Laboratory Investigation最新文献

{"title":"The Molecular Landscape of 227 Adult Granulosa Cell Tumors of the Ovary: Insights into the Progression from Primary to Recurrence","authors":"Romana Michálková ,&nbsp;Adam Šafanda ,&nbsp;Nikola Hájková ,&nbsp;Jan Hojný ,&nbsp;Eva Krkavcová ,&nbsp;Michaela Kendall Bártů ,&nbsp;Marián Švajdler ,&nbsp;Tetiana Shatokhina ,&nbsp;Jan Laco ,&nbsp;Radoslav Matěj ,&nbsp;Gábor Méhes ,&nbsp;Jitka Hausnerová ,&nbsp;Jozef Škarda ,&nbsp;Mária Hácová ,&nbsp;Monika Náležinská ,&nbsp;Tomáš Zima ,&nbsp;Pavel Dundr ,&nbsp;Kristýna Němejcová","doi":"10.1016/j.labinv.2024.102201","DOIUrl":"10.1016/j.labinv.2024.102201","url":null,"abstract":"<div><div>Adult granulosa cell tumors (AGCTs) of the ovary are characterized by their propensity for late recurrences and are primarily managed surgically due to the limited efficacy of systemic treatment. The <em>FOXL2</em> p.C134W somatic mutation has been identified in ∼95% of AGCT cases, and <em>TERT</em> promoter alterations have been linked to worse overall survival. This study highlights the potential prognostic significance of <em>FOXO1</em> mutations, suggesting that they may be associated with poorer overall survival and shorter time to recurrence. A total of 183 primary AGCTs and 44 recurrences without corresponding primary tumors were analyzed. The primary AGCTs were categorized into 3 groups: 77 nonrecurrent tumors, 18 tumors that later recurred (including 9 cases with matched primary-recurrence pairs), and 88 tumors with unknown recurrence status. Targeted next-generation sequencing was conducted on 786 cancer-related genes to investigate their genetic profile. The study aimed to identify the molecular alterations associated with AGCT pathogenesis and recurrence rate, comparing primary versus recurrent tumors, and primary recurrent versus primary nonrecurrent cases.</div><div>Our findings confirmed the high prevalence (99%) of the <em>FOXL2</em> p.C134W mutation in AGCTs. Secondary truncating <em>FOXL2</em> mutations were observed in 5% of cases. Two cases with typical AGCT morphology were <em>FOXL2</em> wild-type, harboring mutations in <em>KRAS</em> or <em>KMT2D</em> instead, suggesting alternative genetic pathways. <em>TERT</em> promoter mutations were found in 43% of cases, more frequently in recurrences. Other recurrent mutations detected in the cohort included <em>KMT2D</em> (10%), <em>FOXO1</em> (7%), <em>CHEK2</em> (5%), <em>TP53</em> (3.5%), <em>PIK3CA</em> (3.5%), and <em>AKT1</em> (3%). Two recurrent, <em>FOXL2</em>-mutated cases also carried <em>DICER1</em> mutations. One tumor exhibited MSI-high status and a tumor mutation burden of 19 mut/Mb.Our results indicate the need for further investigation into the role of <em>FOXO1</em> as a potential prognostic marker in AGCTs.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 3","pages":"Article 102201"},"PeriodicalIF":5.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NKX3.1 Helps Distinguish Hyalinizing Clear Cell Carcinoma From Other Clear Cell Salivary Gland Neoplasms","authors":"Airi Sakyo ,&nbsp;Eijitsu Ryo ,&nbsp;Shogo Nishino ,&nbsp;Kenya Kobayashi ,&nbsp;Seiichi Yoshimoto ,&nbsp;Go Omura ,&nbsp;Chihiro Fushimi ,&nbsp;Toshihiko Sakai ,&nbsp;Azusa Sakai ,&nbsp;Kohtaro Eguchi ,&nbsp;Hideaki Takahashi ,&nbsp;Kazuki Yokoyama ,&nbsp;Yoshitaka Honma ,&nbsp;Akiko Mori ,&nbsp;Hiroko Kato ,&nbsp;Toshiyuki Hatano ,&nbsp;Akihiko Yoshida ,&nbsp;Fumihiko Matsumoto ,&nbsp;Yasushi Yatabe ,&nbsp;Taisuke Mori","doi":"10.1016/j.labinv.2024.102205","DOIUrl":"10.1016/j.labinv.2024.102205","url":null,"abstract":"<div><div>Hyalinized clear cell carcinoma (HCCC) is a rare tumor of the minor salivary gland, characterized by pale cytoplasm and EWSR1::ATF1 fusion. Recently, new fusions, such as EWSR1::LARP4 and SMARCA2::CREM, have also been identified. Histologically, HCCC closely resembles other salivary gland tumors like mucoepidermoid carcinoma and myoepithelial carcinoma, and there are no specific immunohistological markers for its identification. In this study, we investigated potential markers for HCCC based on the characteristics of minor salivary gland acini, from which these tumors may originate. SOX10 is a known marker for serous gland clusters and NKX3.1 for mucus gland clusters. Fluorescence intensity analysis of double staining, objectively evaluated by artificial intelligence, revealed variations in the positive intensity of cells single positive for NKX3.1 and SOX10, as well as cells positive for both markers, which are commonly observed in normal minor salivary glands. We evaluated NKX3.1 expression by immunohistochemistry in 12 HCCC cases (including 9 EWSR1::ATF1, 1 EWSR1::LARP4, and 1 SMARCA2::CREM), 12 myoepithelial carcinoma cases, and tissue microarray containing 88 cases of multiple salivary gland tumors using immunohistochemistry. NKX3.1 was expressed in all 12 HCCC cases (100%), with NKX3.1-positive cells ≧90% in 3 cases, ≧60% 1 case, ≧30% 4 cases, and &lt;30% 4 cases, respectively. SOX10 was negative in 10 cases and weakly positive in 2 cases. This finding mimics the pattern of expression in minor salivary glands and may explain the occurrence of weak NKX3.1 staining and SOX10-positive cases in HCCC. Additionally, in the tissue microarray analysis, NKX3.1 staining was observed in only 1 HCCC case. These findings indicate that NKX3.1 is a useful marker for distinguishing HCCC from other clear cell salivary gland neoplasms. This study suggests that NKX3.1, along with SOX10 and CK7, can be utilized to improve the accuracy of HCCC diagnosis.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 3","pages":"Article 102205"},"PeriodicalIF":5.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Annotation Practices in Computational Pathology: A European Society of Digital and Integrative Pathology (ESDIP) Survey Study","authors":"Diana Montezuma ,&nbsp;Sara P. Oliveira ,&nbsp;Yuri Tolkach ,&nbsp;Peter Boor ,&nbsp;Alex Haragan ,&nbsp;Rita Carvalho ,&nbsp;Vincenzo Della Mea ,&nbsp;Tim-Rasmus Kiehl ,&nbsp;Sabine Leh ,&nbsp;Mustafa Yousif ,&nbsp;David Ameisen ,&nbsp;Mircea-Sebastian Șerbănescu ,&nbsp;Norman Zerbe ,&nbsp;Vincenzo L’Imperio","doi":"10.1016/j.labinv.2024.102203","DOIUrl":"10.1016/j.labinv.2024.102203","url":null,"abstract":"<div><div>Integrating digital pathology and artificial intelligence (AI) algorithms can potentially improve diagnostic practice and precision medicine. Developing reliable, generalizable, and comparable AI algorithms depends on access to meticulously annotated data. However, achieving this requires robust collaboration among pathologists, computer scientists, and other researchers to ensure data quality and consistency. The lack of standardization and scalability is a significant challenge when generating annotations and annotated data sets. Recognizing these limitations, the Scientific Committee of the European Society of Digital and Integrative Pathology (ESDIP) performed a comprehensive international survey to understand the current state of annotation practices and identify actionable areas to address critical needs in the annotation process. The analysis and summary of the survey results provide several insights for all stakeholders involved in data preparation and ground truthing, ultimately contributing to the advancement of AI in computational pathology.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 3","pages":"Article 102203"},"PeriodicalIF":5.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive RNA Sequencing Analysis Identifies Network Hub Genes and Biomarkers Differentiating Desmoid-type Fibromatosis From Reactive Fibrosis","authors":"Eunjin Jeong ,&nbsp;Jamin Ku ,&nbsp;Ji Min Na ,&nbsp;Wonkyung Kim ,&nbsp;Chang Ohk Sung ,&nbsp;Seok-Hyung Kim","doi":"10.1016/j.labinv.2024.102204","DOIUrl":"10.1016/j.labinv.2024.102204","url":null,"abstract":"<div><div>Desmoid-type fibromatosis (DTF) is a benign but locally aggressive neoplasm characterized by persistent fibroblast activation, unlike reactive fibrosis (RF), where fibroblast activation is transient. Although the Wnt/β-catenin signaling pathway is known to play a role in DTF pathogenesis, the specific genetic drivers contributing to this abnormal fibroblast activation are not fully understood. To identify additional driver genes that underlie the persistent activation of fibroblasts in DTF, we conducted a comparative transcriptome analysis between 29 DTF and 14 RF tissue samples, identifying 4267 differentially expressed genes (DEGs) specific to DTF. These DTF-specific DEGs were significantly associated with pathways involved in embryonic limb morphogenesis and muscle contraction, whereas RF-specific DEGs were linked to immune response and apoptosis. Using weighted gene coexpression network analysis to further elucidate the key regulatory circuits associated with persistent activation of DTF fibroblasts, we identified a highly DTF-specific gene module comprising 120 genes. This module was also significantly enriched in other fibroproliferative conditions showing persistent fibroblast activation, such as keloid disease and idiopathic pulmonary fibrosis. Subsequent analyses identified 7 driver transcription factors (<em>ZNF536, IRX5, TWIST2, NKD2, PAX9, SHOX2,</em> and <em>SALL4</em>) within this DTF-specific module that may contribute to the sustained activation of DTF fibroblasts. We further assessed the utility of 5 key genes from this module (TWIST2, LRRC15, CTHRC1, SHOX2, and SALL4) as potential biomarkers to distinguish DTF from RF using immunohistochemistry. All markers demonstrated excellent diagnostic performance, with TWIST2 showing exceptionally high sensitivity and specificity, surpassing β-catenin, the current standard biomarker for DTF. In conclusion, our study identifies gene modules and driver transcription factors that are highly specific to DTF, offering new insights into the genetic underpinnings of abnormal fibroblast activation in DTF. We also propose novel biomarkers that could improve the diagnostic accuracy and clinical management of DTF.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 3","pages":"Article 102204"},"PeriodicalIF":5.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lymph Node Metastasis Prediction From In Situ Lung Squamous Cell Carcinoma Histopathology Images Using Deep Learning","authors":"Lu Xia ,&nbsp;Tao Xu ,&nbsp;Yongsheng Zheng ,&nbsp;Baohua Li ,&nbsp;Yongfang Ao ,&nbsp;Xun Li ,&nbsp;Weijing Wu ,&nbsp;Jiabian Lian","doi":"10.1016/j.labinv.2024.102187","DOIUrl":"10.1016/j.labinv.2024.102187","url":null,"abstract":"<div><div>Lung squamous cell carcinoma (LUSC), a subtype of non–small cell lung cancer, represents a significant portion of lung cancer cases with distinct histologic patterns impacting prognosis and treatment. The current pathological assessment methods face limitations such as interobserver variability, necessitating more reliable techniques. This study seeks to predict lymph node metastasis in LUSC using deep learning models applied to histopathology images of primary tumors, offering a more accurate and objective method for diagnosis and prognosis. Whole slide images (WSIs) from the Outdo-LUSC and the cancer genome atlas cohorts were used to train and validate deep learning models. Multiinstance learning was applied, with patch-level predictions aggregated into WSI-level outcomes. The study employed the ResNet-18 network, transfer learning, and rigorous data preprocessing. To represent WSI features, innovative techniques like patch likelihood histogram and bag of words were used, followed by training of machine learning classifiers, including the ExtraTrees algorithm. The diagnostic model for lymph node metastasis showed strong performance, particularly using the ExtraTrees algorithm, as demonstrated by receiver operating characteristic curves and gradient-weighted class activation mapping visualizations. The signature generated by the ExtraTrees algorithm, named lymph node status-related in situ LUSC histopathology (LN_ISLUSCH), achieved an area under the curve of 0.941 (95% CI: 0.926-0.955) in the training set and 0.788 (95% CI: 0.748-0.827) in the test set. Kaplan-Meier analyses confirmed that the LN_ISLUSCH model was a significant prognostic factor (<em>P</em> = .02). This study underscores the potential of artificial intelligence in enhancing diagnostic precision in pathology. The LN_ISLUSCH model stands out as a promising tool for predicting lymph node metastasis and prognosis in LUSC. Future studies should focus on larger and more diverse cohorts and explore the integration of additional omics data to further refine predictive accuracy and clinical utility.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 1","pages":"Article 102187"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatiotemporal Cellular Dynamics of Germinal Center Reaction in Coronavirus Disease 2019 Lung-Draining Lymph Node Based on Imaging-Based Spatial Transcriptomics","authors":"Taehwan Oh ,&nbsp;YoungMin Woo ,&nbsp;Green Kim ,&nbsp;Bon-Sang Koo ,&nbsp;Seung Ho Baek ,&nbsp;Eun-Ha Hwang ,&nbsp;You Jung An ,&nbsp;Yujin Kim ,&nbsp;Dong-Yeon Kim ,&nbsp;Jung Joo Hong","doi":"10.1016/j.labinv.2024.102180","DOIUrl":"10.1016/j.labinv.2024.102180","url":null,"abstract":"<div><div>Although lymph node structures may be compromised in severe SARS-CoV-2 infection, the extent and parameters of recovery in convalescing patients remain unclear. Therefore, this study aimed to elucidate the nuances of lymphoid structural recovery and their implications for immunologic memory in nonhuman primates infected with SARS-CoV-2. To do so, we utilized imaging-based spatial transcriptomics to delineate immune cell composition and tissue architecture formation in the lung-draining lymph nodes during primary infection, convalescence, and reinfection from COVID-19. We noted the establishment of a germinal center with memory B cell differentiation within lymphoid follicles during convalescence accompanied by contrasting transcriptome patterns indicative of the acquisition of follicular helper T cells versus the loss of regulatory T cells. Additionally, repopulation of germinal center-like B cells was observed in the medullary niche with accumulating plasma cells along with enhanced transcriptional expression of B cell-activating factor receptor over the course of reinfection. The spatial transcriptome atlas produced herein enhances our understanding of germinal center formation with immune cell dynamics during COVID-19 convalescence and lymphoid structural recovery with transcriptome dynamics following reinfection. These findings have the potential to inform the optimization of vaccine strategies and the development of precise therapeutic interventions in the spatial context.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 1","pages":"Article 102180"},"PeriodicalIF":5.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying Cardiac Tissue Composition Using QuPath and Cellpose: An Accessible Approach to Postmortem Diagnosis","authors":"Pernille Heimdal Holm ,&nbsp;Kristine Boisen Olsen ,&nbsp;Richard Denis Maxime De Mets ,&nbsp;Jytte Banner","doi":"10.1016/j.labinv.2024.102181","DOIUrl":"10.1016/j.labinv.2024.102181","url":null,"abstract":"<div><div>Sudden death can be the first symptom of cardiac disease, and establishing a precise postmortem diagnosis is crucial for genetic testing and follow-up of relatives. Arrhythmogenic cardiomyopathy is a structural cardiomyopathy that can be challenging to diagnose postmortem because of differences in structural findings and propagation of the disease at the time of death. Cases can have minimal or no structural findings and later be diagnosed according to genotype, known as concealed cardiomyopathy. Postmortem diagnosis often lacks clinical information, whereas antemortem diagnosis is based on paraclinical investigations that cannot be performed after death. However, the entire substrate is available, which is unique to postmortem diagnosis and research and can provide valuable insights when adding new methods. Reactive changes in the heart, such as myocardial fibrosis and fat, are significant findings. The patterns of these changes in various diseases are not yet fully understood and may be limited by sampling material and conventional microscopic diagnostics. We demonstrate an automated pipeline in QuPath for quantifying postmortem picrosirius red cardiac tissue for collagen, residual myocardium, and adipocytes by integrating Cellpose into a versatile pipeline. This method was developed and tested using cardiac tissues from autopsied individuals. Cases diagnosed with arrhythmogenic cardiomyopathy and age-matched controls were used for validation and testing. This approach is free and easy to implement by other research groups using this paper as a template. This can potentially lead to the development of quantitative diagnostic criteria for postmortem cardiac diseases, eliminating the need to rely on diagnostic criteria from endomyocardial biopsies that are not applicable to postmortem specimens. We propose that this approach serves as a template for creating a more efficient process for evaluating postmortem cardiac measurements in an unbiased manner, particularly for rare cardiac diseases.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 1","pages":"Article 102181"},"PeriodicalIF":5.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selecting Preclinical Animal Models in Hepatology Research: A Call for Uniform Guidelines","authors":"Devaraj Ezhilarasan ,&nbsp;Mustapha Najimi","doi":"10.1016/j.labinv.2024.102179","DOIUrl":"10.1016/j.labinv.2024.102179","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 1","pages":"Article 102179"},"PeriodicalIF":5.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cefadroxil Targeting of SLC15A2/PEPT2 Protects From Colistin Nephrotoxicity","authors":"Raul Fernandez-Prado ,&nbsp;Lara Valiño ,&nbsp;Aranzazu Pintor-Chocano ,&nbsp;Ana B. Sanz ,&nbsp;Alberto Ortiz ,&nbsp;Maria Dolores Sanchez-Niño","doi":"10.1016/j.labinv.2024.102182","DOIUrl":"10.1016/j.labinv.2024.102182","url":null,"abstract":"<div><div>Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered interconnected syndromes, as AKI episodes may accelerate CKD progression, and CKD increases the risk of AKI. Genome-wide association studies (GWAS) may identify novel actionable therapeutic targets. Human GWAS for AKI or CKD were combined with murine AKI transcriptomics data sets to identify 13 (<em>ACACB</em>, <em>ACSM5</em>, <em>CNDP1</em>, <em>DPEP1</em>, <em>GATM</em>, <em>SLC6A12</em>, <em>AGXT2L1</em>, <em>SLC15A2</em>, <em>CTSS</em>, <em>ICAM1</em>, <em>ITGAX</em>, <em>ITGAM</em>, and <em>PPM1J</em>) potentially actionable therapeutic targets to modulate kidney disease severity across species and the AKI-CKD spectrum. Among them, <em>SLC15A2</em>, encoding the cell membrane proton-coupled peptide transporter 2, was prioritized for data mining and functional intervention studies in vitro and in vivo because of its known function to transport nephrotoxic drugs such as colistin and the possibility for targeting with small molecules already in clinical use, such as cefadroxil. Data mining disclosed that <em>SLC15A2</em> was upregulated in the tubulointerstitium of human CKD, including diabetic nephropathy, and the upregulation was localized to proximal tubular cells. Colistin elicited cytotoxicity and proinflammatory response in cultured human and murine proximal tubular cells that was decreased by concomitant exposure to cefadroxil. In proof-of-concept in vivo studies, cefadroxil protected from colistin nephrotoxicity in mice. The GWAS association of <em>SLC15A2</em> with human kidney disease may be actionable and related to the modifiable transport of nephrotoxins causing repeated subclinical episodes of AKI and/or chronic nephrotoxicity.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 1","pages":"Article 102182"},"PeriodicalIF":5.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lymphocyte Activation Gene 3 Expression, γδ T-Cell/Major Histocompatibility Complex Class I Interactions, and Prognosis in Merkel Cell Carcinoma","authors":"Jonathan Lai ,&nbsp;Vrinda Madan ,&nbsp;Aasheen Qadri ,&nbsp;Ludmila Danilova ,&nbsp;Long Yuan ,&nbsp;Victoria Jacobs ,&nbsp;Aleksandra Ogurtsova ,&nbsp;Logan L. Engle ,&nbsp;Joel C. Sunshine","doi":"10.1016/j.labinv.2024.102178","DOIUrl":"10.1016/j.labinv.2024.102178","url":null,"abstract":"<div><div>Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy with a poor prognosis. One of the major mechanisms of immune evasion in MCC involves downregulation of major histocompatibility complex class I (MHC-I). Anti-PD-1/programmed death ligand 1 checkpoint inhibitors have revolutionized treatment for MCC, producing objective responses in approximately 50% of patients, and are now the standard of care; however, a substantial proportion of patients either fail to respond or develop resistance to checkpoint inhibitors. Given these recent successes, identification of other targetable immune checkpoints in the MCC tumor microenvironment is of great interest. Additionally, γδ T cells may play critical roles in response to MHC-I–deficient cancers; therefore, evaluating γδ T cells as a prognostic biomarker is warranted. We characterized the expression of programmed death ligand 1, PD-1, CD3, CD8, lymphocyte activation gene 3 (LAG-3), MHC-I, and γδ T cells by immunohistochemistry in a preimmunotherapy retrospective cohort of 54 cases of MCC and quantified expression levels and marker density using HALO software. The increased density of LAG-3 and γδ T cells correlated with other markers of an inflamed tumor microenvironment, with significant positive associations across all 6 markers (<em>P</em> &lt; .002). Reflective of their putative role in the response to MHC-I–suppressed cancers, cases with low human leukocyte antigen I density showed a trend toward a higher ratio of γδ T cells:CD3+ T cells (Spearman <em>r</em> = −0.1582; <em>P</em> = .21). Importantly, high CD3 density (hazard ratio [HR], 0.23; <em>P</em> = .002), LAG-3 density (HR, 0.47; <em>P</em> = .037), γδ T-cell density (HR, 0.26; <em>P</em> = .02), and CD8 density (HR, 0.27; <em>P</em> = .03) showed associations with improved progression-free survival. Conditional tree analysis demonstrated that high CD8 and TCRδ expression were nonsignificant predictors of improved progression-free survival and overall survival. Overall, LAG-3 is expressed in MCC infiltrates and is prognostic in preimmunotherapy MCC, suggesting a potential role for LAG-3 inhibition in MCC. Additionally, CD8 and γδ T cells may play a critical role in the response to MCC, and γδ T-cell density may represent a novel biomarker in MCC.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 1","pages":"Article 102178"},"PeriodicalIF":5.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}