Publications by authors named "Nigel Burrows"

43 Publications

Fire coral dermatitis.

Arch Dis Child 2020 Nov 5. Epub 2020 Nov 5.

Dermatology, Addenbrooke's Hospital, Cambridge, Cambridgeshire, UK.

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http://dx.doi.org/10.1136/archdischild-2020-320314DOI Listing
November 2020

Effect of a Skin Self-monitoring Smartphone Application on Time to Physician Consultation Among Patients With Possible Melanoma: A Phase 2 Randomized Clinical Trial.

JAMA Netw Open 2020 02 5;3(2):e200001. Epub 2020 Feb 5.

The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

Importance: Melanoma is among the most lethal skin cancers; it has become the fifth most common cancer in the United Kingdom, and incidence rates are rising. Population approaches to reducing incidence have focused on mass media campaigns to promote earlier presentation and potentially improve melanoma outcomes; however, interventions using smartphone applications targeting those with the greatest risk could promote earlier presentation to health care professionals for individuals with new or changing skin lesions.

Objective: To study the effect of a commercially available skin self-monitoring (SSM) smartphone application among individuals with increased risk of melanoma on their decision to seek help for changing skin lesions.

Design, Setting, And Participants: This phase 2 randomized clinical trial was conducted in 12 family practices in Eastern England between 2016 and 2017. A total of 238 participants, aged 18 to 75 years and with an increased risk of melanoma, were identified using a real-time melanoma risk assessment tool in family practice waiting rooms. Analysis was intention to treat. Participants were observed for 12 months, and data analysis was conducted from January to August 2018.

Intervention: The intervention and control groups received a consultation with standard written advice on sun protection and skin cancer detection. The intervention group had an SSM application loaded on their smartphone and received instructions for use and monthly self-monitoring reminders.

Main Outcomes And Measures: The coprimary outcomes were skin consultation rates with family practice physicians and patient intervals, measured as the time between noticing a skin change and consulting with a family practice clinician. Follow-up questionnaires were sent at 6 and 12 months, and consultation rates were extracted from family practice records. Secondary outcomes included skin self-examination benefits and barriers, self-efficacy for consulting without delay, perceived melanoma risk, sun protection habits, and potential harms.

Results: A total of 238 patients were randomized (median [interquartile range] age, 55 [43-65] years, 131 [55.0%] women, 227 [95.4%] white British; 119 [50.0%] randomized to the intervention group). Overall, 51 participants (21.4%) had consultations regarding skin changes during the 12 months of follow-up, and 157 participants (66.0%) responded to at least 1 follow-up questionnaire. There were no significant differences in skin consultation rates (adjusted risk ratio, 0.96; 95% CI, 0.56 to 1.66; P = .89), measures of SSM (adjusted mean difference, 0.08; 95% CI, -0.83 to 1.00; P = .86), or psychological harm (eg, Melanoma Worry Scale: adjusted mean difference, -0.12; 95% CI, -0.56 to 0.31; P = .58).

Conclusions And Relevance: In this study, recruitment, retention, and initial delivery of the intervention were feasible, and this research provided no evidence of harm from the SSM smartphone application. However, no evidence of benefit on skin self-examination or health care consulting was found, and there is no reason at this stage to recommend its implementation in this population at increased risk of melanoma.

Trial Registration: isrctn.org Identifier: ISRCTN16061621.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137684PMC
February 2020

Eruptive papules in a 4-year-old girl.

Pediatr Dermatol 2020 Jan;37(1):e5-e6

Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.

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http://dx.doi.org/10.1111/pde.14023DOI Listing
January 2020

Authors' reply to Mahmood, Borumandi, and Williams.

BMJ 2019 10 23;367:l6125. Epub 2019 Oct 23.

Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

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http://dx.doi.org/10.1136/bmj.l6125DOI Listing
October 2019

Ehlers-Danlos syndromes.

BMJ 2019 Sep 18;366:l4966. Epub 2019 Sep 18.

Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.

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http://dx.doi.org/10.1136/bmj.l4966DOI Listing
September 2019

Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.

Nat Commun 2019 03 8;10(1):1150. Epub 2019 Mar 8.

St. John's Institute of Dermatology, King's College London, London, Guy's Hospital, London, SE1 9RT, UK.

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.
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http://dx.doi.org/10.1038/s41467-019-09117-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408457PMC
March 2019

Atypical COL3A1 variants (glutamic acid to lysine) cause vascular Ehlers-Danlos syndrome with a consistent phenotype of tissue fragility and skin hyperextensibility.

Genet Med 2019 09 6;21(9):2081-2091. Epub 2019 Mar 6.

Ehlers-Danlos Syndrome National Diagnostic Service London, North West Thames Regional Genetics Service, London North West Healthcare University NHS Trust, Harrow, Middlesex, UK.

Purpose: The Ehlers-Danlos syndromes (EDS) are a group of rare inherited connective tissue disorders. Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance.

Methods: Clinical and molecular data for seven families with three different Glu>Lys substitutions in COL3A1 were analyzed.

Results: These Glu>Lys variants were reclassified from variants of unknown significance to either pathogenic or likely pathogenic in accordance with American College of Medical Genetics and Genomics guidelines. All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS and evidence of tissue fragility as seen in individuals with vEDS.

Conclusion: The clinical data demonstrate the overlap between the different EDS subtypes and underline the importance of next-generation sequencing gene panel analysis. The three different Glu>Lys variants point toward a new variant type in COL3A1 causative of vEDS, which has consistent clinical features. This is important knowledge for COL3A1 variant interpretation. Further follow-up data are required to establish the severity of tissue fragility complications compared with patients with other recognized molecular causes of vEDS.
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http://dx.doi.org/10.1038/s41436-019-0470-9DOI Listing
September 2019

Solitary lesion of a newborn's foot.

Pediatr Dermatol 2018 Jul;35(4):523-524

Department of Dermatology, Addenbrooke's Hospital, Cambridge, UK.

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http://dx.doi.org/10.1111/pde.13505DOI Listing
July 2018

Protocol for the melatools skin self-monitoring trial: a phase II randomised controlled trial of an intervention for primary care patients at higher risk of melanoma.

BMJ Open 2017 Nov 28;7(11):e017934. Epub 2017 Nov 28.

Department of Public Health and Primary Care, The Primary Care Unit, University of Cambridge, Cambridge, UK.

Introduction: Melanoma is the fifth most common cancer in the UK. Incidence rates have quadrupled over the last 30 years and continue to rise, especially among younger people. As routine screening of the general population is not currently recommended in the UK, a focus on secondary prevention through early detection and prompt treatment in individuals at increased risk of melanoma could make an important contribution to improve melanoma outcomes. This paper describes the protocol for a phase II, multisite, randomised controlled trial, in the primary care setting, for patients at increased risk of melanoma. A skin self-monitoring (SSM) smartphone 'App' was used to improve symptom appraisal and encourage help seeking in primary care, thereby promoting early presentation with skin changes suspicious of melanoma.

Methods And Analysis: We aim to recruit 200 participants from general practice waiting rooms in the East of England. Eligible patients are those identified at higher melanoma risk (using a real-time risk assessment tool), without a personal history of melanoma, aged 18 to 75 years. Participants will be invited to a primary care nurse consultation, and randomised to the intervention group (standard written advice on skin cancer detection and sun protection, loading of an SSM 'App' onto the participant's smartphone and instructions on use including self-monitoring reminders) or control group (standard written advice alone). The primary outcomes are consultation rates for changes to a pigmented skin lesion, and the patient interval (time from first noticing a skin change to consultation). Secondary outcomes include patient sun protection behaviours, psychosocial outcomes, and measures of trial feasibility and acceptability.

Ethics And Dissemination: NHS ethical approval has been obtained from Cambridgeshire and Hertfordshire research ethics committee (REC reference 16/EE/0248). The findings from the MelaTools SSM Trial will be disseminated widely through peer-reviewed publications and scientific conferences.

Trial Registration Number: ISCTRN16061621.
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http://dx.doi.org/10.1136/bmjopen-2017-017934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719271PMC
November 2017

Randomised controlled trial of silk therapeutic garments for the management of atopic eczema in children: the CLOTHES trial.

Health Technol Assess 2017 04;21(16):1-260

Nottingham Clinical Trials Unit, University of Nottingham, Queen's Medical Centre, Nottingham, UK.

Background: Atopic eczema (AE) is a chronic, itchy, inflammatory skin condition that affects the quality of life of children and their families. The role of specialist clothing in the management of AE is poorly understood.

Objectives: To assess the effectiveness and cost-effectiveness of silk garments for the management of AE in children with moderate to severe disease.

Design: Parallel-group, observer-blind, randomised controlled trial of 6 months' duration, followed by a 2-month observational period. A nested qualitative study evaluated the beliefs of trial participants, health-care professionals and health-care commissioners about the use of silk garments for AE.

Setting: Secondary care and the community in five UK centres.

Participants: Children aged 1-15 years with moderate or severe AE.

Interventions: Participants were randomised (1 : 1 using online randomisation) to standard care or standard care plus 100% silk garments made from antimicrobially protected knitted sericin-free silk [DermaSilk (AlPreTec Srl, San Donà di Piave, Italy) or DreamSkin (DreamSkin Health Ltd, Hatfield, UK)]. Three sets of garments were supplied per participant, to be worn for up to 6 months (day and night). At 6 months the standard care group received the garments to use for the remaining 2-month observational period.

Main Outcome Measures: Primary outcome - AE severity using the Eczema Area and Severity Index (EASI) assessed at 2, 4 and 6 months, by nurses blinded to treatment allocation. EASI scores were log-transformed for analysis. Secondary outcomes - patient-reported eczema symptoms (Patient Oriented Eczema Measure); global assessment of severity (Investigator Global Assessment); quality of life of the child (Atopic Dermatitis Quality of Life, Child Health Utility - 9 Dimensions), family (Dermatitis Family Impact Questionnaire) and main carer (EuroQoL-5 Dimensions-3 Levels); use of standard eczema treatments (e.g. emollients, topical corticosteroids); and cost-effectiveness. The acceptability and durability of the clothing, and adherence to wearing the garments, were assessed by parental/carer self-report. Safety outcomes - number of skin infections and hospitalisations for AE.

Results: A total of 300 children were randomised (26 November 2013 to 5 May 2015): 42% female, 79% white, mean age 5 years. The primary analysis included 282 out of 300 (94%) children ( = 141 in each group). Garments were worn for at least 50% of the time by 82% of participants. Geometric mean EASI scores at baseline, 2, 4 and 6 months were 8.4, 6.6, 6.0, 5.4 for standard care and 9.2, 6.4, 5.8, 5.4 for silk clothing, respectively. There was no evidence of difference between the groups in EASI score averaged over all follow-up visits adjusted for baseline EASI score, age and centre (ratio of geometric means 0.95, 95% confidence interval 0.85 to 1.07;  = 0.43). This confidence interval is equivalent to a difference of -1.5 to 0.5 in the original EASI scale units. Skin infections occurred in 39 out of 141 (28%) and 36 out of 142 (25%) participants for standard care and silk clothing groups, respectively. The incremental cost per QALY of silk garments for children with moderate to severe eczema was £56,811 from a NHS perspective in the base case. Sensitivity analyses supported the finding that silk garments do not appear to be cost-effective within currently accepted thresholds.

Limitations: Knowledge of treatment allocation may have affected behaviour and outcome reporting for some of the patient-reported outcomes.

Conclusions: The addition of silk garments to standard AE care is unlikely to improve AE severity, or to be cost-effective compared with standard care alone, for children with moderate or severe AE. This trial adds to the evidence base to guide clinical decision-making.

Future Work: Non-pharmacological interventions for the management of AE remain a research priority among patients.

Trial Registration: Current Controlled Trials ISRCTN77261365.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 21, No. 16. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta21160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410632PMC
April 2017

Dermpath & Clinic: A persistent scrotal rash.

Eur J Dermatol 2017 Apr;27(2):215-217

Department of Dermatology, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.

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http://dx.doi.org/10.1684/ejd.2017.3001DOI Listing
April 2017

Silk garments plus standard care compared with standard care for treating eczema in children: A randomised, controlled, observer-blind, pragmatic trial (CLOTHES Trial).

PLoS Med 2017 Apr 11;14(4):e1002280. Epub 2017 Apr 11.

Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, United Kingdom.

Background: The role of clothing in the management of eczema (also called atopic dermatitis or atopic eczema) is poorly understood. This trial evaluated the effectiveness and cost-effectiveness of silk garments (in addition to standard care) for the management of eczema in children with moderate to severe disease.

Methods And Findings: This was a parallel-group, randomised, controlled, observer-blind trial. Children aged 1 to 15 y with moderate to severe eczema were recruited from secondary care and the community at five UK medical centres. Participants were allocated using online randomisation (1:1) to standard care or to standard care plus silk garments, stratified by age and recruiting centre. Silk garments were worn for 6 mo. Primary outcome (eczema severity) was assessed at baseline, 2, 4, and 6 mo, by nurses blinded to treatment allocation, using the Eczema Area and Severity Index (EASI), which was log-transformed for analysis (intention-to-treat analysis). A safety outcome was number of skin infections. Three hundred children were randomised (26 November 2013 to 5 May 2015): 42% girls, 79% white, mean age 5 y. Primary analysis included 282/300 (94%) children (n = 141 in each group). The garments were worn more often at night than in the day (median of 81% of nights [25th to 75th centile 57% to 96%] and 34% of days [25th to 75th centile 10% to 76%]). Geometric mean EASI scores at baseline, 2, 4, and 6 mo were, respectively, 9.2, 6.4, 5.8, and 5.4 for silk clothing and 8.4, 6.6, 6.0, and 5.4 for standard care. There was no evidence of any difference between the groups in EASI score averaged over all follow-up visits adjusted for baseline EASI score, age, and centre: adjusted ratio of geometric means 0.95, 95% CI 0.85 to 1.07, (p = 0.43). This confidence interval is equivalent to a difference of -1.5 to 0.5 in the original EASI units, which is not clinically important. Skin infections occurred in 36/142 (25%) and 39/141 (28%) of children in the silk clothing and standard care groups, respectively. Even if the small observed treatment effect was genuine, the incremental cost per quality-adjusted life year was £56,811 in the base case analysis from a National Health Service perspective, suggesting that silk garments are unlikely to be cost-effective using currently accepted thresholds. The main limitation of the study is that use of an objective primary outcome, whilst minimising detection bias, may have underestimated treatment effects.

Conclusions: Silk clothing is unlikely to provide additional benefit over standard care in children with moderate to severe eczema.

Trial Registration: Current Controlled Trials ISRCTN77261365.
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http://dx.doi.org/10.1371/journal.pmed.1002280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388469PMC
April 2017

The 2017 international classification of the Ehlers-Danlos syndromes.

Am J Med Genet C Semin Med Genet 2017 03;175(1):8-26

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.c.31552DOI Listing
March 2017

Ehlers-Danlos syndrome, classical type.

Am J Med Genet C Semin Med Genet 2017 03 13;175(1):27-39. Epub 2017 Feb 13.

Classical EDS is a heritable disorder of connective tissue. Patients are affected with joint hypermobility, skin hyperextensibilty, and skin fragility leading to atrophic scarring and significant bruising. These clinical features suggest consideration of the diagnosis which then needs to be confirmed, preferably by genetic testing. The most recent criteria for the diagnosis of EDS were devised in Villefranche in 1997. [Beighton et al. (1998); Am J Med Genet 77:31-37]. The aims set out in the Villefranche Criteria were: to enable diagnostic uniformity for clinical and research purposes, to understand the natural history of each subtype of EDS, to inform management and genetic counselling, and to identify potential areas of research. The authors recognized that the criteria would need updating, but viewed the Villefranche nosology as a good starting point. Since 1997, there have been major advances in the molecular understanding of classical EDS. Previous question marks over genetic heterogeneity have been largely surpassed by evidence that abnormalities in type V collagen are the cause. Advances in molecular testing have made it possible to identify the causative mutation in the majority of patients. This has aided the further clarification of this diagnosis. The aim of this literature review is to summarize the current knowledge and highlight areas for future research. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.c.31548DOI Listing
March 2017

Subcutaneous Fat Necrosis of the Neonate with a Delayed Second Eruption.

Pediatr Dermatol 2016 Mar-Apr;33(2):e134-6. Epub 2016 Jan 29.

Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.

Subcutaneous fat necrosis (SCFN) of the neonate is a rare panniculitis of early life that occurs in association with gestational diabetes and preeclampsia, as well as perinatal asphyxia, hypothermia, and trauma. A characteristic feature of this condition is its self-limiting and monophasic nature. We report a highly unusual case of delayed SCFN in a male neonate involving an anatomically discrete eruption, reminiscent of erythema nodosum, occurring many weeks after his original eruption had resolved.
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http://dx.doi.org/10.1111/pde.12764DOI Listing
January 2017

A multi-centre, parallel group superiority trial of silk therapeutic clothing compared to standard care for the management of eczema in children (CLOTHES Trial): study protocol for a randomised controlled trial.

Trials 2015 Sep 2;16:390. Epub 2015 Sep 2.

Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, NG7 2UH, UK.

Background: Eczema is a chronic, itchy skin condition that can have a large impact on the quality of life of patients and their families. People with eczema are often keen to try out non-pharmacological therapies like silk therapeutic garments that could reduce itching or the damage caused by scratching. However, the effectiveness and cost-effectiveness of these garments in the management of eczema has yet to be proven. The CLOTHES Trial will test the hypothesis that 'silk therapeutic garments plus standard eczema care' is superior to 'standard care alone' for children with moderate to severe eczema.

Methods/design: Parallel group, observer-blind, pragmatic, multi-centre randomised controlled trial of 6 months' duration. Three hundred children aged 1 to 15 years with moderate to severe eczema will be randomised (1:1) to receive silk therapeutic garments plus standard eczema care, or standard eczema care alone. Primary outcome is eczema severity, as assessed by trained and blinded investigators at 2, 4 and 6 months (using the Eczema Area and Severity Index (EASI)). Secondary outcomes include: patient-reported eczema symptoms (collected weekly for 6 months to capture long-term control); global assessment of severity; quality of life of the child, family and main carer; use of standard eczema treatments (emollients, corticosteroids applied topically, calcineurin inhibitors applied topically and wet wraps); frequency of infections; and cost-effectiveness. The acceptability and durability of the clothing will also be assessed, as will adherence to wearing the garments. A nested qualitative study will assess the views of a subset of children wearing the garments and their parents, and those of healthcare providers and commissioners. Randomisation uses a computer-generated sequence of permuted blocks of randomly varying size, stratified by recruiting hospital and child's age (< 2 years; 2 to 5 years; > 5 years), and concealed using a secure web-based system. The sequence of treatment allocations will remain concealed until randomisation and data collection are complete. Recruitment is taking place from November 2013 to May 2015, and the trial will be completed in 2016. Full details of results will be published in the National Institute for Health Research Journal series.

Trial Registration: Current Controlled Trials ISRCTN77261365 (registered 11 November 2013).
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http://dx.doi.org/10.1186/s13063-015-0921-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557840PMC
September 2015

'This isn't what mine looked like': a qualitative study of symptom appraisal and help seeking in people recently diagnosed with melanoma.

BMJ Open 2014 Jul 21;4(7):e005566. Epub 2014 Jul 21.

Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

Objective: To explore symptom appraisal and help-seeking decisions among patients recently diagnosed with melanomas, and to compare experiences of people with 'thinner' (<1 mm) and 'thicker' (>2 mm) melanomas, as thickness at diagnosis is an important prognostic feature.

Methods: In-depth interviews with patients within 10 weeks of melanoma diagnosis explored the factors impacting on their pathways to diagnosis. Framework analysis, underpinned by the Model of Pathways to Treatment, was used to explore the data with particular focus on patients' beliefs and experiences, disease factors, and healthcare professional (HCP) influences.

Results: 63 patients were interviewed (29-93 years, 31 women, 30 thicker melanomas). All described their skin changes using rich lay vocabulary. Many included unassuming features such as 'just a little spot' as well as common features of changes in size, colour and shape. There appeared to be subtly different patterns of symptoms: descriptions of vertical growth, bleeding, oozing and itch were features of thicker melanomas irrespective of pathological type. Appraisal was influenced by explanations such as normal life changes, prior beliefs and whether skin changes matched known melanoma descriptions. Most decisions to seek help were triggered by common factors such as advice from family and friends. 11 patients reported previous reassurance about their skin changes by a HCP, with little guidance on monitoring change or when it would be appropriate to re-consult.

Conclusions: Patients diagnosed with both thinner and thicker melanomas often did not initially recognise or interpret their skin changes as warning signs or prompts to seek timely medical attention. The findings provide guidance for melanoma awareness campaigns on more appropriate images, helpful descriptive language and the need to stress the often apparently innocuous nature of potentially serious skin changes. The importance of appropriate advice, monitoring and safety-netting procedures by HCPs for people presenting with skin changes is also highlighted.
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http://dx.doi.org/10.1136/bmjopen-2014-005566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120305PMC
July 2014

A novel RASA1 mutation causing capillary malformation-arteriovenous malformation (CM-AVM) presenting during pregnancy.

Am J Med Genet A 2013 Jul 17;161A(7):1690-4. Epub 2013 May 17.

Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.

Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized clinical entity caused by mutation of the RASA1 gene, which encodes p120-RasGAP. Here we describe, for the first time, a patient with CM-AVM presenting during the late stages of pregnancy with pulmonary "capillary level" microvascular shunt, worsening cutaneous capillary malformations, and gross fluid overload. Sequencing revealed a novel mutation of the RASA1 gene involving a frameshift mutation in the RASGAP domain of RASA1. This report extends our current genetic and clinical understanding of CM-AVM.
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http://dx.doi.org/10.1002/ajmg.a.35935DOI Listing
July 2013

Using the 7-point checklist as a diagnostic aid for pigmented skin lesions in general practice: a diagnostic validation study.

Br J Gen Pract 2013 May;63(610):e345-53

Department of Public Health & Primary Care, Strangeways Research Laboratory, Cambridge.

Background: GPs need to recognise significant pigmented skin lesions, given rising UK incidence rates for malignant melanoma. The 7-point checklist (7PCL) has been recommended by NICE (2005) for routine use in UK general practice to identify clinically significant lesions which require urgent referral.

Aim: To validate the Original and Weighted versions of the 7PCL in the primary care setting.

Design And Setting: Diagnostic validation study, using data from a SIAscopic diagnostic aid randomised controlled trial in eastern England.

Method: Adults presenting in general practice with a pigmented skin lesion that could not be immediately diagnosed as benign were recruited into the trial. Reference standard diagnoses were histology or dermatology expert opinion; 7PCL scores were calculated blinded to the reference diagnosis. A case was defined as a clinically significant lesion for primary care referral to secondary care (total 1436 lesions: 225 cases, 1211 controls); or melanoma (36).

Results: For diagnosing clinically significant lesions there was a difference between the performance of the Original and Weighted 7PCLs (respectively, area under curve: 0.66, 0.69, difference = 0.03, P<0.001). For the identification of melanoma, similar differences were found. Increasing the Weighted 7PCL's cut-off score from recommended 3 to 4 improved detection of clinically significant lesions in primary care: sensitivity 73.3%, specificity 57.1%, positive predictive value 24.1%, negative predictive value 92.0%, while maintaining high sensitivity of 91.7% and moderate specificity of 53.4% for melanoma.

Conclusion: The Original and Weighted 7PCLs both performed well in a primary care setting to identify clinically significant lesions as well as melanoma. The Weighted 7PCL, with a revised cut-off score of 4 from 3, performs slightly better and could be applied in general practice to support the recognition of clinically significant lesions and therefore the early identification of melanoma.
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http://dx.doi.org/10.3399/bjgp13X667213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635581PMC
May 2013

A rare cutaneous presentation of metastatic parotid adenocarcinoma.

Australas J Dermatol 2013 May 2;54(2):e40-2. Epub 2012 Mar 2.

Skin Cancer Institute, Dermatological Surgical Unit, Tauranga, New Zealand.

Primary adenocarcinomas of the parotid gland are rare, accounting for < 5% of all head and neck malignant neoplasms. The biological behaviour of these tumours varies considerably. Low-grade tumours are minimally invasive, whereas high-grade tumours show a high incidence of local recurrence and distant metastases. We report a case of metastatic parotid adenocarcinoma which presented with cutaneous features. This case illustrates that such salivary gland malignancies can very rarely present to the dermatologist. These potentially aggressive tumours require prompt diagnosis and management with multidisciplinary team input to ensure that the appropriate treatment is instigated.
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http://dx.doi.org/10.1111/j.1440-0960.2011.00865.xDOI Listing
May 2013

The cost-effectiveness of a novel SIAscopic diagnostic aid for the management of pigmented skin lesions in primary care: a decision-analytic model.

Value Health 2013 Mar-Apr;16(2):356-66

Health Economics Group, University of East Anglia, Norwich, UK.

Objectives: Pigmented skin lesions are commonly presented in primary care. Appropriate diagnosis and management is challenging because the vast majority are benign. The MoleMate system is a handheld SIAscopy scanner integrated with a primary care diagnostic algorithm aimed at improving the management of pigmented skin lesions in primary care.

Methods: This decision-model-based economic evaluation draws on the results of a randomized controlled trial of the MoleMate system versus best practice (ISRCTN79932379) to estimate the expected long-term cost and health gain of diagnosis with the MoleMate system versus best practice in an English primary care setting. The model combines trial results with data from the wider literature to inform long-term prognosis, health state utilities, and cost.

Results: Results are reported as mean and incremental cost and quality-adjusted life-years (QALYs) gained, incremental cost-effectiveness ratio with probabilistic sensitivity analysis, and value of information analysis. Over a lifetime horizon, the MoleMate system is expected to cost an extra £18 over best practice alone, and yield an extra 0.01 QALYs per patient examined. The incremental cost-effectiveness ratio is £1,896 per QALY gained, with a 66.1% probability of being below £30,000 per QALY gained. The expected value of perfect information is £43.1 million.

Conclusions: Given typical thresholds in the United Kingdom (£20,000-£30,000 per QALY), the MoleMate system may be cost-effective compared with best practice diagnosis alone in a primary care setting. However, there is considerable decision uncertainty, driven particularly by the sensitivity and specificity of MoleMate versus best practice, and the risk of disease progression in undiagnosed melanoma; future research should focus on reducing uncertainty in these parameters.
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http://dx.doi.org/10.1016/j.jval.2012.12.008DOI Listing
May 2013

Effect of adding a diagnostic aid to best practice to manage suspicious pigmented lesions in primary care: randomised controlled trial.

BMJ 2012 Jul 4;345:e4110. Epub 2012 Jul 4.

The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 0SR, UK.

Objectives: To assess whether adding a novel computerised diagnostic tool, the MoleMate system (SIAscopy with primary care scoring algorithm), to current best practice results in more appropriate referrals of suspicious pigmented lesions to secondary care, and to assess its impact on clinicians and patients.

Design: Randomised controlled trial.

Setting: 15 general practices in eastern England.

Participants: 1297 adults with pigmented skin lesions not immediately diagnosed as benign.

Interventions: Patients were assessed by trained primary care clinicians using best practice (clinical history, naked eye examination, seven point checklist) either alone (control group) or with the MoleMate system (intervention group).

Main Outcome Measures: Appropriateness of referral, defined as the proportion of referred lesions that were biopsied or monitored. Secondary outcomes related to the clinicians (diagnostic performance, confidence, learning effects) and patients (satisfaction, anxiety). Economic evaluation, diagnostic performance of the seven point checklist, and five year follow-up of melanoma incidence were also secondary outcomes and will be reported later.

Results: 1297 participants with 1580 lesions were randomised: 643 participants with 788 lesions to the intervention group and 654 participants with 792 lesions to the control group. The appropriateness of referral did not differ significantly between the intervention or control groups: 56.8% (130/229) v 64.5% (111/172); difference -8.1% (95% confidence interval -18.0% to 1.8%). The proportion of benign lesions appropriately managed in primary care did not differ (intervention 99.6% v control 99.2%, P=0.46), neither did the percentage agreement with an expert decision to biopsy or monitor (intervention 98.5% v control 95.7%, P=0.26). The percentage agreement with expert assessment that the lesion was benign was significantly lower with MoleMate (intervention 84.4% v control 90.6%, P<0.001), and a higher proportion of lesions were referred (intervention 29.8% v control 22.4%, P=0.001). Thirty six histologically confirmed melanomas were diagnosed: 18/18 were appropriately referred in the intervention group and 17/18 in the control group. Clinicians in both groups were confident, and there was no evidence of learning effects, and therefore contamination, between groups. Patients in the intervention group ranked their consultations higher for thoroughness and reassuring care, although anxiety scores were similar between the groups.

Conclusions: We found no evidence that the MoleMate system improved appropriateness of referral. The systematic application of best practice guidelines alone was more accurate than the MoleMate system, and both performed better than reports of current practice. Therefore the systematic application of best practice guidelines (including the seven point checklist) should be the paradigm for management of suspicious skin lesions in primary care.

Trial Registration: Current Controlled Trials ISRCTN79932379.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389518PMC
http://dx.doi.org/10.1136/bmj.e4110DOI Listing
July 2012

The spectrum of spitzoid tumours: A clinical study.

Australas J Dermatol 2012 Aug 4;53(3):211-5. Epub 2012 Jun 4.

Skin Cancer Institute, Dermatological Surgical Unit, 171 Cameron Rd., Tauranga, New Zealand.

This study explores the relationship between different types of spitzoid tumours, spindle cell naevus of Reed and spitzoid melanomas. Clinical and histopathological data were retrospectively reviewed from our hospital database in Cambridge from January 2006 to July 2009. Clinical images, where available, were recorded. Search headings from our pathology database included 'spitzoid tumours', 'Spitz naevi', 'atypical spitzoid tumours', spitzoid tumours of uncertain malignant potential ('STUMP'), 'spindle cell naevus of Reed' and 'spitzoid melanomas'. The total number of spitzoid tumours was 118 comprising Spitz naevi (72), atypical spitzoid tumours (30), spitzoid melanomas (eight), and other naevi with spitzoid features (eight). In total, 60% of Spitz naevi were diagnosed clinically and 50% reported a history of change with spitzoid melanoma, compared with 32% with Spitz naevi. In all, 60% of Spitz naevi and atypical spitzoid tumours were pigmented in contrast with spitzoid melanomas (83%). Variegated pigmentation was found in 20% of Spitz naevi and atypical spitzoid tumours, however, no spitzoid melanomas had mixed pigmentation. There were 30 atypical spitzoid tumours (9 M : 21 F); 16 occurred on the lower limbs, peaking in the 20-30-years age group. There were eight patients with spitzoid melanomas with a 7:1 F : M ratio, 50% of which were diagnosed clinically. Of the 34 spindle cell naevus of Reed (10 M : 24 F), 31 were misdiagnosed, most commonly as melanoma. Reed naevi peaked in the 30-40 year age group and on the upper limbs and lower limbs in the 20-30-years age group. In summary, age and sex appeared helpful in distinguishing benign from malignant spitzoid tumours, however history was less discriminatory. Spitzoid melanomas, most of which were pigmented occurred more commonly in females. Atypical spitzoid tumours were more common in females and pathologists favoured malignancy in this group beyond 20 years of age.
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http://dx.doi.org/10.1111/j.1440-0960.2012.00902.xDOI Listing
August 2012

Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1.

Nat Genet 2011 Feb 27;43(4):365-9. Epub 2011 Feb 27.

Human Genetics Unit, University of Dundee College of Medicine, Dentistry and Nursing, Dundee, UK.

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome-related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer.
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http://dx.doi.org/10.1038/ng.780DOI Listing
February 2011

Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases.

Arch Dermatol 2011 Jun 21;147(6):681-6. Epub 2011 Feb 21.

Centre for Cutaneous Research, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, 4 Newark St, London E1 2AT, England.

Objective: To assess the clinical outcomes of 45 cases of harlequin ichthyosis and review the underlying ABCA12 gene mutations in these patients.

Design: Multicenter, retrospective, questionnaire-based survey.

Setting: Dermatology research institute.

Participants: Patients with harlequin ichthyosis for whom we had performed ABCA12 mutation analysis.

Main Outcome Measures: Referring physicians were asked to complete a questionnaire using the patients' notes, detailing the clinical outcome of the affected child. In each case, the causative ABCA12 mutation was identified using standard polymerase chain reaction and sequencing techniques.

Results: Of the 45 cases, the ages of the survivors ranged from 10 months to 25 years, with an overall survival rate of 56%. Death usually occurred in the first 3 months and was attributed to sepsis and/or respiratory failure in 75% of cases. The early introduction of oral retinoids may improve survival, since 83% of those treated survived, whereas 76% who were not given retinoids died. Recurrent skin infections in infancy affected one-third of patients. Problems maintaining weight affected 44%. Three children developed an inflammatory arthritis, and developmental delay was reported in 32%. Mutation analysis revealed that 52% of survivors had compound heterozygous mutations, whereas all deaths were associated with homozygous mutations.

Conclusions: Harlequin ichthyosis should be regarded as a severe chronic disease that is not invariably fatal. With improved neonatal care and probably the early introduction of oral retinoids, the number of survivors is increasing. Compound heterozygotes appear to have a survival advantage.
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http://dx.doi.org/10.1001/archdermatol.2011.9DOI Listing
June 2011

Hyperkeratotic papules in a child with Down syndrome. Diagnosis: acquired reactive perforating collagenosis in Down syndrome.

Pediatr Dermatol 2011 Jan-Feb;28(1):53-4

Department of Dermatology, Addenbrooke's Hospital, Cambridge, UK.

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http://dx.doi.org/10.1111/j.1525-1470.2010.01368.xDOI Listing
June 2011

Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF).

Intensive Care Med 2011 Apr 6;37(4):619-26. Epub 2011 Jan 6.

Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland.

Purpose: We performed a survey on acute heart failure (AHF) in nine countries in four continents. We aimed to describe characteristics and management of AHF among various countries, to compare patients with de novo AHF versus patients with a pre-existing episode of AHF, and to describe subpopulations hospitalized in intensive care unit (ICU) versus cardiac care unit (CCU) versus ward.

Methods And Results: Data from 4,953 patients with AHF were collected via questionnaire from 666 hospitals. Clinical presentation included decompensated congestive HF (38.6%), pulmonary oedema (36.7%) and cardiogenic shock (11.7%). Patients with de novo episode of AHF (36.2%) were younger, had less comorbidities and lower blood pressure despite greater left ventricular ejection fraction (LVEF) and were more often admitted to ICU. Overall, intravenous (IV) diuretics were given in 89.7%, vasodilators in 41.1%, and inotropic agents (dobutamine, dopamine, adrenaline, noradrenaline and levosimendan) in 39% of cases. Overall hospital death rate was 12%, the majority due to cardiogenic shock (43%). More patients with de novo AHF (14.2%) than patients with a pre-existing episode of AHF (10.8%) (p = 0.0007) died. There was graded mortality in ICU, CCU and ward patients with mortality in ICU patients being the highest (17.8%) (p < 0.0001).

Conclusions: Our data demonstrated the existence of different subgroups based on de novo or pre-existing episode(s) of AHF and the site of hospitalization. Recognition of these subgroups might improve management and outcome by defining specific therapeutic requirements.
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http://dx.doi.org/10.1007/s00134-010-2113-0DOI Listing
April 2011

Protocol for the MoleMate UK Trial: a randomised controlled trial of the MoleMate system in the management of pigmented skin lesions in primary care [ISRCTN 79932379].

BMC Fam Pract 2010 May 11;11:36. Epub 2010 May 11.

General Practice & Primary Care Research Unit, Department of Public Health & Primary Care, University of Cambridge, Cambridge, UK.

Background: Suspicious pigmented lesions are a common presenting problem in general practice consultations; while the majority are benign a small minority are melanomas. Differentiating melanomas from other pigmented lesions in primary care is challenging: currently, 95% of all lesions referred to a UK specialist are benign. The MoleMate system is a new diagnostic aid, incorporating a hand-held SIAscopy scanner with a primary care diagnostic algorithm. This trial tests the hypothesis that adding the MoleMate system to current best primary care practice will increase the proportion of appropriate referrals of suspicious pigmented lesions to secondary care compared with current best practice alone.

Methods/design: The MoleMate UK Trial is a primary care based multi-centre randomised controlled trial, with randomisation at patient level using a validated block randomisation method for two age groups (45 years and under; 46 years and over). We aim to recruit adult patients seen in general practice with a pigmented skin lesion that cannot immediately be diagnosed as benign and the patient reassured. The trial has a 'two parallel groups' design, comparing 'best practice' with 'best practice' plus the MoleMate system in the intervention group. The primary outcome is the positive predictive value (PPV) of referral defined as the proportion of referred lesions seen by secondary care experts that are considered 'clinically significant' (i.e. biopsied or monitored). Secondary outcomes include: the sensitivity, specificity and negative predictive value (NPV) of the decision not to refer; clinical outcomes (melanoma thickness, 5 year melanoma incidence and mortality); clinician outcomes (Index of Suspicion, confidence, learning effects); patient outcomes (satisfaction, general and cancer-specific worry), and cost-utility.

Discussion: The MoleMate UK Trial tests a new technology designed to improve the management of suspicious pigmented lesions in primary care. If effective, the MoleMate system could reduce the burden on skin cancer clinics of patients with benign pigmented skin lesions, and improve patient care in general practice.
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http://dx.doi.org/10.1186/1471-2296-11-36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881908PMC
May 2010