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174


Cutaneous Melanoma Incidence - Evidence of a Flattening Curve

Berk-Krauss, Juliana; Sharma, Medha; Polsky, David; Geller, Alan C
PMID: 38086518
ISSN: 1097-6787
CID: 5589212

Re-examining melanoma secondary prevention and the role of skin self-examination

Ingrassia, Jenne P; Adotama, Prince; Stein, Jennifer A; Polsky, David
PMID: 37385450
ISSN: 1097-6787
CID: 5540512

Human TLR8 induces inflammatory bone marrow erythromyeloblastic islands and anemia in SLE-prone mice

Maria, Naomi I; Papoin, Julien; Raparia, Chirag; Sun, Zeguo; Josselsohn, Rachel; Lu, Ailing; Katerji, Hani; Syeda, Mahrukh M; Polsky, David; Paulson, Robert; Kalfa, Theodosia; Barnes, Betsy J; Zhang, Weijia; Blanc, Lionel; Davidson, Anne
Anemia commonly occurs in systemic lupus erythematosus, a disease characterized by innate immune activation by nucleic acids. Overactivation of cytoplasmic sensors by self-DNA or RNA can cause erythroid cell death, while sparing other hematopoietic cell lineages. Whereas chronic inflammation is involved in this mechanism, less is known about the impact of systemic lupus erythematosus on the BM erythropoietic niche. We discovered that expression of the endosomal ssRNA sensor human TLR8 induces fatal anemia in Sle1.Yaa lupus mice. We observed that anemia was associated with a decrease in erythromyeloblastic islands and a block in differentiation at the CFU-E to proerythroblast transition in the BM. Single-cell RNAseq analyses of isolated BM erythromyeloblastic islands from human TLR8-expressing mice revealed that genes associated with essential central macrophage functions including adhesion and provision of nutrients were down-regulated. Although compensatory stress erythropoiesis occurred in the spleen, red blood cell half-life decreased because of hemophagocytosis. These data implicate the endosomal RNA sensor TLR8 as an additional innate receptor whose overactivation causes acquired failure of erythropoiesis via myeloid cell dysregulation.
PMCID:10372407
PMID: 37495396
ISSN: 2575-1077
CID: 5592342

Early Detection and Prognostic Assessment of Cutaneous Melanoma: Consensus on Optimal Practice and the Role of Gene Expression Profile Testing

Kashani-Sabet, Mohammed; Leachman, Sancy A; Stein, Jennifer A; Arbiser, Jack L; Berry, Elizabeth G; Celebi, Julide T; Curiel-Lewandrowski, Clara; Ferris, Laura K; Grant-Kels, Jane M; Grossman, Douglas; Kulkarni, Rajan P; Marchetti, Michael A; Nelson, Kelly C; Polsky, David; Seiverling, Elizabeth V; Swetter, Susan M; Tsao, Hensin; Verdieck-Devlaeminck, Alexandra; Wei, Maria L; Bar, Anna; Bartlett, Edmund K; Bolognia, Jean L; Bowles, Tawnya L; Cha, Kelly B; Chu, Emily Y; Hartman, Rebecca I; Hawryluk, Elena B; Jampel, Risa M; Karapetyan, Lilit; Kheterpal, Meenal; Lawson, David H; Leming, Philip D; Liebman, Tracey N; Ming, Michael E; Sahni, Debjani; Savory, Stephanie A; Shaikh, Saba S; Sober, Arthur J; Sondak, Vernon K; Spaccarelli, Natalie; Usatine, Richard P; Venna, Suraj; Kirkwood, John M
IMPORTANCE:Therapy for advanced melanoma has transformed during the past decade, but early detection and prognostic assessment of cutaneous melanoma (CM) remain paramount goals. Best practices for screening and use of pigmented lesion evaluation tools and gene expression profile (GEP) testing in CM remain to be defined. OBJECTIVE:To provide consensus recommendations on optimal screening practices and prebiopsy diagnostic, postbiopsy diagnostic, and prognostic assessment of CM. EVIDENCE REVIEW:Case scenarios were interrogated using a modified Delphi consensus method. Melanoma panelists (n = 60) were invited to vote on hypothetical scenarios via an emailed survey (n = 42), which was followed by a consensus conference (n = 51) that reviewed the literature and the rationale for survey answers. Panelists participated in a follow-up survey for final recommendations on the scenarios (n = 45). FINDINGS:The panelists reached consensus (≥70% agreement) in supporting a risk-stratified approach to melanoma screening in clinical settings and public screening events, screening personnel recommendations (self/partner, primary care provider, general dermatologist, and pigmented lesion expert), screening intervals, and acceptable appointment wait times. Participants also reached consensus that visual and dermoscopic examination are sufficient for evaluation and follow-up of melanocytic skin lesions deemed innocuous. The panelists reached consensus on interpreting reflectance confocal microscopy and some but not all results from epidermal tape stripping, but they did not reach consensus on use of certain pigmented lesion evaluation tools, such as electrical impedance spectroscopy. Regarding GEP scores, the panelists reached consensus that a low-risk prognostic GEP score should not outweigh concerning histologic features when selecting patients to undergo sentinel lymph node biopsy but did not reach consensus on imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status. CONCLUSIONS AND RELEVANCE:For this consensus statement, panelists reached consensus on aspects of a risk-stratified approach to melanoma screening and follow-up as well as use of visual examination and dermoscopy. These findings support a practical approach to diagnosing and evaluating CM. Panelists did not reach consensus on a clearly defined role for GEP testing in clinical decision-making, citing the need for additional studies to establish the clinical use of existing GEP assays.
PMID: 36920356
ISSN: 2168-6084
CID: 5502422

Clinical validation of BRAF mutant circulating tumor DNA (ctDNA) as a prognostic biomarker in patients with stage III melanoma [Meeting Abstract]

Syeda, M M; Wiggins, J M; Ali, S; Long, G V; Atkinson, V; Garrett, J; Adnaik, S B; Hanoteau, N; Brase, J C; Dajee, M; Polsky, D
Currently, there is no validated biomarker to identify patients (pts) with stage III melanoma at high-vs low-risk of early relapse. We studied if ctDNA can predict RFS in these pts. We measured BRAF V600E/K ctDNA at baseline (BL, n = 596), and in plasma samples (73, in n = 41 pts) collected for up to 1 year from COMBI-AD study, comparing dabrafenib + trametinib (D + T) vs placebo in pts with resected BRAF V600 mutant stage III melanoma. We used analytically validated mutation-specific droplet digital PCR assays; ctDNA results were categorized as positive/negative using detection threshold of 0.28 copies/mL (BRAF V600E) and 0.34 copies/mL (BRAF V600K). For visualization of longitudinal analysis, zero cut-off was used. At BL, BRAF ctDNA was detectable in 79/596 pts (13.2%), mostly among pts with higher substage. Pts with detectable BL ctDNA identified a high-risk group with decreased RFS, compared to pts with undetectable BL ctDNA (low-risk group). In placebo arm, median RFS for high-risk group was 3.71 months (mo) vs 24.41 mo for low-risk (HR = 3.1598 [2.1492-4.6456], p < 0.001). In D + T arm, median RFS for high-risk group was 16.59 mo vs 68.11 mo for low-risk (HR = 2.7779 [1.7844-4.3245], p < 0.001). Detectable BL ctDNA was an independent predictor of RFS in a model including age, sex, substage, and treatment (HR = 2.7425 [2.0303-3.7045], p < 0.001). Among subset of pts with longitudinally collected samples, ctDNA was not detectable in 10/11 pts with no relapse events, while ctDNA was detected in 52% of pts with relapse within 3 mo of last longitudinal ctDNA assessment. Further sensitivity and specificity analyses are in progress. The study clinically validates BL BRAF mutant ctDNA as an independent prognostic biomarker for relapse in stage III melanoma. Combined with BL ctDNA assessment, longitudinal ctDNA monitoring may be useful in patient management
EMBASE:640045999
ISSN: 1755-148x
CID: 5511212

To the Editor: Patient and County-Level Factors Associated with Late Stage Merkel Cell Carcinoma at Diagnosis

Shah, Payal; Polsky, David; Shao, Yongzhao; Stein, Jennifer; Liebman, Tracey N
PMID: 35537549
ISSN: 1523-1747
CID: 5214322

A Health Equity Framework to Address Racial and Ethnic Disparities in Melanoma

Kolla, Avani M; Seixas, Azizi; Adotama, Prince; Foster, Victoria; Kwon, Simona; Li, Vivienne; Lee, Ann Y; Stein, Jennifer A; Polsky, David
PMID: 35970385
ISSN: 1097-6787
CID: 5299802

Associations between TERT promoter mutations and survival in superficial spreading and nodular melanomas in a large prospective patient cohort

Chang, Gregory A; Robinson, Eric; Wiggins, Jennifer M; Zhang, Yilong; Tadepalli, Jyothirmayee S; Schafer, Christine N; Darvishian, Farbod; Berman, Russell S; Shapiro, Richard; Shao, Yongzhao; Osman, Iman; Polsky, David
Survival outcomes in melanoma, and their association with mutations in the telomerase reverse transcriptase (TERT) promoter, remain uncertain. In addition, few studies have examined whether these associations are affected by a nearby common germline polymorphism, or vary based on melanoma histopathological subtype. We analyzed 408 primary tumors from a prospective melanoma cohort for somatic TERT-124[C>T] and TERT-146[C>T] mutations, the germline polymorphism rs2853669, and BRAFV600 and NRASQ61 mutations. We tested the associations between these variants and clinicopathologic factors and survival outcomes. TERT-124[C>T] was associated with thicker tumors, ulceration, mitoses (>0/mm2), nodular histotype and CNS involvement. In a multivariable model controlling for AJCC stage, TERT-124[C>T] was an independent predictor of shorter recurrence-free survival (RFS) (HR=2.58, p=0.001), and overall survival (HR=2.47, p=0.029). Patients with the germline variant and TERT-124[C>T] mutant melanomas had significantly shorter RFS than those patients lacking either or both sequence variants (p<0.04). The impact of the germline variant appeared to be more pronounced in superficial spreading compared to nodular melanoma. No associations were found between survival and TERT-146[C>T], BRAF or NRAS mutations. These findings strongly suggest that TERT-124[C>T] mutation is a biomarker of aggressive primary melanomas, an effect that may be modulated by rs2853669.
PMID: 35469904
ISSN: 1523-1747
CID: 5205542

Differentiating Between Lead-Time Bias and True Survival Benefits When Discussing Racial and Ethnic Disparities in Melanoma

Kolla, Avani M; Berwick, Marianne; Polsky, David
PMID: 35442387
ISSN: 2168-6084
CID: 5218332

Cell-Free DNA in Dermatology Research

Wiggins, Jennifer M; Ali, Saim; Polsky, David
In various diseases, particularly cancer, cell-free DNA (cfDNA) has been widely studied as a marker of disease prognosis or to facilitate the detection of therapeutic targets. In dermatology, most studies have focused on melanoma; other skin diseases such as vascular malformations and psoriasis have also been examined. Genetic alterations unique to the tissue of origin such as sequence variations, copy number alterations, chromosomal rearrangements, differential DNA methylation patterns, and fragmentation patterns can be identified in circulation providing information on patient disease status. These alterations can be detected either by PCR-based methods or next-generation sequencing depending on the target of interest. In this article, we discuss the origins of cfDNA, the most common methods of detection, current studies assessing cfDNA as a biomarker, and cfDNA's potential clinical applications in melanoma and other skin diseases. In addition, we provide important factors to consider during blood processing and DNA extraction as well as limitations for each assay.
PMID: 35598899
ISSN: 1523-1747
CID: 5244702