Impact of climate change on atopic dermatitis: A review by the International Eczema Council.

Atopic dermatitis (AD), the most burdensome skin condition worldwide, is influenced by climatic factors and air pollution; however, the impact of increasing climatic hazards on AD remains poorly characterized. Leveraging an existing framework for 10 climatic hazards related to greenhouse gas emissions, we identified 18 studies with evidence for an impact on AD through a systematic search. Most climatic hazards had evidence for aggravation of AD the impact ranged from direct effects like particulate matter-induced AD exacerbations from wildfires to the potential for indirect effects like drought-induced food insecurity and migration. We then created maps comparing the past, present, and future projected burden of climatic hazards to global AD prevalence data. Data are lacking, especially from those regions most likely to experience more climatic hazards. We highlight gaps important for future research: understanding the synergistic impacts of climatic hazards on AD, long-term disease activity, the differential impact on vulnerable populations, and how basic mechanisms explain population-level trends.

The impact of demographics, socioeconomics, and health care access on melanoma outcomes.

Disparities in melanoma care exist in the United States. Disparities in provider type, patient demographics, place of residence, insurance status, socioeconomic status, race/ethnicity, and age impact melanoma outcomes. Melanomas detected by dermatologists are thinner, at an earlier stage, and have better survival outcomes compared with detection by primary care providers or patients. Lower socioeconomic status, race/ethnicity, and place of residence are associated with decreased access to or use of dermatologists, or both, and more advanced melanomas at diagnosis. Additionally, uninsured and publicly insured individuals are more likely to present with late-stage melanomas, resulting in worse outcomes. This review provides a comprehensive overview of how structural and patient-level characteristics influence melanoma outcomes in order to inform clinical care and health care policy as it relates to addressing gaps in melanoma care.

Molecular risk prediction in cutaneous melanoma: A meta-analysis of the 31-gene expression profile prognostic test in 1,479 patients.

BACKGROUND: Multiple studies have reported on the accuracy of the prognostic 31-gene expression profile test for cutaneous melanoma. Consistency of the test results across studies has not been systematically evaluated. OBJECTIVE: To assess the robustness of the prognostic value of the 31-gene expression profile. METHODS: Raw data were obtained from studies identified from systematic review. A meta-analysis was performed to determine overall effect of the 31-gene expression profile. Clinical outcome metrics for the 31-gene expression profile were compared with American Joint Committee on Cancer staging. RESULTS: Three studies met inclusion criteria; data from a novel cohort of 211 patients were included (n = 1,479). Five-year recurrence-free and distant metastasis-free survival rates were 91.4% and 94.1% for Class 1A patients and 43.6% and 55.5% for Class 2B patients (P < .0001). Meta-analysis results showed that Class 2 was significantly associated with recurrence (hazard ratio 2.90; P < .0001) and distant metastasis (hazard ratio 2.75; P < .0001). The 31-gene expression profile identified American Joint Committee on Cancer stage I to III patient subsets with high likelihood for recurrence and distant metastasis. Sensitivity was 76% (95% confidence interval 71%-80%) and 76% (95% confidence interval 70%-82%) for each end point, respectively. When 31-gene expression profile and sentinel lymph node biopsy results were considered together, sensitivity and negative predictive value for distant metastasis-free survival were both improved. CONCLUSION: The 31-gene expression profile test consistently and accurately identifies melanoma patients at increased risk of metastasis, is independent of other clinicopathologic covariates, and augments current risk stratification by reclassifying patients for heightened surveillance who were previously designated as being at low risk.

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

Targeting protein-trafficking pathways alters melanoma treatment sensitivity.

Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the protein-trafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocyte-stimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein-trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents.

The MADS box transcription factor MEF2C regulates melanocyte development and is a direct transcriptional target and partner of SOX10.

Waardenburg syndromes are characterized by pigmentation and autosensory hearing defects, and mutations in genes encoding transcription factors that control neural crest specification and differentiation are often associated with Waardenburg and related disorders. For example, mutations in SOX10 result in a severe form of Waardenburg syndrome, Type IV, also known as Waardenburg-Hirschsprung disease, characterized by pigmentation and other neural crest defects, including defective innervation of the gut. SOX10 controls neural crest development through interactions with other transcription factors. The MADS box transcription factor MEF2C is an important regulator of brain, skeleton, lymphocyte and cardiovascular development and is required in the neural crest for craniofacial development. Here, we establish a novel role for MEF2C in melanocyte development. Inactivation of Mef2c in the neural crest of mice results in reduced expression of melanocyte genes during development and a significant loss of pigmentation at birth due to defective differentiation and reduced abundance of melanocytes. We identify a transcriptional enhancer of Mef2c that directs expression to the neural crest and its derivatives, including melanocytes, in transgenic mouse embryos. This novel Mef2c neural crest enhancer contains three functional SOX binding sites and a single essential MEF2 site. We demonstrate that Mef2c is a direct transcriptional target of SOX10 and MEF2 via this evolutionarily conserved enhancer. Furthermore, we show that SOX10 and MEF2C physically interact and function cooperatively to activate the Mef2c gene in a feed-forward transcriptional circuit, suggesting that MEF2C might serve as a potentiator of the transcriptional pathways affected in Waardenburg syndromes.

Sex disparities in melanoma outcomes: the role of biology.

Melanoma outcomes differ between men and women even when adjusted for prognostic factors such as age, Breslow thickness, body site, ulceration, lymph node dissection, and for treatment, with men having poorer outcomes compared to women. The mechanisms underlying this disparity are not well understood. Behavioral differences between the sexes such as ultraviolet light exposure and health care services utilization have been suggested as contributing, and differences in endogenous biological processes such as immune function, hormonal regulation, oxidative stress response, vitamin D metabolism and sex chromosome gene expression have also been proposed as mechanisms. This review examines the cumulative evidence for biologically based processes that lead to differences in melanoma biology, including inherent sex-based differences in immune function, oxidative stress response and vitamin D metabolism; the complex interplay between sex hormones, the immune system and oxidative stress response; the effect of non-random X chromosome inactivation on tumorigenesis; and the potential contribution of recently identified oncogenes on the Y chromosome.

Artificial intelligence and skin cancer.

Artificial intelligence is poised to rapidly reshape many fields, including that of skin cancer screening and diagnosis, both as a disruptive and assistive technology. Together with the collection and availability of large medical data sets, artificial intelligence will become a powerful tool that can be leveraged by physicians in their diagnoses and treatment plans for patients. This comprehensive review focuses on current progress toward AI applications for patients, primary care providers, dermatologists, and dermatopathologists, explores the diverse applications of image and molecular processing for skin cancer, and highlights AI's potential for patient self-screening and improving diagnostic accuracy for non-dermatologists. We additionally delve into the challenges and barriers to clinical implementation, paths forward for implementation and areas of active research.

Rural-Urban Differences in Sun Exposure and Protection Behaviors in the United States.

BACKGROUND: Evidence regarding whether rural residence is a risk factor for skin cancer is mixed. We compared sun exposure and protection behaviors between rural and urban residents by ethno-racial group in the United States. METHODS: We analyzed data from three (2013-2018) National Health and Nutrition Examination Survey cycles. We compared self-reported sun exposure and protection measures (sunburn, time spent outside, sunscreen use, wearing long sleeves, staying in shade) by rural-urban residential status using survey-weighted logistic regression models stratified by ethno-racial group, adjusting for age, sex, income, education, body mass index, and smoking. RESULTS: Hispanic rural versus urban residents more often reported sunburns in the past year [41.6% vs. 31.2%, adjusted OR (aOR): 1.46 (1.15-1.86)]. White rural versus urban residents more often spent 2+ hours outside on workdays [42.9% vs. 29.1%, aOR: 1.60 (1.27-2.01)] and non-workdays [72.2% vs. 64.8%, aOR: 1.45 (1.12-1.88)] and less often used sunscreen [26.0% vs. 35.1%, aOR: 0.74 (0.59-0.93)] and stayed in the shade [21.7% vs. 26.7%, aOR: 0.72 (0.57-0.89)]. Black rural versus urban residents stayed in the shade less often [31.6% vs. 43.9%, aOR: 0.60 (0.39-0.91)] but less often spent 2+ hours outside on non-workdays [47.6% vs. 56.8%, aOR: 0.67 (0.51-0.90)]. CONCLUSIONS: Across all ethno-racial groups included, rural residents reported greater sun risk behaviors than urban residents, with some nuances by ethno-racial identity, suggesting rural residence is a potential risk factor for skin cancer. IMPACT: Sun protection promotion programs should consider rural-urban settings while also accounting for ethno-racial identities.

Botfly myiasis after travel to Bolivia.

Following a trip to Bolivia, a 32-year-old woman developed a left lower leg ulcer with a sensation of movement within the lesion. After being seen by four primary care providers, she was referred to dermatology 7 weeks after her return from Bolivia. At that time, she was found to have a 5 mm weeping ulcer, with a live larva visible at the base. We conducted a punch biopsy for botfly removal, after which the patient healed well. Herein we discuss the ways in which clinical presentation, history of travel, dermoscopy, and ultrasound can contribute to diagnosing botfly myiasis. While treatment of botfly infestation is not required, we discuss the importance of shared decision-making in considering treatment, as well as methods for extraction, including mechanical or surgical removal, which may help to reduce patient anxiety and the risk for secondary infection. As global travel resumes to levels prior to the Covid-19 pandemic, it is important for dermatologists to be aware of the presenting symptoms and treatment of tropical skin disorders.

Spiny Keratoderma in Association with Melanoma.

Spiny keratoderma (SK) was first described by Brown in 1871 and is characterized by numerous 1-2 mm spines of keratin on the palms and soles, usually sparing the dorsal surfaces, or disseminated over the trunk. Histologically, the "spine" represents a column of hyperkeratosis. Several different forms are known, including familial, sporadic, post-inflammatory and paraneoplastic. Although an association of SK with melanoma has been reported, the significance of such co-occurrence remains unclear due to the limited number of cases. To increase the body of knowledge and shed further light on this rare condition, we present a case of SK in a patient with a recent history of melanoma in situ.

Air Pollution and Atopic Dermatitis, from Molecular Mechanisms to Population-Level Evidence: A Review.

Atopic dermatitis (AD) has increased in prevalence to become the most common inflammatory skin condition globally, and geographic variation and migration studies suggest an important role for environmental triggers. Air pollution, especially due to industrialization and wildfires, may contribute to the development and exacerbation of AD. We provide a comprehensive, multidisciplinary review of existing molecular and epidemiologic studies on the associations of air pollutants and AD symptoms, prevalence, incidence, severity, and clinic visits. Cell and animal studies demonstrated that air pollutants contribute to AD symptoms and disease by activating the aryl hydrocarbon receptor pathway, promoting oxidative stress, initiating a proinflammatory response, and disrupting the skin barrier function. Epidemiologic studies overall report that air pollution is associated with AD among both children and adults, though the results are not consistent among cross-sectional studies. Studies on healthcare use for AD found positive correlations between medical visits for AD and air pollutants. As the air quality worsens in many areas globally, it is important to recognize how this can increase the risk for AD, to be aware of the increased demand for AD-related medical care, and to understand how to counsel patients regarding their skin health. Further research is needed to develop treatments that prevent or mitigate air pollution-related AD symptoms.

Early Detection and Prognostic Assessment of Cutaneous Melanoma: Consensus on Optimal Practice and the Role of Gene Expression Profile Testing.

Importance: Therapy for advanced melanoma has transformed during the past decade, but early detection and prognostic assessment of cutaneous melanoma (CM) remain paramount goals. Best practices for screening and use of pigmented lesion evaluation tools and gene expression profile (GEP) testing in CM remain to be defined. Objective: To provide consensus recommendations on optimal screening practices and prebiopsy diagnostic, postbiopsy diagnostic, and prognostic assessment of CM. Evidence Review: Case scenarios were interrogated using a modified Delphi consensus method. Melanoma panelists (n = 60) were invited to vote on hypothetical scenarios via an emailed survey (n = 42), which was followed by a consensus conference (n = 51) that reviewed the literature and the rationale for survey answers. Panelists participated in a follow-up survey for final recommendations on the scenarios (n = 45). Findings: The panelists reached consensus (≥70% agreement) in supporting a risk-stratified approach to melanoma screening in clinical settings and public screening events, screening personnel recommendations (self/partner, primary care provider, general dermatologist, and pigmented lesion expert), screening intervals, and acceptable appointment wait times. Participants also reached consensus that visual and dermoscopic examination are sufficient for evaluation and follow-up of melanocytic skin lesions deemed innocuous. The panelists reached consensus on interpreting reflectance confocal microscopy and some but not all results from epidermal tape stripping, but they did not reach consensus on use of certain pigmented lesion evaluation tools, such as electrical impedance spectroscopy. Regarding GEP scores, the panelists reached consensus that a low-risk prognostic GEP score should not outweigh concerning histologic features when selecting patients to undergo sentinel lymph node biopsy but did not reach consensus on imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status. Conclusions and Relevance: For this consensus statement, panelists reached consensus on aspects of a risk-stratified approach to melanoma screening and follow-up as well as use of visual examination and dermoscopy. These findings support a practical approach to diagnosing and evaluating CM. Panelists did not reach consensus on a clearly defined role for GEP testing in clinical decision-making, citing the need for additional studies to establish the clinical use of existing GEP assays.

Ultraviolet A radiation exposure and melanoma: a review.

The incidence of cutaneous melanoma has been increasing worldwide, and melanoma disproportionately contributes to skin cancer mortality. The pathogenesis of melanoma involves genetic and environmental factors, and while the effects of ultraviolet B radiation on melanoma development are well researched, fewer studies have investigated the role of ultraviolet A (UVA) radiation. We comprehensively reviewed cell, animal and epidemiology studies on the association between UVA exposure and melanomagenesis. UVA radiation has been found to have negative effects on melanocytes due to the induction of oxidative stress, dysregulation of gene transcription and creation of mutagenic photoproducts in DNA. Animal studies demonstrate adverse effects of UVA on melanocytes, including the development of melanoma. Epidemiology studies, of varying quality, that examined participants' exposure to tanning devices which use UVA radiation primarily found that UVA exposure increased the risk for melanoma. Some studies reported larger associations with increased frequency of device use, suggestive of a dose-response relationship. Overall, we found that many studies supported a positive association between UVA exposure and melanoma on both molecular and population levels. Understanding the role of UVA in the development of melanoma will inform the implementation of preventive health interventions, such as those related to sunscreen development and use and increasing restrictions on indoor tanning.

Disparities in access for melanoma screening by region, specialty, and insurance: A cross-sectional audit study.

Background: Early detection of melanoma is critical for positive outcomes. However, access for the diagnosis of melanoma remains problematic for segments of the general population. Objective: To compare the rates of dermatology and family medicine practitioner acceptances for a public insurance (Medicaid) versus private insurance (Anthem Blue Cross) and clinic wait times for an appointment for a changing pigmented skin lesion concerning melanoma in rural and urban regions in California. Methods: Cross-sectional audit study between June 2017 and March 2019; scripted phone calls were made to dermatology and family medicine practices (FMPs). Results: Family medicine and dermatology practices in both regions had significantly decreased acceptance of Medicaid. Dermatology practices had 11.3% to 13.0% Medicaid acceptance rates that were less than FMP rates of 28% to 36%. In both regions, FMP wait times were 2.4- to 3.2-fold longer for public versus private insurance; there were little differences in wait times for the 2 insurance types in dermatology practices, in both regions. Limitations: Assessment of only 2 regions in the state of California. Conclusion: Delays at FMPs and insurance types limit access to melanoma screening in California for underserved segments of the general population, which has implications for melanoma outcomes and health policy.

Patient and general public attitudes towards clinical artificial intelligence: a mixed methods systematic review.

Artificial intelligence (AI) promises to change health care, with some studies showing proof of concept of a provider-level performance in various medical specialties. However, there are many barriers to implementing AI, including patient acceptance and understanding of AI. Patients' attitudes toward AI are not well understood. We systematically reviewed the literature on patient and general public attitudes toward clinical AI (either hypothetical or realised), including quantitative, qualitative, and mixed methods original research articles. We searched biomedical and computational databases from Jan 1, 2000, to Sept 28, 2020, and screened 2590 articles, 23 of which met our inclusion criteria. Studies were heterogeneous regarding the study population, study design, and the field and type of AI under study. Six (26%) studies assessed currently available or soon-to-be available AI tools, whereas 17 (74%) assessed hypothetical or broadly defined AI. The quality of the methods of these studies was mixed, with a frequent issue of selection bias. Overall, patients and the general public conveyed positive attitudes toward AI but had many reservations and preferred human supervision. We summarise our findings in six themes: AI concept, AI acceptability, AI relationship with humans, AI development and implementation, AI strengths and benefits, and AI weaknesses and risks. We suggest guidance for future studies, with the goal of supporting the safe, equitable, and patient-centred implementation of clinical AI.

Association of Wildfire Air Pollution and Health Care Use for Atopic Dermatitis and Itch.

IMPORTANCE: Air pollution is a worldwide public health issue that has been exacerbated by recent wildfires, but the relationship between wildfire-associated air pollution and inflammatory skin diseases is unknown. OBJECTIVE: To assess the associations between wildfire-associated air pollution and clinic visits for atopic dermatitis (AD) or itch and prescribed medications for AD management. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional time-series study assessed the associations of air pollution resulting from the California Camp Fire in November 2018 and 8049 dermatology clinic visits (4147 patients) at an academic tertiary care hospital system in San Francisco, 175 miles from the wildfire source. Participants included pediatric and adult patients with AD or itch from before, during, and after the time of the fire (October 2018 through February 2019), compared with those with visits in the same time frame of 2015 and 2016, when no large wildfires were near San Francisco. Data analysis was conducted from November 1, 2019, to May 30, 2020. EXPOSURES: Wildfire-associated air pollution was characterized using 3 metrics: fire status, concentration of particulate matter less than 2.5 µm in diameter (PM2.5), and satellite-based smoke plume density scores. MAIN OUTCOMES AND MEASURES: Weekly clinic visit counts for AD or itch were the primary outcomes. Secondary outcomes were weekly numbers of topical and systemic medications prescribed for AD in adults. RESULTS: Visits corresponding to a total of 4147 patients (mean [SD] age, 44.6 [21.1] years; 2322 [56%] female) were analyzed. The rates of visits for AD during the Camp Fire for pediatric patients were 1.49 (95% CI, 1.07-2.07) and for adult patients were 1.15 (95% CI, 1.02-1.30) times the rate for nonfire weeks at lag 0, adjusted for temperature, relative humidity, patient age, and total patient volume at the clinics for pediatric patients. The adjusted rate ratios for itch clinic visits during the wildfire weeks were 1.82 (95% CI, 1.20-2.78) for the pediatric patients and 1.29 (95% CI, 0.96-1.75) for adult patients. A 10-µg/m3 increase in weekly mean PM2.5 concentration was associated with a 7.7% (95% CI, 1.9%-13.7%) increase in weekly pediatric itch clinic visits. The adjusted rate ratio for prescribed systemic medications in adults during the Camp Fire at lag 0 was 1.45 (95% CI, 1.03-2.05). CONCLUSIONS AND RELEVANCE: This cross-sectional study found that short-term exposure to air pollution due to the wildfire was associated with increased health care use for patients with AD and itch. These results may provide a better understanding of the association between poor air quality and skin health and guide health care professionals' counseling of patients with skin disease and public health practice.

The role of technology in melanoma screening and diagnosis.

Melanoma presents challenges for timely and accurate diagnosis. Expert panels have issued risk-based screening guidelines, with recommended screening by visual inspection. To assess how recent technology can impact the risk/benefit considerations for melanoma screening, we comprehensively reviewed non-invasive visual-based technologies. Dermoscopy increases lesional diagnostic accuracy for both dermatologists and primary care providers; total body photography and sequential digital dermoscopic imaging also increase diagnostic accuracy, are supported by automated lesion detection and tracking, and may be best suited to use by dermatologists for longitudinal follow-up. Specialized imaging modalities using non-visible light technology have unproven benefit over dermoscopy and can be limited by cost, access, and training requirements. Mobile apps facilitate image capture and lesion tracking. Teledermatology has good concordance with face-to-face consultation and increases access, with increased accuracy using dermoscopy. Deep learning models can surpass dermatologist accuracy, but their clinical utility has yet to be demonstrated. Technology-aided diagnosis may change the calculus of screening; however, well-designed prospective trials are needed to assess the efficacy of these different technologies, alone and in combination to support refinement of guidelines for melanoma screening.