Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.

BACKGROUND: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. METHODS: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10-6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts. FINDINGS: The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. INTERPRETATION: WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-ß-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. FUNDING: Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.

Impact of Cytomegalovirus Infection on the Outcome of Patients With Cirrhosis: A Preliminary Study.

GOALS: The aims of this study were to evaluate whether cytomegalovirus (CMV) infection is associated with hepatocellular carcinoma (HCC) and liver-related mortality in cirrhotic patients. BACKGROUND: In cirrhotic patients, the determinants of HCC and liver-related death are imperfectly known. CMV infection, by its prooncogenic and proinflammatory properties, may favor both the development of HCC and deleterious systemic inflammation. STUDY: In the 1178 patients included between June 2008 and December 2012 in the CIrrhose et Risque de Carcinome Hépatocellulaire dans le grand-Est (CIRCE) study, a French multicenter case-control study designed to identify risk factors of HCC among cirrhotic patients, we identified 432 patients with interpretable CMV serological status at baseline. They included 159 cases with HCC and 273 controls. We measured factors associated with HCC at baseline and subsequent HCC in controls, and predictors of overall and liver-related death in the whole study population. RESULTS: During a median follow-up of 31 months, 25 cases of HCC developed in controls, and 209 deaths (163 liver-related) were recorded. There were 247 (57.2%) CMV-seropositive patients. CMV seropositivity was not associated with more frequent HCC at baseline or during follow-up, but among CMV-positive patients with HCC, the proportion of multinodular, infiltrative, or metastatic tumors at diagnosis was higher (73.8% vs. 57.3%; P=0.029), inducing higher mortality (74% vs. 52% at 3 years; P=0.004). By Cox-regression adjusted for age, gender, Model for End-stage Liver Disease (MELD) score, HCC at baseline, and diabetes, CMV seropositivity independently predicted all-cause (hazard ratio=1.45; 95% confidence interval, 1.08-1.94; P=0.013) and liver-related mortality (hazard ratio=1.56; 95% confidence interval, 1.04-2.30; P=0.031). CONCLUSIONS: In this preliminary study, CMV-seropositive cirrhotic patients were at higher risk of liver-related death caused by more aggressive HCCs or severe cirrhosis complications. These findings warrant confirmation.

Hepatitis E virus-induced primary cutaneous CD30(+) T cell lymphoproliferative disorder.

BACKGROUND & AIM: Several types of unexplained extra-hepatic manifestations, including haematological disorders, have been reported in the context of hepatitis E virus (HEV) infection. However, the underlying mechanism(s) of these manifestations are unknown. We provide evidence that HEV has an extra-hepatic endothelial tropism that can engage cutaneous T cells towards clonality. METHODS: A patient with a CD30(+) cutaneous T cell lymphoproliferative disorder (T-LPD) and biopsy-proven chronic HEV infection received three rounds of oral ribavirin treatment, administered either without or with interferon, and eventually achieved a sustained virologic response (SVR). Pathologic, virologic and immunologic investigations were carried out on biopsied skin lesion, and peripheral blood mononuclear cells between the 2nd and 3rd round of antiviral treatment and biopsied liver. RESULTS: Remission of T-LPD was observed upon antiviral treatment, and the patient remained in complete remission after achieving SVR. The T cell analysis showed large CD30(+) lymphocytes surrounding the blood vessels within the CD8(+) T cell infiltrate. HEV was detected within dermal microvascular endothelial cells using immunofluorescence staining, in situ hybridisation and electron microscopy. Infiltrating T cells mostly comprised memory CD8(+) T cells with a tissue-resident memory T cell phenotype. Overall, 98% of extracted T cells were CD8(+) T cells with aVß signature skewed towards Vß4 and with an oligoclonal profile. T cell clones from T-LPD were more like T cells in the liver than T cells in the blood [odds ratio=4.55, (3.70-5.60), p<0.0001]. No somatic mutations were found in the T-LPD exomes. CONCLUSION: HEV has an extra-hepatic tissue tropism in humans, including dermal endothelium, and can induce CD30(+) T-LPD that is sensitive to antivirals. LAY SUMMARY: Hepatitis E virus (HEV) has an extra-hepatic tissue tropism and should be added to the list of viruses associated with lymphoproliferative disorders. As such, HEV should be part of the laboratory workup of any lymphoproliferation, particularly those of the T cell phenotype that involve the skin. In the context of HEV-associated cutaneous T cell lymphoproliferative disorders, antiviral treatment could be considered a first-line treatment instead of chemotherapy.

Causes of death in people with chronic HBV infection: A population-based cohort study.

BACKGROUND & AIMS: Mortality related to hepatitis B virus (HBV) is not well known in developed countries. The aim of this study was to investigate in a population-based cohort the excess risk of death in HBV patients compared with mortality in the general population and to identify risk factors related to all-cause mortality and HBV-related mortality. METHODS: A specialized population-based registry has recorded data from patients with chronic HBV infection in a population of one million inhabitants in France since 1994. Standardized mortality rates for all-cause death and HBV-related death were calculated. Cumulative mortality rates were calculated using the Kaplan-Meier method. Multivariate analysis was performed using a Cox model. RESULTS: Between 1994 and 2009, 1117 people were diagnosed with chronic HBV infection. Of these 136 (12.2%) died. All-cause mortality was significantly higher in HBV-infected people (standardized mortality ratio (SMR) 1.7 [1.4-2.0]). There was substantial excess mortality due to hepatocellular carcinoma (SMR 15.9 [10-24.1]), non-Hodgkin lymphoma (SMR 8.6 [3.1-18.6]) and liver disease (SMR 10.2 [5.8-16.6]). The cumulative rates for all-cause mortality were 8.6% at 5 years, 12.6% at 10 years and 18.5% at 15 years. The corresponding values for HBV-related mortality were 3.5%, 4.2%, and 5.8%. The multivariate analysis for all-cause mortality and for HBV-related mortality showed that male sex, age over 45 at diagnosis, current alcoholism and nosocomial risk factors were predictors of increased mortality. CONCLUSION: This study shows increased all-cause mortality in HBsAg-positive patients, with considerable excess mortality due to chronic liver disease, hepatocellular carcinoma and non-Hodgkin lymphoma.

Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis.

BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.

Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data.

UNLABELLED: The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model=1.77; 95% confidence interval [CI]: 1.42-2.19; P=2.78 × 10(-7) ). This association was more pronounced in ALD (OR=2.20; 95% CI: 1.80-2.67; P=4.71 × 10(-15) ) than in CHC patients (OR=1.55; 95% CI: 1.03-2.34; P=3.52 × 10(-2) ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. CONCLUSION: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.

Compound heterozygous PKHD1 variants cause a wide spectrum of ductal plate malformations.

Ductal plate malformations (DPM) present with a wide phenotypic spectrum comprising Von Meyenburg complexes (VMC), Caroli disease (CD), Caroli syndrome (CS), and autosomal recessive polycystic kidney disease (ARPKD). Variants in PKHD1 are responsible for ARPKD and CS with a high inter- and intra-familial phenotypic variability. Rare familial cases of CD had been reported and exceptional cases of CD are associated with PKHD1 variants. In a family of three siblings presenting with a wide spectrum of severity of DPM, we performed whole exome sequencing and identified two PKHD1 compound heterozygous variants (c.10444G>A; p.Arg3482Cys and c.5521C>T; p.Glu1841Lys), segregating with the symptoms. Two compound heterozygous PKHD1 variants, including one hypomorphic variant, were identified in two other familial cases of DPM with at least one patient presenting with CD. This report widens the phenotypic variability of PKHD1 variants to VMC, and others hepatic bile ducts malformations with inconstant renal phenotype in adults and highlights the important intra-familial phenotypic variability. It also showed that PKHD1 might be a major gene for CD. This work adds an example of the contribution of exome sequencing, not only in the discovery of new genes but also in expanding the phenotypic spectrum of well-known disease-associated genes, using reverse phenotyping.

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890.

BACKGROUND & AIMS: In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS: 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS: A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS: The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Effect of diet composition on glandular gastric disease in horses.

BACKGROUND: Nutritional factors are suggested to influence the incidence and severity of glandular gastric disease (GGD) in horses. OBJECTIVES: To retrospectively assess whether dietary fermentable carbohydrates increase the severity of GGD and to prospectively evaluate whether the partial substitution of concentrates by dehydrated alfalfa would decrease GGD severity scores. ANIMALS: In total, 82 trotters from 4 training centers exercised ≥5 days/week. METHODS: Multicenter retrospective observational study, and prospective 2-arm randomized trial. Glandular mucosae were observed by gastroscopy and scored (0-4 severity scale) at day 0 (D0). Biochemical composition of the diet fed was compared between ulcerated and nonulcerated groups. After D0, horses either received the same diet (control, n = 41) or pelleted dehydrated alfalfa substituting 50% concentrates (alfalfa, n = 41). Glandular scores were recorded in both groups after 21 (D21) and 42 days (D42). The first end point was a successful outcome, defined as a horse with a glandular score of 2 to 4 on D0, decreasing to a score of 0 to 1 on days 21 or 42. RESULTS: Horses scored 0 to 1 at D0 ingested more (P = .01) soluble sugars from concentrates than those scored 2 to 4 before D0 (77.5 g/kg BW; 95% confidence interval [CI]: 71.1-84.0, vs 59.1 g/kg BW; 95% CI: 48.0-70.3), whereas starch intake did not differ between groups (P = .24). Among horses scored 2 to 4 at D0, fewer were scored 2 to 4 in the alfalfa group (1 out of 6) compared with the control group (6 out of 6) at D42 (P = .02). Clinical success was 47.7 times more likely in horses fed alfalfa compared with horses in the control group (95% CI: 1.6-1422.8). CONCLUSION AND CLINICAL IMPORTANCE: Relationships were found between diet composition and integrity of the glandular mucosa. Feeding pelleted dehydrated alfalfa could help to reduce the incidence and severity of GGD.

Intravoxel incoherent motion diffusion-weighted imaging in nonalcoholic fatty liver disease: a 3.0-T MR study.

PURPOSE: To compare pure molecular diffusion, D, perfusion-related diffusion, D*, and perfusion fraction, f, determined from diffusion-weighted (DW) magnetic resonance (MR) imaging on the basis of the intravoxel incoherent motion (IVIM) theory in patients with type 2 diabetes with and without liver steatosis. MATERIALS AND METHODS: This prospective study was approved by the appropriate ethics committee, and written informed consent was obtained from all patients. Between December 2009 and September 2011, 108 patients with type 2 diabetes (51 men, 57 women; mean age, 50 years) underwent 3.0-T single-voxel point-resolved proton MR spectroscopy of the liver (segment VII) to calculate the liver fat fraction from water (4.76 ppm) and methylene (1.33 ppm) peaks, corrected for T1 and T2 decay. Steatosis was defined as a liver fat fraction of at least 5.56%. DW imaging was performed by using a single-shot echo-planar sequence with 11 b values (0, 5, 15, 25, 35, 50, 100, 200, 400, 600, 800 sec/mm2). Liver D, D*, and f were measured and compared in patients with and patients without steatosis (Mann-Whitney test). RESULTS: The mean liver fat fraction was 7.8% (standard deviation, 9%; range, 0.99%-45%). Forty patients had liver steatosis. D was significantly lower in steatotic compared with nonsteatotic livers (mean, 1.03×10(-3) mm2/sec±0.23 [standard deviation] vs 1.24×10(-3) mm2/sec±0.15, respectively; P<.0001), as was D* (mean, 72.2×10(-3) mm2/sec±61.4 vs 110.6×10(-3) mm2/sec±79; P=.0025). However, f was significantly higher in steatotic compared with nonsteatotic livers (mean, 33.8%±9.4 vs 26.9%±8.8; P=.0003). CONCLUSION: D is significantly decreased in steatosis. The reduction in D* reflects decreased liver parenchymal perfusion in steatosis. Therefore, steatosis can affect diffusion parameters obtained with IVIM.

Macroscopic heterogeneity of liver fat: an MR-based study in type-2 diabetic patients.

OBJECTIVE: To assess the heterogeneity of liver fat deposition with MR of the liver in type-2 diabetic (T2D) patients. METHODS: We enrolled 121 consecutive T2D patients. The reference standard was 3.0-T (1)H-MR spectroscopy. Hepatic steatosis was defined as liver fat content (LFC) ≥5.56 %. A triple-echo gradient-echo sequence corrected for T1 recovery and T2* decay was used to calculate LFC in left and right livers and hepatic segments. Analyses were performed using a linear mixed model. RESULTS: Fifty-nine (48.8 %) patients had liver steatosis, whereas 62 (51.2 %) did not. Steatosis was greater in the right than in the left liver (P < 0.0001) [mean difference: 1.32 % (range: 0.01-8.75 %)]. In seven patients (5.8 %), LFC was <5.56 % in one side of the liver, whereas it was ≥5.56 % in the other. Steatosis of the left and right liver was heterogeneous at the segmental level in both non-steatotic (P < 0.001 and P < 0.0001 respectively) and steatotic (P < 0.0001 and P = 0.0002 respectively) patients [mean maximum difference: 3.98 % (range: 0.74-19.32 %)]. In 23 patients (19 %), LFC was <5.56 % in one segment, whereas it was ≥5.56 % in at least one other. CONCLUSION: Overall, the mean segmental/lobar variability of steatosis is low. However, segmental variability can sometimes lead to a misdiagnosis. KEY POINTS: There is a need for methods quantifying steatosis over a large region. Steatosis is usually greater in the right than left lobe of the liver. Steatosis within both left and right hepatic lobes is segmentally heterogeneous. Segmental variability of steatosis can result in misdiagnosis.

Prediction for steatosis in type-2 diabetes: clinico-biological markers versus 1H-MR spectroscopy.

OBJECTIVES: The SteatoTest, fatty liver index (FLI) and hepatic steatosis index (HSI) are clinico-biological scores of steatosis validated in general or selected populations. Serum adiponectin (s-adiponectin) and retinol binding protein 4 (s-RBP4) are adipokines that could predict liver steatosis. We investigated whether the Steatotest, FLI, HSI, s-adiponectin and s-RBP4 could be valid predictors of liver steatosis in type-2 diabetic (T2D) patients. METHODS: We enrolled 220 consecutive T2D patients. Reference standard was 3.0 T (1)H-MR spectroscopy (corrected for T1 and T2 decays). Intraclass correlation coefficients (ICCs), Kappa statistic measures of agreement, receiver operating characteristic (ROC) curves were assessed. RESULTS: Median liver fat content was 91 mg triglyceride/g liver tissue (range: 0-392). ICCs among the Steatotest, FLI, HSI, s-adiponectin, s-RBP4 and spectroscopy were low: 0.384, 0.281, 0.087, -0.297 and 0.048. Agreement between scores and spectroscopy was poor (Kappa range: 0.042-0.281). The areas under the ROC curves were low: 0.674, 0.647, 0.637, 0.616 and 0.540. S-adiponectin and s-RBP4 levels were strongly related to the presence of diabetic nephropathy (P = 0.0037 and P = 0.004; Mann-Whitney). CONCLUSION: The SteatoTest, FLI, HSI, s-adiponectin, s-RBP4 are not valid predictors of steatosis in T2D patients. Clino-biological markers cannot replace (1)H-MR spectroscopy for the assessment of liver fat in this population. KEY POINTS: (1) H-MR spectrosopy can reliably estimate the weight fraction of liver steatosis. Type-2 diabetes provides an interesting model for assessing liver steatosis. Clinico-biological markers seem to be invalid predictors for steatosis in type-2 diabetes.

[Health professionals' perceptions and screening for hepatitis B and C among migrants: a qualitative study in Côte-d'Or, France]. / Représentations des professionnels et dépistage des hépatites B et C chez les migrants : une étude qualitative en Côte-d'Or.

Hepatitis B and C continue to be major public health problems in France, particularly among migrants. The fact of being born in hepatitis B and C-endemic countries or of being a long-term resident of these countries are common risk factors, especially in the case of hepatitis B. Screening for both types of infection remains low among migrants. The main purpose of this study was to examine perceptions of the risk of viral hepatitis B and C in migrants among health professionals in Côte-d'Or (Burgundy, France) and to understand the factors promoting or hindering screening. The paper presents the results of a qualitative study based on face-to-face interviews with 23 healthcare providers and 8 social workers. The participating health professionals were interviewed about their involvement in the fight against hepatitis B and C and their perceptions of the risk of infection among migrants. The interviews conducted with social workers focused mostly on the conditions of social and health support provided to migrants. The study found that hepatitis B and C screening among migrants was associated with HIV screening. Screening was found to be associated with formalities relating to the legal and administrative status of migrants, the type of accommodation or housing, health professionals' knowledge of the risk factors associated with the epidemiological and social/health context in the countries of origin, and their own involvement in humanitarian aid. Migrants seeking political asylum and living in reception centers were found to be more likely to undergo screening. The findings suggest that awareness of the importance of systematic screening for hepatitis B and C in migrants from hepatitis B and C-endemic areas needs to be promoted among social workers and health professionals, as recommended by the National Prevention and Control Program (2009-2012).

Visceral fat area as a new independent predictive factor of survival in patients with metastatic renal cell carcinoma treated with antiangiogenic agents.

Purpose. A better identification of patients who are more likely to benefit from vascular endothelial growth factor-targeted therapy is warranted in metastatic renal cell carcinoma (mRCC). As adipose tissue releases angiogenic factors, we determined whether parameters such as visceral fat area (VFA) were associated with outcome in these patients. Experimental Design. In 113 patients with mRCC who received antiangiogenic agents (bevacizumab, sunitinib, or sorafenib) (n = 64) or cytokines (n = 49) as first-line treatment, we used computed tomography to measure VFA and subcutaneous fat area (SFA). We evaluated associations linking body mass index (BMI), SFA, and VFA to time to progression (TTP) and overall survival (OS). Results. High SFA and VFA values were significantly associated with shorter TTP and OS. By multivariate analysis, high VFA was independently associated with shorter TTP and OS. These results were internally validated using bootstrap analysis. By contrast, VFA was not associated with survival in the cytokine group. In the whole population, interaction between VFA and treatment group was significant for TTP and OS, thereby confirming the results. Conclusion. Our study provides the first evidence that high VFA could be a predictive biomarker from shorter survival in patients given first-line antiangiogenic agents for mRCC.

Liver methylene fraction by dual- and triple-echo gradient-echo imaging at 3.0T: Correlation with proton MR spectroscopy and estimation of robustness after SPIO administration.

PURPOSE: To assess the systematic errors in liver methylene fraction (LMF) resulting from fat-fat interference effects with dual- and triple-echo gradient-recalled-echo Dual/Triple GRE) sequences and to test the robustness of these sequences after iron overloading. MATERIALS AND METHODS: Forty type-2 diabetic patients underwent LMF measurement by 3.0T ¹H magnetic resonance spectroscopy (corrected for T1 and T2 decays) as the reference standard and liver fat fraction (%Fat) measurement by four Dual/Triple GRE sequences with 20° and 60° flip angle (α), corrected for T1 recovery. The same four sequences were repeated in eight patients after ferumoxide injection. Corrections for systematic errors were determined from the linear regressions (spectroscopy LMF values over Dual/Triple GRE %Fat values). Robustness was tested using Wilcoxon's signed-rank test. RESULTS: Fat-fat interference effects produced a ∼10% relative systematic error and T2* decay produced a 1.9%-4.2% absolute systematic error in LMF. When comparing before and after ferumoxide, dual-echo imaging with α = 20° and α = 60°, even when corrected, showed absolute differences of 7.23% [2.81%-10.25%] (P = 0.0117) and 5.65% [1.89%-8.216.8%] (P = 0.0117), respectively; compared to only 1.17% [0.08%-2.83%] (P = 0.0251) and 1.15% [0.37%-2.73%] (P = 0.2626) with triple-echo imaging and α = 20° and α = 60°, respectively. CONCLUSION: Triple-echo imaging with α = 60° corrected for both T1 recovery and fat-fat interference effects is robust after superparamagnetic iron oxide (SPIO) administration and can reliably quantify LMF.

PNPLA3 polymorphism influences liver fibrosis in unselected patients with type 2 diabetes.

CONTEXT: Recently, it has been shown that an allele in the adiponutrin (PNPLA3) gene was strongly associated with increased liver fat content (LFC) and liver fibrosis independent of visceral adiposity and insulin resistance. OBJECTIVE: In this study, we set out to determine whether the PNPLA3 rs738409 polymorphism was associated with liver fibrosis in unselected patients with type 2 diabetes. DESIGN, SETTING AND PARTICIPANTS: Two hundred and thirty-four patients with type 2 diabetes were included in this study. MAIN OUTCOME MEASURES: LFC was evaluated using (1) H-MR spectroscopy; fibrosis was measured using the non-invasive FibroTest(®). RESULTS: Advanced liver fibrosis (stage F2 or above) was observed in 10.2% of the patients while 149 (63.6%) patients had steatosis. The prevalence of steatosis and fibrosis was higher in minor G allele carriers than that in C allele homozygote carriers (70.3 vs 57.1%; P=0.04 and 14.7 vs 7.5%; P=0.07 respectively). In multivariate analysis, the predictive variables for advanced liver fibrosis were age (≥60) (P=0.005), sex (female) (P=0.004) and rs 738409 PNPLA3 polymorphism (P=0.01); body mass index (BMI) and LFC were not associated with liver fibrosis. CONCLUSIONS: This study confirms that in patients with type 2 diabetes who were not selected for liver abnormalities, liver fibrosis was related to the rs738409 polymorphism independent of BMI or LFC.

Screening of anticancer drugs for chemoembolization of hepatocellular carcinoma.

The aim of this study was to select the best candidate drug for transarterial chemoembolization by in-vitro cytotoxic evaluations of 11 anticancer drugs on three human hepatocellular carcinoma (HCC) cell lines. The SNU-398, HepG2, and SNU-449 human HCC cell lines were exposed for 30 min to 11 concentrations of doxorubicin, epirubicin, idarubicin, mitoxantrone, carboplatin, cisplatin, oxaliplatin, 5-fluorouracil, gemcitabine, mitomycin C, or paclitaxel. Cytotoxicity was measured using a quantitative colorimetric assay. For each drug and cell line, we calculated the drug concentration that caused 90% cell death (IC90). To enable comparisons of drugs with different concentration ranges, we computed the cytotoxic index (CyI) as the ratio of maximal drug concentration of more than IC90. Parameters were estimated using nonlinear regression models. Idarubicin was the most active drug on all three cell lines. With SNU-398 cells, the idarubicin CyI was 2.4-fold, 2.5-fold, 57-fold, 148-fold, and more than 58 748-fold higher than the CyIs of mitoxantrone, epirubicin, doxorubicin, gemcitabine, and other drugs, respectively. With HepG2 cells, the idarubicin CyI was 27-fold, 28-fold, 51-fold, and more than 1343-fold higher than the CyIs of doxorubicin, epirubicin, mitoxantrone, and other drugs, respectively. On the resistant SNU-449 cell line, the idarubicin CyI was 2.9-fold and 14-fold higher than the CyIs of paclitaxel and gemcitabine, respectively, the only other drugs effective on this cell line. Among 11 chemotherapeutic agents including doxorubicin, cisplatin, and epirubicin, the most effective on three HCC cell lines was idarubicin. Further clinical investigations are needed to evaluate the safety and efficacy of idarubicin for transarterial chemoembolization in HCC.

Visceral fat area is an independent predictive biomarker of outcome after first-line bevacizumab-based treatment in metastatic colorectal cancer.

BACKGROUND: Adipose tissue releases angiogenic factors that may promote tumour growth. OBJECTIVE: To determine whether body mass index (BMI), subcutaneous fat area (SFA) and visceral fat area (VFA) are associated with outcomes in patients given first-line bevacizumab-based treatment for metastatic colorectal cancer (MCC). Patients CT was used to measure SFA and VFA in 120 patients with MCC who received bevacizumab-based treatment (bevacizumab group, n=80) or chemotherapy alone (chemotherapy group, n=40) as first-line treatment. Associations linking BMI, SFA and VFA to tumour response, time-to-progression (TTP) and overall survival (OS) were evaluated. RESULTS: In the bevacizumab group, median follow-up lasted for 24 months (3-70). BMI, SFA and VFA values above the median (ie, high BMI, high VFA and high SFA) were significantly associated with absence of a response. TTP was shorter in patients with high BMI (9 vs 12 months; p=0.01) or high VFA (9 vs 14 months; p=0.0008). High VFA was associated with shorter OS (p=0.0493). By multivariate analysis, high VFA was independently associated with response, TTP and OS (HR=7.18, p=0.008, HR=5.79, p=0.005 and HR=2.88, p=0.027, respectively). In the chemotherapy group, median follow-up lasted for 30 months (4-84). BMI, SFA and VFA were not associated with response, TTP or OS. In the whole population, interaction between VFA and bevacizumab administration was significant for response (OR=3.31, p=0.005) and TTP (HR=1.64, p=0.022), thereby confirming the results. CONCLUSION: This study provides the first evidence that high VFA independently predicts a poorer outcome in patients given first-line bevacizumab-based treatment for MCC. However, this predictive biomarker needs to be validated in a different dataset.

A 30-year, population-based study shows improved management and prognosis of hepatocellular carcinoma.

BACKGROUND & AIMS: Little is known about the impact of changes in the management of hepatocellular carcinoma (HCC) over time. We assessed trends in the pattern of care and in prognosis at a population level. METHODS: Data on diagnostic conditions, treatment, and prognosis from 1976-2005 were collected by the population-based digestive cancer registry of Burgundy (France). A nonconditional logistic regression was used to identify factors associated with treatment for cure. A multivariate relative survival analysis was also performed. RESULTS: The context of HCC diagnosis has changed; the proportion of asymptomatic patients increased from 5.6% (1976-1985) to 37.2% (1996-2005). The proportion of cases diagnosed on the basis of morphologic criteria increased from 14% during 1976-1985 to 35.6% during 1996-2005, whereas histologically verified cases decreased from 62.2% to 41.2% between the same time periods. The proportion of patients who were treated with intent to cure increased from 2.7% (1976-1985) to 19.6% (1996-2005). This increase was associated with improvements in relative survival from 4.7% (1976-1985) to 32.8% (1996-2005) at 1 year and from 1.4% to 10.0% at 5 years. The 5-year relative survival of patients treated with curative intent increased, reaching 46.6% for the 1996-2005 period. In the multivariate relative survival analysis, age, period of diagnosis, clinical presentation, alpha-fetoprotein level, and treatment were independent prognostic factors. CONCLUSIONS: During a 30-year period, there was an increase in the number of HCCs diagnosed in asymptomatic subjects that was associated with the development of new effective therapies; this association might account for improvements in prognosis of patients with HCC.