Based on the IWATE criteria: to investigate the influence of different surgical approaches on the perioperative outcomes of hepatectomy.

BACKGROUND: In terms of perioperative outcomes, compared with traditional open surgery and laparoscopic surgery, studies of robotic liver resection have been limited and must be further clarified. METHODS: Clinical data from 465 patients who underwent liver resection were collected in this retrospective study, and the IWATE criteria were used to evaluate the difficulty level of each operation. We compared perioperative outcomes of open, laparoscopic, or robotic approaches for patients with uncomplicated and complex hepatectomy according to different IWATE scores. Among patients with uncomplicated hepatectomy, the median operation time was significantly longer in the robotic liver resection (RLR) group than in the open liver resection (OLR) and laparoscopic liver resection (LLR) groups; however, the RLR group had the shortest hospital stay. There were no significant differences in intraoperative blood loss, conversion rate, total complication rate, or serious complication rate among the three groups. RESULTS: Among patients with complex hepatectomy, the RLR group had the smallest intraoperative blood loss and shortest mean length of stay. The cases converted to open hepatectomy were lower in the RLR group than in the laparoscopic group, mainly based on the IWATE score of expert hepatectomy. The incidence of general and serious postoperative complications in the RLR group was significantly lower than that in the OLR and LLR groups. CONCLUSIONS: Robotic liver resection is a safe and feasible surgical method that is more advantageous than laparoscopic and open liver resection, especially in complex liver surgery.

Circ-ZEB1 promotes PIK3CA expression by silencing miR-199a-3p and affects the proliferation and apoptosis of hepatocellular carcinoma.

BACKGROUND: Although the prognostic outcomes of liver cancer (LC) cases have improved with the advancement in diagnostic technology and treatment methods, the transferability and recurrence of HCC and the 5-year and 10-year survival rates of patients have remained unsatisfactory. As a result, there is a need for more accurate diagnostic indicators that can detect liver cancer early, effectively improving the prognosis of patients. Whole-genome sequencing (WGS) revealed that circ-ZEB1 and PIK3CA are highly expressed in HCC tissues, whereas miR-199a-3p is significantly downregulated in HCC. Multiple databases search and biological analysis revealed that elevated expression of circ-ZEB1 and PIK3CA was related to poor prognosis of HCC. In vitro and in vivo studies revealed that upregulated levels of PIK3CA and circ-ZEB1 were closely associated with HCC proliferation and apoptosis. Based on these results, we believe that circ-ZEB1 and PIK3CA could be used as biomarkers to diagnose and treat patients with HCC. More importantly, circ-ZEB1 can promotes the expression of PIK3CA by silencing miR-199a-3p and affecting the progression of HCC. METHODS AND RESULTS: Postoperative specimens from 56 patients with HCC who had not undergone chemotherapy from 2015 to 2018 were collected from the Department of Hepatobiliary Surgery, Second Affiliated Hospital of Nanchang University. WGS revealed differential expression of genes in HCC. Furthermore, RT-qPCR detected the expression of circ-ZEB1, miR-199a-3p, and PIK3CA in HCC tissues. MTT, EdU, and plate cloning experiments were conducted to detect cell proliferation, whereas flow cytometry analysis was used to detect apoptosis. FISH was used to co-localize circ-ZEB1 and miR-199a-3p, and biotin-coupled probe pull-down assay was used to detect the specific binding of circ-ZEB1 and miR-199a-3p. The dual-luciferase report assay detected the association of miR-199a-3p with PIK3CA. Western blotting was used to study the expression of PIK3CA protein. Circ-ZEB1 and PIK3CA were upregulated in HCC and predicted a poor prognosis. MiR-199a-3p showed low expression in HCC, whereas downregulation of circ-ZEB1 reduced HCC cell proliferation and promoted cell apoptosis. MiR-199a-3p blocked the effect of circ-ZEB1 on HCC. Circ-ZEB1 served as a biomarker of HCC. Circ-ZEB1 promoted the expression of PIK3CA by silencing miR-199a-3p to affect the progress of HCC. CONCLUSIONS: Circ-ZEB1 promoted the expression of PIK3CA by depleting miR-199a-3p, thereby affecting HCC proliferation and apoptosis.

Knockdown of UCA1 attenuated the progression of alcoholic fatty disease by sponging miR-214.

Alcoholic fatty liver (AFL) is the initial manifestation of Alcoholic liver disease which can develop into alcoholic cirrhosis even extensive necrosis of liver cells, which induces liver failure finally. This study aims to focus on the role of long noncoding RNA UCA1 in AFL and further explored possible mechanism of this disease. We first downloaded GSE28619 to identify the expression of UCA1 in patients with AFL and use lncRNAs microarray to confirm UCA1 expression in serum of patients with AFL. Then we established ethanol-induced L02 cell model to mimic hepatocyte injury condition. By conducting qRT-PCR, we measured the expression of LncRNA UCA1 and miR-214 in serum of patients and ethanol-induced L02 cell. MTT assay, transwell migration, ELISA, qRT-PCR, and western blotting analysis were applied to evaluating the effect of UCA1 on ethanol-induced L02 cell. The bioinformatics analysis and the rescue experiment were devoted to the underlying mechanism. In this study, we first detected the expression of UCA1 was up-regulated in serum of patients with AFL and ethanol-induced L02 cells. And knockdown of UCA1 reversed the inhibiting effect of ethanol on the biological behavior of L02 cells including cell proliferation, migration, and apoptosis. Besides, lncRNA UCA1 regulated the expression of KLF5 by sponging miR-214. LncRNA UCA1 regulated the biological behavior of ethanol-induced L02 cells by sponging miR-214, which may provide novel therapeutic strategies for alcoholic fatty liver.

NCAPG promotes the proliferation of hepatocellular carcinoma through the CKII-dependent regulation of PTEN.

BACKGROUND: NCAPG, non-SMC subunit in the concentrate I complex, might promote the proliferation of hepatocellular carcinoma (HCC), but the mechanism is unclear. The aim of this study was to explore how NCAPG affects PTEN to influence the proliferation of HCC. METHODS: Western blotting, qRT-PCR and immunohistochemistry were used to detect NCAPG expression in HCC tissues. The effect of NCAPG on the proliferation of HCC cell lines was evaluated using an EdU incorporation assay, a Cell Counting Kit-8 assay and Fluorescence in situ hybridization (FISH). BALB/c-nu/nu mice were used for the in vivo proliferation experiment. Transcriptome sequencing was used to determine the relationship between NCAPG and PTEN. Immunocoprecipitation-mass spectrometry (IP-MS), proteomic sequencing and Co-immunoprecipitation (CO-IP) were used to identify and examine the interaction between the NCAPG and CKII proteins. RESULTS: We confirmed that NCAPG was abnormally overexpressed in HCC and promoted the proliferation of HCC cells. Transcriptome sequencing revealed that NCAPG inhibited the transcription of PTEN and promoted the activation of the PI3K-AKT pathway. We found a close association between NCAPG and CKII through proteomic sequencing; their interaction was confirmed by Co-IP. There was a positive correlation between NCAPG and CKII that promoted the phosphorylation of PTEN and thus inhibited its transcription and functions. We also proved that CKII was the key factor in the induction of proliferation by NCAPG. CONCLUSION: We revealed the mechanism by which NCAPG regulates the proliferation of HCC: NCAPG inhibits PTEN through its interaction with CKII, and then activates the PI3K-AKT pathway to promote the proliferation of HCC.

Metabolic signatures of hepatolithiasis using ultra-high performance liquid chromatography-tandem mass spectrometry.

BACKGROUND & AIMS: A metabolomic study of hepatolithiasis has yet to be performed. The purpose of the present study was to characterize the metabolite profile and identify potential biomarkers of hepatolithiasis using a metabolomic approach. METHODS: We comprehensively analyzed the serum metabolites from 30 patients with hepatolithiasis and 20 healthy individuals using ultra-high performance liquid chromatography-tandem mass spectrometry operated in negative and positive ionization modes. Statistical analyses were performed using univariate (Student's t-test) and multivariate (orthogonal partial least-squares discriminant analysis) statistics and R language. Receiver operator characteristic (ROC) curve analysis was performed to identify potential predictors of hepatolithiasis. RESULTS: We identified 277 metabolites that were significantly different between hepatolithiasis serum group and healthy control serum group. These metabolites were principally lipids and lipid-like molecules and amino acid metabolites. The steroid hormone biosynthesis pathway was enriched in hepatolithiasis serum group. In all specific metabolites, 75 metabolites were over-expressed in hepatolithiasis serum group. The AUC values for 60 metabolites exceeded 0.70, 4 metabolites including 18-ß-Glycyrrhetinic acid, FMH, Rifampicin and PC (4:0/16:2) exceeded 0.90. CONCLUSIONS: We have identified serum metabolites that are associated with hepatolithiasis for the first time. 60 potential metabolic biomarkers were identified, 18-ß-Glycyrrhetinic acid, FMH, Rifampicin and PC (4:0/16:2) may have the potential clinical utility in hepatolithiasis.

Clinical application of a three-dimensional reconstruction technique for complex liver cancer resection.

OBJECTIVE: To explore the utility of three-dimensional (3D) visualization technology in liver resection for patients with complex liver cancer. METHODS: In this retrospective cohort study, we collected and analyzed clinic pathological data from 105 patients who underwent complicated liver cancer resection at the authors' unit between January 2014 and June 2019. Observation indicators included general demographic information, operative time, intraoperative blood loss, blood transfusion volume, postoperative liver function, complication rate, hospital stay, and in-hospital mortality. RESULTS: Compared with the complex liver cancer control group, operative time (257.1  ±  63.4 min versus [vs] 326.6 ± 78.3 min; P < 0.001), intraoperative blood loss (256.4 ± 159.1 mL vs 436.1 ± 177.3 mL; P < 0.001), blood transfusion volume (213.3 ± 185.2 mL vs 401.6 ± 211.2 mL; P < 0.001), and length of hospital stay (9.7 ± 3.1 days vs 11.9 ± 3.3 days; P = 0.001) were significantly reduced in the complex liver cancer reconstruction group. Although there was no statistical difference in total postoperative complication rate between the two groups, the incidence of serious postoperative complications in the reconstruction group was significantly lower than that in the control group (3/54 [5.6%] vs 10/51 [19.6%], respectively; P = 0.038). Regarding laboratory investigations, the time to recovery of liver function in the complex liver cancer reconstruction group was shorter than that in the complex liver cancer control group. CONCLUSION: The use of 3D visualization technology was highly influential in formulating meticulous, individualized surgical strategies for complex liver cancer liver resection with safety and reduced perioperative risk.

The imbalance of biliary microflora in hepatolithiasis.

BACKGROUND: The imbalance of microbial flora is thought to be associated with many diseases. However, the characteristics of the biliary microflora and its relation to in hepatolithiasis are unknown. METHODS: This study included 40 patients with hepatolithiasis and 10 control patients. Bile samples were taken during hepatectomy surgeries and 16S rRNA sequencing was performed. The sequencing results were analyzed by operational taxonomic unit (OTU) clustering, species annotation and abundance analyses, sample complexity analyses, diversity analyses, and environmental factor correlation analyses. RESULTS: There were significant differences in bile microflora between the hepatolithiasis group and the control group. We found that the abundance of microflora in the bile of patients with hepatolithiasis was relatively high (52.4% versus 40.2% and 42.1% versus 29.6%). The diversity of microflora in the bile of patients with hepatolithiasis decreased significantly (Shannon (P = 0.004), Observed species (P = 0.001), PD-whole-tree (P = 0.001)). These differences are mainly associated with Enterococcus(P＜0.001), Enterobacter(P = 0.003). In addition, we found that there were intra-group differences in hepatolithiasis, but the differences in the hepatolithiasis group were generally smaller than the differences in the non-hepatolithiasis group. CONCLUSION: There is an imbalance of microflora in the bile duct of patients with hepatolithiasis. The imbalance of biliary flora may be associated with hepatolithiasis pathogenesis.

miR-124-3p combined with miR-506-3p delay hepatic carcinogenesis via modulating sirtuin 1.

OBJECTIVE: Our study aimed at exploring whether miR-124-3p and miR-506-3p collaboratively modulated sirtuin 1 (SIRT1) protein expression in liver cancer. Materials and methods: In this study, cell viability, migration and invasion were assessed using CCK8 and transwell assays, respectively. Immunohistochemical (IHC) staining and immunoblotting analysis were performed to evaluate SIRT1 protein expression levels in tissue specimens and cell lines. Moreover, the nude-mouse transplanted tumour model was used to assess liver cancer cell growth in vivo. Results: Our results showed that SIRT1 protein levels were significantly up-regulated in liver cancer tissues and cancerous cell lines. Conversely, miR-124-3p and miR-506-3p were down-regulated in liver cancer tissues and cell lines. The protein expression of SIRT1 was significantly declined in HepG2 and SMMC7721 cells after transfection with miR-124-3p or miR-506-3p mimics. miR-124-3p and miR-506-3p collaboratively caused a marked inhibition of liver cancer cell growth, migration and invasion, while the phenomena were neutralized by overexpression of SIRT1. In vivo experimental measurements also revealed that miR-124-3p and miR-506-3p synergistically inhibited SIRT1 protein expression and tumour growth in the nude-mouse transplanted tumour model. Conclusion: It was observed that miR-124-3p and miR-506-3p could cooperatively retard liver cancer cell growth via co-inhibiting SIRT1 protein expression.

Modified median hepatic fissure approach for resection of liver tumours located in the angle between the root of the middle and right hepatic veins.

BACKGROUND: Liver tumours between the root angle of the middle and right hepatic veins are a special type of liver segment VIII tumour. In this study, we designed a modified median hepatic fissure approach to remove these tumours. The safety and effectiveness of the approach were evaluated. MATERIALS AND METHODS: From April 2015 to November 2019, 11 patients with liver tumours between the angle of the middle and right hepatic veins underwent this modified median hepatic fissure approach. We retrospectively analysed data from the perioperative periods of these 11 patients, including general condition, operation time, intraoperative bleeding, and postoperative complications. Disease-free survival and overall survival were assessed. RESULTS: Of the 11 patients, 9 patients had primary hepatocellular carcinoma and 2 had colorectal liver metastases. The average intraoperative blood loss was 285 mL (150-450 mL). Two patients developed postoperative bile leakage, but there were no significant serious complications, such as intraabdominal bleeding and liver failure, in any of the patients. The liver function returned to the normal range on the 5th day after surgery. Of the 11 patients, 5 have survived for more than 3 years (45.5%), and 4 have been disease-free for more than 3 years (36.3%). CONCLUSIONS: For liver tumours between the root angle of the middle and right hepatic veins, the modified median hepatic fissure approach is a safe and feasible method.

Gastrointestinal mixed adenoneuroendocrine carcinoma: a population level analysis of epidemiological trends.

BACKGROUND: The rise in incidence and mortality of gastrointestinal mixed adenoneuroendocrine carcinoma (MANEC) has not been well focused. The aim of our study was to examine epidemiological trends in incidence and incidence-based (IB) mortality of gastrointestinal MANEC at a population level. METHODS: The incidence and IB mortality of gastrointestinal MANEC as well as data on affected patients from 2000 to 2016 were obtained from the Surveillance, Epidemiology, and End Results database. Trends in incidence and IB mortality were assessed using Joinpoint regression. The Kaplan-Meier method and log-rank test were used for survival analysis. Cox proportional hazards regression was used to identify independent predictors of mortality. RESULTS: 581 patients diagnosed with gastrointestinal MANEC were enrolled. Gastrointestinal MANEC incidence was 0.23 cases per 1,000,000 individuals in 2000 and 1.16 cases per 1,000,000 individuals in 2016, with an annual percent change (APC) of 8.0% (95% CI 5.7-10.3%, P < 0.05). IB mortality also showed a sustained increase (APC 12.9%, 95% CI 9.0-16.8%, P < 0.05). In Cox regression analysis, age at diagnosis, tumor grade and stage, lymph node metastasis, surgery, and tumor size were independently associated with mortality. Median survival was 75 months (95% CI 60-128 months). Median survival of appendiceal MANEC was significantly longer than that of cecal MANEC (115 vs. 31 months; P < 0.001). CONCLUSIONS: We found a sustained and rapid increase both in incidence and IB mortality of gastrointestinal MANEC, manifesting that there has been no significant improvement in patient outcomes, nor progress in prevention and treatment. Additional resources should be devoted to gastrointestinal MANEC research.

Non-functional pancreatic neuroendocrine tumours: emerging trends in incidence and mortality.

BACKGROUND: Our aim was to determine the epidemiology and recent changes in the trends of non-functional pancreatic neuroendocrine tumours (NF-pNETs) at the population level. In addition, we explored the risk factors that are associated with survival duration. METHODS: Cases were identified form the Surveillance, Epidemiology, and End Results (SEER) Programme database from 2000 to 2014. Data on incidence and incidence-based (IB) mortality for NF-pNET were obtained from this database. Secular trends in age-adjusted incidence and IB mortality were determined by using the Joinpoint Regression program. Data analyses were performed using chi-square tests, Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: Overall, 4766 patients diagnosed with NF-pNET with a median age of 59 years were identified through our descriptive criteria. Caucasian patients accounted for the majority of the study population, and the proportion of patients with distant disease significantly decreased during our study period. Overall, there was an increase in incidence and IB mortality for NF-pNET; however, the rate of increase decreased during the recent years. In addition, the incidence trends of NF-pNET located in the pancreatic head significantly increased, and rates fo increase in IB mortality for NF-pNET in the pancreatic tail decreased in recent years. Additionally, the 1-, 5-, and 10-year survival rates were 79.0, 51.8, 38.1%, respectively. Furthermore, patient age, tumour grade, stage at diagnosis, tumour size, tumour site and resection were associated with mortality. CONCLUSION: Despite increases in incidence and IB mortality, the rate of change in IB mortality for NF-pNET has decreased in recent years. Survival duration displayed a secular increase during the overall period, and the prognosis and survival duration of patients were closely related to the time of diagnosis, age of the patients and size and location of the tumour. Appropriate treatment adjustments based on tumour stage may thus facilitate improvements in patient outcomes.

Combined hepatocellular-cholangiocarcinoma: a population level analysis of incidence and mortality trends.

BACKGROUND: The purpose of this study was to explore trends in incidence, incidence-based (IB) mortality, and survival for combined hepatocellular-cholangiocarcinoma (cHCC-CC) utilizing a population-based database to attract people's attention to this disease. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was utilized to investigate the incidence and IB mortality for cHCC-CC from 2000 to 2014. Trends in age-adjusted incidence and IB mortality were characterized by the Joinpoint Regression program. The Kaplan-Meier method and log-rank test were utilized to implement survival analyses. Cox regression was utilized to estimate independent predictors of mortality. RESULTS: The incidence of cHCC-CC was 0.26 per 1,000,000 individuals in 2000 and 0.59 per 1,000,000 individuals in 2014, with an annual percent change (APC) (i.e., the extent of increase in incidence) of 3.84% (95% confidence interval [CI] 1.7-6.1; P < 0.05). The IB mortality also displayed a sustained increase (APC was 4.59%, 95% CI 1.9-7.4; P < 0.05). Compared to patients not undergoing surgery, patients undergoing surgical treatment experienced a significant increase in median survival (3 vs. 28 months; P < 0.001). However, the median survival decreased in patients with tumor size > 5 cm (20 vs. 9 months; P < 0.001). Based on univariate Cox regression analysis, African-American race, distant stage, regionalized stage, tumor size ≥ 5 cm, and no surgery were risk factors for death. CONCLUSIONS: We identified an overall steady increase in the incidence of cHCC-CC, which indicates that primary prevention strategies for cHCC-CC have not improved much in recent years and that cHCC-CC needs to be taken seriously.

Intrahepatic bile duct exploration lithotomy is a useful adjunctive hepatectomy method for bilateral primary hepatolithiasis: an eight-year experience at a single centre.

BACKGROUND: To evaluate the perioperative and long-term results of intrahepatic bile duct exploration lithotomy (IHBDIL) combined with hepatectomy for patients with complicated bilateral primary hepatolithiasis. METHODS: A study was conducted involving 56 patients with complicated bilateral primary hepatolithiasis who underwent IHBDIL combined with hepatectomy at our hospital from January 2006 to December 2014. The perioperative and long-term outcomes that were retrospectively analysed included the stone clearance rate, operative morbidity and mortality, and stone recurrence rate. Patients with a preoperative diagnosis of cholangiocarcinoma were excluded. RESULTS: In all 56 patients, hepatic duct stones were located in the bilateral IHBD. The surgical method was IHBDIL combined with hepatectomy. Postoperative complications occurred in 15 patients (26.8%), 14 patients responded to conservative management, and there was 1 case of postoperative mortality because of hepatic failure. The overall initial success rate of stone clearance was 85.7%, and the final clearance rate was 92.9% following postoperative choledochoscopic lithotripsy. The stone recurrence rate was 13.5%, and the occurrence of postoperative cholangitis was 10.9% during the follow-up period. CONCLUSION: IHBDIL combined with hepatectomy is a safe, effective, and promising treatment for patients with complicated bilateral primary hepatolithiasis. The perioperative and long-term outcomes are satisfactory for complicated bilateral primary hepatolithiasis.

Learning curve for performing choledochotomy bile duct exploration with primary closure after laparoscopic cholecystectomy.

BACKGROUND: Primary closure after laparoscopic cholecystectomy (LC) and laparoscopic common bile duct exploration (LCBDE) is a safe and effective approach for treating cholecystolithiasis with choledocholithiasis. The aim of this study was to evaluate the learning curve of performing primary closure after LC+LCBDE. METHODS: We retrospectively identified all patients who underwent primary closure after LC+LCBDE performed by a single surgeon from January 2009 to April 2015 in our institution, and analyzed preoperative, intraoperative, and postoperative data using the cumulative sum (CUSUM) analysis to evaluate the learning curve for this procedure. RESULTS: Overall, there were 390 patients. The total postoperative complications rate was 7.2%, including bile leakage in 9 (2.3%) patients and retained common bile duct stone in 3 (0.8%) patients. The CUSUM operating time (OT) learning curve was best modeled by the equation: CUSUMOT = 312.209 × procedure0.599 × e(-0.011×procedure) + 122.608 (R2 = 0.96). The learning curve was composed of two phases, phase 1 (the initial 54 patients) and phase 2 (the remaining 336 patients). A significant decrease in the OT (116.8 ± 22.4 vs. 93.8 ± 17.8 min; p < 0.001) and complication rate (16.7 vs. 5.7%; p < 0.01) including the rate of bile leakage (7.4 vs. 1.5%; p < 0.01) and retained stone (3.7 vs. 0.3%; p < 0.01) was observed between the two phases. In addition, 20 patients had conversion to open surgery. Impacted stones were independently associated with conversion, as indicated by a multivariable analysis. CONCLUSION: The data suggest that the learning curve of this procedure was achieved in approximately 54 cases. An impacted stone was the only risk factor that affected the conversion rate.

Minor hepatectomy combined with cholangioplasty and cholangiojejunostomy for Bismuth II hilar cholangiocarcinoma: A propensity score matching analysis.

BACKGROUND: The optimal surgical approach for Bismuth II hilar cholangiocarcinoma (HCCA) remains controversial. This study compared perioperative and oncological outcomes between minor and major hepatectomy. MATERIALS AND METHODS: One hundred and seventeen patients with Bismuth II HCCA who underwent hepatectomy and cholangiojejunostomy between January 2018 and December 2022 were retrospectively investigated. Propensity score matching created a cohort of 62 patients who underwent minor (n = 31) or major (n = 31) hepatectomy. Perioperative outcomes, complications, quality of life, and survival outcomes were compared between the groups. Continuous data are expressed as the mean ± standard deviation, categorical variables are presented as n (%). RESULTS: Minor hepatectomy had a significantly shorter operation time (245.42 ± 54.31 vs. 282.16 ± 66.65 min; P = 0.023), less intraoperative blood loss (194.19 ± 149.17 vs. 315.81 ± 256.80 mL; P = 0.022), a lower transfusion rate (4 vs. 11 patients; P = 0.038), more rapid bowel recovery (17.77 ± 10.00 vs. 24.94 ± 9.82 h; P = 0.005), and a lower incidence of liver failure (1 vs. 6 patients; P = 0.045). There were no significant between-group differences in wound infection, bile leak, bleeding, pulmonary infection, intra-abdominal fluid collection, and complication rates. Postoperative laboratory values, length of hospital stay, quality of life scores, 3-year overall survival (25.8 % vs. 22.6 %; P = 0.648), and 3-year disease-free survival (12.9 % vs. 16.1 %; P = 0.989) were comparable between the groups. CONCLUSION: In this propensity score-matched analysis, overall survival and disease-free survival were comparable between minor and major hepatectomy in selected patients with Bismuth II HCCA. Minor hepatectomy was associated with a shorter operation time, less intraoperative blood loss, less need for transfusion, more rapid bowel recovery, and a lower incidence of liver failure. Besides, this findings need confirmation in a large-scale, multicenter, prospective randomized controlled trial with longer-term follow-up.

Optimizing hepatocellular carcinoma disease staging systems by incorporating tumor micronecrosis: A multi-institutional retrospective study.

Tumor micronecrosis is a pathological feature that reflects malignant biological behavior in hepatocellular carcinoma (HCC). However, whether micronecrosis can optimize HCC staging systems remains unilluminated. A total of 1632 HCC patients who underwent curative hepatectomy in four institutions from January 2014 to December 2021 were enrolled in this study. Independent prognostic factors were identified, and optimized staging models were established using a training cohort (n = 934). The performance of optimized staging models was validated using an external cohort consisting of cases from three other institutions (n = 232). In addition, patients from our prospectively collected database (n = 379) tested the application effectiveness of the models. Harrel's c-statistics and the corrected Akaike information criterion (AICc) were used to assess the performance of staging models. In most of Barcelona Clinic Liver Cancer (BCLC) and tumor (T) stages, HCC patients with tumor micronecrosis showed poorer prognosis than those without. Tumor micronecrosis, microvascular invasion, multiple tumors and tumor size >2 cm were independent prognostic-related factors. The BCLC and T staging models incorporating tumor micronecrosis showed better performance than the original systems (c-statistic, 0.712 and 0.711 vs. 0.664 and 0.679; AICc, 2314.8 and 2322.3 vs. 2338.2 and 2338.1; respectively). Furthermore, the external validation cohort confirmed that the optimized staging models had improved efficiency compared with the original ones. Moreover, the prospective cohort demonstrated the applicability of the optimized staging systems. Tumor micronecrosis plays a stage-ascending role in HCC patients. The BCLC and T staging systems incorporating tumor micronecrosis can improve the prognosis stratification efficiency of patients.

Rock2 regulates Cdc25A through ubiquitin proteasome system in hepatocellular carcinoma cells.

Rho-associated coiled-coil containing protein kinase 2 (Rock2) belongs to a family of serine/threonine kinases which are actived via interaction with Rho GTPases. Recently, overexpression of Rock2 has been demonstrated in human hepatocellular carcinoma (HCC), but the potential role of Rock2 in tumorigenesis remains unclear. Cdc25A acts as a key checkpoint during the G1/S phase and has also been found to be overexpressed in HCC. Here, we report that Rock2 regulates cell cycle progression via ubiquitination of Cdc25A in HCC. In HCC tissues, Rock2 and Cdc25A were aberrantly upregulated and revealed a significantly positive correlation. Knockdown of Rock2 inhibited HCC cell growth and promoted cell-cycle arrest at the G1/S phase via regulation of Cdc25A. When cells were exposed to DNA damage, Rock2 increased cell survival by regulating Cdc25A. Co-immunoprecipitation and immunofluorescence analyses indicated that Rock2 regulated Cdc25A via direct binding. Furthermore, knockdown of Rock2 activated Cdc25A ubiquitination and promoted its degradation. Our results defined a role for Rock2 in modulation of Cdc25A ubiquitination, indicating a novel mechanism of Cdc25A regulation and a potential function for Rock2 in the development of HCC.

Identification of M2-like macrophage-related signature for predicting the prognosis, ecosystem and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is one of the most common malignancies worldwide, representing a big health-care challenge globally. M2-like macrophages are significantly correlated with tumor progression, metastasis and treatment resistance. METHODS: Integrative 10 machine learning algorithms were performed to developed a M2-like macrophage related prognostic signature (MRPS). Single-cell RNA-sequencing analysis was performed to dissect the ecosystem of HCC. Several approaches, including TIDE score, immunophenoscore, TMB score and tumor escape score were used to evaluate the predictive role of MRPS in immunology response. RESULTS: The optimal MRPS constructed by the combination of stepCox + superPC algorithm served as an independent risk factor and showed stable and powerful performances in predicting the overall survival rate of HCC patients with 2-, 3-, and 4-year AUCs of 0. 763, 0.751, and 0.699 in TCGA cohort. HCC patients with low risk score possessed a more interaction of immunoactivated cells, including NK, CD8+ cytotoxic T, and activated B, and a less interaction of immunosuppressive cells, including Treg, CD4+ exhauster T, and M2-like macrophage. Low risk score indicated a higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score and lower tumor escape score in HCC, suggesting a better immunotherapy response. The IC50 value of docetaxel, gemcitabine, crizotinib and Osimertinib in HCC with high risk score were lower versus that with low risk score. HCC patients with high risk score had a higher score of cancer-related hallmarks, including angiogenesis, DNA repair, EMT, glycolysis, and NOTCH signaling. CONCLUSION: Our study proposed a novel MRPS for predicting the prognosis, ecosystem and immunotherapy response in HCC.

Combining bulk and single-cell RNA-sequencing data to develop an NK cell-related prognostic signature for hepatocellular carcinoma based on an integrated machine learning framework.

BACKGROUND: The application of molecular targeting therapy and immunotherapy has notably prolonged the survival of patients with hepatocellular carcinoma (HCC). However, multidrug resistance and high molecular heterogeneity of HCC still prevent the further improvement of clinical benefits. Dysfunction of tumor-infiltrating natural killer (NK) cells was strongly related to HCC progression and survival benefits of HCC patients. Hence, an NK cell-related prognostic signature was built up to predict HCC patients' prognosis and immunotherapeutic response. METHODS: NK cell markers were selected from scRNA-Seq data obtained from GSE162616 data set. A consensus machine learning framework including a total of 77 algorithms was developed to establish the gene signature in TCGA-LIHC data set, GSE14520 data set, GSE76427 data set and ICGC-LIRI-JP data set. Moreover, the predictive efficacy on ICI response was externally validated by GSE91061 data set and PRJEB23709 data set. RESULTS: With the highest C-index among 77 algorithms, a 11-gene signature was established by the combination of LASSO and CoxBoost algorithm, which classified patients into high- and low-risk group. The prognostic signature displayed a good predictive performance for overall survival rate, moderate to high predictive accuracy and was an independent risk factor for HCC patients' prognosis in TCGA, GEO and ICGC cohorts. Compared with high-risk group, low-risk patients showed higher IPS-PD1 blocker, IPS-CTLA4 blocker, common immune checkpoints expression but lower TIDE score, which indicated low-risk patients might be prone to benefiting from ICI treatment. Moreover, a real-world cohort, PRJEB23709, also revealed better immunotherapeutic response in low-risk group. CONCLUSIONS: Overall, the present study developed a gene signature based on NK cell-related genes, which offered a novel platform for prognosis and immunotherapeutic response evaluation of HCC patients.