Development and validation of a novel preoperative clinical model for predicting lymph node metastasis in perihilar cholangiocarcinoma.

BACKGROUD: We aimed to develop a novel preoperative nomogram to predict lymph node metastasis (LNM) in perihilar cholangiocarcinoma (pCCA) patients. METHODS: 160 pCCA patients were enrolled at Lihuili Hospital from July 2006 to May 2022. A novel nomogram model was established to predict LNM in pCCA patients based on the independent predictive factors selected by the multivariate logistic regression model. The precision of the nomogram model was evaluated through internal and external validation with calibration curve statistics and the concordance index (C-index). Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to evaluate and determine the clinical utility of the nomogram. RESULTS: Multivariate logistic regression demonstrated that age (OR = 0.963, 95% CI: 0.930-0.996, P = 0.030), CA19-9 level (> 559.8 U/mL vs. ≤559.8 U/mL: OR = 3.162, 95% CI: 1.519-6.582, P = 0.002) and tumour diameter (OR = 1.388, 95% CI: 1.083-1.778, P = 0.010) were independent predictive factors of LNM in pCCA patients. The C-index was 0.763 (95% CI: 0.667-0.860) and 0.677 (95% CI: 0.580-0.773) in training cohort and validation cohort, respectively. ROC curve analysis indicated the comparative stability and adequate discriminative ability of nomogram. The sensitivity and specificity were 0.820 and 0.652 in training cohort and 0.704 and 0.649 in validation cohort, respectively. DCA revealed that the nomogram model could augment net benefits in the prediction of LNM in pCCA patients. CONCLUSIONS: The novel prediction model is useful for predicting LNM in pCCA patients and showed adequate discriminative ability and high predictive accuracy.

A CDAHFD-induced mouse model mimicking human NASH in the metabolism of hepatic phosphatidylcholines and acyl carnitines.

Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of a cluster of conditions associated with lipid metabolism disorders. Ideal animal models mimicking the human NASH need to be explored to better understand the pathogenesis. A choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) has recently been used to induce the NASH model, but the advantages are not established. NASH models were induced using the well-known traditional methionine- and choline-deficient (MCD) diet for 5 weeks and the recently used CDAHFD for 3 weeks. Liver phenotypes were analyzed to evaluate the differences in markers related to NASH. Lipidomics and metabolism analyses were used to investigate the effects of dietary regimens on the lipidome of the liver. The CDAHFD induced stronger NASH responses than the MCD, including lipid deposition, liver injury, inflammation, bile acid overload and hepatocyte proliferation. A significant difference in the hepatic lipidome was revealed between the CDAHFD and MCD-induced NASH models. In particular, the CDAHFD reduced the hepatic levels of phosphatidylcholines (PCs) and acylcarnitines (ACs), which was supported by the metabolism analysis and in line with the tendency of human NASH. Pathologically, the CDAHFD could effectively induce a more human-like NASH model over the traditional MCD. The hepatic PCs, ACs and their metabolism in CDAHFD-treated mice were down-regulated, similar to those in human NASH.

Short-Term Monitoring of Graft Regeneration in Partial Liver Transplantation Recipients.

BACKGROUND Liver regeneration after partial liver transplantation, including living donor liver transplantation and split liver transplantation, is important for successful transplantation. MATERIAL AND METHODS We retrospectively analyzed 68 patients who underwent partial liver transplantation and calculated their regeneration index (RI)-based difference in postoperative and preoperative liver volume. We collected clinical data of donors and recipients and analyzed the correlation between clinical characteristics and RI. According to the above results, the generalized estimating equation (GEE) model included white blood cell count (WBC), neutrophils, lymphocytes, platelets, prothrombin time (PT), and activated partial thromboplastin time (APTT) on Days 1, 3, and 7 after LT and was used to predict the RI. RESULTS The mean RI was 40%, which was used as the cutoff value to divide all patients to the high-RI group and the low-RI group. The percentage of Child-Pugh C patients was 44% in the high-RI group, which was significantly more than that (21%) in the low-RI group (P=0.038). Among the postoperative monitoring parameters, neutrophil (P=0.044) and platelet (P=0.036) levels declined in the high-RI group on Day 3, while APTT was higher on Day 1 compared to the low-RI group. The predictive model based on GEE analysis achieved a good effect, with the area under the receiver operating characteristic curve on Day 1 (0.681; 95% CI, 0.556-0.807) and Day 3 (0.705; 95% CI, 0.578-0.832) showing significant differences (P=0.010 and 0.004, respectively). CONCLUSIONS The combination of decreased counts of WBC, neutrophils, lymphocytes, and platelets, as well as elevated PT and APTT on Day 3 after LT showed a good capability to predict a higher rate of liver regeneration after partial liver transplantation.

Comparison of Postoperative Hemorrhage Risk After Partial Liver Transplantation Versus Whole Liver Transplantation: A Single-Center Experience.

BACKGROUND: We aimed to identify risk factors associated with reoperation for postoperative intraperitoneal hemorrhage (PIH) after orthotopic liver transplantation and investigate if partial liver transplantation (PLT) increases the risk of PIH. METHODS: We retrospectively analyzed the medical records of 304 consecutive recipients who underwent orthotopic liver transplantation at the Affiliated Lihuili Hospital, Ningbo University, from January 2016 to July 2022. Data were compared between recipients who experienced PIH requiring reoperation and those who did not. Subgroup propensity score matching analysis was performed to assess the impact of PLT on PIH risk. Neither prisoners nor participants who were coerced or paid were used in the study. RESULTS: Among the 304 recipients, 22 (7.2%) underwent reoperation for PIH. Multivariate analysis revealed that the recipient Model for End-Stage Liver Disease (MELD) score (odds ratio = 1.066, 95% CI [1.025-1.109], P = .001) and volume of intraoperative packed red blood cell transfusion (odds ratio = 1.089, 95% CI [1.032-1.481], P = .002) were independent risk factors for PIH. No significant differences were observed in the risk of PIH between PLT and whole liver transplantation. CONCLUSION: Preoperative MELD score and intraoperative packed red blood cell transfusion should be carefully considered to manage the risk of PIH in liver transplantation recipients. Partial liver transplantation, a crucial approach for addressing donor shortages, does not increase the risk of reoperation for PIH in recipients.

Longitudinal surveillance of three biomarkers to predict recurrence of hepatocellular carcinoma after radical resection.

BACKGROUND: Radical resection is a curative treatment for patients with hepatocellular carcinoma (HCC), but the incidence of recurrence remains high. We aimed to explore the performance of predicting HCC recurrence by longitudinal surveillance of the protein induced by vitamin K absence (PIVKA-II), alpha- fetoprotein (AFP), and lectin-reactive AFP (AFP-L3) during postoperative follow-up. METHODS: Patients who underwent radical resection for HCC at the Ningbo Medical Centre Lihuili Hospital between January 2015 and December 2020 were included. All enrolled patients regularly monitor PIVKA-II, AFP, AFP-L3 every 3 months during postoperative follow-up. The surveillance performance of PIVKA-II, AFP, AFP-L3 during follow-up for the prediction of HCC recurrence was compared in patients. The generalized estimation equation (GEE) was used to analyze the trends of the tumor biomarkers and interactions with time. Area under the receiver operator characteristic (AUROC) curves, the optimal cut-off value, the sensitivity and specificity were calculated to evaluate the performance of the three biomarkers. The recurrence-free survival (RFS) and overall survival (OS) of patients with any of the elevated biomarkers was analyzed by Kaplan-Meier curves and the log-rank test. Multivariate logistic regression models were used to analyze potential risk factors for recurrence. RESULTS: The GEE analysis indicated that PIVKA-II, AFP, AFP-L3 in the recurrence patients were higher than the no recurrence patients during follow-up, PIVKA-II and AFP showed increasing trends from 6 months before recurrence. In predicting recurrence, the AUROCs for PIVKA-II, AFP, AFP-L3 and their combination were 0.885, 0.754, 0.781 and 0.885 respectively, the optimal cut-off value for PIVKA-II, AFP, AFP-L3 was 29.5 mAU/ml, 10.7 ng/L, 1.5% respectively. The sensitivity in predicting recurrence for PIVKA-II, AFP, AFP-L3 and combination were 75.0, 54.7, 57.8 and 79.7% respectively. The RFS and the OS of patients with any of the biomarkers elevated during the follow-up was significantly shorter than that without elevated biomarkers ( P  < 0.001). Multivariate analysis showed that any of the biomarkers elevated was the independent risk factor of recurrence. CONCLUSION: Longitudinal surveillance of PIVKA-II, AFP and AFP-L3 can effectively predict recurrence of HCC after operation.

Macrotrabecular-massive subtype-based nomogram to predict early recurrence of hepatocellular carcinoma after surgery.

OBJECTIVES: To analyze the predictive factors on early postoperative recurrence of hepatocellular carcinoma (HCC) and to establish a new nomogram to predict early postoperative recurrence of HCC. METHODS: A retrospective analysis of 383 patients who had undergone curative resection between February 2012 and September 2020 in our center was performed. The Kaplan-Meier method was used for survival curve analysis. Univariate and multivariate Cox regression were performed to identify independent risk factors associated with early recurrence, and a nomogram for predicting early recurrence of HCC was established. RESULTS: A total of 152/383 patients developed recurrence after surgery, of which 83 had recurrence within 1 year. Multivariate Cox regression analysis showed that preoperative alpha-fetoprotein level ≥400 ng/ml (P = 0.001), tumor diameter ≥5 cm (P = 0.009) and MVI (P = 0.007 and macrotrabecular-massive HCC (P = 0.003) were independent risk factors for early postoperative recurrence of HCC. The macrotrabecular-massive-based nomogram obtained a good C-index (0.74) for predicting early recurrence of HCC, and the area under the curve for predicting early recurrence was 0.767, which was better than the single American Joint Committee on Cancer T stage and Barcelona Clinic Liver Cancer stage. CONCLUSIONS: The nomogram based on macrotrabecular-massive HCC can effectively predict early postoperative recurrence of HCC.

Risk factors for acute rejection in liver transplantation and its impact on the outcomes of recipients.

OBJECTIVE: To determine the risk factors for acute rejection in liver transplantation and its impact on the outcomes of the recipients. METHODS: Clinicopathological data of 290 patients who underwent liver transplantation from January 2012 to December 2021 at our center were retrospectively evaluated. Patients were grouped into an acute rejection (AR) group and a normal (NM) group based on the confirmed histopathological diagnosis of acute rejection. Univariate and multivariate logistic regression were used to determine the risk factors for acute rejection. RESULTS: 244 patients were included in the study. Acute rejection occurred in 27 (11.1%) of the patients. Warm ischemia time (P = 0.137), cold ischemia time (P = 0.064) and chronic liver failure (P = 0.001) were potential risk factors for acute rejection. Chronic liver failure (P < 0.001, OR = 8.22, 95% CI = 2.47-27.32) was the independent risk factor. There was no significant difference in overall survival between recipients with acute rejection and those without it (P = 0.985). The 1-, 3- and 5-year overall survival in the NM group was 98.1%, 85.7% and 78.6% respectively vs 88.9%, 82.5% and 82.5% respectively in the AR group. CONCLUSION: Acute rejection does not appear to affect the long-term survival of the recipients. Only chronic liver failure was an independent risk factor for acute rejection. Our findings further illustrate that contradictions still exist on which factors influence acute rejection in liver transplant recipients. SUMMARY: Clinicopathological data of 290 liver transplant recipients at our center between January 2012 and December 2021 were retrospectively evaluated to determine the risk factors for acute rejection and its impact on the outcomes of the recipients. 244 patients were included in the analysis. 27 of the 244 experienced acute rejection. Propensity score matching was performed to reduce the confounding effect. Patients were assigned to an acute rejection group (n = 27) and a normal group (n = 54). Chronic liver failure (P < 0.001, OR = 8.22, 95% CI = 2.47-27.32) was the determined to be independent risk factor for acute rejection. Acute rejection did not appear to affect the long-term survival of the recipients and there was no significant difference in overall survival between the patients with acute rejection and those without it.

A new prognostic model predicting hepatocellular carcinoma early recurrence in patients with microvascular invasion who received postoperative adjuvant transcatheter arterial chemoembolization.

BACKGROUD: In this study, we aimed to develop a prognostic model to predict HCC early recurrence (within 1-year) in patients with microvascular invasion who received postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE). METHODS: A total of 148 HCC patients with MVI who received PA-TACE were included in this study. The modes were verified in an internal validation cohort (n = 112) and an external cohort (n = 36). Univariate and multivariate Cox regression analyses were performed to identify the independent prognostic factors relevant to early recurrence. A clinical nomogram prognostic model was established, and nomogram performance was assessed via internal validation and calibration curve statistics. RESULTS: After data dimensionality reduction and element selection, multivariate Cox regression analysis indicated that alpha fetoprotein level, systemic inflammation response index, alanine aminotransferase, tumour diameter and portal vein tumour thrombus were independent prognostic factors of HCC early recurrence in patients with MVI who underwent PA-TACE. Nomogram with independent factors was established and achieved a better concordance index of 0.765 (95% CI: 0.691-0.839) and 0.740 (95% CI: 0.583-0.898) for predicting early recurrence in training cohort and validation cohort, respectively. Time-dependent AUC indicated comparative stability and adequate discriminative ability of the model. The DCA revealed that the nomogram could augment net benefits and exhibited a wider range of threshold probabilities than AJCC T stage. CONCLUSIONS: The nomogram prognostic model showed adequate discriminative ability and high predictive accuracy.

Development and validation of a nomogram to predict liver metastasis for pancreatic ductal adenocarcinoma after radical resection.

Objectives: This study aimed to develop and externally validate a nomogram for predicting liver metastasis after radical resection in patients with pancreatic ductal adenocarcinoma (PDAC). Methods: A total of 247 PDAC patients who underwent radical resection were retrospectively reviewed from January 2015 to March 2022 at Ningbo Medical Centre Lihuili Hospital Eastern Section, and used as a training cohort to develop the nomogram. 83 PDAC patients from the Ningbo Medical Centre Lihuili Hospital Xingning Section were enrolled as the validation cohort. The postoperative liver metastasis was recorded during the follow-up, and the liver metastasis-free survival was defined as the time from operation to the date of liver metastasis diagnosis or death. The nomogram was established based on independent prognostic factors selected by LASSO and multivariate Cox regression model. The performance was assessed using the concordance index (C-index) and calibration curves. The receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to determine the clinical utility of the nomogram model. Results: From the training cohort of 247 patients, a total of 132 patients developed liver metastasis during the follow-up, the 1-, 2- and 3- year liver metastasis-free survival were 52.4%, 43.5% and 40% respectively. The LASSO and multivariate Cox regression analysis indicated that postoperative CA125 (hazard ratio [HR] = 1.007, p <0.001), tumor differentiation (HR = 1.640, p = 0.010), tumor size (HR = 1.520, p = 0.029), lymph node ratio (HR = 1.897, p = 0.002) and portal/superior mesenteric/splenic vein invasion degree (PV/SMV/SV) (HR = 2.829, p <0.001) were the independent factors of liver metastasis. A nomogram with independent factors was developed and the C-index was 0.760 (95% confidence interval [CI], 0.720-0.799) and 0.739 (95% CI, 0.669-0.810) in the training and validation cohorts, respectively. The areas under curve (AUC) of the nomogram at 1-, 2- and 3-year were 0.815, 0.803 and 0.773 in the training cohort, and 0.765, 0.879 and 0.908 in the validation cohort, respectively, higher than those in TNM stage. Decision curve analysis (DCA) analysis revealed that the nomogram model provided superior net benefit in clinical utility. Liver metastasis-free survival curves showed a significant discriminatory ability for liver metastasis risk based on the nomogram (p <0.001). Conclusions: The nomogram showed high accuracy in predicting liver metastasis for PDAC after radical resection, and may serve as a clinical support tool to guide personalized and prescient intervention.

Predictive Value of the TP53 p.G245S Mutation Frequency for the Short-Term Recurrence of Hepatocellular Carcinoma as Detected by Pyrophosphate Sequencing.

Aims: We explored the relationship between the mutation at the p.G245S site in TP53 and the short-term recurrence of hepatocellular carcinoma (HCC). Materials and Methods: 101 HCC patients were included in this study. The TP53 p.G245S mutation frequency spectrum was examined by direct sequencing of genomic DNA from tissue specimens of HCC patients. Univariate and multivariate Cox regression analyses were performed to evaluate the independent prognostic factors of tumor recurrence. ROC curve analysis was applied to determine the cut-off value for the p.G245S mutation frequency and to verify the predictive ability of the Cox model compared with single risk factor indices. Results: A multivariate Cox regression analysis showed that TP53 p.G245S mutation frequency (HR = 1.231, 95% CI: 1.006-1.505, p = 0.043), AFP (HR = 2.432, 95% CI: 1.297-4.561, p = 0.006), MTM (HR = 2.656, 95% CI: 0.930-7.583, p = 0.068), and PVTT (HR = 14.297, 95% CI: 3.085-66.243, p = 0.001) were independent prognostic factors for short-term recurrence. The cut-off value for the TP53 p.G245S mutation frequency (18.5%) was determined by ROC analysis. A predictive model integrating the TP53 p.G245S mutation frequency with PVTT, MTM, and AFP values appears to an excellent predictive indicator of short-term recurrence in HCC patients (AUC = 0.849, 95% CI = 0.748-0.950, p = 0.000001). Survival analysis indicated that the probability of short-term recurrence-free survival was significantly different among different TP53 p.G245S mutation frequency, MTM, PVTT, and AFP risk groups (p < 0.05). Conclusion: The mutation frequency of the p.G245S site is a novel prognostic risk factor for the short-term recurrence of HCC.

Nomogram for the Preoperative Prediction of the Macrotrabecular-Massive Subtype of Hepatocellular Carcinoma.

Background: The macrotrabecular-massive subtype of hepatocellular carcinoma (MTM-HCC) is an aggressive histological type and results in poor prognosis. We developed a nomogram model based on laboratory results to predict the presence of MTM-HCC. Methods: A total of 357 HCC patients who underwent radical surgery between January 2015 and December 2020 at Ningbo Medical Center Lihuili Hospital were grouped according to histological type. After propensity score matching (PSM), 267 patients were divided into MTM-HCC (n = 76) and non-MTM-HCC (n = 191) groups. A LASSO regression analysis model was used to select predictive factors. Finally, a nomogram for predicting the presence of MTM-HCC was established. Decision curve analysis (DCA) was conducted to determine the clinical usefulness of the nomogram model by quantifying the net benefits along with the increase in threshold probabilities. Results: The 1-, 3-, and 5-year disease-free survival (DFS) and overall survival (OS) rates for MTM-HCC were 60.0%, 36.0%, 32.4% and 92.1%, 68.7%, 52.2%, respectively. Survival analysis indicated that the probabilities of achieving DFS and OS were significantly worse in the MTM-HCC group than in the non-MTM-HCC group (P < 0.05). The nomogram model that included AST levels, PT and AFP levels achieved a better C-index of 0.723 (95% CI: 0.659-0.787). DCA revealed that the nomogram model could lead to net benefits and exhibited a wider range of threshold probabilities in the prediction of MTM-HCC. Conclusion: The nomogram model included AST, PT and AFP could achieve an optimal performance in the preoperative prediction of MTM-HCC.

Risk Factors of Early Liver Metastasis for Pancreatic Ductal Adenocarcinoma after Radical Resection.

Background: Liver metastasis arises in many postoperative patients with PDAC, occurring in the early stage appears to lead to a very poor prognosis. Objective: We aimed to analyze the risk factors for early liver metastasis after radical resection for patients with pancreatic ductal adenocarcinoma (PDAC) and to indicate the poor prognosis of early liver metastasis. Methods: Patients who underwent pancreatectomy for PDAC at the Ningbo Medical Centre Lihuili Hospital between January 2015 and June 2021 were included. The exclusion criteria were death within 30 days after the operation, complications with other malignancies, and a positive final resection margin (R1). Liver metastasis and its occurrence time were recorded, and risk factors for early (≤6 months) liver metastasis were analyzed by logistic regression models. The prognosis of patients with early liver metastasis and different recurrence patterns was analyzed by Kaplan-Meier curves and the log-rank test. Results: From the identified cohort of 184 patients, 172 patients were included for further analysis. 55 patients developed early liver metastasis within 6 months after the operation. Univariate analysis showed that CA125 ≥ 30 IU/ml, tumor size ≥ 4 cm, poor tumor differentiation, and portal vein/superior mesenteric vein (PV/SMV) reconstruction were risk factors, and multivariate analysis showed that poor tumor differentiation and PV/SMV reconstruction were independent risk factors for early liver metastasis. The prognosis of liver metastasis was the worst among the different recurrence patterns. Early liver metastasis indicates a poor prognosis in patients with PDAC. Conclusions: Poor differentiation and PV/SMV reconstruction are independent risk factors for early liver metastasis in patients with PDAC, and early liver metastasis indicates a poor prognosis.

Development of nomogram models of inflammatory markers based on clinical database to predict prognosis for hepatocellular carcinoma after surgical resection.

BACKGROUND: Inflammation plays a significant role in tumour development, progression, and metastasis. In this study, we focused on comparing the predictive potential of inflammatory markers for overall survival (OS), recurrence-free survival (RFS), and 1- and 2-year RFS in hepatocellular carcinoma (HCC) patients. METHODS: A total of 360 HCC patients were included in this study. A LASSO regression analysis model was used for data dimensionality reduction and element selection. Univariate and multivariate Cox regression analyses were performed to identify the independent risk factors for HCC prognosis. Nomogram prediction models were established and decision curve analysis (DCA) was conducted to determine the clinical utility of the nomogram model. RESULTS: Multivariate Cox regression analysis indicated that the prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) were independent prognostic factors of OS, and aspartate aminotransferase-to-platelet ratio (APRI) was a common independent prognostic factor among RFS, 1-year RFS, and 2-year RFS. The systemic inflammation response index (SIRI) was an independent prognostic factor for 1-year RFS in HCC patients after curative resection. Nomograms established and achieved a better concordance index of 0.772(95% CI: 0.730-0.814), 0.774(95% CI: 0.734-0.815), 0.809(95% CI: 0.766-0.852), and 0.756(95% CI: 0.696-0.816) in predicting OS, RFS, 1-year RFS, and 2-year RFS respectively. The risk scores calculated by nomogram models divided HCC patients into high-, moderate- and low-risk groups (P < 0.05). DCA analysis revealed that the nomogram models could augment net benefits and exhibited a wider range of threshold probabilities in the prediction of HCC prognosis. CONCLUSIONS: The nomograms showed high predictive accuracy for OS, RFS, 1-year RFS, and 2-year RFS in HCC patients after surgical resection. The nomograms could be useful clinical tools to guide a rational and personalized treatment approach and prognosis judgement.

A Meta-Analysis and Systematic Review of Normothermic and Hypothermic Machine Perfusion in Liver Transplantation.

BACKGROUND: The gap between the demand and supply of donor livers is still a considerable challenge. Since static cold storage is not sufficient in marginal livers, machine perfusion is being explored as an alternative. The objective of this study was to assess (dual) hypothermic oxygenated machine perfusion (HOPE/D-HOPE) and normothermic machine perfusion (NMP) in contrast to static cold storage (SCS). METHODS: Three databases were searched to identify studies about machine perfusion. Graft and patient survival and postoperative complications were evaluated using the random effects model. RESULTS: the incidence of biliary complications was lower in HOPE vs. SCS (OR: 0.59, 95% CI: 0.36-0.98, p = 0.04, I2: 0%). There was no significant difference in biliary complications between NMP and SCS (OR: 0.76, 95% CI: 0.41-1.40, p = 0.38, I2: 55%). Graft and patient survival were significantly better in HOPE than in SCS (HR: 0.40, 95% CI: 0.23-0.71, p = 0.002, I2: 0%) and (pooled HR: 0.43, 95% CI: 0.20-0.93, p = 0.03, I2: 0%). Graft and patient survival were not significantly different between NMP and SCS. CONCLUSION: HOPE/D-HOPE and NMP are promising alternatives to SCS for donor liver preservation. They may help address the widening gap between the demand for and availability of donor livers by enabling the rescue and transplantation of marginal livers.

Albumin-Bilirubin (ALBI) and Monocyte to Lymphocyte Ratio (MLR)-Based Nomogram Model to Predict Tumor Recurrence of AFP-Negative Hepatocellular Carcinoma.

PURPOSE: In this study, we aimed to develop a novel liver function and inflammatory markers-based nomogram to predict recurrence-free survival (RFS) for AFP-negative (<20 ng/mL) HCC patients after curative resection. PATIENTS AND METHODS: A total of 166 pathologically confirmed AFP-negative HCC patients were included at the Ningbo Medical Center Lihuili Hospital. A LASSO regression analysis was used for data dimensionality reduction and element selection. Univariate and multivariate Cox regression analyses were performed to identify the independent risk factors relevant to RFS. Finally, clinical nomogram prediction model for RFS of HCC was established. Nomogram performance was assessed via internal validation and calibration curve statistics. Receiver operating characteristic (ROC) and decision curve analysis (DCA) curve were used to validate the performance and clinical utility of the nomogram. RESULTS: Multivariate Cox regression analysis indicated that ALBI grade (hazard ratio, [HR] = 2.624, 95% confidence interval [CI]: 1.391-4.949, P = 0.003), INR (HR = 2.605, 95% CI: 1.061-6.396, P = 0.037), MLR (HR = 1.769, 95% CI: 1.073-2.915, P = 0.025) and MVI (HR = 4.726, 95% CI: 2.365-9.444, P < 0.001) were independent prognostic factors of RFS. Nomogram with independent factors was established and achieved a better concordance index of 0.753 (95% CI: 0.672-0.834) for predicting RFS. The ROC found that the area under curve (AUC) was consistent with the C-index and the sensitivity was 85.4%. The risk score calculated by nomogram could divide AFP-negative HCC patients into high-, moderate- and low-risk groups (P < 0.05). DCA analysis revealed that the nomogram could augment net benefits and exhibited a wider range of threshold probabilities by the risk stratification than the AJCC T and BCLC stage in the prediction of AFP-negative HCC recurrence. CONCLUSION: The ALBI grade- and MLR-based nomogram prognostic model for RFS showed high predictive accuracy in AFP-negative HCC patients after surgical resection.

Therapeutic effectiveness and safety of sintilimab-dominated triple therapy in unresectable hepatocellular carcinoma.

Immune checkpoint inhibitor therapy has shown promising results in patients with unresectable hepatocellular carcinoma. This study aimed to evaluate the effectiveness and safety of sintilimab, a programmed cell death protein-1 (PD-1) blockade, combined with sorafenib and transhepatic arterial chemotherapy and embolization in this patient population, compared with sintilimab monotherapy and sintilimab-sorafenib duotherapy. This was a 22 months single center retrospective cohort study in China. 80 patients with unresectable hepatocellular carcinoma were included, with diagnosis confirmed by either histologic, cytologic or diagnostic imaging analysis. The patients were divided into three groups based on therapeutic regimen: sintilimab monotherapy (sintilimab group, n = 22), sintilimab-sorafenib duotherapy (duplex group, n = 23), sintilimab-sorafenib and transcatheter arterial chemoembolization combined therapy (triple group, n = 35). The principal evaluation criteria were overall survival and progression free survival in the population, assessed according to response evaluation criteria in solid tumors, version 1.1 (RECIST 1.1). Secondary evaluation criteria were safety, objective response rate and disease control rate. From March 1st, 2019 to December 31, 2020, 80 patients with unresectable hepatocellular carcinoma were included and divided into three treatment groups (22 received sintilimab monotherapy, 23 received sintilimab-sorafenib duotherapy, and 35 received sintilimab-sorafenib combined with transcatheter arterial chemoembolization). The median overall survival of all patients was 11.0 months (95% CI 7.7-14.3). Median overall survival was 13.0 months (95% CI NE-NE), 9.0 months(95% CI 6.3-11.7)and 3.0 months (95% CI 1.9-4.1, p < 0.0001) in the triple therapy, duplex and sintilimab groups respectively, while the corresponding median progression-free survival were 5.0 months (95% CI 2.9-7.1, p < 0.001), 4.0 months (95% CI 2.8-5.2) and 2.0 months (95% CI 1.7-2.3). Disease control and clinical benefits rates were higher in the triple therapy group (80%, 95% CI 63.1-91.6, p < 0.001; 54.3%, 95% CI 36.6-71.2, p < 0.01) compared to the sintilimab group. Median duration of disease control was 4.0 months (95% CI NE-NE, p < 0.01) in the triple therapy group, longer than that of the duplex group (2.0 months, 95% CI 0.9-3.1) and sintilimab group (2.0 months, 95% CI 0.8-3.2). Grade 3 or 4 treatment-related adverse events occurred in 26.3% of 80 patients with hypertension was the most common event observed (38, 47.5%), however, other severe toxic effects were infrequent. Sintilimab combined with sorafenib and transcatheter arterial chemoembolization might have more beneficial effects on overall and progression-free survival and on the duration of disease control outcomes than both sintilimab monotherapy and sintilimab-sorafenib duotherapy in patients with unresectable hepatocellular carcinoma. This triple therapy model might represent an innovative and effective option for inoperable liver cancer.

Preoperative nomogram for microvascular invasion prediction based on clinical database in hepatocellular carcinoma.

The presence of microvascular invasion (MVI) is a critical determinant of early hepatocellular carcinoma (HCC) recurrence and prognosis. We developed a nomogram model integrating clinical laboratory examinations and radiological imaging results from our clinical database to predict microvascular invasion presence at preoperation in HCC patients. 242 patients with pathologically confirmed HCC at the Ningbo Medical Centre Lihuili Hospital from September 2015 to January 2021 were included in this study. Baseline clinical laboratory examinations and radiological imaging results were collected from our clinical database. LASSO regression analysis model was used to construct data dimensionality reduction and elements selection. Multivariate logistic regression analysis was performed to identify the independent risk factors associated with MVI and finally a nomogram for predicting MVI presence of HCC was established. Nomogram performance was assessed via internal validation and calibration curve statistics. Decision curve analysis (DCA) was conducted to determine the clinical usefulness of the nomogram model by quantifying the net benefits along with the increase in threshold probabilities. Survival analysis indicated that the probability of overall survival (OS) and recurrence-free survival (RFS) were significantly different between patients with MVI and without MVI (P < 0.05). Histopathologically identified MVI was found in 117 of 242 patients (48.3%). The preoperative factors associated with MVI were large tumor diameter (OR = 1.271, 95%CI: 1.137-1.420, P < 0.001), AFP level greater than 20 ng/mL (20-400 vs. ≤ 20, OR = 2.025, 95%CI: 1.056-3.885, P = 0.034; > 400 vs. ≤ 20, OR = 3.281, 95%CI: 1.661-6.480, P = 0.001), total bilirubin level greater than 23 umol/l (OR = 2.247, 95%CI: 1.037-4.868, P = 0.040). Incorporating tumor diameter, AFP and TB, the nomogram achieved a better concordance index of 0.725 (95%CI: 0.661-0.788) in predicting MVI presence. Nomogram analysis showed that the total factor score ranged from 0 to 160, and the corresponding risk rate ranged from 0.20 to 0.90. The DCA showed that if the threshold probability was > 5%, using the nomogram to diagnose MVI could acquire much more benefit. And the net benefit of the nomogram model was higher than single variable within 0.3-0.8 of threshold probability. In summary, the presence of MVI is an independent prognostic risk factor for RFS. The nomogram detailed here can preoperatively predict MVI presence in HCC patients. Using the nomogram model may constitute a usefully clinical tool to guide a rational and personalized subsequent therapeutic choice.

A potential risk factor of essential hypertension in case-control study: MicroRNAs miR-10a-5p.

Background: Essential hypertension is a multifactorial disease with high morbidity. The researches on the influence of genes on the disease are still in its infancy, and the mechanism of gene regulation is not clear. MiRNAs are key molecules that regulate the expression control of protein-coding or protein-non-coding RNA. It may be an important biological molecule risk factor for essential hypertension.Methods: A case-control study with 98 EH and 98 non-EH was conducted in our experiment. The candidate miRNAs including miR-10a-5p and miR-497-5p were detected and verified by qRT-PCR.Results: The expression level of miRNA in EH cases was significantly lower than the healthy control (P = 0.005). In addition, the relative expression of miR-10a-5p was closely positive correlated with DBP (r = 0.162, P = 0.023) and SBP (r = 0.223, P = 0.002). After adjusting confound factors, the result of the logistic regression indicated that hypo-expression of miR-10a-5p is a risk factor for EH (OR(95%CI) = 1.676(1.302,2.157), adjusted P < 0.0001). And the ROC analysis shows that the combined line with BMI and miR-10a-5p was a values marker for EH (AUC: 0.728, P < 0.0001).Conclusions: Lower expression of miR-10a-5p, as the key role, is significantly related to the risk of EH and maybe as a potential biomolecule for EH.

Hypomethylation of the Interferon γ Gene as a Potential Risk Factor for Essential Hypertension: A Case-Control Study.

Essential hypertension (EH) is a multifactorial disease. Interferon-γ (IFN-γ) plays an important role in the onset of EH through cytokine-mediated systemic inflammatory responses. We aimed to determine whether the methylation status of the IFN-γ gene (IFNG) promoter is involved in the pathogenesis of EH. Six copies of CpG dinucleotides are distributed between 3,203 bp and 3,121 bp upstream from the transcription initiation site of IFNG, termed CpG1 to CpG6 in the 5'-to-3' direction. We recruited 96 patients with EH and 96 sex- and age-matched healthy subjects as controls. Using bisulfate pyrosequencing datasets, we analyzed the methylation status of the six CpG sites and thus found that CpG5 was consistently methylated in all of the 96 EH patients and 96 control subjects. Among the remaining five CpG sites, there was no significant difference in the methylation levels of CpG4 and CpG6 between the two groups. By contrast, CpG1 (P = 0.003) and CpG3 (P = 5.87 × 10-7) were highly methylated among the EH subjects compared with the controls, whereas CpG2 (P = 1.24 × 10-12) was significantly less methylated in among EH subjects. The methylation levels of CpG2 were still lower after adjustment with logistic regression (adjusted P = 0.032). The CpG2 methylation level was an effective marker of EH (area under curve = 0.384; P = 1.40 × 10-15). The present study shows that hypomethylation of the IFNG promoter is significantly related to the risk of EH, providing new insights into the pathogenesis of EH.