18F-Fluciclovine PET metabolic imaging reveals prostate cancer tumour heterogeneity associated with disease resistance to androgen deprivation therapy.

BACKGROUND: Prostate cancer is highly prevalent worldwide. Androgen deprivation therapy (ADT) remains the treatment of choice for incurable prostate cancer, but majority of patients develop disease recurrence following ADT. There is therefore an urgent need for early detection of treatment resistance. METHODS: Isogenic androgen-responsive (CWR22Res) and castration-resistant (22Rv1) human prostate cancer cells were implanted into the anterior lobes of the prostate in CD-1 Nu mice to generate prostate orthografts. Castrated mice bearing CWR22Res and 22Rv1 orthografts mimic clinical prostate cancer following acute and chronic ADT, respectively. 18F-Fluciclovine (1-amino-3-fluorocyclobutane-1-carboxylic acid) with a radiochemical purity of > 99% was produced on a FASTlab synthesiser. Ki67 staining in endpoint orthografts was studied. Western blot, quantitative RT-PCR and next-generation sequencing transcriptomic analyses were performed to assess the expression levels of amino acid transporters (including LAT1 and ASCT2, which have been implicated for Fluciclovine uptake). Longitudinal metabolic imaging with 18F-Fluciclovine-based positron emission tomography (PET) was performed to study tumour response following acute and chronic ADT. RESULTS: Both immunohistochemistry analysis of endpoint prostate tumours and longitudinal 18F-Fluciclovine imaging revealed tumour heterogeneity, particularly following ADT, with in vivo 18F-Fluciclovine uptake correlating to viable cancer cells in both androgen-proficient and castrated environment. Highlighting tumour subpopulation following ADT, both SUVpeak and coefficient of variation (CoV) values of 18F-Fluciclovine uptake are consistent with tumour heterogeneity revealed by immunohistochemistry. We studied the expression of amino acid transporters (AATs) for 18F-Fluciclovine, namely LAT1 (SLC7A5 and SLC3A2) and ASCT2 (SLC1A5). SLC7A5 and SLC3A2 were expressed at relatively high levels in 22Rv1 castration-resistant orthografts following chronic ADT (modelling clinical castration-resistant disease), while SLC1A5 was preferentially expression in CWR22Res tumours following acute ADT. Additional AATs such as SLC43A2 (LAT4) were shown to be upregulated following chronic ADT by transcriptomic analysis; their role in Fluciclovine uptake warrants investigation. CONCLUSION: We studied in vivo 18F-Fluciclovine uptake in human prostate cancer orthograft models following acute and chronic ADT. 18F-Fluciclovine uptakes highlight tumour heterogeneity that may explain castration resistance and can be exploited as a clinical biomarker.

Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women.

OBJECTIVE: To determine whether transdermal progesterone cream has any effect on vasomotor symptoms, mood, sexual response, cardiovascular lipid levels, or bone mineral metabolic markers. DESIGN: A parallel, double-blind, randomized, placebo-controlled trial comparing the effect of a transdermal cream containing a progesterone (32 mg daily) with a placebo cream. Eighty postmenopausal women in the Menopause Centre at the Royal Hospital for Women, Sydney, were randomly allocated to receive either the progesterone cream or the placebo. They were evaluated using the Greene Climacteric Scale and the Menopause Quality of Life Questionnaire, as well as blood analysis for lipids and bone markers over a period of 12 weeks. Women were prescribed a cream containing either progesterone at 32 mg daily or a placebo cream for a period of 12 weeks. RESULTS: There was no detectable change in vasomotor symptoms, mood characteristics, or sexual feelings, nor was there any change in blood lipid levels or in bone metabolic markers, despite a slight elevation of blood progesterone levels. CONCLUSION: The use of the transdermal route to administer progesterone at 32 mg daily does not seem to allow sufficient hormone to enter the body to achieve a biological effect on lipid levels, bone mineral metabolic markers, vasomotor symptoms, or moods.

Progressive multifocal leukoencephalopathy successfully treated with highly active antiretroviral therapy and cidofovir in an adolescent infected with perinatal human immunodeficiency virus (HIV).

Progressive multifocal leukoencephalopathy is an infectious demyelinating brain disease caused by the JC virus that is associated with significant morbidity and mortality in the immunocompromised host. We report a case of progressive multifocal leukoencephalopathy successfully treated with highly active antiretroviral therapy and cidofovir in an adolescent patient perinatally infected with human immunodeficiency virus (HIV).

Incidence and prevalence of HIV encephalopathy in children with HIV infection receiving highly active anti-retroviral therapy (HAART).

OBJECTIVE: To describe neurologic outcomes in children infected with HIV in the era of highly active anti-retroviral therapy (HAART), including rates of progressive HIV encephalopathy (PHE) and clinical sequelae among PHE survivors. STUDY DESIGN: Neurobehavior and school placement was assessed prospectively in the year 2000 in 126 children infected with HIV. PHE, developmental delay, and attention deficit disorder (ADHD) were the main outcome variables analyzed. Predictors of PHE were assessed in controlled analysis among age-matched controls. RESULTS: The rate of active PHE in 2000 was 1.6% (n = 2), and the prevalence of arrested PHE was 10% (n = 13). Residual motor and cognitive sequelae and need for special education was found in the majority of survivors. PHE relapse occurred in 3 (23%) children with previously arrested PHE. Viral load (VL) was the only significant factor associated with PHE. HIV or PHE was not associated with ADHD. Isolated developmental delay was not associated with HIV. CONCLUSIONS: PHE is an infrequent and reversible complication of HIV infection that responds to HAART and that may relapse if control of the virus is lost. Children with arrested PHE show higher rates of residual neurologic, cognitive, and scholastic impairments compared with children who never had PHE. Children with arrested PHE are the group of children with HIV infection most at risk for PHE, in the form of a relapse.