Journal of Pathology Clinical Research最新文献

{"title":"Altered cytoplasmic and nuclear ADP-ribosylation levels analyzed with an improved ADP-ribose binder are a prognostic factor in renal cell carcinoma","authors":"Peter Schraml,&nbsp;Fabio Aimi,&nbsp;Martin Zoche,&nbsp;Domingo Aguilera-Garcia,&nbsp;Fabian Arnold,&nbsp;Holger Moch,&nbsp;Michael O Hottiger","doi":"10.1002/cjp2.320","DOIUrl":"10.1002/cjp2.320","url":null,"abstract":"<p>ADP-ribosylation (ADPR) of proteins is catalyzed by ADP-ribosyltransferases, which are targeted by inhibitors (i.e. poly(ADP-ribose) polymerase inhibitors [PARPi]). Although renal cell carcinoma (RCC) cells are sensitive <i>in vitro</i> to PARPi, studies on the association between ADPR levels and somatic loss of function mutations in DNA damage repair genes are currently missing. Here we observed, in two clear cell RCC (ccRCC) patient cohorts (<i>n</i> = 257 and <i>n</i> = 241) stained with an engineered ADP-ribose binding macrodomain (eAf1521), that decreased cytoplasmic ADPR (cyADPR) levels significantly correlated with late tumor stage, high-ISUP (the International Society of Urological Pathology) grade, presence of necrosis, dense lymphocyte infiltration, and worse patient survival (<i>p</i> &lt; 0.01 each). cyADPR proved to be an independent prognostic factor (<i>p</i> = 0.001). Comparably, absence of nuclear ADPR staining in ccRCC correlated with absence of PARP1 staining (<i>p</i> &lt; 0.01) and worse patient outcome (<i>p</i> &lt; 0.05). In papillary RCC the absence of cyADPR was also significantly associated with tumor progression and worse patient outcome (<i>p</i> &lt; 0.05 each). To interrogate whether the ADPR status could be associated with genetic alterations in DNA repair, chromatin remodeling, and histone modulation, we performed DNA sequence analysis and identified a significant association of increased <i>ARID1A</i> mutations in ccRCC^{cyADPR+++/PARP1+} compared with ccRCC^{cyADPR−/PARP1−} (31% versus 4%; <i>p</i> &lt; 0.05). Collectively, our data suggest the prognostic value of nuclear and cytoplasmic ADPR levels in RCC that might be further influenced by genetic alterations.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 4","pages":"273-284"},"PeriodicalIF":4.1,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/42/02/CJP2-9-273.PMC10240151.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9996631","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":"KRAS mutations and endometriosis burden of disease","authors":"Natasha L Orr,&nbsp;Arianne Albert,&nbsp;Yang Doris Liu,&nbsp;Amy Lum,&nbsp;JooYoon Hong,&nbsp;Catalina L Ionescu,&nbsp;Janine Senz,&nbsp;Tayyebeh M Nazeran,&nbsp;Anna F Lee,&nbsp;Heather Noga,&nbsp;Kate Lawrenson,&nbsp;Catherine Allaire,&nbsp;Christina Williams,&nbsp;Mohamed A Bedaiwy,&nbsp;Michael S Anglesio,&nbsp;Paul J Yong","doi":"10.1002/cjp2.317","DOIUrl":"10.1002/cjp2.317","url":null,"abstract":"<p>The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic <i>KRAS</i> mutations were associated with greater disease burden in endometriosis (i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5–9 years of follow-up. Somatic activating <i>KRAS</i> codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. <i>KRAS</i> mutation status for each subject was coded as present (<i>KRAS</i> mutation in at least one endometriosis sample in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I–IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re-operation. <i>KRAS</i> mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9%; 11/19) and subjects with mixed subtypes (60.6%; 40/66), compared with those with superficial endometriosis only (35.1%; 13/37) (<i>p</i> = 0.04). <i>KRAS</i> mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases (<i>p</i> = 0.02). <i>KRAS</i> mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk [RR] = 1.47, 95% CI: 1.02–2.11) and non-Caucasian ethnicity (RR = 0.64, 95% CI: 0.47–0.89). Pain severities did not differ based on <i>KRAS</i> mutation status, at either baseline or follow-up. Re-operation rates were low overall, occurring in 17.2% with <i>KRAS</i> mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66–4.21). In conclusion, <i>KRAS</i> mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer-driver mutations may inform a future molecular classification of endometriosis.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 4","pages":"302-312"},"PeriodicalIF":4.1,"publicationDate":"2023-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.317","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9624779","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 effectiveness of neoadjuvant chemoradiotherapy in oesophageal adenocarcinoma with presence of extracellular mucin, signet-ring cells, and/or poorly cohesive cells","authors":"Maria J Valkema,&nbsp;Anne-Marie Vos,&nbsp;Rachel S van der Post,&nbsp;Ariadne HAG Ooms,&nbsp;Lindsey Oudijk,&nbsp;Ben M Eyck,&nbsp;Sjoerd M Lagarde,&nbsp;Bas PL Wijnhoven,&nbsp;Bastiaan R Klarenbeek,&nbsp;Camiel Rosman,&nbsp;J Jan B van Lanschot,&nbsp;Michail Doukas","doi":"10.1002/cjp2.321","DOIUrl":"10.1002/cjp2.321","url":null,"abstract":"<p>Oesophageal adenocarcinomas may show different histopathological patterns, including excessive acellular mucin pools, signet-ring cells (SRCs), and poorly cohesive cells (PCCs). These components have been suggested to correlate with poor outcomes after neoadjuvant chemoradiotherapy (nCRT), which might influence patient management. However, these factors have not been studied independently of each other with adjustment for tumour differentiation grade (i.e. the presence of well-formed glands), which is a possible confounder. We studied the pre- and post-treatment presence of extracellular mucin, SRCs, and/or PCCs in relation to pathological response and prognosis after nCRT in patients with oesophageal or oesophagogastric junction adenocarcinoma. A total of 325 patients were retrospectively identified from institutional databases of two university hospitals. All patients were scheduled for ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) nCRT and oesophagectomy between 2001 and 2019. Percentages of well-formed glands, extracellular mucin, SRCs, and PCCs were scored in pre-treatment biopsies and post-treatment resection specimens. The association between histopathological factors (≥1 and &gt;10%) and tumour regression grade 3–4 (i.e. &gt;10% residual tumour), overall survival, and disease-free survival (DFS) was evaluated, adjusted for tumour differentiation grade amongst other clinicopathological variables. In pre-treatment biopsies, ≥1% extracellular mucin was present in 66 of 325 patients (20%); ≥1% SRCs in 43 of 325 (13%), and ≥1% PCCs in 126 of 325 (39%). We show that pre-treatment histopathological factors were unrelated to tumour regression grade. Pre-treatment presence of &gt;10% PCCs was associated with lower DFS (hazard ratio [HR] 1.73, 95% CI 1.19–2.53). Patients with post-treatment presence of ≥1% SRCs had higher risk of death (HR 1.81, 95% CI 1.10–2.99). In conclusion, pre-treatment presence of extracellular mucin, SRCs, and/or PCCs is unrelated to pathological response. The presence of these factors should not be an argument to refrain from CROSS. At least 10% PCCs pre-treatment and any SRCs post-treatment, irrespective of the tumour differentiation grade, seem indicative of inferior prognosis, but require further validation in larger cohorts.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 4","pages":"322-335"},"PeriodicalIF":4.1,"publicationDate":"2023-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a6/c6/CJP2-9-322.PMC10240149.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9677889","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":"Identification and validation of NFIA as a novel prognostic marker in renal cell carcinoma","authors":"Roger de Alwis,&nbsp;Sarah Schoch,&nbsp;Mazharul Islam,&nbsp;Christina Möller,&nbsp;Börje Ljungberg,&nbsp;Håkan Axelson","doi":"10.1002/cjp2.316","DOIUrl":"10.1002/cjp2.316","url":null,"abstract":"<p>Prognostic tools are an essential component of the clinical management of patients with renal cell carcinoma (RCC). Although tumour stage and grade can provide important information, they fail to consider patient- and tumour-specific biology. In this study, we set out to find a novel molecular marker of RCC by using hepatocyte nuclear factor 4A (HNF4A), a transcription factor implicated in RCC progression and malignancy, as a blueprint. Through transcriptomic analyses, we show that the nuclear factor I A (NFIA)-driven transcription network is active in primary RCC and that higher levels of NFIA confer a survival benefit. We validate our findings using immunohistochemical staining and analysis of a 363-patient tissue microarray (TMA), showing for the first time that NFIA can independently predict poor cancer-specific survival in clear cell RCC (ccRCC) patients (hazard ratio = 0.46, 95% CI = 0.24–0.85, <i>p</i> value = 0.014). Furthermore, we confirm the association of HNF4A with higher grades and stages in ccRCC in our TMA cohort. We present novel data that show HNF4A protein expression does not confer favourable prognosis in papillary RCC, confirming our survival analysis with publicly available <i>HNF4A</i> RNA expression data. Further work is required to elucidate the functional role of NFIA in RCC as well as the testing of these markers on patient material from diverse multi-centre cohorts, to establish their value for the prognostication of RCC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 4","pages":"261-272"},"PeriodicalIF":4.1,"publicationDate":"2023-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c0/26/CJP2-9-261.PMC10240150.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9627298","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":"p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study","authors":"Martin Köbel,&nbsp;Eun-Young Kang,&nbsp;Ashley Weir,&nbsp;Peter F Rambau,&nbsp;Cheng-Han Lee,&nbsp;Gregg S Nelson,&nbsp;Prafull Ghatage,&nbsp;Nicola S Meagher,&nbsp;Marjorie J Riggan,&nbsp;Jennifer Alsop,&nbsp;Michael S Anglesio,&nbsp;Matthias W Beckmann,&nbsp;Christiani Bisinotto,&nbsp;Michelle Boisen,&nbsp;Jessica Boros,&nbsp;Alison H Brand,&nbsp;Angela Brooks-Wilson,&nbsp;Michael E Carney,&nbsp;Penny Coulson,&nbsp;Madeleine Courtney-Brooks,&nbsp;Kara L Cushing-Haugen,&nbsp;Cezary Cybulski,&nbsp;Suha Deen,&nbsp;Mona A El-Bahrawy,&nbsp;Esther Elishaev,&nbsp;Ramona Erber,&nbsp;Sian Fereday,&nbsp;AOCS Group,&nbsp;Anna Fischer,&nbsp;Simon A Gayther,&nbsp;Arantzazu Barquin-Garcia,&nbsp;Aleksandra Gentry-Maharaj,&nbsp;C Blake Gilks,&nbsp;Helena Gronwald,&nbsp;Marcel Grube,&nbsp;Paul R Harnett,&nbsp;Holly R Harris,&nbsp;Andreas D Hartkopf,&nbsp;Arndt Hartmann,&nbsp;Alexander Hein,&nbsp;Joy Hendley,&nbsp;Brenda Y Hernandez,&nbsp;Yajue Huang,&nbsp;Anna Jakubowska,&nbsp;Mercedes Jimenez-Linan,&nbsp;Michael E Jones,&nbsp;Catherine J Kennedy,&nbsp;Tomasz Kluz,&nbsp;Jennifer M Koziak,&nbsp;Jaime Lesnock,&nbsp;Jenny Lester,&nbsp;Jan Lubiński,&nbsp;Teri A Longacre,&nbsp;Maria Lycke,&nbsp;Constantina Mateoiu,&nbsp;Bryan M McCauley,&nbsp;Valerie McGuire,&nbsp;Britta Ney,&nbsp;Alexander Olawaiye,&nbsp;Sandra Orsulic,&nbsp;Ana Osorio,&nbsp;Luis Paz-Ares,&nbsp;Teresa Ramón y Cajal,&nbsp;Joseph H Rothstein,&nbsp;Matthias Ruebner,&nbsp;Minouk J Schoemaker,&nbsp;Mitul Shah,&nbsp;Raghwa Sharma,&nbsp;Mark E Sherman,&nbsp;Yurii B Shvetsov,&nbsp;Naveena Singh,&nbsp;Helen Steed,&nbsp;Sarah J Storr,&nbsp;Aline Talhouk,&nbsp;Nadia Traficante,&nbsp;Chen Wang,&nbsp;Alice S Whittemore,&nbsp;Martin Widschwendter,&nbsp;Lynne R Wilkens,&nbsp;Stacey J Winham,&nbsp;Javier Benitez,&nbsp;Andrew Berchuck,&nbsp;David D Bowtell,&nbsp;Francisco J Candido dos Reis,&nbsp;Ian Campbell,&nbsp;Linda S Cook,&nbsp;Anna DeFazio,&nbsp;Jennifer A Doherty,&nbsp;Peter A Fasching,&nbsp;Renée T Fortner,&nbsp;María J García,&nbsp;Marc T Goodman,&nbsp;Ellen L Goode,&nbsp;Jacek Gronwald,&nbsp;David G Huntsman,&nbsp;Beth Y Karlan,&nbsp;Linda E Kelemen,&nbsp;Stefan Kommoss,&nbsp;Nhu D Le,&nbsp;Stewart G Martin,&nbsp;Usha Menon,&nbsp;Francesmary Modugno,&nbsp;Paul DP Pharoah,&nbsp;Joellen M Schildkraut,&nbsp;Weiva Sieh,&nbsp;Annette Staebler,&nbsp;Karin Sundfeldt,&nbsp;Anthony J Swerdlow,&nbsp;Susan J Ramus,&nbsp;James D Brenton","doi":"10.1002/cjp2.311","DOIUrl":"10.1002/cjp2.311","url":null,"abstract":"<p>Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of <i>TP53</i> mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, <i>p</i> = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, <i>p</i> = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of <i>TP53</i> mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 3","pages":"208-222"},"PeriodicalIF":4.1,"publicationDate":"2023-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9760515","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":"Development of multiple AI pipelines that predict neoadjuvant chemotherapy response of breast cancer using H&E-stained tissues","authors":"Bin Shen,&nbsp;Akira Saito,&nbsp;Ai Ueda,&nbsp;Koji Fujita,&nbsp;Yui Nagamatsu,&nbsp;Mikihiro Hashimoto,&nbsp;Masaharu Kobayashi,&nbsp;Aashiq H Mirza,&nbsp;Hans Peter Graf,&nbsp;Eric Cosatto,&nbsp;Shoichi Hazama,&nbsp;Hiroaki Nagano,&nbsp;Eiichi Sato,&nbsp;Jun Matsubayashi,&nbsp;Toshitaka Nagao,&nbsp;Esther Cheng,&nbsp;Syed AF Hoda,&nbsp;Takashi Ishikawa,&nbsp;Masahiko Kuroda","doi":"10.1002/cjp2.314","DOIUrl":"10.1002/cjp2.314","url":null,"abstract":"<p>In recent years, the treatment of breast cancer has advanced dramatically and neoadjuvant chemotherapy (NAC) has become a common treatment method, especially for locally advanced breast cancer. However, other than the subtype of breast cancer, no clear factor indicating sensitivity to NAC has been identified. In this study, we attempted to use artificial intelligence (AI) to predict the effect of preoperative chemotherapy from hematoxylin and eosin images of pathological tissue obtained from needle biopsies prior to chemotherapy. Application of AI to pathological images typically uses a single machine-learning model such as support vector machines (SVMs) or deep convolutional neural networks (CNNs). However, cancer tissues are extremely diverse and learning with a realistic number of cases limits the prediction accuracy of a single model. In this study, we propose a novel pipeline system that uses three independent models each focusing on different characteristics of cancer atypia. Our system uses a CNN model to learn structural atypia from image patches and SVM and random forest models to learn nuclear atypia from fine-grained nuclear features extracted by image analysis methods. It was able to predict the NAC response with 95.15% accuracy on a test set of 103 unseen cases. We believe that this AI pipeline system will contribute to the adoption of personalized medicine in NAC therapy for breast cancer.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 3","pages":"182-194"},"PeriodicalIF":4.1,"publicationDate":"2023-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/49/3e/CJP2-9-182.PMC10073928.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9677869","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":"Low gamma-butyrobetaine dioxygenase (BBOX1) expression as a prognostic biomarker in patients with clear cell renal cell carcinoma: a machine learning approach","authors":"Kyu-Shik Kim,&nbsp;Kyoung Min Moon,&nbsp;Kyueng-Whan Min,&nbsp;Woon Yong Jung,&nbsp;Su-Jin Shin,&nbsp;Seung Wook Lee,&nbsp;Mi Jung Kwon,&nbsp;Dong-Hoon Kim,&nbsp;Sukjoong Oh,&nbsp;Yung-Kyun Noh","doi":"10.1002/cjp2.315","DOIUrl":"10.1002/cjp2.315","url":null,"abstract":"<p>Gamma-butyrobetaine dioxygenase (BBOX1) is a catalyst for the conversion of gamma-butyrobetaine to <span>l</span>-carnitine, which is detected in normal renal tubules. The purpose of this study was to analyze the prognosis, immune response, and genetic alterations associated with low BBOX1 expression in patients with clear cell renal cell carcinoma (RCC). We analyzed the relative influence of BBOX1 on survival using machine learning and investigated drugs that can inhibit renal cancer cells with low BBOX1 expression. We analyzed clinicopathologic factors, survival rates, immune profiles, and gene sets according to BBOX1 expression in a total of 857 patients with kidney cancer from the Hanyang University Hospital cohort (247 cases) and The Cancer Genome Atlas (610 cases). We employed immunohistochemical staining, gene set enrichment analysis, <i>in silico</i> cytometry, pathway network analyses, <i>in vitro</i> drug screening, and gradient boosting machines. BBOX1 expression in RCC was decreased compared with that in normal tissues. Low BBOX1 expression was associated with poor prognosis, decreased CD8+ T cells, and increased neutrophils. In gene set enrichment analyses, low BBOX1 expression was related to gene sets with oncogenic activity and a weak immune response. In pathway network analysis, BBOX1 was linked to regulation of various T cells and programmed death-ligand 1. <i>In vitro</i> drug screening showed that midostaurin, BAY-61-3606, GSK690693, and linifanib inhibited the growth of RCC cells with low BBOX1 expression. Low BBOX1 expression in patients with RCC is related to short survival time and reduced CD8+ T cells; midostaurin, among other drugs, may have enhanced therapeutic effects in this context.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 3","pages":"236-248"},"PeriodicalIF":4.1,"publicationDate":"2023-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.315","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9627270","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 activation of EP300 by F11R leads to EMT and acts as a prognostic factor in triple-negative breast cancers","authors":"Chien-Hsiu Li,&nbsp;Chih-Yeu Fang,&nbsp;Ming-Hsien Chan,&nbsp;Pei-Jung Lu,&nbsp;Luo-Ping Ger,&nbsp;Jan-Show Chu,&nbsp;Yu-Chan Chang,&nbsp;Chi-Long Chen,&nbsp;Michael Hsiao","doi":"10.1002/cjp2.313","DOIUrl":"10.1002/cjp2.313","url":null,"abstract":"<p>Cancer progression is influenced by junctional adhesion molecule (JAM) family members. The relationship between JAM family members and different types of cancer was examined using The Cancer Genome Atlas dataset. mRNA levels of the <i>F11R</i> (F11 receptor) in tumours were inversely correlated to the expression of <i>JAM-2</i> and <i>JAM-3</i>. This relationship was unique to breast cancer (BCa) and was associated with poor prognosis (<i>p</i> = 0.024, hazard ratio = 1.44 [1.05–1.99]). A 50-gene molecular signature (prediction analysis of microarray 50) was used to subtype BCa. <i>F11R</i> mRNA expression significantly increased in human epidermal growth factor receptor 2 (HER2)-enriched (<i>p</i> = 0.0035) and basal-like BCa tumours (<i>p</i> = 0.0005). We evaluated F11R protein levels in two different compositions of BCa subtype patient tissue array cohorts to determine the relationship between BCa subtype and prognosis. Immunohistochemistry staining revealed that a high F11R protein level was associated with poor overall survival (<i>p</i> &lt; 0.001; Taipei Medical University [TMU] cohort, <i>p</i> &lt; 0.001; Kaohsiung Veterans General Hospital [KVGH] cohort) or disease-free survival (<i>p</i> &lt; 0.001 [TMU cohort], <i>p</i> = 0.034 [KVGH cohort]) in patients with BCa. Comparison of F11R levels in different subtypes revealed the association of poor prognosis with high levels of F11R among luminal (<i>p</i> &lt; 0.001 [TMU cohort], <i>p</i> = 0.027 [KVGH cohort]), HER2 positive (<i>p</i> = 0.018 [TMU cohort], <i>p</i> = 0.037 [KVGH cohort]), and triple-negative (<i>p</i> = 0.013 [TMU cohort], <i>p</i> = 0.037 [KVGH cohort]) BCa. <i>F11R</i>-based RNA microarray analysis and Ingenuity Pathway Analysis were successful in profiling the detailed gene ontology of triple-negative BCa cells regulated by <i>F11R</i>. The <i>EP300</i> transcription factor was highly correlated with <i>F11R</i> in BCa (<i>R</i> = 0.51, <i>p</i> &lt; 0.001). By analysing these <i>F11R</i>-affected molecules with the L1000CDs datasets, we were able to predict some repurposing drugs for potential application in <i>F11R</i>-positive BCa treatment.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 3","pages":"165-181"},"PeriodicalIF":4.1,"publicationDate":"2023-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e3/78/CJP2-9-165.PMC10073929.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9996155","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":"CD70 and PD-L1 (CD274) co-expression predicts poor clinical outcomes in patients with pleural mesothelioma","authors":"Shingo Inaguma,&nbsp;Akane Ueki,&nbsp;Jerzy Lasota,&nbsp;Masayuki Komura,&nbsp;Asraful Nahar Sheema,&nbsp;Piotr Czapiewski,&nbsp;Renata Langfort,&nbsp;Janusz Rys,&nbsp;Joanna Szpor,&nbsp;Piotr Waloszczyk,&nbsp;Krzysztof Okoń,&nbsp;Wojciech Biernat,&nbsp;David S Schrump,&nbsp;Raffit Hassan,&nbsp;Markku Miettinen,&nbsp;Satoru Takahashi","doi":"10.1002/cjp2.310","DOIUrl":"10.1002/cjp2.310","url":null,"abstract":"<p>Diffuse pleural mesothelioma (PM) is a highly aggressive tumour typically associated with short survival. Recently, the effectiveness of first-line immune checkpoint inhibitors in patients with unresectable PM was reported. CD70–CD27 signalling plays a co-stimulatory role in promoting T cell expansion and differentiation through the nuclear factor κB (NF-κB) pathway. Conversely, the PD-L1 (CD274)–PD-1 (PDCD1) pathway is crucial for the modulation of immune responses in normal conditions. Nevertheless, pathological activation of both the CD70–CD27 and PD-L1–PD-1 pathways by aberrantly expressed CD70 and PD-L1 participates in the immune evasion of tumour cells. In this study, 171 well-characterised PMs including epithelioid (<i>n</i> = 144), biphasic (<i>n</i> = 15), and sarcomatoid (<i>n</i> = 12) histotypes were evaluated immunohistochemically for CD70, PD-L1, and immune cell markers such as CD3, CD4, CD8, CD56, PD-1, FOXP3, CD68, and CD163. Eight percent (14/171) of mesotheliomas simultaneously expressed CD70 and PD-L1 on the tumour cell membrane. PMs co-expressing CD70 and PD-L1 contained significantly higher numbers of CD8+ (<i>p</i> = 0.0016), FOXP3+ (<i>p</i> = 0.00075), and CD163+ (<i>p</i> = 0.0011) immune cells within their microenvironments. Overall survival was significantly decreased in the cohort of patients with PM co-expressing CD70 and PD-L1 (<i>p</i> &lt; 0.0001). <i>In vitro</i> experiments revealed that PD-L1 and CD70 additively enhanced the motility and invasiveness of PM cells. In contrast, PM cell proliferation was suppressed by PD-L1. PD-L1 enhanced mesenchymal phenotypes such as N-cadherin up-regulation. Collectively, these findings suggest that CD70 and PD-L1 both enhance the malignant phenotypes of PM and diminish anti-tumour immune responses. Based on our observations, combination therapy targeting these signalling pathways might be useful in patients with PM.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 3","pages":"195-207"},"PeriodicalIF":4.1,"publicationDate":"2023-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1d/0d/CJP2-9-195.PMC10073927.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9624260","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":"Predicting microsatellite instability and key biomarkers in colorectal cancer from H&E-stained images: achieving state-of-the-art predictive performance with fewer data using Swin Transformer","authors":"Bangwei Guo,&nbsp;Xingyu Li,&nbsp;Miaomiao Yang,&nbsp;Jitendra Jonnagaddala,&nbsp;Hong Zhang,&nbsp;Xu Steven Xu","doi":"10.1002/cjp2.312","DOIUrl":"10.1002/cjp2.312","url":null,"abstract":"Many artificial intelligence models have been developed to predict clinically relevant biomarkers for colorectal cancer (CRC), including microsatellite instability (MSI). However, existing deep learning networks require large training datasets, which are often hard to obtain. In this study, based on the latest Hierarchical Vision Transformer using Shifted Windows (Swin Transformer [Swin‐T]), we developed an efficient workflow to predict biomarkers in CRC (MSI, hypermutation, chromosomal instability, CpG island methylator phenotype, and BRAF and TP53 mutation) that required relatively small datasets. Our Swin‐T workflow substantially achieved the state‐of‐the‐art (SOTA) predictive performance in an intra‐study cross‐validation experiment on the Cancer Genome Atlas colon and rectal cancer dataset (TCGA‐CRC‐DX). It also demonstrated excellent generalizability in cross‐study external validation and delivered a SOTA area under the receiver operating characteristic curve (AUROC) of 0.90 for MSI, using the Molecular and Cellular Oncology dataset for training (N = 1,065) and the TCGA‐CRC‐DX (N = 462) for testing. A similar performance (AUROC = 0.91) was reported in a recent study, using ~8,000 training samples (ResNet18) on the same testing dataset. Swin‐T was extremely efficient when using small training datasets and exhibited robust predictive performance with 200–500 training samples. Our findings indicate that Swin‐T could be 5–10 times more efficient than existing algorithms for MSI prediction based on ResNet18 and ShuffleNet. Furthermore, the Swin‐T models demonstrated their capability in accurately predicting MSI and BRAF mutation status, which could exclude and therefore reduce samples before subsequent standard testing in a cascading diagnostic workflow, in turn reducing turnaround time and costs.","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 3","pages":"223-235"},"PeriodicalIF":4.1,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/53/91/CJP2-9-223.PMC10073932.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9623034","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}