Identification of a claudin-4 and E-cadherin score to predict prognosis in breast cancer

The elevated expression of claudins (CLDN) and E-cadherin (CDH-1) was found to correlate with poor prognostic features. Our aim was to perform a comprehensive analysis to assess their potential to predict prognosis in breast cancer. The expression of CLDN-1, -3-5, -7, -8, -10, -15, -18, and E-cadherin at the mRNA level was evaluated in correlation with survival in datasets containing expression measurements of 1809 breast cancer patients. The breast cancer tissues of 197 patients were evaluated with tissue microarray technique and immunohistochemical method for CLDN-1-5, -7, and E-cadherin protein expression. An additional validation set of 387 patients was used to test the accuracy of the resulting prognostic score. Based on the bioinformatic screening of publicly-available datasets, the metagene of CLDN-3, -4, -7, and E-cadherin was shown to have the most powerful predictive power in the survival analyses. An immunohistochemical protein profile consisting of CLDN-2, -4, and E-cadherin was able to predict outcome in the most effective manner in the training set. Combining the overlapping members of the above two methods resulted in the claudin-4 and E-cadherin score (CURIO), which was able to accurately predict relapse-free survival in the validation cohort (P=0.029). The multivariate analysis, including clinicopathological variables and the CURIO, showed that the latter kept its predictive power (P=0.040). Furthermore, the CURIO was able to further refine prognosis, separating good versus poor prognosis subgroups in luminal A, luminal B, and triple-negative breast cancer intrinsic subtypes. In breast cancer, the CURIO provides additional prognostic information besides the routinely utilized diagnostic approaches and factors. © 2011 Japanese Cancer Association

SPOCK1 Promotes the Development of Hepatocellular Carcinoma

The extracellular matrix proteoglycan SPOCK1 is increasingly recognized as a contributor to the development and progression of cancers. Here, we study how SPOCK1, which is present in non-tumorous hepatocytes at low concentrations, promotes the development and progression of malignant hepatocellular tumors. Although SPOCK1 is an extracellular matrix proteoglycan, its concentration increases in the cytoplasm of hepatocytes starting with very low expression in the normal cells and then appearing in much higher quantities in cells of cirrhotic human liver and hepatocellular carcinoma. This observation is similar to that observed after diethylnitrosamine induction of mouse hepatocarcinogenesis. Furthermore, syndecan-1, the major proteoglycan of the liver, and SPOCK1 are in inverse correlation in the course of these events. In hepatoma cell lines, the cytoplasmic SPOCK1 colocalized with mitochondrial markers, such as MitoTracker and TOMM20, a characteristic protein of the outer membrane of the mitochondrion and could be detected in the cell nucleus. SPOCK1 downregulation of hepatoma cell lines by siRNA inhibited cell proliferation, upregulated p21 and p27, and interfered with pAkt and CDK4 expression. A tyrosine kinase array revealed that inhibition of SPOCK1 in the liver cancer cells altered MAPK signaling and downregulated several members of the Sarc family, all related to the aggressivity of the hepatoma cell lines. These studies support the idea that SPOCK1 enhancement in the liver is an active contributor to human and rodent hepatocarcinogenesis and cancer progression. However, its mitochondrial localization raises the possibility that it has a currently unidentified physiological function in normal hepatocytes

Hepatitis C-vírus-fertőzés kiújulása májátültetés után. Mi változott az elmúlt 10 évben?

Introduction: Management of hepatitis C virus recurrence is a challenge after liver transplantation. Aim: The aim of the authors was to analyse the outcome of liver transplantation performed in hepatitis C virus positive patients during the past ten years and to compare recent data with a previous report of the authors. Method: The authors retrospectively evaluated the data (donors, recipients, perioperative characteristics, patient and graft survival, serum titer of hepatitis C virus RNA, histology) of 409 patients who underwent liver transplantation between 2003 and 2012. Results: 156 patients were transplanted due to hepatitis C virus associated liver cirrhosis (38%). Worse outcome was observed in these patients in comparison to hepatitis C virus negative recipients. The cumulative patient survival rates at 1, 5, and 10 year were 80%, 61%, 51% in the hepatitis C virus positive group and 92%, 85%, 79% in the hepatitis C virus negative group, respectively (p<0.001). The cumulative graft survival rates at 1, 5 and 10 year were 79%, 59% and 50% in hepatitis C virus positive and 89%, 80% and 70% in hepatitis C virus negative patients (p<0.001). Hepatitis C virus recurrence was observed in the majority of the patients (132 patients, 85%), mainly within the first year (83%). The authors observed recurrence within 6 months in 71 patients (56%), and within 3 months in 26 patients (20%). The mean hepatitis C virus recurrence free survival was 243 days. Higher rate of de novo diabetes was detected in case of early recurrence. The cumulative patient survival rates at 1, 3, 5, 10 years were 98%, 89.5%, 81% and 65% when hepatitis C virus recurrence exceeded 3 months and 64%, 53%, 30.5% and 30.5% in patients with early recurrence (p<0.001). Conclusions: Poor outcome of liver transplantation in hepatitis C virus positive patients is still a challenge. Hepatitis C virus recurrence is observed earlier after liver transplantation in comparison with a previous report of the authors. De novo diabetes occurs more frequently in case of early recurrence. Despite an immediate start of antiviral treatment, early recurrence has a significant negative impact on the outcome of transplantation. Orv. Hetil., 2013, 154, 1058-1066

De novo diabetes és májátültetés, különös tekintettel a hepatitis C-vírus kiújulására = New-onset diabetes mellitus after liver transplantation

A de novo diabetes mellitus a májátültetés gyakori szövődménye. Célkitűzés: A de novo diabetes gyakoriságát, jelentőségét és a kockázati tényezők szerepét vizsgáltuk. Módszer: 1995 és 2009 között 310 májátültetett beteg adatait dolgoztuk fel retrospektív módszerrel. De novo diabetest állapítottunk meg, ha az éhomi vércukor a 3. posztoperatív hónapon túl ismételten >6,8 mmol/l volt, és/vagy a májátültetés után tartós, a 3. posztoperatív hónapot meghaladóan is fenntartott antidiabetikus terápia indult. Eredmények: De novo diabetes a betegek 20%-ánál (63 beteg) alakult ki. A de novo és a kontrollcsoport között az alábbiakban találtunk különbséget. Donor-testtömegindex (24±3 vs. 22,4±3,6 kg/m 2 , p = 0,003), férfi nem (58% vs. 33%, p = 0,002). Recipienséletkor (47,6±7,2 vs. 38,3±14,6 év, p<0,001), -testtömegindex (26,7±3,8 vs. 23,3±5,6 kg/m 2 , p<0,001), férfi nem (60% vs. 44%, p = 0,031). A de novo diabetesesek csoportjában a betegek 66%-át HCV talaján kialakult cirrhosis miatt transzplantálták, a kontrollcsoportban ez csak 23% volt (p<0,001). Az 1, 3, 5 és 8 éves kumulatív betegtúlélés a kontrollcsoportban 95%, 91%, 88% és 88%, a de novo csoportban a megfelelő értékek 87%, 79%, 79% és 64% (p = 0,011). Az 1, 3, 5 és 8 éves kumulatív grafttúlélés a kontrollcsoportban 92%, 87%, 86% és 79%, a de novo csoportban a megfelelő értékek 87%, 79%, 79%, 65% (p = NS). Azoknál a betegeknél, akiknél a C-vírus korai (6 hónapon belüli) kiújulását észleltük, többségben de novo diabetes is kialakult (74% vs. kontroll 26%, p = 0,03). A betegek 53%-ában észleltünk tízszeres vírustiter-emelkedést a műtét utáni 6 hónapon belül a preoperatív értékhez viszonyítva diabetes kialakulása esetén, a kontrollnál ez 20% volt (p = 0,028). A de novo csoportban magasabb volt az átlagos (Ishak-Knodell) fibrosis score az antivirális kezelés megkezdését követően 1 évvel (2,05±1,53 vs. 1,00±1,08, p = 0,039). Következtetés: Májátültetést követő de novo diabetes kockázati tényezői az időskor, elhízás, férfi nem és a C-vírus okozta cirrhosis. Víruspozitív betegek körében a korai rekurrencia, súlyosabb viraemia és az antivirális kezelés ellenére kialakuló súlyosabb fibrosis összefügg a de novo diabetes kialakulásával. | New-onset diabetes is a common complication after liver transplantation. Aim: We aimed to analyze the incidence and rate of known risk factors and the impact of new-onset diabetes mellitus on postoperative outcome. Methods: We retrospectively evaluated the files of 310 patients who underwent liver transplantation between 1995 and 2009. Definition of new-onset diabetes included: repeated fasting serum glucose >6.8 mmol/l and/or sustained antidiabetic therapy that was present 3 months after transplantation. Results: New-onset diabetes occurred in 63 patients (20%). Differences between the new-onset and the control group were the donor body mass index (24±3 vs. 22.4±3.6 kg/m 2 , p = 0.003), donor male gender (58% vs. 33%, p = 0.002), and recipient age (47.6±7.2 vs. 38.3±14.6 year, p<0.001), body mass index (26.7±3.8 vs. 23.3±5.6 kg/m 2 , p<0.001), male gender (60% vs. 44%, p = 0.031). The 66% of patients with new-onset diabetes were transplanted with cirrhosis caused by hepatitis C virus infection, while in the control group the rate was 23% (p<0.001). Cumulative patient survival rates at 1, 3, 5 and 8 year were 95%, 90.6%, 88% and 88% in the control group, and 87%, 79%, 79% and 64% in the de novo group, respectively (p = 0.011). Cumulative graft survival rates at 1, 3, 5 and 8 year in the control group were 92%, 87%, 86% and 79%, in the de novo diabetes group the rates were 87%, 79%, 79%, 65%, respectively (p = NS). In case of early recurrence (in 6 months), majority of patients developed new-onset diabetes (74% vs. control 26%, p = 0.03). More patients had more than 10 times higher increase of the postoperative virus titer correlate to the preoperative titer in the de novo diabetes group (53% vs. 20%, p = 0.028). Mean fibrosis score was higher in new-onset group one year after the beginning of antiviral therapy (2.05±1.53 vs. 1.00±1.08, p = 0.039). Conclusions: Risk factors for new-onset diabetes after transplantation are elder age, obesity, male gender and cirrhosis due to hepatitis C infection. The early recurrence, viremia and more severe fibrosis after antiviral therapy have an impact on the occurrence of new-onset diabetes in hepatitis C positive patients