Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder identified by persistent synovial inflammation, joint destruction, and systemic complications. Affecting approximately 0.5–1 % of the global population, RA poses a considerable burden in terms of disability and healthcare costs. Over the past century, insights into RA pathogenesis—driven by immune dysregulation, genetic predisposition, and environmental triggers—have revolutionized therapeutic strategies. This review provides a detailed overview of the evolving landscape of RA drug development, tracing the progression from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate and sulfasalazine, to targeted synthetic DMARDs (tsDMARDs) like JAK inhibitors, and biologic DMARDs (bDMARDs) including TNF and IL-6 antagonists. We explore the molecular underpinnings of RA, discuss the mechanisms of action and clinical applications of current therapies, and highlight emerging drug candidates under clinical investigation. Despite significant advances, challenges such as incomplete remission rates, variable patient responses, and long-term safety concerns underscore the need for precision medicine and novel therapeutic approaches. This review emphasizes the critical role of immunopathology in guiding RA drug development and the ongoing efforts to achieve personalized, sustained disease control.
{"title":"New frontiers in rheumatoid arthritis therapy: From classic DMARDs to biologics and beyond","authors":"Vanshika , Puja Gulati , Ritika Thakur , Deeksha Bala , Richa Bajaj , Priya , Chetan Bansal , Tamanna Dhiman , Inderjeet Verma , Shivani Pannu","doi":"10.1016/j.prp.2025.156307","DOIUrl":"10.1016/j.prp.2025.156307","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder identified by persistent synovial inflammation, joint destruction, and systemic complications. Affecting approximately 0.5–1 % of the global population, RA poses a considerable burden in terms of disability and healthcare costs. Over the past century, insights into RA pathogenesis—driven by immune dysregulation, genetic predisposition, and environmental triggers—have revolutionized therapeutic strategies. This review provides a detailed overview of the evolving landscape of RA drug development, tracing the progression from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate and sulfasalazine, to targeted synthetic DMARDs (tsDMARDs) like JAK inhibitors, and biologic DMARDs (bDMARDs) including TNF and IL-6 antagonists. We explore the molecular underpinnings of RA, discuss the mechanisms of action and clinical applications of current therapies, and highlight emerging drug candidates under clinical investigation. Despite significant advances, challenges such as incomplete remission rates, variable patient responses, and long-term safety concerns underscore the need for precision medicine and novel therapeutic approaches. This review emphasizes the critical role of immunopathology in guiding RA drug development and the ongoing efforts to achieve personalized, sustained disease control.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156307"},"PeriodicalIF":3.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.prp.2025.156310
Yu Zhao , Liuxin Yang , Peng Wang , Shuang Huo , Xingxing Yuan , Jiakang Jiang
Background
Hepatocellular carcinoma (HCC) is a global health challenge with limited treatment options, largely due to the ability of tumor cells to evade programmed cell death (PCD). Dysregulation of key PCD pathways; apoptosis, necroptosis, pyroptosis, and autophagy plays a pivotal role in hepatocarcinogenesis, progression, and therapy resistance.
Objective
This review comprehensively elucidates the molecular mechanisms governing these PCD pathways, their dysregulation in HCC, and the resulting therapeutic opportunities.
Methods
We systematically analyzed current literature to detail the core regulators of each PCD pathway, summarize how HCC cells evade them, and evaluate preclinical and clinical strategies for therapeutic targeting.
Key findings
HCC cells hijack multiple mechanisms to suppress apoptosis and divert necroptosis. Pyroptosis exhibits a dual role, acting as a tumor suppressor but also contributing to an immunosuppressive microenvironment in established tumors. Autophagy serves a context-dependent function, preventing tumor initiation but sustaining advanced tumors. Promisingly, preclinical studies demonstrate that resensitizing HCC cells to PCD, particularly through combination therapies, can overcome resistance. Early-phase clinical trials targeting these pathways, especially with autophagy inhibitors, have shown manageable safety profiles and hints of efficacy, though larger trials are needed.
Conclusion
The precise modulation of PCD pathways represents a promising frontier in HCC therapy. Future efforts must focus on patient stratification, biomarker development, and rational combination strategies that exploit the crosstalk between different PCD modalities to improve clinical outcomes.
{"title":"Molecular regulation and therapeutic targeting of programmed cell death in hepatocellular carcinoma","authors":"Yu Zhao , Liuxin Yang , Peng Wang , Shuang Huo , Xingxing Yuan , Jiakang Jiang","doi":"10.1016/j.prp.2025.156310","DOIUrl":"10.1016/j.prp.2025.156310","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (HCC) is a global health challenge with limited treatment options, largely due to the ability of tumor cells to evade programmed cell death (PCD). Dysregulation of key PCD pathways; apoptosis, necroptosis, pyroptosis, and autophagy plays a pivotal role in hepatocarcinogenesis, progression, and therapy resistance.</div></div><div><h3>Objective</h3><div>This review comprehensively elucidates the molecular mechanisms governing these PCD pathways, their dysregulation in HCC, and the resulting therapeutic opportunities.</div></div><div><h3>Methods</h3><div>We systematically analyzed current literature to detail the core regulators of each PCD pathway, summarize how HCC cells evade them, and evaluate preclinical and clinical strategies for therapeutic targeting.</div></div><div><h3>Key findings</h3><div>HCC cells hijack multiple mechanisms to suppress apoptosis and divert necroptosis. Pyroptosis exhibits a dual role, acting as a tumor suppressor but also contributing to an immunosuppressive microenvironment in established tumors. Autophagy serves a context-dependent function, preventing tumor initiation but sustaining advanced tumors. Promisingly, preclinical studies demonstrate that resensitizing HCC cells to PCD, particularly through combination therapies, can overcome resistance. Early-phase clinical trials targeting these pathways, especially with autophagy inhibitors, have shown manageable safety profiles and hints of efficacy, though larger trials are needed.</div></div><div><h3>Conclusion</h3><div>The precise modulation of PCD pathways represents a promising frontier in HCC therapy. Future efforts must focus on patient stratification, biomarker development, and rational combination strategies that exploit the crosstalk between different PCD modalities to improve clinical outcomes.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156310"},"PeriodicalIF":3.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.prp.2025.156306
Yinghan Jiang , Jianzhong He , Bingsen He , Lingyan Liu , Li Wang , Huan Li , Yanan Li , Yuebin Shi , Rongsheng Liu , Peiren Tang , Ying Li , Ji Du , Jun Peng , Jie Li , Yang Chen
Background
Differentiating benign from malignant lung tumors remains a critical and often challenging task in histopathological diagnosis. With the advancement of artificial intelligence (AI), large language models such as ChatGPT offer novel opportunities for assisting in diagnostic workflows.
Methods
This study retrospectively collected 250 histopathological images, including 50 cases each of lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), lung neuroendocrine neoplasms, bronchiolar adenoma, and pulmonary hamartoma. ChatGPT-4o was applied to analyze hematoxylin–eosin (HE) stained images and generate diagnostic interpretations. Its performance was compared to diagnoses made by two experienced pathologists, with evaluations based on accuracy, sensitivity, specificity, F1 score, misdiagnosis rate, and diagnostic time.
Results
ChatGPT-4o achieved an overall accuracy of 79.6 %, sensitivity of 81.3 %, specificity of 77.0 %, and F1 score of 82.7 %, significantly lower than the performance of human pathologists (p < 0.001). While its diagnostic accuracy for benign lesions such as bronchiolar adenoma was comparable to human experts, misclassifications frequently occurred in highly differentiated malignancies and poorly visualized neuroendocrine tumors. Notably, ChatGPT-4o achieved near real-time diagnostic speed (<10 s), vastly outperforming human diagnostic time.
Conclusion
ChatGPT-4o shows promise as a rapid, scalable AI-assisted diagnostic tool for lung tumors, particularly for benign lesions that are morphologically challenging. Although not yet a replacement for expert pathologists, it may serve as a valuable adjunct to support decision-making and improve diagnostic efficiency in clinical pathology.
{"title":"Assessing large language model for automated diagnosis of benign and malignant lung tumors","authors":"Yinghan Jiang , Jianzhong He , Bingsen He , Lingyan Liu , Li Wang , Huan Li , Yanan Li , Yuebin Shi , Rongsheng Liu , Peiren Tang , Ying Li , Ji Du , Jun Peng , Jie Li , Yang Chen","doi":"10.1016/j.prp.2025.156306","DOIUrl":"10.1016/j.prp.2025.156306","url":null,"abstract":"<div><h3>Background</h3><div>Differentiating benign from malignant lung tumors remains a critical and often challenging task in histopathological diagnosis. With the advancement of artificial intelligence (AI), large language models such as ChatGPT offer novel opportunities for assisting in diagnostic workflows.</div></div><div><h3>Methods</h3><div>This study retrospectively collected 250 histopathological images, including 50 cases each of lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), lung neuroendocrine neoplasms, bronchiolar adenoma, and pulmonary hamartoma. ChatGPT-4o was applied to analyze hematoxylin–eosin (HE) stained images and generate diagnostic interpretations. Its performance was compared to diagnoses made by two experienced pathologists, with evaluations based on accuracy, sensitivity, specificity, F1 score, misdiagnosis rate, and diagnostic time.</div></div><div><h3>Results</h3><div>ChatGPT-4o achieved an overall accuracy of 79.6 %, sensitivity of 81.3 %, specificity of 77.0 %, and F1 score of 82.7 %, significantly lower than the performance of human pathologists (p < 0.001). While its diagnostic accuracy for benign lesions such as bronchiolar adenoma was comparable to human experts, misclassifications frequently occurred in highly differentiated malignancies and poorly visualized neuroendocrine tumors. Notably, ChatGPT-4o achieved near real-time diagnostic speed (<10 s), vastly outperforming human diagnostic time.</div></div><div><h3>Conclusion</h3><div>ChatGPT-4o shows promise as a rapid, scalable AI-assisted diagnostic tool for lung tumors, particularly for benign lesions that are morphologically challenging. Although not yet a replacement for expert pathologists, it may serve as a valuable adjunct to support decision-making and improve diagnostic efficiency in clinical pathology.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156306"},"PeriodicalIF":3.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality. Microsatellite instability-high (MSI-H) tumors, resulting from defective DNA mismatch repair (MMR), represent a well-defined subtype with distinctive biological behavior and immunogenicity. In contrast, tumors with elevated microsatellite alterations at tetranucleotide repeats (EMAST) are less well characterized. EMAST can manifest with MSI or arise as an isolated form of instability, delineating discrete phenotypes underpinned by distinct mechanisms. This study aimed to characterize MSI and EMAST status in CRCs. By integrating instability profiles with clinicopathological features and mutational profiles of key driver genes, we aimed to refine molecular classification and advance understanding of CRC tumorigenesis. A total of 332 CRCs were analyzed for MSI and EMAST using established panels. Clinicopathological characteristics were recorded, and mutational profiling of KRAS, BRAF, CTNNB1, PIK3CA, and TP53 was performed. MLH1 expression was assessed using immunohistochemistry. MSS/EMAST-S tumors displayed profiles typical of chromosomally stable CRC, dominated by KRAS and followed by TP53 and PIK3CA mutations. MSI-H/EMAST-H tumors were characterized by frequent BRAF mutations, right-sided location, female predominance, and lower TP53 mutation rate, consistent with the classical hypermutated, immunogenic subtype. In contrast, MSS/EMAST-H tumors exhibited unique features, including enrichment for PIK3CA and CTNNB1 mutations, larger tumor size, and poorer differentiation, suggesting an intermediate phenotype between MSS and MSI-H. MSS/EMAST-L tumors aligned with chromosomally stable, KRAS/Wnt-driven CRC. In conclusion, MSS/EMAST-H tumors represent an underrecognized CRC subtype with intermediate genomic instability and a distinctive molecular profile, with potential implications for prognostic assessment and personalized therapeutic strategies.
{"title":"Clinicopathological features and mutational landscape of colorectal cancer subgroups defined by MSI and EMAST status","authors":"Tamara Cacev , Kristina Vuković Đerfi , Anamarija Salar , Sonja Marinović , Emilija Zapletal , Vesna Musani , Anita Škrtić , Arijana Pačić , Sanja Kapitanović","doi":"10.1016/j.prp.2025.156302","DOIUrl":"10.1016/j.prp.2025.156302","url":null,"abstract":"<div><div>Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality. Microsatellite instability-high (MSI-H) tumors, resulting from defective DNA mismatch repair (MMR), represent a well-defined subtype with distinctive biological behavior and immunogenicity. In contrast, tumors with elevated microsatellite alterations at tetranucleotide repeats (EMAST) are less well characterized. EMAST can manifest with MSI or arise as an isolated form of instability, delineating discrete phenotypes underpinned by distinct mechanisms. This study aimed to characterize MSI and EMAST status in CRCs. By integrating instability profiles with clinicopathological features and mutational profiles of key driver genes, we aimed to refine molecular classification and advance understanding of CRC tumorigenesis. A total of 332 CRCs were analyzed for MSI and EMAST using established panels. Clinicopathological characteristics were recorded, and mutational profiling of <em>KRAS</em>, <em>BRAF</em>, <em>CTNNB1</em>, <em>PIK3CA</em>, and <em>TP53</em> was performed. MLH1 expression was assessed using immunohistochemistry. MSS/EMAST-S tumors displayed profiles typical of chromosomally stable CRC, dominated by <em>KRAS</em> and followed by <em>TP53</em> and <em>PIK3CA</em> mutations. MSI-H/EMAST-H tumors were characterized by frequent <em>BRAF</em> mutations, right-sided location, female predominance, and lower <em>TP53</em> mutation rate, consistent with the classical hypermutated, immunogenic subtype. In contrast, MSS/EMAST-H tumors exhibited unique features, including enrichment for <em>PIK3CA</em> and <em>CTNNB1</em> mutations, larger tumor size, and poorer differentiation, suggesting an intermediate phenotype between MSS and MSI-H. MSS/EMAST-L tumors aligned with chromosomally stable, KRAS/Wnt-driven CRC. In conclusion, MSS/EMAST-H tumors represent an underrecognized CRC subtype with intermediate genomic instability and a distinctive molecular profile, with potential implications for prognostic assessment and personalized therapeutic strategies.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156302"},"PeriodicalIF":3.2,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1016/j.prp.2025.156305
Fan Yang , Chi Peng , Sisi Yang , Xiuwu Bian , Xiaohong Yao
Glioblastoma (GBM), a highly vascularized and aggressive primary brain tumor, presents unresolved questions regarding the functional significance of angiogenesis-related genes (ARGs) in disease progression. To systematically investigate this, we employed univariate Cox regression followed by LASSO regression analysis to identify prognosis-associated ARGs. These candidates were subsequently evaluated using six machine learning-derived survival prediction algorithms, with model interpretability achieved through SHapley Additive exPlanations (SHAP) analysis. Our studies revealed that six hub ARGs (BMP2, FSCN1, NET1, AEBP1, SEMA3G, and RAB37) were identified and incorporated into a novel risk stratification model (high and low risk groups). High-risk patients demonstrated significantly poorer overall survival in the CGGA-GBM, GSE43378, and GSE7696 cohorts. Moreover, the high-risk group exhibited an immunosuppressive tumor microenvironment profile (e.g., elevated Treg infiltration, P < 0.0001), increased extracellular matrix stiffness (via mechanosensing markers) and differential drug sensitivity (OncoPredict analysis). Immunofluorescence confirmed co-localization of the hub protein FSCN1 with vascular (CD31⁺), stromal (α-SMA⁺), and mesenchymal (Vimentin⁺) compartments, suggesting its multifunctional role in GBM pathobiology. In summary, our research established the ARG-derived prognostic signature validated across independent GBM cohorts and revealed concomitant immune and mechanical niche dysregulation in high-risk patients. The rationale for combined angiogenesis/stroma/immune modulation strategies was provided, with FSCN1 proposed as the potential therapeutic target.
{"title":"Deciphering the role of angiogenesis in glioblastoma: Integrative insights from transcriptomic profiling, single-cell sequencing and interpretable machine learning approaches","authors":"Fan Yang , Chi Peng , Sisi Yang , Xiuwu Bian , Xiaohong Yao","doi":"10.1016/j.prp.2025.156305","DOIUrl":"10.1016/j.prp.2025.156305","url":null,"abstract":"<div><div>Glioblastoma (GBM), a highly vascularized and aggressive primary brain tumor, presents unresolved questions regarding the functional significance of angiogenesis-related genes (ARGs) in disease progression. To systematically investigate this, we employed univariate Cox regression followed by LASSO regression analysis to identify prognosis-associated ARGs. These candidates were subsequently evaluated using six machine learning-derived survival prediction algorithms, with model interpretability achieved through SHapley Additive exPlanations (SHAP) analysis. Our studies revealed that six hub ARGs (BMP2, FSCN1, NET1, AEBP1, SEMA3G, and RAB37) were identified and incorporated into a novel risk stratification model (high and low risk groups). High-risk patients demonstrated significantly poorer overall survival in the CGGA-GBM, GSE43378, and GSE7696 cohorts. Moreover, the high-risk group exhibited an immunosuppressive tumor microenvironment profile (e.g., elevated Treg infiltration, <em>P</em> < 0.0001), increased extracellular matrix stiffness (via mechanosensing markers) and differential drug sensitivity (OncoPredict analysis). Immunofluorescence confirmed co-localization of the hub protein FSCN1 with vascular (CD31⁺), stromal (α-SMA⁺), and mesenchymal (Vimentin⁺) compartments, suggesting its multifunctional role in GBM pathobiology. In summary, our research established the ARG-derived prognostic signature validated across independent GBM cohorts and revealed concomitant immune and mechanical niche dysregulation in high-risk patients. The rationale for combined angiogenesis/stroma/immune modulation strategies was provided, with FSCN1 proposed as the potential therapeutic target.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156305"},"PeriodicalIF":3.2,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human epidermal growth factor receptor 2 (HER2) is an emerging therapeutic target in endometrial carcinoma (EC). Current guidelines recommend routine HER2 testing for p53 abnormal (p53abn) tumors, potentially underestimating its value in non-p53abn cases. This study aimed to assess the incidence and clinical relevance of HER2 immunoreactivity in advanced non-p53abn EC.
Methods
HER2 immunohistochemistry and next-generation sequencing were performed in 128 advanced EC patients. Clinicopathological features, survival, and molecular alterations were compared according to HER2 immunoreactivity.
Results
Of all patients, 18.8 % were HER2 2 + /3 + , 28.9 % were HER2 1 + , and 52.3 % were HER2 0. Molecular classification included 1.6 % POLE mutant, 35.2 % mismatch repair-deficient/ microsatellite instability-high, 29.7 % p53abn, and 33.6 % no specific molecular profile (NSMP). In the non-p53abn group, HER2 3 + was less frequent than in the p53abn group, whereas the frequencies of HER2 2 + and 1 + did not differ significantly between the two groups. In non-p53abn patients, HER2 2 + /3 + occurred most frequently in clear cell carcinoma (CCC, 6/11, 54.5 %) and was associated with adnexal metastasis (2 +/3 + vs. 1 +, 66.7 % vs. 15.4 %, P < 0.05). No survival differences were observed among non-p53abn patients by HER2 immunoreactivity, however, within the NSMP subgroup, both overall and progression-free survival were worse in HER2 2 + /3 + compared with 1 + (log-rank P < 0.05). In non-p53abn ECs, KRAS mutations were significantly less frequent in HER2 2 + /3 + group (2 +/3 + vs. 1 +, 6.7 % vs. 46.2 %, P < 0.05).
Conclusions
HER2 2 + /3 + immunoreactivity was detected in 16.7 % of advanced non-p53abn EC, particularly enriched in CCC. These findings highlight the potential clinical significance of HER2 testing in non-p53abn patients.
{"title":"HER2 immunoreactivity in advanced non-p53abn endometrial carcinoma: Association with clinical features, prognosis, and molecular characteristics","authors":"Yining Zhen, Yinbo Xiao, Yang Zhou, Longyun Chen, Junyi Pang, Xiaohua Shi, Zhiyong Liang","doi":"10.1016/j.prp.2025.156304","DOIUrl":"10.1016/j.prp.2025.156304","url":null,"abstract":"<div><h3>Background</h3><div>Human epidermal growth factor receptor 2 (HER2) is an emerging therapeutic target in endometrial carcinoma (EC). Current guidelines recommend routine HER2 testing for p53 abnormal (p53abn) tumors, potentially underestimating its value in non-p53abn cases. This study aimed to assess the incidence and clinical relevance of HER2 immunoreactivity in advanced non-p53abn EC.</div></div><div><h3>Methods</h3><div>HER2 immunohistochemistry and next-generation sequencing were performed in 128 advanced EC patients. Clinicopathological features, survival, and molecular alterations were compared according to HER2 immunoreactivity.</div></div><div><h3>Results</h3><div>Of all patients, 18.8 % were HER2 2 + /3 + , 28.9 % were HER2 1 + , and 52.3 % were HER2 0. Molecular classification included 1.6 % <em>POLE</em> mutant, 35.2 % mismatch repair-deficient/ microsatellite instability-high, 29.7 % p53abn, and 33.6 % no specific molecular profile (NSMP). In the non-p53abn group, HER2 3 + was less frequent than in the p53abn group, whereas the frequencies of HER2 2 + and 1 + did not differ significantly between the two groups. In non-p53abn patients, HER2 2 + /3 + occurred most frequently in clear cell carcinoma (CCC, 6/11, 54.5 %) and was associated with adnexal metastasis (2 +/3 + vs. 1 +, 66.7 % vs. 15.4 %, <em>P</em> < 0.05). No survival differences were observed among non-p53abn patients by HER2 immunoreactivity, however, within the NSMP subgroup, both overall and progression-free survival were worse in HER2 2 + /3 + compared with 1 + (log-rank <em>P</em> < 0.05). In non-p53abn ECs, <em>KRAS</em> mutations were significantly less frequent in HER2 2 + /3 + group (2 +/3 + vs. 1 +, 6.7 % vs. 46.2 %, <em>P</em> < 0.05).</div></div><div><h3>Conclusions</h3><div>HER2 2 + /3 + immunoreactivity was detected in 16.7 % of advanced non-p53abn EC, particularly enriched in CCC. These findings highlight the potential clinical significance of HER2 testing in non-p53abn patients.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156304"},"PeriodicalIF":3.2,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MLH1 promoter methylation status may serve as an important diagnostic, prognostic, and predictive biomarker in management of mismatch repair (MMR)-deficient cancers. A new commercial assay for detection of MLH1 promoter hyper-methylation (EntroGen), which interrogates regions C and D, was assessed for its performance characteristics. False positive results were obtained in 5/21 non-lesional cases, with signals limited to region C. Three were explained by overloaded reactions. Two unexplained cases were both muscle samples (2/6 muscle samples, one each of skeletal and smooth). The assay was 100 % concordant (52/52) for lesional samples with expected MLH1 promoter methylation status. These included two exceptional cases—one Lynch-associated, and one POLE-mutated endometrial carcinoma; thus expanding the spectrum of extreme cases, and demonstrate neither germline or somatic NGS results completely rule out MLH1 promoter methylation, and vice versa. The POLEmut/MLH1meth carcinoma was notable for molecular features in keeping with POLE dysfunction, accompanied by multiple, additional genetic lesions in the MMR pathway. Exploring the TCGA dataset, 1/8 cases of POLE (ultramutated) endometrial carcinoma was notable for MLH1 silencing. Comprehensive genomic profiling assay was informative, allowing for correlation of MLH1 methylation and POLE genotype results with tumor mutation burden and mutational signature. Taken together, our data highlight the need for integrated approach in endometrial carcinoma biomarker testing, integrating NGS and MLH1 promoter methylation status, the latter of which benefits from assessing both regions C and D. Finding of MLH1 promoter methylation does not rule out either Lynch syndrome or ultramutated (POLE) carcinoma.
{"title":"Pitfalls in MLH1 promoter methylation assessment, including POLEmut/MLH1meth endometrial adenocarcinoma","authors":"Amelia Flaus , Zhi Cui , Mirko Miladinovic , Ju-Yoon Yoon","doi":"10.1016/j.prp.2025.156303","DOIUrl":"10.1016/j.prp.2025.156303","url":null,"abstract":"<div><div><em>MLH1</em> promoter methylation status may serve as an important diagnostic, prognostic, and predictive biomarker in management of mismatch repair (MMR)-deficient cancers. A new commercial assay for detection of <em>MLH1</em> promoter hyper-methylation (EntroGen), which interrogates regions C and D, was assessed for its performance characteristics. False positive results were obtained in 5/21 non-lesional cases, with signals limited to region C. Three were explained by overloaded reactions. Two unexplained cases were both muscle samples (2/6 muscle samples, one each of skeletal and smooth). The assay was 100 % concordant (52/52) for lesional samples with expected <em>MLH1</em> promoter methylation status. These included two exceptional cases—one Lynch-associated, and one <em>POLE</em>-mutated endometrial carcinoma; thus expanding the spectrum of extreme cases, and demonstrate neither germline or somatic NGS results completely rule out <em>MLH1</em> promoter methylation, and vice versa. The <em>POLE</em><sup>mut</sup>/<em>MLH1</em><sup>meth</sup> carcinoma was notable for molecular features in keeping with POLE dysfunction, accompanied by multiple, additional genetic lesions in the MMR pathway. Exploring the TCGA dataset, 1/8 cases of POLE (ultramutated) endometrial carcinoma was notable for <em>MLH1</em> silencing. Comprehensive genomic profiling assay was informative, allowing for correlation of <em>MLH1</em> methylation and <em>POLE</em> genotype results with tumor mutation burden and mutational signature. Taken together, our data highlight the need for integrated approach in endometrial carcinoma biomarker testing, integrating NGS and <em>MLH1</em> promoter methylation status, the latter of which benefits from assessing both regions C and D. Finding of <em>MLH1</em> promoter methylation does not rule out either Lynch syndrome or ultramutated (POLE) carcinoma.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156303"},"PeriodicalIF":3.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.prp.2025.156301
Haiyang Cui , Xuejiao Fan
Background
Bladder cancer (BCa) is a prevalent malignancy with high recurrence and metastasis rates. Nuclear receptor subfamily 4 group A member 3 (NR4A3), a member of the orphan nuclear receptor superfamily, is implicated in various cancers, but its functional role and mechanisms in BCa have not been well understood. This study aimed to explore the functional significance and diagnostic value of NR4A3 in BCa, with a focus on its regulation of endoplasmic reticulum (ER) stress and anoikis sensitivity via ATF6 and RNF139.
Methods
NR4A3 expression in BCa cell lines was assessed by qRT-PCR and Western blot. Gain-of-function assays were performed to evaluate cell proliferation, apoptosis, and anoikis sensitivity in vitro. ER stress markers and ATF6 degradation were examined by immunoblotting, cycloheximide chase, and ubiquitination assays. The role of RNF139 and its regulation by NR4A3 via KLF2 and KLF4 were determined via various biological assays. In vivo tumorigenesis was assessed using a xenograft mouse model. Additionally, the diagnostic performance of NR4A3 was evaluated in 100 clinical patients using serum ELISA and color Doppler ultrasound.
Results
NR4A3 was downregulated in BCa cells, and its overexpression suppressed cell proliferation, colony formation and promoted apoptosis and anoikis sensitivity. Mechanistically, NR4A3 inhibited ER stress by promoting ATF6 ubiquitination and degradation via transcriptional activation of RNF139 through KLF2 and KLF4. RNF139 directly interacted with ATF6 and mediated its ubiquitination at lysine 152. In vivo, NR4A3 overexpression inhibited tumor growth. Clinically, combining color Doppler ultrasound with serum NR4A3 levels significantly improved diagnostic accuracy for BCa (AUC = 0.986).
Conclusion
NR4A3 suppresses BCa progression via the KLF2/4-RNF139-ATF6 axis and enhances diagnostic efficacy when combined with ultrasound imaging.
{"title":"Targeting the NR4A3-RNF139-ATF6 pathway as a therapeutic and diagnostic strategy in bladder cancer","authors":"Haiyang Cui , Xuejiao Fan","doi":"10.1016/j.prp.2025.156301","DOIUrl":"10.1016/j.prp.2025.156301","url":null,"abstract":"<div><h3>Background</h3><div>Bladder cancer (BCa) is a prevalent malignancy with high recurrence and metastasis rates. Nuclear receptor subfamily 4 group A member 3 (NR4A3), a member of the orphan nuclear receptor superfamily, is implicated in various cancers, but its functional role and mechanisms in BCa have not been well understood. This study aimed to explore the functional significance and diagnostic value of NR4A3 in BCa, with a focus on its regulation of endoplasmic reticulum (ER) stress and anoikis sensitivity via ATF6 and RNF139.</div></div><div><h3>Methods</h3><div>NR4A3 expression in BCa cell lines was assessed by qRT-PCR and Western blot. Gain-of-function assays were performed to evaluate cell proliferation, apoptosis, and anoikis sensitivity <em>in vitro</em>. ER stress markers and ATF6 degradation were examined by immunoblotting, cycloheximide chase, and ubiquitination assays. The role of RNF139 and its regulation by NR4A3 via KLF2 and KLF4 were determined via various biological assays. <em>In vivo</em> tumorigenesis was assessed using a xenograft mouse model. Additionally, the diagnostic performance of NR4A3 was evaluated in 100 clinical patients using serum ELISA and color Doppler ultrasound.</div></div><div><h3>Results</h3><div>NR4A3 was downregulated in BCa cells, and its overexpression suppressed cell proliferation, colony formation and promoted apoptosis and anoikis sensitivity. Mechanistically, NR4A3 inhibited ER stress by promoting ATF6 ubiquitination and degradation via transcriptional activation of RNF139 through KLF2 and KLF4. RNF139 directly interacted with ATF6 and mediated its ubiquitination at lysine 152. <em>In vivo</em>, NR4A3 overexpression inhibited tumor growth. Clinically, combining color Doppler ultrasound with serum NR4A3 levels significantly improved diagnostic accuracy for BCa (AUC = 0.986).</div></div><div><h3>Conclusion</h3><div>NR4A3 suppresses BCa progression via the KLF2/4-RNF139-ATF6 axis and enhances diagnostic efficacy when combined with ultrasound imaging.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156301"},"PeriodicalIF":3.2,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.prp.2025.156295
Javad Omidi
Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with limited therapeutic options and poor prognosis. Recent advances in high-throughput sequencing and integrative bioinformatics have unraveled the complex molecular landscape of ACC, highlighting critical genomic, epigenomic, transcriptomic, and immune-related alterations. This review synthesizes current evidence to provide a comprehensive overview of the key molecular mechanisms driving ACC pathogenesis. The role of recurrent mutations (e.g., TP53, CTNNB1), dysregulated cell cycle genes (e.g., CDK1, CCNB1, AURKA), non-coding RNAs, and epigenetic modifications in shaping tumor behavior is discussed. Multi-omics integration and systems biology approaches have enabled the identification of robust prognostic gene signatures and protein biomarkers, offering novel tools for risk stratification. Furthermore, the tumor immune microenvironment is examined, with hypoxia, immune suppression, and checkpoint pathways highlighted as emerging targets. Finally, computational drug repositioning strategies that nominate repurposed agents such as IGF1R inhibitors and BCLAF1 modulators for therapeutic intervention are explored. Together, these insights pave the way for precision oncology in ACC, while emphasizing the need for rigorous multi-layered validation and standardized clinical integration to enable real-world translational impact.
{"title":"Molecular landscape and biomarker discovery in adrenocortical carcinoma: An integrative review of bioinformatics and translational insights","authors":"Javad Omidi","doi":"10.1016/j.prp.2025.156295","DOIUrl":"10.1016/j.prp.2025.156295","url":null,"abstract":"<div><div>Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with limited therapeutic options and poor prognosis. Recent advances in high-throughput sequencing and integrative bioinformatics have unraveled the complex molecular landscape of ACC, highlighting critical genomic, epigenomic, transcriptomic, and immune-related alterations. This review synthesizes current evidence to provide a comprehensive overview of the key molecular mechanisms driving ACC pathogenesis. The role of recurrent mutations (e.g., TP53, CTNNB1), dysregulated cell cycle genes (e.g., CDK1, CCNB1, AURKA), non-coding RNAs, and epigenetic modifications in shaping tumor behavior is discussed. Multi-omics integration and systems biology approaches have enabled the identification of robust prognostic gene signatures and protein biomarkers, offering novel tools for risk stratification. Furthermore, the tumor immune microenvironment is examined, with hypoxia, immune suppression, and checkpoint pathways highlighted as emerging targets. Finally, computational drug repositioning strategies that nominate repurposed agents such as IGF1R inhibitors and BCLAF1 modulators for therapeutic intervention are explored. Together, these insights pave the way for precision oncology in ACC, while emphasizing the need for rigorous multi-layered validation and standardized clinical integration to enable real-world translational impact.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156295"},"PeriodicalIF":3.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.prp.2025.156300
Zhixing Zhang , Wei Kang , Chunjun Li , Dongdong Zhang , Xiaoyu Chen , Dan Lu , Yuzhen Huang , Lixia Zeng
Purpose
To investigate the presence and clinical significance of tertiary lymphoid structures (TLSs) in HER2-low breast cancer, by focusing on their associations with clinicopathological features and prognosis.
Methods
Hematoxylin and eosin staining and immunohistochemical markers were used in combination with whole-slide imaging (WSI) to delineate invasive carcinoma and adjacent TLSs. WSI-based tools were subsequently utilized to annotate the location, density, and maturity of TLSs.
Results
Among 560 patients with HER2-low breast cancer, the median age was 53 years and the age range was 28–85 years; 34 % (189/560) had TLSs-positive tumors. TLSs were associated with high histological grade, high-grade DCIS, absence of lymphovascular invasion, ER-negative, PR-negative, HER2 2 + , high K-i67, and triple-negative breast cancer subtypes (all P < 0.05). In the low-age cohort, TLSs (+), TLSs density, TLSs maturity, and peritumoral TLSs were significantly associated with poorer DFS (all P < 0.05).Conversely, TLSs (+), TLSs density, TLSs maturity, and peritumoral TLSs were significantly associated with better DFS in the high-age cohort (all P < 0.05).
Conclusion
In HER2-low breast cancer, TLSs were associated with higher histological grade, the presence of DCIS, absence of lymphovascular invasion, as well as expression of ER negative, PR negative, HER2 2 + , high K-i67, and triple-negative breast cancer. Additionally, the clinical prognosis value of TLSs (such as DFS) exhibited a correlation with the patient’s age.
{"title":"The clinical pathological significance of TLSs in HER2-low breast cancer","authors":"Zhixing Zhang , Wei Kang , Chunjun Li , Dongdong Zhang , Xiaoyu Chen , Dan Lu , Yuzhen Huang , Lixia Zeng","doi":"10.1016/j.prp.2025.156300","DOIUrl":"10.1016/j.prp.2025.156300","url":null,"abstract":"<div><h3>Purpose</h3><div>To investigate the presence and clinical significance of tertiary lymphoid structures (TLSs) in HER2-low breast cancer, by focusing on their associations with clinicopathological features and prognosis.</div></div><div><h3>Methods</h3><div>Hematoxylin and eosin staining and immunohistochemical markers were used in combination with whole-slide imaging (WSI) to delineate invasive carcinoma and adjacent TLSs. WSI-based tools were subsequently utilized to annotate the location, density, and maturity of TLSs.</div></div><div><h3>Results</h3><div>Among 560 patients with HER2-low breast cancer, the median age was 53 years and the age range was 28–85 years; 34 % (189/560) had TLSs-positive tumors. TLSs were associated with high histological grade, high-grade DCIS, absence of lymphovascular invasion, ER-negative, PR-negative, HER2 2 + , high K-i67, and triple-negative breast cancer subtypes (all P < 0.05). In the low-age cohort, TLSs (+), TLSs density, TLSs maturity, and peritumoral TLSs were significantly associated with poorer DFS (all P < 0.05).Conversely, TLSs (+), TLSs density, TLSs maturity, and peritumoral TLSs were significantly associated with better DFS in the high-age cohort (all P < 0.05).</div></div><div><h3>Conclusion</h3><div>In HER2-low breast cancer, TLSs were associated with higher histological grade, the presence of DCIS, absence of lymphovascular invasion, as well as expression of ER negative, PR negative, HER2 2 + , high K-i67, and triple-negative breast cancer. Additionally, the clinical prognosis value of TLSs (such as DFS) exhibited a correlation with the patient’s age.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156300"},"PeriodicalIF":3.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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