Inducing the Abscopal Effect in Liver Cancer Treatment: The Impact of Microwave Ablation Power Levels and PD-1 Antibody Therapy.

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.

XperCT facilitates sharp recanalization for the treatment of chronic thoracic venous occlusive disease in hemodialysis patients.

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.

Ferritin Nanocaged Doxorubicin Potentiates Chemo-Immunotherapy against Hepatocellular Carcinoma via Immunogenic Cell Death.

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.

Clinical Implications of Phenotypes of Hemodialysis Patients With Central Venous Occlusion or Central Venous Stenosis Defined by Cluster Analysis.

Objective: This study aims to investigate the association between clinical factors of patients with central (superior vena cava, brachiocephalic, or subclavian) venous occlusion or central venous stenosis (CVO/CVS) and the difficulty of interventional recanalization as well as the duration of postoperative patency. Methods: A total of 103 hemodialysis patients with CVO/CVS treated with endovascular treatment were enrolled. The two-step cluster analysis was selected to differentiate the cases into distinct phenotypes automatically. Differences in characteristics, the difficulty of interventional recanalization, and the duration of postoperative primary patency time between the two clusters were statistically compared. Results: The 103 cases were divided into distinct two clusters by the two-step cluster analysis with 48 (46.6%) in cluster 1 and 55 (53.4%) in cluster 2. Compared to cluster 2, patients in cluster 1 have a higher proportion of blunt stump, side branches, occlusion lesions >2 cm, calcification, or organization. Moreover, the above four factors were, in turn, the most critical four predictors distinguishing 103 patients into two clusters. The remaining six factors were, in turn, occlusion located in the superior vena cava (SVC), duration of central venous catheterization (CVC), lesion location, vessel diameter, number of CVC, and previously failed lesion. Of the four most important factors, with the exception of occlusion lesions exceeding 2 cm, there were significant differences in the length of procedure time between the groups grouped by the remaining three factors. And there was a significant difference in the primary patency rate between the group with blunt stump and the group without blunt stump and also between the group with occlusion lesions ≥ 2 cm and the group with occlusion lesions <2 cm. The operation time of cluster 1 was longer than that of cluster 2. In terms of postoperative patency time, the primary patency time was significantly longer in the patients of cluster 2 compared with cluster 1 (P = 0.025). Conclusion: Patients were divided into distinct two clusters. CVO/CVS of patients in cluster 1 was more challenging to be recanalized than that in cluster 2, and the primary patency time was significantly longer in the patients of cluster 2 compared with cluster 1. Blunt stump, side branches, occlusion lesions exceeding 2 cm, and calcification or organization are the four most critical predictors distinguishing 103 patients into two clusters.

Transradial versus Transfemoral Access for Patients with Liver Cancer Undergoing Hepatic Arterial Infusion Chemotherapy: Patient Experience and Procedural Complications.

PURPOSE: To determine whether transradial access (TRA) is a more favorable and safe method for hepatic arterial infusion chemotherapy (HAIC) than transfemoral access (TFA). MATERIALS AND METHODS: Retrospective and prospective cohorts of patients with liver cancer were included. Sixty-seven patients in the retrospective cohort were divided into 2 groups: (a) TRA-HAIC (n = 24) and (b) TFA-HAIC (n = 43). Another 33 patients were prospectively enrolled to receive both TRA and TFA for HAIC in a crossover design. Prolonged arterial access was required for up to 48 hours. The primary endpoint was quality of life (QOL) using the visual analog scale. The secondary endpoints mainly included procedural success, adverse events, and operation time. RESULTS: Patient QOL measures revealed significantly lower scores of indices in the TRA-HAIC group than in the TFA-HAIC group in the retrospective cohort (all P < .001). The significant improvement of the QOL indices by TRA-HAIC, such as overall discomfort (P = .019) and pain at the access site (P = .018), was validated in the prospective cohort. The satisfaction scores were significantly higher in the TRA-HAIC group than in the TFA-HAIC group, and patients preferred TRA-HAIC (P < .001). Radial artery occlusion (RAO) as an access-related adverse event occurred more frequently in both the retrospective and prospective cohorts (38% and 33%, P < .001 and P = .001, respectively). Notably, the multivariate analysis of RAO-associated factors showed that enoxaparin use was significantly correlated with a reduced risk of postprocedural RAO (P = .036). CONCLUSIONS: TRA was superior to TFA in patient experience. However, because of the high incidence of access-related adverse events, especially for RAO with a total incidence of 35%, strategies should be optimized for patients to benefit from TRA in future procedures.

One-year outcomes and predictive factors for primary patency after stent placement for treatment of central venous occlusive disease in hemodialysis patients.

OBJECTIVE: The study purpose was to determine the outcomes and factors predictive of primary stent patency for the treatment of central venous occlusive disease (CVOD) in hemodialysis patients. METHODS: Data of 71 patients with CVOD treated with stent placement from January 2012 to December 2017 were analyzed. Univariate and multivariate analysis was performed to determine factors associated with stent patency. Adverse events related to stent placement were also examined. RESULTS: The median primary patency duration of the 71 patients was 16 ± 2.2 months. The cumulative 3-, 6-, 9-, and 12- month primary patency rates were 93%, 72%, 55%, and 51%, respectively. Independent predictors of longer primary patency were vessel diameter > 12 mm, the use of a covered stent, and absence of vessel calcifications. Median primary patency of covered stents was 21 months as compared with only 10 months for bare stents (p < 0.001). Procedure-related adverse events occurred in 17 patients (21.8%), and four events (5.1%) required medical intervention. No life-threaten complications occurred. CONCLUSIONS: A vessel diameter > 12 mm, the use of a covered stent, and no vessel calcifications are independently associated with a higher primary patency rate after treatment of CVOD in hemodialysis patients.

Computational fluid dynamics simulation of hemodynamic changes in a hemodialysis patient with central venous stenosis treated with stent.

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.

Sharp recanalization for treatment of central venous occlusive disease in hemodialysis patients.

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.

microRNA-375 inhibits the malignant behaviors of hepatic carcinoma cells by targeting NCAPG2.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. Emerging evidence has revealed the vital functions of microRNAs (miRNAs) in cancer malignant progressions. miR-375 has been verified to serve as an antioncogene in tumorigenesis and a potential therapeutic target in various types of cancer. In this study, we aimed to determine the role of miR-375 in the regulation of chemoresistance and metastasis of HCC. Differentially expressed miR-375 and NCAPG2 were externally validated using expression data from The Cancer Genome Atlas (TCGA) database. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression levels of miR-375 in HCC tissues and cell lines. miR-375 mimics and NCAPG2-overexpression were transfected into HepG2 and Huh7 cells to establish miR-375 overexpression models. Cell Counting Kit-8, Transwell, and flow cytometry experiments were conducted to monitor cell proliferation, migration, and apoptosis. The targeting relationship between miR-375 and non-SMC condensin II complex subunit G 2 (NCAPG2) was determined by qRT-PCR, western blot, and luciferase reporter gene assay. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted using Gene Set Enrichment Analysis (GSEA). The pathway enrichment analysis was used to predict the potential pathways for further study. miR-375 was significantly downregulated in HCC tissues and cells compared to adjacent tissue and normal hepatocyte cell line respectively while NCAPG2 was upregulated. The targeting relationship was verified by luciferase reporting assay, and miR-375 could target the 3'UTR of NCAPG2 mRNA and effectively suppress NCAPG2 protein expression. Replenishing of miR-375 significantly repressed HCC cell proliferation and migration, and induced cell apoptosis. Overexpression of NCAPG2 recovered those biological abilities in miR-375 overexpressed cells. Collective data suggested that miR-375 served as a tumor suppressor via regulating NCAPG2. Replenishing of miR-375 or knockout of NCAPG2 could be therapeutically exploited for HCC.

The earlier, the better: The beneficial effect of different timepoints of the preoperative transarterial embolization on ameliorating operative blood loss and operative time for carotid body tumors.

BACKGROUND: To explore the effect of the optimal time interval from preoperative transarterial embolization to surgery of carotid body tumors by analyzing surgery-related indicators. METHODS: This single-center retrospective review included 103 patients and 108 carotid body tumor resections performed between June 2010 and June 2020. All carotid body tumors were divided into three groups based on interval time between transarterial embolization and surgery: 1-day group (G1), 2-day group (G2), and 3-day group (G3). Demographics, inflammatory biomarkers, periprocedural details, and postoperative outcomes were analyzed. RESULTS: Among 103 patients, 48.54% were women, and the mean age was 37.07 years. The tumor sizes were 43.83, 44.31, and 42.84 mm in G1, G2, and G3, respectively, and the blood loss and operative time were 163.68, 331.54, and 683.68 mL, and 182.32, 216.31, and 280.79 mins with the prolonged time interval, respectively. Compared with pretransarterial embolization, the expression of white blood cells (109/L) and neutrophils (109/L) were obviously increased post-transarterial embolization in the three groups (G1: white blood cells 6.81 vs 9.32; neutrophils 0.54 vs 0.74, all P < .05. G2: white blood cells 7.19 vs 10.01, P = .118; neutrophils 0.54 vs 0.77, P < .05. G3: white blood cells 7.08 v. 12.37; neutrophils 0.59 vs 0.80, all P < .05), and those in G3 were significantly higher than those in G1. The incidences of revascularization, which was 30.26%, 53.85%, and 42.10%, and adverse events (26.32%, 30.77%, and 21.05%) were not significantly different among G1, G2, and G3. CONCLUSION: The optimal time interval between preoperative transarterial embolization and surgical resection resulted as 1 day as patients in this group showed obvious lower blood loss and shorter duration of operation than patients in other groups. Both inflammation and recanalization provided support for these results at some extent.

Prognostic value of splenic volume in hepatocellular carcinoma patients receiving transarterial chemoembolization.

BACKGROUND: Liver function is a key determinant for the survival of hepatocellular carcinoma (HCC) patients receiving transarterial chemoembolization (TACE). However, establishing robust prognostic indicators for liver insufficiencies and patient survival remains an unmet demand. This retrospective study evaluated the prognostic value of splenic volume (SV) in HCC patients undergoing TACE. METHODS: A total of 67 HCC patients who underwent at least two consecutive TACE procedures were retrospectively included in this study. Comprehensive clinical information and follow-up data were collected, and the SV was measured based on dynamic contrast enhanced images. Risk factors of SV enlargement were assessed. The prognostic value of SV on survival was analyzed and compared with Child-Pugh (CP) classification and albumin-bilirubin (ALBI) grade. RESULTS: The baseline SV was 299.74±143.63 cm3, and showed a moderate and statistically significant correlation with CP classification (R=0.31, P<0.05). The SV increased remarkably after the first and second TACE procedures (330.16±155.38 cm3, P<0.01, and 355.63±164.26 cm3, P<0.01, respectively). In survival analysis, the optimal cut-off value of SV was determined as 373 cm3 using X-tile software, and the patients were divided into the small SV group and the large SV groups accordingly. Based on the pre-TACE SV, the median overall survival (mOS) for patients in the small SV group and the large SV group was 458 days and 249 days, respectively (P<0.05). After the first and second TACE, the mOS in the small SV group and the large SV group were 454 vs. 266 days (P<0.05) and 526 vs. 266 days (P<0.05), respectively. No prognostic value of CP classification and ALBI grade was identified for these patients. Furthermore, there were no significant differences between the small and large SV groups in age, tumor stage, and ALBI grade, except for CP classification (P<0.05). CONCLUSIONS: SV was correlated with CP classification and was a robust predictor for HCC patients undergoing TACE treatment.

A versatile UCST-type composite microsphere for image-guided chemoembolization and photothermal therapy against liver cancer.

The development of novel chemoembolization agents to improve the treatment efficacy of transarterial chemoembolization (TACE) against liver cancer remains an urgent need in clinical practice. Herein, a versatile composite microsphere with upper critical solution temperature (UCST) properties was prepared to encapsulate polydopamine coated superparamagnetic iron oxide nanoparticles (SPION@PDA) and doxorubicin for simultaneous chemoembolization and photothermal therapy. The microspheres were spherical with an average diameter of 100-300 µm and exhibited favorable drug loading capability as well as strong photothermal effect. Strikingly, synergistic enhancement of photothermal therapy and chemotherapy against chemoresistant liver cancer cells was achieved. The in vivo therapeutic efficacy and safety evaluations were performed using rabbit VX2 liver tumor models. It was revealed that a single treatment of the combination of TACE and photothermal procedure resulted in 87.5% complete response and 12.5% partial response for the microsphere group, whereas all tumors in the control group progressed rapidly. Contrast-enhanced computed tomography (CT) evaluation indicated that the tumor diameter decreased by 91.5% after treatment, while that in the control group increased by 86.5%. The pathology-proven tumor necrotic rate was 87.2%, which significantly surpassed that of 65.2% in the control group. Furthermore, serum liver enzyme and biochemical studies indicated a temporary liver injury which can be fully recovered. Our findings demonstrated that this microsphere may be advantageous for enhancing therapeutic efficacy of TACE against liver cancer.

A polyethylenimine-based diazeniumdiolate nitric oxide donor accelerates wound healing.

Nitric oxide (NO) plays a pivotal role in the cutaneous healing process and a topical supplement of NO is beneficial for wound repair. In this work, a novel polyethylenimine (PEI) based diazeniumdiolate nitric oxide donor was prepared. The obtained polymer (PEI-PO-NONOate) was characterized by Fourier transform infrared (FTIR) spectroscopy, UV-vis absorption spectra, and nuclear magnetic resonance (NMR). The PEI-PO-NONOate polymer was stable under anhydrous conditions at different temperatures. A total of 0.57 µmol gaseous NO was released from 1.0 mg of the PEI-PO-NONOate polymer in PBS of pH 7.4 and it presented a proton-driven release pattern. Furthermore, the PEI-PO-NONOate polymer exhibited a controlled release profile sustained for over 30 hours within the polyethylene glycol (PEG) mixture system. Cytotoxicity evaluation was performed on L929 cells. Full-thickness excisional cutaneous wound models of mice were prepared and the PEI-PO-NONOate polymer was applied to investigate its effects on wound healing. The results revealed that the PEI-PO-NONOates exhibited good biocompatibility. It was also found that the PEI-PO-NONOate polymer promoted cutaneous wound healing and closure with enhanced granulation tissue formation, collagen deposition, and angiogenesis, as compared to the control. In summary, a novel nitric oxide releasing polymer with high loading efficiency and a controlled release profile was developed which presented the potential for application in the acceleration of cutaneous wound healing.

The earlier, the better: the effects of different administration timepoints of sorafenib in suppressing the carcinogenesis of VEGF in rats.

PURPOSE: To investigate the optimal starting time point of sorafenib therapy in suppressing the tumor-promoting effects of VEGF up-regulation, which is frequently found after local therapy in clinical practice. METHODS: VEGF was intravenously injected to imitate the evaluated expression after local tumor therapy, such as TACE. A total of 40 SD rats bearing hepatic tumors were randomly divided into four groups and sorafenib was administered at different timepoints: (A) control group: VEGF injection only; (B) initiating sorafenib 72 h prior to VEGF injection; (C) initiating sorafenib simultaneously with VEGF injection; (D) initiating sorafenib 72 h post-VEGF injection. The rate of tumor growth, median survival time, expression of VEGF, and microvessel density (MVD), as determined by immunohistochemical (IHC) examination, were compared. RESULTS: The results revealed that the tumor size and median survival time were significantly different between the three sorafenib groups compared to the control group (p < 0.05). Median survival times were 19.6 ± 1.78, 31.2 ± 6.99, 27.4 ± 4.9, and 26.5 ± 4.6 days in group A, B, C, and D, respectively. Furthermore, there was a difference in statistical significance between the two sorafenib groups B and D (p = 0.04). Tumors were collected for HE staining and IHC examination. The expression levels of VEGF in B, C, and D were 42.8 ± 7.96, 71.9 ± 15.73, and 73.6 ± 13.73, and all of them were significantly lower than that in the control group (88.3 ± 13.61). Furthermore, the level of MVD was 109.2 ± 8.98 in the control group, which was significantly higher than in the three sorafenib groups (45.7 ± 16.92, 77.1 ± 16.29, and 93.6 ± 12.87, all p < 0.05). CONCLUSIONS: According to our results, the most suitable regimen for the administration of sorafenib is before the increased expression of VEGF, which showed a potential advantage for controlling the tumor growth and prolonging the survival time of test animal via inhibiting VEGF-receptor expression through the bifunction of VEGF, and the reduction of tumor angiogenesis.