INTRODUCTIONThe advent of prostate specific antigen (PSA) has resulted in an increased incidence of early detection of prostate cancer recurrence. Patients treated with androgen deprivation therapy (ADT) become hormone-resistant after 18 to 24 months. In patients with biochemical failure, where there is a rise in PSA but no objective evidence of metastases, or in whom there are small volume metastases but who are asymptomatic, there is no standard of care after ADT. Ketoconazole, an antimycotic which affects the synthesis of androgens and other steroids, has shown direct cytotoxic effects in prostate cancer cell lines in in-vitro studies. This study describes our experience with ketoconazole treatment for hormone refractory prostate cancer (HRPC).

MATERIALS AND METHODSA retrospective study of HRPC patients given ketoconazole at the National Cancer Centre and The Cancer Institute from 2004 to 2005 was performed. All eligible patients had histologically proven adenocarcinoma of the prostate and a rising PSA level despite ADT with orchidectomy or luteinising hormone-releasing hormone (LHRH) agonist therapy. All patients received 200 mg of ketoconazole thrice daily. Response was defined as a decline in PSA of at least 50% from the pre-treatment level and confirmed by a second PSA value 4 or more weeks later. The endpoints evaluated were the presence and duration of a response and the toxicity profile of the treatment.

RESULTSA total of 32 patients with HRPC were treated with ketoconazole. Twelve (38%) of the 32 patients had a greater than 50% decrease in their PSA values. The median duration of response was 6.75 months. The median time to reach PSA nadir was 3.5 months. Five patients continue to exhibit progression-free response at the time of writing. Ketoconazole was generally well tolerated. Eighteen (56%) patients recorded mild toxicities related to ketoconazole. There were no grade 3 or 4 toxicities.

CONCLUSIONSLow-dose ketoconazole bridges the gap in the continuum of treatment for patients who have failed ADT and in whom cytotoxic chemotherapy would have a significant impact on the quality of life. Its good toxicity profile, low cost and ease of administration makes it a viable option for this group of patients.

Adenocarcinoma ; Aged ; Aged, 80 and over ; Androgen Antagonists ; administration & dosage ; therapeutic use ; Androgens ; biosynthesis ; Humans ; Ketoconazole ; administration & dosage ; pharmacology ; Male ; Middle Aged ; Prostate-Specific Antigen ; Prostatic Neoplasms ; drug therapy ; Retrospective Studies ; Singapore

INTRODUCTIONDengue (DEN) is a mosquito-borne viral disease which has become an increasing economic and health burden for the tropical and subtropical world. Plasma leakage is the most life threatening condition of DEN and may lead to hypovolaemic shock if not properly managed.

MATERIALS AND METHODSWe recently reported a unique dengue virus strain (D2Y98P) which upon intraperitoneal (IP) administration to immunocompromised mice led to systemic viral dissemination, intestine damage, liver dysfunction, and increased vascular permeability, hallmarks of severe DEN in patients (Tan et al, PLoS Negl Trop Dis 2010;4:e672).

RESULTSHere we report the clinical manifestations and features observed in mice subcutaneously (SC) infected with D2Y98P, which is a route of administration closer to natural infection. Similar to the IP route, increased vascular permeability, intestine damage, liver dysfunction, transient lymphopenia (but no thrombocytopenia) were observed in the SC infected mice. Furthermore, the SC route of infection was found more potent than the IP route whereby higher viral titers and earlier time-of-death rates were measured. In addition, various staining approaches revealed structurally intact blood vessels in the moribund animals despite pronounced systemic vascular leakage, as reported in dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) patients. Interestingly, measurement of soluble mediators involved in vascular permeability indicated that vascular leakage may occur at an early stage of the disease, as proposed in DEN patients.

CONCLUSIONWe believe that this novel mouse model of DEN-associated vascular leakage will contribute to a better understanding of DEN pathogenesis and represents a relevant platform for testing novel therapeutic treatments and interventions.

Animals ; Capillary Permeability ; Dengue ; physiopathology ; Dengue Virus ; pathogenicity ; Disease Models, Animal ; Immunocompromised Host ; Mice ; Severe Dengue ; physiopathology