The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.

CRKL has previously been shown to be a major tyrosine phosphorylated protein in neutrophils of patients with BCR-ABL+ chronic myelogenous leukemia and in cell lines expressing BCR-ABL. CRKL and BCR-ABL form a complex as demonstrated by coimmunoprecipitation and are capable of a direct interaction in a yeast two-hybrid assay. We have mapped the site of interaction of CRKL and BCR-ABL to the amino terminal SH3 domain of CRKL with a proline rich region in the C-terminus of ABL. The proline-rich region was mutated and the effect of this deletion on BCR-ABL transforming function was assayed. Our data show that this deletion does not impair the ability of BCR-ABL to render myeloid cells factor independent for growth. In cells expressing the proline deletion mutation of BCR-ABL, CRKL is still tyrosine phosphorylated and forms a complex with BCR-ABL as demonstrated by coimmunoprecipitation. Our data suggest that the interaction between CRKL and the proline deletion mutant of BCR-ABL is an indirect interaction as CRKL does not interact directly with the proline deletion mutant of BCR-ABL in a gel overlay assay or in a yeast two-hybrid assay. Thus, a direct interaction of CRKL and BCR-ABL is not required for CRKL to become tyrosine phosphorylated by BCR-ABL and suggests that CRKL function may still be required for BCR-ABL function through an indirect interaction.

Tests for evaluating incontinence include endoanal ultrasound (EUS) and anorectal manometry. We hypothesized that EUS would be superior to anorectal manometry in identifying the subset of patients with surgically correctable sphincter defects leading to an improvement in clinical outcome in these patients. The purpose of this study was to compare these 2 techniques to determine which is more predictive of outcome for fecal incontinence. Thirty-five unselected patients with fecal incontinence were prospectively studied with EUS and anorectal manometry to evaluate the internal anal sphincter (IAS) and external anal sphincter (EAS). EUS was performed with Olympus GFUM20 echoendoscope and a hypoechoic defect in the EAS or IAS was considered a positive test. Anorectal manometry was performed with a standard water-perfused catheter system. A peak voluntary squeeze pressure of < 60 mm Hg in women and 120 mm Hg in men was considered a positive test. All patients were administered the Cleveland Clinic Continence Grading Scale at baseline and at follow-up. Improvement in fecal control was defined as a 25% or greater decrease in continence score. EUS versus manometry were compared with subsequent surgical treatment and outcome. P-values were calculated using Fisher's exact test. Patients (n = 32; 31 females) were followed for a mean 25 months (range 13-46). Sixteen patients had improved symptoms (50%). There was no correlation between EUS or anorectal manometry sphincter findings and outcome. Seven of 14 (50%) patients who subsequently underwent surgery versus 9 of 18 (50%) without surgery improved (P = .578). In long-term follow-up, approximately half of patients improve regardless of the results of EUS or anorectal manometry, or whether surgery is performed.

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