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Abstract Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with currently suboptimal diagnostic and prognostic approaches. We present a novel system to monitor CCA using exosomal circular RNA (circRNA) via serum and biliary liquid biopsies. A pilot cohort consisting of patients with CCA-induced biliary obstruction (CCA-BO, n = 5) and benign biliary obstruction (BBO, n = 5) was used to identify CCA-derived exosomal circRNAs through microarray analysis. This was followed by a discovery cohort (n = 20) to further reveal a CCA-specific circRNA complex (hsa-circ-0000367, hsa-circ-0021647, and hsa-circ-0000288) in both bile and serum exosomes. In vitro and in vivo studies revealed the three circRNAs as promoters of CCA invasiveness. Diagnostic and prognostic models were established and verified by two independent cohorts (training cohort, n = 184; validation cohort, n = 105). An interpreter-free diagnostic model disclosed the diagnostic power of biliary exosomal circRNA signature (Bile-DS, AUROC = 0.947, RR = 6.05) and serum exosomal circRNA signature (Serum-DS, AUROC = 0.861, RR = 4.04) compared with conventional CA19-9 (AUROC = 0.759, RR = 2.08). A prognostic model of CCA undergoing curative-intent surgery was established by calculating early recurrence score, verified with bile samples (Bile-ERS, C-index=0.783) and serum samples (Serum-ERS, C-index = 0.782). These models, combined with other prognostic factors revealed by COX-PH model, enabled the establishment of nomograms for recurrence monitoring of CCA. Our study demonstrates that the exosomal triple-circRNA panel identified in both bile and serum samples serves as a novel diagnostic and prognostic tool for the clinical management of CCA.

Abstract Background Malignant tumors of the biliary system are characterized by a high degree of malignancy and strong invasiveness, and they are usually diagnosed at late stages with poor prognosis. For patients with advanced biliary tract cancer, chemotherapy and targeted therapy are two of the options available to improve prognosis and delay tumor progression. This study aimed to comprehensively evaluate the safety and effectiveness of various chemotherapy schemes for the treatment of advanced biliary tract cancer in published systematic reviews and meta-analyses (SRoMAs). Methods An umbrella review method was adopted, which aims to summarize the existing evidence from multiple studies around a research topic. SRoMAs up to April 9, 2022, were identified using PubMed, Web of Science, the Cochrane database, and manual screening. Eligible studies were screened according to inclusion and exclusion criteria. This study had been registered at PROSPERO (CRD42022324548). For each eligible study, we extracted the data of general characteristics and the main findings. The methodological quality of the included studies were assessed by the AMSTAR2 scale, and the quality of evidence was evaluated by the GRADE tools. Results A total of 1833 articles were searched; 14 unique articles with 94 outcomes were identified by eligibility criteria. The incidence of skin rash (RR = 18.11, 95% CI 5.13–63.91, GRADE: Moderate) and diarrhea (RR = 2.48, 95% CI 1.2–5.10, GRADE: Moderate) was higher in patients receiving gemcitabine-based chemotherapy plus targeted therapy than in patients receiving gemcitabine monotherapy. The number of patients receiving gemcitabine-based chemotherapy who developed leukopenia (OR = 7.17, 95% CI 1.43–36.08, GRADE: Moderate), anemia (OR = 7.04, 95% CI 2.59–19.12, GRADE: High), thrombocytopenia (RR = 2.45, 95% CI 1.39–4.32, GRADE: Moderate), and neutropenia (RR = 3.30, 95% CI 1.04–10.50, GRADE: Moderate) was significantly higher than that of patients who received gemcitabine-free regimens. In addition, patients receiving S-1 monotherapy had significantly better ORR (RR = 2.46, 95% CI 1.27–4.57, GRADE: Moderate) than patients receiving S-1 + gemcitabine. Patients receiving fluoropyrimidine-based chemotherapy had longer OS (HR = 0.83, 95% CI 0.7–0.99, GRADE: Moderate), higher DCR (0R = 5.18, 95% CI 3.3–10.23, GRADE: Moderate), and higher ORR (0R = 3.24, 95% CI 1.18–8.92, GRADE: Moderate) compared with patients who received 5-FU/LV monotherapy or supportive therapy. Surprisingly, we found evidence that gemcitabine-based chemotherapy did not improve postoperative patients’ OS (HR = 0.91, 95% CI 0.74–1.12, GRADE: Moderate) when compared with best supportive care. Conclusions This study comprehensively evaluated the safety and efficacy of chemotherapy or targeted therapy regimens for advanced biliary tract cancer and found 11 outcomes with “Moderate” or “High” levels; however, most of the outcomes were still at “low” or “very low” levels. More randomized controlled studies are needed in the future to further summarize high levels of evidence.

Abstract Background Diet and nutrition, as a modifiable risk factor, have been demonstrated to play a significant role in the etiology of biliary diseases, whereas few comprehensive studies have been able to evaluate the strength and quality of these evidence. This umbrella review aims to evaluate the evidence pertaining risk factors for biliary diseases in terms of diet and nutrition-related indicators. Methods An umbrella review method was adopted: evidence from observational studies up to 22 November 2021 were identified using PubMed, Web of Science, the Cochrane database, as well as manual screening. Eligible systematic reviews and meta-analyses were screened according to inclusion and exclusion criteria. The inclusion criteria were: (1) meta analysis or systematic review; (2) The theme of the study is the relationship between diet or nutrition and biliary tract diseases; (3) Summarized and reported OR, RR or HR values and corresponding 95% CI; (4) No restrictions on the use of participants and languages; (5) Only extract the data of biliary tract diseases from multiple health outcomes; (6) Only the most recent studies on the same subject were included. This study had been registered at PROSPERO (CRD42021293908). For each eligible systematic review and meta-analysis, we extracted the data of general characteristics and the main findings. The methodological quality of the meta-analyses included in our study were assessed by AMSTAR2 and the quality of evidence was evaluated by the GRADE. Results A total of 323 articles were searched, among which 24 articles with 83 unique outcomes were identified as eligible. 35 of these outcomes were downgraded in GRADE evaluation as they reported heterogeneity. In short, among 83 unique outcomes, 5 were rated as moderate, 16 as low, and the rest as very low. For the prevention of biliary tract diseases, emphasis should be placed on appropriately increasing the intake of fruits, vegetables, coffee and tea, and reducing the intake of alcohol, raw fish and foods with high nitrate. Meanwhile, weight, blood sugar and lipid levels should be controlled, and diabetes should be actively prevented and treated. Drinking is not recommended to prevent gallstones, although studies have shown that it may reduce the risk of cholecystolithiasis. Conclusions Our study summarizes the current multifaceted evidence on the relationship between dietary and nutritional indicators and biliary diseases, but the quality of all evidence was not high. Evidence from additional high-quality prospective studies are needed in the future.

BackgroundCuproptosis is a newly identified type of programmed cell death, characterized by aggregation of mitochondrial lipoylated proteins and the destabilization of Fe–S cluster proteins triggered by copper. However, its role in hepatocellular carcinoma (HCC) remains unclear.MethodsWe analyzed the expression and prognostic significance of cuproptosis-related genes using the data obtained from TCGA and ICGC datasets. A cuproptosis-related genes (CRG) score was constructed and validated via least absolute shrinkage and selection operator (LASSO) Cox regression, multivariate Cox regression and nomogram model. The metabolic features, immune profile and therapy guidance of CRG-classified HCC patients were processed via R packages. The role of kidney-type glutaminase (GLS) in cuproptosis and sorafenib treatment has been confirmed via GLS knockdown.ResultsThe CRG score and its nomogram model performed well in predicting prognosis of HCC patients based on the TCGA cohort (training set), ICGC cohort and GEO cohort (validation set). The risk score was proved as an independent predictor for overall survival (OS) of HCC. The area under the curves (AUCs) of the model in the training and validation cohorts were all around 0.83 (TCGA, 1- year), 0.73 (TCGA, 3- year), 0.92 (ICGC, 1- year), 0.75 (ICGC, 3- year), 0.77 (GEO, 1- year), 0.76(GEO, 3- year). Expression levels of metabolic genes and subtypes of immune cells, and sorafenib sensitiveness varied significantly between the high-CRG group and low-CRG group. One of the model-included gene, GLS, might be involved in the process of cuproptosis and sorafenib treatment in HCC cell line.ConclusionThe five cuproptosis-related genes model contributed to prognostic prediction and provided a new sight for cuproptosis-related therapy in HCC.

The lack of accurate biomarkers impeded the screening, diagnosis and early treatment of hepatocellular carcinoma (HCC). As a result of the development of high-throughput transcriptome analysis techniques, circular RNAs, a newly discovered class of noncoding RNAs, were recognized as potential novel biomarkers. This meta-analysis was performed to update the diagnostic roles of circular RNAs for HCC. We acquired 23 articles from PubMed, Web of Science, EMBASE, and Cochrane Library databases up to September 2021. The overall sensitivity was 0.80 (95% CI: 0.77–0.84), and the specificity was 0.83 (95% CI: 0.79–0.85), with an AUC of 0.88 (0.85–0.91). Considering of the significant heterogeneity, studies were divided into four groups based on the control types. The circular RNAs in exosomes had a sensitivity of 0.69 (95% CI: 0.61–0.75), and a highest specificity of 0.91 (95% CI: 0.83–0.96). The pooled sensitivity of circular RNAs in serum/plasma was 0.84 (95% CI: 0.81–0.87), and the pooled specificity was 0.83 (95% CI: 0.79–0.86). The pooled sensitivity of circular RNAs distinguishing tumor tissue from chronic hepatitis/cirrhosis tissues was 0.56 (95% CI: 0.48–0.64), and specificity was 0.76 (95% CI: 0.67–0.82). When the controls were adjacent tissues, the sensitivity was 0.78 (95% CI: 0.70–0.84), and the specificity was 0.78 (95% CI: 0.71–0.85). Hsa_circ_0001445 with a pooled sensitivity of 0.81, a specificity of 0.76 and an AUC of 0.85 in two studies, might be a suitable diagnostic blood biomarker for HCC. Relying on function in HCC, the AUC of subgroups were 0.88 (95%CI: 0.84–0.90) (function group) and 0.87 (95%CI: 0.84–0.90) (unknown function group). As for only reported in HCC or not, these circular RNAs had an AUC of 0.89 (95%CI: 0.86–0.91) (only in HCC) and 0.85 (95%CI: 0.82–0.88) (not only in HCC). In conclusion, the results suggested that circular RNAs were acceptable biomarkers for detecting HCC, especially those circular RNAs existing in exosomes or serum/plasma.

The lack of an accurate biomarker in hepatocellular carcinoma (HCC) has hindered early detection, diagnosis, and treatment. Circular RNAs (circRNAs), which can be used as novel biomarkers in liquid biopsies, have been brought to light as a result of the advances in research on molecular biomarkers and the progression of genomic medicine. We conducted a meta-analysis of the diagnostic accuracy of serum/plasma circRNAs or the combination of circRNAs and α-fetoprotein (AFP) in HCC. We identified eight studies that met the inclusion/exclusion criteria from PubMed, Web of Science, EMBASE, and Cochrane Library databases. The data were pooled, and the sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) with 95% confidence intervals (CIs) were calculated. The areas under the summary receiver operator characteristic (SROC) curves (AUCs) were also calculated. The sensitivity of circRNAs was 0.82 (95% CI: 0.78–0.85), and the specificity was 0.82 (95% CI: 0.78–0.86). The sensitivity of AFP was 0.65 (95% CI: 0.61–0.68), and the specificity was 0.90 (95% CI: 0.85–0.93). The AUC was 0.89 (95% CI: 0.86–0.91) for circRNAs and 0.77 (95% CI: 0.74–0.81) for AFP. The sensitivity of the combination of circRNAs and AFP was 0.88 (95% CI: 0.84–0.92), specificity was 0.86 (95% CI: 0.80–0.91), and AUC was 0.94 (95% CI: 0.91–0.96). Additionally, a subgroup analysis was conducted based on the control groups used; the diagnostic accuracy was particularly high in the comparison of HCC vs. healthy controls. In summary, serum/plasma circRNAs are accurate biomarkers suitable for clinical use for detecting HCC, and the combination of circRNAs and AFP improved the diagnostic accuracy.