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Homologous recombination deficiency (HRD) is associated with better prognosis and possibly causes a non-inflamed tumour microenvironment in nasopharyngeal carcinoma 同源重组缺陷(HRD)与较好的预后有关,并可能导致鼻咽癌的肿瘤微环境不发炎。
IF 3.4 2区 医学 Q1 PATHOLOGY Pub Date : 2024-08-05 DOI: 10.1002/2056-4538.12391
Xinyi Zhou, Haoxuan Ying, Yujie Sun, Wenda Zhang, Peng Luo, Shuhan Zhu, Jian Zhang

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 BRCA1/2 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; p = 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; p = 0.016) compared with those in the HRD group. In vitro 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.

同源重组缺陷(HRD)评分是基因组不稳定性的可靠指标。HRD在鼻咽癌(NPC)中的意义,尤其是对预后和免疫微环境的影响,还有待充分探讨。全面了解HRD状态可为指导精准治疗提供有价值的见解。我们利用三个队列来研究鼻咽癌的HRD状态:本地收集的珠江队列、公共数据集的香港队列(SRA288429)和新加坡队列(SRP035573)。我们采用了 GATK(基因组分析工具包)最佳实践流程来研究种系和体细胞 BRCA1/2 基因突变,并利用各种生物信息学工具和算法来研究 HRD 状态与临床分子特征之间的关联。我们发现,在珠江队列中,HRD 状态为阴性(no-HRD)的个体表现出更高的复发风险[危险比 (HR),1.43;95% 置信区间 (CI),2.03-333.76;p = 0.012],而在新加坡队列中,与 HRD 组相比,他们的死亡风险更高(HR,26.04;95% CI,1.43-34.21;p = 0.016)。体外实验表明,BRCA1基因敲除的鼻咽癌细胞对化疗放疗的敏感性更高。此外,HRD组的肿瘤突变负荷和肿瘤新抗原负荷水平明显高于无HRD组。免疫浸润分析表明,HRD 组织往往具有非炎症肿瘤微环境。总之,HRD 患者的预后相对较好,这可能与非炎症性免疫微环境有关。这些发现对治疗分层具有积极意义,有助于选择更精确、更有效的治疗方法,并在一定程度上有助于预测治疗反应和预后。
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引用次数: 0
Correlation of PD-L1 expression with CD8+ T cells and oxidative stress-related molecules NRF2 and NQO1 in esophageal squamous cell carcinoma 食管鳞状细胞癌中 PD-L1 表达与 CD8+ T 细胞及氧化应激相关分子 NRF2 和 NQO1 的相关性。
IF 3.4 2区 医学 Q1 PATHOLOGY Pub Date : 2024-07-11 DOI: 10.1002/2056-4538.12390
Xin Zhang, Yanan Yang, Hongying Zhao, Zhongqiu Tian, Qing Cao, Yunlong Li, Yajuan Gu, Qinfei Song, Xiumei Hu, Mulan Jin, Xingran Jiang

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.

氧化应激和免疫微环境都是食管鳞状细胞癌(ESCC)的发病机制。然而,人们对它们之间的相互关系仍然知之甚少。我们的目的是研究参与氧化应激和免疫微环境的关键分子的状态,以及它们之间的关系、与 ESCC 的临床病理特征和预后的关系。我们采用免疫组化方法检测了176例ESCC患者组织样本中程序性死亡配体1(PD-L1)、CD8、核因子红细胞-2相关因子-2(NRF2)和NAD(P)H醌氧化还原酶1(NQO1)的表达。我们采用综合阳性评分(CPS)和肿瘤比例评分(TPS)来评估PD-L1的表达,结果发现CPS和TPS之间呈正相关。值得注意的是,在II-IV期ESCC中,CPS或TPS评估的PD-L1表达与NRF2核评分和NQO1评分均呈正相关。我们还观察到 CD8+ T 细胞密度与 PD-L1 表达呈正相关。此外,高水平的 PD-L1 CPS(而非 TPS)与 TNM 分期晚期和淋巴结转移相关。此外,在II-IV期ESCC中,PD-L1 CPS和NRF2的核表达均可预测较短的总生存期。通过使用Mandard-肿瘤回归分级(TRG)系统评估肿瘤对新辅助化疗(NACT)的病理反应,我们发现与TRG-3 + 4组相比,TRG-5组在NACT前活检样本中的NRF2核评分、PD-L1 CPS和TPS更高。TRG-5组NACT术后手术标本的NQO1评分明显高于TRG 3 + 4组。总之,PD-L1的表达与NRF2信号通路异常、TNM分期晚期、淋巴结转移和预后不良有关。PD-L1 的失调和 NRF2 信号通路的异常激活与 NACT 的耐药性有关。我们的研究结果揭示了 ESCC 中氧化应激和免疫微环境之间复杂的相互关系,这可能对个性化疗法和改善患者预后有影响。
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引用次数: 0
Mesonephric-type adenocarcinomas of the ovary: prevalence, diagnostic reproducibility, outcome, and value of PAX2 卵巢中肾型腺癌:发病率、诊断重现性、预后和 PAX2 的价值。
IF 3.4 2区 医学 Q1 PATHOLOGY Pub Date : 2024-07-06 DOI: 10.1002/2056-4538.12389
Martin Köbel, Eun Young Kang, Sandra Lee, Travis Ogilvie, Tatjana Terzic, Linyuan Wang, Nicholas JP Wiebe, Zainab Al-Shamma, Linda S Cook, Gregg S Nelson, Colin JR Stewart, Andreas von Deimling, Felix KF Kommoss, Cheng-Han Lee

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 (κ = 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; p < 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.

卵巢中肾型(或类)腺癌(MAs)是一种不常见的侵袭性组织类型。它们似乎是从Müllerian病变转化而来,这给诊断带来了挑战。因此,我们旨在开发一种组织学和免疫组化(IHC)方法,以优化卵巢腺癌与其组织学模拟物(如卵巢子宫内膜样癌(EC))的鉴别。首先,我们用 GATA3、TTF1、ER 和 PR 四标记 IHC 面板筛选了 1,537 例卵巢上皮性肿瘤,然后对 EC 进行形态学审查,以在回顾性队列中识别 MA。在 66 例病例中,评估了最初无 IHC 信息和随后有 IHC 信息(四标记面板)的病例在区分 MA 与 EC 时的观察者间再现性。分别评估了 PAX2、CD10 和 calretinin 的表达,并进行了生存分析。我们从中发现了 23 例 MA,其中 22 例最初被报告为 EC(5.7%),1 例为透明细胞癌。随着四标记 IHC 面板的整合,观察者间的可重复性从一般增加到相当高(κ = 0.376-0.727)。PAX2是区分MA和EC最敏感、最特异的标志物,可与ER/PR和GATA3/TTF1一起作为一线标志物。MA患者较早死于疾病的风险明显增加(危险比 = 3.08; 95% CI, 1.62-5.85; p
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引用次数: 0
Volumetric imaging of the tumor microvasculature reflects outcomes and genomic states of clear cell renal cell carcinoma 肿瘤微血管的容积成像反映了透明细胞肾细胞癌的结局和基因组状态。
IF 3.4 2区 医学 Q1 PATHOLOGY Pub Date : 2024-06-26 DOI: 10.1002/2056-4538.12388
Yuta Kaneko, Tsukasa Masuda, Kimiharu Takamatsu, Shuji Mikami, Kohei Nakamura, Hiroshi Nishihara, Ryuichi Mizuno, Nobuyuki Tanaka, Mototsugu Oya

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.

肿瘤结构异质且复杂,二维分析很难获得完整的特征。本研究旨在利用全组织表型和三维光片显微镜观察透明细胞肾细胞癌(ccRCC)肿瘤的体积血管信息并确定其特征。在这里,我们使用诊断免疫标记石蜡包埋清除器官管道进行组织清除、免疫标记和三维成像。通过计算三维密度、血管长度、血管半径和密度曲线,如表达的偏度、峰度和方差,研究了靶向血管的 CD34 和靶向淋巴管的 LYVE-1 的空间分布。然后,我们研究了这些与ccRCC结果和基因改变状态的关联。研究纳入了 46 例 ccRCC 患者的福尔马林固定石蜡包埋肿瘤样本。接收者操作特征曲线分析显示,血管和淋巴管分布与核分级高、肿瘤体积大和存在静脉侵犯等病理因素有关。此外,三维成像参数还对ccRCC患者的生存结果进行了分层。基于体积血管信息参数的基因组改变分析表明,与血管半径相关的PI3K-mTOR通路突变存在显著差异。总之,我们的研究表明,体积血管信息的空间阐释可用于预后,并可作为基因组改变的新生物标志物。高端组织清理技术和容积免疫组化技术可对肿瘤进行三维分析,从而更好地了解肿瘤空间的微血管结构。
{"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}
引用次数: 0
Characterisation of colorectal cancer by hierarchical clustering analyses for five stroma-related markers 通过对五种间质相关标记物进行分层聚类分析,确定结直肠癌的特征。
IF 4.1 2区 医学 Q1 PATHOLOGY Pub Date : 2024-06-18 DOI: 10.1002/2056-4538.12386
Sunao Ito, Akira Koshino, Chengbo Wang, Takahiro Otani, Masayuki Komura, Akane Ueki, Shunsuke Kato, Hiroki Takahashi, Masahide Ebi, Naotaka Ogasawara, Toyonori Tsuzuki, Kenji Kasai, Kunio Kasugai, Shuji Takiguchi, Satoru Takahashi, Shingo Inaguma

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%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCNLowPDPNLow); a PDPN-dominant group (DCNMidPDPNHigh); and a DCN-dominant group (DCNHighPDPNLow), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26–0.96, p = 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.

在结直肠癌(CRC)中,肿瘤基质支持肿瘤能力的证据迅速积累。肿瘤基质由异质细胞和成分组成,包括癌相关成纤维细胞(CAFs)、小血管、免疫细胞和细胞外基质蛋白。本研究通过免疫组化和天狼星红染色法研究了癌症基质的主要成分 CAFs 和胶原蛋白的特征。研究分析了五种独立的CAF相关或基质标记物,即decorin(DCN)、fibroblast activation protein(FAP)、podoplanin(PDPN)、alpha-smooth muscle actin(ACTA2)和胶原蛋白的表达状态,以及它们与临床病理特征和临床结果的关系。高DCN肿瘤患者的5年生存率明显较低(57.3%对79.0%;P = 0.044)。此外,对这五种标记物进行分层聚类分析后发现,有三组显示出特定的特征:实变组(癌细胞丰富,DCNLowPDPNLow);PDPN显性组(DCNMidPDPNHigh);以及DCN显性组(DCNHighPDPNLow),这三组与患者的生存率有显著关联(p = 0.0085)。Cox 比例危险模型发现,与 DCN 优势组相比,PDPN 优势组(危险比 = 0.50,95% CI = 0.26-0.96,p = 0.037)是潜在的有利因素。值得注意的是,DCN主导型肿瘤的pT分期最晚,CD8+和FOXP3+免疫细胞数量最少。这项研究揭示了免疫组化和五种基质因子的特殊染色以及分层聚类分析可用于预测 CRC 患者的预后。癌症基质靶向疗法可能是治疗 CRC 患者的候选疗法。
{"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<sup>Low</sup>PDPN<sup>Low</sup>); a PDPN-dominant group (DCN<sup>Mid</sup>PDPN<sup>High</sup>); and a DCN-dominant group (DCN<sup>High</sup>PDPN<sup>Low</sup>), 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}
引用次数: 0
Clinicopathological features and cancer transcriptomic profiling of poorly cohesive gastric carcinoma subtypes 粘连性差的胃癌亚型的临床病理特征和癌症转录组图谱。
IF 4.1 2区 医学 Q1 PATHOLOGY Pub Date : 2024-06-11 DOI: 10.1002/2056-4538.12387
Hung-Hsuan Yen, Pin-Yu Chen, Ruby Yun-Ju Huang, Jung-Ming Jeng, I-Rue Lai

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 MMP7 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.

胃癌(PCC)表现为弥漫性和多种肿瘤细胞形态,通常预示着较差的预后。为了便于研究,最近的共识是根据肿瘤中标志环细胞(SRC)的比例对 PCC 进行重新分类。两个最明显的亚型,即未另作规定的粘连性差的癌(PCC-NOS)和标志环细胞癌(SRCC),其特征分别是 SRC 的比例低于 10%和高于 90%。然而,比较这些亚型的临床病理学和转录组学差异的研究仍然有限。在本研究中,我们对 55 例晚期 PCC(包括 43 例 PCC-NOS 和 12 例 SRCC)的临床病理特征进行了比较分析。随后,我们随机选取了 12 例 PCC-NOS 和 5 例 SRCC 病例,使用 GeoMx 数字空间图谱分析仪进行了初步的癌症相关基因表达图谱分析和通路富集分析,并在由 16 例 PCC-NOS 和 6 例 SRCC 病例组成的单独验证组中进行了验证。然后将这些转录组研究结果与肿瘤形态学和临床病理学数据相关联。与 SRCC 病例相比,PCC-NOS 病例的肿瘤体积更大,病理 N3 病变发生率更高,1 年无进展生存率更低。利用GeoMx癌症转录组图谱成功实现了PCC-NOS和SRCC的聚类。在所有研究基因中,只有MMP7表现出差异表达,其过表达与PCC-NOS亚型、神经周围侵袭增加和疾病进展提前显著相关。通路分析显示,PCC-NOS 中与囊泡介导的转运、适应性免疫系统、致癌信号转导和细胞外基质组织相关的通路明显富集,而 SRCC 中与呼吸电子转运和细胞周期相关的通路明显富集。总之,本研究采用最新的共识分类和新型分析平台,比较并关联了处于晚期阶段的 PCC-NOS 和 SRCC 的临床病理特征和转录组数据。
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引用次数: 0
The Glasgow Microenvironment Score: an exemplar of contemporary biomarker evolution in colorectal cancer 格拉斯哥微环境评分:当代结直肠癌生物标志物演变的典范。
IF 4.1 2区 医学 Q1 PATHOLOGY Pub Date : 2024-06-09 DOI: 10.1002/2056-4538.12385
Katrina Knight, Christopher Bigley, Kathryn Pennel, Jennifer Hay, Noori Maka, Donald McMillan, James Park, Campbell Roxburgh, Joanne Edwards

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&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&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.

结肠直肠癌仍然是全球死亡的主要原因。分期相似的患者对治疗的反应和存活率明显不同。分子图谱分析凸显了结直肠癌的异质性,但对日常临床实践的影响有限。目前急需具有强大预后和治疗相关性的生物标志物。理想的情况是,生物标志物可以从用于常规病理分期的 H&E 切片中提取,具有可靠的灵敏度和特异性,并且只需最低限度的额外培训。生物标志物的目标将捕捉关键的病理特征,这些特征已被证实对预后和临床有用,如局部炎症反应和肿瘤微环境。格拉斯哥微环境评分(GMS)于2014年首次被描述,它将侵袭边缘的瘤周炎症评估与肿瘤基质含量量化相结合。利用H&E切片,通过对浸润边缘瘤周淋巴细胞浸润的定性形态学评估确定克林特鲁普-迈基宁(KM)分级,并以半定量方式计算肿瘤基质百分比(TSP),即可见视野内基质的百分比。由此得出的三个预后类别具有直接的临床意义:GMS 0 表示肿瘤有密集的炎症浸润/浸润边缘有较高的 KM 等级,生存率较高;GMS 1 表示炎症反应较弱,TSP 较低,生存率处于中等水平;GMS 2 表示肿瘤炎症反应较弱,TSP 较高,生存率较低。GMS 的预后能力已得到广泛验证,其指导化疗的潜力已在一项大型三期试验中得到证实。在此,我们将详细介绍它从构想、验证到临床转化的过程,并概述这一前景广阔且实用的生物标记物的未来。
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引用次数: 0
Gastric cancer immune microenvironment score predicts neoadjuvant chemotherapy efficacy and prognosis 胃癌免疫微环境评分可预测新辅助化疗的疗效和预后
IF 4.1 2区 医学 Q1 PATHOLOGY Pub Date : 2024-05-22 DOI: 10.1002/2056-4538.12378
Shaoji Zhao, Yinan Liu, Li Ding, Chaoyue Zhang, Jinning Ye, Kaiyu Sun, Wu Song, Shirong Cai, Yulong He, Jianjun Peng, Jianbo Xu

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.

新辅助化疗(NACT)对晚期胃癌(GC)患者的疗效差异很大。因此,我们旨在验证肿瘤浸润免疫细胞(TIICs)对晚期胃癌患者NACT治疗反应和预后的预测价值,并探讨NACT对肿瘤免疫微环境(TIME)的影响。本研究收集了晚期 GC 患者的配对肿瘤组织(NACT 前和 NACT 后)。采用免疫组化染色法评估TIIC,并通过逻辑回归分析建立GC免疫微环境评分(ISGC评分),预测NACT疗效。Kaplan-Meier 曲线用于评估患者的生存结果。结果显示,NACT应答患者和非应答患者的TIME差异很大。在验证队列中,ISGC 评分对 NACT 治疗反应具有良好的预测性。此外,高 ISGC 表示晚期 GC 患者的长期生存率更高。此外,NACT治疗后,反应组的肿瘤浸润T细胞(CD3+和CD8+)和CD11c+巨噬细胞显著增加,而CD163+巨噬细胞和FOXP3+Treg细胞减少。然而,无反应组的结果却相反。最后,我们发现程序性细胞死亡配体 1(PD-L1)阳性肿瘤的比例在 NACT 前为 31%(32/104),NACT 后为 49%(51/104),几乎所有 PD-L1 升高的患者都属于 NACT 反应组。ISGC模型准确预测了NACT的疗效,并将GC患者分为不同的生存组。NACT调节了GC的TIME,这可能为个性化免疫疗法提供了策略。
{"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<sup>+</sup> and CD8<sup>+</sup>) and CD11c<sup>+</sup> macrophages were significantly increased in the response group, while CD163<sup>+</sup> macrophages and FOXP3<sup>+</sup> 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}
引用次数: 0
KRT81 and HNF1A expression in pancreatic ductal adenocarcinoma: investigation of predictive and prognostic value of immunohistochemistry-based subtyping 胰腺导管腺癌中 KRT81 和 HNF1A 的表达:基于免疫组化亚型的预测和预后价值研究。
IF 4.1 2区 医学 Q1 PATHOLOGY Pub Date : 2024-05-15 DOI: 10.1002/2056-4538.12377
Jia Rao, Marianne Sinn, Uwe Pelzer, Hanno Riess, Helmut Oettle, Ihsan E Demir, Helmut Friess, Carsten Jäger, Katja Steiger, Alexander Muckenhuber

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 (p < 0.001 and p < 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.

即使经过数十年的研究,胰腺导管腺癌(PDAC)仍然是一种致死率很高的疾病,而且对常规治疗的反应大多不佳。为了进一步改善患者的预后并减少不必要的副作用,不同研究小组提出了将 PDAC 划分为不同生物学亚型的建议。最近,一种基于免疫组化(IHC)的亚型分类方法使用细胞角蛋白-81(KRT81)和肝细胞核因子 1A(HNF1A)可以再现之前建立的一些分子亚型分类方法,同时提供重要的预后信息,并在一定程度上提供预测信息。我们改进了 KRT81/HNF1A 亚型划分方法,将 PDAC 划分为三种不同的生物学亚型。基于 IHC 的方法的预后价值在两个原发切除队列中进行了研究,这两个队列分别包括 269 名和 286 名患者。在第二个队列中,我们还评估了厄洛替尼+吉西他滨治疗反应的预测效果。在这两个PDAC队列中,新的HNF1A阳性亚型与最佳生存率相关,KRT81阳性亚型与最差生存率相关,而双阴性亚型与中等生存率相关(p
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引用次数: 0
Recurrent and novel fusions detected by targeted RNA sequencing as part of the diagnostic workflow of soft tissue and bone tumours 将靶向 RNA 测序作为软组织和骨肿瘤诊断工作流程的一部分,检测复发性和新型融合。
IF 4.1 2区 医学 Q1 PATHOLOGY Pub Date : 2024-05-13 DOI: 10.1002/2056-4538.12376
Rafael Zago Baltazar, Sofie Claerhout, Sara Vander Borght, Lien Spans, Raphael Sciot, Patrick Schöffski, Daphne Hompes, Friedl Sinnaeve, Hazem Wafa, Marleen Renard, Mari FCM van den Hout, Astrid Vernemmen, Louis Libbrecht, An-Katrien De Roo, Filomena Mazzeo, Cédric van Marcke, Karen Deraedt, Claire Bourgain, Isabelle Vanden Bempt

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 in situ 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, BCOR internal tandem duplication or ALK 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 (>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 EWSR1 FISH probe, we observed a gene-dependent disparity (p = 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: NAB2::NCOA2, YAP1::NUTM2B, HSPA8::BRAF, and PDE2A::PLAG1. Overall, targeted RNA-seq has proven extremely valuable in the diagnostic workflow of soft tissue and bone tumours.

基因融合的鉴定已成为软组织和骨肿瘤诊断不可或缺的一部分。我们研究了基于 RNA 的靶向测序(靶向 RNA-seq,Archer FusionPlex)对目前这些肿瘤分子诊断工作流程的附加价值,该流程基于荧光原位杂交(FISH),使用 25 个探针检测基因融合。在一系列 131 个诊断样本中,有 47 个病例(35.9%)的靶向 RNA-seq 发现了基因融合、BCOR 内部串联重复或 ALK 缺失。在 74 个病例(包括 137 项 FISH 分析)中,对 FISH 和靶向 RNA-seq 的一致性进行了评估。在 49 次分析中有 27 次(55.1%)和 88 次分析中有 81 次(92.0%)的 FISH 阳性或阴性结果分别得到了靶向 RNA-seq 的证实。虽然阴性结果的一致性很高,但在 7 个病例中,尽管 FISH 结果为阴性,但靶向 RNA-seq 还是发现了典型基因融合。与一致的 FISH 阳性分析(在 88.9% 的病例中,>41% 的核仁)相比,22 例不一致的 FISH 阳性分析中重排阳性核仁的比例较低(范围为 15-41%)。根据组织学和靶向 RNA-seq 研究结果,有 6 项 FISH 分析(4 例)最终被认为是假阳性。对于 EWSR1 FISH 探针,我们观察到了基因依赖性差异(p = 0.0020),35 个病例中有 8 个病例的 FISH 和靶向 RNA-seq 结果不一致(22.9%)。这项研究表明,在 131 个病例中,有 19 个病例(14.5%)的靶向 RNA-seq 为我们目前的软组织和骨肿瘤诊断工作流程带来了附加值,我们将其归类为改变诊断(3 个病例)、提高精确度(6 个病例)或增强谱系(10 个病例)。在后一亚组中,我们发现了四个新的融合转录本,其临床意义尚不清楚:NAB2::NCOA2、YAP1::NUTM2B、HSPA8::BRAF 和 PDE2A::PLAG1。总之,靶向 RNA-seq 已被证明在软组织和骨肿瘤的诊断流程中极具价值。
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引用次数: 0
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Journal of Pathology Clinical Research
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