Correction: Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

[This corrects the article DOI: 10.1371/journal.pone.

Dermal Granuloma Annulare After SARS-CoV-2 Vaccination: A Rare Complication.

Granuloma annulare (GA) is an inflammatory granulomatous skin disease of unknown etiology that is self-limiting in nature. However, it is hypothesized that trauma, medications, malignancy, viral infections, different vaccines, and hypersensitivity reactions can trigger the formation of GA. Only three cases of post-SARS-CoV-2 vaccination-related GA have been reported so far.

Extensive Perineural Invasion vs Nerve Caliber to Assess Cutaneous Squamous Cell Carcinoma Prognosis.

Importance: Perineural invasion (PNI) is an adverse risk feature in cutaneous squamous cell carcinoma (CSCC) that affects patient prognosis and disease management. However, research comparing different PNI patterns on patient outcomes is limited.

Objective: To compare 4 assessments of PNI in CSCC, their associations with poor outcomes, and implications for their inclusion in the Brigham and Women's Hospital (BWH) staging system.

STAG2 regulates interferon signaling in melanoma via enhancer loop reprogramming.

The cohesin complex participates in the organization of 3D genome through generating and maintaining DNA loops. Stromal antigen 2 (STAG2), a core subunit of the cohesin complex, is frequently mutated in various cancers. However, the impact of STAG2 inactivation on 3D genome organization, especially the long-range enhancer-promoter contacts and subsequent gene expression control in cancer, remains poorly understood.

Diagnostic Biopsy via In-Office Frozen Sections for Clinical Nonmelanoma Skin Cancer.

Background: Treatment of nonmelanoma skin cancer (NMSC) by Mohs surgery has traditionally relied on previous pathologic evaluation of paraffin-embedded tissue. Tissue processing by frozen sections allows for expedited diagnosis and treatment; however, data on its accuracy are limited.

Objective: To measure the accuracy and outcomes of biopsy via frozen sections for clinical NMSC.

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma.

Background: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin caused by either the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet-induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. However, it has been challenging to reliably distinguish between virus positive and UV damaged MCC.

Topographical Evaluation of Penile Lichen Sclerosus Reveals a Lymphocytic Depleted Variant, Preferentially Associated With Neoplasia: A Report of 200 Cases.

Since the seminal study of Hart and Helwig in 1975, there are few detailed pathological studies of lichen sclerosus (LS). The aims of this study were to provide a detailed histopathological description of penile LS, as well as to explore its relationship with penile intraepithelial neoplasia (PeIN) or invasive carcinoma. We evaluated 200 patients and designed a topographical approach for the histological evaluation focusing in alterations of the following anatomical layers: squamous epithelium, lamina propria, dartos, and corpus spongiosum.

Continuous Spatial Sequences of Lichen Sclerosus, Penile Intraepithelial Neoplasia, and Invasive Carcinomas: A Study of 109 Cases.

Lichen sclerosus (LSc) with penile cancer is found in about two thirds of specimens. It has been hypothesized that LSc represents a precancerous condition. To qualify as such, in addition to cytological atypia and similarity with the invasive tumor, a spatial correlation between LSc and neoplastic lesions needs to be demonstrated.

Toward Minimal Residual Disease-Directed Therapy in Melanoma.

Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment.

A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma.

: Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/- MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rationale for combining targeted agents with immunotherapy. : Patients with unresectable Stage III or IV BRAF mutant melanoma were enrolled in a single-center prospective study (n = 6).

Lupus and scleroderma overlap features in a 28-year-old man with anti-PL-12 anti-synthetase syndrome.

A 28-year-old man with clinically and laboratory diagnosed anti-PL-12 anti-synthetase syndrome (AS) in 2009 developed cutaneous lupus lesions, discoid lupus lesions, and sclerodacytly with finger-tip ulcerations four years following his AS diagnosis. Laboratory tests including +ANA, +anti-dsDNA antibody, +anti-Smith antibody, and +anti-RNP antibody in 2014 confirmed the diagnosis of progression to an overlap syndrome including systemic lupus erythematosus. The patient now also has clinical findings (sclerodacytly, Raynaud phenomenon, finger-tip ulcerations) consistent with scleroderma overlap.

Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids.

systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture.

Lethal melanoma in children: a clinicopathological study of 12 cases.

Melanoma in children is rare, representing 3% of paediatric malignancies and <1% of all melanomas. Very few detailed descriptions of bona fide lethal childhood melanomas exist in the literature. We performed a retrospective clinicopathological review of 12 paediatric (≤16 years) melanoma patients who died of metastatic disease, including detailed assessment of architectural and cytomorphological features.

Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma.

The protein kinase B-Raf proto-oncogene, serine/threonine kinase (BRAF) is an oncogenic driver and therapeutic target in melanoma. Inhibitors of BRAF (BRAFi) have shown high response rates and extended survival in patients with melanoma who bear tumors that express mutations encoding BRAF proteins mutant at Val600, but a vast majority of these patients develop drug resistance. Here we show that loss of stromal antigen 2 (STAG2) or STAG3, which encode subunits of the cohesin complex, in melanoma cells results in resistance to BRAFi.

Clear Cell Carcinoma of the Penis: An HPV-related Variant of Squamous Cell Carcinoma: A Report of 3 Cases.

Penile clear cell carcinoma originating in skin adnexal glands has been previously reported. Here, we present 3 morphologically distinctive penile tumors with prominent clear cell features originating not in the penile skin but in the mucosal tissues of the glans surface squamous epithelium. Clinical and pathologic features were evaluated.

Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines.

Melanocytic nevi excised during B-Raf proto-oncogene (BRAF) inhibitor therapy: A study of 19 lesions from 10 patients.

Background: There are limited descriptions of histopathology and immune profiles of new or changing melanocytic nevi in the setting of B-Raf proto-oncogene (BRAF) inhibitor therapy.

Objective: We sought to identify their distinctive features.

Methods: Clinical charts and histologic review, neuroblastoma RAS viral (v-ras) oncogene homolog genotyping, and immunohistochemistry for HMB-45, BRAFV600E, phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated protein kinase B, CD4, and CD8 were performed on 19 melanocytic nevi from 10 patients and 23 control nevi.

Use of Photodynamic Therapy and Sterile Water to Target Adipose Tissue.

Background: Neither photodynamic therapy (PDT) nor sterile water has not been well studied for the treatment of adipose tissue.

Objective: This investigation studied 2 different modalities, verteporfin PDT and sterile water, on adipose tissue compared with control.

Materials And Methods: Four light-skinned pigs were used.

Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation.

Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens. Sox10/MITF expression correlated with and contributed to RNF125 transcription.

Loss of BAP1 Expression in Basal Cell Carcinomas in Patients With Germline BAP1 Mutations.

Objectives: Patients with heterozygous germline mutations in BRCA1-associated protein 1 (BAP1), a tumor suppressor gene, develop a tumor predisposition syndrome (OMIM 614327) with increased risk of uveal and cutaneous melanomas, cutaneous atypical and epithelioid melanocytic lesions, lung adenocarcinoma, clear cell renal cell carcinoma, and other tumors. Early recognition of this syndrome is of clinical importance. In addition, screening for BAP1 mutation, loss, and inactivation by performing BAP1 immunohistochemistry on cutaneous lesions would be a simple method for screening patients suspected of having germline BAP1 mutations.

BAP1 and BRAFV600E expression in benign and malignant melanocytic proliferations.

BAP1 (BRCA1-associated protein 1) is a tumor suppressor gene whose mutations have recently been reported to increase susceptibility for the development of uveal melanoma, cutaneous atypical and epithelioid melanocytic lesions, clear cell renal cell carcinoma, and other tumors. Screening for BAP1 mutation/loss/inactivation and BRAFV600E mutation can be done by immunohistochemistry. We investigated BAP1 and BRAFV600E expression in 193 sporadic melanocytic lesions (11 dermal nevi, 20 congenital nevi, 40 primary and nondesmoplastic melanomas, 40 desmoplastic melanomas, 23 metastatic melanomas, 17 Spitz nevi, 19 atypical Spitz nevi, 8 atypical Spitz tumors, 14 proliferative nodules arising in congenital nevi, 1 nevus during pregnancy) and 30 melanocytic lesions from 3 patients with family history of uveal melanoma and BAP1 germline mutation.

Primary mucosal melanoma of the sinonasal tract: a clinicopathologic and immunohistochemical study of thirty-two cases.

Sinonasal mucosal melanoma is a rare disease with poor survival. These tumors may have associated intraepithelial melanocytic proliferations, which are not extensively characterized. This retrospective analysis of 32 patients with sinonasal mucosal melanoma examined associated intraepithelial melanocytic proliferations in the context of diagnostic and prognostic features.