Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis.

BACKGROUND AND AIMS: The "gut homing" hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here, we examine "the gut homing theory" in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases. APPROACH AND RESULTS: Expression of MAdCAM-1, CCL25, and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from patients with CLD undergoing OLT and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T cells was assessed using flow cytometry. Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was up-regulated in all CLDs compared with normal liver. There were no differences between disease groups. Frequencies of α4ß7, αEß7, CCR9, and GPR15 expressing hepatic T cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. ß7 expressing hepatic T cells displayed an increased inflammatory phenotype compared with ß7 negative cells, although this inflammatory cytokine profile was present in both the inflamed and normal liver. CONCLUSIONS: These findings refute the widely accepted "gut homing" hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T cells is not unique to PSC, but is a panetiological feature of CLD.

Matrix Metalloproteinase-7 and Osteopontin Serum Levels as Biomarkers for Biliary Atresia.

OBJECTIVES: Matrix metallopeptidase-7 (MMP-7) and osteopontin (OPN) are important components in the pathophysiology of fibrosis in biliary atresia (BA). There has been much recent interest in MMP-7 serum level in the diagnosis of BA. We aimed to assess the diagnostic accuracy and prognostic value of both MMP-7 and OPN in a Western BA study. METHODS: Diagnostic value was assessed by comparison of serum MMP-7 and OPN levels in infants with BA and age-matched cholestatic controls. Prognostic value was assessed through subsequent clearance of jaundice (COJ) and need for liver transplantation (LT). RESULTS: Serum was assessed from 32 BA and 27 controls. Median MMP-7 was higher in BA (96.4 vs 35 ng/mL; P < 0.0001) with an optimal cut-off value of 69 ng/mL. Sensitivity and specificity was 68% and 93%, respectively [negative predictive value (NPV) = 71%]. Similarly, median OPN was higher in BA (1952 vs 1457 ng/mL; P = 0.0001) and an optimal cut-off of 1611 ng/mL. Sensitivity and specificity was 84% and 78%, respectively (NPV = 81%). MMP-7 level correlated positively with Ishak liver fibrosis score (r = 0.27, P = 0.04). Neither MMP-7 (70 vs 100 ng/mL; P = 0.2) nor OPN (1969 vs 1939 ng/mL; P = 0.3) were predictive of COJ, or need for LT (99 vs 79 ng/mL; P = 0.7, and 1981 vs 1899 ng/mL; P = 0.2), respectively. CONCLUSIONS: MMP-7 and OPN may have contributory value in the diagnosis of BA, but remain far of the "gold standard" role. Much more prospective data are required and collaborative multi-center initiatives should be the next logical steps.

Transarterial chemoembolization prior to liver transplantation for patients with hepatocellular carcinoma: A meta-analysis.

BACKGROUND AND AIM: A debate exists over whether using preoperative transarterial chemoembolization for patients with hepatocellular carcinoma before liver transplantation. Numerous studies have been investigating on this, but there is still no unanimous conclusion about the effect of preoperative transarterial chemoembolization. We conducted the meta-analysis of all available studies to systematically evaluate the influence of preoperative transarterial chemoembolization on liver transplant. METHODS: A systematic search was performed by two authors (Si TF. and Guan RY.) through PubMed, Embase, Cochrane, and Science Citation Index Expanded, combined with Manual Retrieval and Cited Reference Search. The searching cut-off date was 2016/07/31, and all the data obtained were statistically analyzed using Review Manager version 5.1 software (Copenhagen, The Nordic Cochrane Center, The Cochrane Collaboration, 2011) recommended by Cochrane Collaboration. RESULTS: The study showed that there was no difference between the experimental group and the control group on perioperative mortality (RR = 1.10, 95% confidence interval (CI) = [0.49-2.48], P = 0.82) or biliary complications (RR = 0.96, 95%CI = [0.66-1.39], P = 0.83). Preoperative transarterial chemoembolization had no obvious effect on improving overall survival (HR = 1.05, 95%CI = [0.65-1.72], P = 0. 83) but would result in a higher rate of vascular complications (RR = 2.01, 95%CI = [1.23-3.27], P = 0.005) and a reduction of disease free survival (HR = 1.66, 95%CI = [1.02-2.70], P = 0.04). Subgroup analysis also revealed that patients from transarterial chemoembolization group in Asia had a much lower overall survival rate (HR = 2.65, 95%CI = [1.49-4.71], P = 0.0009) compared with the control group. CONCLUSIONS: Considering the possible adverse impacts on liver transplantation and the variation in sensitivity to transarterial chemoembolization, clinicians should be more cautious when considering transarterial chemoembolization as the bridging therapy for patients in the waiting list.

Preoperative transarterial chemoembolization for resectable hepatocellular carcinoma in Asia area: a meta-analysis of random controlled trials.

OBJECTIVE: We aimed to systematically evaluate the influence of preoperative transarterial chemoembolization (TACE) for resectable hepatocellular carcinoma (HCC) on long-term prognosis and perioperative safety. MATERIALS AND METHODS: Databases including PubMed, Embase, Cochrane, Wanfang, CNKI, VIP data were searched, combined with Manual Retrieval and Cited Reference Search to collect the published randomized controlled trial (RCT) about the influence of pre-TACE for curative resection of HCC. The searching cutoff date was 2016/02/25, all the data obtained were statistically analyzed using RevMan5.2 software recommended by Cochrane Collaboration. RESULTS: A total of 5 RCT including 430 (pre-TACE group: 212, surgery alone group: 218) patients were included. The results of meta-analysis showed that: there was no difference between the 2 groups on overall survival (OS) rate [HR 1.25, 95%CI (0.92-1.68)], disease free survival (DFS) rate [HR 0.95 (0.76-1.19)], perioperative mortality rate [OR 0.70 (0.22-2.30)], or blood loss [SMD 0.07 (-0.14-0.29)], whereas the subgroup analysis revealed that pre-TACE would result in longer operation time [SMD 0.31 (0.06-0.57)], higher postoperative morbidity rate [OR 1.90 (1.02-3.53)] and combined resection rate of perihepatic organs [OR 5.46 (2.73-11.78)] in subgroup with mean tumor diameter >5cm. CONCLUSIONS: According to our study, pre-TACE treatment cannot improve the long-term prognosis of resectable HCC. With the growth of the tumor diameter, especially when it is over 5cm, it might add difficulties to surgery and affect the perioperative safety.

Systematic review with meta-analysis: outcomes of pregnancy in patients with autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is common in females of childbearing age. Although some studies have provided information about the outcomes of pregnancy, there remains uncertainty regarding conclusions. AIM: To comprehensively explore the interactions between pregnancy and AIH. METHODS: Databases including PubMed, Embase, Cochrane Library and Science Citation Index Expanded were searched to collect available studies in relation to pregnancy in AIH patients (from inception to 28 August 2021). Pooled data were calculated using a random effects model with standardised mean difference (SMD), or risk ratio (RR), and 95% confidence intervals (CI). RESULTS: Twelve studies were considered eligible for meta-analysis. Data from 26 case reports/series were extracted for systematic review. AST level in AIH patients was significantly lower during pregnancy (SMD = -0.41, 95% CI = [-0.70, -0.12]; SMD = -1.60, 95% CI = [-2.76, -0.44]) and loss of biochemical remission occurred more frequently in post-partum (RR = 0.31, 95% CI = [0.19, 0.52]). Patients with portal hypertension or without established remission before conception presented as high-risk subgroups and the incidence of pre-term delivery was higher in these groups compared to other AIH patients (RR = 9, 95% CI = [1.22, 51.1]; RR = 0.05, 95% CI = [0.004, 0.38]). In population-based comparison, pre-term birth (RR = 2.45, 95% CI = [1.66, 3.62]) also occurred more often in AIH patients compared with the general population. CONCLUSIONS: Successful pregnancy is a reasonable expectation in AIH. However, hepatic biochemistry should be monitored closely in both the puerperium and the post-partum period. Though some patients may present higher risk, with carefully selected therapeutic manipulation and multi-disciplinary care, the majority of mothers and infants should achieve uneventful outcomes.

Hepatic arterial infusion chemotherapy versus transarterial chemoembolization for unresectable hepatocellular carcinoma: A systematic review with meta-analysis.

Background: Interest has revived in the use of hepatic arterial infusion chemotherapy (HAIC) for intermediate-advanced hepatocellular carcinoma (HCC) while transarterial chemoembolization (TACE) has been a longstanding loco-regional therapy. Aim: We conducted a systematic review and meta-analysis of patients with unresectable HCC treated with HAIC or TACE to look for differences in survival, adverse events, mortality and downstaging. Methods: All studies published before 29 July 2022 were identified by searching PubMed, Embase, Web of Science and Cochrane Library databases for patients with unresectable HCC and received HAIC or TACE as initial treatment. Data extracted from studies was statistically analysed using RevMan5.3 software. Results: A total of one randomized controlled trial (RCT) and 7 cohort studies (5 retrospective, 2 prospective) including 1,060 (TACE group: 534, HAIC group: 526) patients were screened. Compared with the TACE group, patients who received HAIC as initial therapy had better overall survival (OS) (HR = 0.53, 95%CI [0.40, 0.69]) and progression-free survival (PFS) (HR = 0.54, 95%CI [0.40, 0.72]). Further subgroup analysis revealed that HAIC showed priority over TACE on prognosis outcome regardless of tumour stage, especially in patients with advanced portal vein tumour thrombus (PVTT). Utilization of port system will not boost the efficacy of HAIC whereas using a replaced-microcatheter for each procedure could better reduce the progressive disease (PD) rate (RR = 0.55, 95%CI [0.40, 0.76]). The pooled RR favoured the HAIC group with regard to partial response (PR) (RR = 2.87, 95%CI [2.18, 3.78]) and this was validated by both GRADE summary and trial sequential analysis. The rate of resection after treatment was higher in the HAIC group (RR = 2.37, 95%CI [1.54, 3.66]), whilst no difference was found with procedure-related mortality (RR = 0.56, 95%CI [0.13, 2.38]) between two groups. Compared with the traditional chemotherapy regimen (fluorouracil/leucovorin/oxaliplatin) FOLFOX-HAIC appears to be better in improving the treatment efficacy. Conclusion: Patients with unresectable HCC could potentially benefit more from HAIC rather than standard TACE treatment. A re-evaluation of HAIC as a treatment option in intermediate and advanced HCC is warranted.

Expression Levels of Three Key Genes CCNB1, CDC20, and CENPF in HCC Are Associated With Antitumor Immunity.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a low 5-year survival rate. The heterogeneity of HCC makes monotherapy unlikely. The development of diagnostic programs and new treatments targeting common genetic events in the carcinogenic process are providing further insights into the management of HCC. The aim of this study was firstly to validate key genes that are involved in promoting HCC development and as biomarkers for early diagnosis and, secondly, to define their links with antitumor immunity including inhibitory checkpoints. METHODS: Multiple databases including Gene Expression Omnibus (GEO), Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, UALCAN, and Oncomine were used for target gene screening and establishment of a co-expression network. Clinical data and RNAseq of 367 HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database. The diagnostic and prognostic value of screened genes were tested by receiver operating characteristic (ROC) curve and correlation analysis. The links with the key genes in HCC and antitumor immunity were defined using both blood and liver tissue collected prospectively from HCC patients in our center. RESULTS: Upregulation of CCNB1, CDC20, and CENPF was commonly observed in HCC and are involved in the p53 signal pathway. The hepatic mRNA expression levels of these three genes were strongly associated with patients' prognosis and expressed high value of area under the ROC curve (AUC). Further analysis revealed that these three genes were positively correlated with the gene expression levels of IFN-γ, TNF-α, and IL-17 in peripheral blood. In addition, the expression of CENPF showed positive correlation with the percentage of CD8pos T cells and negative correlation with the percentage of CD4pos T cells in the peripheral blood. In the HCC microenvironment, the transcript levels of these three genes and inhibitory checkpoint molecules including PD-1, CTLA-4, and TIM-3 were positively correlated. CONCLUSION: The upregulation of CCNB1, CDC20, and CENPF genes was a common event in hepatocarcinogenesis. Expression levels of CCNB1, CDC20, and CENPF showed potential for early diagnosis and prediction of prognosis in HCC patients. There is a close association between three genes and Th1/Th17 cytokines as well as the count of CD4pos and CD8pos T cells. The positive correlation between the three genes and inhibitory checkpoint genes, PD-1, CTLA-4, and TIM-3, indicates that these genes are linked with weakened antitumor immunity in HCC. Our findings may provide further insights into developing novel therapies for HCC.

Concomitant systemic lupus erythematosus might have a negative impact on the biochemical responses to treatment in patients with primary biliary cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is often overlapping with other autoimmune conditions, including systemic lupus erythematosus (SLE). Since the concomitant PBC and SLE are rare, the impacts of SLE on the response and prognosis in ursodeoxycholic acid (UDCA)-treated patients with PBC remain unclear. METHODS: A PBC database of 769 patients at West China hospital was used to identify 26 patients with concomitant PBC and SLE. The clinical and biochemical characteristics of these patients were collected and analyzed. Propensity score matching was used to compensate for the differences in age, total bilirubin, and alkaline phosphatase. The biochemical responses and prognoses were compared between the patients with and without concomitant SLE. RESULTS: The female-to-male ratio was 25:1 in the PBC patients with concomitant SLE. Compared with the group with PBC alone, the median hemoglobin and albumin values in the PBC-SLE group at the time of diagnosis of PBC were lower (both P < 0.05). After treatment, the group with PBC alone showed lower alanine aminotransferase and glutamyltransferase values and aspartate aminotransferase/platelet ratio indices at the final visit (all P < 0.05). The Kaplan-Meier estimate showed that the adverse event-free survival did not differ between the patients with and without concomitant SLE (P = 0.564). CONCLUSION: The results of this retrospective, single-center study suggested that the concomitant SLE status might have a negative impact on the biochemical responses to the treatment, while the effect of concomitant SLE on PBC progression remains to be further defined.Key Points• The prevalence of SLE in the PBC population being in a large PBC cohort was as low as 3.4%.• Compared with PBC-SLE group, the group with PBC alone showed lower alanine aminotransferase and glutamyltransferase values and aspartate aminotransferase/platelet ratio indices at the final visit, indicating that the concomitant SLE may have a negative impact on the biochemical responses to the treatment of PBC.