Bifurcation analysis and control of improved traffic flow model considering the effect of strong winds.

In recent years, the problem of traffic congestion has become increasingly serious, and research on traffic system control has become a new hotspot. Studying the bifurcation characteristics of traffic flow systems and designing control schemes for unstable support points can alleviate traffic congestion from a new perspective. This article improves the full speed differential model considering strong wind models from the perspective of bifurcation control to adjust traffic flow. This article theoretically proves the existence conditions of Hopf bifurcation and saddle node bifurcation in the model and finds the stability mutation point of the transportation system stability. A nonlinear system feedback controller was designed for unstable bifurcation points using Chebyshev polynomial approximation and random feedback control methods. Without changing the system equilibrium point, the advance, delay, and elimination of Hopf bifurcation were achieved, and the abrupt behavior of the transportation system was controlled, thereby alleviating traffic congestion. This article explains the changes in the stability of complex transportation systems from the perspective of bifurcation analysis, which can better capture the characteristics of traffic flow. By adjusting the control parameters in the feedback controller, the influence of boundary conditions on the stability of the transportation system is fully described, and the influence of unstable focal points and saddle points on the system is suppressed, thereby slowing down the traffic flow. In addition, unstable bifurcation points can be eliminated, and the Hopf bifurcation can be controlled to advance, delay, and disappear, thereby achieving control over the stable behavior of the transportation system. This helps alleviate traffic congestion and also helps describe actual traffic phenomena.

miR-552 promotes the proliferation and metastasis of intrahepatic cholangiocarcinoma by targeting FOXO1.

Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but highly malignant cancer. Few effective systemic targeted therapies are available for patients with unresectable ICC, but there exists an urgent need to explore mechanisms underlying the initiation and progression of ICC. MicroRNA (miRNA) plays vital roles in the initiation, progression, and drug resistance of different cancers. Recently, the biological function of a novel miRNA, miR-552, has been widely analyzed in hepatocellular carcinoma and colorectal, cervical, gastric, and other cancers. However, its role in ICC has not yet been elucidated. In this study, we found that miR-552 expression was upregulated in ICC and that miR-552 predicted poor prognosis. Using functional studies, we found that miR-552 enhanced the proliferation and invasion ability of ICC cells. Mechanistic research identified that forkhead box O1 (FOXO1) is the target of miR-552 in ICC. Moreover, the combined panels of miR-552 and FOXO1 exhibited a better prognostic value for ICC patients than did miR-552 alone. In conclusion, these findings demonstrated that the miR-552/FOXO1 axis drove ICC progression, further suggesting that targeting this axis could be a novel therapeutic strategy for ICC.

Postoperative survival analysis of hepatocellular carcinoma patients with liver cirrhosis based on propensity score matching.

OBJECTIVE: Most hepatocellular carcinoma (HCC) patients in China have some degree of liver cirrhosis. The effect of cirrhosis on the long-term prognosis of HCC patients after hepatectomy is still unclear. This study aimed to investigate the effect of liver cirrhosis on the prognosis of HCC patients after hepatectomy. METHODS: Data from patients who underwent hepatectomy and had pathologically confirmed HCC were retrospectively collected. The patients' clinical pathological data were recorded. Propensity score matching (PSM) was used to eliminate the influence of potential confounding factors. The Kaplan-Meier method was used to calculate the recurrence-free survival (RFS) and overall survival (OS) rates, and Cox regression analysis was used to screen for independent risk factors affecting OS and RFS. RESULTS: A total of 1381 HCC patients who were initially treated with hepatectomy were included, including 797 patients with liver cirrhosis. The RFS and OS rates in the group with cirrhosis were significantly lower than those in the group without cirrhosis (after PSM, RFS: P < 0.001; OS: P = 0.001). Subgroup analysis showed that among patients with Barcelona Clinic Liver Cancer (BCLC) stage 0-B disease, RFS and OS were significantly lower in those with cirrhosis than in those without cirrhosis (both P < 0.05); while in patients with stage C disease, there was no significant difference between those with and without cirrhosis. In the group with cirrhosis, alpha-fetoprotein (AFP) > 400, intraoperative blood loss, tumor diameter > 5 cm, satellite lesions, and large vessel invasion were independent risk factors for RFS, while albumin-bilirubin (ALBI) grade, neutrophil-to-lymphocyte ratio (NLR), tumor diameter > 5 cm, satellite lesions, microvascular invasion, and macrovascular invasion were independent risk factors for OS. CONCLUSION: HCC with liver cirrhosis has specific characteristics. Compared with patients without cirrhosis, patients with cirrhosis have worse long-term survival after surgery. In addition, the independent risk factors for RFS and OS are different between patients with cirrhosis and without cirrhosis; liver cirrhosis is an independent risk factor for the long-term prognosis of HCC patients, especially patients with BCLC stage 0-B disease after hepatectomy.

Preoperative Estimated Risk of Microvascular Invasion is Associated with Prognostic Differences Following Liver Resection Versus Radiofrequency Ablation for Early Hepatitis B Virus-Related Hepatocellular Carcinoma.

OBJECTIVES: The aim of this study was to examine prognostic differences between liver resection (LR) and percutaneous radiofrequency ablation (PRFA) for hepatocellular carcinoma (HCC) based on preoperative predicted microvascular invasion (MVI) risk. METHODS: Data on consecutive patients who underwent LR (n = 1344) or PRFA (n = 853) for hepatitis B virus-related HCC within the Milan criteria (MC) were analyzed. A preoperative nomogram was used to estimate MVI risk. Overall survival (OS), time to recurrence, and patterns of recurrence were compared using propensity score matching. RESULTS: The concordance indices of the nomogram to predict MVI were 0.813 and 0.781 among LR patients with HCC within the MC or ≤ 3 cm, respectively. LR and PRFA resulted in similar 5-year recurrence and OS for patients with nomogram-predicted low-risk of MVI. LR provided better 5-year recurrence and OS versus PRFA for patients with high-risk of MVI (71.6% vs. 80.7%, p = 0.013; 47.9% vs. 34.0%, p = 0.002, for HCC within the MC; 62.3% vs. 78.8%, p = 0.020; 63.6% vs. 38.3%, p = 0.015, for HCC ≤ 3 cm). Among high-risk patients, LR was associated with lower recurrence and improved OS compared with PRFA, on multivariate analysis [hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.63-0.97, and HR 0.68, 95% CI 0.52-0.88, for HCC within the MC; HR 0.51, 95% CI 0.32-0.81, and HR 0.47, 95% CI 0.26-0.84, for HCC ≤ 3 cm], and resulted in less early and local recurrence than PRFA (42.4% vs. 54.8%, p = 0.007, and 31.2% vs. 46.1%, p = 0.007, for HCC within the MC; 27.9% vs. 50.8%, p = 0.016, and 15.6% vs. 39.5%, p = 0.046, for HCC ≤ 3 cm). CONCLUSIONS: LR was oncologically superior over PRFA for early HCC patients with predicted high-risk of MVI. LR was associated with better local disease control than PRFA in these patients.

microRNA-454 promotes liver tumor-initiating cell expansion by regulating SOCS6.

Tumor-initiating cells (T-ICs) are involved in the tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver T-ICs remains unclear. Herein, we find that miR-454 is upregulated in liver T-ICs and has an important function in liver T-ICs. Functional studies have revealed that knockdown of miR-454 inhibits liver T-IC self-renewal and tumorigenesis. Conversely, forced miR-454 expression promotes liver T-IC self-renewal and tumorigenesis. Mechanistically, we found that miR-454 downregulates SOCS6 expression in liver T-ICs. The correlation between miR-454 and SOCS6 is validated in human HCC tissues. Furthermore, HCC cells that overexpress miR-454 are resistant to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrates that miR-454 may predict sorafenib benefits in HCC patients. In conclusion, our findings reveal the crucial role of miR-454 in liver T-IC expansion and sorafenib response.

A nomogram predicting severe COVID-19 based on a large study cohort from China.

BACKGROUND: The use of accurate prediction tools and early intervention are important for addressing severe coronavirus disease 2019 (COVID-19). However, the prediction models for severe COVID-19 available to date are subject to various biases. This study aimed to construct a nomogram to provide accurate, personalized predictions of the risk of severe COVID-19. METHODS: This study was based on a large, multicenter retrospective derivation cohort and a validation cohort. The derivation cohort consisted of 496 patients from Jiangsu Province, China, between January 10, 2020, and March 15, 2020, and the validation cohort contained 105 patients from Huangshi, Hunan Province, China, between January 21, 2020, and February 29, 2020. A nomogram was developed with the selected predictors of severe COVID-19, which were identified by univariate and multivariate logistic regression analyses. We evaluated the discrimination of the nomogram with the area under the receiver operating characteristic curve (AUC) and the calibration of the nomogram with calibration plots and Hosmer-Lemeshow tests. RESULTS: Three predictors, namely, age, lymphocyte count, and pulmonary opacity score, were selected to develop the nomogram. The nomogram exhibited good discrimination (AUC 0.93, 95% confidence interval [CI] 0.90-0.96 in the derivation cohort; AUC 0.85, 95% CI 0.76-0.93 in the validation cohort) and satisfactory agreement. CONCLUSIONS: The nomogram was a reliable tool for assessing the probability of severe COVID-19 and may facilitate clinicians stratifying patients and providing early and optimal therapies.

Exosome-transmitted p120-catenin suppresses hepatocellular carcinoma progression via STAT3 pathways.

Hepatocellular carcinoma (HCC) is a fatal disease with increasing morbidity and poor prognosis due to surgical recurrence and metastasis. Moreover, the molecular mechanism of HCC progression remains unclear. Although the role of p120-catenin (p120ctn) in liver cancer is well studied, the effects of secreted p120ctn transported by exosomes are less understood. Here, we show that p120ctn in exosomes secreted from liver cancer cells suppresses HCC cell proliferation and metastasis and expansion of liver cancer stem cells (CSCs). Mechanically, exosome p120ctn inhibits HCC cell progression via the STAT3 pathway, and the STAT3 inhibitor S3I-201 abolishes the observed effects on growth, metastasis, and self-renewal ability between exosome p120ctn-treated HCC cells and control cells. Taken together, we propose that p120ctn-containing exosomes derived from cancer cells inhibit the progression of liver cancer and may offer a new therapeutic strategy.

Impact of Anatomical Versus Non-anatomical Liver Resection on Short- and Long-Term Outcomes for Patients with Intrahepatic Cholangiocarcinoma.

OBJECTIVE: The aim of this study was to examine the impact of anatomical resection (AR) versus non-anatomical resection (NAR) on the survival outcomes in patients with intrahepatic cholangiocarcinoma (ICC). PATIENTS AND METHODS: Data on 702 consecutive patients who underwent either AR (n = 319) or NAR (n = 383) for ICC were reviewed. Disease-free survival (DFS) and overall survival (OS) following AR versus NAR was compared using propensity score matching (PSM). Subgroups of patients who benefited from AR versus NAR were examined after being stratified by the 8th TNM staging of ICC. RESULTS: AR and NAR had similar complication rates (26.6% vs. 25.1%, p = 0.634). AR was associated with better 1-, 3-, and 5-year DFS and OS rates compared with NAR after PSM (58.1%, 35.7% and 28.1% vs. 44.1%, 23.9% and 18.0%; 72.9%, 45.7% and 36.0% vs. 62.0%, 30.8% and 25.3%; both p = 0.002). On multivariate analysis, NAR was associated with worse DFS and OS than AR [hazard ratio (HR) 1.461 and 1.488; 95% confidence interval (CI) 1.184-1.804 and 1.189-1.863, respectively]. Stratified analysis demonstrated similar outcomes following AR versus NAR for ICC at stages IA, II with vascular invasion, and III with visceral peritoneum perforation, local extrahepatic invasion and nodal metastasis, while NAR was associated with worse DFS and OS versus AR for stages IB (HR 1.897 and 2.321; 95% CI 1.179-3.052 and 1.376-3.914, respectively) or II ICC without vascular invasion (2.071 and 2.077; 95% CI 1.239-3.462 and 1.205-3.579, respectively). CONCLUSIONS: AR was associated with better survival outcomes compared with NAR in ICC patients with stage IB or II tumors without vascular invasion.

Modifications of the AJCC 8th edition staging system for intrahepatic cholangiocarcinoma and proposal for a new staging system by incorporating serum tumor markers.

BACKGROUND: Several studies have noted that the discriminatory ability and stratification performance of the AJCC 8th edition staging system is not entirely satisfactory. We aimed to improve the American Joint Committee on Cancer (AJCC) 8th edition staging system for intrahepatic cholangiocarcinoma (ICC). METHODS: A multicentric database from three Chinese mainland centers (n = 1601 patients) was used to modify the 8th edition staging system. This modified TNM (mTNM) staging system was then validated using the SEER database (n = 761 patients). A new TNM staging system, by incorporating serum tumor markers (TNMIS) into the mTNM staging system was then proposed. RESULTS: The 8th edition staging system did not provide an adequate stratification of prognosis in the Chinese multicentric cohort. The mTNM staging system offered a better discriminatory capacity in the multicentric cohort than the original 8th edition. External validation in the SEER cohort showed that the mTNM staging system also had a good stratification performance. After further incorporating a serum marker stage into the mTNM staging, the TNMIS staging system was able to stratify prognosis even better. CONCLUSION: The proposed mTNM staging system resulted in better stratification performance and the TNMIS staging system provided even more accurate prognostic classification than the conventional TNM system.

Antiviral therapy improves survival in patients with HBV infection and intrahepatic cholangiocarcinoma undergoing liver resection.

BACKGROUND & AIMS: The impact of hepatitis B virus (HBV) infection on outcomes after resection of intrahepatic cholangiocarcinoma (ICC) has not been reported. The aim of this study was to examine the impact of antiviral therapy on survival outcomes after liver resection for patients with ICC and underlying HBV infection. METHODS: Data on 928 patients with ICC and HBV infection who underwent liver resection at two medical centers between 2006 and 2011 were analyzed. Data on viral reactivation, tumor recurrence, cancer-specific survival (CSS) and overall survival (OS) were obtained. Survival rates were analyzed using the time-dependent Cox regression model adjusted for potential covariates. RESULTS: Postoperative viral reactivation occurred in 3.3%, 8.3% and 15.7% of patients who received preoperative antiviral therapy, who did not receive preoperative antiviral therapy with a low, or a high HBV-DNA level (< or ≥2,000 IU/ml), respectively (p <0.001). A high viral level and viral reactivation were independent risk factors of recurrence (hazard ratio [HR] 1.22 and 1.34), CSS (HR 1.36 and 1.46) and OS (HR1.23 and 1.36). Five-year recurrence, CSS and OS were better in patients who received antiviral therapy (70.5%, 46.9% and 43.0%) compared with patients who did not receive antiviral therapy and had a high viral level (86.5%, 20.9% and 20.5%, all p <0.001), respectively. The differences in recurrence, CSS and OS were minimal compared with no-antiviral therapy patients with a low viral level (71.7%, 35.5% and 33.5%, p = 0.057, 0.051 and 0.060, respectively). Compared to patients with a high viral level who received no antiviral therapy, patients who initiated antiviral therapy either before or after surgery had better long-term outcomes (HR 0.44 and 0.54 for recurrence; 0.38 and 0.57 for CSS; 0.46 and 0.54 for OS, respectively). CONCLUSIONS: Viral reactivation was associated with worse prognoses after liver resection for HBV-infected patients with ICC. Antiviral therapy decreased viral reactivation and prolonged long-term survival for patients with ICC and a high viral level. LAY SUMMARY: Postoperative hepatitis B virus reactivation was associated with an increased complication rate and a decreased survival rate after liver resection in patients with ICC and hepatitis B virus infection. Antiviral therapy before liver resection reduced the risk of postoperative viral reactivation. Both pre- and postoperative antiviral therapy was effective in prolonging patient survival.

Prognosis of Intrahepatic Cholangiocarcinomas with HBV Infection is Better than Those with Hepatolithiasis After R0 Liver Resection: A Propensity Score Matching Analysis.

BACKGROUND: The impact of different causative factors of intrahepatic cholangiocarcinoma (ICC) on disease outcome remains largely unknown. This study aimed to evaluate the prognosis of ICC patients with different pathogenic factors after hepatectomy. METHODS: Data of 731 consecutive patients undergoing R0 liver resection for ICC at The Eastern Hepatobiliary Surgery Hospital between 2004 and 2010 were analyzed. These patients were divided into the hepatitis B virus-related (HBV-ICC, n = 519), hepatolithiasis-related (stone-ICC, n = 87), HBV plus hepatolithiasis-related (HBV/stone-ICC, n = 45), and other etiologies-related (other-ICC, n = 80) ICC groups. Propensity score matching (PSM) was used to eliminate the baseline differences between these groups. RESULTS: In these four groups, the 5-year tumor recurrence and overall survival (OS) rates were 75.4, 90.3, 83.0 and 81.9%, and 32.7, 16.3, 17.7 and 22.6%, respectively. The significant differences in recurrence and OS were identified between the HBV- and stone-ICC groups (both p < 0.001). In these two groups, most of the independent prognostic predictors were similar, but tumor diameter >5 cm was demonstrated as a risk factor in the HBV-ICC patients only, and surgical margin <1 cm and human epidermal growth factor receptor 2-positive were demonstrated as risk factors in the stone-ICC patients only. With PSM, 75 patients in each of the HBV- and stone-ICC cohorts were created, and the 5-year recurrence and OS rates were 69.9 versus 88.6, and 34.6 versus 19.2%, respectively (p = 0.017, 0.027). CONCLUSION: Patients with HBV-ICC achieved better outcomes than those with stone-ICC. This prognostic difference was probably associated with biological malignant invasiveness rather than tumor stage.

Adjuvant Transarterial Chemoembolization Following Liver Resection for Intrahepatic Cholangiocarcinoma Based on Survival Risk Stratification.

BACKGROUND: The effectiveness of adjuvant transarterial chemoembolization (TACE) for intrahepatic cholangiocarcinoma (ICC) after hepatectomy remains unclear. This study was performed to identify ICC patients who would benefit from adjuvant TACE. PATIENTS AND METHODS: The study included 553 patients who underwent hepatectomy for ICC between January 2008 and February 2011 at the Eastern Hepatobiliary Surgery Hospital and who were treated with or without TACE (122 with TACE and 431 without TACE). Survival risk stratification was performed using the established prognostic nomogram (ICC nomogram). The predictive performance was evaluated by concordance index and calibration. The tumor recurrence and overall survival (OS) rates were analyzed by the Kaplan-Meier method before and after propensity score matching (PSM). RESULTS: The predictive performance of the ICC nomogram was demonstrated by the well-fitted calibration curves and an optimal c-index of 0.71 for OS prediction. In the whole cohort, the 5-year recurrence and OS rates between the TACE and non-TACE groups were significantly different (5-year recurrence: 72.9% vs. 78.1%; OS: 38.4% vs. 29.7%). After 1:1 PSM, the TACE and non-TACE groups (122 patients each) had similar 5-year recurrence and OS rates (5-year recurrence: 72.9% vs. 74.2%; OS: 38.4% vs. 36.0%). By survival risk stratification based on ICC nomogram, only the patients in the lowest tertile (nomogram scores ≥77) benefited from adjuvant TACE (TACE vs. non-TACE groups: 90.4% vs. 95.9% for 5-year recurrence; 21.3% vs. 6.2% for 5-year OS). CONCLUSION: Adjuvant TACE following liver resection might be suitable for ICC patients with high ICC nomogram scores (≥77). IMPLICATIONS FOR PRACTICE: The accurate predictive performance of the established prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) following liver resection was reconfirmed in an independent cohort with 553 patients. Based on the survival risk stratification using the nomogram, adjuvant transarterial chemoembolization following liver resection might be suitable only for ICC patients with high scores from the nomogram.

Postoperative Prognosis of Non-alcoholic Fatty Liver Disease-Associated Intrahepatic Cholangiocarcinoma: a Multi-center Propensity Score Matching Analysis.

BACKGROUND AND AIMS: The incidence of intrahepatic cholangiocarcinoma (ICC) in non-alcoholic fatty liver disease (NAFLD) is increasing gradually. The prognosis of NAFLD-ICC has not been well studied. We aim to investigate the prognosis of patients with NAFLD-ICC after curative-intent partial hepatectomy (PH). METHODS: Multi-center data from January 2003 to January 2014 were retrospectively analyzed. The prognosis of ICC was analyzed using PSM and compared with hepatitis B virus (HBV)-related ICC. RESULTS: A total of 898 patients with ICC were included in this study. Of them, 199 (22.2%) were NAFLD-ICC, and 699 (77.8%) were HBV-ICC. Multivariate analysis showed that CA19-9 ≥ 37 U/mL, microvascular invasion, tumor size > 5 cm, multiple tumors, and lymph node (LN) metastasis were independent risk factors for early recurrence (ER) in ICC patients. After a 1:1 PSM, NAFLD-ICC has worse 5-year overall survival (OS) (24.0% vs. 48.9%), 5-year recurrence (80.9% vs. 55.0%), and ER (58.5% vs. 30.0%) than that of HBV-ICC (all P < 0.01). Multivariable analysis showed NAFLD was an independent risk factor for OS (hazard ratio [HR] 2.26, 95% CI 1.63-3.13, P < 0.001), tumor recurrence (HR 2.24, 95%CI 1.61-3.10, P < 0.001) and ER (HR 2.23, 95%CI 1.60-3.09, P < 0.001) in patients with ICC after PH. The sensitivity analysis indicated that NAFLD-ICC patients were more likely to experience ER. CONCLUSION: Compared with HBV-ICC, NAFLD-ICC has a worse prognosis and was more likely to relapse early. More frequent surveillance should be considered.

LncRNA HClnc1 facilitates hepatocellular carcinoma progression by regulating PKM2 signaling and indicates poor survival outcome after hepatectomy.

AIM: Long noncoding RNAs (lncRNAs) are key mediators with a wide range of pathophysiological functions, but their role in human hepatocellular carcinoma (HCC) is still unclear. METHODS: An unbiased microarray study evaluated a novel lncRNA, HClnc1, that is linked to the development of HCC. In vitro cell proliferation assays and an in vivo xenotransplanted HCC tumor model were performed to determine its functions, followed by antisense oligo-coupled mass spectrometry to identify HClnc1-interacting proteins. To study relevant signaling pathways, in vitro experiments were performed, including chromatin isolation by RNA purification, RNA immunoprecipitation, luciferase, and RNA pull-down assay. RESULTS: HClnc1 levels were considerably greater in patients with advanced tumor-node-metastatic stages, and it was found to be inversely connected to survival rates. Moreover, the proliferative and invasive potential of the HCC cells was attenuated by HClnc1 RNA knockdown in vitro, while HCC tumor growth and metastasis were found to be reduced in vivo. HClnc1 interacted with pyruvate kinase M2 (PKM2) to prevent its degradation and thus facilitated aerobic glycolysis and PKM2-STAT3 signaling. CONCLUSIONS: HClnc1 is involved in a novel epigenetic mechanism of HCC tumorigenesis and PKM2 regulation. HClnc1 is not only a more accurate prognostic indicator of HCC but also a potential therapeutic target for HCC treatment.

Liver resection versus liver transplantation for hepatocellular carcinoma within the Milan criteria based on estimated microvascular invasion risks.

Background: Preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) may optimize individualized treatment decision-making. This study aimed to investigate the prognostic differences between HCC patients undergoing liver resection (LR) and liver transplantation (LT) based on predicted MVI risks. Methods: We analysed 905 patients who underwent LR, including 524 who underwent anatomical resection (AR) and 117 who underwent LT for HCC within the Milan criteria using propensity score matching. A nomogram model was used to predict preoperative MVI risk. Results: The concordance indices of the nomogram for predicting MVI were 0.809 and 0.838 in patients undergoing LR and LT, respectively. Based on an optimal cut-off value of 200 points, the nomogram defined patients as high- or low-risk MVI groups. LT resulted in a lower 5-year recurrence rate and higher 5-year overall survival (OS) rate than LR among the high-risk patients (23.6% vs 73.2%, P < 0.001; 87.8% vs 48.1%, P < 0.001) and low-risk patients (19.0% vs 45.7%, P < 0.001; 86.5% vs 70.0%, P = 0.002). The hazard ratios (HRs) of LT vs LR for recurrence and OS were 0.18 (95% confidence interval [CI], 0.09-0.37) and 0.12 (95% CI, 0.04-0.37) among the high-risk patients and 0.37 (95% CI, 0.21-0.66) and 0.36 (95% CI, 0.17-0.78) among the low-risk patients. LT also provided a lower 5-year recurrence rate and higher 5-year OS rate than AR among the high-risk patients (24.8% vs 63.5%, P = 0.001; 86.7% vs 65.7%, P = 0.004), with HRs of LT vs AR for recurrence and OS being 0.24 (95% CI, 0.11-0.53) and 0.17 (95% CI, 0.06-0.52), respectively. The 5-year recurrence and OS rates between patients undergoing LT and AR were not significantly different in the low-risk patients (19.4% vs 28.3%, P = 0.129; 85.7% vs 77.8%, P = 0.161). Conclusions: LT was superior to LR for patients with HCC within the Milan criteria with a predicted high or low risk of MVI. No significant differences in prognosis were found between LT and AR in patients with a low risk of MVI.

Effect of different PD-1 inhibitor combination therapies for unresectable intrahepatic cholangiocarcinoma.

BACKGROUND: Immune checkpoint inhibitor (ICI) combination therapy offers a new option for treatment of unresectable intrahepatic cholangiocarcinoma (uICC). AIM: To compare the effect of different anti-PD-1 combination therapies as the first-line treatments for uICC. METHODS: This study included 318 patients who received chemotherapy alone (Chemo), anti-PD-1 plus chemotherapy (ICI-chemo), anti-PD-1 plus targeted therapy (ICI-target) or anti-PD-1 plus targeted therapy and chemotherapy (ICI-target-chemo) as first line for uICC from 22 centres in China. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. RESULTS: Patients with ICI-chemo (median PFS [mPFS], 6.3 months; HR: 0.61, 95% CI: 0.42-0.88; p = 0.008; median OS [mOS], 10.7 months; HR: 0.61, 95% CI: 0.39-0.94; p = 0.026), ICI-target (7.2 months; HR: 0.54, 95% CI: 0.36-0.80; p = 0.002; 15.8 months; HR: 0.54, 95% CI: 0.35-0.84; p = 0.006) or ICI-target-chemo (6.9 months; HR: 0.65, 95% CI: 0.47-0.90; p = 0.009; 14.4 months; HR: 0.47, 95% CI: 0.31-0.70; p < 0.001) achieved better clinical outcomes than those with Chemo (3.8 months; 9.3 months). ICI-target was not inferior to ICI-chemo in survival outcomes (HR for PFS: 0.88, 95% CI: 0.55-1.42; p = 0.614; HR for OS: 0.89, 95% CI: 0.51-1.55; p = 0.680). ICI-target-chemo yielded similar prognoses as ICI-chemo (HR for PFS: 1.07, 95% CI: 0.70-1.62; p = 0.764; HR for OS: 0.77, 95% CI: 0.45-1.31; p = 0.328) and ICI-target (HR for PFS: 1.20, 95% CI: 0.77-1.88; p = 0.413; HR for OS: 0.86, 95% CI: 0.51-1.47; p = 0.583) but resulted in more adverse events (p < 0.001; p = 0.010). Multivariable and propensity score analyses supported these findings. CONCLUSIONS: Among patients with uICC, ICI-chemo or ICI-target provided more survival benefits than Chemo while achieving comparable prognoses and fewer adverse events than ICI-target-chemo.

The Crosstalk Between Immune Infiltration, Circulating Tumor Cells, and Metastasis in Pancreatic Cancer: Identification of HMGB3 From a Multiple Omics Analysis.

Metastasis is the major cause of death in patients with pancreatic ductal adenocarcinoma (PDAC), and circulating tumor cells (CTCs) play an important role in the development of metastasis. However, few studies have uncovered the metastasis mechanism of PDAC based on CTCs. In this study, the existing bulk RNA-sequencing (bulk RNA-seq) and single-cell sequencing (scRNA-seq) data for CTCs in pancreatic cancer were obtained from the Gene Expression Omnibus (GEO) database. Analysis of tumor-infiltrating immune cells (TIICs) by CIBERSORT showed that the CTCs enriched from the peripheral blood of metastatic PDAC were found to contain a high proportion of T cell regulators (Tregs) and macrophages, while the proportion of dendritic cells (DCs) was lower than that enriched from localized PDAC. Through weighted gene co-expression network analysis (WGCNA) and the result of scRNA-seq, we identified the hub module (265 genes) and 87 marker genes, respectively, which were highly associated with metastasis. The results of functional enrichment analysis indicated that the two gene sets mentioned above are mainly involved in cell adhesion and cytoskeleton and epithelial-mesenchymal transition (EMT). Finally, we found that HMGB3 was the hub gene according to the Venn diagram. The expression of HMGB3 in PDAC was significantly higher than that in normal tissues (protein and mRNA levels). HMGB3 expression was significantly positively correlated with both EMT-related molecules and CTC cluster-related markers. Furthermore, it was also found that HMGB3 mutations were favorably related to tumor-associated immune cells through the TIMER2.0 online tool. We further demonstrated that PDAC patients with higher HMGB3 expression had significantly worse overall survival (OS) in multiple datasets. In summary, our study suggests that HMGB3 is a hub gene associated with EMT in CTCs, the formation of CTC clusters, and infiltration patterns of immune cells favorable for tumor progression and metastasis to distant organs.

A Novel Nomogram for Predicting Postoperative Liver Failure After Major Hepatectomy for Hepatocellular Carcinoma.

Background: Post-hepatectomy liver failure (PHLF) is the most common cause of mortality after major hepatectomy in hepatocellular carcinoma (HCC) patients. We aim to develop a nomogram to preoperatively predict grade B/C PHLF defined by the International Study Group on Liver Surgery Grading (ISGLS) in HCC patients undergoing major hepatectomy. Study Design: The consecutive HCC patients who underwent major hepatectomy at the Eastern Hepatobiliary Surgery Hospital between 2008 and 2013 served as a training cohort to develop a preoperative nomogram, and patients from 2 other hospitals comprised an external validation cohort. Least absolute shrinkage and selection operator (LASSO) logistic regression was applied to identify preoperative predictors of grade B/C PHLF. Multivariable logistic regression was utilized to establish a nomogram model. Internal and external validations were used to verify the performance of the nomogram. The accuracy of the nomogram was also compared with the conventional scoring models, including MELD and ALBI score. Results: A total of 880 patients who underwent major hepatectomy (668 in the training cohort and 192 in the validation cohort) were enrolled in this study. The independent risk factors of grade B/C PHLF were age, gender, prothrombin time, total bilirubin, and CSPH, which were incorporated into the nomogram. Good prediction discrimination was achieved in the training (AUROC: 0.73) and validation (AUROC: 0.72) cohorts. The calibration curve also showed good agreement in both training and validation cohorts. The nomogram has a better performance than MELD and ALBI score models. Conclusion: The proposed nomogram showed more accurate ability to individually predict grade B/C PHLF after major hepatectomy in HCC patients than MELD and ALBI scores.

External Validation of Six Liver Functional Reserve Models to predict Posthepatectomy Liver Failure after Major Resection for Hepatocellular Carcinoma.

Objective: To validate and compare the predictive ability of albumin-bilirubin model (ALBI) with other 5 liver functional reserve models (APRI, FIB4, MELD, PALBI, King's score) for posthepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC) who underwent major hepatectomy. Methods: Data of patients undergoing major hepatectomy for HCC from 4 hospitals between January 01, 2008 and December 31, 2019 were retrospectively analyzed. PHLF was evaluated according to the definition of the 50-50 criteria. Performances of six liver functional reserve models were determined by the area under the receiver operating characteristic curve (AUC), calibration plot and decision curve analysis. Results: A total of 745 patients with 103 (13.8%) experienced PHLF were finally included in this study. Among six liver functional reserve models, ALBI showed the highest AUC (0.64, 95% CI: 0.58-0.69) for PHLF. All models showed good calibration and greater net benefit than treating all patients at a limit range of threshold probabilities, but the ALBI demonstrated net benefit across the largest range of threshold probabilities. Subgroup analysis also showed ALBI had good predictive performance in cirrhotic (AUC=0.63) or non-cirrhotic (AUC=0.62) patients. Conclusion: Among the six models, the ALBI model shows more accurate predictive ability for PHLF in HCC patients undergoing major hepatectomy, regardless of having cirrhosis or not.