Risk of dementia in older veterans with multiple sclerosis.

BACKGROUND: While it is widely accepted that multiple sclerosis (MS) often causes cognitive dysfunction, it is thought that these cognitive symptoms rarely progress to dementia. However, this has not been thoroughly investigated. The objectives of this cohort study are to determine whether people with MS have an increased risk of dementia compared to the general population and to identify factors, such as geographic latitude, which may modify this association. METHODS: We studied data from a random sample of US veterans aged ≥ 55 years followed at Veterans Affairs Health Care Systems nationwide from 1999 to 2019. We identified all patients diagnosed with MS using ICD codes over a two-year baseline period. We then identified a comparison cohort of patients without MS matched 1:1 on sex, age, race, and first encounter date. We constructed Cox proportional hazards regression models to determine the association between MS and dementia while controlling for demographic factors and comorbidities, with additional models to examine subgroup effects. We used Fine-Gray subdistribution hazard models accounting for competing risk of death to evaluate the sensitivity of the findings. RESULTS: The study included 4084 MS patients and a matched group of 4084 non-MS patients. Overall, patients had mean age 66, were 93.6% male, and 88.1% non-Hispanic White, with mean follow-up time 9.5 years (MS) and 10.8 years (non-MS). In unadjusted models, veterans with MS had greater risk of dementia compared to matched controls (cumulative incidence 16.7% vs 12.4%; Cox HR 1.58, 95% CI 1.41-1.78). The increased risk remained after adjustment for potential confounders (adjusted HR 1.56, 95% CI 1.39-1.76) and when considering death as a competing risk (Fine-Gray HR 1.36, 95% CI 1.21-1.53). The magnitude of the MS-dementia association increased with rising geographic latitude (North HR 1.86, 1.51-2.30; Central HR 1.61, 1.42-1.82; South HR 1.39, 1.18-1.64; interaction p = 0.04) and younger baseline age (interaction p<0.001). CONCLUSIONS: Among older veterans with MS, risk of dementia diagnosis was higher compared to matched controls even after controlling for comorbidities. The risk difference was highest in northern regions and in younger patients. Clinicians caring for older MS patients should be aware of this risk and offer screening and treatment accordingly.

TERT, BRAF, and NRAS Mutational Heterogeneity between Paired Primary and Metastatic Melanoma Tumors.

Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequencies of intertumoral and intratumoral heterogeneity are controversial. We examined mutational heterogeneity within individual patients with melanoma using multiplatform analysis of commonly mutated driver and nonpassenger genes. We analyzed paired primary and metastatic tumors from 60 patients and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n = 271 tumors). We used a combination of multiplex SNaPshot assays, Sanger sequencing, mutation-specific PCR, or droplet digital PCR to determine the presence of BRAFV600, NRASQ61, TERT-124C>T, and TERT-146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%), and/or TERT (78%). Thirteen patients had TERTmutant discordant tumors; seven of these had a single tumor with both TERT-124C>T and TERT-146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one had different tumors and the other had a single tumor with both mutations. One patient with a BRAFmutant primary lacked mutant BRAF in at least one of their metastases. Overall, we identified mutational heterogeneity in 18 of 99 patients (18%). These results suggest that some primary melanomas may be composed of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.

Risk of Subsequent Cutaneous Melanoma in Moderately Dysplastic Nevi Excisionally Biopsied but With Positive Histologic Margins.

Importance: Little evidence exists to guide the management of moderately dysplastic nevi excisionally biopsied without residual clinical pigmentation but with positive histologic margins (hereafter referred to as moderately dysplastic nevi with positive histologic margins). Objective: To determine outcomes and risk for the development of subsequent cutaneous melanoma (CM) from moderately dysplastic nevi with positive histologic margins observed for 3 years or more. Design, Setting, and Participants: A multicenter (9 US academic dermatology sites) retrospective cohort study was conducted of patients 18 years or older with moderately dysplastic nevi with positive histologic margins and 3 years or more of follow-up data collected consecutively from January 1, 1990, to August 31, 2014. Records were reviewed for patient demographics, biopsy type, pathologic findings, and development of subsequent CM at the biopsy site or elsewhere on the body. The χ2 test, the Fisher exact test, and analysis of variance were used to assess univariate association for risk of subsequent CMs, in addition to multivariable logistic regression models. To confirm histologic grading, each site submitted 5 random representative slide cases for central dermatopathologic review. Statistical analysis was performed from October 1, 2017, to June 22, 2018. Main Outcomes and Measures: Development of CM at a biopsy site or elsewhere on the body where there were moderately dysplastic nevi with positive histologic margins. Results: A total of 467 moderately dysplastic nevi with positive histologic margins from 438 patients (193 women and 245 men; mean [SD] age, 46.7 [16.1] years) were evaluated. No cases developed into CM at biopsy sites, with a mean (SD) follow-up time of 6.9 (3.4) years. However, 100 patients (22.8%) developed a CM at a separate site. Results of multivariate analyses revealed that history of CM was significantly associated with the risk of development of subsequent CM at a separate site (odds ratio, 11.74; 95% CI, 5.71-24.15; P < .001), as were prior biopsied dysplastic nevi (odds ratio, 2.55; 95% CI, 1.23-5.28; P = .01). The results of a central dermatopathologic review revealed agreement in 35 of 40 cases (87.5%). Three of 40 cases (7.5%) were upgraded in degree of atypia; of these, 1 was interpreted as melanoma in situ. That patient remains without recurrence or evidence of CM after 5 years of follow-up. Conclusions and Relevance: This study suggests that close observation with routine skin surveillance is a reasonable management approach for moderately dysplastic nevi with positive histologic margins. However, having 2 or more biopsied dysplastic nevi (with 1 that is a moderately dysplastic nevus) appears to be associated with increased risk for subsequent CM at a separate site.

Impact of primary care provider density on detection and diagnosis of cutaneous melanoma.

INTRODUCTION: Early diagnosis of cutaneous melanoma is critical in preventing melanoma-associated deaths, but the role of primary care providers (PCPs) in diagnosing melanoma is underexplored. We aimed to explore the association of PCP density with melanoma incidence and mortality. METHODS: All cases of cutaneous melanoma diagnosed in the United States from 2008-2012 and reported in the Surveillance, Epidemiology, and End Results (SEER) database were analyzed in 2016. County-level primary care physician density was obtained from the Area Health Resources File (AHRF). We conducted multivariate linear regression using 1) average annual melanoma incidence or 2) average annual melanoma mortality by county as primary outcomes, adjusting for demographic confounders and dermatologist density. Cox proportional hazard regression was conducted using individual outcome data from SEER with the same covariates. RESULTS: Across 611 counties, 167,305 cases of melanoma were analyzed. Per 100,000 people, an additional 10 PCPs per county was associated with 1.62 additional cases of melanoma per year (95% CI 1.06-2.18, p<0.001). This increased incidence occurred disproportionally in early-stage melanoma (Stage 0: 0.69 cases (0.38-1.00), p<0.001; Stage I: 0.63 cases (0.37-0.89), p<0.001; Stage II: 0.11 cases (0.03-0.19), p = 0.005). There was no statistically significant association between PCP density and incidence of stage III or IV melanoma, or with melanoma-specific mortality. Survival analysis demonstrated elimination of 5-year post-diagnosis mortality risk in medically underserved counties after adjusting for stage. CONCLUSIONS: Higher densities of PCPs may be linked to increased diagnosis of early-stage melanoma without corresponding decreases in late-stage diagnoses or melanoma-associated mortality.

Reexamining the Threshold for Reexcision of Histologically Transected Dysplastic Nevi.

Importance: Controversy persists regarding the appropriate management of incompletely excised, biopsy-proven, mild and moderate dysplastic nevi (DN). Objective: To determine long-term risk of associated melanoma in biopsied mild or moderate DN with positive histologic margins that were clinically observed vs reexcised with negative margins. Design, Setting, and Participants: Retrospective cohort study of mixed referral and community patients from an academic pigmented lesion clinic and dermatology clinics of the affiliated Veteran Affairs medical center with biopsy-confirmed DN with positive histologic margins diagnosed from May 15, 1991, to July 8, 2015, and followed up through May 30, 2016. A consecutive sample of 1473 histologically confirmed DN was identified using surgical pathology databases at the study sites; 590 cases in 498 patients met eligibility criteria. Main Outcomes and Measures: The primary outcome was the proportion of biopsied DN that progressed to histologically confirmed invasive or in situ melanoma. Secondary outcomes included local nevus recurrence and development of primary melanoma at other anatomic sites. Results: The 498 patients had a mean (range) age of 57.6 (14-93) years and 90% were male. Among 590 positive-margin DN, 191 were reexcised and 399 clinically observed without further surgery; 170 reexcised and 304 observed DN had available follow-up data, with mean (SD) follow-up of 5.5 (4.6) years. Cases in the observation group were more likely to demonstrate nevus recurrence than those that were reexcised (3.3% vs 0%; P = .02). Six of 304 (2.0%) observed DN subsequently developed melanoma at the same site, compared with 1 of 170 (0.06%) that were reexcised (P = .43). Five of 6 observed patients who developed melanoma initially underwent partial biopsy with grossly positive margins; 1 melanoma in situ evolved from an excisionally biopsied moderately dysplastic nevus 5 years later. Only 1 case of thin invasive melanoma (≤1 mm) was observed, and no deaths from melanoma arising from biopsy-proven DN occurred through the latest dermatology follow-up. New primary melanoma developed at other sites in 9.9% of excised and 9.4% of resected DN. Conclusions and Relevance: In cases of mild and moderate DN with microscopically positive margins and no concerning clinical residual lesion, observation, rather than reexcision, was a reasonable management option. Partial biopsies of pigmented lesions suspicious for melanoma may lead to delayed melanoma diagnosis and should be discouraged.

Genetic associations of the interleukin locus at 1q32.1 with clinical outcomes of cutaneous melanoma.

BACKGROUND: Due to high melanoma immunogenicity, germline genetic variants in immune pathways have been studied for association with melanoma prognosis. However, limited candidate selection, inadequate power, or lack of independent validation have hampered the reproducibility of these prior findings, preventing personalised clinical applicability in melanoma prognostication. Our objective was to assess the prognostic utility of genetic variants in immunomodulatory pathways for prediction of melanoma clinical outcomes. METHODS: We genotyped 72 tag single nucleotide polymorphisms (SNPs) in 44 immunomodulatory genes in a population sample of 1022 melanoma patients and performed Cox regression analysis to test the association between SNPs and melanoma recurrence-free (RFS) and overall survival (OS). We have further investigated the most significant associations using a fine mapping strategy and followed with functional analyses in CD4+ T cells in a subset of 75 melanoma patients. RESULTS: The most significant associations were found with melanoma OS for rs3024493 in IL10 at chromosome 1q32.1 (heterozygous HR 0.58, 95% CI 0.39 to 0.86; p=0.0006), a variant previously shown to be linked with autoimmune conditions. Multiple additional SNPs at 1q32.1 were also nominally associated with OS confirming at least two independent association signals in this locus. In addition, we found rs3024493 associated with the downregulation of interleukin 10 (IL10) secretion in CD4+ T cells. CONCLUSIONS: We discovered novel associations of IL10 with melanoma survival at 1q32.1, suggesting this locus should be considered as a novel melanoma prognostic biomarker with potential for aiding melanoma patient management. Our findings also provide further support for an alternative role of IL10 in stimulation of anti-tumour immune response.

Serum-based miRNAs in the prediction and detection of recurrence in melanoma patients.

BACKGROUND: Identification of primary melanoma patients at the highest risk of recurrence remains a critical challenge, and monitoring for recurrent disease is limited to costly imaging studies. We recently reported our array-based discovery of prognostic serum miRNAs in melanoma. In the current study, we examined the clinical utility of these serum-based miRNAs for prognosis as well as detection of melanoma recurrence. METHODS: Serum levels of 12 miRNAs were tested using qRT-PCR at diagnosis in 283 melanoma patients (training cohort, n = 201; independent validation, n = 82; median follow-up, 68.8 months). A refined miRNA signature was chosen and evaluated. We also tested the potential clinical utility of the miRNAs in early detection and monitoring of recurrence using multiple longitudinal samples (pre- and postrecurrence) in a subset of 82 patients (n = 225). In addition, we integrated our miRNA signature with publicly available Cancer Genome Atlas data to examine the relevance of these miRNAs to melanoma biology. RESULTS: Four miRNAs (miR-150, miR-30d, miR-15b, and miR-425) in combination with stage separated patients by recurrence-free survival (RFS) and overall survival (OS) and improved prediction of recurrence over stage alone in both the training and validation cohorts (training RFS and OS, P < .001; validation RFS, P < .001; OS, P = .005). Serum miR-15b levels significantly increased over time in recurrent patients (P < .001), adjusting for endogenous controls as well as age, sex, and initial stage. In nonrecurrent patients, miR-15b levels were not significantly changed with time (P =.17). CONCLUSIONS: Data demonstrate that serum miRNAs can improve melanoma patient stratification over stage and support further testing of miR-15b to guide patient surveillance.

Analysis of recurrence patterns in acral versus nonacral melanoma: should histologic subtype influence treatment guidelines?

Current surgical treatment of primary melanoma is uniform for all histosubtypes, although certain types of melanoma, such as acral lentiginous melanoma (ALM), have a worse prognosis. No study has explored the effectiveness of standard melanoma treatment guidelines for managing ALM compared with nonacral melanoma (NAM). Study subjects were identified from a prospectively enrolled database of patients with primary melanoma at New York University. Patients with ALM were matched to those with NAM (1:3) by gender and melanoma stage, including substage (ALM, 61; NAM, 183). All patients received standard-of-care treatment. Recurrence and survival outcomes in both cohorts were compared. ALM histologic subtype was an independent negative predictor of recurrence-free survival (hazard ratio [HR], 2.24; P=.001) and melanoma-specific survival (HR, 2.58; P=.001) compared with NAM. Recurrence was significantly more common in patients with ALM than in those with NAM (49% vs 30%; P=.007). For tumors less than 2 mm in thickness, a significantly higher recurrence rate was seen with ALM versus NAM (P=.048). No significant difference was seen in recurrence for tumors greater than 2 mm (P=.12). Notably, the rate of locoregional recurrence was nearly double for ALM compared with NAM (P=.001). The data presented herein reveal a high rate of locoregional failure in ALM compared with NAM when controlling for AJCC stage. These results raise the question of whether ALM may require more aggressive surgical treatment than nonacral cutaneous melanomas of equal thickness, particularly in tumors less than 2 mm thick. Larger multicenter trials are necessary for further conclusions.

PP6C hotspot mutations in melanoma display sensitivity to Aurora kinase inhibition.

UNLABELLED: Recent whole genome melanoma sequencing studies have identified recurrent mutations in the gene encoding the catalytic subunit of serine/threonine phosphatase 6 (PPP6C/PP6C). However, the biochemical, functional, and clinical ramifications of these mutations are unknown. Sequencing PP6C from patients with melanoma (233 primary and 77 metastatic specimens) with extended prospective clinical outcome revealed a large number of hotspot mutations in patients with both primary and metastatic melanoma. Despite minimal association between stage and presence of PP6C mutations in patients with primary melanoma, a subpopulation of cells within each tumor did contain PP6C mutations, suggesting PP6C mutation is an early, but non-tumor-initiating event in melanoma. Among patients with primary melanoma with PP6C mutations, patients with stop mutations had significantly shorter recurrence-free survival compared with patients without stop mutations. In addition, PP6C mutations were independent of commonly observed BRAF and NRAS mutations. Biochemically, PP6C mutations could be classified as those that interact with PP6C regulatory subunits and those that do not. Mutations that did not bind to PP6C regulatory subunits were associated with increased phosphorylation of Aurora kinase, a PP6C substrate, and mitotic defects. However, both classes of PP6C mutations led to increased sensitivity to Aurora kinase inhibition. Together, these data support for the first time that PP6C mutations are molecularly, biochemically, and clinically heterogeneous. IMPLICATIONS: PP6C mutations have distinct functional and clinical consequences in melanoma, and confer sensitivity to Aurora A kinase inhibitors.

Clinicopathological characteristics at primary melanoma diagnosis as risk factors for brain metastasis.

To better identify melanoma patients who are, at the time of primary melanoma diagnosis, at high risk of developing brain metastases, primary melanoma characteristics were examined as risk factors for brain metastasis development. In a study of two patient cohorts, clinicopathological characteristics prospectively collected at primary cutaneous melanoma diagnosis for patients with/without brain metastasis were assessed in univariate and multivariate analyses using data from two prospectively collected databases: the Melanoma Cooperative Group (MCG) (1972-1982) and the Interdisciplinary Melanoma Cooperative Group (IMCG) (2002-2009). Candidate risk factors were evaluated in association with time to brain metastasis using either the log-rank test or Cox proportional hazards regression analysis with/without considering competing risks. Out of 2341 total patients included in the study, 222 (9.5%) developed brain metastases (median follow-up: 98 months). The median time to brain metastases was 30.5 months and the median survival time after brain metastases was 4 months. Increased hazard ratios (HRs) for brain metastasis were found among thicker (logarithmic value in mm) (MCG: HR=1.97, P<0.0001; IMCG: HR=1.31, P=0.018), ulcerated (MCG: HR=1.93, P=0.01; IMCG: HR=3.14, P<0.0001), and advanced-stage (MCG: HR=2.08, P=0.008; IMCG: HR=2.56, P=0.0002) primary melanomas on the basis of multivariate Cox regression analysis assuming the presence of competing risks. Primary cutaneous melanoma thickness, ulceration, and stage were identified and validated as risk factors associated with time to melanoma brain metastasis.

Impact of age on the management of primary melanoma patients.

OBJECTIVES: Age is an understudied factor when considering treatment options for melanoma. Here, we examine the impact of age on primary melanoma treatment in a prospective cohort of patients. METHODS: We used logistic regression models to examine the associations between age and initial treatment, using recurrence and melanoma-specific survival as endpoints. RESULTS: 444 primary melanoma patients were categorized into three groups by age at diagnosis: 19-45 years (24.3%), 46-70 (50.2%), and 71-95 (25.5%). In multivariate models, older patients experienced a higher risk of recurrence (hazard ratio 3.34, 95% confidence interval, CI, 1.53-7.25; p < 0.01). No significant differences were observed in positive biopsy margin rates or extent of surgical margins across age groups. Patients in the middle age group were more likely to receive adjuvant therapy than those in the older group (odds ratio 2.78, 95% CI 1.19-6.45; p = 0.02) and showed a trend to longer disease-free survival when receiving adjuvant therapy (p = 0.09). CONCLUSION: Our data support age as an independent negative prognostic factor in melanoma. Our data suggest that age does not affect primary surgical treatment but may affect decisions of whether or not patients receive postoperative treatment(s). Further work is needed to better understand the biological variables affecting treatment decisions and efficacy in older patients.