Risk Of Melanoma Research Articles

Acceptability of a Hypothetical Reduction in Routinely Scheduled Clinic Visits Among Patients With History of a Localized Melanoma (MEL-SELF): Pilot Randomized Clinical Trial.

After treatment for a localized melanoma, patients attend routinely scheduled clinics to monitor for new primary or recurrent melanoma. Patient-led surveillance (skin self-examination with patient-performed teledermoscopy) is an alternative model of follow-up that could replace some routinely scheduled visits. This study aims to assess the acceptability of a hypothetical reduction in routinely scheduled visits among participants of the Melanoma Self Surveillance (MEL-SELF) pilot randomized clinical trial of patient-led surveillance (intervention) versus usual care (control). Patients previously treated for localized melanoma in New South Wales who were participating in the MEL-SELF pilot randomized clinical trial were asked to respond to a web-based questionnaire at baseline and after 6 months on trial. We used mixed methods to analyze the data. The main outcome of interest was the acceptability of a hypothetical reduction in routinely scheduled visits for melanoma surveillance. Of 100 randomized participants, 87 answered the questionnaire at baseline, 66 answered the questionnaire at 6 months, and 79 provided a free-text explanation at either time point. At 6 months, 33% (17/51) of the control group and 35% (17/49) of the intervention group indicated that a hypothetical reduction in routinely scheduled visits with all melanoma doctors was at least slightly acceptable (difference in proportions -1%, 95% CI -20% to 17%; P=.89). Participants suggested that prerequisites for a reduction in routinely scheduled visits would include that sufficient time had elapsed since the previous diagnosis without a new primary melanoma or recurrence, an unscheduled appointment could be made at short notice if the patient noticed something concerning, their melanoma doctor had suggested reducing their clinic visit frequency, and patients had confidence that patient-led surveillance was a safe and effective alternative. Participants suggested that a reduction in routinely scheduled visits would not be acceptable where they perceived a very high risk of new or recurrent melanoma, low self-efficacy in skin self-examination and in the use of technologies for the patient-led surveillance intervention, and where they had a preference for clinician-led surveillance. Some patients said that a partial reduction to once a year may be acceptable. Some patients may be receptive to a reduction in routinely scheduled visits if they are assured that patient-led surveillance is safe and effective. Australian New Zealand Clinical Trials Registry ACTRN12616001716459; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371865&isReview=true; ClinicalTrials.gov NCT03581188; https://clinicaltrials.gov/ct2/show/NCT03581188. RR2-10.1001/jamadermatol.2021.4704.

A higher risk for melanoma in patients with Parkinson’s disease: Based on the results from National Health and Nutrition Examination Survey 2001 – 2004

The relationship between Parkinson’s disease (PD) and melanoma has been controversial. The present study used data from the 2001 – 2004 National Health and Nutrition Examination Survey database. This study included individuals aged ≥20 years with complete data on PD and melanoma, in which 48 participants were comorbid with the melanoma group, and 5774 were not. Both univariate and multivariate logistic regression analyses were conducted to investigate the connection. There was a higher proportion of PD in the melanoma group than in the non-melanoma group (2.45% vs. 0.30%). Univariate logistic regression analysis revealed that individuals with PD had an 8.32-fold higher risk of developing melanoma than those without PD. In addition, PD was significantly correlated with melanoma (OR, 8.747; 95% CI, 1.264 – 60.506; p = 0.030) after controlling for covariates in multivariate analysis. In conclusion, our research indicates a significant correlation between PD and melanoma in American adults.

BG02 A case of Werner syndrome: undiagnosed progeroid syndrome presenting as female pattern hair loss

Abstract A 27-year-old woman of Pakistani heritage with a background of type 2 diabetes, hypertension, hypothyroidism, infertility and Achilles tendinopathy was referred to the dermatology department for diffuse hair loss. She had greying of the scalp hair from the age of 20 years and, on examination, there were signs of hair fragility and thinning. Biopsies showed female pattern hair loss. Topical minoxidil 5% twice daily was advised. At the consultation, it was noted that her facial features included a thin nose with micrognathia. She had dental implants and had undergone cataract surgery at 19 years of age. Scleroderma-like changes were noted on the face and over the distal joints, alongside axillary freckling and excessive lentigines for her age and skin type. She was of short stature and low weight, with a body mass index (BMI) of 15.4 kg m–2. There was thenar and hypothenar wasting and loss of gluteal fat. Her parents were consanguineous (first cousins). One of her brothers, who had similar facial features, died aged 30 years from osteosarcoma. The patient and her partner had undergone two unsuccessful cycles of in vitro fertilization following 5 years of failure to conceive naturally. Medication consisted of atorvastatin, Calcichew, levothyroxine, lisinopril, metformin, pioglitazone and repaglinide. Routine bloods and hormone profile were normal. Despite her age, BMI and statin treatment, blood lipids were raised and a liver ultrasound showed fatty changes. The dermatology department queried Werner syndrome and referral to a tertiary lipodystrophy clinic was made. The lipodystrophy genetic panel was completed. Homozygous null mutation at the WRN locus was found confirming a diagnosis of Werner syndrome. Werner syndrome is an extremely rare autosomal recessive form of progeroid syndrome first described by Otto Werner in 1904. The hallmark sign is the striking disproportion between the patient’s age and appearance. WRN encodes the eponymous WRN protein, a member of the RecQ-like DNA helicase family. The prognosis is unfavourable, with a mean survival of 54 years. Primary causes of mortality are cardiovascular disease and malignancy, with melanoma, thyroid cancer, osteosarcoma and soft tissue sarcoma being the most common forms. There is currently no specific treatment. Management is close multidisciplinary monitoring and treatment of associated conditions. A 2010 study of the Werner syndrome mouse model found vitamin C supplementation to be beneficial (Massip L, Garand C, Paquet ER et al. Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J 2010; 24:158–72). As the condition results in excess damage on ultraviolet exposure and a high risk of melanoma, as well as nonmelanoma skin cancers, an annual dermatology skin check is required.

DP01 Survey on the management of dysplastic naevus

Abstract Although dysplastic naevus (DN) is a frequent diagnosis, there is significant controversy on its definition and gradation and its relationship to melanoma risk. Therefore, there is no consensus over optimal management, and surveys from Australia, Canada and the USA have shown variation in clinical practice. Dysplastic naevus with involved histological margins has not been shown to progress to melanoma. To assess UK management of DN depending on the grade of atypia and reported excision margin, we circulated a questionnaire via email to dermatologists in Scotland, north Wales, Liverpool and Manchester. Seventy-two responded, of whom 46 (64%) were consultants. The cohort was generally highly experienced, with 10 (14%) responders with 1–5 years’ dermatology experience, 15 (21%) with 6–10 years, 27 (37%) with 11–20 years and 20 (28%) with > 20 years’ experience. Management of DN varied greatly. For mild DN excised with < 1-mm margin, 59 (82%) agreed that no further management was required. Opinions were divided when margins were involved in mild DN, with 14 (19%) agreeing that no further management was required, 42 (58%) choosing to re-excise and six (8%) to re-excising only any residual pigmentation. Most dermatologists reassured patients with moderately DN with margins < 1 mm (49, 68%); 18 (25%) preferred to re-excise. For moderate DN with involved margins, six respondents (8%) felt that no further management was necessary and 54 (75%) would re-excise. For severe DN with margins > 1 mm, 16 (22%) would still re-excise and six (8%) would agree management in the multidisciplinary team meeting (MDT). For severe DN with margins < 1 mm, 41 (57%) would re-excise and seven (10%) would agree management in the MDT. Lastly, for severe DN with involved margins, 62 (86%) would re-excise and seven (10%) would agree management in the MDT. This study has shown comparable results with those from Australia and the USA, whereby most dermatologists would re-excise moderate and severe DN with involved margins. Significant numbers indicated that they would re-excise in the case of close histological margins: this is unnecessary, and more standardized management may reduce expenditure. Limitations of the study include the usual potential sources of bias in a questionnaire survey; it should be noted that reported behaviour may differ from actual practice. However, this is the first UK study on this common clinical scenario. The move to report DN as low- or high-grade may help to reduce variation, but our survey suggests that some patients are currently undergoing unnecessary procedures.

1386-P: Dipeptidyl Peptidase-4 Inhibitors and the Risk of Skin Cancer among Patients with Type 2 Diabetes—Population-Based Cohort Study

Introduction: The dipeptidyl peptidase-4 (DPP-4) enzyme influences carcinogenic pathways in the skin, although its exact role remains uncertain. The objective of this study was to determine whether DPP-4 inhibitors are associated with the incidence of melanoma and nonmelanoma skin cancer, compared with sulfonylureas. Research Design and Methods: Using the United Kingdom Clinical Practice Research Datalink, we assembled two new-user active comparator cohorts for each skin cancer outcome from 2007 to 2019. For melanoma, the cohort included 96,739 DPP-4 inhibitor users and 209,341 sulfonylurea users, and 96,411 DPP-4 inhibitor users and 208,626 sulfonylurea users for nonmelanoma skin cancer. Propensity score fine stratification weighted Cox proportional hazards models were to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of melanoma and nonmelanoma skin cancer, separately. Results: Overall, DPP-4 inhibitors were associated with a 23% decreased risk of melanoma compared with sulfonylureas (49.7 vs. 65.3 per 100,000 person-years, respectively; HR 0.77, 95% CI 0.61-0.96). The HR progressively reduced with increasing cumulative duration of use (0-2 years HR 1.14, 95% CI 0.84-1.54; 2.1-5 years HR 0.44, 95% CI 0.29-0.66; >5 years HR 0.33, 95% CI 0.14-0.74). In contrast, these drugs were not associated with the incidence of nonmelanoma skin cancer, compared with sulfonylureas (448.1 vs. 426.1 per 100,000 person-years, respectively; HR 1.06, 95% CI 0.98-1.15). Conclusions: In this large, population-based cohort study, DPP-4 inhibitors were associated with a reduced risk of melanoma but not nonmelanoma skin cancer, compared with sulfonylureas. Disclosure R.Pradhan: None. L.Azoulay: Advisory Panel; Pfizer Inc., Consultant; Pfizer Inc., Speaker's Bureau; Roche Diagnostics. R.W.Platt: Advisory Panel; Pfizer Inc., Consultant; Boehringer Ingelheim (Canada) Ltd., Biogen, Merck & Co., Inc., Nant Pharma, Other Relationship; Boehringer Ingelheim Inc. O.Yu: Consultant; Novo Nordisk. Funding Canadian Institutes of Health Research (FDN143328)

Climate Change, Skin Health, and Dermatologic Disease: A Guide for the Dermatologist.

Climate change has a pervasive impact on health and is of clinical relevance to every organ system. Climate change-related factors impact the skin's capacity to maintain homeostasis, leading to a variety of cutaneous diseases. Stratospheric ozone depletion has led to increased risk of melanoma and keratinocyte carcinomas due to ultraviolet radiation exposure. Atopic dermatitis, psoriasis, pemphigus, acne vulgaris, melasma, and photoaging are all associated with rising levels of air pollution. Elevated temperatures due to global warming induce disruption of the skin microbiome, thereby impacting atopic dermatitis, acne vulgaris, and psoriasis, and high temperatures are associated with exacerbation of skin disease and increased risk of heat stroke. Extreme weather events due to climate change, including floods and wildfires, are of relevance to the dermatologist as these events are implicated in cutaneous injuries, skin infections, and acute worsening of inflammatory skin disorders. The health consequences as well as the economic and social burden of climate change fall most heavily on vulnerable and marginalized populations due to structural disparities. As dermatologists, understanding the interaction of climate change and skin health is essential to appropriately manage dermatologic disease and advocate for our patients.

Autoimmune alleles at the major histocompatibility locus modify melanoma susceptibility

Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ Tcells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ Tcells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo- and psoriasis-predisposing MHC-I alleles conferred a melanoma-protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (n= 451) and an independent validation set (n= 586), MHC-I autoimmune-allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune-allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veteran Program (OR= 0.962, p= 0.024). Existing melanoma polygenic risk scores (PRSs) did not predict autoimmune-allele carrier status, suggesting these alleles provide orthogonal risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles. However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte-conserved antigens and loss of heterozygosity of autoimmune alleles caused the greatest reduction in presentation for several conserved antigens across individuals with loss of HLA alleles. Overall, this study presents evidence that MHC-I autoimmune-risk alleles modulate melanoma risk unaccounted for by current PRSs.

Synchronous and metachronous multiple primary cancers in melanoma survivors: a gender perspective.

Long-term survivors of cutaneous malignant melanoma (CMM) risk subsequent malignancies due to both host-related and environmental risk factors. This retrospective population-based study differentially assesses the risk of synchronous and metachronous cancers in a cohort of CMM survivors stratified by sex. The cohort study (1999-2018) included 9,726 CMM survivors (M = 4,873, F = 4,853) recorded by the cancer registry of all 5,000,000 residents in the Italian Veneto Region. By excluding subsequent CMM and non-CMM skin cancers, the incidence of synchronous and metachronous malignancies was calculated according to sex and tumor site, standardizing for age and calendar year. The Standardized Incidence Ratio (SIR) was calculated as the ratio between the number of subsequent cancers among CMM survivors and the expected number of malignancies among the regional population. Irrespective of the site, the SIR for synchronous cancers increased in both sexes (SIR = 1.90 in males and 1.73 in females). Both sexes also demonstrated an excess risk for synchronous kidney/urinary tract malignancies (SIR = 6.99 in males and 12.11 in females), and women had an increased risk of synchronous breast cancer (SIR = 1.69). CMM male survivors featured a higher risk of metachronous thyroid (SIR = 3.51, 95% CI [1.87, 6.01]), and prostate (SIR = 1.35, 95% CI [1.12, 1.61]) malignancies. Among females, metachronous cancers featured higher SIR values than expected: kidney/urinary tract (SIR = 2.27, 95% CI [1.29, 3.68]), non-Hodgkin's lymphoma (SIR = 2.06, 95% CI [1.24, 3.21]), and breast (SIR = 1.46, 95% CI [1.22, 1.74]). Females had an overall increased risk of metachronous cancers in the first 5 years after CMM diagnosis (SIR = 1.54 at 6-11 months and 1.37 at 1-5 years). Among CMM survivors, the risk of metachronous non-skin cancers is higher than in the general population and differs significantly by sex. These results encourage sex-tailored interventions for metachronous secondary cancer prevention.

Evidence that Mental Contrasting Reduces Health Information Avoidance.

Although learning health information is beneficial for physical well-being, many people opt to avoid learning this information due to its potentially threatening nature. Such avoidance can lead to delays in seeking treatment. This study tested the effectiveness of a self-regulation technique, mental contrasting (MC), specifically MC of a negative future with a positive current reality, in reducing health information avoidance regarding skin cancer (melanoma). We hypothesized that participants who engaged in MC would be more likely to choose to learn about their melanoma risk than those who completed a control, reflection activity. We conducted a randomized controlled trial (N = 354). Participants were assigned to complete a MC or reflection (control) exercise prior to filling out a melanoma risk calculator. Participants were then asked whether they wanted to learn their melanoma risk, and how much information they would like to know. Chi-Square tests revealed that MC decreased melanoma risk information avoidance compared to the reflection activity (12% vs. 23.4%) but did not make participants more likely seek additional information. MC is a brief, engaging, and effective strategy for reducing health information avoidance that could prove useful in medical settings.

Clinical, Dermoscopic, and Histological Characteristics of Melanoma Patients According to the Age Groups: A Retrospective Observational Study.

Although the role of melanoma risk factors is well documented, their correlation with patients' age is less frequently analyzed. The analysis was performed among 189 melanoma patients in different age groups, including <30 years, 31-60 years, and >60 years, to investigate the risk factors, topography, and coexistence of morphological features of 209 melanomas (dermoscopic and histopathological). Among the youngest age group, no correlation with the presence of estimated risk factors was found. The most common dermoscopic pattern was spitzoid and multicomponent asymmetric. The group of middle-aged patients was the most diverse in terms of the occurrence of risk factors, solar lentiginosis, dermoscopic patterns, topography, histological subtypes, and invasiveness of melanomas. The oldest group characterized a strong correlation between solar lentiginosis, NMSC comorbidity, the prevalence of facial melanomas, the dermoscopic pattern of melanoma arising on chronic sun-damaged skin, and regression. The findings regarding the presence of age-specific features in melanoma patients, especially in the youngest and middle-aged groups, might be helpful for clinicians and to target secondary prevention efforts.

Mastocytosis and Skin Cancer: The Current State of Knowledge.

Mastocytosis is a heterogeneous group of diseases associated with excessive proliferation and accumulation of mast cells in different organs. Recent studies have demonstrated that patients suffering from mastocytosis face an increased risk of melanoma and non-melanoma skin cancer. The cause of this has not yet been clearly identified. In the literature, the potential influence of several factors has been suggested, including genetic background, the role of cytokines produced by mast cells, iatrogenic and hormonal factors. The article summarizes the current state of knowledge regarding the epidemiology, pathogenesis, diagnosis, and management of skin neoplasia in mastocytosis patients.

Risk of incident melanoma among individuals with low-count monoclonal B-cell lymphocytosis (MBL).

7577 Background: Prior research has consistently shown that patients with chronic lymphocytic leukemia (CLL) have an ~2-fold increased risk of developing melanoma compared to controls. MBL is a common condition affecting 8-10 million adults over the age of 40 years in the United States and is a precursor to CLL. Little is known about the association between MBL and melanoma. Herein, we evaluated the risk of incident melanoma in a large cohort of individuals screened for MBL. Methods: Participants from the Mayo Clinic Biobank who had no prior history of hematologic malignancy, were 40 years or older, were residents of counties surrounding Mayo Clinic, and who provided blood samples between 7/2009 and 4/2022 were included in the study. Peripheral blood mononuclear cells were screened for MBL using highly sensitive eight-color flow cytometry. Individuals with MBL were classified as CLL-like MBL (CD5+, CD20dim) or atypical MBL (CD5+, CD20+) based on immunophenotypes, and also classified as low-count MBL (LCMBL) or high-count MBL (HCMBL) based on whether the percent clonal B-cell count was &lt; 85% or ≥85%, respectively. Diagnosis of melanoma was ascertained using ICD codes and review of the electronic health records. All individuals were followed from date of sample upon which MBL screening was performed to the earliest of incident melanoma, loss to follow-up, withdrawal from the study, or September 30, 2022. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for age, sex, and history of melanoma in previous 5 years. Results: A total of 7,334 participants were screened for MBL, of which 1,151 (16%) individuals had MBL. Among those with MBL, 1,107 (96.2%) had CLL-like MBL and 1098 (95.4%) had LC MBL. The median age at entry into the MBL screening cohort was 67 years (range 40-101) and 37% were male; individuals with MBL were older (median age 72 vs 65 years) and male (49% vs 35%). After a median follow-up of 2.9 years (range 0-13.2), 121 of the 7,334 (1.6%) participants developed incident melanoma after the date of MBL screening. The 10-year cumulative incidence of melanoma among individuals with MBL was 7.8% (95% CI 4.5-13.5%) compared to 3.4% (2.7-4.4%) in those who screened negative for MBL. After adjusting for age, sex, and history of prior melanoma, we found a 1.81-fold increased risk of incident melanoma (95% CI 1.19-2.76) among individuals with MBL. The increased risk of melanoma persisted when the analysis was restricted to individuals with LCMBL (HR = 1.84; 95% CI 1.21-2.82). Conclusions: In the largest MBL screening cohort to date, we found that LCMBL, a common condition, was associated with an 84% elevated risk of melanoma, similar to the ~2-fold increased risk observed in patients with CLL. These data, together with our prior findings of a heightened risk of serious infections and lymphoid malignancies, suggest that individuals with LCMBL are at increased risk for adverse health outcomes.

Melanoma literacy and predictors for skin self-examination in three western U.S. states: A population-based survey.

10558 Background: Melanoma is a leading cause of skin cancer deaths, despite being easily treated when detected early. The objective of this study is to investigate the relationship between melanoma knowledge and beliefs, and the performance of skin self-examination (SSE) in three US states with high incidence rates of melanoma. Understanding the barriers to behaviors such as SSE can aid in the development of interventions aimed at increasing the frequency of early detection and reducing melanoma-related deaths. Methods: A total of 15,000 surveys were distributed to households in the states of Oregon, Washington, and Utah using a stratified two-stage sampling design. The survey responses were weighted to resemble the gender and age distributions of the US census. Rural areas were oversampled to ensure sufficient representation. The first objective of this study was to assess melanoma literacy, including knowledge about melanoma risks, attitudes, and preventive behaviors. Our second objective was to investigate the relationship between self-reported SSE and melanoma literacy, self-efficacy, and belief in the benefits of performing SSE. Results: Among 2,326 respondents, characteristics were similar across states (weighted by census-based population percentages), including demographics, baseline knowledge, performance of SSE, and self-efficacy in performing SSE. Rural respondents had a higher frequency of personal history of melanoma (16.2%) compared to urban respondents (9.9%). Only 21.2% of the respondents demonstrated high knowledge of melanoma. 62.8% of respondents reported having performed a SSE at some point in their lives, with only 24.6% of respondents having done so in the past 2 months. Most respondents (84.8%) believed in the effectiveness of SSE in detecting skin cancer, but only 38.3% and 7.3% reported being "fairly" or "very" confident in performing SSE, respectively. The performance of SSE was most strongly correlated with higher melanoma knowledge, higher self-efficacy, and a personal history of melanoma. Conclusions: The results of the survey indicate that melanoma literacy among respondents in 3 high-risk Western states is limited. A higher level of literacy was associated with a higher likelihood of reported early detection behaviors. This study provides a baseline assessment and serves as a foundation for the development of public health campaigns aimed at promoting prevention and early detection of this deadly cancer.

Sun exposure and associated risks: Insight from an international survey with a focus on the population with past medical history of skin cancers.

e21575 Background: This survey investigates knowledge and behaviors regarding sun exposure among population who have been treated for skin cancer (melanoma/non melanoma) or pre-cancerous lesions in 17 countries. Methods: The survey (N = 17,001) was conducted online in 17 countries (5 continents) from 28 September-18 October 2021. Automated selection from the Ipsos online Panel ensured samples of 1,000 individuals in each country fit the quotas method based on gender, age, employment status, and country regions. Data covered demographics, phototype, exposure habits and practices, knowledge and understanding of risks. The current focus in this abstract was defined as individuals with a history of melanoma/non melanoma skin cancer, pre-cancerous lesions. Results: This sub population represents 8% of the general population (n = 1372), it comprised 54% men, average age was 49.9 years (SD:17.6) and 58% were of phototype 1-2. 90% were aware of sun-related skin-health issues (vs 88% in the general population). 79% did know that sun protection is useful when the weather is overcast, a better knowledge compared to the general population (61%). However, 34% indicated it was safe to expose themselves without protection when already tanned, a larger misconception compared to the general population (23%). 54% did not understand the difference between UVA and UVB vs 70% in the general population. Only 28% systematically/often use all protections measures during exposure; still a higher practice compared to the general population (12%). However, 42% said they protected from the sun all year round, a better habit compared to the general population (23%). During sun exposure, among the 91% who declared using sunscreen, 74% applied sunscreen only once or twice a day, a similar practice among general population (74%). And when already tanned 38% decreased frequency of application and/or used lower protection (44% among general population). 82% regretted not having previously used better protection, a much stronger regret compared to the general population (57%). Conclusions: Although individuals who have been treated for skin cancer or pre-cancerous lesions had better knowledge and behavioral attitudes compared to the general population, this survey shows that even a population at high risk of melanoma and having a regular medical follow-up does not sufficiently perceive the importance of photoprotection in a prevention objective. This leads to discuss the implementation of new information tools with more impact.

Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma (AM) in patients with concomitant chronic lymphocytic leukemia (CLL).

e19511 Background: CLL is the most prevalent adult leukemia and is associated with an increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICI in patients with CLL. Immune checkpoint inhibitors (ICI) have revolutionized management of AM, but data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. We, therefore, sought to examine the efficacy of ICI for melanoma in patients with concomitant CLL and AM. Methods: In this international and multicentre retrospective study, review of clinical databases identified patients with concomitant CLL and AM treated with ICI from two US tertiary cancer centers (n = 39) and an Australian multi-institutional experience (AUS, n = 19). Objective response rates (ORR), defined as complete or partial response by RECIST v1.1, and survival outcomes (overall survival, OS, and progression-free survival, PFS) among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Results: Between 1997 and 2020, 58 patients with CLL were treated with ICI for concomitant AM. Among all patients with CLL and AM, ORR to ICI was 41% and median duration of response was 18 months. A majority were untreated for CLL (64%) at the time of ICI. Patients with prior history of treatment for CLL had significantly reduced ORRs (21% vs 51%, p = 0.04), PFS (3.6 vs. 14.6 months, p = 0.005), and OS (7.4 vs. 52.2 months, p = 0.002), compared to patients on observation for their CLL. Prior treatment with T-lymphocyte depleting chemoimmunotherapy (fludarabine, bendamustine, and alemtuzumab) was particularly associated with poor outcomes (median OS of 7.0 months, median PFS of 3.4 months). On univariate analysis, prior treatment for CLL, high risk CLL 17p deletion, and higher CLL Rai stage were associated with shorter PFS from ICI, though CLL treatment was the only factor independently associated with shorter PFS in the multivariate model (HR 6.5, [CI 2.1-20.3], p = 0.001]. Overall, 3 patients developed CLL progression while on ICI, though in two of these patients, the AM had an objective, durable clinical response to ICI. Overall, immune-related adverse events (irAE) occurred following 38% of ICI and rates of irAE were similar by CLL treatment status. Conclusions: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Melanoma Prognosis and Associated Risk Factors: A Retrospective Cohort Study Using Semantic Map Analysis.

The overall patterns of correlations among various melanoma risk factors have not yet been examined. The aim of this study was to assess the impact of different parameters on disease-free and melanoma-related overall survival. A retrospective cohort study was conducted encompassing all patients with a primary cutaneous melanoma diagnosed in a university referral centre. Associations were explored using semantic map analysis, which uses graph theory to find the strongest path of connections between variables. A total of 1,110 melanoma patients (median follow-up 10.6 years) were included. The analysis revealed a clustering of variables around 2 main hubs: Breslow thickness < 1 mm and ≥ 4 mm. Factors connected with high melanoma thickness were: older age, positive sentinel lymph node biopsy findings, presence of ulceration, nodular melanoma type, and light skin phototype. Both disease-free and melanoma-related overall survival were in this cluster and connected with positive sentinel lymph node biopsy and Breslow ≥ 4 mm. Patients with Breslow between 1 and 3.9 mm were also in this cluster and linked with negative sentinel lymph node biopsy, nodular melanoma and safety distance > 10 mm. This semantic analysis confirmed the close link between Breslow thickness, age, sentinel lymph node biopsy findings, skin type, melanoma subtype and prognosis, and provides prognostic information useful for the further stratification and management of patients with melanoma.

Cutaneous malignancies in patients with Parkinson's disease at a dermato-oncological university centre in Hungary.

The possible correlation between melanoma and Parkinson's disease (PD) has been intensively studied. In this work, we aimed to assess the coincidence of skin malignancies and PD at a dermato-oncological university centre in Central-Eastern Europe, Hungary. From 2004 to 2017, a retrospective analysis of the centre's database was performed based on International Statistical Classification of Diseases-10 codes. Out of the patients who visited the clinic during the study period, 20,658 were treated for malignant skin tumours. Over the 14 years, 205 dermatological patients had PD simultaneously, 111 (54%) of whom had at least one type of skin malignancy: melanoma (n=22), basal cell carcinoma (BCC) (n=82), or squamous cell carcinoma (SCC) (n=36) (in some patients, multiple skin tumours were identified). Compared to the age- and sex-matched control group, patients with PD had a significantly lower risk for basal cell carcinoma (OR, 0.65; 95% CI, 0.47-0.89, p=0.0076) and for all skin tumours (OR, 0.74; 95% CI, 0.56-0.98, p=0.0392) but not for melanoma. We found a decreased risk of all skin tumours and basal cell carcinoma and an unchanged risk of melanoma among patients with PD. However, it should be kept in mind that some large-scale meta-analyses suggest a higher incidence of melanoma after a diagnosis of PD, indicating the importance of skin examination in this vulnerable population.

Risk of Syndrome-Associated Cancers Among First-Degree Relatives of Patients With Pancreatic Ductal Adenocarcinoma With Pathogenic or Likely Pathogenic Germline Variants

Increased cancer risk in first-degree relatives of probands with pancreatic ductal adenocarcinoma (PDAC probands) who carry pathogenic or likely pathogenic germline variants (PGVs) in cancer syndrome-associated genes encourages cascade genetic testing. To date, unbiased risk estimates for the development of cancers on a gene-specific basis have not been assessed. To quantify the risk of development of PDAC and extra-PDAC among first-degree relatives of PDAC probands who carry a PGV in 1 of 9 cancer syndrome-associated genes-ATM, BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2, and CDKN2A. This case series focused on first-degree relatives of PDAC probands carrying PGVs in specific cancer syndrome-associated genes. The cohort comprised clinic-ascertained patients enrolled in the Mayo Clinic Biospecimen Resource for Pancreas Research registry with germline genetic testing. In total, 234 PDAC probands carrying PGVs were drawn from the prospective research registry of 4562 participants who had undergone genetic testing of cancer syndrome-associated genes. Demographic and cancer-related family histories were obtained by questionnaire. The data were collected from October 1, 2000, to December 31, 2021. For the PDAC probands, the genetic test results of the presence of PGVs in 9 cancer syndrome-associated genes were obtained by clinical testing. Cancers (ovary, breast, uterus or endometrial, colon, malignant melanoma, and pancreas) among first-degree relatives were reported by the probands. Standardized incidence ratios (SIRs) were used to estimate cancer risks among first-degree relatives of PDAC probands carrying a PGV. In total, 1670 first-degree relatives (mean [SD] age, 58.1 [17.8] years; 853 male [51.1%]) of 234 PDAC probands (mean [SD] age, 62.5 [10.1] years; 124 male [53.0%]; 219 [94.4%] White; 225 [98.7%] non-Hispanic or non-Latino]) were included in the study. There was a significantly increased risk of ovarian cancer in female first-degree relatives of probands who had variants in BRCA1 (SIR, 9.49; 95% CI, 3.06-22.14) and BRCA2 (SIR, 3.72; 95% CI, 1.36-8.11). Breast cancer risks were higher with BRCA2 variants (SIR, 2.62; 95% CI, 1.89-3.54). The risks of uterine or endometrial cancer (SIR, 6.53; 95% CI, 2.81-12.86) and colon cancer (SIR, 5.83; 95% CI, 3.70-8.75) were increased in first-degree relatives of probands who carried Lynch syndrome mismatch repair variants. Risk of PDAC was also increased for variants in ATM (SIR, 4.53; 95% CI, 2.69-7.16), BRCA2 (SIR, 3.45; 95% CI, 1.72-6.17), CDKN2A (SIR, 7.38; 95% CI, 3.18-14.54), and PALB2 (SIR, 5.39; 95% CI, 1.45-13.79). Melanoma risk was elevated for first-degree relatives of probands with CDKN2A variants (SIR, 7.47; 95% CI, 3.97-12.77). In this case series, the presence of PGVs in 9 cancer syndrome-associated genes in PDAC probands was found to be associated with increased risk of 6 types of cancers in first-degree relatives. These gene-specific PDAC and extra-PDAC cancer risks may provide justification for clinicians to counsel first-degree relatives about the relevance and importance of genetic cascade testing, with the goal of higher uptake of testing.

Sex-Specific Associations of MDM2 and MDM4 Variants with Risk of Multiple Primary Melanomas and Melanoma Survival in Non-Hispanic Whites.

MDM2-SNP309 (rs2279744), a common genetic modifier of cancer incidence in Li-Fraumeni syndrome, modifies risk, age of onset, or prognosis in a variety of cancers. Melanoma incidence and outcomes vary by sex, and although SNP309 exerts an effect on the estrogen receptor, no consensus exists on its effect on melanoma. MDM2 and MDM4 restrain p53-mediated tumor suppression, independently or together. We investigated SNP309, an a priori MDM4-rs4245739, and two coinherited variants, in a population-based cohort of 3663 primary incident melanomas. Per-allele and per-haplotype (MDM2_SNP309-SNP285; MDM4_rs4245739-rs1563828) odds ratios (OR) for multiple-melanoma were estimated with logistic regression models. Hazard ratios (HR) for melanoma death were estimated with Cox proportional hazards models. In analyses adjusted for covariates, females carrying MDM4-rs4245739*C were more likely to develop multiple melanomas (ORper-allele = 1.25, 95% CI 1.03-1.51, and Ptrend = 0.03), while MDM2-rs2279744*G was inversely associated with melanoma-death (HRper-allele = 0.63, 95% CI 0.42-0.95, and Ptrend = 0.03). We identified 16 coinherited expression quantitative loci that control the expression of MDM2, MDM4, and other genes in the skin, brain, and lungs. Our results suggest that MDM4/MDM2 variants are associated with the development of subsequent primaries and with the death of melanoma in a sex-dependent manner. Further investigations of the complex MDM2/MDM4 motif, and its contribution to the tumor microenvironment and observed associations, are warranted.

Recent Advances in Characterization of Melanin Pigments in Biological Samples.

The melanin pigments eumelanin (EM) and pheomelanin (PM), which are dark brown to black and yellow to reddish-brown, respectively, are widely found among vertebrates. They are produced in melanocytes in the epidermis, hair follicles, the choroid, the iris, the inner ear, and other tissues. The diversity of colors in animals is mainly caused by the quantity and quality of their melanin, such as by the ratios of EM versus PM. We have developed micro-analytical methods to simultaneously measure EM and PM and used these to study the biochemical and genetic fundamentals of pigmentation. The photoreactivity of melanin has become a major focus of research because of the postulated relevance of EM and PM for the risk of UVA-induced melanoma. Our biochemical methods have found application in many clinical studies on genetic conditions associated with alterations in pigmentation. Recently, besides chemical degradative methods, other methods have been developed for the characterization of melanin, and these are also discussed here.