Journal of Pathology Clinical Research最新文献

{"title":"AXL and SRC in clear cell renal cell carcinoma: absence of mutations, rare alternative splicing events, but association of protein expression with poor prognosis","authors":"Muriel D Brada,&nbsp;Tülay Karakulak,&nbsp;Peter Schraml,&nbsp;Martina Haberecker,&nbsp;Dorothea Rutishauser,&nbsp;Jeffrey S Ross,&nbsp;Daniel Eberli,&nbsp;Holger Moch","doi":"10.1002/2056-4538.70028","DOIUrl":"https://doi.org/10.1002/2056-4538.70028","url":null,"abstract":"<p>Novel treatment options for metastatic renal cell carcinomas (RCC) include specific MET inhibitors, GAS6/AXL inhibitors, and SRC inhibitors. The interplay between c-MET, SRC, AXL expression, and their gene mutation patterns in different renal carcinoma subtypes is unclear. To improve the understanding of these signaling pathways, we analyzed c-MET, AXL, and SRC expression in 590 clear cell RCC (ccRCC) and 127 papillary RCC (pRCC) by immunohistochemistry and integrated sequencing data to investigate the frequency of <i>MET, AXL</i>, and <i>SRC</i> gene mutations, their expression levels, and the presence of splice variants. In TCGA and in Foundation Medicine, Inc. (FMI) datasets, <i>AXL</i> and <i>SRC</i> gene alterations were extremely rare (&lt;2%) or absent in ccRCC (<i>n</i> = 531 and 2,781, respectively) and pRCC (<i>n</i> = 290 and 566, respectively). On the other hand, <i>MET</i> mutations or amplifications were found in 9.7% (TCGA) and 10.2% (FMI) of pRCC. We show that strong SRC staining intensity by immunohistochemistry is associated with high tumor stage, high grade, and shorter survival in ccRCC (<i>p</i> &lt; 0.001 each). AXL expression correlates with high stage and grade in ccRCC (<i>p</i> &lt; 0.001 each). Both SRC and AXL expression were independent prognostic parameters in multivariate analysis (<i>p</i> &lt; 0.05). MET expression is associated with longer survival in pRCC (<i>p</i> &lt; 0.05). Our TCGA data analysis aligns with SRC immunohistochemistry findings on tumor stage and shorter survival in ccRCC. TCGA expression data showed a moderate positive correlation between <i>AXL</i> and <i>c-MET</i> in pRCC. In addition, we identified alternative splicing events reported for <i>AXL</i> in pRCC, and <i>MET</i> and <i>SRC</i> in ccRCC, across various alternative splicing databases. In conclusion, we identified high SRC expression as a biomarker for poor prognosis of ccRCC. Our data demonstrate c-MET, AXL, and SRC signaling pathway interactions independent of c-<i>MET</i>, <i>AXL</i>, and <i>SRC</i> mutations in ccRCC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"11 3","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Netrin-1 and B-cell maturation antigen expression in a large cohort of 361 lymphomas: sensitive and specific staining in plasmablastic lymphomas, and therapeutic perspectives","authors":"Marie Donzel,&nbsp;Alexis Trecourt,&nbsp;Hervé Ghesquières,&nbsp;Thi-Thuy-Trinh Nguyen,&nbsp;Sara Dandash,&nbsp;Morgane Denis,&nbsp;Emeline Cros-Perrial,&nbsp;Juliette Fontaine,&nbsp;Charles Dumontet,&nbsp;Alexandra Traverse-Glehen","doi":"10.1002/2056-4538.70027","DOIUrl":"https://doi.org/10.1002/2056-4538.70027","url":null,"abstract":"<p>Netrin-1 and B-cell maturation antigen (BCMA) are currently being evaluated as therapeutic targets in oncology. However, studies investigating their expression in mature human lymphoid malignancies are sparse. This study aimed to investigate the expression of BCMA and Netrin-1 in a large cohort of lymphomas to determine their potential role as biomarkers or therapeutic targets. BCMA and Netrin-1 expression was investigated comprehensively using immunohistochemistry in a cohort that included 261 B-cell lymphomas, 45 T-cell lymphomas, and 55 classical Hodgkin lymphomas. Netrin-1 displayed a cytoplasmic staining pattern in plasmablastic lymphomas (27/28, 96%) and classical Hodgkin lymphomas (8/55, 15%). BCMA displayed cytoplasmic staining in most plasmablastic lymphomas (17/20, 85%). Among mature B-cell lymphomas, Netrin-1 and BCMA displayed sensitive (96% and 85%, respectively) and specific (100% and 95%, respectively) staining in plasmablastic lymphomas. These results suggest that these proteins may help pathologists in complex diagnoses and reinforce the interest in developing clinical trials assessing Netrin-1 or BCMA-targeted therapies in plasmablastic lymphoma and classical Hodgkin lymphomas, for which our therapeutic arsenal is weak.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"11 3","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic features of liquid biopsies from patients with prostate cancer with and without ductal adenocarcinoma","authors":"Qiyu Zhu,&nbsp;Ting Wang,&nbsp;Yifu Shi,&nbsp;Xiuya Zhou,&nbsp;Dingbang Liu,&nbsp;Junru Chen,&nbsp;Haoyang Liu,&nbsp;Fengnian Zhao,&nbsp;Chenhao Xu,&nbsp;Yuntian Chen,&nbsp;Jiayu Liang,&nbsp;Ni Chen,&nbsp;Pengfei Shen,&nbsp;Hao Zeng,&nbsp;Jinge Zhao","doi":"10.1002/2056-4538.70026","DOIUrl":"https://doi.org/10.1002/2056-4538.70026","url":null,"abstract":"<p>Ductal adenocarcinoma of the prostate (DA) is relatively rare and highly co-existent with prostate adenocarcinoma (AC). This study aimed to investigate the distinctive genomic profiles of patients with DA compared to those without. Blood samples were obtained from 144 patients (36 with DA and 108 without DA) who were diagnosed from 2017 to 2023 at West China Hospital. We performed cell-free DNA sequencing to investigate the genomic differences between patients with DA [DA(+)] and those without [DA(−)], and explored the potential associations between their mutational status and prognosis. Pathogenic and likely pathogenic alterations were included for analysis. We identified that AR pathway [16/36 (44.4%) versus 24/108 (22.2%), <i>p</i> = 0.017] and WNT pathway [6/36 (16.7%) versus 5/108 (4.6%), <i>p</i> = 0.029] mutations were significantly enriched in DA(+) compared to DA(−) patients. Mutation of <i>FOXA1</i>, as a key component of the AR pathway, demonstrated markedly higher prevalence in the DA(+) over the DA(−) cohort [25% (9/36) versus 4.6% (5/108), <i>p</i> = 0.0012]. The DNA damage repair mutation rate and the homologous recombination repair deficiency scores appeared to be comparable between the DA(+) and DA(−) patients. In the metastatic population, DA was characterized by a higher speckle-type POZ protein (<i>SPOP</i>) mutation rate. <i>TP53</i> mutation was associated with a deteriorating prognosis for both DA(+) and DA(−) patients in terms of castration-free survival. In conclusion, our findings provide further genomic insights into prostate cancer with ductal morphology and are instructive for the diagnosis and treatment of DA.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"11 3","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MMR deficiency is frequent in colorectal carcinomas with diffuse SLFN11 immunostaining: clinicopathologic and molecular study of 31 cases identified among 3,300 tumors","authors":"Maciej Kaczorowski,&nbsp;Małgorzata Chłopek,&nbsp;Ondřej Daum,&nbsp;Kris Ylaya,&nbsp;Tomáš Vaněček,&nbsp;Magdalena Szczepaniak,&nbsp;Karol Krawczyk,&nbsp;Artur Kowalik,&nbsp;Michal Michal,&nbsp;Jerzy Lasota,&nbsp;Markku Miettinen","doi":"10.1002/2056-4538.70025","DOIUrl":"https://doi.org/10.1002/2056-4538.70025","url":null,"abstract":"<p>Schlafen 11 (SLFN11), a regulator of cell fate following DNA injury, sensitizes tumor cells to DNA-damaging agents. Patients with SLFN11-positive tumors may benefit from DNA-damaging chemotherapies. SLFN11 has been studied in different types of cancer including colorectal carcinomas. However, colorectal carcinomas with diffuse positivity (expression in ≥80% of tumor cells) have not been meticulously characterized. SLFN11 immunostaining of tumor microarrays (TMAs) with 3,300 primary CRCs identified 65 (~2.0%) tumors with focal staining (&lt;10% of tumor nuclei positive), 83 (~2.5%) with patchy (≥10% and &lt;80%) and 51 (~1.5%) with diffuse (≥80%) SLFN11 positivity. The latter was confirmed on full sections from donor blocks in 31 (~1%) cases, which were further studied including evaluation of additional immunohistochemical markers, genotyping with targeted DNA sequencing, and assessment of microsatellite instability. SLFN11-positive carcinomas were mostly (21/31, 68%) right-sided tumors with a female predominance (21/31, 68%) and median age of 67 years. Eighteen of 31 (58%) contained areas of mucinous differentiation. Deficiency of mismatch repair proteins was detected in 65% (20/31) of SLFN11-positive carcinomas. Moreover, <i>MLH1</i> (<i>n</i> = 2), <i>MSH2</i>, <i>MSH6</i>, and <i>PMS2</i> germline mutations were identified in 25% (5/20) of patients with mismatch repair deficient tumors. <i>BRAF</i> p.V600E mutation was found in 45% (9/20) of mismatch repair deficient, but only 1 of 11 proficient tumors. Colorectal carcinomas with diffuse SLFN11 positivity were often mismatch repair deficient tumors with their typical clinical, morphological, and molecular characteristics.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"11 2","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143645714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Do explainable AI (XAI) methods improve the acceptance of AI in clinical practice? An evaluation of XAI methods on Gleason grading","authors":"Robin Manz,&nbsp;Jonas Bäcker,&nbsp;Samantha Cramer,&nbsp;Philip Meyer,&nbsp;Dominik Müller,&nbsp;Anna Muzalyova,&nbsp;Lukas Rentschler,&nbsp;Christoph Wengenmayr,&nbsp;Ludwig Christian Hinske,&nbsp;Ralf Huss,&nbsp;Johannes Raffler,&nbsp;Iñaki Soto-Rey","doi":"10.1002/2056-4538.70023","DOIUrl":"https://doi.org/10.1002/2056-4538.70023","url":null,"abstract":"<p>This work aimed to evaluate both the usefulness and user acceptance of five gradient-based explainable artificial intelligence (XAI) methods in the use case of a prostate carcinoma clinical decision support system environment. In addition, we aimed to determine whether XAI helps to increase the acceptance of artificial intelligence (AI) and recommend a particular method for this use case. The evaluation was conducted on a tool developed in-house with different visualization approaches to the AI-generated Gleason grade and the corresponding XAI explanations on top of the original slide. The study was a heuristic evaluation of five XAI methods. The participants were 15 pathologists from the University Hospital of Augsburg with a wide range of experience in Gleason grading and AI. The evaluation consisted of a user information form, short questionnaires on each XAI method, a ranking of the methods, and a general questionnaire to evaluate the performance and usefulness of the AI. There were significant differences between the ratings of the methods, with Grad-CAM++ performing best. Both AI decision support and XAI explanations were seen as helpful by the majority of participants. In conclusion, our pilot study suggests that the evaluated XAI methods can indeed improve the usefulness and acceptance of AI. The results obtained are a good indicator, but further studies involving larger sample sizes are warranted to draw more definitive conclusions.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"11 2","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Costs of biomarker testing in advanced non-small cell lung cancer: a global study comparing next-generation sequencing and single-gene testing","authors":"Umberto Malapelle,&nbsp;Chien-Chin Chen,&nbsp;Enrique de Álava,&nbsp;Paul Hofman,&nbsp;Daniel Kazdal,&nbsp;Tae-Jung Kim,&nbsp;Tony Kiat Hon Lim,&nbsp;Aleš Ryška,&nbsp;Angelica A Saetta,&nbsp;Ed Schuuring,&nbsp;Giancarlo Troncone,&nbsp;Michele Biscuola,&nbsp;Yi-Lin Chen,&nbsp;Gek San Tan,&nbsp;Charles Hugo Marquette,&nbsp;Maria Michelli,&nbsp;Arja ter Elst,&nbsp;Hana Vošmiková,&nbsp;Joshua Kapp,&nbsp;Sebastian Gonzalez-McQuire,&nbsp;Andromachi Giannopoulou,&nbsp;Jean Marie Franzini,&nbsp;Victoria Lucia Rabsiun Aramburu,&nbsp;Anna Baggi,&nbsp;Albrecht Stenzinger","doi":"10.1002/2056-4538.70018","DOIUrl":"https://doi.org/10.1002/2056-4538.70018","url":null,"abstract":"<p>Current European/US guidelines recommend that molecular testing in advanced non-small cell lung cancer (aNSCLC) be performed using next-generation sequencing (NGS). However, the global uptake of NGS is limited, largely owing to reimbursement constraints. We compared real-world costs of NGS and single-gene testing (SGT) in nonsquamous aNSCLC. This observational study was conducted across 10 pathology centers in 10 different countries worldwide. Biomarker data collected via structured questionnaires (1 January–31 December 2021) were used to feed micro-costing analyses for three scenarios [‘Starting Point’ (SP; 2021–2022), ‘Current Practice’ (CP; 2023–2024), and ‘Future Horizons’ (FH; 2025–2028)] in both a real-world model, comprising all biomarkers tested by each center, and a standardized model, comprising the same sets of biomarkers across centers. Testing costs (including retesting) encompassed personnel costs, consumables, equipment, and overheads. Overall, 4,491 patients with aNSCLC were evaluated. Mean per-patient costs decreased for NGS relative to SGT over time, with real-world model costs 18% lower for NGS than for SGT in the SP scenario, and 26% lower for NGS than for SGT in the CP scenario. Mean per-biomarker costs also decreased over time for NGS relative to SGT. In the standardized model, the tipping point for the minimum number of biomarkers required for NGS to result in cost savings (per patient) was 10 and 12 in the SP and CP scenarios, respectively. Retesting had a negligible impact on cost analyses, and results were robust to variation in cost parameters. This study provides robust real-world global evidence for cost savings with NGS-based panels over SGT to evaluate predictive biomarkers in nonsquamous aNSCLC when the number of biomarkers to be tested exceeds 10. Widespread adoption of NGS may enable more efficient use of limited healthcare resources.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"11 2","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncocytic and spindle cell typical carcinoids of lung: different immunophenotype and biological behavior","authors":"Giovanna Sabella,&nbsp;Giovanni Centonze,&nbsp;Patrick Maisonneuve,&nbsp;Federica Grillo,&nbsp;Vincenzo Lagano,&nbsp;Giovanna Garzone,&nbsp;Carlotta Pardo,&nbsp;Martina Filugelli,&nbsp;Alessia Mietta,&nbsp;Michele Simbolo,&nbsp;Alessandra Fabbri,&nbsp;Alessandro Mangogna,&nbsp;Natalie Prinzi,&nbsp;Sara Pusceddu,&nbsp;Luigi Rolli,&nbsp;Luisa Bercich,&nbsp;Salvatore Grisanti,&nbsp;Mauro Roberto Benvenuti,&nbsp;Ugo Pastorino,&nbsp;Luca Roz,&nbsp;Aldo Scarpa,&nbsp;Alfredo Berruti,&nbsp;Carlo Capella,&nbsp;Massimo Milione","doi":"10.1002/2056-4538.70020","DOIUrl":"https://doi.org/10.1002/2056-4538.70020","url":null,"abstract":"<p>Pulmonary typical carcinoids (TCs) are uncommon, well-differentiated neuroendocrine tumors of the lung that do not exhibit necrosis and have fewer than two mitoses per 2 mm², as defined by the current World Health Organization classifications. Despite their low-grade status and favorable prognostic impact, the protein expression profile and morphological characteristics associated with tumor progression and metastatic spread remain largely unidentified. Oncocytic and spindle cell histological variants are acknowledged for their role in differential diagnosis, though their clinical significance remains a topic of debate. We centrally reviewed a multicenter series of 297 TCs to identify cases of oncocytic and spindle cell variants. We examined associations with clinicopathological features and immunohistochemical markers (orthopedia homeobox protein, thyroid transcription factor 1, mammalian achaete-scute homologue 1, somatostatin receptor 2A, Ki-67, anti-mitochondria, and S100); these data were further related to disease-free survival (DFS), overall survival, and cancer-specific survival (CSS). Our analysis identified oncocytic TCs (<i>n</i> = 36, 12.1%), spindle cell TCs (<i>n</i> = 55, 18.5%), and ordinary TCs, defined as those without either variant or with variants that were not prominent (<i>n</i> = 206, 69.4%). Interestingly, ordinary tumors were associated with a higher number of tumor-related deaths (<i>p</i> = 0.01) compared to the other histological variants. Additionally, patients with spindle cell morphology had longer CSS compared to those with ordinary morphology (<i>p</i> = 0.04). Parameters such as histological variant, age, tumor stage, and Ki-67 were significantly linked to DFS on multivariable analysis, even after accounting for differences between centers. In conclusion, oncocytic, spindle cell, and ordinary TCs are linked to distinct clinicopathological characteristics and exhibit varying clinical outcomes.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"11 2","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing HER2 testing in breast cancer: predicting fluorescence in situ hybridization (FISH) scores from immunohistochemistry images via deep learning","authors":"Daniel O Macaulay,&nbsp;Wenchao Han,&nbsp;Mark D Zarella,&nbsp;Chris A Garcia,&nbsp;Thomas E Tavolara","doi":"10.1002/2056-4538.70024","DOIUrl":"https://doi.org/10.1002/2056-4538.70024","url":null,"abstract":"<p>Breast cancer affects millions globally, necessitating precise biomarker testing for effective treatment. HER2 testing is crucial for guiding therapy, particularly with novel antibody-drug conjugates (ADCs) like trastuzumab deruxtecan, which shows promise for breast cancers with low HER2 expression. Current HER2 testing methods, including immunohistochemistry (IHC) and <i>in situ</i> hybridization (ISH), have limitations. IHC, a semi-quantitative assay, is prone to interobserver variability. While ISH provides higher precision than IHC, it remains more resource-intensive in terms of cost and workflow. However, turnaround time is typically faster than that of other advanced molecular methods such as next-generation sequencing. We adapted the clustering-constrained-attention multiple-instance deep learning model to improve IHC testing and reduce dependence on reflex fluorescence ISH (FISH) tests. Using 5,731 HER2 IHC images, including 592 cases with FISH testing, we trained two models: one for predicting HER2 scores from IHC images and another for predicting FISH scores from equivocal cases. The HER2 IHC score prediction model achieved 91% ± 0.01 overall accuracy and a receiver operating characteristic (ROC) area under the curve (AUC) of 0.98 ± 0.01. The FISH score prediction model had an ROC AUC of 0.84 ± 0.07, with sensitivity at 0.37 ± 0.13 and specificity at 0.96 ± 0.03. External validation on cases from 203 institutions showed similar performance. The HER2 IHC model maintained a 91% ± 0.01 accuracy and an ROC AUC of 0.98 ± 0.01, while the FISH model had an ROC AUC of 0.75 ± 0.03, with sensitivity at 0.28 ± 0.04 and specificity at 0.93 ± 0.01. Our model advances HER2 scoring by reducing subjectivity and variability in current scoring methods. Despite lower accuracy and sensitivity in the FISH prediction model, it may be a beneficial option for settings where reflex FISH testing is unavailable or prohibitive. With high specificity, our model can serve as an effective screening tool, enhancing breast cancer diagnosis and treatment selection.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"11 2","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between individual Warburg-related proteins and prognosis in colorectal cancer","authors":"Kelly Offermans,&nbsp;Josien CA Jenniskens,&nbsp;Colinda CJM Simons,&nbsp;Iryna Samarska,&nbsp;Gregorio E Fazzi,&nbsp;Kim M Smits,&nbsp;Leo J Schouten,&nbsp;Matty P Weijenberg,&nbsp;Heike I Grabsch,&nbsp;Piet A van den Brandt","doi":"10.1002/2056-4538.70016","DOIUrl":"https://doi.org/10.1002/2056-4538.70016","url":null,"abstract":"<p>We previously showed that Warburg subtyping (low/moderate/high), based on the expression of six glycolytic proteins and transcriptional regulators [glucose transporter 1 (GLUT1), pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), monocarboxylate transporter 4 (MCT4), p53, and PTEN], holds independent prognostic value in colorectal cancer (CRC) patients. The present study aimed to investigate whether the expression level of one of the proteins (GLUT1, PKM2, LDHA, MCT4, p53, and PTEN) can act as a proxy for our previously identified six protein-based Warburg subtypes. Protein expression levels for individual Warburg-related proteins were available for 2,251 CRC patients from the Netherlands Cohort Study. Kaplan–Meier curves and Cox regression were used to explore associations between individual Warburg-related proteins and CRC-specific and overall survival. Previously identified associations between Warburg subtypes and CRC-specific and overall survival were adjusted for individual proteins, showing a significant association with survival in the current study. Multivariable-adjusted analyses showed that the expression of GLUT1, LDHA, MCT4, PKM2, or p53 was associated with neither CRC-specific nor overall survival. Decreasing PTEN expression was associated with significantly poorer overall survival (<i>p-</i>trend_categories = 0.026). Additional adjustment for PTEN expression had minimal impact on the previously identified association between Warburg subtypes and survival, and the six protein-based Warburg-high subtype remained a statistically significant predictor of overall survival (hazard ratio 1.15; 95% CI 1.01–1.32). In conclusion, our results emphasise that individual Warburg-related proteins cannot serve as a proxy or surrogate marker for Warburg subtyping, thereby highlighting the importance of combining the expression levels of multiple Warburg-related proteins when examining the prognostic significance of a complex biological pathway such as the Warburg effect.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"11 2","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive transcriptomic profiling reveals molecular characteristics and biomarkers associated with risk stratification in papillary thyroid carcinoma","authors":"Congcong Yan,&nbsp;Chen Zheng,&nbsp;Jiaxing Luo,&nbsp;Xue Wu,&nbsp;Xinyu Meng,&nbsp;Chaoyue Lv,&nbsp;Shurong Shen,&nbsp;Meng Zhou,&nbsp;Ouchen Wang","doi":"10.1002/2056-4538.70022","DOIUrl":"https://doi.org/10.1002/2056-4538.70022","url":null,"abstract":"<p>Papillary thyroid carcinoma (PTC) is one of the most common endocrine malignancies, with varying levels of risk and clinical behavior. A better understanding of the molecular characteristics could improve molecular diagnosis and risk assessment. In this study, we performed whole transcriptomic sequencing on 113 PTC cases, including 70 high-risk and 43 low-risk Chinese patients. Comparative transcriptional profiling analysis revealed two functionally distinct patterns of gene dysregulation between the risk subtypes. Low-risk PTCs showed significant upregulation of immune-related genes and increased immune cell infiltration, whereas high-risk PTCs presented extensive alterations in gene expression and activation of oncogenic signaling pathways. Additionally, we developed a 31-gene transcriptomic signature (PTCrisk) for differentiating high-risk from low-risk PTCs, which was validated across both in-house and external multicenter cohorts. PTCrisk scores were positively correlated with key clinicopathological features, including tumor size, lymph node metastasis, TNM stage, and <i>BRAF</i> mutation status. Overall, our study provides further molecular insights into PTC risk stratification and may contribute to the development of personalized therapeutic strategies for PTC patients.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"11 2","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.70022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}