Publications by authors named "Emily Y Chu"

87 Publications

Distinct Signatures of Genomic Copy Number Variants Define Subgroups of Merkel Cell Carcinoma Tumors.

Cancers (Basel) 2021 Mar 6;13(5). Epub 2021 Mar 6.

Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Most MCC tumors contain integrated Merkel cell polyomavirus DNA (virus-positive MCC, VP-MCC) and carry a low somatic mutation burden whereas virus-negative MCC (VN-MCC) possess numerous ultraviolet-signature mutations. In contrast to viral oncogenes and sequence mutations, little is known about genomic structural variants in MCC. To identify copy number variants in commonly altered genes, we analyzed genomic DNA from 31 tumor samples using the Nanostring nCounter copy number cancer panel. Unsupervised clustering revealed three tumor groups with distinct genomic structural variant signatures. The first cluster was characterized by multiple recurrent deletions in genes such as and . The second cluster contained eight VP-MCC and displayed very few structural variations. The final cluster contained one VP-MCC and four VN-MCC with predominantly genomic amplifications in genes like , , and and deletions in . Overall, VN-MCC contained more structure variation than VP-MCC but did not cluster separately from VP-MCC. The observation that most MCC tumors demonstrate a deletion-dominated structural group signature, independent of virus status, suggests a shared pathophysiology among most VP-MCC and VN-MCC tumors.
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http://dx.doi.org/10.3390/cancers13051134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961454PMC
March 2021

Guidelines for Micro-Computed Tomography Analysis of Rodent Dentoalveolar Tissues.

JBMR Plus 2021 Mar 3;5(3):e10474. Epub 2021 Mar 3.

Division of Biosciences, College of Dentistry The Ohio State University Columbus OH USA.

Micro-computed tomography (μCT) has become essential for analysis of mineralized as well as nonmineralized tissues and is therefore widely applicable in the life sciences. However, lack of standardized approaches and protocols for scanning, analyzing, and reporting data often makes it difficult to understand exactly how analyses were performed, how to interpret results, and if findings can be broadly compared with other models and studies. This problem is compounded in analysis of the dentoalveolar complex by the presence of four distinct mineralized tissues: enamel, dentin, cementum, and alveolar bone. Furthermore, these hard tissues interface with adjacent soft tissues, the dental pulp and periodontal ligament (PDL), making for a complex organ. Drawing on others' and our own experience analyzing rodent dentoalveolar tissues by μCT, we introduce techniques to successfully analyze dentoalveolar tissues with similar or disparate compositions, densities, and morphological characteristics. Our goal is to provide practical guidelines for μCT analysis of rodent dentoalveolar tissues, including approaches to optimize scan parameters (filters, voltage, voxel size, and integration time), reproducibly orient samples, define regions and volumes of interest, segment and subdivide tissues, interpret findings, and report methods and results. We include illustrative examples of analyses performed on genetically engineered mouse models with phenotypes in enamel, dentin, cementum, and alveolar bone. The recommendations are designed to increase transparency and reproducibility, promote best practices, and provide a basic framework to apply μCT analysis to the dentoalveolar complex that can also be extrapolated to a variety of other tissues of the body. © 2021 The Authors. published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990153PMC
March 2021

SnapshotDx Quiz: March 2021.

J Invest Dermatol 2021 Mar;141(3):e27-e32

Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.12.017DOI Listing
March 2021

Association of the Affordable Care Act's Medicaid expansion with the diagnosis and treatment of clinically localized melanoma: A National Cancer Database study.

J Am Acad Dermatol 2021 Feb 4. Epub 2021 Feb 4.

Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.

Background: The Affordable Care Act's Medicaid expansion is associated with earlier diagnosis and improved care among lower socioeconomic status populations with cancer, but its impact on melanoma is undefined.

Objective: To determine the association of Medicaid expansion with stage of diagnosis and use of sentinel lymph node biopsy in nonelderly adult patients with newly diagnosed clinically localized melanoma.

Methods: Quasi-experimental, difference-in-differences retrospective cohort analysis using data from the National Cancer Database from 2010 to 2017. Patients from expansion versus nonexpansion states and diagnosed before (2010-2013) versus after (2014-2017) expansion were identified.

Results: Of 83,322 patients, 46.6% were female, and the median age was 55 years (interquartile range, 49-60). After risk adjustment, Medicaid expansion was associated with a decrease in the diagnosis of T1b stage or higher melanoma (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.88-0.98; P = .011) and decrease in uninsured status (OR, 0.61; 95% CI, 0.52-0.72; P < .001) but was not associated with a difference in sentinel lymph node biopsy performance when indicated (OR, 1.06; 95% CI, 0.95-1.20; P = .29).

Limitations: Retrospective study using a national database.

Conclusion: In this study of patients with clinically localized melanoma, Medicaid expansion was associated with a decrease in the diagnosis of later T-stage tumors.
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http://dx.doi.org/10.1016/j.jaad.2021.01.097DOI Listing
February 2021

Lymphedematous verrucous changes of the genital skin: an extraintestinal manifestation of Crohn disease.

J Cutan Pathol 2021 Apr 20;48(4):465-468. Epub 2021 Jan 20.

Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1111/cup.13723DOI Listing
April 2021

OPG-Fc treatment partially rescues low bone mass phenotype in mature Bgn/Fmod deficient mice but is deleterious to the young mouse skeleton.

J Struct Biol 2020 12 17;212(3):107627. Epub 2020 Sep 17.

Molecular Biology of Bones and Teeth Section, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, United States. Electronic address:

Biglycan (Bgn) and Fibromodulin (Fmod) are small leucine rich proteoglycans (SLRPs) which are abundant in the extra-cellular matrix (ECM) of mineralized tissues. We have previously generated a Bgn/Fmod double knock-out (DKO) mouse model and found it has a 3-fold increase in osteoclastogenesis compared with Wild type (WT) controls, resulting in a markedly low bone mass (LBM) phenotype. To try and rescue/repair the LBM phenotype of Bgn/Fmod DKO mice by suppressing osteoclast formation and activity, 3- and 26-week-old Bgn/Fmod DKO mice and age/gender matched WT controls were treated with OPG-Fc for 6 weeks after which bone parameters were evaluated using DEXA, micro-computed tomography (μCT) and serum biomarkers analyses. In the appendicular skeleton, OPG-Fc treatment improved some morphometric and geometric parameters in both the trabecular and cortical compartments in Bgn/Fmod DKO female and male mice, especially in the repair module. For many of the skeletal parameters analyzed, the Bgn/Fmod DKO mice were more responsive to the treatment than their WT controls. In addition, we found that OPG-Fc treatment was not able to prevent or ameliorate the formation of ectopic ossification, which are common lesions seen in aged joints and are one of the phenotypical hallmarks of our Bgn/Fmod DKO model. Analysis of skull bones, specifically the occipital bone, showed the treatment recovered some parameters of LBM phenotype in the craniofacial skeleton, more so in the younger rescue module. Using OPG-Fc as treatment alleviated, yet did not completely restore, the severe osteopenia and mineralized tissue structural abnormalities that Bgn/Fmod DKO mice suffer from.
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http://dx.doi.org/10.1016/j.jsb.2020.107627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744403PMC
December 2020

Hypohidrosis as an immune-related adverse event of checkpoint inhibitor therapy.

Immunotherapy 2020 Sep 10;12(13):951-956. Epub 2020 Aug 10.

Department of Dermatology, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.

Immune checkpoint blockade therapies including cytotoxic-T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) inhibitors have become indispensable tools for treating melanoma and other cancers. An increasing number of diverse cutaneous adverse reactions to immunotherapy have been documented in the literature and have been reported to affect up to 40% of patients treated with targeted therapies. Herein, we report a case of a patient with metastatic melanoma treated with checkpoint inhibitor therapy who developed vitiligo, gastritis and hepatitis, all identified as adverse immune events and attributable to his immunotherapy regimen. He subsequently developed acquired idiopathic generalized hypohidrosis with biopsy of lesional skin demonstrating a peri-eccrine lymphocytic infiltrate. These findings suggest this acquired generalized hypohidrosis represents a lymphocyte-mediated adverse immune event related to this patient's checkpoint inhibitor therapy.
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http://dx.doi.org/10.2217/imt-2020-0002DOI Listing
September 2020

Insights into dental mineralization from three heritable mineralization disorders.

J Struct Biol 2020 10 3;212(1):107597. Epub 2020 Aug 3.

Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, USA. Electronic address:

Teeth are comprised of three unique mineralized tissues, enamel, dentin, and cementum, that are susceptible to developmental defects similar to those affecting bone. X-linked hypophosphatemia (XLH), caused by PHEX mutations, leads to increased fibroblast growth factor 23 (FGF23)-driven hypophosphatemia and local extracellular matrix disturbances. Hypophosphatasia (HPP), caused by ALPL mutations, results in increased levels of inorganic pyrophosphate (PP), a mineralization inhibitor. Generalized arterial calcification in infancy (GACI), caused by ENPP1 mutations, results in vascular calcification due to decreased PP, later compounded by FGF23-driven hypophosphatemia. In this perspective, we compare and contrast dental defects in primary teeth associated with XLH, HPP, and GACI, briefly reviewing genetic and biochemical features of these disorders and findings of clinical and preclinical studies to date, including some of our own recent observations. The distinct dental defects associated with the three heritable mineralization disorders reflect unique processes of the respective dental hard tissues, revealing insights into their development and clues about pathological mechanisms underlying such disorders.
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http://dx.doi.org/10.1016/j.jsb.2020.107597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530110PMC
October 2020

Prognostic Gene Expression Profiling in Cutaneous Melanoma: Identifying the Knowledge Gaps and Assessing the Clinical Benefit.

JAMA Dermatol 2020 09;156(9):1004-1011

Stanford University Medical Center and Cancer Institute, Stanford, California.

Importance: Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care.

Objective: To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies.

Evidence Review: The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed.

Findings: The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility.

Conclusions And Relevance: More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.
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http://dx.doi.org/10.1001/jamadermatol.2020.1729DOI Listing
September 2020

Urethral involvement is associated with higher mortality and local recurrence in vulvar melanoma: a single institutional experience.

Hum Pathol 2020 10 20;104:1-8. Epub 2020 Jul 20.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic address:

Vulvar malignant melanoma (VMM), although uncommon, comprises 5-10% of all vulvar malignancies. Local control is notoriously poor in VMM with recurrence rates of 30-50% compared with approximately 3% in cutaneous melanomas. We studied clinicopathologic features of 37 women with VMM, after reviewing three decades of clinical follow-up data in our institutional databases. Most patients were Caucasian (n = 35) with an average age at diagnosis of 60.6 years (range 23-83). The most common subtype was mucosal lentiginous melanoma (n = 25). We compared Kaplan-Meier survival curves of 31 patients defined by clinical and microscopic attributes using exact log-rank tests. Younger patients at diagnosis (23-64 years), those with thin melanomas (≤1 mm), and those with Clark's level II or III tumors had better 5-year survival rates than older patients (65-83 years) and those with thick melanomas (>1 mm) and those with Clark's level IV or V (P ≤ 0.05), respectively, by exact log-rank test. Local recurrence of melanoma occurred in 15 patients. Nine patients (24%) had eventual urethral involvement by malignant melanoma, and this feature was associated with significantly shorter survival (P = 0.036). Patients with urethral involvement had shorter median time to death and worse 5-year survival rates. Given that spread to the urethra is common in VMM and urethral recurrence is also associated with mortality, pathology excision specimens should be carefully reviewed with attention to urethral involvement as a potentially important prognostic factor.
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http://dx.doi.org/10.1016/j.humpath.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669565PMC
October 2020

Evaluation of the Merits and Limitations of Evidence-Based Medicine.

JAMA Dermatol 2020 08;156(8):924-925

Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1001/jamadermatol.2020.1940DOI Listing
August 2020

Gene Expression Profile Testing for Thin Melanoma: Evidence to Support Clinical Use Remains Thin.

JAMA Dermatol 2020 08;156(8):837-838

Department of Internal Medicine, Dell Medical School, The University of Texas at Austin.

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http://dx.doi.org/10.1001/jamadermatol.2020.0894DOI Listing
August 2020

Histologic features of melanoma associated with germline mutations of CDKN2A, CDK4, and POT1 in melanoma-prone families from the United States, Italy, and Spain.

J Am Acad Dermatol 2020 Sep 10;83(3):860-869. Epub 2020 Apr 10.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Background: CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes.

Objective: We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1.

Methods: We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and noncarriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family.

Results: Histologic slides were evaluated for 290 melanomas (139 from 132 noncarriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, and 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in 10 of 15 invasive melanomas (67%) from POT1 carriers (P < .0001 vs noncarriers). This finding was independently confirmed by 3 expert melanoma dermatopathologists in 9 of 15 invasive melanomas (60%). In situ and invasive melanomas from CDKN2A and CDK4 carriers were histologically similar to melanomas from noncarriers.

Limitations: Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1).

Conclusion: Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoid differentiation in melanocytic tumors.
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http://dx.doi.org/10.1016/j.jaad.2020.03.100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505133PMC
September 2020

An Intrapatient Concordance Study of Mismatch Repair Protein Immunohistochemical Staining Patterns in Patients With Muir-Torre Syndrome.

JAMA Dermatol 2020 06;156(6):676-680

Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia.

Importance: Appropriate use criteria for Muir-Torre syndrome (MTS) screening suggest that mismatch repair protein (MMRP) immunohistochemical (IHC) testing is usually appropriate in patients with 2 or more sebaceous neoplasms (SNs). While MTS is known to be caused by a germline mutation in mismatch repair genes, data are limited as to whether individual sebaceous tumors in these patients with multiple lesions show identical MMRP IHC staining patterns.

Objective: To determine concordance of MMRP IHC staining patterns in lesions of patients with MTS who have multiple SNs.

Design, Setting, And Participants: This retrospective single-center case series evaluated 38 SNs in 11 patients with MTS confirmed by genetic testing for MMRP IHC staining patterns. Tumor sites were classified as either facial or extrafacial. Data were collected between January 1, 2007, and January 1, 2018.

Main Outcomes And Measures: In each patient, MMRP IHC staining patterns for SNs were compared with one another to evaluate intrapatient concordance between lesions, and to the patient's known germline mutation.

Results: A total of 11 patients (7 women and 4 men) with MTS, with a mean (SD) age of 59.3 (10.6) years at time of SN biopsy, were identified. There was high concordance between MMRP IHC staining results (2-4 lesions per patient) and the patient's mutation status, with 36 of 38 total lesions (95%) matching (sensitivity, 94.7%; 95% CI, 82.3%-99.4%). Extrafacial site tumors represented 16 of 38 total lesions (42%) and demonstrated 100% concordance of IHC results to germline mutation. Only 1 of 11 patients (9%) demonstrated discordant results, with both lesions in this patient occurring on a facial site.

Conclusions And Relevance: In patients with known MTS, SNs present with highly concordant MMRP IHC staining profiles across multiple lesions. There is also a strong association with underlying germline mutations. A diagnosis of MTS might be supported by MMRP IHC when the pretest probability is high.
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http://dx.doi.org/10.1001/jamadermatol.2020.0433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142808PMC
June 2020

Dental and craniofacial defects in the Crtap mouse model of osteogenesis imperfecta type VII.

Dev Dyn 2020 07 12;249(7):884-897. Epub 2020 Mar 12.

Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.

Background: Inactivating mutations in the gene for cartilage-associated protein (CRTAP) cause osteogenesis imperfecta type VII in humans, with a phenotype that can include craniofacial defects. Dental and craniofacial manifestations have not been a focus of case reports to date. We analyzed the craniofacial and dental phenotype of Crtap mice by skull measurements, micro-computed tomography (micro-CT), histology, and immunohistochemistry.

Results: Crtap mice exhibited a brachycephalic skull shape with fusion of the nasofrontal suture and facial bones, resulting in mid-face retrusion and a class III dental malocclusion. Loss of CRTAP also resulted in decreased dentin volume and decreased cellular cementum volume, though acellular cementum thickness was increased. Periodontal dysfunction was revealed by decreased alveolar bone volume and mineral density, increased periodontal ligament (PDL) space, ectopic calcification within the PDL, bone-tooth ankylosis, altered immunostaining of extracellular matrix proteins in bone and PDL, increased pSMAD5, and more numerous osteoclasts on alveolar bone surfaces.

Conclusions: Crtap mice serve as a useful model of the dental and craniofacial abnormalities seen in individuals with osteogenesis imperfecta type VII.
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http://dx.doi.org/10.1002/dvdy.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727892PMC
July 2020

Comparison of C3d immunohistochemical staining to enzyme-linked immunosorbent assay and immunofluorescence for diagnosis of bullous pemphigoid.

J Am Acad Dermatol 2020 Jul 14;83(1):172-178. Epub 2020 Feb 14.

Department of Dermatology, the University of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background: Bullous pemphigoid (BP), the most common autoimmune blistering disease, may be diagnostically challenging. Direct immunofluorescence (DIF), indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and recently, C3d immunohistochemistry (IHC), are used as adjuncts to diagnosis.

Objective: To compare C3d IHC to DIF, IIF, and ELISA testing in BP diagnosis.

Methods: C3d IHC was performed on skin biopsy specimens from 51 patients (27 with BP and 24 with other blistering diseases) and compared to DIF and IIF, with anti-BP180 or anti-BP230 ELISA results used as the gold standard.

Results: We found C3d IHC, DIF, and IIF had similar sensitivity (74.1%, 63.1%, and 70.4%), specificity (95.8%, 100%, and 100%), positive predictive value (95.2%, 100%, and 100%), and negative predictive value (76.7%, 70.6%, and 75%) for BP. Cases with positive C3d IHC, DIF, and IIF had significantly higher anti-BP180 and anti-BP230 by ELISA than cases with negative testing (P < .0001). False-negative IIF results were associated with lower BP230 compared with true-positive results (P = .03).

Limitations: This was a single-center, retrospective study.

Conclusion: Our study compared C3d IHC to DIF and IIF in BP diagnosis, demonstrating C3d IHC on fixed tissue provides similar diagnostic utility to immunofluorescence and ELISA.
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http://dx.doi.org/10.1016/j.jaad.2020.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480887PMC
July 2020

A Blue-Gray Macule on the Back: Answer.

Am J Dermatopathol 2020 Jan;42(1):65

Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA; and.

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http://dx.doi.org/10.1097/DAD.0000000000001267DOI Listing
January 2020

Use of new molecular tests for melanoma by pigmented-lesion experts.

J Am Acad Dermatol 2020 01 13;82(1):245-247. Epub 2019 Aug 13.

Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City; Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City; Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2019.08.022DOI Listing
January 2020

Generalized congenital epithelioid blue nevi (pigmented epithelioid melanocytomas) in an infant: Report of case and review of the literature.

J Cutan Pathol 2019 Dec 22;46(12):954-959. Epub 2019 Jul 22.

Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

The epithelioid blue nevus (EBN) is a variant of the blue nevus characterized by heavily pigmented epithelioid melanocytes and lightly or nonpigmented spindle cells. It may be associated with Carney complex, a multiple neoplasia syndrome. Congenital cases of EBN not associated with Carney complex are rarely reported. We herein describe an infant who presented with multiple blue-gray nodules and papules involving the head, trunk, and extremities at birth, the corresponding histopathologic findings, and genetic testing results.
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http://dx.doi.org/10.1111/cup.13544DOI Listing
December 2019

Expression of p15 in a spectrum of spitzoid melanocytic neoplasms.

J Cutan Pathol 2019 May 14;46(5):310-316. Epub 2019 Feb 14.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Accurate classification of spitzoid melanocytic lesions is difficult due to overlapping clinical and histopathologic features between Spitz nevi, atypical Spitz tumors (ASTs), and spitzoid melanomas. Expression of p16 (CDKN2A) has been used as a marker of spitzoid lesions. However, its expression may be variable. p15 is a tumor suppressor encoded by CDKN2B, loss of which has been recently shown to promote transition from nevus to melanoma. We sought to determine whether p15 is a useful immunohistochemical marker to distinguish Spitz nevi from spitzoid melanomas and to compare p15 and p16 staining in this population.

Methods: Immunohistochemistry for p15 and p16 was performed on Spitz nevi (n = 19), ASTs (n = 41), and spitzoid melanomas (n = 17). Immunoexpression was categorized by a four-tiered system: 0 (negative), 1+ (weak), 2+ (moderate), 3+ (strong).

Results: 3+/strong p15 staining was observed in 68.4% of Spitz nevi, 34.2% of ASTs, and 17.7% of spitzoid melanomas. By contrast, we observed 3+ p16 staining in roughly equivalent percentages of Spitz nevi (57.9%), ASTs (56.1%), and spitzoid melanomas (58.8%).

Conclusion: These data illustrate that p15 may be more useful than p16 as a biomarker to help distinguish benign from malignant spitzoid lesions.
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http://dx.doi.org/10.1111/cup.13424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506222PMC
May 2019

NRAS Q61R and BRAF G466A mutations in atypical melanocytic lesions newly arising in advanced melanoma patients treated with vemurafenib.

J Cutan Pathol 2019 Mar 27;46(3):190-194. Epub 2018 Dec 27.

Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: BRAF inhibition has improved overall survival in patients with BRAF mutant melanoma, but this is associated with a range of known and predictable cutaneous side effects, including squamous cell carcinomas associated with RAS mutations.

Methods: We identified three severely dysplastic nevi, one atypical intraepidermal melanocytic proliferation, and four melanoma in situ lesions, newly arising in four patients undergoing treatment with vemurafenib. To characterize mutations in these atypical melanocytic lesions, we used a custom iPlex panel detecting 74 mutations in 13 genes known to play a role in melanoma pathogenesis.

Results: We identified an NRAS mutation at codon 61 (Q61R) and a rare BRAF exon 11 mutation (G466A) in atypical melanocytic lesions that arose in patients treated with vemurafenib.

Conclusion: There appears to be development or accelerated growth of atypical melanocytic lesions in the setting of BRAF inhibition. Our results underscore the need for careful surveillance for melanocytic lesions in patients on BRAF inhibitor therapy and shed light on potential mechanisms for melanoma pathogenesis in the context of BRAF pathway blockade. Further studies are warranted to show a causal relationship.
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http://dx.doi.org/10.1111/cup.13401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367041PMC
March 2019

The transcription factor AmeloD stimulates epithelial cell motility essential for tooth morphology.

J Biol Chem 2019 03 30;294(10):3406-3418. Epub 2018 Nov 30.

From the Molecular Biology Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892,

The development of ectodermal organs, such as teeth, requires epithelial-mesenchymal interactions. Basic helix-loop-helix (bHLH) transcription factors regulate various aspects of tissue development, and we have previously identified a bHLH transcription factor, AmeloD, from a tooth germ cDNA library. Here, we provide both and evidence that AmeloD is important in tooth development. We created -knockout (KO) mice to identify the functions of AmeloD that are critical for tooth morphogenesis. We found that -KO mice developed enamel hypoplasia and small teeth because of increased expression of E-cadherin in inner enamel epithelial (IEE) cells, and it may cause inhibition of the cell migration. We used the CLDE dental epithelial cell line to conduct further mechanistic analyses to determine whether AmeloD overexpression in CLDE cells suppresses E-cadherin expression and promotes cell migration. Knockout of epiprofin (Epfn), another transcription factor required for tooth morphogenesis and development, and analysis of AmeloD expression and deletion revealed that AmeloD also contributed to multiple tooth formation in -KO mice by promoting the invasion of dental epithelial cells into the mesenchymal region. Thus, AmeloD appears to play an important role in tooth morphogenesis by modulating E-cadherin and dental epithelial-mesenchymal interactions. These findings provide detailed insights into the mechanism of ectodermal organ development.
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http://dx.doi.org/10.1074/jbc.RA118.005298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416439PMC
March 2019

A Blue-Gray Macule on the Back: Challenge.

Am J Dermatopathol 2020 Jan;42(1):e4

Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA; and.

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http://dx.doi.org/10.1097/DAD.0000000000001268DOI Listing
January 2020

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

JAMA Dermatol 2018 12;154(12):1401-1408

Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia.

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.
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http://dx.doi.org/10.1001/jamadermatol.2018.3359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583364PMC
December 2018

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Cancer 2019 01 3;125(1):18-44. Epub 2018 Oct 3.

Department of Dermatology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.
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http://dx.doi.org/10.1002/cncr.31719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6860362PMC
January 2019

Piloting the Use of Smartphones, Reminders, and Accountability Partners to Promote Skin Self-Examinations in Patients with Total Body Photography: A Randomized Controlled Trial.

Am J Clin Dermatol 2018 Oct;19(5):779-785

Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Objective: The aim of this study was to evaluate the use of a mobile application (app) in patients already using total body photography (TBP) to increase skin self-examination (SSE) rates and pilot the effectiveness of examination reminders and accountability partners.

Design: Randomized controlled trial with computer generated randomization table to allocate interventions.

Setting: University of Pennsylvania pigmented lesion clinic.

Participants: 69 patients aged 18 years or older with an iPhone/iPad, who were already in possession of TBP photographs.

Intervention: A mobile app loaded with digital TBP photos for all participants, and either (1) the mobile app only, (2) skin examination reminders, (3) an accountability partner, or (4) reminders and an accountability partner.

Main Outcome Measure: Change in SSE rates as assessed by enrollment and end-of-study surveys 6 months later.

Results: Eighty one patients completed informed consent, however 12 patients did not complete trial enrollment procedures due to device incompatibility, leaving 69 patients who were randomized and analyzed [mean age 54.3 years, standard deviation 13.9). SSE rates increased significantly from 58% at baseline to 83% at 6 months (odds ratio 2.64, 95% confidence interval 1.20-4.09), with no difference among the intervention groups. The group with examination reminders alone had the highest (94%) overall satisfaction, and the group with accountability partners alone accounted for the lowest (71%).

Conclusion: A mobile app alone, or with reminders and/or accountability partners, was found to be an effective tool that can help to increase SSE rates. Skin examination reminders may help provide a better overall experience for a subset of patients.

Trial Registration: ClinicalTrials.gov Identifier: NCT02520622.
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http://dx.doi.org/10.1007/s40257-018-0372-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126944PMC
October 2018