Management of anastomotic biliary stricture through utilizing percutaneous transhepatic cholangioscopy.

AIM: Occurrence of anastomotic biliary stricture (AS) remains an essential issue following hepatobiliary surgeries, and percutaneous transhepatic cholangioscopy (PTCS) has great therapeutic significance in handling refractory AS for patients with altered gastrointestinal anatomy after cholangio-jejunostomy. This present study aimed to investigate feasibility of PTCS procedures in AS patients for therapeutic indications. MATERIALS AND METHODS: This study was a single-center, retrospective cohort study with a total number of 124 consecutive patients who received therapeutic PTCS due to AS. Clinical success rate, required number, and adverse events of therapeutic PTCS procedures as well as patients survival state were reviewed. RESULTS: These 124 patients previously underwent choledochojejunostomy or hepatico-jejunostomy, and there was post-surgical altered gastrointestinal anatomy. Overall, 366 therapeutic PTCS procedures were performed for these patients through applying rigid choledochoscope, and the median time of PTCS procedures was 3 (1-11). Among these patients, there were 34 cases (27.32%) accompanied by biliary strictures and 100 cases (80.65%) were also combined with biliary calculi. After therapeutic PTCS, most patients presented with relieved clinical manifestations and improved liver functions. The median time of follow-up was 26 months (2-86 months), and AS was successfully managed through PTCS procedures in 104 patients (83.87%). During the follow-up period, adverse events occurred in 81 cases (65.32%), most of which were tackled through supportive treatment. CONCLUSION: PTCS was a feasible, safe and effective therapeutic modality for refractory AS, which may be a promising alternative approach in clinical cases where the gastrointestinal anatomy was changed after cholangio-jejunostomy.

IL-33/ST2 Signaling and its Correlation with Macrophage Heterogeneity and Clinicopathologic Features in Human Intrahepatic Cholangiocarcinoma.

BACKGROUND: IL-33/ST2 signaling plays crucial roles in the development and progression of various human malignancies. However, its significance in intrahepatic cholangiocarcinoma (ICC) still remains unclear. OBJECTIVE: This study aimed to investigate the expression of IL-33/ST2 signaling and its correlations with macrophage heterogeneity and ICC patients' clinicopathologic features. METHODS: The expression of different phenotype macrophage markers and IL-33/ST2 signalingrelated markers was detected. The correlation between L-33/ST2 signaling and different phenotype macrophage markers as well as ICC patients' clinicopathologic data was evaluated. RESULTS: Massive heterogeneous cancer cells and PAS-positive cells were observed in tumor tissues. CD68-positive cells accumulated in tumor tissues and expression of both M1 phenotype markers and M2 phenotype macrophage markers was higher in tumor samples than para-carcinoma samples. However, M2 phenotype macrophages represented the dominant macrophage population in ICC tissues. Plasma levels of IL-33, ST2, and MIF were evidently enhanced in ICC patients compared to healthy controls. IL-33/ST2 signaling-related markers exhibited a massive increase in tumor samples than para-carcinoma samples. IL-33 and ST2 expression in ICC tissues was positively associated with M1 and M2 phenotype macrophages. Plasma levels of IL-33, ST2, and MIF were correlated with the diameter of tumor lesions, lymph node metastasis, TNM stage, and tumor differentiation degree. Multivariate analysis demonstrated IL-33 expression to exhibit a correlation with the diameter of tumor lesions, lymph node metastasis, and TNM stage. Additionally, there was a relationship observed between ST2, MIF expression, and diameter of tumor lesions plus TNM stage. CONCLUSION: IL-33/ST2 signaling exhibited a positive relationship with macrophage heterogeneity in ICC tissues, and upregulated levels of IL-33, ST2, and MIF were associated with aggressive clinicopathologic characteristics. These findings may provide promising diagnostic biomarkers and potential therapeutic strategies for ICC patients targeting IL-33/ST2 signaling.

Exosomes derived from TGF-ß1-pretreated mesenchymal stem cells alleviate biliary ischemia-reperfusion injury through Jagged1/Notch1/SOX9 pathway.

BACKGROUND: This study aimed to evaluate the efficacy of exosomes (EXO) derived from TGF-ß1-pretreated mesenchymal stem cells (MSCs) on biliary ischemia reperfusion injury (IRI) and further reveal the possible mechanisms. METHODS: Bone marrow-derived MSCs were treated with exogenous TGF-ß1, Jagged1/Notch1/SOX9 pathway inhibitor LY450139, or their combination. Then, EXO were isolated from the culture supernatants and further characterized. After establishing IRI model of biliary epithelial cells (EpiCs), EXO derived from differently-treated MSCs were applied to detect their protective effects on EpiCs, and LY450139 was applied in EpiCs to detect the possible mechanisms after treatment with MSCs-EXO. EXO derived from differently-treated MSCs were further injected into the hepatic artery immediately after establishment of intrahepatic biliary IRI for animal studies. RESULTS: Pretreatment with TGF-ß1 significantly enhanced MSCs-EXO production and elevated the levels of massive miRNAs associated with anti-apoptosis and tissue repair, which were evidently decreased after TGF-ß1 plus LY450139 cotreatment. Notable improvement was observed in EpiCs after MSCs-EXO treatment, evidenced by reduced cellular apoptosis, increased cellular proliferation and declined oxidative stress, which were more evident in EpiCs that were treated with EXO derived from TGF-ß1-pretreated MSCs. However, application of EXO derived from TGF-ß1 plus LY450139-cotreated MSCs reversely enhanced cellular apoptosis, decreased cellular proliferation and anti-oxidants production. Interestingly, LY450139 application in EpiCs after treatment with MSCs-EXO also reversed the declined cellular apoptosis and enhanced oxidative stress induced by TGF-ß1 pretreatment. In animal studies, administration of EXO derived from TGF-ß1-pretreated MSCs more effectively attenuated biliary IRI through reducing oxidative stress, apoptosis, inflammation and enhancing the expression levels of TGF-ß1 and Jagged1/Notch1/SOX9 pathway-related markers, which were reversed after administration of EXO derived from TGF-ß1 plus LY450139-cotreated MSCs. CONCLUSION: Our results provided a vital insight that TGF-ß1 pretreatment endowed MSCs-EXO with stronger protective effects to improve biliary IRI via Jagged1/Notch1/SOX9 pathway.

Identification and Experimental Validation of the Prognostic Significance and Immunological Correlation of Glycosylation-Related Signature and ST6GALNAC4 in Hepatocellular Carcinoma.

Purpose: Glycosylation has been demonstrated to be involved in tumorigenesis, progression, and immunoregulation, and to present specific profiles in different tumors. In this study, we aimed to explore the specific glycosylation-related gene (GRG) signature and its potential immunological roles and prognostic implications in hepatocellular carcinoma (HCC). Patients and Methods: The GRG expression profile was defined using the transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Univariate and the least absolute shrinkage and selection operator Cox analyses were performed to develop a GRG-based risk score model. A nomogram was subsequently established and validated. Its correlation with cancer immune microenvironment and drug susceptibility was further analyzed. The role and immunological correlation of ST6GALNAC4 were further experimentally validated at the tissue and cellular levels in HCC. Results: A total of 87 GRGs were identified to be significantly dysregulated in HCC, and a novel risk score model was constructed using eight critical GRGs, which demonstrated superior prognostic discrimination and predictive power in both training and validation groups. High risk scores in HCC patients were associated with lower OS. The model was also identified as an independent risk factor for HCC, and a novel nomogram was subsequently constructed and validated. Notably, significant correlations were found in risk scores with immune cells infiltration, tumor immunophenotyping, immune checkpoint genes' expression, and sensitivities to multiple drugs. Furthermore, we validated in local HCC samples that ST6GALNAC4 was significantly upregulated and its knockdown significantly inhibited the tumor proliferation, migration and invasion ability and affected the expression of immune checkpoints on hepatoma cells. Conclusion: We identified a novel GRG-based model which showed significant prognostic and immunological correlations in HCC, and the oncogenic role of ST6GALNAC4 has been validated and may serve as a potential drug target.

Three's a crowd? Examining evolving public transit crowding standards amidst the COVID-19 pandemic.

The COVID-19 pandemic dramatically affected public transit systems around the globe. Because transit systems typically move many people closely together on buses and trains, public health guidance demanded that riders should keep a distance of about two meters to others changed the definition of "crowding" on transit in 2020. Accordingly, this research examines how U.S. public transit agencies responded to public health guidance that directly conflicted with their business model. To do this, we examined published crowding standards before the COVID-19 pandemic for a representative sample of 200 transit systems, including whether they started or changed their published standards during the pandemic, as well as the reasons whether agencies publicize such standards at all. We present both descriptive statistics and regression model results to shed light on the factors associated with agency crowding standards. We find that 56% of the agencies surveyed published crowding standards before the pandemic, while only 46% published COVID-19-specific crowding standards. Regression analyses suggest that larger agencies were more likely to publish crowding standards before and during the COVID-19 pandemic, likely because they are more apt to experience crowding. Pandemic-specific crowding standards, by contrast, were associated with a more complex set of factors. We conclude that the relative lack of pandemic standards reflects the uncertainty and fluidity of the public health crisis, inconsistent and at times conflicting with the guidance from public health officials, and, in the U.S., a lack national or transit industry consensus on appropriate crowding standards during the first year of the pandemic.

Successful treatment of stage IIIB intrahepatic cholangiocarcinoma using neoadjuvant therapy with the PD-1 inhibitor camrelizumab: A case report.

BACKGROUND: The prognosis of intrahepatic cholangiocarcinoma (ICC) with lymph node metastasis is poor. The feasibility of surgery is not certain, which is a contraindication according to the National Comprehensive Cancer Network guidelines. The role of immunotherapy as a neoadjuvant therapy for ICC is not clear. We herein describe a case of ICC with lymph node metastasis that was successfully treated with neoadjuvant therapy. CASE SUMMARY: A 60-year-old man with a liver tumor was admitted to our hospital. Enhanced computed tomography and magnetic resonance imaging revealed a space-occupying lesion in the right lobe of the liver. Multiple subfoci were found around the tumor, and the right posterior branch of the portal vein was invaded. Liver biopsy indicated poorly differentiated cholangiocytes. According to the American Joint Committee on Cancer disease stage classification, ICC with hilar lymph node metastasis (stage IIIB) and para-aortic lymph node metastasis was suspected. A report showed that two patients with stage IIIB ICC achieved a complete response (CR) 13 mo and 16 mo after chemotherapy with a PD-1 monoclonal antibody. After multidisciplinary consultation, the patient was given neoadjuvant therapy, surgical resection and lymph node dissection, and postoperative adjuvant therapy. After three rounds of PD-1 immunotherapy (camrelizumab) and two rounds of gemcitabine combined with cisplatin regimen chemotherapy, the tumor size was reduced. Therefore, a partial response was achieved. Exploratory laparotomy found that the lymph nodes of Group 16 were negative, and the tumor could be surgically removed. Therefore, the patient underwent right hemihepatectomy plus lymph node dissection. The patient received six rounds of chemotherapy and five rounds of PD-1 treatment postoperatively. After 8 mo of follow-up, no recurrence was found, and a CR was achieved. CONCLUSION: Neoadjuvant therapy combined with surgical resection is useful for advanced-stage ICC. This is the first report of successful treatment of stage IIIB ICC using neoadjuvant therapy with a PD-1 inhibitor.

Upregulation of TMCO3 Promoting Tumor Progression and Contributing to the Poor Prognosis of Hepatocellular Carcinoma.

Background and Aims: TMCO3, a member of the monovalent cation:proton antiporter-2 family, has been annotated as a Na+/H+ antiporter, but its pathophysiological role is still unclear. We aimed to investigate the expression profile, prognostic significance, and oncogenic role of TMCO3 in hepatocellular carcinoma (HCC). Methods: Bioinformatic analyses were conducted using transcriptome data from public databases to determine the expression, prognosis, and functional enrichment of TMCO3 in HCC. TMCO3 expression was further validated in an independent HCC cohort from our institution. The oncogenic role of TMCO3 in HCC was evaluated using in vitro and in vivo experiments. Results: The upregulated expression of TMCO3 was identified and verified in multiple HCC cohorts, and worse overall survival and recurrence-free survival were observed in patients with high TMCO3 expression. The overexpression and knockdown of TMCO3 could affect the proliferation and metastasis of HCC cells, which might be associated with the p53-induced cell cycle regulation and epithelial-mesenchymal transition, respectively. Notably, significant correlations were found between dysregulated TMCO3 and various antitumor agents. Its role in sorafenib sensitivity was further identified by in vitro experiments and the potential mechanism might be related to the regulation of apoptosis. Positive correlations were also identified between upregulation of TMCO3 and the increased infiltration of various immune cells and the elevated expression of multiple immune checkpoint genes in HCC. Conclusions: Upregulated TMCO3 could act as an oncogenic mediator and promote sorafenib resistance in HCC, providing a potential therapeutic target for HCC treatment.

Prognostic Role and Potential Mechanisms of N6-methyladenosine-related Long Noncoding RNAs in Hepatocellular Carcinoma.

Background and Aims: Numerous studies have explored the important role of N6-methyladenosine (m6A) in cancer. Nonetheless, the interaction between m6A and long noncoding RNAs (lncRNAs) is poorly investigated. Herein, we systematically analyzed the role and prognostic value of m6A-related lncRNAs in hepatocellular carcinoma (HCC). Methods: The m6A-related lncRNAs were identified based on the correlation coefficients with m6A-related genes in HCC from The Cancer Genome Atlas. Subsequently, a novel risk score model was determined using the least absolute shrinkage and selection operator Cox regression analyses. Univariate and multivariate Cox analyses were used to identify independent prognostic factors for overall survival (OS) of HCC; thereafter, a prognostic nomogram was constructed. Results: A total of 259 lncRNAs showed significant correlations with m6A in HCC, while 29 lncRNAs had prognostic significance. Further, six critical m6A-related lncRNAs (NRAV, SNHG3, KDM4A-AS1, AC074117.1, AC025176.1, and AL031985.3) were screened out to construct a novel risk score model which classified HCC patients into high- and low-risk groups. Survival analyses revealed that patients in the high-risk group exhibited worse OS, both in the training and validation groups. The risk score was also identified as an independent prognostic factor of OS, and a nomogram was established and verified with superior prediction capacity. Besides, the risk score significantly correlated with the expression of immune checkpoint genes and immune subtypes. Conclusions: These findings indicated the significant role of m6A-related lncRNAs in HCC and the potential application of the novel risk score model for prognostic prediction.

A Novel Nine-Gene Signature Associated With Immune Infiltration for Predicting Prognosis in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its prognosis remains unsatisfactory. The identification of new and effective markers is helpful for better predicting the prognosis of patients with HCC and for conducting individualized management. The oncogene Aurora kinase A (AURKA) is involved in a variety of tumors; however, its role in liver cancer is poorly understood. The aim of this study was to establish AURKA-related gene signatures for predicting the prognosis of patients with HCC. Methods: We first analyzed the expression of AURKA in liver cancer and its prognostic significance in different data sets. Subsequently, we selected genes with prognostic value related to AURKA and constructed a gene signature based on them. The predictive ability of the gene signature was tested using the HCC cohort development and verification data sets. A nomogram was constructed by integrating the risk score and clinicopathological characteristics. Finally, the influence of the gene signature on the immune microenvironment in HCC was comprehensively analyzed. Results: We found that AURKA was highly expressed in HCC, and it exhibited prognostic value. We selected eight AURKA-related genes with prognostic value through the protein-protein interaction network and successfully constructed a gene signature. The nine-gene signature could effectively stratify the risk of patients with HCC and demonstrated a good ability in predicting survival. The nomogram showed good discrimination and consistency of risk scores. In addition, the high-risk group showed a higher percentage of immune cell infiltration (i.e., macrophages, myeloid dendritic cells, neutrophils, and CD4+T cells). Moreover, the immune checkpoints SIGLEC15, TIGIT, CD274, HAVCR2, and PDCD1LG2 were also higher in the high-risk group versus the low-risk group. Conclusions: This gene signature may be useful prognostic markers and therapeutic targets in patients with HCC.

Regulation Network and Prognostic Significance of Aldo-Keto Reductase (AKR) Superfamily Genes in Hepatocellular Carcinoma.

PURPOSE: The aldo-keto reductase (AKR) superfamily members have been proposed with multiple roles in various tumors. Here, a comprehensive analysis on the integral role of AKR genes was conducted to evaluate the expression profile, regulation network, and prognostic significance in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Transcriptome datasets of HCC were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus. Univariate and multivariate Cox regression analyses were used to build a novel risk score model, and then were further used to identify independent prognostic factors for overall survival (OS) of HCC. A prognostic nomogram was developed and validated. The expression of these critical AKR members was also evaluated by quantitative real-time polymerase chain reaction and immunohistochemistry in HCC specimens. RESULTS: Eight differentially expressed AKR genes were identified in HCC. The dysregulation of most AKR genes was negatively correlated with DNA methylation, and a regulation network with transcription factors (TFs) was also established. Then, three critical AKR genes (AKR1B10, AKR1D1, and AKR7A3) were screened out to build a novel risk score model. Worse OS was observed in high-risk patients. Besides, a prognostic nomogram based on the model was further established and validated in both the TCGA and GSE14520 cohorts, which showed superior performance in predicting the OS of HCC patients. Notably, close correlations were identified between the risk score and tumor immune microenvironment, somatic mutation profiles, and drug susceptibilities of HCC. Finally, the upregulated AKR1B10 and downregulated AKR1D1 and AKR7A3 were further verified in HCC tumor and adjacent tissues from our institution. CONCLUSION: The dysregulated AKR genes could be mediated by DNA methylation and TFs in HCC. The risk model established with superior prognostic performance further suggested the significant role of AKR genes involved in the progression of HCC.

Prognostic Role and Potential Mechanisms of the Ferroptosis-Related Metabolic Gene Signature in Hepatocellular Carcinoma.

PURPOSE: Ferroptosis, as a novel regulated cell death form, has a close interaction with metabolism, which is largely unknown in cancer. In the present study, we conducted a comprehensive analysis of ferroptosis-related metabolic genes to delineate the metabolic signatures induced by ferroptosis and evaluate its prognostic significance in hepatocellular carcinoma (HCC). METHODS: The ferroptosis-related metabolic genes (Fer-MRGs) were identified by correlation analyses with transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Then, univariate and the least absolute shrinkage and selection operator Cox regression analysis was used to establish a novel risk score model. Univariate and multivariate COX analyses were used to identify independent prognostic factors for overall survival (OS) of HCC, and a nomogram was developed. The Fer-MRGs' expression was further evaluated by quantitative real-time polymerase chain reaction in HCC. RESULTS: A total of 77 metabolic genes were identified as Fer-MRGs, and 26 were found with prognostic values for OS of HCC. Then, a novel nine-gene (AKR1C3, ATIC, G6PD, GMPS, GNPDA1, IMPDH1, PRIM1, RRM2, and TXNRD1) risk score model was constructed. Survival analyses showed worse OS in high-risk patients both in the training and validation groups. The model was also identified as an independent prognostic factor for HCC, and a prognostic nomogram for OS was further established with superior discriminative capacity and prediction accuracy. Notably, close correlations were also identified between the risk score and the expression of immune checkpoint genes, immune subtypes of tumor, and susceptibility of HCC to chemotherapeutic agents. Finally, elevated expression of eight Fer-MRGs (except for IMPDH1) was further verified in 16 pairs of HCC tumor and adjacent tissues. CONCLUSION: These results indicated the intense interaction between ferroptosis and metabolism, the significant role of ferroptosis-related MRGs, and the great potential of the novel risk score model for prognosis prediction in HCC.

Prognostic value of inflammation-based indices in patients with resected hepatocellular carcinoma.

BACKGROUND: As is well recognized that inflammation plays a crucial role in the genesis and progression of various cancer. Here we investigate the prognostic value of a novel index: the combination of neutrophil to lymphocyte ratio and platelet distribution width (coNLR-PDW) in post-operation patients with resectable hepatocellular carcinoma (HCC). METHODS: The receiver operating characteristic (ROC) curve was utilized to determine the optimal cutoff values of continuous variables, including the neutrophil-lymphocyte ratio (NLR) and platelet distribution width (PDW). Kaplan-Meier method and the Log-rank test were used to compare survival differences across three groups stratified by the coNLR-PDW score. Univariate and multivariate Cox proportional hazard regression analyses were adopted to identify independent factors of HCC patient's prognosis. RESULTS: 1.59 and 13.0 were perceived as the optimal cutoff value for NLR and PDW based on the ROC curve, respectively. Kaplan-Meier method revealed that a higher coNLR-PDW score predicts poorer overall survival (OS) and disease-free survival (DFS) (P < 0.001). coNLR-PDW was demonstrated as an independent factor for both OS and DFS using Cox regression analysis in training and validation cohort. CONCLUSION: coNLR-PDW is recognized as a valuable biomarker for predicting the survival of patients with HCC.

Nomograms based on clinicopathological factors and inflammatory indicators for prediction of early and late recurrence of hepatocellular carcinoma after surgical resection for patients with chronic hepatitis B.

BACKGROUND: Few studies have focused on the prognostic values of inflammation-related factors for different phases of recurrence in hepatocellular carcinoma (HCC). We aimed to identify the different risk factors for overall, early, and late recurrence, and to establish nomograms based on inflammation-related parameters for predicting the risks of recurrence in a group of HCC patients undergoing hepatectomy. METHODS: We retrospectively enrolled 383 HCC patients with chronic hepatitis B (CHB) who underwent hepatectomy. Univariate and multivariate Cox analyses were conducted to identify independent risk factors for recurrence. Nomograms for overall, early, and late recurrence-free survival (RFS) were established. The discrimination and calibration abilities of the nomograms were evaluated by concordance indexes (C-index), calibration plots, and Kaplan-Meier curves. Finally, receiver operating characteristic (ROC) curves were used to compare the derived nomograms with other existing models. RESULTS: Fibrinogen, lymphocyte-to-monocyte ratio, and S-index inflammation-related factors were independently related to overall and early RFS, but only the S-index correlated with late recurrence. Nomograms with tumor number, diameter, and pathological differentiation for overall and early RFS were established, while nomogram for late recurrence was constructed with tumor number and Child-Pugh grade. The C-indexes for overall, early, and late RFS were 0.679, 0.677, and 0.728, respectively. The calibration plots fit well. The nomograms showed superior discrimination capacities and better performance prediction with larger areas under the curve for recurrence. CONCLUSIONS: The developed nomograms that integrated inflammation-related factors showed high predictive accuracy for overall, early, and late recurrence in HCC patients with CHB after hepatectomy.

Association between hepatitis B virus infection and colorectal liver metastasis: a meta-analysis.

The paper aims to assess the association between Hepatitis B Virus infection and colorectal liver metastasis by conducting a meta-analysis. The relevant studies were searched until 24 July 2020, Studies that assessed the correlation between HBV infection and CRLM were recruited. A random effects model was applied to calculate the odds ratio (OR) with 95% confidence interval (CI). All data analyses were performed by STATA 12.0 software. Ten studies involving 17529 participants were included in the study. The results shown that there was obvious association between HBV infection and CRLM (OR: 0.51, 95% CI: 0.28-0.91). The study type and case-control rate may be the main causes of heterogeneity. In addition, HBV infection had no association with extrahepatic metastasis or prognosis of patients with CRLM. Sensitivity analyses confirmed that the results were stable, and Egg's test indicated that there was no publication bias. Patients with HBV infection have the reduced risk of CRLM.

Prognostic value of combined pretreatment fibrinogen and neutrophil-lymphocyte ratio in digestive system cancers: a meta-analysis of 17 retrospective studies.

BACKGROUND: Several epidemiological studies have reported the relationship between the combined pretreatment fibrinogen and neutrophil-lymphocyte ratio (F-NLR) and prognosis of digestive system cancers (DSCs). However, the results are controversial. We aimed to assess the prognostic value of F-NLR in patients with DSCs. METHODS: A comprehensive search for relevant studies was conducted until June, 2020. Studies that evaluated the association of the F-NLR score with survival outcome in patients with any DSCs were included. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using a fixed-effects model. All data analyses were performed using the STATA 12.0 software. RESULTS: A total of 17 studies involving 5,767 participants were included in the meta-analysis. We found that high F-NLR score was significantly associated with poor overall survival (OS) in patients with DSCs (HR =2.0; 95% CI, 1.78-2.24). In addition, patients with high F-NLR score had poor disease-free survival/progression-free survival/recurrence-free survival (DFS/PFS/RFS) (HR =2.01; 95% CI, 1.47-2.74) and DFS (HR =1.97; 95% CI, 1.35-2.87). Sensitivity analyses for OS confirmed that the results were stable. CONCLUSIONS: High F-NLR score is significantly associated with poor prognostic outcomes in patients with DSCs and can serve as an effective prognostic indicator for the Asian population.

Prognostic value of combined preoperative gamma-glutamyl transpeptidase to platelet ratio and fibrinogen in patients with HBV-related hepatocellular carcinoma after hepatectomy.

The gamma-glutamyl transpeptidase to platelet ratio (GPR) has been reported as a non-invasive parameter for evaluating hepatic fibrosis and cirrhosis. However, only a few of studies investigated the relationship between GPR and liver cancer. Here, we sought to clarify the prognostic value of GPR as well as its combination with fibrinogen in patients with HBV-related hepatocellular carcinoma (HCC). We performed a retrospective study using data collected from 302 HCC patients, and evaluated the association between GPR, fibrinogen and clinicopathological characteristics using the chi-square test. Additionally, we assessed disease-free survival (DFS) and overall survival (OS) using the Kaplan-Meier method and log-rank test, then performed univariate and multivariate COX analyses to identify the prognostic factors. The prognostic performance of combined GPR and fibrinogen was evaluated by the receiver operating characteristic curve analysis. Results showed that GPR was associated with gender, history of smoking and drinking, cirrhosis, antiviral treatments, tumor number, and Child-Pugh grade. Univariate analysis revealed a significant correlation between tumor diameter, vascular invasion, BCLC stage, alpha-fetal protein, GPR, fibrinogen, and NLR with both DFS and OS in HCC patients. Only GPR and fibrinogen were found to be independently associated with both DFS and OS according to multivariate analysis. Furthermore, predictive capacity was enhanced by combining GPR with fibrinogen owing to a larger area under the curve than other indexes or models. Overall, preoperative GPR could be an effective non-invasive predictor for prognosis of HBV-related HCC patients, and a combination of GPR and fibrinogen improved the prognostic performance.

The Prognostic Role of a Combined Fibrinogen and Neutrophil-to-Lymphocyte Ratio Score in Patients with Resectable Hepatocellular Carcinoma: A Retrospective Study.

BACKGROUND Inflammation and activation of the coagulation cascades have a role in the pathogenesis of malignancy, including hepatocellular carcinoma (HCC). This retrospective study aimed to investigate the prognostic role of the combined fibrinogen and neutrophil-to-lymphocyte ratio (F-NLR) in patients with resectable HCC. MATERIAL AND METHODS This retrospective study included 292 patients with HCC who underwent surgical resection. The receiver operating characteristic (ROC) curve was used to determine the cut-off value of preoperative fibrinogen (Fib) levels and the neutrophil-to-lymphocyte ratio (NLR). The. Hyperfibrinogenemia was >3.35 g/L, and an increased NLR was ≥2.47. The F-NLR was calculated for all patients. Kaplan-Meier survival curves, univariate analysis, multivariate analysis, and subgroup analysis were used to identify independent prognostic factors for overall survival (OS) and disease-free survival (DFS). The receiver operating characteristic (ROC) curve analysis of the F-NLR score and OS, according to the Barcelona Clinic Liver Cancer (BCLC) stage, was performed. RESULTS Increased F-NLR scores were significantly associated with the presence of tumor thrombus (P=0.001), larger tumor diameter (P<0.001), vascular invasion (P<0.001), and increased BCLC stage (P<0.001). Multivariate analysis showed that the F-NLR score was an independent predictor of OS (P<0.001) and DFS (P=0.002). The prognostic role of F-NLR was significant for BCLC stage 0-I (P=0.004; P<0.001) and BCLC stage II-III (P=0.026; P=0.005) for OS and DFS, respectively. CONCLUSIONS In patients with resectable HCC, the combined F-NLR score, a new indicator of systemic inflammation, was an independent prognostic indicator.

The prognostic significance of neutrophil-to-lymphocyte ratio at different time points in patients with hepatocellular carcinoma receiving liver resection.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been demonstrated a significant association with the prognosis of hepatocellular carcinoma (HCC). The current study aimed to evaluate the prognostic value of NLR at different time points in HCC patients receiving liver resection. METHODS: Data were retrospectively collected from 195 HCC patients receiving liver resection. The preoperative NLR (pre-NLR), postoperative NLR (post-NLR) and corresponding changes of NLR (NLRc) at different time points were calculated. The disease-free survival (DFS) and overall survival (OS) was calculated by the Kaplan-Meier method and compared by the log-rank test. Both univariate and multivariate analyses were performed to evaluate their prognostic values for DFS and OS. And the prognostic significance of pre-NLR, post-NLRs, and NLRcs were further evaluated with subgroup analysis and with early and late recurrence of HCC. RESULTS: Pre-NLR was not significantly correlated with DFS or OS (both P>0.05), whereas higher post-NLR at 4-8 weeks [NLR (4-8 w)] and 3-6 months [(NLR (3-6 m)] predicted worse DFS (P=0.023 and P<0.001, respectively) and OS (P=0.012 and P=0.001, respectively). The value of area under the curve (AUC) of NLR (3-6 m) were higher than NLR (4-8 w) for DFS (0.656 vs. 0.572) and OS (0.650 vs. 0.621). Multivariate analyses showed that NLRc (4-8 w) was not a significant predictor of DFS (P=0.369) or OS (P=0.173), while the NLRc (3-6 m) with 25% increase was found to be an independent factor for adverse DFS in patients with HCC (P=0.041). The AUC of NLRc (3-6 m) for DFS was 0.600. Subgroup analysis showed NLR (3-6 m) was significantly corrected to DFS (P<0.001) and OS (P=0.001) in patients with cirrhosis. And NLR (3-6 m) also showed with significant correlation with early recurrence (P<0.001), while NLR (4-8 w) was found with significant association both with early and late recurrence (P=0.037 and P=0.027, respectively). CONCLUSIONS: The post-NLRs are significant predictors of clinical outcome in HCC patients receiving liver resection, and post-NLR and NLRc with a relatively long-term interval after operation have better prognostic values.

CD8+CXCR5+T cells infiltrating hepatocellular carcinomas are activated and predictive of a better prognosis.

CD8+ T cells are thought to be the primary cytotoxic lymphocytes exerting antitumor effects. However, few studies have focused on the antitumor effects of CD8+ T cell-mediated humoral immunity or on interactions between CD8+ T cells and B cells in hepatocellular carcinoma (HCC). We found that the frequency of IL-21-producing CD8+CXCR5+ T cells was higher in HCC tumor tissue than in peritumoral tissue or peripheral blood from the same patients or in blood from healthy donors. Moreover, CD8+CXCR5+ T cells migrated in response to supernatants from primary HCC (HCC-SN) cells, and HCC-SN cells also powerfully induced CXCR5 expression in CD8+ T cells and IL-21 expression in CD8+CXCR5+ T cells. CD8+CXCR5+ T cells from HCC patients, but not those from healthy individuals, stimulated CD19+ B cells to differentiate into IgG-producing plasmablasts. These findings reveal that CD8+CXCR5+ T cells strongly infiltrate HCC tumors, and their infiltration is predictive of a better prognosis. Surprisingly, moreover, CD8+CXCR5+ T cells produced IL-21, which induced B cells to differentiate into IgG-producing plasmablasts and to play a key role in humoral immunity in HCC.

Preoperative elevated plasma fibrinogen level predicts tumor recurrence and poor prognosis in patients with hepatocellular carcinoma.

BACKGROUND: Elevated plasma fibrinogen has been reported to be associated with poor prognosis in several cancers. The aim of present study was to investigate the prognostic value of preoperative plasma fibrinogen in hepatocellular carcinoma (HCC) patients. METHODS: Data were collected retrospectively from 302 HCC patients who received hepatectomy. The association between fibrinogen and clinicopathological characteristics was evaluated. Both univariate and multivariate analyses were performed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS). And accordingly, the nomograms were constructed. RESULTS: Elevated plasma fibrinogen (>4 g/L) was correlated with larger tumor diameter, the presence of vascular invasion, lower MELD score, higher NLR, advanced Barcelona Clinic Liver Cancer stage and poor-moderate pathological differentiation. On multivariate analysis, the elevated plasma fibrinogen was found independently associated with poor DFS (HR =1.575, P=0.024) and OS (HR =2.051, P=0.025). And the nomograms including fibrinogen were constructed to predict DFS and OS for HCC patients. Both DFS and OS in patients with plasma fibrinogen >4 g/L were significantly lower than those with fibrinogen ≤4 g/L (1-, 3-, 5-year DFS: 34.2%, 19.5% and 0.0% vs. 60.4%, 34.2% and 30.2%; 1-, 3-, 5-year OS: 83.4%, 62.7% and 48.8% vs. 95.4%, 84.3% and 75.8%, both P<0.001). Besides, subgroup analyses also showed the prognostic values of fibrinogen in HCC patients with/without cirrhosis or high AFP levels, and in those with single tumor and BCLC 0-A stage. CONCLUSIONS: Preoperative elevated plasma fibrinogen was an independent prognostic factor associated with poor prognosis in HCC patients receiving liver resection.