KIT or a-platelet-derived growth factor receptor (a-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IMsensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase -AXL -in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growtharrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

Background: Normalization of oesophageal acid exposure using high dose proton pump inhibitors in patients who are candidates for ablation therapy has been suggested to be essential for successful Barrett's reversal. However, the success rate for achieving pH normalization has not been determined. Methods: Patients with Barrett's oesophagus (2–6 cm in length) who were found to be eligible for ablation therapy using multipolar electrocoagulation were included in this prospective study. Patients underwent an upper endoscopy to determine Barrett's length and other anatomic characteristics. Biopsies were obtained to rule out dysplasia. Subsequently, patients were treated with omeprazole 40 mg b.d. Twenty‐four hour oesophageal pH monitoring was performed after a mean period of 8.4 ± 0.6 days of therapy. Results: Twenty‐five patients were enrolled into the study. The pH test was abnormal in four (16%) of the study subjects. An additional two (8%) patients had abnormal supine percentage time with pH less than 4. There was no significant difference in oesophageal acid control between patients with long vs. short segment Barrett's oesophagus. Elderly (> 60 years) patients tended to have less acid control than younger (≤ 60 years) patients. Conclusions: Failure of oesophageal acid control in candidates for Barrett's oesophagus reversal on very high dose of proton pump inhibitor is not uncommon. Our study suggests that ambulatory 24‐h oesophageal pH monitoring should be considered in all candidates for Barrett's reversal who are treated with high dose proton pump inhibitor to ensure normalization of oesophageal acid exposure.

Sixty-seven patients with Barrett's esophagus have been prospectively followed over an average of 36 months (range 6 to 76 months) with standardized endoscopic observation and biopsies of the length of columnar epithelium. The initial length of Barrett's epithelium ranged from 1 to 16 cm, mean 5.5 cm. Specialized columnar epithelium was present in 64 of the 67 patients. Patients were treated predominantly with H2-receptor blocker therapy to relieve symptoms. Eighty-two percent of patients had less than a 1-cm change in length per year. The mean rate of change of length was -0.093 cm per year. These results confirm in a relatively large, prospective study that standard antireflux therapy for Barrett's esophagus does not result in consistent reduction in the extent of Barrett's epithelium over a three-year interval.