Laboratory Investigation最新文献

{"title":"Characterization and Prognostic Impact of Fascin Expression in the Tumor Microenvironment of Triple-Negative Breast Cancer: Clues for a Tailored Therapy","authors":"David Pérez-Parra ,&nbsp;Fátima Postigo-Corrales ,&nbsp;Andreia-Filipa Cruz ,&nbsp;Alberto Sánchez-Espinosa ,&nbsp;Jesús Acosta-Ortega ,&nbsp;Raúl Carrillo-Vicente ,&nbsp;María Dolores López-Abellán ,&nbsp;Pablo Conesa-Zamora ,&nbsp;Ginés Luengo-Gil ,&nbsp;Ana María Hurtado-López","doi":"10.1016/j.labinv.2025.104268","DOIUrl":"10.1016/j.labinv.2025.104268","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) represents 10% to 15% of all cases with breast cancer, predominantly affecting younger women. Due to the absence of hormone receptors and human epidermal growth factor receptor 2 expression, TNBC lacks effective targeted therapies, resulting in poor prognosis, with 5-year survival rates ranging from 91% for localized disease to 12% for metastatic disease. Fascin, encoded by the <em>FSCN1</em> gene, is overexpressed in 88% of cases with TNBC and promotes tumor invasion, metastasis, and chemotherapy resistance. This study explored fascin as a prognostic marker and therapeutic target by analyzing its expression in the largest TNBC cohort to date and by assessing the effects of imipramine, an antidepressant that acts as a fascin inhibitor, on TNBC and luminal breast cancer cell lines. In a retrospective cohort of 145 patients with TNBC, fascin expression in tumor cells and stromal myofibroblasts correlated with high histological grade, Ki67 &gt;30%, and BCL-2 overexpression in myofibroblasts, as well as with higher chemotherapeutic response rates in the surgical setting. Fascin expression in stromal myofibroblasts has been identified as an independent predictive marker of chemotherapeutic response and as a prognostic factor for improved survival in patients undergoing neoadjuvant chemotherapy. In vitro, imipramine significantly reduced <em>FSCN1</em> expression and impaired cell migration in TNBC (MDA-MB-231) and luminal (MCF7) cell lines, with stronger effects on TNBC. These findings highlight the dual role of fascin in tumor cells and the tumor microenvironment and reinforce its potential as a biomarker for personalized TNBC therapies. Ongoing clinical trials, including histological and clinical effects of imipramine in the treatment of patients with cancer overexpressing fascin1 (HITCLIF), are exploring the efficacy of imipramine in patients with fascin-overexpressing cancers, paving the way for targeted treatment strategies.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"106 2","pages":"Article 104268"},"PeriodicalIF":4.2,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145648862","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":"Tumor-Infiltrating Lymphocyte Aggregation Refines Prognosis in Patients With Hepatocellular Carcinoma","authors":"Zehong Zhang ,&nbsp;Yuan’e Lian ,&nbsp;Yijuan Wu ,&nbsp;Zhongchang Weng ,&nbsp;Jiaying Ye ,&nbsp;Siqin Zhang ,&nbsp;Lianhuang Li ,&nbsp;Yannan Bai","doi":"10.1016/j.labinv.2025.104267","DOIUrl":"10.1016/j.labinv.2025.104267","url":null,"abstract":"<div><div>The prognostic role of tumor-infiltrating lymphocytes (TILs) in hepatocellular carcinoma (HCC) remains elusive. This study explored the association between TIL aggregation in early-stage HCC tissues and patient survival. Individual patient-level data from 353 patients diagnosed with HCC who underwent radical hepatectomy were retrospectively analyzed. TIL aggregation was analyzed using an artificial neural network algorithm to define the immune phenotypes (IPs) within hematoxylin and eosin–stained whole-slide images. The association between TIL aggregation and survival was compared among IPs, and an optimized TIL phenotype was validated with clinical variables. Among the 8 IP features measured using the artificial neural network algorithm, TIL density_K50, a metric generated by an assigned density of each cell based on its distance with the 50 nearest lymphocytes, was associated with improved disease-free survival in univariate (hazard ratio, 0.282; 95% CI, 0.181-0.439; <em>P</em> &lt; .0001) and multivariate analyses (hazard ratio, 0.315; 95% CI, 0.115-0.860; <em>P</em> = .024) after adjusting for clinical factors. When TIL density_K50 is combined with clinical factors (TIL-clinical–integrated [TCI] model), area under the curve performance for disease-free survival and overall survival was improved to 0.798 and 0.781 in the training cohort and 0.759 and 0.723 in the validation cohort, respectively. Furthermore, subgroup analyses indicated that its predictive value is particularly strong for very late recurrence and survival up to &lt;8 years. Abundant TILs in HCC tissue are associated with reduced late recurrence risk and improved survival, suggesting a potential time-dependent prognostic role of TILs in early-stage HCC.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"106 1","pages":"Article 104267"},"PeriodicalIF":4.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145635287","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":"Establishment and Multidimensional Characterization of a Novel Epstein-Barr Virus (EBV)–Negative Human Type I Natural Killer T-Cell Line NKT617","authors":"Chencheng Li ,&nbsp;Xixi Liu ,&nbsp;Weiguang Zhang ,&nbsp;Jing Yang ,&nbsp;Xiaoli Zhang ,&nbsp;Reaila Jianati ,&nbsp;Pengjun Jiang ,&nbsp;Fang Tian ,&nbsp;Biqing Chen ,&nbsp;Xuejun Zhu","doi":"10.1016/j.labinv.2025.104266","DOIUrl":"10.1016/j.labinv.2025.104266","url":null,"abstract":"<div><div>Natural killer T cells (NKT), a unique subset of T lymphocytes, remain incompletely understood in terms of their development and functional regulation. Well-characterized immortalized cell lines are critical tools for investigating NKT cell biology in vitro. We established and maintained a novel NKT cell line, NKT617, derived from the peripheral blood of a patient with aggressive large granular lymphocyte leukemia. Cell morphology was assessed using scanning electron microscopy and transmission electron microscopy. Flow cytometry characterized the cell phenotype, whereas T-cell receptor (TCR) clonal gene rearrangement determined lineage. RNA sequencing compared gene expression profiles of NKT617 with other hematological tumor cell lines, such as natural killer (NK) cells, T cells, B cells, and monocytes. Tumorigenic potential was evaluated via in vitro colony formation assays and in vivo zebrafish xenograft models. NKT617 has been continuously cultured for &gt;2 years, exceeding 100 passages, demonstrating monoclonal immortalization. It proliferates in a low-dose recombinant human interleukin-2–dependent manner and grows in suspension culture as single cells and aggregates. Flow cytometric analysis showed that NKT617 exhibits an NK-cell phenotype CD56⁺, CD158a⁺, NKp46⁺, membrane-bound CD3⁻, and T-cell features cytoplasmic CD3⁺, CD2⁺, CD4⁺, CD8⁺, CD45RA⁺, and CD45RO⁺, with clonal TCRβ rearrangement. NKT617 was negative for B-cell and myeloid markers and positive for the TCRα chain (Vα24-Jα18), confirming its identity as a type I NKT cell. Transcriptome analysis showed shared markers with NK-cell and T-cell lines but a gene expression profile closer to NK cells. In vitro and in vivo assays confirmed its tumorigenic capacity. We report the first Epstein-Barr virus–negative human type I NKT cell line, NKT617, which offers significant potential for studying NKT cell development and advancing chimeric antigen receptor–based therapies. This cell line serves as a valuable tool for exploring NKT cell biology and developing targeted immunotherapies.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"106 1","pages":"Article 104266"},"PeriodicalIF":4.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145635203","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":"Comparative Evaluation of Antibody-Oligonucleotide Conjugation Strategies for Multiplexed Imaging Applications","authors":"Chiara Caraccio ,&nbsp;Josie van de Klashorst ,&nbsp;Shelby Cherkas ,&nbsp;Sara Ancel ,&nbsp;Tim Noah Kempchen ,&nbsp;Gustavo Vazquez ,&nbsp;Yury Goltsev ,&nbsp;Yu Xin Wang ,&nbsp;Garry P. Nolan ,&nbsp;John W. Hickey","doi":"10.1016/j.labinv.2025.104262","DOIUrl":"10.1016/j.labinv.2025.104262","url":null,"abstract":"<div><div>Antibody-oligonucleotide conjugates (AOCs) have emerged as versatile tools with applications spanning diagnostics, therapeutics, and high-dimensional imaging. One major application of these is in multiplexed imaging techniques, such as CO-Detection by indEXing, which allow for the visualization of tissue networks at the single-cell level. In this study, we evaluated 4 methods—maleimide-modified, amine-modified, dibenzocyclooctyne (DBCO)-modified, and a site-specific enzyme-based method—to optimize the generation of AOCs for multiplexed imaging applications. Our assessment focused on key performance parameters, including conjugation efficiency, signal brightness, stability, reproducibility, and cost-effectiveness. Each conjugation chemistry proved effective, though the azide chemistry with DBCO oligonucleotides demonstrated more consistent conjugation success and stable signal retention over time. Compared with other protocols, this method produced reliably bright images and offered a more favorable cost profile, as further confirmed in a full-scale CO-Detection by indEXing multiplexed imaging experiment that yielded reproducible spatial data. The observed stability and reproducibility of the DBCO approach suggest that it may help reduce reagent waste and labor costs while facilitating the development of more comprehensive antibody panels. These findings indicate that the DBCO-modified oligonucleotide conjugation method is a valuable option for generating AOCs for multiplexed imaging and target current shortcomings, enabling more consistent, broader, and deeper multiplexed profiling.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"106 1","pages":"Article 104262"},"PeriodicalIF":4.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573939","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":"High Expression of CCL2 Correlated With Dendritic Cell Recruitment in Neuroblastomas Associated With Opsoclonus-Myoclonus Syndrome","authors":"Maureen Voirin ,&nbsp;Alexia Gazeu ,&nbsp;Benoit Dumont ,&nbsp;Aurélien Voissière ,&nbsp;Léo Jannot ,&nbsp;Dominique Plantaz ,&nbsp;Nathalie Sturm ,&nbsp;Nicolas Ber ,&nbsp;Pascal Chastagner ,&nbsp;Cécile Picard ,&nbsp;Frédérique Dijoud ,&nbsp;Christophe Caux ,&nbsp;Nathalie Bendriss-Vermare ,&nbsp;Hervé Sartelet","doi":"10.1016/j.labinv.2025.104263","DOIUrl":"10.1016/j.labinv.2025.104263","url":null,"abstract":"<div><div>Neuroblastoma (NB) accounts for 10% to 15% of cancer-related deaths among children. In rare cases, NB is associated with opsoclonus-myoclonus syndrome (OMS), a neurological paraneoplastic syndrome. These low-risk (LR) NBs with OMS have a favorable prognosis and an immune-enriched microenvironment. The recruitment of dendritic cells (DCs) and T lymphocytes into tumors is known to be mediated by CCL2 and CXCL12, respectively. We investigated whether intratumor CCL2 and CXCL12 promote DC recruitment within the microenvironment of OMS-associated LR-NBs. We conducted a multicentric retrospective case-control study on 44 pediatric patients with NBs associated or not with OMS. The non-OMS population was subdivided into an LR-NB group versus a high-risk (HR)-NB group, with or without <em>MYCN</em> amplification. Immunohistochemistry was performed using anti-CCL2 and anti-CXCL12 antibodies. DC subpopulations were stained using OPAL spectral multiplex immunofluorescence. Immunostaining scores were established by semiquantitative optical analysis. Gene signatures of DC, as well as <em>CCL2</em> and <em>CXCL12</em> mRNA expressions, were also analyzed on a public RNA-Seq data set of NB. We observed a significantly higher protein expression of CCL2 in OMS-associated LR-NBs compared with <em>MYCN</em>-amplified HR-NBs, whereas CXCL12 was not preferentially expressed by any of the NB groups. Furthermore, DC infiltrate was more abundant in OMS-associated LR-NBs compared with any other NB risk groups and positively correlated with CCL2 expression. In silico analysis of public RNA-Seq data demonstrated a higher <em>CCL2</em> expression in LR-NB with or without OMS compared with HR groups, and that the DC transcriptomic signature was higher in OMS-associated LR-NBs compared with HR-NB groups. We also observed a positive correlation between the DC gene signature and <em>CCL2</em> or <em>CXCL12</em> mRNA expression, to a lesser extent. Our results suggest that a DC-prone microenvironment might explain the favorable oncologic outcome of OMS-associated LR-NBs. CCL2 could be a therapeutic target to mobilize DCs in HR-NBs or in tumors characterized by a paucity of tumor-infiltrating DCs.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"106 1","pages":"Article 104263"},"PeriodicalIF":4.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145574001","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":"Interassay Comparison With Digital Image Analysis of 4 Routine Human Epidermal Growth Factor Receptor 2 (HER2) Immunohistochemistry Assays in Primary Breast Cancer and Its Metastasis","authors":"Maaike Anna Hempenius ,&nbsp;Mieke C. Zwager ,&nbsp;Jeppe Thagaard ,&nbsp;Lorian Slagter-Menkema ,&nbsp;Henk J. Buikema ,&nbsp;Ellis Barbé ,&nbsp;Michael A. den Bakker ,&nbsp;Marjolein G.J. Heerema ,&nbsp;Elisabeth G.E. de Vries ,&nbsp;Carolina P. Schröder ,&nbsp;Nils A. ’t Hart ,&nbsp;Bert van der Vegt","doi":"10.1016/j.labinv.2025.104261","DOIUrl":"10.1016/j.labinv.2025.104261","url":null,"abstract":"<div><div>Trastuzumab-deruxtecan, an antibody-drug conjugate targeting human epidermal growth factor receptor 2 (HER2), improves overall survival in patients with breast cancer showing low or ultralow HER2 expression. Differences in HER2 test results have been reported between various HER2 assays and between primary tumors and metastases, but an objective comparison with incorporation of the new HER2-ultralow cutoff values is needed. This study aimed to assess the performance of 4 routine clinical-grade HER2 assays across and between primary tumors and their metastases using digital image analysis. Primary tumors and metastases from 193 patients with breast cancer who participated in the IMaging PAtients for Cancer drug selecTion—Metastatic Breast Cancer trial were incorporated into 6 tissue microarrays. Samples were stained by 4 laboratories using their routine HER2 immunohistochemistry protocols: 4B5 ultraView, 4B5 OptiView, SP3, and HercepTest (DG44). HER2 scores were determined using digital image analysis. The 4 HER2 assays showed significant differences in HER2 status in both primary tumors and metastases. Eighty-five matched primary tumors and metastases were analyzed to investigate concordance in HER2 status. Although no significant differences were found in HER2 scores between primary tumors and metastases for SP3 and both 4B5 assays, DG44 showed significantly higher HER2 scores in the metastasis (<em>P</em> = .004). Concordance between primary tumors and metastases was highest for 4B5 ultraView (69.4%), followed by SP3 (61.2%) and 4B5 OptiView (51.8%). DG44 showed the most variability, with only 36.5% of matched samples receiving the same HER2 category. DG44 identified a significantly higher proportion of HER2-(ultra)low cases and showed the most variability in HER2 status between matched primary tumors and metastases compared with 4B5 and SP3. The choice of HER2 assay can lead to discrepancies in HER2 status assessment, which could directly influence patient eligibility for trastuzumab-deruxtecan treatment.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"106 1","pages":"Article 104261"},"PeriodicalIF":4.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573945","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":"Association Between CD4+/Programmed Cell Death 1+/CD153+ Cell Infiltration to the Aging Liver and Progression of Hepatic Steatosis in a Novel Metabolic Dysfunction–Associated Steatohepatitis Model Nishiura Mouse","authors":"Nobuyoshi Suzuki ,&nbsp;Hiroshi Nishiura ,&nbsp;Misako Okuno ,&nbsp;Mai Imasaka ,&nbsp;Michihiko Sugimoto ,&nbsp;Ikuo Nakamura ,&nbsp;Toshiya Tachibana ,&nbsp;Jiro Fujimoto ,&nbsp;Masaki Ohmuraya","doi":"10.1016/j.labinv.2025.104260","DOIUrl":"10.1016/j.labinv.2025.104260","url":null,"abstract":"<div><div>Metabolic dysfunction–associated steatohepatitis is one of the most important diseases, which progresses to hepatocellular carcinoma through hepatocellular dysfunction caused by steatosis and fibrosis. Recently, CD4+/programmed cell death 1 (PD-1)+/CD153+ cells (commonly referred to as senescence-associated T [SA-T] cells) have been identified as a senescence-associated secretory phenotype that produces chronic inflammation factors in a paracrine manner involved in osteopontin (OPN)-induced signal for the progression of steatosis in aging hepatocytes via antiapoptosis, alanine aminotransferase release, and so on. However, the detailed mechanisms are not fully elucidated. We identified a novel strain Nishiura (NI) mouse fed a normal diet that macroscopically showed yellowish orange discoloration of the liver at 36 weeks of age, followed by tumor-like masses at 48 weeks of age through a decrease in lineage−/CD34−/c-kit+/sca-1+ stem cells in the bone marrow and an increase in SA-T cells in the spleen at 24 weeks of age, infiltration of OPN+ or CD153+ cells in the PD-1+ liver at 36 weeks of age, and an increase in plasma OPN at 48 weeks of age. Conversely, SA-T cells, but not CD4+/PD-1+/CD153− cells, prepared from 36-week-old spleens of NI mice were transplanted into 12-week-old spleens of NI mice, but not into those of B6 mice, inducing severe hepatic steatosis and fibrosis at 36 weeks of age with an increase in OPN in the liver extract. Furthermore, in a cohort study, SA-T-cell rate in the biopsy specimen showed a positive correlation with the hepatitis activity index in patients with steatosis aged at least ≥60 years. In this paper, we discovered an association between CD4+/PD-1+/CD153+ cell infiltration to the aging liver and progression of hepatic steatosis in a novel metabolic dysfunction–associated steatohepatitis model NI mouse.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"106 1","pages":"Article 104260"},"PeriodicalIF":4.2,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530757","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":"Pathologist-Artificial Intelligence Concordance in HER2 Interpretation for Advanced Biliary Tract Cancer: Intraobserver, Interobserver, and Human-Artificial Intelligence Variability","authors":"Hyunchul Kim ,&nbsp;Jinhyung Heo ,&nbsp;Soo Ick Cho ,&nbsp;Beodeul Kang ,&nbsp;Jung Sun Kim ,&nbsp;Chan Kim ,&nbsp;Chang Il Kwon ,&nbsp;Min Je Sung ,&nbsp;Seok-Pyo Shin ,&nbsp;Seok Jeong Yang ,&nbsp;Incheon Kang ,&nbsp;Sung Hwan Lee ,&nbsp;Chansik An ,&nbsp;Seungeun Lee ,&nbsp;Jin Woo Oh ,&nbsp;Hee Yeon Kay ,&nbsp;Jiwon Shin ,&nbsp;Taebum Lee ,&nbsp;Sanghoon Song ,&nbsp;Sukjun Kim ,&nbsp;Hong Jae Chon","doi":"10.1016/j.labinv.2025.104259","DOIUrl":"10.1016/j.labinv.2025.104259","url":null,"abstract":"<div><div>Biliary tract cancer (BTC) is a rare, aggressive malignancy with a poor prognosis. HER2 is overexpressed in a subset of BTC patients, and recent advances in HER2-targeted agents are expanding therapeutic options. However, accurately assessing HER2 expression is challenging in BTC, especially at low levels. This study compared HER2 interpretations in advanced BTC by pathologists (H.K., J.H., and G.K.) using light microscopy (LM) and digital pathology (DP) and evaluated the potential of artificial intelligence (AI)–powered pathology in enhancing HER2-scoring consistency. A total of 309 HER2 immunohistochemistry slides were obtained from advanced BTC patients who received systemic therapy at the CHA Bundang Medical Center between 2019 and 2022. Three pathologists independently evaluated HER2 expression twice, once using LM and once using DP, with a washout period between evaluations. An AI–powered whole slide image analyzer evaluated HER2 expression. The ground truth was selected based on consensus among pathologists. Pathologists showed complete agreement on HER2 results in 62.1% of LM evaluations and 63.4% of DP evaluations. For intraobserver variability, the weighted kappa values ranged from 0.979 to 0.984, whereas interobserver variability ranged from 0.819 to 0.863 for LM and 0.820 to 0.876 for DP. The overall concordance rate of HER2 categories between the AI and the ground truth was 83.5%. Clinical factors such as HER2 expression level and specimen type significantly influenced intraobserver and interobserver variability, whereas histologic grade was a key factor affecting the AI model’s performance. In this study, we quantified intraobserver and interobserver variability in HER2 evaluation for BTC by pathologists and demonstrated that AI–powered HER2 scoring showed high concordance with pathologists’ evaluations. Because the clinical factors underlying the discrepancies in the results from the AI model and pathologists were different, the AI model is expected to help pathologists make more objective assessments of BTC HER2 readings in the future.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"106 1","pages":"Article 104259"},"PeriodicalIF":4.2,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513249","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":"Clues From Strange New Antigens: How Skin Responds to Nonself","authors":"Federico Repetto,&nbsp;Christine G. Lian,&nbsp;George F. Murphy","doi":"10.1016/j.labinv.2025.104258","DOIUrl":"10.1016/j.labinv.2025.104258","url":null,"abstract":"<div><div>Skin is both the most immunogenic transplantable tissue and the easiest to observe clinically, making it an ideal system for understanding alloreactivity. We trace the concept of alloantigens from early transfusion work and the discovery of ABO and major histocompatibility complex/human leukocyte antigen to contemporary lessons learned by treating skin as both clinical grafts and experimental models. We then focus on 3 clinical arenas in which cutaneous alloimmunity is most visible: classic skin-graft rejection, rejection of vascularized composite allografts (VCAs), and graft-versus-host disease (GVHD). Across settings, acute injury is T-cell dominated but with different effector cell “provenance.” Target selection is likewise patterned rather than random. Basal keratinocytes and epidermal/follicular stem-cell niches may be early victims of cytotoxic and cytokine signals. In parallel, the vasculature emerges as a second critical target. Microvascular injury may accompany epithelial targeting in skin-graft and acute-VCA rejection, whereas chronic VCA rejection also shows macrovascular injury akin to inflammatory stages of arteriosclerosis culminating in dermal sclerosis with chronicity with similarities to chronic GVHD and scleroderma. Thus, many of these endpoints of various forms of alloreactivity mirror changes seen in “endogenous” dermatoses—fixed drug eruption for acute interface lesions and lupus/scleroderma for chronic fibrosing change—potentially revealing shared downstream pathways despite distinct triggers. We also highlight practical implications: site-oriented surveillance (notably oral/nasal mucosal biopsies that can outperform external skin early in VCA rejection), emerging tissue and circulating biomarkers, and therapeutic directions that pair immune regulation with tissue protection. Drawn from hundreds of biopsies across experimental models, skin allografts, VCAs, and GVHD, the unifying message is that who the effectors are (host vs donor), where they strike (stem-cell niches vs vasculature), and how those injuries unfold over time determine whether skin heals, scars, or fails—hopefully clarifying mechanisms and guiding more precise, tolerance-leaning, fibrosis-sparing care.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"106 1","pages":"Article 104258"},"PeriodicalIF":4.2,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513196","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":"Corrigendum to “Corrigendum to Tumor Necrosis Factor-α–Dependent Inflammation Upregulates High Mobility Group Box 1 To Induce Tumor Promotion and Anti–Programmed Cell Death Protein-1 Immunotherapy Resistance in Lung Adenocarcinoma”","authors":"Lifei Kang ,&nbsp;Jingjing Cao ,&nbsp;Wenli Guo ,&nbsp;Xiaohui Cui ,&nbsp;Yangxuan Wei ,&nbsp;Jiayu Zhang ,&nbsp;Feiran Liu ,&nbsp;Chenyang Duan ,&nbsp;Qiang Lin ,&nbsp;Ping Lvx ,&nbsp;Zhiyu Ni ,&nbsp;Jing Zuo ,&nbsp;Haitao Shen","doi":"10.1016/j.labinv.2025.104255","DOIUrl":"10.1016/j.labinv.2025.104255","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 12","pages":"Article 104255"},"PeriodicalIF":4.2,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452419","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}