• 16S rRNA gene sequencing
• bacterial components
• hepatocellular carcinoma
• intratumoral microbiome
• tumor-associated immune cells

• Humans
• Carcinoma, Hepatocellular/microbiology
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/microbiology
• Liver Neoplasms/pathology
• Liver Neoplasms/mortality
• Male
• Prognosis
• Female
• Middle Aged
• Microbiota/genetics
• Bacteria/classification
• Bacteria/genetics
• Bacteria/isolation & purification
• RNA, Ribosomal, 16S/genetics
• Aged

• 2021ZQNZD009 Major Science Research Program for Young and Middle-aged Health Professionals of Fujian Province, China
• 2021J01445 | Natural Science Foundation of Fujian Province (Fujian Natural Science Foundation)
• 2023J011262 | Natural Science Foundation of Fujian Province (Fujian Natural Science Foundation)
• 2021Y9197 Joint Fund for the Innovation of Science and Technology of Fujian Province, China
• 2021Y9232 Joint Fund for the Innovation of Science and Technology of Fujian Procince, China
• 福建省科技厅 | Natural Science Foundation of Fujian Province (Fujian Natural Science Foundation)

• LASSO regression
• SEER database
• hepatocellular carcinoma (HCC)
• nomogram
• overall survival (OS)
• radiation therapy (RT)

• Bone fragility
• Bone metastases
• Hepatocellular carcinoma
• Osteopenia
• Osteoporosis
• Sarcopenia

• Humans
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/mortality
• Liver Neoplasms/therapy
• Liver Neoplasms/pathology
• Liver Neoplasms/mortality
• Prognosis
• Sarcopenia/etiology
• Sarcopenia/diagnosis
• Sarcopenia/therapy
• Liver Transplantation
• Quality of Life
• Bone Neoplasms/therapy
• Bone Neoplasms/complications
• Bone Neoplasms/secondary
• Bone Neoplasms/pathology
• Bone Neoplasms/mortality
• Risk Factors
• Bone Density
• Musculoskeletal Diseases/therapy
• Musculoskeletal Diseases/diagnosis
• Musculoskeletal Diseases/etiology
• Musculoskeletal Diseases/physiopathology
• Musculoskeletal System/physiopathology
• Musculoskeletal System/pathology

• SEER database
• external beam radiation therapy
• hepatocellular carcinoma
• overall survival
• web-based nomogram

• Humans
• Carcinoma, Hepatocellular/radiotherapy
• East Asian People
• Internet
• Liver Neoplasms/radiotherapy
• Nomograms

• Sanming Project of Medicine in Shenzhen

No prognostic models specific to hepatocellular carcinoma patients receiving surgical resection have been considered strong and convincing enough for survival prediction thus far, and there are no models including only preoperative predictors. We derived a nomogram to predict disease-free survival in a previous study.

To simplify our score and compare research outcomes among other scoring systems.

We retrospectively reviewed data from 1106 patients with hepatocellular carcinoma who underwent liver resection at the Linkou Chang Gung Memorial Hospital between April 2003 and December 2012. Multivariate analyses were conducted to identify the significant survival predictors. Homogeneity, Harrell’s C-index, and Akaike information criterion were compared between our score, AJCC 8^th edition, Tokyo score, and Taipei Integrated Scoring System (TTV-CTP-AFP model).

Among the 1106 patients, 731 (66.1%) had tumor recurrence at a median follow-up of 83.9 mo. Five risk factors were identified: platelet count, albumin level, indocyanine green retention rate, multiplicity, and radiologic total tumor volume. Patients were divided into three risk groups, and the 5-year survival rates were 61.7%, 39%, and 25.7%, respectively. The C-index was 0.617, which was higher than the Tokyo score (0.613) and the Taipei Integrated Scoring System (0.562) and equal to the value of the AJCC 8^th edition (0.617).

The modified score provides an easier method to predict survival. Appropriate treatment can be planned preoperatively by dividing patients into risk groups.

• Hepatocellular carcinoma
• Preoperative
• Prediction
• Tumor recurrence

Prognostic assessment is imperative for clinical management of patients with hepatocellular carcinoma (HCC). Most reported prognostic signatures are based on risk scores summarized from quantitative expression level of candidate genes, which are vulnerable against experimental batch effects and impractical for clinical application. We aimed to develop a robust qualitative signature to assess individual survival risk for HCC patients.

Long non-coding RNA (lncRNA) pairs correlated with overall survival (OS) were identified and an optimal combination of lncRNA pairs based on the majority voting rule was selected as a classification signature to predict the overall survival risk in the cancer genome atlas (TCGA). Then, the signature was further validated in two external datasets. Besides, biomolecular characteristics, immune infiltration status, and chemotherapeutics efficacy of different risk groups were further compared. Finally, we performed key lncRNA screening and validated it in vitro.

A signature consisting of 50 lncRNA pairs (50-LPS) was identified in TCGA and successfully validated in external datasets. Patients in the high-risk group, when at least 25 of the 50-LPS voted for high risk, had significantly worse OS than the low-risk group. Multivariate Cox, receiver operating characteristic (ROC) curve and decision curve analyses (DCA) demonstrated that the 50-LPS was an independent prognostic factor and more powerful than other available clinical factors in OS prediction. Comparison analyses indicated that different risk groups had distinct biomolecular characteristics, immune infiltration status, and chemotherapeutics efficacy. TDRKH-AS1 was confirmed as a key lncRNA and associated with cell growth of HCC.

The 50-LPS could not only predict the prognosis of HCC patients robustly and individually, but also provide theoretical basis for therapy. Besides, TDRKH-AS1 was identified as a key lncRNA in the proliferation of HCC. The 50-LPS might guide personalized therapy for HCC patients in clinical practice.

The online version contains supplementary material available at 10.1186/s12935-022-02507-z.

• Hepatocellular carcinoma
• LncRNA pairs
• Precision medicine
• Risk stratification

Microvascular invasion (MVI) is a significant risk factor affecting survival outcomes of patients after R0 liver resection (LR) for hepatocellular carcinoma (HCC). However, whether the existing staging systems of hepatocellular carcinoma can distinguish the prognosis of patients with MVI and the prognostic value of MVI in different subtypes of hepatocellular carcinoma remains to be clarified.

A dual-center retrospective data set of 1,198 HCC patients who underwent R0 LR was included in the study between 2014 and 2016. Baseline characteristics and staging information were collected. Homogeneity and modified Akaike information criterion (AICc) were compared between each system. And the prognostic significance of MVI for overall survival (OS) was studied in each subgroup.

In the entire cohort, there were no significant survival differences between Cancer of the Liver Italian Program (CLIP) score 2 and 3 (p = 0.441), and between Taipei Integrated Scoring System (TIS) score 3 and 4 (p = 0.135). In the MVI cohort, there were no significant survival differences between Barcelona Clinic Liver Cancer stages B and C (p=0.161), CLIP scores 2 and 3 (p = 0.083), TIS scores 0 and 1 (p = 0.227), TIS scores 2 and 3 (p =0.794), Tokyo scores 3 and 4 (p=0.353), and American Joint Committee on Cancer Tumor-Node-Metastasis 7^th stage I and II (p=0.151). Among the eight commonly used HCC staging systems, the Hong Kong Liver Cancer (HKLC) staging system showed the highest homogeneity and the lowest AICc value in both the entire cohort and MVI cohort. In each subgroup of the staging systems, MVI generally exhibited poor survival outcomes.

The HKLC staging system was the most accurate model for discriminating the prognosis of MVI patients, among the eight staging systems. Meanwhile, our findings suggest that MVI may be needed to be incorporated into the current HCC staging systems as one of the grading criteria.

• bi-centeric
• hepatocellular carcinoma
• microvascular invasion
• prognosis
• staging system

• Hepatocellular carcinoma (HCC)
• overall survival (OS)
• portal vein tumor thrombus (PVTT)
• staging system

• Hepatocellular carcinoma (HCC)
• drug-eluting beads-transarterial chemoembolization (DEB-TACE)
• initial response
• propensity-score matching (PSM)
• transarterial bland embolization (TABE)

Preoperative locoregional treatment (LRT) for hepatocellular carcinoma (HCC) often induces intratumoral necrosis without affecting the overall tumor size, and residual viable tumor size (VTS) on imaging is an important clinical parameter for assessing post-treatment response. However, for surgical specimens, it is unclear whether the VTS would be more relevant to prognosis compared to total tumor size (TTS).

A total of 142 surgically resected solitary HCC cases were retrospectively reviewed. The TTS and VTS were assessed by applying the modified Response Evaluation Criteria in Solid Tumors method to the resected specimens, and correlated with the clinicopathological features and survival.

As applying VTS, 13/142 cases (9.2%) were down-staged to ypT1a. Although the survival analysis results for overall survival according to TTS or VTS were similar, VTS was superior to predict disease-free survival (DFS; p = .023) compared to TTS (p = .08). In addition, multivariate analysis demonstrated VTS > 2 cm to be an independent predictive factor for decreased DFS (p = .001). In the subpopulation of patients with LRT (n = 54), DFS in HCCs with TTS or VTS > 2 cm were significantly shorter than those with TTS or VTS ≤ 2 cm (p = .047 and p = .001, respectively). Interestingly, HCCs with TTS > 2 cm but down-staged to VTS ≤ 2 cm after preoperative LRT had similar survival to those with TTS ≤ 2 cm.

Although the prognostic impact of tumor size was similar regardless of whether TTS or VTS was applied, reporting VTS may help to increase the number of candidates for surgery in HCC patients with preoperative LRT.

• Hepatocellular carcinoma
• Necrosis
• Neoadjuvant therapy
• Prognosis
• Tumor size

Sex-determining region Y-box 2 (SOX2) is a stem cell transcription factor and a major regulator of self-renewal and pluripotency of cancer stem cells (CSCs). In many types of cancer, SOX2 is dysregulated due to overexpression associated with tumor progression and low survival rate. Many HCC cases encounter recurrence and metastasis which might be due to CSCs and also apoptosis. Since little is known about the expression pattern of SOX2 and apoptotic genes in HCC, we aimed to determine the prognostic significance of SOX2, Bax, and Bcl-2 in clinicopathological features, tumor progression, and survival rate of the HCC patients. The expression of SOX2, Bax, and Bcl-2 were evaluated using qRT-PCR in 53 formalin-fixed, paraffin-embedded tissues (FFPE) of patients and 44 controls. Correlation of these genes was analyzed with clinicopathological features and tumor progression. The correlationship between SOX2 expression and ALBI grade as prognostic indicators were calculated. Survival rates were determined by Kaplan–Meier survival curves. SOX2 and Bcl-2 were remarkably overexpressed in HCC patients compared to controls (p = 0.04 and p = 0.003, respectively). A significant association was found for both SOX2 and Bcl-2 overexpression with TNM staging (p = 0.02, p = 0.04) and tumor grading (p = 0.01, p = 0.003), respectively. A significant correlation was observed: patients with SOX2 overexpression had a lower 5-year overall survival rate (p = 0.04); however, there was no significant association between Bcl-2 and survival (p = 0.5). Collectively, overexpression of SOX2 and Bcl-2, alone or combined, may be a potential marker to evaluate prognosis and response to HCC treatment.

• Bax
• Bcl-2
• SRY-box 2 (SOX2)
• cancer stem cell
• hepatocellular carcinoma

• DAA
• HCC
• HCC recurrence
• HCV
• hepatitis C virus
• hepatocellular carcinoma
• locoregional therapy
• surgery

• NMR spectroscopy
• hepatocellular carcinoma
• metabolomics
• predictive model
• proteomics

• P 28854 Austrian Science Fund FWF
• I 3792 Austrian Science Fund FWF

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Recent studies showed that snRNPs were implicated in human cancer development. The role of SNRPA1, which is a member of U2 snRNPs, in HCC, remains undocumented. Here, we found that SNRPA1 was highly expressed in HCC tissue compared with normal adjacent liver tissues. Up-regulation of SNRPA1 was correlated with the clinical stage of HCC and the overall survival of HCC patients. In vitro and in vivo results showed that knockdown of SNPRA1 inhibited the cell proliferation, colony formation and xenografted tumorigenesis of HCC cells. Apoptosis was induced by SNPRA1 down-regulation. Mechanistically, SNPRA1 was stimulated by mTOR activation. In addition, whole-genome microarray analysis identified that 262 genes were up-regulated and 462 genes were down-regulated by SNPRA1 knockdown in HCC cells. qPCR analysis suggested that the fibroblast growth factor-2 (FGF2), Alpha-fetoprotein (AFP), β-catenin, Ki-67 and cyclin B1 were down-regulated and caspase 3, p53 as well as p21 were up-regulated after SNRPA1 knockdown. Taken together, our findings implicate that SNPRA1 functions as an oncogene in HCC.

• HCC
• SNPRA1
• apoptosis
• cell proliferation
• mTOR

• (SEER) database
• hepatocellular carcinoma
• nomogram
• pulmonary metastasis

Hepatocellular carcinoma (HCC) represents the most common primitive liver malignancy. A relevant concern involves the lack of agreement on staging systems, prognostic scores, and treatment allocation algorithms. 

To compare the survival rates among already developed prognostic scores.

We retrospectively evaluated 140 patients with HCC diagnosed between February 2006 and November 2017. Patients were categorized according to 15 prognostic scoring systems and estimated median survivals were compared with those available from the current medical literature.

The median overall survival of the cohort of patients was 35 (17; 67) mo, and it was statistically different in relation to treatment choice, ultrasound surveillance, and serum alpha-fetoprotein. The Italian Liver Cancer (ITA.LI.CA) tumor staging system performed best in predicting survival according to stage allocation among all 15 evaluated prognostic scores. Using the ITA.LI.CA prognostic system, 28.6%, 40.7%, 22.1%, and 8.6% of patients fell within stages 0-1, 2-3, 4-5 and > 5 respectively. The median survival was 57.9 mo for stages 0-1, 43 mo for stages 2-3, 21.7 mo for stages 4-5, and 10.4 mo for stage > 5. The 1-, 3-, and 5-year survival rates were respectively 95%, 65%, and 20%, for stages 0-1; 94.7%, 43.9% and 26.3% for stages 2-3; 71%, 25.8% and 16.1% for stages 4-5; and 50%, 16.7% and 8.3% for stage > 5. At the same time, although statistically significant in prognostic stratification, the most commonly used Barcelona Clinic Liver Cancer system showed one of the most relevant differences in median survival, especially for stages A and C, when compared to the medical literature. In fact, 10.7%, 59.3%, 27.1%, 1.4%, and 0% of patients were stratified into stages 0, A, B, C, and D respectively. The median survival was > 81.1 mo for stage 0, 44.9 mo for stage A, 21.3 mo for stage B, and 3.1 mo for stage C. The 1-, 3-, and 5-year survival rates were respectively 86.7%, 60%, and 46.7% for stage 0; 91.6%, 50.6%, and 20.5% for stage A; 73.7%, 23.7% and 13.2% for stage B; and 2%, 0% and 0% for stage C.

Survival analysis shows excellent prognostic ability of the ITA.LI.CA scoring system compared to other staging systems.

• Hepatocellular carcinoma
• Prognostic score system
• Prognostic factors
• Survival analysis
• Barcelona Clinic Liver Cancer score system
• Italian Liver Cancer score system

Growing evidence suggests that the superiority of long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) could act as biomarkers for cancer prognosis. However, the prognostic marker for hepatocellular carcinoma with high accuracy and sensitivity is still lacking. In this research, a retrospective, cohort-based study of genome-wide RNA-seq data of patients with hepatocellular carcinoma was carried out, and two protein-coding genes (GTPBP4, TREM-1) and one lncRNA (LINC00426) were sorted out to construct an integrative signature to predict the prognosis of patients. The results show that both the AUC and the C-index of this model perform well in TCGA validation dataset, cross-platform GEO validation dataset, and different subsets divided by gender, stage, and grade. The expression pattern and functional analysis show that all three genes contained in the model are associated with immune infiltration, cell proliferation, invasion, and metastasis, providing further confirmation of this model. In summary, the proposed model can effectively distinguish the high- and low-risk groups of hepatocellular carcinoma patients and is expected to shed light on the treatment of hepatocellular carcinoma and greatly improve the patients' prognosis.

The Child-Pugh score is a scoring system used to measure liver function and predict postoperative outcomes in patients with hepatocellular carcinoma (HCC). Recently, the Albumin-Bilirubin (ALBI) grade has been proposed for the evaluation of hepatic reserve function in HCC. This study aimed to assess and compare the capability of ALBI grade and Child-Pugh score in predicting overall survival (OS).

A total of 196 consecutive HCC patients who treated with hepatectomy were enrolled in this retrospective study. The prognostic values of ALBI grade and Child-Pugh score in predicting postoperative OS were respectively estimated using the Kaplan-Meier method and time-dependent receiver operating curves (ROC). Univariate and multivariate Cox regression analyses were performed to investigate the prognostic factors for OS.

Stratified by the Albumin-Bilirubin (ALBI) system, there were 81 (41.3%) patients with grade 1 and 115 (58.7%) patients with grade 2. The cumulative 1-, 3-, 5-year OS rates in patients with ALBI-1 were 82.7%, 51.5% and 35.5%, respectively. For patients with ALBI-2, the cumulative 1-, 3-, 5-year OS rates were 57.6%, 19.4% and 0%, respectively. Based on the Child-Pugh classification, 136 (69.4%) patients had a score of 5, and 60 (30.6%) patients had a score of 6. Patients with Child-Pugh-A5 showed a better OS than those with Child-Pugh-A6, with respective OS at 1, 3 and 5 years (72.7%, 29.2%, 20.3% vs. 53.9%, 21.1%, 0%, Log-rank P<0.001). Besides, the ALBI grade revealed two prognostic groups within Child-Pugh-A5 (P<0.001), while the Child-Pugh score did not distinguish ALBI-2 in different prognostic groups (P=0.705). The multivariate analysis indicated that both ALBI grade and Child-Pugh score could significantly stratify the patients with different OS [hazard ratio (HR), 3.088 and 1.783; 95% confidence interval (CI), 1.985 to 4.805 and 1.272 to 2.731; P<0.001 and P=0.032 for ALBI grade and Child-Pugh score, respectively]. Additionally, time-dependent ROC analysis in the entire cohort proved that the ALBI grade had a better discriminatory ability than the Child-Pugh score in predicting survival, especially for long-term outcomes. According to the subgroup analyses, the ALBI grade had a better discriminatory ability and survival prediction accuracy in overall subsets than the Child-Pugh score for the prediction of OS.

ALBI grade supplied better prognostic performance and distribution of liver function than Child-Pugh score in stratifying prognosis for HCC patients treated by hepatectomy. These results declared that ALBI grade could be an alternative liver function grading system for stratification in patients with HCC.

• Albumin-Bilirubin grade (ALBI grade)
• Child-Pugh score
• hepatocellular carcinoma (HCC)
• liver resection
• time-dependent receiver operating characteristic curve

Introduction: Transarterial radioembolization (TARE) has been proven as an effective treatment for unresectable liver tumor. In this study, neutron activated, ¹⁵³Sm-labeled microspheres were developed as an alternative to ⁹⁰Y-labeled microspheres for hepatic radioembolization. ¹⁵³Sm has a theranostic advantage as it emits both therapeutic beta and diagnostic gamma radiations simultaneously, in comparison to the pure beta emitter, ⁹⁰Y. Methods: Negatively charged acrylic microspheres were labeled with ¹⁵²Sm ions through electrostatic interactions. In another formulation, the Sm-labeled microsphere was treated with sodium carbonate solution to form the insoluble ¹⁵²Sm carbonate (¹⁵²SmC) salt within the porous structures of the microspheres. Both formulations were neutron-activated in a research reactor. Physicochemical characterization, gamma spectrometry, and radiolabel stability tests were carried out to study the performance and stability of the microspheres. Results: The Sm- and SmC-labeled microspheres remained spherical and smooth, with a mean size of 35 µm before and after neutron activation. Fourier transform infrared (FTIR) spectroscopy indicated that the functional groups of the microspheres remained unaffected after neutron activation. The ¹⁵³Sm- and ¹⁵³SmC-labeled microspheres achieved activity of 2.53 ± 0.08 and 2.40 ± 0.13 GBq·g⁻¹, respectively, immediate after 6 h neutron activation in the neutron flux of 2.0 × 10¹² n·cm⁻²·s⁻¹. Energy-dispersive X-ray (EDX) and gamma spectrometry showed that no elemental and radioactive impurities were present in the microspheres after neutron activation. The retention efficiency of ¹⁵³Sm in the ¹⁵³SmC-labeled microspheres was excellent (~99% in distilled water and saline; ~97% in human blood plasma), which was higher than the ¹⁵³Sm-labeled microspheres (~95% and ~85%, respectively). Conclusion: ¹⁵³SmC-labeled microspheres have demonstrated excellent properties for potential application as theranostic agents for hepatic radioembolization.

• Samarium-153
• liver tumour
• microspheres
• neutron activation
• radioembolization
• radiopharmaceutical

Few studies have reported the clinical characteristics and outcomes of young adult patients diagnosed with hepatocellular carcinoma (HCC). This study aimed to formulate a nomogram to predict the prognosis of young adult HCC patients.

Young adult patients diagnosed with HCC from 2004 to 2015 were screened from the Surveillance, Epidemiology, and End Results (SEER) database. Based on the multivariate analysis results, a nomogram was constructed. The concordance index (c-index) and calibration were used to assess the predictive performance of the nomogram. The clinical benefit was measured by using decision curve analysis (DCA).

The mean follow-up time of the patients was 25.0±34.0 months. Gender, race, AFP level, Edmondson–Steiner classification, treatment and TNM stage were selected as independent prognostic factors and integrated into the nomogram. The c-indexes of the two sets were 0.786 and 0.775, respectively. The calibration curves showed good agreement between the nomogram-predicted probability and the actual observations. Furthermore, the DCA indicated that the nomogram had positive net benefits compared with the conventional staging system.

The nomogram could accurately predict the prognosis of young adult HCC patients.

Although men carry a higher risk of hepatocellular carcinoma (HCC) than women, it is still controversial whether men also have a poorer postoperative prognosis. A retrospective study was conducted to evaluate the postoperative prognostic predictors of HCC focusing on sex differences.

We enrolled 516 consecutive adult patients with HCC (118 women, 398 men), who received surgical resection between January 2000 and December 2007, and were followed-up for >10 years. Clinical and laboratory data together with postoperative outcomes were reviewed.

At baseline, female patients had a higher anti-hepatitis C virus antibody prevalence (P = 0.002); lower hepatitis B virus surface antigen prevalence (P = 0.006); less microvascular invasion (P = 0.019); and lower alpha-fetoprotein (P = 0.023), bilirubin (P = 0.002), and alanine transaminase (P = 0.001) levels. Overall, there were no significant sex differences in terms of intrahepatic recurrence-free survival (RFS), distant metastasis-free survival (MFS), and overall survival (OS). However, subgroup analysis showed that women had favorable RFS (P = 0.019) and MFS (P = 0.034) in patients with alpha-fetoprotein ≤ 35 ng/mL, independent of other clinical variables (adjusted P = 0.008 and 0.043, respectively). Additionally, men had favorable OS in patients with prothrombin time (international normalized ratio [INR]) <1.1 (P = 0.033), independent of other clinical variables (adjusted P = 0.042).

Female sex is independently associated with favorable postoperative RFS and MFS in patients with alpha-fetoprotein ≤35 ng/mL, while male sex is independently associated with favorable OS in patients with prothrombin time INR <1.1.

The online version of this article (10.1186/s12885-019-5453-3) contains supplementary material, which is available to authorized users.

• Alpha-fetoprotein
• Hepatocellular carcinoma
• Prognosis
• Survival

• Hepatocellular carcinoma
• staging
• survival analysis

• Carcinoma, Hepatocellular/pathology
• Disease-Free Survival
• Female
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Neoplasm Staging
• Probability
• Prognosis
• Progression-Free Survival
• Reproducibility of Results
• United States

• Animals
• Carcinoma, Hepatocellular/radiotherapy
• Chemoembolization, Therapeutic/methods
• Clinical Trials as Topic
• Humans
• Liver Neoplasms/radiotherapy
• Microspheres
• Yttrium Radioisotopes/therapeutic use

• Classification systems
• HCC
• Medical image
• Ontology
• Web Ontology Language (OWL)

• Aged
• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Female
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Neoplasm Staging/methods
• Niacinamide/analogs & derivatives
• Niacinamide/therapeutic use
• Phenylurea Compounds/therapeutic use
• Prognosis
• Retrospective Studies
• Sorafenib
• Survival Rate
• Tomography, X-Ray Computed
• alpha-Fetoproteins/analysis

Molecular pathological epidemiology (MPE) is a new discipline which emerged as an integrated approach of molecular pathology and epidemiology and was introduced for the first time by Professor Shuji Ogino and Professor Meir Stampfer in the year of 2010. MPE studies in hepatocellular carcinoma (HCC) investigate the relationship among risk factors, molecular biomarkers, and initiation, progression, and prognosis of HCC, which can be used for exploring the molecular mechanisms of HCC and for the molecular classification of the high risk population. Type 2 diabetes mellitus (DM) has been confirmed as an established risk factor for HCC, and MPE can be helpful to better understand the underlying molecular mechanisms. On December 20, 2017, the first China-Japan Symposium on HCC-MPE was held successfully in Beijing. HCC-MPE provides the opportunities and challenges to solve some problems of HCC, and I believe that it can be helpful to improve the early diagnosis, molecular typing, personalized prevention and treatment, and prognosis of HCC.

• Hepatocellular carcinoma
• Molecular pathological epidemiology
• Molecular pathology
• Molecular epidemiology
• Type 2 diabetes mellitus

• MT1M
• hepatocellular carcinoma
• metallothionein 1M
• tumor marker

This study aimed to explore the efficacy and safety of drug-eluting bead (DEB) embolization (DEB-TACE) when combined with cryoablation in the treatment of unresectable hepatocellular carcinoma (HCC). The study was a single-center randomized controlled trial comprised of 60 patients with HCC conducted between August 2015 and October 2017. The patients were randomly divided into two groups: DEB-TACE combined with cryoablation (DEB-TACE-Cryo group) or cryoablation alone (Cryo group). Inter-group differences in overall survival, progression-free survival, and adverse reactions were assessed. The operative success rates were 82.7% and 77.4% in the DEB-TACE-Cryo group and Cryo group, respectively, with no operative mortality. The overall survival and progression-free survival in the DEB-TACE-Cryo group were significantly higher than those in the Cryo group (16.8 months vs.13.4 months, P = 0.0493; 8.1 months vs. 6.0 months, P = 0.0089, respectively). The postoperative complications in the two groups were rated as grade 1 or grade 2, according to guidelines set by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE V4.0). We demonstrated that DEB-TACE combined with cryoablation was effective, well tolerated, and had a low complication rate. Therefore, this combination therapy may be a better choice for the treatment of unresectable hepatocellular carcinoma.

• cryoablation
• doxorubicin
• hepasphere microsphere
• hepatocellular carcinoma
• transarterial chemoembolization

Spontaneous hepatocellular carcinoma (HCC) rupture can be fatal, and hepatic resection could achieve a favorable long-term survival among all strategies of tumor rupture. However, there is no available prognostic scoring system for patients with ruptured HCC who underwent partial hepatectomy.

From January 2005 to May 2015, 129 patients with spontaneous HCC rupture underwent partial hepatectomy. Preoperative clinical data were collected and analyzed. Independent risk factors affecting overall survival (OS) were used to develop the new scoring system. Harrell’s C statistics, Akaike information criterion (AIC), the relative likelihood, and the log likelihood ratio were calculated to measure the homogeneity and discriminatory ability of a prognostic system.

In the multivariable Cox regression analysis, three factors, including tumor size, preoperative α-fetoprotein level, and alkaline phosphatase level, were chosen for the new tumor-associated antigen (TAA) prognostic scoring system. The 1-year OS rates were 88.1%, 43.2%, and 30.2% for TAA scores of 0–5 points (low-risk group), 6–9 points (moderate-risk group), and 10–13 points (high-risk group), respectively. The TAA scoring system had superior homogeneity and discriminatory ability (Harrell’s C statistics, 0.693 vs. 0.627 and 0.634; AIC, 794.79 vs. 817.23 and 820.16; relative likelihood, both < 0.001; and log likelihood ratio, 45.21 vs. 22.77 and 21.84) than the Barcelona Clinic Liver Cancer staging system and the Cancer of the Liver Italian Program in predicting OS. Similar results were found while predicting disease-free survival (DFS).

The new prognostic scoring system is simple and effective in predicting both OS and DFS of patients with spontaneous ruptured HCC.

• Spontaneous rupture
• discriminatory ability
• disease-free survival
• hepatocellular carcinoma
• homogeneity
• overall survival
• prognostic scoring system

Alpha-fetoprotein (AFP) is a biomarker for hepatocellular carcinoma (HCC). The significance of pre-treatment AFP (pt-AFP) in non-viral HCC (nvHCC) is not clear.

Patients with nvHCC, referred to a Hepatobiliary Clinic from September 2011–2015 were screened. HCC was diagnosed using American Association for the Study of Liver Disease guidelines, and TNM staged. nvHCC was diagnosed when HBsAg and anti-HCVAb was negative. Child-Turcotte-Pugh (CTP) and Model for End-stage Liver Disease (MELD) scores were calculated. AFP level was evaluated against patient characteristics, tumour characteristics and survival.

Three hundred eighty-nine patients with nvHCC [age 64(12–88) years; 344(88.4%) males] were screened. Median AFP was 25.46 ng/ml (1.16–100,000). 41.2% (n = 160) Of patients had normal AFP level. 22.9% (n = 89) had AFP over 400 ng/ml. Female gender (P < 0.05), vascular invasion (P < 0.001), tumours over 5 cm (P < 0.05), late TNM stage (P < 0.001) and non-surgical candidates had higher AFP levels. Diffuse type (P < 0.001), macro vascular invasion (P < 0.001) and late stage tumours (P < 0.001) had AFP over 400 ng/ml. Having AFP below 400 ng/ml was associated with longer survival (16 vs. 7 months, P < 0.001).

Pre treatment AFP has a limited value In diagnosing nvHCC, Having a AFP value over 400 ng/ml was associated with aggressive tumour behaviour and poor prognosis.

• Alpha-fetoproteins/analysis
• Carcinoma hepatocellular/aetiology
• Carcinoma hepatocellular/diagnosis
• Prognosis

• Anti-CTLA-4
• Anti-PD1
• Hepatocellular carcinoma
• Immune checkpoint inhibitors
• Immunotherapy

Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma.

• Hepatocellular
• Cancer
• Epidemiology
• Treatment
• Diagnosis
• Staging
• Transplantation

• Ablation Techniques/methods
• Alcohol Drinking/adverse effects
• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/therapy
• Diagnosis, Differential
• Early Detection of Cancer/methods
• Hepatectomy/methods
• Hepatitis B, Chronic/complications
• Hepatitis B, Chronic/epidemiology
• Hepatitis B, Chronic/virology
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/epidemiology
• Hepatitis C, Chronic/virology
• Humans
• Incidence
• Liver/diagnostic imaging
• Liver/pathology
• Liver/surgery
• Liver Cirrhosis/complications
• Liver Neoplasms/diagnosis
• Liver Neoplasms/epidemiology
• Liver Neoplasms/etiology
• Liver Neoplasms/therapy
• Liver Transplantation/methods
• Neoplasm Staging
• Non-alcoholic Fatty Liver Disease/complications
• Practice Guidelines as Topic
• Prevalence
• Risk Factors
• Tobacco Smoking/adverse effects
• Tomography, X-Ray Computed
• Treatment Outcome

Transarterial chemoembolization (TACE) is the most common oncologic therapy used according to the American Association for the Study of Liver Diseases (AASLD) guidelines established in 2005, revised in 2011. The purpose of this study was to determine how AASLD criteria for the management of hepatocellular carcinoma (HCC) have impacted TACE practice in the community. Clinical, demographic, and cause of death information were collected for patients diagnosed with HCC in the 2012 linkage of the Surveillance, Epidemiology, and End Results Medicare database. Propensity score survival analysis was used to compare survival outcomes in patients whose HCC tumor characteristics were less than, met, or were beyond AASLD criteria. The proportion of patients with HCC receiving TACE who met the AASLD‐recommended criteria increased after the 2005 guidelines were published. Up to 17% of patients treated with TACE had tumor characteristics less than the AASLD criteria and were not offered potentially curative therapies. Propensity score matching demonstrated the largest survival advantage in patients with HCC whose tumor characteristics met the AASLD criteria (hazard ratio, 0.42; 95% confidence interval, 0.38‐0.47). A significant survival advantage was also observed in patients with HCC whose tumor characteristics exceeded the AASLD criteria. Conclusion: The AASLD criteria successfully identify a population of patients with HCC that maximally benefit from TACE therapy. However, patients with HCC with tumor characteristics beyond the AASLD criteria also appear to receive a significant survival advantage with TACE. Further studies are necessary to improve referral patterns and appropriate use of chemoembolization in the management of unresectable HCC. (Hepatology Communications 2017;1:338–346)

Many molecular classification and prognostic gene signatures for hepatocellular carcinoma (HCC) patients have been established based on genome-wide gene expression profiling; however, their generalizability is unclear. Herein, we systematically assessed the prognostic effects of these gene signatures and identified valuable prognostic biomarkers by integrating these gene signatures. With two independent HCC datasets (GSE14520, N = 242 and GSE54236, N = 78), 30 published gene signatures were evaluated, and 11 were significantly associated with the overall survival (OS) of postoperative HCC patients in both datasets. The random survival forest models suggested that the gene signatures were superior to clinical characteristics for predicting the prognosis of the patients. Based on the 11 gene signatures, a functional protein-protein interaction (PPI) network with 1406 nodes and 10,135 edges was established. With tissue microarrays of HCC patients (N = 60), we determined the prognostic values of the core genes in the network and found that RAD21, CDK1, and HDAC2 expression levels were negatively associated with OS for HCC patients. The multivariate Cox regression analyses suggested that CDK1 was an independent prognostic factor, which was validated in an independent case cohort (N = 78). In cellular models, inhibition of CDK1 by siRNA or a specific inhibitor, RO-3306, reduced cellular proliferation and viability for HCC cells. These results suggest that the prognostic predictive capacities of these gene signatures are reproducible and that CDK1 is a potential prognostic biomarker or therapeutic target for HCC patients.

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Eleven gene signatures have promising values for the OS prediction of HCC patients who undergo the surgical treatments.

Various gene signatures for hepatocellular carcinoma (HCC) patients have been reported; however, their generalizability is unclear. Using two HCC patient datasets, we assessed the prognostic values of these gene signatures and identified 11 gene signatures that were associated with overall survival for postoperative HCC patients in both cohorts. Genes derived from these signatures formed a functional protein-protein interaction network with 1,406 nodes and 10,135 edges, and the expression levels of three core genes, RAD21, CDK1, and HDAC2, in the network were negatively associated with the overall survival of HCC patients. Further studies suggested that CDK1 is an independent prognostic factor and that it is a potential therapeutic target for HCC patients.

• Biomarker
• Gene signature
• Hepatocellular carcinoma
• Network
• Overall survival

• consensus
• hepatocellular carcinoma
• multidisciplinary treatment
• portal vein tumor thrombus
• recommendations

• Administration, Oral
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic
• China
• Hepatectomy
• Humans
• Immunotherapy
• Liver Neoplasms/complications
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Medical Oncology/methods
• Medical Oncology/standards
• Microcirculation
• Neoplasm Metastasis
• Neoplastic Cells, Circulating/pathology
• Portal Vein/pathology
• Prognosis
• Radiotherapy/methods
• Thrombosis/complications
• Thrombosis/pathology
• Treatment Outcome

• TNM staging system
• hepatocellular carcinoma
• prognosis
• spontaneous tumor rupture

• Adult
• Aged
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Combined Modality Therapy
• Female
• Follow-Up Studies
• Hospital Mortality
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Multivariate Analysis
• Neoplasm Staging
• Prognosis
• Registries
• Retrospective Studies
• Rupture, Spontaneous
• Shock/etiology
• Survival Analysis

Cytoplasmic polyadenylation element binding protein 4 (CPEB4) is a sequence-specific RNA-binding protein and translational regulator, with expression associated with tumor progression. Nevertheless, CPEB4 seems to play paradoxical roles in cancers–an oncogenic promoter in pancreatic ductal adenocarcinoma (PDA) and glioblastomas but a tumor suppressor in hepatocellular carcinoma (HCC). To assess whether CPEB4-regulated carcinogenesis is tissue-specific, we reevaluated the role of CPEB4 in HCC. Although proliferation of hepatocytes appeared normal in CPEB4-knockout (KO) mice after partial hepatectomy, knockdown (KD) of CPEB4 in HepG2 liver cancer cells promoted colony formation in vitro. Moreover, the growth of CPEB4-KD cells was accelerated in an in vivo xenograft mouse model. In tumorous and adjacent non-tumorous paired liver specimens from 49 HCC patients, the protein level of CPEB4 was significantly upregulated in early-stage HCC but decreased toward late-stage HCC. This finding agrees with changes in CPEB4 mRNA level from analysis of two sets of HCC microarray data from the Gene Expression Omnibus (GEO) database. Taken together, downregulation of CPEB4 likely occurs at the late cancer stage to facilitate HCC progression. Biphasic alteration of CPEB4 expression during HCC progression suggests its complicated role in tumorigenesis.

Intrahepatic recurrence is one of the most important causes of compromised prognosis after surgical resection of hepatocellular carcinoma (HCC). This retrospective study was designed to identify and compare the risks of recurrence, early recurrence and multiple recurrences in a single patient population.

A series of 92 consecutive patients, who received resection for single nodular HCC at our institute from January 2007 to December 2013, were enrolled in this study. The patients were divided into recurrent and non-recurrent groups; the recurrent group was further divided into subgroups by applying two criteria: early and late recurrence (with a cutoff of 18 months), and single and multiple (≥2) recurrence. The potential risk factors were compared using univariate and multivariate analyses. The subgroup analysis was performed to determine the effects of different cut-off values on the analysis.

41 recurrences (44.6%) occurred during a mean follow-up of 42.4 months. The Child-Pugh score, and the portal vein invasion were found to be independent risk factors of recurrence, but differentiation was the only independent risk factor of early recurrence. The serum alpha-fetoprotein, tumor size, tumor necrosis, and hemorrhage were found to be the risk factors of multiple recurrences according to the univariate analysis, but lacked significance according to the multivariate analysis. When the cutoffs for early and multiple recurrences were changed to ≤10 months and >3 nodules, respectively, different risk factors were identified.

Our results implicated that different factors can predict the recurrence, timing, and multiplicity of an HCC recurrence. Further studies should be conducted to prove the complex relationships between tumor burden, invasiveness, and underlying liver cirrhosis for initial tumors, and the timing and multiplicity of recurrent HCC.

• Hepatocellular carcinoma
• Recurrence pattern
• Resection
• Risk factors