At present, the molecular mechanisms underlying the cytolethal effects induced by K. oxytoca in this study remain unknown. Supplementary Material [Supplemental material] Click here to view. Acknowledgments We thank Susanne H?usler for her assistance in performing the PFGE and Christina Strempfl and Bernadette Neuhold for their technical HTC assistance. This work was financed by the University of Graz, the Medical University of Graz (Hygiene Fonds), and Austrian Science Fund FWF project P18607 (to E.L.Z.). Footnotes Published ahead of print on 6 January 2010. ?Supplemental material for this article may be found at http://jcm.asm.org/.
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract.
In 1998, Hirota et al1 made the seminal discovery that these tumors express the KIT tyrosine kinase and commonly harbor oncogenic mutations in the KIT gene. Subsequently, several investigators reported in vitro evidence of antitumor activity of the small molecule KIT inhibitor imatinib mesylate (Glivec/Gleevec; Novartis Pharma AG, Basel, Switzerland) against KIT mutant cell lines.2,3 These observations led to clinical testing of this agent as a medical therapy for patients who have advanced disease.4-7 When the early trials were underway, laboratory studies revealed significant molecular heterogeneity among GISTs. Notably, 75% to 85% of GISTs had an activating mutation of KIT, 5% to 7% had an activating mutation of the homologous PDGFRA kinase, and approximately 12% to 15% of GISTs did not have a detectable mutation of either kinase.
8-11 Correlative molecular studies in phase I to II studies revealed significant differences in objective response, progression-free survival (ie, time to tumor progression [TTP]), and overall survival (OS) between GISTs with different kinase genotypes. Specifically, the outcomes for patients with KIT exon 11�Cmutant GIST were better than for patients with KIT exon 9�Cmutant GIST or tumors without a detectable KIT mutation.7,8,12 Prospective studies of the relationship between kinase genotype and imatinib response were incorporated into two pivotal phase III trials that were designed to compare 400 mg and 800 mg daily doses of imatinib.13-15 In this study, we examine the correlation between kinase genotype, imatinib dose, and clinical outcomes in 397 patients with GIST from the North American phase III trial.14 Our findings confirmed that KIT exon 11 mutation is a positive predictive factor for objective response, TTP, and OS. This study also provides prognostic data for other GIST genotypes, including those with KIT exon 9 mutation, PDGFRA mutation, and wild-type Cilengitide (WT) status.