Laboratory Investigation最新文献

{"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}

{"title":"Multicenter Evaluation of Certainty and Reliability in Calciphylaxis Diagnosis Using a Digital Imaging Platform","authors":"Soma Jobbagy ,&nbsp;Emilio Madrigal ,&nbsp;Houda Bouchouari ,&nbsp;Tianqi Ouyang ,&nbsp;Sagar U. Nigwekar ,&nbsp;Rosalynn M. Nazarian","doi":"10.1016/j.labinv.2025.104169","DOIUrl":"10.1016/j.labinv.2025.104169","url":null,"abstract":"<div><div>The robustness of histopathologic criteria for diagnosing calciphylaxis depends both on dermatopathologists’ confidence in the recognition of individual histologic features and on the interrater reliability (IRR) of these assessments. The aim of this study was to quantify interpretive challenges in calciphylaxis diagnosis through the evaluation of generalized and histopathological feature-specific certainty and IRR and establish which features are most reproducibly recognized. An online diagnostic survey was designed to evaluate accuracy, certainty, and IRR. Case materials comprised a clinical vignette, clinical photograph, and whole slide imaging scans of 1 hematoxylin and eosin and von Kossa-stained section in 20 patients with or without calciphylaxis. Dermatopathologists from multiple institutions independently rendered diagnoses and used a checklist to assess the presence of and certainty in specific histopathologic features. Twenty-three board-certified dermatopathologists (62%) representing 16 institutions responded. Diagnostic accuracy (53% vs 80%) and IRR (Krippendorff alpha [KA]) were lower for calciphylaxis cases compared with mimics (0.171 vs 0.257). Necrosis, finely stippled calcium, and intimal fibroplasia of pannicular arterioles most robustly differentiated calciphylaxis from mimics (<em>P</em> &lt; .05). Among histopathologic features, IRR was the highest for ulceration (KA = 0.66) and necrosis (KA = 0.46) and the lowest for perieccrine calcification (KA = 0.19) and intimal fibroplasia of pannicular arterioles (KA = 0.07). Pathologists’ confidence in correctly identifying the presence or absence of each feature correlated linearly with IRR. Digital imaging platforms can facilitate multi-institutional study of diagnostic concordance for uncommon entities. This study identified necrosis, finely stippled calcium, and intimal fibroplasia of pannicular arterioles as the most robust histopathologic features for diagnosing calciphylaxis, although inter-rater concordance for intimal fibroplasia was low. Quantitative trends in pathologists’ subjective assessments of histologic features may help guide the development of diagnostic guidelines and inform medical education.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 7","pages":"Article 104169"},"PeriodicalIF":5.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911981","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":"Role of Reserve Cells in Metaplasia and the Development of Human Papillomavirus–Associated High-Grade Squamous Intraepithelial Lesions at the Cervical Transformation Zone","authors":"Ademola Aiyenuro ,&nbsp;Heather Griffin ,&nbsp;Konstanze Schichl ,&nbsp;Tanvier Omar ,&nbsp;Jaume Ordi ,&nbsp;Helen Kelly ,&nbsp;Caroline Walker ,&nbsp;Marta del Pino ,&nbsp;Kanan Desai ,&nbsp;Silvia de Sanjosé ,&nbsp;Mark Schiffman ,&nbsp;John Doorbar","doi":"10.1016/j.labinv.2025.104166","DOIUrl":"10.1016/j.labinv.2025.104166","url":null,"abstract":"<div><div>Squamous cervical cancers generally arise as a result of persistent infection with high-risk human papillomaviruses (hrHPVs) and occur near the squamocolumnar junction (SCJ) and within the transformation zone (TZ). The susceptibility of the TZ to HPV-related carcinogenesis appears linked to epithelial cell plasticity, with squamous metaplasia originating from a specialized stem cell population at this site. Two alternative cell populations have been implicated: keratin (K)7+ve cuboidal cells located at the SCJ vs a more broadly distributed K17+ve cervical reserve cell population. To distinguish between the hypotheses, we utilized multiplex immunofluorescence and large-scale digital imaging to map cell populations at the TZ of 165 women with and without hrHPV infections. Our results did not reveal a distinct population of K7+ cuboidal cells at the SCJ but found instead that the cuboidal and columnar cells of the TZ express K7 and K8 throughout and lack the p63 transcription factor required for epithelial stratification. Squamous metaplasia and reserve cells, which are defined by their subcolumnar location and pattern of biomarker expression (K5/K17/P63), were conspicuous at cervical crypt entrances within the TZ extending proximally toward the endocervix. In HPV-infected tissue, crypt-entrance regions with thin high-grade squamous intraepithelial lesion pathology showed prominent expression of hrHPV E6/E7 mRNA, as detected by fluorescence in situ hybridization, and p16/MCM expression, with infection also apparent in neighboring reserve cells. In some instances, normal/uninfected reserve cells (E6/E7 mRNA−ve) and squamous metaplasia were not only seen close to these regions of hrHPV infection but also extended well beyond the infected area both laterally and by depth. Our results confirm that the reserve cells underneath the columnar epithelia at TZ have the potential to undergo malignant squamous transformation via reserve cell proliferation, in agreement with previous histopathological studies. These translational findings highlight the importance of understanding the molecular biology of the epithelial sites where HPV cancers develop and suggest that in high-risk individuals, treatment strategies should target a wider area than previously thought.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 7","pages":"Article 104166"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899962","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":"Inflamed Intestinal Epithelial Cells From Patients With Ulcerative Colitis Restore a Noninflamed Transcriptional Profile Upon In Vitro Expansion","authors":"Alexander Due Hammerhøj ,&nbsp;Theresa Louise Boye ,&nbsp;Jiayi Yao ,&nbsp;Annika Hausmann ,&nbsp;Lauge Kellermann ,&nbsp;Grzegorz Jerzy Maciag ,&nbsp;Albin Sandelin ,&nbsp;Casper Steenholdt ,&nbsp;Kim Bak Jensen ,&nbsp;Ole Haagen Nielsen","doi":"10.1016/j.labinv.2025.104172","DOIUrl":"10.1016/j.labinv.2025.104172","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is characterized by chronic relapsing inflammation starting from the rectum and distal colon, which in severe disease cases may affect the entire colon. Intestinal stem cells (ISCs) directly isolated from inflamed UC colonic tissue specimens have been found to present an inflammatory gene expression profile. However, a critical issue is whether these cells retain memory of exposure to inflammation and/or therapeutics. Here, we aimed to investigate whether human intestinal epithelial cells retain the inflammatory state observed in vivo when expanded in vitro as 3D cultured organoids to assess their suitability for therapeutic transplantation. ISCs were isolated from noninflammatory bowel disease controls (noninflamed; n = 18), as well as from colonoscopy-obtained biopsies of the sigmoid colon from individuals diagnosed with UC (inflamed), who were glucocorticoid naïve (n = 19). Moreover, ISCs were collected from all patients with inflammatory bowel disease following prednisolone treatment. Epithelial cells were cultured as 3D intestinal organoids in media to support stem cell maintenance and differentiation. Subsequently, the 3D intestinal organoids were harvested at the end of passage 2 for bulk RNA sequencing. The data revealed that the cellular phenotype of in vitro–cultured epithelial cells isolated from inflamed tissue did not maintain the hallmarks of inflammation observed in the ulcerated environment from which the cells were initially obtained. Our findings indicate that the autologous reinsertion of in vitro–expanded ISCs in active stages of UC may aid in intestinal healing, which calls for future clinical studies. Additionally, a link between organoid morphology and the inflammatory state of the tissue of origin was identified, as organoids derived from inflamed colon exhibited a lower degree of circularity.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 7","pages":"Article 104172"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878440","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 Value of PARP1 and PARP2 Copy Number Alterations in Prostate Cancer","authors":"Laura Segalés ,&nbsp;Joaquim Bellmunt ,&nbsp;Júlia Perera-Bel ,&nbsp;Gardenia Vargas-Parra ,&nbsp;Nuria Juanpere ,&nbsp;David López ,&nbsp;Alejo Rodriguez-Vida ,&nbsp;Lluís Colomo ,&nbsp;Lluís Cecchini ,&nbsp;Josep Lloreta-Trull ,&nbsp;José Yélamos ,&nbsp;Lluís Fumadó ,&nbsp;Silvia Hernández-Llodrà","doi":"10.1016/j.labinv.2025.104171","DOIUrl":"10.1016/j.labinv.2025.104171","url":null,"abstract":"<div><div>PARP1/2 have overlapping yet nonredundant biological functions in DNA repair and androgen receptor-transcriptional regulation. Studies on PARP alterations in human tumors have yielded conflicting results. In prostate cancer (PCa), PARP1/2 protein overexpression has been related to androgen deprivation therapy resistance, biochemical recurrence, and progression to metastases. PARP inhibitors have been approved for treating metastatic castration-resistant PCa with homologous recombination repair gene mutations. However, the significance of <em>PARP1/2</em> genomic alterations is not fully studied. We aimed to analyze <em>PARP1/2</em> alterations in PCa, assess their value as prognostic markers, and explore their relevance for potential therapeutic stratification. <em>PARP1</em>/<em>2</em> copy number status was evaluated in 121 PCa primary tumors using real-time PCR. In 29 of them, a regional pelvic lymph node involvement was also analyzed. <em>BRCA1</em>/<em>2</em> somatic mutations were analyzed in 24 PCa cases. Relationship with clinicopathological features, progression to metastases, and prostate-specific antigen recurrence was assessed. <em>PARP1</em> loss and <em>PARP2</em> gain were detected in 34.7% and 32.2% of primary tumors, respectively, with a high frequency of co-occurrence (<em>P</em> &lt; .001). Both alterations were statistically associated with locally advanced disease at the time of diagnosis (<em>P</em> = .036; <em>P</em> = .006), metastatic dissemination (<em>P</em> = .014; <em>P</em> = .003), and other aggressive clinicopathological characteristics (such as the presence of Gleason pattern 5, high-grade, and high-stage). Cases with exclusive <em>PARP2</em> gain had the shortest time to prostate-specific antigen recurrence, whereas double <em>wt</em> patients displayed the best outcome (<em>P</em> = .007). In 29 paired primary tumors and regional pelvic lymph node involvement, <em>PARP1</em> loss showed strong concordance (<em>P</em> = .001), whereas <em>PARP2</em> gain did not (<em>P</em> = .411). In conclusion, loss of <em>PARP1</em> and gain of <em>PARP2</em> show strong co-occurrence and are associated with clinicopathological characteristics of aggressiveness. <em>PARP2</em> alterations appear to have a particularly significant impact on disease prognosis. Furthermore, these data suggest that the analysis of <em>PARP1/2</em> copy number status could be useful in predicting PCa outcomes. Its role in therapy warrants further evaluation.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 6","pages":"Article 104171"},"PeriodicalIF":5.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888054","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 “Epstein-Barr Virus–Encoded Latent Membrane Protein 2A Promotes Immune Escape by Upregulating SYK/Nuclear Factor-κB Signaling in Diffuse Large B-cell Lymphoma” [Laboratory Investigation 105 (2025) 104104]","authors":"Xiang-Nan Jiang ,&nbsp;Dong Sheng ,&nbsp;Wan-Hui Yan ,&nbsp;Xiao-Jie Li ,&nbsp;Qing-Xin Xia ,&nbsp;Xiao-Qiu Li","doi":"10.1016/j.labinv.2025.104164","DOIUrl":"10.1016/j.labinv.2025.104164","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 5","pages":"Article 104164"},"PeriodicalIF":5.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792400","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":"EGR1–BDNF–Linking Crosstalk Between Cancer Cells and Nerves for Perineural Invasion in Salivary Duct Carcinoma: Comparison of Salivary Duct Carcinoma De Novo and Ex Pleomorphic Adenoma","authors":"Airi Sakyo ,&nbsp;Eijitsu Ryo ,&nbsp;Seiichi Yoshimoto ,&nbsp;Go Omura ,&nbsp;Chihiro Fushimi ,&nbsp;Toshihiko Sakai ,&nbsp;Yoshifumi Matsumoto ,&nbsp;Azusa Sakai ,&nbsp;Kohtaro Eguchi ,&nbsp;Yo Suzuki ,&nbsp;Kazuki Yokoyama ,&nbsp;Yoshitaka Honma ,&nbsp;Yasushi Yatabe ,&nbsp;Fumihiko Matsumoto ,&nbsp;Taisuke Mori","doi":"10.1016/j.labinv.2025.104167","DOIUrl":"10.1016/j.labinv.2025.104167","url":null,"abstract":"<div><div>Salivary duct carcinoma (SDC) is primarily categorized as de novo (SDCDN) or ex pleomorphic adenoma (SDCXPA). The incidence of HMGA2 and PLAG1 fusion genes has been suggested to be higher in SDCXPA than in SDCDN. Surgical resection remains the main intervention due to limited guidance on new treatment strategies. However, frequent recurrence and challenging management of metastasis highlight the necessity for innovative treatments. This study aimed to investigate SDC characteristics, including perineural invasion (PNI), and elucidate its carcinogenic mechanisms and adverse prognostic factors. We analyzed 52 patients with SDC diagnosed in the National Cancer Center Hospital from 2014 to 2023. To compare gene expression profiles, we performed immunohistochemical staining, including Her2, adrenergic receptor, PLAG1, and HMGA2, followed by human epidermal growth factor receptor 2 (HER2) in situ hybridization and RNA sequencing of 30 cases. Differential analysis identified genes subjected to immunohistochemical staining and statistical analysis. Based on histologic classification using PLAG1 and HMGA2, 52 cases were classified as 26 cases (50%) SDCDN and 26 cases (50%) SDCXPA. Compared with SDCXPA, SDCDN showed higher perineural, venous, and lymphatic invasion rates (<em>P</em> = .0005, .0294, and .0044, respectively). Genetic expression profiling revealed clustering tendencies between these subtypes. Focusing on PNI, gene expression was decreased in early growth response 1 in tumor portions infiltrating perineural tissues, indicating a negative correlation (<em>P</em> &lt; .0001). Additionally, RNA sequencing showed 3 new fusion genes. In conclusion, clinical disparities between SDCDN and SDCXPA based on molecular and pathological features were observed. We found early growth response 1-brain-derived neurotrophic factor–linking crosstalk between cancer cells and nerves for PNI in SDC, offering insights into future treatment and prognostic factors.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 7","pages":"Article 104167"},"PeriodicalIF":5.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911983","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}