Hepatic arterial chemotherapy infusion combined with tyrosine kinase inhibitors and PD-1 inhibitors for advanced hepatocellular carcinoma with high-risk: A propensity score matching study.

OBJECTIVE: To ascertain the therapeutic efficacy and safety of FOLFOX (oxaliplatin, fluorouracil, and leucovorin)-based hepatic arterial infusion chemotherapy (HAIC) combined with tyrosine kinase inhibitors (TKI) and programmed cell death protein-1 inhibitors (PD-1 inhibitors) (triple therapy), as a first-line treatment in high-risk advanced hepatocellular carcinoma (aHCC with Vp4 portal vein invasion or/and tumor diameter ≥ 10 cm). METHODS: This retrospective multicenter study included 466 high-risk aHCC patients treated with either triple therapy (n = 245) or dual therapy (TKI and PD-1 inhibitors, n = 221). The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were compared between the two groups. Propensity score matching (PSM) was performed to reduce bias between the two groups. RESULTS: After PSM (1:1), 194 patients in each group were analyzed. The triple-therapy group showed a longer median OS (24.6 months vs. 11.9 months; HR = 0.43, P < 0.001) and a longer median PFS (10.0 months vs. 7.7 months; HR = 0.68, P = 0.002) than the dual-therapy group. The survival rates at 6, 12, and 24 months were 94.2%, 71.0%, and 50.8% for triple therapy and 75.9%, 49.9%, and 26.8% for dual therapy. The ORR in the triple-therapy group was significantly higher (57.7% vs. 28.9%, P < 0.001). In the triple-therapy group, more patients converted to non-high-risk (68.0% vs. 36.6%, P < 0.001) and received salvage liver resection or ablation after downstaging conversion (16.5% vs. 9.2%, P = 0.033). The grade 3/4 adverse events were 59.2% and 47.4% in the triple-therapy group and dual-therapy group, respectively (P = 0.022). CONCLUSION: FOLFOX-based HAIC plus TKI and PD-1 inhibitors significantly improve survival prognosis compared with TKI plus PD-1 inhibitors. This is a potential first-line treatment for high-risk aHCC, with a relatively controlled safety profile.

Hepatic arterial infusion chemotherapy plus camrelizumab and apatinib for advanced hepatocellular carcinoma.

BACKGROUND AND AIMS: There is limited information on combination of hepatic arterial infusion chemotherapy (HAIC) and systemic therapy for advanced hepatocellular carcinoma (Ad-HCC). We aim to compare the efficacy and safety of HAIC plus camrelizumab (a PD-1 inhibitor) and apatinib (an VEGFR-2 inhibitor) versus camrelizumab and apatinib for Ad-HCC. METHODS: From April 2019 to October 2022, 416 patients with Ad-HCC who received either HAIC plus camrelizumab and apatinib (TRIPLET protocol, n = 207) or camrelizumab and apatinib (C-A protocol, n = 209) were reviewed retrospectively. The propensity score matching (PSM) was used to reduce selective bias. Overall survival (OS) and progression-free survival (PFS) were compared using the Kaplan-Meier method with the log-rank test. Cox regression analyses of independent prognostic factors were evaluated. RESULTS: After PSM 1:1, 109 patients were assigned to two groups. The median OS of not reached in the TRIPLET group was significantly longer than that of 19.9 months in the C-A group (p < 0.001), while in the TRIPLET group, the median PFS of 11.5 months was significantly longer than that of 9.6 months in the C-A group (p < 0.001). Multivariate analyses showed that the factors significantly affected the OS were CTP grade, tumor number > 3, and TRIPLET treatment (p < 0.001). Grade 3/4 adverse events occurred at a rate of 82.1% vs. 71.3% in TRIPLET and C-A groups, respectively. CONCLUSION: The TRIPLET protocol has promising survival benefits in the management of patients with Ad-HCC, with acceptable safety. TRAIL REGISTRATION: The study has been retrospectively registered at Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ , ChiCTR2300075828).

Machine learning-based decision support model for selecting intra-arterial therapies for unresectable hepatocellular carcinoma: A national real-world evidence-based study.

IMPORTANCE: Intra-arterial therapies(IATs) are promising options for unresectable hepatocellular carcinoma(HCC). Stratifying the prognostic risk before administering IAT is important for clinical decision-making and for designing future clinical trials. OBJECTIVE: To develop and validate a machine learning(ML)-based decision support model(MLDSM) for recommending IAT modalities for unresectable HCC. DESIGN, SETTING, AND PARTICIPANTS: Between October 2014 and October 2022, a total of 2,959 patients with HCC who underwent initial IATs were enroled retrospectively from 13 tertiary hospitals. These patients were divided into the training cohort (n = 1700), validation cohort (n = 428), and test cohort (n = 200). MAIN OUTCOMES AND MEASURES: Thirty-two clinical variables were input, and five supervised ML algorithms, including eXtreme Gradient Boosting (XGBoost), Categorical Gradient Boosting (CatBoost), Gradient Boosting Decision Tree (GBDT), Light Gradient Boosting Machine (LGBM) and Random Forest (RF), were compared using the areas under the receiver operating characteristic curve (AUC) with the DeLong test. RESULTS: A total of 1856 patients were assigned to the IAT alone Group(I-A), and 1103 patients were assigned to the IAT combination Group(I-C). The 12-month death rates were 31.9% (352/1103) in the I-A group and 50.4% (936/1856) in the I-C group. For the test cohort, in the I-C group, the CatBoost model achieved the best discrimination when 30 variables were input, with an AUC of 0.776 (95% confidence intervals [CI], 0.833-0.868). In the I-A group, the LGBM model achieved the best discrimination when 24 variables were input, with an AUC of 0.776 (95% CI, 0.833-0.868). According to the decision trees, BCLC grade, local therapy, and diameter as top three variables were used to guide clinical decisions between IAT modalities. CONCLUSIONS AND RELEVANCE: The MLDSM can accurately stratify prognostic risk for HCC patients who received IATs, thus helping physicians to make decisions about IAT and providing guidance for surveillance strategies in clinical practice.

Multimodal imaging-based prediction of recurrence for unresectable HCC after downstage and resection-cohort study.

BACKGROUND: Surgical resection (SR) following transarterial chemoembolization (TACE)-based downstaging is a promising treatment for unresectable hepatocellular carcinoma (uHCC), and identification of patients at high-risk of postoperative recurrence may assist individualized treatment. PURPOSE: To develop and externally validate pre- and postoperative prognostic models integrating multimodal CT and DSA features as well as clinico-therapeutic-pathological features for predicting disease-free survival (DFS) after TACE-based downstaging therapy. MATERIALS AND METHODS: From March 2008 to August 2022, 488 consecutive patients with BCLC A/B uHCC receiving TACE-based downstaging therapy and subsequent SR were included from four tertiary-care hospitals. All CT and DSA images were independently evaluated by two blinded radiologists. In the derivation cohort (n=390), the XGBoost algorithm was used for feature selection, and Cox regression analysis for developing nomograms for DFS (time from downstaging to postoperative recurrence or death). In the external testing cohort (n=98), model performances were compared with five major staging systems. RESULTS: The preoperative nomogram included over three tumors (HR, 1.42; P=0.003), intratumoral artery (HR, 1.38; P=0.006), TACE combined with tyrosine kinase inhibitor (HR, 0.46; P<0.001) and objective response to downstaging therapy (HR, 1.60; P<0.001); while the postoperative nomogram included over three tumors (HR, 1.43; P=0.013), intratumoral artery (HR, 1.38; P=0.020), TACE combined with tyrosine kinase inhibitor (HR, 0.48; P<0.001), objective response to downstaging therapy (HR, 1.69; P<0.001) and microvascular invasion (HR, 2.20; P<0.001). The testing dataset C-indexes of the pre- (0.651) and postoperative (0.687) nomograms were higher than all five staging systems (0.472-0.542; all P<0.001). Two prognostically distinct risk strata were identified according to these nomograms (all P<0.001). CONCLUSION: Based on 488 patients receiving TACE-based downstaging therapy and subsequent SR for BCLC A/B uHCCs, we developed and externally validated two nomograms for predicting DFS, with superior performances than five major staging systems and effective survival stratification.

Hepatic artery infusion chemotherapy combined with camrelizumab plus rivoceranib for hepatocellular carcinoma with portal vein tumor thrombosis: a multicenter propensity score-matching analysis.

BACKGROUND: Portal vein tumor thrombosis (PVTT) signifies late-stage hepatocellular carcinoma (HCC) with high-risk progression and poor prognosis. As a standard treatment, sorafenib monotherapy has limited the efficacy in managing HCC with PVTT. Currently, both hepatic arterial infusion chemotherapy (HAIC) and the combination of camrelizumab and rivoceranib have shown favorable survival benefits for advanced HCC, surpassing the standard sorafenib treatment. In this study, we investigate the safety and efficacy of HAIC combined with camrelizumab and rivoceranib in treating HCC patients with PVTT. METHODS: From January 2020 to December 2021, HCC patients with PVTT, who received either a triple regime of HAIC combined with camrelizumab and rivoceranib or a dual regime of camrelizumab and rivoceranib as their first-line treatment, were reviewed for eligibility at four hospital centers in China. To balance any intergroup differences, propensity score matching (PSM) was applied. The aim of this study is to compare the efficacy of the dual and triple combination treatment regimens based on survival prognosis and tumor response and evaluate the safety based on the occurrence of adverse reactions. RESULT: In this study, a total of 411 patients who received either the triple treatment regime (HAIC combined with camrelizumab plus rivoceranib, referred to as the HAICCR group, n = 292) or the dual treatment regime (camrelizumab combined with rivoceranib, referred to as the CR group, n = 119) between January 2020 and December 2021 were included. The results showed that the HAICCR group exhibited significantly better overall survival (mOS: 19.60 months vs. 11.50 months, p < 0.0001) and progression-free survival (mPFS: 10.0 months vs. 5.6 months, p < 0.0001) compared to the CR group in the overall cohort. Moreover, the HAICCR group also had a significantly higher ORR (objective response rate, 55.5% vs. 42.0%, p = 0.013) and DCR (disease control rate, 89.0% vs. 79.0%) compared to the CR group. After PSM, a final matched cohort of 83 pairs was obtained, and the survival benefits were consistent in this cohort as well (mOS: 18.70 months vs. 11.0 months, p < 0.0001; mPFS: 10.0 months vs. 5.6 months, p < 0.0001). However, there was no significant difference in the ORR between the triple and dual combination regimes. Univariate and multivariate analysis showed that CTP (Child-Turcotte-Pugh) stage, ALBI (albumin-bilirubin index) grade, tumor number, and treatment regime were significant risk factors affecting overall survival, while AFP (α-fetoprotein) level, tumor number, metastasis, and treatment regime were significant risk factors affecting progression-free survival. As for safety, hypertension and hand-foot syndrome were the two most common adverse reactions in both groups, with no significant difference in the occurrence of adverse reactions between the two groups (p < 0.05). CONCLUSION: In the context of advanced HCC patients with PVTT, the combination regime of HAIC and camrelizumab plus rivoceranib demonstrates more excellent capacity for prolonging survival and offers a well-tolerated safety compared to the CR dual therapy approach. This triple regime represents a therapeutic modality of broad prospects and vast potential for HCC patients with PVTT.

Association of serum AFP trajectories and hepatocellular carcinoma outcomes after hepatic arterial infusion chemotherapy: A longitudinal, multicenter study.

AIM: This study aims to investigate α-fetoprotein (AFP) trajectories for prediction of survival outcomes after hepatic arterial infusion chemotherapy (HAIC) treatment in large hepatocellular carcinoma (HCC). METHODS: From May 2014 to June 2020, 889 eligible patients with large HCC underwent HAIC were retrospectively enrolled from five hospitals. A latent class growth mixed (LCGM) model was applied to distinguish potential AFP level dynamic changing trajectories. Inverse-probability-of-treatment weighted (IPTW) analyses were performed to eliminate unmeasured confounders through marginal structural models. Multivariate Cox proportional hazard regression analyses were used to determine the overall survival (OS) in patients with large HCC. Performance of these serum markers for survival prediction was compared by areas under receiver operating characteristic analysis with the Delong test. RESULTS: The median follow-up time was 23.7 (interquartile range, 3.8-115.3). A total of 1009 patients with large HCC, who underwent HAIC with AFP repeatedly measured 3-10 times, were enrolled in the study. Three distinct trajectories of these serum AFP were identified using the LCGM model: high stable (37.0%; n = 373), low stable (15.7%; n = 159), and sharp-falling (47.3%; n = 477). Multivariate Cox proportional hazard regression analyses found that ALBI stage 2-3, BCLC-C stage and high-stable AFP trajectories were associated with OS. AFP trajectories yield the optimal predictive performance in all risk factors. CONCLUSIONS: The AFP trajectories based on longitudinal AFP change showed outstanding performance for predicting survival outcomes after HAIC treatment in large HCC, which provide a potential monitoring tool for improving clinical decision-making.

High-Risk Hepatocellular Carcinoma: Hepatic Arterial Infusion Chemotherapy versus Transarterial Chemoembolization.

Objective: To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with transarterial chemoembolization (TACE) for the treatment of high-risk hepatocellular carcinoma (hHCC) patients. Methods: Between January 2014 and August 2022, a total of 1765 consecutive patients with hHCC who underwent initial intra-arterial therapies were reviewed and divided into a TACE group (n, 507) and a HAIC group (n, 426). The study used propensity score matching (PSM) to reduce selectivity bias. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan‒Meier curves with the Log rank test. The objective response rate (ORR), conversion surgery rate (CSR) adverse event (AE) comparison and subgroup analysis were performed between the two groups. Results: After PSM 1:1, 444 patients were divided into two groups. The patients with hHCC who received HAIC had higher median PFS (6.1 vs 3.3 months, P < 0.001) and OS (10.3 vs 8.2 months, P=0.303) than TACE. Higher ORR (24.8% vs 11.7%) and CSR (15.5% vs 8.9%) were found in the HAIC group than in the TACE group (both P < 0.05). The incidence of grade 3/4 AE was 23.9% and 8.1% in the TACE and HAIC groups, respectively. The subgroup analysis suggest that HAIC appeared to particularly benefit patients with tumor diameter of more than 10 centimeters (hazard ratio [HR], 0.6; 95% CI, 0.47-0.77; p, 0.00) and PVTT Vp4 (HR, 0.56; 95% CI, 0.39-0.8; P, 0.01) for PFS outperforming TACE. Conclusion: HAIC can provide better disease control for hHCC than cTACE, with a comparable long-term OS and safety.

Highly Aligned Graphene Aerogels for Multifunctional Composites.

Stemming from the unique in-plane honeycomb lattice structure and the sp2 hybridized carbon atoms bonded by exceptionally strong carbon-carbon bonds, graphene exhibits remarkable anisotropic electrical, mechanical, and thermal properties. To maximize the utilization of graphene's in-plane properties, pre-constructed and aligned structures, such as oriented aerogels, films, and fibers, have been designed. The unique combination of aligned structure, high surface area, excellent electrical conductivity, mechanical stability, thermal conductivity, and porous nature of highly aligned graphene aerogels allows for tailored and enhanced performance in specific directions, enabling advancements in diverse fields. This review provides a comprehensive overview of recent advances in highly aligned graphene aerogels and their composites. It highlights the fabrication methods of aligned graphene aerogels and the optimization of alignment which can be estimated both qualitatively and quantitatively. The oriented scaffolds endow graphene aerogels and their composites with anisotropic properties, showing enhanced electrical, mechanical, and thermal properties along the alignment at the sacrifice of the perpendicular direction. This review showcases remarkable properties and applications of aligned graphene aerogels and their composites, such as their suitability for electronics, environmental applications, thermal management, and energy storage. Challenges and potential opportunities are proposed to offer new insights into prospects of this material.

Microwave ablation versus liver resection for primary intrahepatic cholangiocarcinoma within Milan criteria: a long-term multicenter cohort study.

Background: Ablation has been recommended by worldwide guidelines as first-line treatment for hepatocellular carcinoma (HCC), while evidence regarding its efficacy for primary intrahepatic cholangiocarcinoma (iCCA) is lacking. We aimed to study the efficacy of ablation in treating iCCA by comparing its prognosis with surgery. Methods: In this real-world multicenter cohort study from January 2009 to June 2022, 10,441 iCCA patients from ten tertiary hospitals were identified. Patients who underwent curative-intent microwave ablation (MWA) or liver resection (LR) for tumors within Milan criteria were included. One-to-many propensity score matching (PSM) at variable ratios (1:n ≤4) was used to balance baseline characteristics. Mediation analysis was applied to identify potential mediators of the survival difference. Findings: 944 patients were finally enrolled in this study, with 221 undergoing MWA and 723 undergoing LR. After PSM, 203 patients in the MWA group were matched with 588 patients in the LR group. The median follow-up time was 4.7 years. Compared with LR, MWA demonstrated similar overall survival (5-year 44.8% versus 40.4%; HR 0.96, 95% CI 0.71-1.29, P = .761). There was an improvement in the 5-year disease-free survival rate for MWA from 17.1% during the period of 2009-2016 to 37.3% during 2017-2022, becoming comparable to the 40.8% of LR (P = .129). The proportion of ablative margins ≥5 mm increased from 25% to 61% over the two periods, while this proportion of surgical margins was 62% and 77%, respectively. 34.5% of DFS disparity can be explained by the mediation effect of margins (P < .0001). Similar DFS was observed when both ablative and surgical margins exceeded 5 mm (HR 0.83, 95% CI 0.52-1.32, P = .41). Interpretation: MWA may be considered as a viable alternative to LR for iCCA within Milan criteria when an adequate margin can be obtained. Funding: National Natural Science Foundation of China.

Efficiency and safety of hepatic arterial infusion chemotherapy (HAIC) combined with anti-PD1 therapy versus HAIC monotherapy for advanced hepatocellular carcinoma: A multicenter propensity score matching analysis.

PURPOSE: To investigate the clinical efficacy and safety of combination therapy of hepatic arterial infusion chemotherapy (HAIC) and anti-programmed cell death protein-1 (PD-1) therapy in the treatment of advanced hepatocellular carcinoma (HCC). METHODS: In this retrospective clinical research, from March 2018 to December 2019, 1158 HCC patients categorized as BCLC stage C were reviewed for eligibility. We utilized propensity score matching (PSM) to mitigate initial disparities between the groups. The evaluation of the best tumor response was conducted in accordance with mRECIST 1.1 criteria. The difference in survival outcomes including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between groups were compared. RESULTS: Following the eligibility review, 453 patients underwent a combined treatment of HAIC with PD1 inhibitors (HAIC-PD1 group), while 221 patients received HAIC monotherapy (HAIC group) met the inclusion criteria and were finally enrolled in this study. In the entire cohort, the HAIC-PD1 group exhibited significantly prolonged overall survival (median overall survival: 40.4 months vs. 9.7 months, p < 0.001) and progression-free survival (median progression-free survival: 22.1 months vs. 5.8 months, p < 0.001). By propensity score, patients were matched according to baseline differences, resulting in all 442 patients in group HAIC-PD1 (n = 221) and group HAIC (n = 221). After PSM adjustment, as well, the survival of the HAIC-PD1 group was still distinctly longer than the HAIC group (median overall survival time, 40.4 months vs 9.7 months, p < 0.001; median progression-free survival, 22.1 months vs 5.7 months, p < 0.001). Univariate and multivariable analysis demonstrated that AFP level, metastasis, and therapeutic schedule were independent predictive factors for overall survival. CONCLUSION: The combination therapy of HAIC and PD1 inhibitors successfully extended OS to advanced HCC patients and could be a better choice than HAIC monotherapy.

Prognosis prediction and risk stratification of transarterial chemoembolization or intraarterial chemotherapy for unresectable hepatocellular carcinoma based on machine learning.

OBJECTIVE: To develop and validate a risk scoring scale model (RSSM) for stratifying prognostic risk after intra-arterial therapies (IATs) for hepatocellular carcinoma (HCC). METHODS: Between February 2014 and October 2022, 2338 patients with HCC who underwent initial IATs were consecutively enrolled. These patients were divided into training datasets (TD, n = 1700), internal validation datasets (ITD, n = 428), and external validation datasets (ETD, n = 200). Five-years death was used to predict outcome. Thirty-four clinical information were input and five supervised machine learning (ML) algorithms, including eXtreme Gradient Boosting (XGBoost), Categorical Gradient Boosting (CatBoost), Gradient Boosting Decision Tree (GBDT), Light Gradient Boosting Machine (LGBT), and Random Forest (RF), were compared using the areas under the receiver operating characteristic (AUC) with DeLong test. The variables with top important ML scores were used to build the RSSM by stepwise Cox regression. RESULTS: The CatBoost model achieved the best discrimination when 12 top variables were input, with the AUC of 0.851 (95% confidence intervals (CI), 0.833-0.868) for TD, 0.817 (95%CI, 0.759-0.857) for ITD, and 0.791 (95%CI, 0.748-0.834) for ETD. The RSSM was developed based on the immune checkpoint inhibitors (ICI) (hazard ratios (HR), 0.678; 95%CI 0.549, 0.837), tyrosine kinase inhibitors (TKI) (HR, 0.702; 95%CI 0.605, 0.814), local therapy (HR, 0.104; 95%CI 0.014, 0.747), response to the first IAT (HR, 4.221; 95%CI 2.229, 7.994), tumor size (HR, 1.054; 95%CI 1.038, 1.070), and BCLC grade (HR, 2.375; 95%CI 1.950, 2.894). Kaplan-Meier analysis confirmed the role of RSSM in risk stratification (p < 0.001). CONCLUSIONS: The RSSM can stratify accurately prognostic risk for HCC patients received IAT. On the basis, an online calculator permits easy implementation of this model. CLINICAL RELEVANCE STATEMENT: The risk scoring scale model could be easily implemented for physicians to stratify risk and predict prognosis quickly and accurately, thereby serving as a more favorable tool to strengthen individualized intra-arterial therapies and management in patients with unresectable hepatocellular carcinoma. KEY POINTS: • The Categorical Gradient Boosting (CatBoost) algorithm achieved the optimal and robust predictive ability (AUC, 0.851 (95%CI, 0.833-0.868) in training datasets, 0.817 (95%CI, 0.759-0.857) in internal validation datasets, and 0.791 (95%CI, 0.748-0.834) in external validation datasets) for prediction of 5-years death of hepatocellular carcinoma (HCC) after intra-arterial therapies (IATs) among five machine learning models. • We used the SHapley Additive exPlanations algorithms to explain the CatBoost model so as to resolve the black boxes of machine learning principles. • A simpler restricted variable, risk scoring scale model (RSSM), derived by stepwise Cox regression for risk stratification after intra-arterial therapies for hepatocellular carcinoma, provides the potential forewarning to adopt combination strategies for high-risk patients.

Pseudo-capsulated Hepatocellular Carcinoma: Hepatic Arterial Infusion Chemotherapy Versus Transcatheter Arterial Chemoembolization.

RATIONALE AND OBJECTIVES: The effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) or transarterial chemoembolization (TACE) for cases with single pseudo-capsuled hepatocellular carcinoma (pHCC), as well as their survival outcomes, were investigated. MATERIALS AND METHODS: A total of 196 cases with single pHCC (diameter >5 cm) receiving initial HAIC (n = 92) and TACE (n = 104) were enrolled. The propensity score match (PSM) approach based on Cox models was employed to tune any possible imbalance in treatment assignment. The overall survival (OS), objective response rate (ORR), progression-free survival (PFS), and partial response rate (PRR) of the subjects were investigated using the log-rank test. The independent risk factors for outcomes were investigated by univariate and multivariate analyses, and the results were analyzed using the Cox regression model. RESULTS: The median follow-up of the subjects was 22.3 months. After PSM, no significant difference was found in the OS of the HAIC and TACE groups (OS, 12.0 vs. 16.8 months; P = .267), while the median PFS of the TACE group was prolonged compared with the HAIC group (PFS, 5.7 vs. 2.8 months; P = .003). Moreover, PRR and ORR of the TACE group were prolonged compared with the HAIC group (PRR, 34.6% vs. 21.7%; P = .046; ORR, 35.6% vs. 21.7%; P = .033). The nomogram model showed high predictive accuracy and significant discrimination. CONCLUSION: TACE therapy could delay tumor progression compared with HAIC for cases with a single pHCC.

Protective Effect of Ginsenoside CK against Autoimmune Hepatitis Induced by Concanavalin A.

Ginsenoside CK, a kind of rare ginsenoside transformed from protopanaxadiol saponins extracted from the genus Panax, has been proven to possess favorable bioactivities such as anti-inflammatory, anti-cancer, anti-diabetes, and hepatoprotective effects. The current study is targeted to determine the effect of ginsenoside CK on hepatitis induced by concanavalin A (Con A). Mice were treated with different dosages of ginsenoside CK for 7 days, and Con A (15 mg/kg) was intravenously injected to induce autoimmune hepatitis (AIH) after the last administration. The results demonstrated that pretreatment with ginsenoside CK (40 mg/kg) could obviously ameliorate the increase in serum indicators related to liver function such as AST, ALT, and ALP, and hepatic lesions induced by Con A. Meanwhile, ginsenoside CK suppressed hepatocyte apoptosis, which was observed in pathological data, and immunoblotting results showed that the expression of Bax, Bcl-2, and other proteins was regulated by CK. Furthermore, the release of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and IL-6 in mice with AIH were lowered by the administration of 40 mg/kg of ginsenoside CK. Furthermore, ginsenoside CK elevated the gene expression of Nrf2 and Sirt1 and augmented downstream target genes such as HO-1. In addition, a significant inhibition effect of the TLR4/NF-κB signal was observed in 40 mg/kg CK-pretreated mice compared with the model group. To sum up, the results indicated that ginsenoside CK has a notable hepatoprotective effect against AIH by activating Sirt1/Nrf2 and suppressing the TLR4/NF-κB signaling pathway.

The impact of erythroblast enucleation efficiency on the severity of anemia in patients with myelodysplastic syndrome.

Anemia is the most common manifestation in myelodysplastic syndrome (MDS) patients, but the cause of ineffective hematopoiesis is not fully understood. Enucleation is an important event in the maturation process of erythroblasts. According to a series of morphological phenotypes of the pathological development of MDS erythroblasts, we speculate that there may be enucleation disorders. To verify this hypothesis, we cultured MDS bone marrow CD34+ cells in vitro and induced erythroblast development. The results showed that erythroblast enucleation in MDS was significantly lower than that in the normal group, and the rate of enucleation was positively correlated with hemoglobin concentration. Risk stratification of MDS was performed to further analyze the differences in enucleation among the normal group, low-middle risk group and high-risk group. The results showed that the enucleation rate of the high risk group was higher than that of the low-middle risk group but still lower than that of the normal group. Moreover, the expression of pERK and pAKT in MDS erythroblasts in the high risk group was higher than that in the normal group, while the expression of pERK and pAKT in the low-middle risk group was lower than that in the normal group. Furthermore, the enucleation of MDS was positively correlated with the phosphorylation degree of ERK and AKT. In conclusion, this study reveals that the enucleation of erythroblasts is one of the possible causes of anemia in MDS. Video Abstract.

The relationship between central obesity and risk of breast cancer: a dose-response meta-analysis of 7,989,315 women.

Purpose: Central obesity may contribute to breast cancer (BC); however, there is no dose-response relationship. This meta-analysis examined the effects of central obesity on BC and their potential dose-response relationship. Methods: In the present study, PubMed, Medline, Embase, and Web of Science were searched on 1 August 2022 for published articles. We included the prospective cohort and case-control studies that reported the relationship between central obesity and BC. Summary effect size estimates were expressed as risk ratios (RRs) or odds ratios (ORs) with 95% confidence intervals (95% CI) and were evaluated using random-effect models. The inconsistency index (I2) was used to quantify the heterogeneity magnitude derived from the random-effects Mantel-Haenszel model. Results: This meta-analysis included 57 studies (26 case-control and 31 prospective cohort) as of August 2022. Case-control studies indicated that waist circumference (WC) (adjusted OR = 1.18; 95% CI: 1.00-1.38; P = 0.051) and waist-to-hip ratio (WHR) (adjusted OR = 1.28; 95% CI: 1.07-1.53; P = 0.008) were significantly positively related to BC. Subgroup analysis showed that central obesity measured by WC increased the premenopausal (adjusted OR = 1.15; 95% CI: 0.99-1.34; P = 0.063) and postmenopausal (adjusted OR = 1.18; 95% CI: 1.03-1.36; P = 0.018) BC risk and the same relationship appeared in WHR between premenopausal (adjusted OR = 1.38; 95% CI: 1.19-1.59; P < 0.001) and postmenopausal (adjusted OR = 1.41; 95% CI: 1.22-1.64; P < 0.001). The same relationship was observed in hormone receptor-positive (HR+) (adjusted ORWC = 1.26; 95% CI: 1.02-1.57; P = 0.035, adjusted ORWHR = 1.41; 95% CI: 1.00-1.98; P = 0.051) and hormone receptor-negative (HR-) (adjusted ORWC = 1.44; 95% CI: 1.13-1.83; P = 0.003, adjusted ORWHR = 1.42; 95% CI: 0.95-2.13; P = 0.087) BCs. Prospective cohort studies indicated that high WC (adjusted RR = 1.12; 95% CI: 1.08-1.16; P < 0.001) and WHR (adjusted RR = 1.05; 95% CI: 1.018-1.09; P = 0.017) may increase BC risk. Subgroup analysis demonstrated a significant correlation during premenopausal (adjusted RR = 1.08; 95% CI: 1.02-1.14; P = 0.007) and postmenopausal (adjusted RR = 1.14; 95% CI: 1.10-1.19; P < 0.001) between BC and central obesity measured by WC, and WHR was significantly positively related to BC both premenopausal (adjusted RRpre = 1.04; 95% CI: 0.98-1.11; P = 0.169) and postmenopausal (adjusted RRpost = 1.04; 95% CI: 1.02-1.07; P = 0.002). Regarding molecular subtype, central obesity was significantly associated with HR+ (adjusted ORWC = 1.13; 95% CI: 1.07-1.19; P < 0.001, adjusted ORWHR = 1.03; 95% CI: 0.98-1.07; P = 0.244) and HR- BCs (adjusted ORWC =1.11; 95% CI: 0.99-1.24; P = 0.086, adjusted ORWHR =1.01; 95% CI: 0.91-1.13; P = 0.808). Our dose-response analysis revealed a J-shaped trend in the relationship between central obesity and BC (measured by WC and WHR) in case-control studies and an inverted J-shaped trend between BMI (during premenopausal) and BC in the prospective cohort. Conclusion: Central obesity is a risk factor for premenopausal and postmenopausal BC, and WC and WHR may predict it. Regarding the BC subtype, central obesity is proven to be a risk of ER+ and ER- BCs. The dose-response analysis revealed that when BMI (during premenopausal) exceeded 23.40 kg/m2, the risk of BC began to decrease, and WC higher than 83.80 cm or WHR exceeded 0.78 could efficiently increase the BC risk. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022365788.

A multitask deep learning radiomics model for predicting the macrotrabecular-massive subtype and prognosis of hepatocellular carcinoma after hepatic arterial infusion chemotherapy.

BACKGROUND: The macrotrabecular-massive (MTM) is a special subtype of hepatocellular carcinoma (HCC), which has commonly a dismal prognosis. This study aimed to develop a multitask deep learning radiomics (MDLR) model for predicting MTM and HCC patients' prognosis after hepatic arterial infusion chemotherapy (HAIC). METHODS: From June 2018 to March 2020, 158 eligible patients with HCC who underwent surgery were retrospectively enrolled in MTM related cohorts, and 752 HCC patients who underwent HAIC were included in HAIC related cohorts during the same period. DLR features were extracted from dual-phase (arterial phase and venous phase) contrast-enhanced computed tomography (CECT) of the entire liver region. Then, an MDLR model was used for the simultaneous prediction of the MTM subtype and patient prognosis after HAIC. The MDLR model for prognostic risk stratification incorporated DLR signatures, clinical variables and MTM subtype. FINDINGS: The predictive performance of the DLR model for the MTM subtype was 0.968 in the training cohort [TC], 0.912 in the internal test cohort [ITC] and 0.773 in the external test cohort [ETC], respectively. Multivariable analysis identified portal vein tumor thrombus (PVTT) (p = 0.012), HAIC response (p < 0.001), HAIC sessions (p < 0.001) and MTM subtype (p < 0.001) as indicators of poor prognosis. After incorporating DLR signatures, the MDLR model yielded the best performance among all models (AUC, 0.855 in the TC, 0.805 in the ITC and 0.792 in the ETC). With these variables, the MDLR model provided two risk strata for overall survival (OS) in the TC: low risk (5-year OS, 44.9%) and high risk (5-year OS, 4.9%). INTERPRETATION: A tool based on MDLR was developed to consider that the MTM is an important prognosis factor for HCC patients. MDLR showed outstanding performance for the prognostic risk stratification of HCC patients who underwent HAIC and may help physicians with therapeutic decision making and surveillance strategy selection in clinical practice.

Identification of Potential Mechanisms of Rk1 Combination with Rg5 in the Treatment of Type II Diabetes Mellitus by Integrating Network Pharmacology and Experimental Validation.

In this study, we aimed to explore the potential targets and functional mechanisms of Rk1 combined with Rg5 (Rk1+Rg5) against type II diabetes mellitus (T2DM). Network pharmacology and molecular docking were used to predict and verify the targets and signaling pathways of Rk1+Rg5 against T2DM. The results were further confirmed by a db/db mouse model and a model using PA-induced L6 cells. According to network pharmacology, a total of 250 core targets of Rk1+Rg5 towards T2DM were identified; the insulin resistance signaling pathways were enriched by KEGG. Results of molecular docking indicated good binding affinity of Rk1 and Rg5 to Akt1. In vivo and in vitro studies further showed that Rk1+Rg5 is an inhibitor of skeletal muscle insulin resistance. The results showed that Rk1+Rg5 significantly improved the hyperglycemic state of db/db mice, alleviated dyslipidemia, and promoted skeletal muscle glucose uptake. This phenomenon was closely related to the alleviation of the insulin resistance in skeletal muscles. Finally, the combination activated the Akt signaling pathway and promoted GLUT4 translocation to the cell membrane for glucose uptake. Altogether, our findings, for the first time, demonstrate that the combination of Rk1 and Rg5 could be beneficial for anti-T2DM, possibly involving ameliorated insulin resistance.

Efficacy and safety of CalliSpheres® Microsphere transcatheter-arterial chemoembolization versus conventional TACE in treating renal angiomyolipoma patients.

Objective: Transcatheter-arterial chemoembolization (TACE) is a well-established interventional technique for various tumor treatments, whereas its application in renal angiomyolipoma (RAML) is seldom reported. Conventional TACE (cTACE) with bleomycin-lipiodol emulsion is effective and tolerable for RAML treatment. In this study, we aimed to further explore the efficacy and safety between bleomycin-loaded CalliSpheres® microsphere TACE (CSM-TACE) and cTACE in treating RAML patients. Methods: We retrospectively analyzed the data of 54 RAML patients treated by CSM-TACE (n = 17) or cTACE (n = 37). Data on tumor size, tumor volume reduction ratio, patient percentage with tumor size reduction, white blood cells (WBCs), creatinine (Cre) after treatment, complications, and adverse events were retrieved. Results: Tumor size (88.66 vs. 81.19 cm3, P = 0.970), patient percentage with tumor size reduction (12 [70.59%] vs. 30 [81.08%], P = 0.486) after treatment, WBCs (P = 0.114), Cre (P = 0.659), and change in Cre after treatment (P = 0.947) were not significantly different between groups, whereas tumor volume reduction ratio was slightly lower in the CSM-TACE group than in the cTACE group (12 ± 34% vs. 32 ± 31%, P = 0.047). The most common postoperative complication was a post-embolization syndrome, including fever, nausea, and abdominal pain, which occurred in 9 (52.94%) and 14 (37.84%) patients from the CSM-TACE and cTACE groups, respectively (P = 0.347). Conclusion: CSM-TACE is effective in and well tolerated by RAML patients, implying its potential as an alternative therapy.

Prediction of local tumor progression after microwave ablation for early-stage hepatocellular carcinoma with machine learning.

Objectives: Local tumor progression (LTP) is a major constraint for achieving technical success in microwave ablation (MWA) for the treatment of early-stage hepatocellular carcinoma (EHCC). This study aims to develop machine learning (ML)-based predictive models for LTP after initial MWA in EHCC. Materials and Methods: A total of 607 treatment-naïve EHCC patients (mean ± standard deviation [SD] age, 57.4 ± 10.8 years) with 934 tumors according to the Milan criteria who subsequently underwent MWA between August 2009 and January 2016 were enrolled. During the same period, 299 patients were assigned to the external validation datasets. To identify risk factors of LTP after MWA, clinicopathological data and ablation parameters were collected. Predictive models were developed according to 21 variables using four ML algorithms and evaluated based on the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (CIs). Results: After a median follow-up time of 28.7 months (range, 7.6-110.5 months), 6.9% (42/607) of patients had confirmed LTP in the training dataset. The tumor size and number were significantly related to LTP. The AUCs of the four models ranged from 0.791 to 0.898. The best performance (AUC: 0.898, 95% CI: [0.842 0.954]; SD: 0.028) occurred when nine variables were introduced to the CatBoost algorithm. According to the feature selection algorithms, the top six predictors were tumor number, albumin and alpha-fetoprotein, tumor size, age, and international normalized ratio. Conclusions: Out of the four ML models, the CatBoost model performed best, and reasonable and precise ablation protocols will significantly reduce LTP.