Systemic Therapy for Lichen Sclerosus: A Systematic Review.

BACKGROUND: Lichen sclerosus (LS) is a chronic, inflammatory process affecting predominantly anogenital skin, with extragenital involvement in up to 20% of cases. The mainstay of therapy for anogenital LS is topical immunosuppression. However, in treatment-refractory cases, severe, or hypertrophic disease, systemic modalities may be used. Currently, there are no guidelines for systemic therapy in LS. OBJECTIVE: This study aimed to provide a review of the current literature on use of systemic therapies for LS, including demographic and clinical features of LS, as well as reported outcomes. METHODS: A primary literature search was conducted using the following databases: PubMed, Ovid, Scopus, and Web of Science, from the year the journal was published until June 2022. RESULTS: Ultimately, 71 studies consisting of 392 patients were included. Of these, 65% (n = 254) had anogenital disease, 9% (n = 36) had extragenital disease, and 19% (n = 73) had both anogenital and extragenital disease, and in 7% (n = 29) of cases, location was not specified. The most frequent therapies, stratified by total cases, included oral retinoids (n = 227), methotrexate (n = 59), hydroxychloroquine (n = 36), and systemic steroids (prednisone, methylprednisolone, prednisolone, oral triamcinolone, and other systemic steroids) (n = 60). Overall, 76% (n = 194) of anogenital, 94% (n = 34) of extragenital, and 81% (n = 59) of patients with both anogenital and extragenital involvement were reported to have clinical or symptomatic improvement. CONCLUSION: Overall, we found many therapies that have been used with reported success for extragenital and genital LS. However, future studies are needed to better define treatment outcomes and directly compare efficacy of different therapies for LS.

ZFTA-RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma.

More than 60% of supratentorial ependymomas harbor a ZFTA-RELA (ZRfus) gene fusion (formerly C11orf95-RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with PLAGL family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks. SIGNIFICANCE: Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (ZFTA- and YAP1-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of ZFTA-RELA-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing.This article is highlighted in the In This Issue feature, p. 2113.