Pathobiology最新文献

{"title":"p16 Immunohistochemical Patterns in Triple-Negative Breast Cancer: Clinical and Genomic Similarities of the p16 Diffuse Pattern to pRB Deficiency.","authors":"Miseon Lee, Ahwon Lee, Byung-Ock Choi, Woo-Chan Park, Jieun Lee, Jun Kang","doi":"10.1159/000541299","DOIUrl":"10.1159/000541299","url":null,"abstract":"<p><strong>Introduction: </strong>Triple-negative breast cancer (TNBC) is associated with alterations in the retinoblastoma pathway. As a consequence of retinoblastoma protein (pRB) loss, compensatory upregulation of p16 occurs due to the loss of phosphorylated pRB-mediated negative feedback on p16 expression. The aim of this study is to investigate the clinicopathological and genomic characteristics associated with the diffuse pattern of p16 immunohistochemistry (IHC) in TNBC.</p><p><strong>Methods: </strong>The study analyzed surgically resected TNBC for whole-exome sequencing in 113 cases and for cDNA microarray in 144 cases. The p16 IHC results were classified into two patterns: diffuse and negative/mosaic.</p><p><strong>Results: </strong>In the entire cohort (n = 257), the diffuse pattern of p16 IHC was observed in 123 (47.9%) patients and the negative/mosaic pattern in 134 (52.1%). Biallelic RB1 inactivation was observed in 14.3% of patients with the diffuse pattern. The diffuse pattern of p16 IHC showed more frequent RB1 alterations and cell cycle progression signatures, a higher Ki-67 labeling index, more frequent chromosome segment copy number changes, a higher frequency of homologous recombination deficiency high, and immune-related signatures. PIK3CA mutations were more frequent in the negative/mosaic pattern. CCND1 amplification was identified in 5 cases, all with the negative/mosaic pattern.</p><p><strong>Conclusion: </strong>In TNBC, the diffuse p16 pattern shows clinical and genomic similarities to pRB-deficient tumors, suggesting shared characteristics. This suggests that p16 IHC testing may provide new therapeutic approaches, underscoring its potential clinical importance.</p><p><strong>Introduction: </strong>Triple-negative breast cancer (TNBC) is associated with alterations in the retinoblastoma pathway. As a consequence of retinoblastoma protein (pRB) loss, compensatory upregulation of p16 occurs due to the loss of phosphorylated pRB-mediated negative feedback on p16 expression. The aim of this study is to investigate the clinicopathological and genomic characteristics associated with the diffuse pattern of p16 immunohistochemistry (IHC) in TNBC.</p><p><strong>Methods: </strong>The study analyzed surgically resected TNBC for whole-exome sequencing in 113 cases and for cDNA microarray in 144 cases. The p16 IHC results were classified into two patterns: diffuse and negative/mosaic.</p><p><strong>Results: </strong>In the entire cohort (n = 257), the diffuse pattern of p16 IHC was observed in 123 (47.9%) patients and the negative/mosaic pattern in 134 (52.1%). Biallelic RB1 inactivation was observed in 14.3% of patients with the diffuse pattern. The diffuse pattern of p16 IHC showed more frequent RB1 alterations and cell cycle progression signatures, a higher Ki-67 labeling index, more frequent chromosome segment copy number changes, a higher frequency of homologous recombination deficiency high, and immune-related signatures. PIK","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":" ","pages":"63-76"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Papilloma Virus-Related Oral Mucosal Lesions in Turkey: A Retrospective Cohort Study.","authors":"Leyla Arslan Bozdag, Sibel Elif Gultekin","doi":"10.1159/000541664","DOIUrl":"10.1159/000541664","url":null,"abstract":"<p><strong>Introduction: </strong>The human papillomavirus (HPV) is the etiological agent of a variety of oral mucosal benign and pre/malignant lesions, which demonstrate a wide range of prevalence according to geographic regions.</p><p><strong>Material and methods: </strong>This study specifically examined the typing of HPV-associated oral mucosal lesions in Turkish patients. The DNA from FFPE blocks of 228 lesions was utilized for this purpose. A total of 87 oral mucosal lesions were classified as benign, 68 as premalignant, and 73 as malignant. DNA from these lesions was amplified using polymerase chain reaction, and genotypes were identified using restriction fragment length polymorphisms (RFLP).</p><p><strong>Results: </strong>HPV-DNA was identified in 17 out of 228 patients, indicating a prevalence incidence of 7.4%. In benign oral lesions, the prevalence of HPV-DNA was 9.2% (8/87 cases), whereas in premalignant, oral epithelial dysplasia, and oral squamous cell carcinoma lesions, it was 6.9% (9/141 cases). A significant statistical difference was found between patients who tested positive for HPV and those who tested negative in terms of the location of the lesion and the age of the patients (p = 0.0097, p = 0.02, respectively).</p><p><strong>Conclusions: </strong>This study underscores the considerable prevalence of HPV infection in oral mucosal lesions among individuals in Central Anatolia, Turkey.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":" ","pages":"90-98"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392282","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}

{"title":"Erratum.","authors":"","doi":"10.1159/000543584","DOIUrl":"10.1159/000543584","url":null,"abstract":"","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":" ","pages":"121-122"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597479","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}

{"title":"Next-Generation Integrated Sequencing Identifies Poor Prognostic Factors in Patients with MYD88-Mutated Chronic Lymphocytic Leukemia in Taiwan.","authors":"Ying-Jung Huang, Jing Quan Lim, Jacob Shujui Hsu, Ming-Chung Kuo, Po-Nan Wang, Hsiao-Wen Kao, Jin-Hou Wu, Chiu-Chen Chen, Shih-Feng Tsai, Choon Kiat Ong, Lee-Yung Shih","doi":"10.1159/000541709","DOIUrl":"10.1159/000541709","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western countries and is very rare in Asia.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Peripheral blood or bone marrow mononuclear cells obtained at initial diagnosis from 215 patients with CLL were analyzed by using next-generation sequencing to investigate the ethnic differences in genetic abnormalities.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Whole-genome sequencing and whole-exome sequencing analyses on 30 cases showed that 9 genes, including IGLL5, MYD88, TCHH, DSCAM, AXDND1, BICRA, KMT2D, MYT1L, and RBM43, were more frequently mutated in our Taiwanese cohort compared with those of the Western cohorts. IGLL5, MYD88, and KMT2D genes were further analyzed by targeted sequencing in another 185 CLL patients, unraveling frequencies of 29.3%, 20.9%, and 15.0%, respectively. The most frequent positional mutation of MYD88 was V217F (26/45, 57.8%), followed by L265P (9/45, 20.0%). MYD88 mutations were significantly associated with IGLL5 mutations (p = 0.0004), mutated IGHV (p &lt; 0.0001) and 13q deletion (p = 0.0164). CLL patients with co-occurrence of MYD88 mutations with KMT2D or/and IGLL5 mutations were associated with a significantly inferior survival compared to those with MYD88 mutation alone (not reached vs. 131.8 months, p = 0.007). In multivariate analysis, MYD88 mutation without KMT2D or IGLL5 mutations was an independently favorable predictor.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;IGLL5, MYD88, and KMT2D mutations were enriched in Taiwanese CLL, and co-occurrence of MYD88 mutations with KMT2D or/and IGLL5 mutations was associated with a poorer prognosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western countries and is very rare in Asia.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Peripheral blood or bone marrow mononuclear cells obtained at initial diagnosis from 215 patients with CLL were analyzed by using next-generation sequencing to investigate the ethnic differences in genetic abnormalities.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Whole-genome sequencing and whole-exome sequencing analyses on 30 cases showed that 9 genes, including IGLL5, MYD88, TCHH, DSCAM, AXDND1, BICRA, KMT2D, MYT1L, and RBM43, were more frequently mutated in our Taiwanese cohort compared with those of the Western cohorts. IGLL5, MYD88, and KMT2D genes were further analyzed by targeted sequencing in another 185 CLL patients, unraveling frequencies of 29.3%, 20.9%, and 15.0%, respectively. The most frequent positional mutation of MYD88 was V217F (26/45, 57.8%), followed by L265P (9/45, 20.0%). MYD88 mutations were significantly associated with IGLL5 mutations (p = 0.0004), mutated IGHV (p &lt; 0.0001) and 13q deletion (p = 0.0164). CLL patients with co-occurrence of MYD88 mutations with KMT2D or/and IGLL5 mutations were associated with a significantly inferior survival compared to those with MYD88 mutation alone (not reached vs","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":" ","pages":"77-89"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering Breast Origin in Malignant Effusions: The Diagnostic Utility of an MGP, GATA-3, and TRPS-1 Immunocytochemical Panel.","authors":"So Hyeon Yang, Jae Seok Lee, Ji Won Koh, Ilias P Nikas, Eun Na Kim, Hyebin Lee, Han Suk Ryu","doi":"10.1159/000540989","DOIUrl":"10.1159/000540989","url":null,"abstract":"<p><strong>Introduction: </strong>Defining the origin of metastatic cancer is crucial for establishing an optimal treatment strategy, especially when obtaining sufficient tissue from secondary malignancies is limited. While cytological examination is often used in this diagnostic setting, morphologic analysis alone often fails to differentiate metastases derived from the breast from other primaries. The hormone receptor, human epidermal growth factor receptor-2, gross cystic disease fluid protein 15, and mammaglobin immunohistochemistry are often used to diagnose metastatic breast cancer. However, their effectiveness decreases in estrogen receptor (ER)-negative breast cancers, including the triple-negative breast cancer (TNBC) subtype.</p><p><strong>Methods: </strong>We conducted a comprehensive evaluation of GATA-binding protein 3 (GATA-3), trichorhinophalangeal syndrome type 1 (TRPS-1), and Matrix Gla Protein (MGP) immunochemistry across 140 effusion cytology specimens with metastatic adenocarcinoma derived from various primaries, including the breast, colon, pancreaticobiliary, lung, tubo-ovarian, and stomach.</p><p><strong>Results: </strong>The expression rates of these immunomarkers were significantly higher in metastatic cancers originating from the breast than other primaries. In TNBC, TRPS-1 (80.00%) and MGP (65.00%) exhibited higher positivity rates compared to GATA-3 (40.00%). Additionally, our data suggest that an immunohistochemical panel comprising MGP, GATA-3, and TRPS-1 significantly enhances the detection of metastatic breast cancer in effusion cytology specimens, including TNBC in particular. When considering dual-marker positivity, the diagnostic accuracy was found to be 89.29% across all breast cancer subtypes and 92.93% for TNBC.</p><p><strong>Conclusions: </strong>MGP appears to be a robust marker for identifying metastatic breast cancer in malignant effusions, especially TNBC. MGP notably enhances diagnostic accuracy when incorporated together with GATA-3 and TRPS-1 in an immunohistochemical panel.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":" ","pages":"40-51"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081175","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}

{"title":"Nodal T-Cell Lymphoma Transdifferentiated from Mantle Cell Lymphoma with Epstein-Barr Virus Infection.","authors":"Paul D Barone, Wayne Tam, Julia T Geyer, John P Leonard, Adrienne Phillips, Madhu M Ouseph","doi":"10.1159/000541974","DOIUrl":"10.1159/000541974","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;We report a case of mantle cell lymphoma (MCL) with an apparent lineage switch to an EBV-positive T-cell lymphoma. Although lineage switch is a well-documented phenomenon in some hematolymphoid diseases, such as acute leukemias or histiocytic/dendritic cell neoplasms, lineage switch from mature B-cell to T-cell lymphoma is exceedingly rare.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Case presentation: &lt;/strong&gt;A 55-year-old man with an established history of MCL presented to our institution. Peripheral blood flow cytometry was consistent with MCL. Biopsy of a lumbar vertebral fracture site demonstrated MCL, EBV-associated, with large cells reminiscent of high-grade transformation (BCL1-positive). Two months later, a lymph node biopsy demonstrated an EBV-positive T-cell lymphoma without phenotypic evidence of B-cell lymphoma (BCL1-negative). Cytogenetic testing revealed CCND1::IGH fusion in all three specimens. IGH/IGK clonality testing revealed conserved monoclonal peaks in all three samples; TCR clonality testing revealed monoclonal peaks in the T-cell lymphoma, only. NGS-based molecular genetic studies revealed shared mutations between the three samples, consistent with a clonal relationship suggesting evolution from MCL to T-cell lymphoma.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This case demonstrates that lineage switch from mature B-cell to mature T-cell phenotype is possible in certain settings. Whether lineage switch in this case was potentiated by EBV infection is unclear. The loss of BCL1 expression in the T-cell lymphoma, despite conservation of the CCND1::IGH fusion, may be attributable to the downregulation of the IGH promoter as part of the shift from B-cell to T-cell phenotype.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;We report a case of mantle cell lymphoma (MCL) with an apparent lineage switch to an EBV-positive T-cell lymphoma. Although lineage switch is a well-documented phenomenon in some hematolymphoid diseases, such as acute leukemias or histiocytic/dendritic cell neoplasms, lineage switch from mature B-cell to T-cell lymphoma is exceedingly rare.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Case presentation: &lt;/strong&gt;A 55-year-old man with an established history of MCL presented to our institution. Peripheral blood flow cytometry was consistent with MCL. Biopsy of a lumbar vertebral fracture site demonstrated MCL, EBV-associated, with large cells reminiscent of high-grade transformation (BCL1-positive). Two months later, a lymph node biopsy demonstrated an EBV-positive T-cell lymphoma without phenotypic evidence of B-cell lymphoma (BCL1-negative). Cytogenetic testing revealed CCND1::IGH fusion in all three specimens. IGH/IGK clonality testing revealed conserved monoclonal peaks in all three samples; TCR clonality testing revealed monoclonal peaks in the T-cell lymphoma, only. NGS-based molecular genetic studies revealed shared mutations between the three samples, consistent with a clonal relationship suggesting evolution from MCL to T-cell lymphoma.&lt;/p&gt;&lt;p&gt;&lt;","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":" ","pages":"109-120"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic Value of Cancer-Associated Fibroblast Marker Expression in the Intratumoral and Marginal Areas of Soft Tissue Sarcoma.","authors":"Michinobu Umakoshi, Yukitsugu Kudo-Asabe, Hiroyuki Tsuchie, Zhuo Li, Kei Koyama, Ken Miyabe, Makoto Yoshida, Hiroyuki Nagasawa, Hiroshi Nanjo, Kyoji Okada, Daichi Maeda, Naohisa Miyakoshi, Masamitsu Tanaka, Akiteru Goto","doi":"10.1159/000539855","DOIUrl":"10.1159/000539855","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;The tumor microenvironment of sarcomas has not been studied in detail; in particular, little is known about cancer-associated fibroblasts (CAFs). Sarcoma cells are difficult to distinguish from CAFs, either histomorphologically or immunohistochemically.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We scored the expression of individual CAF markers (fibroblast-activating protein [FAP], CD10, and podoplanin) in the intratumoral and marginal areas of 133 sarcomas. We also examined the association between these markers, as well as the number of CD163-positive macrophages (i.e., tumor-associated macrophages), and clinical outcome.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In all cases, the log-rank test revealed that those with high marker scores and macrophage counts (except for marginal CD10+ CAFs) showed significantly worse disease-free survival (DFS). Grade 2/3 cases with high CAF scores (excluding the marginal FAP and CD10 scores) showed significantly worse DFS, whereas those with high intratumoral FAP/CD10 and marginal podoplanin scores showed significantly worse metastasis-free survival (MFS), and those with high intratumoral CD10 score showed significantly worse local recurrence-free survival (LFS). Multivariate analysis identified intratumoral CD10/podoplanin scores and marginal FAP/podoplanin scores as independent prognostic factors for DFS, intratumoral FAP/CD10 and marginal FAP/podoplanin/CD163-positive macrophage scores as independent prognostic factors for MFS, and the intratumoral podoplanin score as an independent prognostic factor for LFS. There was a weak-to-moderate correlation between each score and CD163-positive macrophage counts.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Patients with high CAF marker expression in the intratumoral and marginal areas have a poorer outcome.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;The tumor microenvironment of sarcomas has not been studied in detail; in particular, little is known about cancer-associated fibroblasts (CAFs). Sarcoma cells are difficult to distinguish from CAFs, either histomorphologically or immunohistochemically.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We scored the expression of individual CAF markers (fibroblast-activating protein [FAP], CD10, and podoplanin) in the intratumoral and marginal areas of 133 sarcomas. We also examined the association between these markers, as well as the number of CD163-positive macrophages (i.e., tumor-associated macrophages), and clinical outcome.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In all cases, the log-rank test revealed that those with high marker scores and macrophage counts (except for marginal CD10+ CAFs) showed significantly worse disease-free survival (DFS). Grade 2/3 cases with high CAF scores (excluding the marginal FAP and CD10 scores) showed significantly worse DFS, whereas those with high intratumoral FAP/CD10 and marginal podoplanin scores showed significantly worse metastasis-free survival (MFS), and those with high intratumoral CD10 score show","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":" ","pages":"1-17"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11797935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141535056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KRT18 as a Novel Biomarker of Urothelial Papilloma while Evaluating Low-Grade Papillary Urothelial Neoplasms: Bi-Center Analysis.","authors":"Minsun Jung, Bohyun Kim, Jae Seok Lee, Jun Yong Kim, Dohyun Han, Kwangsoo Kim, Sunah Yang, Eun Na Kim, Hyeyooon Kim, Ilias P Nikas, Sohyeon Yang, Kyung Chul Moon, Hyebin Lee, Han Suk Ryu","doi":"10.1159/000540926","DOIUrl":"10.1159/000540926","url":null,"abstract":"<p><strong>Introduction: </strong>Although urothelial papilloma (UP) is an indolent papillary neoplasm that can mimic the morphology of low-grade papillary urothelial carcinoma (PUC), there is no immunomarker to differentiate reliably these two entities. In addition, the molecular characteristics of UP are not fully understood.</p><p><strong>Methods: </strong>We conducted an in-depth proteomic analysis of papillary urothelial lesions (n = 31), including UP and PUC along with normal urothelium. Protein markers distinguishing UP and PUC were selected with machine learning analysis, followed by internal and external validation using immunohistochemistry.</p><p><strong>Results: </strong>In the proteomic analysis, UP and PUC showed overlapping proteomic profiles. We identified EHD4 and KRT18 as candidate diagnostic biomarkers of UP. Through immunohistochemical validation in two independent cohorts (n = 120), KRT18 was suggested as a novel UP diagnostic marker, able to differentiate UP from low-grade PUC. We also found that 3.5% of patients with UP developed urothelial carcinoma in subsequent resections, supporting the malignant potential of UP. KRT18 downregulation was significantly associated with UPs subsequently progressing to urothelial carcinoma, following their initial diagnosis.</p><p><strong>Conclusion: </strong>This is the first study that successfully revealed UPs comprehensive proteomic landscape, while it also identified KRT18 as a potential diagnostic biomarker of UP.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":" ","pages":"28-39"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081176","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}

{"title":"Artificial Intelligence Recognition Model Using Liquid-Based Cytology Images to Discriminate Malignancy and Histological Types of Non-Small-Cell Lung Cancer.","authors":"Ryota Tanaka, Yukihiro Tsuboshita, Mitsuaki Okodo, Rei Settsu, Kohei Hashimoto, Keisei Tachibana, Kazumasa Tanabe, Koji Kishimoto, Masachika Fujiwara, Junji Shibahara","doi":"10.1159/000541148","DOIUrl":"10.1159/000541148","url":null,"abstract":"<p><strong>Introduction: </strong>Artificial intelligence image recognition has applications in clinical practice. The purpose of this study was to develop an automated image classification model for lung cancer cytology using a deep learning convolutional neural network (DCNN).</p><p><strong>Methods: </strong>Liquid-based cytology samples from 8 normal parenchymal (N), 22 adenocarcinoma (ADC), and 15 squamous cell carcinoma (SQCC) surgical specimens were prepared, and 45 Papanicolaou-stained slides were scanned using whole-slide imaging. The final dataset of 9,141 patches consisted of 2,737 N, 4,756 ADC, and 1,648 SQCC samples. Densenet-121 was used as the DCNN to classify N versus malignant (ADC+SQCC) and ADC versus SQCC images. AdamW optimizer and 5-fold cross-validation were used in the training.</p><p><strong>Results: </strong>For malignancy prediction, the sensitivity, specificity, and accuracy were 0.97, 0.85, and 0.94, respectively, in the patch-level classification, and 0.92, 0.88, and 0.91, respectively, in the case-level classification. For SQCC prediction, the sensitivity, specificity, and accuracy were 0.86, 0.91, and 0.90, respectively, in the patch-level classification and 0.73, 0.82, and 0.78, respectively, in the case-level classification.</p><p><strong>Conclusion: </strong>The DCNN model performed excellently in predicting malignancy and histological types of lung cancer. This model may be useful for predicting cytopathological diagnosis in clinical situations by reinforcing training.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":" ","pages":"52-62"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142093666","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}

{"title":"Metabolic Analysis of Three-Dimensional Cultured Gastrointestinal Cancer Cells Suggests that <sc>l</sc>-Arginine Inhibits Tumor Growth by Affecting the Urea Cycle.","authors":"Eri Tanaka, Naoko Taniura, Ken-Ichi Mukaisho, Yusuke Kageyama, Mai Noujima, Hirohito Ishigaki, Takahisa Nakayama, Ryoji Kushima","doi":"10.1159/000543006","DOIUrl":"10.1159/000543006","url":null,"abstract":"<p><strong>Introduction: </strong>There is evidence for the anticancer effects of <sc>l</sc>-arginine (arginine); however, the direct effects on cancer cells and mechanism of action are unclear.</p><p><strong>Methods: </strong>Various upper gastrointestinal cancer cells (OE19, OE33, MKN1, MKN45, MKN74, and AGS) were divided into arginine-treated and -untreated groups and cultured using two-dimensional and three-dimensional culture systems. Proliferation was evaluated using the MTT assay to identify arginine-sensitive (OE33) and arginine-insensitive (OE19) strains. Furthermore, the effects of arginine were evaluated using a mitochondrial stress test, cell cycle assay, comprehensive metabolic analysis, and tracer study using (13C6) <sc>l</sc>-arginine.</p><p><strong>Results: </strong>In OE33 (but not in OE19), the maximal respiratory capacity of mitochondria was lower in the treated group than in the control group. In OE33, S phase cells (determined using BrdU) were significantly reduced. In a comprehensive metabolic analysis of OE33, citrulline/ornithine levels were significantly lower in arginine-treated than in untreated cells. Using OE33, carbamoyl aspartic acid (CAA) levels were significantly lower in arginine-treated than in untreated cells. A tracer study suggested that arginine promotes the urea cycle.</p><p><strong>Conclusion: </strong>Arginine affected urea cycle metabolism, thereby decreasing CAA, which is required for pyrimidine nucleotide synthesis. These findings provide insight into the mechanism underlying the anticancer effects of arginine.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":" ","pages":"1-17"},"PeriodicalIF":3.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807750","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}