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Objective:Discrepancies exist in reports of social cognition deficits in individuals with premanifest Huntington’s disease (HD); however, the reason for this variability has not been investigated. The aims of this study were to (1) evaluate group- and individual-level social cognitive performance and (2) examine intra-individual variability (dispersion) across social cognitive domains in individuals with premanifest HD.Method:Theory of mind (ToM), social perception, empathy, and social connectedness were evaluated in 35 individuals with premanifest HD and 29 healthy controls. Cut-off values beneath the median and 1.5 × the interquartile range below the 25th percentile (P25 – 1.5 × IQR) of healthy controls for each variable were established for a profiling method. Dispersion between social cognitive domains was also calculated.Results:Compared to healthy controls, individuals with premanifest HD performed worse on all social cognitive domains except empathy. Application of the profiling method revealed a large proportion of people with premanifest HD fell below healthy control median values across ToM (>80%), social perception (>57%), empathy (>54%), and social behaviour (>40%), with a percentage of these individuals displaying more pronounced impairments in empathy (20%) and ToM (22%). Social cognition dispersion did not differ between groups. No significant correlations were found between social cognitive domains and mood, sleep, and neurocognitive outcomes.Conclusions:Significant group-level social cognition deficits were observed in the premanifest HD cohort. However, our profiling method showed that only a small percentage of these individuals experienced marked difficulties in social cognition, indicating the importance of individual-level assessments, particularly regarding future personalised treatments.

BRAF inhibitors revolutionised the management of melanoma patients and although resistance occurs, there is a subgroup of patients who maintain durable disease control. For those cases with durable complete response (CR) it is not clear whether it is safe to cease therapy. Here we identified 13 patients treated with BRAF +/− MEK inhibitors, who cease therapy after prolonged CR (median = 34 months, range 20–74). Recurrence was observed in 3/13 (23%) patients. In the remaining 10 patients with sustained CR off therapy, the median follow up after discontinuation was 19 months (range 8–36). We retrospectively measured ctDNA levels using droplet digital PCR (ddPCR) in longitudinal plasma samples. CtDNA levels were undetectable in 11/13 cases after cessation and remained undetectable in patients in CR (10/13). CtDNA eventually became detectable in 2/3 cases with disease recurrence, but remained undetectable in 1 patient with brain only progression. Our study suggests that consideration could be given to ceasing targeted therapy in the context of prolonged treatment, durable response and no evidence of residual disease as measured by ctDNA.

Indexación; Scopus. Background: Recent findings suggest that individuals with Huntington’s disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear. Objectives: To evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments. Methods: Twenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment. Results: Compared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P < 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P < 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test–retest reliability [ICC: 0.61-0.99] for individuals with presymptomatic and prodromal HD and healthy controls. Conclusions: Individuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association https://onlinelibrary-wiley-com.recursosbiblioteca.unab.cl/doi/10.1002/acn3.51142

Background Circulating tumour cells (CTCs) can be assessed through a minimally invasive blood sample with potential utility as a predictive, prognostic and pharmacodynamic biomarker. The large heterogeneity of melanoma CTCs has hindered their detection and clinical application. Methods Here we compared two microfluidic devices for the recovery of circulating melanoma cells. The presence of CTCs in 43 blood samples from patients with metastatic melanoma was evaluated using a combination of immunocytochemistry and transcript analyses of five genes by RT-PCR and 19 genes by droplet digital PCR (ddPCR), whereby a CTC score was calculated. Circulating tumour DNA (ctDNA) from the same patient blood sample, was assessed by ddPCR targeting tumour-specific mutations. Results Our analysis revealed an extraordinary heterogeneity amongst melanoma CTCs, with multiple non-overlapping subpopulations. CTC detection using our multimarker approach was associated with shorter overall and progression-free survival. Finally, we found that CTC scores correlated with plasma ctDNA concentrations and had similar pharmacodynamic changes upon treatment initiation. Conclusions Despite the high phenotypic and molecular heterogeneity of melanoma CTCs, multimarker derived CTC scores could serve as viable tools for prognostication and treatment response monitoring in patients with metastatic melanoma.

Objective Pathological changes within the hypothalamus have been proposed to mediate circadian rhythm and habitual sleep disturbances in individuals with Huntington’s disease (HD). However, investigations examining the relationships between hypothalamic volume and circadian rhythm and habitual sleep in individuals with HD are sparse. This study aimed to comprehensively evaluate the relationships between hypothalamic pathology and circadian rhythm and habitual sleep disturbances in individuals with premanifest HD. Methods Thirty-two individuals with premanifest HD and twenty-nine healthy age- and gender-matched controls participated in this dual-site, cross-sectional study. Magnetic resonance imaging scans were performed to evaluate hypothalamic volume. Circadian rhythm and habitual sleep were assessed via measurement of morning and evening cortisol and melatonin levels, wrist-worn actigraphy, the Consensus Sleep Diary and sleep questionnaires. Information on mood, physical activity levels and body composition were also collected. Results Compared to healthy controls, individuals with premanifest HD displayed significantly reduced grey matter volume in the hypothalamus, decreased habitual sleep efficiency and increased awakenings; however, no alterations in morning cortisol or evening melatonin release were noted in individuals with premanifest HD. While differences in the associations between hypothalamic volume and cortisol and melatonin output existed in individuals with premanifest HD compared to healthy controls, no consistent associations were observed between hypothalamic volume and circadian rhythm or habitual sleep outcomes. Conclusion While significant differences in associations between hypothalamic volume and cortisol and melatonin existed between individuals with premanifest HD and healthy controls, no differences in circadian markers were observed between the groups. This suggests that circadian regulation is maintained despite hypothalamic pathology, perhaps via neural compensation. Longitudinal studies are required to further understand the relationships between the hypothalamus and circadian rhythm and habitual sleep disturbances in HD as the disease course lengthens., Highlights • Circadian rhythm and sleep disturbances are common in Huntington's disease (HD) • Premanifest HD (preHD) individuals show significantly reduced hypothalamic volume • Hypothalamic pathology has been proposed to mediate circadian and sleep changes • Relationships between hypothalamic volume and circadian rhythm differ in preHD • No consistent associations exist between the hypothalamus and circadian rhythm/sleep

Salivary cortisol dysrhythmias have been reported in some, but not all studies assessing hypothalamic–pituitary–adrenal (HPA) axis function in Huntington’s disease (HD). These differences are presumed to be due to environmental influences on temporal salivary cortisol measurement. Further exploration of HPA-axis function using a more stable and longer-term measure, such as hair cortisol, is needed to confirm earlier findings. This study aimed to evaluate hair and salivary cortisol concentrations and their associations with clinical and lifestyle outcomes in individuals with premanifest HD (n = 26) compared to healthy controls (n = 14). Participants provided saliva and hair samples and data were collected on clinical disease outcomes, mood, cognition, physical activity, cognitive reserve, sleep quality and social network size to investigate relationships between clinical and lifestyle outcomes and cortisol concentrations. Hair and salivary cortisol concentrations did not significantly differ between the premanifest HD and control groups. No significant associations were observed between hair or salivary cortisol concentrations and cognitive, mood or lifestyle outcomes. However, hair cortisol concentrations were significantly associated with disease outcomes in individuals with premanifest HD. Significant associations between hair cortisol concentrations and measures of disease burden and onset may suggest a potential disease marker and should be explored longitudinally in a larger sample of individuals with HD.

Objective Dual-tasking deficiencies are common in people with Huntington disease (HD) and contribute to reduced functional independence. To date, few studies have investigated the determinants of dual-tasking deficiencies in this population. The reliability of dual-tasking measures has also been poorly investigated in HD. The purpose of this study was to investigate the influence of clinical determinants on dual-tasking performance and to determine the association of disease burden outcomes on dual-tasking performance in individuals with premanifest HD. Methods Thirty-six individuals with premanifest HD and 28 age- and sex-matched healthy controls were recruited for this study. Participants performed 3 single-task (2 cognitive and 1 motor) and 2 dual-task assessments, comprising motor (postural stability) and cognitive (simple or complex mental arithmetic) components. In addition, participants performed a comprehensive clinical battery comprising motor, cognitive, mood, and sleep assessments as well as lifestyle and disease burden measures. Results Poorer sleep quality was associated with greater cognitive dual-task cost in individuals with premanifest HD. Compared with healthy controls, people with premanifest HD demonstrated an impaired capacity to dual task. Dual-task measures exhibited acceptable test–retest reliability in premanifest HD and healthy control groups. Conclusion These results show that dual-tasking measures are sensitive and reliable in individuals with premanifest HD. Furthermore, poor sleep quality is associated with worse cognitive performance on dual tasks, which should be considered by rehabilitation specialists when examining and therapeutically managing dual-tasking problems in individuals with HD and other neurodegenerative populations in the future. Impact This study adds important knowledge to the sparse literature on dual-tasking deficiencies in people with HD. When examining and therapeutically managing dual-tasking problems in this and other neurodegenerative populations, rehabilitation specialists should consider that people with premanifest HD may have an impaired capacity to dual task. Clinicians also should assess sleep quality, as poorer sleep quality is associated with worse cognitive performance on dual tasks in these individuals. Lay Summary If you have premanifest HD and poor quality of sleep, you may pay more attention to maintaining postural stability rather than performing arithmetic calculations to reduce the risk of falling.

Indexación Scopus The aim of the present study was to quantify explosive joint torque or the ability to develop joint torque rapidly, typically measured as the rate of torque development, in individuals with prodromal Huntington’s disease and healthy controls and its associations with measures of disease burden and striatal pathology. Twenty prodromal Huntington’s disease and 19 healthy control individuals volunteered for this study. Plantar flexor isometric rate of torque development values were evaluated using isokinetic dynamometry. Pathological changes in striatal shape were evaluated using magnetic resonance imaging. Disease burden was evaluated using the disease burden score and cytosine-adenine-guanine age product score. No statistical differences in the rate of torque development were observed between individuals with prodromal Huntington’s disease and healthy controls. However, significant associations were observed between the rate of torque development values and measures of disease burden (r = −0.42 to −0.69) and striatal pathology (r = 0.71–0.60) in individuals with prodromal Huntington’s disease. We found significant associations between lower rate of torque development values and greater striatal shape deflation and disease burden and striatal pathology in individuals with prodromal Huntington’s disease. While no significant differences in the rate of torque development were found between prodromal Huntington’s disease and healthy controls, the noted associations suggest that differences may emerge as the disease advances, which should be investigated longitudinally in future studies. © 2020, The Author(s). https://www-nature-com.recursosbiblioteca.unab.cl/articles/s41598-020-72042-2

Objectives Serum neurofilament light protein (NfL) is a promising marker of disease onset and progression in Huntington's disease (HD). This study investigated associations between lifestyle factors and NfL levels in HD mutation carriers compared to healthy age‐ and sex‐matched controls. Materials and Methods Participants included 29 HD mutation carriers and 15 healthy controls. Associations between serum NfL concentrations and lifestyle factors, including cardiorespiratory fitness, social network size and diversity, physical activity, cognitive reserve, smoking status, and alcohol consumption, were examined using a stepwise multivariable linear regression model. Results Higher NfL levels were associated with lower cognitive reserve, social network size and diversity and cardiorespiratory fitness in HD mutation carriers. Group × lifestyle factor effects were observed between lower serum NfL levels and a greater social network diversity. Conclusion These findings highlight a relationship between lifestyle factors and NfL levels in HD mutations carriers; however, longitudinal studies are required to confirm if these observed relationships persist over time., Serum neurofilament light protein (NfL) is a promising marker of disease onset and progression in Huntington’s disease; however, it is not yet known how lifestyle factors may impact on NfL levels. Here, we report that lifestyle factors, particularly cognitive reserve, cardiorespiratory fitness and social network size and diversity, are significantly associated with NfL levels.

Circulating tumour DNA (ctDNA) has emerged as a promising blood-based biomarker for monitoring disease status of patients with advanced cancers. In melanoma, ctDNA has been shown to have clinical value as an alternative tumour source for the detection clinically targetable mutations for the assessment of response to therapy. This review provides a critical summary of the evidence that gives credence to the utility of ctDNA as a biomarker for monitoring of disease status in advanced melanoma and the steps required for its implementation into clinical settings.

Background Exposure to heat stress after UVB irradiation induces a reduction of apoptosis, resulting in survival of DNA damaged human keratinocytes. This heat-mediated evasion of apoptosis appears to be mediated by activation of SIRT1 and inactivation of p53 signalling. In this study, we assessed the role of SIRT1 in the inactivation of p53 signalling and impairment of DNA damage response in UVB plus heat exposed keratinocytes. Results Activation of SIRT1 after multiple UVB plus heat exposures resulted in increased p53 deacetylation at K382, which is known to affect its binding to specific target genes. Accordingly, we noted decreased apoptosis and down regulation of the p53 targeted pro-apoptotic gene BAX and the DNA repair genes ERCC1 and XPC after UVB plus heat treatments. In addition, UVB plus heat induced increased expression of the cell survival gene Survivin and the proliferation marker Ki67. Notably, keratinocytes exposed to UVB plus heat in the presence of the SIRT1 inhibitor, Ex-527, showed a similar phenotype to those exposed to UV alone; i.e. an increase in p53 acetylation, increased apoptosis and low levels of Survivin. Conclusion This study demonstrate that heat-induced SIRT1 activation mediates survival of DNA damaged keratinocytes through deacetylation of p53 after exposure to UVB plus heat Electronic supplementary material The online version of this article (doi:10.1186/s12895-017-0060-y) contains supplementary material, which is available to authorized users.

Indexación: Scopus. Evidence from small-scale studies indicates that impairments in postural stability are an early and disabling feature of Huntington’s disease (HD) and may be a useful clinical endpoint for disease modifying trials. Larger studies are needed to confirm these preliminary findings and the suitability of postural stability outcomes as clinical endpoints. Static and dynamic postural stability were evaluated in 54 premanifest HD, 36 manifest HD and 45 healthy individuals using the Sensory Organization Test (SOT) and Limits of Stability (LOS) test. Manifest HD displayed significantly lower scores on all SOT conditions and on the SOT composite score and had more falls than healthy and premanifest HD (p < 0.05). Premanifest and manifest HD demonstrated significantly lower endpoint excursion (p < 0.001), maximum excursion (p ≤ 0.001), and directional control (p ≤ 0.004) values than healthy individuals on the LOS test. Deficits in LOS were found to manifest on the left side of premanifest HD. Significant but low associations were observed between UHDRS-TMS, disease burden score, diagnostic confidence level, SOT conditions and SOT composite score. We confirm here that individuals with premanifest and manifest HD display significant impairments in static and dynamic postural stability. Dynamic posturography assessments should be considered as clinical endpoints for future disease modifying trials. © 2018, The Author(s). https://www.nature.com/articles/s41598-018-32924-y

The objective of this study was to investigate the discriminant validity of commonly used depression and anxiety screening tools in order to determine the most suitable tool for patients with chronic obstructive pulmonary disease (COPD). COPD patients ( n = 56) completed the Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI-II) and Beck Anxiety Inventory (BAI). These scores were compared to confirmed clinical diagnoses of depression and anxiety using the Mini Neuropsychiatric Interview. HADS depression subscale (HADS-D) sensitivity/specificity was 78/81%; BDI-II 89/77%; HADS anxiety subscale (HADS-A) 71/81%; and BAI 89/62%. HADS-D sensitivity/specificity was improved (100/83%) with the removal of Q4 ‘I feel as if I am slowed down’ and adjusted cut-off (≥5). Removal of BDI-II Q21 ‘Loss of interest in sex’ with adjusted cut-off ≥12 resulted in similar improvement (100/79%). No problematic items were identified for HADS-A or BAI. Previously reported low sensitivity/specificity of the HADS for COPD patients was not replicated. Furthermore, simple modifications of the HADS-D markedly improved sensitivity/specificity for depression. BDI-II, HADS-A and BAI produced acceptable sensitivity/specificity unmodified. Pending further research for COPD patients we recommend continued use of the HADS-A with standard cut-off (≥8) and removal of Q4 of the HADS-D with lower cut-off ≥5.

Immunotherapy is an important and established treatment option for patients with advanced melanoma. Initial anti-PD1 trials arbitrarily defined a two-year treatment duration, but a shorter treatment duration may be appropriate. In this study, we retrospectively assessed 70 patients who stopped anti-PD1 therapy in the absence of progressive disease (PD) to determine clinical outcomes. In our cohort, the median time on treatment was 11.8 months. Complete response was attained at time of anti-PD1 discontinuation in 61 (87%). After a median follow up of 34.2 months (range: 2&ndash, 70.8) post discontinuation, 81% remained disease free. Using ddPCR, we determine the utility of circulating tumour DNA (ctDNA) to predict progressive disease after cessation (n = 38). There was a significant association between presence of ctDNA at cessation and disease progression (p = 0.012, Fisher&rsquo, s exact test) and this conferred a negative and positive predictive value of 0.82 (95% CI: 0.645&ndash, 0.930) and 0.80 (95% CI 0.284&ndash, 0.995), respectively. Additionally, dichotomised treatment-free survival in patients with or without ctDNA at cessation was significantly longer in the latter group (p &lt, 0.001, HR: 0.008, 95% CI: 0.001&ndash, 0.079). Overall, our study confirms that durable disease control can be achieved with cessation of therapy in the absence of disease progression and undetectable ctDNA at cessation was associated with longer treatment-free survival.

Background Huntington's disease (HD) is a chronic, progressive neurodegenerative condition for which there are currently no proven disease-modifying therapies. Lifestyle factors have been shown to impact on the age of disease onset and progression of disease features. We therefore investigated the effects of a nine-month multidisciplinary rehabilitation intervention on neuroimaging, biological and clinical disease outcomes in individuals with premanifest HD. Methods 31 individuals with premanifest HD participated in the study. Eighteen participants underwent a nine-month multidisciplinary rehabilitation intervention comprising aerobic and resistance exercise, computerised cognitive training, dual-task training and sleep hygiene and nutritional guidance. The remaining 13 participants were allocated to a standard care control group. Neuroimaging, biological, cognitive, motor and cardiorespiratory fitness data was collected. Results Participants displayed good adherence (87%) and compliance (85%) to the intervention. Maintenance of the shape of the right putamen was observed in the intervention group when compared to the control group. The intervention group displayed significant improvements in verbal learning and memory, attention, cognitive flexibility and processing speed following the intervention when compared to the control group. Performance on the mini-social cognition and emotional assessment (mini-SEA) was maintained in the intervention group, but decreased in the control group. No changes were observed in serum neurofilament light protein levels, postural stability outcomes or cardiorespiratory fitness. Conclusion This study adds to the accumulating body of literature to suggest that multidisciplinary rehabilitation is of clinical benefit for individuals with HD. Large randomised controlled trials are necessary to determine the extent to which benefits occur across the spectrum of the disease.

Background Hypothalamic pathology is a well-documented feature of Huntington's disease (HD) and is believed to contribute to circadian rhythm and habitual sleep disturbances. Currently, no therapies exist to combat hypothalamic changes, nor circadian rhythm and habitual sleep disturbances in HD. Objective To evaluate the effects of multidisciplinary rehabilitation on hypothalamic volume, brain-derived neurotrophic factor (BDNF), circadian rhythm and habitual sleep in individuals with preclinical HD. Methods Eighteen individuals with HD (ten premanifest and eight prodromal) undertook a nine-month multidisciplinary rehabilitation intervention (intervention group), which included exercise, cognitive and dual task training and social events, and were compared to a community sample of eleven individuals with premanifest HD receiving no intervention (control group). Hypothalamic volume, serum BDNF, salivary cortisol and melatonin concentrations, subjective sleep quality, daytime somnolence, habitual sleep-wake patterns, stress and anxiety and depression symptomatology were evaluated. Results Hypothalamus grey matter volume loss was significantly attenuated in the intervention group compared to the control group after controlling for age, gender, Unified Huntington's Disease Rating Scale-Total Motor Score and number of cytosine-adenine-guanine repeats. Serum BDNF levels were maintained in the intervention group, but decreased in the control group following the study period. Both groups exhibited decreases in cortisol and melatonin concentrations. No changes were observed in sleep or mood outcomes. Conclusions This exploratory study provides evidence that multidisciplinary rehabilitation can reduce hypothalamic volume loss and maintain peripheral BDNF levels in individuals with preclinical HD but may not impact on circadian rhythm. Larger, randomised controlled trials are required to confirm these findings.

OBJECTIVE The primary objective of this trial was to evaluate the effects of outpatient multidisciplinary therapy, compared to usual care, on measures of physical function and muscle strength in patients with manifest Huntington's disease (HD). METHODS Twenty-two patients with clinically verified HD were randomized to receive 36 weeks of outpatient multidisciplinary therapy or usual care. Outpatient multidisciplinary therapy comprised 9 months of supervised exercise, cognitive therapy and self-directed home-based exercise. Usual care consisted of standard medical care. Patients were assessed at 0 and 36 weeks by blinded assessors. The primary outcome was changed in mobility as measured by the 10-m Timed Walk Test. Secondary outcome measures included changes in manual dexterity (Timed Nut and Bolt Test), balance (Berg Balance Scale), cardiorespiratory endurance (6-Minute Walk Test) and upper and lower extremity muscle strength (isokinetic and isometric muscle strength and 10 Repetition Sit-to-Stand Tests). RESULTS Patients receiving outpatient multidisciplinary therapy demonstrated significantly enhanced manual dexterity (P

© 2018 The implementation of novel therapeutic interventions has improved the survival rates of melanoma patients with metastatic disease. Nonetheless, only 33% of treated cases exhibit long term responses. Circulating tumor cell (CTC) measurements are currently of clinical value in breast, prostate and colorectal cancers. However, the clinical utility of melanoma CTCs (MelCTCs) is still unclear due to challenges that appear intrinsic to MelCTCs (i.e. rarity, heterogeneity) and a lack of standardization in their isolation, across research laboratories. Here, we review the latest developments, pinpoint the challenges in MelCTC isolation and address their potential role in melanoma management.

Melanoma is an aggressive form of skin cancer that is curable by surgical excision in the majority of cases, if detected at an early stage. To improve early stage melanoma detection, the development of a highly sensitive diagnostic test is of utmost importance. Here we aimed to identify antibodies to a panel of tumour associated antigens that can differentiate primary melanoma patients and healthy individuals. A total of 245 sera from primary melanoma patients and healthy volunteers were screened against a high-throughput microarray platform containing 1627 functional proteins. Following rigorous statistical analysis, we identified a combination of 10 autoantibody biomarkers that, as a panel, displays a sensitivity of 79%, specificity of 84% and an AUC of 0.828 for primary melanoma detection. This melanoma autoantibody signature may prove valuable for the development of a diagnostic blood test for routine population screening that, when used in conjunction with current melanoma diagnostic techniques, could improve the early diagnosis of this malignancy and ultimately decrease the mortality rate of patients.

Objective Anxiety and depression are common comorbidities in people diagnosed with chronic obstructive pulmonary disease (COPD). Despite concomitant psychological symptomatology being reported in 22–48% of people with COPD, most literature focuses on identifying the risk factors for anxiety or depression separately. Therefore, our objective was to determine whether there is an association between people living with concomitant anxiety and depression and sociodemographic risk factors in people and living with COPD. Methods This was a cross-sectional study of 242 people living with COPD. Symptomatology of anxiety and depression were assessed using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI-II). Univariate and multivariable logistic regression models were used to test the association between symptomatology and demographic predictor variables. Odds ratios and 95% confidence intervals were derived. Results Of the 242 people included, 48.8% (n = 118) had no symptoms of anxiety or depression and 33.5%% (n = 81) had symptomatology for both. Multivariable modelling suggested younger age, having a carer, having a previous psychological medical history, having a higher number of comorbidities and poorer quality of life were associated with concomitant anxiety and depression compared to those without symptomatology. Conclusion Further work should be done to build upon our results which adds to the limited literature surrounding risk factors for concomitant psychological symptomatology to facilitate future discussion surrounding reducing these detrimental comorbidities in people with COPD.

// Carlos A. Aya-Bonilla 1 , Gabriela Marsavela 1 , James B. Freeman 1 , Chris Lomma 2 , Markus H. Frank 1, 3, 4 , Muhammad A. Khattak 5, 6 , Tarek M. Meniawy 6, 7 , Michael Millward 6, 7 , Majid E. Warkiani 8 , Elin S. Gray 1 and Mel Ziman 1, 9 1 School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia 2 Department of Health, Perth, Western Australia, Australia 3 Transplantation Research Program, Boston Children’s Hospital and Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA 4 Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA 5 Department of Medical Oncology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia 6 School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia 7 Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia 8 School of Mechanical and Manufacturing Engineering, Australian Center for NanoMedicine, University of New South Wales, Sydney, New South Wales, Australia 9 School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia Correspondence to: Carlos A. Aya-Bonilla, email: c.ayabonilla@ecu.edu.au Keywords: circulating tumour cells (CTCs), metastatic melanoma, slanted spiral microfluidics Received: March 10, 2017 Accepted: May 22, 2017 Published: June 27, 2017 ABSTRACT Circulating Tumour Cells (CTCs) are promising cancer biomarkers. Several methods have been developed to isolate CTCs from blood samples. However, the isolation of melanoma CTCs is very challenging as a result of their extraordinary heterogeneity, which has hindered their biological and clinical study. Thus, methods that isolate CTCs based on their physical properties, rather than surface marker expression, such as microfluidic devices, are greatly needed in melanoma. Here, we assessed the ability of the slanted spiral microfluidic device to isolate melanoma CTCs via label-free enrichment. We demonstrated that this device yields recovery rates of spiked melanoma cells of over 80% and 55%, after one or two rounds of enrichment, respectively. Concurrently, a two to three log reduction of white blood cells was achieved with one or two rounds of enrichment, respectively. We characterised the isolated CTCs using multimarker flow cytometry, immunocytochemistry and gene expression. The results demonstrated that CTCs from metastatic melanoma patients were highly heterogeneous and commonly expressed stem-like markers such as PAX3 and ABCB5. The implementation of the slanted microfluidic device for melanoma CTC isolation enables further understanding of the biology of melanoma metastasis for biomarker development and to inform future treatment approaches.

Mobility and balance problems are common and often debilitating features of Huntington's disease (HD). In this exploratory study we aimed to investigate the influence of disease severity, severity of motor deficits, lower limb muscle strength, cognition, executive function, lean muscle mass and reactivity on mobility and balance. Twenty-two individuals with HD were recruited from the North Metropolitan Area Mental Health Service, Perth, Australia. Pertinent demographic, genetic and disease progression information was recorded prior to testing. Balance was assessed using dynamic and static balance tasks. Mobility was assessed using self-paced and fast-paced mobility measures. Cognitive and executive measures were used to assess verbal learning and memory, information processing speed, attention, response inhibition and cognitive flexibility. Lower limb muscle strength was evaluated by maximal isokinetic and isometric voluntary contractions. Lean tissue mass was quantified using Dual-energy X-ray absorptiometry. Reactivity was measured using Moyart equipment. Univariate and multivariate linear regression statistical models were used to examine the influence of these measures on mobility and balance. Univariate analyses showed that disease severity as well as measures of information processing speed, attention, cognitive flexibility, response inhibition and lower limb strength, were strongly related with mobility and balance. Additionally multivariate analyses showed that disease severity, cognitive flexibility and knee flexion strength together were better able to explain mobility and balance performance than any single measure (50–85%). In conclusion, our preliminary results suggest that as well as disease severity, cognitive and executive impairment and reduced lower limb strength contribute significantly to mobility and balance problems.

Undergraduate students accessing on-line tests in Human Biology in three Western Australian universities were asked to complete an on-line post-test reflective survey about their perceptions of their test performance in light of automated feedback. The survey allowed pre-determined choices and comment text boxes relating to students’ perceptions of their performance, self-identified areas of difficulty and suggested strategies for improving test performance. One-third of students undertaking on-line tests responded to the optional survey, and 60% of respondents thought reflecting on feedback was useful. Students reflecting on formative rather than summative assessment reported a more strategic approach to testing, often using it to assess their knowledge and prepare for future assessment. Their reflections were more internally focused on motivation and preparation compared with those assessed summatively. Respondents were more likely to be female, older, more experienced learners who had scored well in th...

Alveolar rhabdomyosarcomas (ARMS) are characterised by a PAX3/7-FKHR translocation, which is presumed to promote a differentiation arrest in the myogenic lineage, in which setting secondary genetic events occur, resulting in sarcomagenesis. The aim of this study was to identify the mechanism by which PAX3/7-FKHR expression results in a myogenic differentiation block, as discrete from the secondary genetic events that complete the sarcomagenic process.We performed a novel differential gene expression analysis comparing normal mesenchymal stem cells with previously generated non-tumorigenic mesenchymal stem cells expressing the PAX7-FKHR fusion gene, as well as with a known tumorigenic, PAX7-FKHR-expressing ARMS cell line, CW9019.This novel analysis uncovered the upregulation of the NF-kappaB pathway as a function of PAX3/7-FKHR expression, but distinct from the secondary sarcomagenic process; thus implicating NF-kappaB as a mediator of the PAX3/7-FKHR differentiation block. We further show that NF-kappaB activity is upregulated in PAX7-FKHR cells when compared to parental MSCs due to upregulation of the PI3K/AKT pathway. In addition we show that NF-kappaB inhibits myogenesis via activation of cyclinD1/ cdk4 complexes, which sequester MyoD1, a key myogenic transcription factor.Our results highlight the importance of the NF-kappaB pathway in myogenesis and sarcomagenesis and suggest that this pathway may be one of the potential therapeutic targets in the treatment of ARMS.

This study analysed the analgesic effect and changes in vital signs associated with administration of inhaled Methoxyflurane (MTX) and/or intranasal Fentanyl (INF) for prehospital management of visceral pain.A retrospective, observational study reviewing 1024 randomly selected records of patients with presumed visceral pain administered MTX (465), INF (397) or both (162) by the Western Australian Ambulance Service between January 2004 and February 2006. Clinical variables assessed included systolic blood pressure, pulse rate, respiration rate and Glasgow Coma Scale score. Pain was assessed utilising Visual/Verbal Analogue Scale pain scores.Overall effects on vital signs appeared favourable 5 min after use and at hospital arrival with either agent alone or in combination. As sole agents, MTX produced the greatest initial pain scores reduction (2.0 (1.7 to 2.2) vs 1.6 (1.4 to 1.8)) (mean (95% CI), and INF provided greater pain reduction by hospital arrival (3.2 (2.9 to 3.5) vs 2.5 (2.1 to 2.9)). While both agents were effective, INF provided a greater pain score reduction for cardiac (3.0 (2.6 to 3.4) vs 2.3 (1.8 to 2.8)), female (3.4 (2.9 to 4.0) v 2.5 (2.0 to 3.0)) and age 75+ patients (3.2 (2.5 to 3.8) vs 1.8 (1.0 to 2.5)). Combined use of agents was not advantageous.MTX and INF are effective agents for providing visceral pain analgesia in the prehospital setting. While MTX provided a more rapid onset of pain relief, INF provided superior analgesia after subsequent doses and in female, cardiac and older patients.

180 Background: Emerging data suggests that ARV7 mRNA (ARV7+) expression and AR copy number gain/amplification (AR+) are associated with resistance to androgen deprivation therapy. Most studies thus far have evaluated either AR copy number or ARV7 mRNA, but not both markers. It is likely that both markers are indicators of genomic changes that are seen in the prostate cancer cells in response to tumour evolution or treatment. Here we developed a digital droplet PCR (ddPCR) based assay to evaluate plasma ARV7 mRNA expression in the same samples used for AR copy number analysis in castrate resistant prostate cancer (CRPC). This assay was use to evaluate the role of AR+ and ARV7+ in CRPC using samples collected from multiple centers and correlated with outcome. Methods: We collected plasma samples from patients with CRPC treated with chemotherapy (C) or next generation androgen targeted agents (NAR) to evaluate circulating tumour DNA (ctDNA) for AR and plasma mRNA for ARV7. Some patients had sequential samples and we correlated PSA response (reduction PSA≥50 confirmed 3wks later (RR)) with AR and ARV7 status and clinical features. Results: A total of 52 samples were included from 26 patients, with matched samples from some patients at different time points. Of the CRPC patients, AR+ was seen in 70% (18/26), AR- in 30% (8/26), ARV7+ in 67% (12/18) and ARV7- in 33% (6/18). 75% (9/12) patients with AR+ also had ARV7+. In matched samples: 3/7 had change in AR status, 2/7 had change in ARV7 status, including 1 patient where both changed; and interestingly there was a group with no AR or ARV7 detected. Number of patients expressing both markers AR+/ARV7+ in 50% (9/18), AR+/ARV7- in 17% (3/18), AR-/ARV7+ 17% (3/18) and AR-/ARV7- in 11% (2/18). RR to C or NAR was 63% (12/19) for AR+ and 75% (9/12) for ARV7+ patients. In AR+ patients, response to NAR was 58% (12/16) but response to chemotherapy was 100% (5/5). Conclusions: AR gain/amplification in CRPC was associated with ARV7+ expression and leads to lower response to NAR compared to C. This approach can be used to undertake integrated DNA and mRNA analysis, has wide-scale utility and may be used for analysis of a larger number of circulating biomarkers.

BACKGROUND: We investigated the use of a simple novel nut and bolt task in premanifest and manifest Huntington's disease (HD) patients to detect and quantify motor impairments at all stages of the disease.METHODS: Premanifest HD (n=24), manifest HD (n=27) and control (n=32) participants were asked to screw a nut onto a bolt in one direction, using three different sized bolts with their left and right hand in turn.RESULTS: We identified some impairments at all stages of HD and in the premanifest individuals, deficits in the non-dominant hand correlated with disease burden scores.CONCLUSION: This simple, cheap motor task was able to detect motor impairments in both premanifest and manifest HD and as such might be a useful quantifiable measure of motor function for use in clinical studies. (Less)

Introduction: Anxiety and depression are common comorbidities in COPD patients. The Hospital Anxiety and Depression Scale (HADS) is recommended for routine screening of COPD patients but has only been validated twice for this population with questionable results; once for anxiety (HADS-A) resulting in sensitivity/specificity of 36/90% and once for depression (HADS-D) of 25/84% at standard cut-offs. These results demand replication before firm conclusions can be drawn. Furthermore, popularly used alternatives—the Beck Depression Inventory (BDI-II) and Beck Anxiety Inventory (BAI)—have yet to be validated in COPD populations. Aim: To determine in a COPD population the concurrent validity of the HADS, BDI-II and BAI to clinical diagnoses of depression and anxiety confirmed by the Mini-International Neuropsychiatric Interview (MINI). Methods: 56 COPD patients completed the HADS, BDI-II, BAI and MINI diagnostic interviews. Results: Compared to confirmed MINI diagnoses: HADS-D 78/81%; BDI-II 89/77%; HADS-A 71/81%; BAI 89/60%. The HADS-D item 9I feel as if I am slowed down9 demonstrated no discriminant validity for COPD patients and was removed, resulting in improved diagnosis (100/83%). A similar result was observed for the BDI-II with removal of 9Loss of interest in sex9 (100/79%). No such items were identified for the HADS-A or BAI. Conclusion: Simple modifications of the HADS-D and BDI-II appear to markedly improve diagnostic validity for depression in COPD patients. Previous poor validity of the HADS-A was not replicated. Rather, both the HADS-A and BAI had similar, moderate-to-good diagnostic validity for COPD patients.

Pax genes are a family of transcriptional regulators vital for embryonic development. One member of the family, Pax7, functions early in neural development to establish dorsal polarity of the neural tube, and continuous refinement of its expression affords regional identity to brain nuclei, in particular the superior colliculus. Pax7 expression within the superior colliculus is eventually restricted to the stratum griseum et fibrosum superficiale (SGFS), the retinorecipient layer to which the optic nerve projects. The key role of Pax7 in specification of the superior colliculus has been highlighted by misexpression studies which result in ectopic formation of superior collicular tissue with characteristic laminae innervated by retinal ganglion cell axons. Here we review the role of Pax7 in formation of the superior colliculus and discuss the possibility that Pax7 may also assist in refinement of correct topographic mapping.

Melanoma is a highly aggressive and drug resistant form of skin cancer. It arises from melanocytes, the pigment producing cells of the skin. The formation of these melanocytes is driven by the transcription factor PAX3 early during embryonic development. As a result of alternative splicing, the PAX3 gene gives rise to eight different transcripts which encode isoforms that have different structures and activate different downstream target genes involved in pathways of cell proliferation, migration, differentiation and survival. Furthermore, post-translational modifications have also been shown to alter the functions of PAX3. We previously identified PAX3 downstream target genes in melanocytes and melanoma cells. Here we assessed the effects of PAX3 down-regulation on this panel of target genes in primary melanocytes versus melanoma cells. We show that PAX3 differentially regulates various downstream target genes involved in cell proliferation in melanoma cells compared to melanocytes. To determine mechanisms behind this differential downstream target gene regulation, we performed immunoprecipitation to assess post-translational modifications of the PAX3 protein as well as RNAseq to determine PAX3 transcript expression profiles in melanocytes compared to melanoma cells. Although PAX3 was found to be post-translationally modified, there was no qualitative difference in phosphorylation and ubiquitination between melanocytes and melanoma cells, while acetylation of PAX3 was reduced in melanoma cells. Additionally, there were differences in PAX3 transcript expression profiles between melanocytes and melanoma cells. In particular the PAX3E transcript, responsible for reducing melanocyte proliferation and increasing apoptosis, was found to be down-regulated in melanoma cells compared to melanocytes. These results suggest that alternate transcript expression profiles activate different downstream target genes leading to the melanoma phenotype.

Objective: To examine the effects of 4-month of respiratory muscle training on pulmonary and swallowing function, exercise capacity and dyspnoea in manifest patients with Huntington’s disease. Design: A pilot randomised controlled trial. Setting: Home based training program. Participants: Eighteen manifest Huntington’s disease patients with a positive genetic test and clinically verified disease expression, were randomly assigned to control group ( n=9) and training group ( n=9). Intervention: Both groups received home-based inspiratory (5 sets of 5 repetitions) and expiratory (5 sets of 5 repetitions) muscle training 6 times a week for 4 months. The control group used a fixed resistance of 9 centimeters of water, and the training group used a progressively increased resistance from 30% to 75% of each patient’s maximum respiratory pressure. Main measures: Spirometric indices, maximum inspiratory pressure, maximum expiratory pressure, six minutes walk test, dyspnoea, water-swallowing test and swallow quality of life questionnaire were assessed before, at 2 and 4 months after training. Results: The magnitude of increases in maximum inspiratory ( d=2.9) and expiratory pressures ( d=1.5), forced vital capacity ( d=0.8), forced expiratory volume in 1 second ( d=0.9) and peak expiratory flow ( d=0.8) was substantially greater for the training group in comparison to the control group. Changes in swallowing function, dyspnoea and exercise capacity were small ( d≤0.5) for both groups without substantial differences between groups. Conclusions: A home-based respiratory muscle training program appeared to be beneficial to improve pulmonary function in manifest Huntington’s disease patients but provided small effects on swallowing function, dyspnoea and exercise capacity.

Background There is a wealth of evidence for grey matter degeneration and loss of cognitive function over time in individuals with Huntington’s disease (HD). Efforts to attenuate disease-related brain and cognitive changes have been unsuccessful to date. Multidisciplinary rehabilitation, comprising motor and cognitive intervention, has been shown to positively impact on functional capacity, depression, quality of life and some aspects of cognition in individuals with HD. Aims This exploratory study aimed to evaluate, for the first time, whether multidisciplinary rehabilitation can slow further deterioration of disease-related brain changes and related cognitive deficits in individuals with manifest HD. Methods Fifteen participants with manifest HD undertook a multidisciplinary rehabilitation intervention spanning nine months. The intervention consisted of once-weekly supervised clinical exercise, thrice weekly self-directed home based exercise and fortnightly occupational therapy. Participants were assessed using MR imaging and validated cognitive measures at baseline and after nine months. Results Participants displayed significantly increased grey matter volume in the right caudate and bilaterally in the dorsolateral prefrontal cortex after nine months of multidisciplinary rehabilitation. Volumetric increases in grey matter were accompanied by significant improvements in verbal learning and memory (Hopkins Verbal Learning-Test). A significant association was found between grey matter volume increases in the dorsolateral prefrontal cortex and performance on verbal learning and memory. Conclusions This study provides preliminary evidence that multidisciplinary rehabilitation positively impacts on grey matter changes and cognitive functions relating to verbal learning and memory in individuals with manifest HD. Larger controlled trials are required to confirm these preliminary findings.

The majority of patients diagnosed with melanoma present with thin lesions and generally these patients have a good prognosis. However, 5% of patients with early melanoma (< 1mm thick) will have recurrence and die within 10 years, despite no evidence of local or metastatic spread at the time of diagnosis. Thus, there is a need for additional prognostic markers to help identify those patients that may be at risk of recurrent disease. Many studies and several meta-analyses have compared gene and protein expression in melanocytes, naevi, primary and metastatic melanoma in an attempt to find informative prognostic markers for these patients. However, although a large number of putative biomarkers have been described, few of these molecules are informative when used in isolation. The best approach is likely to involve a combination of molecules. We believe one approach could be to analyze the expression of a group of interacting proteins that regulate different aspects of the metastatic pathway. This is because a primary lesion expressing proteins involved in multiple stages of metastasis may be more likely to lead to secondary disease than one that does not. This review focuses on five putative biomarkers - melanoma cell adhesion molecule (MCAM), galectin-3 (gal-3), matrix metalloproteinase 2 (MMP-2), chondroitin sulfate proteoglycan 4 (CSPG4) and paired box 3 (PAX3). The goal is to provide context around what is known about the contribution of these biomarkers to melanoma biology and metastasis. Although each of these molecules have been independently identified as likely biomarkers, it is clear from our analyses that each are closely linked with each other, with intertwined roles in melanoma biology.

Studies of the impact of respiratory muscle training (RMT) on central neurodegenerative pathologies have been aimed at improving pulmonary function. However, there is no certainty about the effectiveness of RMT in patients affected by these groups of disorders. The purpose of this review was to assess the evidence regarding the efficacy of inspiratory muscle training (IMT) and expiratory muscle training (EMT) on respiratory function in patients with neurodegenerative disorders of the CNS.A comprehensive search from 1990 to September 2012 on MEDLINE, Physiotherapy Evidence Database (PEDro), PubMed, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases was made. Studies reporting on IMT and EMT in patients with neurodegenerative diseases were included. The selected studies were abstracted using a standardized data collection instrument and were assessed by a quality checklist created and adapted from CONSORT (Consolidated Standards for Reporting Trials) and TREND (Transparent Reporting of Evaluation with Nonrandomized Designs).Twenty-four studies were identified by the search strategy. Only 19 studies met the criteria for full review. Ten studies met all the inclusion criteria and were included in the final analysis. Of the 16 parameters present in the quality assessment checklist, only six were achieved for the studies analyzed.There is some evidence that RMT improves a number of respiratory function parameters in patients with Parkinson disease and multiple sclerosis; however, the number of studies and their quality are not sufficient to conclude whether IMT or EMT is effective in improving respiratory function in patients with neurodegenerative disorders of the CNS.

Background Despite immense scientific efforts, there are still no proven drug agents that delay or treat cognitive impairments in individuals with Huntington’s disease (HD). Recent clinical and preclinical data suggests that environmental interventions have a positive impact on many cognitive domains that are affected by HD. There are, however, no empirical studies on the effect of environmental interventions on cognition in individuals with premanifest HD. Intervening during this early stage of the disease may support and/or boost cognitive abilities in affected individuals. Aims To evaluate the effectiveness of a nine month multidisciplinary therapy intervention on cognition in individuals with premanifest HD. Methods Eighteen individuals with premanifest HD (13 women, 5 men; 43 ± 13 years) undertook a multidisciplinary therapy intervention for nine months. The intervention consisted of three times weekly supervised aerobic and resistance exercise, dual task and computerised cognitive training. Participants were assessed using validated cognitive measures before and after the intervention. Results Participants completed all mandatory training sessions throughout the study. Significant improvements in verbal learning and memory (Hopkins Verbal Learning Test), information processing speed (Symbol Digit Modalities Test), attention (Trail Making Test Part A), cognitive flexibility (Trail Making Test Part B) and problem solving (One Touch Stockings of Cambridge) were observed following the intervention. Conclusions This study provides preliminary evidence on the positive effects of multidisciplinary therapy on cognition in individuals with premanifest HD. Larger controlled trials are, however, required to confirm these promising findings.

Background Subjective and objective sleep disturbances have been reported in premanifest Huntington’s disease (pre-HD). These disturbances have the potential to induce structural and functional changes to the brain, including cognitive deficits, and may facilitate, or even contribute to, disease onset and progression. Treatment of sleep disturbances could therefore improve function in affected individuals. Here, we investigated the effects of a non-pharmaceutical, short duration multidisciplinary therapy intervention on subjective and objective sleep in pre-HD participants. Aims To evaluate the effects of multidisciplinary therapy on sleep patterns and subjective sleep quality in pre-HD participants. Methods Eleven pre-HD participants aged 40 ± 11 years (5 male) underwent a twelve week multidisciplinary therapy intervention consisting of three, two hour sessions per week encompassing supervised group exercise and cognitive training. Objective (actigraphy) and subjective (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Consensus Sleep Diary) measures of sleep were obtained at baseline, six weeks and twelve weeks. Stress, depression and anxiety were measured at each time-point using the Perceived Stress Scale and the Hospital Anxiety and Depression Scale (as potential confounders of sleep abnormalities). Results All participants completed the required number of therapy sessions (30 sessions in total) for the study. Decreases, relative to baseline, in sleep onset latency (d > 0.5) and number and duration of awakenings (d > 0.2) were observed following the 12 week intervention. Subjective sleep quality also improved following 12 weeks of physical and cognitive training (d > 0.5). Conclusion This study provides evidence that multidisciplinary therapy has the potential to improve subjective and objective sleep quality in pre-HD. It is possible that a longer intervention duration may further improve sleep quality outcomes in this population.

The greatest potential for improvement of outcome for patients with melanoma lies in the prevention of systemic metastasis. One prospect is the detection of circulating melanoma cells as an indicator of potential metastatic disease. The challenge is to determine whether quantification of circulating tumor cells (CTCs) or analysis of their phenotype most accurately predicts patient outcome. In this chapter, we address these issues and describe appropriate techniques that ensure the accuracy of such measures. We also compare methods for isolation, quantification and characterization of CTCs and suggest informative markers for their analysis in the peripheral blood of patients with melanoma.

Cutaneous Melanoma is an aggressive cancer which accounts for 80% of skin cancer deaths. Australia has the highest incidence world-wide and rates are increasing annually (10,000 new cases and 1,700 deaths per year). Notably it is the most common cancer in 15-39 year olds and the leading cancer related cause of death in young males (WA Cancer Registry 2007). In the USA, incidence is rising faster than other cancers, with 60,000 new cases and 8,000 deaths in 2007 1. Mortality rates remain high due to metastasis of the tumour. Once melanoma has metastasised, survival is commonly 6 to 9 months, with 5-year survival rate less than 40% 2-4. Several prognostic factors have been identified, based upon pathological evaluation of the primary tumour 5 and lymph node metastases 6. However, metastatic disease particularly micrometastasis, is difficult to detect and occurs in over 30% of patients, including 8-30% of patients with in situ melanoma 7-9 and 15% of patients whose lymph nodes are negative at the time of surgical intervention 10,11. In addition, metastasis can occur up to 35 years after diagnosis 12. Effective therapies providing long term survival are very limited (

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