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.

Effects on resting-state EEG phase-amplitude coupling in insomnia disorder patients following 1 Hz left dorsolateral prefrontal cortex rTMS.

Despite burgeoning evidence for cortical hyperarousal in insomnia disorder, the existing results on electroencephalography spectral features are highly heterogeneous. Phase-amplitude coupling, which refers to the modulation of the low-frequency phase to a high-frequency amplitude, is probably a more sensitive quantitative measure for characterizing abnormal neural oscillations and explaining the therapeutic effect of repetitive transcranial magnetic stimulation in the treatment of patients with insomnia disorder. Sixty insomnia disorder patients were randomly divided into the active and sham treatment groups to receive 4 weeks of repetitive transcranial magnetic stimulation treatment. Behavioral assessments, resting-state electroencephalography recordings, and sleep polysomnography recordings were performed before and after repetitive transcranial magnetic stimulation treatment. Forty good sleeper controls underwent the same assessment. We demonstrated that phase-amplitude coupling values in the frontal and temporal lobes were weaker in Insomnia disorder patients than in those with good sleeper controls at baseline and that phase-amplitude coupling values near the intervention area were significantly enhanced after active repetitive transcranial magnetic stimulation treatment. Furthermore, the enhancement of phase-amplitude coupling values was significantly correlated with the improvement of sleep quality. This study revealed the potential of phase-amplitude coupling in assessing the severity of insomnia disorder and the efficacy of repetitive transcranial magnetic stimulation treatment, providing new insights on the abnormal physiological mechanisms and future treatments for insomnia disorder.

A novel strategy for orthogonal genetic regulation on different RNA targeted loci simultaneously.

No current RNA-targeted interference tools have been reported to simultaneously up and down-regulate different gene expressions. Here we characterized an RNA-targeted genetic regulatory strategy composed of a flap endonuclease 1 (FEN1) and specific mis-hairpin DNA probes (mis-hpDNA), to realize the orthogonal genetic regulation. By targeting mRNA, the strategy hindered the translation and silenced genes in human cells with efficiencies of ~60%. By targeting miRNA, the strategy prevented the combination of miRNA to its specific mRNA and increased this mRNA expression by about 3-folds. In combination, we simultaneously performed CXCR4 gene knock-down (~50%) and EGFR gene activation (1.5-folds) in human cells. Although the functional property can be further improved, this RNA-targeted orthogonal genetic regulating strategy is complementary to classical tools.

DNA and RNA editing without sequence limitation using the flap endonuclease 1 guided by hairpin DNA probes.

Here, we characterized a flap endonuclease 1 (FEN1) plus hairpin DNA probe (hpDNA) system, designated the HpSGN system, for both DNA and RNA editing without sequence limitation. The compact size of the HpSGN system make it an ideal candidate for in vivo delivery applications. In vitro biochemical studies showed that the HpSGN system required less nuclease to cleave ssDNA substrates than the SGN system we reported previously by a factor of ∼40. Also, we proved that the HpSGN system can efficiently cleave different RNA targets in vitro. The HpSGN system cleaved genomic DNA at an efficiency of ∼40% and ∼20% in bacterial and human cells, respectively, and knocked down specific mRNAs in human cells at a level of ∼25%. Furthermore, the HpSGN system was sensitive to the single base mismatch at the position next to the hairpin both in vitro and in vivo. Collectively, this study demonstrated the potential of developing the HpSGN system as a small, effective, and specific editing tool for manipulating both DNA and RNA without sequence limitation.

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.

Safety and Feasibility of Temporary Superior Vena Cava Filter Combined with Balloon Dilatation and Catheter-Directed Thrombolysis for Catheter-Related Thrombosis.

BACKGROUND: The objective was to evaluate the safety and feasibility of temporary superior vena cava (SVC) filter combined with balloon dilatation and catheter-directed thrombolysis for the treatment of catheter-related thrombosis (CRT) caused by implanted ports. METHODS: Between February 2014 and October 2016, 13 patients with implanted port-related CRT in internal jugular vein, brachiocephalic vein, and/or subclavian vein were treated by temporary SVC filter, balloon dilatation, and catheter-directed thrombolysis. Clinical data were retrospectively analyzed with respect to clinical characteristics, SVC filter placement and retrieval, balloon dilatation, and catheter-directed thrombolysis. RESULTS: Filter placement and retrieval, balloon dilatation, and catheter-directed thrombolysis were successful in all patients with complete patency of the suffered vessels. No complications such as local infection, filter migration, bleeding, and pulmonary embolism were found. CONCLUSIONS: Based on the small number of patients, it appears that temporary SVC filter combined with balloon dilatation and catheter-directed thrombolysis is a safe and effective method for the treatment of CRT associated with malfunction of the implanted ports and complete obstruction of affected veins. Further studies are required to demonstrate the cost-effectiveness and complications compared to conventional therapy.

Oroxylin A regulates glucose metabolism in response to hypoxic stress with the involvement of Hypoxia-inducible factor-1 in human hepatoma HepG2 cells.

Metabolic alteration in cancer cells is one of the most conspicuous characteristics that distinguish cancer cells from normal cells. In this study, we investigated the influence and signaling ways of oroxylin A affecting cancer cell energy metabolism under hypoxia. The data showed that oroxylin A remarkably reduced the generation of lactate and glucose uptake under hypoxia in HepG2 cells. Moreover, oroxylin A inhibited HIF-1α expression and its stability. The downstream targets (PDK1, LDHA, and HK II), as well as their mRNA levels were also suppressed by oroxylin A under hypoxia. The silencing or the overexpression of HIF-1α assays suggested that HIF-1α is required for metabolic effect of oroxylin A in HepG2 cells during hypoxia. Furthermore, oroxylin A could reduce the expression of complex III in mitochondrial respiratory chain, and then decrease the accumulation of ROS at moderate concentrations (0-50 µM) under hypoxia, which was benefit for its inhibition on glycolytic activity by decreasing ROS-mediated HIF-1 expression. Besides, oroxylin A didn't cause the loss of MMP under hypoxia and had no obvious effects on the expression of OXPHOS complexes, suggesting that oroxylin A did not affect mitochondrial mass at the moderate stress of oroxylin A. The suppressive effect of oroxylin A on glycolysis led to a significantly repress of ATP generation, for ATP generation mostly depends on glycolysis in HepG2 cells. This study revealed a new aspect of glucose metabolism regulation of oroxylin A under hypoxia, which may contribute to its new anticancer mechanism. © 2015 Wiley Periodicals, Inc.

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.

GL-V9 inhibits the activation of AR-AKT-HK2 signaling networks and induces prostate cancer cell apoptosis through mitochondria-mediated mechanism.

Prostate cancer (PCa) is a serious health concern for men due to its high incidence and mortality rate. The first therapy typically adopted is androgen deprivation therapy (ADT). However, patient response to ADT varies, and 20-30% of PCa cases develop into castration-resistant prostate cancer (CRPC). This article investigates the anti-PCa effect of a drug candidate named GL-V9 and highlights the significant mechanism involving the AKT-hexokinase II (HKII) pathway. In both androgen receptor (AR)-expressing 22RV1 cells and AR-negative PC3 cells, GL-V9 suppressed phosphorylated AKT and mitochondrial location of HKII. This led to glycolytic inhibition and mitochondrial pathway-mediated apoptosis. Additionally, GL-V9 inhibited AR activity in 22RV1 cells and disrupted the feedback activation of AKT signaling in condition of AR inhibition. This disruption greatly increased the anti-PCa efficacy of the AR antagonist bicalutamide. In conclusion, we present a novel anti-PCa candidate and combination drug strategies to combat CRPC by intervening in the AR-AKT-HKII signaling network.

FV-429 induces apoptosis by regulating nuclear translocation of PKM2 in pancreatic cancer cells.

Of all malignancies, pancreatic ductal adenocarcinoma (PDAC), constituting 90% of pancreatic cancers, has the worst prognosis. Glycolysis is overactive in PDAC patients and is associated with poor prognosis. Drugs that inhibit glycolysis as well as induce cell death need to be identified. However, glycolysis inhibitors often fail to induce cell death. We here found that FV-429, a derivative of the natural flavonoid wogonin, can induce mitochondrial apoptosis and inhibit glycolysis in PDAC in vivo and in vitro. In vitro, FV-429 inhibited intracellular ATP content, glucose uptake, and lactate generation, consequently leading to mitochondrial dysfunction and apoptosis in PDAC cells. Furthermore, it decreased the expression of PKM2 (a specific form of pyruvate kinase) through the ERK signaling pathway and enhanced PKM2 nuclear translocation. TEPP-46, the activator of PKM2, reversed FV-429-induced glycolysis inhibition and mitochondrial apoptosis in the PDAC cells. In addition, FV-429 exhibited significant tumor suppressor activity and high safety in BxPC-3 cell xenotransplantation models. These results thus demonstrated that FV-429 decreases PKM2 expression through the ERK signaling pathway and enhances PKM2 nuclear translocation, thereby resulting in glycolysis inhibition and mitochondrial apoptosis in PDAC in vitro and in vivo, which makes FV-429 a promising candidate for pancreatic cancer treatment.

Intratumoral Lactate Depletion Based on Injectable Nanoparticles-Hydrogel Composite System Synergizes with Immunotherapy against Postablative Hepatocellular Carcinoma Recurrence.

Thermal ablation is a crucial therapeutic modality for hepatocellular carcinoma (HCC), but its efficacy is often hindered by the high recurrence rate attributed to insufficient ablation. Furthermore, the residual tumors following insufficient ablation exhibit a more pronounced immunosuppressive state, which accelerates the disease progression and leads to immune checkpoint blockade (ICB) resistance. Herein, evidence is presented that heightened intratumoral lactate accumulation, stemming from the augmented glycolytic activity of postablative residual HCC cells, may serve as a crucial driving force in exacerbating the immunosuppressive state of the tumor microenvironment (TME). To address this, an injectable nanoparticles-hydrogel composite system (LOX-MnO2 @Gel) is designed that gradually releases lactate oxidase (LOX)-loaded hollow mesoporous MnO2 nanoparticles at the tumor site to continuously deplete intratumoral lactate via a cascade catalytic reaction. Using subcutaneous and orthotopic HCC tumor-bearing mouse models, it is confirmed that LOX-MnO2 @Gel-mediated local lactate depletion can transform the immunosuppressive postablative TME into an immunocompetent one and synergizes with ICB therapy to significantly inhibit residual HCC growth and lung metastasis, thereby prolonging the survival of mice postablation. The work proposes an appealing strategy for synergistically combining antitumor metabolic therapy with immunotherapy to combat postablative HCC recurrence.

TaqTth-hpRNA: a novel compact RNA-targeting tool for specific silencing of pathogenic mRNA.

Pathogenic allele silencing is a promising treatment for genetic hereditary diseases. Here, we develop an RNA-cleaving tool, TaqTth-hpRNA, consisting of a small, chimeric TaqTth, and a hairpin RNA guiding probe. With a minimal flanking sequence-motif requirement, in vitro and in vivo studies show TaqTth-hpRNA cleaves RNA efficiently and specifically. In an Alzheimer's disease model, we demonstrate silencing of mutant APPswe mRNA without altering the wild-type APP mRNA. Notably, due to the compact size of TaqTth, we are able to combine with APOE2 overexpression in a single AAV vector, which results in stronger inhibition of pathologies.

Microbial-derived Urolithin A Targets GLS1 to Inhibit Glutaminolysis and Attenuate Cirrhotic Portal Hypertension.

BACKGROUND & AIMS: Cirrhotic portal hypertension (CPH) is the leading cause of mortality in patients with cirrhosis. Over 50% of patients with CPH treated with current clinical pharmacotherapy still present variceal bleeding or sometimes death owing to insufficient reduction in portal pressure. Elevated intrahepatic vascular resistance (IHVR) plays a fundamental role in increasing portal pressure. Because of its potent effect in reducing portal pressure and maintaining normal portal inflow to preserve liver function, lowering the IHVR is acknowledged as an optimal anti-CPH strategy but without clinical drugs. We aimed to investigate the protective effect of microbial-derived Urolithin A (UroA) in IHVR and CPH. METHODS: Carbon tetrachloride or bile duct ligation surgery was administered to mice to induce liver fibrosis and CPH. 16S rRNA gene sequencing was used for microbial analysis. Transcriptomics and metabolomics analyses were employed to study the host and cell responses. RESULTS: UroA was remarkably deficient in patients with CPH and was negatively correlated with disease severity. UroA deficiency was also confirmed in CPH mice and was associated with a reduced abundance of UroA-producing bacterial strain (Lactobacillus murinus, L. murinus). Glutaminolysis of hepatic stellate cells (HSCs) was identified as a previously unrecognized target of UroA. UroA inhibited the activity of glutaminase1 to suppress glutaminolysis, which counteracted fibrogenesis and contraction of HSCs and ameliorated CPH by relieving IHVR. Supplementation with UroA or L. murinus effectively ameliorated CPH in mice. CONCLUSIONS: We for the first time identify the deficiency of gut microbial metabolite UroA as an important cause of CPH. We demonstrate that UroA exerts an excellent anti-CPH effect by suppressing HSC glutaminolysis to lower the IHVR, which highlighted its great potential as a novel therapeutic agent for CPH.

Lenvatinib plus drug-eluting bead transarterial chemoembolization with/without hepatic arterial infusion chemotherapy for hepatocellular carcinoma larger than 7 cm with major portal vein tumor thrombosis: a multicenter retrospective cohort study.

BACKGROUND: The management of hepatocellular carcinoma (HCC) with high tumor burden and major portal vein tumor thrombosis (PVTT) remains a great challenge. We aimed to investigate the efficacy and safety of lenvatinib plus drug-eluting bead transarterial chemoembolization (DEB-TACE) and hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil and leucovorin (Len+DEB-TACE+HAIC) versus lenvatinib plus DEB-TACE (Len+DEB-TACE) for HCC > 7.0 cm accompanied with major PVTT. MATERIALS AND METHODS: This multicenter retrospective cohort study evaluated consecutive patients with HCC (> 7.0 cm) and major PVTT who received Len+DEB-TACE+HAIC (Len+DEB-TACE+HAIC group) or Len+DEB-TACE (Len+DEB-TACE group) between July 2019 and June 2021 from eight institutions in China. Objective response rate (ORR), time to progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between the two groups by propensity score-matching (PSM). RESULTS: A total of 205 patients were included. After PSM, 85-paired patients remained in the study cohorts. Patients in the Len+DEB-TACE+HAIC group had higher ORR (61.2% vs. 34.1%, P < 0.001), longer TTP (median, 9.8 vs. 5.9 months, P < 0.001), and prolonged OS (median, 16.7 vs. 12.5 months, P < 0.001) than those in the Len+DEB-TACE group. The ORR and TTP of both intrahepatic tumor (ORR: 64.7% vs. 36.5%, P < 0.001; median TTP: 10.7 vs. 7.0 months, P < 0.001) and PVTT (ORR: 74.1% vs. 47.1%, P < 0.001; median TTP: 17.4 vs. 7.6 months, P < 0.001) were better in the Len+DEB-TACE+HAIC group than the Len+DEB-TACE group. The frequency of grade 3-4 TRAEs in the Len+DEB-TACE+HAIC group were comparable to those in the Len+DEB-TACE group (38.8% vs. 34.1%, P = 0.524). CONCLUSION: The addition of HAIC to Len+DEB-TACE significantly improved ORR, TTP, and OS over Len+DEB-TACE with an acceptable safety profile for large HCC with major PVTT.

Portal vein thrombosis after partial splenic embolization in liver cirrhosis: efficacy of anticoagulation and long-term follow-up.

PURPOSE: To investigate the treatment and long-term outcome of portal vein thrombosis (PVT) after partial splenic embolization (PSE). MATERIALS AND METHODS: From January 2006 to December 2011, 145 patients with hypersplenism caused by cirrhotic portal hypertension underwent PSE. In 11 cases, PVT was detected 13-42 days after PSE. Among the 11 patients, 5 underwent anticoagulant therapy because of clinical symptoms, and 6 did not receive anticoagulation because they were symptom-free (4 patients) or experienced variceal bleeding (2 patients). The long-term follow-up data from these 11 patients were analyzed retrospectively. RESULTS: The 11 patients with PVT had a mean splenic infarction ratio of 71.5%. The mean duration of follow-up was 37.6 months. During the follow-up period, none of the 5 patients who underwent anticoagulation developed variceal hemorrhage despite presenting with large esophagogastric varices. Four of the five patients achieved complete resolution of thrombosis, and one did not develop thrombus progression. However, among the 6 patients who did not undergo anticoagulation, 2 developed esophagogastric variceal hemorrhage secondary to thrombus progression, 3 developed cavernous transformation of the portal vein and variceal progression, and 1 had partial calcification of the thrombus. Two patients who had variceal bleeding or rebleeding underwent a transjugular intrahepatic portosystemic shunt. Complete recanalization of the portal vein was achieved after the procedures. CONCLUSIONS: PVT is a severe, potentially fatal complication of PSE. Early detection of PVT and prompt anticoagulation are effective to avoid serious consequences of PVT.

[Clinical observation of transcatheter arterial chemoembolization plus sorafenib in the treatment of advanced hepatocellular carcinoma with different types of portal vein tumor thrombosis].

OBJECTIVE: To explore the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus sorafenib in the treatment of advanced hepatocellular carcinoma with different types of portal vein tumor thrombosis. METHODS: A total of 32 patients of advanced hepatocellular carcinoma with tumor thrombosis in portal vein were retrospectively analyzed. All of them took oral sorafenib after TACE. They were divided into 3 groups according to imaging examinations of tumor thrombosis in portal vein. Tumor thrombosis in main portal vein was group A, tumor thrombosis in right/left portal branch group B and tumor thrombosis in the second branch of portal vein group C. Tumor response rate, disease control rate (DCR), overall survival (OS) and time to tumor progression (TTP) was followed up. Liver functions were compared with the pre-treatment level. The occurrences of adverse events were recorded. RESULTS: DCR was 20.0% (Group A), 70.0% (Group B) and 91.7 % (Group C) at 2 months post-treatment. DCR in groups B and C had significant differences with group A (P < 0.05). The median OS was 3 (Group A), 9 (Group B) and 14 months (Group C) and the median TTP 0 (Group A), 3 (Group B) and 6 months (Group C) respectively. The median OS and median TTP were significantly longer in Groups B and C than those in Group A (P < 0.05). Liver function at 2 months post-treatment had no statistical difference with the baseline. The most common adverse effects included hand foot skin reaction (n = 23, 3 cases of grade 3), hypertension (n = 3), diarrhea (n = 25, 3 cases of grade 3), hair loss (n = 12), oral ulcers (n = 1) and gastrointestinal bleeding (n = 2). CONCLUSION: The combined use of TACE and sorafenib is both safe and efficacious in the treatment of advanced hepatocellular carcinoma with tumor thrombosis in portal vein. And it may prolong OS and TTP in hepatocellular carcinoma with tumor thrombosis in right/left portal vein and second branch of portal vein.

[Transarterial chemoembolization plus computed tomography-guided percutaneous radiofrequency ablation for small hepatocellular carcinoma in special locations].

OBJECTIVE: To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus computed tomography (CT)-guided percutaneous radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC) in special locations. METHODS: From June 2008 to December 2011, a total of 36 patients with small HCC (39 lesions) received TACE plus CT-guided percutaneous RFA at our hospital. The follow-up period was over 6 months. They were divided into 2 groups according to the locations of HCC: special location (located at hepatic subcapsular, portal area, next to large blood vessels or other organs) and non-special location groups. All patients underwent TACE at one month pre-RFA.Follow-up imaging with enhanced computed tomography (CT) or magnetic resonance imaging (MRI) was performed one month after combined treatment to evaluate the complete ablation rate in two groups.If a complete ablation was achieved, enhanced CT or MRI was performed every 1-3 months to evaluate the local tumor progression. The occurrence rate of complications, complete ablation rate, local tumor progression and time to tumor progression (TTP) were compared between two groups. RESULTS: In the special location group, a total of 24 TACE and 26 ablations were performed in 20 patients with 22 lesions while there were 18 TACE and 17 ablations in 16 patients with 17 lesions in the non-special location group.In the special location group, 12 patients (46.2%) suffered procedure-related complications, including a major complication (n = 1, left ventricular failure) and a minor complication (n = 11) of vascular injury (n = 6), subcapsular hemorrhage (n = 3) and arterial-portal vein fistula (n = 2); whereas only 3 patients (17.6%) suffered a minor complication of subcapsular hemorrhage (n = 1) and arterial-portal vein fistula (n = 2) in the special location group. The occurrence rate of complications was similar between two groups (P = 0.101). The complete ablation rate after one month was 68.2% (15/22) in the special location group and it was significantly higher than that of the non-special location group (100%, P = 0.012).In the special location group, the 6-month, 1-, 2-, 3-year local tumor progression rates were 31.8%, 40.9%, 45.5%, 45.5% versus 0,0,0, 5.9% in the non-special location group respectively. The mean TTP of 14.4 months in the special location group was markedly shorter than that in the non-special location group (31.5 months, P = 0.001). CONCLUSION: The combined regimen of TACE and percutaneous RFA is both safe and feasible for small HCC in special location. And the rate of local tumor progression is significantly higher than that of non-special location tumor. Postoperative close imaging follow-up is needed for tumor residue or recurrence.

Inhibition of TRPV4 remodels single cell polarity and suppresses the metastasis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor, frequently causing both intrahepatic and extrahepatic metastases. The overall prognosis of patients with metastatic HCC is poor. Recently, single-cell (sc) polarity is proved to be an innate feature of some tumor cells in liquid phase, and directly involved in the cell adhesion to blood vessel and tumor metastasis. Here, we characterize the maintained sc polarity of HCC cells in a suspension culture, and investigate its roles and regulatory mechanisms during metastasis. We demonstrate that transient receptor potential vanilloid 4 (TRPV4) is a promoting regulator of sc polarity via activating Ca2+-dependent AMPK/MLC/ERM pathway. This attenuates the adhesion of metastatic HCC cells to vascular endothelial cells. The reduction of cancer metastases can result from TRPV4 inhibition, which not only impacts the migration and invasion of tumor cells, but also prevents the adhesion to vascular endothelial cells. Additionally, we discover a brand-new TRPV4 inhibitor called GL-V9 that modifies the degree of sc polarization and significantly decreases the metastatic capacity of HCC cells. Taken together, our data shows that TRPV4 and calcium signal are significant sc polarity regulators in metastatic HCC, and that the pharmacological intervention that results in HCC cells becoming depolarized suggests a promising treatment for cancer metastasis.

Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.

Mitochondria dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. Dysregulated mitochondrial dynamics respond rapidly to metabolic cues, and are linked to the initiation and progression of diverse human cancers. Metabolic adaptations significantly contribute to tumor development and escape from tissue homeostatic defenses. In this work, we identified oroxylin A (OA), a dual GLUT1/mitochondrial fusion inhibitor, which restricted glucose catabolism of hepatocellular carcinoma cells and simultaneously inhibited mitochondrial fusion by disturbing SIRT1/PDK2/PARL axis. Based the dual action of OA in metabolic regulation and mitochondrial dynamics, further results revealed that mitochondrial functional status and spare respiratory capacity (SRC) of cancer cells had a close correlation with mitochondrial metabolic plasticity, and played important roles in the susceptibility to cancer therapy aiming at glucose restriction. Cancer cells with healthy mitochondria and high SRC exhibit greater metabolic flexibility and higher resistance to GLUT1 inhibitors. This phenomenon is attributed to the fact that high SRC cells fuse mitochondria in response to glucose restriction, enhancing tolerance to energy deficiency, but undergo less mitochondrial oxidative stress compared to low SRC cells. Thus, inhibiting mitochondrial fusion breaks mitochondrial metabolic plasticity and increases cancer cell susceptibility to glucose restriction therapy. Collectively, these finding indicate that combining a GLUT1 inhibitor with a mitochondrial fusion inhibitor can work synergistically in cancer therapy and, more broadly, suggest that the incorporations of mitochondrial dynamics and metabolic regulation may become the targetable vulnerabilities bypassing the genotypic heterogeneity of multiple malignancies.

Targeting lysosomal HSP70 induces acid sphingomyelinase-mediated disturbance of lipid metabolism and leads to cell death in T cell malignancies.

BACKGROUND: T cell malignancies proliferate vigorously, are highly dependent on lysosomal function, with limited therapeutic options. Deregulation of lysosomal structure and function has been confirmed to be a key role in the treatment of hematologic malignant disease. METHODS: Cell counting kit 8 and Annexin V/PI staining were used to assess the cell viability and apoptosis rate. Flow cytometry, liquid chromatography mass spectrometry, immunofluorescence and western blot were performed to detect the effect on lysosomes. Drug affinity responsive target stability, molecular docking and cellular thermal shift assay were employed to confirm the target protein of V8 on lysosomes. A xenograft model was constructed in NOD/SCID mice to assess the effect and mechanism. RESULTS: V8, a new lysosomotropic compound, could be rapidly trapped by lysosomes and accumulation in lysosomes, contributing to lysosomal-dependent cell death by evoking lysosomal membrane permeabilization (LMP), accompanied with disrupted lysosome and autophagic flux. Mechanistically, heat shock protein 70 (HSP70) was identified as the binding target of V8 in lysosome. As a downstream effect of targeting HSP70, enzymatic activity of acid sphingomyelinase (ASM) was inhibited, which induced disturbance of lipid metabolism, instability of lysosomal membrane, and leakage of cathepsin B and D, leading to LMP-mediated cell death. In vivo study showed V8 well controlled the growth of the tumour and confirmed lysosomal cell death induced by V8. CONCLUSIONS: Collectively, this study suggests targeting lysosomal HSP70-ASM axis by V8 illustrates the great value of drug therapy for T cell malignancies and the unlimited potential of lysosomal targeting for cancer therapy.