A preliminary study of optimal treatment response rates in patients undergoing hepatic arterial infusion chemotherapy combined with molecular targeting and immunotherapy.

Objectives: This study aimed to examine the effectiveness of the best response rate (BRR) as a surrogate for overall survival (OS), using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), in patients with unresectable hepatocellular carcinoma (HCC) undergoing hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) combined with molecular targeting and immunotherapy. Methods: This study enrolled 111 consecutive patients who had complete imaging data. The median age of patients was 58 years (IQR 50.5-65.0). Among the patients, those with Barcelona Clinic Liver Cancer (BCLC) stage A, BCLC stage B, and BCLC stage C comprised 6.4%, 19.1%, and 73.6%, respectively. The optimal threshold of BRR can be determined using restricted cubic splines (RCS) and the rank sum statistics of maximum selection. Survival curves of patients in the high rating and low rating groups were plotted. We then used the change-in-estimate (CIE) method to filter out confounders and the inverse probability of treatment weighting (IPTW) to balance confounders between the two groups to assess the robustness of the results. Results: The median frequency of the combination treatment regimens administered in the overall population was 3 times (IQR 2.0-3.0). The optimal BRR truncation value calculated was -0.2. Based on this value, 77 patients were categorized as the low rating group and 34 as the high rating group. The differences in the OS between the high and low rating groups were statistically significant (7 months [95%CI 6.0-14.0] vs. 30 months [95%CI 30.0-]; p< 0.001). Using the absolute 10% cut-off value, the CIE method was used to screen out the following confounding factors affecting prognosis: successful conversion surgery, baseline tumor size, BCLC stage, serum total bilirubin level, number of interventional treatments, alpha-fetoprotein level, presence of inferior vena cava tumor thrombus, and partial thrombin activation time. The survival curve was then plotted again using IPTW for confounding factors, and it was found that the low rating group continued to have better OS than the high rating group. Finally, the relationship between BRR and baseline factors was analyzed, and inferior vena cava tumor thrombus and baseline tumor size correlated significantly with BRR. Conclusions: BRR can be used as a surrogate endpoint for OS in unresectable HCC patients undergoing FOLFOX-HAIC in combination with molecular targeting and immunotherapy. Thus, by calculating the BRR, the prognosis of HCC patients after combination therapy can be predicted. Inferior vena cava tumor thrombus and baseline tumor size were closely associated with the BRR.

Prognostic value of CD8+T cells related genes and exhaustion regulation of Notch signaling pathway in hepatocellular carcinoma.

Immunotherapy has emerged as the primary treatment modality for patients with advanced Hepatocellular carcinoma (HCC). However, its clinical efficacy remains limited, benefiting only a subset of patients, while most exhibit immune tolerance and face a grim prognosis. The infiltration of immune cells plays a pivotal role in tumor initiation and progression. In this study, we conducted an analysis of immune cell infiltration patterns in HCC patients and observed a substantial proportion of CD8+T cells. Leveraging the weighted gene co-expression network analysis (WGCNA), we identified 235 genes associated with CD8+T cell and constructed a risk prediction model. In this model, HCC patients were stratified into a high-risk and low-risk group. Patients in the high-risk group exhibited a lower survival rate, predominantly presented with intermediate to advanced stages of cancer, displayed compromised immune function, showed limited responsiveness to immunotherapy, and demonstrated elevated expression levels of the Notch signaling pathway. Further examination of clinical samples demonstrated an upregulation of the Notch1+CD8+T cell exhaustion phenotype accompanied by impaired cytotoxicity and cytokine secretion functions that worsened with increasing Notch activation levels. Our study not only presents a prognostic model but also highlights the crucial involvement of the Notch pathway in CD8+T cell exhaustion-a potential target for future immunotherapeutic interventions.

A prognostic signature established based on genes related to tumor microenvironment for patients with hepatocellular carcinoma.

BACKGROUND: Complex cellular signaling network in the tumor microenvironment (TME) could serve as an indicator for the prognostic classification of hepatocellular carcinoma (HCC) patients. METHODS: Univariate Cox regression analysis was performed to screen prognosis-related TME-related genes (TRGs), based on which HCC samples were clustered by running non-negative matrix factorization (NMF) algorithm. Furthermore, the correlation between different molecular HCC subtypes and immune cell infiltration level was analyzed. Finally, a risk score (RS) model was established by LASSO and Cox regression analyses (CRA) using these TRGs. Functional enrichment analysis was performed using gene set enrichment analysis (GSEA). RESULTS: HCC patients were divided into three molecular subtypes (C1, C2, and C3) based on 704 prognosis-related TRGs. HCC subtype C1 had significantly better OS than C2 and C3. We selected 13 TRGs to construct the RS model. Univariate and multivariate CRA showed that the RS could independently predict patients' prognosis. A nomogram integrating the RS and clinicopathologic features of the patients was further created. We also validated the reliability of the model according to the area under the receiver operating characteristic (ROC) curve value, concordance index (C-index), and decision curve analysis. The current findings demonstrated that the RS was significantly correlated with CD8+ T cells, monocytic lineage, and myeloid dendritic cells. CONCLUSION: This study provided TRGs to help classify patients with HCC and predict their prognoses, contributing to personalized treatments for patients with HCC.

Influence of sex on outcomes of liver transplantation for hepatocellular carcinoma: a multicenter cohort study in China.

OBJECTIVE: Sex-specific differences are observed in various liver diseases, but the influence of sex on the outcomes of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains to be determined. This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC. METHODS: Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were analyzed. The associations between donor, recipient, or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching (PSM). The survival associated with different sex-based donor-recipient transplant patterns was further studied. RESULTS: Among 3,769 patients enrolled in this study, the 1-, 3-, and 5-year overall survival (OS) rates of patients with HCC after LT were 96.1%, 86.4%, and 78.5%, respectively, in female recipients, and 95.8%, 79.0%, and 70.7%, respectively, in male recipients after PSM (P = 0.009). However, the OS was comparable between recipients with female donors and male donors. Multivariate analysis indicated that male recipient sex was a risk factor for post-LT survival (HR = 1.381, P = 0.046). Among the donor-recipient transplant patterns, the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival (P < 0.05). CONCLUSIONS: Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients, and the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival. Livers from male donors may provide the most benefit to female recipients. Our results indicate that sex should be considered as a critical factor in organ allocation.

Role of CCR1/5/7 in hepatocellular carcinoma: a study on prognostic evaluation, molecular subtyping, and association with immune infiltration.

This study aims to assess the prognostic value of the C-C motif chemokine receptor (CCR) gene family in hepatocellular carcinoma (HCC) and its relationship with immune infiltration and molecular subtypes of HCC. The evaluation of the GSE14520 dataset and TCGA database confirmed the prognostic significance of CCR. Building upon the correlation between CCR1, CCR5, and CCR7 and favorable prognosis, we further validated the prognostic importance of CCR1, CCR5, and CCR7 in ICGC database and an independent cohort from Guangxi autonomous region. Then, we constructed a risk prognosis model. Additionally, we observed significant positive correlations between CCR1, CCR5, and CCR7 and the infiltration of B cells, T cells, and macrophages in HCC. Subsequently, we conducted CCK assays, Transwell assays, and colony formation assays to evaluate the molecular biological functions of CCR1, CCR5, and CCR7. These experiments further confirmed that upregulation of CCR1, CCR5, and CCR7 can individually inhibit the proliferation, migration, and stemness of HCC cells. By analyzing the relationship between expression levels and tumor mutation frequency, we discovered that patients with high CCR1 expression were more likely to be classified as non-proliferative HCC. Similar conclusions were observed for CCR5 and CCR7. The association of CCR1, CCR5, and CCR7 with the molecular subtypes of HCC suggests that they may serve as intermediary molecules linking immune status and molecular subtypes in HCC. In summary, CCR1, CCR5, and CCR7 have the potential to serve as prognostic biomarkers for HCC and regulate HCC progression by influencing immune cell infiltration.

Liver resection is superior to tumor ablation in patients with multifocal hepatocellular carcinoma.

INTRODUCTION: The management of T2 multifocal hepatocellular carcinoma (MHCC) is controversial, and the comparative impact of liver resection (LR) versus tumor ablation (TA) on survival continues to be debated. The aim of our study was to examine short- and long-term survival for LR and TA in a nationally representative cohort. We hypothesized that patients who underwent LR would have improved survival. METHODS: We utilized the National Cancer Database (2004-2015) to identify patients diagnosed with non-metastatic T2 MHCC. Kaplan-Meier survival curves were generated to compare 10-year overall survival (OS) between LR and TA patients. Kaplan-Meier analysis with stratification was also performed based on lymphovascular invasion, resection margin status, and Charlson-Deyo score. Cox proportional hazard models were used in multivariable analyses. RESULTS: A total of 1225 patients met the inclusion criteria. 991 patients received LR, and 234 received TA. The majority of patients were male, White, and older than ≥60 years old. Clinicodemographic characteristics were generally similar between LR and TA patients. Among patients who underwent LR, 84% had negative margins, and 17% had lymphovascular invasion. Mortality at 30 days was significantly higher among LR patients compared to TA patients (5.4% vs 0.0%, p < 0.001), with those having a Charlson-Deyo score ≥2 facing the highest risk at 7.3%. Nevertheless, 10-year OS for the LR cohort was 27.5% (95% confidence interval [CI]: 24.4%-30.8%) versus 14.7% (95% CI: 9.8%-20.7%, p < 0.001) for TA patients. In stratified analysis, survival benefit was statistically significant only among those with negative resection margin, no lymphovascular invasion, and Charlson-Deyo score ≤1. In multivariable Cox analysis, LR was independently associated with improved survival compared to TA (hazard ratio: 0.80; 95% CI = 0.67-0.95). CONCLUSION: LR poses a higher long-term survival benefit than TA. Prospective studies are warranted to confirm these findings. Although our study patients are a highly selected group of multifocal T2 patients, it gives us a good insight into the fact that LR provides better outcomes if a transplant option is unavailable.

Prognostic Nutritional Index as a Prognostic Factor for Very Early-Stage Hepatocellular Carcinoma.

INTRODUCTION: Field factors play more important roles in predicting the outcomes of patients compared with tumor factors in early-stage hepatocellular carcinoma (HCC). However, the prognostic ability of noninvasive serum marker scores for hepatic fibrosis and liver functional reserve on very early-stage HCC is still not yet determined. We aimed to investigate the performance of these serum marker scores in predicting the prognoses of patients with very early-stage HCC. METHODS: A total of 446 patients with very early-stage HCC from 2012 to 2022 were retrospectively enrolled. Serum biomarkers and prognostic scores determining overall survival (OS) were analyzed by Cox proportional hazards model. We compared the Akaike information criterion among the prognostic nutritional index (PNI), aspartate aminotransferase-to-platelet ratio index, albumin-bilirubin (ALBI) score, EZ (easy)-ALBI score, modified ALBI score, fibrosis-4 score, and lymphocyte-to-monocyte ratio to determine the predictability on the OS. RESULTS: After a median follow-up of 41.0 months (interquartile range 36.9-45.1 months), 81 patients died, with a 5-year OS rate of 71.0%. Among the noninvasive serum marker scores, PNI had the best performance in predicting the OS with the lowest Akaike information criterion (846.407) compared with other scores. Moreover, we stratified the patients into high-risk (PNI <45) and low-risk (PNI ≥45) groups. It showed that the 5-year OS rates were 83.4% and 60.8% in the low-risk and high-risk PNI groups, respectively ( P < 0.001). DISCUSSION: PNI had the best performance in predicting the OS for patients with very early-stage HCC.

Association of nativity with survival among adults with hepatocellular carcinoma.

INTRODUCTION: Immigrants comprise a considerable proportion of those diagnosed with hepatocellular carcinoma (HCC) in the United States. Nativity or birthplace affects incidence and risk factors for HCC, but little is known about its influence on survival after diagnosis. METHODS: We identified 51 533 adults with HCC with available birthplace in the California Cancer Registry between 1988 and 2017. HCC cases were categorized as foreign born or US born and stratified by mutually exclusive race and ethnicity groups. Primary outcome was all-cause mortality. Race and ethnicity-specific Cox regression propensity score-weighted models evaluated the relationship between nativity and death as well as region of birth among foreign-born patients. RESULTS: A total of 40% of all HCC cases were foreign born, and 92.2%, 45.2%, 9.1%, and 5.8% of Asian/Pacific Islander (API), Hispanic, White, and Black patients were foreign born, respectively. Five-year survival rates were higher in foreign-born patients compared with US-born patients: 12.9% vs 9.6% for White patients, 11.7% vs 9.8% for Hispanic patients, 12.8% vs 8.1% for Black patients, and 16.4% vs 12.4% for API patients. Nativity was associated with survival, with better survival in foreign-born patients: White patients: hazard ratio (HR) = 0.86 (95% confidence interval [CI] = 0.81 to 0.90), Hispanic patients: HR = 0.90 (95% CI = 0.86 to 0.93), Black patients: HR = 0.89 (95% CI = 0.76 to 1.05), and API patients: HR = 0.94 (95% CI = 0.88 to 1.00). Among foreign-born patients, lower mortality was observed in those from Central and South America compared with Mexico for Hispanic patients, East Asia compared with Southeast Asia for API patients, and East Europe and Greater Middle East compared with West/South/North Europe for White patients. CONCLUSION: Foreign-born patients with HCC have better survival than US-born patients. Further investigation into the mechanisms of this survival disparity by nativity is needed.

Associations of Race and Ethnicity with Hepatocellular Carcinoma, Decompensation, and Mortality in US Veterans with Cirrhosis.

BACKGROUND: Among patients with cirrhosis, it remains unclear whether there are racial/ethnic differences in cirrhosis complications and mortality. We examined the associations between race/ethnicity and risk for hepatocellular carcinoma (HCC), cirrhosis decompensation, and all-cause mortality overall and by cirrhosis etiology. METHODS: US Veterans diagnosed with cirrhosis from 2001 to 2014 (n = 120,992), due to hepatitis C virus (HCV; n = 55,814), alcohol-associated liver disease (ALD; n = 36,323), hepatitis B virus (HBV; n = 1,972), nonalcoholic fatty liver disease (NAFLD; n = 17,789), or other (n = 9,094), were followed through 2020 for incident HCC (n = 10,242), cirrhosis decompensation (n = 27,887), and mortality (n = 81,441). Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). RESULTS: Compared with non-Hispanic White patients, Hispanic patients had higher risk for HCC overall (aHR, 1.32; 95% CI, 1.24-1.41) and by cirrhosis etiology, particularly for ALD- (aHR, 1.63; 95% CI, 1.42-1.87) and NAFLD-cirrhosis (aHR, 1.76; 95% CI, 1.41-2.20), whereas non-Hispanic Black patients had lower HCC risk in ALD- (aHR, 0.79; 95% CI, 0.63-0.98) and NAFLD-cirrhosis (aHR, 0.54; 95% CI, 0.33-0.89). Asian patients had higher HCC risk (aHR, 1.70; 95% CI, 1.29-2.23), driven by HCV- and HBV-cirrhosis. Non-Hispanic Black patients had lower risk for cirrhosis decompensation overall (aHR, 0.71; 95% CI, 0.68-0.74) and by cirrhosis etiology. There was lower risk for mortality among all other racial/ethnic groups compared with non-Hispanic White patients. CONCLUSIONS: Race/ethnicity is an important predictor for risk of developing HCC, decompensation, and mortality. IMPACT: Future research should examine factors underlying these racial/ethnic differences to inform prevention, screening, and treatment for patients with cirrhosis.

Disparities in Hepatocellular Carcinoma Outcomes Among Subgroups of Asians and Pacific Islanders: A SEER Database Study.

Hepatocellular carcinoma (HCC) is highly prevalent in Asians and Pacific Islanders (API) but this heterogenous group is often aggregated into a single category, despite vast differences in culture, socioeconomic status, education, and access to care among subgroups. There remains a significant knowledge gap in HCC outcomes among different subgroups of API. The Surveillance, Epidemiology, and End Results (SEER) database was accessed, and site/ICD codes were used to identify HCC patients during 2010-2019 who were API ethnicity. Data collected: demographics, socioeconomic status, tumor characteristics, treatment, and survival. Subgroup analyses were performed among different Asian ethnicities in a secondary analysis. 8,249 patients were identified/subdivided into subgroups of Asian ethnicities and Other Pacific Islanders (NHOPI) groups. The median age was 65 years for Asians and 62 years for NHOPI (p < 0.01), and significant differences were found in income (p < 0.01). A higher proportion of NHOPI lived in rural areas compared to Asians (8.1 vs. 1.1%, p < 0.01). There were no statistically significant differences in tumor size, stage, pre-treatment AFP level, or surgical treatments between the two groups. However, Asians had higher overall median survival than NHOPI (20 months v 12 months, p < 0.01). Secondary analyses among different subgroups of Asian ethnicities revealed significant differences in tumor size and staging, surgical resection, transplant rates, and median survival. While API had similar tumor characteristics and treatment, Asians had much higher survival than NHOPI. Socioeconomic differences and access to care may contribute to these differences. This study also found significant survival disparities within API ethnicities.

Impact of skeletal muscle volume on patients with BCLC stage-B hepatocellular carcinoma undergoing sorafenib therapy.

AIM: Skeletal muscle volume has been reported to be an important factor that determines overall survival (OS) and post-progression survival (PPS) in patients with hepatocellular carcinoma (HCC). However, the impact of skeletal muscle volume on HCC with Barcelona Clinic Liver Cancer (BCLC) stage B (BCLC-B) remains unclear. We conducted sub-analyses of a previous study on BCLC-B and compared our findings with data on HCC with BCLC stage C (BCLC-C). METHODS: We retrospectively enrolled 356 patients with HCC (BCLC-B, n = 78; and BCLC-C, n = 278) undergoing sorafenib therapy. Prognostic factors were analyzed using various parameters, including skeletal muscle volume. Muscle volume (MV) depletion was designated as less than the median value of the skeletal muscle index for each gender (cutoff value: 45.0 cm2 /m2 for male and 38.0 cm2 /m2 for female participants). RESULTS: Both OS and PPS showed no significant differences in patients with non-MV depletion and those with MV depletion in the BCLC-B group (Median OS [MST] 19.3 vs. 13.5 months [p = 0.348]; median PPS 9.7 vs. 10.8 months [p = 0.578]). In the BCLC-C group, patients with non-MV depletion had a significantly longer OS and PPS compared to patients with MV depletion (MST 12.4 vs. 9.0 months [p = 0.001] and median PPS 7.9 vs. 5.4 months [p = 0.002]). Multivariate analysis revealed that MV depletion was an independent prognostic factor of OS and PPS in the BCLC-C group but not in the BCLC-B group. CONCLUSIONS: Skeletal muscle volume showed little impact on the clinical outcomes of patients with BCLC-B undergoing sorafenib therapy.

New Pyroptosis -Associated Gene Signature for Overall Survival Forecast among Patients Suffering from Hepatocellular Carcinoma.

Due to the heterogeneity of tumors, we do not understand the given effect of pyroptosis on hepatocellular carcinoma (HCC) fully, particularly its influences on prognosis. The paper aims at exploring the prognostic value of pyroptosis-associated genes and its role in immune status in HCC. A multigene prognostic signature is set up by utilizing the least absolute shrinkage and choosing operator Cox exploration. The comparison of survival between different risk groups is made with the Kaplan-Meier exploration and Cox regression. LASSO Cox regression analysis is adopted to set up a pyroptosis-associated gene signature (CEP55 and MMP1). By comparing with the group at low risks, the high-risk group displayed greatly decreased OS. The fatidic ability of the prognostic gene signature is confirmed by the receiver-running feature curve analysis. According to multivariate Cox exploration, the risk mark is an independent predicting agent for OS. A new signature established with two pyroptosis-associated genes can be adopted for prognostic forecast and influence the immune situation in HCC.

Transarterial chemoembolization combined with camrelizumab for recurrent hepatocellular carcinoma.

PURPOSE: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with camrelizumab (hereafter, TACE-camrelizumab) in the treatment of patients with recurrent hepatocellular carcinoma (R-HCC) after curative resection. PATIENTS AND METHODS: R-HCC patients who underwent TACE plus camrelizumab or TACE-alone from January 2016 to August 2021 were retrospectively evaluated. Patients were assessed for tumor response, progression-free survival, survival rates and adverse events. RESULTS: Seventy-one patients were included in this study, including 20 patients in the TACE- camrelizumab group and 51 patients in the TACE-alone group. The objective response rate was 56.9% in the TACE-alone group and 40% in the TACE-camrelizumab group at 3 months (P = 0.201). The disease control rates were 84.3% in TACE-alone group and 80% in TACE-camrelizumab group at 3 months (P = 0.663). The progression-free survival (PFS) of the TACE-alone group was slightly longer than those of the TACE- camrelizumab group (9 months vs. 6 months). However, there were no statistically significant differences in the median PFS (P = 0.586). Similarly, there were no significant differences in the half-year and one-year survival rates (P = 0.304, P = 0.430). Multivariate analysis revealed that Neutrophil-to-lymphocyte ratio (NLR) was associated with PFS significantly. 75% patients developed at least one type of AEs related to camrelizumab in TACE-camrelizumab group, and no patients developed severe AEs. CONCLUSION: Comparing with TACE-Alone, the efficacy of TACE-camrelizumab for patients with R-HCC was similar. Meanwhile, the results of this study also indicated that TACE is still a better choice for patients with R-HCC.

Development of nomogram models of inflammatory markers based on clinical database to predict prognosis for hepatocellular carcinoma after surgical resection.

BACKGROUND: Inflammation plays a significant role in tumour development, progression, and metastasis. In this study, we focused on comparing the predictive potential of inflammatory markers for overall survival (OS), recurrence-free survival (RFS), and 1- and 2-year RFS in hepatocellular carcinoma (HCC) patients. METHODS: A total of 360 HCC patients were included in this study. A LASSO regression analysis model was used for data dimensionality reduction and element selection. Univariate and multivariate Cox regression analyses were performed to identify the independent risk factors for HCC prognosis. Nomogram prediction models were established and decision curve analysis (DCA) was conducted to determine the clinical utility of the nomogram model. RESULTS: Multivariate Cox regression analysis indicated that the prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) were independent prognostic factors of OS, and aspartate aminotransferase-to-platelet ratio (APRI) was a common independent prognostic factor among RFS, 1-year RFS, and 2-year RFS. The systemic inflammation response index (SIRI) was an independent prognostic factor for 1-year RFS in HCC patients after curative resection. Nomograms established and achieved a better concordance index of 0.772(95% CI: 0.730-0.814), 0.774(95% CI: 0.734-0.815), 0.809(95% CI: 0.766-0.852), and 0.756(95% CI: 0.696-0.816) in predicting OS, RFS, 1-year RFS, and 2-year RFS respectively. The risk scores calculated by nomogram models divided HCC patients into high-, moderate- and low-risk groups (P < 0.05). DCA analysis revealed that the nomogram models could augment net benefits and exhibited a wider range of threshold probabilities in the prediction of HCC prognosis. CONCLUSIONS: The nomograms showed high predictive accuracy for OS, RFS, 1-year RFS, and 2-year RFS in HCC patients after surgical resection. The nomograms could be useful clinical tools to guide a rational and personalized treatment approach and prognosis judgement.

ANP32 Family as Diagnostic, Prognostic, and Therapeutic Biomarker Related to Immune Infiltrates in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, with high incidence and mortality rate. There is an urgent need to identify effective diagnostic and prognostic biomarkers for HCC. Members of the acidic leucine-rich nucleophosphoprotein 32 (ANP32) family, which mainly includes ANP32A, ANP32B, and ANP32E, are abnormally expressed and have prognostic value in certain cancers. However, the diagnostic, prognostic, and therapeutic value of ANP32 family members in HCC has not yet been fully studied. In this study, we identified the diagnostic and prognostic value of ANP32 family members in HCC. Transcriptome data from public databases, such as the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, suggested that ANP32A, ANP32B, and ANP32E were upregulated in HCC tissues, and high expression of ANP32 family members was associated with advanced pathologic stage and histologic grade. Our immunohistochemistry and western blot results further verified the differential expression of ANP32 family members. ANP32A, ANP32B, and ANP32E had an outstanding diagnostic potential. Survival analysis of HCC patients in TCGA databases demonstrated that ANP32A, ANP32B, and ANP32E were associated with poor overall survival (OS) and disease-specific survival (DSS). Univariate and multivariate Cox analyses suggested the capability of ANP32B and ANP32E to independently predict the OS and DSS of HCC patients. Gene set enrichment analysis (GSEA) showed that ANP32 family members were associated with immune response, epidermal cell differentiation, and stem cell proliferation. Expression of ANP32 family members was associated with immune cell infiltration and immune status in the tumor microenvironment of HCC, and patients with high ANP32 family expression had poor sensitivity to immunotherapy. Finally, we identified potential chemotherapy drugs for HCC patients with high ANP32 family expression by CellMiner database. This study suggested the diagnostic, prognostic, and therapeutic roles of the ANP32 family in HCC patients, providing potential therapeutic targets for HCC.

Prognostic utility of systemic inflammatory markers and chronic hepatitis C virus infection status in hepatocellular carcinoma patients treated with local ablation.

BACKGROUND: Hepatocellular carcinoma (HCC) has high incidence and mortality worldwide. Local ablation using radiofrequency ablation (RFA) or microwave ablation (MWA) is potentially curative for early-stage HCC with outcomes comparable to surgical resection. We explored the influence of demographic, clinical, and laboratory factors on outcomes of HCC patients receiving ablation. METHODS: This retrospective cohort study included 221 HCC patients receiving local ablation at Mayo Clinic between January 2000 and October 2018, comprising 140 RFA and 81 MWA. Prognostic factors determining overall survival (OS) and disease-free survival (DFS) were identified using multivariate analysis. RESULTS: There was no clinically significant difference in OS or DFS between RFA and MWA. In multivariate analysis of OS, pre-ablation lymphocyte-monocyte ratio [Hazard ratio (HR) 0.7, 95% confidence interval (CI) 0.58-0.84, P = 0.0001], MELD score [HR 1.12, 95%CI 1.068-1.17, P <  0.0001], tumor number [HR 1.23, 95%CI 1.041-1.46, P = 0.015] and tumor size [HR 1.18, 95%CI 1.015-1.37, P = 0.031] were clinically-significant prognostic factors. Among HCC patients with chronic hepatitis C (HCV) infection, positive HCV PCR at HCC diagnosis was associated with 1.4-fold higher hazard of death, with 5-year survival of 32.8% vs 53.6% in HCV PCR-negative patients. Regarding DFS, pre-ablation lymphocyte-monocyte ratio [HR 0.77, 95%CI 0.66-0.9, P = 0.001], MELD score [HR 1.06, 95%CI 1.022-1.11, P = 0.002], Log2 AFP [HR 1.11, 95%CI 1.033-1.2, P = 0.005], tumor number [HR 1.29, 95%CI 1.078-1.53, P = 0.005] and tumor size [HR 1.25, 95%CI 1.043-1.51 P = 0.016] were independently prognostic. CONCLUSIONS: Pre-ablation systemic inflammation represented by lymphocyte-monocyte ratio is significantly associated with OS and DFS in HCC patients treated with local ablation. HCV viremia is associated with poor OS. Tumor biology represented by tumor number and size are strongly prognostic for OS and DFS while AFP is significantly associated with DFS only.

Racial/ethnic disparities in hepatocellular carcinoma incidence and mortality rates in the United States, 1992-2018.

BACKGROUND AND AIMS: HCC is characterized by racial/ethnic disparities in rates. Recent USA reports suggest that incidence has begun to decline, but it is not clear whether the declines have occurred among all groups, nor whether mortality has declined. Thus, the current study examined USA incidence and mortality between 1992 and 2018. APPROACH & RESULTS: HCC incidence and incidence-based mortality data from the Surveillance, Epidemiology, and End Results program were used to calculate age-standardized rates by race/ethnicity, sex, and age. Trends were analyzed using joinpoint regression to estimate annual percent change (APC). Age-period-cohort models assessed the effects on trends of age, calendar period, and birth cohort. Overall, HCC incidence significantly declined between 2015 and 2018 (APC, -5.6%). Whereas most groups experienced incidence declines, the trends were most evident among Asians/Pacific Islanders, women, and persons <50 years old. Exceptions were the rates among non-Hispanic Black persons, which did not significantly decline (APC, -0.7), and among American Indians/Alaska Natives, which significantly increased (APC, +4.3%). Age-period-cohort modeling found that birth cohort had a greater effect on rates than calendar period. Among the baby boom cohorts, the 1950-1954 cohort had the highest rates. Similar to the overall incidence decline, HCC mortality rates declined between 2013 and 2018 (APC, -2.2%). CONCLUSIONS: HCC incidence and mortality rates began to decline for most groups in 2015, but persistent differences in rates continued to exist. Rates among non-Hispanic Black persons did not decline significantly, and rates among American Indians/Alaska Natives significantly increased, suggesting that greater effort is needed to reduce the HCC burden among these vulnerable groups.

Stereotactic body radiation therapy as a salvage treatment for single viable hepatocellular carcinoma at the site of incomplete transarterial chemoembolization: a retrospective analysis of 302 patients.

BACKGROUND: To evaluate the clinical outcomes of patients who received stereotactic body radiation therapy (SBRT) for single viable hepatocellular carcinoma (HCC) at the site of incomplete transarterial chemoembolization (TACE). METHODS: Patients treated with SBRT for single viable HCC after incomplete TACE between 2012 and 2017 at Asan Medical Center (Seoul, South Korea) were included. Incomplete TACE was defined as (1) evidence of viable HCC at the site of TACE on follow-up dynamic computed tomography (CT) or magnetic resonance imaging following one or more consecutive TACEs, (2) no definite tumor staining on superselective hepatic angiogram, or (3) no definite iodized oil uptake on post-embolization angiogram or CT. Doses of 10-15 Gy per fraction were given over 3-4 consecutive days. The primary outcome was local control rate at 3 years and secondary outcome included tumor response, overall survival rate, out-of-field intrahepatic recurrence-free survival, distant metastasis-free survival and treatment-related toxicities. Treatment-related adverse events were evaluated according to the common terminology criteria for adverse events, version 4.03. RESULTS: A total of 302 patients were analyzed. The median follow-up duration was 32.9 months (interquartile range [IQR], 23.6-41.7) and the median tumor size was 2.0 cm (range, 0.7-6.9). The local control (LC) and overall survival rates at 3 years were 91.2 and 72.7%, respectively. 95.4% of the tumors reached complete response (CR) during the entire follow-up period (anyCR). The median interval from SBRT to anyCR was 3.4 months (IQR, 1.9-4.7), and 39.9 and 83.3% of the lesions reached CR at 3- and 6-months after SBRT, respectively. Radiation-induced liver disease was observed in 8 (2.6%) patients. No patients experienced gastroduodenal bleeding within the radiation field. CONCLUSION: SBRT could be considered a feasible salvage treatment option for HCC after incomplete TACE.

The survival strength of younger patients in BCLC stage 0-B of hepatocellular carcinoma: basing on competing risk model.

BACKGROUND: The number of young patients with hepatocellular carcinoma (HCC) is increasing, but whether patients of different ages have a survival advantage is unclear. This study was conducted to investigate whether age differences in the Barcelona Clinic Liver Cancer (BCLC) classification system contribute to the long-term survival outcomes of patients with HCC. METHODS: A total of 1602 patients with HCC admitted to the Beijing Ditan Hospital was included in this study. Patients were divided into younger (≤45 years) and older (> 45 years) groups. Factors determining overall survival and progression-free survival were analyzed using univariate and multivariate analyses with the Kaplan-Meier method and Cox proportional hazard regression model. We calculated the cumulative incidence function using the Fine-Gray model. The effect of mortality on age was also estimated using a restricted cubic spline. RESULTS: After matching, overall survival and progression-free survival were significantly better in younger patients than in older patients with BCLC stage 0-B (p = 0.015 and p = 0.017, respectively). In BCLC stage 0-B, all-cause mortality increased with age and increased rapidly around the age of 40 years (non-linear, p < 0.05). In BCLC stages 0-B, HCC-related and non-HCC-related deaths significantly differed between younger and older individuals (p = 0.0019). CONCLUSION: In stage BCLC 0-B, age affects the long-term prognosis of patients.

The pyroptosis-related gene signature predicts prognosis and indicates immune activity in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the most common malignant tumors with poor survival. Pyroptosis is a kind of programmed cell death that can regulate the proliferation, invasion, and metastasis of tumor cells. However, the expression levels of pyroptosis-related genes (PRGs) in HCC and their relationship with prognosis are still unclear. METHODS: Our study identified 35 PRGs through bioinformatics analysis that were differentially expressed between tumor samples and nontumor samples. According to these differentially expressed genes, HCC patients could be divided into two groups, cluster 1 and cluster 2. The least absolute shrinkage and selection operator (LASSO) Cox regression method was performed to construct a 10-gene signature that classified HCC patients in the cancer genome atlas (TCGA) database into low-risk and high-risk groups. RESULTS: The results showed that the survival rate of HCC patients in the low-risk group was significantly higher than that in the high-risk group (p < 0.001). The validation cohort, the Gene Expression Omnibus (GEO) cohort, was divided into two risk groups based on the median risk score calculated by the TCGA cohort. The overall survival (OS) of the low-risk group was significantly better than that of the high-risk group (p = 0.007). Univariate and multivariate Cox regression analyses revealed that the risk score was an independent factor in predicting OS in HCC patients. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that immune-related high-risk groups were rich in genes and had reduced immune status. CONCLUSIONS: PRGs play a significant role in tumor immunity and have the potential capability to predict the prognosis of HCC patients.