Laboratory Investigation最新文献

{"title":"Neoadjuvant Therapy associated CDX2 Expression and Its Prognostic Implication in Esophageal Adenocarcinoma.","authors":"Heong Ahn, Madhurya Ramineni, Hangchuan Shi, Rena X Li, Moises Velez, Yansheng Hao","doi":"10.1016/j.labinv.2025.104135","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104135","url":null,"abstract":"<p><p>Neoadjuvant chemoradiotherapy followed by surgery is the standard care for locally advanced esophageal adenocarcinoma. However, reliable postoperative prognostic biomarkers are still needed to stratify patients with different clinical outcomes. This study aimed to investigate postneoadjuvant expression changes of CDX2 and its association with histopathological features, biomarkers for targeted therapy, distant metastasis and survival status. A total of 62 esophagogastrectomy specimens from one institution were evaluated. A tissue microarray was constructed and immunohistochemical stains were performed. CDX2 expression was found in twenty-seven (43.5%) cases with well to poor differentiation. Compared with preoperative biopsies, 68.8% of cases demonstrated induced or enhanced CDX2 expression. There were no significant differences in age, tumor location, histologic grade, lymph node metastasis, tumor stage and treatment response between CDX2-positive and CDX2-negative groups. Neuroendocrine and Paneth cell differentiation induced by neoadjuvant therapy were more commonly seen in CDX2-positive cases. CDX2 expression was associated with higher MDR1 and HER-2 expression. Patients with CDX2-positive diseases showed a higher risk of distant metastasis and a worse prognosis than those with CDX2-negative diseases.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104135"},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730730","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":"Systematic Analysis of Factors Affecting HER2 Interpretation Consistency: Staining Protocols, AI-Based Image Standardization, and Classification Criteria.","authors":"Chen Jiang, Mei Li, Chengyou Zheng, Shumei Yan, Lingzhi Kong, Yu Wu, Jinhui Zhang, Xue Chao, Xi Cai, Wentai Feng, Jiehua He, Rongzhen Luo, Shuoyu Xu, Yuanzhong Yang, Peng Sun","doi":"10.1016/j.labinv.2025.104134","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104134","url":null,"abstract":"<p><p>The efficacy of HER2-targeting antibody-drug conjugates (ADCs) has underscored the critical need for precise HER2 diagnostics in breast cancer treatment. Despite the clinical importance, variability in immunohistochemical (IHC) staining protocols and inter-observer inconsistencies challenge the reliability of HER2 status assessment, which is critical for guiding patient treatment strategies. To investigate the factors affecting HER2 interpretation consistency, tissue microarrays (TMAs) from 1063 breast carcinoma cases underwent three distinct IHC protocols, and a novel artificial intelligence (AI) model was developed to standardize HER2-stained images. A total of five sets of TMAs (Nordi QC, Protocol 1, Protocol 2, Protocol 1 AI, Protocol 2 AI) were independently reviewed by eight pathologists. The Fleiss Kappa value and overall agreement rate measured inter-observer agreement, with logistic regression analyzing the impact of variables on diagnostic accuracy. Our results showed that the Nordi QC protocol had the highest inter-observer agreement (Kappa 0.754). AI-based image normalization notably enhanced consistency, particularly for HER2 low cases, aligning scores towards the Nordi QC standard. Logistic regression analysis indicated that both staining protocol and AI-based image standardization significantly influenced diagnostic accuracy (p<0.001). The ASCO/CAP 2018 binary criteria demonstrated the highest HER2 inter-observer consistency (Kappa > 0.95). Compared to the ASCO/CAP 2023 criteria, the newly proposed NULP criteria, merging HER2 low and ultra-low categories, demonstrated improved reliability and agreement, especially in distinguishing the challenging HER2 ultra-low cases, which showed an exceedingly low inter-observer agreement (Kappa < 0.20) across all protocols. Overall, variability in IHC staining protocols and HER2 classification criteria significantly affect the diagnostic consistency among pathologists. The integration of an AI model for image standardization and the adoption of the NULP criteria may refine diagnostic precision and bolster clinical decision-making in breast cancer treatment.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104134"},"PeriodicalIF":5.1,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710491","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":"Erratum to “Virtual Tissue Microarrays for Validating Digital Biomarker Analysis in Colorectal Carcinoma” (Lab Invest 105(2025) 104098)","authors":"Margarita Melnikova Jørgensen ,&nbsp;Stephen Jacques Hamilton-Dutoit ,&nbsp;Jesper Bertram Bramsen ,&nbsp;Claus Lindbjerg Andersen ,&nbsp;Ida Elisabeth Holm","doi":"10.1016/j.labinv.2025.104122","DOIUrl":"10.1016/j.labinv.2025.104122","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 5","pages":"Article 104122"},"PeriodicalIF":5.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143685405","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":"Monoclonal Antibodies from Children with Acute Kawasaki Disease Identify a Common Antigenic Target in Fatal Cases Over Five Decades.","authors":"Anne H Rowley, Robert Byrd, David Arrollo, Amornrat O'Brien, Stanford Shulman, Masaru Terai, Kwang-Youn Kim, Kassandra Mercado, Krystine Wylie, Robert Fialkowski, Susan C Baker","doi":"10.1016/j.labinv.2025.104131","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104131","url":null,"abstract":"<p><p>Kawasaki Disease (KD) is a unique febrile illness of young children that can result in coronary artery aneurysms, myocardial infarction, aneurysm rupture, and sudden death. The epidemiologic features, including the young age group affected, the rarity of recurrence, and the presence of epidemics and outbreaks, point to a single infectious causative agent. The recent decrease in KD cases worldwide during pandemic mitigation supports transmission of the agent via a respiratory route. However, substantial research over decades has shown that KD etiology cannot be linked to any currently known infectious agent. We previously identified the presence of intracytoplasmic inclusion bodies (ICI) in bronchial epithelium in children with fatal KD and a convergent plasmablast-derived antibody response to a specific protein epitope, supporting one predominant respiratory causative agent. Here we report immunohistochemistry and epitope binding using an expanded pool of KD monoclonal antibodies prepared from single peripheral blood plasmablasts from 12 children with acute KD. We identified one or more monoclonal antibodies from each of the 12 patients that recognized ICI in KD bronchial epithelium. Using one representative monoclonal antibody, ICI were detected in 20/20 children with fatal KD across five decades, 10 from the US and 10 from Japan, and were absent in 19/20 infant controls (P<0.001). We also found that all 12 children with acute KD generated plasmablast(s) recognizing the previously reported peptide antigen. Taken together, these results point to one predominant causative agent of KD across many decades and geographic areas and should direct future KD research studies.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104131"},"PeriodicalIF":5.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692689","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 correlation of the extracellular matrix to immune cell phenotypes in the tumor boundary of ccRCC revealed by cyclic immunohistochemistry.","authors":"Grigor Andreev, Tino Vollmer, Max Zirngibl, Martin Werner, Markus Grabbert, Oliver Schilling, Manuel Rogg, Christoph Schell","doi":"10.1016/j.labinv.2025.104130","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104130","url":null,"abstract":"<p><p>The significance of the tumor microenvironment (TME) in predicting immunotherapy efficacy is increasingly acknowledged. However, the complexity of the TME necessitates novel technological approaches for the precise characterization of individual cell types, functional phenotypes, and heterocellular spatial interactions. This study utilizes a streamlined multiplex cyclic immunohistochemistry (cycIHC) protocol for detailed TME annotation. Unlike proprietary methods, cycIHC relies on iterative cycles of conventional immunohistochemistry, using off-the-shelf antibodies and reagents, followed by digitalization, chromogen removal, and antibody stripping. The method was combined with open-source tools for the co-registration of individual staining cycles. Using clear cell renal cell carcinoma (ccRCC) as a model, the protocol was applied for granular annotation of cellular and acellular structures in the tumor boundary zone. Our results demonstrate that the tumor periphery, particularly the pseudocapsule of ccRCC, is homogeneously organized across the 3D scale yet exhibits distinct cellular distribution gradients of T and B cells. These patterns correspond to deposited extracellular matrix proteins, especially collagen types I and VI. Our findings indicate an instructive impact of extracellular matrix (ECM) proteins on defining the spatial organization of immune cells in the TME of ccRCC. The developed cycIHC method facilitates detailed characterization of the TME and may enhance the understanding of tumor-immune cell interactions.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104130"},"PeriodicalIF":5.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692690","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":"Pathology Education for Undergraduate and Graduate Students: It is Not Just for Clinical Trainees","authors":"Avrum I. Gotlieb ,&nbsp;Richard N. Mitchell","doi":"10.1016/j.labinv.2025.104126","DOIUrl":"10.1016/j.labinv.2025.104126","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 5","pages":"Article 104126"},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630587","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":"Hepatoma-derived growth factor promotes liver carcinogenesis by inducing phosphatase and tensin homolog inactivation.","authors":"Shih-Ming Yang, Tsung-Hui Hu, Jian Ching-Wu, Li-Na Yi, Hsiao-Mei Kuo, Mei-Lang Kung, Tian-Huei Chu, Shih-Tsung Huang, Chao-Cheng Huang, Yu-Wei Lin, Ming-Hong Tai","doi":"10.1016/j.labinv.2025.104127","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104127","url":null,"abstract":"<p><p>Hepatoma-derived growth factor (HDGF) is located on chromosome 1q21-23, a locus frequently amplified in hepatocellular carcinoma (HCC), and has been proposed as an oncogenic factor by stimulating PI3K/Akt signaling. Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor that antagonizes PI3K/Akt signaling, suggesting a possible regulatory effect of HDGF on PTEN. Here, we aimed to investigate the regulatory role of HDGF on PTEN. The Cancer Genome Atlas (TCGA) cohort study was used to explore molecular significance and outcomes in liver cancer. Resected clinical specimens, consisting of paired tumor and adjacent non-tumor tissue, were analyzed for expressions of HDGF and PTEN in the liver cancer cohort. Liver tissue and primary hepatocytes derived from HDGF knockout mice were analyzed for PTEN status. The influence of HDGF on PTEN was investigated through in vitro and in vivo genetic manipulation studies. The TCGA cohort study revealed an inverse correlation between HDGF and PTEN, with HDGF overexpression emerging as a dominant factor independent of PTEN levels and correlated with poor outcomes in HCC patients. Paired clinical specimens revealed HDGF upregulation in tumor tissue is relevant to elevated α-fetoprotein, and poor survival and recurrent outcomes in liver cancer cohort. HDGF knockout mice exhibited increased liver p-PTEN levels and decreased PTEN expression. Furthermore, in vitro study validated that overexpression of HDGF increased p-PTEN levels and tumor growth, while knockdown of HDGF yielded inverse results. Treatment with recombinant HDGF confirmed the stimulation of p-PTEN and accumulation of PIP₃. Blockade of HDGF and CK2 signaling using anti-HDGF and a CK2 inhibitor validated the stimulation of p-PTEN. Our results reveal that HDGF is an oncogene frequently amplified and upregulated, leading to suppression of PTEN expression and activity, thereby contributing to malignant progression in liver cancer. HDGF upregulation in resected paired-HCC specimens may constitute a valuable prognostic biomarker for HCC patients.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104127"},"PeriodicalIF":5.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625455","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":"Clinicopathological Characteristics of a Distinct Tumor Phenotype: Invasive Lobular Carcinoma With Tubular Elements in the West German Study Group ADAPTcycle Trial","authors":"Martin Radner ,&nbsp;Sandy Burmeister ,&nbsp;Katarzyna Jóźwiak ,&nbsp;Nora Schaumann ,&nbsp;Malte Gronewold ,&nbsp;Mieke Raap ,&nbsp;Stephan Bartels ,&nbsp;Henriette Christgen ,&nbsp;Leonie D. Kandt ,&nbsp;Pia Hillmann ,&nbsp;Ulrich Lehmann ,&nbsp;Oleg Gluz ,&nbsp;Monika Graeser ,&nbsp;Sherko Kümmel ,&nbsp;Christine zu Eulenburg ,&nbsp;Nadia Harbeck ,&nbsp;Hans Kreipe ,&nbsp;Matthias Christgen","doi":"10.1016/j.labinv.2025.104125","DOIUrl":"10.1016/j.labinv.2025.104125","url":null,"abstract":"<div><div>Invasive lobular carcinoma with tubular elements (ILC-TE) is a recently identified variant of invasive lobular breast carcinoma (ILC). The histology of ILC-TE is defined by noncohesive carcinoma cells mixed with cohesive tubular elements and complete loss of epithelial (E)-cadherin. Cell–cell adhesion is partially restored by switching from an E-cadherin–deficient to a placental (P)-cadherin–proficient status (EPS). The prevalence of ILC-TE remains unknown. Here, we report data from the central pathology review of &gt;4500 hormone receptor–positive/HER2-negative breast cancer (BC) cases recruited to the West German Study Group (WSG) ADAPTcycle trial (NCT04055493). The central pathology review included prospective assessment of BC types, variants, and E-cadherin expression. Cases classified as ILC-TE were analyzed for their molecular features and clinicopathological characteristics. Pure ILC with complete loss of E-cadherin accounted for 630 of 4619 (13.6%) BC cases. ILC-TE accounted for 47 of 630 (7.5%) lobular carcinomas, making it more than twice as prevalent as mixed BC (NST/ILC). ILC-TE harbored deleterious <em>CDH1</em>/E-cadherin mutations in 27 of 35 (77%) cases tested. EPS was detected in 43 of 47 (91%) ILC-TE cases. EPS was significantly more common in ILC-TE than in classic ILC or other ILC variants (<em>P</em> &lt; .001). Clinically, ILC-TE was associated with cT1 stage (<em>P</em> = .023), cN0 status (<em>P</em> = .024), lower histologic grade (<em>P</em> = .004), and lower Ki67 (<em>P</em> = .012). In contrast, solid ILC was associated with higher Ki67 (<em>P</em> = .006). Following preoperative endocrine therapy, higher post–preoperative endocrine therapy Ki67 levels were observed in trabecular ILC, solid-papillary ILC, and pleomorphic ILC (<em>P</em> &lt; .001, <em>P</em> = .006, and <em>P</em> = .021, respectively). In summary, ILC-TE is a quite common ILC variant that is associated with EPS, less-aggressive clinical features, and slow growth.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 6","pages":"Article 104125"},"PeriodicalIF":5.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573401","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":"Development of a Technique for Diagnosis and Screening of Superficial Bladder Cancer by Cell-Pellet DNA From Urine Sample","authors":"Jaekwon Seok ,&nbsp;Hee Jeong Kwak ,&nbsp;Chan-Koo Kang ,&nbsp;Ah Ram Kim ,&nbsp;Woo Suk Choi ,&nbsp;Hyoung Keun Park ,&nbsp;Sung Hyun Paick ,&nbsp;Hyeong Gon Kim ,&nbsp;Yeonjoo Kwak ,&nbsp;Tak-Il Jeon ,&nbsp;Kyung Min Lim ,&nbsp;Baeckseung Lee ,&nbsp;Aram Kim ,&nbsp;Ssang-Goo Cho","doi":"10.1016/j.labinv.2025.104124","DOIUrl":"10.1016/j.labinv.2025.104124","url":null,"abstract":"<div><div>Bladder cancer (BCa) is the most common malignancy of the urinary system with high incidence and recurrence rates. There are several ways to detect BCa. However, different approaches have different accuracy, which essentially depends on the sensitivity and specificity of the technique. Alternative noninvasive diagnostic tools for BCa are needed. We isolated and compared urinary cell-pellet DNA (cpDNA), cell-free DNA, and exosomal DNA from patients with localized BCa. Consequently, we analyzed 12 tissues and cpDNA samples by next-generation sequencing and then used bioinformatic tools to analyze genomic and transcriptomic alterations in coding and noncoding sequences. Then, cpDNA and tissue DNA from 12 patients were analyzed using next-generation sequencing to verify that the genomic characteristics of cpDNA are concordant with those of tissue. We also detected somatic mutation patterns between tissues and their corresponding cpDNA samples. An overlapping variant analysis was performed based on somatic mutation data and a high similarity was observed. Moreover, we identified frequently mutated signaling pathways. In these results, several point mutations were analyzed in <em>FGFR3</em>, <em>TTN</em>, and <em>LEPROTL1</em> from the cpDNA of patients with BCa. Tumor mutational burden analysis showed that cpDNA had no significant difference in tumor mutational burden compared with tumor tissue. These results provide that cpDNA is a potential diagnostic source for detecting and managing BCa using alternative noninvasive methods from patient urine. Our findings may serve as a clinical tool for early detection or recurrence screening of nonmuscle invasive BCa using urinary cpDNA.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 6","pages":"Article 104124"},"PeriodicalIF":5.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567575","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":"74 Sarcomas Associated with Hemosiderotic Fibrolipomatous Tumor (HFLT): A Series of 16 Cases Detailing Clinical and Pathologic Features","authors":"Alexander Perez ,&nbsp;Jeanne Meis","doi":"10.1016/j.labinv.2024.102297","DOIUrl":"10.1016/j.labinv.2024.102297","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 3","pages":"Article 102297"},"PeriodicalIF":5.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143678898","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}