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Refereed/Peer-reviewed Cutaneous melanoma is one of the most aggressive forms of skin cancer, with the development of advanced stage disease resulting in a high rate of patient mortality. Accurate diagnosis of melanoma at an early stage is essential to improve patient outcomes, as this enables treatment before the cancer has metastasised. Histopathologic analysis is the current gold standard for melanoma diagnosis, but this can be subjective due to discordance in interpreting the morphological heterogeneity in melanoma and other skin lesions. Immunohistochemistry (IHC) is sometimes employed as an adjunct to conventional histology, but it remains occasionally difficult to distinguish some benign melanocytic lesions and melanoma. Importantly, the complex morphology and lack of specific biomarkers that identify key elements of melanoma pathogenesis can make an accurate confirmation of diagnosis challenging. We review the diagnostic constraints of melanoma heterogeneity and discuss issues with interpreting routine histology and problems with current melanoma markers. Innovative approaches are required to find effective biomarkers to enhance patient management.

Warming the skin is a key means of promoting solute permeation through the skin. Changes in solute permeation associated with variations in skin temperature also assist in understanding the mechanism by which solutes permeate the skin. However, few studies have considered the relative impact of temperature on the main determinants of the maximum flux for a solute across the skin, the solubility of a solute and its diffusivity in the stratum corneum. In this study, we quantified for the first time the thermodynamics associated with the maximum skin fluxes for a series of phenolic compounds of similar size but with varying lipophilicity (defined by the logarithms of their octanol/water partition coefficient, log P). These studies were undertaken using aqueous donor solutions (along with testosterone as a reference solute) across human epidermal membranes in vertical Franz diffusion cells at 4 °C, 24 °C and 37 °C with intermittent receptor sampling and volume replacement over 24 h. Kinetic and thermodynamic analyses included the estimation of the stratum corneum (SC) apparent SC diffusivity from the SC maximum fluxes and SC solubilities and the associated activation energies, enthalpies and entropies for diffusion. The key findings were that the differences in the maximum flux of phenolic compounds varying in lipophilicity mainly arose from differences in SC solubility at the various temperatures and that, at the highest temperature, SC permeability and SC diffusion were affected by SC lipid fluidisation and that variations in SC - water partitioning enthalpies explain some of the previously low activation energies for permeation of the more lipophilic phenols. Higher enthalpies for diffusion were seen for solutes with addition hydrogen bonding capacity and the highest negative entropy was observed with the more compact solutes. Various relationships between the derived thermodynamic parameters were explored and interpreted in a proposed model for solute partitioning into and permeation through the SC intercellular lipid lamellae. Refereed/Peer-reviewed

Purpose Subcutaneous fentanyl injection is commonly prescribed to manage acute pain in older patients; however, there is a gap in the literature describing the pharmacokinetic parameters for this route of administration in this population. The aim of this study was to develop and evaluate a population pharmacokinetic model for subcutaneous fentanyl injection in older patients. Methods Twenty-one patients who received subcutaneous fentanyl injections (50 to 75 mu g) were recruited. Fentanyl concentrations were determined using a validated liquid chromatography/tandem mass spectrometry method. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. A base model was selected based on the Akaike information criterion. Age, sex, body weight, number of previous fentanyl doses, number of prescribed medications, creatinine clearance, Charlson Comorbidity Index, Identification of Seniors at Risk score and concurrent use of CYP3A4 inhibitors were covariates considered for inclusion. A p value of < 0.05 was considered statistically significant for inclusion of covariates in the final model by stepwise addition. The simulation performance of the model was assessed by visual predictive check. Results A one-compartment, first-order absorption with lag time and linear elimination model was the best to fit to the fentanyl concentration data. The absorption rate constant was 0.136 h(-1) (between subject variability (BSV), 46%), lag time 0.66 h (BSV 51%), apparent volume of distribution 6.28 L (BSV 30%), and apparent clearance 16.3 L.h(-1) (BSV 54%). The Charlson Comorbidity Index was the only covariate included in the final model, where a higher value of the index increased fentanyl exposure and C-max. Conclusion This is the first report of subcutaneous fentanyl population pharmacokinetic model to evaluate fentanyl pharmacokinetic in older patients. The between subject variability in clearance and subcutaneous absorption rate was relatively high, and some patients recorded high fentanyl concentrations in the context of their titration to effect. Refereed/Peer-reviewed

Background Opioids are commonly prescribed to managing chronic pain in older persons. However, these patients are often at risk of drug-opioid interactions due to polypharmacy. Objectives To identify the prevalence of opioid prescribing and drug-opioid interactions in poly-medicated older patients and factors associated with opioid prescribing. Setting Patients were included if they were admitted to the Royal Adelaide Hospital between September 2015 and August 2016, aged ≥ 75 years and took ≥ 5 medications at discharge. Methods After ethics approval, data of were retrospectively collected from case notes. The Charlson Comorbidity Index and Drug Burden Index were determined and opioids were classified as strong or weak. The association between opioid use and concurrent medications was computed using logistic regression and the results presented as odds ratios (OR) and 95% confidence intervals (95% CI), adjusted for age, sex, Charlson Comorbidity Index, number of prescribed medications and modified-Drug Burden Index. Main outcome measure Association between concurrent medications and opioid prescribing. Results 15,000 geriatric admissions were identified, of which 1192 were included. A total of 283 (23.7%) patients were prescribed opioids, with oxycodone accounting for 56% of these prescriptions. Opioid users were prescribed more medications (11.2 vs. 9.0, P