Analysis of Geographic and Environmental Factors and Their Association with Cutaneous Melanoma Incidence in Canada.

BACKGROUND: Over 90% of skin cancers including cutaneous melanoma (CM) are related directly to sun exposure. Despite extensive knowledge on ultraviolet radiation's (UVR) detrimental impact, many still fail to implement sun protection/sun avoidance. Human behavior, attitudes, and cultural norms of individuals and communities heavily depend on the surrounding climate/environment. In many instances, the climate shapes the culture/norms of the society. Canada has vast geographic/environmental differences. METHODS: In the current ecological study, we sought to examine the relationship between various geographic and environmental factors and the distribution of CM incidence by Forward Sortation Area (FSA) postal code across Canada. CM incidence data were extracted from the Canadian Cancer Registry, while environmental data were extracted from the Canadian Urban Environmental Health Research Consortium (greenspace, as measured by the normalized difference vegetation index; annual highest temperature; absolute number and average length of yearly heat events; annual total precipitation [rain and snow]; absolute number and average length of events with precipitation [rain and snow]; and summer UVR index). The above geographic/environmental data by FSA were correlated with the respective CM incidence employing negative binomial regression model. RESULTS: Our analysis highlights that increases in annual average temperature, summer UVR, and greenspace were associated with higher expected incidence of CM cases, while higher number of annual heat events together with highest annual temperature and higher average number of annual rain events were associated with a decrease in CM incidence rate. This study also highlights regional variation in environmental CM risk factors in Canada. CONCLUSIONS: This national population-based study presents clinically relevant conclusions on weather/geographic variations associated with CM incidence in Canada and will help refine targeted CM prevention campaigns by understanding unique weather/geographic variations in high-risk regions.

Skin Surface pH

The role of skin surface pH, also referred to as "acid mantle," was described more than 90 years ago and due to developing insights has now returned into focus.1

Clinical Insights About the Role of pH in Acne

Acne vulgaris is the most common dermatological disorder globally.1,2 Psychological and emotional distress due to acne, including poor self-esteem, social anxiety, depression, and suicidal ideation have been reported in various studies.3,4, Acne is a complex multifactorial disease with its pathophysiology incompletely elucidated.

Ultraviolet radiation and the skin: Photobiology and sunscreen photoprotection.

The efficacy of sunscreens can be measured by different methods, involving in vitro, ex vivo, or in vivo techniques. There is a need for a worldwide standardization of these methods to avoid misunderstanding and confusion among sunscreen users. The clinical benefits of sunscreens have been demonstrated in randomized controlled trials that established the role of sunscreens in the prevention of actinic keratoses, squamous cell carcinomas, nevi, and melanomas. Sunscreens also prevent photoimmunosuppression and signs of photoaging. Continued efforts in public education on the proper application of sunscreens and the practice of photoprotection in general are needed.

Chocolate flavanols and skin photoprotection: a parallel, double-blind, randomized clinical trial.

BACKGROUND: Solar ultraviolet (UV) radiation has deleterious effects on the skin, including sunburn, photoaging and cancer. Chocolate flavanols are naturally-occurring antioxidant and anti-inflammatory molecules that could play a role in preventing cutaneous UV damage. We investigated the influence of 12-week high-flavanol chocolate (HFC) consumption on skin sensitivity to UV radiation, measured by minimal erythema dose (MED). We also evaluated skin elasticity and hydration. METHODS: In this 2-group, parallel, double-blind, randomized controlled trial, 74 women aged 20-65 years and Fitzpatrick skin phototypes I or II were recruited from the general community in Quebec City, for randomization to either HFC (n = 33) or low-flavanol chocolate (LFC) (n = 41). A blocked randomisation (4), considering date of entry, skin type and age as factors, generated a sequentially-numbered allocation list. Study participants and research assistants were blinded. Totally, 30 g of chocolate were consumed daily for 12 weeks, followed by a 3-week washout period. MED was assessed at baseline and at 6, 9, 12 and 15 weeks. Main outcome was changes in MED at week 12. RESULTS: 33 participants in the HFC group and 41 in the LFC group were analyzed with 15 weeks of follow-up. Both groups showed similarly-increased MED at 12 weeks (HFC: 0.0252 ± 0.1099 J/cm2 [mean ± standard deviation (SD)]; LFC: 0.0151 ± 0.1118; mean difference (MD): 0.0100 J/cm2; 95% confidence interval (CI): -0.0417 to 0.0618). However, after 3-week washout, the HFC group presented decreased MED (-0.0248 ± 0.1145) whereas no effect was seen in the LFC group (0.0168 ± 0.1698) (MD: -0.0417; 95% CI: -0.1106 to 0.0272). Net temple elasticity increased slightly but significantly by 0.09 ± 0.12 mm in the HFC group at 12 weeks compared to 0.02 ± 0.12 mm in the LFC group (MD: 0.06; 95% CI: 0.01 to 0.12 ). No significant adverse events were reported. CONCLUSION: Our study failed to demonstrate a statistically-significant protective effect of HFC vs. LFC consumption on skin sensitivity to UV radiation as measured by MED. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01444625.

Metastatic melanoma: optimizing outcomes by managing dermatologic toxicities associated with novel therapies.

The last couple of years have seen the beginning of a new era in the treatment of metastatic melanoma. This disease is typically characterized by its poor prognosis and limited choice of therapy. Two mechanistically diverse classes of agents - BRAF inhibitors and immune modulators - have demonstrated an overall survival benefit. Along with their significant clinical benefits, there are also unique adverse events (AEs) related to these agents. While most of the AEs are mild and easily managed with supportive treatment, others require more aggressive management strategies. Education of all members of the multidisciplinary care team and awareness of these toxicities are crucial in order to optimize patient outcomes. The landscape of melanoma is continually evolving as ongoing trials are evaluating monotherapy and combination options. While these regimens continue to show promise for the future, understanding and managing toxicities of currently available therapies is required.

Assessing Skin Cancer Risk Factors, Sun Safety Behaviors and Melanoma Concern in Atlantic Canada: A Comprehensive Survey Study.

BACKGROUND: The incidence of cutaneous melanoma (CM) is increasing at an alarming rate in Canada and elsewhere around the world. Significant regional differences in CM incidence have been identified in Atlantic provinces. The goal of this study is to compare ultraviolet exposure, sun protective behaviours, level of worry and baseline CM knowledge in provinces with a high versus low incidence of CM as well, as between various demographic groups. METHODS: A cross-sectional survey study was conducted in Atlantic provinces between July 2020 and August 2022. All participants aged ≥ 16 years with a completed survey were eligible. Survey responses were summarized using frequency counts, percentages, and means. Two-sided Z-tests for equality of proportions and logistic regression models were used to compare the survey results between geographic and demographic groups. RESULTS: In total, 7861 participants were included (28.0% men; mean age 61.3 years; response rate 28%). Our results (gender- and age-adjusted odds ratio, 95% confidence interval) show that high-incidence provinces for CM (Prince Edward Island and Nova Scotia) had significantly more sunburns (OR 2.00, 1.72-2.31), total sun exposure (OR 2.05, 1.68-2.50), recreational sun exposure (OR 1.95, 1.61-2.35) and tans (OR 1.77, 1.53-2.05) than individuals in low-incidence provinces (Newfoundland and Labrador). However, individuals in high-incidence provinces displayed more protective behaviors: there were less tanning bed users (OR 0.82, 0.71-0.95), they checked their skin more frequently for new moles (OR 1.26, 1.06-1.51) and practiced more sun protection overall. Additional analyses are presented based on education, income, sexual orientation and gender. DISCUSSION: These findings suggest that future efforts aimed at reducing the CM burden in Atlantic Canada should be tailored for target geographic and/or demographic groups. LIMITATIONS: the study participants are not representative of the population in Atlantic Canada due to recruitment strategies.

A case of eruptive xanthomas associated with pregnancy unmasking a G188E heterozygous mutation of the lipoprotein lipase gene: A case report.

A case of eruptive xanthomas with exceptionally high levels of blood triglycerides without any complication during pregnancy is reported. Eruptive xanthomas may develop in the setting of severe hypertriglyceridemia. Clinically, patients present with small and smooth papules with a characteristic yellow hue. The condition can also be associated with morbid systemic complications. Estrogen replacement therapy is a known cause of secondary hypertriglyceridemia. Estrogen increase in pregnancy is associated with a physiologic elevation of blood triglycerides in order to provide sufficient nutrition for the fetus. However, in the setting of primary dyslipidemia, severe hypertriglyceridemia can occur. The case presented here was explained by a partial primary lipoprotein lipase deficiency with a heterozygous G188E mutation of the LPL gene. The delivery by induced labor and the introduction of fenofibrate led to a rapid decrease of triglycerides and a resolution of cutaneous lesions without any complication for the patient or her baby.

Population-Based Study Detailing Cutaneous Melanoma Incidence and Mortality Trends in Canada.

Background: Cutaneous melanoma (CM) is one of the most fatal types of skin cancer. Alarmingly, increases in incidence and mortality were noted globally for this malignancy, despite increase in understanding of melanoma pathogenesis and enhanced prevention efforts. Methods: Data was extracted for CM patients for provinces and territories (except Quebec) using two independent, population-based registries. Analysis was performed using both clinical and pathological characteristics: tumor morphologic classification, age, sex, anatomic site affected and place of residence. Mortality trends were assessed over a 7-year period. Results were compared to prior findings for 1992-2010. Results: During 2011-2017 39,610 patients were diagnosed with CM, with 5,890 reported deaths. National crude CM incidence was 20.75 (age-standardized incidence: 14.12) cases per 100,000 individuals per year. Females accounted for 45.8% of cases and 37.1% of deaths. While CM incidence rates continue to increase in both sexes, since 2013 the CM mortality is declining. We observed important differences across the provinces/territories, where Nova Scotia, Prince Edward Island, southern Ontario/British Columbia and certain coastal communities of New Brunswick demonstrated higher CM incidence and mortality rates. The observed incidence and mortality trends for 2011-2017 validate and extend earlier observations from 1992 to 2010 for CM. Conclusion: This population-based study highlights that while melanoma's incidence is increasing in Canada, mortality rates are for the first time decreasing since 2013. We detail regional distribution of this cancer highlighting communities in southern/coastal areas, as being most at risk as well as the latest trends of melanoma incidence by age, sex and anatomic site. In males, melanoma is more common on the head/trunk, while in females on the extremities. Notably, Acral Lentiginous Melanoma was the only CM subtype that was more common in females, which primarily affects hands and feet.

Asymptomatic Left Ventricular Malignant Psammomatous Melanotic Schwannoma.

Malignant psammomatous melanotic schwannoma (MPMS) is a rare type of tumour, occasionally reported to occur with mediastinal involvement. Histopathologic similarities with melanoma may lead to a wrong diagnosis, but distinguishing between types of tumours is mandatory for adequate management and prognosis. MPMS may be aggressive and manifest unpredictable behavior, with a poor midterm prognosis despite benign histopathologic features. We discuss the challenges that come with a diagnosis of MPMS, and the rationale for our treatment strategy, in this first report regarding MPMS involving the left heart ventricle.

Le schwannome mélanotique psammomateux malin (SMPM) est un type de tumeur rare qui est à l'occasion observé au niveau du médiastin. Ses similitudes histologiques avec le mélanome peuvent conduire à un diagnostic erroné, mais il est impératif de savoir faire la distinction entre ces types de tumeur pour optimiser la prise en charge et le pronostic. Le SMPM peut être agressif et avoir une évolution imprévisible, avec un pronostic défavorable à moyen terme malgré des caractéristiques histopathologiques bénignes. Dans cette première étude de cas de SMPM présentant une atteinte du ventricule gauche, nous décrivons les défis posés par un diagnostic de SMPM et justifions notre stratégie de traitement.

Management of Pyrexia Associated with the Combination of Dabrafenib and Trametinib: Canadian Consensus Statements.

The combination of dabrafenib and trametinib is a well-established treatment for BRAF-mutated melanoma. However, the effectiveness of this approach may be hindered by the development of treatment-related pyrexia syndrome, which occurs in at least 50% of treated patients. Without appropriate intervention, pyrexia syndrome has the potential to worsen and can result in hypotension secondary to dehydration and associated organ-related complications. Furthermore, premature treatment discontinuation may result in a reduction in progression-free and overall survival. Despite existing guidance, there is still a wide variety of therapeutic approaches suggested in the literature for both the definition and management of dabrafenib and trametinib-related pyrexia. This is reflected in the practice variation of its prevention and treatment within and between Canadian cancer centres. A Canadian working group was formed and consensus statements were constructed based on evidence and finalised through a two-round modified Delphi approach. The statements led to the development of a pyrexia treatment algorithm that can easily be applied in routine practice. The Canadian working group consensus statements serve to provide practical guidance for the management of dabrafenib and trametinib-related pyrexia, hopefully leading to reduced discontinuation rates, and ultimately improve patients' quality of life and cancer-related outcomes.

Defining the Criteria for Reflex Testing for BRAF Mutations in Cutaneous Melanoma Patients.

Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients <50, visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). While BRAF mutation testing is recommended for stage III-IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB.

Multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine in patients with post-resection melanoma at high risk of recurrence.

BACKGROUND: Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. METHODS: Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. RESULTS: For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). CONCLUSIONS: Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. TRIAL REGISTRATION NUMBER: NCT01546571.

Predictive factors for sentinel lymph nodes and non-sentinel lymph nodes metastatic involvement: a database study of 1,041 melanoma patients.

BACKGROUND: Sentinel lymph node (SLN) biopsy may identify patients who may need completion lymphadenectomy and adjuvant therapy. METHODS: Univariate and multivariate analysis were conducted for SLN status in a prospective cohort of 1,041 patients. A biopsy was recommended for melanoma greater than or equal to 1 mm thick or greater than or equal to .75 mm with poor prognostic features. RESULTS: For sentinel node status, mitotic rate is very significant in univariate analysis. In multivariate analysis, Breslow, lymphovascular invasion, and primary site were significant. Breslow thickness greater than or equal to 2 mm and SLN with macroscopic burden greater than or equal to 2 mm are the only statistically significant variables predicting the non-SLN status in multivariate analysis. CONCLUSIONS: The data confirm the importance of Breslow, lymphovascular invasion, and body site for SLN status. The cutoff of 2 mm for tumor load in SLN appears to be a simple technique to find the high-risk patients with further lymph node disease.

Real-world treatment practice in patients with advanced melanoma in the era before ipilimumab: results from the IMAGE study.

The therapeutic landscape for advanced melanoma has recently been transformed by several novel agents (immune checkpoint inhibitors and molecular-targeted agents). The prospective, multi-site, observational study IMAGE (ipilimumab: management of advanced melanoma in real practice) included a retrospective cohort to describe real-world treatment prior to approval of the immune checkpoint inhibitor ipilimumab. This retrospective cohort of patients, who started second-line/subsequent treatment (index therapy) for advanced melanoma within 3 years before ipilimumab approval, was selected randomly by chart review. Collected data included treatment history, patient outcomes, and healthcare resource utilization. All patients had ≥1 year of follow-up data. This analysis included 177 patients from Europe (69%) and North America (31%). The most common index therapies (used alone or in combination) were fotemustine (23%), dacarbazine (21%), temozolomide (14%), and platinum-based chemotherapy (14%). Most patients (89%) discontinued index treatment during the study period; the most common reason was disease progression (59%). Among patients with tumor assessment (153/177; 86%), 2% had complete response, 5% had partial response, and 12% had stable disease on last tumor assessment. At 1-year study follow-up, median progression-free survival was 2.6 months (95% confidence interval [CI], 2.1-2.9) and median overall survival was 8.8 months (95% CI, 6.5-9.7). During follow-up, 95% of the patients had healthcare visits for advanced melanoma, 74% of whom were hospitalized or admitted to a hospice facility. These results provide insights into patient care with advanced melanoma in the era before ipilimumab and may serve as a benchmark for new agents in future real-world studies.

Non-melanoma Skin Cancer in Canada Chapter 3: Management of Actinic Keratoses.

BACKGROUND: Actinic keratosis (AK) and cheilitis (AC) are lesions that develop on photodamaged skin and may progress to form invasive squamous cell carcinomas (SCCs). OBJECTIVE: To provide guidance to Canadian health care practitioners regarding management of AKs and ACs. METHODS: Literature searches and development of graded recommendations were carried out as discussed in the accompanying introduction (chapter 1 of the NMSC guidelines). RESULTS: Treatment of AKs allows for secondary prevention of skin cancer in sun-damaged skin. Because it is impossible to predict whether a given AK will regress, persist, or progress, AKs should ideally be treated. This chapter discusses options for the management of AKs and ACs. CONCLUSIONS: Treatment options include surgical removal, topical treatment, and photodynamic therapy. Combined modalities may be used in case of inadequate response. AKs are particularly common following the long-term immunosuppression in organ transplant patients, who should be monitored frequently to identify emerging lesions that require surgery.

Non-melanoma Skin Cancer in Canada Chapter 4: Management of Basal Cell Carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy. Growth of BCCs leads to local destruction of neighbouring healthy skin and underlying tissue and can result in significant functional and cosmetic morbidity. OBJECTIVE: To provide guidance to Canadian health care practitioners regarding management of BCCs. METHODS: Literature searches and development of graded recommendations were carried out as discussed in the accompanying Introduction. RESULTS: Although BCCs rarely metastasize, they can be aggressive and disfiguring. This chapter describes the natural history and prognosis of BCCs. Risk stratification is based on clinical features, including the site and size of the tumour, its histologic subtype (nodular vs sclerosing), and its history of recurrence. CONCLUSIONS: Various options should be considered for BCC treatment, including cryosurgery, curettage, and topical or photodynamic approaches, as well as fixed-margin surgery and Mohs micrographic surgery. Stratification of recurrence risk for individual BCCs determines the most appropriate therapeutic course.

Vemurafenib and radiosensitization.

IMPORTANCE: The BRAF inhibitor, vemurafenib, was recently approved for the treatment of patients with BRAFV600 metastatic melanoma. Wider use of this drug and longer follow-up periods of treatment are resulting in the emergence of a growing number of reports detailing new adverse effects. Cutaneous adverse effects are preeminent with UV-A-dependent phototoxicity, hyperkeratotic folliculitis, hand-foot skin reaction, hair changes, verrucous papillomas, keratoacanthomas, and squamous cell carcinomas. OBSERVATIONS: We report 2 cases of dermatitis occurring on a previously irradiated skin area in patients treated with vemurafenib for a BRAFV600-mutated metastatic melanoma. The first case occurred 10 days after a low dose of radiation was delivered that usually does not induce any radiodermatitis, suggesting radiosensitization by vemurafenib. The second case occurred 30 days after radiotherapy and was diagnosed as radiation recall dermatitis. CONCLUSIONS AND RELEVANCE: Vemurafenib should be considered a potential cutaneous radiosensitizer and an inducer of radiation recall dermatitis. However, these adverse effects are easily managed with topical corticosteroids. Dose reduction or interruption of vemurafenib is not required. Further studies and reports will enlighten us as to whether this pharmacodynamic interaction between x-rays and vemurafenib is also seen with other BRAF or MEK inhibitors on the same mitogen-activated protein kinase pathway currently under development.