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Tumor burden score (TBS) was proposed to represent tumor burden in solid tumors, including hepatocellular carcinoma (HCC). The prognostic role of TBS in HCC patients in relation to recently introduced liver reserve markers, albumin-bilirubin (ALBI) grade, and easy (EZ)-ALBI grade, is unclear. We aimed to investigate the feasibility of TBS in HCC patients undergoing radiofrequency ablation (RFA).A total of 576 treatment-naïve patients with HCC undergoing RFA were analyzed. The multivariate Cox analysis was used to identify independent predictors associated with tumor recurrence and long-term survival.Patients with high TBS had increased risk of tumor recurrence and mortality compared with those with low TBS. The Cox analysis showed that serum ɑ-fetoprotein (AFP) level20 ng/mL, medium and high TBS, ALBI grade 2 and grade 3, EZ-ALBI grade 2 and grade 3 were associated with tumor recurrence and decreased patient survival (all p0.05). In addition, TBS can reliably stratify tumor recurrence and overall survival in different ALBI and EZ-ALBI grade groups.TBS is a simple and feasible prognostic surrogate to predict tumor recurrence and survival in HCC patients undergoing RFA. Its prognostic ability remains stable in patients with variable liver functional reserve.

The characteristics and prognosis of cryptogenic hepatocellular carcinoma (HCC) remain unclear. The albumin-bilirubin (ALBI) grade and its updated version, the easy ALBI (EZ-ALBI) grade, are important prognostic predictors for HCC. We aimed to investigate the long-term survival of patients with cryptogenic HCC and the prognostic role of ALBI and EZ-ALBI grade in these patients.A prospective cohort of 2,937 HCC patients with viral or cryptogenic etiology were retrospectively analyzed. The multivariate Cox model was used to determine prognostic predictors.Cryptogenic HCC patients were often older and diabetic, had lower serum ɑ-fetoprotein (AFP) levels, larger tumor burden, poor performance status, advanced cancer stage, and received non-curative treatments compared with hepatitis B or C-related HCC. The Cox analysis showed that age65 years, serum AFP400 ng/mL, presence of vascular invasion or distant metastasis, presence of ascites, performance status 2-4, ALBI grade 2 and 3, EZ-ALBI grade 2 and 3, and non-curative treatment, were independent predictors of decreased survival in cryptogenic HCC (Patients with cryptogenic HCC have a larger tumor burden and advanced cancer stage at disease presentation compared with those with viral HCC. The ALBI and EZ-ALBI score are robust models to evaluate liver functional reserve for these patients independent of treatment modality.

Albumin-bilirubin (ALBI) grade is used to evaluate the outcome of patients with hepatocellular carcinoma (HCC) which is often associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. This study aimed to investigate the clinical characteristics, outcome, and prognostic role of ALBI grade in dual HBV/HCV-related HCC.A total 3341 HCC patients with viral etiology were prospectively enrolled and retrospectively analyzed. Multivariate Cox proportional hazards model was used to identify independent prognostic predictors.Of all patients, 2083 (62%), 1068 (32%), and 190 (6%) patients had HBV, HCV, and dual HBV/HCV infection, respectively. The mean age of HBV, HCV, and dual virus group was 60, 68, and 64 years (p 0.001), respectively. There was no significant survival difference between HBV, HCV, and dual HBV/HCV-related HCC group (p = 0.712). Multivariate Cox analysis in dual HBV/HCV-related HCC showed that multiple tumors [hazard ratio (HR): 1.537, p = 0.044], tumor size3 cm (HR 2.014, p = 0.044), total tumor volume (TTV)50 cmDual viral infection does not accelerate the development of HCC in HBV carriers. Patient survival is similar between dual HBV/HCV-related HCC and single HBV- or HCV-related HCC group. The ALBI grade is a robust prognostic model in dual virus-related HCC to discriminate patient long-term survival.

Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non–small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis in NSCLC. We previously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through a MAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR–MAPK–ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC. Significance: The circRNA C190 is identified as a mediator of multiple pro-oncogenic signaling pathways in lung cancer and can be targeted to suppress tumor progression.

Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non–small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis in NSCLC. We previously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through a MAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR–MAPK–ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC.Significance:The circRNA C190 is identified as a mediator of multiple pro-oncogenic signaling pathways in lung cancer and can be targeted to suppress tumor progression.

List of differentially expressed genes from RNA-seq

Supplementary materials and methods, supplementary tables, and supplementary figures to support the main manuscript

Alpha fetoprotein (AFP) is the most widely used tumor marker for hepatocellular carcinoma (HCC). Nevertheless, few studies have investigated the prognostic factors of HCC patients with normal serum AFP levels.We retrospectively enrolled 2198 patients with HCC and normal serum AFP levels (20 ng/mL) from 2007 to 2020. Overall survival (OS) rates were calculated by the Kaplan-Meier method, and analyses of the prognostic factors were performed using a Cox proportional hazard model.Among the enrolled patients, 1385 (63%) patients were in the low-normal AFP group (serum AFP levels ≤7 ng/mL), and 813 (37%) patients were in the high-normal AFP group (serum AFP levels between 7 and 20 ng/mL). The high-normal AFP group had poorer liver functional reserve, more multiple tumors, and smaller tumor size compared to those in the low-normal AFP group. After a median follow-up of 32.4 months, 942 patients died, and the 5-year OS rate was 54.4%. The 5-year OS rates were 57.4% and 49.8% in the low-normal AFP group and high-normal AFP group, respectively (p = 0.001). A multivariate analysis showed the independent prognostic factors of poor OS were no anti-viral therapy, advanced albumin-bilirubin grades, the presence of vascular invasion, tumor size ≥5 cm, and non-curative treatment modalities. Serum AFP levels were not associated with OS according to the multivariate analysis.Liver functional reserve, anti-viral therapy, tumor size, vascular invasion, and treatment modalities, determined the outcomes of HCC patients with normal serum AFP levels, but serum AFP levels did not.

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

Tumor burden score (TBS), estimated by the diameter and number of tumor nodules, was recently proposed to assess the tumor burden in hepatocellular carcinoma (HCC). We aimed to evaluate the prognostic impact of TBS on HCC patients within the Milan criteria undergoing radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). A total of 883 patients undergoing RFA and TACE were included. The multivariate Cox proportional hazards model was used to determine independent prognostic predictors in different patient cohorts. The TACE group had significantly higher TBS compared with the RFA group. The RFA group had better long-term survival than the TACE group in patients within the Milan criteria in univariate survival analysis. In the Cox model, serum α-fetoprotein (AFP) > 20 ng/mL, performance status 1–2, medium and high TBS, albumin–bilirubin (ALBI) grade 2 and grade 3 were independent predictors linked with mortality (all p < 0.001). Overall, TACE was not an independent predictor; among patients with low TBS, TACE was independently associated with decreased survival compared with RFA (p = 0.034). Conclusions: TBS is a feasible prognostic marker for HCC patients within the Milan criteria. TACE may be an effective treatment alternative for these patients. Among patients with low TBS, RFA should be considered the priority treatment modality.

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.

We investigated the outcomes of patients with ruptured hepatocellular carcinoma (HCC) and identified the optimal treatment modality for such patients. We retrospectively enrolled 91 patients with treatment-naive HCC and tumor rupture at diagnosis, including 38 patients who underwent surgical resection (SR) alone, 28 patients who were treated with transarterial chemoembolization (TACE) only, 20 patients who had a sequential combination therapy of TACE and SR, and 5 patients who received best supportive care. After a median follow-up of 13.1 months, 54 patients died. The cumulative 5 years overall survival (OS) rates were 55.1% and 0% in the SR group and non-SR group, respectively (p p

PurposeHepatic function is a key prognostic marker in patients with hepatocellular cancer (HCC) and central to patient selection for transarterial chemoembolization (TACE). We investigated the clinical utility of the Albumin-Bilirubin (ALBI) grade, an emerging prognostic model, in this heterogenous cohort via a meta-analysis of published studies.MethodsPublications including full text articles and abstracts regarding ALBI grade were sourced by two independent researchers from databases including PubMed, Embase, Medline and Cochrane Library. Studies analysing patients with HCC undergoing TACE treatment were systematically screened utilising the PRISMA tool for data extraction and synthesis, after exclusion of duplicates, irrelevant studies and overlapping cohorts. The primary outcome was overall survival (OS), as determined by ALBI grade and assessed by hazard ratio (HRs) with 95% confidence intervals (CIs), with analysis of collated data using comprehensive meta-analysis, version 3.0 software.ResultsEight studies were included, with a pooled population of 6538 patients with HCC that underwent TACE treatment. Higher pre-treatment grade was associated with poor OS, with median OS of 12.0 months (P ConclusionsHigh pre-treatment ALBI grade is associated with poorer prognosis in patients with HCC undergoing TACE therapy. The ALBI grade demonstrates clinical utility for clinical prognostication and patient selection for TACE.

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

Patients with hepatocellular carcinoma (HCC) often have co-existing ascites, which is a hallmark of liver decompensation. The albumin-bilirubin (ALBI) grade and EZ (easy)-ALBI grade are used to assess liver functional reserve in HCC, but the predictive accuracy of these two models in HCC patients with ascites is unclear. We aimed to determine the prognostic role of ALBI and EZ-ALBI grades in these patients. A total of 4431 HCC patients were prospectively enrolled and retrospectively analyzed. Independent prognostic predictors were identified by the multivariate Cox proportional hazards model. Of all patients, 995 (22.5%) patients had ascites. Grade 1, 2, and 3 ascites were found in 16%, 4%, and 3% of them, respectively. A higher ascites grade was associated with higher ALBI and EZ-ALBI scores and linked with decreased overall survival. In the Cox multivariate analysis, serum bilirubin level > 1.1 mg/dL, creatinine level ≥ 1.2 mg/dL, α-fetoprotein ≥ 20 ng/mL, total tumor volume > 100 cm3, vascular invasion, distant metastasis, poor performance status, ALBI grade 2 and 3, EZ-ALBI grade 2 and 3, and non-curative treatments were independently associated with increased mortality (all p < 0.05) among HCC patients with ascites. The ALBI and EZ-ALBI grade can adequately stratify overall survival in both the entire cohort and specifically in patients with ascites. Ascites is highly prevalent and independently predict patient survival in HCC. The ALBI and EZ-ALBI grade are feasible markers of liver dysfunction and can stratify long-term survival in HCC patients with ascites.

The prognosis of hepatocellular carcinoma (HCC) varies widely due to variable tumor extent and liver reserve. We aimed to develop and validate a new prognostic model based on tumor burden score (TBS) and albumin–bilirubin (ALBI) grade for HCC. We prospectively identified 3794 HCC patients who were randomized into derivation and validation groups. Survival predictors were evaluated by a multivariate Cox model. The TBS–ALBI system allocated two points for high TBS and ALBI grade 3, and one point each for the presence of ascites, serum α-fetoprotein ≥ 400 ng/mL, vascular invasion or distant metastasis, performance status 2–4, medium TBS, and ALBI grade 2, with a maximal score of 8 points. Significant survival differences were found across different TBS–ALBI score groups in the validation cohort (all p < 0.001). The TBS–ALBI system had the lowest corrected Akaike information criterion (AICc) and the highest homogeneity compared with other proposed staging models. The discriminative ability of the TBS–ALBI system was consistently stable across different viral etiologies, cancer stages, and treatment strategies. Conclusions: This new TBS–ALBI system is a feasible and robust prognostic system in comparison with other systems; it is a user-friendly tool for long-term outcome assessment independent of treatment modality and cancer stage in HCC.

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.

Non-viral gene delivery holds promises for treating inherited diseases. However, the limited cloning capacity of plasmids may hinder the co-delivery of distinct genes to the transfected cells. Previously, the conjugation of maleimide-functionalized polyurethane grafted with small molecular weight polyethylenimine (PU-PEI600-Mal) using 1,6-hexanedithiol (HDT) could promote the co-delivery and extensive co-expression of two different plasmids in target cells. Herein, we designed HDT-conjugated PU-PEI600-Mal for the simultaneous delivery of CRISPR/Cas9 components to achieve efficient gene correction in the induced pluripotent stem cell (iPSC)-derived model of Fabry cardiomyopathy (FC) harboring GLA IVS4 + 919 G > A mutation. This FC in vitro model recapitulated several clinical FC features, including cardiomyocyte hypertrophy and lysosomal globotriaosylceramide (Gb3) deposition. As evidenced by the expression of two reporter genes, GFP and mCherry, the addition of HDT conjugated two distinct PU-PEI600-Mal/DNA complexes and promoted the co-delivery of sgRNA/Cas9 and homology-directed repair DNA template into target cells to achieve an effective gene correction of IVS4 + 919 G > A mutation. PU-PEI600-Mal/DNA with or without HDT-mediated conjugation consistently showed neither the cytotoxicity nor an adverse effect on cardiac induction of transfected FC-iPSCs. After the gene correction and cardiac induction, disease features, including cardiomyocyte hypertrophy, the mis-regulated gene expressions, and Gb3 deposition, were remarkably rescued in the FC-iPSC-differentiated cardiomyocytes. Collectively, HDT-conjugated PU-PEI600-Mal-mediated dual DNA transfection system can be an ideal approach to improve the concurrent transfection of non-viral-based gene editing system in inherited diseases with specific mutations.

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

Pluripotency and cell fates can be modulated through the regulation of super-enhancers; however, the underlying mechanisms are unclear. Here, we showed a novel mechanism in which Ash2l directly binds to super-enhancers of several stemness genes to regulate pluripotency and self-renewal in pluripotent stem cells. Ash2l recruits Oct4/Sox2/Nanog (OSN) to form Ash2l/OSN complex at the super-enhancers of Jarid2, Nanog, Sox2 and Oct4, and further drives enhancer activation, upregulation of stemness genes, and maintains the pluripotent circuitry. Ash2l knockdown abrogates the OSN recruitment to all super-enhancers and further hinders the enhancer activation. In addition, CRISPRi/dCas9-mediated blocking of Ash2l-binding motifs at these super-enhancers also prevents OSN recruitment and enhancer activation, validating that Ash2l directly binds to super-enhancers and initiates the pluripotency network. Transfection of Ash2l with W118A mutation to disrupt Ash2l–Oct4 interaction fails to rescue Ash2l-driven enhancer activation and pluripotent gene upregulation in Ash2l-depleted pluripotent stem cells. Together, our data demonstrated Ash2l formed an enhancer-bound Ash2l/OSN complex that can drive enhancer activation, govern pluripotency network and stemness circuitry.

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.

The with-no-lysine (WNK) kinase family, comprising four serine-threonine protein kinases (WNK1-4), were first linked to hypertension due to their mutations in association with pseudohypoaldosteronism type II (PHAII). WNK kinases regulate crucial blood pressure regulators, SPAK/OSR1, to mediate the post-translational modifications (PTMs) of their downstream ion channel substrates, such as sodium chloride co-transporter (NCC), epithelial sodium chloride (ENaC), renal outer medullary potassium channel (ROMK), and Na/K/2Cl co-transporters (NKCCs). In this review, we summarize the molecular pathways dysregulating the WNKs and their downstream target renal ion transporters. We summarize each of the genetic variants of WNK kinases and the small molecule inhibitors that have been discovered to regulate blood pressure via WNK-triggered PTM cascades.

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.