the intent-to-treat (ITT) and per protocol populations were analysed. RESULTSThe primary endpoint of the trial was suppression of testosterone to ≤ 0.5 ng/mL at all monthly measurements from day 28 to day 364, thus defining the treatment response. This was achieved by 97.2%, 98.3% and 96.4% of patients in the degarelix 240/ 80 mg, degarelix 240/160 mg and leuprolide groups, respectively (ITT population). At 3 days after starting treatment, testosterone levels were ≤ 0.5 ng/mL in 96.1% and 95.5% of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively, and in none in the leuprolide group. The median PSA levels at 14 and 28 days were significantly lower in the degarelix groups than in the leuprolide group ( P < 0.001). The hormonal side-effect profiles of the three treatment groups were similar to previously reported effects for androgen-deprivation therapy. The s.c. degarelix injection was associated with a higher rate of injectionsite reactions than with the i.m. leuprolide injection (40% vs < 1%; P < 0.001, respectively). There were additional differences between the degarelix and leuprolide groups for urinary tract infections (3% vs 9%. P < 0.01, respectively), arthralgia (4% vs 9%, P < 0.05, respectively) and chills (4% vs 0%, P < 0.01, respectively). There were no systemic allergic reactions. CONCLUSIONSDegarelix was not inferior to leuprolide at maintaining low testosterone levels over a 1-year treatment period. Degarelix induced testosterone and PSA suppression significantly faster than leuprolide; PSA suppression was also maintained throughout the study. Degarelix represents an effective therapy for inducing and maintaining androgen deprivation for up to 1 year in patients with prostate cancer, and has a different mechanism of action from traditional GnRH agonists. Its immediate onset of action achieves a more rapid suppression of testosterone and PSA than leuprolide. Furthermore, there is no need for antiandrogen supplements to prevent the possibility of clinical 'flare' . KEYWORDSadenocarcinoma, prostate neoplasm, gonadotrophin-releasing hormone, prostate-specific antigen, testosterone Study Type -Therapy (RCT) Level of Evidence 1b OBJECTIVETo evaluate the efficacy and safety of degarelix, a new gonadotrophin-releasing hormone (GnRH) antagonist (blocker), vs leuprolide for achieving and maintaining testosterone suppression in a 1-year phase III trial involving patients with prostate cancer. PATIENTS AND METHODSIn all, 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/mL, median prostate-specific antigen, PSA, level 19.0 ng/mL) were randomized and received study treatment. Androgen-deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator's assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intramuscular (i.m.) leuprolide doses of 7.5 mg mont...

Data support the statistically significant prostate specific antigen progression-free survival benefit for degarelix over leuprolide seen during year 1 and the use of degarelix as first line androgen deprivation therapy as an alternative to a gonadotropin-releasing hormone agonist.

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Immediate treatment with 150 mg. bicalutamide daily, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with localized or locally advanced prostate cancer. This benefit must be balanced with the morbidity associated with long-term hormonal therapy. Followup is ongoing to determine potential survival benefits of this treatment approach.

The hydraulic water permeability (LP) of the cell membranes of Necturus gallbladder epithelial cells was estimated from the rate of change of cell volume after a change in the osmolality of the bathing solution . Cell volume was calculated from computer reconstruction of light microscopic images of epithelial cells obtained by the "optical slice" technique. The tissue was mounted in a miniature Ussing chamber designed to achieve optimal optical properties, rapid bath exchange, and negligible unstirred layer thickness . The control solution contained only 80% of the normal NaCl concentration, the remainder of the osmolality was made up by mannitol, a condition that did not significantly decrease the fluid absorption rate in gallbladder sac preparations . The osmotic gradient ranged from 11 .5 to 41 mosmol and was achieved by the addition or removal of mannitol from the perfusion solutions . The Lp of the apical membrane of the cell was 1 .0 X 10-3 CM/S . osmol (Po n, = 0.055 cm/s) and that of the basolateral membrane was 2 .2 X 10-3 Cm/s " osmol (P. = 0.12 cm/s) . These values were sufficiently high so that normal fluid absorption by Necturus gallbladder could be accomplished by a 2 .4-mosmol solute gradient across the apical membrane and a 1 .1-mosmol gradient across the basolateral membrane . After the initial cell shrinkage or swelling resulting from the anisotonic mucosal or serosal medium, cell volume returned rapidly toward the control value despite the fact that one bathing solution remained anisotonic . This volume regulatory response was not influenced by serosal ouabain or reduction of bath NaCl concentration to 10 mM . Complete removal of mucosal perfusate NaCl abolished volume regulation after cell shrinkage . Estimates were also made of the reflection coefficient for NaCl and urea at the apical cell membrane and of the velocity of water flow across the cytoplasm .

No abstract

Degarelix treatment for 1 year resulted in a fast, profound and sustained suppression of testosterone and prostate specific antigen with no evidence of testosterone surge. Degarelix was well tolerated.

Between 1981 and 1986, 279 consecutive patients with clinical stage I (CS1) nonseminomatous germ cell tumors (NSGCT) of the testis underwent pathological staging (PS) with retroperitoneal lymphadenectomy (RPLND). Patients with retroperitoneal metastases (PS2) received adjuvant chemotherapy. The median follow-up time after RPLND was 50 months (range, 30 to 90). Clinical and histopathologic features were registered prospectively and analyzed for association with risk of having PS2, relapse despite pathological stage 1 (PS1) or the combined risk of either event, metastatic disease (MET). Seventy-five (26.9%) of the patients had PS2 disease, and 30 (14.7%) of the 204 PS1 patients relapsed, indicating that at least 105 (37.6%) of this CS1 population had subclinical MET at the time of orchiectomy. Four (1.4%) of the 279 CS1 patients died of testicular cancer. Multivariate analyses showed several variables to be significantly associated with outcome for the CS1 patients; vascular invasion in primary tumor and normal preorchiectomy serum alpha-fetoprotein (Pre-AFP) level indicated PS2 disease. If Pre-AFP was excluded from the model, the absence of teratoma or yolk sac elements in the primary tumor became significant predictors of PS2. Vascular invasion, absence of teratoma, and a short interval between orchiectomy and RPLND indicated increased risk of relapse in PS1 patients. Vascular invasion, normal Pre-AFP, absence of teratoma elements, and a short orchiectomy to RPLND interval were predictive of MET. Our results indicate that prognostic factors useful for stratification of CS1 patients with NSGCT to different treatment options may be established.