BackgroundIn the AVAGAST study, fluoropyrimidine and cisplatin plus bevacizumab did not significantly improve overall survival (OS) versus fluoropyrimidine and cisplatin plus placebo in patients with advanced gastric cancer. Geographic differences in efficacy were observed in AVAGAST, but the study only included 12 Chinese patients. AVATAR, a study similar in design to AVAGAST, was a randomized, double-blind, phase III study conducted in Chinese patients with advanced gastric cancer.MethodsPatients more than 18 years of age with gastric adenocarcinoma were randomized 1:1 to capecitabine–cisplatin plus either bevacizumab or placebo. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS) and safety.ResultsIn total, 202 patients were included (placebo n = 102; bevacizumab n = 100). Baseline characteristics were well balanced. The primary analysis result did not show a difference in OS for the bevacizumab arm compared to the placebo arm [hazard ratio, 1.11 (95 % CI, 0.79–1.56); P = 0.5567]. Median PFS was also similar in both arms. Bevacizumab plus capecitabine–cisplatin was well tolerated. Grade 3–5 adverse events (AEs) occurred in 60 % of bevacizumab-treated and 68 % of placebo-treated patients, respectively. Grade 3–5 AEs of special interest with bevacizumab occurred in 8 % of bevacizumab-treated patients and 15 % of placebo-treated patients, mainly grade 3–5 hemorrhage (bevacizumab 4 %, placebo 12 %).ConclusionsAddition of bevacizumab to capecitabine–cisplatin in Chinese patients with advanced gastric cancer did not improve outcomes in AVATAR. There was no difference in OS between the two arms and PFS was similar in both arms. Safety findings were as previously experienced with bevacizumab, including AVAGAST; no new safety signals were reported.

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5 Background: Trastuzumab (H) + capecitabine/fluorouracil + cisplatin is standard of care for 1st-line HER2-positive MGC/GEJC but there is no established HER2-targeted 2nd-line regimen. T-DM1 (H linked to DM1) is approved for HER2-positive metastatic breast cancer previously treated with H + TAX (separately or in combination). This and preclinical HER2-positive GC models provided the rationale for GATSBY (NCT01641939). Methods: GATSBY is a 3-arm randomized, adaptive, seamless phase 2/3 global study of T-DM1 vs TAX in pts with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization-positive), unresectable LA/MGC/GEJC who progressed during or after 1st-line fluoropyrimidine + platinum ± HER2-targeted therapy. Pts were initially randomized 2:2:1 to T-DM1 3.6 mg/kg every 3 weeks (q3w), T-DM1 2.4 mg/kg weekly (qw), or physician’s choice of paclitaxel 80 mg/m2 qw or docetaxel 75 mg/m2q3w. An independent data monitoring committee selected T-DM1 qw for further study and subsequent patients were randomized 2:1 to this or TAX. The primary endpoint is overall survival (OS); all T-DM1 qw data are analyzed, including dose selection. Results: At clinical cutoff, 06/30/15, 415 pts had been randomized overall: 228 to T-DM1 qw, 117 to TAX (70 T-DM1 q3w pts reported separately); 77.4% had prior HER2-targeted therapy; 29.9% prior gastrectomy; 46.1% were Asian. Efficacy/safety are tabulated. Conclusions: T-DM1 2.4 mg/kg qw did not show an efficacy benefit over TAX. Grade ≥3 AE rates were numerically lower with T-DM1 vs TAX and rates of SAEs, fatal AEs, and treatment discontinuations due to AEs were comparable between arms. Clinical trial information: NCT01641939. [Table: see text]

The complete nucleotide sequence of pRGO1, a cryptic plasmid from Propionibacterium acidipropionici E214, was determined. pRGO1 is 6,868 bp long, and its G؉C content is 65.0%. Frame analysis of the sequence revealed six open reading frames, which were designated Orf1 to Orf6. The deduced amino acid sequences of Orf1 and Orf2 showed extensive similarities to an initiator of plasmid replication, the Rep protein, of various plasmids of gram-positive bacteria. The amino acid sequence of the putative translation product of orf3 exhibited a high degree of similarity to the amino acid sequences of DNA invertase in several bacteria. For the putative translation products of orf4, orf5, and orf6, on the other hand, no homologous sequences were found. The function of these open reading frames was studied by deletion analysis. A shuttle vector, pPK705, was constructed for shuttling between Escherichia coli and a Propionibacterium strain containing orf1 (repA), orf2 (repB), orf5, and orf6 from pRGO1, pUC18, and the hygromycin B-resistant gene as a drug marker. Shuttle vector pPK705 successfully transformed Propionibacterium freudenreichii subsp. shermanii IFO12426 by electroporation at an efficiency of 8 ؋ 10 6 CFU/g of DNA under optimized conditions. Transformation of various species of propionibacteria with pPK705 was also performed at efficiencies of about 10 4 to 10 7 CFU/g of DNA. The vector was stably maintained in strains of P. freudenreichii subsp. shermanii, P. freudenreichii, P. pentosaceum, and P. freudenreichii subsp. freudenreichii grown under nonselective conditions. Successful manipulation of a host-vector system in propionibacteria should facilitate genetic studies and lead to creation of genes that are useful industrially.Propionibacteria, which have a wide range of probiotic activity, are used in making dairy foods, such as cheese, for the production of vitamin B 12 , tetrapyrrole compounds, and propionic acid (8,15,21), in bread baking, as starters for ensilage, and in some pharmaceutical preparations (35). To elucidate the biosynthetic pathways of vitamin B 12 and siroheme in Propionibacterium, we previously identified several genes coding for the enzymes involved in production of tetrapyrrole derivatives (hemYHBXRL) (11,12) and vitamin B 12 (cobA, cbiO) (30).Development of genetic manipulation in propionibacteria has progressed slowly due to a lack of detailed information on the genetics of the bacteria and a lack of an appropriate plasmid that can serve as a possible transformation vector. A number of plasmids from Propionibacterium acidipropionici, P. freudenreichii, and P. jensenii, ranging in size from 4.4 to more than 119 MDa, have been described (19,24). However, neither analysis of a plasmid DNA sequence nor construction of a vector for propionibacteria has been reported. To establish a versatile vector system to facilitate genetic analysis and to allow the transfer of a gene of interest, we investigated the development of a host-vector system in propionibacteria.We succeeded in determining the co...

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