Nathaniel Fleming

All Publications

• Reexamining the Threshold for Reexcision of Histologically Transected Dysplastic Nevi JAMA DERMATOLOGY Fleming, N. H., Egbert, B. M., Kim, J., Swetter, S. M. 2016; 152 (12): 1327-1334

  Abstract

  Controversy persists regarding the appropriate management of incompletely excised, biopsy-proven, mild and moderate dysplastic nevi (DN).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.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.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.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.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.

  View details for DOI 10.1001/jamadermatol.2016.2869

  View details for Web of Science ID 000391291900006

  View details for PubMedID 27542070

• Serum-based miRNAs in the prediction and detection of recurrence in melanoma patients. Cancer Fleming, N. H., Zhong, J., da Silva, I. P., Vega-Saenz de Miera, E., Brady, B., Han, S. W., Hanniford, D., Wang, J., Shapiro, R. L., Hernando, E., Osman, I. 2015; 121 (1): 51–59

  Abstract

  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.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.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).Data demonstrate that serum miRNAs can improve melanoma patient stratification over stage and support further testing of miR-15b to guide patient surveillance.

  View details for DOI 10.1002/cncr.28981

  View details for PubMedID 25155861

  View details for PubMedCentralID PMC4270907

• Impact of age on the management of primary melanoma patients. Oncology Fleming, N. H., Tian, J., Vega-Saenz de Miera, E., Gold, H., Darvishian, F., Pavlick, A. C., Berman, R. S., Shapiro, R. L., Polsky, D., Osman, I. 2013; 85 (3): 173-181

  Abstract

  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.We used logistic regression models to examine the associations between age and initial treatment, using recurrence and melanoma-specific survival as endpoints.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).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.

  View details for DOI 10.1159/000351499

  View details for PubMedID 24008821

  View details for PubMedCentralID PMC3842185

• Genetic associations of the interleukin locus at 1q32.1 with clinical outcomes of cutaneous melanoma. Journal of medical genetics Rendleman, J., Vogelsang, M., Bapodra, A., Adaniel, C., Silva, I., Moogk, D., Martinez, C. N., Fleming, N., Shields, J., Shapiro, R., Berman, R., Pavlick, A., Polsky, D., Shao, Y., Osman, I., Krogsgaard, M., Kirchhoff, T. 2015; 52 (4): 231–39

  Abstract

  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.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.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.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.

  View details for DOI 10.1136/jmedgenet-2014-102832

  View details for PubMedID 25604082

  View details for PubMedCentralID PMC5166523

• Analysis of Recurrence Patterns in Acral Versus Nonacral Melanoma: Should Histologic Subtype Influence Treatment Guidelines? JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Gumaste, P. V., Fleming, N. H., Silva, I., Shapiro, R. L., Berman, R. S., Zhong, J., Osman, I., Stein, J. A. 2014; 12 (12): 1706-1712

  Abstract

  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.

  View details for Web of Science ID 000346190900008

  View details for PubMedID 25505211

  View details for PubMedCentralID PMC4469335

• PP6C Hotspot Mutations in Melanoma Display Sensitivity to Aurora Kinase Inhibition MOLECULAR CANCER RESEARCH Gold, H. L., Wengrod, J., de Miera, E. V., Wang, D., Fleming, N., Sikkema, L., Kirchhoff, T., Hochman, T., Goldberg, J. D., Osman, I., Gardner, L. B. 2014; 12 (3): 433-439

  Abstract

  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.PP6C mutations have distinct functional and clinical consequences in melanoma, and confer sensitivity to Aurora A kinase inhibitors.

  View details for DOI 10.1158/1541-7786.MCR-13-0422

  View details for Web of Science ID 000333255500012

  View details for PubMedID 24336958

  View details for PubMedCentralID PMC3962698

• Clinicopathological characteristics at primary melanoma diagnosis as risk factors for brain metastasis MELANOMA RESEARCH Qian, M., Ma, M. W., Fleming, N. H., Lackaye, D. J., Hernando, E., Osman, I., Shao, Y. 2013; 23 (6): 461-467

  Abstract

  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.

  View details for DOI 10.1097/CMR.0000000000000015

  View details for Web of Science ID 000326582600006

  View details for PubMedID 24165034

  View details for PubMedCentralID PMC4419696