Transcatheter arterial chemoembolization using CalliSpheres beads loaded with arsenic trioxide for unresectable large or huge hepatocellular carcinoma: a prospective study.

OBJECTIVES: To determine the safety and efficacy of transcatheter arterial chemoembolization with CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) in the first-line treatment of patients with large (5 cm ≤ maximum diameter < 10 cm) or huge (maximum diameter ≥ 10 cm) hepatocellular carcinoma (HCC). METHODS: Patients were randomly allocated to the CBATO-TACE group and the conventional transcatheter arterial chemoembolization (cTACE) group. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall survival (OS), treatment response, and treatment-related adverse events (TRAEs). The extrahepatic collateral arteries, liver function, and liver fibrosis after the first TACE were also evaluated. RESULTS: From September 2018 to September 2020, a total of 207 patients who underwent TACE were consecutively enrolled in this study. The median PFS was 9.5 months (range: 8.0 - 11.0) in the CBATO group, which was significantly longer than that in the cTACE group (6.0 months, range: 4.0-6.0) (p < 0.0001). Patients in the CBATO group had a median OS of 22 months (range: 20.0 - 27.0) compared with 16 months (range: 15.0 - 20.0) in the cTACE group (p = 0.0084). The most common TRAEs were fever (p = 0.043), and nausea and vomiting (p = 0.002), which were more observed in the cTACE group. In addition, the progressive disease time, pulmonary metastasis rate (p = 0.01), the mean number of extrahepatic collateral arteries (p = 0.01), and average number of TACE sessions (p = 0.025) were significantly decreased in the CBATO group. CONCLUSIONS: CBATO-TACE achieved better therapeutic outcomes and similar safety profile compared to cTACE in large or huge HCC patients. Furthermore, CBATO-TACE was able to reduce extrahepatic collateral arteries production and extrahepatic lung metastasis. CLINICAL RELEVANCE STATEMENT: Our study showed that CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) were effective and safe for the treatment of large and giant HCC. In addition, CBATO-TACE can reduce lateral hepatic branch artery formation and extrahepatic pulmonary metastasis, which provides a new treatment approach for unresectable HCC. KEY POINTS: • We compare long-term efficacy and safety of transcatheter arterial chemoembolization with CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) and conventional transcatheter arterial chemoembolization (cTACE) in patients with large (5 cm ≤ maximum diameter < 10 cm) or huge HCC (maximum diameter ≥ 10 cm). • Compared with cTACE, CBATO-TACE significantly improved therapeutic outcomes, overall survival, and progression-free survival in patients with large or huge HCC. The safety assessment suggested that CBATO-TACE is a safe treatment that improves the quality of life and has good treatment adherence.

Covered SEMS failed to cure airway fistula closed by an amplatzer device.

BACKGROUND: Airway fistula is a rare but threatening complication associated with high rates of morbidity and mortality. We report the experience of Amplatzer device application in airway fistulae that failed to be cured with a covered self-expandable metallic stent (SEMS). MATERIALS AND METHODS: Patients who failed occlusion with a covered self-expandable metallic stent and received Amplatzer device placement from Jan 2015 to Jan 2020 were retrospectively enrolled. A total of 14 patients aged 42 to 66 years (55.14 ± 7.87) were enrolled in this study. The primary diseases, types of fistula, types of stents, duration, size of fistula, and follow-up were recorded. RESULTS: All 14 patients with airway fistula failed to be occluded with a covered metallic stent and received Amplatzer device placement. Among the 14 patients, 6 had BPF, 3 had TEF and 5 had GBF. The average stent time was 141.93 ± 65.83 days. The sizes of the fistulae ranged from 3 to 6 mm. After Amplatzer device placement, the KPS score improved from 62.14 ± 4.26 to 75.71 ± 5.13 (P < 0.05). No procedure-related complications occurred. During the 1-month, 3-month and 6-month follow-ups, all the Amplatzer devices were partially surrounded with granulation. Only 1 patient with BPF failed with Amplatzer device occlusion due to the recurrence of lung cancer. CONCLUSION: In conclusion, the application of the Amplatzer device is a safe and effective option in the treatment of airway fistula that failed to be occluded with SEMSs.

Liposome quercetin enhances the ablation effects of microwave ablation in treating the rabbit VX2 liver tumor model.

OBJECTIVE: This study aimed to investigate whether liposomal quercetin (LQ) could enhance the effects of microwave ablation (MVA) in treating the rabbit VX2 liver tumor model. METHODS: Rabbits with VX2 liver tumors were randomly divided into three groups: intravenous LQ group (LQ group), MWA group and LQ combined with MWA (LQ + MWA) group. Five rabbits were randomly selected and sacrificed from each group at 12 h and on days 3, 7 and 14 of the operation. The tumor samples were detected and quantified by immunohistochemistry, Western blot, and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: For up to 7 days, the coagulation necrosis volume (CV) of the LQ + MWA group was larger than that of MWA and LQ groups (p < 0.05). Fourteen days after the operation, the total tumor volume of the LQ + MWA group was smaller than that of the LQ group and the MWA group (p < 0.05). The survival time of the LQ + MWA group was significantly longer than that of the MWA and LQ groups (p < 0.01). Heat shock protein 70 (HSP70), hypoxia inducible factor-1 α (HIF-1 α), vascular endothelial growth factor (VEGF), tumor microvessel density (MVD) were lower in the LQ + MWA group than the MWA and LQ groups at 12 h, on days 3 and 7. At hour 12 and on days 3 and 7, HSP70 mRNA and HIF-1α mRNA expression of MWA group were significantly higher than that of the LQ and LQ + MWA groups (p < 0.001). At 12 h, and on days 3 and 7, apoptotic rate of tumor cells in LQ + MWA group was higher than that of the MWA and LQ groups (p < 0.05). At 12 h and on days 3, 7 and 14, the proliferation index of tumor cells in residual tumor in LQ + MWA group was lower than that in the MWA and LQ groups (p < 0.05). CONCLUSION: Preoperative infusion of LQ can significantly enhance the MWA effects of liver VX2 tumor, inhibit the excessive proliferation of residual tumor and angiogenesis, and decrease metastasis and prolong the survival period of experimental animals.

Development and validation of a novel luciferase reporter gene assay to detect pyrogen.

To develop and validate a novel reporter gene assay (RGA) to detect pyrogen, HL60 cells were transfected with an NF-κB-RE plasmid containing the luciferase gene to generate stably transfected cells. Through stimulation with pyrogens, a signal was obtained that was dose-dependent with the concentration of pyrogen. Using the cells, we selected and optimized the parameters and found that the optimal conditions may be with 5 × 105/ml cells that were seeded and incubated with pyrogen for 3-6 h in IMDM medium with 2% FBS. Based on the optimized parameters, a novel RGA was developed. Then, the RGA was validated and the results showed that the linearity was greater than 0.95 between the signals and the concentrations of pyrogen, the recoveries of pyrogen were all between 50% and 200%, and the precision was less than 35%. There was no difference in the sensitivity, specificity or reproducibility between RGA and BET, and the results from RGA and MAT and RPT were consistent. Furthermore, the RGA can be applied to the pyrogen detection of monoclonal antibodies. Due to its advantages including a fast detection speed, high sensitivity, convenient mode of operation and wide-pyrogen spectrum detection, RGA is promising as a supplementary method to detect pyrogen.

Intermittent aortic balloon occlusion combined with cesarean section for the treatment of patients with placenta previa complicated by placenta accreta: A retrospective study.

AIM: To compare the efficacy of cesarean section (CS) combined with intermittent aortic balloon occlusion with that of CS alone for treating patients with placenta previa complicated by placenta accreta. METHODS: Forty-five patients with placenta previa complicated by placenta accreta who underwent CS were retrospectively studied. Twenty-two patients had undergone CS combined with intermittent aortic balloon occlusion (combination group) and 23 patients received conventional hemostatic support only (control group). The postpartum hemorrhage, transfusion requirements, operation time and recovery time, and the ability to preserve the uterus and fertility were analyzed. RESULTS: Intermittent aortic balloon occlusion significantly decreased the volume of blood loss in the combination group relative to the control group (597 ± 359 mL vs 2687 ± 575 mL; P < 0.001), and transfusion requirements were also reduced (498 ±195 mL vs 2390 ±789 mL; P <0.001). We observed shorter operation time in the combination group relative to the control group (63.8 ± 12.3 min vs 118.8 ± 22.4 min; P < 0.001), and fewer patients required uterine cavity stuffing followed by uterine artery embolization (n = 2 vs n = 10; P <0.05), uterine artery ligation (n = 1 vs n = 9; P < 0.05), and hysterectomy (n = 0 vs n =7; P < 0.05). CONCLUSION: Intermittent aortic balloon occlusion may control postpartum hemorrhage in pregnancies complicated by placenta accreta, and improve the postoperative conditions.

Comparison of temporary abdominal aortic occlusion with internal iliac artery occlusion for patients with placenta accreta - a non-randomised prospective study.

BACKGROUND: To compare the efficacy of temporary abdominal aortic occlusion with internal iliac artery occlusion for the management of placenta accreta. PATIENTS AND METHODS: 105 patients with placenta accreta were selected for treatment with temporary abdominal aortic occlusion (n = 57, group A) or bilateral iliac artery occlusion (n = 48, group B). Temporary abdominal aortic and internal iliac artery balloon occlusions were performed during caesarean sections. Data regarding the clinical success, blood loss, blood transfusion, balloon insertion time, fluoroscopy time, balloon occlusion time, foetal radiation dose, and complications were collected. RESULTS: Temporary abdominal aortic occlusion and bilateral internal iliac artery occlusion were technically successful in all patients. The amount of blood loss (P < 0.001), amount of blood transfusion (P < 0.001), balloon insertion time (P < 0.001), foetal radiation dose (P < 0.001) and fluoroscopy time (P < 0.01) in group A were significantly lower than those of patients in group B. No marked differences were found between these 2 groups with respect to age, mean postoperative hospital stay, balloon occlusion time, and Apgar score (p > 0.05). CONCLUSIONS: Temporary abdominal aortic balloon occlusion resulted in better clinical outcomes with less blood loss, blood transfusion, balloon insertion time, fluoroscopy time and foetal radiation dose than those in bilateral internal iliac balloon occlusion.
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Urgent transcatheter arterial embolization for the treatment of ruptured renal angiomyolipoma with spontaneous hemorrhage.

Background The rich neovascularization of renal angiomyolipoma (AML) has a tendency for spontaneous rupture with subsequent hemorrhage. Nephrectomy or nephron-sparing surgery has rarely been used as a primary treatment in urgent situations. Purpose To evaluate the safety and long-term outcomes for patients treated by urgent transcatheter arterial embolization (TAE) for spontaneous ruptured renal AML with severe hemorrhage. Material and Methods A retrospective evaluation was performed of 25 renal AML cases with spontaneous hemorrhage confirmed by imaging. Polyvinyl alcohol (PVA) particles and coils of multiple sizes were used to embolize the spontaneous renal AML ruptures. Results The technical success rate of TAE was 96% (24/25). One week post-TAE, 1 patient with recurrent hemorrhage underwent emergency nephrectomy. Minor complications affected 16 patients with post-embolization syndrome; 15 patients resolved using conservative measures and one patient received nephrectomy post TAE 1 week later. All patients were followed up for 24-72 months (median, 50.2 months). Surgical treatment was avoided for 92% (23/25) of patients, and the re-embolization rate was 0% at 2 years post TAE. In the 23 patients without surgical treatment, the mean maximum diameter of renal AML was reduced from 12.4 ± 5.5 cm to 6.3 ± 2.5 cm and no hemorrhage occurred during follow-up. Conclusion Urgent TAE is a technically feasible and minimally invasive procedure for controlling severe hemorrhage and preservation of renal function following spontaneous ruptured renal AML.

Percutaneous transhepatic cholangiography and intraductal radiofrequency ablation combined with biliary stent placement for malignant biliary obstruction.

PURPOSE: To determine the safety and feasibility of percutaneous transhepatic cholangiography (PTC) and intraductal radiofrequency (RF) ablation combined with biliary stent placement for malignant biliary obstruction. MATERIALS AND METHODS: Data from patients with unresectable malignant biliary obstruction who underwent PTC, intraductal RF ablation, and biliary stent placement (n = 12) or PTC and biliary stent placement only (control group; n = 14) were reviewed. Postoperative complications, jaundice remission, and stent patency were assessed. RESULTS: All procedures were successful. No severe complications (eg, biliary bleeding, perforation) occurred. Two experimental group patients developed cholangitis, which resolved with conservative treatment. The 1-week jaundice remission and 3-month stent patency rates were similar in both groups, but the 6-month stent patency rate was higher in the experimental group (P < .05). In the experimental group, one death occurred as a result of gastrointestinal hemorrhage (unrelated to stent placement) by 3 months, and there were two cases of recurrent jaundice by 6 months. The latter two patients underwent repeat PTC, ablation, and stent placement. In the control group, one death occurred as a result of hepatic failure caused by progressive jaundice at 3 months, and another death resulted from disseminated intravascular coagulation caused by jaundice recurrence at 138 days after stent placement. In addition, seven patients developed jaundice recurrence (50-151 d after stent placement). PTC and repeat stent placement were performed in these patients. CONCLUSIONS: Percutaneous transhepatic cholangiography and intraductal RF ablation combined with biliary stent placement for malignant biliary obstruction is safe and feasible and effectively prolongs stent patency time.

Clinical features and endovascular treatment of visceral artery pseudoaneurysms.

BACKGROUND: To analyze our experience with clinical features and endovascular treatment of visceral artery pseudoaneurysms (VAPAs). METHODS: We performed endovascular treatments on 52 patients (34 men and 18 women) affected by VAPA. These cases were pseudoaneurysms of the celiac axis, superior mesenteric artery, and their branches. Endovascular treatments of VAPA using isolation techniques were performed after failure of conservative treatments. Follow-up was carried out via assessment of contrast-enhanced computed tomography or computed tomography angiography images. RESULTS: The initial technical success rate of endovascular treatment is 100% with only 4 patients rebled during 2-week follow-up. One patient among no rebleeding died of multisystem organ failure 28 days after intervention; thus, 30-day mortality rate was 1.9%. Four patients (7.7%) required secondary interventions because of rebleeding and were successfully treated by reintervention; however, one of the patients died from uncontrolled sepsis 39 days after reintervention. Postembolization syndrome developed in 3 patients (5.8%); one of these patients underwent splenectomy. During follow-up, no change of hepatic function was observed, no bowel ischemia was reported, and VAPA remained absent in all patients. CONCLUSIONS: Endovascular management is minimally invasive and highly successful in treating VAPA. It is particularly useful in poor surgical candidates.

Radiofrequency ablation combined with transcatheter therapy in rabbit VX2 liver tumors: effects and histopathological characteristics.

BACKGROUND: Transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) treatment (TACE-RFA) has been confirmed superior to TACE or RFA alone in animal liver tumors. TACE before RFA was shown to increase hepatocellular damage. Further optimization of the combination strategy for transcatheter arterial embolization (TAE) or TACE combined with RFA is warranted. PURPOSE: To determine the optimal strategy for radiofrequency ablation combined with transcatheter therapies in VX2 liver tumors in a rabbit model. MATERIAL AND METHODS: Twenty-four Japanese White rabbits with VX2 liver tumors were randomly divided into four groups: TACE-RFA (TACE-RFA group), transcatheter arterial embolization (TAE) combined with RFA treatment (TAE-RFA group), RFA only group, and TACE only group. Blood samples were collected 1 day before the operation and at 3 and 7 days postoperatively. Seven days after the operation, maximal diameters of coagulation or infarcted zones in the gross specimens, CT images, histopathological characteristics, tumor necrotic rate, and growth rate were compared. RESULTS: Significantly larger mean long-axis (P < 0.05) and short-axis (P < 0.05) diameters of coagulation and infarction were observed in the TACE-RFA group compared with the TAE-RFA, RFA, and TACE groups on day 7; and the TAE-RFA group showed a significant (P < 0.05) increase versus the RFA and TACE groups on day 7. There were no significant differences in tumor growth rate (109.3 ± 37.5 vs. 119.0 ± 43.1%, P = 0.45) and necrotic rate (89.5 ± 12.0 vs. 83.5 ± 9.3%, P = 0.73) between the TACE-RFA and TAE-RFA groups. TACE-RFA was more effective for achieving tumor destruction than the other treatment strategies, but led to increased rabbits discomfort and more severe liver dysfunction compared with TAE-RFA. CONCLUSION: TAE-RFA appears to be a beneficial therapeutic modality for treating VX2 liver tumors in a rabbit model.

Endovascular embolization for managing anastomotic bleeding after stapled digestive tract anastomosis.

BACKGROUND: Anastomotic bleeding is an infrequent but life-threatening complication after stapled digestive tract anastomosis. Endovascular embolization is one of the available treatments, but precise clinical outcomes are yet to be evaluated. PURPOSE: To evaluate the efficacy and safety of endovascular embolization for managing anastomotic bleeding after stapled digestive tract anastomosis. MATERIAL AND METHODS: Twenty-eight patients were diagnosed with anastomotic bleeding after stapled digestive tract anastomosis by digital subtraction angiography (DSA). Curative effect was summed for analysis. RESULTS: All bleeding arteries were located in the stoma and were identified by contrast agent spillover by DSA. The offending arteries were superselectively catheterized and embolized with microcoils and/or gelatin sponge particles. Laboratory examinations showed normal hemoglobin and red blood cell counts when the patients' abdominal cavity drainage tubes stopped draining blood. The follow-up period was 3.2-84.7 months (median, 19.7 months). Four patients died during this time, of which two had cholangiocarcinoma, one had gastric cancer with tumor recurrence and multiple organ failure, and the final patient had a subarachnoid hemorrhage 4 months after embolization. In the surviving patients, no rebleeding occurred after embolization and no additional intervention or surgery was required. CONCLUSION: Endovascular embolization is safe and effective for managing anastomotic bleeding after stapled digestive tract anastomosis.

Comparison of percutaneous transhepatic variceal embolization (PTVE) followed by partial splenic embolization versus PTVE alone for the treatment of acute esophagogastric variceal massive hemorrhage.

PURPOSE: To compare the efficacy of percutaneous transhepatic variceal embolization (PTVE) followed by partial splenic embolization (PSE) with that of PTVE alone for the treatment of acute massive hemorrhage of esophagogastric varices in patients with cirrhosis unable to undergo alternative procedures. MATERIALS AND METHODS: Sixty-five patients with acute variceal massive hemorrhage were retrospectively studied, including 31 who underwent PTVE/PSE and 34 who underwent PTVE and refused PSE. Recurrent bleeding rate, survival rate, postoperative complications, number of days of hospitalization after PTVE, and outcome were evaluated. Peripheral blood cell counts and hemoglobin levels before and at 1 week and 6, 12, and 24 months after intervention were analyzed. RESULTS: Cumulative recurrent bleeding rates at 6, 12, and 24 months after intervention in the PTVE/PSE group were 3.2%, 6.7%, and 13.3%, compared with 20.6%, 36.7%, and 53.6%, respectively, in the PTVE group; the difference at each time point was statistically significant (all P < .01). There were more cases of ascites and portal hypertensive gastropathy after PTVE than after PTVE/PSE (P < .05). Survival rates at 6, 12, and 24 months in the PTVE/PSE group were 100%, 96.8%, and 96.8%, compared with 94.1%, 88.2%, and 82.4%, respectively, in the PTVE group. There were significant differences in peripheral blood cell counts and hemoglobin levels between the PTVE/PSE and PTVE groups at all observed time points (all P < .01). CONCLUSIONS: PTVE/PSE not only has long-term efficacy in alleviating hypersplenism, but decreases recurrent bleeding and maintains hepatic reserve in patients with cirrhosis and esophagogastric variceal massive hemorrhage unable to undergo other procedures.

Assessment of 64-row computed tomographic angiography for diagnosis and pretreatment planning in pulmonary sequestration.

PURPOSE: This study was done to evaluate the clinical implications and results of a prospective protocol using 64-row computed tomographic angiography (CTA) for diagnosis and pre-treatment planning in pulmonary sequestration (PS). MATERIALS AND METHODS: Forty-five patients with suspected PS were referred for CTA examination. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of measures used to detect PS were determined by patient-based and aberrant systemic artery-based evaluations. The location, the size and the number of aberrant systemic arteries, and the feasibility of endovascular treatment were analysed. The capability of CTA to provide a working view and the accuracy of measurements in choosing a coil were also assessed. RESULTS: Digital subtraction angiography and/or surgery revealed PS in 38 patients, and 7 patients had no PS. The patient-based evaluation yielded an accuracy of 97.8 %, sensitivity of 97.4 %, specificity of 100 %, PPV of 100 % and NPV of 87.5 %, in the detection of PS. CTA clearly depicted the PS in all 38 patients, and the aberrant systemic artery was accurately demonstrated in 37 out of 38 patients where endovascular treatment was possible. Working views for endovascular treatment were found in all patients with PS, and the choice of coil was correct in 37 out of 38 patients using CTA. CONCLUSIONS: 64-row CTA appears to be effective in terms of supporting accurate diagnosis and pre-treatment planning in PS. CTA is not only able to provide clear visualisation of aberrant systemic arteries but also provides detailed images of abnormal lung parenchyma and the airways.

Pioglitazone, a peroxisome proliferator­activated receptor γ agonist, induces cell death and inhibits the proliferation of hypoxic HepG2 cells by promoting excessive production of reactive oxygen species.

Hypoxia is a hallmark of solid tumors. Hypoxic cancer cells adjust their metabolic characteristics to regulate the production of cellular reactive oxygen species (ROS) and facilitate ROS-mediated metastasis. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that regulates the transcription of fatty acid metabolism-related genes that have a key role in the survival and proliferation function of hypoxic cancer cells. In the present study, mRNA expression in HepG2 cells under chemically induced hypoxia was assessed. The protein expression levels of hypoxia-inducible factor 1α (HIF-1α) were measured using western blotting. Following treatment with the PPARγ agonist pioglitazone, cell viability was assessed using a Cell Counting Kit-8 assay, whilst cell proliferation and death were determined using 5-ethynyl-2'-deoxyuridine incorporation staining, and calcein-acetoxymethyl ester and propidium iodide staining, respectively. Cellular ROS production was assessed using dihydroethidium staining. Cobalt chloride was used to induce hypoxia in HepG2 cells, which was evaluated using HIF-1α expression. The results revealed that the mRNA expression of PPARγ, CD36, acetyl-co-enzyme A dehydrogenase (ACAD) medium chain (ACADM) and ACAD short-chain (ACADS) was downregulated in hypoxic HepG2 cells. The PPARγ agonist pioglitazone decreased the cell viability of hypoxic HepG2 cells by inhibiting cell proliferation and inducing cell death. Following treatment with the PPARγ agonist pioglitazone, hypoxic HepG2 cells produced excessive ROS. ROS-mediated cell death induced by the PPARγ agonist pioglitazone was rescued with the antioxidant N-acetyl-L-cysteine. The downregulated mRNA expression of PPARγ, CD36, ACADM and ACADS was not reverted by a PPARγ agonist in hypoxic HepG2 cells. By contrast, the PPARγ agonist suppressed the mRNA expression of BCL2, which was upregulated in hypoxic HepG2 cells. In summary, the PPARγ agonist stimulated excessive ROS production to inhibit cell proliferation and increase the death of hypoxic HepG2 cells by decreasing BCL2 mRNA expression, suggesting a negative association between PPARγ and BCL2 in the regulation of ROS production in hypoxic HepG2 cells.

Blocking TGFßR synergistically enhances anti-tumor effects of anti-PD-1 antibody in a mouse model of incomplete thermal ablation.

The mechanism of early tumor recurrence after incomplete microwave ablation (iMWA) is poorly understood. The anti-programmed cell death protein 1 (anti-PD-1) monotherapy is reported to be ineffective to prevent the progression of residual tumor resulted from iMWA. Transforming growth factor-ß (TGFß) signaling pathway plays an important role in tumorigenesis and development. We assume blocking transforming growth factor-ß receptor (TGFßR) after incomplete iMWA may synergistically enhance the effect of anti-PD-1 antibody to prevent the progression of residual tumor. We construct an iMWA model with mice harboring Hepa1-6 derived xenograft. The Tgfb1 expression and phosphorylated-Smad3 protein expression is upregulated in the residual tumor after iMWA. With the application of TGFßR inhibitor SB431542, the cell proliferation potential, the tumor growth, the mRNA expression of epithelial mesenchymal transition (EMT) markers including Cdh2, and Vim, and cancer stem cell marker Epcam, and the infiltrating Treg cells are reduced in the residual tumor tissue. In addition, iMWA combined with TGFßR blocker and anti-PD-1 antibody further decreases the cell proliferation, tumor growth, expression of EMT markers and cancer stem cell marker, and the infiltrating Treg cells in the residual tumor tissue. Blocking TGFßR may alleviate the pro-tumoral effect of tumor microenvironment thereby significantly prevents the progression of residual tumor tissue. Our study indicates that blocking TGFßR may be a novel therapeutic strategy to enhance the effect of anti-PD-1 antibody to prevent residual hepatocellular carcinoma (HCC) progression after iMWA.

Cell Membrane Hybrid Lipid Nanovesicles Enhance Innate Immunity for Synergistic Immunotherapy by Promoting Immunogenic Cell Death and cGAS Activation.

Immunotherapy shows great therapeutic potential for long-term protection against tumor relapse and metastasis. Innate immune sensors, such as cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), dissolve DNA and induce type I interferon. Through activation of the cGAS/STING pathway, chemotherapy drugs and reversine (REV) may provide synergetic anti-tumor effects. Here, we prepared drug-loaded cell membrane hybrid lipid nanovesicles (LEVs) (designated LEV@DOX@REV) by fusion of cell membranes, phospholipids, doxorubicin (DOX), and REV, to realize accurate delivery to tumors and chemo-immunotherapy. The cell membranes of LEVs confer "homing" abilities. DOX can induce immunogenic cell death as a result of its specific immunomodulatory effects, which promotes the maturation of immune cells and improves the microenvironment of the immune system. REV is proven to efficiently activate cGAS/STING signaling, thereby enhancing the immune system. The antitumor efficacy of LEV@DOX@REV was evaluated in a 4T1 subcutaneous tumor xenograft model, a distant metastatic tumor model, and a liver metastatic tumor model. LEV@DOX@REV facilitated the infiltration of cytotoxic T lymphocytes within tumors, increased the secretion of proinflammatory cytokines, and modified the tumor microenvironment. In conclusion, LEV@DOX@REV displayed favorable antitumor effects and extended the survival of tumor-bearing mice. We therefore successfully developed nanoparticles capable of enhancing immune activation that have potential therapeutic applications for cancer immunotherapy.

Delivery of SiRNA-PD-L1 by attenuated Salmonella in combination with oxaliplatin in a hepatocellular carcinoma mouse model.

Oxaliplatin is currently used for chemotherapy in patients with hepatocellular carcinoma, but its increasing tolerance to tumours over time limits its clinical application. Studies have shown that high PD-L1 expression promotes the polarization of M2 macrophages. The increased infiltration of M2 macrophages, including those in HCC, is positively correlated with poor prognosis in various solid tumours. We found that oxaliplatin promoted the expression of PD-L1 in liver cancer cells, which might be attributed partly to the tolerance of tumours to oxaliplatin. Therefore, in this study, we explored the antitumour effect of attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin via Western blotting, immunohistochemistry, immunofluorescence, and flow cytometry. The results revealed that attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin more significantly inhibited tumour growth in tumour-bearing mice, suppressed the expression of PD-L1 in tumour tissue, increased the apoptosis of tumour cells and the expression of the tumour-related protein cleaved-caspase3, and increased the infiltration of M1 macrophages and T lymphocytes in tumour tissues. Moreover, the combination therapy increased the activation of T cells and the number of T lymphocytes and NK cells in the spleens of the mice and improved the overall antitumour immune response in the mice. Our results confirmed that attenuated Salmonella harbouring siRNA-PD-L1 combined with oxaliplatin had a significant antitumour effect and did not increase the incidence of toxic side effects, providing a theoretical reference for addressing oxaliplatin tolerance in the treatment of hepatocellular carcinoma.

SiRNA-HIF-1α delivered by attenuated Salmonella enhances the efficacy of Lenvatinib against hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1-3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor.

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.

Correlation between magnetic resonance images of peritumor margin enhancement and prognosis in hepatocellular carcinoma after drug-eluting bead transcatheter arterial chemoembolization.

Purpose: The aim of this study is to investigate the morphological characteristics and clinical significance of magnetic resonance (MR) images of peritumor margin enhancement in hepatocellular carcinoma (HCC) after drug-eluting bead transcatheter arterial chemoembolization (DEB-TACE). Methods: From January 2017 to December 2020, a total of 162 patients who received a diagnosis of HCC were included in our study. We began the follow-up with magnetic resonance imaging (MRI) for complete response assessment, and peritumor margin enhancements were classified as sharp and rough types according to morphology. During the follow-up, data such as progression or remission of the two enhancement modalities, morphological changes in terms of margin enhancements observed in MR images, and alpha-fetoprotein (AFP) levels were recorded. Results: In the follow-up period of 36 months, 70 and 92 patients with sharp- and rough-type peritumor margins, respectively, were observed. At the end of the follow-up, patients with sharp-type margins had lower AFP levels and longer progression-free survival than those with rough-type margins (P < 0.05). Furthermore, the sharp-type margin was thinner than the rough-type margin (all P < 0.05). Moreover, the sharp-type group had a high incidence of tumors with a diameter of < 5 cm, whereas the rough-type group had a high incidence of tumors with a diameter of ≥ 5 cm. Continuous enhancements of peritumor margins in MRI were greater in the sharp-type group than in the rough-type group. Most of the patients with a sharp-type margin achieved disease remission (94.3%, P < 0.05), whereas most of those with a rough-type margin experienced disease progression (84.8%, P < 0.05). Conclusions: Patients with HCC with a sharp-type margin enhancement on MRI after DEB-TACE mostly demonstrated benign lesions with a good prognosis, whereas those with a rough-type margin mostly demonstrated malignant growth.