Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. METHODS: In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon's two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. RESULTS: Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6-51.9) and 90.3% (56/62, 95% CI, 80.1-96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8-not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7-94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. CONCLUSIONS: Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04401800).

Does depressurization of the portal vein before liver transplantation affect the recurrence of HCC? A nested case-control study.

BACKGROUND: Portal hypertension (PHT) has been proven to be closely related to the development of hepatocellular carcinoma (HCC). Whether PHT before liver transplantation (LT) will affect the recurrence of HCC is not clear. METHODS: 110 patients with depressurization of the portal vein (DPV) operations (Transjugular Intrahepatic Portosystemic Shunt-TIPS, surgical portosystemic shunt or/and splenectomy) before LT from a HCC LT cohort, matched with 330 preoperative non-DPV patients; this constituted a nested case-control study. Subgroup analysis was based on the order of DPV before or after the occurrence of HCC. RESULTS: The incidence of acute kidney injury and intra-abdominal bleeding after LT in the DPV group was significantly higher than that in non-DPV group. The 5-year survival rates in the DPV and non-DPV group were 83.4% and 82.7% respectively (P = 0.930). In subgroup analysis, patients in the DPV prior to HCC subgroup may have a lower recurrence rate (4.7% vs.16.8%, P = 0.045) and a higher tumor free survival rate (88.9% vs.74.4%, P = 0.044) after LT under the up-to-date TNMI-II stage, while in TNM III stage, there was no difference for DPV prior to HCC subgroup compared with the DPV after HCC subgroup or the non-DPV group. CONCLUSION: Compared with DPV after HCC, DPV treatment before HCC can reduce the recurrence rate of HCC after early transplantation (TNM I-II). DPV before LT can reduce the recurrence of early HCC.

Clinical prognosis and related molecular features of hepatitis B-associated adolescent and young adult hepatocellular carcinoma.

BACKGROUND: Inattention has been given to the pathogenesis of adolescent and young adult (AYA) hepatocellular carcinoma (HCC). Due to the more advanced tumor progression and poorer prognosis of AYA-HCC, together with a better tolerance ability, noncirrhotic background, and a stronger willingness to treat AYA-HCC, clinical and molecular biology studies are urgent and necessary, especially for those with hepatitis B infection. METHODS: For clinical aspects, the overall survival, the recurrence-free survival, and the Cox analyses were performed. Then, functional analysis, gene clustering, metabolic-related analysis, immune infiltration and competing endogenous RNA (ceRNA) construction were carried out using whole transcriptome sequencing technique. RESULTS: Based on the clinical information of our HCC cohort, the overall survival and recurrence-free survival rates were worse in the AYA group than in the elderly group as previously described. According to our whole transcriptome sequencing results, functional analysis revealed that metabolism-related pathways as well as protein translation and endoplasmic reticulum processing were enriched. Then the hub metabolism-related genes were screened by metabolite-protein interactions (MPIs) and protein-protein interactions (PPIs). Fatty acid metabolism is a crucial component of metabolic pathways, abnormalities of which may be the reason for the worse prognosis of HBV-AYA HCC. Finally, the relationship of disrupted expression of metabolism-related genes with immune infiltration was also analyzed, and the lncRNA‒miRNA‒mRNA-related ceRNA network for HBV-AYA HCC was constructed, which may provide new cues for HBV-AHA HCC prevention. CONCLUSION: The worse prognosis and recurrence rate of HBV-AYA HCC may be related to abnormalities in metabolism-related pathways, especially disorders of fatty acid metabolism.

Reliability and Validity of the Chinese Version of the Nurses' Cancer Pain Management Competency Scale.

BACKGROUND: The Nurses' Cancer Pain Management Competency Scale (NCPMCS) is a tool to explore nurses' competencies and subjective experiences in cancer pain management, and to help nurses understand their current shortcomings in cancer pain management. The scale, currently available only in English and translated into Chinese for wider adoption abroad, provides a tool for Chinese nurses to assess their level of cancer pain management. Furthermore, based on the scale's specific score, they can evaluate their lack of understanding about cancer pain management, advance research into this area, and enhance their capacity to control cancer pain while providing patient care. OBJECTIVE: The purpose of this study was to translate and localize the new scale, and to measure its reliability and validity. The study was also to provide a way to quickly and accurately measure the competency of cancer pain management among nursing staff in China. METHODS: The Bristling translation approach was used to translate, translate back, and culturally modify the English version of the cancer pain management competency scale for nurses to create the Chinese version. A convenience sample was used for the study, 220 clinical nurses from three Grade III hospitals in Zhengzhou, Henan Province, China, were chosen by convenience sampling. The Chinese version of the scale was used for this investigation. RESULTS: The Cancer Pain Management Competency Scale for Nurses has 14 items over 4 dimensions in its Chinese form. From the exploratory factor analysis, four common components were recovered; the cumulative variance rate was 81.994%, the scale's Cronbach's α coefficient was 0.902, and the Cronbach's α coefficient for each dimension ranged from 0.800 to 0.938. Retest reliability was 0.915, scale content validity was 0.865, and Spearman-Brown's broken half reliability was 0.808. CONCLUSION: Nurses' cancer pain management competency in clinics can be assessed using the Chinese version of the Nurses' Cancer Pain Management Competency Scale, which has strong validity and reliability.

SIRT5 alleviates hepatic ischemia and reperfusion injury by diminishing oxidative stress and inflammation via elevating SOD1 and IDH2 expression.

Hepatic ischemia/reperfusion (I/R) injury, a common and unavoidable pathophysiological process during liver transplantation or resection operation, may impede postoperative liver function recovery, and its mechanism and targeted therapy remain largely unknown. SIRT5 is a well-known deacetylase and participates in the regulation of many physiological and pathological processes, including I/R. The role of SIRT5 in I/R is controversial or tissue-specific, restricting I/R progression in the heart while deteriorating injury in the kidney and brain, while its effect on hepatic I/R remains unclear. In this study, we investigated the function of SIRT5 in hepatic I/R using AAV8 and lentivirus to overexpress SIRT5 in vivo and in vitro. The data showed that SIRT5 overexpression alleviated liver I/R injury in mice and hypoxia/reoxygenation treated AML-12 cells. Moreover, gain- and loss-of-function of SIRT5, SOD1 and IDH2 experiments in AML-12 were performed. Our results demonstrated that SOD1 and IDH2 knockdown abolished the effect of SIRT5 on restraining oxidative stress and inflammation. Therefore, our work revealed that SIRT5 may alleviates hepatic I/R injury by diminishing oxidative stress and inflammation via up-regulating the SOD1 and IDH2 expression, which enriches the theory and therapeutic strategies of hepatic I/R injury.

A new method for predicting the microvascular invasion status of hepatocellular carcinoma through neural network analysis.

AIMS: To determine the relationship between microvascular invasion (MVI) and the clinical features of hepatocellular carcinoma (HCC) and provide a method to evaluate MVI status by neutral network analysis. METHODS: The patients were divided into two groups (MVI-positive group and MVI-negative group). Univariate analysis and multivariate logistic regression analysis were carried out to identify the independent risk factors for MVI positivity. Neural network analysis was used to analyze the different importance of the risk factors in MVI prediction. RESULTS: We enrolled 1697 patients in this study. We found that the independent prognostic factors were age, NEU, multiple tumors, AFP level and tumor diameter. By neural network analysis, we proposed that the level of AFP was the most important risk factor for HCC in predicting MVI status (the AUC was 0.704). However, age was the most important risk factor for early-stage HCC with a single tumor (the AUC was 0.605). CONCLUSION: Through the neutral network analysis, we could conclude that the level of AFP is the most important risk factor for MVI-positive patients and the age is the most important risk factor for early-stage HCC with a single tumor.

Construction of Two Independent RAB Family-Based Scoring Systems Based on Machine Learning Algorithms and Definition of RAB13 as a Novel Therapeutic Target for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) remains a global health challenge with a low early diagnosis rate and high mortality. The Rab GTPase (RAB) family plays an essential role in the occurrence and progression of HCC. Nonetheless, a comprehensive and systematic investigation of the RAB family has yet to be performed in HCC. We comprehensively assessed the expression landscape and prognostic significance of the RAB family in HCC and systematically correlated these RAB family genes with tumor microenvironment (TME) characteristics. Then, three RAB subtypes with distinct TME characteristics were determined. Using a machine learning algorithm, we further established a RAB score to quantify TME features and immune responses of individual tumors. Moreover, to better evaluate patient prognosis, we established a RAB risk score as an independent prognostic factor for patients with HCC. The risk models were validated in independent HCC cohorts and distinct HCC subgroups, and their complementary advantages guided clinical practice. Furthermore, we further confirmed that the knockdown of RAB13, a pivotal gene in risk models, suppressed HCC cell proliferation and metastasis by inhibiting the PI3K/AKT signaling pathway, CDK1/CDK4 expression, and epithelial-mesenchymal transition. In addition, RAB13 inhibited the activation of JAK2/STAT3 signaling and the expression of IRF1/IRF4. More importantly, we confirmed that RAB13 knockdown enhanced GPX4-dependent ferroptosis vulnerability, highlighting RAB13 as a potential therapeutic target. Overall, this work revealed that the RAB family played an integral role in forming HCC heterogeneity and complexity. RAB family-based integrative analysis contributed to enhancing our understanding of the TME and guided more effective immunotherapy and prognostic evaluation.

The appropriate method of hepatectomy for hepatocellular carcinoma within University of California San Francisco (UCSF) criteria through neural network analysis.

BACKGROUND: This study aimed to find effective treatments for the patient within UCSF criteria. METHODS: This study enrolled 1006 patients meeting UCSF criteria, undergoing hepatic resection (HR), divided into two groups: single tumor group and multiple tumors group. We compared and analyzed the risk factors between these two groups' long-term outcomes, through log-rank test, cox proportional hazards model and using neural network analysis to identify the independent risk factors. RESULTS: The 1-, 3-, and 5-year OS rates in single tumor were significantly higher than multiple tumors (95.0%, 73.2% and 52.3% versus 93.9%, 69.7% and 38.0%, respectively, p < 0.001). The 1-, 3- and 5-year RFS rates were 90.3%, 60.7%, and 40.1% in single tumor and 83.4%, 50.7% and 23.8% in multiple tumors, respectively (p < 0.001). And tumor type, anatomic resection and MVI were the independent risk factors for the patient within UCSF criteria. MVI was the most important risk factor affecting OS and RFS rates in neural network analysis. The method of hepatic resection and the number of tumors were also affected OS and RFS rates. CONCLUSION: Anatomic resections should be applied to patients within UCSF criteria, especially for patients with single MVI negative tumours.

[Application Value of Novel Coagulation Markers in Predicting Postoperarative Complications in the Early Stage After Liver Transplantation].

Objective: To investigate the relationship between thrombin-antithrombin complex (TAT), plasmin-α 2-plasmininhibitor complex (PIC), soluble thrombomodulin (sTM), and tissue plasminogen activator-inhibitor complex (tPAIC) and postoperative complications in the early stage after liver transplantation (LT). Methods: We analyzed the perioperative clinical data, including plasma TAT, PIC, sTM, and tPAIC, of 130 post-LT patients admitted to the intensive care unit (ICU), West China Hospital, Sichuan University between December 2021 and November 2022. Patients were divided into two groups, a complication group and a non-complication group, according to whether they experienced complications of Clavien-Dindo (CD) grade Ⅲb and above within 30 days after the surgery. Univariate analysis and binary multivariate logistic regression models were used to determine the risk factors for complications within 30 days post-LT. Results: The incidence of complications of CD grade Ⅲb and above within 30 days post-LT was 33.1% (43/130). Patients in the complication group had significantly higher scores for the Model for End-Stage Liver Disease (MELD), operative time, intraoperative red blood cell transfusion volume, intraoperative plasma transfusion volume, and plasma TAT, PIC, sTM and tPAIC measured at the time of admission to ICU after the operation than those in the non-complication group did (all P<0.05). Logistic regression showed that for every single U of red blood cells transfused during the transplant surgery, the probabilities of complications within 30 days post-LT increased by 15.1% (95% confidence interval [ C I]: 1.070-1.239, P<0.001) and for the increase of every single TU/mL of plasma sTM measured upon post-LT admission to ICU, the probabilities of complications increased by 13.7% (95% CI: 1.060-1.220, P<0.001). Conclusion: Plasma sTM measured upon admission to ICU after LT is an independent risk factor for complications within 30 days post-LT, and additional assessment of sTM may help predict complications in the early stage post-LT.

When immunotherapy meets liver transplantation for hepatocellular carcinoma: A bumpy but promising road.

Liver transplantation (LT) is a highly curative therapy for patients with hepatocellular carcinoma (HCC). However, due to the shortage of donor livers and rapid progression of HCC, a majority of patients are dropped out from the waitlist. Recently, immunotherapy has shown great promise in the treatment of advanced HCC. However, the use of immunotherapy is limited in LT mainly due to the potentially increasing risk of graft rejection. One of the main challenges for researchers is the protection of donor graft from an immunotherapy-boosted immune response mounted by the host. Besides, the safety, availability, and costs of immunotherapy are other challenges that need to be addressed. Here, we reviewed the literature involving patients who received immunotherapy prior to transplant to avoid waitlist dropouts and following transplantation to prevent the progression of tumor recurrence and metastasis. Statistically, the incidence of rejection was 25.0% pre-transplant and 18.5% post-transplant. Based on the review of these clinical studies, we can conclude that conducting clinical trials on the safety and efficacy of currently available immunotherapy drugs and identifying novel immunotherapy targets through extensive research may be promising for patients who do not meet the selection criteria for LT and who experience post-transplant recurrence. To date, the clinical experience on the use of immunotherapy before or after LT comes from individual case studies. Although some of the reported results are promising, they are not sufficient to support the standardized use of immunotherapy in clinical practice.

Brahma-Related Gene 1 Inhibition Prevents Liver Fibrosis and Cholangiocarcinoma by Attenuating Progenitor Expansion.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) is closely correlated with hepatic progenitor cell (HPC) expansion and liver fibrosis. Brahma-related gene 1 (Brg1), an enzymatic subunit of the switch/sucrose nonfermentable complex that is critical in stem cell maintenance and tumor promotion, is prominently up-regulated in both HPCs and iCCA; however, its role in this correlation remains undefined. APPROACH AND RESULTS: A retrospective cohort study indicated that high Brg1 expression suggests poor prognosis in patients with iCCA. In chronically injured livers induced by a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet or bile duct ligation surgery, HPCs were dramatically activated, as indicated by their enhanced expression of Brg1 and a subset of stem cell markers; however, Brg1 ablation in HPCs strongly suppressed HPC expansion and liver fibrosis. Furthermore, in a chemically induced iCCA model, inhibition of Brg1 by a specific inhibitor or inducible gene ablation markedly improved histology and suppressed iCCA growth. Mechanistically, in addition to transcriptionally promoting both Wnt receptor genes and target genes, Brg1 was found to bind to the ß-catenin/transcription factor 4 transcription complex, suggesting a possible approach for regulation of Wnt/ß-catenin signaling. CONCLUSIONS: We have demonstrated the function of Brg1 in promoting HPC expansion, liver cirrhosis, and, ultimately, iCCA development in chronically injured livers, which is largely dependent on Wnt/ß-catenin signaling. Our data suggest that therapies targeting Brg1-expressing HPCs are promising for the treatment of liver cirrhosis and iCCA.

An Endoplasmic Reticulum Stress-MicroRNA-26a Feedback Circuit in NAFLD.

BACKGROUND AND AIMS: Endoplasmic reticulum (ER) stress is an adaptive response to excessive ER demand and contributes to the development of numerous diseases, including nonalcoholic fatty liver disease (NAFLD), which is hallmarked by the accumulation of lipid within hepatocytes. However, the underlying mechanisms remain elusive. MicroRNAs (miRNAs) play an indispensable role in various stress responses, but their implications in ER stress have not yet been systemically investigated. In this study, we identify a negative feedback loop consisting of hepatic ER stress and miR-26a in NAFLD pathogenesis. APPROACH AND RESULTS: Combining miRNA dot blot array and quantitative PCR, we find that miR-26a is specifically induced by ER stress in liver cells. This induction of miR-26a is critical for cells to cope with ER stress. In human hepatoma cells and murine primary hepatocytes, overexpression of miR-26a markedly alleviates chemical-induced ER stress, as well as palmitate-triggered ER stress and lipid accumulation. Conversely, deficiency of miR-26a exhibits opposite effects. Mechanistically, miR-26a directly targets the eukaryotic initiation factor 2α, a core ER stress effector controlling cellular translation. Intriguingly, miR-26a is reduced in the livers of patients with NAFLD. Hepatocyte-specific restoration of miR-26a in mice significantly mitigates high-fat diet-induced ER stress and hepatic steatosis. In contrast, deficiency of miR-26a in mice exacerbates high-fat diet-induced ER stress, lipid accumulation, inflammation and hepatic steatosis. CONCLUSIONS: Our findings suggest ER stress-induced miR-26a up-regulation as a regulator for hepatic ER stress resolution, and highlight the ER stress/miR-26a/eukaryotic initiation factor 2α cascade as a promising therapeutic strategy for NAFLD.

Laparoscopic Segmentectomy IV Using Hepatic Round Ligament Approach Combined with Fluorescent Negative Staining Method.

BACKGROUND: Laparoscopic segmentectomy, which maximizes the preservation of the functional hepatic reserve and the possibility for future repeat hepatectomy while ensuring adequate surgical margin, is a feasible alternative to hemihepatectomy for hepatocellular carcinoma (HCC) (Vigano et al. in Ann Surg 270(5):842-851, 2019, Ishizawa et al. in Ann Surg 256(6):959-964, 2012). Herein, we present a video of laparoscopic segmentectomy IV for HCC using hepatic round ligament approach combined with fluorescent negative staining method. PATIENT AND METHODS: A 44-year-old male with history of chronic hepatitis B virus (HBV) infection for 22 months was referred for treatment of a single HCC in segment IV. The procedure was performed according to the following steps: (1) lowering the hilar plate based on Laennec's capsule (Sugioka et al. in J Hepatobiliary Pancreat Sci 24(1):17-23, 2017) after cholecystectomy; (2) cutting the Glisson's pedicles to segment IV along the fissure for the round ligament; (3) the first parenchyma transection was along the falciform ligament, while cutting some deep pedicles to segment IV; (4) clamping the left Glisson's pedicle and using fluorescent negative staining method (Abo et al. in Eur J Surg Oncol 41(2):257-264, 2015, Funamizu et al. in J Hepatobiliary Pancreat Sci, 2021, Xu et al. in Surg Endosc 34(10):4683-4691, 2020); (5) the second parenchyma transection was performed along the boundary of negative fluorescence region to expose the middle hepatic vein (MHV) using a combination of cranial and caudal approaches. RESULTS: The operative time was 190 min, and blood loss during operation was 80 mL. The histopathologic examination showed a solitary HCC, 2.5 cm in diameter, with negative surgical margin and no microvascular invasion. The patient had an uneventful postoperative recovery and was discharged on postoperative day 5. CONCLUSION: The round ligament approach combined with fluorescent negative staining method for laparoscopic anatomic segmentectomy IV is a feasible and effective technique.

Hepatic Resection Combined with Intraoperative Radiofrequency Ablation Versus Hepatic Resection Alone for Selected Patients with Moderately Advanced Multifocal Hepatocellular Carcinomas.

BACKGROUND: The role of hepatic resection (HR) combined with radiofrequency ablation (RFA) versus HR alone remains unclear for patients with multifocal hepatocellular carcinomas (HCCs). The aim of this study was to assess the outcomes of selected patients with moderately advanced multifocal HCCs after HR combined with intraoperative RFA versus HR alone. METHODS: A total of 304 selected patients with multifocal HCCs (three or fewer lesions, with the largest lesion > 4.5 cm and the residual lesion[s] ≤ 3 cm) who underwent HR plus RFA (HR+RFA group) or HR alone (HR group) were included. Propensity score matching (PSM) was used to adjust for baseline differences. Multivariable and subgroup analyses estimated the effects of clinical factors on survival. RESULTS: Both overall survival (OS) and recurrence-free survival (RFS) were comparable between both groups before and after PSM. Subgroup analysis showed that HR was associated with better RFS than HR+RFA for those patients with two tumors, or with all lesions located in the same lobe or without microvascular invasion (MVI) [all p < 0.05]. Moreover, en bloc resection provided a higher RFS than separate resection for those with all lesions in the same lobe (p = 0.039). CONCLUSION: For selected patients with moderately advanced multifocal HCCs, HR+RFA may offer similar OS and RFS as HR alone. However, HR may be more suitable for those with two tumors, or with all lesions in the same lobe or without MVI. Moreover, en bloc resection may be recommended for those with all lesions in the same lobe.

A simple CD4+ T cells to FIB-4 ratio for evaluating prognosis of BCLC-B hepatocellular carcinoma: a retrospective cohort study.

INTRODUCTION: Immunotherapy has become a new therapy for advanced hepatocellular carcinoma (HCC); however, its treatment results are considerably different. CD4+ T cells (CD4+) are the key to immunotherapy, but patients with HCC that have low CD4+ are rarely observed for clinical evidence. Hepatitis B virus-related HCC is often accompanied by cirrhosis and portal hypertension; therefore, CD4+ tend to be relatively low in number. TACE is the standard treatment for Barcelona Clinic Liver Cancer (BCLC)-B HCC, which may further reduce the number of CD4 + . METHODS: This retrospective cohort study further reduced CD4+ by including patients with human immunodeficiency virus (HIV) to observe the relationship between CD4+ and Chronic hepatitis B virus (CHB) induced HCC. A total of 170 BCLC-B HCC patients (42 HIV+) were included. Univariate and multivariate analyses, and artificial neural networks (ANNs) were used to evaluate the independent risk factors for the two-year survival. RESULTS: The statistical analysis of the two-year survival rate showed that the main factors influencing survival were liver function and immune indices, including CD4+, platelet, alanine aminotransferase, aspartate aminotransferase, aspartate aminotransferase-to-platelet ratio index, and fibrosis-4 (FIB-4) (P < 0.05). Compared with that in other indices, in logistic and ANN multivariate analysis, CD4 + -to-FIB-4 ratio (CD4+/FIB-4) had the highest importance with 0.716 C-statistic and 145.93 cut-off value. In terms of overall survival rate, HIV infection was not a risk factor (P = 0.589); however, CD4+/FIB-4 ≤ 145.93 significantly affected patient prognosis (P = 0.002). CONCLUSION: HIV infection does not affect the prognosis of BCLC-B HCC, but CD4+ have a significant predictive value. CD4+ played a vital role in HCC and this deserves the attention from physicians. Further, the CD4+/FIB-4 is a clinically valuable effective prognostic indicator for these patients.

Cellular crosstalk during liver regeneration: unity in diversity.

The liver is unique in its ability to regenerate from a wide range of injuries and diseases. Liver regeneration centers around hepatocyte proliferation and requires the coordinated actions of nonparenchymal cells, including biliary epithelial cells, liver sinusoidal endothelial cells, hepatic stellate cells and kupffer cells. Interactions among various hepatocyte and nonparenchymal cells populations constitute a sophisticated regulatory network that restores liver mass and function. In addition, there are two different ways of liver regeneration, self-replication of liver epithelial cells and transdifferentiation between liver epithelial cells. The interactions among cell populations and regenerative microenvironment in the two modes are distinct. Herein, we first review recent advances in the interactions between hepatocytes and surrounding cells and among nonparenchymal cells in the context of liver epithelial cell self-replication. Next, we discuss the crosstalk of several cell types in the context of liver epithelial transdifferentiation, which is also crucial for liver regeneration. Video abstract.

Laparoscopic anatomic bi-segmentectomy (S3 and S4b) using the Glisson's pedicle-first and intrahepatic anatomic markers approach.

BACKGROUND: With the advancement of laparoscopic technology, more precise anatomical hepatectomies such as segmentectomy or even bi-segmentectomy have been recommended by updated expert consensus to treat a single small hepatocellular carcinoma (HCC) [1, 2]. Herein, we presented a video of laparoscopic anatomic bi-segmentectomy (S3 and S4b) using the Glisson's pedicle-first and intrahepatic anatomic markers approach. METHODS: A 66-year-old male was referred for treatment of a single HCC adjacent to the Sagittal part of the left portal vein. The procedure was performed according to the following steps: (1) dissecting and transecting the Glisson's pedicle to S3 and S4b based on Laennec's capsule [3]; (2) identification of the ischemia boundary on the liver surface and confirming the presence of adequate surgical margins within the boundary, ensuing the integrity of segment 2 and 4a by the intraoperative ultrasonography meanwhile; (3) the left parenchymal transection was begun along the demarcation line, exposing the Glisson's pedicle to S2, left hepatic vein, and umbilical fissure vein; (4) the right parenchymal transection was performed to expose the V5, V4b, and V4a. And this operation was approved by the Institutional Review Board of the West China Hospital and written informed consent was obtained from patient of Sichuan University and written informed consent was obtained from patient. (5) The blood supply of residual liver surface was observed, and the integrity of segment 2 and 4a hepatic pedicle was ensured by intraoperative ultrasonography. RESULTS: The operative time was 224 min and blood loss during operation was 50 ml. The histopathologic examination showed a solitary HCC, 4 cm in diameter, with negative surgical margin and no microvascular invasion. The patient had an uneventful postoperative recovery and was discharged on postoperative day 5. CONCLUSION: Laparoscopic bi-segmentectomy (S3 and S4b) using the Glisson's pedicle-first and intrahepatic anatomic markers approach is feasible and effective. Its advantages lie in obtaining the benefits of anatomical hepatectomy, while maximizing the postoperative functional hepatic reserve [4-6].

Overexpression of transcription factor 3 drives hepatocarcinoma development by enhancing cell proliferation via activating Wnt signaling pathway.

BACKGROUND: Transcription factor 3 (TCF3) plays pivotal roles in embryonic development, stem cell maintenance and carcinogenesis. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. This study aimed to analyze the correlation between TCF3 expression and clinicopathological features of HCC, and further explore the underlying mechanism in HCC progression. METHODS: The expression of TCF3 was collected from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) HCC datasets, and further confirmed by immunostaining and Western blotting assays. The correlation between TCF3 expression and the clinicopathological features was evaluated. Bioinformatical analysis and in vitro experiments were conducted to explore the potential role of TCF3 in HCC development. RESULTS: Both the mRNA and protein levels of TCF3 were significantly higher in HCC tumor tissues compared to tumor adjacent tissues (P < 0.001 and P < 0.01). Analysis based on TCGA datasets showed that TCF3 was positively correlated with tumor clinical stage and grade, and patients with high TCF3 expression had shorter overall survival (P = 0.012), disease-specific survival (P = 0.022) and progression-free survival (P = 0.013). Similarly, the immunostaining results revealed that the high expression of TCF3 was closely correlated with tumor size (P = 0.001) and TNM stage (P = 0.002), and TCF3 was an independent risk factor of HCC. In vitro study exhibited that TCF3 knockdown dramatically suppressed cancer cell proliferation, and the underlying mechanism might be that the silencing of TCF3 reduced the expression of critical regulating proteins towards cell cycle and proteins involved in Wnt signaling pathways. CONCLUSIONS: TCF3 expression is significantly elevated in HCC and positively associated with the tumor size and TNM stage, as well as poor prognosis of HCC patients. The mechanism might be that TCF3 promotes cancer cell proliferation via activating Wnt signaling pathway.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

A Predictive Model to Evaluate the HbeAg Positivity of Chronic Hepatitis B Virus Patients in Clinics: A Cross-Sectional Study.

Background and Objective: The study aims to investigate the correlation between Hepatitis B 'e' antigen (HBeAg) and HBV DNA levels, and to find a convenient tool to estimate the HBV DNA level for clinicians. Materials and Methods: We enrolled 1020 patients in this cross-sectional study and divided them into four groups: an HbeAg-positive and -negative group, and high and low HBV DNA levels groups. Results: Alanine aminotransferase (ALT), Albumin (ALB) and HBeAg are independent risk factors for CHB patients. When the level of HBeAg is higher than 16.15 S/CO, it is four times more likely that the patients will have high levels of HBV DNA than those who do not. The ALT and TB are independent risk factors in HBeAg-negative patients with a high HBV DNA level. We have drawn three predictive models to estimate the HBV DNA levels for those with the chronic hepatitis B virus (CHB), and those that are HBeAg-positive and HBeAg-negative (Y1 = 0.004 × ALT(IU/L) + 1.412 × HBeAg (S/CO) - 0.029 × ALB (g/L) + 0.779, the AUC is 0.672, and the cutoff value is -0.072, there the sensitivity is 0.615, the specificity is 0.648, PPV is 65.182% and NPV is 60.837%; Y2 = 0.007 × HBeAg (S/CO) - 0.016 × HGB (g/L) + 3.070, the AUC is 0.724, and the cutoff value is 1.216, where the sensitivity is 0.626, the specificity is 0.897, PPV is 94.118% and NPV is 34.437%; Y3 = -0.005 × ALT(IU/L) + 0.006 × TB (umol/L) + 0.385, the AUC is 0.661, and the cutoff value is 0.263, where the sensitivity is 0.677, the specificity is 0.587, PPV is 66.820% and NPV is 40.774%, respectively). We propose that HBeAg is the most important risk factor for the patient with a high HBV DNA level, however, it is not as important in the HBeAg-positive group. Conclusions: HBeAg is an independent risk factor that reflects the level of HBV DNA with a strong correlation. Patient with HBeAg (-) should combine TB and ALT to estimate the level of HBV DNA.