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.).

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.

Biologic treatment sequences in moderate-to-severe psoriasis.

BACKGROUND: The advent of novel biologics has led to an increase in biologic-switching as patients and clinicians pursue improved clinical outcomes. However, guidance on treatment sequencing in an Australian setting is sparse. This study examines the patterns of care across two tertiary centres in Australia and characterizes the factors contributing to biologic-switching. METHODS: A retrospective study of patients who attended the outpatient Dermatology biologic clinics across two tertiary hospitals was conducted. Data on treatment sequencing and patients' PASI at every visit from April 2006 to December 2020 were collected. Patterns of biologic-switching were examined. The speed of treatment response for each biologic was determined by the time to achieve PASI-90 and -100 for each treatment course. RESULTS: A total of 440 treatment courses were analysed. Ustekinumab and adalimumab were the most frequently prescribed first-line biologics. The highest proportion of biologic-switching was observed among patients on TNF-α inhibitors (63.8%). After 2015, more patients were prescribed IL-12/23 and IL-17 inhibitors in favour of TNF-α inhibitors. IL-17 inhibitors demonstrated the most rapid treatment response and low PASI scores relative to other biologics. Patients who did not switch biologics had lower rates of psoriatic arthritis and lower BMI, compared to patients who switched biologics. The median PASI on discontinuation generally exceeded 3.0, while on continuation, it was less than 1.2, reflecting patients' and clinicians' thresholds for biologic-switching. CONCLUSIONS: This study demonstrates an increased uptake of more novel biologics as they become available, due to improved safety profiles and clinical outcomes.

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.

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.

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.

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.

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.

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.

Merkel cell carcinoma in situ: A systematic review of prognosis and management.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumour. While dermally invasive MCC is known to have a five-year survival of only 30-40%, the prognosis and management of MCC in situ (MCCis) is not widely reported. OBJECTIVE: We present a systematic review to elucidate the prognosis and management of MCCis. METHODS: We performed a systematic review, searching three databases to 01 June 2021. Case reports, cohort studies, clinical trials and literature reviews were considered for inclusion. RESULTS: We identified 26 cases of MCCis published in the literature with a median age of 74 years and involving 19 males and 7 females. Most cases were on the face and neck (n = 17), followed by upper limb (n = 8) and lower limb (n = 1). Sentinel lymph node biopsy was performed in three patients, and all were negative. One subject underwent adjuvant radiotherapy. No MCCis-associated deaths were reported. CONCLUSION: This review suggests that MCCis has an excellent prognosis with minimal, if any, risk of mortality and a very low risk of dermal invasion and recurrence when treated with wide local excision alone. Sentinel lymph node biopsy is unlikely to be useful for MCCis.

Clinicopathological characteristics of new primary melanomas in patients receiving immune checkpoint inhibitor therapy for metastatic melanoma.

BACKGROUND: Immune checkpoint inhibitors have improved survival in advanced stage melanoma patients. Rates of new primary melanomas (NPM) in patients with prior melanoma have been reported to be as high as 12%. Little is currently known regarding the frequency or characteristics of NPMs occurring in melanoma patients treated with immune checkpoint inhibitors. AIM: To determine the frequency and describe clinicopathologic characteristics of NPMs diagnosed in patients during or after treatment with immune checkpoint inhibitors for metastatic melanoma. METHODS: A retrospective analysis of prospectively collected data from the Melanoma Institute Australia and Westmead Hospital Dermatology databases. Clinicopathological data for the initial primary melanoma (IPM) and NPM were compared. RESULTS: Between 2013-2017, 14 NPMs in 13 patients (out of a total of 1047) treated with checkpoint inhibitors were identified. NPMs were significantly thinner than the IPM (median Breslow thickness 0.35 mm vs 2.0 mm, P = 0.0003), less likely to be ulcerated (0/14 vs 6/13, P = 0.004) and less likely to have nodal metastases (0/14 vs 6/13, P = 0.004). NPMs were significantly more likely to be detected in the in-situ stage (6/14 vs 0/13, P = 0.0016). CONCLUSION: NPMs are infrequent in patients treated with checkpoint inhibitors. When they occur, they are usually detected at an early stage and have features associated with a favourable prognosis, most likely reflecting close surveillance. Further study is required to determine long-term risk in patients achieving a durable response to immune checkpoint inhibitors, and to determine whether the immunotherapy itself influences both their development and biology.

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).

Reflectance confocal microscopy role in mycosis fungoides follow-up.

BACKGROUND: Reflectance confocal microscopy (RCM) is a useful tool for many skin cancers, allowing non-invasive evaluation over time and identifying areas of active disease. Its role to follow-up mycosis fungoides (MF) patients has not yet been evaluated. OBJECTIVE: To assess the level of agreement between RCM and histopathology and to develop a RCM checklist that could help monitoring MF patients. METHOD: Prospective study in a cutaneous lymphoma clinic of a tertiary hospital in Australia. RCM and biopsies were performed on the same area at baseline, before commencing or changing treatment, and at 6 months after starting treatment. Normal skin sites were also analysed and acted as controls. RCM features and histopathological findings were blindly evaluated by the confocalist and pathologist. Correlation between RCM and histology was measured by overall per cent of agreement (OPA), kappa and ROC curves. Additionally, RCM images before and after treatment were assessed blinded from clinical information and correlated to clinical assessment. RESULTS: Thirty-eight MF lesions were included. Nineteen of these 38 were re-assessed by RCM 6 months later. Fifty biopsies were performed (38 at baseline and 12 after 6 months). The combination of four RCM features corresponding to Pautrier's microabscess, epidermal and junctional lymphocytes and interface dermatitis formed the RCM checklist for MF that predicted the severity of disease with AUC of 0.95 (P = .003). CONCLUSION: Reflectance confocal microscopy can assess activity within a lesion and over time and assist in the clinical management of patients with MF.

Adherence to suggestions after dermatology consultation in a tertiary hospital - a retrospective analysis.

Dermatology consultation is a valuable inpatient service in Australian hospitals. Adherence rates to consultative advice in international literature range between 67.4% and 93%. This study identifies that adherence rates to suggested investigations and management in a tertiary Australian hospital are at the lower end of the range reported in previous literature.

Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.

BACKGROUND: The treatment response to new immunotherapy in advanced melanoma patients remains varied between individuals. Immune-related cutaneous side effects might have prognostic value. OBJECTIVE: To determine whether development of ≥1 of the 3 immune-mediated cutaneous events (eczema, lichenoid reaction, or vitiligo-like depigmentation) is associated with improved progression-free survival. METHODS: A cohort study of adults with stage IIIC-IV melanoma treated with pembrolizumab or nivolumab during May 1, 2012-February 1, 2018, at Westmead Hospital, Sydney, Australia. Treatment response was based on iRECIST version 1.1. RESULTS: In total, 82 patients of an average age of 59.9 years were included. Median follow-up was 40.7 months; 33 patients had ≥1 target skin reaction. Skin reactions developed in one-third of individuals by 6 months. At any given time, the instantaneous risk of disease progression and death was lower for individuals who had ≥1 cutaneous adverse event (CAE) develop. Compared with individuals with no CAE, the hazard ratio for disease progression and death for individuals who had ≥1 CAE develop was 0.46 (95% confidence interval 0.23-0.91; P = .025) by the time-dependent Cox proportional hazards model. LIMITATIONS: Single-center study. CONCLUSION: This study demonstrates an association between the development of ≥1 of 3 CAEs and improved progression-free survival in this cohort of patients.

Systematic review and proposal of an in vivo reflectance confocal microscopy assessment tool for cutaneous lymphoma.

BACKGROUND: Reflectance confocal microscopy (RCM) is a non-invasive imaging technique that provides dynamic information and allows in vivo monitoring, with excellent histologic correlation. In the last decade, the use of RCM for cutaneous T-cell lymphomas (CTCL) has been reported. CTCL may require multiple biopsies for diagnosis due to its equivocal clinical presentation. RCM was described as a possible tool to help determine the best site for skin biopsy. This study aims to systematically review all RCM features reported in literature for CTCL. METHOD: A systematic literature search concerning CTCL evaluated by RCM was performed in eight electronic databases until May 2019 following PRISMA-DTA quality assessment. RESULTS: Eighteen RCM features were described in patients with CTCL. The most frequent were: interface dermatitis (89%), epidermal lymphocytes (82%), epidermal architectural disarray (81%), and vesicle-like structure (Pautrier microabscess) (51%). CONCLUSION: In order to establish comparable parameters among the studies identified, we proposed descriptors for CTCL features and a grading system to quantify them. This will facilitate to define the role of RCM in the diagnosis and monitoring of CTCL patients.

Mohs Micrographic Surgery in Patients Younger Than 40 Years.

BACKGROUND: As the availability of Mohs micrographic surgery (MMS) continues to expand in Australia and incidence of keratinocyte cancer increases in adolescents and young adults, there has been rising interest in the use of MMS in this population. OBJECTIVE: This study aimed to evaluate the characteristics of MMS cases in patients younger than 40 years. METHODS: A review was performed of all MMS cases in patients younger than 40 years at the time of their surgery from 2012 to 2017 at the Skin and Cancer Foundation Australia, with comparison to a control group, aged older than 40 years. Patient, tumor and management characteristics were analyzed. RESULTS: Four hundred ninety-three cases were eligible. Study and control groups differed significantly regarding gender (p < .001), tumor pathology (p < .001), anatomic site of tumor (p < .001), Mohs surgery stages (p = .039), defect size (p < .001), and repair method (p < .001). LIMITATIONS: Retrospective study at a single institution. CONCLUSION: Mohs micrographic surgery cases in patients younger than 40 years exhibit unique patient and tumor characteristics influencing choice of repair method.

Mohs Micrographic Surgery at the Skin and Cancer Foundation Australia, 20 Years Later (1997-2017).

BACKGROUND: The availability of Mohs micrographic surgery (MMS) in Australia has increased dramatically since its inception in the 1980s. OBJECTIVE: This study aimed to describe the evolution of MMS practices at the Skin and Cancer Foundation Australia (SCFA) over the past 20 years (1997-2017). METHODS: Retrospective analysis of Mohs surgery cases at SCFA in 2017, 2007, and 1997, comparing data on sex, age, tumor type and site, initial tumor and final defect size, number of surgical stages and sections, and closure management. The present study is limited by being a retrospective analysis from a single institution. RESULTS: There was a 415% increase in the number of Mohs surgery cases from 1997 to 2017, and a significant increase in Mohs surgery-treated squamous cell carcinoma. The preoperative tumor and final defect size have decreased. More side-to-side closures and fewer grafts are being performed over time. LIMITATIONS: Retrospective analysis from a single institution. CONCLUSION: Over the last 20 years, MMS has remained appropriate in its application and is being increasingly used for treatment of squamous cell carcinoma suggesting improved access.

Reflectance confocal microscopy as a new diagnostic tool in transformed mycosis fungoides.

Patients with mycosis fungoides typically experience an indolent disease. In some cases, the disease undergoes a process of large cell transformation which often heralds a more aggressive course with shortened overall survival. In order to rule out large cell transformation, biopsy specimens are often collected from patients with established disease who develop new papules, plaques or tumours. In some cases, multiple biopsies are needed and scar, infection and sampling error can occur. Our aim was to evaluate lesions suggestive of large cell transformation using in vivo reflectance confocal microscopy and to correlate confocal features with histopathologic findings in three patients with biopsy-proven mycosis fungoides who developed new lesions during follow-up. A total of six lesions, two lesions per patient, were examined. Reflectance confocal microscopy demonstrated large bright roundish pleomorphic cells in the epidermis, dermoepidermal junction, dermis and hair follicle in 5 of 6 lesions. The same 5 lesions were confirmed as large cell transformation by histopathology. Dermoepidermal junction obscuration, Pautrier microabscesses, epidermal disarray, spongiosis and dendritic cells were also detected by reflectance confocal microscopy and correlated to histopathology. In conclusion, reflectance confocal microscopy is useful in identifying large cell transformation within mycosis fungoides lesions. Reflectance confocal microscopy can therefore be of value in targeting the biopsy site, thereby reducing the chance of a false-negative histopathological finding.

Allergic Contact Dermatitis of the Anogenital Region in Men and Women.

OBJECTIVES: Allergic contact dermatitis is an uncommon but important cause of skin disease in the anogenital region. Relevant allergens are described in women and less commonly in men. The aim of this study was to describe outcomes of patch testing in men and women presenting with anogenital dermatoses. MATERIALS AND METHODS: Cases patch tested for anogenital conditions at 2 patch test clinics in Sydney, Australia, from 2002 to 2017 were reviewed. Positive and relevant patch test reactions were recorded. RESULTS: Thirty-seven women and 27 men were included. Dermatitis was the most common diagnosis, followed by psoriasis and lichen sclerosus. Thirty percent had a final diagnosis of allergic contact dermatitis. The most frequent relevant allergens were fragrance mix I (9%), patients own products (9%), Myroxylon pereirae (8%), cocamidopropyl betaine (3%), and benzocaine (3%). CONCLUSIONS: The top positive and relevant allergens seen were in concordance with other reports from Australia and the rest of the world. Fragrances and medicaments are common allergens, and it is recommended that products used on anogenital skin be fragrance free. Testing patients own products is imperative.