Surgical treatment of rectal cancer: results of a strategy for selective preoperative radiotherapy.

AIM: The indications for preoperative adjuvant therapy in rectal cancer are still a subject of debate. The objective of this study was to analyze the results of surgical resection and selective radiotherapy in a group of high-risk patients (Dukes B and C) taken from a series of 148 consecutive patients with rectal cancer. METHODS: All patients with rectal cancer considered for resection during the period 1994-2004 were prospectively included. The policy was to deliver preoperative radiotherapy in cases of fixed or tethered tumors or when imaging predicted T3 tumors with positive circumferential margins. Other tumors were resected without neoadjuvant therapy. All resections were done using the total mesorectal excision (TME) technique. RESULTS: One hundred and forty-eight consecutive patients underwent rectal resection during the study period. A sphincter-saving technique was carried out in 134 patients (90%). No patient was excluded from the analysis. The perioperative mortality was 2/148 (1.5%). Curative surgery was obtained in 135 patients. The 94 patients with a Dukes B or C tumor formed the high-risk group that was the basis of our study. The mean follow-up in this group was 58 months (range 24-120). Twenty patients (21%) received preoperative radiotherapy (PRT) and 74 (79%) underwent surgical resection alone. A positive circumferential margin, defined as one that was < or =1 mm, was found in seven of the 85 patients (8.2%) for whom this measure was available. The actuarial five-year overall survival was 74%. Local recurrence developed in eight patients (8.4%): four in the PRT group (20%), and four in the non-PRT group (5.4%). Only two patients developed an isolated local recurrence. CONCLUSIONS: Preoperative adjuvant therapy can be safely omitted in patients who demonstrate clear circumferential margins on preoperative imaging, provided that adequate surgery is subsequently performed.

Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b.

Germinal activating mutations of FGFR3 are responsible for several forms of dwarfism due to the inhibitory effect of FGFR3 on bone growth. Surprisingly, identical somatic activating mutations have been found at the somatic level in tumours: at high frequency in benign epithelial tumours (seborrheic keratosis, urothelial papilloma) and in low-grade, low-stage urothelial carcinomas, and at a lower frequency in other types of urothelial carcinoma, in cervix carcinoma, and in haematological cancer, multiple myeloma. FGFR3 exists as two isoforms, FGFR3b and FGFR3c, differs in ligand specificity and tissue expression. FGFR3b is the main form in epithelial cells and derived tumours, whereas FGFR3c is the main form in mesenchyme-derived cells and multiple myeloma. Several lines of evidence suggest that mutated FGFR3c has transforming properties. Although mutated FGFR3b is mostly found in benign epithelial tumours or carcinomas of low malignant potential, we present evidence here that mutated FGFR3b is oncogenic. All bladder tumours presenting FGFR3 mutations expressed this receptor more strongly than normal urothelium or non-mutated tumours. NIH-3T3 cells transfected with a mutated form of FGFR3b--FGFR3b-S249C, the most common mutation in bladder tumours--presented a spindle-cell morphology, grew in soft agar and gave rise to tumours when xenografted into nude mice. We identified one line of 17 bladder cell lines tested (MGH-U3) that expressed a mutated form of FGFR3b, FGFR3b-Y375C. We showed using siRNA and SU5402, an FGFR inhibitor, that the tumour properties of MGH-U3 depended on mutated receptor activity. Thus, in two different models, mutated FGFR3b presents oncogenic properties.

Absence of FGFR3 mutations in urinary bladder tumours of rats and mice treated with N-butyl-N-(-4-hydroxybutyl)nitrosamine.

Frequent activating mutations of FGFR3 (fibroblast growth factor receptor 3) are found in human urothelial cell carcinomas, particularly in superficial papillary tumours (in 74%-84% of pTaG1-G2), but not in carcinomas in situ (CIS) and at a low rate in invasive tumours (in 16%-21% of pT1-4). In mice and rats, BBN (N-butyl-N-(4-hydroxybutyl)nitrosamine) specifically induces bladder tumours. In rats, superficial papillary tumours are mostly observed. In mice, tumour progression follows the CIS pathway: CIS are first observed, followed by tumours that invade surrounding muscle. Therefore, we looked for FGFR3 mutations in these two animal models of bladder cancer. Only the FGFR3b isoform is expressed in human urothelium and derived tumours. We identified the FGFR3b isoform in rats for the first time and showed that this is the main isoform expressed in the bladder urothelium and derived carcinomas in mice and rats, as in humans. SSCP and sequence analysis of FGFR3b showed sequence changes (polymorphisms or silent mutations) in four BBN-induced rat and mouse bladder tumours. The absence of activating mutations of FGFR3 in the mouse model was in agreement with the fact that mouse BBN-induced bladder tumour progression mimics the CIS pathway. The absence of FGFR3 mutations in the rat bladder tumours suggests that, at least at the genetic level, rat superficial papillary tumours differ from their human counterparts.