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.

The role of surveillance imaging for resected high-risk melanoma.

BACKGROUND: Recommendations for surveillance imaging for resected melanoma vary considerably. This study examined the utility of imaging in patients with a high-risk primary melanoma undergoing a protocolized imaging schedule. METHODS: This retrospective study involved data collection regarding imaging, recurrence, and outcome characteristics for patients referred to the Victorian Melanoma Service from January 2016-April 2020 and managed for resected stage IIC or III melanoma. Patients with a T4b tumor who did not undergo a sentinel lymph node biopsy were included (T4bNX). Recurrences were "clinically detected" if they were primarily detected by patient symptoms or physical examination, or 'imaging-detected' if the patient was asymptomatic. Cox regression models including time-varying co-variates were used to assess the impact of imaging-detected versus clinically-detected recurrence on overall survival. RESULTS: Over a median follow-up time of 2.7 years, 199 patients underwent surveillance imaging (T4bNX:22, IIC:33, IIIA:22, IIIB:60, IIIC:61, IIID:1), and 44% (n = 88) experienced disease recurrence. Imaging detected over half (53%) of all recurrences. In adjusted analyses, mortality risk was reduced after an imaging-detected compared to clinically-detected recurrence at any given time from the start of surveillance (hazard ratio 0.25, 95% confidence interval 0.10-0.66, p = .005). CONCLUSION: Our study indicates that routine imaging in the early follow-up period of resected T4bNX, stage IIC and III melanoma plays an important role in the detection of asymptomatic recurrences. Imaging-detected recurrence may be associated with a survival benefit and studies with more prolonged follow-up are required to confirm these findings.

Immune checkpoint inhibitors and the risk of major atherosclerotic cardiovascular events in patients with high-risk or advanced melanoma: a retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICI) are associated with immune-mediated adverse effects, potentially involving any organ. ICI has also been associated with an increased risk of cardiovascular disease in cancer populations. OBJECTIVE: To characterize the incidence and risk of major atherosclerotic cardiovascular events associated with ICI use in a high-risk and advanced melanoma population. METHODS: We conducted a retrospective cohort study of patients with high-risk or advanced melanoma (AJCC stage II, III or IV) presenting to an academic tertiary hospital between 2015-2020. The main outcome was major atherosclerotic cardiovascular events (MACE) including acute myocardial infarction, ischemic stroke, acute limb ischemia and coronary revascularization. RESULTS: The study cohort consisted of 646 patients, including 289 who had been treated with ICI. The incidence of MACE was higher in the ICI treated group (3.6 vs. 0.9 events per 100-person years). After adjusting for age, sex, smoking history and prior BRAF and/or MEK inhibitor use, ICI treatment was associated with an increased risk of MACE (HRadj 2.8, 95% CI 1.1-6.9, p = 0.03). Elevated risk was especially pronounced in patients with a past history of MACE (HR 14.4, 95% CI 1.9-112.3, p = 0.01). CONCLUSION: Patients with high-risk or advanced melanoma are at an increased risk of atherosclerotic cardiovascular events following ICI treatment, particularly those with a history of cardiovascular disease.

Association Between Low-Dose Methotrexate Exposure and Melanoma: A Systematic Review and Meta-analysis.

Importance: Methotrexate is widely used for the treatment of inflammatory disorders, including rheumatoid arthritis. Studies suggest that methotrexate may be associated with an increased risk of melanoma. Objective: To determine whether methotrexate exposure is associated with an increased risk of cutaneous melanoma. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from inception to May 12, 2022, for eligible studies. Study Selection: Case-control studies, cohort studies, or randomized clinical trials (RCTs) were included if they examined the odds or risk of cutaneous melanoma in individuals exposed to low-dose methotrexate in comparison with individuals unexposed. No language limitations were applied. Data Extraction and Synthesis: Two independent reviewers extracted data on study characteristics and outcome data. The Meta-analysis of Observational Studies in Epidemiology guidelines were followed. To assess study quality, the Cochrane risk of bias tool was used for RCTs, and the Joanna Briggs Institute Checklist was used for cohort and case-control studies. Odds ratio from case-control studies and relative risk or hazard ratio from cohort studies or RCTs were pooled, and a random-effects model meta-analysis was conducted. Main Outcomes and Measures: Prespecified outcome was the odds ratio, hazard ratio, or risk ratio of cutaneous melanoma comparing low-dose methotrexate exposure with nonexposure. Results: Seventeen studies (8 RCTs, 5 cohort studies, 4 case-control studies) were eligible for inclusion, and of these, 12 studies with 16 642 cases of melanoma were pooled in the primary analysis. Indications for methotrexate included rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease and were unknown in 5 studies. Compared with unexposed individuals, study participants with methotrexate exposure had a small increased risk of melanoma (pooled relative risk, 1.15; 95% CI, 1.08-1.22), but this did not persist in a sensitivity analysis excluding the largest study (pooled relative risk, 1.11; 95% CI, 1.00-1.24). Subgroup analyses according to comparator group (comparing methotrexate exposure with either immunomodulator alone vs immunomodulator and methotrexate) or the indication for methotrexate being rheumatoid arthritis provided similar risk estimates. Using geographical population melanoma incidence rates, a number needed to harm of 18 630 was calculated in Australia, and 41 425 in North America. Conclusions and Relevance: In this systematic review and meta-analysis, low-dose methotrexate exposure was associated with an increased melanoma risk, but the absolute risk increase could be considered negligible.

Association between hypertension and cutaneous melanoma, and the effect of aspirin: extended follow-up of a large randomised controlled trial.

BACKGROUND: The association between hypertension and melanoma is unclear, and previous analyses of data from the ASPirin in Reducing Events in the Elderly (ASPREE) study demonstrated a reduced number of invasive melanoma events amongst aspirin-exposed hypertensive individuals. METHODS: Data from the ASPREE study which included (1) the intervention period with a median follow-up of 4.7 years, and (2) the observational period with an additional 2 years follow-up, were combined for this analysis. Logistic regression analyses examined the association between baseline hypertension and treatment status and past melanoma history. Survival analyses examined the association between hypertension and melanoma risk, and the effect of aspirin across hypertension groups. Cox proportional hazards models were used to compare incidence across groups. RESULTS: 19,114 participants (median age of 74 years) were randomised to daily 100 mg aspirin or placebo. At baseline, hypertension and past melanoma history were recorded in 14,195 and 685 individuals, respectively. After adjustment for confounders, hypertension was significantly associated with past melanoma history (OR=1.34, 95%CI: 1.11-1.62). In a prospective analysis, baseline hypertension was not associated with melanoma risk. However, aspirin was associated with a reduced risk of incident melanoma amongst individuals with uncontrolled hypertension (blood pressure ≥140/90 mmHg; HR=0.63, 95%CI 0.44-0.89), but not in those with controlled hypertension (HR=1.04, 95%CI 0.74-1.46). CONCLUSION: Our results support a reduced melanoma incidence amongst individuals with uncontrolled hypertension exposed to aspirin. Additional studies are required to confirm these findings.

Effect of Aspirin on Melanoma Incidence in Older Persons: Extended Follow-up of a Large Randomized Double-blind Placebo-controlled Trial.

The effects of aspirin on melanoma are unclear, with studies reporting conflicting results. Data from two periods of the ASPirin in Reducing Events in the Elderly (ASPREE) study; the randomized placebo-controlled trial period examining daily 100 mg aspirin in older adults with a median follow-up of 4.7 years, and the second period, an additional 2 years of observational follow-up, were utilized in this secondary analysis to examine whether aspirin exposure is associated with a reduced cutaneous melanoma incidence. All melanoma cases were adjudicated and Cox proportional hazards models were used to compare incidence between randomized treatment groups. ASPREE recruited 19,114 participants with a median age of 74 years. During the trial period, 170 individuals (76 aspirin, 94 placebo) developed an invasive melanoma, and no significant effect of aspirin was observed on incident melanoma [HR = 0.81; 95% confidence interval (CI), 0.60-1.10]. Including the additional 2 years of observational follow-up (median follow-up of 6.3 years), 268 individuals (119 aspirin, 149 placebo) developed an invasive melanoma, and similar results were observed (HR = 0.81; 95% CI, 0.63-1.03). A reduced number of events was observed with aspirin among females in a subgroup analysis (HR = 0.65; 95% CI, 0.44-0.92); however, the interaction effect with males (HR = 0.92; 95% CI, 0.68-1.25) was nonsignificant (P = 0.17). Our findings from this randomized trial do not provide strong support that aspirin is associated with a reduced risk of invasive melanoma in older individuals. Additional studies are required to further explore this relationship. PREVENTION RELEVANCE: Melanoma prevention is an important strategy to improve outcomes and while preventive efforts have largely focused on sun protection, the role of potential chemopreventive agents such as aspirin warrants investigation.

Yield of baseline imaging for distant metastases in high-risk primary melanoma.

BACKGROUND: The yield of baseline imaging in patients presenting with higher risk primary tumours, at least American Joint Committee on Cancer 8th edition stage IIC or III melanoma, is unclear. METHODS: This retrospective study included patients referred to the Victorian Melanoma Service from January 2017 to April 2020, diagnosed with at least stage IIC or stage III melanoma. Patients with a T4b tumour and no sentinel lymph node biopsy were included as 'T4bNX'. RESULTS: One hundred and sixty-four patients (median age 65 years) with baseline imaging (T4bNX: 19, IIC: 30, IIIA: 21, IIIB: 43, IIIC: 50, IIID: 1) were included. The majority were male (73%), and those with T4bNX melanoma tended to be older (median age 79 years). Distant metastases were detected in 21% (4/19) of T4bNX, 3% (1/30) of stage IIC, 0% (0/21) of stage IIIA, and 6% (6/94) of stages IIIB-D melanoma patients. All stage III patients with distant metastases had palpable lymphadenopathy a presentation. Two patients had brain metastases, both of whom had T4bNX melanoma and synchronous extra-cranial metastases. CONCLUSIONS: Compared to stage IIC, baseline imaging detects higher rates of extra-cranial distant disease in stages IIIB-D and T4bNX melanoma. Intracranial imaging has greater yield in patients with distant extra-cranial disease.

Opportunities and barriers for the use of Australian cancer registries as platforms for randomized clinical trials.

It is well recognized that randomized controlled trials (RCTs) are a powerful tool to investigate causal relationships, and are considered the gold standard level of research evidence. However, RCTs can be expensive and time-consuming, and when they employ strict eligibility criteria, it results in an unrepresentative population and limited external validity. Recently, the registry-based randomized clinical trial (RRCT) has emerged as an alternative trial design. Utilizing registries to underpin such studies, RRCTs can have advantages including rapid recruitment, and enhanced generalizability. In Australia, legislated mandatory reporting of cancer diagnoses means that jurisdictional cancer registries are a rich source of systematically collected patient details, representing sound platforms for comprehensive data capture that can serve as a key tool for further research. We review the roles of cancer registries in Australia, discuss important considerations relevant to the design of RRCTs, and outline the opportunities provided by cancer registries to strengthen cancer research.

Genomic Risk Score for Melanoma in a Prospective Study of Older Individuals.

BACKGROUND: Recent genome-wide association meta-analysis for melanoma doubled the number of previously identified variants. We assessed the performance of an updated polygenic risk score (PRS) in a population of older individuals, where melanoma incidence and cumulative ultraviolet radiation exposure is greatest. METHODS: We assessed a PRS for cutaneous melanoma comprising 55 variants in a prospective study of 12 712 individuals in the ASPirin in Reducing Events in the Elderly Trial. We evaluated incident melanomas diagnosed during the trial and prevalent melanomas diagnosed preenrolment (self-reported). Multivariable models examined associations between PRS as a continuous variable (per SD) and categorical (low-risk [0%-20%], medium-risk [21%-80%], high-risk [81%-100%] groups) with incident melanoma. Logistic regression examined the association between PRS and prevalent melanoma. RESULTS: At baseline, mean participant age was 75 years; 55.0% were female, and 528 (4.2%) had prevalent melanomas. During follow-up (median = 4.7 years), 120 (1.0%) incident cutaneous melanomas occurred, 98 of which were in participants with no history. PRS was associated with incident melanoma (hazard ratio = 1.46 per SD, 95% confidence interval [CI] = 1.20 to 1.77) and prevalent melanoma (odds ratio [OR] = 1.55 per SD, 95% CI = 1.42 to 1.69). Participants in the highest-risk PRS group had increased risk compared with the low-risk group for incident melanoma (OR = 2.51, 95% CI = 1.28 to 4.92) and prevalent melanoma (OR = 3.66, 95% CI = 2.69 to 5.05). When stratifying by sex, only males had an association between the PRS and incident melanoma, whereas both sexes had an association between the PRS and prevalent melanoma. CONCLUSIONS: A genomic risk score is associated with melanoma risk in older individuals and may contribute to targeted surveillance.

Ocular injuries resulting from commercial cosmetic procedures.

The prevalence of potentially precarious cosmetic facial procedures appears to be on the rise. A significant amount of these cosmetic procedures are offered and performed by operators without formal medical training and anatomical knowledge, and with variable degrees of skill. Some of these procedures can result in devastating sight-threatening complications, and many of the individuals undergoing such treatments are relatively young and healthy. Patients need to be aware of the potential risks, including permanent visual loss, before embarking on any cosmetic facial procedure. Optometrists may be the first point of contact for patients with ocular complaints following these treatments. Hence, the authors present here a review on the various ocular injuries that may result from commercial cosmetic procedures.

Transnational review of visual standards for driving: How Australia compares with the rest of the world.

IMPORTANCE: Driving is a highly visual task and a primary mode of transportation for many people around the world. BACKGROUND: There appears to be little uniformity of vision standards across the world for driving. We reviewed the basic screening visual requirements for obtaining standard private and commercial driving licences for a total of 70 jurisdictions, and reviewed the evidence behind these standards. DESIGN: Systematic review of basic screening vision standards worldwide for driving and literature review. SAMPLES: Published online documentation on visual acuity and field requirements for driving. METHODS: Journal articles, government reports and websites obtained via a Google search were used to review the regulations for driving. This was limited by the comprehensiveness of resources, and countries were excluded if the requirements were unclear or unattainable. A literature review was performed using Medline with keywords vision, driving and visual field. MAIN OUTCOME MEASURES: Visual parameters used for driving assessment. RESULTS: The results suggest significant variations across the world. The visual acuity requirements for a private licence range from a minimum of 6/9 to 6/60. The minimum binocular horizontal field requirement ranges from 110° to 150°. In general, standards for a commercial licence are stricter compared to a private licence. A literature review could not support the current driving standards as evidence-based. CONCLUSIONS AND RELEVANCE: The disunity of driving vision requirements worldwide likely reflects the inconclusive evidence base. Accounting for individual differences and the ability to predict individual risk is important in the context of determining driving licensure.

Refractive regression after laser in situ keratomileusis.

Uncorrected refractive errors are a leading cause of visual impairment across the world. In today's society, laser in situ keratomileusis (LASIK) has become the most commonly performed surgical procedure to correct refractive errors. However, regression of the initially achieved refractive correction has been a widely observed phenomenon following LASIK since its inception more than two decades ago. Despite technological advances in laser refractive surgery and various proposed management strategies, post-LASIK regression is still frequently observed and has significant implications for the long-term visual performance and quality of life of patients. This review explores the mechanism of refractive regression after both myopic and hyperopic LASIK, predisposing risk factors and its clinical course. In addition, current preventative strategies and therapies are also reviewed.

Vitamin supplements in type 2 diabetes mellitus management: A review.

Type 2 diabetes mellitus (T2DM) is a major public health challenge that affects countries across the world. The use of pharmacological therapy is often limited in some patients due to a loss of effect over time or development of adverse effects such as weight gain or hypoglycaemia. This has prompted searches into the role of non-pharmacological therapies in T2DM. The availability and use of vitamin supplements in developed countries have increased significantly and there is evidence that certain vitamins may have roles in the management of T2DM. This review examines the literature assessing the use of vitamins A, C, E, D, K and the B group vitamins (B1, B3, B7, B6, B9, B12) in the management of T2DM. No clear evidence supporting the beneficial role of any specific vitamin in the treatment of T2DM was found. Thus, it is recommended that until further studies are conducted to clarify the role of such vitamins in T2DM management, they should not be routinely recommended in clinical practice.