Drug survival of biologics in psoriasis: An Australian multicentre retrospective study.

BACKGROUND: Drug survival, which refers to the time from treatment initiation to discontinuation, provides a surrogate measure of the effectiveness of a biologic in a real-world setting (J Invest Dermatol, 2015, 135, 1). The aim of this study was to determine the drug survival of biologics that are currently available in Australia. We also analysed the treatment efficacy of these biologics and reasons for discontinuation. METHODS: Retrospective data from outpatient Dermatology biologic clinics in Westmead Hospital and Royal Prince Alfred Hospital (Sydney, Australia) from April 2006 to December 2020 were collected. Kaplan-Meier analysis was used to calculate drug survival. RESULTS: A total of 306 patients who underwent 566 treatment courses were analysed. Guselkumab was observed to have the longest drug survival, with cumulative drug survival rates of 94.2% ± 4.0 at 1- and 5-years. This was followed by ixekizumab which had a 1-year survival rate of 87.2% ± 4.5 and 5-year survival rate of 59.4% ± 9.5. Ixekizumab and guselkumab were also noted to have superior treatment efficacy compared with other biologics, with PASI-75 rates of 94.9% and 93.8%, respectively. The most common reasons for treatment discontinuation were a lack of initial efficacy to treatment and a loss of efficacy over time despite an initial response, respectively. CONCLUSION: To our knowledge, this is the first Australian study to report on outcomes of multiple new biologics that are currently in use for the treatment of chronic plaque psoriasis. Overall, this study provides insight into patterns of care from a local experience that may help guide the management of moderate-to-severe psoriasis.

Non-invasive diagnosis of early cutaneous squamous cell carcinoma.

Early cutaneous squamous cell carcinoma (cSCC) can be challenging to diagnose using clinical criteria as it could present similar to actinic keratosis (AK) or Bowen's disease (BD), precursors of cSCC. Currently, histopathological assessment of an invasive biopsy is the gold standard for diagnosis. A non-invasive diagnostic approach would reduce patient and health system burden. Therefore, this study used non-invasive sampling by tape-stripping coupled with data-independent acquisition mass spectrometry (DIA-MS) proteomics to profile the proteome of histopathologically diagnosed AK, BD and cSCC, as well as matched normal samples. Proteomic data were analysed to identify proteins and biological functions that are significantly different between lesions. Additionally, a support vector machine (SVM) machine learning algorithm was used to assess the usefulness of proteomic data for the early diagnosis of cSCC. A total of 696 proteins were identified across the samples studied. A machine learning model constructed using the proteomic data classified premalignant (AK + BD) and malignant (cSCC) lesions at 77.5% accuracy. Differential abundance analysis identified 144 and 21 protein groups that were significantly changed in the cSCC, and BD samples compared to the normal skin, respectively (adj. p < 0.05). Changes in pivotal carcinogenic pathways such as LXR/RXR activation, production of reactive oxygen species, and Hippo signalling were observed that may explain the progression of cSCC from premalignant lesions. In summary, this study demonstrates that DIA-MS analysis of tape-stripped samples can identify non-invasive protein biomarkers with the potential to be developed into a complementary diagnostic tool for early cSCC.

Outcome Measures for the Evaluation of Treatment Response in Hidradenitis Suppurativa for Clinical Practice: A HiSTORIC Consensus Statement.

Importance: Although several clinician- and patient-reported outcome measures have been developed for trials in hidradenitis suppurativa (HS), there is currently no consensus on which measures are best suited for use in clinical practice. Identifying validated and feasible measures applicable to the practice setting has the potential to optimize treatment strategies and generate generalizable evidence that may inform treatment guidelines. Objective: To establish consensus on a core set of clinician- and patient-reported outcome measures recommended for use in clinical practice and to establish the appropriate interval within which these measures should be applied. Evidence Review: Clinician- and patient-reported HS measures and studies describing their psychometric properties were identified through literature reviews. Identified measures comprised an item reduction survey and subsequent electronic Delphi (e-Delphi) consensus rounds. In each consensus round, a summary of outcome measure components and scoring methods was provided to participants. Experts were provided with feasibility characteristics of clinician measures to aid selection. Consensus was achieved if at least 67% of respondents agreed with use of a measure in clinical practice. Findings: Among HS experts, response rates for item reduction, e-Delphi round 1, and e-Delphi round 2 surveys were 76.4% (42 of 55), 90.5% (38 of 42), and 92.9% (39 of 42), respectively; among patient research partners (PRPs), response rates were 70.8% (17 of 24), 100% (17 of 17), and 82.4% (14 of 17), respectively. The majority of experts across rounds were practicing dermatologists with 18 to 19 years of clinical experience. In the final e-Delphi round, most PRPs were female (12 [85.7%] vs 2 males [11.8%]) and aged 30 to 49 years. In the final e-Delphi round, HS experts and PRPs agreed with the use of the HS Investigator Global Assessment (28 [71.8%]) and HS Quality of Life score (13 [92.9%]), respectively. The most expert-preferred assessment interval in which to apply these measures was 3 months (27 [69.2%]). Conclusions and Relevance: An international group of HS experts and PRPs achieved consensus on a core set of HS measures suitable for use in clinical practice. Consistent use of these measures may lead to more accurate assessments of HS disease activity and life outcomes, facilitating shared treatment decision-making in the practice setting.

ACEMID cohort study: protocol of a prospective cohort study using 3D total body photography for melanoma imaging and diagnosis.

INTRODUCTION: Three-dimensional (3D) total body photography may improve early detection of melanoma and facilitate surveillance, leading to better prognosis and lower healthcare costs. The Australian Centre of Excellence in Melanoma Imaging and Diagnosis (ACEMID) cohort study will assess long-term outcomes from delivery of a precision strategy of monitoring skin lesions using skin surface imaging technology embedded into health services across Australia. METHODS AND ANALYSIS: A prospective cohort study will enrol 15 000 participants aged 18 years and above, across 15 Australian sites. Participants will attend study visits according to their melanoma risk category: very high risk, high risk or low/average risk, every 6, 12 and 24 months, respectively, over 3 years. Participants will undergo 3D total body photography and dermoscopy imaging at study visits. A baseline questionnaire will be administered to collect sociodemographic, phenotypic, quality of life and sun behaviour data. A follow-up questionnaire will be administered every 12 months to obtain changes in sun behaviour and quality of life. A saliva sample will be collected at the baseline visit from a subsample. ETHICS AND DISSEMINATION: The ACEMID cohort study was approved by the Metro South Health Human Research Ethics Committee (approval number: HREC/2019/QMS/57206) and the University of Queensland Human Research Ethics Committee (approval number: 2019003077). The findings will be reported through peer-reviewed and lay publications and presentations at conferences. TRIAL REGISTRATION NUMBER: ACTRN12619001706167.

Long-term cost-effectiveness of a melanoma prevention program using genomic risk information compared with standard prevention advice in Australia.

PURPOSE: Evidence indicates that a melanoma prevention program using personalized genomic risk provision and genetic counseling can affect prevention behaviors, including reducing sunburns in adults with no melanoma history. This analysis evaluated its longer-term cost-effectiveness from an Australian health system perspective. METHODS: The primary outcome was incremental cost effectiveness ratio (ICER) of genomic risk provision (intervention) compared with standard prevention advice. A decision-analytic Markov model was developed using randomized trial data to simulate lifetime cost-effectiveness. All costs were presented in 2018/19 Australian dollars (AUD). The intervention effect on reduced sunburns was stratified by sex and traditional risk, which was calculated through a validated prediction model. Deterministic and probabilistic sensitivity analyses were undertaken for robustness checks. RESULTS: The per participant cost of intervention was AUD$189. Genomic risk provision targeting high-traditional risk individuals produced an ICER of AUD$35,254 (per quality-adjusted life year gained); sensitivity analyses indicated the intervention would be cost-effective in more than 50% of scenarios. When the intervention was extended to low-traditional risk groups, the ICER was AUD$43,746 with a 45% probability of being cost-effective. CONCLUSION: Genomic risk provision targeted to high-traditional melanoma risk individuals is likely a cost-effective strategy for reducing sunburns and will likely prevent future melanomas and keratinocyte carcinomas.

Molecular Classifiers in Skin Cancers: Challenges and Promises.

Skin cancers are common and heterogenous malignancies affecting up to two in three Australians before age 70. Despite recent developments in diagnosis and therapeutic strategies, the mortality rate and costs associated with managing patients with skin cancers remain high. The lack of well-defined clinical and histopathological features makes their diagnosis and classification difficult in some cases and the prognostication difficult in most skin cancers. Recent advancements in large-scale "omics" studies, including genomics, transcriptomics, proteomics, metabolomics and imaging-omics, have provided invaluable information about the molecular and visual landscape of skin cancers. On many occasions, it has refined tumor classification and has improved prognostication and therapeutic stratification, leading to improved patient outcomes. Therefore, this paper reviews the recent advancements in omics approaches and appraises their limitations and potential for better classification and stratification of skin cancers.

Proteomic profiling of cutaneous melanoma explains the aggressiveness of distant organ metastasis.

Despite recent developments in managing metastatic melanomas, patients' overall survival remains low. Therefore, the current study aims to understand better the proteome-wide changes associated with melanoma metastasis that will assist with identifying targeted therapies. The latest development in mass spectrometry-based proteomics, together with extensive bioinformatics analysis, was used to investigate the molecular changes in 60 formalin-fixed and paraffin-embedded samples of primary and lymph nodes (LN) and distant organ metastatic melanomas. A total of 4631 proteins were identified, of which 72 and 453 were significantly changed between the LN and distant organ metastatic melanomas compared to the primary lesions (adj. p-value <0.05). An increase in proteins such as SLC9A3R1, CD20 and GRB2 and a decrease in CST6, SERPINB5 and ARG1 were associated with regional LN metastasis. By contrast, increased metastatic activities in distant organ metastatic melanomas were related to higher levels of CEACAM1, MC1R, AKT1 and MMP3-9 and decreased levels of CDKN2A, SDC1 and SDC4 proteins. Furthermore, machine learning analysis classified the lesions with up to 92% accuracy based on their metastatic status. The findings from this study provide up to date proteome-level information about the progression of melanomas to regional LN and distant organs, leading to the identification of protein signatures with potential for clinical translation.

Study protocol for a randomised controlled trial to evaluate the use of melanoma surveillance photography to the Improve early detection of MelanomA in ultra-hiGh and high-risk patiEnts (the IMAGE trial).

INTRODUCTION: Melanoma surveillance photography (MSP) is a comprehensive surveillance method that comprises two- or three-dimensional total body photography with tagged digital dermoscopy, performed at prescribed intervals. It has the potential to reduce unnecessary biopsies and enhance early detection of melanoma, but it is not yet standard care for all high-risk patients in Australia. This protocol describes a randomised controlled trial (RCT) designed to evaluate the clinical impact and cost-effectiveness of using MSP for the surveillance of individuals at ultra-high or high risk of melanoma from a health system perspective. METHODS AND DESIGN: This is a registry-based, unblinded, multi-site, parallel-arm RCT that will be conducted over 3 years. We aim to recruit 580 participants from three Australian states: Victoria, New South Wales and Queensland, via state cancer registries or direct referral from clinicians. Eligible participants within 24 months of a primary cutaneous melanoma diagnosis will be randomised 1:1 to receive either MSP in addition to their routine clinical surveillance (intervention group) or routine clinical surveillance without MSP (control group). Most participants will continue surveillance with their usual care provider, and the frequency of follow-up visits in both groups will depend on the stage of their primary melanoma and risk factors. The primary outcome measure of the study is the number of unnecessary biopsies (i.e. false positives, being cases where a lesion is biopsied due to suspected melanoma on clinical examination, either with or without MSP, but the resulting histopathology finding is negative for melanoma). Secondary outcomes include the evaluation of health economic outcomes, quality of life and patient acceptability. Two sub-studies will explore the benefit of MSP in high-risk patients prior to a melanoma diagnosis and the diagnostic performance of MSP in the teledermatology setting compared to the en face clinical setting. DISCUSSION: This trial will determine the clinical efficacy, cost-effectiveness and affordability of MSP to facilitate policy decision-making at the national and local levels, across primary and specialist care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385732 . Registered on May 13, 2020.

Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

BACKGROUND: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. RESULTS: A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. CONCLUSIONS: In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).

Tape stripped stratum corneum samples are suitable for diagnosis and comprehensive proteomic investigation in mycosis fungoides.

BACKGROUND: Mycosis Fungoides (MF) is a common cutaneous T-cell lymphoma. It can sometimes be challenging to diagnose MF using current clinico-histopathological criteria. Non-invasive molecular profiling analysis has the potential to aid the diagnosis and understanding of MF. METHOD: Lesional and body site matched normal stratum corneum samples were obtained from the same MF patients (n = 28) using adhesive discs, followed by proteomic analyses using data-independent acquisition mass spectrometry (DIA-MS). Differential abundance analyses and bioinformatic analyses were performed to identify differentially abundant proteins and altered biofunctions between the MF and normal stratum corneum samples. RESULTS: In total, 1303 proteins were identified, of which 290 proteins were significantly changed in the MF cohort compared to the normal stratum corneum. Ingenuity pathway analysis (IPA) predicted the significant inhibition of cell death of cancer cells and significant activation of immune-related activities and viral infection in the MF lesions. MF lesions were also associated with upstream regulators relating to immuno-oncologic dysfunctions. The top-250 variating proteins efficiently separated normal stratum corneum from matched MF samples. CONCLUSION: Non-invasive proteomic analysis could transform the diagnosis of MF by reducing the need for invasive biopsy. The identification of altered biological functions may serve as useful biomarkers to predict MF progression.

Informing a position statement on the use of artificial intelligence in dermatology in Australia.

Artificial Intelligence (AI) is the ability for computers to simulate human intelligence. In dermatology, there is substantial interest in using AI to identify skin lesions from images. Due to increasing research and interest in the use of AI, the Australasian College of Dermatologists has developed a position statement to inform its members of appropriate use of AI. This article presents the ACD Position Statement on the use of AI in dermatology, and provides explanatory information that was used to inform the development of this statement.

Genomic and proteomic findings in early melanoma and opportunities for early diagnosis.

Overdiagnosis of early melanoma is a significant problem. Due to subtle unique and overlapping clinical and histological criteria between pigmented lesions and the risk of mortality from melanoma, some benign pigmented lesions are diagnosed as melanoma. Although histopathology is the gold standard to diagnose melanoma, there is a demand to find alternatives that are more accurate and cost-effective. In the current "omics" era, there is gaining interest in biomarkers to help diagnose melanoma early and to further understand the mechanisms driving tumor progression. Genomic investigations have attempted to differentiate malignant melanoma from benign pigmented lesions. However, genetic biomarkers of early melanoma diagnosis have not yet proven their value in the clinical setting. Protein biomarkers may be more promising since they directly influence tissue phenotype, a result of by-products of genomic mutations, posttranslational modifications and environmental factors. Uncovering relevant protein biomarkers could increase confidence in their use as diagnostic signatures. Currently, proteomic investigations of melanoma progression from pigmented lesions are limited. Studies have previously characterised the melanoma proteome from cultured cell lines and clinical samples such as serum and tissue. This has been useful in understanding how melanoma progresses into metastasis and development of resistance to adjuvant therapies. Currently, most studies focus on metastatic melanoma to find potential drug therapy targets, prognostic factors and markers of resistance. This paper reviews recent advancements in the genomics and proteomic fields and reports potential avenues, which could help identify and differentiate melanoma from benign pigmented lesions and prevent the progression of melanoma.

The impact of skin cancer prevention efforts in New South Wales, Australia: Generational trends in melanoma incidence and mortality.

BACKGROUND: In Australia, skin cancer awareness campaigns have focused on raising the awareness and consequences of skin cancer and highlighting the importance of utilising sun protection. METHODS: Trends in melanoma incidence and mortality have been explored elsewhere in Australia and this study sought to examine the trends in NSW. Anonymised incidence and mortality data for in situ and invasive melanoma from 1988 to 2014 were obtained from the NSW Cancer Registry. Trends of melanoma incidence and mortality were analysed using segmented regression to allow for changes over time. Birth cohort patterns were assessed using age-period-cohort models. RESULTS: Over the period, incidence of in situ melanoma increased in all age groups although the rates were lowest in those under 40 years of age. Incidence of invasive melanoma was either stable or decreased in people under 60, while it increased in those aged 60 and above, particularly in men. Age-period-cohort analysis revealed decreasing age-specific incidence of invasive melanoma under 40 years of age. Melanoma mortality over the period was stable or decreased in all groups except in men aged 60 or over. Overall, mortality rates generally declined or remained stable particularly in recent years. CONCLUSION: It is encouraging that rates of invasive melanoma are declining in the younger age cohorts - which could be attributed to both primary prevention efforts with individuals protecting their skin as well as early detection through self assessment and clinician performed skin checks. In addition, whilst it is important to monitor the increasing rates of in situ melanoma, the increase is likely due to early detection and treatment of melanoma that could have progressed to invasive melanoma and therefore detection whilst still in situ is an improved outcome. Overall, the results demonstrate the need to continue to improve the understanding of and compliance with primary skin cancer prevention measures in order to reduce population UVR exposure and overall melanoma incidence.

Development of melanoma clinical quality indicators for the Australian melanoma clinical outcomes registry (MelCOR): A modified Delphi study.

BACKGROUND: Clinical quality registries aim to identify significant variations in care and provide anonymised feedback to institutions to improve patient outcomes. Thirty-six Australian organisations with an interest in melanoma, raised funds through three consecutive Melanoma Marches, organised by Melanoma Institute Australia, to create a national Melanoma Clinical Outcomes Registry (MelCOR). This study aimed to formally develop valid clinical quality indicators for the diagnosis and early management of cutaneous melanoma as an important step in creating the registry. METHODS: Potential clinical quality indicators were identified by examining the literature, including Australian and international melanoma guidelines, and by consulting with key melanoma and registry opinion leaders. A modified two-round Delphi survey method was used, with participants invited from relevant health professions routinely managing melanoma as well as relevant consumer organisations. RESULTS: Nineteen participants completed at least one round of the Delphi process. 12 of 13 proposed clinical quality indictors met the validity criteria. The clinical quality indicators included acceptable biopsy method, appropriate excision margins, standardised pathology reporting, indications for sentinel lymph node biopsy, and involvement of multidisciplinary care and referrals. CONCLUSION: This study provides a multi-stakeholder consensus for important clinical quality indicators that define optimal practice that will now be used in the Australian Melanoma Clinical Outcomes Registry (MelCOR).

Infectious eccrine hidradenitis: sweat glands as the portal of entry for cellulitis.

Neutrophilic eccrine hidradenitis (NEH) is a rare neutrophilic dermatosis involving the eccrine glands. It is commonly associated with haematological malignancy and administration of chemotherapy. An infective aetiology for NEH is termed infectious eccrine hidradenitis (IEH). Pathogens that have been associated with IEH include Nocardia, Serratia, Enterobacter sp., Staphylococcus aureus and Mycobacterium chelonae We describe a case of IEH in a patient with prolonged use of a compression sleeve for their upper limb lymphoedema. The histopathological findings of NEH and IEH are almost identical. Skin tissue culture and rapid clinical improvement with antibiotic therapy are keys in delineating the two subtypes.

Warfarin-induced skin necrosis after the use of an anticoagulation reversal agent.

Anticoagulant-induced skin necrosis is a rare and potentially life-threatening complication of anticoagulant therapy. The majority of cases of anticoagulant-induced skin necrosis have been attributed to warfarin, known as warfarin-induced skin necrosis (WISN). The use of anticoagulation reversal agents such as Prothrombinex-VF in the development of WISN is not a commonly documented phenomenon. The authors present a case of WISN post-recommencement of warfarin and the use of Prothrombinex-VF.