Previous karyotyping showed a combined trisomy of chromosome 7 and 17 in sporadic and hereditary papillary renal cell tumours (RCT). A recent molecular analysis revealed a mutation in the MET tyrosine kinase (chromosome 7q31) in the germline of four out of seven families with hereditary papillary RCT (HPRCT). We have analysed germline cells as well as multiple tumours obtained from HPRCT families and sporadic cases for alteration of the MET tyrosine kinase and for allelic duplication at chromosome 7 and 17. We have detected a germ line mutation in the MET tyrosine kinase in one of the two families with HPRCTs and also found the same mutation in the germ line of one patient with clinically recognized multiple, bilateral papillary RCTs but without family history. The mutant MET allele is consequently duplicated and overexpressed in tumour cells indicating that duplication of the mutant MET allele is necessary before cells enter the tumorigenic pathway. The lack of germline mutation in two members of another HPRT family and duplication of the same parental allele of chromosome 7 in multiple tumours suggests that a germ line event other than mutation of MET tyrosine kinase is involved in the development of these tumours. Duplication of di erent alleles of chromosome 7 in sporadic and of chromosome 17 in both types of tumours excludes a germline mutation at these chromosomal sites.

OBJECTIVE To assess the feasibility and activity of a neoadjuvant treatment combining a luteinizing hormone‐releasing hormone (LHRH)‐analogue, estramustine and docetaxel before radical retropubic prostatectomy (RRP) in patients with high‐risk prostate cancer. PATIENTS AND METHODS High‐risk patients were defined as clinical stage ≥T3 and/or a prostate‐specific antigen (PSA) level of ≥15 ng/mL, and/or biopsy a Gleason sum of ≥8. Patients received LHRH analogue treatment until the PSA nadir (a stable PSA level for two consecutive determinations) and then, continuing hormone therapy, a combined regimen of estramustine and docetaxel. Patients had RRP within a month of completing the neoadjuvant regimen. All patients were assessed for toxicity and surgical complications. A clinical response was defined as complete (CR, the disappearance of all palpable and radiological abnormalities and a decline in PSA level of ≥90%) or partial (PR, a decline in PSA level of half or more with stable or improved palpable and/or radiological abnormalities). A pathological response was defined as ‘complete’ (undetectable cancer), ‘substantial’ (residual cancer in ≤10% of the surgical specimen) or ‘minimal’ (residual cancer in >10% of the surgical specimen). The biomarkers p53, bcl‐2, MIB1, erbB2 and factor VIII were also evaluated. RESULTS Of 22 patients enrolled between March 1999 and January 2002, 21 (mean age 63 years; mean PSA level 61 ng/mL; median biopsy Gleason sum 8) completed the neoadjuvant therapy. The clinical stage was organ‐confined in three patients (15%); five (25%) had pelvic lymphadenopathy on computed tomography. The neoadjuvant treatment was well tolerated, with only one grade 2 toxicity (Eastern Cooperative Oncology Group grading). All PSA values decreased by >90% from baseline after hormonal therapy only, and the mean reduction from before to after chemotherapy was statistically significant (P = 0.001). Three patients (15%) had a CR, 16 (80%) had a PR and one (5%), with sarcomatoid tumour, had progression; 19 had non‐nerve‐sparing RRP and there were no major complications during or after RRP. The pathological assessment showed that one patient (5%) had no tumour (pT0) and six (32%) had a ‘substantial’ response. The overall rate of organ‐confined disease was 58%, vs a mean 8% predicted likelihood from the Kattan nomogram. Five patients (26%) had positive surgical margins and four (21%) had positive lymph nodes. At a median follow‐up of 53 months, eight patients (42%) were disease‐free. Organ‐confined disease (P = 0.022), residual cancer at pathology in ≤10% of the surgical specimen (P = 0.007) and no seminal vesicle invasion (P = 0.001) correlated with disease‐free survival. CONCLUSION A neoadjuvant chemohormonal regimen before RRP is feasible and active in patients with high‐risk prostate cancer. The rate of pathological organ‐confined disease was higher than expected and responding patients had an 85% disease‐free survival rate at 5 years.

Introduction: To identify risk factors for biochemical failure after radical prostatectomy (RP) in men with pathologically organ-confined (OC) prostate cancer (PCa). Materials and Methods: Clinical and pathological features of 350 consecutive patients with pathologically OC PCa treated only with RP and bilateral pelvic lymphadenectomy were analyzed, retrospectively, to identify predictor parameters of prostate-specific antigen (PSA) failure (PSA ≧0.4 ng/ml). The median follow-up was 58.6 months (range: 3.9–183 months). All pathological specimens were step sectioned at 4-mm intervals. Kaplan-Meier progression-free survival rates and χ² test were adopted for statistical analyses. Multivariate Cox proportional hazard regression models were used to test the association between pathological Gleason score and surgical margin status. Results: 67 patients (19.1%) failed at a median follow-up of 40.2 months (range 1.9–123.3). Age and preoperative PSA failed to reveal significance also in patients with serum PSA ≧20 ng/ml (p = 0.46). Patients with T3 clinical stage had a higher progression rate compared to T1C and T2 (43.5 vs. 27.8 and 17.3%, respectively) even if no high statistical significance was pointed out. Presence of perineural infiltration (p = 0.04) and prostatic apex infiltration (p = 0.74) in the prostatectomy specimens failed to reveal significance. A high pathological Gleason score (≧7; p = 0.0003) and surgical margin status (p < 0.0001) were shown to be the most powerful predictive parameters of biochemical progression. Conclusions: In patients with pathologically OC PCa the presence of a high pathological Gleason score and positive surgical margins appear to represent the most important factors for prediction of outcome following RP.

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