Journals
2012 EN
Stéphanie Ghislin · Dorian Obino · Sandrine Middendorp
+3 more
Background Patients with metastatic melanoma have a poor median rate of survival. It is therefore necessary to increase our knowledge about melanoma cell dissemination which includes extravasation, where cancer cells cross the endothelial barrier. Extravasation is well understood during travelling of white blood cells, and involves integrins such as LFA-1 (composed of two chains, CD11a and CD18) expressed by T cells, while ICAM-1 is induced during inflammation by endothelial cells. Although melanoma cell lines cross endothelial cell barriers, they do not express LFA-1. We therefore hypothesized that melanoma-endothelial cell co-culture might induce the LFA-1/ICAM ligand/receptor couple during melanoma transmigration. Methods A transwell approach has been used as well as blocking antibodies against CD11a, CD18 and ICAM-1. Data were analyzed with an epifluorescence microscope. Fluorescence intensity was quantified with the ImageJ software. Results We show here that HUVEC-conditioned medium induce cell-surface expression of LFA-1 on melanoma cell lines. Similarly melanoma-conditioned medium activates ICAM-1 expression in endothelial cells. Accordingly blocking antibodies of ICAM-1, CD11a or CD18 strongly decrease melanoma transmigration. We therefore demonstrate that melanoma cells can cross endothelial monolayers in vitro due to the induction of ICAM-1 and LFA-1 occurring during the co-culture of melanoma and endothelial cells. Our data further suggest a role of LFA-1 and ICAM-1 in the formation of melanoma cell clumps enhancing tumor cell transmigration. Conclusion Melanoma-endothelial cell co-culture induces LFA-1 and ICAM-1 expression, thereby favoring in vitro melanoma trans-migration.
Journals
2012 EN
Fiona Collinson · Walter M. Gregory · Christopher McCabe
+11 more
Background Over recent years a number of novel therapies have shown promise in advanced renal cell carcinoma (RCC). Internationally the standard of care of first-line therapy is sunitinib™, after a clear survival benefit was demonstrated over interferon-α. Convention dictates that sunitinib is continued until evidence of disease progression, assuming tolerability, although there is no evidence that this approach is superior to intermittent periods of treatment. The purpose of the STAR trial is to compare the standard treatment strategy (conventional continuation strategy, CCS) with a novel drug free interval strategy (DFIS) which includes planned treatment breaks. Methods/Design The STAR trial is an NIHR HTA-funded UK pragmatic randomised phase II/III clinical trial in the first-line treatment of advanced RCC. Participants will be randomised (1:1) to either a sunitinib CCS or a DFIS. The overall aim of the trial is to determine whether a DFIS is non-inferior, in terms of 2-year overall survival (OS) and quality adjusted life years (QALY) (averaged over treatment and follow up), compared to a CCS. The QALY primary endpoint was selected to assess whether any detriment in terms of OS could be balanced with improvements in quality of life (QoL). This is a complex trial with a number of design challenges, and to address these issues a feasibility stage is incorporated into the trial design. Predetermined recruitment (stage A) and efficacy (stage B) intermediary endpoints must be met to allow continuation to the overall phase III trial (stage C). An integral qualitative patient preference and understanding study will occur alongside the feasibility stage to investigate patients’ feelings regarding participation or non-participation in the trial. Discussion The optimal duration of continuing sunitinib in advanced RCC is unknown. Novel targeted therapies do not always have the same constraints to treatment duration as standard chemotherapeutic agents and currently there are no randomised data comparing different treatment durations. Incorporating planned treatment breaks has the potential to improve QoL and cost effectiveness, hopefully without significant detriment on OS, as has been demonstrated in other cancer types with other treatments. Trial Registration Controlled-trials.com ISRCTN 06473203
Journals
2012 EN
Mariko Carey · Rob SansonFisher · Finlay Macrae
+4 more
Background Colorectal cancer (CRC) is among the leading causes of cancer-related morbidity and mortality worldwide. Despite clinical practice guidelines to guide surveillance care for those who have completed treatment for this disease as well as screening for first degree relatives of people with CRC, the level of uptake of these recommendations remains uncertain. If outcomes for both patients and their families are to be improved, it is important to establish systematic and cost-effective interventions to improve adherence to guideline recommendations for CRC surveillance and screening. Methods/Design A randomized controlled trial will be used to test the effectiveness of a print-based intervention to improve adherence to colonoscopy surveillance among people with CRC and adherence to CRC screening recommendations among their first degree relatives (FDRs). People diagnosed with CRC in the past 10 months will be recruited through a population-based cancer registry. Consenting participants will be asked if their first degree relatives might also be willing to participate in the trial. Information on family history of CRC will be obtained from patients at baseline. Patients and their families will be randomized to either minimal ethical care or the print-based intervention. The print-based intervention for FDRs will be tailored to the participant's level of risk of CRC as determined by the self-reported family history assessment. Follow up data on surveillance and screening participation will be collected from patients and their FDRs respectively at 12, 24 and 36 months' post recruitment. The primary analyses will relate to comparing levels of guideline adherence in usual care group versus print-based group in the patient sample and the FDR sample respectively. Discussion Results of this study will provide contribute to the evidence base about effective strategies to a) improve adherence to surveillance recommendation for people with CRC; and b) improve adherence to screening recommendation for FDRs of people with CRC. The use of a population-based cancer registry to access the target population may have significant advantages in increasing the reach of the intervention. Trial registration This trial is registered with the Australian and New Zealand Clinical Trials Registry Registration Number (ACTRN): ACTRN12609000628246 .
Journals
2012 EN
Josephine Gwynn · Victoria Flood · Catherine D’Este
+5 more
Background The purpose of this study was to describe the food and nutrient intake of a population of rural Australian children particularly Indigenous children. Participants were aged 10 to 12 years, and living in areas of relative socio-economic disadvantage on the north coast of New South Wales. Methods In this descriptive cross-sectional study 215 children with a mean age of 11.30 (SD 0.04) years (including 82 Indigenous children and 93 boys) completed three 24-hour food recalls (including 1 weekend day), over an average of two weeks in the Australian summer of late 2005. Results A high proportion of children consumed less than the Australian Nutrient Reference Values for fibre (74-84% less than Adequate Intake (AI)), calcium (54-86% less than Estimated Average Requirement (EAR)), folate and magnesium (36% and 28% respectively less than EAR among girls), and the majority of children exceeded the upper limit for sodium (68-76% greater than Upper Limit (UL)). Energy-dense nutrient-poor (EDNP) food consumption contributed between 45% and 49% to energy. Hot chips, sugary drinks, high-fat processed meats, salty snacks and white bread were the highest contributors to key nutrients and sugary drinks were the greatest per capita contributor to daily food intake for all. Per capita intake differences were apparent by Indigenous status. Consumption of fruit and vegetables was low for all children. Indigenous boys had a higher intake of energy, macronutrients and sodium than non-Indigenous boys. Conclusions The nutrient intake and excessive EDNP food consumption levels of Australian rural children from disadvantaged areas are cause for concern regarding their future health and wellbeing, particularly for Indigenous boys. Targeted intervention strategies should address the high consumption of these foods.
Journals
2012 EN
Patricia C. Valery · Peter S Morris · Keith Grimwood
+7 more
Background The prevalence of chronic suppurative lung disease (CSLD) and bronchiectasis unrelated to cystic fibrosis (CF) among Indigenous children in Australia, New Zealand and Alaska is very high. Antibiotics are a major component of treatment and are used both on a short or long-term basis. One aim of long-term or maintenance antibiotics is to reduce the frequency of acute pulmonary exacerbations and symptoms. However, there are few studies investigating the efficacy of long-term antibiotic use for CSLD and non-CF bronchiectasis among children. This study tests the hypothesis that azithromycin administered once a week as maintenance antibiotic treatment will reduce the rate of pulmonary exacerbations in Indigenous children with bronchiectasis. Methods/design We are conducting a multicentre, randomised, double-blind, placebo controlled clinical trial in Australia and New Zealand. Inclusion criteria are: Aboriginal, Torres Strait Islander, Maori or Pacific Island children aged 1 to 8 years, diagnosed with bronchiectasis (or probable bronchiectasis) with no underlying disease identified (such as CF or primary immunodeficiency), and having had at least one episode of pulmonary exacerbation in the last 12 months. After informed consent, children are randomised to receive either azithromycin (30 mg/kg once a week) or placebo (once a week) for 12–24 months from study entry. Primary outcomes are the rate of pulmonary exacerbations and time to pulmonary exacerbation determined by review of patient medical records. Secondary outcomes include length and severity of pulmonary exacerbation episodes, changes in growth, school loss, respiratory symptoms, forced expiratory volume in 1-second (FEV 1 ; for children ≥6 years), and sputum characteristics. Safety endpoints include serious adverse events. Antibiotic resistance in respiratory bacterial pathogens colonising the nasopharynx is monitored. Data derived from medical records and clinical assessments every 3 to 4 months for up to 24 months from study entry are recorded on standardised forms. Discussion Should this trial demonstrate that azithromycin is efficacious in reducing the number of pulmonary exacerbations, it will provide a much-needed rationale for the use of long-term antibiotics in the medical management of bronchiectasis in Indigenous children. Trial registration Australian New Zealand Clinical Trials Registry: ACTRN12610000383066
Journals
2012 EN
Katharine Steinbeck · Philip Hazell · Robert G. Cumming
+17 more
Background Adolescence is characterized by marked psychosocial, behavioural and biological changes and represents a critical life transition through which adult health and well-being are established. Substantial research confirms the role of psycho-social and environmental influences on this transition, but objective research examining the role of puberty hormones, testosterone in males and oestradiol in females (as biomarkers of puberty) on adolescent events is lacking. Neither has the tempo of puberty, the time from onset to completion of puberty within an individual been studied, nor the interaction between age of onset and tempo. This study has been designed to provide evidence on the relationship between reproductive hormones and the tempo of their rise to adult levels, and adolescent behaviour, health and wellbeing. Methods/Design The ARCHER study is a multidisciplinary, prospective, longitudinal cohort study in 400 adolescents to be conducted in two centres in regional Australia in the State of New South Wales. The overall aim is to determine how changes over time in puberty hormones independently affect the study endpoints which describe universal and risk behaviours, mental health and physical status in adolescents. Recruitment will commence in school grades 5, 6 and 7 (10–12 years of age). Data collection includes participant and parent questionnaires, anthropometry, blood and urine collection and geocoding. Data analysis will include testing the reliability and validity of the chosen measures of puberty for subsequent statistical modeling to assess the impact over time of tempo and onset of puberty (and their interaction) and mean-level repeated measures analyses to explore for significant upward and downward shifts on target outcomes as a function of main effects. Discussion The strengths of this study include enrollment starting in the earliest stages of puberty, the use of frequent urine samples in addition to annual blood samples to measure puberty hormones, and the simultaneous use of parental questionnaires.
Journals
2012 EN
Fanny Minime-Lingoupou · Narcisse Beyam · Jean Chrusostome Gody
+7 more
Background Tuberculosis (TB) is a major cause of childhood morbidity and mortality in developing countries. One of the main difficulties is obtaining adequate specimens for bacteriological confirmation of the disease in children. The aim of this study is to evaluate the adequacy of fine-needle aspiration (FNA) for the diagnosis of TB. Methods In a prospective study conducted at the paediatric hospital in Bangui in 2007–2009, we used fine-needle aspiration to obtain samples for diagnosis of TB from 131 children aged 0–17 years with persistent lymphadenitis. Results Fine-needle aspiration provided samples that could be used for bacteriological confirmation of TB. Ziehl-Neelsen staining for acid-fast bacilli was positive in 42.7% of samples, and culture identified TB in 67.2% of cases. Of 75 samples that were stain-negative, 49 (65.3%) were culture-positive, while 12 stain-positive samples remained culture-negative. Ten of the 12 stain-positive, culture-negative samples were from patients who had received previous antimicrobial therapy. With regard to phenotypic drug susceptibility, 81/88 strains (91.1%) were fully susceptible to isoniazid, rifampicin, ethambutol and streptomycin, six (6.8%) were resistant to one drug, and one multidrug-resistant strain was found. Conclusions Fine-needle aspiration is simple, cost-effective and non-invasive and can be performed by trained staff. Combined with rapid molecular diagnostic tests, fine-needle aspirates could improve the diagnosis of TB and provide valuable information for appropriate treatment and drug resistance.
Journals
2012 EN
F F Hamers · Catherine Rumeau-Pichon
Background Five diseases are currently screened on dried blood spots in France through the national newborn screening programme. Tandem mass spectrometry (MS/MS) is a technology that is increasingly used to screen newborns for an increasing number of hereditary metabolic diseases. Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is among these diseases. We sought to evaluate the cost-effectiveness of introducing MCADD screening in France. Methods We developed a decision model to evaluate, from a societal perspective and a lifetime horizon, the cost-effectiveness of expanding the French newborn screening programme to include MCADD. Published and, where available, routine data sources were used. Both costs and health consequences were discounted at an annual rate of 4%. The model was applied to a French birth cohort. One-way sensitivity analyses and worst-case scenario simulation were performed. Results We estimate that MCADD newborn screening in France would prevent each year five deaths and the occurrence of neurological sequelae in two children under 5 years, resulting in a gain of 128 life years or 138 quality-adjusted life years (QALY). The incremental cost per year is estimated at €2.5 million, down to €1 million if this expansion is combined with a replacement of the technology currently used for phenylketonuria screening by MS/MS. The resulting incremental cost-effectiveness ratio (ICER) is estimated at €7 580/QALY. Sensitivity analyses indicate that while the results are robust to variations in the parameters, the model is most sensitive to the cost of neurological sequelae, MCADD prevalence, screening effectiveness and screening test cost. The worst-case scenario suggests an ICER of €72 000/QALY gained. Conclusions Although France has not defined any threshold for judging whether the implementation of a health intervention is an efficient allocation of public resources, we conclude that the expansion of the French newborn screening programme to MCADD would appear to be cost-effective. The results of this analysis have been used to produce recommendations for the introduction of universal newborn screening for MCADD in France.
Journals
2012 EN
Bruno Grollemund · Antoine Guédeney · MariePaule Vazquez
+9 more
Background The birth of a child with a cleft lip, whether or not in association with a cleft palate, is a traumatic event for parents. This prospective, multidisciplinary and multi-centre study aims to explore the perceptions and feelings of parents in the year following the birth of their child, and to analyse parent–child relationships. Four inclusion centres have been selected, differing as to the date of the first surgical intervention, between birth and six months. The aim is to compare results, also distinguishing the subgroups of parents who were given the diagnosis in utero and those who were not. Methods/Design The main hypothesis is that the longer the time-lapse before the first surgical intervention, the more likely are the psychological perceptions of the parents to affect the harmonious development of their child. Parents and children are seen twice, when the child is 4 months (T0) and when the child is one year old (T1). At these two times, the psychological state of the child and his/her relational abilities are assessed by a specially trained professional, and self-administered questionnaires measuring factors liable to affect child–parent relationships are issued to the parents. The Alarme Détresse BéBé score for the child and the Parenting Stress Index score for the parents, measured when the child reaches one year, will be used as the main criteria to compare children with early surgery to children with late surgery, and those where the diagnosis was obtained prior to birth with those receiving it at birth. Discussion The mental and psychological dimensions relating to the abnormality and its correction will be analysed for the parents (the importance of prenatal diagnosis, relational development with the child, self-image, quality of life) and also, for the first time, for the child (distress, withdrawal). In an ethical perspective, the different time lapses until surgery in the different protocols and their effects will be analysed, so as to serve as a reference for improving the quality of information during the waiting period, and the quality of support provided for parents and children by the healthcare team before the first surgical intervention. Trial Registration ClinicalTrials.gov Identifier: NCT00993993.
Journals
2012 EN
Louise Sharpe · Catherine B. Gittins · Helen Correia
+5 more
Background With an ageing population in most Western countries, people are living longer but often with one or more chronic physical health problems. Older people in physically poor health are at greater risk of developing clinical depression. Cognitive Behavioural Therapy (CBT) and Problem Solving Therapy (PST) have both been found to be efficacious in treating late-life depression, however patients with “multi-morbidity” (i.e. more than one chronic condition) are often excluded from these trials. The aim of this study is to compare the efficacy of CBT and PST in treating older adults who have one or more chronic physical health conditions and a diagnosable depressive disorder. This study will be the first to explicitly target the treatment of depression in older people in primary care settings presenting with a range of health problems using behavioural interventions. Methods/design The PROMISE-D study is a randomised controlled trial of two evidence-based treatments for late-life major or minor depression for patients who also have at least one co-morbid chronic health problem. Participants will be randomised to two active interventions (PST or CBT) or enhanced treatment-as-usual (E-TAU). Primary outcomes will be depression diagnostic status and severity of depression (according to the Hamilton Depression Rating Scale and the Geriatric Depression Scale). Secondary outcomes will be anxiety severity, quality of life and health care utilisation. Assessments will be conducted by a researcher who remains blind to the patient’s treatment allocation and will be conducted pre and post-treatment and at six and 12 months follow-up. Health care utilisation will be assessed throughout a two year period following entry to the trial. Executive function, rumination and emotion regulation will also be measured to determine the impact of these factors on treatment response in two treatment groups. Discussion Multi-morbidity, the experience of two or more chronic health problems, is becoming an increasing problem internationally, particularly amongst the elderly. Evidence-based psychological treatments exist for late-life depression and these have been shown to be effective for participants with individual health problems and depression. However, there are no studies that have compared the two leading psychotherapies shown to be effective in the treatment of late-life depression. In addition, many trials of psychotherapy with older adults exclude those with multi-morbidity. Hence, this trial will confirm whether CBT and PST are efficacious in the treatment of depression in the context of complex medical needs and determine which of these two interventions is most efficacious. Trial registration ACTRN12612000854831