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BACKGROUND AND AIM Size and number are major determinants of tumor burden in hepatocellular carcinoma (HCC). Patients with HCC undergoing transarterial chemoembolization (TACE) have variable outcomes due to heterogeneity of tumor burden. Recently, tumor burden score (TBS) was proposed to evaluate the extent of tumor involvement. However, the prognostic accuracy of TBS has not been well evaluated in HCC. This study aimed to assess its prognostic role in HCC patients undergoing TACE. METHODS A total of 935 treatment-naive HCC patients receiving TACE were retrospectively analyzed. Multivariate Cox proportional hazards model was used to determine independent prognostic predictors. RESULTS Tumor burden score tended to increase with increasing size and number of tumors in study patients. The Cox model showed that serum creatinine ≥ 1.2 mg/dL (hazard ratio [HR]: 1.296, 95% confidence interval [CI]: 1.077-1.559, P = 0.006), serum α-fetoprotein ≥ 400 ng/dL (HR: 2.245, 95% CI: 1.905-2.645, P

BACKGROUND Liver functional reserve is a major prognostic determinant in patients with hepatocellular carcinoma (HCC). The albumin-bilirubin (ALBI) score is an objective method to assess the severity of cirrhosis in this setting. However, calculation of the ALBI score is complex and difficult to access in clinical practice. Recently, the EZ (easy)-ALBI score was proposed as an alternative biomarker of liver injury. We aimed to evaluate the prognostic role of the EZ-ALBI score in HCC from early to advanced stages. METHODS A total of 3794 newly diagnosed HCC patients were prospectively enrolled and retrospectively analyzed. Independent prognostic predictors were determined by using the multivariate Cox proportional hazards model. RESULTS The EZ-ALBI score showed good correlation with the ALBI score (correlation coefficient, 0.965; p 65 years, male sex, serum α-fetoprotein >20 ng/ml, large or multiple tumors, total tumor volume >100 cm3 , vascular invasion or distant metastasis, ascites, poor performance status, EZ-ALBI grade 2 and 3, and noncurative treatments were independently associated with increased mortality (all p

BACKGROUND: Patients with hepatocellular carcinoma (HCC) may develop end-stage renal disease and receive dialysis, but the impact of dialysis on the prognosis is unclear. This study aimed to evaluate the outcome of dialysis HCC patients and the prognostic role of albumin-bilirubin (ALBI) grade in these patients. METHODS: Among the consecutive 3,794 HCC patients between 2002–2017, 43 patients undergoing dialysis, and 129 age, sex-matched controls were analyzed. Multivariate Cox hazards model was used to identify independent prognostic predictors. RESULTS: Dialysis patients had decreased overall survival when compared with non-dialysis patients (n=3,751) and matched controls (n=129; each P=0.004). Patients with ALBI grade 1 had the best survival in the pooled cohort of dialysis and matched controls (n=172). In the Cox model, total tumor volume >33 cm(3) [hazard ratio (HR): 6.763, P

BACKGROUND/AIM: Patients with cirrhosis have poor outcomes once decompensation occurs; however, we lack adequate predictors of decompensation. To use a national claim database to compare the predictive accuracy of seven models for decompensation and hospitalization in patients with compensated cirrhosis. METHODS: We defined decompensation as ascites, hepatic encephalopathy, hepato-renal syndrome, and variceal bleeding. Patients without decompensation at the time of cirrhosis diagnosis were enrolled from 2001 to 2015. Patients with hepatitis B and/or C were grouped as viral cirrhosis. We compared the predictive accuracy of models with the AUC (area under the curve) and c-statistic. The cumulative incidence of decompensation and incidence risk ratios of hospitalization were calculated with the Fine–Gray competing risk and negative binomial models, respectively. RESULTS: A total of 3722 unique patients were enrolled with a mean follow-up time of 524 days. The mean age was 59 (standard deviation 12), and the majority were male (55%) and white (65%). Fifty-three percent of patients had non-viral cirrhosis. Sixteen and 20 percent of patients with non-viral and viral cirrhosis, respectively, developed decompensation (P = 0.589). The FIB-4 model had the highest 3-year AUC (0.73) and overall c-statistic (0.692) in patients with non-viral cirrhosis. The ALBI-FIB-4 model had the best 1-year (AUC = 0.741), 3-year (AUC = 0.754), and overall predictive accuracy (c-statistic = 0.681) in patients with viral cirrhosis. The MELD score had the best predictive power for hospitalization in both non-viral and viral patients. CONCLUSIONS: FIB-4-based models provide more accurate prediction for decompensation, and the MELD model has the best predictive ability of hospitalization.

Background Gene therapy is the advanced therapeutics for supplying or replacing the genetic material in patients with inherited disorders. Recent clinical studies have made some progress in a wide range of applications, including monogenic disorders, neurodegenerative diseases, malignant tumors, and congenital diseases. Heart diseases, especially myocardial ischemia, remain one of the leading causes of mortality worldwide and usually result in irreparable cardiomyocyte damage and severe heart failure. Methods Most advances in induced pluripotent stem cell (iPSC) technologies for promoting regenerative medicine and stem cell research. However, the driver molecules of myocardial-lineage differentiation and the functional reconstruction capacity of iPSC-derived cardiomyocytes are still an open question. Nanomedicine-based gene delivery provided a crucial platform to carry on the biogenomic materials for equipping functionalities and engineering the living organ environment. Nanodiamond (ND), a carbon-based nanomaterial, has been discovered and shown the high biocompatible and less toxicity for transporting protein, drug, and genomic plasmids. Results Here, we applied ND as a gene delivery vehicle to carry microRNA (miR-181a), and then transfected into iPS to promote cardiomyocyte-lineage differentiation. Notably, miR-181a plays a key role in iPS-derived cardiomyocyte differentiation which directly targets Hox-A11, leading to elevated MyoD expression and enhanced cardiomyocyte differentiation. Conclusion Our study demonstrated that miR-181a promotes iPSC differentiation into functional cardiomyocytes. Delivery of NANO-DIAMOND-miR-181a may host clinical potential to enhance the differentiation and recovery of the cardiogenic function in injured cardiomyocytes.

Background Age-related macular degeneration (AMD) is one of the leading causes of vision loss. Once the retinal pigment epithelium (RPE) layers are destroyed, the poor visual acuity and recognition are generally irreversible. Cell therapy that possesses enormous potential in regenerative medicine may provide an alternative treatment for several incurable diseases such as AMD. In this study, we developed an innovative polydimethylsiloxane (PDMS)-based biomimetic scaffolds with cylinder micropillars for the cultivation of induced pluripotent stem cell-derived RPEs (iPSC-RPEs). RPEs were cultured on the PDMS-based biomimetic scaffolds and validated the cells gene expression. Methods The biomimetic PDMS scaffold was fabricated through spin coating and lithography method. It was further modified on surface with biomolecules to improve cell affinity and stability. The iPSC-RPEs were seeded on the scaffold and analyzed with characteristic gene expression. Results PDMS biomimetic scaffold was analyzed with Fourier transform infrared spectroscopy and proved its chemical composition. iPSC-RPEs demonstrated confluent cell monolayer on the scaffold and maintained RPE-specific gene expression, which proved the PDMS-based biomimetic scaffold to be supportive for iPSC-RPEs growth. Conclusion The PDMS interface allowed regular growth of iPSC-RPEs and the design of cylinder micropillars further provided the bioscaffold high motion resistance may improve the engraftment stability of iPSC-RPEs after transplantation. Taken together, this innovative PDMS-based biomimetic scaffold may serve as an ideal interface for in vitro iPSC-RPE cultivation and subsequent transplantation in vivo. This novel device exhibits better bioavailability than conventional injection of donor cells and may be an alternative option for the treatment of AMD.

BACKGROUND & AIMS: Thrombocytosis is associated with more aggressive tumour biology in many malignancies. There are limited data in patients with hepatocellular carcinoma (HCC), which often occurs in patients with cirrhosis and portal hypertension. We aimed to explore the prognostic value of thrombocytosis in two cohorts of patients with HCC. METHODS: We included 3561 patients from Taiwan and 1145 patients from the USA. Thrombocytopenia was defined as platelet count < 150×10(9)/L and thrombocytosis as ≥ 300 × 10(9)/L at HCC diagnosis. We used multivariable Cox proportional hazard models to identify independent predictors of survival. RESULTS: Thrombocytosis was present in 9.0% and 6.9% of Taiwan and USA patients respectively. Compared to patients with normal platelet counts and those with thrombocytopenia, patients with thrombocytosis had larger tumours, increased vascular invasion and a higher proportion had extrahepatic metastases in both cohorts. In multivariable analysis, thrombocytosis (aHR 1.40, 95% CI 1.23–1.60) and thrombocytopenia (aHR 1.13, 95% CI 1.04–1.23) were both associated with worse survival after adjusting for age, gender, liver disease aetiology, Child-Pugh score, maximal tumour size, tumour nodularity, vascular invasion, lymph node or distant metastasis, performance status and alpha-fetoprotein level. Patients with thrombocytosis had a median survival of 6 and 4 months in the Taiwan and USA cohorts, compared to 32 and 14 months for those with normal platelet counts and 38 and 16 months for thrombocytopenic patients. CONCLUSION: Thrombocytosis is independently associated with increased tumour burden and worse overall survival among HCC patients.

OBJECTIVE The use of nonselective beta blockers in cirrhotic patients experiencing complications is controversial. We aimed to investigate the association between propranolol treatment and outcomes for cirrhotic patients with hepatic encephalopathy. METHODS Using data from the Taiwan National Health Insurance Research Database, we identified 4754 cirrhotic patients newly diagnosed with hepatic encephalopathy between 2001 and 2010. Among them, 519 patients received propranolol treatment and the other 519 patients without exposure to propranolol were enrolled into our study, both of which were matched by sex, age, and propensity score. The Kaplan-Meier method and time-dependent-modified Cox proportional hazards models were employed for survival and multivariate-stratified analyses. RESULTS The median overall survival (OS) was significantly longer in the propranolol-treated cohort than in the untreated cohort (3.46 versus 1.88 years, P

Background/Purpose: Whether esophagogastric varices (EGV) can determine the outcome of patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) remains unknown. This study aimed to assess the impact of EGV on the prognosis of HCC patients after TACE. Methods: From 2007 to 2012, we retrospectively enrolled 251 treatment-naïve HCC patients who underwent TACE and received esophagogastroduodenoscopy when HCC was diagnosed. The prognostic factors were analyzed using a Cox proportional hazards model and propensity score-matching analysis. Results: There were 120 (47.8%) patients with EGV. Compared to those without EGV, patients with EGV had worse liver functional reserve. After a median follow-up of 14.7 months (25th–75th percentiles, 6.4–35.6 months), 152 patients died. The cumulative 5-year overall survival (OS) rates were 11.2% and 38.8% in patients with and without EGV, respectively (p 5 cm, serum alpha-fetoprotein >20 ng/mL, progressive disease by modified Response Evaluation Criteria in Solid Tumors, Assessment for Retreatment with TACE score ≥2.5, and higher albumin-bilirubin grades were the independent predictors of poor OS. Subgroup analysis also demonstrated that EGV was associated with poor OS in most of the subgroups. After propensity score matching, the EGV group still had a lower OS rate than their counterparts (p = 0.004). Conclusion: HCC patients with EGV had worse liver functional reserve compared to those without EGV. Moreover, EGV was an independent risk factor to predict poor prognosis in patients with HCC after TACE. Keywords: Hepatocellular carcinoma, Esophageal varices, Prognosis, Cirrhosis

Diabetes mellitus (DM) is common in patients with hepatocellular carcinoma (HCC) and may impact survival. Very few studies focused on the influence of DM in different clinical scenarios. We evaluated the prognostic impact of DM on HCC patients stratified by liver dysfunction, Milan criteria, and performance status defined in the Barcelona Clinic Liver Cancer staging parameters. A prospective dataset of 3573 HCC patients between 2002 and 2016 was retrospectively analyzed. The multivariate Cox proportional hazards model was used to identify independent prognostic predictors. The Kaplan–Meier method with a log-rank test was applied to compare the survival distributions between different patient groups. Among all, DM was not an independent prognostic predictor in the Cox multivariate analysis (p = 0.1044). In the subgroup analysis, DM was not a significant prognostic predictor in Child–Turcotte–Pugh class A or class B/C patients. However, DM was associated with a decreased survival in patients within the Milan criteria (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.155–1.601, p = 0.0002) and in those with the performance status 0 (HR 1.213, 95% CI 1.055–1.394, p = 0.0067) in the multivariate Cox analysis, but not in those beyond the Milan criteria and poor performance status. DM is highly prevalent in HCC patients and has a distinct survival impact. DM is an independent survival predictor among patients within the Milan criteria and good performance status. These high-risk patients should be closely monitored, and aggressive anticancer treatment should be considered.

Background/Purpose: The risk of recurrence after resection of hepatocellular carcinoma (HCC) is high. Apart from nucleos(t)ide analogues therapy, population-based studies suggest statin, nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin have chemopreventive effect on recurrence. The role of those drugs on HCC recurrence should be delineated. Methods: Consecutive 430 hepatitis B surface antigen (HBsAg)-positive patients undergoing curative resection of HCC were enrolled. The detailed medical records including the use of statin, NSAID and aspirin were reviewed. All the patients had regular image study surveillance after the surgery. Predictors associated with recurrence were analyzed by Cox's proportional hazards models. Results: There were 58.8% patients in Barcelona Clinic Liver Cancer (BCLC) stage A, and 37.6% had severe liver fibrosis or cirrhosis. Of them, 47 (10.9%) patients had received potential chemoprophylactic agents either at the time of HCC diagnosis or before their HCC recurrence. During a median 50.3 months of follow-up, 54.7% patients experienced recurrence. The median time to recurrence was 15.4 months. In the univariate analysis, aspirin and statins use were significantly associated a low risk of recurrence (hazard ratio [HR]: 0.18; p = 0.016, and HR: 0.50; p = 0.031, respectively). After adjusting competing factors, large tumor size, severe liver fibrosis, and high alpha-fetoprotein (AFP) level were significantly associated with recurrence. Importantly, aspirin use was found to significantly decrease the risk for HCC recurrence with the adjusted HRs of 0.22–0.24 based on the models. Conclusion: Aspirin use may have chemo-preventive effect on recurrence of hepatitis B virus-related HCC after curative resection. Keywords: Aspirin, HBV, HCC, Recurrence, Resection

Background: We developed an easy and minimally invasive method of transmeatal tympanoplasty using meatal areolar tissue (MAT) grafts to achieve less postoperative morbidity or surgical scarring. We compared the functional and anatomical results of the developed method with conventional endaural tympanoplasty with a temporalis fascia (TF) graft. Methods: In this retrospective cohort study, 58 patients (59 ears) with simple chronic otitis media who underwent type I tympanoplasty between January 2016 and August 2018 were included. All surgeries were performed in a tertiary referral hospital and by the same senior surgeon. The tympanic membrane (TM) was repaired with either a TF or an MAT graft. Results: Healing of the perforated TM and improvement in a hearing test by air-bone gap (ABG) closure were identified. Postoperative wound conditions were also evaluated. Twenty-eight ears were grafted with MAT, and 31 ears were grafted with TF. Graft success was observed in 26 patients (92.9%) in the MAT group and 28 patients (90.3%) in the TF group. Both groups showed functional improvement compared with the preoperative measurements. The postoperative pure tone audiogram (p = 0.737), ABG closure (p = 0.547), and graft success rate (p = 0.726) were not significantly different between the two groups. Neither wound dehiscence nor keloid formation was observed in our patients. Conclusion: Both MAT and TF grafts revealed satisfactory surgical and functional results. Compared with the conventional endaural approach with TF grafts, the new transmeatal approach method with an MAT graft causes relatively minimal trauma and results in better wound cosmetics. This method represents an easy, minimally invasive surgery and shows comparatively good results.

Background Tumor size and numbers are major determinants of tumor burden in hepatocellular carcinoma (HCC). Patients with HCC undergoing transarterial chemoembolization (TACE) have variables outcomes due to heterogeneity of tumor burden. Recently, tumor burden score (TBS) was proposed to evaluate the extent of tumor involvement. However, the prognostic accuracy of TBS has not been evaluated in HCC. This study aimed to assess its prognostic role in HCC patients undergoing TACE. Methods A total of 935 treatment-naive HCC patients receiving TACE were retrospectively analyzed. Multivariate Cox proportional hazard model was used to determine independent prognostic predictors.TBS was defined as the distance from the origin of the Cartesian plane and the comparison of two variables: maximum tumor size (X-axis) and number of tumors (Y-axis) so that TBS2=(maximum tumor diameter)2+ (number of tumors)2. Patients have divided accordingly into three groups:high TBS (over 13.74), medium TBS (3.36-13.74),and low TBS (less than 3.36). Results TBS tended to increase with the increasing size and number of tumors in this study (IDDF2021-ABS-0071 Figure 1. The association of TBS with tumor diameter and numbers).The Cox model showed that serum creatinine ≥1.2mg/dl (hazard ratio(HR):1.296,95% confidence interval(CI):1.077-1.559,p=0.006), serum α-fetoprotein≥400ng/dl(HR:2.245,95%CI:1.905-2.465, p Conclusions TBS is a feasible new prognostic surrogate marker of tumor burden in HCC and can well discriminate survival in patients undergoing TACE across different baseline characteristics.

Sodium glucose cotransporter-2 inhibitors (SGLT2i), a novel antidiabetic drug blocks the reabsorption of glucose in proximal tubules of kidney, are demonstrated to have cardiovascular and renal benefits for people with diabetes. The benefits are associated with the significant increase of intrarenal angiotensin-converting enzyme II (ACE2) expression and blood volume contraction. However, the increased ACE2 may be detrimental to patients infected with the coronavirus infection 2019 (COVID-19), which is found to invade cells via the entry receptor of ACE2. Besides, an SGLT2i-induced natriuretic effect may also increase the risk of acute kidney injury and affect the hemodynamic stability during systemic infection disease. In this article, we explain the mechanisms why the use of SGLT2i in people with diabetes may lead to worse outcomes and suggest clinician to judiciously use it during COVID-19 pandemic.

Hepatitis C virus (HCV) infection is the major etiology for cirrhosis and hepatocellular carcinoma (HCC). The severity of liver fibrosis is a crucial factor in prognostic prediction. We aimed to evaluate the prognostic role of Metavir fibrosis stage in HCV-related HCC and its association with noninvasive liver reserve models. Between 2004 and 2016, 172 patients with HCV-related HCC undergoing surgical resection were enrolled. Multivariate Cox proportional hazards model was used to identify prognostic predictors. The area under receiver operating curve (AUROC) was used for comparison in predicting cirrhosis among different noninvasive liver reserve models. In the multivariate Cox analysis, AST > 45 IU/mL, multiple tumors, tumor size greater than 3 cm, and serum AFP > 20 ng/mL were independent risk factors linked with tumor recurrence. There was no significant association between Metavir fibrosis stage/ inflammatory activity and tumor recurrence. In the Cox model, Child-Turcotte-Pugh class B, tumor size greater than 3 cm, and Metavir fibrosis stage F3-F4 were independent predictors associated with decreased survival (all p 3 cm) HCC group. Among the noninvasive models, FIB-4 had the highest predictive accuracy (AUROC = 0.768, p

The Milan criteria are recommended as the major reference for liver transplantation in patients with small hepatocellular carcinoma (HCC). However, alternative anticancer treatments are often utilized due to severe donor organ shortage. This study aimed to develop and validate an albumin-bilirubin (ALBI) grade-based prognostic model to stratify survival in patients within Milan criteria undergoing nontransplant therapy.A total of 1655 patients were assigned into the derivation and validation cohort according to treatment modalities. Multivariate analysis was used to identify independent predictors of survival in the derivation cohort. An ALBI-based model was evaluated in the validation cohort.In the Cox multivariate model, age 65 years or older (hazard ratio [HR]=1.576, P0.001), serum α-fetoprotein (AFP) level100 ng/mL (HR=1.671, P0.001), ascites (HR=1.808, P0.001), performance status 1 to 4 (HR=1.738, P0.001), ALBI grade 2 (HR=1.827, P0.001), and ALBI grade 3 (HR=3.589, P0.001) were independent predictors of poor survival in the derivation cohort. An ALBI-based prognostic model with a total of 0 to 6 points was derived with the sum of 5 variables: 1 point each for age 65 years or older, AFP100 ng/mL, presence of ascites, performance status 1 to 4, and ALBI grade 2, and 2 points for ALBI grade 3. This model can accurately predict long-term outcome in the validation cohort (P0.001) and discriminate survival in patients stratified by curative and noncurative treatments (both P0.001).The proposed ALBI grade-based model is feasible in predicting survival in HCC patients within the Milan criteria, and helps identify high-risk patients who need timely liver transplantation.

BACKGROUND & AIMS Transarterial chemoembolization (TACE) is a standard treatment for Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC), but the outcome varied. This study aimed to develop a model to predict the outcome of TACE in HCC patients. METHODS Consecutive 570 treatment-naive BCLC stage B HCC patients undergoing TACE as the initial treatment from 2007 to 2016 were retrospectively enrolled. Factors associated with survival were analysed. Patients undergoing TACE from 2007 to 2011 constituted the training cohort (n = 293), while patients undergoing TACE from 2012 to 2016 constituted the validation cohort (n = 277). Homogeneity and corrected Akaike information criterion (AICc) were compared between each prognostic model. RESULTS A total of 1796 TACE sessions were performed for the 570 patients during the median follow-up period of 18.3 months. By multivariate analysis, beyond up-to-11 criteria (hazard ratio [HR] = 1.694, P 200 ng/mL (HR = 1.771, P

Background Tumor recurrence after curative resection is common in hepatocellular carcinoma (HCC), but large-scale long-term prediction on an individual basis has seldom been reported. We aimed to construct an albumin-bilirubin (ALBI) grade-based nomogram to predict tumor recurrence in patients with HCC undergoing surgical resection. Methods A total 1038 patients with newly diagnosed HCC undergoing curative resection between 2002 and 2016 were enrolled. Baseline characteristics, tumor status and severity of liver functional reserve were collected. The Cox proportional hazards model was used to predict tumor recurrence and construct the nomogram. The performance of the nomogram was evaluated by the discrimination and calibration tests. Results After a mean follow up time of 30 months, 510 (49%) patients developed tumor recurrence. The cumulative recurrence-free survival at 1, 3, 5, and 10 years were 79%, 51%, 38% and 26%, respectively. In the Cox multivariate model, ALBI grade 2–3, multiple tumors, tumor size equal or large than 2 cm, serum ɑ-fetoprotein level equal or greater than 20 ng/ml and total tumor volume equal or larger than 227 cm3 were independent risk factors associated with tumor recurrence. A nomogram was constructed based on these five variables. Internal validation with 10,380 bootstrapped sample sets had a good concordance of 0.607 (95% of confidence interval: 0.587–0.627). The calibration plots for 1-, 3- and 5-year recurrence-free survival well matched the idealized 45-degree line. Conclusions ALBI is a feasible marker for tumor recurrence. This easy-to-use ALBI grade-based nomogram may predict tumor recurrence for individual HCC patient undergoing surgical resection.

Researchers have hypothesized that the long-term use of proton pump inhibitors (PPIs) can increase the risk of developing cancer. However, the association between PPI use and hepatocellular carcinoma (HCC) risk is unclear. Using data from the Taiwan National Health Insurance Research Database for the period between 2003 and 2013, we identified 35,356 patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. One-to-one propensity score matching by gender, age, cohort entry year, comorbidity, and medication resulted in the inclusion of 7,492 pairs of patients (PPI users and non-PPI users) for analyses. We performed multivariate and stratified analysis using the Kaplan-Meier method and Cox proportional hazards models in order to estimate the association between PPI use and the risk of developing HCC. In the HBV cohort, 237 patients developed HCC during a median follow-up of 53 months. However, PPI use was not associated with an increased risk of developing HCC (adjusted hazard ratio [aHR], 1.25; 95% confidence interval [CI], 0.90-1.73; P = 0.18). In the HCV cohort, 211 patients developed HCC; but again, PPI use was not associated with an increase in the risk of developing HCC (aHR, 1.19; 95% CI, 0.88-1.61; P = 0.25). We observed no relationship between a dose-dependent effect of PPI use and HCC risk. Subgroup analysis also confirmed that PPI use was not correlated to an increased HCC risk. Conclusion: Based on a retrospective population-based cohort study throughout Taiwan, where the prescription of PPI is tightly regulated, PPI use is not associated with the risk of developing HCC among patients with chronic HBV or HCV infections.

Toll-like receptor 4 (TLR4) signaling plays a key role in liver inflammation and fibrosis. The therapeutic effects of eritoran, a TLR4 antagonist, in mice with chronic liver injury remained unclear. C57BL/6 mice were fed a fast-food diet (FFD) or treated with carbon tetrachloride (CCl4) to induce chronic liver injury. Eritoran (10 mg/kg) or a vehicle was randomly intraperitoneally administered to the FFD-fed mice and the CCl4-injured mice. Primary mouse liver cells were cultured with lipopolysaccharide (LPS) or eritoran. In both FFD and CCl4 mouse models, eritoran significantly reduced serum ALT levels and decreased hepatic inflammatory cell infiltration without altering hepatic steatosis. Additionally, eritoran attenuated liver fibrosis by decreasing hepatic stellate cells (HSCs) activation and the abundance of α-smooth muscle actin and transforming growth factor-β1. Hepatic TLR4 downstream signaling including MyD88 expression, NF-κB p65 nuclear translocation, p38 and JNK phosphorylation were successfully inhibited by eritoran. In the in vitro study, LPS-induced nuclear translocation of NF-κB in primary HSCs and Kupffer cells was significantly suppressed by eritoran. In conclusion, eritoran attenuated hepatic inflammation and fibrosis by inhibition of the TLR4 signaling pathway in mice with chronic liver injury. Eritoran may serve as a potential drug for chronic liver disease.

BACKGROUND Direct-acting antivirals (DAA) improve sustained virological response (SVR) rates with normalization of liver enzymes in patients with hepatitis C. However, liver inflammation may persist despite virus eradication. We aimed to investigate the rate and risk factors for persistent elevated aminotransferase levels in patients with advanced fibrosis after DAA-induced SVR. METHODS From January 2017 to April 2018, chronic hepatitis C patients with advanced fibrosis and SVR after DAA treatment at the Taipei Veterans General Hospital were prospectively enrolled. Persistent liver inflammation after SVR was defined as an increase in levels of alanine aminotransferase (ALT) (>40 U/L) at SVR12. RESULTS A total of 461 patients were included (57.9% females, mean age 64 years, 69.6% genotype 1b, 46.4% cirrhosis). At SVR12, there was a decline in ALT levels (90.5 ± 80.8 U/L to 25.3 ± 26.5 U/L) from baseline levels. Persistent liver inflammation at SVR12 was detected in 45 patients (9.8%). The presence of cirrhosis, markers of impaired liver functions, history of interferon-based therapy, steatosis, and elevated ALT levels at baseline was associated with persistent liver inflammation after SVR12. Results of multivariate analysis indicated that levels of baseline serum total bilirubin (odds ratio [OR]: 2.605, 95% CI: 1.158-5.858), international normalized ratio (OR: 14.389, 95% CI: 1.754-118.049), ALT (OR: 1.006, 95% CI: 1.003-1.009), and the presence of steatosis (OR: 3.635, 95% CI: 1.716-7.698) were independent predictors of persistent liver inflammation at SVR12. CONCLUSION Persistent liver inflammation is not uncommon in chronic hepatitis C patients with advanced fibrosis after DAA-induced SVR. It is associated with impaired baseline liver function and steatosis. Long-term follow-up is required to assess the implication of liver inflammation on disease progression.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background/Purpose Hepatocellular carcinoma (HCC) is a highly recurrent tumor. Antiviral therapy with nucleos(t)ide analogues (NUCs) may reduce the risk of recurrence in hepatitis B virus (HBV)-related HCC. The risk factors associated with recurrence in HCC patients after surgical resection and with NUCs treatment should be delineated. Methods Consecutive 339 HBV-related HCC patients receiving surgical resection of HCC with NUCs therapy (including 256 entecavir, 36 tenofovir, and 18 lamivudine) after the surgery were retrospectively reviewed. Factors related to the recurrence-free survival (RFS) and overall survival (OS) were evaluated. Results After a median of 48.5 months of follow-up, 183 (54%) patients developed HCC recurrence, with the 5-year RFS of 42.8% and OS of 79%. Male gender (HR = 1.736, p = 0.037), baseline HBsAg level >200 IU/ml (HR = 1.748, p = 0.008), platelet count ≦100 (109/L) (HR = 1.592, p = 0.023), presence of microscopic vascular invasion (MVI) (HR = 1.499, p = 0.026), safety cut margin of ≦0.5 cm (HR = 1.507, p = 0.013), and Ishak fibrosis score 5–6 (HR = 1.579, p = 0.009) were independent factors associated with RFS in multivariate analysis. While tumor burden, platelet count, MVI, and safety cut margin were factors associated with early recurrence; baseline HBsAg level, and platelet count were independent factors associated with late recurrence. Ishak fibrosis score 5–6, poor differentiation, MVI, diabetes mellitus were factors associated with OS in multivariate analysis. Conclusions For HBV-HCC patients on NUCs treatment, tumor factors are associated with early recurrence, while HBsAg level and thrombocytopenia determines late recurrence. For patient with a high baseline HBsAg level, warning of higher risk of recurrence is required even under NUCs treatment.

Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). The prognostic role of albumin-bilirubin (ALBI) grade in this special setting is unclear. We aimed to investigate the role of ALBI grade associated with the impact of RI on HCC. A prospective cohort of 3690 HCC patients between 2002 and 2016 were retrospectively analyzed. The Kaplan&ndash, Meier method and multivariate Cox proportional hazards model were used to determine survival and independent prognostic predictors. Of all patients, RI was an independent predictor associated with decreased survival. In multivariate Cox analysis for patients with RI, &alpha, fetoprotein level &ge, 20 ng/mL, tumor size &gt, 3 cm, vascular invasion, distant metastasis, presence of ascites, performance status 1&ndash, 2, performance status 3&ndash, 4, and ALBI grade 2 and grade 3 were independent predictors of decreased survival (all p &lt, 0.05). In subgroup analysis of patients with RI undergoing curative and non-curative treatments, the ALBI grade remained a significant prognostic predictor associated with decreased survival (p &lt, 0.001). In summary, HCC patients with RI have decreased survival compared to those without RI. The ALBI grade can discriminate the survival in patients with RI independent of treatment strategy and is a feasible prognostic tool in this special patient population.

As the outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread over the world, the World Health Organization has declared the outbreak of COVID-19 an international public health emergency. Besides typical respiratory symptoms and signs of COVID-19, digestive symptoms and liver injury have been frequently reported during the course of the disease. In this review, we summarized the recent studies reporting of gastrointestinal and liver manifestations during the course of COVID-19. Digestive symptoms, including anorexia, nausea, vomiting, and diarrhea, are not uncommon in patients with COVID-19, and in some cases digestive symptoms may occur in the absence of any respiratory symptoms. Furthermore, SARS-CoV-2 could be detected in the stool of infected patients, implicating the possibility of fecal-oral transmission. Attention should also be paid to monitor liver function during the course of COVID-19, especially in patients with higher disease severity.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, but its current status is unclear. We aimed to investigate the evolution of etiology, presentation, management and prognostic tool in HCC over the past 12 years. A total of 3349 newly diagnosed HCC patients were enrolled and retrospectively analyzed. The comparison of survival was performed by the Kaplan-Meier method with the log-rank test. Hepatitis B and C virus infection in HCC were continuously declining over the three time periods (2004–2007, 2008–2011, 2012–2015; p

BACKGROUND: For patients with solitary huge (>10 cm in size) hepatocellular carcinoma (HCC) and without major vascular invasion, the treatment efficacy between surgical resection (SR) and transarterial chemoembolization (TACE) is not well studied. We aimed to compare the prognoses between SR and TACE for patients with solitary huge HCC. METHODS: We enrolled 143 patients with treatment-naïve, solitary HCC (>10 cm) who had received either SR or TACE treatment between 2007–2016. Factors of overall survival (OS) were analyzed by multivariate analysis. Propensity scores matching (PSM) method was adopted to adjust baseline demographic differences for further analysis. RESULTS: Ninety patients underwent SR and 53 patients received TACE. After a median follow-up of 17.0 (interquartile range 7.7–45.6) months, 83 patients had died. The cumulative 5-year OS rate was 44.7% and 11.7% for the SR group and the TACE group, respectively (P1 (HR: 2.181, 95% CI: 1.343–3.543, P=0.002) were the independent risk factors associated with poorer OS. After PSM, 37 pairs of matched patients were selected from each treatment arm. After matching, patients who underwent SR still evinced a significantly higher OS than did those who underwent TACE (P=0.010). CONCLUSIONS: SR provided a better OS than did TACE for patients with solitary huge (≥10 cm) HCC. As such, SR is recommended as the therapeutic priority for these patients.

There has been insufficient investigation of the differences in long-term outcomes between surgical resection (SR) and radiofrequency ablation (RFA) among patients with hepatocellular carcinoma (HCC) and esophagogastric varices (EGV). We retrospectively enrolled 251 patients with treatment-naïve HCC and EGV who underwent SR or RFA as a first-line treatment. Prognostic factors were analyzed using a Cox proportional hazards model. A total of 68 patients underwent SR, and the remaining 183 patients received RFA. Patients who underwent SR were younger, had better liver functional reserves, and had larger tumors. After a median follow-up duration of 45.1 months, 151 patients died. The cumulative 5-year overall survival (OS) rate was significantly higher among patients who underwent SR than those treated with RFA (66.7% vs. 36.8%, p 65 years, multiple tumors, RFA, albumin bilirubin grade > 1, and the occurrence of major peri-procedural morbidity were the independent risk factors that are predictive of poor OS. In conclusion, SR could be recommended as a first-line treatment modality for HCC patients with EGV if the patients are carefully selected and liver function is well preserved.

The prognostic factors of patients who undergo radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is not fully elucidated. We aimed to investigate the role of liver stiffness (LS) and spleen stiffness (SS) measured by acoustic radiation force impulse (ARFI) elastography in determining the prognoses of patients with HCC after RFA. We prospectively enrolled 173 patients with HCC who underwent ARFI elastography for measurement of LS and SS on the same day of RFA. Overall survival (OS), recurrence-free survival (RFS) after adjusting for competing mortality, and presence of hepatic decompensation were investigated. Patients with LS > 1.5 m/s had significantly shorter OS and RFS than their counterparts. Anti-viral treatment (hazard ratio [HR]: 0.396, p = 0.015) and LS > 1.5 m/s (HR 4.105, p = 0.028) correlated with OS by a multivariate analysis. Besides, serum alpha fetoprotein >10 ng/mL and LS > 1.5 m/s independently predicted poorer RFS. On the other hand, anti-viral treatment (HR: 0.315, p = 0.010), creatinine > 1.5 mg/dL (HR: 9.447, p = 0.006), and SS > 2.7 m/s (HR: 2.869, p = 0.044) predicted a higher risk of hepatic decompensation. In conclusion, LS but not SS measured by ARFI elastography predicted tumor recurrence and OS in RFA-treated HCC; whereas, SS predicted development of hepatic decompensation in these patients.

OBJECTIVE The predictive value of esophageal varices (EV) in determining the patient outcome in hepatocellular carcinoma (HCC) remains unresolved. We aimed to assess the impact of EV on the prognosis of HCC patients after surgical resection. MATERIALS AND METHODS We consecutively enrolled 446 treatment-naive HCC patients who underwent surgical resection and esophagogastroduodenoscopy from 2003 to 2015. Prognostic factors were analyzed using the Cox proportional hazards model and a propensity score matching analysis. RESULTS A total of 89 (20.0%) HCC patients presented with EV. Compared with those without EV, patients with EV had poorer preservation of liver function and higher rates of cirrhosis in the nontumor part of liver specimens. After a median follow-up period of 34.6 months (25-75 percentiles; 12.8-59.3 months), 130 patients had died. The cumulative 5-year overall survival (OS) rates were 62.3 and 70.6% in patients with and without EV, respectively (P=0.102). A multivariate analysis showed that serum albumin level less than or equal to 4 g/dl (P=0.020), α-fetoprotein level greater than 20 ng/ml (P

Portal vein tumor thrombosis (PVTT) commonly occurs in patients with hepatocellular carcinoma (HCC). Patients with PVTT usually have an aggressive disease course, decreased liver function reserve, limited treatment options, higher recurrence rates after treatment, and, therefore, worse overall survival. Among untreated HCC patients with PVTT, the median overall survival has been reported as low as 2 to 4 months. Historically, many aspects of PVTT have impacted the theoretical and practical safety and efficacy of treatment, for example, disordered blood flow and associated impairment of liver function, heat-sink effects of blood flow in the area of the PVTT, and risk of recurrence due to tumor location in the blood vessel. The current Barcelona Clinic Liver Cancer staging system categorizes HCC patients with PVTT as advanced stage, for which the standard of care is targeted therapy with sorafenib. However, sorafenib is associated with only marginal benefits among patients with PVTT. First-line lenvatinib, which was shown to be noninferior to sorafenib, excluded patients with main portal trunk invasion. Regorafenib and nivolumab, an immune-based therapy, were recently approved in the United States for second-line therapy after sorafenib. Preliminary results for cabozantinib suggest a benefit in the second-/third-line after sorafenib failure. In addition, rapid advances in many fields (surgery, interventional radiology, nuclear medicine, and immunotherapy) have increased the potential treatment options for the management of this complex disease entity. A large portion of the emerging evidence focuses on the broader category of advanced HCC of which PVTT is a subgroup. While many of these studies show promising results, the efficacy among PVTT patients requires validation in prospective studies. Real-world data may help fill the evidence gap for patients not eligible for clinical trials due to common hepatic function requirements. The variety of new treatment advances for the heterogeneous and complex disease entity of HCC with PVTT means that personalized, multidisciplinary management may be necessary to achieve optimal outcomes. In this narrative review, we summarize the evolving management strategies for patients with HCC and PVTT.

Background Liver cirrhosis is associated with increased intrahepatic resistance due to hepatic fibrosis and exaggerated vasoconstriction. Recent studies have indicated that proton pump inhibitors (PPIs), in addition to acid suppression, modulate vasoactive substances and vasoresponsiveness. PPIs are frequently prescribed in patients with cirrhosis due to a higher prevalence of peptic ulcers, however other impacts are unknown. Methods Liver cirrhosis was induced in Sprague–Dawley rats with common bile duct ligation (BDL). On the 29th day after BDL and after hemodynamic measurements, the intrahepatic vascular responsiveness to high concentrations of endothelin-1 (ET-1) was evaluated after preincubation with (1) Krebs solution (vehicle), (2) esomeprazole (30 μM), or (3) esomeprazole plus N ω -nitro l -arginine (NNA, a non-selective NO synthase (NOS) inhibitor, 10 −4 M). After perfusion, the hepatic protein expressions of endothelial NOS (eNOS), inducible NOS (iNOS), cyclooxygenase (COX)-1, COX-2, endothelin-1, DDAH-1 (dimethylarginine dimethylaminohydrolase-1, ADMA inhibitor), DDAH-2, ADMA (asymmetrical dimethyl arginine, NOS inhibitor) were evaluated. In the chronic model, the BDL rats received (1) vehicle; or (2) esomeprazole (3.6 mg/kg/day, oral gavage) from the 1st to 28th day after BDL. On the 29th day and after hemodynamic measurements, plasma liver biochemistry and liver fibrosis were evaluated. Results Esomeprazole did not affect hepatic ET-1 vasoresponsiveness. The hepatic protein expressions of the aforementioned factors were not significantly different among the groups. There were no significant differences in hemodynamics, liver biochemistry and hepatic fibrosis after chronic esomeprazole administration. Conclusion PPIs did not affect hepatic vasoresponsiveness or the release of vasoactive substances. Furthermore, they did not influence hemodynamics, liver biochemistry or severity of hepatic fibrosis in the cirrhotic rats.

Background/Aims: Whether single large hepatocellular carcinoma (SLHCC) is classified as Barcelona Clinic Liver Cancer (BCLC) stage A or B is still controversial. We aimed to compare the clinical manifestations, treatment modalities, and prognoses among patients with SLHCC and those in BCLC stage A and B. Methods: We enrolled 2,285 treatment-naive hepatocellular carcinoma (HCC) patients with BCLC stage A or B from October 2007 to December 2015. Factors in terms of prognoses were analyzed by multivariate analysis. Results: We enrolled 1,210, 466, and 609 patients in a BCLC-A, SLHCC, and BCLC-B group, respectively. After a median follow-up duration of 21.2 months, 898 patients had died. The cumulative 5-year survival rates were 57.0, 42.6, and 27.3% for patients in the BCLC-A, SLHCC, and BCLC-B groups, respectively, which were significantly different (p < 0.001). Multivariate analysis indicated that the following independent risk factors were associated with poor prognosis: age > 65 years, alkaline phosphatase > 100 U/L, creatinine > 1.0 mg/dL, alpha-fetoprotein > 20 mg/mL, noncurative treatment, albumin-bilirubin (ALBI) grade, and HCC staging. Subgroup analysis also confirmed that patients in the SLHCC group had a survival rate intermediate to those in the BCLC-A and BCLC-B groups. However, for patients in the SLHCC group and with ALBI grade 1, outcomes were close to those in the BCLC-A group, especially in the setting of curative treatment. For those with ALBI grades 2 or 3, the prognoses were similar to those of the SLHCC and BCLC-B groups. Conclusion: Patients in the SLHCC group had an overall survival rate intermediate to those of the BCLC-A and BCLC-B groups. It is suggested that the SLHCC group could be classified as occupying a different stage from the BCLC stages A and B. The ALBI grade could help to stratify SLHCC into a different prognostic group. However, the results need to be validated externally in other regions of the world.

Liver functional capacity is a crucial survival determinant for hepatocellular carcinoma (HCC). Noninvasive models were proposed to assess hepatic reserve, but their performance in outcome prediction is unclear. We aimed to investigate 10 currently used liver function models in HCC patients undergoing radiofrequency ablation (RFA). A total 499 HCC patients were prospectively identified. Homogeneity and corrected Akaike information criteria (AICc) were compared. Cox proportional hazards model was used to identify independent survival predictors. Significance survival differences were found across 10 noninvasive models (all p

Background and Aims Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) but is challenging after treatment failure. Appropriate criteria for enrolling patients into second-line trials are still limited. In this study, we aimed to establish more objective criteria based on Albumin-Bilirubin (ALBI) grade to select patients with better post-progression survival (PPS) for second-line treatment. Methods Consecutive 404 advanced HCC patients receiving sorafenib were retrospectively enrolled. All patients were in Child-Pugh class A and BCLC stage C with either portal vein invasion or extrahepatic metastasis at the beginning of sorafenib treatment. Radiologic evaluation based on mRECIST criteria and clinical assessments with compliance were performed on schedule. Results During the median follow-up period of 5.8 months, 310 patients developed progressive disease (PD) and 350 deaths occurred. The PD patients were randomized into derivation and validation cohorts by a 1:1 ratio. The independent predictors of poor PPS in derivation cohort were ALBI grade 3 at PD (hazard ratio [HR]=3.24, p=0.002), new extrahepatic lesions (NEH) (HR=1.75, p=0.011), and early PD within 4 months (HR=1.88, p=0.037). ALBI-PD criteria were proposed by incorporating these three risk factors. In the validation cohort, PPS could be independently predicted by presence of early PD, NEH as well as ALBI grade 3 at PD. Patients within ALBI-PD criteria had significant longer median PPS than those beyond it even in Child-Pugh A (9.7 vs. 4.9 months, p=0.005) subpopulations. Conclusions ALBI-PD criteria can differentiate PPS and stratify the patients with advanced HCC for the second-line trials or salvage therapy. This article is protected by copyright. All rights reserved.

The nomogram of the Barcelona Clinic Liver Cancer (BCLC) has accurate outcome prediction. This study aims to propose a treatment-integrated nomogram derived from BCLC for patients with hepatocellular carcinoma (HCC). A total of 3,371 patients were randomly grouped into derivation (n = 2,247) and validation (n = 1,124) sets. Multivariate Cox proportional hazards model was used to generate the nomogram from tumor burden, cirrhosis, performance status (PS) and primary anti-cancer treatments. Concordance indices and calibration plots were used to evaluate the performance of nomogram. The derivation and validation sets had the same concordance index of 0.774 (95% confidence intervals: 0.717–0.826 and 0.656–0.874, respectively). In calibration plots, survival distributions predicted by the nomogram and observed by the Kaplan-Meier method were similar at 3- and 5-year for patients from derivation and validation sets. Validation group patients divided into 10 subgroups by the original and new treatment-integrated BCLC nomogram were used to evaluate the prognostic performance of integrating primary anti-cancer treatments. Compared to the nomogram of original BCLC system, the treatment-integrated nomogram of BCLC system had larger linear trend and likelihood ratio X2. In conclusion, based on the results of concordance index tests, integrating primary anti-cancer treatments into the BCLC system provides similar discriminatory ability.

Background and Aim The severity of liver dysfunction in hepatocellular carcinoma (HCC) is often estimated with Child–Turcotte–Pugh (CTP) classification or model for end-stage liver disease (MELD) score. We aim to investigate the performance of albumin-bilirubin (ALBI) and platelet-albumin-bilirubin (PALBI) grade, which are recently reported to be simple and objective measurements for liver reserve in HCC. Methods Between 2002 and 2014, consecutive 3182 HCC patients were enrolled to follow up their survival. The area under receiver-operator-characteristic curve (AUC) was calculated to test the discriminatory powers over 1-year, 3-year, and 5-year survival. Results Significant survival differences were found across all ALBI and PALBI grades (both P

Patients suffering from liver cirrhosis are often complicated with the formation of portosystemic collateral vessels, which is associated with the progression of a splanchnic hyperdynamic circulatory state. Alleviating pathological angiogenesis has thus been proposed to be a feasible treatment strategy. Indole-3-carbinol (C9H9NO, I3C) and 3,3&prime, diindolymethane (DIM), formed by the breakdown of glucosinolate glucobrassicin, are prevalent in cruciferous vegetables and have anti-angiogenesis properties. We aimed to evaluate their influences on portal hypertension, the severity of mesenteric angiogenesis, and portosystemic collaterals in cirrhosis. Sprague-Dawley rats with common bile duct ligation (CBDL)-induced liver cirrhosis or sham operation (surgical control) were randomly allocated to receive I3C (20 mg/kg/3 day), DIM (5 mg/kg/day) or vehicle for 28 days. The systemic and portal hemodynamics, severity of portosystemic shunting, mesenteric angiogenesis, and mesenteric proangiogenic factors protein expressions were evaluated. Compared to vehicle, both DIM and I3C significantly reduced portal pressure, ameliorated liver fibrosis, and down-regulated mesenteric protein expressions of vascular endothelial growth factor and phosphorylated Akt. DIM significantly down-regulated pErk, and I3C down-regulated NF&kappa, B, pI&kappa, B&alpha, protein expressions, and reduced portosystemic shunting degree. The cruciferous vegetable byproducts I3C and DIM not only exerted a portal hypotensive effect but also ameliorated abnormal angiogenesis and portosystemic collaterals in cirrhotic rats.