Weighted metrics are required when evaluating the performance of prediction models in nested case-control studies.

BACKGROUND: Nested case-control (NCC) designs are efficient for developing and validating prediction models that use expensive or difficult-to-obtain predictors, especially when the outcome is rare. Previous research has focused on how to develop prediction models in this sampling design, but little attention has been given to model validation in this context. We therefore aimed to systematically characterize the key elements for the correct evaluation of the performance of prediction models in NCC data. METHODS: We proposed how to correctly evaluate prediction models in NCC data, by adjusting performance metrics with sampling weights to account for the NCC sampling. We included in this study the C-index, threshold-based metrics, Observed-to-expected events ratio (O/E ratio), calibration slope, and decision curve analysis. We illustrated the proposed metrics with a validation of the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in data from the population-based Rotterdam study. We compared the metrics obtained in the full cohort with those obtained in NCC datasets sampled from the Rotterdam study, with and without a matched design. RESULTS: Performance metrics without weight adjustment were biased: the unweighted C-index in NCC datasets was 0.61 (0.58-0.63) for the unmatched design, while the C-index in the full cohort and the weighted C-index in the NCC datasets were similar: 0.65 (0.62-0.69) and 0.65 (0.61-0.69), respectively. The unweighted O/E ratio was 18.38 (17.67-19.06) in the NCC datasets, while it was 1.69 (1.42-1.93) in the full cohort and its weighted version in the NCC datasets was 1.68 (1.53-1.84). Similarly, weighted adjustments of threshold-based metrics and net benefit for decision curves were unbiased estimates of the corresponding metrics in the full cohort, while the corresponding unweighted metrics were biased. In the matched design, the bias of the unweighted metrics was larger, but it could also be compensated by the weight adjustment. CONCLUSIONS: Nested case-control studies are an efficient solution for evaluating the performance of prediction models that use expensive or difficult-to-obtain biomarkers, especially when the outcome is rare, but the performance metrics need to be adjusted to the sampling procedure.

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.

Cumulative incidence and timing of subsequent cutaneous squamous cell carcinomas stratified for patients with organ transplantation and hematologic malignancies: A nationwide cohort study.

BACKGROUND: There is lack of nationwide data on the cumulative incidence and timing of subsequent cutaneous squamous cell carcinomas (cSCCs) among patients with a first cSCC. OBJECTIVE: To investigate the cumulative incidence and timing of subsequent cSCCs. METHODS: Patients with a first cSCC in 2007/2008 from the Netherlands Cancer Registry were linked to the Netherlands Pathology Registry for subsequent cSCCs and the Netherlands Organ Transplant Registry. Cumulative incidence function curves were calculated for subsequent cSCCs and stratified for immune status. RESULTS: Among the 12,345 patients, second to sixth cSCC occurred in 4325, 2010, 1138, 739, and 501 patients, with median time intervals of 1.4, 1.2, 0.9, 0.6, and 0.5 years after the previous cSCC, respectively. The cumulative incidence of a subsequent cSCC at 5 years increased from 28% to 67% for the second to sixth cSCC. For solid organ transplant recipients, the cumulative incidences increased from 74% to 92% and from 41% to 64% for patients with hematologic malignancy. LIMITATIONS: Only histopathologically confirmed cSCCs were included. CONCLUSION: The risk of a subsequent cSCC steeply rises with the number of prior cSCCs and immune status, while the time interval decreases. This can support more informed decisions about follow-up management.

Global epidemiology of actinic keratosis in the general population: a systematic review and meta-analysis.

BACKGROUND: Actinic keratosis (AK) is a common dermatological condition, and among the most common dermatological diagnoses in older populations. Although the prevalence of AK depends on demographic and environmental factors, little is known about the global context of AK. OBJECTIVES: To provide a comprehensive and updated analysis of the global prevalence rate and incidence of AK in the general population through a systematic review and meta-analysis, and - through subgroup analyses - to identify high-risk phenotypes, demographic and lifestyle risk factors and regional variations in disease prevalence. METHODS: A systematic search of Embase, MEDLINE, Web of Science and Google Scholar was performed on 20 May 2022. Two reviewers independently screened and assessed the quality of each study using a validated critical appraisal checklist. Epidemiological measurements (e.g. prevalence) from individual studies performed in the general population were then pooled in a random-effects meta-analysis. Subgroup analyses (i.e. population age, geographical region, occupation, sex and study quality) were conducted. RESULTS: Of the 65 articles that made it through the full-text screening, 60 reported a point prevalence. A meta-analysis of these articles yielded an overall point prevalence of 14% [95% confidence interval (CI) 14-15]. In further analyses, the calculated prevalence rate varied depending on subgroup. The pooled incidence rate from the seven eligible studies analysed was 1928 per 100 000 person-years (PY; 95% CI -439 to 4294). CONCLUSIONS: This comprehensive meta-analysis provides an updated global prevalence rate of AK of 14%, indicating a significant worldwide disease burden. The incidence rate of AK was found to be 1928 per 100 000 PY, emphasizing a growing public health concern. However, high heterogeneity among studies suggests that various factors influence the AK prevalence rate, necessitating further research to understand the observed differences.

Genetic Concordance in Primary Cutaneous Melanoma and Matched Metastasis: A Systematic Review and Meta-Analysis.

Studying primary melanoma and its corresponding metastasis has twofold benefits. Firstly, to better understand tumor biology, and secondly, to determine which sample should be examined in assessing drug targets. This study systematically analyzed all the literature on primary melanoma and its matched metastasis. Following PRISMA guidelines, we searched multiple medical databases for relevant publications from January 2000 to December 2022, assessed the quality of the primary-level studies using the QUIPS tool, and summarized the concordance rate of the most reported genes using the random-effects model. Finally, we evaluated the inter-study heterogeneity using the subgroup analysis. Thirty-one studies investigated the concordance of BRAF and NRAS in 1220 and 629 patients, respectively. The pooled concordance rate was 89.4% [95% CI: 84.5; 93.5] for BRAF and 97.8% [95% CI: 95.8; 99.4] for NRAS. When high-quality studies were considered, only BRAF mutation status consistency increased. Five studies reported the concordance status of c-KIT (93%, 44 patients) and TERT promoter (64%, 53 patients). Lastly, three studies analyzed the concordance of cancer genes involved in the signaling pathways, apoptosis, and proliferation, such as CDKN2A (25%, four patients), TP53 (44%, nine patients), and PIK3CA (20%, five patients). Our study found that the concordance of known drug targets (mainly BRAF) during melanoma progression is higher than in previous meta-analyses, likely due to advances in molecular techniques. Furthermore, significant heterogeneity exists in the genes involved in the melanoma genetic makeup; although our results are based on small patient samples, more research is necessary for validation.

Personalised decision making to predict absolute metastatic risk in cutaneous squamous cell carcinoma: development and validation of a clinico-pathological model.

Background: Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer, affecting more than 2 million people worldwide yearly and metastasising in 2-5% of patients. However, current clinical staging systems do not provide estimates of absolute metastatic risk, hence missing the opportunity for more personalised treatment advice. We aimed to develop a clinico-pathological model that predicts the probability of metastasis in patients with cSCC. Methods: Nationwide cohorts from (1) all patients with a first primary cSCC in The Netherlands in 2007-2008 and (2) all patients with a cSCC in 2013-2015 in England were used to derive nested case-control cohorts. Pathology records of primary cSCCs that originated a loco-regional or distant metastasis were identified, and these cSCCs were matched to primary cSCCs of controls without metastasis (1:1 ratio). The model was developed on the Dutch cohort (n = 390) using a weighted Cox regression model with backward selection and validated on the English cohort (n = 696). Model performance was assessed using weighted versions of the C-index, calibration metrics, and decision curve analysis; and compared to the Brigham and Women's Hospital (BWH) and the American Joint Committee on Cancer (AJCC) staging systems. Members of the multidisciplinary Skin Cancer Outcomes (SCOUT) consortium were surveyed to interpret metastatic risk cutoffs in a clinical context. Findings: Eight out of eleven clinico-pathological variables were selected. The model showed good discriminative ability, with an optimism-corrected C-index of 0.80 (95% Confidence interval (CI) 0.75-0.85) in the development cohort and a C-index of 0.84 (95% CI 0.81-0.87) in the validation cohort. Model predictions were well-calibrated: the calibration slope was 0.96 (95% CI 0.76-1.16) in the validation cohort. Decision curve analysis showed improved net benefit compared to current staging systems, particularly for thresholds relevant for decisions on follow-up and adjuvant treatment. The model is available as an online web-based calculator (https://emc-dermatology.shinyapps.io/cscc-abs-met-risk/). Interpretation: This validated model assigns personalised metastatic risk predictions to patients with cSCC, using routinely reported histological and patient-specific risk factors. The model can empower clinicians and healthcare systems in identifying patients with high-risk cSCC and offering personalised care/treatment and follow-up. Use of the model for clinical decision-making in different patient populations must be further investigated. Funding: PPP Allowance made available by Health-Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships.

Longitudinal Assessment of the Prevalence of Actinic Keratosis and Extensive Risk Factor Evaluation: An Update from the Rotterdam Study.

Population-based studies available to analyze the prevalence, risk factors, and longitudinal outlook of actinic keratoses (AKs) are limited. These features mentioned earlier were assessed using Rotterdam study participants aged ≥40 years who underwent a full-body skin examination by a dermatology-trained physician. ORs with 95% confidence intervals were calculated for the associations between risk factors and the presence of AK. Among 8,239 eligible participants, the prevalence of one or more AKs was 21.1% (95% confidence interval = 20.2-22.0) and was higher in men. Male sex, age, lighter hair and eye color, baldness, genetic risk score, and digital photoaging measures (digitally assessed pigmented spots, telangiectasias, and global facial wrinkling) had a positive association with AK. Cigarette smokers had reduced odds of having AK, with current smokers having the lowest risk. Among patients with two AK assessments, there was no difference in the presence of AK during follow-up between treated and untreated participants. In conclusion, genetic risk score and digital photoaging measures showed associations with increased lesion count. At the individual level, patients were most likely to decrease in AK severity group over time, possibly regardless of whether or not participants were treated.

An artificial intelligence based app for skin cancer detection evaluated in a population based setting.

Artificial intelligence (AI) based algorithms for classification of suspicious skin lesions have been implemented in mobile phone apps (mHealth), but their effect on healthcare systems is undocumented. In 2019, a large Dutch health insurance company offered 2.2 million adults free access to an mHealth app for skin cancer detection. To study the impact on dermatological healthcare consumption, we conducted a retrospective population-based pragmatic study. We matched 18,960 mHealth-users who completed at least one successful assessment with the app to 56,880 controls who did not use the app and calculated odds ratios (OR) to compare dermatological claims between both groups in the first year after granting free access. A short-term cost-effectiveness analysis was performed to determine the cost per additional detected (pre)malignancy. Here we report that mHealth-users had more claims for (pre)malignant skin lesions than controls (6.0% vs 4.6%, OR 1.3 (95% CI 1.2-1.4)) and also a more than threefold higher risk of claims for benign skin tumors and nevi (5.9% vs 1.7%, OR 3.7 (95% CI 3.4-4.1)). The costs of detecting one additional (pre)malignant skin lesion with the app compared to the current standard of care were €2567. Based on these results, AI in mHealth appears to have a positive impact on detecting more cutaneous (pre)malignancies, but this should be balanced against the for now stronger increase in care consumption for benign skin tumors and nevi.

Sebaceous carcinoma epidemiology, associated malignancies and Lynch/Muir-Torre syndrome screening in England from 2008 to 2018.

BACKGROUND: Sebaceous carcinomas (SC) may be associated with the cancer predisposition syndrome Muir-Torre/Lynch syndrome (MTS/LS), identifiable by SC mismatch repair (MMR) screening; however, there is limited data on MMR status of SC. OBJECTIVE: To describe the epidemiology of SC, copresentation of other cancers, and population level frequency of MMR screening in SC. METHODS: A population-based retrospective cohort study of SC patients in the National Cancer Registration and Analysis Service in England. RESULTS: This study included 1077 SC cases (739 extraocular, 338 periocular). Age-standardized incidence rates (ASIR) were higher in men compared with women, 2.74 (95% CI, 2.52-9.69) per 1,000,000 person-years for men versus 1.47 person-years (95% CI, 1.4-1.62) for women. Of the patients, 19% (210/1077) developed at least one MTS/LS-associated malignancy. MMR immunohistochemical screening was performed in only 20% (220/1077) of SC tumors; of these, 32% (70/219) of tumors were MMR deficient. LIMITATIONS: Retrospective design. CONCLUSIONS: Incorporation of MMR screening into clinical practice guidelines for the management of SC will increase the opportunity for MTS/LS diagnoses, with implications for cancer surveillance, chemoprevention with aspirin, and immunotherapy treatment targeted to MTS/LS cancers.

Trends in incidence, treatment and survival of Merkel cell carcinoma in England 2004-2018: a cohort study.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare tumour with neuroendocrine differentiation and high associated mortality. Studies that describe the epidemiology of MCC are often limited by small sample size, short duration of follow-up, absence of nationwide data and paucity of data on different risk factors. OBJECTIVES: To determine the incidence, demographics and survival for MCC in England between 2004 and 2018. METHODS: This national retrospective cohort study identified all cases of MCC in England from 2004 to 2018 using national population-based data from the National Disease Registration Service. Crude counts, European age-standardized incidence rates (EASRs) and joinpoint analysis were conducted. Patient demographics and treatments received were described. Multivariable Cox regression analysis was used to study risk factors for MCC-specific mortality, by including a priori defined demographic factors, tumour characteristics and immunosuppression. Treatment data were not included in the Cox regression analysis. RESULTS: A total of 3775 MCC tumours were registered. The median age at diagnosis was 81 years (interquartile range 74-87). Overall, 96·6% of patients identified as White ethnicity, and 8·3% of patients were immunosuppressed. The most common site was the face (27·4%). Patients most often presented with stage one disease (22·8%); however, stage was unknown in 31·0%. In total, 80·7% of patients underwent surgical excision, 43·5% radiotherapy and 9·2% systemic therapy. The EASR increased from 0·43 per 100 000 person-years (PYs) to 0·65 per 100 000 person-years between 2004 and 2018, representing a significant annual percentage change of 3·9%. The EASR was greater in men than in women for all years, with an overall male-to-female ratio of 1·41 : 1. The highest EASR was in South West England. Five-year disease-specific survival was 65·6% [95% confidence interval (CI) 63·8-67·4], with a median follow-up of 767 days. MCC-specific mortality increased with age [hazard ratio (HR) 1·02, 95% CI 1·02-1·03], deprivation (HR 1·43, 95% CI 1·16-1·76), immunosuppression (HR 2·80, 95% CI 2·34-3·34) and stage at diagnosis (HR 8·24, 95% CI 5·84-11·6). CONCLUSIONS: This study presents the largest national MCC dataset in Europe, and the most complete reporting of MCC incidence and survival ever published. With the EASR of MCC increasing and high associated mortality, this study encourages further research into the pathology, diagnosis and therapeutic options for MCC to support management guidelines.

The association between atopic eczema and lymphopenia: Results from a UK cohort study with replication in US survey data.

BACKGROUND: Lymphocyte skin homing in atopic eczema (AE) may induce lymphopenia. OBJECTIVE: To determine if AE is associated with lymphopenia. METHODS: We used UK primary care electronic health records (Clinical Practice Research Datalink GOLD) for a matched cohort study in adults (18 years+) (1997-2015) with at least one recorded lymphocyte count. We matched people with AE to up to five people without. We used multivariable logistic regression to estimate the association between AE and lymphopenia (two low lymphocyte counts within 3 months) and linear mixed effects regression to estimate the association with absolute lymphocyte counts using all available counts. Cox proportional hazard models were used to investigate the effect of lymphopenia on common infections. We replicated the study using US survey data (National Health and Nutrition Examination Survey [NHANES]). RESULTS: Among 71,731 adults with AE and 126,349 adults without AE, we found an adjusted odds ratio (OR) for lymphopenia of 1.16 (95% CI: 1.09-1.23); the strength of association increased with increasing eczema severity. When comparing all recorded lymphocyte counts from adults with AE (n = 1,497,306) to those of people without AE (n = 4,035,870) we saw a lower mean lymphocyte (adjusted mean difference -0.047 × 109 /L [95% CI: -0.051 to -0.043]) in those with AE. The difference was larger for men, with increasing age, and with increasing AE severity and was present among people with AE not treated with immunosuppressive drugs. In NHANES (n = 22,624), the adjusted OR for lymphopenia in adults with AE was 1.30 (95% CI: 0.80-2.11), and the adjusted mean lymphocyte count difference was -0.03 × 109 /L (95% CI: -0.07 to 0.02). Despite having a lower lymphocyte count, adjusting for time with lymphopenia, did not alter risk estimates of infections. CONCLUSION: Atopic eczema, including increasing AE severity, is associated with a decreased lymphocyte count, regardless of immunosuppressive drug use. Whether the lower lymphocyte count has wider health implications for people with severe eczema warrants further investigation.

Development and Validation of an Algorithm to Identify Patients with Advanced Cutaneous Squamous Cell Carcinoma from Pathology Reports.

To facilitate nationwide epidemiological research on advanced cutaneous squamous cell carcinoma (cSCC), that is, locally advanced, recurrent, or metastatic cSCC, we sought to develop and validate a rule-based algorithm that identifies advanced cSCC from pathology reports. The algorithm was based on both hierarchical histopathological codes and free text from pathology reports recorded in the National Pathology Registry. Medical files from the Erasmus Medical Center of 186 patients with stage III/IV/recurrent cSCC and 184 patients with stage I/II cSCC were selected and served as the gold standard to assess the performance of the algorithm. The rule-based algorithm showed a sensitivity of 91.9% (95% confidence interval = 88.0‒95.9), a specificity of 96.7% (95% confidence interval = 94‒2-99.3), and a positive predictive value of 78.5% (95% confidence interval = 74.2‒82.8) for all advanced cSCC combined. The sensitivity was lower per subgroup: locally advanced (52.3‒86.2%), recurrent cSCC (23.3%), and metastatic cSCC (70.0%). The specificity per subgroup was above 97%, and the positive predictive value was above 78%, with the exception of metastatic cSCC, which had a positive predictive value of 62%. This algorithm can be used to identify advanced patients with cSCC from pathology reports and will facilitate large-scale epidemiological studies of advanced cSCC in the Netherlands and internationally after external validation.

Using a Clinicopathologic and Gene Expression (CP-GEP) Model to Identify Stage I-II Melanoma Patients at Risk of Disease Relapse.

Background: The current standard of care for patients without sentinel node (SN) metastasis (i.e., stage I−II melanoma) is watchful waiting, while >40% of patients with stage IB−IIC will eventually present with disease recurrence or die as a result of melanoma. With the prospect of adjuvant therapeutic options for patients with a negative SN, we assessed the performance of a clinicopathologic and gene expression (CP-GEP) model, a model originally developed to predict SN metastasis, to identify patients with stage I−II melanoma at risk of disease relapse. Methods: This study included patients with cutaneous melanoma ≥18 years of age with a negative SN between October 2006 and December 2017 at the Sahlgrenska University Hospital (Sweden) and Erasmus MC Cancer Institute (The Netherlands). According to the CP-GEP model, which can be applied to the primary melanoma tissue, the patients were stratified into high or low risk of recurrence. The primary aim was to assess the 5-year recurrence-free survival (RFS) of low- and high-risk CP-GEP. A secondary aim was to compare the CP-GEP model with the EORTC nomogram, a model based on clinicopathological variables only. Results: In total, 535 patients (stage I−II) were included. CP-GEP stratification among these patients resulted in a 5-year RFS of 92.9% (95% confidence interval (CI): 86.4−96.4) in CP-GEP low-risk patients (n = 122) versus 80.7% (95%CI: 76.3−84.3) in CP-GEP high-risk patients (n = 413; hazard ratio 2.93 (95%CI: 1.41−6.09), p < 0.004). According to the EORTC nomogram, 25% of the patients were classified as having a 'low risk' of recurrence (96.8% 5-year RFS (95%CI 91.6−98.8), n = 130), 49% as 'intermediate risk' (88.4% 5-year RFS (95%CI 83.6−91.8), n = 261), and 26% as 'high risk' (61.1% 5-year RFS (95%CI 51.9−69.1), n = 137). Conclusion: In these two independent European cohorts, the CP-GEP model was able to stratify patients with stage I−II melanoma into two groups differentiated by RFS.

Risk factors for metastatic cutaneous squamous cell carcinoma: Refinement and replication based on 2 nationwide nested case-control studies.

BACKGROUND: Risk factors for cutaneous squamous cell carcinoma (cSCC) metastasis have been investigated only in relatively small data sets. OBJECTIVE: To analyze and replicate risk factors for metastatic cSCC. METHODS: From English and Dutch nationwide cancer registry cohorts, metastatic cases were selected and 1:1 matched to controls. The variables were extracted from pathology reports from the National Disease Registration Service in England. In the Netherlands, histopathologic slides from the Dutch Pathology Registry were revised by a dermatopathologist. Model building was performed in the English data set using backward conditional logistic regression, whereas replication was performed using the Dutch data set. RESULTS: In addition to diameter and thickness, the following variables were significant risk factors for metastatic cSCC in the English data set (n = 1774): poor differentiation (odds ratio [OR], 4.56; 95% CI, 2.99-6.94), invasion in (OR, 1.69; 95% CI, 1.05-2.71)/beyond (OR, 4.43; 95% CI, 1.98-9.90) subcutaneous fat, male sex (OR, 2.59; 95% CI, 1.70-3.96), perineural/lymphovascular invasion (OR, 2.12; 95% CI, 1.21-3.71), and facial localization (OR, 1.57; 95% CI, 1.02-2.41). Diameter and thickness showed significant nonlinear relationships with metastasis. Similar ORs were observed in the Dutch data set (n = 434 cSCCs). LIMITATIONS: Retrospective use of pathology reports in the English data set. CONCLUSION: cSCC staging systems can be improved by including differentiation, clinical characteristics such as sex and tumor location, and nonlinear relationships for diameter and thickness.

Limited impact of COVID-19-related diagnostic delay on cutaneous melanoma and squamous cell carcinoma tumour characteristics: a nationwide pathology registry analysis.

BACKGROUND: The COVID-19 pandemic reduced the number of skin cancer diagnoses, potentially causing a progression to unfavourable tumour stages. OBJECTIVES: To identify the impact of delayed diagnostics on primary invasive melanoma and cutaneous squamous cell carcinoma (cSCC) by comparing tumour (pT) stage, Breslow thickness and invasion depth from before to after the first and second lockdown periods. METHODS: In this population-based cohort study, histopathology reports registered between 1 January 2018 and 22 July 2021 were obtained from the nationwide histopathology registry in the Netherlands. The Breslow thickness of melanomas, invasion depth of cSCCs, and pT stage for both tumour types were compared across five time periods: (i) pre-COVID, (ii) first lockdown, (iii) between first and second lockdowns, (iv) second lockdown and (v) after second lockdown. Breslow thickness was compared using an independent t-test. pT-stage groups were compared using a χ2 -test. Outcomes were corrected for multiple testing using the false discovery rate. RESULTS: In total, 20 434 primary invasive melanomas and 68 832 cSCCs were included in this study. The mean primary melanoma Breslow thickness of the prepandemic era (period i) and the following time periods (ii-v) showed no significant difference. A small shift was found towards unfavourable pT stages during the first lockdown compared with the pre-COVID period: pT1 52·3% vs. 58·6%, pT2 18·9% vs. 17·8%, pT3 13·2% vs. 11·0%, pT4 9·1% vs. 7·3% (P = 0·001). No relevant changes were seen in subsequent periods. No significant change in pT stage distribution was observed between the pre-COVID (i) and COVID-affected periods (ii-v) for cSCCs. CONCLUSIONS: To date, the diagnostic delay caused by COVID-19 has not resulted in relatively more unfavourable primary tumour characteristics of melanoma or cSCC. Follow-up studies in the coming years are needed to identify a potential impact on staging distribution and survival in the long term.

Efficacy, cost-minimization, and budget impact of a personalized discharge letter for basal cell carcinoma patients to reduce low-value follow-up care.

BACKGROUND: The incidence of keratinocyte carcinomas is high and rapidly growing. Approximately 80% of keratinocyte carcinomas consist of basal cell carcinomas (BCC) with 50% of these being considered as low-risk tumors. Nevertheless, 83% of the low-risk BCC patients were found to receive more follow-up care than recommended according to the Dutch BCC guideline, which is one visit post-treatment for this group. More efficient management could reduce unnecessary follow-up care and related costs. OBJECTIVES: To study the efficacy, cost-utility, and budget impact of a personalized discharge letter for low-risk BCC patients compared with usual care (no personalized letter). METHODS: In a multi-center intervention study, a personalized discharge letter in addition to usual care was compared to usual care in first-time BCC patients. Model-based cost-utility and budget impact analyses were conducted, using individual patient data gathered via surveys. The outcome measures were number of follow-up visits, costs and quality adjusted life years (QALY) per patient. RESULTS: A total of 473 first-time BCC patients were recruited. The personalized discharge letter decreased the number of follow-up visits by 14.8% in the first year. The incremental costs after five years were -€24.45 per patient. The QALYs were 4.12 after five years and very similar in both groups. The national budget impact was -€2,7 million after five years. CONCLUSIONS: The distribution of a personalized discharge letter decreases the number of unnecessary follow-up visits and implementing the intervention in a large eligible population would results in substantial cost savings, contributing to restraining the growing BCC costs.

Validation of four cutaneous squamous cell carcinoma staging systems using nationwide data.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer worldwide with relatively low metastatic potential (2-5%). Developments in therapeutic options have highlighted the need to better identify high-risk patients who could benefit from closer surveillance, adjuvant therapies and baseline/follow-up imaging, while at the same time safely omitting low-risk patients from further follow-up. Controversy remains regarding the predictive performance of current cSCC staging systems and which methodology to adopt. OBJECTIVES: To validate the performance of four cSCC staging systems [American Joint Committee on Cancer 8th edition (AJCC8), Brigham and Women's Hospital (BWH), Tübingen and Salamanca T3 refinement] in predicting metastasis using a nationwide cohort. METHODS: A nested case-control study using data from the National Disease Registration Service, England, 2013-2015 was conducted. Metastatic cSCC cases were identified using an algorithm to identify all potential cases for manual review. These were 1 : 1 matched on follow-up time to nonmetastatic controls randomly selected from 2013. Staging systems were analysed for distinctiveness, homogeneity, monotonicity, specificity, positive predictive value (PPV), negative predictive value (NPV) and c-index. RESULTS: We included 887 metastatic cSCC cases and 887 nonmetastatic cSCC controls. The BWH system showed the highest specificity [92.8%, 95% confidence interval (CI) 90.8-94.3%, PPV (13.2%, 95% CI 10.6-16.2) and c-index (0.84, 95% CI 0.82-0.86). The AJCC8 showed superior NPV (99.2%, 95% CI 99.2-99.3), homogeneity and monotonicity compared with the BWH and Tübingen diameter and thickness classifications (P < 0.001). Salamanca refinement did not show any improvement in AJCC8 T3 cSCC staging. CONCLUSIONS: We validated four cSCC staging systems using the largest nationwide dataset of metastatic cSCC so far. Although the BWH system showed the highest overall discriminative ability, PPV was low for all staging systems, which shows the need for further improvement and refining of current cSCC staging systems.

Cumulative incidence and disease-specific survival of metastatic cutaneous squamous cell carcinoma: A nationwide cancer registry study.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) represents the most serious form of keratinocyte cancers because of its metastatic potential. Studies on nationwide incidence and disease-specific survival rates of metastatic cSCC (mcSCC) are lacking. OBJECTIVE: To investigate the cumulative incidence and disease-specific survival of patients with mcSCC in the Dutch population and assess patient-based risk factors. METHODS: We conducted a nationwide cancer registry study including all patients with the first cSCC in 2007 or 2008, using data from the Netherlands Cancer Registry, the nationwide network and registry of histopathology and cytopathology, and Statistics Netherlands. Cumulative incidence and Kaplan-Meier curves were calculated, and time-dependent Cox proportional hazards regression analyses were used. RESULTS: Of the 11,137 patients, metastases developed in 1.9% (n = 217). The median time to metastasis was 1.5 years (interquartile range 0.6-3.8 years). The risk factors were age (adjusted hazard ratio [aHR] 1.03, 95% CI 1.02-1.05), male sex (aHR 1.7, 95% CI 1.3-2.3), and immunosuppression (aHR [organ transplant recipient] 5.0, 95% CI 2.5-10.0; aHR [hematologic malignancy] 2.7, 95% CI 1.6-4.6). The 5-year disease-specific survival for patients with mcSCC was 79.1%. LIMITATIONS: Only histopathologically confirmed mcSCCs were included. CONCLUSION: About 2% of cSCCs metastasize, with higher risk for men, increasing age, and immunocompromised patients. Disease-specific survival for patients with mcSCC is high.