Minor hepatectomy combined with cholangioplasty and cholangiojejunostomy for Bismuth II hilar cholangiocarcinoma: A propensity score matching analysis.

BACKGROUND: The optimal surgical approach for Bismuth II hilar cholangiocarcinoma (HCCA) remains controversial. This study compared perioperative and oncological outcomes between minor and major hepatectomy. MATERIALS AND METHODS: One hundred and seventeen patients with Bismuth II HCCA who underwent hepatectomy and cholangiojejunostomy between January 2018 and December 2022 were retrospectively investigated. Propensity score matching created a cohort of 62 patients who underwent minor (n = 31) or major (n = 31) hepatectomy. Perioperative outcomes, complications, quality of life, and survival outcomes were compared between the groups. Continuous data are expressed as the mean ± standard deviation, categorical variables are presented as n (%). RESULTS: Minor hepatectomy had a significantly shorter operation time (245.42 ± 54.31 vs. 282.16 ± 66.65 min; P = 0.023), less intraoperative blood loss (194.19 ± 149.17 vs. 315.81 ± 256.80 mL; P = 0.022), a lower transfusion rate (4 vs. 11 patients; P = 0.038), more rapid bowel recovery (17.77 ± 10.00 vs. 24.94 ± 9.82 h; P = 0.005), and a lower incidence of liver failure (1 vs. 6 patients; P = 0.045). There were no significant between-group differences in wound infection, bile leak, bleeding, pulmonary infection, intra-abdominal fluid collection, and complication rates. Postoperative laboratory values, length of hospital stay, quality of life scores, 3-year overall survival (25.8 % vs. 22.6 %; P = 0.648), and 3-year disease-free survival (12.9 % vs. 16.1 %; P = 0.989) were comparable between the groups. CONCLUSION: In this propensity score-matched analysis, overall survival and disease-free survival were comparable between minor and major hepatectomy in selected patients with Bismuth II HCCA. Minor hepatectomy was associated with a shorter operation time, less intraoperative blood loss, less need for transfusion, more rapid bowel recovery, and a lower incidence of liver failure. Besides, this findings need confirmation in a large-scale, multicenter, prospective randomized controlled trial with longer-term follow-up.

Optimizing hepatocellular carcinoma disease staging systems by incorporating tumor micronecrosis: A multi-institutional retrospective study.

Tumor micronecrosis is a pathological feature that reflects malignant biological behavior in hepatocellular carcinoma (HCC). However, whether micronecrosis can optimize HCC staging systems remains unilluminated. A total of 1632 HCC patients who underwent curative hepatectomy in four institutions from January 2014 to December 2021 were enrolled in this study. Independent prognostic factors were identified, and optimized staging models were established using a training cohort (n = 934). The performance of optimized staging models was validated using an external cohort consisting of cases from three other institutions (n = 232). In addition, patients from our prospectively collected database (n = 379) tested the application effectiveness of the models. Harrel's c-statistics and the corrected Akaike information criterion (AICc) were used to assess the performance of staging models. In most of Barcelona Clinic Liver Cancer (BCLC) and tumor (T) stages, HCC patients with tumor micronecrosis showed poorer prognosis than those without. Tumor micronecrosis, microvascular invasion, multiple tumors and tumor size >2 cm were independent prognostic-related factors. The BCLC and T staging models incorporating tumor micronecrosis showed better performance than the original systems (c-statistic, 0.712 and 0.711 vs. 0.664 and 0.679; AICc, 2314.8 and 2322.3 vs. 2338.2 and 2338.1; respectively). Furthermore, the external validation cohort confirmed that the optimized staging models had improved efficiency compared with the original ones. Moreover, the prospective cohort demonstrated the applicability of the optimized staging systems. Tumor micronecrosis plays a stage-ascending role in HCC patients. The BCLC and T staging systems incorporating tumor micronecrosis can improve the prognosis stratification efficiency of patients.

LncTUG1 promotes hepatocellular carcinoma immune evasion via upregulating PD-L1 expression.

HCC is one of the most common malignant tumors worldwide. Although traditional treatment methods have been improved in recent years, the survival rate of HCC patients has not been significantly improved. Immunotherapy has shown extremely high clinical value in a variety of tumors. In this study, we found that TUG1 could regulate the expression of PD-L1 through JAK2/STAT3 to mediate immunosuppression. Here, The expression of TUG1 and PD-L1 in HCC tissues was evaluated through analysis of databases and verified in HCC tissue and HCC cancer cells by qRT-PCR. The effect of TUG1 on tumor immune escape was detected by coculture, and cell viability was detected with a CCK8 assay. The results demonstrated that TUG1 was closely associated with anticancer immunity. TUG1 and PD-L1 were highly expressed in HCC tissues and HCC cancer cells, and high expression of TUG1 and PD-L1 was related to the poor prognosis of HCC patients. In addition, knocking down TUG1 expression could reduce PD-L1 expression and enhance the cancer cell-killing capability of T cells. Downregulating TUG1 expression could also decrease the mRNA and protein expression of JAK2 and STAT3. To sum up, TUG1 and PD-L1 are overexpressed in patients with liver cancer and are related to the poor prognosis of these patients. Silencing TUG1 expression reduced the mRNA and protein expression of PD-L1 by affecting the JAK2/STAT3 pathway.

Identification of M2-like macrophage-related signature for predicting the prognosis, ecosystem and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is one of the most common malignancies worldwide, representing a big health-care challenge globally. M2-like macrophages are significantly correlated with tumor progression, metastasis and treatment resistance. METHODS: Integrative 10 machine learning algorithms were performed to developed a M2-like macrophage related prognostic signature (MRPS). Single-cell RNA-sequencing analysis was performed to dissect the ecosystem of HCC. Several approaches, including TIDE score, immunophenoscore, TMB score and tumor escape score were used to evaluate the predictive role of MRPS in immunology response. RESULTS: The optimal MRPS constructed by the combination of stepCox + superPC algorithm served as an independent risk factor and showed stable and powerful performances in predicting the overall survival rate of HCC patients with 2-, 3-, and 4-year AUCs of 0. 763, 0.751, and 0.699 in TCGA cohort. HCC patients with low risk score possessed a more interaction of immunoactivated cells, including NK, CD8+ cytotoxic T, and activated B, and a less interaction of immunosuppressive cells, including Treg, CD4+ exhauster T, and M2-like macrophage. Low risk score indicated a higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score and lower tumor escape score in HCC, suggesting a better immunotherapy response. The IC50 value of docetaxel, gemcitabine, crizotinib and Osimertinib in HCC with high risk score were lower versus that with low risk score. HCC patients with high risk score had a higher score of cancer-related hallmarks, including angiogenesis, DNA repair, EMT, glycolysis, and NOTCH signaling. CONCLUSION: Our study proposed a novel MRPS for predicting the prognosis, ecosystem and immunotherapy response in HCC.

Combining bulk and single-cell RNA-sequencing data to develop an NK cell-related prognostic signature for hepatocellular carcinoma based on an integrated machine learning framework.

BACKGROUND: The application of molecular targeting therapy and immunotherapy has notably prolonged the survival of patients with hepatocellular carcinoma (HCC). However, multidrug resistance and high molecular heterogeneity of HCC still prevent the further improvement of clinical benefits. Dysfunction of tumor-infiltrating natural killer (NK) cells was strongly related to HCC progression and survival benefits of HCC patients. Hence, an NK cell-related prognostic signature was built up to predict HCC patients' prognosis and immunotherapeutic response. METHODS: NK cell markers were selected from scRNA-Seq data obtained from GSE162616 data set. A consensus machine learning framework including a total of 77 algorithms was developed to establish the gene signature in TCGA-LIHC data set, GSE14520 data set, GSE76427 data set and ICGC-LIRI-JP data set. Moreover, the predictive efficacy on ICI response was externally validated by GSE91061 data set and PRJEB23709 data set. RESULTS: With the highest C-index among 77 algorithms, a 11-gene signature was established by the combination of LASSO and CoxBoost algorithm, which classified patients into high- and low-risk group. The prognostic signature displayed a good predictive performance for overall survival rate, moderate to high predictive accuracy and was an independent risk factor for HCC patients' prognosis in TCGA, GEO and ICGC cohorts. Compared with high-risk group, low-risk patients showed higher IPS-PD1 blocker, IPS-CTLA4 blocker, common immune checkpoints expression but lower TIDE score, which indicated low-risk patients might be prone to benefiting from ICI treatment. Moreover, a real-world cohort, PRJEB23709, also revealed better immunotherapeutic response in low-risk group. CONCLUSIONS: Overall, the present study developed a gene signature based on NK cell-related genes, which offered a novel platform for prognosis and immunotherapeutic response evaluation of HCC patients.

Robotic approach together with an enhanced recovery programme improve the perioperative outcomes for complex hepatectomy.

Objective: Robotic surgery has more advantages than traditional surgical approaches to complex liver resection; however, the robotic approach is invariably associated with increased cost. Enhanced recovery after surgery (ERAS) protocols are beneficial in conventional surgeries. Methods: The present study investigated the effects of robotic surgery combined with an ERAS protocol on perioperative outcomes and hospitalization costs of patients undergoing complex hepatectomy. Clinical data from consecutive robotic and open liver resections (RLR and OLR, respectively) performed in our unit in the pre-ERAS (January 2019-June 2020) and ERAS (July 2020-December 2021) periods were collected. Multivariate logistic regression analysis was performed to determine the impact of ERAS and surgical approaches-alone or in combination-on LOS and costs. Results: A total of 171 consecutive complex liver resections were analyzed. ERAS patients had a shorter median LOS and decreased total hospitalization cost, without a significant difference in the complication rate compared with the pre-ERAS cohort. RLR patients had a shorter median LOS and decreased major complications, but with increased total hospitalization cost, compared with OLR patients. Comparing the four combinations of perioperative management and surgical approaches, ERAS + RLR had the shortest LOS and the fewest major complications, whereas pre-ERAS + RLR had the highest hospitalization costs. Multivariate analysis found that the robotic approach was protective against prolonged LOS, whereas the ERAS pathway was protective against high costs. Conclusions: The ERAS + RLR approach optimized postoperative complex liver resection outcomes and hospitalization costs compared with other combinations. The robotic approach combined with ERAS synergistically optimized outcome and overall cost compared with other strategies, and may be the best combination for optimizing perioperative outcomes for complex RLR.

Epidemiology and outcome of individuals with intraductal papillary neoplasms of the bile duct.

BACKGROUND: Intraductal papillary neoplasm of the bile duct (IPNB) is a rare distinct subtype of precursor lesions of biliary carcinoma. IPNB is considered to originate from luminal biliary epithelial cells, typically displays mucin-hypersecretion or a papillary growth pattern, and results in cystic dilatation[1]. IPNB develops anywhere in the intrahepatic and extrahepatic biliary tracts, and can occur in various pathological stages from low-grade dysplasia to invasive carcinoma. IPNBs have similar phenotypic changes in the occurrence and development of all subtypes, and the prognosis is significantly better than that of traditional (non-papillary) cholangiocarcinoma. AIM: To evaluate the clinicopathological features of IPNB to provide evidence-based guidance for treatment. METHODS: Invasive IPNB, invasive intraductal papillary mucinous neoplasm of the pancreas (IPMN), and traditional cholangiocarcinoma data for affected individuals from 1975 to 2016 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Annual percentage changes (APCs) in the incidence and incidence-based (IB) mortality were calculated. We identified the independent predictors of overall survival (OS) and cancer-specific survival (CSS) in individuals with invasive IPNB. RESULTS: The incidence and IB mortality of invasive IPNB showed sustained decreases, with an APC of -4.5% (95%CI: -5.1% to -3.8%) and -3.3% (95%CI: -4.1% to -2.6%) (P < 0.001), respectively. Similar decreases in incidence and IB mortality were seen for invasive IPMN but not for traditional cholangiocarcinoma. Both OS and CSS for invasive IPNB were better than for invasive IPMN and traditional cholangiocarcinoma. A total of 1635 individuals with invasive IPNB were included in our prognosis analysis. The most common tumor sites were the pancreaticobiliary ampulla (47.9%) and perihilar tract (36.7%), but the mucin-related subtype of invasive IPNB was the main type, intrahepatically (approximately 90%). In the univariate and multivariate Cox regression analysis, age, tumor site, grade and stage, subtype, surgery, and chemotherapy were associated with OS and CSS (P < 0.05). CONCLUSION: Incidence and IB mortality of invasive IPNB trended steadily downward. The heterogeneity of IPNB comprises site and the tumor's mucin-producing status.

Epidemiological trends for functional pancreatic neuroendocrine tumors: A study combining multiple imputation with age adjustment.

Purpose: The purpose of this study was to examine trends in the incidence and incidence-based (IB) mortality of functional pancreatic neuroendocrine tumors(F-PNETs), and to identify factors associated with survival times. Methods: Data were obtained from the Surveillance, Epidemiology, and End Results database from 2000 to 2017. Trends in the age-adjusted incidence of F-PNETs and IB mortality were examined using the Joinpoint Regression Program. Statistical analyses were run using chi-square tests, Kaplan-Meier curves, and the Cox proportional hazards model. Multiple imputation was used to deal with missing data. Results: A total of 142 patients with F-PNETs met the study inclusion criteria. It was found that the incidence of F-PNETs decreased over the study period, with an annual percent change (APC) of -2. 5% (95% CI [-4. 3, -0. 5], P<0. 05). This decrease was found to be significant for women, and also when limited to cases with distant disease or rare F-PNETs, with APCs of -4. 2% (95% CI [-7. 4, -0. 9], P<0. 05), -6. 7% (95% CI [-10. 4, -2. 8], P<0. 05), and -9. 1% (95% CI [-13. 5, -4. 4], P<0. 05), respectively. The Cox regression analysis revealed that the tumor size, tumor stage, tumor type, and surgical resection were associated with F-PNETs mortality. Conclusions: This was the first population-based epidemiological study of F-PNETs and we found a continual decrease in the incidence of F-PNETs from 2000 to 2017. The prognosis and survival times were closely related to the calendar year at diagnosis, tumor stage, and tumor size.

Pancreatic adenosquamous carcinoma: A population level analysis of epidemiological trends and prognosis.

BACKGROUND: The incidence and mortality of pancreatic adenosquamous carcinoma (PASC) have received little attention. The goal of our study was to explore the overall epidemiological trend of PASC at the population level. METHODS: The Surveillance, Epidemiology, and End Results database was used to collect the incidence, incidence-based (IB) mortality, and patient details for PASC from 2000 to 2017. The Joinpoint regression tool was used to examine the trends in incidence and IB mortality. The Kaplan-Meier approach was used for survival analysis. Univariate and multivariate Cox regression analyses were used to determine the independent prognostic factors. RESULTS: We included 815 patients with PASC in the study. The incidence of PASC continuously increased from 2000 to 2017, with an annual percentage change (APC) of 3.9% (95% CI: 2.2%-5.7%, p < 0.05). IB mortality also increased continuously, with an APC of 5.0% (95% CI: 2.5%-7.6%, p < 0.05). Multivariate Cox regression analysis revealed that age, treatment, regional lymph node involvement, and tumor size were independent prognostic factors. Nomograms were created for PASC to predict 1- and 2-year survival probabilities, respectively. CONCLUSIONS: The incidence and IB mortality of PASC had a sustained and rapid increase, indicating that the preventive and treatment measures for PASC were not ideal. We must identify the significance of this condition as soon as possible, and commit greater attention and resources to PASC research.

Validation of a supplementary condition of eighth AJCC staging system for stage II hepatocellular carcinoma.

INTRODUCTION: The eighth American Joint Committee on Cancer (AJCC) staging system was flawed regarding the prognosis of stage II hepatocellular carcinoma (HCC). The aims of this study were to reveal the defect and make updates. METHODS: Clinical and survival data of HCC patients from the Surveillance, Epidemiology, and End Results database were used. We re-classified stage II into T2aN0M0 (tumors >2 cm with vascular invasion) and T2bN0M0 (multiple tumors ≤5 cm). The Kaplan-Meier method and log-rank test were used to estimate differences in overall survival (OS). Three propensity score matching analyses without (PSM1) or with (PSM2 and PSM3) consideration of surgical treatment were performed. Cox regression was used to reveal risk factors. RESULTS: HCC patients identified as T1bN0M0, T2aN0M0, T2bN0M0, and T3N0M0 were recruited. OS in T2N0M0 was consistent with the eighth AJCC staging system after PSM1. T2bN0M0 had increased OS compared with T2aN0M0 after PSM2 (hazard ratio [HR] = 1.36; 95% confidence interval [CI] = 1.06-1.73; P = 0.0141) or PSM3 (HR = 1.18; 95%CI = 1.01-1.37; P = 0.0283). No survival benefit existed between T1bN0M0 and T2bN0M0 after PSM2 (HR = 0.92; 95%CI = 0.80-1.05; P = 0.2171) or PSM3 (HR = 0.92; 95%CI = 0.84-1.01; P = 0.0888). Compared with T2aN0M0, T3N0M0 had shorter OS after PSM2 (HR = 0.64; 95%CI = 0.50-0.82; P = 0.0003) or PSM3 (HR = 0.63; 95%CI = 0.54-0.73; P < 0.0001). Cox regression analysis revealed that surgical treatment was associated with better prognosis (HR = 0.3; 95%CI = 0.3-0.4; P < 0.001). CONCLUSIONS: The current staging for T2N0M0 is imprecise because surgical treatment is not adequately evaluated and would be ineffective if the proportion of T2bN0M0 patients with surgical treatment was increased.

Validation of the Prognostic Role for Surgical Treatment in Stage II Intrahepatic Cholangiocarcinoma: A SEER Population-Based Study.

Background: This study aimed to determine the role of surgical treatment in patients with stage II intrahepatic cholangiocarcinoma (iCCA). Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We divided stage II iCCAs into solitary tumors with vascular invasion (T2sN0M0) and multiple tumors with/without vascular invasion (T2mN0M0) according to the criteria of AJCC v.8. The Kaplan−Meier method and log-rank test were used to evaluate differences in overall survival (OS). We performed two propensity score-matching analyses with (PSM2) or without (PSM1) surgical treatment. Results: 667 and 778 iCCA patients with stage II and IIIB were recruited. After PSM2, there was no survival difference in stage II iCCA patients in hypothetical conditions with similar surgical proportions (p = 0.079). However, OS was significantly worse in patients with T2mN0M0 than T2sN0M0 when the actual surgical proportion existed after PSM1 (p < 0.001). OS was similar between T2mN0M0 and IIIB regardless of whether PSM1 (p = 0.907) or PSM2 (p = 0.699) was performed. The surgical treatment was verified to associate with prognosis. Conclusions: The survival benefit by surgical treatment was existed in Stage II but not in Stage IIIB iCCA patients. The OS for T2mN0M0 will approach that of T2sN0M0 if the surgical proportion is gradually increased.

Based on the IWATE criteria: to investigate the influence of different surgical approaches on the perioperative outcomes of hepatectomy.

BACKGROUND: In terms of perioperative outcomes, compared with traditional open surgery and laparoscopic surgery, studies of robotic liver resection have been limited and must be further clarified. METHODS: Clinical data from 465 patients who underwent liver resection were collected in this retrospective study, and the IWATE criteria were used to evaluate the difficulty level of each operation. We compared perioperative outcomes of open, laparoscopic, or robotic approaches for patients with uncomplicated and complex hepatectomy according to different IWATE scores. Among patients with uncomplicated hepatectomy, the median operation time was significantly longer in the robotic liver resection (RLR) group than in the open liver resection (OLR) and laparoscopic liver resection (LLR) groups; however, the RLR group had the shortest hospital stay. There were no significant differences in intraoperative blood loss, conversion rate, total complication rate, or serious complication rate among the three groups. RESULTS: Among patients with complex hepatectomy, the RLR group had the smallest intraoperative blood loss and shortest mean length of stay. The cases converted to open hepatectomy were lower in the RLR group than in the laparoscopic group, mainly based on the IWATE score of expert hepatectomy. The incidence of general and serious postoperative complications in the RLR group was significantly lower than that in the OLR and LLR groups. CONCLUSIONS: Robotic liver resection is a safe and feasible surgical method that is more advantageous than laparoscopic and open liver resection, especially in complex liver surgery.

Robotic versus open extended cholecystectomy for T1a-T3 gallbladder cancer: A matched comparison.

Background: The feasibility and safety of robotic extended cholecystectomy (REC) are still uncertain. This study was performed to compare the short- and long-term outcomes of REC with those of open extended cholecystectomy (OEC) for T1a-T3 gallbladder cancer. Methods: From January 2015 to April 2022, 28 patients underwent REC in our center. To minimize any confounding factors, a 1:2 propensity score-matching analysis was conducted based on the patients' demographics, liver function indicators, T stage, and symptoms. The data regarding demographics, perioperative outcomes, and long-term oncologic outcomes were reviewed. Results: The visual analogue scale score was significantly lower in the REC than OEC group immediately postoperatively (3.68 ± 2.09 vs. 4.73 ± 1.85, P = 0.008), on postoperative day 1 (2.96 ± 1.75 vs. 3.69 ± 1.41, P = 0.023), and on postoperative day 2 (2.36 ± 1.55 vs. 2.92 ± 1.21, P = 0.031). In addition, the REC group exhibited a shorter time to first ambulation (P = 0.043), a shorter time to drainage tube removal (P = 0.038), and a shorter postoperative stay (P = 0.037), but hospital costs were significantly higher in the REC group (P < 0.001). However, no statistically significant difference was found in the operation time (P = 0.134), intraoperative blood loss (P = 0.467), or incidence of postoperative morbidity (P = 0.227) or mortality (P = 0.289) between the REC and OEC groups. In regard to long-term outcomes, the 3-year disease-free survival rate was comparable between the OEC and REC groups (43.1% vs. 57.2%, P = 0.684), as was the 3-year overall survival rate (62.8% vs. 75.0%, P = 0.619). Conclusion: REC can be an effective and safe alternative to OEC for selected patients with T1a-T3 gallbladder cancer with respect to short- and long-term outcomes.

Simple cholecystectomy is an adequate treatment for grade I T1bN0M0 gallbladder carcinoma: Evidence from 528 patients.

BACKGROUND: T1b gallbladder carcinoma (GBC) is defined as a tumor that invades the perimuscular connective tissue without extension beyond the serosa or into the liver. However, controversy still exists over whether patients with T1b GBC should undergo cholecystectomy alone or radical GBC resection. AIM: To explore the optimal surgical approach in patients with T1b gallbladder cancer of different pathological grades. METHODS: Patients with T1bN0M0 GBC who underwent surgical treatment between 2000 and 2017 were included in the Surveillance, Epidemiology, and End Results database. The Kaplan-Meier method and log-rank test were used to analyze the overall survival (OS) and disease-specific survival (DSS) of patients with T1b GBC of different pathological grades. Cox regression analysis was used to identify independent predictors of mortality and explore the selection of surgical methods in patients with T1b GBC of different pathological grades and their relationship with prognosis. RESULTS: Of the 528 patients diagnosed with T1bN0M0 GBC, 346 underwent simple cholecystectomy (SC) (65.5%), 131 underwent SC with lymph node resection (SC + LN) (24.8%), and 51 underwent radical cholecystectomy (RC) (9.7%). Without considering the pathological grade, both the OS (P < 0.001) and DSS (P = 0.003) of T1b GBC patients who underwent SC (10-year OS: 27.8%, 10-year DSS: 55.1%) alone were significantly lower than those of patients who underwent SC + LN (10-year OS: 35.5%, 10-year DSS: 66.3%) or RC (10-year OS: 50.3%, 10-year DSS: 75.9%). Analysis of T1b GBC according to pathological classification revealed no significant difference in OS and DSS between different types of procedures in patients with grade I T1b GBC. In patients with grade II T1b GBC, obvious survival improvement was observed in the OS (P = 0.002) and DSS (P = 0.039) of those who underwent SC + LN (10-year OS: 34.6%, 10-year DSS: 61.3%) or RC (10-year OS: 50.5%, 10-year DSS: 78.8%) compared with those who received SC (10-year OS: 28.1%, 10-year DSS: 58.3%). Among patients with grade III or IV T1b GBC, SC + LN (10-year OS: 48.5%, 10-year DSS: 72.2%), and RC (10-year OS: 80%, 10-year DSS: 80%) benefited OS (P = 0.005) and DSS (P = 0.009) far more than SC (10-year OS: 20.1%, 10-year DSS: 38.1%) alone. CONCLUSION: Simple cholecystectomy may be an adequate treatment for grade I T1b GBC, whereas more extensive surgery is optimal for grades II-IV T1b GBC.

TP53 mutation detected in circulating exosomal DNA is associated with prognosis of patients with hepatocellular carcinoma.

Exosome DNA (exoDNA) can be used for liquid biopsy. This study was the first to use droplet digital PCR (ddPCR) to detect tumor-specific mutations in exoDNA and to evaluate the prognosis of hepatocellular carcinoma (HCC) patients. 60 HCC patients were enrolled in the study. We used ddPCR to detect c.747 G > T mutation in TP53 gene. We analyzed the correlation between detectable mutation in exoDNA and clinicopathologic characteristics using Multivariate logistics regression analysis. We performed Cox regression to assess the correlation between mutation frequency (mutant droplets/total droplets, MD/TD) and prognostic. We found that 48 of 60 patients had c.747 G > T mutation in TP53 gene in exoDNA (80.0%). We found that detectable mutation in exoDNA and age were associated with microvascular invasion (MVI) (P < .01). The ROC curve analysis revealed that the best cutoff value of mutation frequency to predict MVI was 67% (sensitivity 48.15%, specificity 93.94%,), the corresponding AUC was 0.761 (95%CI, 0.640-0.866; P < .01). Furthermore, we found that patients suffered high-frequency mutation (>67%) had shorted median recurrence-free survival (RFS) with 63 days (range, 53-202 days), compared with 368 days (range, 51-576 days) for patients with low-frequency mutation (<67%) (HR:4.61; 95% CI, 1.70-12.48; P = 0 .003). We also found that high-frequency mutation was associated with poor prognosis though patients had better pathological characteristics, such as AFP (<400 ng/mL), Liver cirrhosis (Negative), Tumor thrombus (Negative), Tumor numbers (Single) and Post-operation TACE (Executed). We provided evidence that the mutations in exoDNA might be used to predict patients with poor RFS.Abbreviations: TP53: Tumor protein p53; ExoDNA: Exosomal DNA; HCC: Hepatocellular carcinoma; ddPCR: Droplet digital Polymerase Chain Reaction (PCR); MD/TD: The ratio of mutant droplets/total droplets; AFP: Alpha-fetoprotein; MVI: Microvascular invasion; RFS: Recurrence-free survival.

Comprehensive analysis of the effects of KIF2C on prognosis, biological functions and immune infiltration in PAAD.

Kinesin family member 2 C (KIF2C), a modulator of microtubule depolymerization, bipolar spindle formation, and chromosome segregation, has been reported to play roles in cancer biology. Moreover, many articles have reported that KIF2C expression is closely associated with the progression and prognosis of a variety of tumors. However, the role of KIF2C in pancreatic cancer is unclear. In this study, we used various databases to investigate the correlation between KIF2C expression and pancreatic cancer. METHODS: First, we determined the location of KIF2C in tumour cell lines via The Human Protein Atlas and immunofluorescence staining. Then, we analysed the GEPIA2 and TISIDB databases to assess KIF2C expression in pancreatic cancer cells and its correlation with the prognosis of pancreatic cancer. Through the Linkdeomics database, we identified the mRNAs whose expression was correlated with KIF2C expression. Next, we used the miRDB, miRanda, miRTairBase, Targetscan and miRmap databases to predict miRNAs that interact with KIF2C. Furthermore, we performed PPI analysis of KIF2C using the STRING database and Cytoscape Mcode software. The TISIDB database was used to analyse the correlation between KIF2C expression and immunity in pancreatic cancer. Finally, datasets GSE62452 and PACA-UA(https://xenabrowser.net/datapages/?cohort=PACA-AU&removeHub=http%3 A%2 F%2F127.0.0.1%3A7222) were used to validate the results of survival analysis and immune analysis. RESULTS: It was revealed that KIF2C was mainly located in the nuclei of pancreatic cancer cells. We found that the KIF2C mRNA expression levels in pancreatic cancer tissues were higher than those in normal tissues. Notably, elevated KIF2C mRNA expression was significantly associated with decreased overall survival and disease-free survival in patients with pancreatic cancer. Furthermore, KIF2C expression was closely related to the expression of multiple proteins and miRNAs in pancreatic cancer tissues. In addition, KIF2C expression was closely related to CD4+T cells. These results indicated that the expression of KIF2C was closely related to the prognosis of pancreatic cancer. CONCLUSION: KIF2C expression is negatively correlated with the prognosis of pancreatic cancer patients, and one of the main mechanisms underlying this relationship may be related to the tumor immune microenvironment.

Metabolic signatures of hepatolithiasis using ultra-high performance liquid chromatography-tandem mass spectrometry.

BACKGROUND & AIMS: A metabolomic study of hepatolithiasis has yet to be performed. The purpose of the present study was to characterize the metabolite profile and identify potential biomarkers of hepatolithiasis using a metabolomic approach. METHODS: We comprehensively analyzed the serum metabolites from 30 patients with hepatolithiasis and 20 healthy individuals using ultra-high performance liquid chromatography-tandem mass spectrometry operated in negative and positive ionization modes. Statistical analyses were performed using univariate (Student's t-test) and multivariate (orthogonal partial least-squares discriminant analysis) statistics and R language. Receiver operator characteristic (ROC) curve analysis was performed to identify potential predictors of hepatolithiasis. RESULTS: We identified 277 metabolites that were significantly different between hepatolithiasis serum group and healthy control serum group. These metabolites were principally lipids and lipid-like molecules and amino acid metabolites. The steroid hormone biosynthesis pathway was enriched in hepatolithiasis serum group. In all specific metabolites, 75 metabolites were over-expressed in hepatolithiasis serum group. The AUC values for 60 metabolites exceeded 0.70, 4 metabolites including 18-ß-Glycyrrhetinic acid, FMH, Rifampicin and PC (4:0/16:2) exceeded 0.90. CONCLUSIONS: We have identified serum metabolites that are associated with hepatolithiasis for the first time. 60 potential metabolic biomarkers were identified, 18-ß-Glycyrrhetinic acid, FMH, Rifampicin and PC (4:0/16:2) may have the potential clinical utility in hepatolithiasis.

Identification of a Necroptosis-Related Prognostic Signature and Associated Regulatory Axis in Liver Hepatocellular Carcinoma.

Background: Liver hepatocellular carcinoma (LIHC) ranks the sixth in global cancer incidence with poor prognosis. Necroptosis is a kind of regulated cell death and has been proved to be of significance in cancer occurrence and progression. However, few studies comprehensively discuss the potential applications of necroptosis-related genes (NRGs) in the prognostic evaluation and immunotherapy of LIHC. Methods: The prognostic signature in the present study was built up using LASSO Cox regression analysis. Integrated bioinformatics tools were utilized to explore the potential mRNA-miRNA-lncRNA regulatory axis in LIHC. Furthermore, qRT-PCR method was used to verify the EZH2 expression in LIHC tissues. Furthermore, prognostic performance of EZH2 in LIHC was assessed by Kaplan-Meier method. Results: A total of 14 NRGs were differentially expressed in LIHC tissues. The overall genetic mutation status of these NRGs in LIHC was also shown. NRGs were significantly correlated with programmed necrotic cell death, as well as Toll-like receptor signaling pathway in GO and KEGG pathway analysis. Kaplan-Meier analysis revealed that ALDH2, EZH2, NDRG2, PGAM5, RIPK1, and TRAF2 were related to the prognosis. A prognostic signature was constructed by these six genes and showed medium to high accuracy in the prediction of LIHC patients' prognosis. Further analysis revealed that NRGs were correlated with pathological stage, immune infiltration, and drug resistance in LIHC. Moreover, we identified a potential lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis in LIHC, which might affect the progression of LIHC. qRT-PCR suggested a higher mRNA level of EZH2 in LIHC tissues. And a poor overall survival rate was detected in LIHC patients with high EZH2 expression. Moreover, EZH2 expression and cancer stage were identified as the independent risk factors affecting LIHC patients' prognosis. Conclusion: In the present study, we conducted comprehensive bioinformatic analyses and built up a necroptosis-related prognostic signature containing four genes (ALDH2, EZH2, NDRG2, and PGAM5) for patients with LIHC, and this prognostic signature showed a medium to high predictive accuracy. And our study also identified a lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis, which might be of great significance in LIHC progression. In addition, based on the data from our center, the result of qRT-PCR and survival analysis showed a higher mRNA level of EZH2 in LIHC tissues and an unfavorable prognosis in high EZH2 expression group, respectively.