Outcome of metastatic GIST in the era before tyrosine kinase inhibitors.

BACKGROUND: Treatment of metastatic GIST with imatinib mesylate results in a 2-year survival of approximately 72%. The outcome of patients with metastatic GIST not treated with tyrosine kinase inhibitors is not well defined. METHODS: One hundred nineteen patients with metastatic GIST diagnosed prior to July 1, 1998 (approximately 2 years prior to the use of imatinib for GIST) were identified from an institutional database of patients with pathologically confirmed GIST. Mutational analysis was performed in cases with available tissue. The log rank test and Cox regression models were used to assess prognostic factors. RESULTS: Median survival was 19 months with a 41% 2-year survival and a 25% 5-year survival. Resection of metastatic GIST was performed in 81 patients (68%), while 50 (42%) received conventional chemotherapy. Twelve patients (10%) were eventually started on imatinib. Primary tumor size <10 cm, <5 mitoses/50 HPF in the primary tumor, epithelioid morphology, longer disease-free interval, and surgical resection were independent predictors of improved survival on multivariate analysis. Mutational status did not predict outcome. In patients who underwent resection, the 2 year survival was 53%, and negative microscopic margins also independently predicted improved survival. CONCLUSIONS: Treatment with imatinib appears to improve 2-year survival of metastatic GIST by approximately 20% when compared to surgery alone. The combination of imatinib and surgery for the treatment of metastatic GIST therefore warrants investigation.

Gastrointestinal stromal tumor: 5 years later.

There is now considerable interest in gastrointestinal stromal tumor (GIST) because it can be treated effectively with a targeted molecular agent. The majority of GISTs contain an activating mutation in the KIT protooncogene or, occasionally, in the platelet-derived growth factor-alpha (PDGFRA) gene. Five years ago, imatinib mesylate, a specific molecular inhibitor of the protein products of these 2 genes, was applied to metastatic GIST. Approximately 80% of patients with metastatic GIST benefit from imatinib, although acquired resistance to the agent may develop. For patients with primary GIST, surgery remains the treatment of choice, and whether outcome is improved by adjuvant imatinib is currently under broad investigation. A combination of imatinib therapy and surgery also may be effective in a subset of patients with metastatic or unresectable primary GIST. In this review, the authors summarize the new multimodality approach to GIST. The integration of surgery and molecular therapy in GIST will serve as a prototype for the management of other solid tumors for which targeted agents become available.

Physical interaction between GATA-5 and hepatocyte nuclear factor-1alpha results in synergistic activation of the human lactase-phlorizin hydrolase promoter.

GATA-4, -5, and -6 zinc finger and hepatocyte nuclear factor-1alpha (HNF-1alpha) homeodomain transcription factors are expressed in the intestinal epithelium and synergistically activate the promoter of intestinal genes. Here, we demonstrate that GATA-5 and HNF-1alpha physically associate both in vivo and in vitro and that this interaction is necessary for cooperative activation of the lactase-phlorizin hydrolase promoter. Furthermore, physical association is mediated by the C-terminal zinc finger of GATA factors and the homeodomain of HNF-1alpha. Deletion of HNF-1alpha activation domains or interruption of HNF-1-binding sites in the lactase-phlorizin hydrolase promoter resulted in a complete loss of cooperativity, whereas deletion of GATA-5 activation domains or interruption of GATA-binding sites resulted in a reduction, but not an elimination, of cooperativity. We hypothesize that GATA/HNF-1alpha cooperativity is mediated by HNF-1alpha through its activation domains, which are oriented for high levels of activation through binding to DNA and physical association with GATA factors. These data suggest a paradigm whereby intestine-specific gene expression is regulated by unique interactions among tissue-restricted transcription factors coexpressed in the intestine. Parallel mechanisms in other tissues as well as in Drosophila suggest that zinc finger/homeodomain interactions are an efficient pathway of cooperative activation of gene transcription that has been conserved throughout evolution.