Liver stiffness and spleen stiffness predict distinct liver-related events after hepatitis C eradication with direct-acting antivirals.

BACKGROUND: /Purpose: This study aimed to directly compare the utility of liver stiffness (LS) and spleen stiffness (SS) at sustained virologic response (SVR) for predicting hepatocellular carcinoma (HCC) and non-HCC events in patients with chronic hepatitis C (CHC) after direct-acting antiviral therapy. METHODS: This retrospective study included 695 CHC patients who achieved SVR and underwent LS and SS measurements. LS and SS were measured using point shear wave elastography and compared head-to-head. RESULTS: During a median follow-up of 29.5 months, 49 (7.1%) patients developed liver-related events (LREs), including 28 HCC and 22 non-HCC events after SVR. Multivariable Cox regression analysis revealed that age, albumin level, and LS (≥ versus <1.46 m/s) at SVR (adjusted hazard ratio [aHR]: 5.390; 95% confidence interval [CI]: 2.349-12.364; p < 0.001), but not SS at SVR, significantly predicted the overall risk of post-SVR LREs (n = 49). Furthermore, age and LS (≥ versus <1.46 m/s) at SVR (aHR: 6.759; 95% CI: 2.317-19.723; p < 0.001), but not SS at SVR, independently predicted the risk of post-SVR incident HCC. In contrast, SS (≥ versus <2.87 m/s) at SVR (aHR: 11.212; 95% CI: 1.564-20.132; p = 0.021) and albumin level, but not LS at SVR, significantly predicted the risk of post-SVR non-HCC events. CONCLUSION: Post-SVR LS better predicts HCC risk. Post-SVR SS helps predict non-HCC risk after antiviral therapy for CHC. LS and SS at SVR provide complementary prognostic information regarding risks of HCC and non-HCC events in the post-SVR setting. Further validation is warranted in larger cohorts.

Combined CRAFITY score and α-fetoprotein response predicts treatment outcomes in patients with unresectable hepatocellular carcinoma receiving anti-programmed death-1 blockade-based immunotherapy.

Biomarkers for predicting the treatment efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with unresectable hepatocellular carcinoma (uHCC) are crucial. Previous studies demonstrated that C-reactive protein and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) score at baseline predicted treatment outcomes and that patients with uHCC with AFP response, defined as > 15% decline in AFP level within the initial 3 months of ICI-based therapy, had favorable outcomes when receiving ICI-based therapy. However, whether the combination of CRAFITY score and AFP response could be used to predict treatment efficacy of programmed death-1 (PD-1) blockade-based therapy in uHCC patients remains unclear. We retrospectively enrolled 110 consecutive uHCC patients from May 2017 to March 2022. The median ICI treatment duration was 2.85 (1.67-6.63) months, and 87 patients received combination therapies. The objective response and disease control rates were 21.8% and 46.4%, respectively. The duration of progression-free survival (PFS) and overall survival (OS) was 2.87 (2.16-3.58) months and 8.20 (4.23-12.17) months, respectively. We categorized patients into three groups based on CRAFITY score (2 vs 0/1) and AFP response: patients with a CRAFITY score of 0/1 and AFP response (Group 1), those with a CRAFITY score of 2 and no AFP response (group 3), and those who did not belong to Group 1 and 3 (i.e., Group 2). The combination of CRAFITY score and AFP response could predict disease control and could predict PFS compared with CRAFITY score or AFP response alone. The combination of CRAFITY score and AFP response was an independent predictor of OS (Group 2 vs Group 1, HR: 4.513, 95% CI 1.990-10.234; Group 3 vs Group 1, HR: 3.551, 95% CI 1.544-8.168). Our findings indicated that the combination of CRAFITY score and AFP response could predict disease control, PFS, and OS in uHCC patients receiving PD-1 blockade-based immunotherapy.

Combined Liver Stiffness and Α-fetoprotein Further beyond the Sustained Virologic Response Visit as Predictors of Long-Term Liver-Related Events in Patients with Chronic Hepatitis C.

Aims: Long-term risk stratification using combined liver stiffness (LS) and clinically relevant blood tests acquired at the baseline further beyond the sustained virologic response (SVR) visit for chronic hepatitis C (CHC) has not been thoroughly investigated. This study retrospectively investigated the prognostics of liver-related events (LREs) further beyond the SVR visit. Methods: Cox regression and random forest models identified the key factors, including longitudinal LS and noninvasive test results, that could predict LREs, including hepatocellular carcinoma, during prespecified follow-ups from 2010 to 2021. Kaplan-Meier survival analysis estimated the significance of between-group risk stratification. Results: Of the entire eligible cohort (n = 520) of CHC patients with SVR to antiviral therapy, 28 (5.4%) patients developed post-SVR LREs over a median follow-up period of 6.1 years (interquartile range = 3.5-8.7). The multivariate Cox regression analysis identified two significant predictors of LREs after the year 3 post-SVR (Y3PSVR) baseline (LRE, n = 15 of 28, 53.6%, median follow-up = 4.1 [1.6-6.4] years after Y3PSVR): LS at Y3PSVR (adjusted hazard ratio [aHR] = 3.980, 95% confidence interval [CI] = 2.085-7.597, P < 0.001), and α-fetoprotein (AFP) at Y3PSVR (aHR = 1.017, 95% CI = 1.001-1.034, P=0.034). LS ≥1.45 m/s and AFP ≥3.00 ng/mL for Y3PSVR yielded positive likelihood ratios of 4.24 and 2.62, respectively. Kaplan-Meier analysis revealed that among the stratified subgroups, the subgroup with concurrent LS ≥1.45 m/s and AFP ≥3.00 ng/mL at Y3PSVR exhibited the highest risk of LREs after Y3PSVR (log-rank P < 0.001). Conclusion: We recommend the combined use of concurrent LS and AFP in future prediction models for LREs in CHC. Patients with concurrently high LS and AFP values further beyond the SVR visit may require a recall policy involving intense surveillance.

Long-term surveillance of liver histological changes in chronic hepatitis C patients completing pegylated interferon-α plus ribavirin therapy: an observational cohort study.

BACKGROUND: For chronic hepatitis C (CHC) patients completing pegylated interferon (PegIFN)-α/ribavirin therapy, long-term liver histological changes remain largely unexplored. METHODS: This observational cohort study included 85 CHC patients completing PegIFN-α/ribavirin therapy with liver biopsies performed at baseline and the end of surveillance (EOS). Median years between paired biopsies were 6.75 (interquartile range: 5.63-7.54). RESULTS: In patients with baseline METAVIR fibrosis stages (F) <4 (able to undergo fibrosis progression; n = 77), cases achieving sustained virological response (SVR) (n = 52) had a significantly lower rate of fibrosis progression than non-SVR cases (n = 25) (3.8% versus 24.0%, p = 0.012). Among the entire cohort (n = 85), the rate of activity response [METAVIR activity grades (A) decreasing or maintaining at A0] in SVR cases (n = 59) was significantly higher than that in non-SVR cases (n = 26) (94.9% versus 65.4%, p = 0.001). For SVR cases among the entire cohort, independent predictors of fibrosis clearance included baseline F <2 [odds ratio (OR) = 7.877, p = 0.042] and aspartate transaminase (AST) levels declining by >70% at EOS compared with baseline (OR = 9.013, p = 0.038). For non-SVR cases among the entire cohort, baseline AST levels >80 U/l and glucose levels ⩽ 105 mg/dl independently predicted significant fibrosis (F2/F3/F4) at EOS (OR = 12.558, p = 0.049) and activity response (OR = 17.741, p = 0.047), respectively. CONCLUSIONS: Among CHC patients completing PegIFN-α/ribavirin therapy, SVR lowers the risk of liver histological progression but does not guarantee fibrosis clearance. For SVR cases, those with baseline F ⩾ 2 or without significantly declined follow-up AST levels should be specifically monitored. As for non-SVR cases, those with a higher baseline AST or glucose level should preferentially receive retreatment.

Liver and Spleen Stiffness Surveillance Through Elastography During and After Direct-Acting Antiviral Therapy in Patients With Chronic Hepatitis C.

OBJECTIVES: Direct-acting antiviral agents achieve a high cure rate, resulting in early hepatic necroinflammatory resolution and sustained fibrosis regression. This study aimed to obtain longitudinal, concurrent within-subject measurements of liver stiffness (LS) and spleen stiffness (SS) and their correlates over time. METHODS: Participants with hepatitis C (n = 592) receiving direct-acting antiviral-based therapy were monitored through point shear-wave elastography from the treatment baseline (TW0) across follow-up visits in terms of LS and SS. RESULTS: Generalized linear mixed modeling indicated that all LS values (2301 visits) were negatively correlated with the follow-up times (all P < .05) from TW0 to 24 weeks (PW24) after the end of treatment (EOT) and positively correlated with baseline LS values (P < .001). The slopes of declines (preceding minus next) differed significantly (P < .001) between TW0-TW4 (treatment week 4) (0.060 [-0.050 to 0.225] meter/second/month [m/s/mo]) and TW4-EOT (0.010 [-0.030 to 0.075] m/s/mo). All SS values (1704 visits) were negatively correlated with time only at PW24 (P < .001) and positively correlated with baseline SS values (P < .001). The slopes of the SS values differed significantly (P < .001) only between EOT-PW12 (-0.010 [-0.110 to 0.083] m/s/mo) and PW12-PW24 (0.043 [-0.063 to 0.160] m/s/mo). CONCLUSIONS: The biphasic fast-to-slow decline in LS occurred early in the on-treatment phase, which is consistent with the resolution of hepatic necroinflammation. The slow-to-fast decline in SS occurred off treatment. Future studies should investigate the association with regressions in liver fibrosis and portal hypertension.

Do peripartum and postmenopausal women with primary liver cancer have a worse prognosis? A nationwide cohort in Taiwan.

BACKGROUND: While primary liver cancer (PLC) is one of the most common cancers around the world, few large-scale population-based studies have been reported that evaluated the clinical survival outcomes among peripartum and postmenopausal women with PLC. AIM: To investigate whether peripartum and postmenopausal women with PLC have lower overall survival rates compared with women who were not peripartum and postmenopausal. METHODS: The Taiwan National Health Insurance claims data from 2000 to 2012 was used for this propensity-score-matched study. A cohort of 40 peripartum women with PLC and a reference cohort of 160 women without peripartum were enrolled. In the women with PLC with/without menopause study, a study cohort of 10752 menopausal females with PLC and a comparison cohort of 2688 women without menopause were enrolled. RESULTS: Patients with peripartum PLC had a non-significant risk of death compared with the non-peripartum cohort [adjusted hazard ratios (aHR) = 1.40, 95% confidence intervals (CI): 0.89-2.20, P = 0.149]. The survival rate at different follow-up durations between peripartum PLC patients and those in the non-peripartum cohort showed a non-significant difference. Patients who were diagnosed with PLC younger than 50 years old (without menopause) had a significant lower risk of death compared with patients diagnosed with PLC at or older than 50 years (postmenopausal) (aHR = 0.64, 95%CI: 0.61-0.68, P < 0.001). The survival rate of women < 50 years with PLC was significantly higher than older women with PLC when followed for 0.5 (72.44% vs 64.16%), 1 (60.57% vs 51.66%), 3 (42.92% vs 31.28%), and 5 year(s) (37.02% vs 21.83%), respectively (P < 0.001). CONCLUSION: Peripartum females with PLC have no difference in survival rates compared with those patients without peripartum. Menopausal females with PLC have worse survival rates compared with those patients without menopause.

On-Treatment Albumin-Bilirubin Grade: Predictor of Response and Outcome of Sorafenib-Regorafenib Sequential Therapy in Patients with Unresectable Hepatocellular Carcinoma.

In the RESORCE study, regorafenib after sorafenib therapy improved survival in patients with advanced hepatocellular carcinoma (HCC). In total, 88 patients with unresectable HCC who received sorafenib-regorafenib sequential therapy were enrolled. The objective response rate and disease control rate were 19.3% and 48.9%, respectively, for regorafenib therapy (median duration: 8.1 months). Median progression-free survival (PFS) after regorafenib therapy was 4.2 months (95% CI: 3.2-5.1). The median overall survival (OS; from initiation of either sorafenib or regorafenib) was not reached in this cohort. According to multivariate Cox regression analyses, albumin-bilirubin (ALBI) grade at the initiation of regorafenib therapy is an independent predictor of disease control, PFS, and OS. Moreover, the combination of ALBI grade 2 and an alpha-fetoprotein (AFP) level of ≥20 ng/mL was an independent predictor of PFS (hazard ratio (HR): 3.088, 95% CI: 1.704-5.595; p < 0.001) for regorafenib therapy, and OS for both regorafenib (HR: 3.783, 95% CI: 1.316-10.88; p = 0.014) and sorafenib-regorafenib sequential (HR: 4.603, 95% CI: 1.386-15.29; p = 0.013) therapy. A combination of ALBI grade and AFP level can be used to stratify patients with unresectable HCC by PFS and OS probability for sorafenib-regorafenib sequential therapy.

Prognostic roles of diabetes mellitus and hypertension in advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND & AIMS: It remains limited whether diabetes mellitus (DM) and hypertension (HTN) affect the prognosis of advanced hepatocellular carcinoma (HCC) treated with sorafenib. Our study attempted to elucidate the roles of DM/HTN and the effects of diabetes medications among advanced HCC patients receiving sorafenib. METHODS: From August 2012 to February 2018, 733 advanced HCC patients receiving sorafenib were enrolled at China Medical University, Taichung, Taiwan. According to the presence/absence of DM or HTN, they were divided into four groups: control [DM(-)/HTN(-), n = 353], DM-only [DM(+)/HTN(-), n = 91], HTN-only [DM(-)/HTN(+), n = 184] and DM+HTN groups [DM(+)/HTN(+), n = 105]. Based on the types of diabetes medications, there were three groups among DM patients (the combined cohort of DM-only and DM+HTN groups), including metformin (n = 63), non-metformin oral hypoglycemic agent (OHA) (n = 104) and regular insulin (RI)/neutral protamine hagedorn (NPH) groups (n = 29). We then assessed the survival differences between these groups. RESULTS: DM-only and DM+HTN groups significantly presented longer overall survival (OS) than control group (control vs. DM-only, 7.70 vs. 11.83 months, p = 0.003; control vs. DM+HTN, 7.70 vs. 11.43 months, p = 0.008). However, there was no significant OS difference between control and HTN-only group (7.70 vs. 8.80 months, p = 0.111). Besides, all groups of DM patients showed significantly longer OS than control group (control vs. metformin, 7.70 vs. 12.60 months, p = 0.011; control vs. non-metformin OHA, 7.70 vs. 10.80 months, p = 0.016; control vs. RI/NPH, 7.70 vs. 15.20 months, p = 0.026). CONCLUSIONS: Rather than HTN, DM predicts better prognosis in advanced HCC treated with sorafenib. Besides, metformin, non-metformin OHA and RI/NPH are associated with longer survival among DM-related advanced HCC patients receiving sorafenib.

Performance of Acoustic Radiation Force Impulse Elastography for Staging Liver Fibrosis in Patients With Chronic Hepatitis C After Viral Eradication.

BACKGROUND: Data on noninvasive liver fibrosis staging after viral eradication are unclear. This histology-based study validated the performance of liver stiffness (LS) measurements after viral eradication. METHODS: Consecutive participants with chronic hepatitis C (CHC) who received concomitant LS measurements through acoustic radiation force impulse (ARFI) elastography and percutaneous liver biopsy were prospectively screened and analyzed. RESULTS: Of the 644 patients, 521 (80.9%) underwent a biopsy at treatment baseline, and the remaining 123 (19.1%) underwent a biopsy at 3 years (median; interquartile range, 0.1) after the sustained virological response (SVR) to pegylated interferon-based and direct-acting antiviral treatments. The proportions of histological fibrosis stages did not differ significantly between the pretreatment and post-SVR groups (P = .0615). However, the LS values differed significantly (P < .0001). The median LS values (presented as shear wave velocities in meters per second) were 1.51 (0.92) for the pretreatment group and 1.22 (0.77) for the post-SVR group. The cutoffs (areas under the receiver operating characteristic curve, obtained using the bootstrap method) to dichotomize between METAVIR fibrosis stage F1 versus stages F2-F4, F1-F2 versus F3-F4, and F1-F3 versus F4 were 1.47 (0.8333, 95% confidence interval [CI] 0.7981-0.8663), 1.81 (0.8763, 95% CI 0.8376-0.9107), and 1.86 (0.8811, 95% CI 0.8378-0.9179) in the pretreatment group, respectively, and 1.22 (0.7872, 95% CI 0.7001-0.8624), 1.59 (0.8808, 95% CI 0.8034-0.9422), and 1.75 (0.9018, 95% CI 0.8201-0.9644) in the post-SVR group, respectively. CONCLUSIONS: The performance of LS measurements through ARFI elastography is promising to determine the liver fibrosis stage on necroinflammation-resolved histology in CHC after viral eradication.

Recruitment of CCR6+ Foxp3+ regulatory gastric infiltrating lymphocytes in Helicobacter pylori gastritis.

Helicobacter pylori (H. pylori) infection is associated with an inflammatory response in the gastric mucosa, leading to chronic gastritis, peptic ulcers, and gastric cancer. Increased T-cell infiltration is found at sites of H. pylori infection. The CCR6+ subset of CD4+ regulatory T cells (Tregs), a newly characterized subset of Tregs, has been reported to contribute to local immune inhibition. However, whether CCR6+ Tregs are present in H. pylori gastritis, and what their relationship is to disease prognosis, remains to be elucidated. In this study, gastric infiltrating lymphocytes were isolated from endoscopic biopsy specimens of H. pylori gastritis patients and analyzed. We found that in gastric infiltrating lymphocytes, CCR6+  CD4+  CD25high Tregs, which express high levels of CD45RO, are positively associated with more severe inflammation in gastric mucosa during H. pylori infection. Furthermore, the frequency of CCR6+ Tregs in gastric infiltrating lymphocytes, but not CCR6- Tregs, is significantly increased in inflamed gastric tissues, which is inversely correlated with significantly lower expression of IFN-γ+  CD8+ T cells. We also found that the frequency of CCR6+ Tregs is positively correlated with the frequency of CD4+  IFN-γ+ T cells. In addition, the frequency of CCR6+ Tregs, but not that of CCR6- Tregs, is significantly correlated with increased inflammation in H. pylori gastritis. This study demonstrates that immunosuppression in H. pylori gastritis might be related to the activity of CCR6+ Tregs, which could influence disease prognosis.

GSK-3 inhibitors enhance TRAIL-mediated apoptosis in human gastric adenocarcinoma cells.

Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis has been reported in some cancer cells, including AGS human gastric adenocarcinoma cells. Reducing this resistance might shed light on the treatment of human gastric adenocarcinoma. In this study, we examined whether glycogen synthase kinase-3 (GSK-3) inhibitors can restore TRAIL responsiveness in gastric adenocarcinoma cells. The effect of two GSK-3 inhibitors, SB-415286, and LiCl, on apoptosis signaling of TRAIL in human gastric adenocarcinoma cell lines and primary gastric epithelial cells was analyzed. Both inhibitors can sensitize gastric adenocarcinoma cells, but not primary gastric epithelial cells, to TRAIL-induced apoptosis by increasing caspase-8 activity and its downstream signal transmission. Adding p53 siRNA can downregulate GSK-3 inhibitor-related sensitization to TRAIL-induced apoptosis and caspase-3 activity. GSK-3 inhibitors strongly activate the phosphorylation of JNK. Inhibition of JNK leads to earlier and more intense apoptosis, showing that the activation of JNK may provide anti-apoptotic equilibrium of pro-apoptotic cells. Our observations indicate that GSK-3 inhibitors can sentize AGS gastric adenocarcinoma cells to TRAIL-induced apoptosis. Therefore, in certain types of gastric adenocarcinoma, GSK-3 inhibitor might enhance the antitumor activity of TRAIL and mightbe a promising candidate for the treatment of certain types of gastric adenocarcinoma.

PD-1 and PD-L1 Up-regulation Promotes T-cell Apoptosis in Gastric Adenocarcinoma.

BACKGROUND/AIM: The programmed death 1 (PD-1) receptor and its ligand (PD-L1) play pivotal roles in regulating host immune responses. However, the inhibitory effects of this pathway on the function of tumor infiltrating T lymphocytes in gastric adenocarcinoma patients are not well-defined. MATERIALS AND METHODS: We characterized the expression of PD-1 and PD-L1 in peripheral blood and tumor infiltrating cells and analyzed the association between PD-1/PD-L1 expression and disease progression in a cohort of 60 patients with Helicobacter pylori infection, including 18 with gastric adenocarcinoma, 23 with gastritis, and 19 asymptomatic controls. RESULTS: Relative to controls, the expression of PD-1 on peripheral blood and tumor infiltrating T cells increased with disease progression. In vitro, T cells induced PD-L1 expression on primary gastric adenocarcinoma epithelial cells in an IFN-γ-dependent manner, which in turn promoted T cells apoptosis. Blocking of PD-L1 reversed this effect. CONCLUSION: This study provides evidence for a new therapeutic target in gastric adenocarcinoma patients.

Changes in liver stiffness measurement using acoustic radiation force impulse elastography after antiviral therapy in patients with chronic hepatitis C.

BACKGROUND: To compare on-treatment and off-treatment parameters acquired using acoustic radiation force impulse elastography, the Fibrosis-4 (FIB-4) index, and aspartate aminotransferase-to-platelet ratio index (APRI) in patients with chronic hepatitis C (CHC). METHODS: Patients received therapies based on pegylated interferon or direct-acting antiviral agents. The changes in paired patient parameters, including liver stiffness (LS) values, the FIB-4 index, and APRI, from baseline to sustained virologic response (SVR) visit (24 weeks after the end of treatment) were compared. Multiple regression models were used to identify significant factors that explained the correlations with LS, FIB-4, and APRI values and SVR. RESULTS: A total of 256 patients were included, of which 219 (85.5%) achieved SVR. The paired LS values declined significantly from baseline to SVR visit in all groups and subgroups except the nonresponder subgroup (n = 10). Body mass index (P = 0.0062) and baseline LS (P < 0.0001) were identified as independent factors that explained the LS declines. Likewise, the baseline FIB-4 (P < 0.0001) and APRI (P < 0.0001) values independently explained the declines in the FIB-4 index and APRI, respectively. Moreover, interleukin-28B polymorphisms, baseline LS, and rapid virologic response were identified as independent correlates with SVR. CONCLUSIONS: Paired LS measurements in patients treated for CHC exhibited significant declines comparable to those in FIB-4 and APRI values. These declines may have correlated with the resolution of necroinflammation. Baseline LS values predicted SVR.

Clinical Efficacy and Post-Treatment Seromarkers Associated with the Risk of Hepatocellular Carcinoma among Chronic Hepatitis C Patients.

This follow-up study enrolled chronic hepatitis C patients to evaluate the treatment efficacy and to identify post-treatment seromarkers associated with risk of hepatocellular carcinoma (HCC) among patients with a sustained virological response (SVR) or nonsustained virological response (NSVR). A total of 4639 patients who received pegylated interferon and ribavirin during 2004-2013 were followed until December 2014. HCC was confirmed through health examinations and data linkage with a national database. A total of 233 HCC cases were reported after 26,163 person-years of follow-up, indicating an incidence of 8.9 per 1000 person-years: 6.9 for SVR and 21.6 for NSVR per 1000 person-years. The associated risk of HCC in patients with SVR was 0.37 (0.22-0.63) for those without cirrhosis and 0.54 (0.31-0.92) for those with cirrhosis compared with their respective counterparts with NSVR. Among patients with SVR, advanced age, male gender, cirrhosis, decreased platelet count, and increased aspartate aminotransferase and α-fetoprotein levels were associated with HCC (p < 0.001). The treatment of chronic hepatitis C patients before they developed cirrhosis showed a higher efficacy than did the treatment of those who had already developed cirrhosis. Patients with SVR may still have a risk of HCC and need to be regularly monitored.

IL-6 significantly correlates with p-STAT3 expression and presents high variceal bleeding with mortality in cirrhotic patients: A cross-sectional study.

BACKGROUND/PURPOSE: Effective mediators activate downstream transducers regulating inflammation and angiogenesis. Correlation among mediators IL-6, IL-27, TNF-α, and VEGF with STAT proteins at diverse clinical-pathologic stages of cirrhotic patients remains limited. METHODS: Plasma mediators were assayed from 158 naïve liver cirrhosis (LC-total group) and 144 non-LC individuals. The LC-total group included 69 hepatitis B virus-infected (LC-HBV) patients, 40 hepatitis C virus-infected (LC-HCV) patients, and 49 patients without HBV-/HCV- infection (LC-NBNC). Another 144 non-LC individuals comprised 54 healthy persons (HG) and 90 chronic hepatitis patients (CH-total) as the control group. To correlate with plasma mediators, 52 paired liver tissues (CH: 41 and LC: 11 cases) served for p-STAT1 and p-STAT3 immunostaining. RESULTS: Although IL-6, IL-27, TNF-α, and VEGF were expressed significantly in CH-total versus HG (p = 0.011, p < 0.001, p = 0.007, p = 0.004, respectively) and overall viral hepatitis patients versus HG (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively), only IL-6 presented the strongest correlation in cirrhotic patients than noncirrhotic patients (LC-HBV vs. HG, p < 0.001, vs. CH-HBV, p = 0.001; LC-HCV vs. HG, p = 0.001, vs. CH-HCV, p = 0.031; LC-NBNC vs. HG, p < 0.001). Over-expressed IL-6 linked with poorer liver function (albumin: r = -0.346, p < 0.001; bilirubin: r = 0.271, p = 0.001; INR: r = 0.308, p < 0.001; Child-Turcotte-Pugh Classification C vs. A or B, p = 0.001, p = 0.007, respectively), variceal severity (p = 0.045), and bleeding (p = 0.047), as well as patients' mortality (p = 0.005). Furthermore, plasma IL-6 significantly correlated with tissues p-STAT3 expression (r = 0.737, p = 0.010) (IL-27: r = 0.078, p = 0.820; TNF-α: r = -0.145, p = 0.670; VEGF: r = 0.142, p = 0.678) in cirrhotic patients than noncirrhotic patients. CONCLUSION: Over-expression of IL-6 reflects hepatic dysfunction and varices bleeding with mortality, as well as correlates p-STAT3 expression in cirrhotic patients.

Comparison of collagen proportionate areas in liver fibrosis quantification between chronic hepatitis B and C.

Few studies have compared the distinct hepatic collagen morphometrics of chronic hepatitis B (CHB) and chronic hepatitis C (CHC). This study compared the discrepancies between CHB and CHC in liver fibrosis (F) quantification by using the collagen proportionate area (CPA) and liver stiffness (LS) measured with shear wave velocity (SWV).This study enrolled 274 eligible consecutive patients diagnosed with CHB (n = 137) or CHC (n = 137). Their ages ranged from 20 to 80 years (median = 50). In total, 154 patients (56.2%) were male. Participant LS was measured by using acoustic radiation force impulse elastography preceding an immediate percutaneous liver biopsy. The total proportion of the collagen stained with picrosirius red to the total tissue area was expressed as the CPA percentage, which was stratified into portal-bridging (PB) and perisinusoidal (PS) proportionate areas (PAs).Based on the METAVIR F staging system, 36 (26.3%), 36 (26.3%), 28 (20.4%), and 37 (27.0%) participants in the CHB group and 34 (24.8%), 45 (32.9%), 34 (24.8%), and 24 (17.5%) participants in the CHC group were staged as F1, F2, F3, and F4, respectively. Both the total CPAs and PBPAs were significantly (P < 0.05) higher in the CHC group than in the CHB group within all F-stratified subgroups. The SWVs were significantly (P < 0.05) higher in the CHC group than in the CHB group only within the F2, F3, and F4 subgroups. However, the PSPAs did not differ significantly between the CHC and CHB groups within all subgroups. Multiple regression analysis revealed that viral hepatitis etiology (P < 0.001), METAVIR F stages (P < 0.001), and platelet count (P = 0.007) were independent factors correlated with the CPA (R = 0.543, P < 0.001).In conclusion, both the F stage-stratified CPAs and SWVs tended to be higher in cases of CHC than in those of CHB. The type of viral hepatitis significantly affected both the CPA and SWV values. The PBPAs were more closely correlated with F stages and SWV than were the PSPAs.

Evaluation of dose-efficacy of sorafenib and effect of transarterial chemoembolization in hepatocellular carcinoma patients: a retrospective study.

BACKGROUND: Transarterial chemoembolization (TACE) and sorafenib are the therapeutic standard for intermediate and advanced stage hepatocellular carcinoma (HCC) patients respectively. High costs with adverse events (AE) of sorafenib might limit sorafenib dosage, further affecting therapeutic response. To attain greatest benefit, we evaluated the efficacy of different doses and effect of TACE during and after sorafenib discontinuation in patients representing Child-Pugh Classification Class A with venous or extra-hepatic invasion. METHODS: A total 156 patients met the criteria and were divided into Groups I (n = 52) accepting 800 mg/day; II (n = 58) accepting 800 mg/day and reduced to 400 mg/day owing to AE; and III (n = 46) accepting 400 mg/day. TACE was performed during and after sorafenib discontinuation and therapeutic response bimonthly to four-monthly was rated thereafter. RESULTS: Median duration of sorafenib treatment and patients' survival were 4.00 ± 0.45 and 7.50 ± 1.44 months in all cases; 2.50 ± 0.90 and 5.00 ± 1.10 months in Group I; 5.50 ± 1.27 and 16.50 ± 1.86 months in Group II; 4.00 ± 0.94 and 6.50 ± 2.49 months in Group III. Group II presented the best response and survival benefit (p = 0.010 and p = 0.011 respectively). Child-Pugh Classification score 5 (Hazard Ratio = 0.492, p = 0.049), absent AE (3.423, p = 0.015), tumor numbers ≤ 3 (0.313, p = 0.009), sorafenib duration ≤ 1 cycle (3.694, p = 0.004), and absent TACE (3.197, p = 0.008) significantly correlated with patient survival. TACE benefit appeared in separate and total cases during (p = 0.002, p = 0.595, p = 0.074, p = 0.002 respectively) and after discontinuation of sorafenib administration (p = 0.001, p = 0.034, p = 0.647, p = 0.001 respectively). CONCLUSIONS: Low-dosage sorafenib not only appeared tolerable and lowered economic pressure but also provided satisfactory results. TACE benefited patient's survival during and after sorafenib discontinuation.

Head-to-Head Comparison between Collagen Proportionate Area and Acoustic Radiation Force Impulse Elastography in Liver Fibrosis Quantification in Chronic Hepatitis C.

BACKGROUND: The aim of this study was to compare the diagnostic performances of the collagen proportionate area (CPA) and liver stiffness measurement (LSM) for liver fibrosis quantification in chronic hepatitis C (CHC). METHODS: A total of 137 eligible consecutive Taiwanese patients (74 women and 63 men; age 21-80 years; median age 54 years), with CHC underwent LSM by using acoustic radiation force impulse (ARFI) elastography and an immediate percutaneous liver biopsy for METAVIR scoring. Liver tissue sections were stained using picrosirius red. Areas of the stained collagen and the tissue parenchyma were calculated in pixels. The ratio between the two areas was expressed as a CPA percentage. The result of LSM was presented as shear wave velocity (SWV). RESULTS: METAVIR fibrosis (F) stages were dichotomized using the CPA (%) and SWV (m/s), and the optimal cut-off values were 7.47 and 1.59 for F1 versus F2-4; 12.56 and 1.73 for F1, 2 versus F3, 4; 15.32 and 1.96 for F1-3 versus F4. To dichotomize F1 versus F2-4, the areas under receiver operating characteristic curves for the CPA was 0.9349 (95% confidence interval: 0.8943-0.9755) and for SWV was 0.8434 (0.7762-0.9105) (CPA versus SWV, P = 0.0063). For F1, 2 versus F3, 4, the CPA was 0.9436 (0.9091-0.9781); SWV was 0.8997 (0.8444-0.9551) (P = 0.1587). For F1-3 versus F4, the CPA was 0.8647 (0.7944-0.9349); SWV was 0.9036 (0.8499-0.9573) (P = 0.2585). The CPA could be predicted in a linear regression formula by using SWV and platelet count (R2 = 0.524). CONCLUSIONS: The CPA and ARFI elastography are promising tools for liver fibrosis evaluation. The CPA was superior to ARFI elastography in the diagnosis of significant fibrosis (≥ F2). The CPA may be independent of severe necroinflammation, which may augment liver stiffness.

IL-6, through p-STAT3 rather than p-STAT1, activates hepatocarcinogenesis and affects survival of hepatocellular carcinoma patients: a cohort study.

BACKGROUND: Biologic activities of functional mediators activate downstream transducers regulating inflammation and carcinogenesis. Correlation among mediators (IL-6, IL-27, TNF-α, and VEGF) with STAT proteins at diverse clinical-pathologic stages of hepatocellular carcinoma (HCC) remains limited. METHODS: Serum mediators assayed from 147 untreated HCC cases (HCC-total group) included 70 HBV-infected (HCC-HBV group), 64 HCV-infected (HCC-HCV group), and 13 without HBV-/HCV-infection (HCC-NBNC group). Another 156 non-HCC individuals comprised 54 healthy individuals (HG) and 102 chronic hepatitis patients (CH-total group) as control group. To correlate with serum mediators, 86-paired liver tissues (CH: 52 and HCC: 34 cases) served for p-STATs proteins immunostain. RESULTS: Although four mediators (IL-6, IL-27, TNF-α, and VEGF) significantly over-expressed, IL-6 presented the strongest correlation in HCC-total versus CH-total or HG groups (HCC-total versus CH-total: P < 0.001; HCC-total versus HG: P < 0.001). Over-expressed IL-6 concentration linked with poor liver function (Albumin: r = -0.383, P < 0.001; Bilirubin: r = 0.280, P = 0.001; INR: r = 0.299, P < 0.001; AST: 0.212, P = 0.016), tumor progression (TNM system: r = 0.370; P < 0.001), clinical condition severity (BCLC system: r = 0.471; P < 0.001; terminal- versus early-stage HCC, P = 0.001; advanced- versus early-stage HCC, P = 0.007; terminal- versus intermediate- stage HCC P = 0.003; advanced- versus intermediate-stage HCC P = 0.019), and 6-month mortality (P = 0.024). Likewise, serum IL-6 (r = 0.501, P = 0.003) as compared to IL-27 (r = 0.052, P = 0.770), TNF-α (r = 0.019, P = 0.917), and VEGF (r = 0.096, P = 0.595) expression reflected positive correlation with activation of tissues p-STAT3 rather than p-STAT1. CONCLUSIONS: Serum IL-6, through p-STAT3 rather than p-STAT1 signal pathway, affected hepatic function, tumor progression, and determine HCC patient survival.

Increased incidence of gastrointestinal cancers among patients with pyogenic liver abscess: a population-based cohort study.

BACKGROUND & AIMS: The relationship between pyogenic liver abscess (PLA) and gastrointestinal (GI) cancer was first reported more than 20 years ago, yet little is known about this connection. We evaluated this association in a population-based, retrospective, cohort study. METHODS: Using Taiwan National Health Insurance claims data, we collected data on a cohort of 14,690 patients with PLA diagnosed from 2000 to 2007. A reference cohort of 58,760 persons without PLA (controls) was selected from the same database, frequency matched by age, sex, and index year. Both cohorts were followed up until the end of 2009, and incidences of GI cancer were calculated. RESULTS: The incidence of GI cancer was 4.30-fold higher among patients with PLA compared with controls (10.8 vs 2.51/1000 person-years). Site-specific analysis showed that the highest incidence of colorectal cancer was among patients with PLA and diabetes mellitus, followed by patients with PLA without diabetes and controls with diabetes (9.58, 5.76, and 1.49/10,000 person-years, respectively). The PLA cohort also had a high risk of small intestine cancer (adjusted hazard ratio [aHR], 12.7; 95% confidence interval [CI], 5.79-27.7) and biliary tract cancer (aHR, 9.56; 95% CI, 6.68-13.7). Their risk of pancreatic cancer (aHR, 2.51; 95% CI, 1.68-3.76) was also significant. However, patients with PLA did not have an increased risk of gastric cancer compared with controls. CONCLUSIONS: In a population-based study, we found that the incidence of GI cancer is increased more than 4-fold among patients with PLA compared with controls. PLA might therefore be an indicator of GI cancer. Patients with PLA had the highest incidence of colorectal cancer, followed by cancers of the biliary tract, pancreas, and small intestine.