Silymarin Synergizes with Antiviral Therapy in Hepatitis B Virus-Related Liver Cirrhosis: A Propensity Score Matching Multi-Institutional Study.

Hepatitis B virus (HBV)-related liver cirrhosis (HBV-LC) presents a substantial mortality and hepatocellular carcinoma (HCC) risk. While antiviral therapy (AVT) is the standard, complete HBV clearance remains elusive and may not reduce the risk of death in patients with decompensated cirrhosis. Silymarin, a centuries-old herbal remedy, has shown promise against HBV infection and as an antifibrosis therapy. This study explores the potential of silymarin combined with AVT to reduce mortality and HCC incidence in patients with HBV-LC. This research, spanning from 2001 to 2019, entailed a multi-institutional retrospective cohort study which included 8447 HBV-LC patients all undergoing AVT. After applying inclusion and exclusion criteria, the study comprised two cohorts: a case cohort receiving silymarin alongside AVT for at least 30 days, and a control cohort on AVT alone. Propensity score matching, based on baseline parameters including HBV-DNA levels, comorbidity, and an important LC medication, namely, non-selective ß-blockers, was employed to ensure balanced groups, resulting in 319 patients in each cohort for subsequent analyses. Overall mortality was the primary outcome, with HCC occurrence as a secondary outcome. Among 319 patients in both cohorts, the case cohort exhibited significant improvements in the international normalized ratio (INR), model for end-stage liver disease (MELD) score and the Charlson comorbidity index (CCI) one year after the index date. A competing risk survival analysis demonstrated superior one-year and two-year mortality outcomes in the case cohort. However, no significant impact on one-year and two-year HCC occurrence was observed in either cohort. The combination of silymarin and AVT in HBV-LC patients demonstrated a synergistic effect, leading to decreased overall mortality and an improved comorbidity index. While the incidence of HCC remained unchanged, our results suggested promising potential for further clinical trials investigating the synergistic role of silymarin in the treatment of HBV-LC.

A combination of locoregional treatment with systemic therapy after atezolizumab plus bevacizumab failure for unresectable hepatocellular carcinoma provides survival benefit.

Atezolizumab plus bevacizumab (A+B) is used to treat unresectable hepatocellular carcinoma (HCC), but the optimal rescue therapy after A+B remains unclear. Combining locoregional therapy (LRT) with systemic treatment has been shown to improve tumor control, but the role in patients who fail A+B is unknown. We retrospectively enrolled patients who experienced radiological progression after A+B. Objective response rate (ORR), disease control rate (DCR), post progression survival (PPS), and secondary progression-free survival (PFS) were evaluated by modified RECIST. Inverse probability weighting (IPW) was used to balance baseline clinical features. A total of 61 patients were enrolled with a median age of 60.7 years, 83.6% male, 88.5% viral hepatitis-related, and 60.7% without prior systemic treatment before A+B. Patients receiving sequential therapies had significantly longer PPS than supportive care (10.5 vs. 2.3 months, P<0.0001). Among 37 patients received sequential systemic treatment, 18 received combined LRT. The median follow-up after post A+B failure was 6.6 months. The combined LRT group had higher ORR (27.8 vs. 0%, P=0.0197) and DCR (72.2 vs. 26.3%, P=0.0052) than systemic alone group. The median PPS and secondary PFS were significantly longer in combined LRT group (PPS: 12.2 vs. 5.8 months, P=0.0070; PFS: 5.0 vs. 2.6 months, P=0.0134) than systemic alone group. After IPW analysis, patients with combined LRT had superior PPS and secondary PFS. The incidence rates of AEs were higher in LRT combination compared to systemic alone (any grade AEs: 94.4 vs. 63.2%, P=0.0422; severe AEs: 33.3 vs. 5.3%, P=0.0422). No significant albumin-bilirubin index changed in the first 3 months in combined LRT group (0.966 [0.647-1.443], P=0.867) though a trend of deterioration in systemic alone group. In conclusion, sequential systemic therapy provides survival benefits after A+B failure. Furthermore, combining LRT with systemic treatment could provide better tumor responses and survival benefits with acceptable toxicity than systemic therapy alone.

Adding nutritional status to the original BCLC stage improves mortality prediction for hepatocellular carcinoma patients in HBV-endemic regions.

Hepatocellular carcinoma (HCC) is associated with high mortality, especially in Asian populations where chronic HBV infection is a major cause. Accurate prediction of mortality can assist clinical decision-making. We aim to (i) compare the predicting ability of Barcelona Clinic Liver Cancer classification (BCLC) stage, neutrophil-to-lymphocyte ratio (NLR), and Albumin-Bilirubin (ALBI) score in predicting short-term mortality (one- and two-year) and (ii) develop a novel model with improved accuracy compared to the conventional models. This study enrolled 298 consecutive HCC patients from our hepatology department. The prognostic values for mortality were assessed by area under the receiver operating characteristic curve (AUROC) analysis. A novel model was established and internally validated using 5-fold cross-validation, followed by external validation in a cohort of 100 patients. The primary etiology of cirrhosis was hepatitis B virus (HBV), with 81.2% of HCC patients having preserved liver function. Significant differences were observed in hemoglobin (Hb) and serum albumin levels, which reflect patients' nutrition status, between patients who survived for one year and those who died. BCLC exhibited superior predictive accuracy compared to NLR but had borderline superiority to the ALBI score. Therefore, a novel model incorporating BCLC, Hb, and serum albumin was developed, internally and externally validated, as well as subgroup sensitivity analysis. The model exhibited significantly higher predictive accuracy for one- and two-year mortality than conventional prognostic predictors, with AUROC values of 0.841 and 0.805, respectively. The novel "BCLC-Nutrition Model", which incorporates BCLC, Hb, and serum albumin, may provide improved predictive accuracy for short-term mortality in HCC patients compared to commonly used prognostic scores. This emphasizes the importance of nutrition in the management of HCC patients.

Murine cytotoxic CD4+ T cells in the tumor microenvironment are at a hyper-maturation stage of Th1 CD4+ T cells sustained by IL-12.

The roles of tumor-infiltrating CD4+Foxp3- T cells are not well characterized due to their plasticity of differentiation, and varying levels of activation or exhaustion. To further clarify this issue, we used a model featuring subcutaneous murine colon cancer and analyzed the dynamic changes of phenotype and function of the tumor-associated CD4+ T-cell response. We found that, even at a late stage of tumor growth, the tumor-infiltrating CD4+Foxp3- T cells still expressed effector molecules, inflammatory cytokines and molecules that are expressed at reduced levels in exhausted cells. We used microarrays to examine the gene-expression profiles of different subsets of CD4+ T cells and revealed that the tumor-infiltrating CD4+Foxp3- T cells expressed not only type 1 helper (Th1) cytokines, but also cytolytic granules such as those encoded by Gzmb and Prf1. In contrast to CD4+ regulatory T cells, these cells exclusively co-expressed natural killer receptor markers and cytolytic molecules as shown by flow-cytometry studies. We used an ex vivo killing assay and proved that they could directly suppress CT26 tumor cells through granzyme B and perforin. Finally, we used pathway analysis and ex vivo stimulation to confirm that the CD4+Foxp3- T cells expressed higher levels of IL12rb1 genes and were activated by the IL-12/IL-27 pathway. In conclusion, this work finds that, in late-stage tumors, the tumor-infiltrating lymphocyte population of CD4+ cells harbored a sustained, hyper-maturated Th1 status with cytotoxic function supported by IL-12.

Prognostic Effects of Liver Fibrosis and Steatosis Determined Using Transient Elastography in Patients with Chronic Hepatitis B or C.

BACKGROUND: The prognostic effects of liver fibrosis and steatosis in patients with chronic hepatitis B or C are unclear. We investigated the prognostic effects of liver fibrosis and steatosis determined through transient elastography (TE) in patients with chronic hepatitis B or C. METHODS: This retrospective cohort study enrolled 5528 patients with chronic hepatitis B or C who received TE. Multivariate Cox regression was used to evaluate the associations between fibrosis and steatosis grades and the occurrence of hepatic-related events, cardiovascular events, and mortality. Liver stiffness measurements of ≥ 7.1, ≥ 9.5, and ≥ 12.5 kPa were considered to indicate significant fibrosis (≥ F2), advanced fibrosis (≥ F3), and cirrhosis (≥ F4), and controlled attenuation parameters of ≥ 230 and ≥ 264 dB/m were considered to indicate mild (S1) and moderate-to-severe (S2-S3) steatosis, respectively. RESULTS: During a median follow-up of 3.1 years, 489 patients died, 814 had hepatic-related events, and 209 had cardiovascular events. The incidences of these outcomes were lowest among individuals with no- or mild-fibrosis (F0-F1), and increased with fibrosis severity. The incidence of adverse outcomes was highest among patients without steatosis (S0) and lowest among those with moderate-to-severe steatosis. Adjusted models indicated that F2, F3, and F4 were independent risk factors and that moderate-to-severe steatosis was a favorable marker for hepatic-related events. Cirrhosis was an independent factor for mortality. CONCLUSIONS: According to TE, increasing fibrosis grades and absence of steatosis were associated with higher risks of hepatic-related events, whereas cirrhosis was a risk factor for mortality in patients with chronic hepatitis B or C.

Immunophenotype and antitumor activity of cytokine-induced killer cells from patients with hepatocellular carcinoma.

BACKGROUND: Cytokine-induced killer (CIK) cells are heterogeneous lymphocytes from human peripheral blood mononucleated cells (PBMCs) co-cultured with several cytokines. The main purpose of this study is to evaluate the functional characteristics and anticancer ability of CIK cells from hepatocarcinoma (HCC) patients. METHODS: CIK cells were activated ex-vivo and expanded from PBMCs from HCC patients. The immunophenotype and the ex-vivo killing ability of CIK cells were evaluated. Human CIK cells were intravenously injected into NOD/SCID mice to evaluate the in vivo anticancer ability. RESULTS: More than 70% of CIK cells were CD3+CD8+, and 15%-30% were CD3+CD56+. These cells expressed an increased number of activated natural killer (NK) receptors, such as DNAM1 and NKG2D, and expressed low-immune checkpoint molecules, including PD-1, CTLA-4, and LAG-3. Among the chemokine receptors expressed by CIKs, CXCR3 and CD62L were elevated in CD8+ T cells, representing the trafficking ability to inflamed tumor sites. CIK cells possess the ex-vivo anticancer activity to different cell lines. To demonstrate in vivo antitumor ability, human CIK cells could significantly suppress the tumor of J7 bearing NOD/SCID mice. Furthermore, human immune cells could be detected in the peripheral blood and on the tumors after CIK injection. CONCLUSIONS: This study revealed that CIK cells from HCC patients possess cytotoxic properties, and express increased levels of effector NK receptors and chemokine molecules and lower levels of suppressive checkpoint receptors. CIK cells can suppress human HCC ex-vivo and in vivo. Future clinical trials of human CIK cell therapy for HCC are warranted.

Dynamic Change of Albumin-Bilirubin Score Is Good Predictive Parameter for Prognosis in Chronic Hepatitis C-hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization.

Background and Aims: The Albumin-Bilirubin (ALBI) grade is a good index for liver function evaluation and is also associated with the outcomes of hepatocellular carcinoma patients receiving TACE. However, the correlation between the dynamic change to the ALBI score and clinical outcome is seldom discussed. Therefore, this study aimed to investigate the application of ALBI grade and dynamic change of ALBI grade (delta ALBI grade) after first TACE for prognosis prediction in HCC patients with chronic hepatitis C infection. Method: From January 2005 to December 2015, newly diagnosed naive chronic hepatitis C-hepatocellular carcinoma (CHC-HCC) patients who were treated with TACE as the initial treatment at the Chang Gung Memorial Hospital, Linkou Medical Center, were retrospectively recruited. The pre-treatment host factors, tumor status and noninvasive markers were collected. The Cox regression model was used to identify independent predictors of overall survival and tumor recurrence. Results: Among 613 treatment-naive CHC-HCC patients, 430 patients died after repeated TACE during a median follow-up of 26.9 months. Complete remission after repeated TACE occurred in 46.2% patients, and 208 patients (33.9%) had tumor recurrence, with a median recurrence-free interval of 8.5 months. In Cox regression analysis, ALBI grade II/III (aHR: 1.088, p = 0.035) and increased delta ALBI grade (aHR: 1.456, p = 0.029) were independent predictive factors for tumor recurrence. Furthermore, ALBI grade II/III (aHR: 1.451, p = 0.005) and increased delta ALBI grade during treatment (aHR: 1.436, p = 0.006) were predictive factors for mortality, while achieving complete response after repeated TACE (aHR: 0.373, p < 0.001) and anti-viral therapy (aHR: 0.580, p = 0.002) were protective factors for mortality. Conclusion: Both ALBI and delta ALBI grade are independent parameters to predict survival and tumor recurrence of CHC-HCC patients receiving TACE treatment.

Sexual Crossing, Chromosome-Level Genome Sequences, and Comparative Genomic Analyses for the Medicinal Mushroom Taiwanofungus Camphoratus (Syn. Antrodia Cinnamomea, Antrodia Camphorata).

Taiwanofungus camphoratus mushrooms are a complementary and alternative medicine for hangovers, cancer, hypertension, obesity, diabetes, and inflammation. Though Taiwanofungus camphoratus has attracted considerable biotechnological and pharmacological attention, neither classical genetic nor genomic approaches have been properly established for it. We isolated four sexually competent monokaryons from two T. camphoratus dikaryons used for the commercial cultivation of orange-red (HC1) and milky-white (SN1) mushrooms, respectively. We also sequenced, annotated, and comparatively analyzed high-quality and chromosome-level genome sequences of these four monokaryons. These genomic resources represent a valuable basis for understanding the biology, evolution, and secondary metabolite biosynthesis of this economically important mushrooms. We demonstrate that T. camphoratus has a tetrapolar mating system and that HC1 and SN1 represent two intraspecies isolates displaying karyotypic variation. Compared with several edible mushroom model organisms, T. camphoratus underwent a significant contraction in the gene family and individual gene numbers, most notably for plant, fungal, and bacterial cell-wall-degrading enzymes, explaining why T. camphoratus mushrooms are rare in natural environments, are difficult and time-consuming to artificially cultivate, and are susceptible to fungal and bacterial infections. Our results lay the foundation for an in-depth T. camphoratus study, including precise genetic manipulation, improvements to mushroom fruiting, and synthetic biology applications for producing natural medicinal products. IMPORTANCETaiwanofungus camphoratus (Tc) is a basidiomycete fungus that causes brown heart rot of the aromatic tree Cinnamomum kanehirae. The Tc fruiting bodies have been used to treat hangovers, abdominal pain, diarrhea, hypertension, and other diseases first by aboriginal Taiwanese and later by people in many countries. To establish classical genetic and genomic approaches for this economically important medicinal mushroom, we first isolated and characterized four sexually competent monokaryons from two dikaryons wildly used for commercial production of Tc mushrooms. We applied PacBio single molecule, real-time sequencing technology to determine the near-completed genome sequences of four monokaryons. These telomere-to-telomere and gapless haploid genome sequences reveal all genomic variants needed to be studied and discovered, including centromeres, telomeres, retrotransposons, mating type loci, biosynthetic, and metabolic gene clusters. Substantial interspecies diversities are also discovered between Tc and several other mushroom model organisms, including Agrocybe aegerita, Coprinopsis cinerea, and Schizophyllum commune, and Ganoderma lucidum.

Innate-like bystander-activated CD38+ HLA-DR+ CD8+ T cells play a pathogenic role in patients with chronic hepatitis C.

BACKGROUND AND AIMS: HCV-specific T cells are few and exhausted in patients with chronic hepatitis C (CHC). Whether these T cells are responsible for the liver damage and fibrosis is still debated. However, cluster of differentiation 38-positive (CD38+ ) human leukocyte antigen DR-positive (HLA-DR+ ) CD8+ T cells are regarded as bystander CD8+ T cells that cause liver injury in acute hepatitis. We propose that these innate CD8+ T cells play a pathogenic role in CHC. METHODS: Lymphocytes from peripheral blood were obtained from 108 patients with CHC and 43 healthy subjects. Immunophenotyping, functional assays, T-cell receptor (TCR) repertoire, and cytotoxic assay of CD38+ HLA-DR+ CD8+ T cells were studied. RESULTS: The percentage of CD38+ HLA-DR+ CD8+ T cells increased significantly in patients with CHC. These cells expressed higher levels of effector memory and proinflammatory chemokine molecules and showed higher interferon-γ production than CD38- HLA-DR- CD8 T cells. They were largely composed of non-HCV-specific CD8+ T cells as assessed by HLA-A2-restricted pentamers and next-generation sequencing analysis of the TCR repertoire. In addition, these CD38+ HLA-DR+ CD8+ T cells had strong cytotoxicity, which could be inhibited by anti-DNAX accessory molecule 1, anti-NKG2 family member D, and anti-natural killer NKp30 antibodies. Lastly, the percentage of CD38+ HLA-DR+ CD8+ T cells was significantly associated with liver injury and fibrosis and decreased significantly along with serum alanine aminotransferase normalization after successful direct-acting antiviral treatment. CONCLUSIONS: The TCR-independent, cytokine-responsive bystander CD38+ HLA-DR+ CD8+ T cells are strongly cytotoxic and play a pathogenic role in patients with CHC.

Complete response at first transarterial chemoembolization predicts favorable outcome in hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the mainstay of treatment for patients with intermediate/advanced stage or unresectable hepatocellular carcinoma (HCC). Despite the palliative nature of TACE treatment, embolizing the tumor feeding vessels and leading to progressive tumor necrosis, complete response (CR) after TACE could still be observed in a certain population. Thus, this study aimed to investigate both the predictors for CR and the long-term prognosis of the patients with CR after TACE. The study recruited new diagnosed HCC patients initially treated with TACE from 2010 to 2013. Post TACE response was assessed by scheduled image studies according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Then, pre-TACE factors were compared between patients with and without CR. After the first session of TACE, 22.3% of the 669 TACE treated patients achieved CR. During a median of 26.6 months follow-up, patients with CR had better overall survival than those without (median: 35.8 vs. 24.0 months, P<0.001). By multivariate logistic regression analysis, Child-Turcotte-Pugh class B (OR: 0.419, P=0.005), tumor burden beyond up-to-7 criteria (OR: 0.118, P<0.001), bilobar tumor extent (OR: 0.236, P<0.001), higher alpha-fetoprotein (AFP) level (≥20 ng/ml, OR: 0.614, P=0.039) and higher platelet counts (>150 k/µl, OR: 0.482, P=0.002) were unfavorable predictors for CR after first TACE. In addition, macrovascular invasion (HR: 3.113, P=0.001) and higher AFP levels (≥15 ng/ml, HR: 2.601, P=0.007) were predictors for early HCC recurrence whereas diabetes mellitus (DM) (HR: 2.166, P=0.006) was the only significant predictor for late HCC recurrence in CR patients. In conclusion, more than one-fifth of HCC patients achieved CR after first TACE and these patients had favorable prognosis. Furthermore, tailored post-TACE follow-up strategies shall be considered in patients with different risk factors of early or late recurrence after CR.

MELD score is the better predictor for 30-day mortality in patients with ruptured hepatocellular carcinoma treated by trans-arterial embolization.

BACKGROUND AND AIMS: Spontaneous hepatocellular carcinoma (HCC) rupture is a catastrophic life-threatening complication that could be rescued by trans-arterial embolization (TAE). However, deteriorated liver function with total bilirubin more than 3 mg/dL was deemed as a relative contraindication. This study was aimed to re-evaluate this relative contraindication. METHODS: Patients with ruptured HCC and treated by TAE between February 2005 and December 2016 in Chang Gung Memorial Hospital, Linkou branch were recruited. Pre-TAE characteristics including age, gender, etiology, liver biochemistry, Child-Pugh classification, Model for End-Stage Liver Disease (MELD) score, the presence of shock, tumor staging and post TAE liver function were compared between patients with and without post-TAE 30-day mortality. RESULTS: A total of 186 patients were enrolled. The successful hemostatic rate after embolization was 91.4% and the median overall survival was 224 days. The 30-day cumulative mortality rate is 20.4%. By multivariate logistic regression analysis, male [aOR: 0.25, P=0.034] MELD score [aOR: 13.61, P<0.001], tumor size [aOR: 1.21, P=0.023] are the independent predictors for 30-day mortality. MELD score has better predictability of post-TAE 30-day mortality than total bilirubin level (AUROC: 0.818 vs. 0.668). The cut-off points of MELD score 13 has higher negative predictive value of 95% for post-TAE 30-day mortality. CONCLUSION: TAE is effective for the initial hemostasis in patients with HCC rupture. MELD score ≥13 rather than only total bilirubin level >3 mg/dL be more predictive of post TAE 30-day mortality.

Comparing CLIF-C ACLF, CLIF-C ACLFlactate, and CLIF-C ACLF-D Prognostic Scores in Acute-on-Chronic Liver Failure Patients by a Single-Center ICU Experience.

Patients with liver cirrhosis have a higher risk of developing acute-on-chronic liver failure (ACLF). Poor prognosis with a high rate of short-term mortality leads to limited opportunities for further liver transplantation. Thus, precise prognostic evaluation of patients with ACLF is necessary before transplant surgery. In this study, a total of one hundred and thirty-five patients with ACLF admitted to the hepato-gastroenterologic intensive care unit (ICU) for intensive monitoring and treatment at Chang-Gung Memorial Hospital (CGMH, Linkou, Taiwan) were screened from November 2012 to April 2015 and tracked until April 2017. Three new prognostic scores of ACLF, including CLIF-C ACLF (Chronic Liver Failure Consortium Acute-on-chronic Liver Failure score), CLIF-C ACLF-D (CLIF-C ACLF Development score), and CLLF-C ACLFlactate (lactate-adjusted CLIF-C ACLF score) were compared. The primary outcome considered was overall mortality. Mortality predictions at 28, 90, 180, and 365 days were also calculated. By area under the receiver operating characteristic curve (AUROC) analysis, the CLIF-C ACLF and CLIF-C ACLF-D scores were superior to CLIF-C ACLFlactate scores in predicting 28-day mortality. The CLIF-C ACLF-D score had the highest AUROC in predicting overall mortality as well as at 90, 180, and 365 days. In conclusion, our study demonstrates that CLIF-C ACLF and CLIF-C ACLF-D scores are significant predictors of outcome in critical patients with liver cirrhosis and ACLF. The CLIF-C ACLF-D score may have a superior predictive power for the prediction of 3-month, 6-month, and one-year mortality.

Therapeutic Role of Inducible Nitric Oxide Synthase Expressing Myeloid-Derived Suppressor Cells in Acetaminophen-Induced Murine Liver Failure.

Background: Acetaminophen (APAP) overdose is one of the major etiologies of liver failure. Hepatocyte necrosis induced by toxic metabolites of APAP can activate proinflammatory responses, including elastase-expressing neutrophils, to exacerbate liver injury. Myeloid-derived suppressor cells (MDSCs) increased in inflammation can inhibit proinflammatory responses. Our aim is to investigate the role of MDSC in APAP-induced liver failure and the possible therapeutic application. Methods: BLAB/c mice were injected with a sublethal/lethal dose of APAP as the murine model of liver failure. MDSCs were defined as CD11b+Gr-1+ cells with the ability of T-cell suppression. Results: A sublethal challenge of APAP could increase the intrahepatic MDSC and protect mice against subsequent lethal challenge of APAP, lipopolysaccharide (LPS)/D-galatosamine or concanavalin A. This protection was lost if MDSCs were depleted and inducible nitric oxide synthase (iNOS) was the key molecule in this MDSC-mediated protection. Taking advantage of these observations, different bone marrow-derived MDSCs (BM-MDSCs) were generated. Among different cytokine-treated BM-MDSCs, tumor necrosis factor alpha/LPS-primed MDSCs (TNF-α/LPS MDSCs) had the strongest liver-protection ability after adoptive transfer. Further mechanistic explorations showed, iNOS-expressing TNF-α/LPS MDSCs induced the apoptosis of activated neutrophil and decreased the intrahepatic infiltration of elastase-expressing neutrophil. Moreover, we generated MDSCs from human peripheral blood mononuclear cells (PBMCs) with similar phenotype. Conclusion: We demonstrated the protective role of MDSCs and therapeutic effect of TNF-α/LPS MDSCs in APAP-induced liver failure. MDSC might protect against the APAP-induced liver failure by reducing the intrahepatic infiltration of activated neutrophil to limit inflammation. Therefore, a therapeutic role of MDSCs for APAP-induced liver failure was proposed.

The incidence and predictors of post transarterial chemoembolization variceal bleeding in hepatocellular carcinoma patients.

BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is the standard of care for intermediate stage hepatocellular carcinoma (HCC) patients. Variceal bleeding is a life-threatening complication and may alter the initial treatment plan. This study was aimed to elucidate the risk factors for variceal bleeding in HCC patients receiving TACE treatment. METHODS: From 2005 to 2016, a total of 1233 treatment-naive HCC patients receiving first time TACE treatment in Chang Gung Memorial Hospital, Linkou medical center were recruited. Pre-TACE status including baseline characteristics, prior history of ascites, and parameters for liver function evaluation were analyzed. All the variables were compared between patients with and without variceal bleeding. RESULTS: Among the 1233 patients, the median age was 63.7 (range 25.8-91.5) years old, and 73.5% were male. Variceal bleeding events were documented in 19 patients (1.5%) within 3 months post TACE treatment. Patients with younger age, cirrhosis, pre-treatment ascites and advanced fibrosis status (higher MELD score, CTP score, ALBI grade, FIB-4 and APRI score) were more likely to encounter post-treatment variceal bleeding. Multivariate Cox regression analysis revealed existence of ascites (adjusted HR: 4.859 (1.947-12.124), p = 0.001), and higher FIB-4 score (adjusted HR: 4.481 (1.796-11.179), p = 0.001) were the independent predictive factors for variceal bleeding. Patients with post-TACE variceal bleeding are more likely to encounter tumor progression (42.1% vs. 20.3%, p = 0.039) and mortality owing to GI bleeding (15.8% vs. 3%, p = 0.032). CONCLUSION: The incidence of post-TACE variceal bleeding was 1.5%. Patients with post-TACE variceal bleeding have poorer TACE treatment response. The pre-treatment ascites and FIB-4 score are the independent predictors for post-TACE variceal bleeding.

Add-on sorafenib is beneficial for hepatocellular carcinoma patients with transarterial chemoembolization refractoriness: a real-world experience.

BACKGROUND AND AIMS: Sorafenib is the first proved target therapy that shows significant survival benefit in advanced hepatocellular carcinoma. This study was aimed to investigate whether add-on sorafenib be beneficial for those experienced transarterial chemoembolization refractoriness. METHODS: From 2005 to 2016, a total of 656 treatment-naive hepatocellular carcinoma patients receiving transarterial chemoembolization treatment were recruited. Transarterial chemoembolization refractoriness was defined as progressive disease after two consecutive of transarterial chemoembolization treatment within 6 months. Patient's baseline characteristics, tumor burden, and parameters for liver function evaluation during treatment were analyzed. All the variables were compared between patients with and without transarterial chemoembolization refractoriness, as well as with and without add-on sorafenib. RESULTS: Among the 656 patients, the median age was 62.5 (range 27.3-91.5) years old, and 74.5% were male. Transarterial chemoembolization refractoriness events were documented in 202 patients (30.8%). After multivariate logistic regression analysis, tumor size ≧5 cm, baseline alpha-fetoprotein level ≧200 mg/dl, elevation of alpha-fetoprotein ≧20%, and elevation of Child-Turcotte-Pugh score ≧2 points after first transarterial chemoembolization were the independent predictive factors for transarterial chemoembolization refractoriness. Twenty-two patients (10.9%) received add-on sorafenib treatment and 146 (72.3%) patients continued transarterial chemoembolization treatment alone. After 1:2 propensity score matching, patients with add-on sorafenib therapy had significantly longer median overall survival than transarterial chemoembolization treatment alone (23.1 vs. 11.0 months, log-rank P = 0.001). CONCLUSION: The tumor size, baseline alpha-fetoprotein, and elevation of alpha-fetoprotein and Child-Turcotte-Pugh score after first transarterial chemoembolization were the predictors for transarterial chemoembolization refractoriness. For patients with transarterial chemoembolization refractoriness, add-on sorafenib achieved better survival benefit than transarterial chemoembolization treatment alone.

Interferon Is Superior to Direct Acting Antiviral Therapy in Tertiary Prevention of Early Recurrence of Hepatocellular Carcinoma.

The elimination of chronic hepatitis C infection (CHC) by pegylated interferon plus ribavirin (Peg-IFN/RBV) decreases hepatocellular carcinoma (HCC) recurrence rate. However, the tertiary prevention of HCC recurrence by direct acting antiviral agents (DAA) remains controversial. This study aims to compare the tertiary prevention effect between DAA and Peg-IFN/RBV in CHC-HCC patients. Three hundred and one patients who received curative HCC treatment were retrospectively recruited. The recurrence incidence rate (IR) was compared among patients either receiving Peg-IFN/RBV or DAA regimen or untreated by three timeframes (I: from HCC treatment to antiviral therapy; II: during antiviral therapy; III: after antiviral therapy). The prevention effect between Peg-IFN/RBV and DAA were compared in frame II and III after propensity score matching (PSM) with age, tumor staging, HCC treatment modality, and cirrhotic status. Before PSM, the recurrence IRs in three arms were comparable in frame I, while being lower in the Peg-IFN/RBV and DAA arm compared to the untreated arm in frame II. In frame III, the tertiary prevention effect lasted in the Peg-IFN/RBV arm (p < 0.001), but diminished in the DAA arm (p = 0.135) compared to untreated patients. After PSM, the HCC recurrence IR was higher in the DAA arm than the Peg-IFN/RBV arm in frame II (2724 vs. 666 per 104 person-years, log-rank p = 0.042) and III (5259 vs. 3278 per 104 person-years, log-rank p = 0.048). Preantiviral ALBI grade therapy is the only predictor for postantiviral therapy HCC recurrence. In conclusion, the tertiary prevention effect of HCC recurrence was not durable in DAA-treated patients, but persisted in Peg-IFN/RBV treatment patients.

In HCV-related liver cirrhosis, local pulse wave velocity increases and in decompensated patients correlates with poorer survival.

BACKGROUND: Cirrhotic cardiomyopathy (CCM) refers to cardiac dysfunction in patients with liver cirrhosis, in the absence of other known cardiac disease. METHODS: Control group and patients diagnosed of liver cirrhosis without known cardiac disease or hepatocellular carcinoma were enrolled for this clinical observation study. Patients with diabetes mellitus, hypertension were excluded. Absolute global longitudinal strain, one-point carotid pulse wave velocity (one-point PWV) and various parameters were measured in resting status. RESULTS: There were 29 participants in the control group and 80 patients in the liver cirrhosis group. 27.8% of cirrhotic patients presented with normal systolic but abnormal diastolic functions and QTc prolongation that were compatible with CCM. 34.2% of cirrhotic patients presented with diastolic dysfunction in resting state comparing to 24.1% in control group. Systolic functions did not show conspicuous difference between cirrhosis and control group nor between compensated and decompensated cirrhosis, neither. Furthermore, one-point PWV was significantly higher in liver cirrhosis than in control group and higher in CCM than in non-CCM patients. One-point PWV predicted CCM and diastolic dysfunction in cirrhosis. Most importantly, its value > 1370cm/s predicted overall mortalities in decompensated cirrhosis (multivariable Cox analysis OR = 6.941) in addition to CTP score specifically in HCV related cirrhotic patients (AUC = 0.817). CONCLUSIONS: In patients with cirrhosis, 27.8% were diagnosed with CCM by resting cardiovascular parameters. One-point PWV increased in CCM, correlated with diastolic dysfunction. It also correlated with overall mortality in patients with hepatitis C virus (HCV) related decompensated cirrhosis. Further study may be needed to confirm its capability for assessing CV and mortality risks in HCV related decompensated cirrhotic patients.

Timely eradication of HCV viremia by PegIFN/RBV is crucial in prevention of post RFA recurrence in CHC-HCC patients.

BACKGROUND: Secondary prevention of hepatocellular carcinoma (HCC) among patients with chronic hepatitis C (CHC) who achieve sustained virologic response (SVR) with interferon-based therapy has been proved effective. However, tertiary prevention with PegIFN/RBV therapy of HCC recurrence seems limited effect in CHC-HCC patients post curative therapies. This study aims to investigate the timing and impact of PegIFN/RBV treatment on prevention of HCC recurrence in patients after RFA treatment. METHODS: From 2013 to 2016, a total of 137 CHC-HCC patients from a 508 patient based cohort receiving complete RFA treatment in Chang Gung Memorial Hospital, Linkou Medical Center were retrospectively recruited. Pre-RFA patient demographics were analyzed by cox regression analysis for prediction on tumor recurrence. Statistics analysis was performed with SPSS V.20 (IBM, USA). RESULTS: The mean age of the 137 patients were 69.6 year-old and 71.5% of patients were cirrhotic. After propensity score matching, one hundred and two patients were enrolled into the analysis. Fifty-one patients (50%) received PegIFN/RBV therapy and twenty-seven patients (52.9%) achieved SVR. Patients who could achieve SVR had lower tumor recurrence rate than non-SVR and untreated groups (29.6% vs. 66.7% vs. 49.0%, P = 0.030). The effect is more prominent in those achieve SVR prior to compared with after RFA despite not reach statistically significant (26.1% vs. 50.0%, P = 0.334). CONCLUSION: Timely treatment with SVR achievement has the lowest tumor recurrence rate in CHC-HCC patients. Secondary prevention might be even more important than tertiary prevention in CHC patients, especially regarding prevention of post RFA HCC recurrence.