Background: ​Surgery represents the only curative-intent treatment option for intrahepatic cholangiocarcinoma (ICC). However, its safety and efficacy in patients with Child-Pugh B (CP-B) cirrhosis remain uncharacterized. This study aimed to evaluate survival outcomes and develop an integrated model predicting both safety and survival to guide individualized CP-B ICC therapy. Methods: We identified all CP-B patients from a prospective cohort of 4,164 patients resected for histopathologically confirmed ICC between January 2010 and December 2023 at three tertiary hospitals. Severe complications, overall survival (OS), and recurrence-free survival (RFS) were assessed. Multivariable modeling identified preoperative predictors for nomogram development and validation. Median follow-up was 31 months (IQR, 15–62). Findings: Among 682 resected CP-B ICC patients (median age 65 years; 58·8% male), severe complications occurred in 20·1% (mortality, 3·7%). Predictors included age, Charlson comorbidity index (CCI), total bilirubin, platelet count, albumin, underweight/obesity, hepatolithiasis, MASLD, and laparoscopic resection (OR range, 0·24–10·87; all p≤0·031). The complication nomogram (C-index, 0·80–0·82) outperformed MELD, ALBI, and Child-Pugh scores (C-indices, 0·59–0·65; all p<0·0001). Five-year OS and RFS after curative-intent resection were 40·5% and 20·8%. Predictors integrating CCI, Child-Pugh score, CA19-9, hepatolithiasis, multifocality, nodal metastasis, and tumor size (HR range, 1·08–2·86; all p≤0·016) formed the OS nomogram (C-indices, 0·70–0·75), stratifying patients into groups with median OS of 76 months (95% CI, 58–NR) and 18 months (95% CI, 14–23; p<0·0001). Combined complication and survival prediction identified four subgroups: low-risk/favorable-survival (43·5%) had superior 5-year OS versus low-risk/unfavorable-survival (26·2%) (55·2% vs 19·7%; p<0·0001) despite similar low complications (8·8% vs 6·9%; p=0·87); high-risk/favorable-survival (16·7%) showed better 5-year OS than high-risk/unfavorable-survival (13·7%) (51·6% vs 7·9%; p<0·0001) with similarly elevated complications (36·1% vs 47·1%; p=0·41). Interpretation: Surgery offers survival benefits in selected CP-B ICC patients. An integrated risk stratification model aids surgical decision-making and informs alternative therapies, optimizing survival while mitigating treatment-related risks.

Background: There’s no prognostic prediction model for advanced unresectable intrahepatic cholangiocarcinoma (ICC) patients undergoing immunochemotherapy as the first-line treatment. This research aimed to develop and validate a prognostic model and risk stratification system for patients with advanced ICC. Methods: This multicenter, retrospective study included unresectable ICC patients who received PD-(L)1 inhibitor in combination with gemcitabine plus platinum agents (cisplatin or oxaliplatin) as first-line treatment between 2017 and 2024 as training cohort. Patients clinicopathological characteristics and follow-up data were collected and analyzed. Four machine learning (ML) based survival models were optimized through a repeated 5-fold cross validation and hyperparameter tuning, simplified through recursive feature elimination. The study endpoint was overall survival (OS). The final model was internally validated using the 1000 bootstrap method, and was externally validated using data from another cohort. Findings: A total of 140 patients included in the training cohort, and 64 patients in the validation cohort. Among the four ML models, the final Random Survival Forest (RSF) model showed the best predictive performance, and identified carbohydrate antigen 19-9 (CA19-9), fibrosis index (FI), platelet-to-lymphocyte ratio (PLR), prothrombin time (PT), albumin-bilirubin (ALBI) grade, serum albumin (Alb), and age as the most important predictive features. The model C-index was 0.736 in the training cohort and 0.699 in the external validation cohort, and exhibited significant discrimination between high- and low-risk groups (log-rank P < 0.0001). Furthermore, the SHAP algorithm was used to reveal the linear or non-linear relationships between the 7 predictors and mortality rate. The shiny app (link: https://rsfmodel.shinyapps.io/shinyappRSF/) was applied for model deployment. Interpretation: This study developed and validated an interpretable prognostic prediction model by ML for patients with advanced ICC receiving first-line immunochemotherapy. It may serve as a practical clinical decision-support tool for identifying patients who are most likely to benefit from immunochemotherapy.

‘Liver injury-liver fibrosis/cirrhosis-liver cancer’ is the key evolution pathway of hepatocellular carcinoma (HCC), chronic inflammation serving as a major driving force in this process. However, the regulatory mechanisms underlying this process require further clarification. Here, the carcinogen-induced liver injury, liver fibrosis, and HCC models were investigated in the wild-type and STK39-knockout mice. Mass spectrometry analysis and immunoprecipitation assays were used to identify the interaction factors of STK39. QPCR, ELISA, and immunofluorescence were applied for the expression of inflammatory factors. In this study, we report that STK39 is gradually upregulated during the evolution of HCC (liver injury-liver fibrosis-liver cancer). Consequently, overexpression of STK39 further encouraged the evolution of HCC by facilitating a macrophage inflammatory response, as demonstrated in carcinogen-induced liver injury, liver fibrosis, and HCC models. Pharmacological inhibition of STK39 significantly slows the progression of HCC; however, this effect was considerably diminished after macrophage clearance. Mechanistically, mass spectrometry analysis and immunoprecipitation assays identified that STK39 interacted with PKR and promoted the activation of the PKR/NF-κB axis. Which, in turn, enhanced the macrophage inflammatory response and accelerated the evolution of HCC. The inflammatory factor TNF-α further induces the expression of STK39, suggesting a positive feedback regulation process exists. More notably, STK39 inhibition improves the efficacy of sorafenib and anti-PD1 therapy. In conclusions, our study reveals that STK39 holds significant potential for the early diagnosis and treatment of HCC.

PurposeTo develop nomogram models predicting the prognosis for patients with hepatocellular carcinoma (HCC) before hepatectomy.MethodsPatients treated at the Eastern Hepatobiliary Surgery Hospital and Zhongda Hospital, Southeast University, from January 2012 to July 2014, were retrospectively enrolled. Prediction models for overall survival (OS) and recurrence-free survival (RFS) were constructed.ResultsA total of 1117 patients with HCC were enrolled in this study, and were divided into a training cohort (n=838) and a validation cohort (n=279). A prediction model for OS in the training cohort (OS-nomo, C-index=0.71), including alpha-fetoprotein (AFP), estimated hepatectomy extent, and tumor burden score (TBS) as independent factors (all P<0.05), was constructed. For clinical application, we stratified all patients into three distinct risk groups: low-, medium-, and high-risk group for OS, based on total points (TPs). Patients undergoing major hepatectomy, with AFP>20 ng/mL and high level of TBS had the worst OS.ConclusionWhen selecting patients with HCC for hepatectomy, factors including sex, CPS, AFP level, estimated hepatectomy extent, and TBS should be carefully considered. OS-nomo model could serve as important tool for personalized survival prediction.

BACKGROUND:RNA splicing dysregulation plays an important role in hepatocellular carcinoma (HCC). However, the critical functions of zinc finger CCHC type and RNA binding motif 1 (ZCRB1), one of the key components of the minor spliceosome, in HCC remains unclear. METHODS:The mRNA and protein expression of ZCRB1 were evaluated by bioinformatics analysis, western blotting and immunohistochemistry. The role of ZCRB1 on biological functions of HCC were measured in vitro and in vivo. rMATS software analyzes RNA-seq data to identify ZCRB1-related alternative splicing (AS) events. Therapeutic targeting of ZCRB1 using GalNAc-conjugated small-interfering RNA was investigated in the HCC mouse model. RESULTS:We discovered that ZCRB1 was dramatically upregulated in HCC tissues, and high ZCRB1 expression was associated with poor prognosis in HCC patients. Knockdown of ZCRB1 significantly reduced HCC cell proliferation and promoted cell apoptosis. In addition, high enrichment levels of H3K27ac in the promoter region activated ZCRB1 expression. Mechanistically, AS event analysis revealed that knockdown ZCRB1 resulted in retention of intron 11 of USP21 thereby reducing USP21 expression. USP21 overexpression partially rescued the attenuation of malignant behavior of HCC cells caused by inhibition of ZCRB1, and inhibition of USP21 reduced proliferation in HCC cells. Furthermore, therapeutic targeting of ZCRB1 using GalNAc-conjugated small-interfering RNA significantly reduced tumor burden and increased the infiltration level of CD8+ T cells in the HCC mouse model. CONCLUSIONS:This study identified ZCRB1 as an oncogenic U12-type splicing factor that supports malignant growth through blocking intron 11 retention of USP21 in HCC cells. Thus, ZCRB1 could serve as a new target for HCC therapy and a potential biomarker for HCC prognosis.

Background & Aims: N6-methyladenosine (m6A) modification regulates mRNA stability and translation to promote cancer progression. FK506-binding protein 9 (FKBP9), a peptidyl-prolyl isomerase, is associated with carcinogenesis, but its role in m6A modification remains unclear. In this study we aimed to explore how FKBP9 regulates m6A modification during the development of hepatocellular carcinoma (HCC). Methods: The expression of FKBP9 in HCC was profiled by reverse-transcription quantitative PCR, western blot, ELISA, and immunohistochemistry. Cell proliferation, migration, invasion, apoptosis, and mRNA stability were examined using CCK-8, colony formation, flow cytometry, and cycloheximide treatment. An orthotopic allograft tumor model was constructed for in vivo analysis. Immunoprecipitation, mass spectrometry, methylated RNA immunoprecipitation sequencing, and RNA sequencing were performed to elucidate underlying mechanisms. Results: FKBP9 was significantly upregulated in both HCC tissues and serum (p <0.05) and correlated with unfavorable clinical outcomes in patients (p <0.05). Its overexpression enhanced HCC cell proliferation and metastasis, while its depletion triggered cell cycle arrest and apoptosis. Mechanistically, FKBP9 interacted with the KH3-4 domains of IGF2BP1 through its peptidyl-prolyl isomerase domain, thereby stabilizing the binding of IGF2BP1 to m6A-modified MYC and PDGFB. Clinical analysis further confirmed that FKBP9 expression was positively associated with the expression of MYC and PDGFB at both the mRNA and protein levels (p <0.05). Co-overexpression of FKBP9 with MYC or PDGFB was linked to a worse prognosis (p <0.05). Conclusions: FKBP9 promotes HCC progression by facilitating IGF2BP1 recognition of m6A-modified transcripts, thereby stabilizing MYC and PDGFB. The FKBP9–IGF2BP1 axis represents a potential therapeutic target in HCC. Impact and implications: This study highlights the critical role of FKBP9 in hepatocellular carcinoma progression by regulating IGF2BP1-mediated m6A RNA recognition, thereby enhancing the stability of key oncogenic transcripts such as MYC and PDGFB. These findings provide new insights into the molecular mechanisms driving hepatocellular carcinoma and identify potential therapeutic opportunities for patients with poor prognosis linked to high FKBP9 expression. The FKBP9–IGF2BP1 axis may serve as both a biomarker and a therapeutic target to guide the development of new treatment strategies. Further studies are warranted to validate these results in larger patient cohorts and to assess the clinical feasibility of targeting this pathway.

BACKGROUND:The treatment of hepatocellular carcinoma (HCC) remains thorny, due to that just few molecules have been defined as pathogenic drivers. Ribosome biogenesis and alternative splicing (AS) are dysregulated during the development of HCC, but how both processes coordinate remains unexplored. METHODS:Pan-cancer analyses and tissue microarray were used to assess the clinical relevance of BRIX1. Functional studies employed CCK-8 assays, colony formation assays, Transwell migration/invasion assays, flow cytometry analysis, and animal studies. Splicing networks were analyzed by RNA-seq and validated through isoform-specific qRT-PCR. Molecular mechanisms were dissected via ChIP-PCR, Co-IP/MS, immunofluorescence, EU RNA Synthesis, and puromycin incorporation assay. RESULTS:BRIX1 is upregulated in HCC, involved in the mTORC1-SP1 signaling, correlated with a poor prognosis, suggesting it as a critical oncogene. BRIX1 depletion suppresses the proliferation, migration and invasion, and induces the apoptosis of HCC cells. Mechanically, BRIX1 localizes to the nucleolus to interact with UBTF and POLR1A, thus promoting rDNA transcription and ribosomal biogenesis. BRIX1 depletion triggers ribosomal stress, disturbs pre-rRNA synthesis, and inhibits global protein translation. Furthermore, BRIX1 knockdown suppresses SRSF1-mediated oncogenic AS, reduces the production of carcinogenic isoforms MKNK2 and S6K1, and silences mTORC1-4EBP1 signaling. SRSF1 overexpression reverses the phenotypic and molecular changes induced by BRIX1 knockdown. CONCLUSION:BRIX1 activated by mTORC1-SP1 signaling regulates ribosome biogenesis and AS to promote HCC progression. Our findings establish BRIX1 as a governor on both ribosome biogenesis and AS in HCC, and a possible prognostic or therapeutic biomarker.

Background: The location relative to the hepatic and peritoneal sides of T2 gallbladder cancer (GBC) clearly affects the prognosis, but it remains unknown whether the location and extent of T3 tumors impact survival. To investigate the influence of a novel T3 subclassification on the prognosis of patients who received radical resection. Methods: This retrospective multicenter cohort study analyzes pT3 data collected between 2013 and 2018. The T3 category is divided into subgroups of T3p (T3p1 and T3p2), T3h, and T3p + 3h. The T3p is defined as an invasion of the peritoneal side alone. T3p1 indicates serosal penetration alone, and T3p2 refers to involvement of one adjacent organ/structure; T3h means liver invasion on hepatic side alone, while T3p + 3h represents a combination of T3p and T3h. Overall survival (OS) and disease-free survival (DFS) of T3 subgroups were calculated and compared. Cox multivariable analysis was performed to identify prognostic factors. Results: A total of 424 patients were included in the derivation (n=252) and validation cohorts (n=172). Subtypes T3p2, T3h, and T3p + 3h (other than T3p1 as T3b) displayed the worst median OS of 15.0, 15.0, and 11.0 months, respectively, compared to T3p1 (T3a) (44.0 months) (P<0.001). This subclassification enabled further prognostic stratification and comparisons in American Joint Committee on Cancer stage IIIA [5-year OS: 58.0% (T3aN0M0) vs. 29.8% (T3bN0M0), P<0.001] and IIIB [32.4% (T3aN1M0) vs. 10.9% (T3bN1M0), P=0.005]. T3b disease was identified as an independent predictor of worse OS or DFS. The prognostic discriminative ability of T3 subclassification was consistent in the validation cohort.Conclusions: A novel T3 subclassification (T3a and T3b) is worthwhile considering for GBC TNM grouping. T3aN0M0 should be distinguished as a new and the foremost subgroup of stage III (ChiCTR2400090220).

Background: HBV infection leads to HCC and affects immunotherapy. We are exploring the tumor ecosystem in HCC to help gain a deeper understanding and design more effective immunotherapy strategies for patients with HCC with or without HBV infection. Methods: Single-cell RNA sequencing series were integrated as a discovery cohort to interrogate the tumor microenvironment of HBV-positive (HBV+) HCC and HBV-negative (HBV−) HCC. We further dissect the intratumoral immune status of HBV+ HCC and HBV− HCC. An independent cohort, including samples treated with immune checkpoint blockade therapy, was used to validate the major finding and investigate the effect of HBV infection on response to immunotherapy. Results: The interrogation of tumor microenvironment indicated that regulatory T cells, exhausted CD8+ T cells, and M1-like Macrophage_MMP9 were enriched in HBV+ HCC, while mucosa-associated invariant T cells were enriched in HBV− HCC. All subclusters of T cells showed high expression of immune checkpoint genes in HBV+ HCC. Regulatory T cells enriched in HBV+ HCC also showed more robust immunosuppressive properties, which was confirmed by cross talk between immune cell subsets. The ability of antigen presentation with major histocompatibility complex-II was downregulated in HBV+ HCC and this phenomenon can be reversed by immunotherapy. Two types of HCC also present different responses to immunotherapy. Conclusions: There is a more immunosuppressive and exhausted tumor microenvironment in HBV+ HCC than in HBV− HCC. This in-depth immunophenotyping strategy is critical to understanding the impact of HBV and the HCC immune microenvironment and helping develop more effective treatments in patients with HCC.

Liver fibrosis is a progressive scarring process primarily caused by chronic inflammation and injury, often closely associated with viral hepatitis, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), drug-induced liver injury, and autoimmune liver disease (AILD). Currently, there are very few clinical antifibrotic drugs available, and effective targeted therapy is lacking. Recently, emerging antifibrotic drugs and immunomodulators have shown promising results in animal studies, and some have entered clinical research phases. This review aims to systematically review the molecular mechanisms underlying liver fibrosis, focusing on advancements in drug treatments for hepatic fibrosis. Furthermore, since liver fibrosis is a progression or endpoint of many diseases, it is crucial to address the etiological treatment and secondary prevention for liver fibrosis. We will also review the pharmacological treatments available for common hepatitis leading to liver fibrosis.

Aim: To evaluate the perioperative outcomes and postoperative survival of applying staging laparoscopy (SL) in intrahepatic cholangiocarcinoma (ICC) patients undergoing surgical resection. Methods: A retrospective analysis was performed on all selected ICC patients who underwent curative-intent resection with/without applying staging laparoscopy from January 2010 to August December 2021. Perioperative outcomes and postoperative survival were analyzed. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to reduce the bias due to confounding variables in the SL group and the non-SL group. Multivariate Cox analysis was used to ascertain the independent predictor of survival for ICC patients. Results: A total of 279 patients (24.1%) were included in the SL group, while 881 patients (75.9%) were included in the non-SL group. Compared with the non-SL group, the SL group had lower blood loss, smaller tumor size, higher R0 resection rate, and shorter hospital stay, but a higher incidence of postoperative complications. The OS of the SL group was better than that of the non-SL group (Median OS: 31 months vs. 20 months). The 1-, 3-, and 5-year overall survival rates of the SL group were 77.9%, 45.1%, and 32.9%, respectively, while the non-SL group had rates of 63.9%, 31.3%, and 18.4%. SL was confirmed as an independent predictor of survival by multivariate Cox analysis. Conclusion: ICC patients receiving SL had better perioperative outcomes and significantly prolonged overall survival after resection surgery. The subgroup analysis results support the use of routine SL.

Background Preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) may optimize individualized treatment decision-making. This study aimed to investigate the prognostic differences between HCC patients undergoing liver resection (LR) and liver transplantation (LT) based on predicted MVI risks. Methods We analysed 905 patients who underwent LR, including 524 who underwent anatomical resection (AR) and 117 who underwent LT for HCC within the Milan criteria using propensity score matching. A nomogram model was used to predict preoperative MVI risk. Results The concordance indices of the nomogram for predicting MVI were 0.809 and 0.838 in patients undergoing LR and LT, respectively. Based on an optimal cut-off value of 200 points, the nomogram defined patients as high- or low-risk MVI groups. LT resulted in a lower 5-year recurrence rate and higher 5-year overall survival (OS) rate than LR among the high-risk patients (23.6% vs 73.2%, P < 0.001; 87.8% vs 48.1%, P < 0.001) and low-risk patients (19.0% vs 45.7%, P < 0.001; 86.5% vs 70.0%, P = 0.002). The hazard ratios (HRs) of LT vs LR for recurrence and OS were 0.18 (95% confidence interval [CI], 0.09-0.37) and 0.12 (95% CI, 0.04-0.37) among the high-risk patients and 0.37 (95% CI, 0.21-0.66) and 0.36 (95% CI, 0.17-0.78) among the low-risk patients. LT also provided a lower 5-year recurrence rate and higher 5-year OS rate than AR among the high-risk patients (24.8% vs 63.5%, P = 0.001; 86.7% vs 65.7%, P = 0.004), with HRs of LT vs AR for recurrence and OS being 0.24 (95% CI, 0.11-0.53) and 0.17 (95% CI, 0.06-0.52), respectively. The 5-year recurrence and OS rates between patients undergoing LT and AR were not significantly different in the low-risk patients (19.4% vs 28.3%, P = 0.129; 85.7% vs 77.8%, P = 0.161). Conclusions LT was superior to LR for patients with HCC within the Milan criteria with a predicted high or low risk of MVI. No significant differences in prognosis were found between LT and AR in patients with a low risk of MVI.

Objective:To establish a predictive model for survival benefit of patients with intrahepatic cholangiocarcinoma (ICC) who received adjuvant chemotherapy after radical resection.Methods:The clinical and pathological data of 249 patients with ICC who underwent radical resection and adjuvant chemotherapy at 8 hospitals in China from January 2010 to December 2018 were retrospectively collected. There were 121 males and 128 females,with 88 cases>60 years old and 161 cases≤60 years old. Feature selection was performed by univariate and multivariate Cox regression analysis. Overall survival time and survival status were used as outcome indicators,then target clinical features were selected. Patients were stratified into high-risk group and low-risk group,survival differences between the two groups were analyzed. Using the selected clinical features, the traditional CoxPH model and deep learning DeepSurv survival prediction model were constructed, and the performance of the models were evaluated according to concordance index(C-index).Results:Portal vein invasion, carcinoembryonic antigen>5 μg/L,abnormal lymphocyte count, low grade tumor pathological differentiation and positive lymph nodes>0 were independent adverse prognostic factors for overall survival in 249 patients with adjuvant chemotherapy after radical resection (all P<0.05). The survival benefit of adjuvant chemotherapy in the high-risk group was significantly lower than that in the low-risk group ( P<0.05). Using the above five features, the traditional CoxPH model and the deep learning DeepSurv survival prediction model were constructed. The C-index values of the training set were 0.687 and 0.770, and the C-index values of the test set were 0.606 and 0.763,respectively. Conclusion:Compared with the traditional Cox model, the DeepSurv model can more accurately predict the survival probability of patients with ICC undergoing adjuvant chemotherapy at a certain time point, and more accurately judge the survival benefit of adjuvant chemotherapy.

目的 分析肝内胆管癌(intrahepatic cholangiocarcinoma,ICC)不同大体病理类型对预后的影响以及不同大体病理类型与临床特征的关系.方法 采用回顾性病例对照研究方法,收集于2010-2020 年中国 13 家三级甲等医院行根治性切除术的 660 例 ICC 病人的临床和病理学资料,进行1∶1倾向性评分匹配(卡钳值:0.02),采用 Kaplan-Meier 法绘制生存曲线,log-rank 检验进行生存分析.单因素分析采用χ2 检验,P＜0.05 为差异有统计学意义.结果 1∶1 倾向性评分匹配后,肿块型 ICC病人与管周浸润型 ICC病人的预后差异有统计学意义(P＜0.05).当 ICC病人处于 T1 分期时,肿块型 ICC病人与管周浸润型 ICC病人的预后差异有统计学意义(P＜0.05).肿块型 ICC 病人(513 例)和管周浸润型 ICC病人(102 例)在地区、年龄、结石病史、Child-Pugh 分级、腹痛、腹胀、黄疸、发热、中性粒细胞计数、淋巴细胞计数、谷丙转氨酶、总胆红素、总白蛋白、肿瘤位置、肿瘤大小方面比较,差异均有统计学意义(均P＜0.05);肿块型 ICC 和管内生长型 ICC 病人(45 例)在地区、年龄、谷丙转氨酶、肿瘤大小情况比较,差异均有统计学意义(均P＜0.05).结论 与肿块型相比,管周浸润型 ICC病人具有更良好的预后.可进一步探究对管周浸润型 ICC病人进行免疫治疗的有效性,以及肿块型 ICC病人对靶向治疗的敏感性.

AIM:Long noncoding RNAs (lncRNAs) are key mediators with a wide range of pathophysiological functions, but their role in human hepatocellular carcinoma (HCC) is still unclear. METHODS:An unbiased microarray study evaluated a novel lncRNA, HClnc1, that is linked to the development of HCC. In vitro cell proliferation assays and an in vivo xenotransplanted HCC tumor model were performed to determine its functions, followed by antisense oligo-coupled mass spectrometry to identify HClnc1-interacting proteins. To study relevant signaling pathways, in vitro experiments were performed, including chromatin isolation by RNA purification, RNA immunoprecipitation, luciferase, and RNA pull-down assay. RESULTS:HClnc1 levels were considerably greater in patients with advanced tumor-node-metastatic stages, and it was found to be inversely connected to survival rates. Moreover, the proliferative and invasive potential of the HCC cells was attenuated by HClnc1 RNA knockdown in vitro, while HCC tumor growth and metastasis were found to be reduced in vivo. HClnc1 interacted with pyruvate kinase M2 (PKM2) to prevent its degradation and thus facilitated aerobic glycolysis and PKM2-STAT3 signaling. CONCLUSIONS:HClnc1 is involved in a novel epigenetic mechanism of HCC tumorigenesis and PKM2 regulation. HClnc1 is not only a more accurate prognostic indicator of HCC but also a potential therapeutic target for HCC treatment.

Objectives:To construct a nomogram for prediction of intrahepatic cholangiocarcinoma (ICC) lymph node metastasis based on inflammation-related markers,and to conduct its clinical verification.Methods:Clinical and pathological data of 858 ICC patients who underwent radical resection were retrospectively collected at 10 domestic tertiary hospitals in China from January 2010 to December 2018. Among the 508 patients who underwent lymph node dissection,207 cases had complete variable clinical data for constructing the nomogram,including 84 males,123 females,109 patients≥60 years old,98 patients<60 years old and 69 patients were pathologically diagnosed with positive lymph nodes after surgery. Receiver operating characteristic curve was drawn to calculate the accuracy of preoperative imaging examinations to determine lymph node status,and the difference in overall survival time was compared by Log-rank test. Partial regression squares and statistically significant preoperative variables were screened by backward stepwise regression analysis. R software was applied to construct a nomogram,clinical decision curve and clinical influence curve,and Bootstrap method was used for internal verification. Moreover,retrospectively collecting clinical information of 107 ICC patients with intraoperative lymph node dissection admitted to 9 tertiary hospitals in China from January 2019 to June 2021 was for external verification to verify the accuracy of the nomogram. 80 patients with complete clinical data but without lymph node dissection were divided into lymph node metastasis high-risk group and low-risk group according to the score of the nomogram among the 858 patients. Log-rank test was used to compare the overall survival of patients with or without lymph node metastasis diagnosed by pathology.Results:The area under the curve of preoperative imaging examinations for lymph node status assessment of 440 patients was 0.615,with a false negative rate of 62.8% (113/180) and a false positive rate of 14.2% (37/260). The median survival time of 207 patients used to construct a nomogram with positive or negative postoperative pathological lymph node metastases was 18.5 months and 27.1 months,respectively ( P<0.05). Five variables related to lymph node metastasis were screened out by backward stepwise regression analysis,which were combined calculi,neutrophil/lymphocyte ratio,albumin,liver capsule invasion and systemic immune inflammation index,according to which a nomogram was constructed with concordance index(C-index) of 0.737 (95% CI: 0.667 to 0.806). The C-index of external verification was 0.674 (95% CI:0.569 to 0.779). The calibration prediction curve was in good agreement with the reference curve. The results of the clinical decision curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.32,the maximum net benefit could be obtained by 0.11,and the cost/benefit ratio was 1∶2. The results of clinical influence curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.6,the probability of correctly predicting lymph node metastasis could reach more than 90%. There was no significant difference in overall survival time between patients with high/low risk of lymph node metastasis assessed by the nomogram and those with pathologically confirmed lymph node metastasis or without lymph node metastasis (Log-rank test: P=0.082 and 0.510,respectively). Conclusion:The prediction accuracy of preoperative nomogram for ICC lymph node metastasis based on inflammation-related markers is satisfactory,which can be used as a supplementary method for preoperative diagnosis of lymph node metastasis and is helpful for clinicians to make personalized decision of lymph node dissection for patients with ICC.

Objective: To explore the clinical value of adjuvant therapy in patients with T3 gallbladder cancer (GBC) who have undergone R0 resection. Methods: Clinical and pathological data from 415 patients with T3 GBC who underwent surgical treatment in 7 tertiary centers in China from January 2013 to December 2018 were collected,including 251 males and 164 females,aged (61±11)years (range: 26 to 88 years). Depending on whether to receive adjuvant therapy after radical resection,the patients were divided into the radical resection group alone (group A,n=358) and the radical resection combined with the postoperative adjuvant therapy group (group B,n=57). The general data of the two groups were matched 1∶1 by propensity score matching method,and the caliper value was 0.02.Clinicopathological characteristics,overall survival and disease-free survival of the two groups were compared.The Cox regression model was used for multivariate analysis,and patients with at least one or more independent risk factors were classified as high-risk clinicopathological subtypes. Subgroup analysis was performed to assess the clinical value of adjuvant therapy after radical resection in patients with high-risk clinicopathological subtypes. Results: After the matching,there were 42 patients in each of the two groups. The incidence of gallbladder cancer and the number of dissected lymph nodes in group B after cholecystectomy were higher than those in group A (χ2=9.224,2.570,both P<0.05). There were no significant differences in overall survival rate and disease-free survival rate between the two groups before and after matching (all P>0.05). The results of the univariate and multivariate analysis showed that CA19-9>39 U/ml,nerve invasion,tumor location (liver side or bilateral),TNM stage ⅢB to ⅣB ,poorly differentiated tumor were independent prognostic factors of overall survival and disease-free survival of patients with T3 stage gallbladder cancer (all P<0.05).Three hundred and twenty-nine patients(79.3%) had high-risk clinicopathological subtypes,and the median survival time after curative resection with and without adjuvant therapy was 17 months and 34 months respectively,and the 3-year and 5-year overall survival rates were respectively 40.0%,21.3% and 46.0%,46.0% (χ2=4.042,P=0.044);the median disease-free survival time was 9 months and 13 months,and the 3-year and 5-year disease-free survival rates were 23.4%,13.6% and 30.2%,18.2% (χ2=0.992,P=0.319). Conclusions: Postoperative adjuvant therapy following radical surgery did not yield significant improvements in the overall survival and disease-free survival rates of patients diagnosed with T3 gallbladder cancer. However, it demonstrated a significant extension in the overall survival rate for patients presenting high-risk clinicopathological subtypes.

Objective:To investigate the preoperative clinicopathological features of patients who obtained survival benefit from lymph node dissection in resection of intrahepatic cholangiocarcinoma (ICC).Methods:Clinical data of 415 patients who underwent ICC radical resection in 8 hospitals in China from January 2010 to December 2018 were retrospectively analyzed. The informed consents of all patients were obtained and the local ethical committee approval was received. Among them, 225 patients were male and 190 female,aged from 27 to 83 years, with a median age of 59 years. All patients were divided into the dissection and non-dissection groups according to whether intraoperative lymph node dissection was performed. Propensity score matching (PSM) was used to balance the differences between the dissection and non-dissection groups. Survival analysis was performed by Kaplan-Meier method and Log-rank test. Preoperative clinicopathological characteristics of patients obtaining survival benefit in the dissection group were analyzed.Results:Prior to PSM, 283 patients were allocated in the dissection group and 132 cases in the non-dissection group. After 1∶1 PSM, 228 patients were selected, with 114 cases in each group. The median survival in the dissection and non-dissection groups was 35.4 and 25.0 months, and the overall survival rate in the dissection group was significantly higher than that in the non-dissection group (χ2=5.404, P<0.05). Glisson's capsule invasion,CA19-9>37 kU/L, abnormal neutrophil and lymphocyte count were the preoperative clinicopathological features of ICC patients obtaining survival benefit from lymph node dissection (χ2=9.548, 4.800, 13.715, 13.412; P<0.05).Conclusions:Lymph node dissection in ICC radical resection can bring survival benefit to patients with hepatic capsule invasion, preoperative CA19-9>37 kU/L, abnormal neutrophil and lymphocyte count.

Background Microvascular invasion (MVI) has been reported to be an independent prognostic factor of recurrence and poor overall survival in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the preoperative independent risk factors of MVI and establish a Bayesian network (BN) prediction model to provide a reference for surgical diagnosis and treatment.Methods A total of 531 patients with ICC who underwent radical resection between 2010 and 2018 were used to establish and validate a BN model for MVI. The BN model was established based on the preoperative independent variables. The ROC curves and confusion matrix were used to assess the performance of the model.Results MVI was an independent risk factor for relapse-free survival (RFS) (P < 0.05). MVI has a correlation with postoperative recurrence, early recurrence (< 6 months), median RFS and median overall survival (all P < 0.05). The preoperative independent risk variables of MVI included obstructive jaundice, prognostic nutritional index, CA19-9, tumor size, and major vascular invasion, which were used to establish the BN model. The AUC of the BN model was 78.92% and 83.01%, and the accuracy was 70.85% and 77.06% in the training set and testing set, respectively.Conclusion The BN model established based on five independent risk variables for MVI is an effective and practical model for predicting MVI in patients with ICC.

Objective:To explore the predictive value of tumor burden score (TBS) combined with lymph node staging (TBS-N staging) for postoperative survival of patients with intrahepatic cholangiocarcinoma (ICC).Methods:Clinical data of 335 ICC patients who underwent hepatectomy in Zhongda Hospital of Southeast University School of Medicine, Eastern Hepatobiliary Surgery Hospital and Affiliated Hospital of North Sichuan Medical College from January, 2013 to December, 2019 were retrospectively analyzed. Among them, 169 patients were male and 166 female, aged from 23 to 87 years, with a median age of 62 years. The informed consents of all patients were obtained and the local ethical committee approval was received. The TBS of all patients was calculated. All the patients were divided into stageⅠ, Ⅱ and Ⅲ according to TBS score and lymph node metastasis. The predictive ability of TBS-N staging for clinical prognosis of ICC patients after hepatectomy was analyzed by the receiver operating characteristic (ROC) curve. The risk factors of clinical prognosis of ICC patients after hepatectomy were identified by Cox proportional hazard regression model.Results:The optimal cut-off value of TBS was 4.22, including84 cases of TBS-N stageⅠ, 202 cases of stageⅡand 49 cases of stage Ⅲ. TBS-N staging was correlated with tumor diameter (F=77.639, P<0.05), intraoperative blood loss (Z=11.385, P<0.05), HBV infection rate (χ2=6.590, P<0.05), surgical resection range (χ2=9.796, P<0.05), vascular invasion (χ2=12.332, P<0.05), TNM staging (P<0.05) and postoperative complications (χ2=7.210, P<0.05) of ICC patients. Cox multivariate analysis showed that TBS>4.22, N1 stage and poor tumor differentiation were the independent risk factors for clinical prognosis of ICC patients after hepatectomy (HR=1.529, 2.100, 1.724; P<0.05). The median overall survival of patients with TBS-N stage Ⅰ, Ⅱ and Ⅲ was 51.4, 22.7 and 12.0 months, respectively, where significant differences were observed (χ2=25.797, P<0.05). The area under ROC curve (AUC) of TBS, N staging and TBS-N model for predicting clinical prognosis of ICC patients after hepatectomy was 0.596, 0.602 and 0.660, respectively.Conclusions:TBS and N staging are the independent risk factors for clinical prognosis of ICC patients after hepatectomy. Compared with TBS or N staging alone, TBS-N staging can better evaluate the clinical prognosis of ICC patients after hepatectomy.