"No-Touch" Left Approach for Recipient Hepatectomy: A Promising Strategy to Minimize Hepatocellular Carcinoma Recurrence in Liver Transplantation.

Background: Managing hepatocellular carcinoma (HCC) presents significant clinical challenges, often necessitating orthotopic liver transplantation (OLT). To mitigate the risk of iatrogenic metastasis during OLT and reduce posttransplantation recurrence (PTR), we introduced the "no-touch" left (NTL) approach for recipient hepatectomy in OLT. Methods: In this retrospective cohort study, our aim was to compare the safety and PTR rates in patients undergoing OLT via either the NTL technique or the conventional approach for recipient hepatectomy. We included 106 patients who met the Hangzhou criteria and exhibited a high tumor burden in the right lobe, with 50 patients assigned to the NTL group and 56 to the conventional group. The primary endpoint was the 1-y PTR rate, whereas secondary endpoints encompassed the safety of the NTL approach, PTR rates at 2 and 5 y, and overall survival. Results: Baseline demographics and clinical characteristics showed no significant differences between the groups. The NTL approach exhibited major surgical outcomes similar to those of the conventional approach. The cumulative PTR rates at 1, 2, and 5 y were 14.0% in the NTL group, compared with 24.5%, 35.8%, and 35.8% in the conventional group (P = 0.013). Cumulative overall survival rates at 1, 2, and 5 y were 94.0%, 91.9%, and 89.7% in the NTL group and 88.7%, 75.5%, and 72.5% in the conventional group (P = 0.03). Conclusions: This innovative surgical technique enhances safety and significantly reduces the risk of PTR, leading to improved long-term survival. Further prospective studies with larger cohorts and longer follow-up periods are needed to validate our findings and establish the NTL approach as a standard practice in OLT.

Long-term complete remission and peripheral biomarkers in Hodgkin lymphoma patients after decitabine-plus-camrelizumab epi-immunotherapy and treatment cessation.

Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine-plus-camrelizumab therapy, while long-term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine-plus-camrelizumab. Patients were divided into two groups and received consolidation treatment every 3-4 or 6-12 weeks, and 1-year of continuous CR was guaranteed for treatment cessation. At a median follow-up of 5.3 years, the median relapse-free survival (RFS) after achieving CR with decitabine-plus-camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3-4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty-seven patients completed and discontinued decitabine-plus-camrelizumab, and their median RFS had not been reached. The 2-year RFS rate after treatment cessation was 78% (95% CI, 67-90%). Patients in the high-risk subgroup with higher pretreatment IL-6 and LDH levels showed poor treatment-free remission. Moreover, decitabine-plus-camrelizumab therapy was safe and cost-effective. In conclusion, patients who obtained CR with decitabine-plus-camrelizumab and received consolidation per 3-4 weeks can achieve long-term remission after treatment discontinuation.

Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells' resistance to anti-tumour drugs.

Background and aims: The outcomes of current treatment for non-small cell lung cancer (NSCLC) are unsatisfactory and development of new and more efficacious therapeutic strategies are required. The Notch pathway, which is necessary for cell survival to avert apoptosis, induces the resistance of cancer cells to antitumour drugs. Notch pathway activation is controlled by the cleavage of Notch proteins/receptors mediated by A disintegrin and metalloproteinase 17 (ADAM17); therefore, ADAM17 is a reliable intervention target for anti-tumour therapy to overcome the drug resistance of cancer cells. This work aims to develop and elucidate the activation of Compound 2b, a novel-structured small-molecule inhibitor of ADAM17, which was designed and developed and its therapeutic efficacy in NSCLC was assessed via multi-assays. Methods and results: A lead compound for a potential inhibitor of ADAM17 was explored via pharmacophore modelling, molecular docking, and biochemical screening. It was augmented by substituting two important chemical groups [R1 and R2 of the quinoxaline-2,3-diamine (its chemical skeleton)]; subsequently, serial homologs of the lead compound were used to obtain anoptimized compound (2b) with high inhibitory activity compared with leading compound against ADAM17 to inhibit the cleavage of Notch proteins and the accumulation of the Notch intracellular domain in the nuclei of NSCLC cells. The inhibitory activity of compound 2b was demonstrated by quantitative polymerase chain reaction and Western blotting. The specificity of compound 2b on ADAM17 was confirmed via point-mutation. Compound 2b enhanced the activation of antitumor drugs on NSCLC cells, in cell lines and nude mice models, by targeting the ADAM17/Notch pathway. Conclusion: Compound 2b may be a promising strategy for NSCLC treatment.

Oxidative Stress Amplifiers as Immunogenic Cell Death Nanoinducers Disrupting Mitochondrial Redox Homeostasis for Cancer Immunotherapy.

Reactive oxygen species (ROS)-induced oxidative stress in the endoplasmic reticulum (ER) is generally believed to be an important prerequisite for immunogenic cell death (ICD) which can trigger antitumor immune responses for cancer immunotherapy. However, thus far, little is known between the oxidative stress in a certain organelle other than ER and ICD. Herein, polymers for preparing ROS-responsive nanoparticles (NP-I-CA-TPP) with mitochondrial targeting performance as ICD nanoinducers are designed. It is believed that NP-I-CA-TPP can target mitochondria which are extremely important organelles intimately involved in cellular stress signaling to play an important role in the induction of ICD. NP-I-CA-TPP can amplify cinnamaldehyde (CA)-induced ROS damage by iodo-thiol click chemistry-mediated glutathione depletion in cancer cells. Finally, NP-I-CA-TPP is shown to disrupt mitochondrial redox homeostasis, amplify mitochondrial oxidative stress, promote cancer cell apoptosis via inducing ICD, and triggering the body's antitumor immune response for cancer immunotherapy.

Synergistic Effect of Biejia-Ruangan on Fibrosis Regression in Patients With Chronic Hepatitis B Treated With Entecavir: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Long-term nucleos(t)ide analogue (NA) treatment can reverse liver fibrosis in chronic hepatitis B (CHB), but its effect on fibrosis regression remains limited. Biejia-Ruangan (BR) has been approved in China as an antifibrotic traditional Chinese medicine drug in patients with chronic liver diseases. A multicenter randomized controlled trial aims to evaluate the effect of BR on fibrosis regression in CHB patients treated with NAs. METHODS: CHB patients with histologically confirmed advanced fibrosis or cirrhosis were randomly assigned to receive entecavir (ETV) (0.5 mg per day) plus BR (2 g 3 times a day) or placebo for 72 weeks. Liver fibrosis regression was defined as a reduction of ≥ 1 point by the Ishak fibrosis stage (IFS). RESULTS: Overall, 500 patients were enrolled in each group as the intention-to-treat population. The rate of fibrosis regression after 72 weeks of treatment was significantly higher in the ETV + BR group (40% vs 31.8%; P = .0069). Among 388 patients with cirrhosis (ie, IFS ≥ 5) at baseline, the rate of cirrhosis reversal (ie, IFS ≤ 4) was significantly higher in the ETV + BR group (41.5% vs 30.7%; P = .0103). CONCLUSIONS: Addition of BR to the current standard treatment with NAs in CHB patients with advanced fibrosis or cirrhosis can improve liver fibrosis regression. CLINICAL TRIALS REGISTRATION: NCT01965418.

PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies.

In spite of impressive success in treating hematologic malignancies, adoptive therapy with chimeric antigen receptor modified T cells (CAR T) has not yet been effective in solid tumors, where identification of suitable tumor-specific antigens remains a major obstacle for CAR T-cell therapy due to the "on target off tumor" toxicity. Protein tyrosine kinase 7 (PTK7) is a member of the Wnt-related pseudokinases and identified as a highly expressed antigen enriched in cancer stem cells (CSCs) from multiple solid tumors, including but not limited to triple-negative breast cancer, non-small-cell lung cancer, and ovarian cancer, suggesting it may serve as a promising tumor-specific target for CAR T-cell therapy. In this study, we constructed three different PTK7-specific CAR (PTK7-CAR1/2/3), each comprising a humanized PTK7-specific single-chain variable fragment (scFv), hinge and transmembrane (TM) regions of the human CD8α molecule, 4-1BB intracellular co-stimulatory domain (BB-ICD), and CD3ζ intracellular domain (CD3ζ-ICD) sequence, and then prepared the CAR T cells by lentivirus-mediated transduction of human activated T cells accordingly, and we sequentially evaluated their antigen-specific recognition and killing activity in vitro and in vivo. T cells transduced with all three PTK7-CAR candidates exhibited antigen-specific cytokine production and potent cytotoxicity against naturally expressing PTK7-positive tumor cells of multiple cancer types without mediating cytotoxicity of a panel of normal primary human cells; meanwhile, in vitro recursive cytotoxicity assays demonstrated that only PTK7-CAR2 modified T cells retained effective through multiple rounds of tumor challenge. Using in vivo xenograft models of lung cancers with different expression levels of PTK7, systemic delivery of PTK7-CAR2 modified T cells significantly prevented tumor growth and prolonged overall survival of mice. Altogether, our results support PTK7 as a therapeutic target suitable for CAR T-cell therapy that could be applied for lung cancers and many other solid cancers with PTK7 overexpression.

Novel small molecule inhibitors of the transcription factor ETS-1 and their antitumor activity against hepatocellular carcinoma.

The transcription factor ETS-1 (E26 transformation specific sequence 1) is the key regulator for malignant tumor cell proliferation and invasion by mediating the transcription of the invasion/migration related factors, e.g. MMPs (matrix metalloproteinases). This work aims to identify the novel small molecule inhibitors of ETS-1 using a small molecule compound library and to study the inhibitors' antitumor activity against hepatocellular carcinoma (HCC). The luciferase reporter is used to examine the inhibition and activation of ETS-1's transcription factor activity in HCC cells, including a highly invasive HCC cell line, MHCC97-H, and five lines of patient-derived cells. The inhibition of the proliferation of HCC cells is examined using the MTT assay, while the invasion of HCC cells is examined using the transwell assay. The anti-tumor activity of the selected compound on HCC cells is also examined in a subcutaneous tumor model or intrahepatic tumor model in nude mice. The results show that for the first time, four compounds, EI1~EI-4, can inhibit the transcription factor activation of ETS-1 and the proliferation or invasion of HCC cells. Among the four compounds, EI-4 has the best activation. The results from this paper contribute to expanding our understanding of ETS-1 and provide alternative, the safer and more effective, HCC molecular therapy strategies.

Breaking the Intracellular Redox Balance with Diselenium Nanoparticles for Maximizing Chemotherapy Efficacy on Patient-Derived Xenograft Models.

Excessive oxidative stress in cancer cells can induce cancer cell death. Anticancer activity and drug resistance of chemotherapy are closely related to the redox state of tumor cells. Herein, five lipophilic Pt(IV) prodrugs were synthesized on the basis of the most widely used anticancer drug cisplatin, whose anticancer efficacy and drug resistance are closely related to the intracellular redox state. Subsequently, a series of cisplatin-sensitive and drug-resistant cell lines as well as three patient-derived primary ovarian cancer cells have been selected to screen those prodrugs. To verify if the disruption of redox balance can be combined with these Pt(IV) prodrugs, we then synthesized a polymer with a diselenium bond in the main chain for encapsulating the most effective prodrug to form nanoparticles (NP(Se)s). NP(Se)s can efficiently break the redox balance via simultaneously depleting GSH and augmenting ROS, thereby achieving a synergistic effect with cisplatin. In addition, genome-wide analysis via RNA-seq was employed to provide a comprehensive understanding of the changes in transcriptome and the alterations in redox-related pathways in cells treated with NP(Se)s and cisplatin. Thereafter, patient-derived xenograft models of hepatic carcinoma (PDXHCC) and multidrug-resistant lung cancer (PDXMDR) were established to evaluate the therapeutic effect of NP(Se)s, and a significant antitumor effect was achieved on both models with NP(Se)s. Overall, this study provides a promising strategy to break the redox balance for maximizing the efficacy of platinum-based cancer therapy.

Near-Infrared Light Irradiation Induced Mild Hyperthermia Enhances Glutathione Depletion and DNA Interstrand Cross-Link Formation for Efficient Chemotherapy.

DNA alkylating agents generally kill tumor cells by covalently binding with DNA to form interstrand or intrastrand cross-links. However, in the case of cisplatin, only a few DNA adducts (<1%) are highly toxic irreparable interstrand cross-links. Furthermore, cisplatin is rapidly detoxified by high levels of intracellular thiols such as glutathione (GSH). Since the discovery of its mechanism of action, people have been looking for ways to directly and efficiently remove intracellular GSH and increase interstrand cross-links to improve drug efficacy and overcome resistance, but there has been little breakthrough. Herein, we hypothesized that the anticancer efficiency of cisplatin can be enhanced through iodo-thiol click chemistry mediated GSH depletion and increased formation of DNA interstrand cross-links via mild hyperthermia triggered by near-infrared (NIR) light. This was achieved by preparing an amphiphilic polymer with platinum(IV) (Pt(IV)) prodrugs and pendant iodine atoms (iodides). The polymer was further used to encapsulate IR780 and assembled into Pt-I-IR780 nanoparticles. Induction of mild hyperthermia (43 °C) at the tumor site by NIR light irradiation had three effects: (1) it accelerated the GSH-mediated reduction of Pt(IV) in the polymer main chain to platinum(II) (Pt(II)); (2) it boosted the iodo-thiol substitution click reaction between GSH and iodide, thereby attenuating the GSH-mediated detoxification of cisplatin; (3) it increased the proportion of highly toxic and irreparable Pt-DNA interstrand cross-links. Therefore, we find that mild hyperthermia induced via NIR irradiation can enhance the killing of cancer cells and reduce the tumor burden, thus delivering efficient chemotherapy.

Downregulated Expression of Tropomyosin 1 in Intrahepatic Cholangiocarcinoma: A Predictor of Recurrence and Prognosis.

BACKGROUND The downregulation of tropomyosin 1 (TPM1) has been observed in various tumors, but few studies have focused on the clinical significance of TPM1 in intrahepatic cholangiocarcinoma (ICC). In the present study, we investigated the prognostic significance of TPM1 in ICC. MATERIAL AND METHODS A total of 124 patients with ICC were enrolled in this study. Quantitative real-time polymerase chain reaction (qRT-RCR) was performed to examine the mRNA levels of TPM1 in ICC tissue samples and adjacent noncancerous tissue specimens, while the protein level of TPM1 in tissue specimens were investigated using immunohistochemistry assay. The correlation of TPM1 with clinicopathological features of ICC was analyzed by chi-square test. Survival analysis was performed with Kaplan-Meier method. The Cox proportional hazards model was used to evaluate the prognostic value of TPM1 in patients with ICC. RESULTS TPM1 expression was significantly downregulated in ICC tissues at mRNA and protein levels (P<0.001 for both). Downregulated TPM1 mRNA was negatively associated with tumor size (P=0.001) and TNM stage (P=0.007). Moreover, survival analysis demonstrated that patients with low TPM1 expression had a shorter overall survival (OS) (P<0.001) and recurrence-free survival (RFS) (P<0.001) than those with high TPM1 expression. Additionally, multivariate analysis showed that TPM1 could be a potential biomarker for predicting the recurrence (HR=4.632, 95% CI: 3.832-10.368, P<0.001) and survival outcome (HR=5.320, 95% CI: 2.627-11.776, P<0.001) of ICC. CONCLUSIONS TPM1 may serve as a useful biomarker for predicting tumor recurrence and prognosis in patients with ICC.

Which is the best combination of TACE and Sorafenib for advanced hepatocellular carcinoma treatment? A systematic review and network meta-analysis.

The aim of this study was to assess the comparative efficacy and safety of combination therapy with transarterial chemoembolization (TACE) and Sorafenib for patients with advanced hepatocellular carcinoma (HCC) through a systematic review and network meta-analysis and identify the best combination of TACE and Sorafenib. We searched databases for publications prior to May 2018. The prespecified efficacy outcomes were the objective response rate, overall survival rate, and time to progression. adverse effects included dermatologic, gastrointestinal, and general disorders. Subgroup analyses, meta-regression, and a network meta-analysis regarding two types of outcomes by different chemotherapy agents in TACE (5-fluorouracil, Adriamycin, Platinum, mitomycin C, hydroxycamptothecin) were included. The study is registered with PROSPERO (CRD42018098541). For efficacy outcomes, subgroups which included 5-fluorouracil and hydroxycamptothecin ranked higher than other chemotherapy agents, while mitomycin C ranked the lowest. For advanced effects, the use of mitomycin C or 5-fluorouracil as the chemotherapy agent ranked higher, while hydroxycamptothecin ranked the lowest. Therefore, we excluded 5-Fu and Mitomycin C in subsequent studies. Additionally, in the evaluation of primary adverse effects by the network meta-analysis, Platinum ranked the highest while hydroxycamptothecin ranked the lowest. Therefore, we excluded Platinum this time. Furthermore, all types of Adriamycin are not same, and some studies included two types of Adriamycin. The network meta-analysis results showed that the TACE (hydroxycamptothecin + pirarubicin) +Sorafenib arm and TACE (hydroxycamptothecin + epirubicin) +Sorafenib arm had significant efficacy differences. In conclusion, for patients with advanced HCC, combination therapy with HCPT plus THP/EPI in TACE and Sorfenib may be used as a first-line treatment.

Protective effect of the total flavonoids from Apocynum venetum L. on carbon tetrachloride-induced hepatotoxicity in vitro and in vivo.

Apocynum venetum L., belonging to the family Apocynaceae, is a popular medicinal plant, which is commonly used in the treatment of hypertension, neurasthenia, and hepatitis in China. In the present study, the total flavonoids (TFs) were prepared from the leaves of A. venetum, and its protective effects on carbon tetrachloride (CCl4)-induced hepatotoxicity in a cultured HepG2 cell line and in mice were investigated. Cell exposed to 0.4% CCl4 (v/v) for 6 h led to a significant decrease in cell viability, increased LDH leakage, and intracellular reactive oxygen species (ROS). CCl4 also induced cell marked apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP). Pretreatment with TFs at concentrations of 25, 50, and 100 µg/mL effectively relieved CCl4-induced cellular damage in a dose-dependent manner. In vivo, TFs (100, 200, and 400 mg/kg BW) were administered via gavage daily for 14 days before CCl4 treatment. The high serum ALT and AST levels induced by CCl4 were dose-dependently suppressed by pretreatment of TFs (200 and 400 mg/kg BW). Histological analysis also supported the results obtained from serum assays. Furthermore, TFs could prevent CCl4-caused oxidative damage by decreasing the MDA formation and increasing antioxidant enzymes (CAT, SOD, GSH-Px) activities in liver tissues. In summary, both in vitro and in vivo data suggest that TFs, prepared from A. venetum, showed a remarkable hepatoprotective and antioxidant activity against CCl4-induced liver damage.

The "Vessel through Strait" Sign is a Signature Radiological Sign for the Diagnosis of Left Hepatic Artery Variation.

An aberrant artery (AA) can frequently be observed coursing through the fissure for the ligamentum venosum (FLV) which was termed the "vessel through strait" sign (VTSS) by us. Fundamental data including the incidence, anatomical composition and clinical significance of VTSS and the AAs composing VTSS are still lacking. We sought to give a systematic demonstration on this issue in the present study. VTSS was respectively analyzed in 2,275 patients and was observed in 357 of them. Interestingly, 319 (89.4%) out of the 357 patients exhibiting VTSS were proved to have left hepatic artery variation (LHAV) (247 with replaced left hepatic artery, 64 with accessory left hepatic artery and 8 with variant common hepatic artery). We therefore hypothesized that VTSS could be a sign that strongly associated with LHAV and could be used for its diagnosis. In the following validating analysis, VTSS gained a sensitivity of 96.3% and a specificity of 98.3% for the diagnosis of LHAV in another bicenter cohort consisted of 1,329 patients. In conclusion, VTSS is a signature radiological sign of LHAV which could be used as an easy and specific method for the diagnosis of LHAV.

Long-term outcomes of percutaneous cryoablation for patients with hepatocellular carcinoma within Milan criteria.

BACKGROUND: Accumulating evidences have suggested that percutaneous cryoablation could be a valuable alternative ablation therapy for HCC but there has been no large cohort-based analysis on its long-term outcomes. METHODS: A series of 866 patients with Child-Pugh class A-B cirrhosis and HCC within Milan criteria who underwent percutaneous cryoablation was long-term followed. The safety, efficacy, 5-year survival, and prognostic factors of percutaneous cryoablation in the treatment of HCC were analyzed. RESULTS: A total of 1197 HCC lesions were ablated with 1401 cryoablation sessions. Complete response (CR) was achieved in 1163 (97.2%) lesions and 832 (96.1%) patients with 34 (2.8%) major complications, but no treatment-related mortality. After a median of 30.9 months follow-up, 502 (60.3%) patients who achieved CR developed different types of recurrence. The cumulative local tumor recurrence rate was 24.2% at 5-years. Multiple tumor lesions, tumor size > 3 cm, and repeated ablation of same lesion were independent risk factors associated with local recurrence. The 5-year overall survival (OS) rates were 59.5%. Age < 36 years, HCC family history, baseline hepatitis B virus DNA >106 copies/ml, and three HCC lesions were independently and significantly negative predictors to the post-cryoablation OS. CONCLUSIONS: Percutaneous cryoablation is an effective therapy for patients with HCC within Milan criteria, with comparable efficacy, safety and long-term survival to the reported outcomes of radiofrequency ablation.

Incidence and risk factors for hepatocellular carcinoma in primary biliary cirrhosis.

The incidence, risk factors, and clinical features of hepatocellular carcinoma (HCC) in primary biliary cirrhosis (PBC) have been a long-standing subject of interest. We took advantage of a large cohort of 1865 well-defined Chinese patients with PBC for whom follow-up was conducted for up to 20 years to study the incidence of HCC. Our goal was to address the incidence and prevalence of HCC in PBC and the risk factors, including hepatitis B virus (HBV) infection, and finally to compare the tumor characteristics of PBC-related HCC, including size, location, mortality, and long-term outcomes, to that of HBV-related HCC. In this cohort, HCC occurred in 70 of 1865 PBC patients with a prevalence of 3.75 % and an incidence of 0.66 cases per 100 patient-years. The 5- and 10-year cumulative incidences were 2.6 % (95 % confidence interval (CI) 1.8-3.4) and 8.9 % (95 % CI 5.5-12.3), respectively. Age >54 years (odds ratio [OR] = 5.5, 95 % CI 3.0-10.1, p = 0.001), male sex (OR = 2.2, 95 % CI 1.2-4.0, p = 0.001), co-existence of diabetes mellitus (DM) (OR = 3.1, 95 % CI 1.6-6.2, p = 0.002), and previous HBV infection (OR = 6.6, 95 % CI 3.7-11.9, p = 0.001) were independently associated with the development of HCC. The tumor size, number, location, and 5-year survival were not significantly different in PBC-related HCC compared to HBV-related HCC. Alpha-fetoprotein was elevated in only 20 % of the cases with PBC-related HCC. Although HCC was uncommon, occurring in fewer than 5 % of patients, the risk is significantly increased by age, sex, DM, and past HBV infection.

Cryotherapy for cirrhosis-based hepatocellular carcinoma: a single center experience from 1595 treated cases.

Cryoablation is a less prevalent percutaneous ablative therapy for hepatocellular carcinoma (HCC), and current evidence about its usefulness is limited. We report our experience in treating 1595 HCC cases with percutaneous cryoablation to give a comprehensive profile about the effectiveness, safety and long-term outcome of this therapy. From January 2003 to December 2013, 1595 patients with 2313 HCC nodules were ablated with 2958 cryoablation sessions in our center. Complete ablation was achieved in 1294 patients for 1893 nodules with a mean diameter of 3.4 ± 2.2 cm. The complete ablation rate was 81.2%, 99.4%, 94.4%, and 45.6% in all tumors, tumors < 3 cm, tumors < 5 cm, and tumors > 5 cm, respectively. Major complications were observed after 80 (3.4%) of the 2958 cryoablations and minor complications were observed after 330 cryoablations with no treatment-related deaths. After a median follow-up of 33.4 months, 937 patients developed different types of recurrence. The 5- and 10-year overall survival was 25.7% and 9.2%, respectively. Cryoablation showed reliable safety and efficacy and should be considered as a promising technique, particularly when a large zone of ablation is required.

Blocking and reversing hepatic fibrosis in patients with chronic hepatitis B treated by traditional Chinese medicine (tablets of biejia ruangan or RGT): study protocol for a randomized controlled trial.

BACKGROUND: Chronic hepatitis B (CHB) can progress to cirrhosis, hepatocellular carcinoma (HCC) and ultimately liver-related death. Although oral antiviral therapy for patients with CHB reduces the risk of such complications, once cirrhosis is established, the benefits of antiviral therapy are not robustly demonstrated. According to traditional Chinese medicine (TCM), some Chinese herbal medicines promote blood circulation and soften hard masses, and therefore they may block and reverse hepatic fibrosis. The aim of this study is to evaluate the effects of TCM tablets of the compound biejia ruangan (RGT) administered for fibrosis, and entecavir (ETV), on the development of HCC in patients with CHB or hepatitis B virus (HBV)-related compensated cirrhosis. METHODS/DESIGN: This multicenter, centrally randomized, double-blind, placebo-controlled, parallel-group study is planned to complete within 5 years. For the study, 1,000 with CHB or HBV-related compensated cirrhosis are randomly assigned in a 1:1 ratio to a treatment group (0.5 mg ETV once daily; 2 g RGT three times daily) or a control group (0.5 mg ETV once daily; 2 g RGT dummy agent three times daily). The primary end points are the development of HCC and liver-related death. Secondary end points include disease progression and overall survival. DISCUSSION: Although antiviral therapy can achieve sustained suppression of HBV replication, thereby preventing cirrhosis, patients with CHB treated with nucleos(t)ide analogs (NUCs) retain a higher risk for HCC compared with patients with inactive disease. Although previous clinical trials with RGT have confirmed the efficacy of blocking and reversing hepatic fibrosis in patients with CHB or compensated cirrhosis, the long-term risk for HCC or disease progression in these patients treated with combination of RGT and NUCs compared with NUCs alone is unclear. Therefore, it is necessary to investigate the effects of the RGT blockade and reversal of hepatic fibrosis on the development of HCC in patients with CHB or HBV-related compensated cirrhosis in large, prospective, multicenter, double-blind, randomized, controlled trials in China. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01965418. Date registered: 17 October 2013.

IL-17A stimulates the progression of giant cell tumors of bone.

PURPOSE: Giant cell tumors of bone (GCTB) exhibit aggressive bone lytic behavior. Studies have shown that interleukin 17A (IL-17A) is involved pathologic bone resorption in various skeletal disorders. Thus, we have investigated the role of IL-17A in GCTBs. EXPERIMENTAL DESIGN: We evaluated the progression of GCTBs using Campanacci grading and Enneking staging systems in 74 patients with GCTB. The expression of IL-17A and the IL-17A receptor A (IL-17RA) was assessed in GCTB tissues and in both multinucleated giant cells (MNGC) and stromal cells cultured in vitro using immunostaining and reverse transcription PCR (RT-PCR). The effects of IL-17A on the osteolytic activity of the MNGCs and the proliferation of the stromal cells were investigated using the "pit" formation and MTT assays, respectively. The effects of IL-17A on the expression of proosteolytic factors were examined in primary cultured MNGCs and stromal cells using RT-PCR, Western blotting, and gene expression microarrays. RESULTS: In GCTBs, we detected abundant levels of IL-17A, which were associated with tumor extension and grade. IL-17A is predominantly produced by MNGCs, whereas IL-17RA is expressed by both MNGCs and stromal cells in GCTBs. In the MNGCs, the IL-17A increased the mRNA expression of IL-17A and proosteolytic enzymes, and also enhanced osteolytic ability. In the stromal cells, the IL-17A stimulated cellular proliferation and the expression of proosteolytic factors, including RANKL through myc and STAT3, respectively. In addition, IL-17A stimulated in vivo tumor growth and the extent of angiogenesis in GCTBs. CONCLUSION: IL-17A stimulates the progression of GCTBs and might represent a useful candidate marker for progression and as a therapeutic target for GCTBs.