SummaryResearchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras incolorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. © 2001 Cancer Research Campaign http://www.bjcancer.comIt is widely accepted that mutations in the Kirsten ras (Ki-ras) gene in patients with colorectal cancer develop early in the progression from adenoma to carcinoma. Our first collaborative study including 2721 patients, clarified that Ki-ras mutations are not only 692

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Transgenic mice expressing either the neu proto-oncogene or transforming growth factor (TGF-␣) in the mammary epithelium develop spontaneous focal mammary tumors that occur after a long latency. Since the epidermal growth factor receptor (EGFR) and Neu are capable of forming heterodimers that are responsive to EGFR ligands such as TGF-␣, we examined whether coexpression of TGF-␣ and Neu in mammary epithelium could cooperate to accelerate the onset of mammary tumors. To test this hypothesis, we interbred separate transgenic strains harboring either a mouse mammary tumor virus/TGF-␣ or a mouse mammary tumor virus/neu transgene to generate bitransgenic mice that coexpress TGF-␣ and neu in the mammary epithelium. Female mice coexpressing TGF-␣ and neu developed multifocal mammary tumors which arose after a significantly shorter latency period than either parental strain alone. The development of these mammary tumors was correlated with the tyrosine phosphorylation of Neu and the recruitment of c-Src to the Neu complex. Immunoprecipitation and immunoblot analyses with EGFR-and Neu-specific antisera, however, failed to detect physical complexes of these two receptors. Taken together, these observations suggest that Neu and TGF-␣ cooperate in mammary tumorigenesis through a mechanism involving Neu and EGFR transactivation.

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The current study was undertaken to determine the effect of chronic urinary diversion on both the morphology and absorptive function of intestine. Adult female Wistar rats (N = 8) underwent urinary diversion by interposing a 10-12 cm. segment of distal ileum between the bladder and sigmoid colon following urethral ligation. Control animals (N = 8) underwent sham laparotomies. Three months later, the diverted segment and a 10-12 cm. segment of distal ileum in control animals were studied. The intestinal segments were studied morphologically by both light microscopy and transmission electron microscopy. By using a previously reported in vivo intestinal perfusion model, the transport properties of the intestinal segments were examined. There were prominent and consistent morphological alterations in the diverted segments when compared with normal ileum. These changes consisted of marked mucosal atrophy evidenced by loss of microvilli with decreased villi-to-crypt ratio in diverted segments. Diverted ileum secreted more sodium and absorbed less chloride than normal ileum though this difference was not statistically significant. Water flux into the intestinal lumen was higher in diverted bowel (p = .06). The absorption of ammonium, potassium, and urea, as well as bicarbonate secretion, was the same in the diverted ileum as in normal ileum. There was also no significant difference in pH change or osmolar flux between the two groups. In conclusion, the results of this study indicate that despite morphological changes as a result of chronic exposure of urine, intestinal segments continue to transport urinary solutes similar to normal nondiverted segments. This represents the first convincing evidence that the reason for the low incidence of metabolic alterations following urinary diversion is not due to decreased absorptive capacity of the intestinal mucosa.