Journal of Pathology Clinical Research最新文献

{"title":"Homologous recombination deficiency (HRD) is associated with better prognosis and possibly causes a non-inflamed tumour microenvironment in nasopharyngeal carcinoma","authors":"Xinyi Zhou,&nbsp;Haoxuan Ying,&nbsp;Yujie Sun,&nbsp;Wenda Zhang,&nbsp;Peng Luo,&nbsp;Shuhan Zhu,&nbsp;Jian Zhang","doi":"10.1002/2056-4538.12391","DOIUrl":"10.1002/2056-4538.12391","url":null,"abstract":"<p>Homologous recombination deficiency (HRD) score is a reliable indicator of genomic instability. The significance of HRD in nasopharyngeal carcinoma (NPC), particularly its influence on prognosis and the immune microenvironment, has yet to be adequately explored. Understanding HRD status comprehensively can offer valuable insights for guiding precision treatment. We utilised three cohorts to investigate HRD status in NPC: the Zhujiang cohort from local collection and the Hong Kong (SRA288429) and Singapore (SRP035573) cohorts from public datasets. The GATK (genome analysis toolkit) best practice process was employed to investigate germline and somatic <i>BRCA1/2</i> mutations and various bioinformatics tools and algorithms to examine the association between HRD status and clinical molecular characteristics. We found that individuals with a negative HRD status (no-HRD) exhibited a higher risk of recurrence [hazard ratio (HR), 1.43; 95% confidence interval (CI), 2.03–333.76; <i>p</i> = 0.012] in the Zhujiang cohort, whereas, in the Singapore cohort, they experienced a higher risk of mortality (HR, 26.04; 95% CI, 1.43–34.21; <i>p</i> = 0.016) compared with those in the HRD group. <i>In vitro</i> experiments demonstrated that NPC cells with BRCA1 knockdown exhibit heightened sensitivity to chemoradiotherapy. Furthermore, the HRD group showed significantly higher tumour mutational burden and tumour neoantigen burden levels than the no-HRD group. Immune infiltration analysis indicated that HRD tissues tend to have a non-inflamed tumour microenvironment. In conclusion, patients with HRD exhibit a comparatively favourable prognosis in NPC, possibly associated with a non-inflammatory immune microenvironment. These findings have positive implications for treatment stratification, enabling the selection of more precise and effective therapeutic approaches and aiding in the prediction of treatment response and prognosis to a certain extent.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894624","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":"Correlation of PD-L1 expression with CD8+ T cells and oxidative stress-related molecules NRF2 and NQO1 in esophageal squamous cell carcinoma","authors":"Xin Zhang,&nbsp;Yanan Yang,&nbsp;Hongying Zhao,&nbsp;Zhongqiu Tian,&nbsp;Qing Cao,&nbsp;Yunlong Li,&nbsp;Yajuan Gu,&nbsp;Qinfei Song,&nbsp;Xiumei Hu,&nbsp;Mulan Jin,&nbsp;Xingran Jiang","doi":"10.1002/2056-4538.12390","DOIUrl":"10.1002/2056-4538.12390","url":null,"abstract":"<p>Oxidative stress and the immune microenvironment both contribute to the pathogenesis of esophageal squamous cell carcinoma (ESCC). However, their interrelationships remain poorly understood. We aimed to examine the status of key molecules involved in oxidative stress and the immune microenvironment, as well as their relationships with each other and with clinicopathological features and prognosis in ESCC. The expression of programmed death-ligand 1 (PD-L1), CD8, nuclear factor erythroid-2 related factor-2 (NRF2), and NAD(P)H quinone oxidoreductase 1 (NQO1) was detected using immunohistochemistry in tissue samples from 176 patients with ESCC. We employed both combined positive score (CPS) and tumor proportion score (TPS) to evaluate PD-L1 expression and found a positive correlation between CPS and TPS. Notably, PD-L1 expression, as assessed by either CPS or TPS, was positively correlated with both NRF2 nuclear score and NQO1 score in stage II–IV ESCC. We also observed a positive correlation between the density of CD8+ T cells and PD-L1 expression. Furthermore, high levels of PD-L1 CPS, but not TPS, were associated with advanced TNM stage and lymph node metastases. Moreover, both PD-L1 CPS and the nuclear expression of NRF2 were found to be predictive of shorter overall survival in stage II–IV ESCC. By using the Mandard-tumor regression grading (TRG) system to evaluate the pathological response of tumors to neoadjuvant chemotherapy (NACT), we found that the TRG-5 group had higher NRF2 nuclear score, PD-L1 CPS, and TPS in pre-NACT biopsy samples compared with the TRG-3 + 4 group. The NQO1 scores of post-NACT surgical specimens were significantly higher in the TRG-5 group than in the TRG 3 + 4 group. In conclusion, the expression of PD-L1 is associated with aberrant NRF2 signaling pathway, advanced TNM stage, lymph node metastases, and unfavorable prognosis. The dysregulation of PD-L1 and aberrant activation of the NRF2 signaling pathway are implicated in resistance to NACT. Our findings shed light on the complex interrelationships between oxidative stress and the immune microenvironment in ESCC, which may have implications for personalized therapies and improved patient outcomes.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12390","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141591784","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":"Mesonephric-type adenocarcinomas of the ovary: prevalence, diagnostic reproducibility, outcome, and value of PAX2","authors":"Martin Köbel,&nbsp;Eun Young Kang,&nbsp;Sandra Lee,&nbsp;Travis Ogilvie,&nbsp;Tatjana Terzic,&nbsp;Linyuan Wang,&nbsp;Nicholas JP Wiebe,&nbsp;Zainab Al-Shamma,&nbsp;Linda S Cook,&nbsp;Gregg S Nelson,&nbsp;Colin JR Stewart,&nbsp;Andreas von Deimling,&nbsp;Felix KF Kommoss,&nbsp;Cheng-Han Lee","doi":"10.1002/2056-4538.12389","DOIUrl":"10.1002/2056-4538.12389","url":null,"abstract":"<p>Mesonephric-type (or -like) adenocarcinomas (MAs) of the ovary are an uncommon and aggressive histotype. They appear to arise through transdifferentiation from Müllerian lesions creating diagnostic challenges. Thus, we aimed to develop a histologic and immunohistochemical (IHC) approach to optimize the identification of MA over its histologic mimics, such as ovarian endometrioid carcinoma (EC). First, we screened 1,537 ovarian epithelial neoplasms with a four-marker IHC panel of GATA3, TTF1, ER, and PR followed by a morphological review of EC to identify MA in retrospective cohorts. Interobserver reproducibility for the distinction of MA versus EC was assessed in 66 cases initially without and subsequently with IHC information (four-marker panel). Expression of PAX2, CD10, and calretinin was evaluated separately, and survival analyses were performed. We identified 23 MAs from which 22 were among 385 cases initially reported as EC (5.7%) and 1 as clear cell carcinoma. The interobserver reproducibility increased from fair to substantial (<i>κ</i> = 0.376–0.727) with the integration of the four-marker IHC panel. PAX2 was the single most sensitive and specific marker to distinguish MA from EC and could be used as a first-line marker together with ER/PR and GATA3/TTF1. Patients with MA had significantly increased risk of earlier death from disease (hazard ratio = 3.08; 95% CI, 1.62–5.85; <i>p</i> &lt; 0.0001) compared with patients with EC, when adjusted for age, stage, and p53 status. A diagnosis of MA has prognostic implications for stage I disease, and due to the subtlety of morphological features in some tumors, a low threshold for ancillary testing is recommended.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545402","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":"Volumetric imaging of the tumor microvasculature reflects outcomes and genomic states of clear cell renal cell carcinoma","authors":"Yuta Kaneko,&nbsp;Tsukasa Masuda,&nbsp;Kimiharu Takamatsu,&nbsp;Shuji Mikami,&nbsp;Kohei Nakamura,&nbsp;Hiroshi Nishihara,&nbsp;Ryuichi Mizuno,&nbsp;Nobuyuki Tanaka,&nbsp;Mototsugu Oya","doi":"10.1002/2056-4538.12388","DOIUrl":"10.1002/2056-4538.12388","url":null,"abstract":"<p>Tumor structure is heterogeneous and complex, and it is difficult to obtain complete characteristics by two-dimensional analysis. The aim of this study was to visualize and characterize volumetric vascular information of clear cell renal cell carcinoma (ccRCC) tumors using whole tissue phenotyping and three-dimensional light-sheet microscopy. Here, we used the diagnosing immunolabeled paraffin-embedded cleared organs pipeline for tissue clearing, immunolabeling, and three-dimensional imaging. The spatial distributions of CD34, which targets blood vessels, and LYVE-1, which targets lymphatic vessels, were examined by calculating three-dimensional density, vessel length, vessel radius, and density curves, such as skewness, kurtosis, and variance of the expression. We then examined those associations with ccRCC outcomes and genetic alteration state. Formalin-fixed paraffin-embedded tumor samples from 46 ccRCC patients were included in the study. Receiver operating characteristic curve analyses revealed the associations between blood vessel and lymphatic vessel distributions and pathological factors such as a high nuclear grade, large tumor size, and the presence of venous invasion. Furthermore, three-dimensional imaging parameters stratified ccRCC patients regarding survival outcomes. An analysis of genomic alterations based on volumetric vascular information parameters revealed that PI3K-mTOR pathway mutations related to the blood vessel radius were significantly different. Collectively, we have shown that the spatial elucidation of volumetric vasculature information could be prognostic and may serve as a new biomarker for genomic alterations. High-end tissue clearing techniques and volumetric immunohistochemistry enable three-dimensional analysis of tumors, leading to a better understanding of the microvascular structure in the tumor space.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11200083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460061","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":"Characterisation of colorectal cancer by hierarchical clustering analyses for five stroma-related markers","authors":"Sunao Ito,&nbsp;Akira Koshino,&nbsp;Chengbo Wang,&nbsp;Takahiro Otani,&nbsp;Masayuki Komura,&nbsp;Akane Ueki,&nbsp;Shunsuke Kato,&nbsp;Hiroki Takahashi,&nbsp;Masahide Ebi,&nbsp;Naotaka Ogasawara,&nbsp;Toyonori Tsuzuki,&nbsp;Kenji Kasai,&nbsp;Kunio Kasugai,&nbsp;Shuji Takiguchi,&nbsp;Satoru Takahashi,&nbsp;Shingo Inaguma","doi":"10.1002/2056-4538.12386","DOIUrl":"10.1002/2056-4538.12386","url":null,"abstract":"<p>Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer-associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF-related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha-smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN-high tumours had a significantly worse 5-year survival rate (57.3% versus 79.0%; <i>p</i> = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCN^LowPDPN^Low); a PDPN-dominant group (DCN^MidPDPN^High); and a DCN-dominant group (DCN^HighPDPN^Low), with a significant association with patient survival (<i>p</i> = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26–0.96, <i>p</i> = 0.037) as a potential favourable factor compared with the DCN-dominant group. Of note, DCN-dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma-targeting therapies may be candidate treatments for patients with CRC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12386","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421421","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":"Clinicopathological features and cancer transcriptomic profiling of poorly cohesive gastric carcinoma subtypes","authors":"Hung-Hsuan Yen,&nbsp;Pin-Yu Chen,&nbsp;Ruby Yun-Ju Huang,&nbsp;Jung-Ming Jeng,&nbsp;I-Rue Lai","doi":"10.1002/2056-4538.12387","DOIUrl":"10.1002/2056-4538.12387","url":null,"abstract":"<p>Gastric poorly cohesive carcinoma (PCC) manifests with a diffuse pattern and diverse tumor cell morphologies, often indicating a more unfavorable prognosis. Recent consensus has reclassified PCC based on the proportion of signet-ring cells (SRCs) in tumors for research purposes. The two most distinct subtypes, poorly cohesive carcinoma not otherwise specified (PCC-NOS) and signet-ring cell carcinoma (SRCC), are characterized by less than 10% and more than 90% SRCs, respectively. However, research comparing the clinicopathological and transcriptomic differences between these subtypes remains limited. In this study, we conducted a comparative analysis of clinicopathological features in 55 advanced-stage PCCs, consisting of 43 PCC-NOS and 12 SRCC cases. Subsequently, 12 PCC-NOS and 5 SRCC cases were randomly selected for initial cancer-related gene expression profiling and pathway enrichment analysis using the GeoMx digital spatial profiler, followed by validation in a separate validation group comprising 16 PCC-NOS and 6 SRCC cases. These transcriptomic findings were then correlated with tumor morphology and clinicopathological data. PCC-NOS cases exhibited larger tumor size, a higher prevalence of pathological N3 disease, and a worse 1-year progression-free survival rate compared to SRCC cases. Clustering of PCC-NOS and SRCC was successfully achieved using the GeoMx Cancer Transcriptome Atlas. Among all studied genes, only <i>MMP7</i> showed differential expression, with its overexpression significantly associated with the PCC-NOS subtype, increased perineural invasion, and earlier disease progression. Pathway analysis revealed significantly enriched pathways in PCC-NOS related to vesicle-mediated transport, adaptive immune systems, oncogenic signaling, and extracellular matrix organization, while SRCC displayed significant enrichment in pathways associated with respiratory electron transport and the cell cycle. In conclusion, this study compares and correlates clinicopathological features and transcriptomic data between PCC-NOS and SRCC at advanced stages, employing the latest consensus classification and a novel platform for analysis.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12387","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141301800","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":"The Glasgow Microenvironment Score: an exemplar of contemporary biomarker evolution in colorectal cancer","authors":"Katrina Knight,&nbsp;Christopher Bigley,&nbsp;Kathryn Pennel,&nbsp;Jennifer Hay,&nbsp;Noori Maka,&nbsp;Donald McMillan,&nbsp;James Park,&nbsp;Campbell Roxburgh,&nbsp;Joanne Edwards","doi":"10.1002/2056-4538.12385","DOIUrl":"10.1002/2056-4538.12385","url":null,"abstract":"<p>Colorectal cancer remains a leading cause of mortality worldwide. Significant variation in response to treatment and survival is evident among patients with similar stage disease. Molecular profiling has highlighted the heterogeneity of colorectal cancer but has had limited impact in daily clinical practice. Biomarkers with robust prognostic and therapeutic relevance are urgently required. Ideally, biomarkers would be derived from H&amp;E sections used for routine pathological staging, have reliable sensitivity and specificity, and require minimal additional training. The biomarker targets would capture key pathological features with proven additive prognostic and clinical utility, such as the local inflammatory response and tumour microenvironment. The Glasgow Microenvironment Score (GMS), first described in 2014, combines assessment of peritumoural inflammation at the invasive margin with quantification of tumour stromal content. Using H&amp;E sections, the Klintrup–Mäkinen (KM) grade is determined by qualitative morphological assessment of the peritumoural lymphocytic infiltrate at the invasive margin and tumour stroma percentage (TSP) calculated in a semi-quantitative manner as a percentage of stroma within the visible field. The resulting three prognostic categories have direct clinical relevance: GMS 0 denotes a tumour with a dense inflammatory infiltrate/high KM grade at the invasive margin and improved survival; GMS 1 represents weak inflammatory response and low TSP associated with intermediate survival; and GMS 2 tumours are typified by a weak inflammatory response, high TSP, and inferior survival. The prognostic capacity of the GMS has been widely validated while its potential to guide chemotherapy has been demonstrated in a large phase 3 trial cohort. Here, we detail its journey from conception through validation to clinical translation and outline the future for this promising and practical biomarker.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12385","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141297008","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":"Gastric cancer immune microenvironment score predicts neoadjuvant chemotherapy efficacy and prognosis","authors":"Shaoji Zhao,&nbsp;Yinan Liu,&nbsp;Li Ding,&nbsp;Chaoyue Zhang,&nbsp;Jinning Ye,&nbsp;Kaiyu Sun,&nbsp;Wu Song,&nbsp;Shirong Cai,&nbsp;Yulong He,&nbsp;Jianjun Peng,&nbsp;Jianbo Xu","doi":"10.1002/2056-4538.12378","DOIUrl":"10.1002/2056-4538.12378","url":null,"abstract":"<p>The efficacy of neoadjuvant chemotherapy (NACT) in patients with advanced gastric cancer (GC) varies greatly. Thus, we aimed to verify the predictive value of tumor-infiltrating immune cells (TIICs) on the treatment response to NACT and the prognosis of patients with advanced GC, and to explore the impact of NACT on the tumor immune microenvironment (TIME). Paired tumor tissues (pre- and post-NACT) from patients with advanced GC were collected for this study. TIICs were assessed using immunohistochemistry staining and analyzed using logistic regression to establish an immune microenvironment score for GC (ISGC score) and predict NACT efficacy. Kaplan–Meier curves were used to evaluate the survival outcome of patients. The results showed that TIME was dramatically heterogeneous between NACT response and nonresponse patients. In the validation cohort, the ISGC score demonstrated good predictive performance for treatment response to NACT. Moreover, high ISGC indicated better long-term survival in patients with advanced GC. Furthermore, tumor-infiltrated T cells (CD3⁺ and CD8⁺) and CD11c⁺ macrophages were significantly increased in the response group, while CD163⁺ macrophages and FOXP3⁺ Treg cells were decreased after NACT. However, opposite results were exhibited in the nonresponse group. Finally, we found that the percentage of programmed cell death ligand 1 (PD-L1)-positive tumors was 31% (32/104) pre-NACT and 49% (51/104) post-NACT, and almost all patients with elevated PD-L1 were in the NACT response group. The ISGC model accurately predicted NACT efficacy and classified patients with GC into different survival groups. NACT regulates the TIME in GC, which may provide strategies for personalized immunotherapy.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12378","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080983","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":"KRT81 and HNF1A expression in pancreatic ductal adenocarcinoma: investigation of predictive and prognostic value of immunohistochemistry-based subtyping","authors":"Jia Rao,&nbsp;Marianne Sinn,&nbsp;Uwe Pelzer,&nbsp;Hanno Riess,&nbsp;Helmut Oettle,&nbsp;Ihsan E Demir,&nbsp;Helmut Friess,&nbsp;Carsten Jäger,&nbsp;Katja Steiger,&nbsp;Alexander Muckenhuber","doi":"10.1002/2056-4538.12377","DOIUrl":"10.1002/2056-4538.12377","url":null,"abstract":"<p>Even after decades of research, pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease and responses to conventional treatments remain mostly poor. Subclassification of PDAC into distinct biological subtypes has been proposed by various groups to further improve patient outcome and reduce unnecessary side effects. Recently, an immunohistochemistry (IHC)-based subtyping method using cytokeratin-81 (KRT81) and hepatocyte nuclear factor 1A (HNF1A) could recapitulate some of the previously established molecular subtyping methods, while providing significant prognostic and, to a limited degree, also predictive information. We refined the KRT81/HNF1A subtyping method to classify PDAC into three distinct biological subtypes. The prognostic value of the IHC-based method was investigated in two primary resected cohorts, which include 269 and 286 patients, respectively. In the second cohort, we also assessed the predictive effect for response to erlotinib + gemcitabine. In both PDAC cohorts, the new HNF1A-positive subtype was associated with the best survival, the KRT81-positive subtype with the worst, and the double-negative with an intermediate survival (<i>p</i> &lt; 0.001 and <i>p</i> &lt; 0.001, respectively) in univariate and multivariate analyses. In the second cohort (CONKO-005), the IHC-based subtype was additionally found to have a potential predictive value for the erlotinib-based treatment effect. The revised IHC-based subtyping using KRT81 and HNF1A has prognostic significance for PDAC patients and may be of value in predicting treatment response to specific therapeutic agents.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12377","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945814","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":"Recurrent and novel fusions detected by targeted RNA sequencing as part of the diagnostic workflow of soft tissue and bone tumours","authors":"Rafael Zago Baltazar,&nbsp;Sofie Claerhout,&nbsp;Sara Vander Borght,&nbsp;Lien Spans,&nbsp;Raphael Sciot,&nbsp;Patrick Schöffski,&nbsp;Daphne Hompes,&nbsp;Friedl Sinnaeve,&nbsp;Hazem Wafa,&nbsp;Marleen Renard,&nbsp;Mari FCM van den Hout,&nbsp;Astrid Vernemmen,&nbsp;Louis Libbrecht,&nbsp;An-Katrien De Roo,&nbsp;Filomena Mazzeo,&nbsp;Cédric van Marcke,&nbsp;Karen Deraedt,&nbsp;Claire Bourgain,&nbsp;Isabelle Vanden Bempt","doi":"10.1002/2056-4538.12376","DOIUrl":"10.1002/2056-4538.12376","url":null,"abstract":"<p>The identification of gene fusions has become an integral part of soft tissue and bone tumour diagnosis. We investigated the added value of targeted RNA-based sequencing (targeted RNA-seq, Archer FusionPlex) to our current molecular diagnostic workflow of these tumours, which is based on fluorescence <i>in situ</i> hybridisation (FISH) for the detection of gene fusions using 25 probes. In a series of 131 diagnostic samples targeted RNA-seq identified a gene fusion, <i>BCOR</i> internal tandem duplication or <i>ALK</i> deletion in 47 cases (35.9%). For 74 cases, encompassing 137 FISH analyses, concordance between FISH and targeted RNA-seq was evaluated. A positive or negative FISH result was confirmed by targeted RNA-seq in 27 out of 49 (55.1%) and 81 out of 88 (92.0%) analyses, respectively. While negative concordance was high, targeted RNA-seq identified a canonical gene fusion in seven cases despite a negative FISH result. The 22 discordant FISH-positive analyses showed a lower percentage of rearrangement-positive nuclei (range 15–41%) compared to the concordant FISH-positive analyses (&gt;41% of nuclei in 88.9% of cases). Six FISH analyses (in four cases) were finally considered false positive based on histological and targeted RNA-seq findings. For the <i>EWSR1</i> FISH probe, we observed a gene-dependent disparity (<i>p</i> = 0.0020), with 8 out of 35 cases showing a discordance between FISH and targeted RNA-seq (22.9%). This study demonstrates an added value of targeted RNA-seq to our current diagnostic workflow of soft tissue and bone tumours in 19 out of 131 cases (14.5%), which we categorised as altered diagnosis (3 cases), added precision (6 cases), or augmented spectrum (10 cases). In the latter subgroup, four novel fusion transcripts were found for which the clinical relevance remains unclear: <i>NAB2::NCOA2</i>, <i>YAP1::NUTM2B</i>, <i>HSPA8::BRAF</i>, and <i>PDE2A::PLAG1</i>. Overall, targeted RNA-seq has proven extremely valuable in the diagnostic workflow of soft tissue and bone tumours.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 3","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12376","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140913232","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}