Absolute Configuration of Oxabornyl Polyenes Prugosenes A1-A3 and Structural Revision of Prugosene A2.

Oxabornyl polyenes represent a unique group of polyketides characterized by a central polyene core flanked by a conserved oxabornyl moiety and a structurally diverse oxygen heterocyclic ring. They are widely distributed in fungi and possess a variety of biological activities. Due to the significant spatial separation between the two stereogenic ring systems, it is difficult to establish their overall relative configurations. Here, we isolated three oxabornyl polyenes, prugosenes A1-A3 (1-3), from Talaromyces sp. JNU18266-01. Although these compounds were first reported from Penicillium rugulosum, their overall relative and absolute configurations remained unassigned. By employing ozonolysis in combination with ECD calculations, we were able to establish their absolute configurations, and additionally obtained seven new chemical derivatives (4-10). Notably, through NMR data analysis and quantum chemical calculations, we achieved the structural revision of prugosene A2. Furthermore, prugosenes A1-A3 exhibited potent antiviral activity against the respiratory syncytial virus, with compound 1 displaying an IC50 value of 6.3 µM. Our study thus provides a valuable reference for absolute configuration assignment of oxabornyl polyene compounds.

PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma.

OBJECTIVE: Patients with increased PD-L1+ host cells in tumours are more potent to benefit from antiprogrammed death-1/programmed death ligand-1 (PD-L1) treatment, but the underlying mechanism is still unclear. We aim to elucidate the nature, regulation and functional relevance of PD-L1+ host cells in hepatocellular carcinoma (HCC). DESIGN: A total of untreated 184 HCC patients was enrolled randomly. C57BL/6 mice are given injection of Hepa1-6 cells to form autologous hepatoma. ELISpot, flow cytometry and real-time PCR are applied to analyse the phenotypic characteristics of PD-L1+ cells isolated directly from HCC specimens paired with blood samples or generated from ex vivo and in vitro culture systems. Immunofluorescence and immunohistochemistry are performed to detect the presence of immune cells on paraffin-embedded and formalin-fixed samples. The underlying regulatory mechanisms of metabolic switching are assessed by both in vitro and in vivo studies. RESULTS: We demonstrate that PD-L1+ host macrophages, which constructively represent the major cellular source of PD-L1 in HCC tumours, display an HLA-DRhighCD86high glycolytic phenotype, significantly produce antitumourigenic IL-12p70 and are polarised by intrinsic glycolytic metabolism. Mechanistically, a key glycolytic enzyme PKM2 triggered by hepatoma cell derived fibronectin 1, via a HIF-1α-dependent manner, concurrently controls the antitumourigenic properties and inflammation-mediated PD-L1 expression in glycolytic macrophages. Importantly, although increased PKM2+ glycolytic macrophages predict poor prognosis of patients, blocking PD-L1 on these cells eliminates PD-L1-dominant immunosuppression and liberates intrinsic antitumourigenic properties. CONCLUSIONS: Selectively modulating the 'context' of glycolytic macrophages in HCC tumours might restore their antitumourigenic properties and provide a precise strategy for anticancer therapy.

CT-based radiomics to predict development of macrovascular invasion in hepatocellular carcinoma: A multicenter study.

BACKGROUND: Macrovascular invasion (MaVI) occurs in nearly half of hepatocellular carcinoma (HCC) patients at diagnosis or during follow-up, which causes severe disease deterioration, and limits the possibility of surgical approaches. This study aimed to investigate whether computed tomography (CT)-based radiomics analysis could help predict development of MaVI in HCC. METHODS: A cohort of 226 patients diagnosed with HCC was enrolled from 5 hospitals with complete MaVI and prognosis follow-ups. CT-based radiomics signature was built via multi-strategy machine learning methods. Afterwards, MaVI-related clinical factors and radiomics signature were integrated to construct the final prediction model (CRIM, clinical-radiomics integrated model) via random forest modeling. Cox-regression analysis was used to select independent risk factors to predict the time of MaVI development. Kaplan-Meier analysis was conducted to stratify patients according to the time of MaVI development, progression-free survival (PFS), and overall survival (OS) based on the selected risk factors. RESULTS: The radiomics signature showed significant improvement for MaVI prediction compared with conventional clinical/radiological predictors (P < 0.001). CRIM could predict MaVI with satisfactory areas under the curve (AUC) of 0.986 and 0.979 in the training (n = 154) and external validation (n = 72) datasets, respectively. CRIM presented with excellent generalization with AUC of 0.956, 1.000, and 1.000 in each external cohort that accepted disparate CT scanning protocol/manufactory. Peel9_fos_InterquartileRange [hazard ratio (HR) = 1.98; P < 0.001] was selected as the independent risk factor. The cox-regression model successfully stratified patients into the high-risk and low-risk groups regarding the time of MaVI development (P < 0.001), PFS (P < 0.001) and OS (P = 0.002). CONCLUSIONS: The CT-based quantitative radiomics analysis could enable high accuracy prediction of subsequent MaVI development in HCC with prognostic implications.

Single-Agent versus Combination Doxorubicin-Based Transarterial Chemoembolization in the Treatment of Hepatocellular Carcinoma: A Single-Blind, Randomized, Phase II Trial.

OBJECTIVES: It was the aim of this study to find an optimal therapeutic regimen of transarterial chemoembolization (TACE) by comparing the efficacy of chemoembolization with different anticancer agents in hepatocellular carcinoma (HCC) patients. METHODS: A single-blind, three-group parallel, randomized trial was conducted in Guangdong General Hospital, Guangzhou, China, with patients with biopsy-confirmed HCC. Group 1 received single-drug (doxorubicin) chemoembolization, while group 2 received double-drug (doxorubicin and mitomycin C) chemoembolization. Patients in group 3 were treated with triple-drug (doxorubicin, mitomycin C, and gemcitabine) chemoembolization. Lipiodol was used as embolization agent in all protocols. We compared the overall survival (OS), time to progression (TTP), and objective response rate (ORR) between groups. Response assessment was performed according to modified RECIST (Response Evaluation Criteria In Solid Tumors) criteria. RESULTS: Between January 2008 and January 2011, 162 patients (group 1, n = 50; group 2, n = 59; group 3, n = 53) were recruited. The OS and TTP in groups 1, 2, and 3 were 14.9 and 6.4, 13.2 and 6.4, and 20.5 and 6.8 months, respectively. OS and TTP were statistically significant among groups (p = 0.002 and p = 0.037). The ORR was 22.0, 40.7, and 56.6%, respectively. The ORR was significantly different across the three groups (p < 0.002). CONCLUSIONS: TACE with multiple chemotherapeutic agents might significantly increase survival and tumor response; additionally, gemcitabine was likely to have an advantage in improving the prognosis of HCC patients. © 2015 S. Karger AG, Basel.

Genetic variants in the KDR gene is associated with the prognosis of transarterial chemoembolization treated hepatocellular carcinoma.

Kinase insert domain receptor (KDR) is the principal receptor that promotes the proangiogenic action of vascular endothelial growth factor and is involved in the tumorigenesis and progression of many malignancies, including hepatocellular carcinoma (HCC). Single-nucleotide polymorphisms (SNPs) of KDR have been reported to be with the risk and prognosis of several malignancies. Our aim was to determine whether SNPs in KDR gene are associated with clinical outcomes in HCC patients treated with transcatheter arterial chemoembolization. A total of 192 HCC patients were tested for KDR SNPs, and the SNP results were correlated with progression-free survival (PFS) and overall survival (OS). The association of the SNPs with the overall survival (OS) of patients was assessed by Kaplan-Meier method, and then Cox proportional hazards model was used to assess the variables resulted significant at univariate analysis. No significant differences were found in correlation between KDR SNPs and patients' PFS. Our data showed that genotype AA+TA of rs1870377 and genotype CC+TC of rs2071559 were significantly associated with overall survival of HCC patients (P<0.001 and P<0.001, respectively) and remained as significant predictors for OS adjusting for high level of serum AFP (>400 µg/L), existence of portal vein tumor thrombus, and high BCLC stage (HR=0.61; 95% CI, 0.36-0.88; P=0.003 and HR=0.54; 95% CI, 0.40-0.94; P=0.002, respectively). Our results suggest that SNPs rs1870377 and rs2071559 in the KDR gene may serve as independent prognosis biomarkers for unresectable HCC patient, which warranted further validating investigation.

Landscape and prognostic values of lymphocytes in patients with hepatocellular carcinoma undergoing transarterial embolization.

Transarterial embolization, the first-line treatment for hepatocellular carcinoma, does not always lead to promising outcomes in all patients. A better understanding of how the immune lymphocyte changes after transarterial embolization might be the key to improve the efficacy of transarterial embolization. However, there are few studies evaluating immune lymphocytes in transarterial embolization patients. Therefore, we aimed to evaluate the short- and long-term effects of transarterial embolization on lymphocyte subsets in patients with hepatocellular carcinoma to identify those that predict transarterial embolization prognosis. Peripheral blood samples were collected from 44 patients with hepatocellular carcinoma at the following time points: 1 d before the initial transarterial embolization, 3 d after the initial transarterial embolization, and 1 mo after the initial transarterial embolization and subjected to peripheral blood mononuclear cell isolation and flow cytometry. Dynamic changes in 75 lymphocyte subsets were recorded, and their absolute counts were calculated. Tumor assessments were made every 4 to 6 wk via computed tomography or magnetic resonance imaging. Our results revealed that almost all lymphocyte subsets fluctuated 3 d after transarterial embolization, but only Tfh and B cells decreased 1 mo after transarterial embolization. Univariate and multivariate Cox regression showed that high levels of Th2 and conventional killer Vδ2 cells were associated with longer progressive-free survival after transarterial embolization. Longer overall survival after transarterial embolization was associated with high levels of Th17 and viral infection-specific Vδ1 cells and low levels of immature natural killer cells. In conclusion, transarterial embolization has a dynamic influence on the status of lymphocytes. Accordingly, several lymphocyte subsets can be used as prognostic markers for transarterial embolization.

Transarterial Chemoembolization with Epirubicin-Loaded Microspheres for Hepatocellular Carcinoma: A Prospective, Single-Arm, Multicenter, Phase 2 Study (STOPPER Trial).

PURPOSE: While the role of drug-eluting beads transarterial chemoembolization (DEB-TACE) for hepatocellular carcinoma (HCC) is established, questions regarding appropriate bead size for use in patients remain. This trial evaluated the effectiveness and safety of DEB-TACE using small-size (≤ 100 µm) microspheres loaded with epirubicin. MATERIALS AND METHODS: This prospective, single-arm, multicenter study enrolled patients diagnosed with HCC who underwent DEB-TACE using 40 (range, 30-50), 75 (range, 60-90), or 100 (range, 75-125) µm epirubicin-loaded microspheres (TANDEM microspheres, Varian Medical). Bead size was at the discretion of treating physicians and based on tumor size and/or vascular structure. The primary outcome measure was 6-month objective response rate (ORR). Secondary outcome measures were 30-day and 3-month ORR, time to tumor progression and extrahepatic spread, proportion of progression-free survival and overall survival (OS) at one year, and incidence of treatment-associated adverse events. RESULTS: Data from 108 patients from ten centers was analyzed. Six-month ORR was 73.3 and 71.3% based on European association for the study of the liver (EASL) and modified response evaluation criteria in solid tumors (mRECIST) criteria, respectively. Thirty-day ORR was 79.6% for both EASL and mRECIST criteria with 3-month ORR being 80.0 and 81.0%, respectively, for each criteria. One-year PPF and OS rate were 60.3 and 94.3%. There was a total of 30 SAEs reported to be likely to definitely associated with microsphere (n = 9), epirubicin (n = 9), or procedure (n = 12) with none resulting in death. CONCLUSION: DEB-TACE using epirubicin-loaded small-sized (≤ 100 µm) microspheres demonstrates promising local tumor control and acceptable safety in patients with HCC. TRIAL REGISTRATION: Clinicaltrials.gov NCT03113955; registered April 14, 2017. Trial Registration Clinicaltrials.gov NCT03113955; registered April 14, 2017. LEVEL OF EVIDENCE: 2, Prospective, Non-randomized, Single-arm, study.

[Prognostic significance of serum level of vascular endothelial growth factor receptor-2 in hepatocellular carcinoma patients after transcatheter arterial chemoembolization].

OBJECTIVE: To explore the prognostic significance of serum vascular endothelial growth factor receptor-2 (VEGFR-2) in patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). METHODS: A total of 69 HCC patients undergoing TACE from October 2008 to April 2012 were recruited and examined. Their serum level of VEGFR-2 level was measured by enzyme-linked immunosorbent assay (ELISA). The relationship between VEGFR-2 and their clinicopathologic features were observed. Prognostic significance of VEGFR-2 was assessed for their survival. RESULTS: Significant differences existed when the serum level of VEGFR-2 was categorized by tumor number and liver cirrhosis (P = 0.021, P = 0.049). The post-treatment serum level of VEGFR-2 was significant higher than that at pre-treatment (P = 0.045). When the mean pre-treatment serum level of VEGFR-2 (8709 ng/L) was used as a cut-off point, the patients with a low serum level of VEGFR-2 had better overall and progression-free survival than those with a high serum level of VEGF (17 vs. 28 months, P = 0.001 and 10 vs. 15 months P = 0.031 respectively). As revealed by multivariate Cox analysis, the pre-treatment serum level of VEGFR-2 was an independent and significant prognostic factor of survival for HCC patients at post-TACE. CONCLUSION: The pre-treatment serum level of VEGFR-2 may predict the post-TACE prognosis in HCC patients.

[Expression of serum microRNAs (miR-222, miR-181, miR-216) in human hepatocellular carcinoma and its clinical significance].

OBJECTIVE: To investigate the abnormal expression of microRNAs (miR-216, miR-222, miR-181) in the serum of patients with hepatocellular carcinoma (HCC) and its clinical significance. METHODS: Serum miRNAs expression was investigated in 49 patients with HCC and 25 healthy normal controls by using real-time PCR technique, and then correlations between miRNAs expression and the clinicopathological features and prognosis of HCC patients were evaluated. RESULTS: No differences were observed between the HCC patients and healthy controls with respect to the expressions of serum miR-181 and miR-216 (P > 0.05), while miR-222 was found to be significantly overexpressed in HCC serum samples (6.1 ± 6.6 vs 1.2 ± 0.6, P < 0.01). According to the median fold change of miR-222 (3-fold) in all HCC serum samples, we divided the 49 patients into two groups:a low expression group (25 patients) and a high expression group (24 patients).High level of miR-222 expression was correlated with cirrhosis (P < 0.01), tumor number (P = 0.013), portal vein tumor thrombosis (P = 0.002) and TNM stage (P = 0.020), while not correlated with serum alpha-fetoprotein level, tumor size and HbsAg. Kaplan-Meier survival analysis showed that the median overall survival in the high miR-222 expression group was significantly shorter than that in the low expression group (8.7 months vs 16.5 months, P = 0.036). In multivariate Cox analysis, TNM stage and serum miR-222 expression were two independent prognostic factors. CONCLUSION: Serum miR-222, upregulated in HCC, maybe helpful in prognosis of HCC patients.

Cordythiazole A, the first member of thiazole alkaloids from Chinese cordyceps, with α-glucosidase inhibitory activity.

Chinese cordyceps, also known as Dong-Chong-Xia-Cao, is widely recognized as a famous precious tonic herb, and used as traditional Chinese medicine for centuries. It is mainly used for regulating the immune system and improving functions of the lung and kidney, with anti-tumor, anti-inflammatory, and anti-diabetic activities. Due to its rarity and preciousness, a few chemical components are isolated and identified. Moreover, most of them are common chemical components and widely distributed in other natural resources, such as nucleosides, sterols, fatty acids, sugar alcohols, and peptides. Therefore, a large number of active substances of Chinese cordyceps is still unclear. During our search for chemical constituents of Chinese cordyceps, a new thiazole alkaloid, cordythiazole A (1), was isolated and identified. Its structure was elucidated by comprehensive spectroscopic analysis and single-crystal X-ray diffraction analysis. This is the first report of the presence of thiazole alkaloid in Chinese cordyceps, which adds a new class of metabolite of Chinese cordyceps. Furthermore, a putative biosynthesis pathway of cordythiazole A was proposed based on possible biogenic precursor, genes, and literatures. In addition, it showed α-glucosidase inhibitory activity with potency close to that of acarbose. The discovery of cordythiazole A with α-glucosidase inhibitory activity adds a new class of potential anti-diabetes ingredient in Chinese cordyceps.

Irradiation stent with 125 I plus TACE versus sorafenib plus TACE for hepatocellular carcinoma with major portal vein tumor thrombosis: a multicenter randomized trial.

BACKGROUND AND AIM: Treatment strategy for hepatocellular carcinoma (HCC) and Vp4 [main trunk] portal vein tumor thrombosis (PVTT) remains limited due to posttreatment liver failure. We aimed to assess the efficacy of irradiation stent placement with 125 I plus transcatheter arterial chemoembolization (TACE) (ISP-TACE) compared to sorafenib plus TACE (Sora-TACE) in these patients. METHODS: In this multicenter randomized controlled trial, participants with HCC and Vp4 PVTT without extrahepatic metastases were enrolled from November 2018 to July 2021 at 16 medical centers. The primary endpoint was overall survival (OS). The secondary endpoints were hepatic function, time to symptomatic progression, patency of portal vein, disease control rate, and treatment safety. RESULTS: Of 105 randomized participants, 51 were assigned to the ISP-TACE group, and 54 were assigned to the Sora-TACE group. The median OS was 9.9 months versus 6.3 months (95% CI: 0.27-0.82; P =0.01). Incidence of acute hepatic decompensation was 16% (8 of 51) versus 33% (18 of 54) ( P =0.036). The time to symptomatic progression was 6.6 months versus 4.2 months (95% CI: 0.38-0.93; P =0.037). The median stent patency was 7.2 months (interquartile range, 4.7-9.3) in the ISP-TACE group. The disease control rate was 86% (44 of 51) versus 67% (36 of 54) ( P =0.018). Incidences of adverse events at least grade 3 were comparable between the safety populations of the two groups: 16 of 49 (33%) versus 18 of 50 (36%) ( P =0.73). CONCLUSION: Irradiation stent placement plus TACE showed superior results compared with sorafenib plus TACE in prolonging OS in patients with HCC and Vp4 PVTT.

[Relationship between sorafenib-associated hand-food skin reaction and efficacy in treatment of advanced hepatocellular carcinoma].

OBJECTIVE: To investigate the link between the antitumor efficacy of sorafenib and its cutaneous side effects in advanced hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed the incidence of hand-foot skin reactions (HFRS) of 51 patients with advanced HCC who treated by sorafenib combined with transcatheter arterial chemoembolization (TACE), comparing tumor disease control rate (DCR), median progression free survival (mPFS) and median overall survival (mOS) in the different severity HFRS groups. The Cox proportional hazard model was applied to the multivariate survival analysis for the PFS. RESULTS: Fifty-one HCC patients treated with sorafenib combined with TACE were included in this study. 13/51 without HFRS (grade 0), 38/51 developed at all grade 1-3, 27 developed at grade 1-2, 11 developed at grade 3. The DCR were 38.5%, 70.4% and 90.9% in the three groups (P < 0.05). Group grade 0 vs grade 1-3, P = 0.031, the difference had statistical significance. Group grade 1-2 vs grade 3, P = 0.352, the difference had no statistical significance. The mPFS were 2.8 months (95%CI 1.6 - 4.0), 4.5 (95%CI 1.3 - 7.7) months and 12.8 (95%CI 3.7 - 21.9) months (P < 0.05), group grade 0 vs grade 1-2, P = 0.019, HR (hazard ratio): 2.8 (95%CI 1.3 - 6.3), P = 0.010, group grade 0 vs grade 3, P < 0.01, HR 6.6 (95%CI 2.3 - 19.0), P < 0.01, group grade 1-2 vs grade 3, P = 0.054; the three groups' mOS were 8.5 months (95%CI 5.9 - 11.1), 13.0 (95%CI 10.1 - 15.9) months and 25.4 months, P < 0.05, there were statistically significant differences between the any two groups. CONCLUSIONS: HFRS should be closely monitored in HCC patients treated with sorafenib in relation to its potential role as a surrogate marker of efficacy, but it has yet to be demonstrated whether the efficacy increasing with the severity of HFRS or not.

Bibliometric Analysis of γδ T Cells as Immune Regulators in Cancer Prognosis.

γδ T cells are one of only three immune cell types that express antigen receptors that undergo somatic recombination, and they contribute to immune responses to infection, cellular transformation, and tissue damage. As a "bridge" between the innate and adaptive immune systems, γδ T cells have been noted to be involved in various immune responses during cancer progression. The purpose of our study was to review current published information on γδ T cells and investigate their functions in different types of malignancy using bibliometric and bioinformatic methods. Our results indicated that studies on γδ T cells and cancer progression increased from 2014, and the number had peaked by 2021. We discovered that there is international cooperation in the performance of studies among 26 countries, where China was identified as the most productive with the highest citations. Using keyword co-occurrence analysis, we found that among all the cancer types investigated, gastric and breast cancers were most closely related to γδ T cells. Furthermore, interleukin (IL)-17 and IL-2 were the most common cytokines linked to γδ T cells and our investigation of their potential involvement in the prognosis of gastric and breast cancers, identified their different roles in various malignancies. Thus, we concluded that γδ T cells might influence the progression of different cancers in diverse ways.

Biodegradable PTX-PLGA-coated magnesium stent for benign esophageal stricture: An experimental study.

Biodegradable stents can degrade step by step and thereby avoid secondary removal by endoscopic procedures in contrast to metal stents. Herein, a biodegradable composite stent, a magnesium (Mg)-based braided stent with a surface coating of poly (lactic-co-glycolic acid) (PLGA) containing paclitaxel (PTX), was designed and tested. By adding this drug-loaded polymer coating, the radial force of the stent increased from 33 Newton (N) to 83 N. PTX was continuously released as the stent degraded, and the in vitro cumulative drug release in phosphate-buffered saline for 28 days was 115 ± 13.5 µg/mL at pH = 7.4 and 176 ± 12 µg/mL at pH = 4.0. There was no statistically significant difference in the viability of fibroblasts of stent extracts with different concentration gradients (P > 0.05), while the PTX-loaded stents effectively promoted fibroblast apoptosis. In the animal experiment, the stents were able to maintain esophageal patency during the 3-week follow-up and to reduce the infiltration of inflammatory cells and the amount of fibrous tissue. These results showed that the PTX-PLGA-coated Mg stent has the potential to be a safe and effective approach for benign esophageal stricture. STATEMENT OF SIGNIFICANCE: We designed a biodegradable composite stent, having poly (lactic-co-glycolic acid) (PLGA) containing paclitaxel (PTX) coated the surface of the magnesium (Mg)-based braided stent. We evaluated in vitro and in vivo characteristics of the Mg esophageal stent having a PLGA coating plus a variable concentration of PTX in comparison with the absence of PTX PLGA coating. The PTX PLGA stents exerted higher radial force than stents without coating, degraded more quickly in an acid medium, and effectively promoted fibroblast apoptosis in vitro experiments. In a rabbit model of caustic-induced esophageal stricture, there was an increased lumen and decreased inflammation of the esophageal wall in the animals stented with PTX-PLGA versus the sham group, indicating a potential approach for benign esophageal stricture.

Malignant peripheral nerve sheath tumor in an elderly patient with superficial spreading melanoma: A case report.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a type of spindle cell sarcoma originating from the peripheral nerve, which usually results in the corresponding nerve sign on magnetic resonance imaging (MRI). Patients with MPNST may also have neurofibromatosis type 1. CASE SUMMARY: A 78-year-old male was admitted to the hospital due to a tumor in his left knee. He had a previous history of superficial spreading melanoma on the left thigh. Color Doppler ultrasonography showed a hypoechoic mass in the subcutaneous soft tissues of the medial left knee with an abundant rich blood flow. Computed tomography scanning did not show obvious signs of bone destruction, but the skin adjacent to the tumor was slightly thickened. MRI examination revealed that the hypervascular lesion was well-circumscribed, lobulated, invaded the surrounding soft tissues and demonstrated heterogeneous enhancement but lacked an entering and exiting nerve sign. The MRI result indicated the invasiveness of the tumor. The patient underwent a left knee joint mass expanded resection and the first histopathological examination showed a MPNST with positive surgical margins. Therefore, the second extended resection was performed, and the patient had a good outcome in the short term. CONCLUSION: MRI is a useful technique for revealing the biological characteristics of MPNST and provides clinical support for evaluation of the surgical area before operation.

Nano-enabled coordination platform of bismuth nitrate and cisplatin prodrug potentiates cancer chemoradiotherapy via DNA damage enhancement.

The combination of chemotherapy and radiotherapy (chemoradiotherapy) is a promising strategy, extensively studied and applied clinically. Meanwhile, radiosensitizers play an important role in improving clinical radiotherapy therapeutic efficacy. There are still some disadvantages in practical applications, because radiosensitizers and drugs are difficult to deliver spatio-temporally to tumor sites and work simultaneously with low efficiency for DNA damage and repair inhibition, leading to an inferior synergistic effect. Herein, a suitable radiosensitizer of nano-enabled coordination platform (NP@PVP) with bismuth nitrate and cisplatin prodrug is developed by a simple synthetic route to improve the effectiveness of chemo-radiation synergistic therapy. When NP@PVP is internalized by a tumor cell, the bismuth in NP@PVP can sensitize radiation therapy (RT) by increasing the amount of reactive oxygen species generation to enhance DNA damage after X-ray radiation; meanwhile, the cisplatin in NP@PVP can inhibit DNA damage repair with spatio-temporal synchronization. NP@PVP is demonstrated to exhibit higher sensitization enhancement ratio (SER) of 2.29 and excellent tumor ablation capability upon irradiation in vivo in comparison with cisplatin (SER of 1.78). Our strategy demonstrates that the RT sensitization effect of bismuth and cisplatin based NP@PVP has great anticancer potential in chemo-radiation synergistic therapy, which is promising for clinical application.

[Clinical analysis of the treatment:transcatheter arterial chemoembolization combined with sorafenib in advanced hepatocellular carcinoma].

OBJECTIVE: To provide more evidence sources to the standard treatment for patients with advanced hepatocellular carcinoma, the writer analyze patients' time to progression (TTP) and overall survival (OS) after patients receiving transcatheter arterial chemoembolization (TACE) combined with sorafenib as a treatment of advanced hepatocellular carcinoma (HCC); observe the healing effect embolization combined with anti-angiogenic treatment for advanced hepatocellular carcinoma; and also analyze treatment of security. METHODS: There are 36 patients, 33 male and 3 female had been Pathologically or clinical diagnosis. After receiving Transcatheter Arterial Chemoembolization (TACE) therapy, in the following 3 to 7 days, this group of patients continuously take sorafenib (brand name: Nexavar) (per tablet 200 mg), 2 tablets each time, 2 times a day. Every 4 to 8 weeks is called as one period of treatment. Referring to RECIST Evaluation, the writers mainly observe patients' tumor progression (TTP) and overall survival (OS), record adverse events. Using life table method to analyze survival rate, using Kaplan-Meier method to analyze all the survival curves. RESULTS: Till March, 2010, 14 of 36 evaluable patients died and 22 survive; the median time to tumor progression (mTTP) to 8.62 months (95%CI: 6.51-10.24 months); the median survival time (mOS) of 12.41 months (95%CI: 9.57-14.80 months). The overall survival rate to observation period is 61.1%; 36 patients had been studied, 22 survive. Among the survivals, there is no CR cases, and 1 case PR, 15 patients SD, 6 patients PD; disease control rate (DCR) (CR + PR + SD) is 44.4%. The side effects of taking Sorafenib mainly are hand-foot skin reaction, diarrhea, fatigue and loss of appetite. These side effects can be markedly eased after symptomatic treatment. CONCLUSION: Combined with sorafenib treatment may give patients with advanced hepatocellular carcinoma a longer longevity and keep the disease in a steady state. This therapy can be added into the treatments to patients with advanced hepatocellular carcinoma. The side effects of taking Sorafenib (Nexavar) could be stand.

Clinical efficacy of absolute ethanol combined with n-butyl cyanoacrylate sclerotherapy in the treatment of Puig's classified advanced venous malformation in children.

The aim of the present retrospective study was to investigate the clinical safety and efficacy of absolute ethanol combined with n-butyl cyanoacrylate sclerotherapy in the treatment of Puig's classified advanced venous malformation. Sclerotherapy was performed in 121 children (52 males and 69 females; age range, 5 months to 16 years) with venous malformations under general anesthesia between April 2009 and October 2014 at the Department of Interventional Radiology and Vascular Anomalies, Guangzhou Women and Children's Medical Center, Guangzhou, China. The patients with venous malformations were diagnosed and classified according to the diagnostic criteria of the International Society for the Study of Vascular Anomalies. According to the characteristics of intraoperative percutaneous angiography, 21 patient cases (9 males and 12 females; age range, 6 months to 14 years) were classified as advanced Puig's venous malformation. These 21 patients were treated with absolute ethanol combined with n-butyl cyanoacrylate. The patients were followed-up for 6-24 months (average, 15 months) after treatment. Following treatment with absolute ethanol combined with n-butyl cyanoacrylate, 15 cases were controlled and the total effective rate was 71% (15/21). However, 1 patient developed skin ulcerations, which was classed as a minor complication, 1 patient developed ectopic embolism caused by n-butyl cyanoacrylate reflux, and 1 patient developed transient pulmonary hypertension, the latter two complications were classified as major. Notably, the incidence rate of minor and major complications were 14.3%. To conclude, the present findings indicated that absolute ethanol combined with n-butyl cyanoacrylate sclerotherapy was a safe and effective method with a low complication rate in the treatment of Puig's classified advanced venous malformation in patients.

Activation of MET promotes resistance to sorafenib in hepatocellular carcinoma cells via the AKT/ERK1/2-EGR1 pathway.

Sorafenib is an oral multikinase inhibitor that has become an established therapeutic approach in advanced hepatocellular carcinoma (HCC). However, the benefit of sorafenib in clinical therapy is often affected by drug resistance. Therefore, it is important to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with this problem. In this study, we found that addition of HGF to sorafenib-treated HCC cells activated MET and re-stimulated the downstream AKT and ERK1/2 pathways. Thereby, restored sorafenib-treated HCC cells proliferation, migration and invasion ability, and rescued cells from apoptosis. In addition, we found that HGF treatment of HCC cells induced early growth response protein (EGR1) expression, which is involved in sorafenib resistance. Importantly, the HGF rescued effect in sorafenib-treated HCC cells could be abrogated by inhibiting MET activation with PHA-665752 or by downregulating EGR1 expression with small interfering RNA (siRNA). Therefore, inhibition of the HGF/MET pathway may improve response to sorafenib in HCC, and combination therapy should be further investigated.

[Research of high frequency induced thermotherapy efficiency for treatment of hepatocellular carcinoma].

OBJECTIVE: To investigate the effectiveness of high frequency induced thermotherapy in the treatment of hepatocellular carcinoma. METHODS: We included a 65 proven cases of hepatocellular carcinoma in which the diagnosis was confirmed by pathology, radio-imaging and AFP value. The patients were randomly divided into 2 group by odd or even hospitalization number. A total of 32 patients were enrolled in the TACE + PEI only group and 33 patients were enrolled in the TACE + HITT therapy group. RESULTS: For the 32 patients in TACE + PEI only therapy group, the 1, 2, and 3 year of survival rates were 73%, 56%, and 23%, respectively, with a median survival of 1.876 years. For patients in the therapy group, the 1, 2, and 3 year survival rates were 87%, 76%, and 51%, respectively, with a median survival of 2.134 years. Survival rate and duration in the therapy group was significantly greater in the combination therapy group compared to the control group (P < 0.05). There was a negative correlation between the effectiveness of combination therapy and the mortality risk (P < 0.05). CONCLUSION: HiTT + TACE can significantly increase survival rate and extend length of survival in patients with hepatocellular carcinoma.