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Virtual Tissue Microarrays for Validating Digital Biomarker Analysis in Colorectal Carcinomaf
IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-31 DOI: 10.1016/j.labinv.2025.104098
Margarita Melnikova Jørgensen , Stephen Jacques Hamilton-Dutoit , Jesper Bertram Bramsen , Claus Lindbjerg Andersen , Ida Elisabeth Holm
Tissue microarrays (TMAs) are used for high-throughput biomarker discovery and validation. Although TMAs have numerous advantages, they may not always be representative of the tissue heterogeneity present in whole tissue sections (WTS) leading to inadequate biomarker quantification. In this pilot study, we studied biomarker expression in 50 randomly selected colorectal cancers and 36 microsatellite unstable cases with or without BRAF variants. We used virtual TMAs to determine the minimum number of tissue cores needed to quantify biomarkers with the same precision as when using WTS. Paraffin sections were immunohistochemically stained for markers of T cells, B cells, cancer-associated fibroblasts, and macrophages. Digitized WTS were divided into tumor center (TC) and invasive margin regions. The minimum number of virtual TMA cores in each region was determined by Bland-Altman plots with 95% limits of agreement. Bland-Altman plots showed substantial disagreement between TMAs and WTS, being highest for 3 cores and decreasing with increasing core numbers. However, even when using 8 cores, the limits of agreement between TMA and WTS were wide, indicating a high degree of measuring uncertainty using TMAs. When using 3 or 4 cores, TMAs underestimated the expression of all the biomarkers in the TC; similarly, levels of macrophage markers in the TC, and levels of B cells in both the TC and the invasive margin remained considerably underestimated, even when using the maximum number of cores possible. However, 3 cores were sufficient to adequately classify biomarkers into categoric low and high expression groups. Microsatellite unstable tumors were characterized by high heterogeneity, which was further increased in the presence of BRAF variant(s). The virtual TMA technique is a useful method to establish the minimum number of cores to be included when constructing tumor TMAs for biomarker analysis. Our results emphasize the importance of TMA validation for a specific biomarker prior to conducting larger clinical studies.
{"title":"Virtual Tissue Microarrays for Validating Digital Biomarker Analysis in Colorectal Carcinomaf","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.2025.104098","DOIUrl":"10.1016/j.labinv.2025.104098","url":null,"abstract":"<div><div>Tissue microarrays (TMAs) are used for high-throughput biomarker discovery and validation. Although TMAs have numerous advantages, they may not always be representative of the tissue heterogeneity present in whole tissue sections (WTS) leading to inadequate biomarker quantification. In this pilot study, we studied biomarker expression in 50 randomly selected colorectal cancers and 36 microsatellite unstable cases with or without <em>BRAF</em> variants. We used virtual TMAs to determine the minimum number of tissue cores needed to quantify biomarkers with the same precision as when using WTS. Paraffin sections were immunohistochemically stained for markers of T cells, B cells, cancer-associated fibroblasts, and macrophages. Digitized WTS were divided into tumor center (TC) and invasive margin regions. The minimum number of virtual TMA cores in each region was determined by Bland-Altman plots with 95% limits of agreement. Bland-Altman plots showed substantial disagreement between TMAs and WTS, being highest for 3 cores and decreasing with increasing core numbers. However, even when using 8 cores, the limits of agreement between TMA and WTS were wide, indicating a high degree of measuring uncertainty using TMAs. When using 3 or 4 cores, TMAs underestimated the expression of all the biomarkers in the TC; similarly, levels of macrophage markers in the TC, and levels of B cells in both the TC and the invasive margin remained considerably underestimated, even when using the maximum number of cores possible. However, 3 cores were sufficient to adequately classify biomarkers into categoric low and high expression groups. Microsatellite unstable tumors were characterized by high heterogeneity, which was further increased in the presence of <em>BRAF</em> variant(s). The virtual TMA technique is a useful method to establish the minimum number of cores to be included when constructing tumor TMAs for biomarker analysis. Our results emphasize the importance of TMA validation for a specific biomarker prior to conducting larger clinical studies.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 4","pages":"Article 104098"},"PeriodicalIF":5.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080562","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}
引用次数: 0
Microsatellite-Stable Gastric Cancer Can be Classified into 2 Molecular Subtypes with Different Immunotherapy Response and Prognosis Based on Gene Sequencing and Computational Pathology
IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-31 DOI: 10.1016/j.labinv.2025.104101
Zhiyi Ye , Xiaoyang Wu , Zheng Wei , Qiuyan Sun , Yanli Wang , Tan Li , Yuan Yuan , Jingjing Jing
Most patients with gastric cancer (GC) exhibit microsatellite stability, yet comprehensive subtyping for prognostic prediction and clinical treatment decisions for microsatellite-stable GC is lacking. In this work, RNA-sequencing gene expression data and clinical information of patients with microsatellite-stable GC were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. We employed several machine learning methods to develop and validate a signature based on immune-related genes (IRGs) for subtyping patients with microsatellite-stable GC. Moreover, 2 deep learning models based on the Vision Transformer (ViT) architecture were developed to predict GC tumor tiles and identify microsatellite-stable GC subtypes from digital pathology slides. Microsatellite status was evaluated by immunohistochemistry, and prognostic data as well as hematoxylin and eosin whole-slide images were collected from 105 patients with microsatellite-stable GC to serve as an independent validation cohort. A signature comprising 5 IRGs was established and validated, stratifying patients with microsatellite-stable GC into high-risk (microsatellite-stable-HR) and low-risk (microsatellite-stable-LR) groups. This signature demonstrated consistent performance, with areas under the receiver operating characteristic curve (AUC) of 0.65, 0.70, and 0.70 at 1, 3, and 5 years in the TCGA cohort, and 0.70, 0.60, and 0.62 in the GEO cohort, respectively. The microsatellite-stable-HR subtype exhibited higher levels of tumor immune dysfunction and exclusion, suggesting a greater potential for immune escape compared with the microsatellite-stable-LR subtype. Moreover, the microsatellite-stable-HR/LR subtypes showed differential sensitivities to various therapeutic drugs. Leveraging morphologic differences, the tumor recognition segmentation model achieved an impressive AUC of 0.97, whereas the microsatellite-stable-HR/LR identification model effectively classified microsatellite-stable-HR/LR subtypes with an AUC of 0.94. Both models demonstrated promising results in classifying patients with microsatellite-stable GC in the external validation cohort, highlighting the strong ability to accurately differentiate between microsatellite-stable GC subtypes. The IRG-related microsatellite-stable-HR/LR subtypes had the potential to enhance outcome prediction accuracy and guide treatment strategies. This research may optimize precision treatment and improve the prognosis for patients with microsatellite-stable GC.
{"title":"Microsatellite-Stable Gastric Cancer Can be Classified into 2 Molecular Subtypes with Different Immunotherapy Response and Prognosis Based on Gene Sequencing and Computational Pathology","authors":"Zhiyi Ye ,&nbsp;Xiaoyang Wu ,&nbsp;Zheng Wei ,&nbsp;Qiuyan Sun ,&nbsp;Yanli Wang ,&nbsp;Tan Li ,&nbsp;Yuan Yuan ,&nbsp;Jingjing Jing","doi":"10.1016/j.labinv.2025.104101","DOIUrl":"10.1016/j.labinv.2025.104101","url":null,"abstract":"<div><div>Most patients with gastric cancer (GC) exhibit microsatellite stability, yet comprehensive subtyping for prognostic prediction and clinical treatment decisions for microsatellite-stable GC is lacking. In this work, RNA-sequencing gene expression data and clinical information of patients with microsatellite-stable GC were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. We employed several machine learning methods to develop and validate a signature based on immune-related genes (IRGs) for subtyping patients with microsatellite-stable GC. Moreover, 2 deep learning models based on the Vision Transformer (ViT) architecture were developed to predict GC tumor tiles and identify microsatellite-stable GC subtypes from digital pathology slides. Microsatellite status was evaluated by immunohistochemistry, and prognostic data as well as hematoxylin and eosin whole-slide images were collected from 105 patients with microsatellite-stable GC to serve as an independent validation cohort. A signature comprising 5 IRGs was established and validated, stratifying patients with microsatellite-stable GC into high-risk (microsatellite-stable-HR) and low-risk (microsatellite-stable-LR) groups. This signature demonstrated consistent performance, with areas under the receiver operating characteristic curve (AUC) of 0.65, 0.70, and 0.70 at 1, 3, and 5 years in the TCGA cohort, and 0.70, 0.60, and 0.62 in the GEO cohort, respectively. The microsatellite-stable-HR subtype exhibited higher levels of tumor immune dysfunction and exclusion, suggesting a greater potential for immune escape compared with the microsatellite-stable-LR subtype. Moreover, the microsatellite-stable-HR/LR subtypes showed differential sensitivities to various therapeutic drugs. Leveraging morphologic differences, the tumor recognition segmentation model achieved an impressive AUC of 0.97, whereas the microsatellite-stable-HR/LR identification model effectively classified microsatellite-stable-HR/LR subtypes with an AUC of 0.94. Both models demonstrated promising results in classifying patients with microsatellite-stable GC in the external validation cohort, highlighting the strong ability to accurately differentiate between microsatellite-stable GC subtypes. The IRG-related microsatellite-stable-HR/LR subtypes had the potential to enhance outcome prediction accuracy and guide treatment strategies. This research may optimize precision treatment and improve the prognosis for patients with microsatellite-stable GC.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 4","pages":"Article 104101"},"PeriodicalIF":5.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080561","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}
引用次数: 0
Automated Scoring to Assess RAD51-Mediated Homologous Recombination in Ovarian Patient-Derived Tumor Organoids
IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-23 DOI: 10.1016/j.labinv.2025.104097
Lucie Thorel , Nicolas Elie , Pierre-Marie Morice , Louis-Bastien Weiswald , Romane Florent , Marion Perréard , Florence Giffard , Agathe Ricou , Raphaël Leman , Guillaume Babin , Jean-François Lebrun , Sandrine Martin , Mélanie Briand , Bernard Lambert , Florence Joly , Cécile Blanc-Fournier , Dominique Vaur , Enora Dolivet , Benoit Plancoulaine , Laurent Poulain
Poly(ADP-ribose) polymerase inhibitors (PARPi) have been shown to improve progression-free survival, particularly in homologous recombination-deficient ovarian cancers. Identifying patients eligible for PARPi is currently based on next-generation sequencing, but the persistence of genomic scars in tumors after restoration of homologous recombination (HR) or epigenetic changes can be a limitation. Functional assays could thus be used to improve this profiling and faithfully identify homologous recombination-deficient tumors. The repair capacity (RECAP) test assesses the formation of RAD51 foci in proliferating cells after irradiation and can be used on tumors as well as on patient-derived tumor organoids (PDTO). However, RAD51 foci scoring is often performed manually without standardization. The purpose of this translational study was to develop an automated tool for scoring RAD51-mediated HR based on whole slide imaging of ovarian PDTO. To that end, we quantified Cyclin A2 and RAD51 immunofluorescence on 9 PDTO models derived from 8 ovarian cancer patients, and next, we compared the RECAP test results to genome instability score and to the patient clinical response. We therefore developed a standardized and automatized quantitative histoimaging tool allowing a comparative RAD51 foci evaluation and thus to define the HR status in PDTO. Our RECAP-based classification was correlated to the genome instability score, offering a new opportunity for standardization of HR assessment in PDTO. This new automated tool to score HR status, which remains to be validated on a large cohort of patients, may thus be used as a complement to next-generation sequencing-based tests in order to improve the identification of the number of patients eligible for PARPi.
{"title":"Automated Scoring to Assess RAD51-Mediated Homologous Recombination in Ovarian Patient-Derived Tumor Organoids","authors":"Lucie Thorel ,&nbsp;Nicolas Elie ,&nbsp;Pierre-Marie Morice ,&nbsp;Louis-Bastien Weiswald ,&nbsp;Romane Florent ,&nbsp;Marion Perréard ,&nbsp;Florence Giffard ,&nbsp;Agathe Ricou ,&nbsp;Raphaël Leman ,&nbsp;Guillaume Babin ,&nbsp;Jean-François Lebrun ,&nbsp;Sandrine Martin ,&nbsp;Mélanie Briand ,&nbsp;Bernard Lambert ,&nbsp;Florence Joly ,&nbsp;Cécile Blanc-Fournier ,&nbsp;Dominique Vaur ,&nbsp;Enora Dolivet ,&nbsp;Benoit Plancoulaine ,&nbsp;Laurent Poulain","doi":"10.1016/j.labinv.2025.104097","DOIUrl":"10.1016/j.labinv.2025.104097","url":null,"abstract":"<div><div>Poly(ADP-ribose) polymerase inhibitors (PARPi) have been shown to improve progression-free survival, particularly in homologous recombination-deficient ovarian cancers. Identifying patients eligible for PARPi is currently based on next-generation sequencing, but the persistence of genomic scars in tumors after restoration of homologous recombination (HR) or epigenetic changes can be a limitation. Functional assays could thus be used to improve this profiling and faithfully identify homologous recombination-deficient tumors. The repair capacity (RECAP) test assesses the formation of RAD51 foci in proliferating cells after irradiation and can be used on tumors as well as on patient-derived tumor organoids (PDTO). However, RAD51 foci scoring is often performed manually without standardization. The purpose of this translational study was to develop an automated tool for scoring RAD51-mediated HR based on whole slide imaging of ovarian PDTO. To that end, we quantified Cyclin A2 and RAD51 immunofluorescence on 9 PDTO models derived from 8 ovarian cancer patients, and next, we compared the RECAP test results to genome instability score and to the patient clinical response. We therefore developed a standardized and automatized quantitative histoimaging tool allowing a comparative RAD51 foci evaluation and thus to define the HR status in PDTO. Our RECAP-based classification was correlated to the genome instability score, offering a new opportunity for standardization of HR assessment in PDTO. This new automated tool to score HR status, which remains to be validated on a large cohort of patients, may thus be used as a complement to next-generation sequencing-based tests in order to improve the identification of the number of patients eligible for PARPi.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 4","pages":"Article 104097"},"PeriodicalIF":5.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143039224","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}
引用次数: 0
HMGB1 Encapsulated in Podocyte-Derived Exosomes Plays a Central Role in Glomerular Endothelial Cell Injury in Lupus Nephritis by Regulating TRIM27 Expression
IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-21 DOI: 10.1016/j.labinv.2025.104096
Jinxi Liu , Tongyu Zhao , Huixin Cui , Yuexin Tian , Xinyan Miao , Lingling Xing , Xiaorong Wang , Jie Huang , Qingjuan Liu , Wei Zhang , Ke Shi , Yunhe Liu , Baiyun Jia , Lihua Kang , Yu Tian , Weicheng Yuan , Shiwei He , Xiaojuan Feng , Shuxia Liu
Exosomes play a role in cell communication by transporting content between cells. Here, we tested whether renal podocyte-derived exosomes affect the injury of glomerular endothelial cells in lupus nephritis (LN). We found that exosomes containing high levels of high mobility group protein B1 (HMGB1) were released from podocytes in patients with LN, BALB/c mice injected with pristane (which induces lupus-like disease in mice), and cultured human renal glomerular endothelial cells (HRGECs) treated with LN plasma. In vitro, GW4869 (an inhibitor of exosome biogenesis/release) or exosome removal alleviated the injury of HRGECs induced by LN plasma. Additionally, leptomycin B or knockdown of HMGB1 in podocyte-derived exosomes reduced endothelial cell injury and the expression of tripartite motif-containing protein 27 (TRIM27). Knockdown or overexpression of TRIM27 attenuated or promoted the damage of HRGECs treated with LN plasma. In vivo, knockdown of HMGB1 in podocytes ameliorated the injury of glomerular endothelial cells in a mouse model of LN. Furthermore, the injection of podocyte-derived exosomes into mice caused glomerular endothelial cell dysfunction. In conclusion, our study revealed that podocyte-derived exosomes may mediate the injury of glomerular endothelial cells seen in LN.
{"title":"HMGB1 Encapsulated in Podocyte-Derived Exosomes Plays a Central Role in Glomerular Endothelial Cell Injury in Lupus Nephritis by Regulating TRIM27 Expression","authors":"Jinxi Liu ,&nbsp;Tongyu Zhao ,&nbsp;Huixin Cui ,&nbsp;Yuexin Tian ,&nbsp;Xinyan Miao ,&nbsp;Lingling Xing ,&nbsp;Xiaorong Wang ,&nbsp;Jie Huang ,&nbsp;Qingjuan Liu ,&nbsp;Wei Zhang ,&nbsp;Ke Shi ,&nbsp;Yunhe Liu ,&nbsp;Baiyun Jia ,&nbsp;Lihua Kang ,&nbsp;Yu Tian ,&nbsp;Weicheng Yuan ,&nbsp;Shiwei He ,&nbsp;Xiaojuan Feng ,&nbsp;Shuxia Liu","doi":"10.1016/j.labinv.2025.104096","DOIUrl":"10.1016/j.labinv.2025.104096","url":null,"abstract":"<div><div>Exosomes play a role in cell communication by transporting content between cells. Here, we tested whether renal podocyte-derived exosomes affect the injury of glomerular endothelial cells in lupus nephritis (LN). We found that exosomes containing high levels of high mobility group protein B1 (HMGB1) were released from podocytes in patients with LN, BALB/c mice injected with pristane (which induces lupus-like disease in mice), and cultured human renal glomerular endothelial cells (HRGECs) treated with LN plasma. In vitro, GW4869 (an inhibitor of exosome biogenesis/release) or exosome removal alleviated the injury of HRGECs induced by LN plasma. Additionally, leptomycin B or knockdown of HMGB1 in podocyte-derived exosomes reduced endothelial cell injury and the expression of tripartite motif-containing protein 27 (TRIM27). Knockdown or overexpression of TRIM27 attenuated or promoted the damage of HRGECs treated with LN plasma. In vivo, knockdown of HMGB1 in podocytes ameliorated the injury of glomerular endothelial cells in a mouse model of LN. Furthermore, the injection of podocyte-derived exosomes into mice caused glomerular endothelial cell dysfunction. In conclusion, our study revealed that podocyte-derived exosomes may mediate the injury of glomerular endothelial cells seen in LN.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 4","pages":"Article 104096"},"PeriodicalIF":5.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029128","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}
引用次数: 0
Monospecies Bacteria-Induced Chronic Apical Periodontitis Triggers the Aortic Inflammatory Response Via Modulation of Systemic Inflammation and Lipid Metabolism 单种细菌诱导的慢性根尖牙周炎通过调节全身炎症和脂质代谢触发主动脉炎症反应。
IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-16 DOI: 10.1016/j.labinv.2025.104095
Huaxiang Lei , Shuai Chen , Xiaojing Huang , Dianfu Ma , Yufang Luo , Suli Xiao , Pingping Li , Guowu Gan , Zhiyu Cai
Cardiovascular disease (CVD) is the leading cause of death worldwide and has been confirmed to be associated with a common oral bacterial infection—chronic apical periodontitis (CAP). However, the detailed mechanisms remain controversial. CAP can potentially alter systemic inflammation, lipid metabolism, and gut microbiota, all of which contribute to the progression of the aortic inflammatory response. This study aimed to explore the differential effects between Enterococcus faecalis and Porphyromonas gingivalis-CAP on the aortic inflammatory response, which focused on changes in systemic inflammation, lipid metabolism, and gut microbiota, to explore potential mechanisms linking oral disease to CVD. Our results showed P. gingivalis-CAP could activate more serious aortic inflammatory cytokine micro RNA expression (TNF-α, MCP-1, and ICAM-1) than E. faecalis-CAP by promoting higher serum inflammation (TNF-α, IL-6, IL-1α, and MCP-1) and lipid (low-density lipoprotein cholesterol and total cholesterol) levels. Simultaneously, there was no significant change in gut microbiota between them. Furthermore, all serum inflammatory cytokines showed substantial correlations with aortic inflammatory cytokine micro RNA expression, and certain serum lipid indicators showed significant correlations, but only 2 gut microorganisms (Ruminococcaceae and Prevotellaceae) showed significant correlations. The combined results suggest that CAP might activate the aortic inflammatory response in association with changes in the 3 potential mechanisms. However, the promotion of gut microbiota might be relatively weak. Using experimental CAP induced by specific bacteria, in which bacteria are sequestered in the medullary cavity, avoids the direct influence of blood or intestinal pathways and provides new perspectives for studying the mechanism of CVD associated with oral disease. Overall, these findings suggest that CAP may exacerbate systemic inflammation and serum lipid levels in patients with CVD, highlighting the importance of educating such patients on oral hygiene.
心血管疾病(CVD)是世界范围内导致死亡的主要原因,并已被证实与一种常见的口腔细菌感染——慢性根尖牙周炎(CAP)有关。然而,其具体机制仍存在争议。CAP可以潜在地改变全身炎症、脂质代谢和肠道微生物群,所有这些都有助于主动脉炎症反应的进展。本研究旨在探讨粪肠球菌和牙龈卟啉卟啉链球菌对主动脉炎症反应的差异影响,重点关注全身炎症、脂质代谢和肠道微生物群的变化,以探索口腔疾病与心血管疾病之间的潜在机制。结果表明,与粪孢杆菌相比,牙龈假单胞菌- cap可通过提高血清炎症因子(TNF-α、IL-6、IL-1α和MCP-1)和脂质(LDL-C和TC)水平,激活更严重的主动脉炎性细胞因子mRNA (TNF-α、MCP-1和ICAM-1)表达。同时,它们之间的肠道菌群没有显著变化。此外,所有血清炎症细胞因子与主动脉炎症细胞因子mRNA表达均呈显著相关性,某些血脂指标与主动脉炎症细胞因子mRNA表达呈显著相关性,但只有Ruminococcaceae和Prevotellaceae两种肠道微生物与主动脉炎症细胞因子mRNA表达呈显著相关性。综合结果表明,CAP可能与三种潜在机制的变化相关,从而激活主动脉炎症反应。然而,肠道菌群的促进可能相对较弱。利用特定细菌诱导的实验性CAP,细菌被隔离在髓腔内,避免了血液或肠道通路的直接影响,为研究口腔疾病相关CVD的机制提供了新的视角。总的来说,这些发现表明,CAP可能会加剧CVD患者的全身性炎症和血脂水平,强调了对这些患者进行口腔卫生教育的重要性。
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引用次数: 0
Molecular and Immunohistochemical Classification of Extrapulmonary Small Cell Neuroendocrine Carcinomas: A Study of 181 Cases 181例肺外小细胞神经内分泌癌的分子和免疫组织化学分类研究。
IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-16 DOI: 10.1016/j.labinv.2025.104093
Klára Pavlíčková , Jan Hojný , Petr Waldauf , Marián Švajdler , Pavel Dundr , Pavel Fabian , Eva Krkavcová , Jiří Dvořák , Romana Michálková , Iva Staniczková Zambo , Nikola Hájková , Miroslava Flídrová , Jan Laco , Helena Hornychová , Patricie Delongová , Jozef Škarda , Jan Hrudka , Radoslav Matěj
Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Most patients with EP-SCNC have metastatic disease upon presentation, and their average overall survival (OS) is less than 12 months. Our study aimed to conduct a complex analysis of EP-SCNC. One hundred eighty-one EP-SCNC tissue samples were subjected to a complex analysis. One hundred fifty-five tumors were pure EP-SCNC, whereas 26 were combined tumors. Immunohistochemistry for ASCL1, NEUROD1, YAP1, POU2F3, Rb1, p53, cyclin D1, p16, PTEN, DLL3, PD-L1, CD56, synaptophysin, chromogranin A, and INSM1 was performed, and 128 samples were analyzed molecularly using next-generation sequencing, comprising DNA and RNA analyses. Detailed results on immunohistochemical and molecular analyses were provided for each primary origin of EP-SCNC separately. Median survival for the whole cohort of patients was 8.94 months. Patient age (≥70 years), tumor mutational burden <15, and TP53 and BRCA2 mutations were negative prognostic factors. High expression of ASCL-1 was associated with shorter OS, whereas high expression of YAP1 was associated with longer OS. Patients with genitourinary tumors had significantly better OS than those with gastrointestinal tract EP-SCNC tumors. Rb1 expression loss was detected more often in genitourinary tract SCNCs. In contrast, p16 overexpression was found more often in genitourinary tract SCNCs. POU2F3 expression was detected more often in combined tumors, whereas NEUROD1 was detected more often in pure EP-SCNC. Regarding “druggable markers,” DLL3 was expressed in 66% of tumors and PD-L1 in 17.4%. Detailed analyses of different prognostic and predictive markers are needed to better understand EP-SCNC biology and create more personalized therapy to improve patient prognosis.
肺外小细胞神经内分泌癌(EP-SCNC)是一种罕见的恶性肿瘤,预后差。大多数EP-SCNC患者在就诊时都有转移性疾病,其平均总生存期(OS)少于12个月。本研究旨在对EP-SCNC进行复杂分析。181个EP-SCNC组织样本进行了复杂分析。纯EP-SCNC 155例,合并EP-SCNC 26例。对ASCL1、NEUROD1、YAP1、POU2F3、Rb1、p53、cyclin D1、p16、PTEN、DLL3、PD-L1、CD56、synaptophysin、chromogranin A和INSM1进行免疫组化,并使用下一代测序(NGS)对128个样本进行分子分析,包括DNA和RNA分析。详细的免疫组织化学和分子分析结果分别提供了EP-SCNC的每个主要来源。整个队列患者的中位生存期为8.94个月。患者年龄(≥70岁)、肿瘤突变负担(TMB) < 15、TP53和BRCA2突变为预后不良因素。ASCL-1的高表达与较短的生存期相关,而YAP1的高表达与较长的生存期相关。泌尿生殖系统肿瘤患者的OS明显优于胃肠道EP-SCNC肿瘤患者。Rb1表达缺失在泌尿生殖道scnc中更为常见。相比之下,p16过表达在泌尿生殖道scnc中更为常见。POU2F3在合并肿瘤中表达较多,而NEUROD1在纯EP-SCNC中表达较多。关于“可药物标记物”,DLL3在66%的肿瘤中表达,PD-L1在17.4%中表达。需要对不同的预后和预测标志物进行详细分析,以更好地了解EP-SCNC生物学,并制定更个性化的治疗方案,以改善患者预后。
{"title":"Molecular and Immunohistochemical Classification of Extrapulmonary Small Cell Neuroendocrine Carcinomas: A Study of 181 Cases","authors":"Klára Pavlíčková ,&nbsp;Jan Hojný ,&nbsp;Petr Waldauf ,&nbsp;Marián Švajdler ,&nbsp;Pavel Dundr ,&nbsp;Pavel Fabian ,&nbsp;Eva Krkavcová ,&nbsp;Jiří Dvořák ,&nbsp;Romana Michálková ,&nbsp;Iva Staniczková Zambo ,&nbsp;Nikola Hájková ,&nbsp;Miroslava Flídrová ,&nbsp;Jan Laco ,&nbsp;Helena Hornychová ,&nbsp;Patricie Delongová ,&nbsp;Jozef Škarda ,&nbsp;Jan Hrudka ,&nbsp;Radoslav Matěj","doi":"10.1016/j.labinv.2025.104093","DOIUrl":"10.1016/j.labinv.2025.104093","url":null,"abstract":"<div><div>Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Most patients with EP-SCNC have metastatic disease upon presentation, and their average overall survival (OS) is less than 12 months. Our study aimed to conduct a complex analysis of EP-SCNC. One hundred eighty-one EP-SCNC tissue samples were subjected to a complex analysis. One hundred fifty-five tumors were pure EP-SCNC, whereas 26 were combined tumors. Immunohistochemistry for ASCL1, NEUROD1, YAP1, POU2F3, Rb1, p53, cyclin D1, p16, PTEN, DLL3, PD-L1, CD56, synaptophysin, chromogranin A, and INSM1 was performed, and 128 samples were analyzed molecularly using next-generation sequencing, comprising DNA and RNA analyses. Detailed results on immunohistochemical and molecular analyses were provided for each primary origin of EP-SCNC separately. Median survival for the whole cohort of patients was 8.94 months. Patient age (≥70 years), tumor mutational burden &lt;15, and <em>TP53</em> and <em>BRCA2</em> mutations were negative prognostic factors. High expression of ASCL-1 was associated with shorter OS, whereas high expression of YAP1 was associated with longer OS. Patients with genitourinary tumors had significantly better OS than those with gastrointestinal tract EP-SCNC tumors. Rb1 expression loss was detected more often in genitourinary tract SCNCs. In contrast, p16 overexpression was found more often in genitourinary tract SCNCs. POU2F3 expression was detected more often in combined tumors, whereas NEUROD1 was detected more often in pure EP-SCNC. Regarding “druggable markers,” DLL3 was expressed in 66% of tumors and PD-L1 in 17.4%. Detailed analyses of different prognostic and predictive markers are needed to better understand EP-SCNC biology and create more personalized therapy to improve patient prognosis.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 4","pages":"Article 104093"},"PeriodicalIF":5.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007960","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}
引用次数: 0
Leveraging Deep Learning for Immune Cell Quantification and Prognostic Evaluation in Radiotherapy-Treated Oropharyngeal Squamous Cell Carcinomas 利用深度学习进行放射治疗口咽鳞状细胞癌的免疫细胞定量和预后评估。
IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-16 DOI: 10.1016/j.labinv.2025.104094
Fanny Beltzung , Van-Linh Le , Ioana Molnar , Erwan Boutault , Claude Darcha , François Le Loarer , Myriam Kossai , Olivier Saut , Julian Biau , Frédérique Penault-Llorca , Emmanuel Chautard
The tumor microenvironment plays a critical role in cancer progression and therapeutic responsiveness, with the tumor immune microenvironment (TIME) being a key modulator. In head and neck squamous cell carcinomas (HNSCCs), immune cell infiltration significantly influences the response to radiotherapy (RT). A better understanding of the TIME in HNSCCs could help identify patients most likely to benefit from combining RT with immunotherapy. Standardized, cost-effective methods for studying TIME in HNSCCs are currently lacking. This study aims to leverage deep learning (DL) to quantify immune cell densities using immunohistochemistry in untreated oropharyngeal squamous cell carcinoma (OPSCC) biopsies of patients scheduled for curative RT and assess their prognostic value. We analyzed 84 pretreatment formalin-fixed paraffin-embedded tumor biopsies from OPSCC patients. Immunohistochemistry was performed for CD3, CD8, CD20, CD163, and FOXP3, and whole slide images were digitized for analysis using a U-Net-based DL model. Two quantification approaches were applied: a cell-counting method and an area-based method. These methods were applied to stained regions. The DL model achieved high accuracy in detecting stained cells across all biomarkers. Strong correlations were found between our DL pipeline, the HALO Image Analysis Platform, and the open-source QuPath software for estimating immune cell densities. Our DL pipeline provided an accurate and reproducible approach for quantifying immune cells in OPSCC. The area-based method demonstrated superior prognostic value for recurrence-free survival, when compared with the cell-counting method. Elevated densities of CD3, CD8, CD20, and FOXP3 were associated with improved recurrence-free survival, whereas CD163 showed no significant prognostic association. These results highlight the potential of DL in digital pathology for assessing TIME and predicting patient outcomes.
肿瘤微环境(tumor microenvironment, TME)在肿瘤进展和治疗反应中起着关键作用,肿瘤免疫微环境(tumor immune microenvironment, TIME)是一个关键的调节因子。在头颈部鳞状细胞癌(HNSCC)中,免疫细胞浸润显著影响放射治疗(RT)的反应。更好地了解HNSCC的时间可以帮助确定最有可能从RT联合免疫治疗中获益的患者。目前缺乏标准化的、具有成本效益的方法来研究HNSCC中的TIME。本研究旨在利用深度学习(DL),利用免疫组织化学(IHC)在计划进行治愈性放疗的未治疗口咽鳞状细胞癌(OPSCC)活检中量化免疫细胞密度,并评估其预后价值。我们分析了84例术前福尔马林固定石蜡包埋(FFPE)肿瘤活检的OPSCC患者。对CD3、CD8、CD20、CD163和FOXP3进行免疫组化,并对全片图像(wsi)进行数字化处理,使用基于u - net的DL模型进行分析。采用两种定量方法:细胞计数法和基于区域的方法。这些方法适用于染色区域。DL模型在检测所有生物标志物的染色细胞方面具有很高的准确性。我们的DL管道、HALO®图像分析平台和用于估计免疫细胞密度的开源QuPath软件之间存在很强的相关性。我们的DL管道为定量OPSCC中的免疫细胞提供了一种准确且可重复的方法。与细胞计数法相比,基于区域的方法在无复发生存(RFS)方面显示出更高的预后价值。CD3、CD8、CD20和FOXP3的浓度升高与RFS改善相关,而CD163的浓度升高与预后无显著相关性。这些结果突出了数字病理学中DL在评估时间和预测患者预后方面的潜力。
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引用次数: 0
Immune Biomarkers on Tissue Microarray Cores Support the Presence of Adjacent Tertiary Lymphoid Structures in Soft Tissue Sarcoma 组织微阵列核心上的免疫生物标志物支持软组织肉瘤中邻近三级淋巴结构的存在。
IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-10 DOI: 10.1016/j.labinv.2025.104091
Elahe Shenasa , Shelby Thornton , Dongxia Gao , Felix K.F. Kommoss , Torsten O. Nielsen
Immunotherapy has emerged as a new treatment modality in some soft tissue sarcomas, particularly for tumors associated with tertiary lymphoid structures (TLSs). These structures are functional lymphoid aggregates, and their presence is indicative of an active anticancer immune response in the tumor microenvironment. The assessment of TLS as a predictive biomarker at scale on patient specimens remains challenging. Although tissue microarrays (TMAs) could facilitate this assessment, it is unclear whether small microarray cores can represent and identify associated TLS responses.
We sought to use multiplex immunohistochemistry to identify key components of TLS: T cells, B cells, and dendritic cells. The multiplex panels (CD3, CD20, CD208, and PNAd) were applied to 80 cases both on TMAs and on their cognate available full-faced sections from epithelioid sarcoma and dedifferentiated/well-differentiated liposarcoma case series. TMAs were digitally scored for the number of immune cells using the HALO image analysis platform, and cognate full-faced sections were visually evaluated for the presence of TLS. An independent validation set of soft tissue sarcomas (N = 49) was stained with the CD3, CD20, and CD208, and scored by QuPath.
A combined immune marker (defined as the presence of more than 24% CD3+ T cells, or 0.51% CD20+ B cells, or >0.14% CD208+ mature dendritic cells on tissue microarray cores) is highly specific (100%) and moderately sensitive (61%) to predict the existence of TLS on full-faced sections. The combined immune marker showed a sensitivity of 25% and specificity of 91% on the validation set.
The combined immune marker assessed on tissue microarrays is highly specific in inferring the presence of TLS on cognate full-faced sections. Therefore, despite the small area sampled, tissue microarrays may be utilized to assess the clinical value of TLS on data sets where specificity is critical and large sample size can mitigate low-to-moderate sensitivity.
免疫治疗已成为一些软组织肉瘤的一种新的治疗方式,特别是与三级淋巴结构(TLS)相关的肿瘤。这些结构是功能性淋巴细胞聚集体,它们的存在表明肿瘤微环境中存在活跃的抗癌免疫反应。在患者标本上大规模评估TLS作为预测性生物标志物仍然具有挑战性。虽然组织微阵列可以促进这种评估,但尚不清楚小型微阵列核心是否可以代表和识别相关的TLS响应。我们试图使用多重免疫组织化学鉴定TLS的关键成分:T细胞、B细胞和树突状细胞。多重面板(CD3、CD20、CD208和PNAd)应用于80例上皮样肉瘤和去分化/高分化脂肪肉瘤病例系列的组织微阵列和同源全面切片。使用HALO图像分析平台对组织微阵列的免疫细胞数量进行数字评分,并对同源全面切片进行视觉评估,以确定是否存在TLS。对49例软组织肉瘤(N=49)进行CD3、CD20和CD208染色,并通过QuPath评分。联合免疫标记(定义为在组织微阵列核心上存在超过24%的CD3+T细胞,或0.51%的CD20+B细胞,或超过0.14%的CD208+成熟树突状细胞)对预测全面切片上TLS的存在具有高度特异性(100%)和中等敏感性(61%)。联合免疫标记在验证集上的敏感性为25%,特异性为91%。在组织微阵列上评估的联合免疫标记具有高度特异性,可以推断同源全面切片上存在TLS。因此,尽管取样面积小,但组织微阵列可用于评估TLS在数据集上的临床价值,其中特异性至关重要,大样本量可以减轻低至中等灵敏度。
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引用次数: 0
CD248 Cleaved Form in Human Colorectal Cancer Stroma: Implications for Tumor Behavior and Prognosis 人类结直肠癌基质中的 CD248 裂解形式:对肿瘤行为和预后的影响。
IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.1016/j.labinv.2024.102188
Elisa Pothin , Yosra Bedoui , Caroline Michault , Johanna Zemour , Emmanuel Chirpaz , Philippe Gasque , Mohamed Khettab , Franck Ah-Pine
CD248 (endosialin/tumor endothelial marker 1) is upregulated in cancer, including colorectal cancer (CRC), but its exact role in tumor progression remains to be elucidated. Previous studies have shown that the extracellular domain of CD248 mediates the interaction between tumor cells and extracellular matrix proteins and that interfering with this interaction may reduce tumor invasion and migration activities. We have examined the expression of CD248 in 117 human CRC samples by immunohistochemistry and investigated the association with various clinicopathologic features, including the occurrence of metastasis, intratumoral immune cell density and overall survival. Of the 117 specimens analyzed, 76.1% (89/117) exhibited CD248-high stromal expression, whereas 23.9% (28/117) demonstrated CD248-low stromal expression. Interestingly, we detected the presence of a cleaved form of CD248, which appears to accumulate in the stromal extracellular matrix. A higher metastasis rate (lymph node and distant) was observed in the CD248-low group (21/28, 75.0% vs 44/89, 49.4%; P = .02). In addition, CD248-low tumors had fewer CD163-positive macrophages and FoxP3-positive regulatory T cells (P < .05) with no significant difference in CD8-positive T-cell infiltration and PD-L1 expression between the groups (P > .05). Finally, overall survival was lower in CD248-low tumors than in CD248-high tumors, with 5-year survival rates of 35.7% and 57.3%, respectively (P = .01). In a multivariate analysis, the hazard ratio of CD248-low tumors vs CD248-high tumors was 1.93 (95% CI, 1.09-3.41; P = .02). Our findings suggest that CD248 stromal expression may influence the tumor microenvironment, impacting tumor behavior and prognosis, and can serve as a promising prognostic biomarker in CRC.
CD248(Endosialin/TEM-1)在包括结直肠癌(CRC)在内的癌症中上调,但其在肿瘤进展中的确切作用仍有待阐明。以前的研究表明,CD248 的胞外结构域介导肿瘤细胞与细胞外基质蛋白之间的相互作用,干扰这种相互作用可能会降低肿瘤的侵袭和迁移活动。我们用免疫组化方法检测了 117 例人类 CRC 标本中 CD248 的表达,并研究了其与各种临床病理特征(包括转移的发生、瘤内免疫细胞密度和总生存期)的关系。在分析的 117 份标本中,76.1%(89/117)显示 CD248 高基质表达,而 23.1%(28/117)显示 CD248 低基质表达。有趣的是,我们检测到了CD248的裂解形式,它似乎积聚在基质细胞外基质中。CD248 低表达组的转移率(淋巴结和远处)较高(21/28,75.0% 对 44/89,49.4%,P=0.02)。此外,CD248-low 组肿瘤中 CD163 阳性巨噬细胞和 FoxP3 阳性调节性 T 细胞较少(P0.05)。最后,CD248低的肿瘤的总生存率低于CD248高的肿瘤,5年生存率分别为35.7%和57.3%(P=0.01)。在多变量分析中,CD248-低肿瘤与CD248-高肿瘤的危险比为1.93(95%置信区间:1.09 - 3.40;P=0.02)。我们的研究结果表明,CD248基质表达可能会影响TME,从而影响肿瘤的行为和预后,并可作为一种有前途的CRC预后生物标志物。
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引用次数: 0
Spatial Lipidomics Reveals Myelin Defects and Protumor Macrophage Infiltration in Malignant Peripheral Nerve Sheath Tumor Adjacent Nerves 空间脂质组学揭示了 MPNST 邻近神经的髓鞘缺陷和促肿瘤巨噬细胞浸润。
IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.1016/j.labinv.2024.102186
Rick Ursem , Justus L. Groen , Martijn J.A. Malessy , Inge Briaire-de Bruijn , Liam A. McDonnell , Bram P.A.M. Heijs , Judith V.M.G. Bovee
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas arising from peripheral nerves, accounting for 3% to 5% of soft tissue sarcomas. MPNSTs often recur locally, leading to poor survival. Achieving tumor-free surgical margins is essential to prevent recurrence, but current methods for determining tumor margins are limited, highlighting the need for improved biomarkers. In this study we investigated the degree to which MPNST extends into nerves adjacent to tumors. Alterations to the lipidome of MPNST and adjacent peripheral nerves were assessed using spatial lipidomics. Tissue samples from 5 patients with MPNST were analyzed, revealing alterations of the lipid profile extending into the peripheral nerves beyond what was expected based on macroscopic and histologic observations. Integration of spatial lipidomics and high-resolution accurate-mass profiling identified distinct lipid profiles associated with healthy nerves, connective tissue, and tumors. Notably, histologically normal nerves exhibited myelin degradation and infiltration of protumoral M2 macrophages, particularly near the tumor. Furthermore, aberrant osmium staining patterns and loss of H3K27me3 staining in the absence of atypia were observed in a case with tumor recurrence. This exploratory study thereby highlights the changes occurring in the nerves affected by MPNST beyond what is visible on hematoxylin and eosin staining and provides leads for further biomarker studies, including aberrant osmium staining, to assess resection margins in MPNST.
恶性周围神经鞘瘤(MPNST)是一种由周围神经引起的侵袭性肉瘤,占软组织肉瘤的 3-5%。恶性周围神经鞘瘤经常局部复发,导致生存率低下。实现无肿瘤手术切缘对防止复发至关重要,但目前确定肿瘤切缘的方法有限,这凸显了对改良生物标记物的需求。在这项研究中,我们调查了 MPNST 向肿瘤邻近神经延伸的程度。我们使用空间脂质组学评估了 MPNST 和邻近周围神经脂质体的变化。对 5 名 MPNST 患者的组织样本进行了分析,结果发现脂质谱的改变延伸到了外周神经,超出了宏观和组织学观察的预期。空间脂质组学与高分辨率精确质量分析相结合,确定了与健康神经、结缔组织和肿瘤相关的不同脂质特征。值得注意的是,组织学上正常的神经表现出髓鞘降解和亲肿瘤 M2 巨噬细胞的浸润,尤其是在肿瘤附近。此外,在一个肿瘤复发的病例中,还观察到异常的锇染色模式和 H3K27me3 染色缺失,但没有非典型性。因此,这项探索性研究强调了受 MPNST 影响的神经中发生的变化,这些变化超出了 H&E 所能看到的范围,并为进一步的生物标记物研究提供了线索,包括异常锇染色,以评估 MPNST 的切除边缘。
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Laboratory Investigation
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