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

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

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

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

Development and validation of a 14-gene signature for prognosis prediction in hepatocellular carcinoma.

Worldwide, hepatocellular carcinoma (HCC) remains a crucial medical problem. Precise and concise prognostic models are urgently needed because of the intricate gene variations among liver cancer cells. We conducted this study to identify a prognostic gene signature with biological significance. We applied two algorithms to generate differentially expressed genes (DEGs) between HCC and normal specimens in The Cancer Genome Atlas cohort (training set included) and performed enrichment analyses to expound on their biological significance. A protein-protein interactions network was established based on the STRING online tool. We then used Cytoscape to screen hub genes in crucial modules. A multigene signature was constructed by Cox regression analysis of hub genes to stratify the prognoses of HCC patients in the training set. The prognostic value of the multigene signature was externally validated in two other sets from Gene Expression Omnibus (GSE14520 and GSE76427), and its role in recurrence prediction was also investigated. A total of 2000 DEGs were obtained, including 1542 upregulated genes and 458 downregulated genes. Subsequently, we constructed a 14-gene signature on the basis of 56 hub genes, which was a good predictor of overall survival. The prognostic signature could be replicated in GSE14520 and GSE76427. Moreover, the 14-gene signature could be applied for recurrence prediction in the training set and GSE14520. In summary, the 14-gene signature extracted from hub genes was involved in some of the HCC-related signalling pathways; it not only served as a predictive signature for HCC outcome but could also be used to predict HCC recurrence.

Outcomes of hemi- versus whole liver transplantation in patients from mainland china with high model for end-stage liver disease scores: a matched analysis.

BACKGROUND: Adult hemiliver transplantation (AHLT) is an important approach given the current shortage of donor livers. However, the suitability of AHLT versus adult whole liver transplantation (AWLT) for recipients with high Model for End-Stage Liver Disease (MELD) scores remains controversial. METHODS: We divided patients undergoing AHLT and AWLT into subgroups according to their MELD scores (≥ 30: AHLT, n = 35; AWLT, n = 88; and < 30: AHLT, n = 323; AWLT, n = 323). Patients were matched by demographic data and perioperative conditions according to propensity scores. A cut-off value of 30 for MELD scores was determined by comparing the overall survival data of 735 cases of nontumor liver transplantation. RESULTS: Among patients with an MELD score ≥ 30 and < 30, AHLT was found to be associated with increased warm ischemia time, operative time, hospitalization time, and intraoperative blood loss compared with AWLT (P < 0.05). In the MELD ≥ 30 group, although the 5-year survival rate was significantly higher for AWLT than for AHLT (P = 0.037), there was no significant difference between AWLT and AHLT in the MELD < 30 group (P = 0.832); however, we did not observe a significant increase in specific complications following AHLT among patients with a high MELD score (≥ 30). Among these patients, the incidence of complications classified as Clavien-Dindo grade III or above was significantly higher in patients undergoing AHLT than in those undergoing AWLT (25.7% vs. 11.4%, P = 0.047). For the MELD < 30 group, there was no significant difference in the incidence of complications classified as Clavien-Dindo grade III or above for patients undergoing AHLT or AWLT. CONCLUSION: In patients with an MELD score < 30, AHLT can achieve rates of mortality and overall survival comparable to AWLT. In those with an MELD score ≥ 30, the prognosis and incidence of complications classified as Clavien-Dindo III or above are significantly worse for AHLT than for AWLT; therefore, we may need to be more cautious regarding the conclusion that patients with a high MELD score can safely undergo AHLT.

Splenectomy before adult liver transplantation: a retrospective study.

BACKGROUND: A considerable number of patients with portal hypertension (PHT) have to undergo splenectomy because they do not meet the requirements for liver transplantation (LT) or cannot find a suitable liver donor. However, it is not known whether pre-transplantation splenectomy may create occult difficulties for patients who require LT in future. METHODS: We analyzed 1059 consecutive patients who underwent adult liver transplantation (ADLT). Patients with pre-transplantation splenectomy Sp(+) and without splenectomy Sp(-) were compared using a propensity score analysis to create the best match between groups. RESULTS: There were no differences between patients in group Sp(+) and group Sp(-) with respect to the main post-operative infections (12.20% vs. 15.85%, P = 0.455), and the incidence of major complications (6.10% vs. 10.98%, P = 0.264). The post-operative platelet count was significantly higher in group Sp(+) (P = 0.041), while group Sp(-) had a higher rate of post-operative thrombocytopenia (91.46% vs. 74.39%, P = 0.006) and early allograft dysfunction (EAD) (23.20% vs. 10.98%, P = 0.038). The 5-year overall survival rates were similar in groups Sp(-) and Sp(+) (69.7% vs. 67.6%, P = 0.701). CONCLUSIONS: Compared with Sp(-), the risk of infection and post-operative complications in group Sp(+) was not increased, while group Sp(-) had a higher rate of post-operative EAD. Moreover, pre-transplantation splenectomy is very effective for the prevention of thrombocytopenia after LT. Pre-transplantation splenectomy is recommended in cases with risky PHT patients without appropriate source of liver for LT.

Investigation on the dynamic characteristic of occupant during the frontal collision between high-speed train and obstacle.

High-speed train may collide with many obstacles, which can cause serious occupant injury. This study aims to investigate the dynamic characteristic of occupant during the frontal collision between high-speed train and obstacle. The finite element method was used to establish the collision model between the head vehicle of the train and obstacle. The frontal collision simulation tests under three collision conditions were established. The dynamic characteristics of occupants under different collision speeds and collision angles were explored. According to the above research, the influences of collision angle and speed on occupant injuries were systematically studied, and the risk boundaries for Railway Group Standard GMRT2100: Rail Vehicle Structures and Passive Safety (GM/RT2100) and Abbreviated injury scale ≥ 3 (AIS 3 + ) injury risk ≤ 5 % were finally proposed. The results show that the occupant injuries increased with the increase of collision speed, and most of the injury values at the collision angle of 20° were the minimum. The risk boundary for AIS 3 + injury risk ≤ 5 % was higher than that for GM/RT2100. The findings in this study are helpful to understand the occupant injury mechanism during the frontal collision between high-speed train and obstacle.

Mitochondrial miR-23b-5p is a new biomarker of warm ischaemic injury in donor livers and a candidate for graft evaluation: experimental studies.

BACKGROUND AND AIMS: Warm ischaemic injury (WII) stems from incorrect energy metabolism and is the main cause of graft dysfunction. Mitochondria, as the centre of cellular metabolic activities, may be the key in identifying accurate indicators for evaluating the quality of grafts. Our research focuses on the screening, clinical application, and mechanism of the optimal WII mitochondrion biomarker. APPROACH AND RESULTS: Using a 100% hepatic warm ischaemia mouse model, without reperfusion, transmission electron microscopy demonstrated evident morphological changes of hepatic mitochondria at 15 min of ischaemia. However, all 13 mt-mRNAs could not display continuously upregulated consistency at 0-15-30-60 min during WII. High-throughput analysis of miRNA expression in both purified mitochondria and liver tissues suggested miR-23b-5p was a potential mitochondrial microRNA (mitomiR) biomarker with high sensitivity and 0-15-30-60 min change consistency. Fluorescence in-situ hybridization and reverse transcription quantitative polymerase chain reaction (RT-qPCR) further confirmed the results. Through overexpression and inhibition, the functionality of this mitomiR during WII was identified as a protective regulator in vitro and then verified in Dicer1 fl/fl Alb Cre mice by downregulation of other miRNAs and supplementation of mature mitomiR-23b-5p. Dual-luciferase reporter assay and the Seahorse XF analyzer determined that mitomiR-23b-5p reduced mitochondrial respiratory function by silencing mt-RNR2 (16S). Clinically, mitomiR-23b-5p was positively correlated with serum alanine aminotransferase levels 3 days after the operation ( P =0.032), and the C-statistic for 90-day graft survival rate was 0.698. CONCLUSIONS: MitomiR-23b-5p plays a protective regulatory role and implements a special mitochondrial regulation mechanism not yet reported in WII. These clinical results further support the experimental result that the expression of MitomiR-23b-5p is closely related to the prognosis of clinical liver transplantation patients. This is a promising new biomarker for WII evaluation of donor livers.

Use of Hybrid Mineral Filler with High Emissivity in Asphalt Mixture for Cooling Road Pavements.

Road asphalt pavements cover a high percentage of urban size and contribute to heat islands. This study proposed a new method to cool asphalt pavement by incorporating a kind of hybrid mineral filler (HMF) with high emissivity into a reference asphalt mixture prepared with limestone mineral filler (LMF). The physical, emissive, solar reflective, and rheological properties of asphalt mastic and the thermal performances of asphalt mixture were covered to investigate the possibility of the proposed strategy. From Fourier transform infrared spectrum test, it can be found that HMF was physically blended with asphalt. The emissivity results show that HMF increased the emissivity of asphalt mastic from 0.9204 to 0.9820. The asphalt mastic containing HMF had similar solar reflectance with the control one. In addition, HMF could enhance the rutting resistance of asphalt mastic according to the results of multiple stress creep recovery tests. When HMF replaced LMF, the thermal conductivity of the asphalt mixture with HMF increased by 0.26 W/(m·K) (the reference value was 1.72 W/(m·K)). The combined effect of high emissivity and thermal conductivity led to a lower surface temperature (i.e., -5.4 °C) in the tests. The results of this study demonstrate that HMF is a potential material to cool asphalt pavements.

Outcome of TACE treatment in HIV infected patients with hepatocellular carcinoma.

The surgical treatment and transcatheter arterial chemoembolization (TACE) rate of human immunodeficiency virus (HIV)-infected hepatocellular carcinoma (HCC) patients is relatively low in West China. For various reasons, most patients do not receive timely surgical treatment. Upon transfer to an infectious disease centralized hospital, they were already classified in the Barcelona Clinic Liver Cancer (BCLC)-B stage. A total of 2249 BCLC-B HCC patients were analyzed. The eligible population was divided into three groups for analysis of survival and prognostic factors; These were 21 HIV infected (HIV+) HCC patients treated with TACE (TACE+), 1293 non-HIV-infected (HIV-) HCC patients treated with TACE, and 150 HIV- HCC patients who only receive medication (TACE-) as a second control group. After 1:2 matching, 1- and 2-year survival of HIV+ TACE+ and HIV- TACE+ groups was 64.3% and 76.5% (P = 0.453) and 45.5% vs. 50.0% (P = 0.790) respectively. We also compared one and two-year survival between HIV+ TACE+ and HIV- TACE-. One-year overall survival was 64.3% vs. 45.7% (P = 0.097) and 2-year survival was 45.5% vs. 7.1% (P = 0.004). Multivariate analysis showed that the most important prognostic factors for survival were serum alpha-fetoprotein (AFP) and Child-Pugh score and tumor size, while HIV status had no significant effect on prognosis statistically. CD4 levels below 200 may increase the risk of opportunistic infection after surgery, but after anti-infection and systematic supportive therapy, it has no effect on survival. HIV+ patients should have the same treatment opportunities as HIV- patients. If the patient's immune status permits, we suggest that early TACE treatment should be administered to BCLC-B HCC patients, regardless of HIV infection.

Use of donor-specific red blood cell transfusions for patients undergoing liver transplantation during the COVID-19 pandemic.

BACKGROUND: Increased risks have been found for patients undergoing liver transplantation due to the blood supply shortage following the ongoing coronavirus disease 2019 (COVID-19) pandemic. Hence, exploring a method to alleviate this dilemma is urgent. This phase I, nonrandomized, prospective trial aimed to evaluate the safety and feasibility of using donor-specific red blood cell transfusion (DRBCT) as an urgent measurement to alleviate the blood supply shortage in deceased donor liver transplantation (DDLT). METHODS: The outcomes of 26 patients who received DRBCT and 37 patients in the control group who only received 3rd party packed red blood cells (pRBCs) transfusion between May 2020 and January 2021 were compared. RESULTS: Patients receiving DRBCT did not develop transfusion-related complications, and the incidence of postoperative infection was similar to that in the control group (23.1% vs. 18.9%, P=0.688). Because the patients received the red blood cells from organ donors, the median volume of intraoperative allogeneic red blood cell transfusion from blood bank was 4.0 U (IQR 1.1-8.0 U) in the DRBCT group, which is significantly lower than that (7.5 U, IQR 4.0-10.0 U) in the control group (P=0.018). The peak aspartate aminotransferase (AST) level was significantly lower in the DRBCT group than in the control group (P=0.008) and so were the AST levels in the first two days after the operation (P=0.006 and P=0.033). CONCLUSIONS: DRBCT is a safe and effective procedure to lower the need for blood supply and is associated with a reduction in AST levels after transplantation. DRBCT is beneficial to patients receiving life-saving transplantation without sufficient blood supply during the COVID-19 pandemic.

MicroRNA­29c­3p acts as a tumor suppressor gene and inhibits tumor progression in hepatocellular carcinoma by targeting TRIM31.

Aberrant expression of microRNAs (miRNAs) has been widely reported in many malignant tumors, and dysregulated miRNAs play an important role in the malignant progression of tumors. It has been reported that miR­29c­3p expression is dysregulated in tumors and promotes the development of tumors, especially in hepatocellular carcinoma (HCC). However, the specific mechanism of miR­29c­3p in HCC is not clear. The present study demonstrated that miR­29c­3p was expressed at low levels in HCC patients and cell lines and that its decreased expression was closely related to poor prognosis of HCC patients. Overexpression of miR­29c­3p could significantly inhibit the proliferation and migration of HCC cells in vitro and suppress the HCC tumor growth in vivo. The luciferase reporter assay demonstrated that miR­29c­3p directly bound to tripartite motif containing 31 (TRIM31) and suppressed TRIM31 expression. Finally, upregulation of TRIM31 could partially abolish the tumor suppressing roles of miR­29c­3p in HCC. Overall, miR­29c­3p, as a tumor suppressor gene, was revealed to inhibit the malignant progression of HCC by reducing the expression of TRIM31 and may be used as a potential therapeutic target for the precise treatment of HCC.

A simple four-factor preoperative recipient scoring model for prediction of 90-day mortality after adult liver Transplantation:A retrospective cohort study.

BACKGROUND: Although numerous scoring models are available to predict the prognosis of patients undergoing liver transplantation (LT), the field lacks a simple model for quick prediction of the short-term survival of patients after LT in the event that the donor's information is not available in advance. METHODS: A total of 1495 adult patients underwent LT in the present study. Three-quarters of recipients were randomly selected into the test set (n = 1121), while the remaining 25% formed the validation set (n = 374). Univariate and multivariate analysis and machine-learning techniques were applied to evaluate possible influencing factors. To further simplify the model, a weighted-scoring system was designed considering each influencing factor and its importance in an artificial neural network (ANN). RESULTS: In the test set, multivariate analysis identified creatinine, age, and total bilirubin as independent risk factors, while albumin was an independent protective factor. Logistic regression analysis showed the C-statistic to be 0.650, while ANN indicated this to be 0.698. We simplified the model to obtain the final scoring model, for which the C-statistic was 0.636, and defined four risk grades. The 90-day mortality rates corresponding to the four risk levels were 6.2%, 11.8%, 24.0%, and 34.9%, respectively. In the validation set, the C-statistic value of the original model was 0.668 and that of the simplified model was 0.647. CONCLUSION: We developed a simple scoring system for the preliminary prediction of the postoperative 90-day mortality of adult LT based on preoperative characteristics of LT recipients.

Adult split liver transplantation: A PRISMA-compliant Chinese single-center retrospective case-control study.

ABSTRACT: Although pediatric split liver transplantation (SLT) has been proven safe and the waitlist mortality rate has been successfully reduced, the safety of adult SLT has not been confirmed.Using 1:2 matching, 47 recipients who underwent adult SLT were matched to 94 of 743 recipients who underwent adult whole graft liver transplantation (WGLT). Eventually, 141 recipients were included in the case-control study. Subgroup analysis of 43 recipients in the SLT group was performed based on the presence of the middle hepatic vein (MHV) in the grafts.No significant differences in 5-year survival (80.8% vs 81.6%, P = .465) were observed between the adult SLT and WGLT groups. However, compared to recipients in the WGLT group, those in the SLT group had more Clavien-Dindo grade III-V complications, longer hospitalization duration, and higher mortality within 45 days. Furthermore, on multivariate analysis, 45-day postoperative mortality in recipients in the SLT group was mainly affected by hyperbilirubinemia within postoperative day (POD) 7-14, surgery time, and intraoperative blood loss. Subgroup analysis showed no significant differences in hyperbilirubinemia within POD 7-14, complications, and survival rate between SLTMHV(+) and SLTMHV [-].Adult SLT is safe and effective based on long-term survival rates; however, a reduction in the incidence of short-term complications is required. Non-obstructive hyperbilirubinemia within POD 7 to 14 is an independent predictor of short-term mortality after SLT.

The postoperative hepatic artery resistance index after living donor liver transplantation can predict early allograft dysfunction.

To investigate whether postoperative hepatic hemodynamics have an impact on graft function.Using a retrospective cohort with 262 adult living donor liver transplantation (LDLT) recipients, we discussed the relationship between postoperative hepatic hemodynamics and patient outcomes.According to the definition of early allograft dysfunction (EAD), the patients were classified into the EAD group (43 patients) and the non-EAD group (219 patients). In terms of postoperative hemodynamic parameters, there was no significant differences between these 2 groups regarding hepatic artery flow (HAF), hepatic artery velocity (HAV), portal vein flow (PVF), and portal vein velocity (PVV), except for the hepatic artery resistance index (HARI) which was somewhat higher in the EAD group on postoperative day 3 (POD3) (0.70 vs 0.61, P < .05). According to these results, we used a ROC curve and found that a HARI of 0.68 was the cutoff point (with 73.8% sensitivity and 58.3% specificity) for predicting EAD after LDLT. In addition, multivariate analysis showed that fulminant hepatic failure, pretransplant hepatorenal syndrome, and HARI ≥ 0.68 on POD3 were independent risk factors for postoperative EAD.Our results showed that postoperative hemodynamics might influence graft function by altering hepatic artery flow.

Liver fibrosis is a major risk factor for liver regeneration: A comparison between healthy and fibrotic liver.

BACKGROUND: Blood flow factors, such as congestion or ischemia after hepatectomy, have a significant impact on liver regeneration, but with the popularization of precise hepatectomy technology, segmental hepatectomy without congestion or ischemia has become the preferred treatment. Our aim is to investigate the factors affecting liver regeneration after hepatectomy without blood flow changes, and to provide clinical evidence for surgeons on the timing of second hepatectomy for cirrhosis patients with hepatocellular carcinoma (HCC). METHODS: This study retrospectively analyzed data from patients who underwent right hepatectomy without middle hepatic vein (MHV) in West China Hospital between January 2016 and January 2018. Eighteen living-donors without MHV as normal group and 45 HCC patients, further classified into 3 subgroups based on the severity of fibrosis using the Scheure system. Demographic data, pre- and postoperative liver function indexes, and remnant liver volume (RLV) were retrospectively compared. We also analyzed the remnant liver regeneration rate (RLRR) post-operatively in each group. The significant indexes in univariate analysis were further analyzed using both receiver operating characteristic (ROC) analysis and multivariate regression analysis. RESULTS: Liver regeneration occurred in both living-donor and HCC groups after hepatectomy; the RLRRs at 1 month were 59.46 ±â€Š10.39% and 57.27 ±â€Š4.77% (P = .509), respectively. Regeneration in the cirrhosis group occurred more slowly and less completely compared with that in other groups. The regeneration rate in the first 6 months showed rapid increase and the RLRR reached above 70% in cirrhosis group. Multivariate and ROC analyses revealed that Alb and the hepatic fibrosis grade in the early postoperative period were significant predictors of remnant liver regeneration. CONCLUSION: The liver regenerated in all HCC patients; however, regeneration was significantly slower and less complete compared with the normal liver, especially in the patients with cirrhosis. Therefore, it can be concluded that the degree of liver fibrosis is a major predictor of liver regeneration. Furthermore, the optimal time for second resection in recurrent HCC patients with cirrhosis was 6 months after the first operation.

Dicer1 facilitates liver regeneration in a manner dependent on the inhibitory effect of miR-21 on Pten and Rhob expression.

AIMS: Tamoxifen-induced liver-specific Dicer1 deletion (iDicer1-/-) in mature mice may provide clues demonstrating the genuine effects of acute loss of Dicer1 and miRNAs in the liver regeneration process. MAIN METHODS: In this study, mice with tamoxifen-induced Dicer1 deletion through the Cre/LoxP system were constructed and then underwent classic 70% partial hepatectomy or CCl4-induced liver injury. To rescue the inhibitory effect of Dicer1 ablation on liver regeneration, miR-21 agomir was injected into the tail vein of iDicer1-/- mice. KEY FINDINGS: Unlike constitutive embryonic deletion of Dicer1, tamoxifen-induced Dicer1 deletion did not result in severe liver injury or lesions, providing an ideal model for investigating acute loss of Dicer1 and miRNAs in liver regeneration. Dicer1 deletion led to impaired liver regeneration through the inhibitory effect of miR-21 on PTEN and Rhob expression. SIGNIFICANCE: In our previous study, we found that embryonic loss of Dicer1 impairs hepatocyte survival and leads to chronic inflammation and progenitor cell activation, while the role of Dicer1 in liver regeneration remains largely unknown. We clearly identified the promotion effect of Dicer1 on liver regeneration by increasing miR-21 expression, which inhibits the expression of two negative cell proliferation regulators, Pten and Rhob.

Diagnostic accuracy of midkine on hepatocellular carcinoma: A meta-analysis.

OBJECTIVE: To evaluate the dependability and accuracy of midkine (MK) in the diagnosis of hepatocellular carcinoma (HCC). METHODS: PubMed, EMBASE, Web of Science, China Biology Medicine disc and grey literature sources were searched from the date of database inception to January 2019. Two authors (B-H.Z. and B.L.) independently extracted the data and evaluated the study quality using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were estimated using a bivariate model. Moreover, hierarchical summary receiver operating characteristic curves were generated. The diagnostic odds ratio (DOR) and area under the curve (AUC) were pooled using a univariate model. RESULTS: Nine articles (11 studies) were included (1941 participants). The bivariate analysis revealed that the sensitivity and specificity of MK for HCC diagnosis were 0.85 (95% CI 0.78-0.91) and 0.83 (95% CI 0.76-0.88), respectively. We also found a LR+ of 5.05 (95% CI 3.33-7.40), a LR- of 0.18 (95% CI 0.11-0.28), a DOR of 31.74 (95% CI 13.98-72.09) and an AUC of 0.91 (95% CI 0.84-0.99). Subgroup analyses showed that MK provided the best efficiency for HCC diagnosis when the cutoff value was greater than 0.5 ng/mL. CONCLUSIONS: MK has an excellent diagnostic value for hepatocellular carcinoma.

Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice.

BACKGROUND: Hepatocellular carcinoma (HCC) is associated with inflammation, and roughly 30 % of the global population shows serological evidence of current or past infection with hepatitis B or hepatitis C virus. Resident hepatic macrophages, known as Kupffer cells (KCs), are considered as the specific tumor-associated macrophages (TAMs) of HCC, and can produce various cytokines-most importantly interleukin (IL)-6-to promote tumorigenesis of HCC. However, the roles of KCs and IL-6 in carcinogenesis in the liver are still unclear. METHODS: We analyzed leukocyte-related peripheral blood data of 192 patients and constructed a mouse model in which the bone marrow was cleared out by irradiation and reconstructed using bone marrow donated from IL-6-deficient mice to further elucidate the hepatic pathological changes in response to toxic challenge and oncogenic gene mutation. RESULTS: Peripheral monocyte counts and serum IL-6 levels were significantly higher in patients with HCC than in those without HCC. In addition, there was a significant difference in the levels of IL-6 among individuals with different histopathological grades. In mice with selective IL-6 ablation in monocytes/KCs, we observed decreased toxic liver injury, inflammatory infiltration, and systemic inflammation. In Mdr2-deficient mice, which spontaneously developed HCC, the loss of IL-6 in monocytes/KCs resulted in inhibition of IL-6/signal transducer and activator of transcription 3 signaling, decreased serum IL-6 levels, and delayed tumorigenesis. CONCLUSIONS: Our findings demonstrate that increased TAM-derived IL-6 had an amplifying effect on the inflammation response, thereby promoting the occurrence and development of HCC.