This study shows that the microenvironment and probably the phenotype of neoplastic T cells of early-stage mycosis fungoides (MF) samples from patients with MF who suffered progression or remained stable are different. Moreover, we propose that the overexpression of CD30, CXCL13 and BIRC3 in early-stage MF is related to progression. Further spatial transcriptomic studies or single-cell analysis in further case series are needed to corroborate our findings.

Taqman probes used for quantitative PCR.

Cancer remains one of the most significant global health challenges due to its high mortality rates and the limited understanding of its progression. Early diagnosis is critical to improving patient outcomes, especially in skin cancer, where timely detection can significantly enhance recovery rates. Histopathological analysis is a widely used diagnostic method, but it is a time-consuming process that heavily depends on the expertise of highly trained specialists. Recent advances in Artificial Intelligence have shown promising results in image classification, highlighting its potential as a supportive tool for medical diagnosis. In this study, we explore the application of hybrid Artificial Intelligence models for melanoma diagnosis using histopathological images. The dataset used consisted of 506 histopathological images, from which 313 curated images were selected after quality control and preprocessing. We propose a two-step framework that employs an Autoencoder for dimensionality reduction and feature extraction of the images, followed by a classification algorithm to distinguish between melanoma and nevus, trained on the extracted feature vectors from the bottleneck of the Autoencoder. We evaluated Support Vector Machines, Random Forest, Multilayer Perceptron, and K-Nearest Neighbours as classifiers. Among these, the combinations of Autoencoder with K-Nearest Neighbours achieved the best performance and inference time, reaching an average accuracy of approximately 97.95% on the test set and requiring 3.44 min per diagnosis. The baseline comparison results were consistent, demonstrating strong generalisation and outperforming the other models by 2 to 13 percentage points.

Dual inhibition of ENG and MEK efficiently blocks ENG-Smad1/5 and MAPK/ERK pathway activation in ST88-14 cells.

Dual inhibition of ENG and MEK efficiently blocks ENG-Smad1/5 and MAPK/ERK pathway activation in ST88-14 cells.

ENG knockdown does not affect MPNST cell apoptosis in vivo.

Significant deregulated genes in shENG versus shScramble STS26T cells.

Background and Objective: subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma with indolent behavior, mostly present in women and associated with immunological diseases whose pathogenic background is still poorly understood. SPTCL is associated with lupus erythematosus panniculitis (LEP) and histologically misdiagnosed.Objectives: the aim of our study was to identify mutations affecting the pathogenesis of both SPTCL and LEP.Materials and Methods: we studied a total of 10 SPTCL and 10 LEP patients using targeted Next Generation Sequencing and pyrosequencing. Differences in gene expression between molecular subgroups were investigated using NanoString technology. Clinical data were collected, and correlations sought with the molecular data obtained.Results: the mutational profile of SPTCL and LEP is different. We identified fewer pathogenic mutations than previously reported in SPTCL, noting a single HAVCR2-mutated SPTCL case. Interestingly, 40% of our SPTCL cases showed the pathogenic TP53 (p.Pro72Arg) (P72R) variant. Although cases showing HAVCR2 mutations or the TP53 (P72R) variant had more severe symptomatic disease, none developed hemophagocytic syndrome (HPS). Furthermore, TP53 (P72R)-positive cases were characterized by a lower metabolic signaling pathway and higher levels of CD28 expression and Treg signaling genes. In addition, 30% of our cases featured the same mutation (T735C) of the epigenetic modificatory gene DNMT3A. None of the LEP cases showed mutations in any of the studied genes.Conclusions: the mutational landscape of SPTCL is broader than previously anticipated. We describe, for the first time, the involvement of the TP53 (P72R) pathogenic variant in this subgroup of tumors, consider the possible role of different genetic backgrounds in the development of SPTCL, and conclude that LEP does not follow the same pathogenic pathway as SPTCL.

Analysis of ENG expression and plasma circulating sEVs in human PNSTs.

Combined anti-ENG/anti-MEK therapy inhibits MPNST growth without toxicity in vivo.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 12% survival rate, highlighting the need for novel therapies. c-MYC overexpression, driven by upstream mutations and amplifications, reprograms tumor metabolism and promotes proliferation, migration and metastasis. This study identifies ELOVL6, a fatty acid elongase regulated by c-MYC, as a potential therapeutic target. Using PDAC mouse models and cell lines, we show that c-MYC directly upregulates ELOVL6 during tumor progression. Genetic or chemical inhibition of ELOVL6 reduces proliferation and migration by altering fatty acid composition, affecting membrane rigidity, permeability and pinocytosis. These changes increase Abraxane uptake and show a synergistic effect when combined with ELOVL6 inhibition in vitro. In vivo, ELOVL6 interference significantly suppresses tumor growth and improves Abraxane response, prolonging survival. These findings position ELOVL6 as a promising target for improving PDAC treatment outcomes.

Anti-ENG therapy is active against MPNST xenografts.

ENG knockdown leads to downregulation of pro-angiogenic and pro-metastatic gene signatures in MPNST cells.

BACKGROUND:Lichen planopilaris (LPP) and folliculitis decalvans (FD) are two of the most common types of primary scarring alopecia. Several Janus kinase inhibitors (JAKis) have been used effectively in their treatment. We conducted an immunohistochemical (IHC) study to evaluate whether any member of the JAK family was overexpressed in the primary inflammatory infiltrate of FD and LPP. Additionally, we performed an exploratory retrospective study on the efficacy and safety of oral JAKis in LPP. METHODS:Pathology scalp samples from seven healthy controls and 28 patients with LPP or FD were selected for staining with anti-JAK1, anti-JAK2, anti-JAK3, and anti-TYK2 antibodies. Cases and controls were compared using the H-score of the inflammatory cells. On the other hand, an exploratory retrospective clinical study was conducted in which patients with LPP who were treated with JAKis for at least three months were included. Clinical characteristics, severity scores, and the presence of adverse events were collected. RESULTS:The IHC study determined that JAK1 and JAK2 exhibited similar expression patterns in cases and controls. However, JAK3 and TYK2 were expressed solely in cases of primary scarring alopecia and were negative in the controls. In the exploratory clinical study, 19 patients with LPP were treated with JAKis. Severity scores improved in follow-up visits, with adverse events generally being mild. CONCLUSIONS:JAK3 and TYK2 were overexpressed in LPP and FD samples compared to healthy controls, supporting JAKs as potential pharmacological targets of interest. JAKis could be an effective and safe treatment for LPP patients.

INTRODUCTION AND AIM:Non-small cell lung cancer (NSCLC) can arise from insertions in exon 20 of the EGFR gene, among other alterations. We carried out an external quality assessment (EQA) to evaluate the accuracy of laboratory methods and to highlight the importance of detecting and identifying genetic alterations, such as EGFR exon 20 insertion, in patients with NSCLC. MATERIALS AND METHODS:The 2021 EGRF exon 20 EQA program consisted of two rounds, in which four formalin-fixed paraffin-embedded specimens (round 1: two positive for EGFR exon 20 insertions/duplications, one positive for a common EGFR alteration, and one wild-type; round 2: three positive for EGFR exon 20 insertions/duplications and one wild-type) obtained from patients with NSCLC were tested. RESULTS:Approximately 80% of the invited laboratories participated in each round. The most common DNA isolation techniques used were the cobas® DNA Sample Preparation Kit (46.7%) in round 1 and QIAamp (37.1%) in round 2. The most frequently used genotyping method in both rounds was the cobas® EGFR Mutation Test (round 1: 53.3%; round 2: 37.1%). In both rounds, 71.1% and 73.6% of the tests, respectively, reported the expected result. The lowest success rate was observed in the H773delinsRY Exon 20 determination (round 1: 17.8%; round 2: 31.4%). This alteration was correctly determined only by next-generation sequencing. CONCLUSIONS:The variability in the genotyping methods and the success rate obtained in our study highlight the importance of EQA in Spain to ensure high performance.

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required ex vivo TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRβ repertoire in non-small cell lung cancer (NSCLC) tumors and in ex vivo expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TILSTAb) and tested their antitumor efficacy in vitro and in vivo using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into hIL-2 NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TILSTAb both in vitro and in vivo when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR+ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4+ TIL bearing non-tumor dominant clonotypes.

Mycosis fungoides (MF) has been widely reported to mimick a considerable number of different dermatoses, including scarring alopecia, bullous dermatoses or cysts, and comedones. In atypical presentations, histopathology is essential for the diagnosis. We present two cases of MF with clinical urticarial lesions and a striking blood involvement that responded to mogamulizumab treatment. Histopathologically, both cases had classic MF features and shared a peculiar immunophenotype, with positivity for CD25 and FOXP3. Differential diagnoses included urticarial lymphomatoid drug reactions and other lymphomas, like T-cell prolymphocytic leukemia, atypical Sézary syndrome, or adult T-cell lymphocytic leukemia. A low suspicion threshold is necessary for the diagnosis of atypical presentations of MF.

Este es el segundo artículo de una serie de dos publicados en esta revista, en los que examinamos las características histopatológicas, así como el diagnóstico diferencial, de las principales entidades que se presentan en forma de estructuras quísticas y pseudoquísticas en la biopsia cutánea. En este segundo artículo, abordamos los quistes cutáneo ciliado, branquial, de Bartholino, onfalomesentérico, tímico, del conducto tirogloso, sinovial, y del rafe medio, así como el mucocele, el ganglión y los pseudoquistes auricular y mixoide digital.

This is the second article in a two-part series published in this journal, in which we examine the histopathological characteristics, as well as the differential diagnosis, of the main entities that present as cystic and pseudocystic structures in cutaneous biopsy. In this second article, we address ciliated cutaneous cysts, branchial cysts, Bartholin's cysts, omphalomesenteric cysts, thymic cysts, thyroglossal duct cysts, synovial cysts, and median raphe cysts, as well as mucocele, ganglion, and auricular and digital myxoid pseudocysts.