Laboratory Investigation最新文献

{"title":"Deep Learning–Powered Whole Slide Image Analysis in Cancer Pathology","authors":"Chengrun Dang ,&nbsp;Zhuang Qi ,&nbsp;Tao Xu ,&nbsp;Mingkai Gu ,&nbsp;Jiajia Chen ,&nbsp;Jie Wu ,&nbsp;Yuxin Lin ,&nbsp;Xin Qi","doi":"10.1016/j.labinv.2025.104186","DOIUrl":"10.1016/j.labinv.2025.104186","url":null,"abstract":"<div><div>Pathology is the cornerstone of modern cancer care. With the advancement of precision oncology, the demand for histopathologic diagnosis and stratification of patients is increasing as personalized cancer therapy relies on accurate biomarker assessment. Recently, rapid development of whole slide imaging technology has enabled digitalization of traditional histologic slides at high resolution, holding promise to improve both the precision and efficiency of histopathologic evaluation. In particular, deep learning approaches, such as Convolutional Neural Network, Graph Convolutional Network, and Transformer, have shown great promise in enhancing the sensitivity and accuracy of whole slide image (WSI) analysis in cancer pathology because of their ability to handle high-dimensional and complex image data. The integration of deep learning models with WSIs enables us to explore and mine morphologic features beyond the visual perception of pathologists, which can help automate clinical diagnosis, assess histopathologic grade, predict clinical outcomes, and even discover novel morphologic biomarkers. In this review, we present a comprehensive framework for incorporating deep learning with WSIs, highlighting how deep learning–driven WSI analysis advances clinical tasks in cancer care. Furthermore, we critically discuss the opportunities and challenges of translating deep learning–based digital pathology into clinical practice, which should be considered to support personalized treatment of cancer patients.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 7","pages":"Article 104186"},"PeriodicalIF":5.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971291","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":"NSD2 serves as a potential prognostic biomarker in mantle cell lymphoma.","authors":"Yu Zhu, Binshen Ouyang, Xuan Wang, Xu Wang, Chaofu Wang","doi":"10.1016/j.labinv.2025.104181","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104181","url":null,"abstract":"<p><p>NSD2 has been implicated in the pathogenesis of multiple cancers, exhibiting mutations or overexpression that contribute to tumor progression and poor clinical outcomes. In Mantle Cell Lymphoma (MCL), approximately 15% of patients harbor NSD2 mutations; however, its clinical significance remains to be fully elucidated. In our study, we analyzed Next Generation Sequencing (NGS) data from 147 MCL patients and identified NSD2 mutations in 8.84% (13/147) of cases, with 92.31% (12/13) demonstrating bone marrow involvement. Immunohistochemical (IHC) evaluation of NSD2 protein expression in 39 patients revealed that high levels of NSD2 protein expression were associated with higher Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, poorer treatment response, inferior overall survival (OS) and progression-free survival (PFS). Furthermore, NSD2 expression is strongly associated with aggressive histologic variants, including elevated c-MYC protein expression and a high Ki-67 proliferation index. Our analysis of the cBioPortal database, encompassing lymphoma patients, uncovered that NSD2 mutations are most prevalent in MCL. Specifically, E1099K and T1150A point mutations were linked to poorer prognoses. Additionally, our examination of the Gene Expression Omnibus (GEO) database (GSE93291) revealed a correlation between NSD2 mRNA expression levels and MKI67, with elevated NSD2 mRNA expression being associated with reduced survival rates. Tumor-infiltrating Immune Cell Analysis with CIBERSORT in GSE93291 revealed the correlation with increased intratumoral regulatory T cells (Tregs). According to our research, NSD2 mutations exhibit extremely aggressive biological behavior, and a worse prognosis is associated with higher levels of NSD2 in both mRNA and protein expression. We believe that NSD2 stands as a valuable prognostic marker and a potential therapeutic target in MCL.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104181"},"PeriodicalIF":5.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002560","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":"Maturation-Related and Functional-Associated Phenotypic Profile of Tumor T Cells in Mature/Peripheral T-Cell Neoplasms: Association With the Diagnostic Subtype of the Disease","authors":"F. Javier Morán-Plata ,&nbsp;Noemí Muñoz-García ,&nbsp;Susana Barrena ,&nbsp;Ana Yeguas ,&nbsp;Ana Balanzategui ,&nbsp;Sonia Carretero-Domínguez ,&nbsp;Julio Pozo ,&nbsp;Quentin Lécrevisse ,&nbsp;María González-González ,&nbsp;Paloma Bárcena ,&nbsp;Miguel Alcoceba ,&nbsp;María Herrero-García ,&nbsp;Fernando Solano ,&nbsp;Miriam López-Parra ,&nbsp;Alejandro Martín García-Sancho ,&nbsp;Cristiane de Sá Ferreira-Facio ,&nbsp;Neus Villamor ,&nbsp;Catarina Lau ,&nbsp;Maria Dos Anjos Teixeira ,&nbsp;Vitor Botafogo ,&nbsp;Julia Almeida","doi":"10.1016/j.labinv.2025.104180","DOIUrl":"10.1016/j.labinv.2025.104180","url":null,"abstract":"<div><div>T-cell chronic lymphoproliferative disorders (T-CLPD) are a heterogeneous group of mature T-cell malignancies, the classification of which remains challenging. In this study, we classified tumor cells from 86 patients diagnosed with either T-CLPD (n = 81) or T-cell acute lymphoblastic leukemia (n = 5) into precise functional and maturation-associated compartments, based on their phenotypic similarities with their normal maturation-related and functional associated T-cell counterparts. A database was generated using blood samples from 6 sex- and age-matched healthy donors as a template for normal T-cell subset flow cytometric immunophenotypes, to which tumor cells of individual patients were compared. Except for nodal T follicular–helper cell lymphoma and adult T-cell leukemia/lymphoma, which showed phenotypes overlapping with that of T follicular–helper and T regulatory cells, respectively, all other T-CLPD displayed immunophenotypic profiles consistent with conventional T helper (Th) cells, with different maturation-associated profiles per diagnostic category. These included predominant naive/naive-central memory phenotypes in T-cell prolymphocytic leukemia to terminal effector cytotoxic cellular profiles in T-cell large granular lymphocytic leukemia; other T-CLPD diagnostic categories (mostly Sézary syndrome/mycosis fungoides) resembled the diverse memory T-cell subsets. Interestingly, immunophenotypically less-mature tumor cells (T-cell prolymphocytic leukemia) displayed more heterogeneous Th profiles, whereas those with memory T-cell profiles showed more consistent Th-associated patterns (eg, Th2 or Th17 in Sézary syndrome/mycosis fungoides), and the most mature neoplasms (eg, T-cell large granular lymphocytic leukemia) systematically displayed a Th1-like pattern, reflecting progressively lower plasticity for the more advanced tumor-associated maturation stages. These findings confirm the presence of distinct phenotypic patterns resembling specific maturation-associated and Th-related profiles of normal T cells among distinct diagnostic categories of T-CLPD, which might contribute to a more precise classification of T-CLPD.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 8","pages":"Article 104180"},"PeriodicalIF":5.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989935","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":"Intelligent Diagnosis of Pancreatic Biopsy From Endoscopic Ultrasound-Guided Fine-Needle Aspiration Via Stimulated Raman Histopathology","authors":"Tao Tan ,&nbsp;Liyang Ma ,&nbsp;Yuheng Guo ,&nbsp;Tianyin Chen ,&nbsp;Lili Meng ,&nbsp;Kuan Luo ,&nbsp;Pinghong Zhou ,&nbsp;Mingyan Cai ,&nbsp;Minbiao Ji ,&nbsp;Hao Hu","doi":"10.1016/j.labinv.2025.104182","DOIUrl":"10.1016/j.labinv.2025.104182","url":null,"abstract":"<div><div>Endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) has become one of the most important preoperative diagnostic methods for pancreatic tumors, but it often faces challenges of redundant sampling from patients and complex tissue processing that hinders timely diagnosis. Intraoperative rapid on-site evaluation is an auxiliary diagnostic technique that helps assess sample quality in real time, but it heavily depends on pathologists and involves subjectivity and complex procedures. Here, we developed a rapid and label-free approach for intraoperative histology on EUS-FNA specimen via deep learning–based stimulated Raman scattering microscopy, aimed at replacing rapid on-site evaluation and providing a more efficient and objective diagnostic approach. Fresh pancreatic EUS-FNA tissues were imaged with stimulated Raman scattering and compared with hematoxylin and eosin staining to identify key histologic features. Using images from 76 patients, a convolutional neural network model was established to identify benign, malignant, and nondiagnostic areas, achieving a validation accuracy &gt;96% on an external test set of 33 cases. Furthermore, gradient-weighted class activation mapping was able to highlight histologic profiles within individual biopsy. Our approach has potential application in efficient intraoperative assessment of pancreatic biopsy through EUS-FNA.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 8","pages":"Article 104182"},"PeriodicalIF":5.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975297","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":"Quantitative Digital Image Analysis for Assessing Cutaneous Fibrosis Correlates With Histopathological Scoring in Patients With Systemic Sclerosis","authors":"Ruben Oganesyan ,&nbsp;Dimitra Pouli ,&nbsp;Bo Shi ,&nbsp;Mary Carns ,&nbsp;Kathleen Dennis-Aren ,&nbsp;Maria E. Teves ,&nbsp;John Varga ,&nbsp;Rosalynn M. Nazarian","doi":"10.1016/j.labinv.2025.104177","DOIUrl":"10.1016/j.labinv.2025.104177","url":null,"abstract":"<div><div>Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by progressive fibrosis of the skin, blood vessels, and internal organs. Accurate assessment of skin fibrosis is essential for disease monitoring and treatment evaluation, yet reliable quantitative methods are lacking. We compared computer-assisted digital image analysis with traditional semiquantitative histopathological scoring. Patients with SSc and healthy controls were identified from a hospital database. Clinical data, modified Rodnan skin score, and hematoxylin and eosin–stained skin biopsies were collected. Biopsies were scored using modified Keyser and Farge criteria. Whole-slide images were analyzed using QuPath open source digital pathology software (v0.5.1) for area annotation, normalized cellularity, and collagen density, whereas collagen alignment was evaluated using CurveAlign (MATLAB) software. Seven SSc and 7 healthy controls (no significant demographic differences) were studied. SSc samples showed significant differences in hyalinized collagen (<em>P</em> &lt; .001), dermal fibroblast cellularity (<em>P</em> = .009), and total histopathological score (<em>P</em> = .007). Quantitative analysis confirmed decreased dermal cellularity (<em>P</em> = .024), increased collagen density (<em>P</em> = .009), and higher collagen alignment, with reduced fiber orientation variability, reflecting extracellular matrix restructuring in SSc. Tools such as QuPath and CurveAlign improve objectivity and reproducibility in SSc skin assessment, correlating well with traditional scores. These findings support the integration of computer-aided quantitative analysis into clinical practice and trials, advancing personalized fibrosis evaluation. Larger, longitudinal studies are needed for further validation.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 8","pages":"Article 104177"},"PeriodicalIF":5.1,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937118","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":"Computer-Based Detection of Colorectal Serrated Lesions: Digital Flatness, a Novel Metric Designed for Whole-Slide Images","authors":"Margherita Mottola ,&nbsp;Costantino Ricci ,&nbsp;Federico Chiarucci ,&nbsp;Caterina Ravaioli ,&nbsp;Alessia Grillini ,&nbsp;Alessandro Gherardi ,&nbsp;Michelangelo Fiorentino ,&nbsp;Alessandro Bevilacqua ,&nbsp;Francesca Ambrosi","doi":"10.1016/j.labinv.2025.104178","DOIUrl":"10.1016/j.labinv.2025.104178","url":null,"abstract":"<div><div>Colorectal sessile serrated lesions (SSLs) and hyperplastic polyps (HPs) are characterized by sawtooth or stellate epithelial architecture. Distinguishing between SSLs and HPs is crucial as SSLs are precursors of colorectal carcinomas in 30% of cases, whereas HPs are likely precursors to SSLs. The differentiation of SSL from HP is primarily based on architectural features. Indeed, the hallmark of SSL is a substantial distortion of the typical crypt design and silhouette, which shows horizontal expansion along the muscularis mucosae and enlargement of the crypt base, especially in the lower third of the crypt. The ability to analyze digitized histologic images has led to innovative automated tissue analysis, thereby improving reproducibility and objectivity in pathologists' reports. Some recent studies explored colorectal cancer diagnosis and grading through automated quantitative analysis, but none of them focused on SSL detection. This study aimed to develop an automated method for SSL diagnosis by defining specific metrics to characterize their most common visual features. We developed a processing pipeline involving the automatic segmentation of all the tissue structures required for computing quantitative morphologic and architectural features, which allows detection of SSLs. In particular, we designed a novel metric, digital flatness, which numerically characterizes the parallelism of the gland's contour edges with the muscolaris mucosa profile. In a data set of 759 polyp glands, 41 of which were reported as SSLs by expert pathologists, our novel detection method achieved specificity of 92% and sensitivity of 83%, with accuracy of 92%. Our results represent a first approach to a simple, common, but still debated issue among gastrointestinal pathologists, thus providing valid support for the objective and standardized individuation of SSLs.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 8","pages":"Article 104178"},"PeriodicalIF":5.1,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937115","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":"SATB2 Loss Is a Sensitive Biomarker for Dysplasia in Inflammatory Bowel Disease","authors":"Madhurya Ramineni,&nbsp;Mark Ettel,&nbsp;Yansheng Hao,&nbsp;Xiaoyan Liao","doi":"10.1016/j.labinv.2025.104179","DOIUrl":"10.1016/j.labinv.2025.104179","url":null,"abstract":"<div><div>Loss of SATB2 expression has emerged as a promising biomarker for dysplasia in inflammatory bowel disease (IBD), but its sensitivity and specificity remain unclear. We retrospectively evaluated immunohistochemical (IHC) staining of SATB2 and p53 in colorectal biopsies from 37 IBD patients (25 men and 12 women; median age: 48 years) with suspected dysplasia. The cohort included 26 ulcerative colitis (70%) and 11 Crohn’s disease (30%). Fourteen patients (38%) developed IBD-associated invasive carcinoma, and 18 (49%) had persistent dysplasia on follow-up. Histologic review identified 80 lesions initially diagnosed as negative (16%), indefinite (39%), low-grade (36%), and high-grade (9%) dysplasia. IHC revealed aberrant p53 in 35 lesions (44%) and SATB2 loss in 42 lesions (53%), with 19 (24%) showing both abnormalities. Reappraisal of diagnoses combining histology and IHC reclassified lesions into indefinite (20%), low-grade (63%), and high-grade (17%) dysplasia. Lesions with SATB2 loss alone were more frequently of lower grade (<em>P</em> = .003). Dysplasia types included 15 conventional dysplasia (19%) and 65 nonconventional dysplasia (81%). The rates of p53 abnormality, SATB2 loss, and their combination were similar in nonconventional dysplasia (45%, 55%, and 75%, respectively) and conventional dysplasia (40%, 47%, and 67%, respectively) and comparable between cancer patients (50%, 56%, and 74%, respectively) and noncancer patients (39%, 50%, and 72%, respectively). Missed dysplasias in cancer patients were all nonconventional, and lesions with p53 abnormality more likely progressed to cancer (<em>P</em> = .002). In conclusion, SATB2 loss is a sensitive marker for IBD-associated dysplasia. Combined use of SATB2 and p53 IHC improves dysplasia detection and reduces false-negative diagnosis, supporting its application into routine diagnostic practice.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 8","pages":"Article 104179"},"PeriodicalIF":5.1,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937114","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":"Spatial Analysis Identifies CD147 as a Novel Marker of High-Grade Childhood Posterior Fossa Ependymoma","authors":"Donatella Lucchetti ,&nbsp;Filomena Colella ,&nbsp;Antonio d’Amati ,&nbsp;Tiziana Servidei ,&nbsp;Marco Gessi ,&nbsp;Parillo Chiara ,&nbsp;Beatrice Cellini ,&nbsp;Federica Toma ,&nbsp;Luciano Giacò ,&nbsp;Federica Persiani ,&nbsp;Luigi Perelli ,&nbsp;Giulia Mantini ,&nbsp;Giannicola Genovese ,&nbsp;Ivan Masetto ,&nbsp;Antonio Ruggiero ,&nbsp;Alessandro Sgambato","doi":"10.1016/j.labinv.2025.104175","DOIUrl":"10.1016/j.labinv.2025.104175","url":null,"abstract":"<div><div>Ependymoma (EPN) is the third most common malignant tumor of the central nervous system in children. The spatial and temporal heterogeneity of cancer cell populations can impact the ability of EPN to overcome microenvironmental constraints. Data set analysis revealed that CD147 expression is increased in glioma, and its expression correlates with detrimental survival and higher mutational burden. We performed spatial phenotyping of tumor microenvironment in childhood posterior fossa type A EPN (PFA-EPN) central nervous system World Health Organization grade 2 (G2; n = 5) and grade 3 (G3; n = 7). Tumors were comprehensively assessed using multiplex immunofluorescence panels to detect immune, microglial, endothelial, and tumor cells. We observed significant differences in immune cell populations according to grading: a high number of T cells and cytotoxic T cell infiltration were features of G2 when compared with G3 cancers. The distance between CD4+ and CD8+ cells was lower in G3 tumors, highlighting an increase in cell interactions between T-cell populations in more aggressive tumors. Two tumor-associated macrophage subsets with distinct functional phenotypes (CD68+MCP1+ and CD68+CD44+), associated with tumor progression, were previously identified by single-cell RNA sequencing analyses in spinal EPN. We demonstrated that the CD68+CD44+ population was higher in G3 compared with G2 PFA. CD147+ microglia cells were closer to CD8+ cells and CD147+ tumor-proliferating cells in G3 than G2 counterparts. In G3 tumors, CD4+ cells were more distant from CD147+ microglial cells and from CD8+ lymphocytes and were closer to CD147+ tumor-proliferating cells. We provided evidence that CD147+ microglial cells could be playing a key role in PFA-EPN progression, promoting CD8+ T cells’ exclusion. These findings highlight grading-related differences in PFA-EPN tumor microenvironment.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 7","pages":"Article 104175"},"PeriodicalIF":5.1,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911982","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":"Prognostic and Predictive Value of Microsatellite Instability Analysis in Circulating Tumor DNA Using Digital Droplet PCR for Patients With Microsatellite Instability Colorectal Cancers","authors":"Camille Evrard ,&nbsp;Tristan Rochelle ,&nbsp;Marine Martel ,&nbsp;Anis Al Achkar ,&nbsp;Aurélie Ferru ,&nbsp;Violaine Randrian ,&nbsp;Lucie Karayan-Tapon ,&nbsp;David Tougeron","doi":"10.1016/j.labinv.2025.104176","DOIUrl":"10.1016/j.labinv.2025.104176","url":null,"abstract":"<div><div>Deficient mismatch repair (dMMR) and/or microsatellite instability (MSI) colorectal cancer (CRC) is highly sensitive to immune checkpoint inhibitors (ICI). It is thus becoming increasingly relevant to monitor circulating tumor DNA (ctDNA) and to determine the MSI status (ctDNA-MSI) in CRC. So far, few studies have explored this, even though it could be particularly relevant in evaluating treatment efficacy in patients with dMMR and/or MSI CRC. The ctDNA DIgestive cancers MSI study (ADI-MSI) aims to assess the value of ctDNA-MSI as a predictor of ICI efficacy. Blood samples were collected prospectively in a single-center cohort to analyze circulating cell-free DNA (cfDNA) and ctDNA-MSI before the start of and during treatment. ctDNA-MSI was measured using digital droplet PCR with the 5 microsatellite markers of the Pentaplex panel (Promega Corporation). The primary endpoint was to evaluate ctDNA-MSI levels as a predictor of progression-free survival (PFS). We included 54 patients with dMMR and/or MSI CRC, most of whom had metastatic disease (77.8%) treated in the first (25.9%) or second line (42.6%) with ICI. High-baseline cfDNA and ctDNA-MSI were associated with worse PFS and overall survival. ctDNA-MSI kinetics, but not cfDNA kinetics, was associated with treatment response (<em>P</em> = .006), PFS (<em>P</em> = .03), and overall survival (<em>P</em> = .04). ctDNA-MSI kinetics divided into 3 groups (increase, decrease, and negative) correlated strongly with PFS (PFS at 24 months was 0%, 53.0%, and 77.0%, respectively; <em>P</em> &lt; .001) and remained significant in multivariate analysis (hazard ratio = 7.93; 95% CI, 2.23-28.21; <em>P</em> = .005). As there is no strong predictor of ICI efficacy in patients with dMMR and/or MSI CRC, these results suggest that ctDNA-MSI could help physicians in treatment decision-making in the future.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 8","pages":"Article 104176"},"PeriodicalIF":5.1,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937293","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":"Clinicopathologic Features and the Spectrum of Myelokathexis in Warts, Hypogammaglobulinemia, Infections, Myelokathexis Syndrome","authors":"Jingwei Li ,&nbsp;Marine Delecourt-Billet ,&nbsp;Odile Fenneteau ,&nbsp;Jadee L. Neff ,&nbsp;Lilian Roland ,&nbsp;Bérénice Schell ,&nbsp;Vanessa Gourhand ,&nbsp;Marion Espeli ,&nbsp;Karl Balabanian ,&nbsp;Sarah Taplin ,&nbsp;Myriam Defontis ,&nbsp;Chi Huu Nguyen ,&nbsp;Julia Mordhorst ,&nbsp;Robert Johnson ,&nbsp;Arthur Taveras ,&nbsp;Christoph B. Geier ,&nbsp;Catharina Schuetz ,&nbsp;Christian Thiede ,&nbsp;Melis Yilmaz ,&nbsp;Inga Sakovich ,&nbsp;Jacob R. Bledsoe","doi":"10.1016/j.labinv.2025.104174","DOIUrl":"10.1016/j.labinv.2025.104174","url":null,"abstract":"<div><div>Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency disorder predominantly caused by germline <em>CXCR4</em> variants. Bone marrow (BM) evaluation showing myelokathexis helps to establish the diagnosis of WHIM syndrome, but unfamiliarity with pertinent diagnostic features and variability in morphologic and clinical findings may result in disease underrecognition. We aimed to characterize the clinical, BM, and peripheral blood (PB) features of 30 patients with germline <em>CXCR4</em> variants, including genotype–phenotype analysis and correlation between morphologic features and functional CXCR4 receptor internalization defect. We also aimed to examine PB features of a mouse model of WHIM syndrome (<em>Cxcr4</em>^+/1013) and examine WHIM syndrome and WHIM mouse PB morphologic changes after CXCR4 antagonist therapy. Carboxy-terminal nonsense/frameshift <em>CXCR4</em> variants were associated with myelokathectic neutrophil morphology in 32% to 80% (median, 66%) and 4% to 14% (median, 9%) of total neutrophils in the BM and PB, respectively. In contrast, myelokathectic neutrophils were infrequent in 5 missense <em>CXCR4</em> variants (3 CXCR4^D84H and 2 CXCR4^S341Y). Compared with neutropenic controls, carboxy-terminal CXCR4 nonsense/frameshift variants were associated with &gt;10% BM or &gt;5% PB myelokathectic neutrophils (100% specific; 100% [BM] or 93% [PB] sensitive), as well as more frequent neutrophil apoptosis (BM, <em>P</em> = .0093; PB, <em>P</em> &lt; .0001), dysmorphic/vacuolated eosinophils (BM, <em>P</em> = .012; PB, <em>P</em> &lt; .0001), neutrophil vacuolization (BM, <em>P</em> &lt; .0001), and nonparatrabecular neutrophil clusters in the BM (<em>P</em> = .0059). BM myeloid hyperplasia occurred in 54% of carboxy-terminal CXCR4 nonsense/frameshift variants and in no controls. BM myelokathectic neutrophil percentage correlated with the functional CXCR4 internalization defect (<em>P</em> ≤ .0042). Like humans, WHIM mice (<em>Cxcr4</em>^+/1013) demonstrated circulating myelokathectic-like neutrophils with nuclear hypersegmentation. CXCR4 antagonist therapy in patients with WHIM syndrome (n = 5) and mice increased both morphologically normal and myelokathectic neutrophils in PB. We demonstrated notable genotype–phenotype heterogeneity between <em>CXCR4</em> variants and myelokathexis, which correlates with functional CXCR4 internalization defect. The morphologic features of WHIM syndrome may be subtle, resulting in misdiagnosis. We described key morphologic features that are useful to facilitate diagnosis.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 8","pages":"Article 104174"},"PeriodicalIF":5.1,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942392","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}