Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Mechanism of Key Ingredient of Astragalus membranaceus on Lung Adenocarcinoma via PI3K/AKT Signaling Clarified by Utilizing Network Pharmacology Approach and Experimental Validation / 中国结合医学杂志

OBJECTIVE@#To investigate the mechanism of the effect of Astragalus membranaceus (A. membranaceus) on lung adenocarcinoma at the molecular level to elucidate the specific targets according to the network pharmacology approach.@*METHODS@#The active components of A. membranaceus and their potential targets were collected from the Traditional Chinese Medicine Systems Pharmacology Database. Lung adenocarcinoma-associated genes were acquired based on GeneCards, Online Mendelian Inheritance in Man (OMIM), PharmGKB, and Therapeutic Targets databases. The PI3K/AKT signaling pathway-related genes were obtained using Reactome portal. Networks of "ingredient-target" and "ingredient-target-pathway-disease" were constructed using the Cytoscape3.6.0 software. The relationships among targets were analyzed according protein-protein interaction (PPI) network. Finally, molecular docking was applied to construct the binding conformation between active ingredients and core targets. Cell counting kit 8 (CCK8) and Western blot assays were performed to determine the mechanism of the key ingredient of A. membranaceus.@*RESULTS@#A total of 20 active components and their 329 targets, and 7,501 lung adenocarcinoma-related genes and 130 PI3K/AKT signaling pathway-related genes were obtained. According to Venn diagram and PPI network analysis, 2 mainly active ingredients, including kaempferol and quercetin, and 6 core targets, including TP53, MAPK1, EGF, AKT1, ERBB2, and EGFR, were identified. The two important active ingredients of A. membranaceus, kaempferol and quercetin, exert the therapeutic effect in lung adenocarcinoma partly by acting on the 6 core targets (TP53, MAPK1, EGF, AKT1, ERBB2, and EGFR) of PI3K/AKT signaling pathway. Expressions of potential targets in lung adenocarcinoma and normal samples were analyzed by using UALCAN portal and found that ERBB2 was overexpressed in lung adenocarcinoma tissues and upregulation of it correlated with clinicopathological characteristics. Finally, quercetin repressed viabilities of lung adenocarcinoma cells by targeting ERBB2 on PI3K/AKT signaling confirmed by CCK8 and Western blot.@*CONCLUSION@#Our finding unraveled that an active ingredient of A. membranaceus, quercetin, significantly inhibited the lung adenocarcinoma cells proliferation by repressing ERBB2 level and inactivating the PI3K/AKT signaling pathway.

Preoperatively predicting early response of HCC to TACE using clinical indicators and MRI features.

BACKGROUND: We aimed to evaluate the value of using preoperative magnetic resonance imaging (MRI) features and clinical indicators to predict the early response of hepatocellular carcinoma (HCC) to transcatheter arterial chemoembolization (TACE). We also aimed to establish a preoperative prediction model. METHODS: We retrospectively reviewed data of 111 patients with HCC who underwent magnetic resonance imaging (MRI) before the first TACE and underwent MRI or computed tomography between 30 and 60 days after TACE. We used the modified response evaluation criteria in solid tumors for evaluating the TACE response. We used univariate and multivariate logistic regression analyses to identify independent predictors based on MRI features and clinical indicators. Moreover, receiver operating characteristic (ROC) curve analyses were performed to assess the diagnostic performance of the prediction model and each independent predictor. RESULTS: Among the 111 included patients, 85 were men (76.6%). Patient age was 31-86 years (average age, 61.08 ± 11.50 years). After the first treatment session, 56/111 (50.5%) patients showed an objective response (complete response + partial response), whereas the remaining showed non-response (stable disease + local progressive disease). In the univariate analysis, we identified irregular margins, number of nodules, and satellite nodules as predictors of early objective response. However, in the multivariate logistic regression analysis, irregular margins, number of nodules and pretreatment platelet were identified as the independent predictors of early objective response. A combined prediction model was then established, which factored in irregular margins, the number of nodules, and the pretreatment platelet count. This model showed good diagnostic performance (area under the ROC curve = 0.755), with the sensitivity, specificity, positive predictive value, and negative predictive value being 78.6%, 69.1%, 72.1%, and 76.0%, respectively. CONCLUSIONS: Irregular margins, the number of nodules and the pretreatment platelet count are independent predictors of the early response of HCC to TACE. Our clinical combined model can provide a superior predictive power to a single indicator.

Colorimetric Immunosensor Based on Au@g-C3N4-Doped Spongelike 3D Network Cellulose Hydrogels for Detecting α-Fetoprotein.

A colorimetric immunoassay is a powerful tool for detecting tumor markers, with outstanding advantages of visualization and convenience. This study designed a colorimetric immunoassay using the antibody/antigen to control the catalytic activity to be "switched on/off". This system, where Au NPs (18.5 ± 3.9 nm) were loaded on the g-C3N4 nanosheets that were fixed in a three-dimensional porous cellulose hydrogel, was used as a binding site for the antibody/antigen. After being incubated with an antibody of a cancer marker, the turned-off catalytic sites on Au NPs in Au@g-C3N4/microcrystalline cellulose hydrogels would not be "turned on" until the corresponding antigen was added. The number of the recovered Au active sites was related to the amount of the antigen added. The Fourier transform infrared and X-ray photoelectron spectroscopy measurements did not detect the existence of Au-S bonds. Catalyzed by the turned-on Au NPs, 4-nitrophenol was reduced to 4-aminophenol accompanied by a color fading. The color and the absorption spectrum changes in the process were used as the colorimetric quantitative basis for immunoassays. The colorimetric immunoassay showed a linear relationship with the liver cancer marker (α-fetoprotein, AFP) in the range of 0.1-10 000 ng/mL with the detection limit of 0.46 ng/mL. In addition, 4-nitrophenol had a significant color fading when the AFP concentration exceeded the healthy human threshold. The clinical patient's serum test results obtained from the developed colorimetric immunosensor were consistent with those obtained from the commercial enzyme-linked immunosorbent assay. Furthermore, the immunosensor exhibited a good selectivity, repeatability, and stability, which demonstrated its potential for practical diagnostic application.

Incomplete radiofrequency ablation promotes the development of CD133+ cancer stem cells in hepatocellular carcinoma cell line HepG2 via inducing SOX9 expression.

BACKGROUND: Cancer stem cells (CSCs) accelerate the growth of hepatocellular carcinoma (HCC) residual after incomplete radiofrequency ablation (In-RFA). The present study aimed to detect the effects of In-RFA on stemness transcription factors (STFs) expression which are important for the production and function of CSCs, and to find which STFs promote HCC stemness after In-RFA. METHODS: HepG2 cells were used for in vitro and in vivo studies. Flow cytometry and sphere-formation assays were used to detect the level and function of CD133+CSCs in the models. PCR array and ELISA were applied to analyze the altered expression of 84 STFs in CD133+CSCs in two models. Specific lentiviral shRNA was used to knockdown STFs expression, followed by detecting In-RFA's effects on the levels and function of CD133+CSCs. RESULTS: In-RFA was identified to induce CD133+CSCs and increase their tumorigenesis ability in vitro and in vivo. The mRNA levels of 84 STFs in CD133+CSCs were detected by PCR array, showing that 15 and 22 STFs were up-regulated in two models, respectively. Meanwhile, the mRNA levels of seven common STFs were up-regulated in both models. ELISA assay demonstrated that only the protein of sex determining region Y-box 9 (SOX9) was up-regulated in both models, the protein levels of the other 6 common STFs did not increase in both models. Finally, SOX9 was identified to play an important role in inducing, maintaining stemness and promoting tumorigenesis ability of CD133+CSCs in both models. CONCLUSION: In-RFA-induced SOX9 stimulates CD133+CSCs proliferation and increases their tumorigenesis ability, suggesting that SOX9 may be a good target for HCC treatment.

Rasch analysis on stroke-specific quality of life (SS-QOL) scale of acupuncture intervention on stroke / 中国针灸

<p><b>OBJECTIVE</b>To optimize the evaluation level of active motor threshold and the functional domain of upper limbs of stroke-specific quality of life (SS-QOL) scale with Rasch analysis.</p><p><b>METHODS</b>Sixty patients with acute ischemic stroke that were in accord with research criterid were randomly divided into a test group (30 cases) and a control group (30 cases). Acupuncture treatment and routine western medicine were applied on the test group, and single treatment of routine western medicine was applied on the control group. Selected acupoints were MS 5, Fengchi (GB 20), Hegu (LI 4), etc. Active motor threshold and the functional domain of upper limbs of SS-QOL were self-tested by patients after one treating course. The characteristics of the above mentioned items were tested with Rasch model.</p><p><b>RESULTS</b>The statistical result on fitness of active motor threshold and the functional domain of upper limbs of SS-QOL showed that every reference of samples and items wosin accord with the Rasch model and has well inner reliability and validity. The Infit and Outfit MnSq values of active motor threshold and the functional domain of upper limbs of SS-QOL are basically between 0.5 and 1.5.</p><p><b>CONCLUSION</b>The application of Rasch analysis on the assessment of patient reported outcome (PRO) has optimized the PRO scale (the activity and upper limb function domain of SS-QOL scale) and enhanced evaluation level of active motor threshold and the functional domain of upper limbs of SS-QOL scale.</p>