Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma.

Introduction: Quantitative, multiplexed imaging is revealing complex spatial relationships between phenotypically diverse tumor infiltrating leukocyte populations and their prognostic implications. The underlying mechanisms and tissue structures that determine leukocyte distribution within and around tumor nests, however, remain poorly understood. While presumed players in metastatic dissemination, new preclinical data demonstrates that blood and lymphatic vessels (lymphovasculature) also dictate leukocyte trafficking within tumor microenvironments and thereby impact anti-tumor immunity. Here we interrogate these relationships in primary human cutaneous melanoma. Methods: We established a quantitative, multiplexed imaging platform to simultaneously detect immune infiltrates and tumor-associated vessels in formalin-fixed paraffin embedded patient samples. We performed a discovery, retrospective analysis of 28 treatment-naïve, primary cutaneous melanomas. Results: Here we find that the lymphvasculature and immune infiltrate is heterogenous across patients in treatment naïve, primary melanoma. We categorized five lymphovascular subtypes that differ by functionality and morphology and mapped their localization in and around primary tumors. Interestingly, the localization of specific vessel subtypes, but not overall vessel density, significantly associated with the presence of lymphoid aggregates, regional progression, and intratumoral T cell infiltrates. Discussion: We describe a quantitative platform to enable simultaneous lymphovascular and immune infiltrate analysis and map their spatial relationships in primary melanoma. Our data indicate that tumor-associated vessels exist in different states and that their localization may determine potential for metastasis or immune infiltration. This platform will support future efforts to map tumor-associated lymphovascular evolution across stage, assess its prognostic value, and stratify patients for adjuvant therapy.

Evidence-Based Communication to Increase Melanoma Knowledge and Skin Checks.

Rates of melanoma-the deadliest form of skin cancer-have increased. Early detection can save lives, and patients have a critical role to play in checking their skin. We aim to identify health communication messages that best educate the public and increase intentions toward skin checks. After viewing messages intended to increase melanoma knowledge, participants correctly identified a greater proportion (74.6 vs 70.4%) of moles (mean number = 17.9, 95% confidence interval [CI] = 17.5-18.3 vs 16.9, 95% CI = 16.6-17.3; P < .001, partial eta-squared = 0.03) and had knowledge of more melanoma warning signs (mean number = 5.8, 95% CI = 5.7-5.8 vs 5.6, 95% CI = 5.5-5.7, P = .01, partial eta-squared = 0.02). After viewing messages intended to increase self-confidence in checking their skin accurately, they were also more likely to report greater intentions to do a skin check on a scale of 1-5 (mean number = 3.8, 95% CI = 3.7-3.9 vs 3.6, 95% CI = 3.4-3.7, P = .005, partial eta-squared = 0.02). Online melanoma messages aimed at increasing both melanoma knowledge and skin-check confidence may be most effective in improving the accuracy of skin self-examinations and intentions to do them.

Examining the Role of Estheticians in Skin Cancer Surveillance.

BACKGROUND: Melanoma and non-melanoma skin cancer are significant causes of mortality. Previous studies regarding skin cancer education in nonmedical professionals have shown increases in favorable attitudes and likelihood of approaching clients about concerning lesions with training. However, few studies have investigated the use of estheticians in skin cancer screening. OBJECTIVES: The objective of this study was to develop an education course to train estheticians to recognize concerning lesions, to assess the baseline knowledge of estheticians toward skin cancer detection, and to determine the effect that our curriculum has on lesion detection. METHODS: We administered an education course and corresponding cross-sectional surveys to estheticians to evaluate current knowledge and assess for improvements in attitudes and behaviors regarding skin cancer detection. RESULTS: Of 504 estheticians, most estheticians (85-98%) indicated the correct level of concern for "extremely concerning" lesions on pre- and post-training surveys. Estheticians were more likely to recommend that their client see a medical professional if they previously attended a course on skin cancer (p = 0.012) or had greater than 1 year of work experience (p < 0.001). After completion of the training module, most participants felt "very comfortable," suggesting that clients see a doctor for a suspicious lesion. CONCLUSION: Our findings suggest that estheticians are capable of indicating the appropriate level of concern for abnormal lesions. Estheticians may serve as a valuable screening partner for dermatologists in the detection of skin cancer.

The benefit of early-stage diagnosis: A registry-based survey evaluating the quality of life in patients with melanoma.

Background: The morbidity associated with advanced stage melanoma is an important consideration in the dialog surrounding early detection and overdiagnosis. Few studies have stratified melanoma patient quality of life (QoL) by stage at diagnosis. Objective: We sought to investigate if melanoma stage is independently associated with changes in QoL within a large, community-based melanoma registry. Secondarily, we investigated whether demographic factors such as age, geographic location or level of education are associated with changes in QoL in the same population. Methods: 1108 melanoma patients were surveyed over a three-month period using the QoL in Adult Cancer Survivors Survey, consisting of 47 items on a 7-point frequency scale. Data were analysed using both descriptive statistical models and adjusted multivariate logistic regression. Results: There were 677 respondents generating a 61% response rate. Overall, higher stage at diagnosis correlated with the largest decreases in QoL as it pertained to both general (p = 0.001) and Cancer-Specific stressors (p < 0.001). Education level (p = 0.020), age (p < 0.001), rural area code designation (p = 0.020) and family history of melanoma (p = 0.017) were also independently associated with changes in QoL. Conclusion: Earlier stage at melanoma diagnosis is associated with better QoL and thus represents a crucial intervention in patient care. Given our findings and the growing body of evidence surrounding morbidity in late-stage melanoma, it is essential that QoL be included in assessing the benefits of early detection.

Melanoma literacy among the general population of three western US states.

Melanoma is a significant cause of cancer death, despite being detectable without specialized or invasive technologies. Understanding barriers to preventive behaviors such as skin self-examination (SSE) could help to define interventions for increasing the frequency of early detection. To determine melanoma knowledge and beliefs across three high-incidence US states, 15,000 surveys were sent to a population-representative sample. We aimed to assess (1) melanoma literacy (i.e., knowledge about melanoma risks, attitudes, and preventive behaviors) and (2) self-reported SSE and its association with melanoma literacy, self-efficacy, and belief in the benefits of SSE. Of 2326 respondents, only 21.2% provided responses indicating high knowledge of melanoma, and 62.8% reported performing an SSE at any time in their lives. Only 38.3% and 7.3% reported being "fairly" or "very" confident about doing SSE, respectively. SSE performance among respondents was most strongly associated with higher melanoma knowledge, higher self-efficacy, and personal history of melanoma. Melanoma literacy among survey respondents was modest, with greater literacy associated with a higher likelihood of reported preventive behavior. This assessment establishes a baseline and provides guidance for public health campaigns designed to increase prevention and early detection of this lethal cancer.

The Family Lifestyles, Actions and Risk Education (FLARE) study: Protocol for a randomized controlled trial of a sun protection intervention for children of melanoma survivors.

BACKGROUND: Children of parents who had melanoma are more likely to develop skin cancer themselves owing to shared familial risks. The prevention of sunburns and promotion of sun-protective behaviors are essential to control cancer among these children. The Family Lifestyles, Actions and Risk Education (FLARE) intervention will be delivered as part of a randomized controlled trial to support parent-child collaboration to improve sun safety outcomes among children of melanoma survivors. METHODS: FLARE is a two-arm randomized controlled trial design that will recruit dyads comprised of a parent who is a melanoma survivor and their child (aged 8-17 years). Dyads will be randomized to receive FLARE or standard skin cancer prevention education, which both entail 3 telehealth sessions with an interventionist. FLARE is guided by Social-Cognitive and Protection Motivation theories to target child sun protection behaviors through parent and child perceived risk for melanoma, problem-solving skills, and development of a family skin protection action plan to promote positive modeling of sun protection behaviors. At multiple assessments through one-year post-baseline, parents and children complete surveys to assess frequency of reported child sunburns, child sun protection behaviors and melanin-induced surface skin color change, and potential mediators of intervention effects (e.g., parent-child modeling). CONCLUSION: The FLARE trial addresses the need for melanoma preventive interventions for children with familial risk for the disease. If efficacious, FLARE could help to mitigate familial risk for melanoma among these children by teaching practices which, if enacted, decrease sunburn occurrence and improve children's use of well-established sun protection strategies.

A Systematic Review of Evidence-Based High School Melanoma Prevention Curricula.

Incorporation of melanoma prevention behaviors into daily lifestyles is difficult. Data suggest that high school educational programs on skin cancer prevention can be successful and should incorporate evidence-based teaching and learning strategies to achieve greatest impact. The goal of this systematic review is to describe evidence-based educational practices for a high-school melanoma curriculum through a comprehensive review of the literature. Ovid MEDLINE, Embase, CINAHL, and PyscINFO were searched in June 2020 for all original articles published between June 18, 1946 and June 17, 2020. All studies that used an educational curriculum to promote sun safety, skin exams, and early detection to high school students were included. A total of 25 studies with 22,683 adolescent participants were analyzed. Sixteen studies showed a significant increase in knowledge, twenty-one studies showed changes in behavior, and fifteen studies showed significant changes in attitudes. Limitations of this review include the heterogeneity of implementation and outcome reporting of educational curricula. These findings support incorporating active learning strategies as key aspects of creating an effective curriculum aimed at the prevention and early detection of melanoma.

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.

T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control.

Antigen-specific CD8+ T cell accumulation in tumors is a prerequisite for effective immunotherapy, and yet the mechanisms of lymphocyte transit are not well defined. Here we show that tumor-associated lymphatic vessels control T cell exit from tumors via the chemokine CXCL12, and intratumoral antigen encounter tunes CXCR4 expression by effector CD8+ T cells. Only high-affinity antigen downregulates CXCR4 and upregulates the CXCL12 decoy receptor, ACKR3, thereby reducing CXCL12 sensitivity and promoting T cell retention. A diverse repertoire of functional tumor-specific CD8+ T cells, therefore, exit the tumor, which limits the pool of CD8+ T cells available to exert tumor control. CXCR4 inhibition or loss of lymphatic-specific CXCL12 boosts T cell retention and enhances tumor control. These data indicate that strategies to limit T cell egress might be an approach to boost the quantity and quality of intratumoral T cells and thereby response to immunotherapy.

MITF Is Regulated by Redox Signals Controlled by the Selenoprotein Thioredoxin Reductase 1.

TR1 and other selenoproteins have paradoxical effects in melanocytes and melanomas. Increasing selenoprotein activity with supplemental selenium in a mouse model of UV-induced melanoma prevents oxidative damage to melanocytes and delays melanoma tumor formation. However, TR1 itself is positively associated with progression in human melanomas and facilitates metastasis in melanoma xenografts. Here, we report that melanocytes expressing a microRNA directed against TR1 (TR1low) grow more slowly than control cell lines and contain significantly less melanin. This phenotype is associated with lower tyrosinase (TYR) activity and reduced transcription of tyrosinase-like protein-1 (TYRP1). Melanoma cells in which the TR1 gene (TXNRD1) was disrupted using Crispr/Cas9 showed more dramatic effects including the complete loss of the melanocyte-specific isoform of MITF; other MITF isoforms were unaffected. We provide evidence that TR1 depletion results in oxidation of MITF itself. This newly discovered mechanism for redox modification of MITF has profound implications for controlling both pigmentation and tumorigenesis in cells of the melanocyte lineage.

Clinically Significant Risk Thresholds in the Management of Primary Cutaneous Melanoma: A Survey of Melanoma Experts.

BACKGROUND: Risk-based thresholds to guide management are undefined in the treatment of primary cutaneous melanoma but are essential to advance the field from traditional stage-based treatment to more individualized care. METHODS: To estimate treatment risk thresholds, hypothetical clinical melanoma scenarios were developed and a stratified random sample was distributed to expert melanoma clinicians via an anonymous web-based survey. Scenarios provided a defined 5-year risk of recurrence and asked for recommendations regarding clinical follow-up, imaging, and adjuvant therapy. Marginal probability of response across the spectrum of 5-year recurrence risk was estimated. The risk at which 50% of respondents recommended a treatment was defined as the risk threshold. RESULTS: The overall response rate was 56% (89/159). Three separate multivariable models were constructed to estimate the recommendations for clinical follow-up more than twice/year, for surveillance cross-sectional imaging at least once/year, and for adjuvant therapy. A 36% 5-year risk of recurrence was identified as the threshold for recommending clinical follow-up more than twice/year. The thresholds for recommending cross-sectional imaging and adjuvant therapy were 30 and 59%, respectively. Thresholds varied with the age of the hypothetical patient: at younger ages they were constant but increased rapidly at ages 60 years and above. CONCLUSIONS: To our knowledge, these data provide the first estimates of clinically significant treatment thresholds for patients with cutaneous melanoma based on risk of recurrence. Future refinement and adoption of thresholds would permit assessment of the clinical utility of novel prognostic tools and represents an early step toward individualizing treatment recommendations.