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See detailOrthotopic liver transplantation for hepatocellular car- cinoma after successful downstaging: results from the Belgian multicentre cohort
Schreiber, J.; Lerut, J; Verslype, C et al

in Hepatology (Baltimore, Md.) (2014, October), 60(S1), 468550

Purpose: Successful downstaging of hepatocellular carcinoma (HCC) into the Milan criteria (MC) remains a controversial indication for orthotopic liver transplantation (OLT). In Belgium, successful ... [more ▼]

Purpose: Successful downstaging of hepatocellular carcinoma (HCC) into the Milan criteria (MC) remains a controversial indication for orthotopic liver transplantation (OLT). In Belgium, successful downstaging of HCC is an accepted non-standard- ized exception (NSE) for liver allocation. This NSE group rep- resents a unique cohort to analyse if OLT can be safely offered to patients with those extended allocation criteria. The aim of this study is to compare the overall and recurrence free survival after cadaveric OLT between patients with successful downstaging (MILDOWN) and patients always inside the MC (MILIN) from all Belgian transplant centres. Methods: We ret- rospectively analysed all patients listed for OLT with HCC and underlying cirrhosis between 12/2006 and 12/2011 from all Belgian liver transplant centres. Successful downstaging was defined as bringing a patient who was outside the MC into the MC after locoregional therapy (LRT). Results: Overall 381 patients were listed in Belgium during the study period. Of these, 320 received OLT. 248 were MILIN, 62 were MIL- DOWN and 10 were transplanted outside MC. Downstaging treatment included transarterial chemoembolization (TACE; n=26), radiofrequency (RF; n=9), transarterial radioembolisa- tion (TARE; n=4), resection (n=3), percutaneous ethanol injec- tion (n=2) and a combination of the above-mentioned therapies in 18 cases. In the MILIN group 67.3% received locoregional therapy before transplantation, with no significant differences in the distribution of treatment type compared to the MIL- DOWN group. At listing there were no significant differences between the MILIN and MILDOWN group for age, gender and underlying liver disease. Median time on waiting list between the two groups was similar (120 days vs. 115.5 days). Overall survival at 1 year was not significantly different between MILIN and MILDOWN (87.1% vs. 79%; p=0.120). 1.6% of patients were lost to follow-up in both groups. Although not significant, recurrence free survival at 1 year tended to be higher in the MILIN group than in the MILDOWN group (83.9% vs. 74.2%; p=0.073). Conclusion: In this large Belgian multicentre cohort, overall and recurrence free survival at 1 year are not signifi- cantly different between patients who have been downstaged successfully and patients who were always inside the Milan criteria. However, a longer follow up period will define, if the trend of lower survival in the successfully downstaged group becomes significant. Factors associated with HCC recurrence have to be identified. [less ▲]

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See detailOrganized Proteomic Heterogeneity in Colorectal Cancer Liver Metastases and Implications for Therapies
Turtoi, Andrei ULg; Blomme, Arnaud; Debois, Delphine et al

in Hepatology (Baltimore, Md.) (2013)

Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems ... [more ▼]

Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach. Because to date no similar information is available at the protein (phenotype) level, we employed matrix assisted laser desorption ionization (MALDI) image-guided proteomics and explored the heterogeneity of extracellular and membrane subproteome in a unique collection of eight fresh human colorectal carcinoma (CRC) liver metastases. Monitoring the spatial distribution of over 1,000 proteins, we found unexpectedly that all liver metastasis lesions displayed a reproducible, zonally delineated pattern of functional and therapeutic biomarker heterogeneity. The peritumoral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis dis- played increased cellular growth, movement, and drug metabolism, whereas the center of the lesion was characterized by elevated carbohydrate metabolism and DNA-repair activity. From the aspect of therapeutic targeting, zonal expression of known and novel biomarkers was evident, reinforcing the need to select several targets in order to achieve optimal coverage of the lesion. Finally, we highlight two novel antigens, LTBP2 and TGFBI, whose expression is a consistent feature of CRC liver metastasis. We demon- strate their in vivo antibody-based targeting and highlight their potential usefulness for clinical applications. Conclusion: The proteome heterogeneity of human CRC liver metastases has a distinct, organized pattern. This particular hallmark can now be used as part of the strategy for developing rational therapies based on multiple sets of target- able antigens. [less ▲]

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See detailADAM metallopeptidase with thrombospondin type 1 motif 2 inactivation reduces the extent and stability of carbon tetrachloride-induced hepatic fibrosis in mice
Kesteloot, Frédéric ULg; Desmoulière, Alexis; Leclercq, Isabelle et al

in Hepatology (Baltimore, Md.) (2007), 46(5), 1620-1631

ADAMTS2 belongs to the "ADAM metallopeptidase with thrombospondin type I motif" (ADAMTS) family. Its primary function is to process collagen type I, II, III, and V precursors into mature molecules by ... [more ▼]

ADAMTS2 belongs to the "ADAM metallopeptidase with thrombospondin type I motif" (ADAMTS) family. Its primary function is to process collagen type I, II, III, and V precursors into mature molecules by excising the aminopropeptide. This process allows the correct assembly of collagen molecules into fibrils and fibers, which confers to connective tissues their architectural structure and mechanical resistance. To evaluate the impact of ADAMTS2 on the pathological accumulation of extracellular matrix proteins, mainly type I and III collagens, we evaluated carbon tetrachloride-induced liver fibrosis in ADAMTS2-deficient (TS2(-/-)) and wild-type (WT) mice. A single carbon tetrachloride injection caused a similar acute liver injury in deficient and WT mice. A chronic treatment induced collagen deposition in fibrous septa that were made of thinner and irregular fibers in TS2(-/-) mice. The rate of collagen deposition was slower in TS2(-/-) mice, and at an equivalent degree of fibrosis, the resorption of fibrous septa was slightly faster. Most of the genes involved in the development and reversion of the fibrosis were similarly regulated in TS2(-/-) and NW mice. Conclusion: These data indicate that the extent of fibrosis is reduced in TS2(-/-) mice in comparison with their WT littermates. Inhibiting the maturation of fibrillar collagens may be a beneficial therapeutic approach to interfering with the development of fibrotic lesions. [less ▲]

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See detailPeginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis.
Buster, Erik H C J; Hansen, Bettina E; Buti, Maria et al

in Hepatology (Baltimore, Md.) (2007), 46(2), 388-94

Chronic hepatitis B (CHB) patients with advanced fibrosis are often not considered for treatment with peginterferon (PEG-IFN) because IFN therapy may precipitate immunological flares, potentially inducing ... [more ▼]

Chronic hepatitis B (CHB) patients with advanced fibrosis are often not considered for treatment with peginterferon (PEG-IFN) because IFN therapy may precipitate immunological flares, potentially inducing hepatic decompensation. We investigated the efficacy and safety of treating hepatitis B e antigen (HBeAg)-positive CHB patients with 52 weeks of PEG-IFN-alpha-2b (100 microg weekly) alone or in combination with lamivudine (100 mg daily). Seventy patients with advanced fibrosis (Ishak fibrosis score 4-6) and 169 patients without advanced fibrosis, all with compensated liver disease, participated in the study. Virologic response, defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA < 10,000 copies/ml at week 78, occurred significantly more often in patients with advanced fibrosis than in those without (25% versus 12%, respectively; P = 0.02). Also patients with cirrhosis (n = 24) exhibited a virologic response more frequently than did patients without cirrhosis (30% versus 14%, respectively; P = 0.02). Improvement in liver fibrosis occurred more frequently in patients with advanced fibrosis (66% versus 26%, P < 0.001). HBV genotype A was more prevalent among patients with advanced fibrosis than among those without (57% versus 24%, P < 0.001). Most adverse events, including serious adverse events, were observed equally as frequently in patients with advanced fibrosis and those without. Fatigue, anorexia, and thrombocytopenia occurred more often in patients with advanced fibrosis than in those without (P < 0.01). Necessary dose reduction or discontinuation of therapy was comparable for both patient groups (P = 0.92 and P = 0.47, respectively). CONCLUSION: PEG-IFN is effective and safe for HBeAg-positive patients with advanced fibrosis. Because PEG-IFN therapy results in a high rate of sustained off-therapy response, patients with advanced fibrosis or cirrhosis but compensated liver disease should not be excluded from PEG-IFN treatment. [less ▲]

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See detailPatients with hepatocellular carcinoma (HCC) listed for liver transplantation (LTX) outside the MELD system: outcome of a multicenter Eurotransplant series
Adler, Michael; De Pauw, Filip; Fancello, Agnese et al

in Hepatology (Baltimore, Md.) (2005, October), 42(4, suppl 1), 323-324

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