Purpose of this study was to analyse the surgical management and long-term clinical outcome of patients diagnosed with colorectal liver metastases (CLM) over a period of 10 years using data from a German tumour registry. Retrospective analysis of 5772 patients diagnosed with colorectal adenocarcinoma between 2002 and 2007. Follow-up was continued until 2012. 1426 patients (24.7%) had CLM; 1019 patients (71%) had synchronous, 407 patients (29%) developed metachronous CLM. Hepatic resection was performed in 374 of the 1426 CLM patients (26%). A significant increase in liver resection rate from 16.6% for the 2002 cohort to 32% in later cohorts was observed. In centers specialized in liver surgery, CLM resection rates reached 46.6%. However, up to 52% of patients diagnosed with three or less CLM did not undergo liver surgery, although, if resected, patients with 1 CLM show a similar long-time survival as CRC patients who do not develop any CLM. Univariate and multivariate analyses adjusted for age, sex, year of resection, time of CLM diagnosis and number of CLM revealed a significant survival benefit for CLM resection (HR =0.355; CI 0.305-0.414). Furthermore, significant impact on OS was seen for age at diagnosis, perioperative chemotherapy and number of CLM. We here present the first long-term, population-based analysis of the surgical management of CLM in Germany. Significant increase in hepatic resection rates, translating to a significant benefit in OS, was seen over years. However, we still see a striking potential for further improvements in interdisciplinary CLM management.

Split liver transplantation: Current developments

The prevalence of hepatic cirrhosis in Europe and the United States, currently 250 patients per 100000 inhabitants, is steadily increasing. Thus, we observe a significant increase in patients with cirrhosis and portal hypertension needing liver resections for primary or metastatic lesions. However, extended liver resections in patients with underlying hepatic cirrhosis and portal hypertension still represent a medical challenge in regard to perioperative morbidity, surgical management and postoperative outcome. The Barcelona Clinic Liver Cancer classification recommends to restrict curative liver resections for hepatocellular carcinoma in cirrhotic patients to early tumor stages in patients with Child A cirrhosis not showing portal hypertension. However, during the last two decades, relevant improvements in preoperative diagnostic, perioperative hepatologic and intensive care management as well as in surgical techniques during hepatic resections have rendered even extended liver resections in higher-degree cirrhotic patients with portal hypertension possible. However, there are few standard indications for hepatic resections in cirrhotic patients and risk stratifications have to be performed in an interdisciplinary setting for each individual patient. We here review the indications, the preoperative risk-stratifications, the morbidity and the mortality of extended resections for primary and metastatic lesions in cirrhotic livers. Furthermore, we provide a review of literature on perioperative management in cirrhotic patients needing extrahepatic abdominal surgery and an overview of surgical options in the treatment of hepatic cirrhosis.

Purpose: Aim of the present study was to investigate the sensitivity of high resolution ultrasound (HRU), standard contrast-enhanced ultrasound (CEUS) and CEUS using a novel vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast agent for the detection of hepatic metastases in a mouse model of colorectal cancer using clinical standard technology. Materials and Methods: The human colon cancer cell line HT29, transfected with luciferase cDNA for in vivo bioluminescence monitoring, was injected intrasplenically into CB17.SCID mice. Mice were monitored weekly by bioluminescence and after 2 and 4.5 weeks by HRU and CEUS. Contrast media (untargeted BR1, targeted BR55) was applied and digital cine loops from the arterial phase (15 – 45 sec), portal venous phase (50 – 120 s) and late phases (3 – 5 min, 1hour) of the whole liver were analyzed. Data were correlated with postmortem histopathology. Results: Without contrast enhancement, lesions > 4 mm were reliably detected. After use of untargeted CEUS, lesions > 2 mm were reliably detected and enhanced rim vascularization and late-phase wash-out was shown. With BR55, lesions > 0.8 mm were reliably detected with excellent documentation of vascularization. A persistent contrast enhancement was seen > 30 min after injection. Contrast-enhancement patterns with BR55 significantly correlated with CD31 (R2 = 0.74) and VEGFR2-immunohistochemistry (R2 = 0.66). Conclusion: Detection of metastases by HRU and CEUS was earlier and more accurate than monitoring via bioluminescence. In vivo monitoring of hepatic micrometastases can thus be performed without prior modification of cancer cells using standard technology. Ziel: Ziel der vorliegenden Studie war die Bestimmung der Sensitivität hochauflösender Sonografie, standardisierter kontrastverstärkter Sonografie und kontrastverstärkter Sonografie mittels eines den vaskulären endothelialen Wachstumsfaktor-Rezeptor 2 (VEGFR2) gezielt bindenden Ultraschallkontrastmittels in der Detektion hepatischer Metastasen im präklinischen Mausmodell des Kolonkarzinoms mithilfe klinischer Standardtechnologie. Material und Methoden: Die humane Kolonkarzinomzelllinie HT29, transfiziert mit Luciferase cDNA zur Ermöglichung eines Biolumineszenz-Monitorings, wurde intrasplenisch in CB17.SCID Mäuse injiziert. Es erfolgten wöchentliche Biolumineszenzmessungen sowie Ultraschalluntersuchungen nach 2 und 4,5 Wochen. Als Kontrastmittel kamen BR1 und gezieltes BR55 zur Anwendung. Videosequenzen der arteriellen Phase (15 – 45 s), der portalvenösen (50 – 120 s), und zweier Spätphasen (3 – 5 min, 1 h) der gesamten Leber wurden analysiert. Die Ultraschallergebnisse wurden mit postmoraler Histologie korreliert. Ergebnisse: Hochauflösende Sonografie ohne Kontrastmittel konnte hepatische Metastasen > 4 mm reproduzierbar detektieren. Mithilfe von BR1-Kontrastverstärkung wurden Metastasen > 2 mm zuverlässig detektiert, zudem eine verstärkte Randperfusion und Spätphasen-washout nachgewiesen. Mit BR55 konnten Metastasen ab 0,8 mm detektiert werden mit exzellenter Dokumentation der Vaskularisation. Zudem wurde hier in den Metastasen eine persistente Kontrastmittelanreicherung auch > 30 min nach Injektion detektiert. Die Kontrastmittelverteilung von BR55 korrelierte signifikant mit der Immunhistochemie für CD31 (R2 = 0,74) und VEGFR2 (R2 = 0,66). Schlussfolgerung: Die Metastasendetektion mittels hochauflösender und kontrastverstärkter Sonografie erfolgte früher und akkurater als mittels Biolumineszenz. Somit kann ein in vivo monitoring hepatischer Metastasen in diesem Modell zukünftig auch ohne zuvor nötige Zellalteration und unter Anwendung klinischer Standardtechnologie erfolgen.

Melanoma is one of the most aggressive and lethal cancers worldwide. Despite recent progress in melanoma therapy, the prognosis for metastasized melanoma continues to be poor. Xanthohumol (XN), a prenylated chalcone derived from hop cones, is known to possess a broad spectrum of chemopreventive and anticancer activities. However, few studies have analyzed functional XN effects on melanoma cells and there have been no previous in vivo studies of its effects on metastasis. The aim of this study was to investigate the impact of XN on the tumorigenic and liver metastatic activity of melanoma cells. XN exhibited dose-dependent cytotoxic effects on human melanoma cell lines (Mel Ju; Mel Im) in vitro. Functional analysis in the subtoxic dose-range revealed that XN dose-dependently inhibited proliferation, colony formation, and migratory activity of melanoma cells. Subtoxic XN doses also induced markers of endoplasmic reticulum stress but inhibited the phosphorylation of the protumorigenic c-Jun N-terminal kinases (JNK). Furthermore, XN effects on hepatic metastasis were analyzed in a syngeneic murine model (splenic injection of murine B16 melanoma cells in C57/BL6 mice). Here, XN significantly reduced the formation of hepatic metastasis. Metastases formed in the liver of XN-treated mice revealed significantly larger areas of central necrosis and lower Ki67 expression scores compared to that of control mice. In conclusion, XN inhibits tumorigenicity of melanoma cells in vitro and significantly reduced hepatic metastasis of melanoma cells in mice. These data, in conjunction with an excellent safety profile that has been confirmed in previous studies, indicate XN as a promising novel agent for the treatment of hepatic (melanoma) metastasis.

Mammalian target of rapamycin complex 2 (mTORC2) with its pivotal component rapamycin-insensitive companion of mTOR (RICTOR) is the major regulator of AKT phosphorylation and is increasingly implicated in tumor growth and progression. In cutaneous melanoma, an extremely aggressive and highly metastatic disease, RICTOR overexpression is involved in tumor development and invasiveness. Therefore, we investigated the impact of RICTOR inhibition in melanoma cells in vitro and in vivo with special emphasis on hepatic metastasis. Moreover, our study focused on the interaction of tumor cells and hepatic stellate cells (HSC) which play a crucial role in the hepatic microenvironment. In silico analysis revealed increased RICTOR expression in melanoma cells and tissues and indicated higher expression in advanced melanoma stages and metastases. In vitro, transient RICTOR knock-down via siRNA caused a significant reduction of tumor cell motility. Using a syngeneic murine splenic injection model, a significant decrease in liver metastasis burden was detected in vivo. Moreover, stimulation of melanoma cells with conditioned medium (CM) from activated HSC or hepatocyte growth factor (HGF) led to a significant induction of AKT phosphorylation and tumor cell motility. Blocking of RICTOR expression in cancer cells diminished constitutive and HGF-induced AKT phosphorylation as well as cell motility. Interestingly, RICTOR blockade also led to an abrogation of CM-induced effects on AKT phosphorylation and motility in melanoma cells. In conclusion, these results provide first evidence for a critical role of mTORC2/RICTOR in melanoma liver metastasis via cancer cell/HSC interactions.