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.

The relationship of kinase insert domain receptor gene polymorphisms and clinical outcome in advanced hepatocellular carcinoma patients treated with sorafenib.

Kinase insert domain receptor (KDR) is the principal receptor that promotes the pro-angiogenic action of vascular endothelial growth factor and has been the principal target of anti-angiogenic therapies. Our aim was to determine whether single-nucleotide polymorphisms (SNPs) in KDR gene are associated with clinical outcomes after first-line sorafenib therapy in advanced hepatocellular carcinoma (HCC). The SNPs in KDR were tested in 78 advanced HCC patients receiving first-line sorafenib. Correlations with clinicopathological features and survival were analyzed. Patients with AA genotype of rs1870377 and AA genotype of rs2305948 were significantly associated with a better response and longer time to progression (TTP) (5.8 vs 4.0 months, P=0.001; 5.8 vs 4.5 months, P=0.016, respectively). Patients harboring AA genotype in rs1870377 and TT/TC genotype in rs2071559 had a longer overall survival (OS) (15.0 vs 9.6 months, P=0.001; 13.0 vs 9.0 months, P=0.007, respectively). At multivariate analysis, major vascular invasion and rs1870377 were independent factors in TTP and performance status, rs1870377, and rs2071559 were independent factors in OS. Our results suggest that SNPs in KDR gene can predict clinical outcome in advanced HCC patients receiving first-line sorafenib.

Sorafenib continuation after first disease progression could reduce disease flares and provide survival benefits in patients with hepatocellular carcinoma: a pilot retrospective study.

BACKGROUND: Sorafenib is a promising drug for advanced hepatocellular carcinoma (HCC); however, treatment may be discontinued for multiple reasons, such as progressive disease, adverse events, or the cost of treatment. The consequences of sorafenib discontinuation and continuation are uncertain. MATERIALS AND METHODS: We retrospectively analyzed 88 HCC patients treated with sorafenib from July 2007 to January 2013. Overall survival (OS), post-disease progression overall survival (pOS), and time to disease progression (TTP) were compared for survival analysis. Cox proportional hazard regression was performed to assess the effect of important factors on OS in the overall patient population and on pOS in patients who continued sorafenib treatment. RESULTS: Sorafenib was discontinued and continued in 24 and 64 patients, respectively. The median OS (355 vs 517 days respectively; p=0.015) and median post-PD OS (260 vs 317 days, respectively; p=0.020) were statistically different between the discontinuation and continuation groups. Neither the median time to first PD nor the time to second PD were significantly different between the 2 groups. In the discontinuation group, 3 of the 24 patients (12.5%) suffered disease outbreaks. In Cox proportional hazard regression analysis after correction for confounding factors, BCLC stage (p=0.002) and PD site (p=0.024) were significantly correlated with pOS in patients who continued sorafenib treatment. CONCLUSIONS: Sorafenib discontinuation may cause HCC flares or outbreaks. It is advisable to continue sorafenib treatment after first PD, particularly in patients with Barcelona Clinic Liver Cancer stage B disease or only intrahepatic PD.

The blood neutrophil-to-lymphocyte ratio predicts survival in patients with advanced hepatocellular carcinoma receiving sorafenib.

BACKGROUND AND AIM: Increasing evidence correlates the presence of systemic inflammation with poor survival in patients with hepatocellular carcinoma (HCC). The aim of this study was to investigate the prognostic significance of the blood neutrophil-to-lymphocyte ratio (NLR) in patients with advanced HCC who received sorafenib monotherapy. METHODS: A total of sixty-five patients with advanced HCC, not eligible for locoregional therapy, treated with sorafenib were enrolled. Potential prognostic factors such as age, gender, tumoral characteristics, performance status and NLR were analyzed. RESULTS: Median OS and TTP for the entire cohort were 10.0 months (95%CI, 7.6-12.3 months) and 4.5 months (95% CI, 4.0-4.9 months). The mean NLR at baseline was 2.89. The median OS of patients with a high NLR (>4) was 6.5 months (95%CI, 5.2-7.7 months) compared with 12.5 months (95%CI, 9.9-15.0) for patients with a normal NLR (≤ 4) (P = 0.01). Age ≤ 65, NLR >4, extrahepatic metastases and vascular invasion were all predictors of poorer overall survival. Multivariate analysis showed that NLR > 4, vascular invasion and extrahepatic metastases were independent predictors of poorer overall survival. The median TTP of patients with a high NLR was 2.5 months (95%CI, 1.4-3.6 months) compared with 4.5 months (95%CI, 3.9-5.1 months) for patients with a normal NLR (P=0.012). CONCLUSIONS: High baseline NLR was associated with worse OS and TTP for patients with advanced HCC treated with sorafenib.

Effects of sorafenib combined with chemoembolization and radiofrequency ablation for large, unresectable hepatocellular carcinomas.

BACKGROUND: The prognosis of unresectable large hepatocellular carcinomas is poor. This study evaluated the efficacy and safety of sorafenib combined with transcatheter arterial chemoembolization and radiofrequency ablation in the treatment of hepatocellular carcinomas larger than 5 cm. METHODS: The treatment of 22 patients with large, unresectable hepatocellular carcinomas (5.0-16.5 cm) treated with sorafenib after transcatheter arterial chemoembolization combined with radiofrequency ablation between 2007 and 2011 was reviewed. The local effects, survival rates, toxicity, and prognostic factors were analyzed. RESULTS: During a follow-up of 9-49 months, 19 patients died and three survived. The median overall survival was 32 months. The overall cumulative 12, 24, and 36-month survival rates were 85.9%, 66.8%, and 23.5% respectively. Technical effectiveness was achieved in 12 out of 28 lesions (42.85%) at the first CT check. The median time to tumor progression was 21 months. The progression-free survival rates at 6, 12, and 24 months were 90.9%, 72.0%, and 38.4%, respectively. Combined therapy was generally well tolerated. There was only one major procedure-related complication, biloma (4.5%). Sorafenib-related adverse events exceeding grade 3 were hand-foot skin reaction (2/22, 9.1%), gastrointestinal hemorrhage (1/22, 4.5%), and diarrhea (2/22, 9.1%). The absence of vascular invasion before treatment was found to be the best prognostic factor in the univariate analysis. CONCLUSIONS: Sorafenib combined with transcatheter arterial chemoembolization and radiofrequency ablation is a promising approach to the treatment of large, unresectable hepatocellular carcinomas. However, large-scale randomized clinical trials are needed to determine the future role of this treatment.

Sorafenib in combination with transarterial chemoembolization and radiofrequency ablation in the treatment for unresectable hepatocellular carcinoma.

The purpose of this study is to assess clinical efficacy and safety of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) on patients with unresectable hepatocellular carcinoma (HCC). Efficacy and safety profiles of sorafenib in combination with TACE and RFA were evaluated based on retrospective data for thirty patients with unresectable HCC. Patients were treated with TACE initially when admitted to hospital, followed by RFA 3 days after TACE. All TACE and RFA were performed by the same team of doctors. Seven days after the first TACE, patients started taking continuous sorafenib 400 mg bid without breaks until unacceptable toxicities or disease progression. The response to treatment, overall survival (OS), time to progression (TTP), and adverse effects were evaluated. The disease control rate was 33.3% by RECIST criteria. The median TTP was 15.3 months (95% CI 4.8-23.5). The median OS was 28.8 months (95% CI 12.8-39.6). At the time of data record, 13 patients (43.3%) were dead. Median OS in patients with or without portal vein thrombosis was 12.3 months (95% CI 7.6-14.5) and 30.2 months (95% CI 24.2-34.5), respectively, P = 0.018. The most common adverse events related to sorafenib were hand-foot skin reaction (53.3%) and diarrhea (33.3%). The combination of sorafenib, TACE, and RFA proved both safe and effective in the treatment for unresectable hepatocellular carcinoma patients.

Roles played by chemolipiodolization and embolization in chemoembolization for hepatocellular carcinoma: single-blind, randomized trial.

BACKGROUND: The aim of our study was to compare the efficacy and safety of: 1) transarterial chemolipiodolization with gelatin sponge embolization vs chemolipiodolization without embolization, and 2) chemolipiodolization with triple chemotherapeutic agents vs epirubicin alone. METHODS: A single-blind, three parallel arm, randomized trial was conducted at three clinical centers with patients with biopsy-confirmed unresectable hepatocellular carcinoma. Arm 1 received triple-drug chemolipiodolization and sponge embolization, whereas Arm 2 received triple-drug chemolipiodolization only. Patients in arm 3 were treated with single-drug chemolipiodolization and sponge embolization. We compared overall survival and time to progression. Event-time distributions were estimated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: From July 2007 to November 2009, 365 patients (Arm 1: n = 122; Arm 2: n = 121; Arm 3: n = 122) were recruited. The median tumor size was 10.9cm (range = 7-22cm), and 34.5% had macrovascular invasion. The median survivals and time to progression in Arm 1, Arm 2, and Arm 3 were 10.5 and 3.6 months, 10.1 and 3.1 months, and 5.9 and 3.1 months, respectively. Survival was statistically significantly better in Arm 1 than in Arm 3 (P < .001), whereas there was no statistically significant difference between Arm 1 and Arm 2 (P = .20). Objective response rates were 45.9%, 29.7%, and 18.9% for Arm 1, Arm 2, and Arm 3, respectively. CONCLUSIONS: Chemolipiodolization played an important role in transarterial chemoembolization, and the choice of chemotherapy regimen may largely affect survival outcomes. However, the removal of embolization from chemoembolization might not statistically significantly decrease survival.

[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.

[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.

[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.

[Transarterial oily chemoembolization combined with interstitial laser thermotherapy for treatment of hepatocellular carcinoma].

OBJECTIVE: To evaluate the therapeutic effects and adverse effects of transarterial oily chemoembolization combined with interstitial laser thermotherapy (TOCE+ILT) in the treatment of hepatocellular carcinoma. METHODS: Totally 120 patients with hepatocellular carcinoma were randomized into two groups and received interventions with TOCE+ILT or TOCE combined with percutaneous ethanol injection (TOCE+PEI). The treatment was repeated when necessary until the tumor was completely ablated, after which the therapeutic effects were evaluated and the patients were the followed up for observing long-term clinical outcome. RESULTS: Of the 120 patients enrolled in this observation, 105 were followed up for two years (54 in TOCE+ILT group and 51 in TOCE+PEI group). The complete tumor necrosis rate of TOCE+ILT group was significantly higher than that of the TOCE+PEI group (84.8% vs 73.9%,Chi(2)=4.405, P=0.036), and TOCE+ILT was associated with a significantly higher negative conversion rate of AFP positivity (77.8% vs 56.1%, Chi(2)=4.592, P=0.032). The 1-year survival rate were similar between two groups, but the 2-year survival rate was significantly higher in patients with TOCE+ILT (79.6% vs 60.8%, Chi(2)=4.477, P=0.034). The hepatic function was comparable between the two groups before treatment, and 1 week after treatment, the ALT level in patients undergoing TOCE+ILT was significantly lower than that in patients with TOCE+PEI (95.90-/+56.06 U/L vs 116.31-/+45.27 U/L, t=2.04, P=0.043). Post-embolization syndrome was observed in the patients in two groups, but no severe adverse events were found. CONCLUSION: TOCE+ILT has good therapeutic effects and mild side effects in the treatment of hepatocellular carcinoma.