Rami Al-Rohil

Myoepithelial neoplasms of the skin and soft tissue are rare and share histopathologic features with their salivary gland counterpart. We present a case of an atypical myoepithelial neoplasm from the back of a 72-year-old female. This lesion harbored an EWSR1::NR4A3 gene fusion, a genetic signature characteristically seen in extraskeletal myxoid chondrosarcoma. To our knowledge, this is a unique case of an atypical cutaneous myoepithelial neoplasm harboring EWSR1::NR4A3 fusion.

Molecular diagnostics, with the subsequent development of novel immunohistochemical markers, continues to advance and expand the field of soft tissue pathology. As such, the ever-evolving molecular diagnostic landscape will continue to shape and refine our understanding and classification of neoplasms. This article reviews the current literature on various tumors of mesenchymal origin, including fibroblastic/fibrohistiocytic, adipocytic, vascular, and tumors of uncertain origin. We aim to give the reader a detailed understanding and pragmatic approach to various new and established immunohistochemical stains in diagnosing these neoplasms and also discuss various pitfalls with significant repercussions.

<jats:p>&lt;p&gt;Supplementary Figure S4: Protein Expression Patterns Did Not Predict KRT-232 Responsiveness in Group III PDX lines Compared to Group II PDX Lines&lt;/p&gt;</jats:p>

<jats:p>&lt;div&gt;AbstractPurpose:&lt;p&gt;Over 60% of patients with melanoma respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on &lt;i&gt;BRAF&lt;/i&gt; mutation status, but no available agents are available for &lt;i&gt;NRAS, NF1, CDKN2A, PTEN&lt;/i&gt;, and &lt;i&gt;TP53&lt;/i&gt; mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to &lt;i&gt;BRAF&lt;/i&gt; or &lt;i&gt;NRAS&lt;/i&gt; mutations, while loss or mutation of &lt;i&gt;CDKN2A&lt;/i&gt; occurs in approximately 40% of melanomas, resulting in unregulated MDM2-mediated ubiquitination and degradation of p53. Here, we investigated the therapeutic efficacy of over-riding MDM2-mediated degradation of p53 in melanoma with an MDM2 inhibitor that interrupts MDM2 ubiquitination of p53, treating tumor-bearing mice with the MDM2 inhibitor alone or combined with MAPK-targeted therapy.&lt;/p&gt;Experimental Design:&lt;p&gt;To characterize the ability of the MDM2 antagonist, KRT-232, to inhibit tumor growth, we established patient-derived xenografts (PDX) from 15 patients with melanoma. Mice were treated with KRT-232 or a combination with BRAF and/or MEK inhibitors. Tumor growth, gene mutation status, as well as protein and protein–phosphoprotein changes, were analyzed.&lt;/p&gt;Results:&lt;p&gt;One-hundred percent of the 15 PDX tumors exhibited significant growth inhibition either in response to KRT-232 alone or in combination with BRAF and/or MEK inhibitors. Only &lt;i&gt;BRAF&lt;sup&gt;V600WT&lt;/sup&gt;&lt;/i&gt; tumors responded to KRT-232 treatment alone while &lt;i&gt;BRAF&lt;sup&gt;V600E/M&lt;/sup&gt;&lt;/i&gt; PDXs exhibited a synergistic response to the combination of KRT-232 and BRAF/MEK inhibitors.&lt;/p&gt;Conclusions:&lt;p&gt;KRT-232 is an effective therapy for the treatment of either &lt;i&gt;BRAF&lt;sup&gt;WT&lt;/sup&gt;&lt;/i&gt; or PAN&lt;sup&gt;&lt;i&gt;WT&lt;/i&gt;&lt;/sup&gt; &lt;i&gt;(BRAF&lt;sup&gt;WT&lt;/sup&gt;, NRAS&lt;sup&gt;WT&lt;/sup&gt;) TP53&lt;sup&gt;WT&lt;/sup&gt;&lt;/i&gt; melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may be an effective treatment strategy for BRAF&lt;sup&gt;V600&lt;/sup&gt;-mutant tumors.&lt;/p&gt;&lt;/div&gt;</jats:p>