Lenvatinib, sintilimab plus transarterial chemoembolization for advanced stage hepatocellular carcinoma: A phase II study.

BACKGROUND & AIMS: Our retrospective study has suggested encouraging outcomes of lenvatinib combined with PD-1 inhibitor and transarterial chemoembolization (TACE) on advanced hepatocellular carcinoma (HCC). This phase II trial was conducted to prospectively investigate the efficacy and safety of lenvatinib, sintilimab (a PD-1 inhibitor) plus TACE (Len-Sin-TACE) in patients with advanced stage HCC. METHODS: This was a single-arm phase II trial. Patients with BCLC stage C HCC were recruited. They received lenvatinib (bodyweight ≥60 kg, 12 mg; bodyweight <60 kg, 8 mg) orally once daily, sintilimab (200 mg) intravenously once every 3 weeks, and on demand TACE. The primary endpoint was progression-free survival (PFS) per mRECIST. RESULTS: Thirty patients were enrolled. The primary endpoint was met with a median PFS of 8.0 (95% confidence interval [CI]: 6.1-9.8) months per mRECIST, which was the same as that per RECIST 1.1. The objective response rate was 60.0% per mRECIST and 30.0% per RECIST 1.1. The disease control rate was 86.7% per mRECIST/RECIST 1.1. The median duration of response was 7.4 (95% CI: 6.6-8.2) months per mRECIST (n = 18) and 4.3 (95% CI: 4.0-4.6) months per RECIST 1.1 (n = 9). The median overall survival was 18.4 (95% CI: 14.5-22.3) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 12 patients (40.0%). There were no grade 4/5 TRAEs. CONCLUSIONS: Len-Sin-TACE showed promising antitumour activities with a manageable safety profile in patients with advanced stage HCC. The preliminary results need to be further evaluated with phase III randomized trials.

High Expression of Ten Eleven Translocation 1 Is Associated with Poor Prognosis in Hepatocellular Carcinoma.

Background: DNA methylation patterns have been found to be distinct between tumor and normal patients. However, the effect of DNA demethylation enzymes, ten eleven translocation (TET) proteins, has not been comprehensively characterized in liver cancer. In this research, we sought to unravel the linkage of TET proteins with prognosis, immune characteristics and biological pathways in hepatocellular carcinoma (HCC). Materials and Methods: Four independent datasets with gene expression data and clinical data of HCC samples were downloaded from public databases. CIBERSORT, single sample Gene Set Enrichment Analysis (ssGSEA), MCP-counter, and TIMER were implemented to evaluate immune cell infiltration. limma was employed to screen differentially expressed genes (DEGs) between two groups. The demethylation-related risk model was established by using univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO), and stepwise Akaike information criterion (stepAIC). Results: TET1 was significantly higher expressed in tumor samples than that in normal samples. HCC patients with advanced stages (III+IV) and grades (G3+G4) had higher TET1 expression compared to early stages (I+II) and grades (G1+G2). HCC samples with high TET1 expression had worse prognosis than that with low expression. High and low TET1 expression groups had distinct immune cell infiltration and response to immunotherapy and chemotherapy. We identified 90 DEGs related to DNA demethylation in high vs. low TET1 expression groups. Furthermore, we established a risk model based on 90 DEGs containing seven key prognostic genes (SERPINH1, CDC20, HACD2, SPHK1, UGT2B15, SLC1A5, and CYP2C9) with effectiveness and robustness in predicting HCC prognosis. Conclusions: Our study suggested TET1 as a potential indicator in HCC progression. TET1 was closely involved in immune infiltration and activation of oncogenic pathways. The DNA demethylation-related risk model was potential to be applied for predicting HCC prognosis in clinics.

Prognosis of patients with hepatocellular carcinoma and portal vein tumor thrombus treated with combination of transarterial chemoembolization and palliative thermal ablation.

PURPOSE: Transarterial chemoembolization (TACE) was obtained acceptable benefit for advanced hepatocellular carcinoma (HCC). Here in this study, we compared the benefit of TACE combined palliative thermal ablation with TACE alone for HCC with portal vein tumor thrombus (PVTT). METHODS: Patients with HCC and PVTT were retrospectively analyzed from January 2012 to December 2017, who accepted treatment of TACE alone (TACE group) or TACE plus palliative thermal ablation (TACE + P-ablation group). Propensity score matching (PSM) was applied to balance differences between the two groups. Overall survival (OS) and progression-free survival (PFS) rates were compared between groups. RESULTS: Median follow-up time was 7.4 (3.0-60.0) months. In the cohort, 142 patients were enrolled in TACE group and 86 patients were enrolled in TACE + P-ablation group. The pre-PSM estimated 6-, 12-, and 18-month OS rates for the TACE + P-ablation group were 70.9, 46.5, and 31%, respectively, whereas rates for the TACE group were 57, 23.1, and 10%, respectively. After PSM, OS and PFS rates remained coincident with the pre-PSM. Risk factors for poor OS included PVTT type III and type II relative to type I (HR = 1.76; 95% CI, 1.13-2.74; p = .01) and (HR = 1.86; 95% CI, 1.2-2.88; p = .006), TACE alone (HR = 1.40; 95% CI, 1.01-1.96; p = .04), a single TACE treatment (HR = 2.69; 95% CI, 1.79-4.03; p < .001), 2 or 3 TACE treatments (HR = 2.02; 95% CI, 1.32-3.09; p = .001). CONCLUSIONS: The combination of TACE and palliative thermal ablation for HCC with PVTT could obtain delayed progression and longer survival.

Hepatitis B Virus-Induced Imbalance of Inflammatory and Antiviral Signaling by Differential Phosphorylation of STAT1 in Human Monocytes.

It is not clear how hepatitis B virus (HBV) modulates host immunity during chronic infection. In addition to the key mediators of inflammatory response in viral infection, monocytes also express a high-level IFN-stimulated gene, CH25H, upon response to IFN-α exerting an antiviral effect. In this study, the mechanism by which HBV manipulates IFN signaling in human monocytes was investigated. We observed that monocytes from chronic hepatitis B patients express lower levels of IFN signaling/stimulated genes and higher levels of inflammatory cytokines compared with healthy donors. HBV induces monocyte production of inflammatory cytokines via TLR2/MyD88/NF-κB signaling and STAT1-Ser727 phosphorylation and inhibits IFN-α-induced stat1, stat2, and ch25h expression through the inhibition of STAT1-Tyr701 phosphorylation and in an IL-10-dependent, partially autocrine manner. Further, we found that enhancement of STAT1 activity with a small molecule (2-NP) rescued HBV-mediated inhibition of IFN signaling and counteracted the induction of inflammatory cytokines. In conclusion, HBV contributes to the monocyte inflammatory response but inhibits their IFN-α/ß responsiveness to impair antiviral innate immunity. These effects are mediated via differential phosphorylation of Tyr701 and Ser727 of STAT1.

Transcatheter arterial chemoembolization combined with Hippo/YAP inhibition significantly improve the survival of rats with transplanted hepatocellular carcinoma.

BACKGROUND: This study aimed to explore the effect of inhibiting the Hippo/Yes-associated protein (YAP) signaling pathway on the outcomes of transcatheter arterial chemoembolization (TACE) in treating transplanted hepatocellular carcinoma (HCC). METHODS: A transplanted HCC rat model was established. Then, rats were randomly divided into four groups: Sham, TACE, verteporfin (inhibitor of Hippo/YAP), and TACE+verteporfin. Lent-OE-YAP was transfected into rats to overexpress YAP in vivo. After treatments, morphological changes, tumor weight, and the overall survival of rats in different groups were analyzed. Real-time PCR, immunohistochemistry staining, and Western blotting were used to determine the expression of factors related to the Hippo/YAP signaling pathway. RESULTS: Tumor weight and tissue lesions in the TACE and verteporfin groups were significantly reduced compared with the Sham group. Verteporfin significantly decreased tumor weight after TACE treatment. In addition, verteporfin significantly improved the overall survival of rats with transplanted HCC after TACE treatment. Compared with the Sham group, both TACE and verteporfin groups exhibited significantly decreased expression of macrophage-stimulating (MST)1, MST2, long-acting thyroid stimulator 1, transcriptional co-activator with PDZ-binding motif (TAZ), Yes-associated protein (YAP), TEA domain transcription factor (TEAD)1, TEAD2, TEAD3, and TEAD4. TACE plus verteporfin significantly enhanced the downregulation of effectors in the Hippo/YAP signaling pathway and decreased tumor size, while the overexpression of YAP exerted opposite effects. CONCLUSION: The inhibition of the Hippo/YAP signaling pathway via verteporfin significantly improved the outcomes of TACE in treating transplanted HCC.

Preoperative radiomic signature based on multiparametric magnetic resonance imaging for noninvasive evaluation of biological characteristics in rectal cancer.

OBJECTIVES: To develop and validate radiomic models in evaluating biological characteristics of rectal cancer based on multiparametric magnetic resonance imaging (MP-MRI). METHODS: This study consisted of 345 patients with rectal cancer who underwent MP-MRI. We focused on evaluating five postoperative confirmed characteristics: lymph node (LN) metastasis, tumor differentiation, fraction of Ki-67-positive tumor cells, human epidermal growth factor receptor 2 (HER-2), and KRAS-2 gene mutation status. Data from 197 patients were used to develop the biological characteristics evaluation models. Radiomic features were extracted from MP-MRI and then refined for reproducibility and redundancy. The refined features were investigated for usefulness in building radiomic signatures by using two feature-ranking methods (MRMR and WLCX) and three classifiers (RF, SVM, and LASSO). Multivariable logistic regression was used to build an integrated evaluation model combining radiomic signatures and clinical characteristics. The performance was evaluated using an independent validation dataset comprising 148 patients. RESULTS: The MRMR and LASSO regression produced the best-performing radiomic signatures for evaluating HER-2, LN metastasis, tumor differentiation, and KRAS-2 gene status, with AUC values of 0.696 (95% CI, 0.610-0.782), 0.677 (95% CI, 0.591-0.763), 0.720 (95% CI, 0.621-0.819), and 0.651 (95% CI, 0.539-0.763), respectively. The best-performing signatures for evaluating Ki-67 produced an AUC value of 0.699 (95% CI, 0.611-0.786), and it was developed by WLCX and RF algorithm. The integrated evaluation model incorporating radiomic signature and MRI-reported LN status had improved AUC of 0.697 (95% CI, 0.612-0.781). CONCLUSION: Radiomic signatures based on MP-MRI have potential to noninvasively evaluate the biological characteristics of rectal cancer. KEY POINTS: • Radiomic features were extracted from MP-MRI images of the rectal tumor. • The proposed radiomic signatures demonstrated discrimination ability in identifying the histopathological, immunohistochemical, and genetic characteristics of rectal cancer. • All MRI sequences were important and could provide complementary information in radiomic analysis.

Medium or Large Hepatocellular Carcinoma: Sorafenib Combined with Transarterial Chemoembolization and Radiofrequency Ablation.

Purpose To determine the safety and efficacy of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) (hereafter, S-TACE-RFA) in patients with medium or large (range, 3.1-7.0 cm in diameter) hepatocellular carcinoma (HCC). Materials and Methods This retrospective study evaluated the medical records of consecutive patients with medium or large HCC who underwent S-TACE-RFA or combined TACE and RFA (hereafter, TACE-RFA) from January 2010 to December 2014. Sorafenib was started 3-5 days after TACE, and RFA was performed 1-2 weeks after TACE. Treatment complications, recurrence-free survival (RFS), and overall survival (OS) in patients who underwent S-TACE-RFA were compared with those in patients who underwent TACE-RFA. Results Of the 174 patients who underwent S-TACE-RFA or TACE-RFA, 106 who met the eligibility criteria were included in this study. Among them, 40 underwent S-TACE-RFA and 66 underwent TACE-RFA. The patients who underwent S-TACE-RFA had longer RFS (median, 24.0 vs 10.0 months; P = .04) and better OS (median, 63.0 vs 36.0 months, P = .048) than those who underwent TACE-RFA. S-TACE-RFA and α-fetoprotein level were independent prognostic factors for survival in uni- and multivariable analyses. The rate of complications in patients who underwent S-TACE-RFA was similar to that in patients who underwent TACE-RFA (22.5% vs 18.2%, P = .59). Conclusion S-TACE-RFA resulted in longer RFS and better OS than did TACE-RFA in patients with medium or large HCC. © RSNA, 2018 Online supplemental material is available for this article.

Co-Delivery of Doxorubicin and Anti-BCL-2 siRNA by pH-Responsive Polymeric Vector to Overcome Drug Resistance in In Vitro and In Vivo HepG2 Hepatoma Model.

Drug resistance, developed through multiple mechanisms, is a major hindrance to successful chemotherapy of tumor. Combination therapy of chemotherapeutic drugs and siRNA represents an emerging strategy which may improve anticancer effect by synergistic actions. In this study, triblock copolymer of poly(ethylene glycol)- block-poly(l-lysine)- block-poly aspartyl ( N-( N', N'-diisopropylaminoethyl)) (PEG-PLL-PAsp(DIP)) was synthesized for the first time to enable the codelivery of BCL-2 siRNA and DOX. The system is supposed to not only bypass drug efflux but also down-regulate the antiapoptotic gene and consequently confronting against chemoresistance as well. Moreover, the pH responsive ability of the codelivery system can prevent drug leakage during circulation and guarantee swift drug release at tumors. The codelivered siRNA serves to suppress the expression of antiapoptotic BCL-2 and hence sensitize the cancer cells to anticancer drugs and produce improved therapeutic effect. Consequently, the codelivery of BCL-2 siRNA and anticancer drug DOX serves as a promising strategy against drug resistance in chemotherapy.

Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid.

Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A2 (TXA2), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft-polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA2 pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH.

Partial splenic embolization for thrombocytopenia in liver cirrhosis: predictive factors for platelet increment and risk factors for major complications.

OBJECTIVES: To investigate the predictors of platelet increment and risk factors for major complications after partial splenic embolization (PSE) in cirrhosis. METHODS: Between March 2010 and June 2012, 52 cirrhotic patients with severe thrombocytopenia underwent PSE. Multiple variables were analyzed to identify the correlated factors affecting platelet increment and major complications after PSE. RESULTS: Linear mixed model analysis indicated the splenic infarction ratio (P < 0.001), non-infarcted splenic volume (P = 0.012), and cholinesterase level (P < 0.001) were significantly associated with the platelet increment after PSE. In receiver operating characteristic (ROC) analysis, the cut-off values of the splenic infarction ratio, and non-infarcted splenic volume for achieving an increment of ≥60.0 × 10(9)/L in platelet counts at 1 year after PSE were 64.3% and 245.8 mL, respectively. After PSE, eight patients developed major complications. Multivariate logistic regression analysis indicated major complications were significantly associated with the infarcted splenic volume (P = 0.024) and Child-Pugh score (P = 0.018). In ROC analysis, the cut-off values of these two factors for discriminating the uncomplicated and complicated were 513.1 mL and 9.5, respectively. CONCLUSIONS: The platelet increment after PSE depends on the splenic infarction ratio, non-infarcted splenic volume and cholinesterase level. But a large infarcted splenic volume and a high Child-Pugh score may cause complications. KEY POINTS: • The platelet increment after PSE greatly depends on the splenic infarction ratio. • The non-infarcted splenic volume significantly affects the efficacy of PSE. • A high cholinesterase level contributes to the improvement of thrombocytopenia after PSE. • The non-infarcted splenic volume significantly affects the relapse of hypersplenism. • Complications are significantly associated with the infarcted splenic volume and Child-Pugh score.

Survival benefit of chemoembolization plus Iodine125 seed implantation in unresectable hepatitis B-related hepatocellular carcinoma with PVTT: a retrospective matched cohort study.

OBJECTIVES: To investigate the survival benefit of transarterial chemoembolization (TACE) plus Iodine125 seed implantation (TACE-Iodine125) in hepatitis B-related HCC patients with portal vein tumour thrombus (PVTT) and the underlying prognostic factors. METHODS: A retrospective matched cohort study was performed on consecutive HCC patients with PVTT from January 2011 to June 2014. Seventy patients (TACE-Iodine125 group) who underwent TACE-Iodine125 were compared with a historical case-matched control group of 140 patients (TACE group) who received TACE alone. The survival of patients and the underlying prognostic factors were analysed. RESULTS: The median survival times of the TACE-Iodine125 and TACE groups were 11.0 and 7.5 months, respectively (p < 0.001). The survival probability at 12, 24, and 36 months was 50 %, 14.5 %, and 14.5 % vs. 25 %, 9 %, and 5 % in the TACE-Iodine125 and TACE groups, respectively (p < 0.001). The PVTT responders had better survival than the PVTT non-responders (p < 0.001). For the PVTT non-responders, there were no differences in the survival curves between the groups (p = 0.353). Multivariate analysis showed that type III PVTT (p < 0.001) and APS (p < 0.001) were independent predictors of poor prognosis. In contrast, the treatment modality of TACE-Iodine125 (p < 0.001) and PVTT response (p = 0.001) were favourable prognostic features. CONCLUSIONS: TACE combined with Iodine125 seed implantation may be a good choice for selected HB-HCC patients with PVTT. KEY POINTS: • TACE-Iodine125 was more effective than TACE for patients with HCC-PVTT. • The TACE-Iodine125 procedure was safe. • TACE-Iodine125 was conditional for patients with HCC-PVTT. • TACE-Iodine125 resulted in a better PVTT response compared to TACE alone. • A good PVTT response is a favourable prognostic factor.

Safety and Efficacy of Transarterial Chemoembolization Combined with CT-Guided Radiofrequency Ablation for Hepatocellular Carcinoma Adjacent to the Hepatic Hilum within Milan Criteria.

PURPOSE: To retrospectively evaluate safety and efficacy of conventional transarterial chemoembolization with ethiodized oil (Lipiodol) combined with CT-guided radiofrequency (RF) ablation for hepatocellular carcinoma (HCC) adjacent to the hepatic hilum. MATERIALS AND METHODS: Between January 2007 and December 2010, conventional transarterial chemoembolization combined with CT-guided RF ablation was performed in 40 patients with HCC adjacent to the hepatic hilum within Milan criteria (group A). Major complications, complete tumor ablation rate, local tumor progression rate, and overall survival were compared with 107 patients with HCC nonadjacent to the hepatic hilum (group B) treated by conventional transarterial chemoembolization combined with CT-guided RF ablation during the same period. RESULTS: Major complications included one case of large hepatic artery-portal vein fistula in group A (2.5%; 1/40) and one case of acute portal vein thrombosis, left heart failure, and tumor seeding in group B (2.8%; 3/107); the difference was not significant between the two groups (P = 1.000). There were no significant differences between the two groups in complete tumor ablation rate (80.0% vs 86.0%; P = .374), local tumor progression rates (1-year, 12.5% vs 14.1%; 2-year, 28.2% vs 24.2%; 3-year, 32.0% vs 27.6%; P = .723), and overall survival (1-year, 92.3% vs 91.8%; 3-year, 79.1% vs 79.3%; 5-year, 59.5% vs 58.4%; P = .555). CONCLUSIONS: Conventional transarterial chemoembolization combined with CT-guided RF ablation was safe and effective in selected patients with HCC adjacent to the hepatic hilum within Milan criteria.

A multicentre retrospective study of transcatheter angiographic embolization in the treatment of delayed haemorrhage after percutaneous nephrolithotomy.

OBJECTIVE: The objective is to determine the timing and indications of transcatheter angiographic embolization (TAE) for delayed haemorrhage after percutaneous nephrolithotomy (PCNL). METHODS: The medical records of 144 patients who underwent arteriography and TAE for delayed post-PCNL haemorrhage at five university hospitals between January 2005 and December 2012 were reviewed retrospectively. RESULTS: The mean time to the onset of post-PCNL haemorrhage was 10.5 days (2 - 30 days). Clinical presentation included sudden onset bleeding in 51 patients (35.4 %), intermittent bleeding in 67 patients (46. 5 %), and continuous slow bleeding in 26 patients (18.1 %). Hemodynamic instability occurred in 32 patients (22.2 %). The mean haemoglobin decrease from the first post-PCNL day to the day of TAE was 49.5 g/L (31.0 - 79.0 g/L). Renal arteriography showed pseudoaneurysms in 69 (47.9 %) patients, arteriovenous fistulas in 28 (19.4 %) patients, mixed arterial and arteriovenous lesions in 17 (11.8 %) patients, arterial lacerations in 23 (16.0 %) patients, and negative angiographic finding in seven (4.9 %) patients. TAE was successful in stopping bleeding in all 137 patients with vascular lesions. There were no major complications associated with TAE. CONCLUSIONS: TAE should be the recommended treatment for delayed post-PCNL haemorrhage in patients with hemodynamic instability and/or corrected haemoglobin decrease >30 g/L following conservative management. KEY POINTS: • Delayed haemorrhage after percutaneous nephrolithotomy occurs more than 24 hours postoperatively. • Angio-embolization is a safe and effective treatment for delayed post-PCNL haemorrhage. • Angio-embolization can treat hemodynamic instability and/or corrected haemoglobin decrease >30 g/L.

[Study of apparent diffusion coefficient value and histopathological differentiation of hepatocellular carcinoma].

OBJECTIVE: To determine the relationship between apparent diffusion coefficient (ADC) and histopathological differentiation of hepatocellular carcinoma (HCC). METHODS: Magnetic resonance examinations of magnetic resonance imaging (MRI) plain scan, LAVA dynamic enhanced scan and diffusion weighted imaging (DWI)(1.5 T, b values: 0 and 600 s/mm²) were retrospectively reviewed for 229 surgically resected HCCs. Histopathology revealed 34 well, 170 moderately and 25 poorly-differentiated HCCs. The incidence of each ADC value was measured. The relationship between ADC and histopathological differentiation was also evaluated. RESULTS: The ADC value of well-differentiated HCCs (1.68 ± 0.13 × 10⁻³ mm²/s) was significantly higher those of moderately HCCs (1.31 ± 0.16 × 10⁻³ mm²/s) (P < 0.05) and poorly-differentiated HCCs (1.08 ± 0.11 × 10⁻³ mm²/s) (P < 0.05). There was a significant positive correlation between ADC value and differentiation of HCCs (r = 0.693, P < 0.05). ROC analysis showed that the optimal cutoff point of ADC value was 1.500 × 10⁻³ mm²/s in diagnosing well-differentiated HCCs. A cutoff ADC value equal to or under 1.5 × 10⁻³ mm²/s was used to differentiate well-differentiated HCC from moderately and poorly-differentiated ones with a sensitivity of 100% and a specificity of 94.36%. ROC analysis showed that the optimal cutoff point of ADC value was 1.235 × 10⁻³ mm²/s in diagnosing poorly-differentiated HCCs. A cutoff ADC value equal to or above 1.235 × 10⁻³ mm²/s was used for differentiating poorly-differentiated HCC from well and moderately-differentiated ones with a sensitivity of 73.5% and a specificity of 96%. CONCLUSION: In clinical practice, ADC value is important for predicting histopathological differentiation of HCC and improving its diagnostic accuracy.

[Clinical features and risk factors of biloma formation after transcatheter arterial chemoembolization].

OBJECTIVE: To explore the risk factors, treatment and outcomes of biloma after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). METHODS: A total of 481 patients with a diagnosis of HCC underwent TACE at our hospital from January 2011 to December 2013. Biloma was tracked by the follow-ups of computed tomography or magnetic resonance imaging (CT/ MRI) . Retrospective analyses were conducted for their clinical features, treatments and prognosis. The statistically significant factors for univariate analysis were introduced into Logistic regression models for multivariate analysis to obtain the risk factors of biloma post-TACE. RESULTS: There were 43 cases of complicated biloma after TACE. And 38 patients (88.4% ) developed biloma at 0.5-3 months post-TACE while another 5 (9.7%) did so at 3-5 months. The multivariate analysis showed that bile duct dilation, a history of hepatectomy prior to TACE, use of polyvinyl alcohol (PVA) particles and nonsuperselective embolization were the risk factors of biloma formation after TACE. Among 9 symptomatics, there were jaundice (n =2) and fever (n =7). The diameter of bilomas was (8.07 ± 3.53) cm for 9 symptomatics and (2.81 ± 1.26) cm for 35 asymptomatics. And the difference was statistically significant (P <0. 01). Nine symptomatic patients underwent percutaneous drainage with tube and biloma diminished (n = 7) and even vanished (n = 2). Only conservative treatment was offered for 35 asymptomatics. During the follow-ups, it showed no change (n = 24) , diminishing (n = 8) and disappearance (n = 2). One case died from a greatly enlarged biloma due to hepatic failure and septic shock via a rupture into abdominal cavity and choleperitonitis. CONCLUSION: The risk factors of biloma formation after TACE for HCC are bile duct dilation, a history of hepatectomy before TACE, use of PVA particles and nonsuperselective embolization. For symptomatics, drainage must be performed timely and the prognosis is fair. For asymptomatics, regular imaging follow-ups are needed. Drainage must be performed timely when the diameter of biloma increased significantly during the follow-ups.

Hepatocellular carcinoma with portal vein tumor thrombus: treatment with transarterial chemoembolization combined with sorafenib--a retrospective controlled study.

PURPOSE: To determine the safety and efficacy of transarterial chemoembolization (TACE) combined with sorafenib (hereafter, TACE-sorafenib) in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). MATERIALS AND METHODS: This study was approved by the institutional review board, and the requirement for informed consent was waived. The medical records of consecutive patients with HCC and PVTT who underwent TACE-sorafenib or TACE alone from January 2010 to December 2012 were retrospectively evaluated. Sorafenib (400 mg) was administered twice daily. Outcomes of patients who underwent TACE-sorafenib were compared with outcomes of patients who underwent TACE by using the Kaplan-Meier method according to types of PVTT: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). RESULTS: Ninety-one patients were included in the analysis; 46 patients underwent TACE-sorafenib and 45 underwent TACE. TACE-sorafenib showed significant survival benefits compared with TACE in patients with type B (median survival, 13 months vs 6 months; P = .002) or type C (median survival, 15 months vs 10 months; P = .003) PVTT. TACE-sorafenib and main PVTT were the independent prognostic factors for survival at uni- and multivariate analysis. Liver function after TACE-sorafenib worsened only in patients with main PVTT. Sorafenib-related adverse events of grade 3 or higher occurred in 16 patients (35%). CONCLUSION: TACE-sorafenib side effects were acceptable, and this treatment may improve overall survival in patients with HCC with first-order or lower-branch PVTT when compared with patients who underwent TACE alone.

[Application of hepatocellular carcinoma targeted multifunctional nanocarriers].

OBJECTIVE: To synthesize the RGD-modified magnetic resonance imaging (MRI)-visible gene transfer nanocarrier and assess its gene delivery ability and MRI visibility for hepatocellular carcinoma. METHODS: The multifunctional nanocarrier RGD-PEG-PEI-SPION was constructed. And the degree of binding between nanocarrier and siRNA was determined by agarose gel electrophoresis. The zeta potential and particle size of cationic polymer vectors were measured with a Zeta-Plus instrument. Immunocytochemical assay was performed for detecting the expression of α(v)ß(3) in Bel-7402 cells. The active targeting ability of nanocarrier to Bel-7402 cells was evaluated by flow cytometry and laser confocal microcopy. The MRI visibility of nanocarrier to Bel-7402 cells was assessed. RESULTS: RGD-PEG-PEI-SPION could condense siRNA entirely at a N/P ratio of 2.8; the membranes of Bel-7402 cells possessed an enrichment of α(v)ß(3) receptors. At a nitrogen/phosphate ratio of 10, the particle size of RGD-PEG-PEI-SPION/siRNA attained a constant size of 85.2 ± 5.6 nm, the zeta potential reached +12.4 ± 1.2 mV, the gene transfection efficiency of nanocarrier to Bel-7402 cells attained 71.2% ± 2.1% and the cells showed significantly stronger RGD-PEG-PEI-SPION (red) and siRNA (green) fluorescence under laser confocal microcopy. The cells incubated with RGD-PEG-PEI-SPION exhibited significantly lower normalized MR T(2)(*)WI signal intensity. CONCLUSION: A RGD-modified MRI-visible gene delivery nanocarrier RGD-PEG-PEI-SPION has been successfully synthesized.It has a higher transfection efficiency of transferring siRNA into Bel-7402 cells and could sensitively detect hepatocellular carcinoma with MRI.

Harnessing the potential of hydrogels for advanced therapeutic applications: current achievements and future directions.

The applications of hydrogels have expanded significantly due to their versatile, highly tunable properties and breakthroughs in biomaterial technologies. In this review, we cover the major achievements and the potential of hydrogels in therapeutic applications, focusing primarily on two areas: emerging cell-based therapies and promising non-cell therapeutic modalities. Within the context of cell therapy, we discuss the capacity of hydrogels to overcome the existing translational challenges faced by mainstream cell therapy paradigms, provide a detailed discussion on the advantages and principal design considerations of hydrogels for boosting the efficacy of cell therapy, as well as list specific examples of their applications in different disease scenarios. We then explore the potential of hydrogels in drug delivery, physical intervention therapies, and other non-cell therapeutic areas (e.g., bioadhesives, artificial tissues, and biosensors), emphasizing their utility beyond mere delivery vehicles. Additionally, we complement our discussion on the latest progress and challenges in the clinical application of hydrogels and outline future research directions, particularly in terms of integration with advanced biomanufacturing technologies. This review aims to present a comprehensive view and critical insights into the design and selection of hydrogels for both cell therapy and non-cell therapies, tailored to meet the therapeutic requirements of diverse diseases and situations.

Manganese oxide-constructed multifunctional biomimetic nanovaccine for robust tumor-specific T cell priming and chemodynamic therapy.

The development of manganese oxide-based chemodynamic immunotherapy is emerging as a key strategy against solid tumors. However, the limited efficacy of nanoplatform in inducing efficient tumor therapeutic effects and creating the prominent antitumor immune responses remains a crucial issue. In this study, we construct a novel multifunctional biomimetic nanovaccine comprising manganese oxide-loaded poly(2-diisopropylaminoethyl methacrylate) (MP) nanoparticles and a coating layer of hybrid cell membrane (RHM) derived from manganese oxide-remodeled 4T1 cells and dendritic cells (DCs) (collectively called MP@RHM) for combination chemodynamic immunotherapy. Compared with the nanovaccines coated with the single cell membrane, the MP@RHM nanovaccine highly efficiently activates both DCs and T cells to boost tumor-specific T cell, owing to the synergistic effects of abundant damage-associated molecular patterns, Mn2+, and T cell-stimulating moieties. Upon peritumoral injection, the MP@RHM nanovaccine targets both the tumor site for focused chemodynamic therapy and the lymph nodes for robust tumor-specific T cell priming, thereby achieving highly efficient chemodynamic immunotherapy. Moreover, as a preventive cancer nanovaccine, MP@RHM generates strong immunological memory to inhibit postoperative tumor metastasis and recurrence. Our study findings highlight a promising approach to construct a multifunctional biomimetic nanovaccine for personalized chemodynamic immunotherapy against solid tumors.

Synthesis and characterization of 3-in-1 multifunctional lipiodol-doped Fe3O4@Poly (diallyl isophthalate) microspheres for arterial embolization, chemotherapy, and imaging.

Transcatheter arterial embolization plays a pivotal role in treating various diseases. However, the efficacy of embolization therapy in cancer treatment can be limited by several factors, such as inevitable incomplete or non-target embolization, and the tumor recurrence and metastasis caused by the hypoxic microenvironment. Moreover, it is essential to explore simpler, more economical, and efficient methods for microsphere synthesis. Herein, we achieved one-step photocatalytic synthesis of lipiodol-doped Fe3O4@Poly (diallyliso-phthalate) multifunctional microspheres (IFeD MS) for arterial embolization, chemotherapy, and imaging. The prepared microspheres are in the shape of dried plums, with a particle size of 100-300 µm. Lipiodol demonstrates a certain degree of chemotherapeutic activity, and the incorporation of Fe3O4enables the microspheres to exhibit magnetothermal response and magnetic resonance imaging capabilities. Furthermore, the radiopaque characteristics of both agents provide the microspheres with promising potential for computed tomography and digital radiography imaging. The renal embolization experiment in rabbits demonstrated that IFeD MS achieved significant embolization and chemotherapeutic effects. Biocompatibility experiments revealed that this embolic agent did not induce tissue damage or inflammation beyond the treatment area. Additionally, IFeD MS exhibited promising imaging potential. The results of this study imply that the developed multifunctional embolic agent IFeD MS may have significant potential in transforming tumors previously only suitable for palliative cares into resectable radical treatments.