Diagnostic accuracy of autofluorescence-Raman spectroscopy for surgical margin assessment during Mohs micrographic surgery of basal cell carcinoma.

BACKGROUND: Autofluorescence (AF) - Raman spectroscopy is a technology that can detect residual basal cell carcinoma (BCC) on the resection margin of fresh surgically excised tissue specimens. The technology does not require tissue fixation, staining, labelling, or sectioning, and provides quantitative diagnosis maps of the surgical margins in 30 minutes. OBJECTIVES: To determine the accuracy of the AF-Raman instrument to detect incomplete excisions of BCC during Mohs micrographic surgery, using histology as reference standard. METHODS: Skin layers from 130 patients undergoing Mohs surgery at the Nottingham University Hospitals NHS Trust (September 2022 to July 2023) were investigated with the AF-Raman instrument. The layers were measured fresh, immediately after excision. The AF-Raman results and the intra-operative assessment by Mohs surgeons were compared to a post-operative consensus-derived reference produced by three dermatopathologists. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS: The AF-Raman analysis was successfully completed for 125 out of the 130 layers. The AF-Raman analysis covered 91% of the specimen surface area on average, with the lowest being 87% for eyelid and the highest being 94% for forehead specimens. The AF-Raman instrument identified positive margins in 24 out of 36 BCC-positive cases, resulting in a 67% sensitivity (95% confidence intervals (CI): 49%-82%) and negative margins in 65 out of 89 BCC-negative cases, resulting in a 73% specificity (95% CI 63%-82%). Only one out of the 12 false negative cases was caused by misclassification by the AF-Raman algorithm. The other 11 false negatives cases were produced because no valid Raman signal was recorded at the location of the residual BCC due to either occlusion by blood or poor contact between tissue and cassette window. The intra-operative diagnosis by Mohs surgeons identified positive margins in 31 out of 36 BCC-positive cases, 86% sensitivity (95% CI: 70%-95%), and negative margins in 79 out of 89 BCC-negative cases, 89% specificity (95% CI: 81%-95%). CONCLUSIONS: This study shows that the AF-Raman instrument has potential for intra-operative microscopic assessment of surgical margins in surgery of BCC. Further improvements are required for tissue processing to ensure complete coverage of the surgical specimens. ClinicalTrials.gov ID NCT03482622.

'Get Data Out' Skin: national cancer registry incidence and survival rates for all registered skin tumour groups for 2013-2019 in England.

BACKGROUND: Providing detailed skin cancer statistics, including incidence and survival, by tumour type and patient characteristics is important for up-to-date epidemiological information. OBJECTIVES: To create a new clinically relevant consensus-based classification for registered skin tumours using tumour type and patient characteristics and to describe its application to all registered tumours in England between 2013 and 2019. METHODS: Tumours with skin topographical codes (ICD-10) and morphology and behaviour (ICD-O3) were grouped together in an iterative process creating a hierarchical tree structure. The primary-level grouping partitioned skin tumours into skin cancer, melanoma in situ, extramammary Paget disease (EMPD) and tumours of uncertain malignant potential. Second-level groups split skin cancer into keratinocyte cancer (KC), melanoma and rare cancers. The third-level group split KC into basal cell carcinoma (BCC) and squamous cell carcinoma (cSCC). Further groups were split into genital or non-genital, first or subsequent tumour, age, gender, stage, or National Health Service (NHS) region. Incidence counts, Kaplan-Meier and net survival estimates and referral routes [two-week wait (TWW), general practitioner (GP), outpatient] categorisations were calculated for each grouping across all years. RESULTS: A total of 1 445 377 skin cancers and 49 123 precancerous lesions and undefined entities were registered in England between 2013 and 2019. Skin tumours and skin cancer incidence rates are increasing for most tumour types. The most common type of skin cancer was BCC with an incidence rate of 282.36 per 100 000 person-years (PYs) [n = 158 934, 95% confidence interval (CI) 280.98-283.76] in 2019, followed by cSCC with an incidence rate of 85.24 per 100 000 PYs (n = 47 977, 95% CI 84.48-86.00) and melanoma with 27.24 (n = 15 332, 95% CI 26.81-27.67) per 100 000 PYs. Each year approximately 1800 rare skin cancers, 1500 genital cSCCs and 100 cases of EMPD are registered. Of 15 000 melanoma cases, 120 cases of melanoma occur in individuals aged < 25 years annually. One-year and five-year overall net survival varies by tumour type. cSCC 5-year net survival (89.8%, 95% CI 88.8-90.9) was comparable to the net survival of all melanomas (89.6%, 95% CI 88.7-90.6). BCC had excellent survival (overall net survival > 100%). Patients with late-stage melanoma, Merkel cell carcinoma and genital cSCC have a 5-year net survival < 60%. Older patients received fewer TWW referrals than their younger counterparts with the same tumour type at the same location. Patients with acral lentiginous melanoma had fewer TWW referrals and more standard GP referrals than patients with common melanomas. CONCLUSIONS: 'Get Data Out' Skin provides detailed and up-to-date statistics on all registrable skin tumours in England, including for the first time precancerous lesions and rare subtypes of common cancers. These data can be used by clinicians, researchers and commissioners to better understand skin cancer and improve resource allocation.

Analgesic utilization in people with knee osteoarthritis: A population-based study using primary care data.

PURPOSE: Osteoarthritis (OA) is a chronic painful condition that often affects large joints such as the knee. Treatment guidelines recommend paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. Antidepressants and anti-epileptic drugs (AEDs) are commonly prescribed for chronic noncancer pain conditions including OA, as an off-label use. This study describes analgesic utilization in patients with knee OA at population level using standard pharmaco-epidemiological methods. METHOD: This was a cross-sectional study between 2000 and 2014 using data from the U.K. Clinical Practice Research Datalink (CPRD). The use of antidepressants, AEDs, opioids, NSAIDs, and paracetamol was studied in adults with knee OA using the following measures: annual number of prescriptions, defined daily doses (DDD), oral morphine equivalent dose (OMEQ), and days' supply. RESULTS: In total, there were 8,944,381 prescriptions prescribed for 117,637 patients with knee OA during the 15-year period. There was a steady increase in the prescribing of all drug classes, except for NSAIDs, over the study period. Opioids were the most prevalent class prescribed in every study year. Tramadol was the most commonly prescribed opioid, with the number of DDD increasing from 0.11 to 0.71 DDDs per 1000 registrants in 2000 and 2014, respectively. The largest increase in prescribing was for AEDs, where the number of prescriptions increased from 2 to 11 per 1000 CPRD registrants. CONCLUSION: There was an overall increase in the prescribing of analgesics apart from NSAIDs. Opioids were the most frequently prescribed class; however, the greatest increase in prescribing between 2000 and 2014 was observed in AEDs.

Using the Vitiligo Noticeability Scale in clinical trials: construct validity, interpretability, reliability and acceptability.

BACKGROUND: Validated outcome measures are needed for vitiligo trials. OBJECTIVES: To assess construct validity, interpretability, reliability and acceptability of the Vitiligo Noticeability Scale (VNS). METHODS: We used images of vitiligo before and after treatment, plus outcome data, from the HI-Light Vitiligo trial. We compared outcome assessments made by trial participants with assessments of images by clinicians and people with vitiligo who were not trial participants [Patient and Public Involvement (PPI) panel]. Hypothesis testing assessed psychometric properties of the VNS, with κ statistics to assess agreement between outcomes. Three focus groups and two online discussion groups provided insight into the use of VNS by people with vitiligo. RESULTS: Our hypothesis of a positive association between VNS and participant-reported global treatment success was supported for trial participants (κ = 0·41 if VNS success was defined as ≥ 4; κ = 0·71 if VNS success was defined as ≥ 3), but not for the blinded PPI panel (κ = 0·28). As hypothesized, the association with participant-reported global success was higher for VNS (κ = 0·41) than for clinician-reported percentage repigmentation (κ = 0·17). Seventy-five per cent of trial participants valued a VNS of 3 (partial response) as a treatment success. Test-retest reliability was good: κ = 0·69 (95% confidence interval 0·63-0·74). Age and skin phototype did not influence interpretation of the VNS scores. To people with vitiligo, the VNS is an acceptable and meaningful patient-reported outcome measure. CONCLUSIONS: Trial participants may assess their vitiligo differently compared with blinded assessors. A VNS score of 3 may be more highly valued by people undergoing vitiligo treatment than was previously thought. What is already known about this topic? Vitiligo is a common condition, and can have a considerable psychological impact. A Vitiligo Core Outcome Set is being developed, to enable the results of vitiligo trials to be compared and combined more easily. The Vitiligo Noticeability Scale (VNS) is a patient-reported outcome measure (PROM) developed in partnership with people with vitiligo; initial validation studies have been promising. What does this study add? The VNS shows good construct validity, reliability and acceptability; it can be used in all ages and skin phototypes. All five levels of the VNS scale should be reported for transparency, to aid interpretation of trial findings, and to facilitate meta-analysis in systematic reviews. VNS assessments made by trial participants and independent observers are likely to be qualitatively different, making blinded assessment of VNS by independent observers difficult to interpret. Blinding of participants to trial interventions is recommended whenever possible. What are the clinical implications of the work? The VNS can be used as a PROM to assess the cosmetic acceptability of repigmentation at individual patches of vitiligo. A VNS score of 3 or more is likely to be valued by patients as a treatment success.

Dermatofibrosarcoma Protuberans Re-excision and Recurrence Rates in the Netherlands Between 1989 and 2016.

Dermatofibrosarcoma protuberans is a rare soft tissue tumour with a very low (p < 0.5%) rate of metastasis. Rates of re-excision and recurrence were determined using data from the Netherlands Cancer Registry between 1989 and 2016. Of the 1,890 instances of dermatofibrosarcoma protuberans included, 87% were treated with excision, 4% with Mohs micrographic surgery, and 9% otherwise or unknown. Linked pathology data were retrieved for 1,677 patients. Half of all excisions (847/1,644) were incomplete and 29% (192/622) of all re-excisions were incomplete. The cumulative incidence of a recurrence was 7% (95% confidence interval (95% CI) 6-8) during a median follow-up of 11 years (interquartile range (IQR) 6-17). After Mohs micrographic surgery (n = 34), there were no recurrences during a median follow-up of 4 years (IQR 3-6). Due to the high rate of incomplete excisions and recurrences after excision, this study supports the European guideline, which recommends treating dermatofibrosarcoma protuberans with Mohs micrographic surgery in order to decrease the rate of recurrence.

"Application of five different strategies to define a cohort of patients with knee osteoarthritis in a large primary care database".

BACKGROUND: Electronic health records (EHR) are frequently used for epidemiological research including drug utilisation studies in a defined population such as the population with knee osteoarthritis (KOA). We sought to describe the process of defining a cohort of patients with KOA from a large UK primary care database and estimate the annual incidence of diagnosed KOA between 2000 and 2015. METHOD: This was a retrospective study using data from the clinical practice research datalink (CPRD). CPRD is a large primary care longitudinal electronic medical records' database that contains anonymous records of patients from general practices across United Kingdom. Five different cohort definition strategies were applied including symptoms-based or diagnosis-based strategies or a combination of both. To validate results, the annual incidence of KOA was estimated and compared to published data. RESULTS: The study defined 898,690 patients when symptoms-based strategy was applied, 137,541 patients when diagnosis based and 83,294 when a combination of both strategies were applied. The final cohort was defined using a diagnosis-based strategy that avoided overestimation (with symptoms-based definition) or underestimation (with a combination of symptoms and diagnosis). The incidence of KOA ranged from 1.33 per 1000 CPRD registrants in 2000, 1.76 in 2008 and 1.45 patients in 2015. CONCLUSION: This study logically/sensibly defined a cohort of patients with diagnosed KOA through the application of several strategies. This was an essential step to avoid subsequent over or underestimation of the prevalence of drug utilisation and the associated adverse clinical outcomes within primary care patients with KAO.

The majority of observational studies in leading peer-reviewed medicine journals are not registered and do not have a publicly accessible protocol: a scoping review.

OBJECTIVES: Observational studies are not subject to the same requirements as randomized controlled trials, such as registration or publishing a protocol. The aim of this scoping review was to estimate the registration rate of observational studies in leading peer-reviewed medicine journals and to evaluate whether protocols were available in the public domain. STUDY DESIGN AND SETTING: In March 2023, we searched OVID Medline for observational studies published in 2022 in the top five general medicine journals according to impact factor (The Lancet, The British Medical Journal (BMJ), The Journal of the American Medical Association, The New England Journal of Medicine, and Annals of Internal Medicine). We defined an observational study as a cohort study, a case-control study, a cross-sectional study, or a case series. Information on i) the proportion of observational studies that have been registered and ii) the proportion of observational studies that have a protocol available in the public domain was extracted from a random sample of studies. RESULTS: Our search identified 699 studies; 290 studies were selected as full text, and a random sample of 200 studies was included. For half of the studies, the first author worked at a US institution. Most studies were cohort studies (n = 126, 63.0%) and used administrative healthcare records, electronic healthcare records, and registries. Of the 200 observational studies, 20 (10.0%) were registered. Among those, 14 were prospectively registered. Twenty-four studies (12.0%) had a protocol available in the public domain. Studies that were registered or had a protocol, were more frequently published in the BMJ (n = 12/28, 42.9%), had a first author working in the UK (n = 10/28, 35.7%) and used electronic health care records (n = 13/28, 46.4%) compared to studies with no registration and no protocol. CONCLUSION: The rate of prospectively registered observational studies is worryingly low. Prospective registration of observational studies should be encouraged and standardized to ensure transparency in clinical research and reduce research waste.

Current use of analgesics and the risk of falls in people with knee osteoarthritis: A population-based cohort study using primary care and hospital records.

Objective: To examine the association between the current use of analgesics and the risk of falls in people with knee osteoarthritis (KOA). Methods: A retrospective cohort study using data from the UK Clinical Practice Research Datalink, with linkage to Hospital Episode Statistics data. People diagnosed with KOA in England between 2000 and 2014 were included. The studied analgesic classes were antidepressants, antiepileptic drugs (AEDs), opioids, non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol. Cox Proportional Hazards model was used to estimate the risk of fall with current use of analgesics within one year of KOA diagnosis, reported as Hazard Ratio (HR) with 95% Confidence Intervals (CI). Results: This study included 57,383 patients (mean age [SD] 67.0 [12.8] years, 59.3% were female); 44,010 (76.7%) were prescribed analgesics at least once within one year of KOA diagnosis. Within the first six months of KOA diagnosis, the reported HR (95%CI) were 1.46 (1.20, 1.78), 1.40 (0.91, 2.16), 2.40 (2.01, 2.85), 1.72 (1.43, 2.07), 1.98 (1.68, 2.33), while between 6 and 12 months after KOA diagnosis, the HR (95%CI) were 2.68 (2.14, 3.36), 2.22 (1.70, 2.91), 1.96 (1.70, 2.26), 1.47 (1.21, 1.78), 1.92 (1.63, 2.26) for antidepressants, AEDs, opioids, NSAIDs and paracetamol, respectively and adjusted for important potential confounders. Conclusion: The current use of analgesics was associated with an increased risk of falls within one year of KOA diagnosis. These findings identify people with KOA who use analgesics as a priority for fall prevention programs/interventions, in an effort to optimise safety of analgesics in this population.

Long-term oral prednisolone exposure in primary care for bullous pemphigoid: population-based study.

BACKGROUND: Oral prednisolone is the mainstay treatment for bullous pemphigoid, an autoimmune blistering skin disorder affecting older people. Treatment with moderate-to-high doses is often initiated in secondary care, but then continued in primary care. AIM: To describe long-term oral prednisolone prescribing in UK primary care for adults with bullous pemphigoid from 1998 to 2017. DESIGN AND SETTING: A prospective cohort study using routinely collected data from the Clinical Practice Research Datalink, a primary care database containing the healthcare records for over 17 million people in the UK. METHOD: Oral prednisolone exposure was characterised in terms of the proportion of individuals with incident bullous pemphigoid prescribed oral prednisolone following their diagnosis, and the duration and dose of prednisolone. RESULTS: In total, 2312 (69.6%) of 3322 people with bullous pemphigoid were prescribed oral prednisolone in primary care. The median duration of exposure was 10.6 months (interquartile range [IQR] 3.4-24.0). Of prednisolone users, 71.5% were continuously exposed for >3 months, 39.7% for >1 year, 14.7% for >3 years, 5.0% for >5 years, and 1.7% for >10 years. The median cumulative dose was 2974 mg (IQR 1059-6456). Maximum daily doses were ≥10 mg/day in 74.4% of prednisolone users, ≥20 mg/day in 40.7%, ≥30 mg/day in 18.2%, ≥40 mg/day in 6.6%, ≥50 mg/day in 3.8%, and ≥60 mg/day in 1.9%. CONCLUSION: A high proportion of people with incident bullous pemphigoid are treated with oral prednisolone in UK primary care. Action is required by primary and second care services to encourage use of steroid-sparing alternatives and, where switching is not possible, ensure prophylactic treatments and proactive monitoring of potential side effects are in place.

Validation study of bullous pemphigoid and pemphigus vulgaris recording in routinely collected electronic primary healthcare records in England.

OBJECTIVES: The validity of bullous pemphigoid and pemphigus vulgaris recording in routinely collected healthcare data in the UK is unknown. We assessed the positive predictive value (PPV) for bullous pemphigoid and pemphigus vulgaris primary care Read codes in the Clinical Practice Research Datalink (CPRD) using linked inpatient data (Hospital Episode Statistics (HES)) as the diagnostic benchmark. SETTING: Adult participants with bullous pemphigoid or pemphigus vulgaris registered with HES-linked general practices in England between January 1998 and December 2017. Code-based algorithms were used to identify patients from the CPRD and extract their benchmark blistering disease diagnosis from HES. PRIMARY OUTCOME MEASURE: The PPVs of Read codes for bullous pemphigoid and pemphigus vulgaris. RESULTS: Of 2468 incident cases of bullous pemphigoid and 431 of pemphigus vulgaris, 797 (32.3%) and 85 (19.7%) patients, respectively, had a hospitalisation record for a blistering disease. The PPV for bullous pemphigoid Read codes was 93.2% (95% CI 91.3% to 94.8%). Of the bullous pemphigoid cases, 3.0% had an HES diagnosis of pemphigus vulgaris and 3.8% of another blistering disease. The PPV for pemphigus vulgaris Read codes was 58.5% (95% CI 48.0% to 68.9%). Of the pemphigus vulgaris cases, 24.7% had an HES diagnosis of bullous pemphigoid and 16.5% of another blistering disease. CONCLUSIONS: The CPRD can be used to study bullous pemphigoid, but recording of pemphigus vulgaris needs to improve in primary care.

Protocol for a case-control diagnostic accuracy study to develop diagnostic criteria for psoriasis in children (DIPSOC study): a multicentre study recruiting in UK paediatric dermatology clinics.

INTRODUCTION: Diagnosing psoriasis in children can be challenging. Early and accurate diagnosis is important to ensure patients receive psoriasis specific treatment and monitoring. It is recognised that the physical, psychological, quality of life, financial and comorbid burden of psoriasis are significant. The aim of this study is to develop clinical examination and history-based diagnostic criteria for psoriasis in children to help differentiate psoriasis from other scaly inflammatory rashes. The criteria tested in this study were developed through a consensus study with a group of international psoriasis experts (International Psoriasis Council). METHODS AND ANALYSIS: Children and young people (<18 years) with psoriasis (cases) and other scaly inflammatory skin diseases (controls) diagnosed by a dermatologist are eligible for recruitment. All participants complete a single research visit including a diagnostic criteria assessment by a trained investigator blinded to the participant's diagnosis. The reference standard of a dermatologist's diagnosis is extracted from the medical record. Sensitivity and specificity of the consensus derived diagnostic criteria will be calculated and the best predictive criteria developed using multivariate logistic regression. ETHICS AND DISSEMINATION: Health Regulatory Authority and National Health Service Research Ethics Committee approvals were granted in February 2017 (REC Ref: 17/EM/0035). Dissemination will be guided by stakeholders; patients, children and young people, dermatologists, primary care and paediatric rheumatologists. The aim is to publish the study results in a high-quality peer-reviewed journal, present the findings at international academic meetings and disseminate more widely through social media and working with patient associations. TRIAL REGISTRATION NUMBER: ISRCTN98851260.

Association Between Topical Corticosteroid Use and Type 2 Diabetes in Two European Population-Based Adult Cohorts.

OBJECTIVE: Topical corticosteroids (CSs) are commonly used to treat inflammatory skin conditions including eczema and psoriasis. Although topical CS package inserts describe hyperglycemia and glycosuria as adverse drug reactions, it is unclear whether topical CS use in real life is also associated with an increased risk of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Two matched case-control studies and one cohort study were conducted using routinely collected health care data from Denmark and the U.K. A total of 115,218 and 54,944 adults were identified as case subjects with new-onset T2D in the Danish and U.K. case-control study, respectively. For the Danish cohort study, 2,689,473 adults were included. The main exposure was topical CSs, and the outcome was incident T2D. RESULTS: Topical CS was significantly associated with T2D in the Danish (adjusted odds ratio [OR] 1.25 [95% CI 1.23-1.28]) and U.K. (adjusted OR 1.27 [95% CI 1.23-1.31]) case-control studies. Individuals who were exposed to topical CSs had significantly increased risk of incident T2D (adjusted hazard ratio 1.27 [95% CI 1.26-1.29]). We observed significant dose-response relationships between T2D and increasing potency of topical CSs in the two Danish studies. The results were consistent across all sensitivity analyses. CONCLUSIONS: We found a positive association between topical CS prescribing and incident T2D in Danish and U.K. adult populations. Clinicians should be cognizant of possible diabetogenic effects of potent topical CSs.