Armin Thelen

Simultaneous versus staged liver resection of synchronous liver metastases from colorectal cancer

Background and aimsThe surgical strategy for treatment of synchronous liver metastases from colorectal cancer remains controversial. This retrospective analysis was conducted to compare the postoperative outcome and survival of patients receiving simultaneous resection of liver metastases and primary colorectal cancer to those receiving staged resection.Materials and methodsBetween January 1988 and September 2005, 219 patients underwent liver resection for synchronous colorectal liver metastases, of whom, 40 patients received simultaneous resection of liver metastases and primary colorectal cancer, and 179 patients staged resections. Patients were identified from a prospective database, and records were retrospectively reviewed. Patient, tumor, and operative parameters were analyzed for their influence on postoperative morbidity and mortality as well as on long-term survival.ResultsSimultaneous liver resections tend to be performed for colon primaries rather than for rectal cancer (pu2009=u20090.004) and used less extensive liver resections (pu2009<u20090.001). The postoperative morbidity was comparable between both groups, whereas the mortality was significantly higher in patients with simultaneous liver resection (pu2009=u20090.012). The mortality after simultaneous liver resection (nu2009=u20094) occurred after major hepatectomies, and three of these four patients were 70xa0years of age or older. There was no significant difference in long-term survival after formally curative simultaneous and staged liver resection.ConclusionSimultaneous liver and colorectal resection is as efficient as staged resections in the treatment of patients with colorectal cancer and synchronous liver metastases. To perform simultaneous resections safely a careful patient selection is necessary. The most important criteria to select patients for simultaneous liver resection are age of the patient and extent of liver resection.

Extended Resections of Liver Metastases from Colorectal Cancer

BackgroundIndications for resection of liver metastases from colorectal cancer and surgical strategies are still under debate.MethodsWe have retrospectively reviewed the outcome of 660 patients after 685 liver resections for metastases of colorectal cancer in our institution from 1988 to 2004. All surviving patients have a minimum follow-up period of 1 year. The longest follow-up in these patients is 16 years. Three different time periods of 5 to 6 years each were analyzed.ResultsThe 30- and 60-day mortality rates were 1.5% (n = 10) and 2.2 % (n = 15), respectively. The rate of formally curative (R0) resections was 84%. Five-year survival rates in all patients and in patients after R0 resection were 37% and 42%, respectively. If only resections from 1999 to 2004 were considered, 5-year survival in patients after R0 resection was 50%. In a multivariate analysis, surgical radicality, ligamental lymph node involvement, number of liver metastases, and time period, in which the liver resection had been performed, were independent prognostic parameters.ConclusionsOutcome after liver resection for metastases from colorectal cancer has constantly improved. A formally curative resection is the most relevant prognostic parameter. Number of liver metastases and, in the few patients concerned, lymph node infiltration of the hepatoduodenal ligament, were further prognostic parameters.

Liver Resection for Metastases from Renal Cell Carcinoma

BackgroundThis study was conducted to evaluate the safety and efficacy of liver resection in patients with hepatic metastases from renal cell carcinoma and to identify selection criteria for patients suitable for resection.MethodsBetween January 1988 and March 2006, 31 patients underwent liver resection for metastases from renal cell carcinoma. Patients were identified from a prospective database and retrospectively reviewed. Patient, tumor, and operative parameters were analyzed for their influence on long-term survival.ResultsThe overall 1-, 3- and 5-year survival rates were 82.2%, 54.3%, and 38.9%, respectively. One patient was deceased and 4 developed complications during the postoperative course. In the univariate analysis, site of the primary tumor (Pxa0=xa00.013), disease-free interval (Pxa0=xa00.012), and resection margins (Pxa0=xa00.008) showed significant influence on long-term survival. In the multivariate analysis, only the resection margins were identified as an independent prognostic factor after liver resection.ConclusionsLiver resection is effective and safe in the treatment of patients with hepatic metastases from renal cell carcinoma and offers the chance of long-term survival and cure. Achieving a margin-negative resection is the most important criterion in the selection of suitable patients for liver resection. However, the number of patients in the present study was small, and investigations of larger series may provide further prognostic parameters in these patients.

Liver resection for metastatic gastric cancer

AIMSnLiver resection represents a curative treatment approach in patients suffering from liver metastases from gastric cancer. However, its value in the treatment of these patients remains controversial. This study was conducted to evaluate the safety and effectiveness of liver resection in these conditions and to identify criteria for the selection of suitable patients.nnnMETHODSnFrom January 1988 to December 2002, 24 patients underwent liver resection for metastatic gastric cancer. The outcome of these 24 patients was retrospectively reviewed using a prospective database. Patient, tumour and operative parameters were analyzed for their influence on long-term survival.nnnRESULTSnOne patient died and four patients (17%) developed complications during the postoperative course. The overall one-, three- and five-year survival was 38%, 16% and 10%, respectively. After curative resection (n=17), the one-, three- and five-year survival rate was 53%, 22% and 15%, respectively, and patients with metachronous metastases restricted to the liver (n=5) had a one-, three- and five-year survival of 80%, 40% and 40%, respectively. In the univariate analysis, extrahepatic manifestation showed in tendency (p=0.069) and resection margins statistically significant (p=0.005) influence on survival. The multivariate analysis revealed only resection margins as an independent prognostic factor for survival.nnnCONCLUSIONSnLong-term survival can be achieved by liver resection in well selected patients and may be considered in the multidisciplinary treatment approach of metastatic gastric cancer. Patients with metastatic disease restricted to the liver in whom a curative resection can be achieved seem to be most suitable for liver resection.

VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma.

Lymphatic spread is an important clinical determinant for the prognosis of hepatocellular carcinoma (HCC), but little is known about the control of lymphangiogenesis in HCC. We addressed expression and biological role of the pro‐(lymph), angiogenic protein VEGF‐D in this tumor entity. Using immunohistochemistry and in situ hybridization on specimens of HCC, cirrhotic and normal liver we found abundant expression of VEGF‐D exclusively in the tumor cells. The cognate receptor VEGFR‐3 was detected on blood and lymphatic vessels. By clinicopathological analysis VEGF‐D expression was correlated with pT‐stage of the primary, lymph node metastasis and lymphangiosis carcinomatosa. Three out of 4 human HCC cell lines expressed and secreted VEGF‐D. To approach its biological function, VEGF‐D deficient SKHep‐1 cells were stably transfected with VEGF‐D cDNA and effects on tumor progression were determined in vivo. Compared to mock‐transfected controls, subcutaneous tumors derived from VEGF‐D expressing cells were larger and more frequently metastasized to regional lymph nodes. VEGF‐D expressing tumors exhibited increased microvessel density and increased abundance of peri‐ and intratumoral lymphatics, as assessed by immunostaining for CD31 and for LYVE‐1 and/or podoplanin, respectively. Furthermore, coexpression of the soluble extracellular VEGFR‐3 domain blocked VEGF‐D‐induced tumor growth and lymphatic spread via reduction of angiogenesis and lymphangiogenesis. In the orthotopic approach, VEGF‐D expression resulted in an increased rate of intra‐ and extrahepatic as well as lymph node metastasis. In conclusion, our study suggests that expression of VEGF‐D is involved in growth and lymphatic spread of HCC. Therefore, VEGF‐D might represent a therapeutic target in HCC.

Tumor-Associated Lymphangiogenesis Correlates with Lymph Node Metastases and Prognosis in Hilar Cholangiocarcinoma

BackgroundTumor-associated lymphangiogenesis has been shown to promote nodal spread and is of prognostic significance in some tumor entities. Currently, nothing is known about the impact of lymphangiogenesis on progression and prognosis in hilar cholangiocarcinoma.MethodsWe analyzed tissue specimens of normal liver and hilar cholangiocarcinoma (nxa0=xa060) by immunohistochemistry using the lymphendothelial-specific antibody D2-40 and subsequently quantified lymphatic microvessel density (LVD). The LVD was correlated with clinicopathological characteristics and recurrence pattern of the tumors as well as patients’ survival.ResultsIn contrast to the low abundance of lymphatic vessels in nontransformed liver tissue, we found an induction of lymphangiogenesis in hilar cholangiocarcinoma. Tumors with a high LVD (34 out of 60) had a significant higher incidence of lymph node involvement (pxa0<xa00.001), perivascular (pxa0=xa00.017), and perineural (pxa0=xa00.033) lymphangiosis and local recurrence (pxa0<xa00.001). Furthermore, a high LVD was identified to be a significant overall (three-year: 24.4% versus 90.5%; five-year: 7.0% versus 76.4%; pxa0<xa00.001) and disease-free (three-year: 8.3% versus 76.6%; five-year: 5.9% versus 61.4%; pxa0<xa00.001) survival disadvantage, with LVD representing an independent prognostic factor for survival (pxa0<xa00.001) in the multivariate analysis.ConclusionsLymphangiogenesis is associated with increased frequency of tumor cells in lymphatics and lymph nodes in hilar cholangiocarcinoma. The prognostic importance of tumor-associated lymphangiogenesis was reflected by LVD serving as an independent prognostic factor. In addition, lymphangiogenesis may represent a potential target in the development of new therapeutic approaches in hilar cholangiocarcinoma.

Retrograde reperfusion via vena cava lowers the risk of initial nonfunction but increases the risk of ischemic-type biliary lesions in liver transplantation – a randomized clinical trial

Initial nonfunction (INF) and biliary complications such as ischemic‐type biliary lesion (ITBL) remain two major complications in clinical orthotopic liver transplantation (OLT). The influence of ischemia and reperfusion injury (I/R) as a significant risk factor for both complications is widely unquestioned. A new reperfusion technique that reduces I/R injury should lead to a reduction in both INF and ITBL. One hundred and thirty two OLT patients were included in this study and randomized into two groups. Group A underwent standard reperfusion with anterograde simultaneous arterial and portal reperfusion and group B received retrograde reperfusion via the vena cava before sequential anterograde reperfusion of portal vein and hepatic artery. Serum transaminase level as a surrogate parameter for I/R injury and serum bilirubin level as a parameter for graft function were significantly reduced during the first week after OLT in group B. INF rate was 7.7% in group A and 0% in group B (Pu2003=u20030.058). ITBL incidence was 4.55% in group A versus 12.3% in group B (Pu2003=u20030.053). Retrograde reperfusion seemed to be beneficial for hepatocytes, but was detrimental for the biliary epithelium. The unexplained increased incidence of ITBL after retrograde reperfusion will be focus of further investigation.

Microvessel density correlates with lymph node metastases and prognosis in hilar cholangiocarcinoma.

BackgroundNeovascularization was shown to be critically involved in the progression of multiple cancers, and treatment approaches targeting tumor-associated neovascularization provide convincing results in recent years in some tumor entities. However, little is known about the tumor-associated neovascularization in hilar cholangiocarcinoma. The present study was conducted to analyze tumor-associated neovascularization in hilar cholangiocarcinoma and to determine its influence on tumor growth, metastasis, recurrence, and prognosis.MethodsWe analyzed tissue specimens of hilar cholangiocarcinoma (n = 60) by immunohistochemistry using the endothelial-specific antibody CD31 and subsequently quantified the microvessel density (MVD). The MVD was correlated with clinicopathological characteristics and recurrence pattern of the tumors as well as survival of patients.ResultsHilar cholangiocarcinoma revealed a high degree of vascularization, with a calculated mean MVD of 28.1 ± 14.5 vessels. Tumors with a high MVD had a significant higher incidence of lymph node involvement (P = 0.009) and local recurrence (P < 0.001). Furthermore, a high MVD was identified to be a significant overall survival disadvantage (3-year, 28% vs. 93%; 5-year, 8% vs. 78%; P < 0.001) as well as disease-free survival disadvantage (3-year, 7% vs. 88%, 5-year, 7% vs. 72%; P < 0.001), with MVD representing an independent prognostic factor for survival.ConclusionsNeovascularization is associated with nodal spread as well as local recurrence and serves as an independent prognostic factor for survival after curative resection of hilar cholangiocarcinoma. Therefore, tumor-associated neovascularization seems to be critically involved in the progression of this tumor entity. In addition, neovascularization may represent a potential target in he development of new therapeutic approaches in hilar cholangiocarcinoma.