This paper is on nonzero-sum piecewise deterministic Markov games (PDMGs) with the expected discounted payoffs. Both gradual controls and boundary impulsive controls act on the transition laws and the payoffs. We construct static games associated with the PDMGs, where the time-dependent controls have to be considered due to the presence of the flow in PDMGs. Since the state space of PDMGs is uncountable, we introduce set-valued mappings with functions as variables rather than those with policies as variables in most of previous works. Under some suitable assumptions, the set-valued mapping, from the uniformly essentially bounded functions to the set of payoffs corresponding to all Nash equilibria for the static games, is proven to have a fixed point. Moreover, by Filippov's theorem, the existence of a Nash equilibrium is ensured for the static games associated with the fixed-point function. The relations on fixed-point equations as well as Nash equilibria between the associated static games and the PDMGs are established, which eventually leads to the existence of a stationary Nash equilibrium for the PDMGs. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

This paper studies multi-objective infinite-horizon discounted continuous-time Markov decision processes (CTMDPs) with distinct discount rates across the objectives. We start the analysis through the weighted sum method. A counterexample demonstrates the absence of Pareto-optimal stationary policies, contrasting with the classic discounted CTMDP results. Inspired by the idea for finite-horizon scenarios, we derive the Hamilton-Jacobi-Bellman equation with time as the differential variable for the infinite-horizon weighted sum optimization. To solve the new equation, we introduce a novel dynamic programming operator along with a carefully constructed initial function. Our value iteration method establishes the existence of weighted-optimal Markov deterministic policies, thereby ensuring the existence of Pareto-optimal policies. Moreover, we prove weak Pareto sufficiency of weighted-optimal policies by the occupation measure technique. Finally, we characterize the structure of ε -optimal policies—they are ultimately stationary under specific conditions, and provide an algorithm to calculate ε -optimal policies for finite-state cases.

In this paper, we investigate a two-person zero-sum semi-Markov games on finite horizon. The performance criterion is the expected-positive-deviation (EPD) of finite horizon payoff from a given level. Under suitable conditions, we not only establish the existence of the value and $ \epsilon (\geq 0) $ & varepsilon;(>= 0)-saddle points, but also provide an algorithm for computing (at least approximating) the value and & varepsilon;-saddle points. Finally, we analyse the relationship between the EPD criterion and the average-value-at-risk (AVaR) criterion in semi-Markov games.

The liver is one of the most frequent sites of primary malignancies in humans. Hepatocellular carcinoma (HCC) is one of the most prevalent solid tumors with poor prognosis. Current treatments showed limited efficacy in some patients, and, therefore, alternative strategies, such as immunotherapy, cancer vaccines, adoptive cell therapy (ACT), and recently chimeric antigen receptors (CAR)-T cells, are developed to offer better efficacy and safety profile in patients with HCC. Unlike other ACTs like tumor-infiltrating lymphocytes (TILs), CAR-T cells are equipped with engineered CAR receptors that effectively identify tumor antigens and eliminate cancer cells without major histocompatibility complex (MHC) restriction. This process induces intracellular signaling, leading to T lymphocyte recruitment and subsequent activation of other effector cells in the tumor microenvironment (TME). Until today, novel approaches have been used to develop more potent CAR-T cells with robust persistence, specificity, trafficking, and safety. However, the clinical application of CAR-T cells in solid tumors is still challenging. Therefore, this study aims to review the advancement, prospects, and possible avenues of CAR-T cell application in HCC following an outline of the CAR structure and function.

This paper studies Borel models of nonstationary Markov decision processes (MDPs) with average criteria. We establish a suitable fixed point theorem, which is used to show the existence of solutions to the average optimality equation (AOE), without using contractions. The existence of optimal policies follows from the obtained solutions to the AOE. Furthermore, we show that versions of the rolling horizon algorithm can be used to produce an optimal policy or an epsilon-optimal policy. Finally, we compare the optimality conditions imposed in this paper with the existing ones in the literature, and demonstrate that they can be satisfied while the previous ones are not.

This paper studies two-person zero-sum risk-sensitive stochastic games for continuous time jump processes with the following features: (1) the payoff and transition rates are unbounded and time-dependent, (2) the state and action spaces are general Borel sets, (3) the discount factors can vary in time. Differing from those with the risk-sensitive parameter as a differential variable in previous works, we introduce a new type of Shapley equation (NSE) with the time as a differential variable. Under some technical assumptions, we derive a representation of a solution to the NSE, which in turn is used to establish the existence of a solution to the NSE by iterations and approximation. With the help of the NSE, we prove the existence of the value of the game and a saddle-point equilibrium depending on the time, which explicitly shows the nonstationarity of the risk-sensitive discounted equilibria. We illustrate our results by two examples with unbounded transition and payoff rates.

e16175 Background: The combination of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) used for hepatic arterial infusion chemotherapy (HAIC) has shown promise for advanced hepatocellular carcinoma (HCC) patients. The combined therapy of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) is now an approved first-line approach for unresectable HCC. This study evaluated the safety and the effect of combining Adebelimumab (a PD-L1 inhibitors) and Apatinib (a tyrosinase kinase inhibitor) with HAIC-FOLFOX for unresectable HCC patients. Methods: The records of patients with unresectable HCC treated with HAIC from March 2023 to November 2023 at our center were retrospectively reviewed. Eligible patients were given a maximum of four cycles of FOLFOX-HAIC, along with Adebelimumab and Apatinib, until either disease progression or intolerable toxicities emerged. The primary outcome measured was the safety and the objective response rate (ORR) based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modify RECIST of combined therapy. Results: Twenty patients were enrolled in the study. The most frequent grade ≥3 or above treatment-related adverse events included elevation of AST (50%) and diminished PLT count (15%). There was no treatment related death. Based on RECIST v1.1 and mRECIST criteria, the confirmed ORR stood at 35% and 70%, with a disease control rate of 85% both. Conclusions: The combination of Adebelimumab, apatinib, and FOLFOX-HAIC demonstrated manageable safety and encouraging results for unresectable HCC.

Objective: Our objective was to evaluate the feasibility of XperCT combined fluoroscopy to guide sharp recanalization for the treatment of chronic thoracic venous occlusive disease in hemodialysis patients. Methods: The records of hemodialysis patients with chronic thoracic venous occlusive disease who received endovascular sharp recanalization after conventional techniques failed were retrospectively reviewed. The sharp devices used for recanalization included the stiff end of a guidewire, Chiba biopsy needle, RUPS-100 set, and transseptal needle. The needle was advanced toward a target placed at the opposite end of the occlusion and was guided by fluoroscopy and/or XperCT. While the guidewire crossed the occlusion, endovascular procedures such as percutaneous angioplasty were performed for the treatment of the occlusion. Results: The analysis included 32 sharp thoracic vein recanalization procedures in 29 patients. Two attempts in one patient failed, and in one patient the first attempt failed but the second attempt was successful. In one patient, two separate successful procedures were performed, and the other 26 procedures in 26 patients were successful. The overall technical success rate of sharp recanalization was 90%. The mean number of puncture attempts in the combined group was less than that of the fluoroscopy-guided alone group (2 vs 5, p < 0.05). The success rate of sharp recanalization in the combined group was higher (100% vs 86%), and the recanalization time (28.5 min vs 36 min, p > 0.05) was no different. There was no statistical difference in procedure-related complications between the groups. Conclusion: XperCT can facilitate sharp recanalization for the treatment of chronic thoracic venous occlusive disease in hemodialysis patients.

BACKGROUND:To investigate the impact of preoperative embolization (p-TAE) on CBT surgical resection and explore the optimal tumor volume for p-TAE of CBT resection. METHODS:This retrospective study reviewed 139 surgically excised CBTs. According to Shamblin classification, tumor volumes, and whether to carry out the p-TAE, the patients were classified into different groups. The demographic, clinical features, and the intraoperative and post-operative information about the patients were retrieved and analyzed from the patient records. RESULTS:A total of 139 CBTs was excised in 130 patients. According to the results of subgroup analysis, there were no significant differences in surgical time, blood loss, adverse events (AEs), and the revascularization when compared with non-embolization group (NEG) for type I, II, III, respectively (all p > 0.05) except for the surgical time in type I (p < 0.05). Then the X-tile program was employed and determine the cutoff point (tumor volume = 6670 mm3) for tumor volumes and blood loss. The average tumor volume was (29,782.37 vs. 31,345.10 mm3, p = 0.65) for embolization group (EG) and NEG. The mean surgical time (208.86 vs. 264.67 min, p > 0.05) and intraoperative blood loss (252.78 vs. 430.00 mL, p < 0.05) were less, and the incidence of revascularization required (35.56 vs. 52.38%, p > 0.05) and total complications (27.78 vs. 57.14%, p < 0.05) were lower in EG when compared with NEG (tumor volume ≥ 6670 mm3). However, the results were not statistically significant when the tumor size was less than 6670 mm3. No surgery-related mortality was observed during the follow-up. CONCLUSIONS:Preoperative selective embolization of CBT is an effective and safe adjunct for surgical resection, especially for Shamblin class II and III tumors (≥ 6670 mm3).

Although immunotherapy of hepatocellular carcinoma using immune checkpoint inhibitors has achieved certain success, only a subset of patients benefits from this therapeutic strategy. The combination of immunostimulatory chemotherapeutics represents a promising strategy to enhance the effectiveness of immunotherapy. However, it is hampered by the poor delivery of conventional chemotherapeutics. Here, it is shown that H-ferritin nanocages loaded with doxorubicin (DOX@HFn) show potent chemo-immunotherapy in hepatocellular carcinoma tumor models. DOX@HFn is constructed with uniform size, high stability, favorable drug loading, and intracellular acidity-driven drug release. The receptor-mediated targeting of DOX@HFn to liver cancer cells promote cellular uptake and tumor penetration in vitro and in vivo. DOX@HFn triggers immunogenic cell death to tumor cells and promotes the subsequent activation and maturation of dendritic cells. In vivo studies in H22 subcutaneous hepatoma demonstrate that DOX@HFn significantly inhibits the tumor growth with >30% tumors completely eliminated, while alleviating the systemic toxicity of free DOX. DOX@HFn also exhibits robust antitumor immune response and tumoricidal effect in a more aggressive Hepa1-6 orthotopic liver tumor model, which is confirmed by the in situ magnetic resonance imaging and transcriptome sequencing. This study provides a facile and robust strategy to improve therapeutic efficacy of liver cancer.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy (HAIC) treatment is widely accepted as one of the alternative therapeutic modalities for HCC owing to its local control effect and low systemic toxicity. Nevertheless, although accumulating high-quality evidence has displayed the superior survival advantages of HAIC of oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX) compared with standard first-line treatment in different scenarios, the lack of standardization for HAIC procedure and remained controversy limited the proper and safe performance of HAIC treatment in HCC. Therefore, an expert consensus conference was held on March 2023 in Guangzhou, China to review current practices regarding HAIC treatment in patients with HCC and develop widely accepted statements and recommendations. In this article, the latest evidence of HAIC was systematically summarized and the final 22 expert recommendations were proposed, which incorporate the assessment of candidates for HAIC treatment, procedural technique details, therapeutic outcomes, the HAIC-related complications and corresponding treatments, and therapeutic scheme management.

Microwave ablation (MWA) is an effective treatment for liver cancer (LC), but its impact on distant tumors remains to be fully elucidated. This study investigated the abscopal effects triggered by MWA treatment of LC, at different power levels and with or without combined immune checkpoint inhibition (ICI). We established a mouse model with bilateral subcutaneous LC and applied MWA of varied power levels to ablate the right-sided tumor, with or without immunotherapy. Left-sided tumor growth was monitored to assess the abscopal effect. Immune cell infiltration and distant tumor neovascularization were quantified via immunohistochemistry, revealing insights into the tumor microenvironment and neovascularization status. Th1- and Th2-type cytokine concentrations in peripheral blood were measured using ELISA to evaluate systemic immunological changes. It was found that MWA alone, especially at lower power, promoted distant tumor growth. On the contrary, combining high-power MWA with anti-programmed death (PD)-1 therapy promoted CD8+ T-cell infiltration, reduced regulatory T-cell infiltration, upregulated a Th1-type cytokine (TNF-α) in peripheral blood, and inhibited distant tumor growth. In summary, combining high-power MWA with ICI significantly enhances systemic antitumor immune responses and activates the abscopal effect, offering a facile and robust strategy for improving treatment outcomes.

This paper is devoted to zero-sum piecewise deterministic Markov games with Borel state and action spaces, where the expected infinite-horizon discounted payoff criterion is considered. Both the transition rate and payoff rate are allowed to be unbounded. The policies of the two players are history-dependent, and the controls continuously act on the transition rate and the payoff rate. Under suitable conditions, Dynkin’s formula and the comparison theorem are developed in our setup, via which the game is shown to have the value function as the unique solution to the associated Shapley equation. By the Shapley equation in the form of a differential equation, we establish the existence of a saddle point with a very simple form, which only depends on the current state and can be applied at any time. A potential algorithm for computing saddle points is proposed.

Objective: Evaluate the efficacy and safety of transarterial chemoembolization (TACE) sequential with hepatic arterial infusion chemotherapy (HAIC) and a tyrosine kinase inhibitor (TKI) for unresectable large hepatocellular carcinoma (HCC). Methods: Patients with HCC size > 70 mm were included. They received 1-3 cycles of TACE and sequential HAIC every 3-6 weeks for 2-6 cycles, with each cycle given over a period of 48 hours (oxaliplatin plus fluorouracil/leucovorin). Patients also received sorafenib or lenvatinib beginning at the first TACE cycle and continuing until disease progression. Objective response rate (ORR) at 3 months was the primary endpoint. Progression-free survival (PFS) and safety were the secondary endpoints. Results: From January 2020 to December 2020, 41 patients were included, who were divided into the drug-eluting bead TACE (DEB-TACE) group (n=13) and conventional TACE (cTACE) group (n=28). The overall ORR was 56.1% (23/41) using mRECIST criteria and 34.1% (14/41) using RECIST1.1 criteria. The median PFS of the cohort was 8 months. The ORR of the DEB-TACE group was 76.9% (10/13) vs. 46.4% (13/28) for the cTACE group (p = 0.06). The median PFS of the DEBTACE group was 12 months, and 6 months in the cTACE group (p = 0.09). Conversion hepatectomy was performed in 2 patients in the DEB-TACE group (15.4%), and in 3 patients in the cTACE group (10.7%). ALT/AST elevated, hypertension, nausea, and vomiting were the common treatment related adverse events. There was no treatment related death. Conclusion: TACE sequential with HAIC combined a TKI is a well-tolerated and promising tripletherapy for large, unresectable HCC.

Purpose: The study aims to investigate the suppressing tumor-promoting effects via multi-anti-angiogenesis activity of the copper chelator (ammonium tetrathiomolybdate, TM) combined with lenvatinib for hepatocellular carcinoma. Methods: A total of 55 C57 mice were injected subcutaneously with Hepa1-6 hepatoma cell suspensions into the right posterior thigh. After 7 days, the subcutaneous tumors were formed, and the mice were randomly divided into five groups: TM (G1), Lenvatinib (G2), TM+Lenvatinib (G3), Control (G4), and Copper (II) Gluconate (G5). The copper concentrations in serum and tumors were measured at the predetermined time points. After 14 days of treatments, tumor weight and volumes were analyzed, histology was observed, and the expressions of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in tumor tissues were measured by immunohistochemistry. Results: The median concentration of copper in serum was 401.70, 469.40, and 665.35 mu g/L in normal mice, in mice 7 days after implantation, and in the control group, respectively. The intratumoral copper concentrations were higher in G4 mice than in mice 7 days after implantation (P < 0.05). The serum concentration of copper was higher in G5 than all the other groups (P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G2, P = 0.013; G2 vs. G3, P = 0.018; G1 vs. G3, P = 0.903. The intratumoral copper concentrations were 608.40, 980.00, 539.31, and 2938.90 mu g/L in G1, G2, G3, and G5, respectively. The average tumor weight was 0.55, 0.44, 0.08, 1.37, and 3.11 in G1, G2, G3, G4, and G5, respectively. G5 vs. other groups, P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05; G1 vs. G2, P > 0.05. Furthermore, the expression levels of VEGF were significantly lower in G1, G2, and G3 than in G4 and G5 (P < 0.05). A similar trend was observed for MVD in the five groups, but no significant difference was detected in G1 and G2. Conclusion: The study showed a significant positive correlation between tumor load and copper. Copper promotes tumor progression, but copper chelating suppresses tumor growth. The combination of TM with lenvatinib reduces tumor angiogenesis and improves the effect of antitumor treatment. These findings underlie the clinical application of combination therapy.

Objectives: The aim of this study was to synthesize and characterize a novel NO donor, PEI-PO-NONOate, using propylene oxide and to investigate its biosafety and therapeutic efficacy via nasal administration in vitro and vivo. Experimental procedures: The PEI-PO-NONOate was synthesized based on polyethylenimine (PEI) with different molecular weights and characterized using Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR), and ultraviolet (UV) spectroscopy. Cytotoxicity assays were performed on mouse fibroblast cells L929 and human nasal mucosa epithelial cells (HNEpC), and a rat middle cerebral artery occlusion (MCAO) model was established to evaluate the therapeutic efficacy of PEI-PO-NONOate via nasal administration. Results: The PEI-PO-NONOate was found to be stable under dark, dry, and airproof conditions, and its release was accelerated in an aqueous phase or acidic environment, while it was slowed down in a polyethylene glycol (PEG) mixture system. The NO donor released approximately 0.4, 0.5, and 0.6 mu mol of gaseous NO from 1.0 mg of the polymer based on PEI600, PEI1800, and PEI10K, respectively. Cytotoxicity assays showed that the PEI-PO-NONOates had a cryoprotective effect as compared with PEI and PEI-PO. Furthermore, nasal administration of PEI-PO-NONOates resulted in a significant reduction in overall necrotic ratio as compared with the control group (16.4% versus 24.6%, p < 0.05). Conclusion: The findings of this study suggest that PEI-PO-NONOates may have potential as an adjuvant therapy for acute ischemic stroke when administered via the nasal route.

Biliary stricture is a less common complication after hepatic radiofrequency ablation (RFA) [1, 2]. Patients with biliary stricture often present with recurrent jaundice, fever or chills, and require endoscopic or percutaneous biliary drainage, and in some cases recanalization of the biliary tract [3]. Establishing guide-wire passage through the stricture is essential for biliary recanalization. However, in some cases of complete biliary obstruction, a more aggressive technique is needed when ordinary methods fail to establish. Herein, we report a novel technique of extraluminal recanalization for biliary strictures using a Chiba biopsy needle, which is similar to sharp endovascular recanalization.

[目的]评价经远桡动脉入路对肝肿瘤患者行肝动脉持续灌注化疗(HAIC)的安全性和舒适性.[方法]纳入中山大学附属第一医院放射介入科行经远桡动脉入路进行HAIC的肝肿瘤患者,患者进行1次股动脉入路和1次远桡动脉入路穿刺置管进行自身交叉对照.患者留置导管于肝动脉内行FOLFOX4方案持续动脉灌注化疗.使用生活质量评分量表比较患者远桡动脉入路和股动脉入路的生活质量评分以及记录手术相关并发症.[结果]共纳入患者18例肝肿瘤患者,其中9例先进行股动脉入路后进行远桡动脉入路HAIC,其余9例则先远桡入路再进行股动脉入路HAIC.dTRA期间,穿刺点血肿2例,穿刺点持续疼痛3例,左手掌麻木1例,均为1～2级手术相关的不良事件.没有发生3～4级手术相关的不良事件.术后超声检查显示近端桡动脉均通畅.dTRA和TFA之间的穿刺时间差异有统计学意义(4分vs.3分,P＜0.05).然而,dTRA的生活质量评分均优于TFA.患者更倾向选择dTRA(7.89 vs.2.72,P＜0.001)o dTRA的压迫止血时间比TFA更短(2 hvs.7 h,P＜0.05).[结论]经远桡动脉入路安全可耐受,有利于肝肿瘤患者行持续动脉灌注化疗期间的生活质量和舒适度提升.

Background It has not been demonstrated that computational fluid dynamics (CFD) can be used to model central venous stenosis (CVS), nor that hemodynamic changes in CVS treated with stent placement can be anticipated. The purpose of this study was to demonstrate the hemodynamic performance of CVS patients treated with stent placement. Methods Patient-specific geometric models were constructed using computed tomography images of veins from hemodialysis patients treated with stent placement. CFD simulation based on geometry was performed using ANSYS-15 to compare pressure quantitatively, wall shear stress (WSS), and flow velocity in the brachial vein before and after stent placement. Results Following a covered stent placement, the swelling of the left upper extremity was relieved. Prior to stent implantation, the maximum and mean brachial vein wall pressures were 465.2 Pa and 224.609 Pa, respectively. It was determined that the maximum WSS value was 8.449 Pa and that the mean WSS value was 0.743 Pa. The maximum and mean flow velocities were 1.16 and 0.173 m/s, respectively. After stent placement, the maximum wall pressure, maximum WSS, and maximum flow velocity dropped by 59.4%, 71.2%, and 57.8%, respectively. The mean wall pressure, mean WSS, and mean flow rate decreased by 43.5%, 52.7%, and 17.6%, respectively. Conclusion Hemodynamics of CVS in hemodialysis patients exhibited turbulent, imbalances and disorders, which can be improved by stent placement.

BACKGROUND:The purpose of the present study was to evaluate the technical feasibility and safety of sharp recanalization for central venous occlusive disease (CVOD) in patients requiring hemodialysis.METHODS:Patients with CVOD requiring hemodialysis who had undergone endovascular recanalization using sharp devices, including the stiff end of a guidewire, Chiba needle, or RUS-100 to cross occluded segments after conventional techniques had failed were included. The needle was guided toward a target placed at the opposite end of the occlusion. Although the guidewire was passed though the occlusion, subsequent procedures such as percutaneous transluminal angioplasty could be performed.RESULTS:A total of 27 sharp recanalization procedures in 25 patients were performed. Two attempts failed, 1 patient had undergone two separate successful procedures, and 23 procedures in 23 patients were successful. The overall technique success was 92.6%. The stiff end of a guidewire was the first choice for all the procedures, and recanalization was achieved in 18 patients (66.7%). A Chiba biopsy needle was used in six procedures (22.2%), with 100% technical success. A RUPS-100 set was used in two procedures (7.4%), with one aborted because of concern for complications. The occlusion was subsequently crossed using a Chiba needle. Four minor adverse events (two of mediastinal hematoma and two of chest pain) had occurred, and two major adverse events (pericardial tamponade and acute pleural effusion in one patient [4%], treated with the guidewire stiff-end technique, who recovered after drainage) had occurred.CONCLUSIONS:Sharp recanalization is safe and feasible with high technical success for CVOD in patients requiring hemodialysis who cannot be recanalized using conventional techniques.