Combined low‐dose flutamide plus finasteride vs low‐dose flutamide monotherapy for recurrent prostate cancer: a comparative analysis of two phase II trials with a long‐term follow‐up

OBJECTIVE

To compare the efficacy and tolerability of peripheral androgen blockade using combined low‐dose flutamide plus finasteride vs low‐dose flutamide monotherapy for treating biochemical relapse after the definitive management of prostate adenocarcinoma.

PATIENTS AND METHODS

Fifty‐six men treated for biochemical relapse of prostate cancer were enrolled prospectively in a phase II trial at the Walter Reed Army Medical Center from 1997 to 2001. Thirty‐six men were treated with flutamide (125 mg twice daily) and finasteride (5 mg twice daily), and 20 men received low‐dose flutamide only after biochemical recurrence (prostate‐specific antigen, PSA, level ≥0.4 ng/mL). Cox proportional hazards analyses were used to compare the risk of progression between the groups.

RESULTS

Patients on combined and monotherapy had a median follow‐up of 54 and 43.5 months, respectively. Seven men (19%) in the combined arm remain in the study with no progression, while five (25%) on monotherapy continue and are progression‐free. Men on combined therapy had a greater decrease in their PSA level (P = 0.002). Multivariate analysis showed that men on combined therapy had significantly less risk of progression than men on monotherapy (hazard ratio 0.21, 95% confidence interval 0.07–0.63, P = 0.005). There was no significant difference in the frequency of side‐effects between the groups. Toxicities were reported to be mild.

CONCLUSIONS

Our analysis suggests the therapeutic value of low‐dose flutamide alone or combined with finasteride as first‐line agents in a possible graduated approach for treating PSA‐only recurrent prostate cancer. Due to unwanted metabolic effects associated with traditional hormonal agents, phase III trials comparing both regimens with current therapies are warranted.     

Activation marker expression and apoptotic susceptibility of T-cell clones derived from CD34(+), young and SENIEUR donors

T-cell clones (TCC) derived from human peripheral blood lymphocytes of a young control, a healthy elderly (SENIEUR) donor, or from CD34(+) hematopoietic progenitor cells were utilised in this study to examine how in vivo and in vitro ageing affects T-cell apoptotic capability. The role of CD25, CD28 and the intracellular proteins, FLICE-inhibitory protein (FLIP), receptor-interacting protein (RIP) and caspase 3 were investigated. We observed an age-related decline in the expression of the IL-2 receptor alpha chain CD25, and absence of the co-stimulatory receptor CD28 on three of the four TCC studied. In young donor- and CD34 cell-derived TCC, but not in SENIEUR donor-derived TCC, we observed an age-related increase in susceptibility of the cells to mFas-L-induced apoptosis, which correlated with the age-related decrease of CD25 expression. Expression levels of full-length RIP and FLIP did not show any correlation to apoptotic susceptibility. However, expression levels of the cleaved form of RIP were greatly reduced in the SENIEUR donor-derived TCC, which together with a trend towards increased caspase 3 activity, could indicate an age-related alteration in utilisation of different apoptotic signalling pathways.     

Likelihood of residential aged care use in later life: a simple approach to estimation with international comparison

Objectives: In New Zealand (NZ), place of death among decedents aged 65+ years has been reported as residential aged care (RAC, 38%), acute hospital (34%) or elsewhere (28%). However, lifetime risk of use of RAC (or nursing homes) is unknown. A simple method of estimation is demonstrated for NZ and Australia, with comparisons to other countries. Methods: Deaths of RAC residents in acute hospitals were estimated for NZ from four separate studies and added to deaths occurring in RAC, to derive the likelihood of using RAC after age 65 years. Academic and other sources were searched for comparative reports. Results: An estimated 18% of RAC residents died in acute hospital in NZ. When added to those who died in RAC, the proportion using RAC for late‐life care was estimated at over 47% (66% if aged 85+ years). Of 12 US reports, the median report was 41%. Elsewhere, Finland was 47%, UK 28%, Australia 34% to 53%, and Germany 22% & 26%. Conclusions: Simple estimation using existing data demonstrates that RAC in late life is common. Implications: Late‐life care services will continue to evolve. Monitoring RAC utilisation is necessary for informed debate about palliative care provision in RAC, use of hospital by RAC residents and for planning and policy setting.     

Mechanism of decongestant activity of alpha 2-adrenoceptor agonists

The vascular bed in nasal mucosa of different species, including human, is highly vascularized and an extensive sinusoidal network of large capacitance vessels is present deep within the submucosa. When this network of venous sinusoids is engorged with blood, the swollen mucosa reduces the size of the airway lumen and congestion ensues. Nasal vasculature tone is strongly influenced by the sympathetic nervous system and the only drugs approved specifically to relieve vascular nasal obstruction are alpha-adrenoceptor sympathomimetic agents. Due to their vasoconstrictor action, the sympathomimetic decongestants oppose vasodilation, reducing nasal airway resistance and thus facilitating nose breathing. However, standard decongestants that are non-selective alpha-adrenoceptor agonists are associated with the potential for side-effect liabilities including hypertension, stroke, insomnia and nervousness. We propose than a selective alpha 2-adrenoceptor agonist, by acting preferentially on nasal venous capacitance vessels, will elicit decongestion with a reduced side-effect liability. In the present study, we evaluated the effects of the selective alpha 2-adrenoceptor agonist BHT-920 in a real-time tissue contractility assay using isolated pig nasal explants and in an in vivo cat model of congestion. The vasoconstrictor and decongestant effects of BHT-920 were compared to the non-selective alpha-adrenoceptor agonist epinephrine and the standard decongestant oxymetazoline. Our results showed that the alpha 2-adrenoceptor agonist BHT-920 preferentially contracts venous sinusoids confirming previous observations [Corboz MR, Varty LM, Rivelli MA, Mutter JC, Mingo G, McLeod R, et al. Effects of an alpha 2-adrenoceptor agonist in nasal mucosa. Arch Physiol Biochem 2003;11: 335-6, Corboz MR, Rivelli MA, Varty LM, Mutter J, Cartwright M, Rizzo CA, et al. Pharmacological characterization of postjunctional alpha-adrenoceptor in human nasal mucosa. Am J Rhinol 2005;19: 495-502] and displays decongestion without affecting blood pressure. Therefore, an alpha 2-adrenoceptor agonist, by causing constriction in the capacitance vessels of nasal mucosa, can produce nasal decongestion without the effects on blood pressure observed with the standard selective alpha 1-adrenoceptor and non-selective alpha-adrenoceptor sympathomimetic decongestants.     

In vivo metabolism of the designer anabolic steroid hemapolin in the thoroughbred horse

Hemapolin (2α,3α‐epithio‐17α‐methyl‐5α‐androstan‐17β‐ol) is a designer steroid that is an ingredient in several “dietary” and “nutritional” supplements available online. As an unusual chemical modification to the steroid A‐ring could allow this compound to pass through antidoping screens undetected, the metabolism of hemapolin was investigated by an in vivo equine drug administration study coupled with GC‐MS analysis. Following administration of synthetically prepared hemapolin to a thoroughbred horse, madol (17α‐methyl‐5α‐androst‐2‐en‐17β‐ol), reduced and dihydroxylated madol (17α‐methyl‐5α‐androstane‐2β,3α,17β‐triol), and the isomeric enone metabolites 17β‐hydroxy‐17α‐methyl‐5α‐androst‐3‐en‐2‐one and 17β‐hydroxy‐17α‐methyl‐5α‐androst‐2‐en‐4‐one, were detected and confirmed in equine urine extracts by comparison with a library of synthetically derived reference materials. A number of additional madol derivatives derived from hydroxylation, dihydroxylation, and trihydroxylation were also detected but not fully identified by this approach. A yeast cell‐based androgen receptor bioassay of available reference materials showed that hemapolin and many of the metabolites identified by this study were potent activators of the equine androgen receptor. This study reveals the metabolites resulting from the equine administration of the androgen hemapolin that can be incorporated into routine GC‐MS antidoping screening and confirmation protocols to detect the illicit use of this agent in equine sports.     

Towards a consensus for classification of mandibular condyle fractures

The merits of surgical treatment of fractures of the mandibular condyle versus non-surgical management remains highly controversial, despite a large volume of literature dedicated to this topic. One reason the controversy remains, is because most of the outcomes in the literature are not directly comparable. The disparate range of condylar fracture classifications used is one of the reasons that studies are not comparable. We sought to review classification systems for condylar fractures used in the recent scientific literature.Review of the literature from 2016 to 2019, looking for papers relating to fractures of the mandibular condyle. Papers identified were assessed for type of study, focus of study, classification system used.88 studies were identified, including prospective and retrospective cohort studies, randomised and non-randomised prospective studies, randomised controlled trials and case series. More studies focussed on epidemiological factors than surgical access, fixation or outcomes. 31 used no classification system, whilst 17 used unique classification systems and 40 used previously referenced classification systems.Classification systems are used to help separate clinical problems into distinguishable groups, where there is a difference in management or outcome depending on the distinguishing features.There is currently a wide diversity of classification systems used for condyle fractures, and as a result, comparisons of surgical access, fixation and outcomes are difficult to make. Having a single classification system across the published literature would allow easier comparison and the classification proposed by the AO group is recommended for future use.