Sabatolimab in combination with spartalizumab in patients with non-small cell lung cancer or melanoma who received prior treatment with anti-PD-1/PD-L1 therapy: a phase 2 multicentre study.

OBJECTIVE: This study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC). DESIGN, SETTING AND PARTICIPANTS: This is a phase 1-1b/2, open-label, multinational, multicentre study of patients with advanced/metastatic melanoma or NSCLC with ≥1 measurable lesion. INTERVENTIONS: Patients were given sabatolimab 800 mg every 4 weeks plus spartalizumab 400 mg every 4 weeks until unacceptable toxicity, disease progression and/or treatment discontinuation. OUTCOME MEASURES: The phase 2 primary outcome measure was overall response rate and secondary objectives included evaluation of the safety, tolerability, efficacy and pharmacokinetics of sabatolimab in combination with spartalizumab. RESULTS: 33 patients (melanoma n=16, NSCLC n=17) received sabatolimab plus spartalizumab. 31 (94%) experienced ≥1 adverse event (AE); 15 (46%) experienced grade 3/4 events. The most frequent grade ≥3 AEs for NSCLC were anaemia, dyspnoea and pneumonia (each n=2, 12%); for patients with melanoma, the most frequent grade ≥3 AEs were physical health deterioration, hypokalaemia, hypophosphataemia, pathological fracture and tumour invasion (each n=1; 6%). One (3%) patient discontinued treatment due to AE. Stable disease was seen in three patients with melanoma (19%) and six patients with NSCLC (35%). Median progression-free survival was 1.8 (90% CI 1.7 to 1.9) and 1.7 (90% CI 1.1 to 3.4) months for patients with melanoma and NSCLC, respectively. Patients with stable disease had higher expression levels of CD8, LAG3, programmed death-ligand 1 and anti-T-cell immunoglobulin and mucin-domain containing-3 at baseline. The pharmacokinetics profile of sabatolimab was consistent with the phase 1 study. CONCLUSIONS: Sabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types. TRIAL REGISTRATION NUMBER: NCT02608268.

PRESOLRE: study protocol for a primary school-based, cluster randomised controlled trial of three sun exposure risk prevention strategies on Reunion Island.

INTRODUCTION: Reunion Island, a French overseas department, is located in the southern hemisphere, close to the Capricorn tropic. This island has a multicultural and multiethnic population of 860 000 inhabitants, a quarter of whom are at high risk of developing skin cancer due to intense ultraviolet radiation. Melanoma is responsible for the majority of skin cancer deaths. The early prevention of melanoma is based on sun protection in childhood, but French regulations are not adapted to the environmental conditions of this tropical region.The main objective of our study is to evaluate the effectiveness of three sun protection programs conducted in Reunionese primary schools through a pupil knowledge questionnaire. METHODS AND ANALYSIS: PRESOLRE is an interventional, open-label, cluster-randomised controlled trial, in four parallel arms, that is being conducted throughout 2022-2023 on Reunion Island. The trial design assumes an escalation interventional effect using: first, a control arm without proposed intervention (arm 1); second, an arm whose classes are encouraged to use the validated educational programme 'Living With the Sun' (LWS) (arm 2); third, an arm whose classes are encouraged to use both 'LWS' combined with 'Mission Soleil Réunion's sun protection awareness programme (arm 3); fourth, an arm benefiting from an intervention similar to arm 3, combined with the distribution of hats, sunglasses and sun creams (arm 4). In all, 1780 pupils from 18 classes of 20 pupils, on average, will be included. Randomisation applies to the classes of pupils (so defined as clusters). The primary outcome is based on the proportion of correct answers to the knowledge questions after the awareness programme, compared between the four arms using a linear mixed model with random intercept. ETHICS AND DISSEMINATION: The study obtained ethics approval in 2022 (ID: 2022-A00350-43). Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05367180.

BioMEL: a translational research biobank of melanocytic lesions and melanoma.

INTRODUCTION: Diagnosing invasive cutaneous melanoma (CM) can be challenging due to subjectivity in distinguishing equivocal nevi, melanoma in situ and thin CMs. The underlying molecular mechanisms of progression from nevus to melanoma must be better understood. Identifying biomarkers for treatment response, diagnostics and prognostics is crucial. Using biomedical data from biobanks and population-based healthcare data, translational research can improve patient care by implementing evidence-based findings. The BioMEL biobank is a prospective, multicentre, large-scale biomedical database on equivocal nevi and all stages of primary melanoma to metastases. Its purpose is to serve as a translational resource, enabling researchers to uncover objective molecular, genotypic, phenotypic and structural differences in nevi and all stages of melanoma. The main objective is to leverage BioMEL to significantly improve diagnostics, prognostics and therapy outcomes of patients with melanoma. METHODS AND ANALYSIS: The BioMEL biobank contains biological samples, epidemiological information and medical data from adult patients who receive routine care for melanoma. BioMEL is focused on primary and metastatic melanoma, but equivocal pigmented lesions such as clinically atypical nevi and melanoma in situ are also included. BioMEL data are gathered by questionnaires, blood sampling, tumour imaging, tissue sampling, medical records and histopathological reports. ETHICS AND DISSEMINATION: The BioMEL biobank project is approved by the national Swedish Ethical Review Authority (Dnr. 2013/101, 2013/339, 2020/00469, 2021/01432 and 2022/02421-02). The datasets generated are not publicly available due to regulations related to the ethical review authority. TRIAL REGISTRATION NUMBER: NCT05446155.

Perioperative treatment with tranexamic acid in melanoma (PRIME): protocol for a Danish multicentre randomised controlled trial investigating the prognostic and treatment-related impact of the plasminogen-plasmin pathway.

INTRODUCTION: Inflammation is a hallmark of cancer and is involved in tumour growth and dissemination. However, the hallmarks of cancer are also the hallmarks of wound healing, and modulating the wound inflammatory response and immune contexture in relation to cancer surgery may represent effective targets of therapies.Repurposing anti-inflammatory drugs in a cancer setting has gained increasing interest in recent years. Interestingly, the known and thoroughly tested antifibrinolytic drug tranexamic acid reduces the risk of bleeding, but it is also suggested to play important roles in anti-inflammatory pathways, improving wound healing and affecting anti-carcinogenic mechanisms.As a novel approach, we will conduct a randomised controlled trial using perioperative treatment with tranexamic acid, aiming to prevent early relapses by >10% for patients with melanoma. METHODS AND ANALYSIS: Design: investigator-initiated parallel, two-arm, randomised, blinded, Danish multicentre superiority trial. PATIENTS: ≥T2 b melanoma and eligible for sentinel lymph node biopsy (n=1204).Project drug: tranexamic acid or placebo. TREATMENT: before surgery (intravenous 15 mg/kg) and daily (peroral 1000 mg x 3) through postoperative day 4. PRIMARY OUTCOME: relapse within 2 years after surgery.Primary analysis: risk difference between the treatment arms (χ2 test). SECONDARY OUTCOMES: postoperative complications, adverse events and survival.Inclusion period: summer 2023 to summer 2026. ETHICS AND DISSEMINATION: The trial will be initiated during the summer of 2023 and is approved by the National Committee on Health Research Ethics, the Danish Medicine Agency, and registered under the Data Protection Act. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Patients included in the study will adhere to normal Danish treatment protocols and standards of care, and we expect only mild and temporary side effects. Positive and negative results will be published in peer-reviewed journals, with authorships adhering to the Vancouver rules. TRIAL REGISTRATION NUMBER: NCT05899465; ClinicalTrials.gov Identifier.

Predictive accuracy of risk prediction models for recurrence, metastasis and survival for early-stage cutaneous melanoma: a systematic review.

OBJECTIVES: To identify prognostic models for melanoma survival, recurrence and metastasis among American Joint Committee on Cancer stage I and II patients postsurgery; and evaluate model performance, including overall survival (OS) prediction. DESIGN: Systematic review and narrative synthesis. DATA SOURCES: Searched MEDLINE, Embase, CINAHL, Cochrane Library, Science Citation Index and grey literature sources including cancer and guideline websites from 2000 to September 2021. ELIGIBILITY CRITERIA: Included studies on risk prediction models for stage I and II melanoma in adults ≥18 years. Outcomes included OS, recurrence, metastases and model performance. No language or country of publication restrictions were applied. DATA EXTRACTION AND SYNTHESIS: Two pairs of reviewers independently screened studies, extracted data and assessed the risk of bias using the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies checklist and the Prediction study Risk of Bias Assessment Tool. Heterogeneous predictors prevented statistical synthesis. RESULTS: From 28 967 records, 15 studies reporting 20 models were included; 8 (stage I), 2 (stage II), 7 (stages I-II) and 7 (stages not reported), but were clearly applicable to early stages. Clinicopathological predictors per model ranged from 3-10. The most common were: ulceration, Breslow thickness/depth, sociodemographic status and site. Where reported, discriminatory values were ≥0.7. Calibration measures showed good matches between predicted and observed rates. None of the studies assessed clinical usefulness of the models. Risk of bias was high in eight models, unclear in nine and low in three. Seven models were internally and externally cross-validated, six models were externally validated and eight models were internally validated. CONCLUSIONS: All models are effective in their predictive performance, however the low quality of the evidence raises concern as to whether current follow-up recommendations following surgical treatment is adequate. Future models should incorporate biomarkers for improved accuracy. PROSPERO REGISTRATION NUMBER: CRD42018086784.

Skin cancer-related conditions managed in general practice in Australia, 2000-2016: a nationally representative, cross-sectional survey.

OBJECTIVE: Skin cancer is Australia's most common and costly cancer. We examined the frequency of Australian general practice consultations for skin cancer-related conditions, by patient and general practitioner (GP) characteristics and by time period. DESIGN: Nationally representative, cross-sectional survey of general practice clinical activity. SETTING, PARTICIPANTS: Patients aged 15 years or older having a skin cancer-related condition managed by GPs in the Bettering the Evaluation And Care of Health study between April 2000 and March 2016. PRIMARY OUTCOME MEASURES: Proportions and rates per 1000 encounters. RESULTS: In this period, 15 678 GPs recorded 1 370 826 patient encounters, of which skin cancer-related conditions were managed 65 411 times (rate of 47.72 per 1000 encounters, 95% CI 46.41 to 49.02). Across the whole period, 'skin conditions' managed were solar keratosis (29.87%), keratinocyte cancer (24.85%), other skin lesion (12.93%), nevi (10.98%), skin check (10.37%), benign skin neoplasm (8.76%) and melanoma (2.42%). Over time, management rates increased for keratinocyte cancers, skin checks, skin lesions, benign skin neoplasms and melanoma; but remained stable for solar keratoses and nevi. Skin cancer-related encounter rates were higher for patients aged 65-89 years, male, living in Queensland or in regional or remote areas, with lower area-based socioeconomic status, of English-speaking background, Veteran card holders and non-healthcare card holders; and for GPs who were aged 35-44 years or male. CONCLUSION: These findings show the spectrum and burden of skin cancer-related conditions managed in general practice in Australia, which can guide GP education, policy and interventions to optimise skin cancer prevention and management.

Impact of COVID-19 pandemic on the diagnosis of patients with skin cancer: a systematic review protocol.

INTRODUCTION: The COVID-19 pandemic has changed aspects of patient care in the many scheduled medical activities, restricted access to healthcare facilities, and affected the diagnosis and organisation of patients with other health problems, specifically skin cancer. Skin cancer, the uninhibited progress of atypical skin cells, happens with unrepaired DNA genetic faults that lead them to multiply and create malignant tumours. Currently, dermatologists perform skin cancer diagnosis based on their specialised experience using the results of pathological tests from the skin biopsy. Sometimes, some specialists advise sonography imaging to check the skin tissue as a non-invasive method. The outbreak has led to postponements in the treatment and diagnosis of patients with skin cancer, including diagnostic delays because of limitations of diagnostic capacities and delays in referring patients to the physician. The purpose of this review is to improve our understanding of the impact of the COVID-19 outbreak on the diagnosis of patients with skin cancer and conduct a scoping review to identify whether routine skin cancer diagnoses are affected by the persistent incidence of COVID-19. METHODS AND ANALYSIS: The structure of research was compiled using Population/Intervention/Comparison/Outcomes/Study Design and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. First, we will find the main keywords to capture scientific studies related to the impact of the COVID-19 pandemic on the diagnosis of skin cancer: COVID-19 and skin neoplasms. To warrant sufficient coverage and identify potential articles, we will search the combination of four electronic databases PubMed/MEDLINE, Scopus, Web of Science and EMBASE, and ProQuest from 1 January 2019 until 30 September 2022. The screening, selection and data extraction of studies will be performed by two independent authors, who will then assessed the quality of the included studies according to Newcastle-Ottawa Scale. ETHICS AND DISSEMINATION: As this study will be a systematic review without human participants' involvement, no formal ethical assessment is required. Findings will be presented at conferences related to this field and will be disseminated in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022361569.

Stakeholders barriers and facilitators for the implementation of a personalised digital care pathway: a qualitative study.

OBJECTIVE: A prerequisite for patient-centredness in healthcare organisations is offering patients access to adequate health information, which fits their needs. A personalised digital care pathway (PDCP) is a tool that facilitates the provision of tailored and timely information. Despite its potential, barriers influence the implementation of digital tools in healthcare organisations. Therefore, we investigated the perceived barriers and facilitators for implementation of the PDCP among stakeholders. DESIGN: A qualitative study was conducted to acquire insight into perceptions of the stakeholders involved in the implementation of a digital care pathway in three diverse patient groups. SETTING: This study is part of the PDCP research project in a large academic hospital in the Netherlands. PARTICIPANTS: Purposive sampling was used to recruit internal stakeholders (eg, healthcare professionals, employees of the supporting departments) and external stakeholders (eg, employees of the external PDCP supplier). In addition, existing semistructured interviews with patients involved in pilot implementation (n=24) were used to verify the findings. RESULTS: We conducted 25 semistructured interviews using the Consolidated Framework for Implementation Research. Content analyses yielded four themes: (1) stakeholders' perceptions of the PDCP (eg, perceived usefulness); (2) characteristics of the individuals involved and the implementation process (eg, individuals express resistance to change); (3) organisational readiness (eg, lack of resources); and (4) collaboration within the organisation (eg, mutual communication, multidisciplinary codesign). The main barriers mentioned by patients were duration of first activation and necessity for up-to-date content. In addition, the most facilitating factor for patients was user-friendliness. CONCLUSION: Our findings emphasise the importance of gaining insights into the various perspectives of stakeholder groups, including patients, regarding the implementation of the PDCP. The perceived barriers and facilitators can be used to improve the PDCP implementation plan and tailor the development and improvement of other digital patient communication tools.

Protocol for an open randomised controlled trial investigating Fibrin Glue in Skin grafts for Skin cancer (FiGSS).

INTRODUCTION: Skin cancer is a common disease in the tropics, and oncological resection typically requires reconstruction with skin grafts. Fibrin glue, initially established as a haemostatic agent, has been studied extensively as an adhesive for skin grafts in burns. This study aims to investigate the use of fibrin as an adhesive for split skin grafts in skin cancers. METHODS AND ANALYSIS: The study design is a prospective randomised controlled trial with the aim of investigating the impact of two different methods of split skin graft fixation. The intervention of fibrin glue will be compared with the control of staples or sutures. The trial will be conducted at two sites, a public hospital and a private hospital in Townsville, Australia, over a 24-month period with 334 participants to be recruited. Consecutive patients presenting for skin excisions and grafting will be eligible to participate in this study. Randomisation will be on the level of the patient. The primary outcome is graft take based on wound healing at 1 month. Secondary outcomes will be pain on dressing changes and operative time. ETHICS AND DISSEMINATION: The study has been approved by The Townsville University Hospital Human Research Ethics Committee. Findings will be disseminated in conference presentations and journals and through online electronic media. TRIAL REGISTRATION NUMBER: ACTRN12618000484246.

Study protocol of the BASINEL Study: a pragmatic randomised controlled trial investigating treatment versus no treatment of low-risk basal cell carcinomas in older persons.

INTRODUCTION: Basal cell carcinomas (BCCs) represent 70% of all skin cancers. These tumours do not metastasise but are locally invasive if left untreated. There is a high incidence of BCC in the elderly, and clinicians frequently face important treatment dilemmas. The approach to BCC in the elderly should be investigated thoroughly. METHODS AND ANALYSIS: Data on health-related quality of life (HrQoL), survival and complication rate will be examined in a treatment and a non-treatment arm (1:1 allocation). In the non-treatment arm, in vivo biological behaviour of low-risk BCCs in elderly patients will be examined. The main objective is to combine tumour characteristics with demographic data, in order to determine whether treatment will positively affect the patients' HrQoL within a predetermined time frame. A monocentric randomised controlled trial (RCT) was designed at the Ghent University Hospital. The study population consists of patients with the minimum age of 75 years and a new diagnosis of (a) low-risk BCC(s). Patients in the treatment arm will receive standard care. Patients in the non-treatment arm will be closely monitored: the tumour will be intensively evaluated using multispectral dermoscopy, reflectance confocal microscopy and high-definition optical coherence tomography. All patients will be asked to fill in a questionnaire concerning their HrQoL at consecutive time points. Patient-reported side effects will be evaluated via an additional questionnaire.Primary outcomes will include the difference in HrQoL and the difference in complication risks (treatment vs non-treatment) at different time points of the study. Secondary endpoints are the evolution of the BCCs in the non-treatment arm and the long-term survival in both study arms. Tertiary endpoint is the treatment effectiveness in the treatment arm. The sample size calculation was performed and resulted in a target sample size of 272 patients in this study with a 1:1 allocation. ETHICS AND DISSEMINATION: Subjects can withdraw from participating in this study at any time for any reason without any consequences. Approval for this study was received from the Ethics Committee of the Ghent University Hospital on 26 August 2021.The results of this RCT will be submitted for publication in one or more international, peer-reviewed medical journals, regardless of the nature of the study results. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT05110924).

The Copenhagen Actinic Keratosis Study (COAKS). A decentralised clinical trial to evaluate tolerability, safety and efficacy of daily field-directed topical treatment with cytosolic phospholipase A2 inhibitor, AVX001, in participants with actinic keratosis: protocol for a randomised controlled phase I/IIa trial.

INTRODUCTION: Actinic keratosis (AK) is the most common precancerous skin condition caused by long-term UV exposure. Given the high recurrence rate of 15%-53%, identifying safe and effective treatment options is warranted. AVX001, a cytosolic phospholipase A2α (cPLA2α) enzyme inhibitor, is a novel anti-inflammatory drug for field-directed, self-administered, topical therapy of AK. METHODS AND ANALYSIS: This study is a single-centre, randomised, vehicle-controlled, double-blind, parallel-group hybrid clinical trial in adults with multiple AK lesions Olsen grade 1 or 2. The hybrid design combines decentralised participant tasks and assessments with conventional in-clinic visits. Recruitment using targeted advertising on social media and eligibility prescreening are conducted via the Studies&Me online recruitment platform. Participants (n=60) are randomly assigned to 1 of 3 treatment arms: AVX001 gel 1%, AVX001 gel 3% or vehicle gel. The trial consists of a 4-week treatment period with daily field-directed topical application of the gel and an 8-week follow-up period. Participants attend in-clinic visits at baseline, week 4 and week 12. The remote participant trial tasks include questionnaires and upload of smartphone-obtained photos of the treated skin area using a study-specific web-based app. Both remote and in-clinic assessments of safety and efficacy will be performed. The primary objective is to evaluate the local tolerability of daily application of AVX001 gel (1% or 3%) compared with vehicle gel. Secondary objectives include safety, efficacy, dose-response efficacy relationship, treatment satisfaction and cosmetic outcome. Exploratory objectives include evaluations of tolerability and efficacy assessed by dermatologists using smartphone photos uploaded by participants, comparisons of in-clinic and remote assessments and assessment of AK-related skin changes by non-invasive optical imaging. ETHICS AND DISSEMINATION: Approved by the Ethics Committee of the Capital Region of Denmark (H-21018064) and the Danish Medicines Agency (2021032485). Results will be submitted for publication in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBERS: 2021-000934-32; NCT05164393.

Describing, predicting and explaining adherence to total skin self-examination (TSSE) in people with melanoma: a 12-month longitudinal study.

OBJECTIVES: To describe trajectories in melanoma survivors' adherence to monthly total skin self-examination (TSSE) over 12 months, and to investigate whether adherence trajectories can be predicted from demographic, cognitive or emotional factors at baseline. DESIGN: A longitudinal observational study nested within the intervention arm of the ASICA (Achieving Self-Directed Integrated Cancer Aftercare) randomised controlled trial. SETTING: Follow-up secondary care in Aberdeen and Cambridge UK. PARTICIPANTS: n=104 adults (48 men/56 women; mean age 58.83 years, SD 13.47, range 28-85 years; mean Scottish Index of Multiple Deprivation score 8.03, SD 1.73, range 2-10) who had been treated for stage 0-IIC primary cutaneous melanoma in the preceding 60 months and were actively participating in the intervention arm of the ASICA trial. INTERVENTIONS: All participants were using the ASICA intervention-a tablet-based intervention designed to support monthly TSSE. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was adherence to guideline recommended (monthly) TSSE over 12 months. This was determined from time-stamped TSSE data recorded by the ASICA intervention app. RESULTS: Latent growth mixture models identified three TSSE adherence trajectories (adherent -41%; drop-off -35%; non-adherent -24%). People who were non-adherent were less likely to intend to perform TSSE as recommended, intending to do it more frequently (OR=0.21, 95% CI 0.06 to 0.81, p=0.023) and were more depressed (OR=1.31, 95% CI 1.06 to 1.61, p=0.011) than people who were adherent. People whose adherence dropped off over time had less well-developed action plans (OR=0.78, 95% CI 0.63 to 0.96, p=0.016) and lower self-efficacy about TSSE (OR=0.92, 95% CI 0.86 to 0.99, p=0.028) than people who were adherent. CONCLUSIONS: Adherence to monthly TSSE in people treated for melanoma can be differentiated into adherent, drop-off and non-adherent trajectories. Collecting information about intentions to engage in TSSE, depression, self-efficacy and/or action planning at outset may help to identify those who would benefit from additional intervention. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03328247).

To identify the association between dietary vitamin D intake and serum levels and risk or prognostic factors for melanoma-systematic review and meta-analysis.

OBJECTIVE: To evaluate the association of serum vitamin D levels and dietary intake with melanoma risk and prognostic factors. METHODS: Two independent investigators systematically searched PubMed, Embase and ISI Web of Knowledge (Thomson Scientific Technical Support, New York) databases for eligible studies published between January 1992 and September 2020 using the following combinations of search terms: (vitamin D, or 25-hydroxyvitamin D) AND (melanoma, malignant melanoma, cutaneous melanoma, or cutaneous malignant melanoma). Articles not written in English but with English titles and abstracts were also checked. We obtained the full text of all potentially eligible articles, and reference lists of all studies retrieved at the first stage were also checked to identify other eligible papers. Review articles not reporting original data were excluded, but their reference lists were inspected. RESULTS: Six studies including 212 723 cases reported the association between dietary intake of 25(OH) D serum levels and melanoma risk. The total relative risk for the comparison between the highest and lowest quantiles of the distribution of vitamin D intake was 1.10 (95% CI 0.96 to 1.26) with I 2=56%. Another six studies including 12 297 cases evaluated the association between serum vitamin D levels and melanoma risk. The total relative risk for the comparison of serum vitamin D levels between the highest and lowest quantiles was 1.12 (95% CI 0.53 to 2.35) with I 2=91%. Four studies with 2105 cases investigated the association between serum 25(OH)D (nmol/L) and Breslow thickness, three of which found an inverse association between serum 25(OH)D (nmol/L) and melanoma thickness. CONCLUSIONS: Vitamin D intake and serum 25(OH)D levels were not closely related with melanoma risk, but an inverse association between serum 25(OH)D levels with melanoma thickness was discovered. As the positive correlation between melanoma thickness and melanoma mortality has been recognised, hence it is concluded that a moderate dietary vitamin D supplement to avoid the serum 25(OH)D deficient might be beneficial to the long-term survival of patients with melanoma.

DNA Methylation Analysis to predict Regression of high-grade anal Intraepithelial Neoplasia in HIV+ men (MARINE): a cohort study protocol.

INTRODUCTION: Anal cancer precursors, or high-grade anal intraepithelial neoplasia (HGAIN), are highly prevalent in HIV-seropositive (HIV+) men who have sex with men (MSM). Around 30% of lesions regress within 1 year, but current histopathological assessment is unable to distinguish between HGAIN likely to regress and HGAIN likely to persist or progress to cancer. We aim to assess if host cell DNA methylation markers can predict regression of HGAIN, thus determining the need for immediate treatment or active surveillance. This could reduce overtreatment and the associated anal and psycho-sexual morbidity. METHODS AND ANALYSIS: This is an active surveillance cohort study in three centres located in Amsterdam, the Netherlands, in 200 HIV+ MSM diagnosed with HGAIN. Participants will not be treated, but closely monitored during 24 months of follow-up with 6 monthly visits including cytology, and high-resolution anoscopy with biopsies. The primary study endpoint is histopathological regression of each baseline HGAIN lesion at the end of the study. Regression is defined as ≤low grade anal intraepithelial neoplasia in the exit biopsy at 24 months. Regression proportions in lesions with low versus high methylation levels (ASCL1, ZNF582), other biomarkers (HPV genotype, HPV-E4, p16INK4A, Ki-67) and immunological markers at baseline will be compared. Main secondary endpoints are the histological and clinical outcome (ie, the number of octants affected by HGAIN) of each baseline HGAIN lesion and overall HGAIN disease (i.e., all lesions combined) after each visit. The health-related quality of life of the study group will be compared with that of a control group of 50 HIV+ MSM receiving regular HGAIN treatment. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Institutional Review Board of the Academic Medical Center (Amsterdam, The Netherlands; reference no. 2021_099). Participants are required to provide written informed consent. Findings will be disseminated through publication in peer-reviewed scientific journals and presentations at international scientific conferences; dissemination to policy makers and the target patient group will be achieved through our (inter-)national network, professional associations and collaboration with a patient representative organisation. TRIAL REGISTRATION NUMBER: NL9664.

BESPOKE IO protocol: a multicentre, prospective observational study evaluating the utility of ctDNA in guiding immunotherapy in patients with advanced solid tumours.

INTRODUCTION: Immunotherapy (IO) has transformed the treatment paradigm for a wide variety of solid tumours. However, assessment of response can be challenging with conventional radiological imaging (eg, iRECIST), which do not precisely capture the unique response patterns of tumours treated with IO. Emerging data suggest that circulating tumour DNA (ctDNA) can aid in response assessment in patients with solid tumours receiving IO. The short half-life of ctDNA puts it in a unique position for early treatment response monitoring. The BESPOKE IO study is designed to investigate the clinical utility of serial ctDNA testing to assess treatment response using a tumour-informed, bespoke ctDNA assay (Signatera) and to determine its impact on clinical decision-making with respect to continuation/discontinuation, or escalation/de-escalation of immunotherapy in patients with advanced solid tumours. METHODS AND ANALYSIS: The BESPOKE IO is a multicentre, prospective, observational study with a goal to enroll over 1500 patients with solid tumours receiving IO in up to 100 US sites. Patients will be followed for up to 2 years with serial ctDNA analysis, timed with every other treatment cycle. The primary endpoint is to determine the percentage of patients who will have their treatment regimen changed as guided by post-treatment bespoke ctDNA results along with standard response assessment tools. The major secondary endpoints include progression-free survival, overall survival and overall response rate based on the ctDNA dynamics. ETHICS AND DISSEMINATION: The BESPOKE IO study was approved by the WCG Institutional Review Board (Natera-20-043-NCP BESPOKE Study of ctDNA Guided Immunotherapy (BESPOKE IO)) on 22 February 2021. Data protection and privacy regulations will be strictly observed in the capturing, forwarding, processing and storing patients' data. Natera will approve the publication of any study results in accordance with the site-specific contract. TRIAL REGISTRATION NUMBER: NCT04761783.

Protocol for the implementation of a stepped-care model to address fear of cancer recurrence in patients previously diagnosed with early-stage (0-II) melanoma.

INTRODUCTION: Fear of cancer recurrence (FCR) is commonly reported by patients diagnosed with early-stage (0-II) melanoma and can have a significant impact on daily functioning. This study will pilot the implementation of the Melanoma Care Program, an evidence-based, psychological intervention to reduce FCR, into routine practice, using a stepped-care model. METHODS AND ANALYSIS: Intervention effectiveness and level of implementation will be investigated using a hybrid type I design. Between 4 weeks before and 1 week after their next dermatological appointment, patients with melanoma will be invited to complete the Fear of Cancer Recurrence Inventory Short-Form, measuring self-reported FCR severity. Using a stepped-care model, clinical cut-off points will guide the level of support offered to patients. This includes: (1) usual care, (2) Melanoma: Questions and Answers psychoeducational booklet, and (3) three or five psychotherapeutic telehealth sessions. This longitudinal, mixed-methods pilot implementation study aims to recruit 108 patients previously diagnosed with stage 0-II melanoma. The primary effectiveness outcome is change in FCR severity over time. Secondary effectiveness outcomes include change in anxiety, depression, stress, health-related quality of life and melanoma-related knowledge over time. All outcomes are measured at baseline, within 1 week of the final telehealth session, and 6 and 12 months post-intervention. Implementation stakeholders at each study site and interested patients will provide feedback on intervention acceptability and appropriateness. Implementation stakeholders will also provide feedback on intervention cost, feasibility, fidelity and sustainability. These outcomes will be measured throughout implementation, using questionnaires and semistructured interviews/expert group discussions. Descriptive statistics, linear mixed-effects regression and thematic analysis will be used to analyse study data. ETHICS AND DISSEMINATION: Ethics approval was granted by the Sydney Local Health District-Royal Prince Alfred Zone (2020/ETH02518), protocol number: X20-0495. Results will be disseminated through peer-reviewed journals, conference presentations, social media and result summaries distributed to interested participants. TRIAL REGISTRATION DETAILS: (ACTRN12621000145808).

Process evaluation of a multicentre randomised clinical trial of substituting surgical excisions of low-risk basal cell carcinomas from secondary to primary care.

OBJECTIVES: In 2016, the SKINCATCH Trial, a clustered multi-centre randomised trial, was initiated to assess whether low-risk basal cell carcinomas (BCCs) can be treated by general practitioners (GPs) without loss of quality of care. The trial intervention consisted of a tailored 2-day educational course on skin cancer management. The aim of this process evaluation was to investigate GPs' exposure to the intervention, implementation of the intervention and experiences with the intervention and trial. RESEARCH DESIGN AND METHODS: Data on exposure to the intervention, implementation and experiences were obtained at several points during the trial. Complementary quantitative components (ie, surveys, database analysis, medical record analysis) and qualitative components (ie, interviews and focus groups) were used. Quantitative data were analysed using descriptive statistics; qualitative data were summarised (barrier interviews) or audiorecorded, transcribed verbatim and thematically analysed using Atlas.Ti (focus groups). RESULTS: Following a 100% intervention exposure, results concerning the implementation of the trial showed that aside from the low inclusion rate of patients with low-risk BCCs (n=54), even less excisions of low-risk BCCs were performed (n=40). Although the intervention was experienced as highly positive, several barriers were mentioned regarding the trial including administrative challenges, lack of time and high workload of GPs, low volume of BCC patients and patients declining to participate or requesting a referral to a dermatologist. CONCLUSIONS: Although GPs' participation in the highly valued training was optimal, several barriers may have contributed to the low inclusion and excision rate of low-risk BCCs. While some of the issues were trial-related, other barriers such as low patient-volume and patients requesting referrals are applicable outside the trial setting as well. This may question the feasibility of substitution of surgical excisions of low-risks BCCs from secondary to primary care in the current Dutch setting. TRIAL REGISTRATION NUMBER: Trial NL5631 (NTR5746).

Improving Skin cancer Management with ARTificial Intelligence (SMARTI): protocol for a preintervention/postintervention trial of an artificial intelligence system used as a diagnostic aid for skin cancer management in a specialist dermatology setting.

INTRODUCTION: Convolutional neural networks (CNNs) can diagnose skin cancers with impressive accuracy in experimental settings, however, their performance in the real-world clinical setting, including comparison to teledermatology services, has not been validated in prospective clinical studies. METHODS AND ANALYSIS: Participants will be recruited from dermatology clinics at the Alfred Hospital and Skin Health Institute, Melbourne. Skin lesions will be imaged using a proprietary dermoscopic camera. The artificial intelligence (AI) algorithm, a CNN developed by MoleMap Ltd and Monash eResearch, classifies lesions as benign, malignant or uncertain. This is a preintervention/postintervention study. In the preintervention period, treating doctors are blinded to AI lesion assessment. In the postintervention period, treating doctors review the AI lesion assessment in real time, and have the opportunity to then change their diagnosis and management. Any skin lesions of concern and at least two benign lesions will be selected for imaging. Each participant's lesions will be examined by a registrar, the treating consultant dermatologist and later by a teledermatologist. At the conclusion of the preintervention period, the safety of the AI algorithm will be evaluated in a primary analysis by measuring its sensitivity, specificity and agreement with histopathology where available, or the treating consultant dermatologists' classification. At trial completion, AI classifications will be compared with those of the teledermatologist, registrar, treating dermatologist and histopathology. The impact of the AI algorithm on diagnostic and management decisions will be evaluated by: (1) comparing the initial management decision of the registrar with their AI-assisted decision and (2) comparing the benign to malignant ratio (for lesions biopsied) between the preintervention and postintervention periods. ETHICS AND DISSEMINATION: Human Research Ethics Committee (HREC) approval received from the Alfred Hospital Ethics Committee on 14 February 2019 (HREC/48865/Alfred-2018). Findings from this study will be disseminated through peer-reviewed publications, non-peer reviewed media and conferences. TRIAL REGISTRATION NUMBER: NCT04040114.

Embedding electronic patient-reported outcome measures into routine care for patients with stage III MELanoma (ePROMs-MEL): protocol for a prospective, longitudinal, mixed-methods pilot study.

INTRODUCTION: The benefits of patient-reported feedback, using questionnaires that allow patients to report how they feel and function without any interpretation from healthcare professionals, are well established. However, patient-reported outcomes measures (PROMs) are not routinely collected in patients with melanoma in Australia. The aim of this study is to evaluate the feasibility and acceptability of implementing electronic PROMs (ePROMs) into routine care from the perspectives of patients with stage III melanoma and their treating clinical team. METHODS AND ANALYSIS: A minimum of 50 patients and 5 clinicians will be recruited to this prospective, longitudinal pilot study (ePROMs-MELanoma). The study uses a mixed-methods approach (quantitative PROMs questionnaires and end-of-study surveys with qualitative interviews) and commenced in May 2021 in surgical and medical melanoma clinics at two sites in metropolitan Sydney, Australia. The primary outcomes are measures of feasibility and acceptability, comprising descriptive questionnaire completion statistics, and proportion of patients who reported that these PROMs were easy to complete and measured items they considered important. Clinician and clinic staff views will be canvassed on the appropriateness of these PROMs for their patients, change in referral practice and uptake and incorporation into routine practice. Secondary aims include measurement of improvements in patients' emotional and physical health and well-being, and utility of real-time data capture and clinician feedback. All participants will complete the Distress Thermometer and EQ-5D-5L questionnaires in the clinic using a tablet computer at baseline and two to three subsequent follow-up appointments. Participants who report a score of 4 or higher on the Distress Thermometer will be triaged to complete an additional three questionnaires: the QLQ-C30, Depression, Anxiety and Stress Scale and Melanoma Concerns Questionnaire-28. Results will be generated in real time; patients with psychosocial distress or poor quality of life will discuss possible referral to appropriate allied health services with their clinician. Thematic analysis of interviews will be conducted. ETHICS AND DISSEMINATION: Ethics approval obtained from St Vincent's Hospital Human Research Ethics Committee on 19 September 2019 (2019/ETH10558), with amendments approved on 8 June 2022. Patient consent is obtained electronically prior to questionnaire commencement. Dissemination strategies will include publication in peer-reviewed journals and presentation at international conferences, tailored presentations for clinical societies and government bodies, organisational reporting through multidisciplinary meetings and research symposia for local clinicians and clinic staff, and more informal, lay reports and presentations for consumer melanoma representative bodies and patient participants and their families. TRIAL REGISTRATION NUMBER: ACTRN12620001149954.

Developing an Australian Melanoma Clinical Outcomes Registry (MelCOR): a protocol paper.

INTRODUCTION: Australia has the highest incidence of melanoma in the world with variable care provided by a diverse range of clinicians. Clinical quality registries aim to identify these variations in care and provide anonymised, benchmarked feedback to clinicians and institutions to improve patient outcomes. The Australian Melanoma Clinical Outcomes Registry (MelCOR) aims to collect population-wide, clinical-level data for the early management of cutaneous melanoma and provide anonymised feedback to healthcare providers. METHODS AND ANALYSIS: A modified Delphi process will be undertaken to identify key clinical quality indicators for inclusion in the MelCOR pilot. MelCOR will prospectively collect data relevant to these quality indicators, initially for all people over the age of 18 years living in Victoria and Queensland with a melanoma diagnosis confirmed by histopathology, via a two-stage recruitment and consent process. In stage 1, existing State-based cancer registries contact the treating clinician and provide an opportunity for them to opt themselves or their patients out of direct contact with MelCOR. After stage 1, re-identifiable clinical data are provided to the MelCOR under a waiver of consent. In stage 2, the State-based cancer registry will approach the patient directly and invite them to opt in to MelCOR and share identifiable data. If a patient elects to opt in, MelCOR will be able to contact patients directly to collect patient-reported outcome measures. Aggregated data will be used to provide benchmarked, comparative feedback to participating institutions/clinicians. ETHICS AND DISSEMINATION: Following the successful collection of pilot data, the feasibility of an Australia-wide roll out will be evaluated. Key quality indicator data will be the core of the MelCOR dataset, with additional data points added later. Annual reports will be issued, first to the relevant stakeholders followed by the public. MelCOR is approved by the Alfred Ethics Committee (58280/127/20).