Adjuvant icotinib versus observation in patients with completely resected EGFR-mutated stage IB NSCLC (GASTO1003, CORIN): a randomised, open-label, phase 2 trial.

Background: This phase 2 trial aimed to compare adjuvant icotinib with observation in patients with epidermal growth factor receptor (EGFR) mutation-positive resected stage IB non-small cell lung cancer (NSCLC). Methods: We performed a randomised, open-label, phase 2 trial from May 1, 2015 to December 29, 2020 at Sun Yat-sen University Cancer Center in China. Patients with completely resected, EGFR-mutant, stage IB (the 7th edition of TNM staging) NSCLC without adjuvant chemotherapy were randomised (1:1) to receive adjuvant therapy with icotinib (125 mg, three times daily) for 12 months or to undergo observation until disease progression or intolerable toxicity occurred. The primary endpoint was 3-year disease-free survival (DFS). CORIN (GASTO1003) was registered with Clinicaltrials.gov, with the number NCT02264210. Findings: A total of 128 patients were randomised, with 63 patients in the icotinib group and 65 patients in the observation group. The median duration of follow-up was 39.9 months. The three-year DFS was significantly higher in the icotinib group (96.1%, 95% confidence interval [CI], 91.3-99.9) than in the observation group (84.0%, 95% CI, 75.1-92.9; P = 0.041). The DFS was significantly longer in the icotinib group than in the observation group, with a hazard ratio (HR) of 0.23 (95% CI, 0.07-0.81; P = 0.013). The OS data were immature, with three deaths in the observation arm. In the icotinib group, adverse events (AEs) of any grade were reported in 49 patients (77.8%), and grade 3 or greater AEs occurred in four patients (6.3%). No treatment-related deaths occurred. Interpretation: Our findings suggested that adjuvant icotinib improved the 3-year DFS in patients with completely resected EGFR-mutated stage IB NSCLC with a manageable safety profile. Funding: This study was sponsored by Betta Pharmaceutical Co., Ltd.

[Expression of prostaglandin transporter in colorectal cancer tissues and its relationship with clinicopathological features].

OBJECTIVE: To investigate the expression of prostaglandin transporter (PGT) in colorectal cancer (CRC) tissues and its relationship with clinicopathological features. METHODS: The mRNA and protein levels of PGT were determined by real-time PCR, Western blot and immunohistochemical methods in cancer tissues and adjacent normal tissue from 80 patients with colorectal cancer and their relationship with clinicopathological features was analyzed. RESULTS: Compared with the adjacent normal tissue of colorectal cancer, the PGT mRNA relative expression (0.57 ± 0.33 vs. 2.33 ± 1.20) and the PGT protein expression in cancer tissues decreased significantly [PGT/GAPDH 0.45 ± 0.16 vs. 0.78 ± 0.23, integral A 718.7 ± 359.4 vs. 10412.0 ± 6423.3, average A 0.03 ± 0.01 vs. 0.12 ± 0.09, all P<0.01]. Lower mRNA and protein expressions of PGT in colorectal cancer were associated with depth of invasion T3 to T4 and TNM stage III( to IIII( (P<0.01), while not associated with gender, age, tumor location and differentiation degree (all P>0.05). CONCLUSION: Expression levels of PGT mRNA and protein in colorectal cancer tissue are significantly down-regulation. PGT expression is associated with invasion depth and late stages.

Effect of BZG-4000, a novel multi-targeted kinase inhibitor with potent anticancer activity, on a hepatocellular carcinoma xenograft model.

The present study was to synthesize a novel multi-targeted kinase inhibitor and evaluated its anticancer effects on a hepatocellular carcinoma xenograft model. In our study, in vivo efficacy was determined in nude mice bearing HuH7 human HCC xenografts. The mice were randomly divided into the following five groups with the use of a randomization chart (n = 8 in each group): high-dose BZG-4000 group, medium-dose BZG-4000 group, low-dose BZG-4000 group, sorafenib group, and model group. Tumor size measurements included the length (L) and width (W) measured with calipers, and tumor volume was calculated as (LW∧2)/2. Tumor tissues slides were hematoxylin and eosin (HE) stained for histopathological examination. Immunohistochemistry detected CD31 expression, and Western blotting measured VEGF protein expression. We found that when BZG-4000 was administered orally to xenograft HuH7 nude mice, tumor growth was inhibited and significant tumor shrinkage was evident. After oral administration of BZG-4000 at 40 mg/kg/day, the tumor weight and volume were significantly lower than tumors of the sorafenib group. BZG-4000 considerably decreased the expression of CD31 and VEGF in tumors compared to tumors treated with positive control drug. It was concluded that BZG-4000 has the potential to inhibit the tumorigenesis of hepatocellular carcinoma in vivo by decreasing the expression of CD31 and VEGF.

Discovery of potent, orally active compounds of tyrosine kinase and serine/threonine-protein kinase inhibitor with anti-tumor activity in preclinical assays.

Traditional medicines have become the most productive source of leads for drugs development, particularly as anti-cancer agents. Various screening approaches are being applied. Sorafenib, a multikinase inhibitor, is used to treat primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer. A small library of compounds analogous to sorafenib were designed and screened for the treatment of liver cancer. Multiple members of the family in an assay panel of tyrosine kinase family and serine/threonine-protein kinase family, including VEGFR, Abl, Aurora A, p 38, Lck, Src, PDGFR, Flt3, c-RAF, c-KIT, MEK(MAPKK) were selected to test these compounds. Analysis of the selectivity patterns for these compounds shows specificity for many kinase families. IC50 were measured for the selected compounds. Multiple compounds have very similar kinase inhibition profiles of VEGFR, Flt3, FGFR to that of sorafenib. The IC50 of c-RAF of BB1 is lower than sorafenib. The IC50 of c-RAF of BB3-12 is higher than that of sorafenib. For Flt3, IC50 of BB1-4 is less than sorafenib. The IC50 value of KDR of BB1-10 is less than sorafenib. especially against c-RAF, PDGFR, c-KIT, KDR compared to sorafenib. These compounds are potent Raf1 and Flt4 kinase inhibitors.

[Transjugular intrahepatic portosystemic shunt and combination with percutaneous transhepatic or transsplenic approach for the treatment of portal vein thrombosis with or without cavernomatous transformation].

OBJECTIVE: To evaluate retrospectively the feasibility, efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) or percutaneous transhepatic or transsplenic approach to the portal vein with the combination of TIPS for the treatment of patients with portal vein thrombosis with or without cavernous transformation. METHODS: Sixty-five patients with portal vein thrombosis from July 2002 to August 2007 at our hospital were analyzed retrospectively. Indirect portography through superior mesenteric artery was performed to determine the approaches for TIPS procedure. If the intrahepatic portal vein branches were visualized, TIPS was implemented directly from transjugular approach; if the intrahepatic portal vein branches failed to be visualized, an ultrasound-guided percutaneous transhepatic or transsplenic approach was performed to recanalize the thrombosed portal vein initially followed by TIPS placement to reconstruct the portal venous flow. Efficacy and complications were observed and revision and survival rates monitored during the follow-up. RESULTS: TIPS were successfully created in 54 of 65 patients with portal vein thrombosis with a success rate of 83.1%. Among them, TIPS were performed directly in 36 of 40 patients; portal vein recanalization were successfully performed via transhepatic access in 15 of 25 patients, and 3 of remaining 5 who failed the transhepatic approach were successfully done from transsplenic access. Then TIPS placement was accomplished with a success rate of 72.0% (18/25). The success rate in cirrhotic patients was 82.4% (42/51) and it was not significant different from those without cirrhosis 85.7% (12/14) (P = 0.766). While the success rate in the patients with cavernous transformation 71.8% (28/39) showed a significant difference compared to that without cavernous transformation 100% (26/26) (P = 0.002). The success rates in portal vein thrombosis and cavernous transformation with or without cirrhosis were 42.9% (18/42) and 83.3% (10/12) respectively, exhibiting a significant difference (P = 0.021). The mortality rate of 30 days post-operation was 3.7% (2/54). From Day 1 to 63 months follow-up, The incidence rate of hepatic encephalopathy was 27.8% (15/54); revision rate 22.2% (12/54); median survival time 31.4 months. CONCLUSIONS: Conventional TIPS or percutaneous transhepatic or transsplenic approach combined with TIPS for the treatment of portal vein thrombosis with or without cavernous transformation are feasible, safe and effective. It is essential to recanalize the thrombosed portal vein initially followed by TIPS placement to reconstruct the portal venous flow.

[Clinical and epidemiological features of the five kinds of new epileptic syndrome].

OBJECTIVE: To investigate the clinical and epidemiological feature of the five kinds of new epilectically syndrome. METHOD: A retrospective study was conducted, by computer inquiry and manual retrieval, on 5300 patients with complete history records who had been followed up regularly in the epilepsy center of the First Affiliated Hospital of Chongqing University in the past 20 years to discover the cases that could be diagnosed as with the five kinds of new epileptic syndromes. RESULTS: Survey was finished in 4894 of the 5300 patients. Two cases of familial temporal lobe epilepsy, one case of familial partial epilepsy with variable foci, fourteen cases with mesial temporal epilepsy, and five cases with startle-provoked epileptic were discovered. CONCLUSION: Patients with the five kinds of new epileptic syndrome have been discovered in China too. It is beneficial to study the clinical and epidemiological features of those new epileptic syndromes.