Polygenic Risk Score Predicts Earlier-Onset Adult Systemic Lupus Erythematosus and First-Year Renal Diseases in a Taiwanese Cohort.

OBJECTIVES: This study aimed to develop a predictive model using polygenic risk score (PRS) to forecast renal outcomes for adult systemic lupus erythematosus (SLE) in a Taiwanese population. METHODS: Patients with SLE (n=2782) and matched non-SLE controls (n=11 128) were genotyped using Genome-Wide TWB 2.0 single-nucleotide polymorphism (SNP) array. PRS models (C+T, LDpred2, Lassosum, PRSice-2, PRS-continuous shrinkage (CS)) were constructed for predicting SLE susceptibility. Logistic regression was assessed for C+T-based PRS association with renal involvement in patients with SLE. RESULTS: In the training set, C+T-based SLE-PRS, only incorporating 27 SNPs, outperformed other models with area under the curve (AUC) values of 0.629, surpassing Lassosum (AUC=0.621), PRSice-2 (AUC=0.615), LDpred2 (AUC=0.609) and PRS-CS (AUC=0.602). Additionally, C+T-based SLE-PRS demonstrated consistent predictive capacity in the testing set (AUC=0.620). Individuals in the highest quartile exhibited earlier SLE onset (39.06 vs 44.22 years, p<0.01), higher Systemic Lupus Erythematosus Disease Activity Index scores (3.00 vs 2.37, p=0.04), elevated risks of renal involvement within the first year of SLE diagnosis, including WHO class III-IV lupus nephritis (OR 2.36, 95% CI 1.47 to 3.80, p<0.01), estimated glomerular filtration rate <60 mL/min/1.73m2 (OR 1.49, 95% CI 1.18 to 1.89, p<0.01) and urine protein-to-creatinine ratio >150 mg/day (OR 2.07, 95% CI 1.49 to 2.89, p<0.01), along with increased seropositivity risks, compared with those in the lowest quartile. Furthermore, among patients with SLE with onset before 50 years, the highest PRS quartile was significantly associated with more serious renal diseases within the first year of SLE diagnosis. CONCLUSIONS: PRS of SLE is associated with earlier onset, renal involvement within the first year of SLE diagnosis and seropositivity in Taiwanese patients. Integrating PRS with clinical decision-making may enhance lupus nephritis screening and early treatment to improve renal outcomes in patients with SLE.

Locoregional treatment improves overall survival for liver cancer during second-line regorafenib or immune checkpoint inhibitor.

For advanced hepatocellular carcinoma (HCC), the best second-line treatment after first-line treatment with sorafenib is unclear. This study aimed to compared the efficacy of second-line regorafenib (a tyrosine kinase inhibitor) and immune checkpoint inhibitors (ICIs) in patients with advanced HCC after sorafenib therapy. This retrospective study included 89 patients with HCC treated with sorafenib, and then regorafenib (n = 58) or an ICI (n = 31). Treatment response, overall survival (OS) and progression-free survival (PFS) of the 2 groups were compared, and factors associated with post-treatment mortality or disease progression were evaluated. During follow-up period, compared to regorafenib, treatment with an ICI results in a slight increase in a 20% decrease of AFP (35.7% vs. 31.8%), complete response rate (6.5% vs. 0%), objective response rate (16.1% vs. 6.9%), median overall survival (13.3 vs. 5 months), and median PFS (3.0 vs. 2.6 months). Combined locoregional treatment (LRT) (hazard ratio [HR] = 0.40, 95% confidence interval [CI]: 0.15-0.99) during second-line treatment was associated with a decreased risk of post-treatment mortality. After propensity scoring matching, combined LRT during second-line treatment had longer post-treatment OS than patients without combined LRT. A 20% decrease of AFP (HR = 0.54, 95% CI: 0.31-0.94) was associated with a decreased risk of post-treatment disease progression. In conclusions, second-line treatment with regorafenib or ICI prolongs OS in patients with advanced HCC treated with sorafenib. Combined LRT during second-line treatment is associated with decreased post-treatment mortality. A 20% decrease of AFP level may be predictive of a lower rate of disease progression.

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.

A Validated Composite Score Demonstrates Potential Superiority to MELD-Based Systems in Predicting Short-Term Survival in Patients with Liver Cirrhosis and Spontaneous Bacterial Peritonitis-A Preliminary Study.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a severe complication in cirrhosis patients with ascites, leading to high mortality rates if not promptly treated. However, specific prediction models for SBP are lacking. AIMS: This study aimed to compare commonly used cirrhotic prediction models (CTP score, MELD, MELD-Na, iMELD, and MELD 3.0) for short-term mortality prediction and develop a novel model to improve mortality prediction. METHODS: Patients with the first episode of SBP were included. Prognostic values for mortality were assessed using AUROC analysis. A novel prediction model was developed and validated. RESULTS: In total, 327 SBP patients were analyzed, with HBV infection as the main etiologies. MELD 3.0 demonstrated the highest AUROC among the traditional models. The novel model, incorporating HRS, exhibited superior predictive accuracy for in-hospital in all patients and 3-month mortality in HBV-cirrhosis, with AUROC values of 0.827 and 0.813 respectively, surpassing 0.8. CONCLUSIONS: MELD 3.0 score outperformed the CTP score and showed a non-significant improvement compared to other MELD-based scores, while the novel SBP model demonstrated impressive accuracy. Internal validation and an HBV-related cirrhosis subgroup sensitivity analysis supported these findings, highlighting the need for a specific prognostic model for SBP and the importance of preventing HRS development to improve SBP prognosis.

Similar efficacy and safety between lenvatinib versus atezolizumab plus bevacizumab as the first-line treatment for unresectable hepatocellular carcinoma.

BACKGROUND: Lenvatinib and atezolizumab plus bevacizumab(A + B) have been used for unresectable hepatocellular carcinoma (HCC) as first-line therapy. Real-world studies comparison of efficacy and safety in these two regimens are limited, we therefore conduct this study to investigate these issues. METHODS: We retrospectively reviewed patients received lenvatinib (n = 46) and A + B (n = 46) as first-line systemic therapy for unresectable HCC in a tertiary medical center. Objective response rate (ORR), progression free survival (PFS), and overall survival (OS) were evaluated according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Inverse probability weighting (IPW) was performed for baseline clinical features balance. RESULTS: A total of 92 patients with median age of 63.8 year-old, 78.3% male, 85.9% viral hepatitis infected, 67.4% BCLC stage C were enrolled. The median treatment and follow-up duration were 4.7 months and 9.4 months, respectively. There was no significant difference in ORR (26.1% vs. 41.3%, p = 0.1226), PFS (5.9 vs. 5.3 months, p = 0.4066), and OS (not reached vs. not reached, p = 0.7128) between the lenvatinib and A + B groups. After IPW, the results of survival and response rate were also compared. Subgroup analysis suggested that using lenvatinib was not inferior to A + B in regards of PFS, including those with elder, Child-Pugh class B, beyond up-to-seven, or portal vein invasion VP4 patients. Among the lenvatinib treated patients, multivariate analysis showed patients elder than 65-year-old was an independent predictor associated with shorter PFS (adjust HR: 2.085[0.914-4.753], p = 0.0213). The incidence rates of adverse events were similar between two groups (76 vs. 63%, p = 0.1740). Both of two regimens had similarly few impact on liver function by comparison of baseline, third month, and sixth month albumin-bilirubin index and Child-Pugh score. CONCLUSIONS: The efficacy and safety of lenvatinib are similar to A + B as a first-line systemic therapy for unresectable HCC.

Comparing Predictability of Non-invasive Tools for Hepatocellular Carcinoma in Treated Chronic Hepatitis C Patients.

BACKGROUND: Non-invasive tools including liver stiffness measurement (LSM) or FIB-4, assessed before or after direct acting antivirals (DAA), have been suggested to predict hepatocellular carcinoma (HCC). AIMS: This study aims to compare predictability of HCC by these methods at different time points, to validate the HCC surveillance suggestion by guidelines, and to propose personalized strategy. METHODS: Chronic hepatitis C whose LSM and FIB-4 were available at pretherapy and after sustained virological response (SVR) were enrolled. Advanced chronic liver disease (ACLD) was defined as pretherapy LSM ≥ 10 kPa or FIB-4 index ≥ 3.25 or ultrasound signs of cirrhosis plus platelet count < 150,000/µL. The predictabilities were compared by area under ROC. The cumulative HCC incidences were calculated by Kaplan-Meier analysis. RESULTS: Among 466 ACLD patients, 40 patients developed HCC during a follow-up duration of 26.8 months. Comparable predictive performances for HCC between LSM and FIB-4 at pretherapy and SVR were noted. By guidelines suggestion using pretherapy LSM = 10 kPa (advanced fibrosis) and 13 kPa (cirrhosis) for risk stratification, the annual HCC incidences of those with LSM of < 10, 10-12.9 and ≥ 13 kPa were 1.1, 3.6, and 5.0%, respectively. Combination of baseline LSM < 12 kPa and SVR FIB-4 < 3.7 could further stratify relatively low risk of HCC in ACLD patients of annal incidence of 1.2%. CONCLUSIONS: ACLD patients who met advanced fibrosis but not cirrhosis by guidelines' cut-offs still posed high risk of HCC. Baseline LSM with SVR FIB-4 can be applied to stratify low, intermediate, and high risk of HCC for personalizing surveillance strategies after SVR.

Serum HBcrAg and Hepatocellular Carcinoma in a Taiwanese Population Seronegative for HBsAg and Anti-HCV.

BACKGROUND & AIMS: Hepatitis B core-related antigen (HBcrAg) is a surrogate seromarker of intrahepatic hepatitis B virus covalently closed circular DNA quantity and activity and a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B patients. We assess association between HBcrAg and HCC in individuals seronegative for hepatitis B surface antigen and anti-hepatitis C virus (NBNC) in Taiwan. METHODS: A total of 129 newly developed HCC cases and 520 frequency-matched non-HCC controls were drawn from the REVEAL-NBNC cohort. Serum HBcrAg and other risk factors measured at recruitment were compared between cases and controls. Regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The proportion of baseline HBcrAg positivity (≥1000 U/mL) was significantly higher in HCC cases than in controls (12.4% vs 1.4%, P < .001). In multivariate analysis, HBcrAg positivity was associated with significantly higher risk of HCC (adjusted OR [95% CI]: 9.3 [3.3-26.4]; P < .001]. The HCC population attributable to HBcrAg positivity was 11.1% (95% CI: 9.7%-12.5%). CONCLUSIONS: Seropositivity of HBcrAg might identify a subset of the NBNC population at higher risk of HCC in hepatitis B virus endemic areas.

Combination of CRAFITY score with Alpha-fetoprotein response predicts a favorable outcome of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma.

Immune checkpoint inhibitors (ICIs) with atezolizumab plus bevacizumab are promising agents for unresectable hepatocellular carcinoma (HCC). We tried to guide the treatment based on recent developed CRAFITY score combining with on-treatment AFP response. Eighty-nine patients who received atezolizumab plus bevacizumab regardless of as a first-line therapy or not for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). The objective response rate (ORR) and disease control rate (DCR) were 25.0% and 65.5%, respectively. Multivariate analysis showed that low CRAFITY score (AFP<100 ng/ml or CRP<10 mg/l) and satisfactory AFP response at 6 weeks (≥75% decrease or ≤10% increase from baseline) were independent factors determining good overall survival (OS) (hazard ratio [HR]=0.143, P=0.002 & HR=0.337, P=0.031), progression-free survival (PFS) (HR=0.419, P=0.022 & HR=0.429, P=0.025) and good responder (odds ratio [OR]=1.763, P=0.044 & OR=3.881, P=0.011). Patients were further divided into three classes by combination of CRAFITY score and AFP response at 6 weeks [The CAR (CRAFITY score and AFP-Response) classification)]: low CRAFITY score with satisfactory AFP response at 6 weeks (class I), either high CRAFITY score or unsatisfactory AFP response at 6 weeks (class II) and high CRAFITY score together with unsatisfactory AFP response at 6 weeks (class III). ORR was 35.0%, 18.2%, and 0% in class I, II and III patients, respectively (overall P=0.034). Patients in the class I had the best OS and PFS, followed by class II and class III (median OS: not reached vs. 11.1 vs. 4.3 months, log-rank P<0.001; median PFS: 7.9 vs. 6.6 vs. 2.6 months, log-rank P=0.001). Combination CRAFITY score and AFP response at 6 weeks with AUROC predicts OS and tumor response to be 0.809 and 0.798, respectively, better than either CRAFITY score (0.771 & 0.750) or AFP response at 6 weeks (0.725 & 0.680) alone. In conclusions, the CAR classification which combining CRAFITY score and AFP response at 6 weeks provides a practical guidance for atezolizumab plus bevacizumab therapy in unresectable HCC patients.

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.

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.

Incidence of hepatocellular carcinoma in a community-based Taiwanese population without chronic HBV/HCV infection.

BACKGROUND & AIMS: In addition to HBV/HCV causing hepatocellular carcinoma (HCC), other risk factors including obesity and alcohol drinking also increase risk. We describe the cumulative risk of HCC and mortality from liver-related disease by selected modifiable risk factors among a non-hepatitis virus-infected population. METHODS: For a community-based cohort, residents aged 30-65 years living in 7 townships in Taiwan were recruited, and have been followed up since 1991. A total of 18,541 individuals were seronegative for markers of chronic infection of HBV/HCV and with no history of HCC at baseline. New non-HBV/HCV HCC cases and liver-related deaths were ascertained through data linkage to the National Cancer Registry and Death Certification System from 1 January 1991 through 31 December 2017. RESULTS: There were 207 HCC cases and 215 liver-related deaths identified. The incidence rate of non-HBV/HCV HCC was 47.2 per 100,000 person-years. The mortality rate of liver-related death was 49.0 per 100,000 person-years. Baseline information on alcohol consumption, heart disease, diabetes, elevated aspartate aminotransferase, and alanine aminotransferase predicted higher risks of HCC, with hazard ratios (HRs) (95% CIs) of 1.7 (1.1-2.5), 2.2 (1.1-4.1), 1.9 (1.0-3.5), 1.7 (1.1-2.4), and 1.6 (1.0-2.4), respectively. The HRs (95% CIs) of liver-related death were 2.3 (1.6-3.2) for alcohol consumption, 1.4 (1.1-1.9) for BMI ≥25 kg/m2, 2.2 (1.4-3.3) for elevated aspartate aminotransferase, and 1.5 (1.0-2.4) for elevated alanine aminotransferase. The HR (95% CI) was 8.1 (3.6-18.5) for those with diabetes and elevated aspartate aminotransferase. CONCLUSIONS: Individuals with elevated liver enzymes are at high risk of liver disease. Prevention and treatment of diabetes and heart disease are critical for non-hepatitis B, non-hepatitis C (NonB/C)-HCC. LAY SUMMARY: We followed up individuals with no chronic HBV or HCV infection and described the risk of hepatocellular carcinoma (HCC, the most common form of primary liver cancer) and mortality from liver-related disease by modifiable risk factors. This study estimated the incidence rate of HCC by selected lifestyle risk factors and chronic diseases conditions. Alcohol consumption, heart disease, diabetes, and abnormal blood liver function tests showed a strong association with HCC risk and mortality.

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.

Liver resection for hepatocellular carcinoma larger than 10 cm: A multi-institution long-term observational study.

BACKGROUND: The treatment of hepatocellular carcinoma (HCC) ≥ 10 cm remains a challenge. AIM: To consolidate the role of surgical resection for HCC larger than 10 cm. METHODS: Eligible HCC patients were identified from the Chang Gung Research Database, the largest multi-institution database, which collected medical records of all patients from Chang Gung Memorial Foundation. The surgical outcome of HCC ≥ 10 cm (L-HCC) was compared to that of HCC < 10 cm (S-HCC) (model 1). The survival of L-HCC after either liver resection or transarterial chemoembolization (TACE) was also analyzed (model 2). The long-term risks of all-cause mortality and recurrence were assessed to consolidate the role of surgery for L-HCC. RESULTS: From January 2004 to July 2015, a total of 32403 HCC patients were identified from the Chang Gung Research Database. Among 3985 patients who received liver resection, 3559 (89.3%) had S-HCC, and 426 had L-HCC. The L-HCC patients had a worse disease-free survival (0.27 for L-HCC vs 0.40 for S-HCC) and overall survival (0.18 for L-HCC vs 0.45 for S-HCC) than the S-HCC after liver resection (both P < 0.001). However, the surgical and long-term outcome of resected L-HCC had improved dramatically in the recent decades. After adjusting for covariates, surgery could provide a better outcome for L-HCC than TACE (adjusted hazard ratio of all-cause mortality: 0.46, 95% confidence interval: 0.38-0.56 for surgery). Subgroup analysis stratified by different stages showed similar trend of survival benefit among L-HCC patients receiving surgery. CONCLUSION: Our study demonstrated an improving surgical outcome for HCC larger than 10 cm. Under selected conditions, surgery is better than TACE in terms of disease control and survival and should be performed. Due to inferior survival, a subclassification within T1 stage should be considered. Future studies are mandatory to confirm our findings.

Switching monopolar radiofrequency ablation improves long-term outcomes of medium-sized hepatocellular carcinoma.

OBJECTIVES: Radiofrequency ablation (RFA) of medium-sized (3-5 cm) hepatocellular carcinoma (HCC) is suboptimal. Switching monopolar RFA (SW-RFA) enlarges the ablative volume to better cover larger tumors. This study aims to compare the long-term outcomes of medium-sized HCC treated by either SW-RFA or single-monopolar RFA (S-RFA). METHODS: We retrospectively reviewed 139 cases (147 medium-size HCC) between 2008 and 2014. Under propensity score matching, a total of 43 paired patients with medium-size HCC and balanced clinical variables treated by either SW-RFA or S-RFA were selected for comparison. RESULTS: SW-RFA showed a higher rate of achieving an adequate safety margin (p = 0.002). After a mean follow-up period of 40.4 months, SW-RFA produced significantly lower global RFA failure rates (p < 0.001) and better overall survival (p = 0.005) compared to S-RFA. SW-RFA was independently associated with a decreased risk of global RFA failure (hazard ratio [HR]: 0.136, 95% confidence interval [CI]: 0.030-0.607, p = 0.009) and improved overall survival (HR: 0.337, 95% CI: 0.152-0.747, p = 0.007). By last follow-up, the SW-RFA group maintained a superior tumor-free rate (p = 0.010) and fewer progressions to Barcelona Clinic Liver Cancer stage C (p = 0.011). Major complication rates were comparable in both groups (SW-RFA: 2.3% vs. S-RFA: 4.7%, p = 1.000). CONCLUSIONS: The switching multi-monopolar ablation technique could be beneficial for patients with medium-sized HCCs given sustained control of larger tumors with better overall survival. KEY POINTS: • Switching monopolar ablation could provide a sustained local tumor control and better overall survival than single-monopolar ablation for the medium-sized hepatocellular carcinoma. • Compared to single-monopolar ablation, switching monopolar ablation could create a larger homogeneous coagulation volume by using a shorter total ablation time to achieve a higher rate of adequate safety margin for a medium-sized HCC. • Patients with medium-sized HCC can be maintained at a higher rate of tumor-free status and at a lower risk of progression into BCLC stage C in the follow-up period after ablation by switching monopolar than by single-monopolar ablation.

Real-time virtual sonography-assisted radiofrequency ablation in liver tumors with conspicuous or inconspicuous images or peritumoral landmarks under ultrasonography.

OBJECTIVES: The objectives of this study were to determine the primary technique effectiveness (PTE), to compare the complete response and local recurrence rates between conspicuous and inconspicuous tumors using single and switching electrodes of real-time virtual sonography (RVS)-assisted radiofrequency ablation (RFA) in conspicuous and inconspicuous hepatic tumors under conventional ultrasonography (US). SUBJECTS AND METHOD: We compared the complete ablation of inconspicuous tumors with and without anatomical landmark (N = 54) with conspicuous liver tumors (N = 272). Conventional US imaging was done initially, and then these images were fused with CT or MRI arterial-venous-wash-out cross-sectional studies and synchronized with real-time US images. RESULTS: RVS-assisted RFA was technically feasible in all patients. The PTE rate after the first ablation was 94% (245/261) for conspicuous tumors, 88% (7/8) in inconspicuous tumors with landmark, and 78% (36/46) in inconspicuous tumors without landmark. The complete response (p = 0.1912 vs. p = 0.4776) and local recurrence rate (p = 0.1557 vs. p = 0.7982) were comparable in conspicuous tumors of both HCC and liver metastasis group when single or multiple switching was used. The cumulative local recurrence in the conspicuous and inconspicuous tumors of the HCC group (p = 0.9999) was almost parallel after 12 (10% vs. 4%) and 24 (13% vs. 4%) months of follow-up. In the liver metastasis group, the cumulative local recurrence for conspicuous tumors (p = 0.9564) was nearly equal after 12 and 24 months of monitoring (24% vs. 27%) while no recurrence was incurred for the inconspicuous tumors. CONCLUSION: RVS-assisted RFA is an effective tool for the treatment of conspicuous and inconspicuous HCC and hepatic metastasis.

Incidence and predictors for abnormal liver function during direct-acting antiviral agents in chronic hepatitis C patients.

Abrupt alanine aminotransferase (ALT) elevation during direct-acting antiviral agents (DAA) treatment is an uncommon but noticeable adverse event in chronic hepatitis C (CHC) patients, which may lead to early termination of treatment. This study aims to investigate the incidence, outcome and predictors of the on-treatment ALT elevation during DAA therapy.CHC patients treated with DAA regimen in Chang Gung Memorial Hospital, Linkou branch during March 2015 to March 2019 were recruited. Prospective scheduled ALT assessment at baseline, 2nd, 4th, 8th, and 12th/24th weeks were recorded. Pretherapy host and viral factors were compared between patients with and without on-treatment ALT elevation. Multivariate logistic regression was used for independent factors for on-treatment ALT elevation.A total of 1563 CHC patients treated with grazoprevir/elbasvir, glecaprevir/pibrentasvir and sofosbuvir-based regimen were analyzed. On-treatment ALT elevation occurred in 10.9% patients while those treated with glecaprevir/pibrentasvir had the least possibility (5.4%). Only 1.4% patients had ≥grade 3 ALT elevation events. The presence of such events had no impact on sustained virological response 12 rates. Hepatitis B virus coinfection (aOR: 3.599, P < 0.001) and higher pretherapy ALT (1-5x, ≥5x upper limit of normal: aOR: 2.632, P = 0.024, aOR: 4.702, P = .011, respectively) were significant predictors for ALT elevation.On-treatment ALT elevation occurred in one-tenth CHC patients treated with preferred DAAs but had no impact on sustained virological response rate.

Serum metabolites may be useful markers to assess vascular invasion and identify normal alpha-fetoprotein in hepatocellular carcinoma undergoing liver resection: a pilot study.

PURPOSE: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a dismal prognosis. Vascular invasion, among others, is the most robust indicator of postoperative recurrence and overall survival after liver resection for HCC. Few studies to date have attempted to search for effective markers to predict vascular invasion before the operation. The current study would examine the plasma metabolic profiling via 1H-NMR of HCC patients undergoing liver resection and aim to search for potential biomarkers in the early detection of HCC with normal alpha-fetoprotein (AFP) and the diagnosis of vascular invasion preoperatively. MATERIALS AND METHODS: HCC patients scheduled to receive liver resections for their HCC were recruited and divided into two separate groups, investigation cohort and validation cohort. Their preoperative blood samples were collected and subjected to a comprehensive metabolomic profiling using 1H-nuclear magnetic resonance spectroscopy (NMR). RESULTS: There were 35 HCC patients in the investigation group and 22 patients in the validation group. Chronic hepatitis B remained the most common etiology of HCC, followed by chronic HCV infection. The two study cohorts were essentially comparable in terms of major clinicopathological variables. After 1H-nuclear NMR analysis, we found in the investigation cohort that HCC with normal alpha-fetoprotein (AFP < 15 ng/mL) had significantly higher serum level of O-acetylcarnitine than those with higher AFP (AFP ≥ 15 ng/mL, P = 0.025). In addition, HCC with microscopic vascular invasion (VI) had significantly higher preoperative serum level of formate than HCC without microscopic VI (P = 0.023). These findings were similar in the validation cohort. CONCLUSION: A comprehensive metabolomic profiling of HCC demonstrated that serum metabolites may be utilized to assist the early diagnosis of AFP-negative HCC patients and recognition of microvascular invasion in order to facilitate preoperative surgical planning and postoperative follow-up. Further, larger scale prospective studies are warranted to consolidate our findings.

Real-world experience of elbasvir/grazoprevir in Taiwan: This study was focused on liver and renal adverse effects.

Elbasvir/grazoprevir with or without ribavirin has excellent efficacy and safety for the treatment of hepatitis C virus (HCV) genotype 1 and 4 patients. The real-world experience has been reported but the detailed analysis of liver and renal adverse effects is lacking. This study evaluated the real-world experience relating to the effectiveness and liver/renal safety of elbasvir/grazoprevir in HCV genotype 1 patients with compensated liver disease. In the four medical centres of Chang Gung Medical System, 350 HCV genotype 1 patients with compensated liver disease who were treated with elbasvir/grazoprevir were enrolled. Clinical characteristics and laboratory data were collected. The effectiveness (sustained virologic response 12 weeks after end of treatment, SVR12) and safety were assessed. A consecutive series of 350 patients with a mean age of 68.8 ± 10.0 years old were enrolled. The majority were treatment-naïve (72.3%), genotype 1b (97.7%) and advanced fibrosis/cirrhosis (94.3%). Seventy-nine (22.6%) had hepatocellular carcinoma and 23 (6.6%) had coinfection with hepatitis B. The effectiveness of SVR12 was 94.6% (95% CI: 92.2%-97.0%) in the full analysis set and 99.1% (95% CI: 98.1%-100.1%) in the per-protocol set. There were two relapses and one nonresponder. Seven (2.0%) patients had adverse events resulting in premature discontinuation of treatment. Five of them were considered drug-related. One was due to autoimmune hepatitis. Contrary to previous reports, around 49% of ALT elevation was observed after 8 weeks, and in two patients was due to hepatitis B flares. As to the renal function during the course of therapy, a minor deterioration of eGFR was observed in patients with baseline eGFR ≥60 mL/min/1.73 m2 , but not in those with baseline eGFR <60, <60-30 or <30 mL/min/1.73 m2 . In this real-world data, elbasvir/grazoprevir was effective with few liver/renal adverse effects. One patient developed autoimmune hepatitis.

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.