Molecular and metabolic changes in human liver clear cell foci resemble the alterations occurring in rat hepatocarcinogenesis.

BACKGROUND & AIMS: Activation of the AKT/mTOR and Ras/MAPK pathways and the lipogenic phenotype occurs in both a rat model of insulin-induced hepatocarcinogenesis and in human hepatocellular carcinoma (HCC). In the rat model, activation of these pathways is evident within the earliest morphologic detectable alterations, i.e., clear cell foci (CCF) of altered hepatocytes. CCF have also been described in the human liver, but molecular and metabolic alterations within these foci remain to be determined. METHODS: A collection of human liver specimens was examined using electron microscopy, histology, enzyme- and immunohistochemistry, and molecular analysis. Human data were compared to rat preneoplastic CCF and HCC induced by N-nitrosomorpholine administration. RESULTS: CCF occurred in ∼33% of extrafocal tissues of human non-cirrhotic livers. Electron microscopy showed massive glycogen storage within CCF, largely due to the reduced activity of the glycogenolytic enzyme glucose-6-phosphatase. Hepatocytes in CCF overexpressed the insulin receptor and glucose transporter proteins. AKT/mTOR and Ras/MAPK pathways as well as enzymes of glycolysis, de novo lipogenesis, beta-oxidation, and cholesterol synthesis were upregulated, both in human CCF, and in CCF and HCC of N-nitrosomorpholine-treated rats. The Ki-67 proliferation index was 2-fold higher in human CCF than in extrafocal tissue. CONCLUSIONS: The high degree of similarity between human CCF and pre-neoplastic lesions from experimental models of hepatocarcinogenesis in terms of morphologic, molecular and metabolic features suggests a low-grade dysplastic nature of these lesions in human non-cirrhotic livers.

Population-based patterns of care in the first-line treatment of patients with advanced esophagogastric adenocarcinoma in Germany.

BACKGROUND: Randomized studies proved the efficacy of new drugs for the systemic treatment of advanced gastric cancer in the past 5 years. However, little is known about the use of firstline chemotherapy in clinical practice in patients with advanced or metastatic adenocarcinoma of the esophagogastric junction (AEG) and the stomach. We investigated temporal trends in therapy and factors influencing treatment decisions for these patients during a 4-year period. PATIENTS AND METHODS: 1058 patients (median age 67 years) with advanced AEG or gastric cancers undergoing treatment decisions were documented with the Therapiemonitor® in 2006-2009. Therapiemonitor collects population-based data regarding treatment decisions and strategies. Time trends of drug use and intensity in the first-line treatment were analyzed in the entire patient group and according to age (cut-off 65 years) and Karnofsky performance status (KPS; cut-off 80%). RESULTS: Over time, the use of oxaliplatin and docetaxel as well as capecitabine increased while cisplatin and irinotecan use slightly declined. The use of chemotherapy triplets rose from 10.1% in 2006 to 47.0% in 2009. Treatment patterns significantly varied by age and KPS: Older patients were significantly less likely to receive chemotherapy triplets, cisplatin and docetaxel but tended to more often receive oxaliplatin. Likewise, triplets, cisplatin and docetaxel were less frequently used in patients with KPS < 80%, while capecitabine and irinotecan were significantly more often used in this patient group. CONCLUSIONS: A clear tendency towards the use of more intensive chemotherapy regimens in patients with AEG and gastric cancer was observed over time. Older or less fit patients were treated preferably with monotherapy or chemotherapy doublets during 2006-2009. Oxaliplatin and docetaxel use has substantially risen.

Laparoscopic radiofrequency ablation of unresectable hepatic malignancies: indication, limitation and results.

BACKGROUND/AIMS: Radiofrequency-ablation (RFA) is an effective therapeutic option for destruction of irresectable primary and secondary liver tumors and has been successfully performed transcutaneously using sonographic or computer tomographic guidance or by laparotomy. The laparoscopic approach combines a minimal invasiveness with optimal diagnosis. METHODOLOGY: Between 02/2003 and 10/2005, 14 patients with a total of 45 unresectable liver tumors were treated with laparoscopic radiofrequency-ablation in our hospital. Laparoscopic RFA was primarily performed in patients' superficial lesions adjacent to neighboring organs that could be displaced by laparoscopic maneuvers, deep-sited lesions with a very difficult or impossible percutaneous approach and in combination with other laparoscopic operations. RESULTS: All intrahepatic tumors could be detected safely by laparoscopic intraoperative ultrasound. Additional liver lesions were identified in 5 (35.7%) of the 14 patients. All 45 tumors of the 14 patients were able to be completely ablated. Laparoscopic RFA yielded no mortality and only one case of postoperative bleeding. During a mean follow-up period of 23.2 months one patient locally recurred, three patients had new malignant nodules and two patients died with disease. CONCLUSIONS: Laparoscopic RFA is safe and provides a minimally invasive procedure with the option of simultaneous inflow-occlusion during thermoablation. Even more, neighboring organs can be protected, simultaneous resections can be performed and intraoperative ultrasound is used to gain further diagnosis.

Radiofrequency-ablation of unresectable primary and secondary liver tumors: results in 88 patients.

BACKGROUND AND AIMS: Radiofrequency-ablation (RFA) is increasingly used for destruction of unresectable primary and secondary liver tumors. We report our experience in the use of RFA for the management of unresectable hepatic malignancies. PATIENTS AND METHODS: Between February 2000 and December 2004 we have undertaken 120 RFA procedures to ablate 426 unresectable primary or metastatic liver tumors in 88 patients. RFA was performed via laparotomy (n=68), laparoscopy (n=9) or a percutaneous approach (n=43). Primary liver cancer was treated in seven patients (8%) and metastatic liver tumors were treated in 81 patients (92%). All patients were followed to assess complications, treatment response and recurrence of malignant disease. RESULTS: Procedure-related complication rate was low (3.4%). During a mean follow-up of 21.2 months, 15 patients had local tumor progression (17%), 21 patients (23.9%) had new malignant disease and 27 patients (30.7%) died from intervention-unrelated complications of their malignant disease. Additional liver lesions were identified in 27 (35%) of 77 cases by intraoperative ultrasound. Thirty-six patients received simultaneous resection and RFA. CONCLUSION: RFA is a safe, well-tolerated and effective treatment for patients with unresectable primary and secondary liver malignancies.

Vascular closure staples-a new technique for biliary reconstruction: prospective randomized comparison with manual suture in an animal model.

BACKGROUND: In orthotopic liver transplantation the incidence of biliary complications is up to 49%. In view of the relative frequency of such complications despite seemingly good preconditions, method-related disadvantages of conventional suture must also be considered as a possible cause. These include perforating needle injury of the choledochal wall with at least temporary exposure of suture material in the lumen, suboptimal approximation of the mucosa, and an additional decrease in blood flow in the choledochal stumps as a result of suture-related tissue strangulation. Hence the search for alternative anastomosis techniques. METHODS: To evaluate the surgical suitability of extramucosal titanium clips (Vascular Closure Staples; VCS) in comparison with conventional manual suture, a study was performed in 36 pigs, which were randomly assigned to 4 groups, each containing 9 animals. Choledochal excision was performed in 18 pigs and transection in the other 18 pigs; end-to-end anastomosis was then carried out, using a VCS stapler in half of the animals in each of these two groups and conventional manual suture in the other half. Pre- and postanastomotic blood flow was measured during the surgery with the aid of a laser Doppler flow meter. The long-term behavior of the closure techniques was ascertained by regular laboratory checks over the ensuing 6-month observation period, after which the pigs were killed so that the specimens could be harvested. RESULTS: Using medium-sized VCS clips, we were able to create a tension-free, everted biliary anastomosis with exact mucosal approximation and no narrowing of the lumen, and without any technical problems during the performance of the procedure. Measurements with the laser Doppler flow meter showed well-preserved anastomotic blood flow after clip reconstruction, with significantly higher perfusion values than after manual suture. The postoperative courses of the investigated laboratory parameters did not reveal any significant differences between the two methods. In contrast, histomorphometric evaluation showed wall thickness and thus fibrosis in the anastomosis region to be less in the clip group than in the suture group (median: 510 microm versus 660 microm, P<0.001). In the pigs in which clip anastomosis was used, there were no detectable anastomotic stenoses; in the pigs in which conventional suture was used, however, ultrasonography revealed five anastomoses with varying degrees of narrowing. CONCLUSIONS: Extramucosal VCS clip anastomosis not only offers potential advantages with respect to nonpenetrating and optimal mucosal contact, investigations in animals also show it to be superior to conventional manual suture as regards anastomotic blood flow and medium-term fibrosis formation. We believe that our data and the available literature warrant a clinical evaluation of this technique in appropriate studies.