Multiomics identifies tumor-intrinsic SREBP1 driving immune exclusion in hepatocellular carcinoma.

Immune checkpoint inhibitors (ICI) have improved patient outcomes in hepatocellular carcinoma (HCC); however, most patients do not experience durable benefit. The non-T cell-inflamed tumor microenvironment, characterized by limited CD8 T-cell infiltration, reduced dendritic cell function, and low interferon-γ-associated gene expression, is associated with a lower likelihood of response to ICI. To nominate new therapeutic targets for overcoming ICI resistance in HCC, we conducted a large-scale multiomic analysis on 900+human specimens (RNA sequencing (RNA-seq), proteomics) and 31 tumor single-cell (sc) RNA-seq samples, with tissue validation through imaging mass cytometry (IMC) and spatial lipidomics by matrix-assisted laser desorption/ionization (MALDI), with experimental investigation by in vitro CD8 T-cell recruitment and macrophage polarization functional assays using three-dimensional (3D) co-culture models.

NTRK Fusions in Xanthogranuloma, a Clinicopathologic and Molecular Analysis of 23 Cases.

Xanthogranuloma is the most common category of histiocytic neoplasia, with a range of clinical behaviors from solitary cutaneous lesions to multiple cutaneous lesions and less frequent cases with evolution to disseminated disease. Solitary lesions make up 78% to 81% of total cases. We encountered 2 consecutive index patients with solitary cutaneous xanthogranuloma with NTRK overexpression by immunostaining and confirmed the presence of an NTRK1 fusion with both RNA and DNA sequencing.

Genomic and Transcriptomic Characterization of Protein Kinase C Fusion Melanocytic Neoplasms With Distinctive Hypopigmented Histomorphology: A Single-Institution Study.

Background: Genomic fusions involving Protein Kinase C (PKC or PRKC) have been classically identified in a subset of melanocytic neoplasms with heavy melanin pigmentation as described in older series. They were recently reclassified from the pigmented epithelioid melanocytoma (PEM) category to the blue nevus (BN) category in the fifth edition of the World Health Organization (WHO) Classification of Skin Tumors.

Methods: Herein, we report a series of eight mostly hypopigmented PRKC fusion melanocytic tumors with novel comprehensive molecular characterization.

Cutaneous Hemangioma With Epithelioid Features Harboring TPM3/4::ALK Fusions : A Distinct Entity or a Molecular Variant of Epithelioid Hemangioma?

Vascular neoplasms with epithelioid cytomorphology encompass a wide spectrum of benign and malignant lesions, including epithelioid hemangioma (EH), cutaneous epithelioid angiomatous nodule (CEAN), epithelioid hemangioendothelioma (EHE), and epithelioid angiosarcoma (EAS). Recently, the first case of a cutaneous hemangioma with epithelioid features harboring a TPM3::ALK fusion was reported. Herein, we report 4 additional cases, including 1 case with an alternate TPM4::ALK fusion, and expand on the clinicopathologic and molecular genetic features of these unusual vascular lesions.

Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas.

Background: While the prognostic role of tertiary lymphoid structures (TLS) has been well studied in solid cancers, the prevalence and impact of immature precursor lymphoid structures known as lymphoid aggregates (LA) remain unresolved in relation to the disease process. In this study, we examined characteristics and the prognostic utility of LA and TLS status in histological samples from patients with melanoma.

Methods: We assessed The Cancer Genomic Atlas-skin cutaneous melanoma digital slides and melanoma specimens from the University of Pittsburgh for the presence of LA and TLS using H&E staining, multiplex immunofluorescence (mIF) and transcriptomic analyses.

Use of Albumin In Situ Hybridization to Diagnose Cutaneous Metastatic Hepatocellular Carcinoma With Poorly Differentiated Features: A Case Report and Review of the Literature.

Hepatocellular carcinoma (HCC) rarely metastasizes to the skin. When it occurs, it is often poorly differentiated making the diagnosis challenging. There exists a male predominance, and clinical presentation usually includes papules or nodules resembling pyogenic granulomas or dermal deposits.

Histopathologic, genomic, transcriptomic, and functional characteristics of eight melanocytic tumors with BRAF fusions showing stronger MAPK pathway activation compared to BRAF V600E tumors.

Background: Activating BRAF gene alterations are central to melanocytic tumor pathogenesis. A small, emerging subset of melanocytic tumors driven by BRAF fusions has distinct therapeutic implications and has been described to have Spitzoid morphology patterns. However, such morphological patterns do not encompass all cases, and little is known about the functional molecular events.

Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma.

Acral melanoma (AM) has distinct characteristics as compared with cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICIs). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging.

Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma.

Background: Acral melanoma (AM) has distinct characteristics as compared to cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICI). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM.

Methods: We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging.

Tumor cell p38 inhibition to overcome immunotherapy resistance.

Patients with tumors that do not respond to immune-checkpoint inhibition often harbor a non-T cell-inflamed tumor microenvironment, characterized by the absence of IFN-γ-associated CD8 T cell and dendritic cell activation. Understanding the molecular mechanisms underlying immune exclusion in non-responding patients may enable the development of novel combination therapies. p38 MAPK is a known regulator of dendritic and myeloid cells however a tumor-intrinsic immunomodulatory role has not been previously described.

Expression of lymphoid structure-associated cytokine/chemokine gene transcripts in tumor and protein in serum are prognostic of melanoma patient outcomes.

Background: Proinflammatory chemokines/cytokines support development and maturation of tertiary lymphoid structures (TLS) within the tumor microenvironment (TME). In the current study, we sought to investigate the prognostic value of TLS-associated chemokines/cytokines (TLS-kines) expression levels in melanoma patients by performing serum protein and tissue transcriptomic analyses, and to then correlate these data with patients clinicopathological and TME characteristics.

Methods: Levels of TLS-kines in patients' sera were quantitated using a custom Luminex Multiplex Assay.

Sentinel Lymph Node Gene Expression Signature Predicts Recurrence-Free Survival in Cutaneous Melanoma.

We sought to develop a sentinel lymph node gene expression signature score predictive of disease recurrence in patients with cutaneous melanoma. Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips.

Poorer survival outcomes in patients with multiple versus single primary melanoma.

Background: Given equivocal results related to overall survival (OS) for patients with multiple primary melanomas (MPMs) compared with those with single primary melanomas (SPMs) in previous reports, the authors sought to determine whether OS differs between these 2 cohorts in their center using their UPCI-96-99 database. Secondary aims were to assess the differences in recurrence-free survival (RFS). In a subset of patients, transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) was performed to assess disease-associated genes of interest.

Neutrophils in Fixed Drug Eruptions: Correction of a Mistaken Hypothesis.

Classical histopathological findings of fixed drug eruption (FDE) include a lichenoid/interface dermatitis and perivascular infiltrate in the upper and deep dermis composed of lymphocytes and eosinophils accompanied by pigment incontinence. The presence of neutrophils is also an established finding but is less investigated. Sporadic cases of "neutrophilic FDE" have been reported and suggested as a separate entity, a rare variant, or an early stage of the condition.

Aptima HPV messenger RNA testing and histopathologic follow-up in women with HSIL cytology: A study emphasizing additional review of HPV-negative cases.

Background: High-risk human papillomavirus (hrHPV) messenger RNA (mRNA) testing, the Food and Drug Administration-approved testing platform since 2013, has been increasing as a cervical screening alternative to hrHPV DNA testing methods. This study reports the largest routine clinical follow-up study reported to date of hrHPV mRNA cotesting and histopathologic follow-up results for women with high-grade squamous intraepithelial lesion (HSIL) cytology results.

Methods: HSIL Papanicolaou test results for women cotested with Aptima hrHPV mRNA testing between June 2015 and November 2020 were analyzed along with recorded histopathologic follow-up results within 6 months of screening.

GBM-Targeted oHSV Armed with Matrix Metalloproteinase 9 Enhances Anti-tumor Activity and Animal Survival.

The use of mutant strains of oncolytic herpes simplex virus (oHSV) in early-phase human clinical trials for the treatment of glioblastoma multiforme (GBM) has proven safe, but limited efficacy suggests that more potent vector designs are required for effective GBM therapy. Inadequate vector performance may derive from poor intratumoral vector replication and limited spread to uninfected cells. Vector replication may be impaired by mutagenesis strategies to achieve vector safety, and intratumoral virus spread may be hampered by vector entrapment in the tumor-specific extracellular matrix (ECM) that in GBM is composed primarily of type IV collagen.

Congenital Epidermoid Cyst of the Liver: A Rare Entity Characterized by Antenatal Onset, Slow Postnatal Growth, and Consistent Histologic and Immunohistologic Features.

Background: There are only 15 reported hepatic epidermoid cysts; they include patients presenting congenitally through adulthood, with varied speculations about pathogenesis. Aside from recently reported pancytokeratin staining, no other descriptions have included immunohistochemistry. Splenic epidermoid cysts were recently characterized as positive for HBME-1, p63, CEA, CK7 (luminal), and CK19.

Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV.

Glioblastoma multiforme (GBM) is an aggressive brain cancer for which there is no effective treatment. Oncolytic HSV vectors (oHSVs) are attenuated lytic viruses that have shown promise in the treatment of human GBM models in animals, but their efficacy in early phase patient trials has been limited. Instead of attenuating the virus with mutations in virulence genes, we engineered four copies of the recognition sequence for miR-124 into the 3'UTR of the essential ICP4 gene to protect healthy tissue against lytic virus replication; miR-124 is expressed in neurons but not in glioblastoma cells.