Publications by authors named "Jeffrey North"

88 Publications

The utility of PRAME staining in identifying malignant transformation of melanocytic nevi.

J Cutan Pathol 2021 Jan 12. Epub 2021 Jan 12.

Department of Dermatology, University of California San Francisco, San Francisco, California, USA.

Background: PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemical (IHC) staining is used to aid melanoma diagnosis. PRAME expression in nevus-associated melanoma (NAM) has not been evaluated.

Methods: PRAME IHC was applied to cases of NAM; staining for each population of melanocytes (benign and malignant) was graded based on the percentage of labeled cells. No labeling was graded 0, 1% to 25% labeling was 1+, 26% to 50% was 2+, 51% to 75% was 3+, and >76% was 4+.

Results: Thirty-six cases were reviewed. Sixty-seven percent (24/36) of melanomas were PRAME positive (4+) while no (0/36) nevi showed 4+ positivity. Eighty-one percent (29/36) of nevi were completely PRAME negative compared to 17% (6/36) of melanomas. In 67% of cases (24/36) PRAME differentiated between benign and malignant melanocyte populations.

Conclusions: We identified a high rate (67%) of differential PRAME staining in adjacent benign and malignant melanocyte populations in NAM. In PRAME positive (4+) melanomas, PRAME differentiates 100% (24/24) of benign and malignant melanocyte populations. When 4+ staining is used as the threshold for positivity, PRAME staining has a sensitivity of 67% (24/36) and a specificity of 100% (36/36). These results support PRAME IHC can assist in distinguishing melanocyte populations in melanoma arising within nevi.
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http://dx.doi.org/10.1111/cup.13958DOI Listing
January 2021

Impact of second-opinion dermatopathology reviews on surgical management of malignant neoplasms.

J Am Acad Dermatol 2021 May 13;84(5):1385-1392. Epub 2021 Jan 13.

Department of Dermatology, University of California-San Francisco, San Francisco, California. Electronic address:

Background: Second-opinion review is linked to error reduction and treatment changes in anatomic pathology.

Objective: We sought to establish the rate of diagnostic discrepancy identified by second-opinion dermatopathologic review and the effect on surgical treatment.

Methods: Cases referred for treatment of a malignant neoplasm diagnosed by an outside pathologist were reviewed. The external and internal second-opinion dermatopathologic reports were compared. Discordance in diagnosis, subtype, and treatment change owing to second-opinion review was recorded. The referring pathologist's level of dermatopathologic training was also documented.

Results: A total of 358 cases were included. Dermatopathologic second-opinion diagnosis was discordant with the outside diagnosis in 37 of 358 cases (10.3%). In 32 of 358 cases (8.9%), second-opinion review resulted in a change in treatment, with 28 of 32 (87.5%) of these changes resulting in cancelled surgery. Dermatologists without dermatopathologic fellowship training had the highest rate of discordant diagnoses compared with pathologists and dermatopathologists.

Limitations: This was a retrospective study at a tertiary care facility.

Conclusion: Second-opinion dermatopathologic review is associated with identification of discordant diagnoses and a substantial influence on treatment, with both cancellation of surgery and augmented management. Secondary pathologic review should be considered in high-volume surgical practices.
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http://dx.doi.org/10.1016/j.jaad.2020.12.022DOI Listing
May 2021

Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8 T cells in autoimmunity and cancer.

J Allergy Clin Immunol 2020 Dec 9. Epub 2020 Dec 9.

Department of Dermatology, University of California San Francisco, San Francisco, Calif. Electronic address:

Background: Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8 T cells have been identified as pathogenic drivers.

Objective: Our study focused on comprehensively characterizing the phenotypic variation of CD8 T cells in psoriatic lesions.

Methods: We used single-cell RNA sequencing to compare CD8 T-cell transcriptomic heterogeneity between psoriatic and healthy skin.

Results: We identified 11 transcriptionally diverse CD8 T-cell subsets in psoriatic and healthy skin. Among several inflammatory subsets enriched in psoriatic skin, we observed 2 Tc17 cell subsets that were metabolically divergent, were developmentally related, and expressed CXCL13, which we found to be a biomarker of psoriasis severity and which achieved comparable or greater accuracy than IL17A in a support vector machine classifier of psoriasis and healthy transcriptomes. Despite high coinhibitory receptor expression in the Tc17 cell clusters, a comparison of these cells with melanoma-infiltrating CD8 T cells revealed upregulated cytokine, cytolytic, and metabolic transcriptional activity in the psoriatic cells that differed from an exhaustion program.

Conclusion: Using high-resolution single-cell profiling in tissue, we have uncovered the diverse landscape of CD8 T cells in psoriatic and healthy skin, including 2 nonexhausted Tc17 cell subsets associated with disease severity.
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http://dx.doi.org/10.1016/j.jaci.2020.11.028DOI Listing
December 2020

Positive MITF and NKI/C3 Expression in Cellular Neurothekeoma and Dermatofibroma.

Appl Immunohistochem Mol Morphol 2020 Dec 1. Epub 2020 Dec 1.

Departments of Pathology.

Background: Cellular neurothekeoma (CNT) is a benign mesenchymal tumor with uncertain cellular differentiation. Studies have found evidence of myofibroblastic differentiation and possible relation to dermatofibromas (DFs). As microphthalmia transcription factor (MITF) and NKI/C3 stains are routinely positive in CNT, we compared expression patterns of both markers in CNT and DF to assess their relationship.

Materials And Methods: We assessed cases of CNT (n=25) and DFs (n=35) for histopathologic characteristics and MITF and NKI/C3 expression. Immunostaining results were classified as negative, focally positive (<50%), and diffusely positive (>50%). At least 1 additional melanocytic marker was assessed in each case of CNT.

Results: Both DFs and CNTs showed a female predilection and a wide age range. Immunostaining in CNTs for MITF was positive in the vast majority (focal 68%, diffuse 24%), as was NKI/C3 (focal 72%, diffuse 24%). All DFs were MITF positive (diffuse 74%, focal 26%), and most DFs were NKI/C3 positive (focal 57%, diffuse 3%).

Conclusion: CNT and DF share demographic, histopathologic, and immunohistochemical features, including shared expression of MITF and NKI/C3, especially cellular DF.
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http://dx.doi.org/10.1097/PAI.0000000000000889DOI Listing
December 2020

Single-Cell Profiling Reveals Divergent, Globally Patterned Immune Responses in Murine Skin Inflammation.

iScience 2020 Oct 19;23(10):101582. Epub 2020 Sep 19.

Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.

Inflammatory response heterogeneity has impeded high-resolution dissection of diverse immune cell populations during activation. We characterize mouse cutaneous immune cells by single-cell RNA sequencing, after inducing inflammation using imiquimod and oxazolone dermatitis models. We identify 13 CD45 subpopulations, which broadly represent most functionally characterized immune cell types. Oxazolone pervasively upregulates / expression across T cells and antigen-presenting cells (APCs). Oxazolone also induces / expression in newly infiltrating basophils, and and most prominently in APCs. In contrast, imiquimod broadly upregulates / and /. A comparative analysis of single-cell inflammatory transcriptional responses reveals that APC response to oxazolone is tightly restricted by cell identity, whereas imiquimod enforces shared programs on multiple APC populations in parallel. These global molecular patterns not only contrast immune responses on a systems level but also suggest that the mechanisms of new sources of inflammation can eventually be deduced by comparison to known signatures.
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http://dx.doi.org/10.1016/j.isci.2020.101582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648132PMC
October 2020

Quantitative Assessment of Eosinophils in Dermatomyositis Skin Biopsies With Correlation of Eosinophils to Pruritus and Other Clinical Features.

Am J Dermatopathol 2021 Apr;43(4):287-290

Departments of Dermatology; and.

Abstract: The objective of this retrospective study was to analyze dermatomyositis skin biopsies for the presence of eosinophils and correlate this finding with other histopathologic and clinical characteristics. Cases of dermatomyositis evaluated in a single dermatologist's adult autoimmunity practice over a 2.5-year period were identified via ICD-10 diagnosis code. Dermatopathology archives were then searched for any corresponding biopsies consistent with dermatomyositis, and those identified were assessed for eosinophils, adnexal involvement, epidermal atrophy, dermal mucin, and basement membrane thickening. Histopathologic findings were correlated with key clinical features, including itch. A total of 39 biopsies from 17 patients were included. Eosinophils were noted in 44% of biopsies (n = 17) from 12 patients. Dermal mucin deposition and adnexal interface dermatitis were noted in 72% (n = 28) and 44% (n = 17) of biopsy specimens, respectively. Of 12 patients with eosinophils present in at least 1 biopsy specimen, 11 (92%) patients had a clinical history of pruritus of their skin lesions (P = 0.052). Limitations of this study include retrospective design and small number of patients.
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http://dx.doi.org/10.1097/DAD.0000000000001765DOI Listing
April 2021

Diagnosing Calciphylaxis: A Review With Emphasis on Histopathology.

Am J Dermatopathol 2020 Jul;42(7):471-480

Assistant Professor, Departments of Pathology and Dermatology, University of California, San Francisco, CA.

Calciphylaxis is a cutaneous vasculopathy with high morbidity and mortality characterized by vascular intimal fibrosis, calcification, stenosis, thrombosis, and eventual tissue death due to ischemia. Histopathologic diagnosis is often difficult, frequently necessitating multiple tissues samples due to lack of specific histopathologic features and subtle changes on biopsies of early lesions. In this study, we review the reported clinical and histopathologic features of calciphylaxis, correlating them with relevant imaging, ancillary studies, and pathophysiology. Although many histopathologic changes seen in calciphylaxis are also reported in other conditions (eg, Mönckeberg sclerosis, lupus panniculitis, pancreatic panniculitis, and peripheral artery disease), calcification of subcutaneous small vessels, thrombosis and/or ischemic changes, pseudoxanthoma elasticum-like changes in the subcutis, and perieccrine calcification may serve as helpful clues. von Kossa and Alizarin red stains can assist in the identification of subtle calcification. Netlike calcification of the affected blood vessels on imaging further supports the diagnosis. Studies into the pathophysiology of calciphylaxis are ongoing and will hopefully facilitate the development of additional diagnostic adjuncts to increase sensitivity and specificity for the diagnosis of this disease.
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http://dx.doi.org/10.1097/DAD.0000000000001526DOI Listing
July 2020

Patch-type granuloma annulare: An institution-based study of 23 cases.

J Cutan Pathol 2020 Sep 27;47(9):785-793. Epub 2020 Apr 27.

Department of Dermatology, University of California, San Francisco, California, USA.

Background: Granuloma annulare (GA) is a skin disorder of uncertain etiology. Patch (type) GA is an uncommon variant of GA with a paucity of data characterizing it. We describe the features of 23 cases of patch GA.

Methods: The archives of dermatopathology were searched for cases of patch GA. The clinical history and morphology for each patient were reviewed. Only cases with patch clinical morphology were included. The clinical and histopathologic features were assessed including the pattern of granulomatous inflammation and presence of other inflammatory cell types.

Results: Most patients were female (19/23) with erythematous patches on the trunk and proximal extremities. The most common clinical differential diagnosis included mycosis fungoides (MF), morphea and contact dermatitis. Dyslipidemia was the most common comorbidity (30%), followed by diabetes (15%) and hypertension (15%). Histopathologic features included interstitial lymphocytes and histiocytes with dermal mucin. Two cases showed focal palisaded granulomas. Eosinophils and plasma cells were present in 1/3 of cases.

Conclusion: Patch GA is an uncommon GA variant with an interstitial granulomatous histopathologic pattern that predominantly affects women over 50. It can mimic interstitial MF and early morphea both clinically and histopathologically. Awareness of this GA variant can help prevent misdiagnosis and inappropriate treatment for these patients.
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http://dx.doi.org/10.1111/cup.13707DOI Listing
September 2020

Spitz melanoma is a distinct subset of spitzoid melanoma.

Mod Pathol 2020 06 3;33(6):1122-1134. Epub 2020 Jan 3.

Departments of Pathology and Dermatology, University of California San Francisco, San Francisco, CA, USA.

Melanomas that have histopathologic features that overlap with those of Spitz nevus are referred to as spitzoid melanomas. However, the diagnostic concept is used inconsistently and genomic analyses suggest it is a heterogeneous category. Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations, such as kinase fusions or HRAS mutations. It is unclear what fraction of "spitzoid melanomas" defined solely by their histopathologic features belong to the category of Spitz melanoma or to other melanoma subtypes. We assembled a cohort of 25 spitzoid melanomas diagnosed at a single institution over an 8-year period and performed high-coverage DNA sequencing of 480 cancer related genes. Transcriptome wide RNA sequencing was performed for select cases. Only nine cases (36%) had genetic alterations characteristic of Spitz melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8. The remaining cases were divided into those with an MAPK activating mutation and those without an MAPK activating mutation. Both Spitz melanoma and spitzoid melanomas in which an MAPK-activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid melanomas with non-Spitz MAPK-activating mutations. The MAPK-activating mutations identified affected non-V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1, and KIT, while BRAF V600 mutations, the most common mutations in melanomas of the WHO low-CSD category, were entirely absent. While the "spitzoid melanomas" comprising our cohort were enriched for bona fide Spitz melanomas, the majority of melanomas fell outside of the genetically defined category of Spitz melanomas, indicating that histomorphology is an unreliable predictor of Spitz lineage.
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http://dx.doi.org/10.1038/s41379-019-0445-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286778PMC
June 2020

Clinicopathologic overlap of psoriasis, eczema, and psoriasiform dermatoses: A retrospective study of T helper type 2 and 17 subsets, interleukin 36, and β-defensin 2 in spongiotic psoriasiform dermatitis, sebopsoriasis, and tumor necrosis factor α inhibitor-associated dermatitis.

J Am Acad Dermatol 2020 Feb 16;82(2):430-439. Epub 2019 Dec 16.

Department of Pathology, University of California, San Francisco, CA; Department of Dermatology, University of California, San Francisco, CA; UCSF Dermatopathology Service, University of California, San Francisco, CA. Electronic address:

Background: T helper (Th) type 17 and Th2 cells mediate psoriasis and eczema, respectively. Some dermatoses exhibit overlapping clinicopathologic features, and their immunopathology is relatively unexplored.

Objective: To determine whether Th17 and Th2 subsets and interleukin (IL) 36 and β-defensin 2 (BD-2) markers of IL-17 signaling expression can discriminate between biopsy samples of psoriasis and eczematous/spongiotic dermatitis and to use those markers to immunophenotype cases with clinicopathologic overlap.

Methods: A retrospective study was performed on biopsy samples of psoriasis, eczema/spongiotic dermatitis, sebopsoriasis, tumor necrosis factor α inhibitor-associated psoriasiform dermatitis, and ambiguous cases diagnosed as spongiotic psoriasiform dermatitis. Dual CD4/GATA3 and CD4/RORC, IL-36, and BD-2 immunohistochemistry was performed.

Results: IL-36 and BD-2 were strongly expressed in biopsy samples of psoriasis compared with eczema/spongiotic dermatitis. No significant differences were observed in the percentages of Th2 and Th17 cells between disease types. Strong expression of IL-36 and BD-2 was observed in a subset of spongiotic psoriasiform dermatitis, sebopsoriasis, and tumor necrosis factor α inhibitor-associated psoriasiform dermatitis biopsy samples.

Limitations: This was an exploratory study with a small sample size. No multiple testing adjustment was done. Clinical follow-up was limited.

Conclusions: In cases with clinicopathologic overlap between psoriasis and spongiotic dermatitis, IL-36, and to a lesser extent BD-2, may be used to assess for a psoriasis-like/IL-17 phenotype, which could inform therapeutic clinical decisions.
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http://dx.doi.org/10.1016/j.jaad.2019.08.023DOI Listing
February 2020

Large-cell variant of Merkel cell carcinoma with clear-cell change.

J Cutan Pathol 2020 Jan;47(1):1-5

Department of Dermatology, University of California, San Francisco.

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http://dx.doi.org/10.1111/cup.13583DOI Listing
January 2020

Progressive Hyperpigmented Plaques: Answer.

Am J Dermatopathol 2019 Nov;41(11):862-863

Departments of Dermatology, and.

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http://dx.doi.org/10.1097/DAD.0000000000001239DOI Listing
November 2019

Loss of ZNF750 in ocular and cutaneous sebaceous carcinoma.

J Cutan Pathol 2019 Oct 8;46(10):736-741. Epub 2019 Jul 8.

Department of Dermatology, University of California, San Francisco, San Francisco, California.

Background: Sebaceous carcinoma (SeC) is an uncommon malignancy arising from sebaceous glands of the conjunctiva and skin. Recurrent mutations in the ZNF750 were recently identified in ocular SeC. We assessed whether ZNF750 loss is a specific feature of ocular SeC or a general feature of sebaceous tumors.

Methods: Immunostaining for ZNF750 expression was performed in 54 benign and malignant sebocytic proliferations. Staining for ZNF750 was scored on a three-tier scale: positive (>75%), partially positive (5%-74%), and negative (<5%).

Results: ZNF750 expression was negative in 4/11 ocular SeC, and partially positive in 4/11 ocular SeC and 6/13 cutaneous SeC. No extraocular tumors were negative. No loss was found in sebaceous adenoma or sebaceous hyperplasia. In nine previously sequenced ocular SeCs, two lacked detectable somatic mutations in ZNF750, but showed complete loss of staining, indicating non-mutational inactivation of ZNF750.

Conclusion: We show complete loss of the ZNF750 epidermal differentiation regulator in about half of ocular SeC, highlighting the most common genetic defect in this cancer type. Loss of ZNF750 expression is seen even in tumors without truncating mutations and reduced in many of the remaining ocular and cutaneous SeC. In contrast, no ZNF750 loss was detected in benign sebaceous proliferations.
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http://dx.doi.org/10.1111/cup.13516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744339PMC
October 2019

Preparation, Characterization, and In vitro Evaluation of Curcumin- and Resveratrol-Loaded Solid Lipid Nanoparticles.

AAPS PharmSciTech 2019 Mar 18;20(4):145. Epub 2019 Mar 18.

Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska, USA.

Curcumin and resveratrol are natural compounds with significant anticancer activity; however, their bioavailability is limited due to poor solubility. This study aimed to overcome the solubility problem by means of solid lipid nanoparticles (SLN). 2-Hydroxypropyl β-cyclodextrin (HPβCD) was selected from a range of polymers based on miscibility and molecular interactions. SLNs were obtained by probe sonication and freeze-drying curcumin-resveratrol with/without HPβCD incorporated in gelucire 50/13. SLNs were characterized by dynamic light scattering (DLS), zeta potential, powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and physical stability. The in vitro release of drugs from the SLNs was performed by the direct dispersion method and analyzed using a validated UV-visible method. In vitro efficacy was tested using a colorectal cancer cell line. Curcumin-resveratrol-gelucire 50/13-HPβCD (CRG-CD) and curcumin-resveratrol-gelucire 50/13(CRG) SLNs showed a particle size from 100 to 150 nm and were not in the crystalline state per PXRD results. MDSC results complimented PXRD results by the absence of melting endotherm of curcumin; TGA showed no weight loss, confirming the absence of organic solvent residual, and the shape of the SLNs was confirmed as spherical by SEM. CRG SLNs were stable for 21 days with respect to particle size and zeta potential. MTT assay indicated better IC value for CRG as compared to CRG-CD. Hence, novel SLNs of curcumin and resveratrol incorporated in gelucire 50/13 and HPβCD were prepared and characterized to improve their bioavailability and anticancer activity.
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http://dx.doi.org/10.1208/s12249-019-1349-4DOI Listing
March 2019

Direct Inhibition of MmpL3 by Novel Antitubercular Compounds.

ACS Infect Dis 2019 06 28;5(6):1001-1012. Epub 2019 Mar 28.

Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology , Colorado State University , 1682 Campus Delivery , Fort Collins , Colorado 80523 , United States.

MmpL3, an essential transporter involved in the export of mycolic acids, is the proposed target of a number of antimycobacterial inhibitors under development. Whether MmpL3 serves as the direct target of these compounds, however, has been called into question after the discovery that some of them dissipated the proton motive force from which MmpL transporters derive their energy. Using a combination of in vitro and whole-cell-based approaches, we here provide evidence that five structurally distinct MmpL3 inhibitor series, three of which impact proton motive force in Mycobacterium tuberculosis, directly interact with MmpL3. Medium- to high-throughput assays based on these approaches were developed to facilitate the future screening and optimization of MmpL3 inhibitors. The promiscuity of MmpL3 as a drug target and the mechanisms through which missense mutations located in a transmembrane region of this transporter may confer cross-resistance to a variety of chemical scaffolds are discussed in light of the exquisite vulnerability of MmpL3, its apparent mechanisms of interaction with inhibitors, and evidence of conformational changes induced both by the inhibitors and one of the most commonly identified resistance mutations in MmpL3.
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http://dx.doi.org/10.1021/acsinfecdis.9b00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580365PMC
June 2019

Expression of programmed cell death ligand 1 and programmed cell death 1 in cutaneous warts.

J Am Acad Dermatol 2019 Nov 11;81(5):1127-1133. Epub 2019 Mar 11.

Department of Dermatology, University of California, San Francisco, California; Department of Pathology, University of California, San Francisco, California.

Background: Cutaneous warts have high prevalence and cause significant morbidity. Understanding the mechanisms by which warts evade the immune system could lead to targeted and improved treatments.

Objective: To determine whether cutaneous warts express programmed cell death ligand 1 (PD-L1) and to characterize the expression of programmed cell death 1 (PD-1) within the immune infiltrate of inflamed lesions.

Methods: In total, 44 biopsies of cutaneous warts were retrieved from the Department of Dermatopathology archives of the University of California, San Francisco. Biopsies were stained with hematoxylin and eosin and PD-L1 monoclonal antibody, and biopsies of inflamed lesions were stained with PD-1 monoclonal antibody.

Results: PD-L1 was expressed on keratinocytes in cases of verrucae vulgares (12/30, 40%) and myrmecia (7/14, 50%) and was associated with an interface inflammatory reaction. PD-1 was expressed by the inflammatory infiltrate in verrucae vulgares (21/24, 88%) and myrmecia (5/8, 63%).

Limitations: This was a retrospective observational study conducted at a single institution.

Conclusion: Many cutaneous warts express PD-L1, suggesting that human papillomavirus might use this pathway to promote immune dysfunction. This discovery helps explain the recalcitrance of warts to current therapies and provides a rationale for investigating anti-PD-1 immunotherapy as a potential treatment for warts.
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http://dx.doi.org/10.1016/j.jaad.2019.02.063DOI Listing
November 2019

Targeted Genomic Profiling of Acral Melanoma.

J Natl Cancer Inst 2019 10;111(10):1068-1077

Background: Acral melanoma is a rare type of melanoma that affects world populations irrespective of skin color and has worse survival than other cutaneous melanomas. It has relatively few single nucleotide mutations without the UV signature of cutaneous melanomas, but instead has a genetic landscape characterized by structural rearrangements and amplifications. BRAF mutations are less common than in other cutaneous melanomas, and knowledge about alternative therapeutic targets is incomplete.

Methods: To identify alternative therapeutic targets, we performed targeted deep-sequencing on 122 acral melanomas. We confirmed the loss of the tumor suppressors p16 and NF1 by immunohistochemistry in select cases.

Results: In addition to BRAF (21.3%), NRAS (27.9%), and KIT (11.5%) mutations, we identified a broad array of MAPK pathway activating alterations, including fusions of BRAF (2.5%), NTRK3 (2.5%), ALK (0.8%), and PRKCA (0.8%), which can be targeted by available inhibitors. Inactivation of NF1 occurred in 18 cases (14.8%). Inactivation of the NF1 cooperating factor SPRED1 occurred in eight cases (6.6%) as an alternative mechanism of disrupting the negative regulation of RAS. Amplifications recurrently affected narrow loci containing PAK1 and GAB2 (n = 27, 22.1%), CDK4 (n = 27, 22.1%), CCND1 (n = 24, 19.7%), EP300 (n = 20, 16.4%), YAP1 (n = 15, 12.3%), MDM2 (n = 13, 10.7%), and TERT (n = 13, 10.7%) providing additional and possibly complementary therapeutic targets. Acral melanomas with BRAFV600E mutations harbored fewer genomic amplifications and were more common in patients with European ancestry.

Conclusion: Our findings support a new, molecularly based subclassification of acral melanoma with potential therapeutic implications: BRAFV600E mutant acral melanomas with characteristics similar to nonacral melanomas that could benefit from BRAF inhibitor therapy, and non-BRAFV600E mutant acral melanomas. Acral melanomas without BRAFV600E mutations harbor a broad array of therapeutically relevant alterations. Expanded molecular profiling would increase the detection of potentially targetable alterations for this subtype of acral melanoma.
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http://dx.doi.org/10.1093/jnci/djz005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792090PMC
October 2019

Indole-2-Carboxamides Are Active against in a Mouse Model of Acute Infection.

Antimicrob Agents Chemother 2019 03 26;63(3). Epub 2019 Feb 26.

Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska, USA

Nontuberculous mycobacteria (NTM) pathogens particularly infect patients with structural lung disorders. We previously reported novel indole-2-carboxamides (ICs) that are active against a wide panel of NTM pathogens. This study discloses data for two lead molecules (compounds 5 and 25) that were advanced for efficacy studies in -infected mouse models. Oral administration of the lead molecules showed a statistically significant reduction in the bacterial loads in lung and spleen of -infected mice.
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http://dx.doi.org/10.1128/AAC.02245-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395937PMC
March 2019

Wong-type dermatomyositis during anti-PD-1 therapy.

JAAD Case Rep 2018 Nov 10;4(10):1049-1051. Epub 2018 Nov 10.

Department of Dermatology, University of California, San Francisco, San Francisco, California.

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http://dx.doi.org/10.1016/j.jdcr.2018.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232637PMC
November 2018

Distinguishing histopathologic features of acantholytic dermatoses and the pattern of acantholytic hypergranulosis.

J Cutan Pathol 2019 Jan 5;46(1):6-15. Epub 2018 Nov 5.

Department of Dermatology, University of California San Francisco, San Francisco, California.

Background: Acantholysis can be seen in multiple skin diseases. Adnexal acantholysis has been regarded as a feature distinguishing pemphigus vulgaris (PV) from acantholytic conditions.

Methods: A retrospective review of the histopathologic features of diseases with acantholysis including PV, pemphigus foliaceus (PF), Hailey-Hailey disease (HHD), Darier disease (DD), Grover disease, and pityriasis rubra pilaris (PRP) was performed.

Results: Biopsies of PV (n = 49), HHD (n = 27), DD (n = 25), Grover disease (n = 65), and PRP (n = 33) showed suprabasilar acantholysis. Acantholysis was limited to the lower epidermis in PV and PRP, and involved all epidermal layers in HHD, DD, and Grover disease. Acantholysis in PF (n = 38) mainly involved the upper epidermis. Follicular acantholysis occurred more frequently in PV and PF (P < 0.0001). Eccrine acantholysis was found in PV (42%), HHD (18%), PF (13%), and DD (4%). Grover disease, DD, and HHD had greater dyskeratosis (P < 0.0001). Neutrophils were more common in PV, PF, and HHD, while eosinophils were more common in Grover disease and DD. A pattern termed acantholytic hypergranulosis occurred predominantly in PF.

Conclusion: Adnexal acantholysis does not reliably distinguish PV from PF. The level of acantholysis, degree of dyskeratosis, and acantholytic hypergranulosis are distinguishing features between the two types of pemphigus and other acantholytic disorders.
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http://dx.doi.org/10.1111/cup.13356DOI Listing
January 2019

Progressive Hyperpigmented Plaques: Challenge.

Am J Dermatopathol 2019 Nov;41(11):e134-e135

Departments of Dermatology, and.

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http://dx.doi.org/10.1097/DAD.0000000000001238DOI Listing
November 2019

MmpL3 as a Target for the Treatment of Drug-Resistant Nontuberculous Mycobacterial Infections.

Front Microbiol 2018 10;9:1547. Epub 2018 Jul 10.

Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States.

Nontuberculous mycobacterial (NTM) pulmonary infections are emerging as a global health problem and pose a threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. complex (MAC) and complex (MABSC) species account for 70-95% of the pulmonary NTM infections worldwide. Treatment options for these pathogens are limited, involve lengthy multidrug regimens of 12-18 months with parenteral and oral drugs, and their outcome is often suboptimal. Development of new drugs and improved regimens to treat NTM infections are thus greatly needed. In the last 2 years, the screening of compound libraries against in culture has led to the discovery of a number of different chemotypes that target MmpL3, an essential inner membrane transporter involved in the export of the building blocks of the outer membrane of all mycobacteria known as the mycolic acids. This perspective reflects on the therapeutic potential of MmpL3 in and NTM and the possible reasons underlying the outstanding promiscuity of this target. It further analyzes the physiological and structural factors that may account for the apparent looser structure-activity relationship of some of these compound series against compared to NTM.
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http://dx.doi.org/10.3389/fmicb.2018.01547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048240PMC
July 2018

Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation.

Cancer Cell 2018 07;34(1):56-68.e9

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Dermatology, University of California San Francisco, San Francisco, CA 94115, USA. Electronic address:

Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression. Loss of the CDKN2A protein product p16 permitted metastatic dissemination of human melanoma lines in mice, a phenotype rescued by inhibition of BRN2. These results demonstrate a mechanism by which CDKN2A suppresses the initiation of melanoma invasion through inhibition of BRN2.
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http://dx.doi.org/10.1016/j.ccell.2018.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084788PMC
July 2018

Genomic and Transcriptomic Analysis Reveals Incremental Disruption of Key Signaling Pathways during Melanoma Evolution.

Cancer Cell 2018 07;34(1):45-55.e4

University of California San Francisco, Department of Dermatology, San Francisco, CA, USA; University of California San Francisco, Helen Diller Comprehensive Cancer Center, San Francisco, CA, USA; University of California San Francisco, Department of Pathology, San Francisco, CA, USA. Electronic address:

We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent.
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http://dx.doi.org/10.1016/j.ccell.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319271PMC
July 2018

Cutaneous fibrolipomatous hamartoma: Report of 2 cases with retrocalcaneal location.

Pediatr Dermatol 2018 Jul 15;35(4):498-501. Epub 2018 May 15.

Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.

Precalcaneal congenital fibrolipomatous hamartoma is an underreported benign entity that has been described in the literature under different names. We present two cases of unilateral fibrolipomatous hamartoma (FLH) appearing in a unique location: on the posterior aspect of the foot overlying the heel. We propose the term "FLH of the skin" as a more inclusive and less confusing term for this condition, thus allowing distinction with FLH arising from neural tissue. High-frequency ultrasonography appears to be a useful diagnostic tool that may avoid unnecessary biopsies for this condition.
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http://dx.doi.org/10.1111/pde.13522DOI Listing
July 2018

Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma.

Nat Commun 2018 05 14;9(1):1894. Epub 2018 May 14.

Department of Dermatology, University of California, San Francisco, CA, 94115, USA.

Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.
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http://dx.doi.org/10.1038/s41467-018-04008-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951856PMC
May 2018

Postherpetic isotopic responses with 3 simultaneously occurring reactions following herpes zoster.

Cutis 2018 Mar;101(3):195-197

Department of Dermatology, University of California, San Francisco, USA.

Inflammatory, infectious, and neoplastic processes can all occur in prior areas of herpes infection (postherpetic isotopic response [PHIR]). Postzoster granulomatous dermatitis is among the most frequently encountered PHIR, but the exact pathogenesis has not been fully elucidated. Rarely, multiple diseases manifest concurrently in a PHIR. We report a case of cutaneous chronic lymphocytic leukemia (CLL) with an associated granulomatous dermatitis and medium-vessel vasculitis occurring simultaneously at the site of prior herpes zoster. Clinicians and dermatopathologists should be aware of the multiplicity of postzoster isotopic responses and should consider the possibility of multiple diseases manifesting in the same clinical lesion in this setting.
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March 2018

An enlarging, ulcerated scalp nodule.

JAAD Case Rep 2018 Apr 21;4(3):211-213. Epub 2018 Feb 21.

Department of Dermatology, University of California, San Francisco, San Francisco, California.

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http://dx.doi.org/10.1016/j.jdcr.2017.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842285PMC
April 2018

Midline anterior neck inclusion cyst: A novel superficial congenital developmental anomaly of the neck.

Pediatr Dermatol 2018 Jan 20;35(1):55-58. Epub 2017 Dec 20.

Division of Pediatric Dermatology, Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.

Background/objectives: A variety of congenital developmental anomalies arise on the neck because of the many fusion planes and complex embryologic structures in this region. We describe a series of seven patients with a novel type of superficial midline congenital anomaly.

Methods: Retrospective case series. Clinical and histopathologic features were compared and used to describe this entity.

Results: Seven patients with nearly identical clinical findings were identified. In all cases, a small superficial cyst resembling a giant milium was observed at birth. There were no significant changes during infancy and no evidence of underlying abnormalities. The histopathologic findings were identical to those of an infundibular follicular cyst.

Conclusion: We have termed this entity midline anterior neck inclusion cyst. We believe it is a superficial developmental anomaly, probably a forme fruste of a midline fusion developmental defect, which has not to our knowledge, previously been described.
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http://dx.doi.org/10.1111/pde.13371DOI Listing
January 2018

Merkel cell carcinoma: An update and review: Pathogenesis, diagnosis, and staging.

J Am Acad Dermatol 2018 03 9;78(3):433-442. Epub 2017 Dec 9.

Department of Dermatology, University of California San Francisco, San Francisco, California.

Merkel cell carcinoma (MCC) is an uncommon primary cutaneous neuroendocrine cancer. It most commonly presents as an indurated plaque or nodule on sun-damaged skin in elderly patients and is characterized by high rates of local recurrence and nodal metastasis. Survival at 5 years is 51% for local disease and as low as 14% for distant disease, which underscores the aggressive nature of this tumor and challenges in management. Advances in immunology and molecular genetics have broadened our understanding of the pathophysiology of MCC and expanded our therapeutic arsenal. With this comprehensive review, we provide an update of MCC epidemiology, pathogenesis, clinical presentation, diagnostic evaluation and prognostic markers. The second article in this continuing medical education series explores the evolving landscape in MCC management.
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http://dx.doi.org/10.1016/j.jaad.2017.12.001DOI Listing
March 2018