, Illner W‐D, Tarabichi A, Dieterle C, Land W, Jauch K‐W, Hoffmann JN. Antithrombin therapy in pancreas retransplantation and pancreas‐after‐kidney/pancreas‐transplantation‐alone patients.
Clin Transplant 2011: 25: E499–E508.