Treatment of High Risk Resected Melanoma in Australia: Current Landscape and Practises

Stage III melanoma involves regional lymph nodes and/or in-transit or satellite disease, without spread to distant metastatic sites. Stage IIIA melanoma includes a T1a-T2a primary lesion with N1a or N2a nodal involvement, whilst stage IIID melanoma includes a T4b primary lesion with N3a-N3c nodal involvement. With surgery alone, patients with stage IIIA melanoma have 10-year survival rates of ~88%; however, patients with stage IIID melanoma have 10-year survival rates of only ~24%. Targeted therapy and immunotherapy are being explored in stage III disease as adjuvant therapy after surgical resection, to eliminate micro-metastatic disease and thereby prevent relapse of melanoma and increase patient survival. A number of pivotal trials published in the last two years have shown improved relapse-free survival (RFS) and overall survival in patients with stage III melanoma treated with adjuvant therapy. COMBI-AD showed adjuvant dabrafenib and trametinib improving RFS compared with placebo (HR 0.49; 95% CI 0.40–0.59). Checkmate-238 demonstrated an improvement in RFS of adjuvant nivolumab over ipilimumab (HR 0.68, P < 0.001) whilst Keynote-054 demonstrated an improvement in RFS with adjuvant pembrolizumab over placebo (HR 0.57, P < 0.001). Many nuances need to be considered when interpreting this data, including implications of an updated staging system, which patients are suitable for adjuvant therapy and the choice between adjuvant targeted therapy and immunotherapy in BRAF mutant patients. This review article summaries the currently available literature on adjuvant targeted therapy and provides a guide on applying this data in everyday practise.     

Improved Speech Hearing in Noise with Invasive Electrical Brain Stimulation

Speech perception in noise is a challenging everyday task with which many listeners have difficulty. Here, we report a case in which electrical brain stimulation of implanted intracranial electrodes in the left planum temporale (PT) of a neurosurgical patient significantly and reliably improved subjective quality (up to 50%) and objective intelligibility (up to 97%) of speech in noise perception. Stimulation resulted in a selective enhancement of speech sounds compared with the background noises. The receptive fields of the PT sites whose stimulation improved speech perception were tuned to spectrally broad and rapidly changing sounds. Corticocortical evoked potential analysis revealed that the PT sites were located between the sites in Heschl''s gyrus and the superior temporal gyrus. Moreover, the discriminability of speech from nonspeech sounds increased in population neural responses from Heschl''s gyrus to the PT to the superior temporal gyrus sites. These findings causally implicate the PT in background noise suppression and may point to a novel potential neuroprosthetic solution to assist in the challenging task of speech perception in noise.SIGNIFICANCE STATEMENT Speech perception in noise remains a challenging task for many individuals. Here, we present a case in which the electrical brain stimulation of intracranially implanted electrodes in the planum temporale of a neurosurgical patient significantly improved both the subjective quality (up to 50%) and objective intelligibility (up to 97%) of speech perception in noise. Stimulation resulted in a selective enhancement of speech sounds compared with the background noises. Our local and network-level functional analyses placed the planum temporale sites in between the sites in the primary auditory areas in Heschl''s gyrus and nonprimary auditory areas in the superior temporal gyrus. These findings causally implicate planum temporale in acoustic scene analysis and suggest potential neuroprosthetic applications to assist hearing in noise.     

Sphingomyelin metabolism in erythrocyte membrane in asthma

Background. Sphingomyelin (SM), a major lipid constituent of outer leaflet of plasma membranes, with cholesterol, constitutes microdomains, which are termed as lipid rafts. These rafts provide support to proteins, receptors, enzymes, and so on and organize and orient them to conduct cellular functions including transmembrane signaling to substances in external milieu. The SM contents are regulated by its metabolism, changes in which may affect the composition of lipid rafts and cell response to the triggers of asthma which may lead to the pathophysiology. For studying changes in membranes, erythrocytes, which contain lipid rafts, are considered to be the best cell type. Hence, this study was conducted on plasma membrane of erythrocytes of asthmatic patients. Objective. The objective is to understand the changes in SM metabolism in asthma. Methods. The study included 50 subjects (25 asthmatics and 25 healthy subjects). Erythrocytes were isolated from the peripheral blood and membrane prepared. This was followed by determination of total cholesterol, phospholipids, SM, and sphingomyelinase activity. P < .05 was considered significant. Results and conclusions In asthmatics, there was a significant decrease in cholesterol contents (p < .05), decrease in total phospholipid contents (p < .005), increase in SM (p < .01), decrease in cholesterol: SM ratio (p < .001) and increase in sphingomyelinase activity (p < .001) in erythrocyte membranes. We conclude that in asthma, the increase in SM contents is associated with increased sphingomyelinase activity which shows an imbalance in SM metabolism, directed toward its accumulation. The ratio of cholesterol to SM, critical for maintenance of lipid rafts, was significantly lower in asthmatics. This indicates changes in structure of lipid rafts which may lead to the pathophysiology and development of asthma. Regulation of SM metabolism may help in disease regulation and its control.     

Prevalence of extended spectrum beta-lactamase producing Escherichia coli and Klebsiella isolates in a large community teaching hospital in Connecticut

The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (ESC) and Klebsiella (KS) among consecutive non-urine isolates were evaluated. Twenty-four of 392 isolates produced ESBLs. Among these half were from respiratory sites and all were susceptible to meropenem. Pulse field-gel electrophoresis (PFGE) showed 12 clonally distinct ESBLs and iso-electric focusing (IEF) revealed that most (83%) produced multiple enzymes.     

Pharmacokinetics of meropenem 0.5 and 2 g every 8 hours as a 3-hour infusion

STUDY OBJECTIVE: To assess the pharmacokinetics of meropenem administered as a 3-hour infusion. DESIGN: Randomized, crossover, open-label study. SETTING: Clinical research center. SUBJECTS: Six healthy adult male volunteers. INTERVENTION: Each subject received meropenem 0.5 or 2 g every 8 hours as a 3-hour infusion for three doses and then crossed over to the other dosage regimen. MEASUREMENT AND MAIN RESULTS: Pharmacokinetic parameters of both regimens were compared, and no significant differences between 0.5- and 2-g doses for the dose-independent parameters (half-life, clearance, and volume of distribution at steady state) were observed. The regimens displayed dose proportionality and were consistent with that of a traditional 0.5-hour infusion. The 3-hour infusion optimized the pharmacodynamic profile of meropenem and worked within the constraints of stability at room temperature stability. CONCLUSION: Prolonging the percentage of time above the minimum inhibitory concentration is a feasible option with meropenem; however, further studies are needed to quantify how this increase translates to efficacy.     

A randomized,double‐blind,placebo‐controlled exploratory study to evaluate the potential of pycnogenol® for improving allergic rhinitis symptoms

The potential of Pycnogenol® for relieving allergic rhinitis (birch pollen) symptoms was explored in a double‐blind, placebo‐controlled trial. In 2008 19 subjects started treatment 3 weeks prior to the onset of birch pollen season in Ontario, Canada. While there was an improvement of eye and nasal symptoms with Pycnogenol, there was no significance versus placebo. It was postulated that Pycnogenol may require a lag‐time between the start of therapy and the onset of action. Therefore 39 subjects were treated 5–8 weeks prior to the 2009 birch allergy season. The evaluation of subjects in 2009 showed much lower scores for eye (?35%) and nasal (?20.5%) symptoms with Pycnogenol compared with placebo. In succession of the allergy season birch specific IgE increased by 31.9% in the placebo group compared with only 19.4% in the Pycnogenol group. Detailed analysis suggested that symptom‐relief was better the longer subjects were on Pycnogenol prior to the allergen exposure. The best results were found with subjects who took Pycnogenol 7–8 weeks ahead of the allergy season. With the limited number of 39 patients statistical predications were unattainable. In conclusion, Pycnogenol improved allergic rhinitis symptoms when supplementation was started at least 5 weeks before the onset of the allergy season. Copyright © 2010 John Wiley & Sons, Ltd.     

Distinct Biomarker Profiles in Ex Vivo T Cell Depletion Graft Manipulation Strategies: CD34+ Selection versus CD3+/19+ Depletion in Matched Sibling Allogeneic Peripheral Blood Stem Cell Transplantation

Various approaches have been developed for ex vivo T cell depletion in allogeneic stem cell transplantation to prevent graft-versus-host disease (GVHD). Direct comparisons of T cell depletion strategies have not been well studied, however. We evaluated cellular and plasma biomarkers in 2 different graft manipulation strategies, CD3⁺CD19⁺ cell depletion (CD3/19D) versus CD34⁺ selection (CD34S), and their associations with clinical outcomes. Identical conditions, including the myeloablative preparative regimen, HLA-identical sibling donor, GVHD prophylaxis, and graft source, were used in the 2 cohorts. Major clinical outcomes were similar in the 2 groups in terms of overall survival, nonrelapse mortality, and cumulative incidence of relapse; however, the cumulative incidence of acute GVHD trended to be higher in the CD3/19D cohort compared with the CD34S cohort. A distinct biomarker profile was noted in the CD3/19D cohort: higher levels of ST2, impaired Helios^? FoxP3⁺Treg reconstitution, and rapid reconstitution of naïve, Th2, and Th17 CD4 cells in the early post-transplantation period. In vitro graft replication studies confirmed that CD3/19D disproportionately depleted Tregs and other CD4 subset repertoires in the graft. This study confirms the utility of biomarker monitoring, which can be directly correlated with biological consequences and possible future therapeutic indications.