Melanoma Group Research Articles

A single center case series of immune checkpoint inhibitor-induced type 1 diabetes mellitus, patterns of disease onset and long-term clinical outcome.

Type 1 diabetes mellitus (T1DM) is a rare, but serious immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). Our goal was to characterize treatment outcomes associated with ICI-induced T1DM through analysis of clinical, immunological and proteomic data. This was a single-center case series of patients with solid tumors who received ICIs and subsequently had a new diagnosis of T1DM. ICD codes and C-peptide levels were used to identify patients for chart review to confirm ICI-induced T1DM. Baseline blood specimens were studied for proteomic and immunophenotypic changes. Between 2011 and 2023, 18 of 3744 patients treated at Huntsman Cancer Institute with ICIs were confirmed to have ICI-induced T1DM (0.48%). Eleven of the 18 patients received anti-PD1 monotherapy, 4 received anti-PD1 plus chemotherapy or targeted therapy, and 3 received ipilimumab plus nivolumab. The mean time to onset was 218 days (range 22-418 days). Patients had sudden elevated serum glucose within 2-3 weeks prior to diagnosis. Sixteen (89%) presented with diabetic ketoacidosis. Three of 12 patients had positive T1DM-associated autoantibodies. All patients with T1DM became insulin-dependent through follow-up. At median follow-up of 21.9 months (range 8.4-82.4), no patients in the melanoma group had progressed or died from disease. In the melanoma group, best responses were 2 complete response and 2 partial response while on active treatment; none in the adjuvant group had disease recurrence. Proteomic analysis of baseline blood suggested low inflammatory (IL-6, OSMR) markers and high metabolic (GLO1, DXCR) markers in ICI-induced T1DM cohort. Our case series demonstrates rapid onset and irreversibility of ICI-induced T1DM. Melanoma patients with ICI-induced T1DM display excellent clinical response and survival. Limited proteomic data also suggested a unique proteomic profile. Our study helps clinicians to understand the unique clinical presentation and long-term outcomes of this rare irAE for best clinical management.

Contraception and sterilization selection at delivery among pregnant patients with malignancy.

Since malignancy during pregnancy is uncommon, information regarding contraception selection or sterilization at delivery is limited. The objective of this study was to examine the type of long-acting reversible contraception or surgical sterilization procedure chosen by pregnant patients with malignancy at delivery. This cross-sectional study queried the Healthcare Cost and Utilization Project's National Inpatient Sample in the USA. The study population was vaginal and cesarean deliveries in a hospital setting from January 2017 to December 2020. Pregnant patients with breast cancer (n = 1605), leukemia (n = 1190), lymphoma (n = 1120), thyroid cancer (n = 715), cervical cancer (n = 425) and melanoma (n = 400) were compared with 14 265 319 pregnant patients without malignancy. The main outcome measures were utilization of long-acting reversible contraception (subdermal implant or intrauterine device) and performance of permanent surgical sterilization (bilateral tubal ligation or bilateral salpingectomy) during the index hospital admission for delivery, assessed with a multinomial regression model controlling for clinical, pregnancy and delivery characteristics. When compared with pregnant patients without malignancy, pregnant patients with breast cancer were more likely to proceed with bilateral salpingectomy (adjusted odds ratio [aOR] 2.30) or intrauterine device (aOR 1.91); none received the subdermal implant. Pregnant patients with leukemia were more likely to choose a subdermal implant (aOR 2.22), whereas those with lymphoma were more likely to proceed with bilateral salpingectomy (aOR 1.93) and bilateral tubal ligation (aOR 1.76). Pregnant patients with thyroid cancer were more likely to proceed with bilateral tubal ligation (aOR 2.21) and none received the subdermal implant. No patients in the cervical cancer group selected long-acting reversible contraception, and they were more likely to proceed with bilateral salpingectomy (aOR 2.08). None in the melanoma group chose long-acting reversible contraception. Among pregnant patients aged <30, the odds of proceeding with bilateral salpingectomy were increased in patients with breast cancer (aOR 3.01), cervical cancer (aOR 2.26) or lymphoma (aOR 2.08). The odds of proceeding with bilateral tubal ligation in pregnant patients aged <30 with melanoma (aOR 5.36) was also increased. The results of this nationwide assessment in the United Statessuggest that among pregnant patients with malignancy, the preferred contraceptive option or method of sterilization at time of hospital delivery differs by malignancy type.

Clinical outcomes of head and neck mucosal melanoma treated with surgery: a single-center study in Japan.

Head and neck mucosal melanomas are rare malignancies. Although the prognosis is poor owing to the high incidence of distant metastases, locoregional control remains important. It is difficult to obtain results in a large cohort because of its rarity. This study aimed to elucidate the survival outcomes of patients with head and neck mucosal melanoma treated with surgery in Japan. Patients with head and neck mucosal melanoma who were surgically treated between 2007 and 2021 at the National Cancer Center Hospital were retrospectively analyzed. A total of 47 patients were included in this study. The 5-year overall survival, disease-specific survival, locoregional control and relapse-free survival rates were 42%, 50%, 79% and 13%, respectively. The disease-specific survival of the oral mucosal melanoma group was significantly better than that of the sinonasal mucosal melanoma group (5-year disease-specific survival rate: 70% versus 37%, respectively; P=0.04). Multivariate analyses revealed that sinonasal mucosal melanoma were independently significant adverse prognostic factor, for overall survival and disease-specific survival. Patients with oral mucosal melanoma patients had a higher incidence of lymph node metastasis than those with sinonasal mucosal melanoma patients (P<0.0001). This study demonstrated the survival outcomes of the largest cohort of patients with head and neck mucosal melanomas treated surgically at a single institution within the past 20years in Japan. We found that survival outcomes and incidence of nodal metastases varied by site.

Phenotypic and Genetic Features that Differ Between Hereditary and Sporadic Melanoma: Results of a Preliminary Study from a Single Center from Turkey.

Most melanoma patients under our supervision lack characteristic phenotypic features for melanoma. In contrast, history of cancers other than melanoma and early age at onset were common. This observation was in favor of hereditary melanoma. To search for the phenotypic and genetic features that differ between sporadic and hereditary melanomas. In order to reveal phenotypic features, detailed physical exam was conducted to all melanoma patients (N = 43) and for genetic features. CDKN2A and MC1R mutations were detected with Sanger sequencing method. Assignment to hereditary and sporadic groups was done according to the "melanoma cancer syndrome assessment tool". Patients who were diagnosed before the age of 50 were also assigned to the hereditary melanoma group. Thirty-one patients were assigned to the hereditary group and 12 to the sporadic group. Fair eye color was statistically significantly higher in the sporadic group (P = 0.000). CDKN2A was detected in only 1 patient in the hereditary group. MC1R mutations were found in 12 out of 13 (92.3%) in the hereditary group with a score =3 points, 13 out of 18 (72.2%) in the early age at onset group and 5 out of 12 (41.7%) in the sporadic group (P = 0.024). Incidence of CDKN2A mutations in our hereditary group is in accordance with the reported incidences from Mediterranean countries. The difference between the hereditary and sporadic groups in terms of MC1R mutations supports the idea that MC1R genetic testing might help to determine patients with higher risk for hereditary melanoma.

Vitamin D Receptor and Retinoid X Receptor Alpha in Melanocytic Benign Lesions and Melanoma.

Vitamin D receptor (VDR) exerts its biological effects when it heterodimerizes to a nuclear receptor of the retinoid family called retinoid X receptor α (RXRα), stimulating or inhibiting DNA transcription. VDR stimulation by vitamin D analogs led to in vitro antiproliferative effects, and experimental RXRα knockout led to loss of proliferation control in melanoma cells. The aim of this study was to determine VDR and RXRα positivity in melanocytic lesions, compared with normal skin species. By immunohistochemistry assays, nuclear VDR, cytoplasmic VDR, and RXRα and RXRα in keratinocytes surrounding melanocytes were evaluated in 77 controls, 92 intradermal nevi, 54 dysplastic nevi, and 83 melanomas in this retrospective cross-sectional study. Nuclear VDR, cytoplasmic VDR, and RXRα were less expressed in exposed areas ( P < 0.001, P = 0.0006, and P < 0.001, respectively) than covered areas. All melanocytic lesions had loss of VDR and RXRα comparing with the control group. In the melanoma group, nuclear VDR tended to inversely correlate with the Breslow index (r = -0.11, P = 0.29) but directly correlated with histological regression ( P = 0.0293). RXRα inversely correlated with mitosis (r = -0.245; P = 0.0263). We can suggest that sun exposure affected VDR and RXRα immunopositivity. Nuclear VDR tendency of inverse correlation with the Breslow index showed that worse melanomas have a greater loss of VDR. RXRα inversely correlated with mitosis, indicating that RXRα can have a role in proliferation control. VDR and RXRα may participate in the development of melanocytic lesions and be a future target of new studies and directed therapies.

Outcomes for Malignant Pleural Effusions Because of Melanoma Treated With Indwelling Pleural Catheters.

Indwelling pleural catheters (IPCs) reduce dyspnea and improve quality of life in patients with malignant pleural effusions (MPEs). Data on outcomes of MPEs secondary to metastatic melanoma managed with IPCs are scarce. We aimed to evaluate outcomes of patients receiving IPCs for MPEs secondary to melanoma compared with other malignancies. We identified patients from our prospectively collected database of all patients who had an IPC insertion for MPEs at our tertiary care center for melanoma between May 2006 and November 2018 and for nonmelanoma between May 2006 and June 2013. Chart reviews were conducted to obtain patient demographics, catheter complications, time of IPC removal or death, x-ray imaging, and pleural fluid characteristics. We identified 27 MPEs because of melanoma and 1114 because of nonmelanoma malignancies treated with IPC. The most frequent complication was pleural fluid loculation requiring fibrinolytics which was significantly higher in the melanoma (14.8%) compared with the nonmelanoma group (3.8%; P=0.02). Cumulative incidence functions for catheter removal (P=0.8) or death with catheter in situ (P=0.3) were not significant between melanoma and nonmelanoma groups in competing risk analysis. Baseline radiographic pleural effusion scores were similar, but became significantly higher (increased pleural opacity) in the melanoma group at time points following IPC insertion (P<0.05). MPEs because of melanoma had a higher rate of loculations requiring fibrinolytics and less radiographic improvement after IPC insertion suggesting this patient subgroup has a more complicated pleural space which may be less responsive to drainage.

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&amp;rsquo;s disease (PD) and melanoma has been controversial. The present study used data from the 2001 &amp;ndash; 2004 National Health and Nutrition Examination Survey database. This study included individuals aged &amp;ge;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 &amp;ndash; 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.

MTHFR act as a potential cancer biomarker in immune checkpoints blockades, heterogeneity, tumor microenvironment and immune infiltration

PurposeTo evaluate the role and landscape of 5-10-Methylenetetrahydrofolate reductase (MTHFR) to immune infiltration, tumor microenvironment, heterogeneity, immune checkpoints blockades, prognostic significance across cancer types.MethodsData sets of genomic, transcriptomic and clinic features of MTHFR across > 60,000 patients and up to 44 cancer types were comprehensively analyzed using R software.ResultsExpression of MTHFR gene is significantly lower in 17 tumors and correlated with overall survival (OS), disease-specific survival (DSS), progression-free interval (PFI) in specific tumors. Gene alterations of MTHFR are observed significant differences across tumor types. Expression of MTHFR is negatively correlated with the stemness index (mDNAsi, mRNAsi, DMPsi, ENHsi, EREG-mDNAsi and EREG-mRNAsi) in the most cancers. MTHFR showed significantly correlated with 67 types of immune cell infiltration scores in 44 cancer types by XCELL algorithm. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis are conducted to show the core tumor mechanism and biological process. Correlations between MTHFR and biomarkers of heterogeneity (MSI, TMB, MATH, HRD, LOH, Neoantigen, ploidy and purity) are also significant in specific tumors. MTHFR is significantly positively correlated with biomarkers of immune related genes (CD19, CD274, CD80, CD86) and mismatched repair genes (MLH1, PMS2, MSH2, MSH6, EPCAM, MLH3, PMS1, EXO1) in most cancer types. Receiver Operating Characteristics (ROC) analyses show MTHFR could act as a potential biomarker in anti-PD-1 (nivolumab to melanoma) and anti-CTLA4 (ipilimumab to melanoma) group of ontreatment, in anti-PD-1 (pembrolizumab to melanoma) group of pretreatment. Two immunohistochemistry antibodies HPA076180 and HPA077255 are verified in 20 types of tumor and could be used to detect the expression of MTHFR efficiently in clinic.ConclusionsMTHFR could predict the response of immune checkpoints blockades, heterogeneity, tumor microenvironment and immune infiltration.

Causes of death among patients with cutaneous melanoma: a US population-based study

Research on mortality outcomes and non-cancer-related causes of death in patients with cutaneous melanoma (CM) remains limited. This study aimed to identify the prevalence of non-cancer-related deaths following CM diagnosis. The data of 224,624 patients diagnosed with malignant CM in the United States between 2000 and 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We stratified our cohort based on their melanoma stage at diagnosis and further calculated standardized mortality ratios (SMRs) for each cause of death, comparing their relative risk to that of the general US population. The total number of fatalities among melanoma patients was 60,110, representing 26.8% of the total cases. The percentage of deaths is directly proportional to the disease stage, reaching 80% in distant melanoma. The highest fatalities among the localized melanoma group (25,332; 60.5%) occurred from non-cancer causes, followed by melanoma-attributable deaths (10,817; 25.8%). Conversely, melanoma is the leading cause of death in regional and distant melanoma cohorts. Cardiovascular and cerebrovascular diseases were the most prevalent non-cancer causes of death among the three disease-stage cohorts. Compared to the general population, we did not observe an increased risk of death due to non-cancer causes in the localized CM cohort, while patients diagnosed with regional and distant CMs had a statistically significant higher risk of death from all the reported major causes of death.

Retreatment and rechallenge with BRAF/MEK inhibitors in patients with metastatic melanoma: Results from the observational study GEM1801.

9547 Background: Most patients with BRAF-mutant melanoma eventually develop resistance to therapy with BRAF/MEK inhibitors and immune-checkpoint blockade. Alternative treatment strategies are required in these patients since further therapy options lack survival benefit. Small series have shown promising activity from re-exposure to BRAF/MEK inhibitors after a treatment free interval of targeted therapy (TT), probably due to regression of resistant tumors and proliferation of clones that maintain sensitivity to BRAF/MEKi. However, prospective evidence for this approach is limited. Here we report the results of 30 patients who received a second course of TT at relapse after adjuvant therapy (retreatment) or after first progression on TT in the advanced setting (rechallenge). Methods: GEM1801 is a prospective observational study from the Spanish Melanoma Group (GEM) including 893 patients with melanoma treated in 37 centers. This is a descriptive analysis of basal characteristics, response rates (RR), progression free survival (PFS) and overall survival (OS) from 30 patients that received retreatment or rechallenge with BRAF/MEKi in GEM1801 study. Results: 4 patients received retreatment and 26 rechallenge. For retreatment, BRAF/MEKi median free interval from end of adjuvant TT to subsequent retreatment was 17.8 months (range: 12.4 - 57.7). RR with retreatment were 25%, with a median PFS and OS of 5.7 and 8.5 months. For rechallenge, RR was 38.5% and median PFS and OS 11.1 and 22.2 months respectively. Patients who were selected for rechallenge had higher complete response (CR) rates to first TT (26.9% vs 20.3%; p= 0.026). Patients who experimented deeper responses with 1st TT in the metastatic setting showed a correlation to longer PFS to 2nd TT with 12-m PFS rates of 66.7% versus 35.7% (HR 9.09 [95%CI: 1.42-58]; p= 0.02). OS showed a not statistically significant improvement in patients who reported CR to first TD (24-m OS rate of 75% versus 40.7% respectively). BRAF/MEKi free interval since first progression and retreatment or rechallenge was not associated with prognosis. Prognostic factors as LDH and number of metastatic sites did not correlate with the efficacy of retreatment. Conclusions: Retreatment or rechallenge with BRAF/MEKi in the metastatic setting achieved encouraging efficacy and may be a valid therapeutic strategy in a selected group of patients. Response to first treatment, retreatment and rechallenge with BRAF/MEKi. Clinical trial information: NCT03605771 . [Table: see text]

Impact of second opinion pathology review in the diagnosis and management of atypical melanocytic lesions: A prospective study of the Italian Melanoma Intergroup (IMI) and EORTC Melanoma Group

BackgroundThe clinical value of an expert pathological review in patients with an atypical melanocytic lesion diagnosis remains unclear. Herein, we evaluate its impact in a prospective clinical study. MethodsPatients with newly diagnosed or suspected atypical melanocytic proliferations and challenging skin tumours were reviewed prospectively by a specialised dermatopathologist through the nationwide ‘Second Opinion Platform’ of the Italian Melanoma Intergroup (IMI) network. The primary aim was the rate of major discrepancies that impacted patient management. Major discrepancies in diagnosis between referral and specialised review were blindly re-analysed by a panel of European Organisation for Research and Treatment (EORTC) Melanoma pathologists. ResultsThe samples submitted to central review included 254 lesions from 230 patients. The most frequent referral diagnoses were atypical melanocytic nevi of different subtypes (74/254, 29.2%), invasive melanomas (61/254, 24.0%), atypical melanocytic proliferations (37/254, 14.6%), AST (21/254, 8.3%) and in situ melanomas (17/254, 6.7%). There was disagreement between referral diagnosis and expert review in 90/254 cases (35.4%). Most importantly, 60/90 (66.7%) were major discordances with a change to the patient's clinical management. Among the 90 discordant cases, the most frequent new diagnosis occurred in World Health Organisation (WHO) Pathway I, followed by WHO Pathway IV (64/90 and 12/90, respectively). In total, 51/60 cases with major discrepancies were blindly re-evaluated by EORTC Melanoma pathologists with a final interobserver agreement in 90% of cases. ConclusionThe study highlights that a second opinion for atypical melanocytic lesions affects clinical management in a minor, but still significant, proportion of cases. A central expert review supports pathologists and clinicians to limit the risk of both over- and under-treatment.

In Memoriam: Soldano Ferrone MD, PhD (1940–2023)

In Memoriam: Soldano Ferrone MD, PhD (1940–2023)

Clinical, histopathological and molecular features of dedifferentiated melanomas: An EORTC Melanoma Group Retrospective Analysis

PurposeDedifferentiated melanoma (DedM) poses significant diagnostic challenges. We aimed to investigate the clinical, histopathological and molecular features of DedM. Methylation signature (MS) and copy number profiling (CNP) were carried out in a subgroup of cases. Patients and methodsA retrospective series of 78 DedM tissue samples from 61 patients retrieved from EORTC (European Organisation for Research and Treatment of Cancer) Melanoma Group centres were centrally reviewed. Clinical and histopathological features were retrieved. In a subgroup of patients, genotyping through Infinium Methylation microarray and CNP analysis was carried out. ResultsMost patients (60/61) had a metastatic DedM showing most frequently an unclassified pleomorphic, spindle cell, or small round cell morphology akin to undifferentiated soft tissue sarcoma, rarely associated with heterologous elements. Overall, among 20 successfully analysed tissue samples from 16 patients, we found retained melanoma-like MS in only 7 tissue samples while a non-melanoma-like MS was observed in 13 tissue samples. In two patients from whom multiple specimens were analysed, some of the samples had a preserved cutaneous melanoma MS while other specimens exhibited an epigenetic shift towards a mesenchymal/sarcoma-like profile, matching the histological features. In these two patients, CNP was largely identical across all analysed specimens, in line with their common clonal origin, despite significant modification of their epigenome. ConclusionsOur study further highlights that DedM represents a real diagnostic challenge. While MS and genomic CNP may help pathologists to diagnose DedM, we provide proof-of-concept that dedifferentiation in melanoma is frequently associated with epigenetic modifications.

Surgical resection margin for T3–T4 primary acral melanoma: a multicenter retrospective cohort study

Although the National Comprehensive Cancer Network (NCCN) guidelines include clear recommendations for the appropriate resection margins in non-acral cutaneous melanoma, the required margin for acral melanoma is controversial. In this retrospective study, we aimed to investigate whether narrow-margin excision is warranted for thick acral melanoma. Records from 277 melanoma patients with stage T3–T4 disease who underwent radical surgery in three centers in China from September 2010 to October 2018 were reviewed. Clinicopathologic data, including age, gender, excision margin (1–2 cm versus ≥ 2 cm), Clark level, Breslow thickness, ulceration, N stage and adjuvant therapy, were included for survival analysis. The patients were followed up until death or March 31, 2021. Log-rank and Cox regression analyses were used to identify prognostic factors for overall survival (OS), disease-free survival (DFS) and local and in-transit recurrence-free survival (LITRFS). Among all enrolled patients, 207 (74.7%) had acral melanoma, and 70 (25.3%) had non-acral cutaneous melanoma. No significant difference in baseline characteristics was identified between non-acral and acral melanoma, except for age (p = 0.004), gender (p = 0.009) and ulceration (p = 0.048). In non-acral melanoma, a resection margin of 1–2 cm was a poor independent prognostic factor for OS [p = 0.015; hazard ratio (HR) (95% CI), 0.26 (0.009–0.77)] and LITRFS [p = 0.013; HR (95% CI), 0.19 (0.05–0.71)] but not for DFS [p = 0.143; HR (95% CI), 0.51 (0.21–1.25)]. Forty-three (20.8%) patients in the acral melanoma group had a 1–2-cm resection margin. The resection margin was not correlated with patients’ OS (p = 0.196 by log-rank analysis, p = 0.865 by multivariate survival analysis), DFS (p = 0.080 by log-rank analysis, p = 0.758 by multivariate survival analysis) or LITRFS (p = 0.354 by log-rank analysis) in acral melanoma. As recommended in the NCCN guidelines, a resection margin ≥ 2 cm is required for non-acral cutaneous melanoma. Meanwhile, a narrow resection margin (1–2 cm) may be safe for patients with acral melanoma.

Routine imaging guided by a 31-gene expression profile assay results in earlier detection of melanoma with decreased metastatic tumor burden compared to patients without surveillance imaging studies

Patients with early-stage disease typically have a good prognosis, but still have a risk of recurrence, even with negative sentinel lymph node biopsy (SLNB). This study explores the utility of routine imaging to detect metastases in patients with negative SLNB but high-risk 31 gene expression profile (31-GEP) scores. We retrospectively identified melanoma patients with negative SLNBs. Patients with high-risk GEP results were placed in the experimental group and patients without GEP testing were placed in the control group. Among both cohorts, recurrent melanoma groups were identified. The tumor burden at the time of recurrence and the time to recurrence were compared between experimental group patients with routine imaging and control group patients without imaging schedules. We identified 327 control patients and 307 experimental patients, of which 14.1% versus 20.5% had melanoma recurrence, respectively. Of the patients with recurrent melanoma, those in the experimental group were older (65.75 versus 59.20), had higher Breslow depths (3.72 mm versus 3.31 mm), and had advanced tumor staging (89.5% versus 71.4% of patients presenting clinical stage ≥ II) compared to the control group at primary diagnosis. However, melanoma recurrence was detected earlier (25.50 months versus 35.35 months) in the experimental group at a lower overall tumor burden (73.10 mm versus 27.60 mm). A higher percentage of experimental patients started immunotherapy when offered (76.3% and 67.9%). Patients who received routine imaging after high-risk GEP test scores had an earlier recurrence diagnosis with lower tumor burden, leading to better clinical outcomes.

FoxP3 Expression in Tumor-Infiltrating Lymphocytes as Potential Predictor of Response to Immune Checkpoint Inhibitors in Patients with Advanced Melanoma and Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICI) are the main therapy currently used in advanced malignant melanoma (MM) and non-small cell lung cancer (NSCLC). Despite the wide variety of uses, the possibility of predicting ICI efficacy in these tumor types is scarce. The aim of our study was to find new predictive biomarkers for ICI treatment. We analyzed, by immunohistochemistry, various cell subsets, including CD3+, CD8+, CD68+, CD20+, and FoxP3+ cells, and molecules such as LAG-3, IDO1, and TGFβ. Comprehensive genomic profiles were analyzed. We evaluated 46 patients with advanced MM (31) and NSCLC (15) treated with ICI monotherapy. When analyzing the malignant melanoma group, shorter median progression-free survival (PFS) was found in tumors positive for nuclear FoxP3 in tumor-infiltrating lymphocytes (TILs) (p = 0.048, HR 3.04) and for CD68 expression (p = 0.034, HR 3.2). Longer PFS was achieved in patients with tumors with PD-L1 TPS ≥ 1 (p = 0.005, HR 0.26). In the NSCLC group, only FoxP3 positivity was associated with shorter PFS and OS. We found that FoxP3 negativity was linked with a better response to ICI in both histological groups.

TERT Promoter Mutational Analysis as an Ancillary Diagnostic Tool for Diagnostically Challenging Melanocytic Neoplasms.

Telomerase reverse transcriptase promoter mutations (TPMs) have been shown to be common in melanoma and uncommon in benign nevi. To assess the use of TPMs as an ancillary diagnostic tool, we report the concordance of the TPM status with the final diagnosis in clinical cases with distinct differential diagnostic scenarios: dysplastic nevus versus melanoma, atypical Spitz nevus versus melanoma, atypical deep penetrating nevus (DPN) versus melanoma, and atypical blue nevus versus malignant blue nevus. In a control cohort, we found a positive TPM in 51/70 (73%) of the total melanomas with the highest frequency in vertical growth phase melanoma cases. Conversely, only 2/35 (6%) dysplastic nevi in our control cases were TPM-positive and b were severely atypical dysplastic nevi. Our clinical cohort of 257 cases had a positive TPM in 24% of cases diagnosed as melanoma and in 1% of cases with a benign diagnosis. The overall concordance of the TPM status with the final diagnosis was 86%. The TPM status had the greatest concordance (95%) with the final diagnosis in the atypical DPN versus melanoma group, with the rest of the groups ranging between 50% and 88%. Overall, our results suggest that TPMs are most useful in the differential diagnosis of atypical DPN versus melanoma. It also has some value in the differential diagnosis of atypical Spitz tumor versus melanoma and dysplastic nevus versus melanoma, whereas in our cohort, it did not contribute meaningfully to differentiating malignant blue nevus and atypical blue nevus.

Facebook Intervention for Young-Onset Melanoma Survivors and Families: Protocol for a Randomized Controlled Trial

Individuals diagnosed with melanoma before the age of 40 years (young-onset melanoma survivors) and their first-degree relatives (FDRs) are a growing population at risk for developing recurrent melanoma or new melanomas. Regular surveillance using clinical skin examination (CSE) and skin self-examination (SSE) and engagement in preventive behaviors including sun protection are recommended. Given the growing population of survivors and their families who are at increased risk, it is surprising that no behavioral interventions have been developed and evaluated to improve risk-reduction behaviors. We describe the rationale and methodology for a randomized controlled trial evaluating the efficacy of a Facebook intervention providing information, goal setting, and peer support to increase CSE, SSE, and sun protection for young-onset melanoma survivors and their FDRs. Overall, 577 survivors and 577 FDRs will be randomly assigned to either the Young Melanoma Family Facebook Group or the Melanoma Family Healthy Lifestyle Facebook Group condition. Participants will complete measures of CSE, SSE, and sun protection, and mediator measures of attitudes and beliefs before and after the intervention. The primary aim is to evaluate the impact of the Young Melanoma Family Facebook intervention versus the Melanoma Family Healthy Lifestyle Facebook intervention on CSE, SSE frequency and comprehensiveness, and sun protection among FDRs. The secondary aims examine the efficacy of the Young Melanoma Family Facebook intervention on survivors' SSE frequency and comprehensiveness and sun protection behaviors and mechanisms of intervention efficacy for intervention impact on FDR and survivor outcomes. The exploratory aim is to evaluate the efficacy of the 2 interventions on perceived stress, physical activity, and healthy eating. This project was funded by the National Institutes of Health (R01CA221854). The project began in May 2018, and recruitment started in January 2019. We anticipate completing enrollment by November 2023. Power calculations recommended a sample size of 577 survivors and 577 FDRs. Multilevel modeling treating family as the upper-level sampling unit and individual as the lower-level sampling unit will be the primary data analytic approach. Fixed effect predictors in these models will include condition, role, sex, all 2- and 3-way interactions, and covariates. The Young Melanoma Family Facebook intervention aims to improve primary and secondary skin cancer prevention for young-onset melanoma survivors and their family members. The intervention's delivery via a popular, freely available social media platform increases its impact because of the potential for dissemination in many contexts. If efficacious, this program could be disseminated by dermatologist practices, public health or nonprofit organizations focused on melanoma, and existing melanoma and skin cancer Facebook groups, thereby expanding its reach. This project will produce a content library of posts and a moderation guide for others. ClinicalTrials.gov NCT03677739; https://clinicaltrials.gov/ct2/show/NCT03677739. DERR1-10.2196/39640.

Micro-nevi in peri-tumoral skin of cutaneous melanoma and basal cell carcinoma

Background: Harboring many melanocytic nevi is a risk factor for melanoma. The prevalence of micro-nevi, melanocytic nevi that can only be detected microscopically, has been studied scarcely and the significance is unknown. Objectives: To systematically analyze the presence of micro-nevi in cutaneous excisions from cutaneous melanoma and basal cell carcinoma to achieve an insight in the density of micro-nevi per mm peri-tumoral skin. Also to speculate in the relevance and significance of micro-nevi for evolving melanoma at the same anatomical site. Methods: We re-examined histologically peri-tumoral skin of primary and re-excised melanomas and primary excisions of basal cell carcinomas for comparison. The size of a micro-nevus was defined to a diameter < 2 mm, of either a junctional, compound or intradermal nevus. Results: 104 melanoma and 208 basal cell carcinoma cases were microscopically re-examined. In the melanoma group 6 micro-nevi were found. The sum of the peri-tumoral skin was 1768 mm, giving a density of 1 nevus per 295 mm. In the basal cell carcinoma group 5 micro-nevi were found. The sum of the peri-tumoral skin was 1370 mm, giving a density of 1 nevus per 274 mm. No difference in the density of micro-nevi in the two groups of skin cancer was found. Conclusions: The significance of these micro-nevi remains unclear. The aim with this study is to draw attention to the existence of micro-nevi and further studies are needed to determine the significance of the presence of micro-nevi.

SARS-CoV-2 infection in patients with melanoma: results of the Spanish Melanoma Group registry.

The Spanish Melanoma Group (GEM) developed a national registry of patients with melanoma infected by SARS-CoV-2 ("GRAVID"). The main objective was to describe the COVID-19 fatality rate in patients with melanoma throughout the pandemic, as well as to explore the effect of melanoma treatment and tumor stage on the risk of COVID-19 complications. These are the final data of the register, including cases from February 2020 to September 2021. One hundred-fifty cases were registered. Median age was 68years (range 6-95), 61 (40%) patients were females, and 63 (42%) patients had stage IV. Thirty-nine (26%) were on treatment with immunotherapy, and 17 (11%) with BRAF-MEK inhibitors. COVID-19 was resolved in 119 cases, including 85 (57%) patients cured, 15 (10%) that died due to melanoma, and 20 (13%) that died due to COVID-19. Only age over 60years, cardiovascular disorders, and diabetes mellitus increased the risk of death due to COVID-19, but not advanced melanoma stage nor melanoma systemic therapies. Three waves have been covered by the register: February-May 2020, August-November 2020, and December 2020-April 2021. The first wave had the highest number of registered cases and COVID-19 mortality. Tumor stage or melanoma treatments are non-significant prognostic factors for COVID-19 mortality. During the pandemic in Spain there was a downward trend in the number of patients registered across the waves, as well as in the severity of the infection. NCT04344002.