Cholangiocarcinoma combined with biliary obstruction: an exosomal circRNA signature for diagnosis and early recurrence monitoring.

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.

METTL3-mediated m6A modification of lncRNA TSPAN12 promotes metastasis of hepatocellular carcinoma through SENP1-depentent deSUMOylation of EIF3I.

In a previous study, we discovered that the level of lnc-TSPAN12 was significantly elevated in hepatocellular carcinoma (HCC) and correlated with a low survival rate. However, the function and mechanism of lnc-TSPAN12 in modulating epithelial-mesenchymal transition (EMT) and metastasis in HCC remains poorly understood. This study demonstrates that lnc-TSPAN12 positively influences migration, invasion, and EMT of HCC cells in vitro and promotes hepatic metastasis in vivo. The modification of N6-methyladenosine, driven by METTL3, is essential for the stability of lnc-TSPAN12, which may partially contribute to the upregulation of lnc-TSPAN12. Mechanistically, lnc-TSPAN12 exhibits direct interactions with EIF3I and SENP1, acting as a scaffold to enhance the SENP1-EIF3I interaction. As a result, the SUMOylation of EIF3I is inhibited, preventing its ubiquitin-mediated degradation. Ultimately, this activates the Wnt/ß-catenin signaling pathway, stimulating EMT and metastasis in HCC. Our findings shed light on the regulatory mechanism of lnc-TSPAN12 in HCC metastasis and identify the lnc-TSPAN12-EIF3I/SENP1 axis as a novel therapeutic target for HCC.

Cuproptosis-related genes score: A predictor for hepatocellular carcinoma prognosis, immunotherapy efficacy, and metabolic reprogramming.

Background: Cuproptosis 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. Methods: We 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. Results: The 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. Conclusion: The five cuproptosis-related genes model contributed to prognostic prediction and provided a new sight for cuproptosis-related therapy in HCC.

The role of diet and nutrition related indicators in biliary diseases: an umbrella review of systematic review and meta-analysis.

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.

Prognostic value of exosomal noncoding RNA in hepatocellular carcinoma: a meta-analysis.

High morbidity, recurrence and mortality make hepatocellular carcinoma (HCC) a leading cause of cancer-related burden and deaths. The lack of prognostic evaluation methods weakened the therapeutic efficacy for HCC. Exosomal noncoding RNAs (ncRNAs) play a key role in cancer development. Our meta-analysis aimed to assess the prognostic value of exosome-transferred noncoding RNAs in predicting the outcomes of patients with HCC. We obtained 16 articles from PubMed, Web of Science, Scopus, and EMBASE up to 4 November 2021. The ncRNAs were divided into three parts: microRNAs (miRNA), long noncoding RNAs (lncRNA), and circular RNAs (circRNA). In the pooled hazard ratios (HRs), upregulated miRNAs were 3.06 (95% CI = 2.51-3.73), downregulated miRNAs were 3.28 (95% CI = 2.61-4.11), lncRNAs were 3.34 (95% CI = 1.87-5.96), and circRNAs were 1.76 (95% CI = 1.36-2.14). As the results of subgroup analysis, upregulated miRNAs had a pooled HR of 3.10 (95% CI = 1.66-5.81), and the HR of downregulated miRNAs was 3.04 (95% CI = 2.17-4.28) for multivariate analysis of overall survival (OS). Meanwhile, upregulated miRNAs had a pooled HR of 2.61 (95% CI = 1.89-3.60), and the HR of downregulated miRNAs was 3.77 (95% CI = 1.11-12.73) for multivariate analysis of other endpoints. Remarkably, miR-21 has a pooled HR of 2.48 (95%CI = 1.52-4.05, I2 = 0) for disease-free survival (DFS). In conclusion, the expression of exosomal noncoding RNAs can be used to evaluate the prognosis of patients with HCC. Exosome-transferred miR-21 might serve as a potential prognostic biomarker in HCC.

Prediction of Early Recurrence After R0 Resection for Gallbladder Carcinoma of Stage T1b-T3.

PURPOSE: The time-to-tumor recurrence can predict the prognosis of hepatobiliary cancers following curative-intent resection. Therefore, for patients with gallbladder carcinoma (GBC) of stage T1b-T3 who had undergone R0 resection, we investigated the risk factors for early recurrence of GBC and their prognosis. PATIENTS AND METHODS: A total of 260 patients with GBC with T1b-T3 disease and an R0 margin were identified. Their clinicopathologic characteristics, perioperative details and prognostic data were reviewed. Survival analyses were carried out using the Kaplan-Meier method. Logistic regression models were used to identify the risk factors for early recurrence. RESULTS: The optimal cutoff for early recurrence was 29 months. Early recurrence tended to result in relapse far from the primary tumor, and such patients tended to have significantly worse overall survival. Multivariate analysis revealed that T3 disease, N1/N2 stage, poor differentiation of tumor, and lymphovascular invasion (LI) were associated with a greater risk of early recurrence. Patients diagnosed as having GBC incidentally and who had the risk factors of early recurrence were more likely to benefit from re-resection 2-4 weeks after a cholecystectomy. CONCLUSION: T3 stage, N1-N2 stage, poor differentiation, and LI were independent risk factors associated with early recurrence for patients with GBC with stage T1b-T3 disease after R0 resection.

Diagnostic Accuracy of Serum/Plasma Circular RNAs and the Combination of Circular RNAs and α-Fetoprotein for Detecting Hepatocellular Carcinoma: A Meta-Analysis.

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.

Diagnostic Accuracy of Circular RNAs in Different Types of Samples for Detecting Hepatocellular Carcinoma: A Meta-Analysis.

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.

Laparoscopic appendectomy is safe and feasible in pregnant women during second trimester: A retrospective study in a top-level Chinese center.

Acute appendicitis (AA) is the most common nonobstetric surgical emergency during pregnancy. According to the current guidelines and meta-analyses, traditional open appendectomy (OA) is still recommended for pregnant patients over laparoscopic appendectomy (LA), which might be associated with higher rates of fetal loss. Previous studies and experiences indicated that LA might be safe in the second trimester of pregnancy. The current study aimed to evaluate the safety and feasibility of LA in pregnant women during the second trimester.At our institution, a retrospective study was conducted with pregnant patients who underwent LA or OA during the second trimester between January 2016 and August 2018.A total of 48 patients were enrolled. Of them, 12 were managed with laparoscopy and 36 with the open approach. We found that the LA group had higher BMIs than the OA group (4.0 ±â€Š4.3 vs 21.5 ±â€Š2.9, P = .031). The financial results showed that the average daily medical costs for patients who underwent LA was higher than those who underwent OA (444 ±â€Š107 US$ vs 340 ±â€Š115 US$, P = .009), while the total cost of hospitalization was comparable between the 2 approaches. The perioperative and obstetric outcomes were comparable between LA and OA. In each group, only 1 patient had fetal loss. No "Yinao" was found in any of the patients in the LA group.In this study, with the proven advantages of the laparoscopic techniques, LA was found to be safe and feasible for pregnant women during the second trimester.

Elevated platelet distribution width predicts poor prognosis in hilar cholangiocarcinoma.

Although the platelet distribution width (PDW) has been reported as a reliable predictor of prognosis in several types of cancer, to our knowledge the prognostic value of PDW in hilar cholangiocarcinoma (HC) has not been studied. The aim of the study was to investigate the prognostic value of PDW in HC patients. A retrospective analysis of 292 consecutively recruited HC patients undergoing radical resection with at least a 5-year follow-up. The optimal cutoff value of PDW was determined by receiver operating characteristic (ROC) curve. Survival analysis by the Kaplan-Meier method and the difference between the clinico-pathologic variables and survival was evaluated by log-rank analysis. Multivariate analysis identified independent prognostic risk factors of overall survival (OS). ROC curve analysis suggested that the optimal cutoff value for the PDW was 16.55. There were significant associations of high PDW with high white blood cell (P < .001) and high neutril-to-lymph ratio (P < .001). In a multivariate analysis, the PDW was an independent prognostic factor for overall survival (HR = 2.521, 95% CI 1.832-3.470, P < .001). In conclusions, our findings indicate that PDW may have clinical significance in predicting OS after surgery in HC patients.

Lymphocyte to Monocyte Ratio Predicts Resectability and Early Recurrence of Bismuth-Corlette Type IV Hilar Cholangiocarcinoma.

BACKGROUND: The objective of our research was to investigate the value of the lymphocyte to monocyte ratio (LMR) and its dynamic changes (LMRc) in predicting tumor resectability and early recurrence of radiologically resectable type IV hilar cholangiocarcinoma (HC). METHODS: A total of 411 patients with radiologically resectable type IV HC were included. Data on their clinicopathologic characteristics, perioperative features, and survival outcomes were analyzed. Receiver operating characteristic (ROC) analysis was conducted to assess the ability of preoperative LMR (pre-LMR) to predict tumor resectability, and the ability of postoperative LMR (post-LMR) to discriminate between early and late recurrence. Survival curves were calculated using the Kaplan-Meier estimate. Univariate and multivariate logistic regression models were used to identify factors associated with resectability and early recurrence. RESULTS: Of 411 patients with potentially curative type IV HC, 254 underwent curative surgery. The optimal cutoff value of pre-LMR as an indicator of resectability was 3.67, and the optimal cutoff value of post-LMR for detecting early recurrence was 4.10. In the multivariate logistic regression model, CA19-9 > 200 U/mL, pre-LMR ≤ 3.67, and tumor size > 3 cm were found to be independent risk factors for poor resectability. Moreover, multivariate analysis showed that LMRc, resection margin, AJCC N stage, and lymphovascular invasion were independent risk factors associated with early recurrence. DISCUSSION: Pre-LMR is a valuable indicator of resectability and LMRc is a valuable predictor of early recurrence in patients with curative type IV HC.

A simple scoring system to predict early recurrence of Bismuth-Corlette type IV perihilar cholangiocarcinoma.

BACKGROUND: Early recurrence has been reported to be predictive of a poor prognosis for patients with perihilar cholangiocarcinoma (pCCA) after resection. The objective of our study was to construct a useful scoring system to predict early recurrence for Bismuth-Corlette type IV pCCA patients in clinic and to investigate the value of early recurrence in directing post-operative surveillance and adjuvant therapy. METHODS: In total, 244 patients who underwent radical resection for type IV pCCA were included. Data on clinicopathological characteristics, perioperative details and survival outcomes were analyzed. Survival curves were generated using the Kaplan-Meier method. Univariate and multivariate logistic-regression models were used to identify factors associated with early recurrence. RESULTS: Twenty-one months was defined as the cutoff point to distinguish between early and late recurrence. Univariate and multivariate analysis revealed that CA19-9 level >200 U/mL, R1 resection margin, higher N category and positive lymphovascular invasion were independent predictors of early recurrence. The scoring system was constructed accordingly. The early-recurrence rates of patients with scores of 0, 1, 2, 3, 4, and 5 were 23.9%, 38.7%, 60.0%, 78.6%, 83.4%, and 100%, respectively. Adjuvant therapy was significantly associated with higher overall survival rate for patients with early recurrence, but not for those with late recurrence. Patients in the early-recurrence group with scores ≥2 had better prognoses after adjuvant therapy. CONCLUSIONS: A simple scoring system using CA19-9 level, N category, resection margin and lymphovascular invasion status could predict early recurrence, and thus might direct post-operative surveillance and adjuvant therapy for patients with type IV pCCA.