Efficacy of adjuvant XELOX and FOLFOX6 chemotherapy after D2 dissection for gastric cancer

AIM: To compare the efficacy of capecitabine and oxaliplatin (XELOX) with 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX6) in gastric cancer patients after D2 dissection. METHODS: Between May 2004 and June 2010, patients in our gastric cancer database who underwent D2 dissection for gastric cancer at the First Affiliated Hospital of Sun Yat-Sen University were retrospectively analyzed. A total of 896 patients were enrolled into this study according to the established inclusion and exclusion criteria. Of these patients, 214 received the XELOX regimen, 48 received FOLFOX6 therapy and 634 patients underwent surgery only without chemotherapy. Overall survival was compared among the three groups using Cox regression and propensity score matchedpair analyses. RESULTS: Patients in the XELOX and FOLFOX6 groups were younger at the time of treatment (median age 55.2 years; 51.2 years vs 58.9 years), had more undifferentiated tumors (70.1%; 70.8% vs 61.4%), and more lymph node metastases (80.8%; 83.3% vs 57.7%), respectively. Overall 5-year survival was 57.3% in the XELOX group which was higher than that (47.5%) in the surgery only group (P = 0.062) and that (34.5%) in the FOLFOX6 group (P = 0.022). Multivariate analysis showed that XELOX therapy was an independent prognostic factor (hazard ratio = 0.564, P < 0.001). After propensity score adjustment, XELOX significantly increased overall 5-year survival compared to surgery only (58.2% vs 44.2%, P = 0.025) but not compared to FOLFOX6 therapy (48.5% vs 42.7%, P = 0.685). The incidence of grade 3/4 adverse reactions was similar between the XELOX and FOLFOX6 groups, and more patients suffered from hand-foot syndrome in the XELOX group (P = 0.018). CONCLUSION: Adjuvant XELOX therapy is associated with better survival in patients after D2 dissection, but does not result in a greater survival benefit compared with FOLFOX6 therapy.

(-)-Epigallocatechin-3-gallate inhibits VEGF expression induced by IL-6 via Stat3 in gastric cancer

AIM: To demonstrate that (-)-Epigallocatechin-3-gallate (EGCG) inhibits vascular endothelial growth factor (VEGF) expression and angiogenesis induced by interleukin-6 (IL-6) via suppressing signal transducer and activator of transcription 3 (Stat3) activity in gastric cancer. METHODS: Human gastric cancer (AGS) cells were treated with IL-6 (50 ng/mL) and EGCG at different concentrations. VEGF, total Stat3 and activated Stat3 protein levels in the cell lyses were examined by Western blotting, VEGF protein level in the conditionedmedium was measured by enzyme-linked immunosorbent assay, and the level of VEGF mRNA was evaluated by reverse transcription polymerase chain reaction (RTPCR). Stat3 nuclear translocation was determined by Western blotting with nuclear extract, and Stat3-DNA binding activity was examined with Chromatin immunoprecipitation (ChIP) assay. IL-6 induced endothelial cell proliferation was measured with 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazoliumbromide assay, in vitro angiogenesis was determined with endothelial cell tube formation assay in Matrigel, and IL-6-induced angiogenesis in vitro was measured with Matrigel plug assay. RESULTS: There was a basal expression and secretion of VEGF in AGS cells. After stimulation with IL-6, VEGF expression was apparently up-regulated and a 2.4-fold increase was observed. VEGF secretion in the conditioned medium was also increased by 2.8 folds. When treated with EGCG, VEGF expression and secretion were dose-dependently decreased. IL-6 also increased VEGF mRNA expression by 3.1 folds. EGCG treatment suppressed VEGF mRNA expression in a dose-dependent manner. EGCG dose-dependently inhibited Stat3 activation induced by IL-6, but did not change the total Stat3 expression. When treated with EGCG or AG490, VEGF expressions were reduced to the level or an even lower level in the tumor cells not stimulated with IL-6. However, PD98059 and LY294002 did not change VEGF expression induced by IL-6. EGCG inhibited Stat3 nucleus translocation, and Stat3-DNA binding activity was also markedly decreased by EGCG. Furthermore, EGCG inhibited IL-6 induced vascular endothelial cell proliferation and tube formation in vitro and angiogenesis in vitro . CONCLUSION: EGCG inhibits IL-6-induced VEGF expression and angiogenesis via suppressing Stat3 activity in gastric cancer, which has provided a novel mechanistic insight into the anti-angiogenic activity of EGCG.

Vagina vasorum dissection during D2 lymphadenectomy for gastric carcinoma

AIM: To explore the relationship between metastasis and vagina vasorum in the progress of gastric carcinoma and to find some facts and references for gastric surgeons. METHODS: One hundred and seven specimens of left or right gastric arteries (55 left and 52 right) were gathered from 59 patients undergoing radical gastrectomy for gastric carcinoma. All the frozen specimens were cut into 3 μm-thick sections and stained with hematoxylin-eosin (HE) and immunohistochemical method separately. Cytokeratin (CK) and mesothelial cells (MC) were stained with immunohistochemical method. Cancer cells inside vagina vasorum were detected and the structure of artery wall was observed under microscope. RESULTS: Metastatic cancer cells or tubercles were found inside vagina vasorum in some stage Ⅲ or Ⅳ specimens, but not in stageⅠor Ⅱ specimens. Tumor cells in vagina vasorum were CK positive in 26 specimens of 14 tumors. Among them, stage Ⅲ was found in 4 specimens of 2 tumors, and stage Ⅳ in 22 specimens of 12 tumors. None of these specimens was positive for MC. The positive rate of CK increased with TNM staging. Compared with the lower part, tumors in the upper and middle parts of stomach were more likely to metastasize into vagina vasorum. CONCLUSION: Vagina vasorum dissection should be performed during D2 lymphadenectomy for TNM stage Ⅲ or Ⅳ gastric carcinoma.

Detection of hMSH2 and hMLH1 mutations in Chinese hereditary non-polyposis colorectal cancer kindreds

AIM： To establish and validate the mutation testing for identification and characterization of hereditary non-polyposis colorectal cancer （HNPCC） in suspected Chinese patients. METHODS： Five independent Chinese kindreds with HNPCC fulfilling the classical Amsterdam criteria were collected. Genomic DNA was extracted after informed consent was obtained. The coding region of hMSH2 and hMLH1 genes was detected by polymerase chain reaction （PCR） and denaturing high-performance liquid chromatography （DHPLC）. Mutations identified in the proband by DHPLC were directly sequenced using a 377 DNA sequencer, analyzed with a basic local alignment tool （BLAST）, and tested in the corresponding family members by direct DNA sequencing. RESULTS： Mutations were identified in two Chinese HNPCC kindreds. One was the missense mutation of hMSH2 c.1808A→G resulting in Asp 603 Gly identified in the proband of the fifth HNPCC （HNPCCS） kindred. In the HNP5 kindred, three family members were found to have this mutation and two of them had colorectal cancer. The other mutation of hMLH1 c.1882A→G was identified in the HNP2 kindred＇s proband, which might be the nonsense mutation analyzed by BLAST. CONCLUSION： Pedigree investigation and mutation testing of hMSH2 and hMLH1 are the practical methods to identify high-risk HNPCC patients in China.

Shock tube study of n-decane ignition at low pressures

Ignition delay times for n-decane/O2/Ar mixtures were measured behind reflected shock waves using endwall pressure and CH＊ emission measurements in a heated shock tube. The initial postshock conditions cover pressures of 0.09-0.26 MPa, temperatures of 1 227-1 536 K, and oxygen mole fractions of 3.9%-20.7% with an equivalence ratio of 1.0. The correlation formula of ignition delay dependence on pressure, temperature, and oxygen mole fraction was obtained. The current data are in good agreement with available low-pressure experimental data, and they are then compared with the prediction of a kinetic mechanism. The current measurements extend the kinetic modeling targets for the n-decane combustion at low pressures.

RAD51 potentiates synergistic effects of chemotherapy with PCI-24781 and cis-diamminedichloroplatinum on gastric cancer

AIM:To explore the efficacy of PCI-24781,a broadspectrum,hydroxamic acid-derived histone deacetylase inhibitor,in the treatment of gastric cancer(GC).METHODS:With or without treatment of PCI-24781and/or cis-diamminedichloroplatinum(CDDP),GC cell lines were subjected to functional analysis,including cell growth,apoptosis and clonogenic assays.Chromatin immunoprecipitation and luciferase reporter assays were used to determine the interacting molecules and the activity of the enzyme.An in vivo study was carried out in GC xenograft mice.Cell culture-based assays were represented as mean±SD.ANOVA tests were used to assess differences across groups.All pairwise comparisons between tumor weights among treatment groups were made using the Tukey-Kramer method for multiple comparison adjustment to control experimental-wise typeⅠ error rates.Significance was set at P<0.05.RESULTS:PCI-24781 significantly reduced the growth of the GC cells,enhanced cell apoptosis and suppressed clonogenicity,and these effects synergized with the effects of CDDP.PCI-24781 modulated the cell cycle and significantly reduced the expression of RAD51,which is related to homologous recombination.Depletion of RAD51 augmented the biological functions of PCI-24781,CDDP and the combination treatment,whereas overexpressing RAD51 had the opposite effects.Increased binding of the transcription suppressor E2F4 on the RAD51 promoter appeared to play a major role in these processes.Furthermore,significant suppression of tumor growth and weight in vivo was obtained following PCI-24781 treatment,which synergized with the anticancer effect of CDDP.CONCLUSION:These data suggest that RAD51 potentiates the synergistic effects of chemotherapy with PCI-24781 and CDDP on GC.

Laser absorption spectroscopy for high temperature H_2O time-history measurement at 2.55 μm during oxidation of hydrogen

Concentration time-histories of H20 were measured behind reflected shock waves during hydrogen combustion. Experiments were conducted at temperatures of 1117-1282 K, the equivalence ratios of 0.5 and 0.25, and a pressure at 2 atm using a mixture of H2/O2 highly diluted with argon. H2O was monitored using tunable mid-infrared diode laser absorption at 2.55 μm （3920.09 cm-1）. These time-histories provide kinetic targets to test and refine reaction mechanisms for hydrogen. Comparisons were made with the predictions of four detailed kinetic mechanisms published in the last four years. Such comparisons of H2O concentration profiles indicate that the AramcoMech 2.0 mechanism yields the best agreement with the experimental data, while CRECK, San Diego, and HP-Mech mechanisms show significantly poor predictions. Reaction pathway analysis for hydrogen oxidation indicates that the reaction H ＋ OH ＋ M = H20 ＋ M is the key reaction for controlling the H2O formation by hydrogen oxidation. It is inferred that the discrepancy of the conversion percentage from H to H20 among these four mechanisms induces the difference of performance on H2O time-history predictions. This work demonstrates the potential of time-history measurement for validation of large reaction mechanisms.