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Simple Summary: Hepatocellular carcinoma (HCC) is a highly aggressive and lethal form of liver cancer, and most patients with HCC die due to HCC-related causes. Although most patients die of HCC-related causes, non–HCC-related death represents a competing event among patients who engage in alcohol use and receive curative treatment and among patients 75 years and older in the hepatitis B virus and all-negative groups who receive curative treatments. All negative was defined as negative for hepatitis C virus, hepatitis B virus, and alcohol-related causes. The results of the current study underscore the importance of assessing and managing underlying comorbidities, especially among certain subgroups of patients with HCC. This study was conducted to determine whether the causes of death among patients with hepatocellular carcinoma (HCC) differ according to chronic liver disease (CLD) etiology. Between 2011 and 2020, 3977 patients who were newly diagnosed with HCC at our institution were enrolled in this study. We determined whether the cause of death was HCC-related and non-HCC-related. For patients with multiple CLD etiologies, etiology was classified using the following hierarchy: hepatitis C virus (HCV) > hepatitis B virus (HBV) > alcohol-related causes > all negative. All negative was defined as negative for HCV, HBV, and alcohol-related causes. Among 3977 patients, 1415 patients were classified as HCV-related, 1691 patients were HBV-related, 145 patients were alcohol-related, and 725 patients were all negative. HCC-related mortality was the leading cause of death, irrespective of etiology. Among patients who underwent curative treatment, HCC-related mortality was the leading cause of death for patients in the HCV, HBV, and all-negative groups, but not for patients in the alcohol-related group. Among patients 75 years and older who underwent curative treatment, HCC-related mortality was the leading cause of death in the HCV but not HBV or all-negative groups. In conclusion, although most patients with HCC die due to HCC-related causes, non-HCC-related mortality represents a competing event in certain patient subgroups. The current study results underscore the importance of assessing and managing underlying comorbidities, particularly among patients with HCC at risk of non-HCC-related mortality. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we demonstrated that overall 51.2% of patients with hepatocellular carcinoma (HCC) had elevated alpha-fetoprotein (AFP) levels. The proportion of patients with elevated AFP levels was stationary in the period from 2011 to 2020. The proportion of patients with Barcelona Clinic Liver Cancer classification (BCLC) stages 0–A HCC decreased from 2011 to 2020, whereas the proportion of patients with non-HBV- and non-HCV (NBNC)-HCC increased in the same period. Furthermore, the proportion of patients with early-stage HCC (i.e., BCLC stages 0–A) was lower for NBNC-HCC than for HBV- or HCV-related HCC. Advanced tumor stage, severe underlying liver disease, viral etiology, and female gender are associated with elevated AFP levels in HCC patients. A recent study from the US showed a decreasing trend in the elevated serum alpha-fetoprotein (AFP) level (i.e., ≥20 ng/mL) in hepatocellular carcinoma (HCC) patients at the time of diagnosis. Furthermore, advanced tumor stage and severe underlying liver disease were associated with elevated AFP levels. We aimed to evaluate this issue in an area endemic for hepatitis B virus (HBV). Between 2011 and 2020, 4031 patients were newly diagnosed with HCC at our institution. After excluding 54 patients with unknown AFP data, the remaining 3977 patients were enrolled in this study. Elevated AFP level was defined as ≥20 ng/mL. Overall, 51.2% of HCC patients had elevated AFP levels; this proportion remained stationary between 2011 and 2020 (51.8% vs. 51.1%). Multivariate analysis showed that female gender (odds ratio (OR) = 1.462; p < 0.001), tumor size per 10 mm increase (OR = 1.155; p < 0.001), multiple tumors (OR = 1.406; p < 0.001), Barcelona Clinic Liver Cancer stages B–D (OR = 1.247; p = 0.019), cirrhosis (OR = 1.288; p = 0.02), total bilirubin > 1.4 mg/dL (OR = 1.218; p = 0.030), and HBV- or hepatitis C virus (HCV)-positive status (OR = 1.720; p < 0.001) were associated with elevated AFP levels. In conclusion, a stationary trend in elevated serum AFP level in HCC patients has been noted in the past 10 years. Advanced tumor stage, severe underlying liver disease, viral etiology, and female gender are associated with elevated AFP levels in HCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The tumor burden score (TBS) is calculated using the Pythagorean theorem based on the largest tumor size and tumor number (α2 + β2 = γ2, where α is the largest tumor size, β is the tumor number, and γ is the TBS). Patients who underwent liver resection (LR) for Barcelona Clinic Liver Cancer stage 0, A, or B hepatocellular carcinoma (HCC) between 2011 and 2018 were enrolled. Among 743 patients, 193 (26.0%) patients had a low TBS (<2.6), 474 (63.8%) had a moderate TBS (2.6–7.9), and 75 (10.1%) had a high TBS (>7.9). Combining radiographic TBS and alpha-fetoprotein levels could stratify overall survival among HCC patients after LR. We evaluated whether combining the radiographic tumor burden score (TBS) and alpha-fetoprotein (AFP) level could be used to stratify overall survival (OS) among hepatocellular carcinoma (HCC) patients after liver resection (LR). Patients who underwent LR for Barcelona Clinic Liver Cancer stage 0, A, or B HCC between 2011 and 2018 were enrolled. TBS scores were calculated using the following equation: TBS2 = (largest tumor size (in cm))2 + (tumor number)2. Among 743 patients, 193 (26.0%) patients had a low TBS (<2.6), 474 (63.8%) had a moderate TBS (2.6–7.9), and 75 (10.1%) had a high TBS (>7.9). Those with a TBS ≤ 7.9 and AFP < 400 ng/mL had a significantly better OS than those with a TBS > 7.9 and an AFP < 400 ng/mL (p = 0.003) or ≥ 400 ng/mL (p < 0.001). A multivariate analysis using TBS ≤ 7.9 and AFP < 400 ng/mL as the reference values showed that a TBS > 7.9 and an AFP < 400 ng/mL (hazard ratio (HR): 2.063; 95% confidence interval [CI]: 1.175–3.623; p = 0.012) or ≥ 400 ng/mL (HR: 6.570; 95% CI: 3.684–11.719; p < 0.001) were independent predictors of OS. In conclusion, combining radiographic TBSs and AFP levels could stratify OS among HCC patients undergoing LR. [ABSTRACT FROM AUTHOR]

Simple Summary: Atezolizumab plus bevacizumab has been approved as the first-line systemic treatment for unresectable hepatocellular carcinoma (uHCC) patients. However, the real-world practice of this combination is limited. We reported 48 uHCC patients who received atezolizumab plus bevacizumab, the median progression-free survival (PFS) was 5.0 months, and the objective response rate and disease control rate were 27.1% and 68.8%, respectively. The severity of most adverse events was predominantly grade 1–2, and most patients tolerated the toxicities. We also used inflammatory biomarkers to predict PFS, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Univariate and multivariate analyses revealed NLR and PLR were independent prognostic factors for superior PFS. The significance of our study is the first research to investigate the prognostic value of NLR and PLR among uHCC patients receiving atezolizumab plus bevacizumab. It would bring more information to physicians about the efficacy and safety of atezolizumab plus bevacizumab in real-world clinical practice. Atezolizumab plus bevacizumab has been approved as the first-line systemic treatment for patients with unresectable hepatocellular carcinoma (uHCC). This study was designed to assess the clinical impact of atezolizumab plus bevacizumab in uHCC patients. A total of 48 uHCC patients receiving atezolizumab plus bevacizumab were identified, including first-line, second-line, third-line, and later-line settings. In these patients, the median progression-free survival (PFS) was 5.0 months, including 5.0 months for the first-line treatment, not reached for the second-line treatment, and 2.5 months for the third line and later line treatment. The objective response rate and disease control rate to atezolizumab plus bevacizumab were 27.1% and 68.8%, respectively. The severity of most adverse events was predominantly grade 1–2, and most patients tolerated the toxicities. The ratios of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) were used to predict PFS in these patients. The optimal cutoff values of NLR and PLR were 3 and 230, and NLR and PLR were independent prognostic factors for superior PFS in the univariate and multivariate analyses. Our study confirms the efficacy and safety of atezolizumab plus bevacizumab in uHCC patients in clinical practice and demonstrates the prognostic role of NLR and PLR for PFS in these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Growing evidence has reported the role of sorafenib in hepatocellular carcinoma (HCC) patients with liver transplantation (LT). However, the clinical impact of lenvatinib in this population is limited. Our study enrolled 10 HCC patients who received lenvatinib after LT in our institute. Partial response was 20% and disease control rate was 70%. The median progression-free survival and overall survival were 3.7 and 16.4 months, respectively. Adverse events (AEs) were predominantly grade 1–2 in severity, and the majority of patients tolerated. Additionally, 25 HCC patients without LT who underwent lenvatinib treatment were identified as the control group; there was no significant difference in survival or AEs between these two groups. The significance of our study is that it is the first to investigate the efficacy and safety of lenvatinib among HCC patients with LT. It provides more information to physicians about the role of lenvatinib in this special population in clinical practice. Tumor recurrence is the most common cause of death in hepatocellular carcinoma (HCC) patients who received liver transplantation (LT). Recently, lenvatinib was approved for the systemic treatment of unresectable HCC patients; however, the role of lenvatinib in HCC patients after LT remains unclear. There were 56 patients with recurrent HCC after LT from 2008 to 2018 in our institute, and 10 patients who received lenvatinib were identified. Additionally, to understand the difference in the clinical impact of lenvatinib in the LT and non-LT settings, 25 HCC patients without LT who underwent lenvatinib treatment were identified from our HCC database and regarded as the control group. In the LT group, partial response was 20% and stable disease was 50%, resulting in a disease control rate of 70%; the median progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS) were 3.7, 3.6 and 16.4 months, respectively. Adverse events (AEs) were predominantly grade 1–2 in severity, and the majority of patients tolerated the side effects. There was no significant difference in PFS/OS, and we observed a similar pattern of AEs between these two groups. Our study confirms the comparable efficacy and safety of lenvatinib in HCC patients with LT and non-LT in clinical practice. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world. Previous studies have identified the importance of alcohol and hepatitis B (HBV) infection on HCC carcinogenesis, indicating synergy in the methods by which these etiologies advance cancer. However, the specific molecular mechanism behind alcohol and HBV-mediated carcinogenesis remains unknown. Because the microbiome is emerging as a potentially important regulator of cancer development, this study aims to classify the effects of HBV and alcohol on the intratumoral liver microbiome. RNA-sequencing data from The Cancer Genome Atlas (TCGA) were used to infer microbial abundance. This abundance was then correlated to clinical variables and to cancer and immune-associated gene expression, in order to determine how microbial abundance may contribute to differing cancer progression between etiologies. We discovered that the liver microbiome is likely oncogenic after exposure to alcohol or HBV, although these etiological factors could decrease the abundance of a few oncogenic microbes, which would lead to a tumor suppressive effect. In HBV-induced tumors, this tumor suppressive effect was inferred based on the downregulation of microbes that induce cancer and stem cell pathways. Alcohol-induced tumors were observed to have distinct microbial profiles from HBV-induced tumors, and different microbes are clinically relevant in each cohort, suggesting that the effects of the liver microbiome may be different in response to different etiological factors. Collectively, our data suggest that HBV and alcohol operate within a normally oncogenic microbiome to promote tumor development, but are also able to downregulate certain oncogenic microbes. Insight into why these microbes are downregulated following exposure to HBV or alcohol, and why the majority of oncogenic microbes are not downregulated, may be critical for understanding whether a pro-tumor liver microbiome could be suppressed or reversed to limit cancer progression. [ABSTRACT FROM AUTHOR]

Immunotherapy has emerged in recent years as arguably the most effective treatment for advanced hepatocellular carcinoma (HCC), but the failure of a large percentage of patients to respond to immunotherapy remains as the ultimate obstacle to successful treatment. Etiology-associated dysregulation of immune-associated (IA) genes may be central to the development of this differential clinical response. We identified immune-associated genes potentially dysregulated by alcohol or viral hepatitis B in HCC and validated alcohol-induced dysregulations in vitro while using large-scale RNA-sequencing data from The Cancer Genome Atlas (TCGA). Thirty-four clinically relevant dysregulated IA genes were identified. We profiled the correlation of all genomic alterations in HCC patients to IA gene expression while using the information theory-based algorithm REVEALER to investigate the molecular mechanism for their dysregulation and explore the possibility of genome-based patient stratification. We also studied gene expression regulators and identified multiple microRNAs that were implicated in HCC pathogenesis that can potentially regulate these IA genes' expression. Our study identified potential key pathways, including the IL-7 signaling pathway and TNFRSF4 (OX40)- NF-κB pathway, to target in immunotherapy treatments and presents microRNAs as promising therapeutic targets for dysregulated IA genes because of their extensive regulatory roles in the cancer immune landscape. [ABSTRACT FROM AUTHOR]