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Changcheng Tao,1,&ast; Fan Wu,1,&ast; Hongwei Wang,1,&ast; Liming Wang,1 Yue Liu,1 Anke Wu,1 Linlin Zheng,1 Yaru Wang,1 Bo Chen,2 Weiqi Rong,1 Jianxiong Wu1 1Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianxiong Wu; Weiqi Rong, Email dr_wujx@163.com; dr_rongweiqi@163.comObjective: Although surgical resection is one of the most effective way to treat liver cancer, its efficacy and safety in treatment of centrally located hepatocellular carcinoma (HCC) remains elusive. Therefore, it is very important to find a comprehensive treatment mode, such as radical resection combined with neoadjuvant radiotherapy (neoRT).Methods: The centrally located HCC patients who underwent radical resection from July 2015 to April 2021 were enrolled. According to whether the neoRT was implemented or not, these patients were allocated into neoadjuvant radiotherapy combined with liver resection (neoRT+LR) and liver resection alone (LR) group. The research method used propensity-score analysis and Cox proportional-hazards regression models. We generated an E-value to assess the sensitivity to unmeasured confounding. This study is a real-world, retrospective study based on phase II clinical trial.Results: A total of 168 patients were enrolled, including 38 patients treating with neoRT+LR and 130 patients with LR. The 1-, 3-, 5-year disease free survival (DFS) rates were 74%, 55% and 39% in the neoRT+LR group, and 44%, 28%, and 24% in the LR group, respectively. Neoadjuvant radiotherapy was an independent prognostic factor for postoperative recurrence ([HR]0.42, 95% CI [0.25, 0.69]). There was significant association between neoRT+LR and longer disease-free survival (Match, [HR] 0.43, 95% CI [0.24, 0.76]; GenMatch, [HR] 0.32, 95% CI [0.23, 0.43]; Adjusted for propensity score, [HR] 0.41, 95% CI [0.23, 0.73]; Inverse probability weighting, [HR] 0.38, 95% CI [0.22, 0.65], respectively). DFS before and after matching analysis was statistically different in two groups (p-value=0.005, p-value=0.0024, respectively). Neoadjuvant radiotherapy can significantly reduce the postoperative early recurrence (p-value < 0.05). E-value analysis suggested robustness to unmeasured confounding.Conclusion: Liver resection combined with neoadjuvant radiotherapy was effective and safe for treatment of centrally located HCC patients, which improved the prognosis of patients and reduced the incidence of early recurrence.Keywords: centrally located hepatocellular carcinoma, neoadjuvant radiotherapy, radical resection, recurrence

Liver cancer as the main leading cancer has caused heavy burdens globally. The prognosis of liver cancer is closely related with postoperative nutrition support. Corn oligopeptides (COPs) are protein hydrolysates produced by enzymatic treatments, which have shown potential bioactivities, such as inhibiting angiotensin I-converting enzyme, resisting lipid peroxidation and anti-oxidant. However, the correlation between COPs and liver cancer patients is still unknown and the potential mechanism of COPs on liver cancer is unclear as well. The aim of this study was to assess effects of 7-day intervention of COPs after surgery on liver function and serum metabolic profiles of liver cancer patients.Patients were assigned into COPs intervention group (n=50) and control group (n=91) for 7 days. Investigations were scheduled at 1Seven-day supplementation of COPs on early post-surgery liver cancer patients down-regulated levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin and up-regulated prothrombin time activity and prealbumin levels. LC/MS analysis revealed metabolic signatures including regulation of 16 metabolites, which was closely related with two metabolic pathways (nicotinate and nicotinamide metabolism, fatty acid metabolism).COPs supplementation has displayed the potentials on alleviating the injury of liver function and it may be due to regulation of fatty acid metabolism, nicotinate and nicotinamide metabolism, lipid peroxidation and anti-inflammatory action. More researches are warranted in future to confirm the exact mechanisms.

Embryonic development and tumorigenesis have a certain degree of similarity. Alpha-fetoprotein (AFP), a protein related to embryonic development, is a well-known biomarker for the diagnosis and prognosis of hepatocellular carcinoma (HCC). In this study, we analyzed the differences in gene expression profiles and molecular mechanisms in human HCC tissues from patients in AFPhigh (serum AFP level ≥ 25 ng/mL) and AFPlow (serum AFP level < 25 ng/mL) groups. The results indicated that AFPhigh HCC has more malignant biological characteristics. Single-sample gene set enrichment analysis (ssGSEA) showed significantly higher levels of genes expressed in dendritic cells, neutrophils, and natural killer cells in the AFPlow group than in the AFPhigh group. Then, we defined a rhesus monkey fetal liver developmental landscape and compared it to the HCC gene expression profile. The gene signatures of AFPhigh HCC tissues were similar to those of early embryonic liver tissues. In this study, we comprehensively analyzed the rhesus monkey liver transcriptome during development and human primary HCC AFP-related gene expression profiles and clarified the function of AFP in the occurrence and development of HCC from the perspective of developmental biology, which might provide a new perspective on the pathogenesis of HCC., Graphical abstract, Based on microarray data, Rong et al. focus on the differences in gene expression and immune infiltration in HCC patients with different AFP status and combine the fetal liver of rhesus monkeys, expounding the characteristics of HCC from the perspective of developmental biology.

Kai Zhang, Changcheng Tao, Fan Wu, Tana Siqin, Jianxiong Wu, Weiqi Rong Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100021, People’s Republic of ChinaCorrespondence: Weiqi Rong; Jianxiong WuDepartment of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), #17 Panjiayuannanli, Chaoyang District, Beijing, 100021, People’s Republic of ChinaTel +86-10-87787100Email rong125wq@163.com; wujianx_iong@126.comObjective: The present study aimed to identify the risk factors for early postoperative recurrence of hepatocellular carcinoma (HCC) in patients with microvascular invasion (MVI) and develop a predictive model.Inclusion Population and Methods: Patients who underwent surgery for HCC with pathological identification of MVI at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2014 to June 2019 were consecutively enrolled in this study. A total of 416 patients were included, divided into an early recurrence group (N = 169) and a non-early recurrence group (N = 247), taking 12 months as the cut-off point for early recurrence. Univariate and multivariate Cox analysis was adopted to screen for risk factors for recurrence, and independence of risk factors was determined by logistic regression analysis. All variables were included in the logistic regression analysis. As previous studies have shown that tumor diameter is a risk factor for recurrence, this was also included in the analyses. A predictive model for early recurrence was established and evaluated.Results: The results indicate that MVI grouping, preoperative serum AFP, number of tumors, satellite nodules, hepatic capsule invasion, tumor diameter, and lymph node metastasis are independent risk factors for early postoperative recurrence. The above factors were adopted to develop a predictive model. The model had good discrimination and calibration in predicting early postoperative recurrence. Decision curve analysis demonstrated good clinical utility.Conclusion: MVI grouping, preoperative serum AFP, number of tumors, satellite nodules, hepatic capsule invasion, tumor diameter, and lymph node metastasis were shown to be independent risk factors for early postoperative recurrence. The predictive model developed by applying the above risk factors had good predictive value in patients with early postoperative recurrence.Keywords: hepatocellular carcinoma, microvascular invasion, prognosis, early recurrence, predictive model, nomogram, risk factor

Background The presence of lymph node (LN) metastases is associated with poor survival outcomes in hepatocellular carcinoma (HCC) patients. Because of the low probability of LN metastasis, research into the prognoses of these patients is difficult. The present study developed a nomogram model to predict the prognosis of HCC patients with LN metastasis. Methods This retrospective, noninterventional study enrolled patients from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. The following inclusion criteria were used: (I) site recode ICD-O-3 (International Classification of Diseases for Oncology, Third Edition) of 8170-8175 and malignant histological behavior; (II) seventh edition American Joint Committee on Cancer (AJCC) stage N1; (III) older than 18 years; and (IV) available information. Potential prognostic factors were collected from the SEER database; the primary outcomes of interest were overall survival (OS) and disease status. Cox and Lasso regression were used to investigate independent prognostic factors for survival. A prognostic nomogram using these independent risk factors was constructed. The concordance index (C-index) and calibration curves were used to evaluate the model's predictive performance. The clinical benefit was assessed via decision curve analysis (DCA). Results Patients were randomized into a training group (944 patients) and a validation group (402 patients) in a 70:30 ratio. Grade, T stage, liver surgery, chemotherapy, radiation recode, alpha-fetoprotein level, fibrosis score, tumor size group, and M stage were selected as independent prognostic factors, and a nomogram was developed using these variables. The C-indices of the training and validation groups were 0.70 and 0.73, respectively. Calibration curves for the probability of survival showed good agreement. DCA indicated that the nomogram had positive net benefits. Conclusions The constructed nomogram may assist clinicians in predicting the prognosis of HCC patients with LN metastasis and may provide a rationale for treatment options.

Objective A prospective randomized control study investigated the feasibility and efficacy of adjuvant radiotherapy on patients with central hepatocellular carcinoma (HCC) after narrow-margin hepatectomy (

BackgroundsThis is the first study to build and evaluate a predictive model for early relapse after R0 resection in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI).MethodsThe consecutive HCC patients with MVI who underwent hepatectomy in Cancer Hospital of Chinese Academy of Medical Science from Jan 2014 to June 2019 were retrospectively enrolled and randomly allocated into a derivation (N = 286) and validation cohort (N = 120) in a ratio of 7:3. Cox regression and Logistic regression analyses were performed and a predictive model for postoperative early-relapse were developed.ResultsA total of 406 HCC patients with MVI were included in our work. Preoperative blood alpha-fetoprotein (AFP) level, hepatitis B e antigen (HBeAg) status, MVI classification, largest tumor diameter, the status of serosal invasion, number of tumors, and the status of satellite nodules were incorporated to construct a model. The concordance index (C-index) was 0.737 and 0.736 in the derivation and validation cohort, respectively. The calibration curves showed a good agreement between actual observation and nomogram prediction. The C-index of the nomogram was obviously higher than those of the two traditional HCC staging systems.ConclusionWe have developed and validated a prediction model for postoperative early-relapse in HCC patient with MVI after R0 resection.

Postoperative radiotherapy (RT) is known to play an important role in the treatment of hepatocellular carcinomas (HCCs), but the specific role of intraoperative electron radiotherapy (IOERT) in HCCs remains unclear. The aim of this study was to investigate the safety and efficacy of IOERT in centrally located HCCs treated with narrow-margin (1 cm) hepatectomy.This was a single-center, phase 2, prospective non-randomized controlled study, including 268 patients with centrally located HCCs who underwent narrow-margin hepatectomy. The patients were subsequently allocated to the IOERT group (n=59) or to the control group (n=65). The primary outcome of the study was to compare recurrence-free survival (RFS) between the IOERT group and the control group, and the secondary outcome was to compare overall survival (OS) rate between the two groups.Of 268 patients enrolled, a total of 124 were included in the study: 59 in IOERT group, 65 in control group. The 1-, 2-, 3-year RFS rates were 79.3%, 62.1% and 45.8% for patients in the IOERT group, and 47.6%, 28.6%, and 22.9% for patients in the control group, respectively (P=0.025). The 1-, 2-, and 3-year OS rates were 100.0%, 94.9%, and 83.7% for patients in the IOERT group, and 92.3%, 87.5%, and 79.4% for patients in the control group, respectively (P=0.314). Subgroup analysis of MVI (+) patients revealed that RFS and OS are significantly prolonged in the IOERT subgroup as compared to the control, whereas there was no significant difference of RFS and OS between the two groups in MVI (-) patients.IOERT for centrally located HCCs with concurrent narrow-margin hepatectomy was feasible and safe. Statistically better RFS rate was observed in the IOERT group compared to the control group. Subgroup analysis revealed that IOERT was more beneficial for postoperative survival of HCC patients with MVI.ChiCTR-TRC-12002802; www.who.int/ictrp.

e16162 Background: Partial hepatectomy is potentially curative treatment in selected patients (pts) with hepatocellular carcinoma (HCC). Microvascular invasion (MVI) is one of the strongest predictors of prognosis and recurrence of HCC. In this study, we analyzed the gene mutation signature and immune factors associated with MVI, and the prognostic value. Methods: Pts who were diagnosed with HCC between Jan 2018 and Sep 2020 in Cancer Hospital of Chinese Academy of Medical Sciences were retrospectively enrolled in this study. Next-generation sequencing (NGS) was performed on tumor tissues after radical partial hepatectomy. The different immune makers (PD1, PD-L1, CD3, CD8, CD68, and CD163) of tumor-infiltrating lymphocytes (TILs) were identified with immunofluorescence-based microenvironment analysis panel (MAP). Results: In the MVI+ group (n = 39, 59.1 %), there were significantly more pts with larger tumor size, and capsules invasion by tumors. The mutation spectra revealed that 61 (92.4%) pts harbored somatic mutations and the most frequently mutated gene was telomerase reverse transcriptase (TERT), which was present in 31.8% (n = 20) HCC pts. Mutations in the promoter of TERT were found in 95.2% (20/21) pts. 90.0% (18/20) had one hotspot point mutation located 124bp upstream of the translation start site. The mutation frequency in the TERT promoter was significantly higher in the MVI+ group compared with the MVI- group (41.0% vs. 14.8%, p < 0.05). Pts with TERT promoter mutations tend to be MVI+ rather than MVI- and more HCC driver mutations were detected in MVI+ pts with TERT promoter mutations (p < 0.05). Based on MAP, we found MVI+ pts had significantly lower CD3+ TILs (p < 0.05). The multivariable analysis indicated that pts with copy number variations (CNV, hazard ratios [HR] 2.62, 95% confidence interval [CI] 1.07-6.40; p = 0.028), elevated PT/INR (HR 0.29, 95% CI 0.11-0.77; p = 0.008), and lower serum prealbumin concentration (PALB, HR 3.03, 95% CI 1.08-8.51; p = 0.027) had significantly shorter recurrence-free survival (RFS) after surgery. Similar findings were also observed for immune factors within cancer parenchyma, including CD68+ (HR 7.14, 95% CI 0.95-53.55; p = 0.025), CD163+ (HR 3.07, 95% CI 1.10-8.53; p = 0.023), CD68+/CD163- (HR 11.35, 95% CI 1.51-85.05; p = 0.003), CD68+/CD163+ (HR 3.51, 95% CI 1.4-8.79; p = 0.004), which indicated tumor-associated macrophage (TAM) infiltration was independent risk factor for RFS. Conclusions: In this study, we characterized the molecular and immune landscape of MVI in HCC patients. MVI presence highly correlated with adverse biological markers, mutations in the promoter of TERT, and higher CD3+ TILs. Some risk factors of HCC recurrence were identified, including CNV, PT/INR, CA 19-9, PALB, and TAM. Transcriptional alterations and immune tumor microenvironment change may contribute to MVI in HCC.

In recent years, a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma (HCC), including sorafenib, lenvatinib, and regorafenib. Immunotherapy is considered to be an effective treatment for advanced HCC. Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC. However, treating advanced HCC is still a great challenge, and the need for new treatments remains urgent. This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.

Background: Lymph node (LN) metastasis is associated with poor survival outcomes in patients with hepatocellular carcinoma (HCC) patients and because of the reported low probability of lymph node metastasis, research into the Anchorprognoses of such patients is difficult to conduct. In this study, we aimed to develop a nomogram model to predict the prognosis of HCC patients with lymph node metastasis. Methods: HCC patients diagnosed with LN metastasis from 2010 to 2015 were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate Cox regression and lasso regression were used to screen prognostic factors. Cox multiple-factor analysis was used to investigate the independent risk factors for survival. We developed a prognostic nomograms using these independent risk factors. The predictive performance of our nomogram model was evaluated according to the concordance index (C-index) and calibration curve. The net clinical benefit was assessed via decision curve analysis (DCA). Patients were divided into different risk groups according to the model. A survival curve was drawn using the Kaplan-Meier method and the difference was compared by the log-rank test. Results: There were 944 patients in the training cohort and 402 patients in the validation cohort. Grade, T stage, surgery to the liver, chemotherapy, radiation recode, AFP, fibrosis score, tumor size group, M stage were selected as independent prognostic factors, and we developed nomograms using these variables. The calibration curves for probability of survival showed good agreement between the prediction by our model and actual observation in both the training and validation groups. DCA indicated that the nomogram had positive net benefits. Conclusions: The nomogram can accurately predict the prognosis of HCC patients with lymph nodes metastasis and provide a reasonable basis for treatment. Keywords: Hepatocellular carcinoma, prognosis, lymph nodes metastasis, prediction model, nomogram

Background: Lymphoepithelioma-like hepatic carcinoma is a rare distinctive variant of liver cancer with unique epidemiological and pathological characteristics, characterized by dense lymphocyte infiltration. It can be divided into lymphoepithelioma-like hepatocellular carcinoma and lymphoepithelioma-like intrahepatic cholangiocarcinoma. Existing research shows that its prognosis is good. Up to now, only 101 cases have been reported. More rarely, combined lymphoepithelioma-like hepatocellular carcinoma and cholangiocarcinoma has been found. Case presentation: The first patient was a 62 years old Chinese man with hepatitis B virus infection presented with a single lesion in the liver. The patient underwent surgical treatment and was discharged on the 4th day. The patient was diagnosed as combined lymphoepithelioma-like hepatocellular carcinoma and cholangiocarcinoma and has been alive for 15 months. The second patient was a 63 years old Chinese woman with right upper abdominal pain and hepatitis B virus infection. The imaging examination a single lesion in the liver. The patient underwent surgical treatment and was discharged one week later. The patient was diagnosed as lymphoepithelioma-like hepatocellular carcinoma and was considered to be the recurrence of lymph nodes about 2 years after operation. The patient underwent local radiotherapy and has been alive for 60 months. The third patient was a 50 years old Chinese man with hepatitis B virus infection presented with a single lesion in the liver and two enlarged lymph nodes. The patient received liver puncture before operation to indicate lymph node metastasis and had local recurrence after liver resection. The patient underwent chemotherapy and radiotherapy. The patient was diagnosed as lymphoepithelioma-like hepatocellular carcinoma. Finally, the patient died at 24 months follow-up. Conclusions: This article reports 3 cases of LELC and reviews the current research discovery, which suggests that even the locally advanced patients of LELC with postoperative recurrence and preoperative lymph node metastasis should be actively treated and intervened for a longer survival period. Keywords: Liver Cancer, Lymphoepithelioma-like carcinoma, Hepatocellular carcinoma, Cholangiocarcinoma