The DNA index as a prognostic tool in hilar cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: Due to the devastating prognosis of patients suffering from hilar cholangiocarcinoma (HCCA) valid prognostic factors are urgently needed to guide treatment decisions in a personalized concept. The aim of this study was to analyze the predictive value of the DNA index in a large single-center cohort of patients undergoing resection of HCCA. METHODS: A total of 154 patients who underwent resection of HCCA were included in this prospective study. The DNA index was assessed by image cytometry of fresh tumor samples and correlated, as well as standard histopathological parameters, with patient survival. RESULTS: The median DNA index was 1.61 ± 0.32. Univariate survival analysis identified eight parameters including DNA index, but not DNA ploidy as prognostic markers. In the Cox proportional hazard model DNA index (P = 0.021), tumor size (P = 0.029) and lymph nodes status (P = 0.039) could be shown to be independent predictors of patient survival. CONCLUSION: The DNA index represents an independent prognostic marker in HCCA which is superior to most standard histopathological factors. Since the DNA index can be assessed not only post- but also preoperatively, it might be a potential tool in the preoperative decision-making process.

Ataxia-telangiectasia-mutated protein kinase levels stratify patients with pancreatic adenocarcinoma into prognostic subgroups with loss being a strong indicator of poor survival.

OBJECTIVES: Recently, aberrations in the gene encoding for ataxia-telangiectasia-mutated (ATM) protein kinase have been reported for pancreatic ductal adenocarcinomas (PDAC). These findings argue that ATM deficiency may play a role during carcinogenesis. Therefore, in this study, we investigated the clinical relevance of ATM expression and ATM activation in PDAC. METHODS: Both ATM expression and nuclear phosphoSer1981-ATM levels were assessed by immunohistochemistry in a cohort of 133 PDAC and correlated with clinicopathological parameters. RESULTS: We found stratification in prognostic subgroups. Complete loss of Ser1981-ATM was indicative of the worst prognosis (median survival, 10.8 vs 14.3 months [low expression] vs 31.1 months [high expression], P < 0.001). Similarly, analysis of ATM expression demonstrated absent expression levels of ATM to be associated with dismal prognosis (median survival, 9.6 months), whereas expression of ATM in general was associated with increased survival (17.7 months, P = 0.001). CONCLUSIONS: Our analysis shows that both ATM expression and activated ATM are prognostic markers in PDAC with respect to standard clinicopathological parameters. These results suggest that ATM should be further explored as prognostic as well as predictive factor with respect to conventional chemotherapies and for putative synthetic lethal approaches.

Hedgehog pathway as a potential treatment target in human cholangiocarcinoma.

BACKGROUND: Innovative treatment concepts targeting essential signaling pathways may offer new chances for patients suffering from cholangiocarcinoma (CCC). For that, we performed a systematic molecular genetic analysis concerning the Hedgehog activity in human CCC samples and analyzed the effect of Hh inhibition on CCC cells in vitro and in vivo. METHODS: Activation of the Hh pathway was analyzed in 50 human CCC samples using quantitative polymerase chain reaction (qPCR). The efficacy of Hh inhibition using cyclopamine and BMS-833923 was evaluated in vitro. In addition, the effect of BMS-833923, alone or in combination with gemcitabine, was analyzed in vivo in a murine subcutaneous xenograft model. RESULTS: Expression analysis revealed a significant activation of the Hh-signaling pathway in nearly 50% of CCCs. Hh inhibition resulted in a significant decrease in cell proliferation of CCC cells. Moreover, a distinct inhibition of tumor growth could be seen as a result of a combined therapy with BMS-833923 and gemcitabine in CCC xenografts. CONCLUSION: The results of our study suggest that the Hh pathway plays a relevant role at least in a subset of human CCC. Inhibition of this pathway may represent a possible treatment option for CCC patients in which the Hh pathway is activated.

DNA index is a strong predictive marker in intrahepatic cholangiocarcinoma: the results of a five-year prospective study.

PURPOSE: Predictive markers for risk stratification among patients with intrahepatic cholangiocarcinoma (IHC) are still lacking. Therefore, recent studies have focused on identifying the biological aspects of tumors that can provide more information about the tumor aggressiveness. The aim of this study was to prospectively evaluate the prognostic potential of the DNA index in patients undergoing liver resection for IHC. METHODS: In a prospective long-term follow-up study, the DNA index of 65 IHC patients undergoing liver resection was assessed by DNA image cytometry, and this parameter, as well as standard histopathological parameters, correlated with the patient survival. RESULTS: The mean DNA index was 1.69 ± 0.66 (range, 0.9-4.3). The univariate survival analysis showed that the DNA index (p = 0.024) and tumor stage (p = 0.017) were associated with patient survival, whereas all other standard histopathological factors had no predictive value. The multivariate analysis identified the DNA index (p = 0.050) and tumor stage (p = 0.028) as independent prognostic parameters. CONCLUSIONS: The DNA index is an independent predictive marker for IHC after liver resection. It is superior to most standard histopathological parameters and can be assessed pre- and postoperatively. Therefore, the DNA index might represent a promising tool in the decision-making process for patients with IHC.

DNA index as a strong prognostic factor in patients with adenocarcinoma of the pancreatic head: results of a 5-year prospective study.

OBJECTIVES: To improve the devastating prognosis of pancreatic cancer; the identification of reliable predictive factors is crucial. The aim of the present study was to prospectively assess the prognostic value of DNA index determined by image cytometry as an predictive factor in pancreatic head cancer. METHODS: The DNA ploidy and the DNA index of 61 patients were evaluated by DNA image cytometry and were found to be correlated, as well as standard histopathologic parameters, with patient survival. RESULTS: Through the DNA image cytometry, 15 tumors (24.6%) were identified as diploid and 46 (75.6%) as nondiploid. The median DNA index in the entire cohort was 1.9 (range, 1.0-2.5). Tumor stage, lymph node status, lymph node index, lymphatic invasion, and DNA index were identified as prognostic factors in the univariate analysis, but only DNA index (hazard ratio, 3.137; 95% confidence interval, 1.149-8.566; P = 0.026) and lymph node status (hazard ratio, 0.377; 95% confidence interval, 0.186-0.765; P = 0.007) were identified as independent predictive factors in the multivariate analysis. CONCLUSIONS: The DNA index represents an independent predictive marker in patients with pancreatic head cancer and a potential tool in designing specific treatment strategies for patients with pancreatic cancer.

Postoperative complications deteriorate long-term outcome in pancreatic cancer patients.

BACKGROUND: Different tumor-specific prognostic factors have been identified in recent years for patients who undergo surgery due to pancreatic head cancer, but the results often were inconsistent. Furthermore, the impact of postoperative complications on patient long-term survival has not been described. METHODS: The long-term outcome of 428 patients who underwent resection of pancreatic head cancer at our center during a 17-year period was evaluated. Perioperative details, including postoperative complications, as well as the follow-up of all patients who left the hospital postoperatively were collected in a prospective database. Univariate and multivariate models were used to identify potential prognostic factors and to evaluate the impact of postoperative complications on long-term survival. RESULTS: The median survival was 15.5 months with a postoperative complication rate (grade I-IV) of 32.7%. Independent prognostic significance was detected for grading (P < 0.001), R status (P = 0.001), and lymph node status (P = 0.003). The occurrence of severe postoperative complications (grade III-IV) was associated with a significantly shortened survival (16.5 vs. 12.4 months; P = 0.002) and was identified as an independent prognostic factor (P = 0.002). CONCLUSIONS: This large study demonstrates that severe postoperative complications have a strong impact on the long-term survival of patients with pancreatic head cancer comparable to tumor characteristics, such as lymph node status, grading, or R status. As a result, the improvement of surgical procedures in specialized centers might lead to a survival benefit in these patients.

Induction of bona fide regulatory T cells after liver transplantation - the potential influence of polyclonal antithymocyte globulin.

T-cell-depleting strategies are an integral part of immunosuppressive regimens used in the hematological and solid organ transplant setting. Besides prevention of alloreactivity, treatment with rabbit antithymocyte globulin (rATG) has been related to the induction of immunoregulatory T cells (Treg) in vitro and in vivo. To investigate Treg induced by rATG, we prospectively studied the effect of rATG induction therapy in liver-transplanted recipients in vivo (n = 28). Treg induction was further evaluated by means of Treg-specific demethylation region (TSDR) analysis within the FOXP3 locus. Whereas no induction of CD4(+) CD25(high) CD127(-) Treg could be observed by phenotypic analysis, we could demonstrate an induction of TSDR(+) T cells within CD4(+) T cells exclusively for rATG-treated patients in the long-term (day 540) compared with controls (P = NS). Moreover, although in vitro experiments confirm that rATG primarily led to a conversion of CD4(+) CD25(-) into CD4(+) CD25(+) T cells displaying immunosuppressive capacities, these cells cannot be classified as bona fide Treg based on their FOXP3 demethylation pattern. Consequently, the generation of Treg after rATG co-incubation in vitro does not reflect the mechanisms of Treg induction in vivo and therefore the potential clinical relevance of these cells for transplant outcome remains to be determined.

Safety of liver resection and effect on quality of life in patients with benign hepatic disease: single center experience.

BACKGROUND: Although liver resection has long been established for selected patients with benign hepatic disease, the success of surgical treatment of these patients cannot be evaluated exclusively through postoperative morbidity and mortality. Therefore, the aim of the study was to prove the safety of liver resection in the treatment of benign liver tumors and to evaluate the effect of surgical treatment on the patients' quality of life. METHODS: A total of 146 patients who underwent liver resection because of benign liver tumors were included in this study. Postoperative outcome was assessed and patients evaluated their quality of life before surgery and at the present time using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ C-30). RESULTS: The rate of serious (> grade 2) complications was 4.1% with no postoperative death. The quality of life assessment revealed an overall improvement of general health status after resection (0.7 vs. 0.56, p < 0.001) and additionally a significant reduction of 6 out of 9 symptoms. Furthermore, compelling benefits in the patients' social and emotional coping could be detected after surgery. CONCLUSIONS: Liver resection for benign liver disease is a safe procedure and leads to a significant improvement of quality of life in selected patients.

Nonresponse to pre-operative chemotherapy does not preclude long-term survival after liver resection in patients with colorectal liver metastases.

BACKGROUND: Liver resection is the only curative treatment offering a chance of long-term survival in patients with colorectal liver metastases (CRM). Recent data indicated that liver resection in patients with tumor progression while receiving chemotherapy was associated with poor outcome. The aim of the study was to identify risk factors for poor outcome in patients with pre-operative chemotherapy of CRM. METHODS: We analyzed 160 patients after liver resection for CRM with preoperative systemic. chemotherapy. Three groups of patients were identified: 44 patients (27.5%) had a tumor response, 20 (12.5%) showed stable disease, and 96 (60%) patients had tumor progression while on chemotherapy. Median follow-up was 2.4 years (range, 6 days-11.1 years). All available clinicopathologic variables possibly associated with outcome were evaluated. RESULTS: Survival was 88%, 53%, and 37% at 1, 3, and 5 years. Noncurative resection, carcinoembryonic antigen levels >200 ng/ml, tumor grading, size of the largest tumor >5 cm, and number of metastases were associated with poor patient outcome. In the multivariate analysis, tumor free margin and tumor grading correlated with the outcome. Tumor progression while on chemotherapy had no influence on the long-term survival. CONCLUSION: Liver resection offers a long-term survival benefit for patients with CRM, even when tumor growth proceeds during pre-operative chemotherapy.