A series of three dose escalating studies were conducted to investigate the ability of the 17a-hydroxylase/C 17,20 -lyase inhibitor abiraterone acetate, to cause maximum suppression of testosterone synthesis when delivered to castrate and noncastrate males with prostate cancer. Study A was a single dose study in castrate males. Study B was a single dose study in noncastrate males and study C was a multiple dose study in noncastrate males. The drug was given orally in a once-daily dose and blood samples taken to assess pharmacokinetic (PK) parameters and hormone levels in all patients. The study drug was well tolerated with some variability in PKs. Suppression of testosterone levels to o0.14 nmol l À1 was seen in four out of six castrate males treated with a single dose of 500 mg. At 800 mg given days 1 -12 in noncastrate males, target suppression was achieved in three out of three patients, but a two-to threefold increase of Luteinising Hormone (LH) levels in two out of three patients overcame suppression within 3 days. All patients in the multiple dose study developed an abnormal response to a short Synacthen test by day 11, although baseline cortisol levels remained normal. This is the first report of the use of a specific 17a-hydroxylase/ 17,20 -lyase inhibitor in humans. Repeated treatment of men with intact gonadal function with abiraterone acetate at a dose of 800 mg can successfully suppress testosterone levels to the castrate range. However, this level of suppression may not be sustained in all patients due to compensatory hypersecretion of LH. The enhanced testosterone suppression achieved in castrate men merits further clinical study as a second-line hormonal treatment for prostate cancer. Adrenocortical suppression may necessitate concomitant administration of replacement glucocorticoid.

BackgroundIntravesical therapy with Bacillus Calmette-Guérin (BCG) aims to reduce the incidence of tumour recurrence following transurethral resection (TUR) for patients with superficial bladder cancer. ObjectivesThe objective of this review was to compare the incidence of tumour recurrence a er the standard therapy of transurethral resection versus transurethral resection plus intravesical Bacillus Calmette-Guérin.

BackgroundOur prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies.MethodsOverall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed.ResultsWe identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53–0.71], Doc (HR = 0.77, 95% CI 0.68–0.87), ZA + Cel (HR = 0.78, 95% CI 0.62–0.97), ZA + Doc (HR = 0.79, 95% CI 0.66–0.94), Cel (HR = 0.94 95% CI 0.75–1.17) and ZA (HR = 0.90 95% CI 0.79–1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability).ConclusionsUniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Malignant melanoma represents the most common tumour responsible for donor-derived post transplan-tation malignancies. We report the varied presentation and outcome of three graft recipients (two kidney and hepatic) who developed metastatic melanoma following cadaveric organ transplantation from a single multiorgan donor. Two of the recipients presented with symptomatic metastatic lesions and the third patient , despite being carefully monitored, developed evidence of metastatic cutaneous melanoma. Two of the patients died as a direct result of their melanomas. The recipients of corneal and cardiac grafts remain disease-free. We conclude that despite careful screening , donor-derived tumours remain a not uncommon clinical entity. The identification of a lesion in one recipient should prompt immediate examination and investigation of the remaining recipients of multiorgan donations. A 42-year-old Caucasian female who had died in a local hospital from a subarachnoid haemorrhage was the organ donor. The donor HLA type was HLA A: 1,2; B: 60,14; DR: 4,13. The donor had a diagnosis of grade II cervical intraepithelial neoplasia 8 years previously, however , clinical examination was unremarkable at the time of donation. Her family consented for multiorgan trans-plantation including the kidneys, liver, heart and corneas. At the time of organ retrieval no intra-abdominal or in-trathoracic abnormalities were noted and no autopsy was performed. Recipient 1 The recipient of the first kidney, a 55-year-old Caucasian female with a lifelong history of pyelonephritis, had been maintained on haemodialysis for 2 years before transplan-tation. Her tissue type was HLA A: 2,3; B: 7,44; DR: 4,13 and the mismatch was 1 : 2 : 0. Postoperatively she experienced good immediate graft function and received immunosuppression with tacrolimus (Prograf ® , Fujisawa, Osaka, Japan)-based triple therapy (tacrolimus, azathio-prine and prednisolone). No antibody induction therapy was instituted. At 3 months post-transplantation the patient had normal renal function and the protocol renal biopsy performed was reported as normal. However 6 months post-transplantation, the patient had an emergency admission with severe abdominal pain and vomiting. Routine haematological and biochemical investigations were unremarkable as was a plain abdominal X-ray. Upper and lower gastrointestinal endoscopy were performed with no abnormalities visualized. During the admission the patient became increasingly confused , however, the CT scans of the head and thorax and abdomen performed were nondiagnostic. In view of the persisting symptoms a laparoscopy was performed which demonstrated numerous black plaques on the peri-toneal surface of the abdominal wall and on the omentum. Multiple biopsies were taken and the histological examination was compatible with metastatic melanoma. Post-operatively the patient's skin and mucosal surfaces were reexamined but no site of primary melanoma was identified. The antitumour management consisted of the withdrawal of immunosuppression...

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