Journal of Pathology Clinical Research最新文献

{"title":"A novel telomere biology disease-associated gastritis identified through a whole exome sequencing-driven approach","authors":"Namrata Setia,&nbsp;Daniela del Gaudio,&nbsp;Priscilla Kandikatla,&nbsp;Kelly Arndt,&nbsp;Melissa Tjota,&nbsp;Peng Wang,&nbsp;Jeremy Segal,&nbsp;Mir Alikhan,&nbsp;John Hart","doi":"10.1002/cjp2.349","DOIUrl":"10.1002/cjp2.349","url":null,"abstract":"<p>A whole exome sequencing (WES)-driven approach to uncover the etiology of unexplained inflammatory gastritides has been underutilized by surgical pathologists. Here, we discovered the pathobiology of an unusual chronic atrophic gastritis in two unrelated patients using this approach. The gastric biopsies were notable for an unusual pattern of gastritis with persistent dense inflammation, loss of both parietal and neuroendocrine cells in the oxyntic mucosa, and sparing of the antral mucosa. The patients were found to harbor pathogenic variants in telomeropathic genes (<i>POT1</i> and <i>DCLRE1B</i>). Clonality testing for one of the patients showed evidence of evolving clonality of TCR-gene rearrangement. Both patients showed significantly decreased numbers of stem/progenitor cells by immunohistochemistry, which appears to be responsible for the development of mucosal atrophy. No such cases of unusual chronic atrophic gastritis in the setting of telomeropathy have been previously reported. The loss of stem/progenitor cells suggests that stem/progenitor cell exhaustion in the setting of telomere dysfunction is the likely mechanism for development of this unusual chronic atrophic gastritis. The results underscore the need for close monitoring of these gastric lesions, with special regard to their neoplastic potential. This combined WES-driven approach has promise to identify the cause and mechanism of other uncharacterized gastrointestinal inflammatory disorders.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.349","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138296218","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-burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation","authors":"Tamás László,&nbsp;Lili Kotmayer,&nbsp;Viktória Fésüs,&nbsp;Lajos Hegyi,&nbsp;Stefánia Gróf,&nbsp;Ákos Nagy,&nbsp;Béla Kajtár,&nbsp;Alexandra Balogh,&nbsp;Júlia Weisinger,&nbsp;Tamás Masszi,&nbsp;Zsolt Nagy,&nbsp;Péter Farkas,&nbsp;Judit Demeter,&nbsp;Ildikó Istenes,&nbsp;Róbert Szász,&nbsp;Lajos Gergely,&nbsp;Adrienn Sulák,&nbsp;Zita Borbényi,&nbsp;Dóra Lévai,&nbsp;Tamás Schneider,&nbsp;Piroska Pettendi,&nbsp;Emese Bodai,&nbsp;László Szerafin,&nbsp;László Rejtő,&nbsp;Árpád Bátai,&nbsp;Mária Á Dömötör,&nbsp;Hermina Sánta,&nbsp;Márk Plander,&nbsp;Tamás Szendrei,&nbsp;Aryan Hamed,&nbsp;Zsolt Lázár,&nbsp;Zsolt Pauker,&nbsp;Gáspár Radványi,&nbsp;Adrienn Kiss,&nbsp;Gábor Körösmezey,&nbsp;János Jakucs,&nbsp;Péter J Dombi,&nbsp;Zsófia Simon,&nbsp;Zsolt Klucsik,&nbsp;Mihály Gurzó,&nbsp;Márta Tiboly,&nbsp;Tímea Vidra,&nbsp;Péter Ilonczai,&nbsp;András Bors,&nbsp;Hajnalka Andrikovics,&nbsp;Miklós Egyed,&nbsp;Tamás Székely,&nbsp;András Masszi,&nbsp;Donát Alpár,&nbsp;András Matolcsy,&nbsp;Csaba Bödör","doi":"10.1002/cjp2.351","DOIUrl":"10.1002/cjp2.351","url":null,"abstract":"<p><i>TP53</i> aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden <i>TP53</i> mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden <i>TP53</i> mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of <i>TP53</i> mutations using a sensitive, NGS-based mutation analysis in a ‘real-world’ cohort of 901 patients with CLL. In total, 225 <i>TP53</i> mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden <i>TP53</i> mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden <i>TP53</i> mutation. Patients harbouring low-burden <i>TP53</i> mutations had significantly lower time to first treatment compared to patients with wild-type <i>TP53</i>. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden <i>TP53</i> mutations. By demonstrating that patients with sole low-burden <i>TP53</i> variants represent more than one-third of patients with <i>TP53</i> mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of <i>TP53</i> variant reporting to below 10% in the routine diagnostic setting.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.351","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138177610","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":"Immunohistochemical characteristics and potential therapeutic regimens of hepatoid adenocarcinoma of the stomach: a study of 139 cases","authors":"Xuesong Yang,&nbsp;Yan Wu,&nbsp;Anqiang Wang,&nbsp;Xiuli Ma,&nbsp;Kai Zhou,&nbsp;Ke Ji,&nbsp;Xin Ji,&nbsp;Ji Zhang,&nbsp;Xiaojiang Wu,&nbsp;ZhongWu Li,&nbsp;Zhaode Bu","doi":"10.1002/cjp2.343","DOIUrl":"10.1002/cjp2.343","url":null,"abstract":"<p>Hepatoid adenocarcinoma of stomach (HAS) is a special subtype of gastric cancer with poor prognosis. Immunohistochemical analysis could provide important clues for the treatment of HAS. A total of 159 patients were diagnosed as HAS and 139 were enrolled in this study. Statistical differences were determined using relative test methods and survival analyses were performed by the Kaplan–Meier method to find survival differences. All tumors in this study were negative for Epstein–Barr virus-encoded small RNAs (EBERs) and almost all showed no loss of mismatch repair (MMR) proteins and were positive for alpha fetoprotein (AFP or spalt like transcription factor 4 (SALL4). About half of the tumors had a positive programmed death-ligand 1 combined positive score (CPS) and 17.3% were positive for human epidermal growth factor receptor 2 (HER2). In addition, there was a relatively high proportion of cmet expression. We also found that HAS patients with recurrent disease treated by emerging therapy had a better survival than those treated with traditional chemotherapy (<i>p</i> = 0.002, median recurrence-to-death survival: 23 months versus 6 months); HAS patients who received anti-HER2 therapy or harbored MMR deficiency had favorable prognosis. Overall, high proportions of MMR protein proficiency, positivity for AFP or SALL4, overexpression of HER2, CPS and cmet, as well as negative EBER findings, are distinctive characteristics of HAS patients. While negative EBER and MMR proficiency indicate molecular features of HAS, positivity for AFP or SALL4 could aid in the diagnosis of HAS. In addition, HAS patients could benefit from anti-HER2 therapy, immunotherapy, and anti-angiogenesis therapy.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.343","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136399897","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":"Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma","authors":"Ayako Ura,&nbsp;Takuo Hayashi,&nbsp;Kazumasa Komura,&nbsp;Masaki Hosoya,&nbsp;Kazuya Takamochi,&nbsp;Eiichi Sato,&nbsp;Satomi Saito,&nbsp;Susumu Wakai,&nbsp;Takafumi Handa,&nbsp;Tsuyoshi Saito,&nbsp;Shunsuke Kato,&nbsp;Kenji Suzuki,&nbsp;Takashi Yao,&nbsp;the Tokyo Metropolitan Innovative Oncology Research Group (TMIG)","doi":"10.1002/cjp2.350","DOIUrl":"10.1002/cjp2.350","url":null,"abstract":"<p>A limited number of patients with lung squamous cell carcinoma (SCC) benefit clinically from molecular targeted drugs because of a lack of targetable driver alterations. We aimed to understand the prevalence and clinical significance of lysine-specific demethylase 5D (<i>KDM5D</i>) copy number loss in SCC and explore its potential as a predictive biomarker for ataxia-telangiectasia and Rad3-related (ATR) inhibitor treatment. We evaluated <i>KDM5D</i> copy number loss in 173 surgically resected SCCs from male patients using fluorescence <i>in situ</i> hybridization. <i>KDM5D</i> copy number loss was detected in 75 of the 173 patients (43%). Genome-wide expression profiles of the transcription start sites (TSSs) were obtained from 17 SCCs, for which the cap analysis of gene expression assay was performed, revealing that upregulated genes in tumors with the <i>KDM5D</i> copy number loss are associated with ‘cell cycle’, whereas downregulated genes in tumors with <i>KDM5D</i> copy number loss were associated with ‘immune response’. Clinicopathologically, SCCs with <i>KDM5D</i> copy number loss were associated with late pathological stage (<i>p</i> = 0.0085) and high stromal content (<i>p</i> = 0.0254). Multiplexed fluorescent immunohistochemistry showed that the number of tumor-infiltrating CD8⁺/T-bet⁺ T cells was lower in SCCs with <i>KDM5D</i> copy number loss than in wild-type tumors. In conclusion, approximately 40% of the male patients with SCC exhibited <i>KDM5D</i> copy number loss. Tumors in patients who show this distinct phenotype can be ‘cold tumors’, which are characterized by the paucity of tumor T-cell infiltration and usually do not respond to immunotherapy. Thus, they may be candidates for trials with ATR inhibitors.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.350","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136399896","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":"Engineering the future of 3D pathology","authors":"Jonathan TC Liu,&nbsp;Sarah SL Chow,&nbsp;Richard Colling,&nbsp;Michelle R Downes,&nbsp;Xavier Farré,&nbsp;Peter Humphrey,&nbsp;Andrew Janowczyk,&nbsp;Tuomas Mirtti,&nbsp;Clare Verrill,&nbsp;Inti Zlobec,&nbsp;Lawrence D True","doi":"10.1002/cjp2.347","DOIUrl":"10.1002/cjp2.347","url":null,"abstract":"<p>In recent years, technological advances in tissue preparation, high-throughput volumetric microscopy, and computational infrastructure have enabled rapid developments in nondestructive 3D pathology, in which high-resolution histologic datasets are obtained from thick tissue specimens, such as whole biopsies, without the need for physical sectioning onto glass slides. While 3D pathology generates massive datasets that are attractive for automated computational analysis, there is also a desire to use 3D pathology to improve the visual assessment of tissue histology. In this perspective, we discuss and provide examples of potential advantages of 3D pathology for the visual assessment of clinical specimens and the challenges of dealing with large 3D datasets (of individual or multiple specimens) that pathologists have not been trained to interpret. We discuss the need for artificial intelligence triaging algorithms and explainable analysis methods to assist pathologists or other domain experts in the interpretation of these novel, often complex, large datasets.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.347","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71428087","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":"AI-based intra-tumor heterogeneity score of Ki67 expression as a prognostic marker for early-stage ER+/HER2− breast cancer","authors":"Wenqi Lu,&nbsp;Ayat G Lashen,&nbsp;Noorul Wahab,&nbsp;Islam M Miligy,&nbsp;Mostafa Jahanifar,&nbsp;Michael Toss,&nbsp;Simon Graham,&nbsp;Mohsin Bilal,&nbsp;Abhir Bhalerao,&nbsp;Nehal M Atallah,&nbsp;Shorouk Makhlouf,&nbsp;Asmaa Y Ibrahim,&nbsp;David Snead,&nbsp;Fayyaz Minhas,&nbsp;Shan E Ahmed Raza,&nbsp;Emad Rakha,&nbsp;Nasir Rajpoot","doi":"10.1002/cjp2.346","DOIUrl":"10.1002/cjp2.346","url":null,"abstract":"<p>Early-stage estrogen receptor positive and human epidermal growth factor receptor negative (ER+/HER2−) luminal breast cancer (BC) is quite heterogeneous and accounts for about 70% of all BCs. Ki67 is a proliferation marker that has a significant prognostic value in luminal BC despite the challenges in its assessment. There is increasing evidence that spatial colocalization, which measures the evenness of different types of cells, is clinically important in several types of cancer. However, reproducible quantification of intra-tumor spatial heterogeneity remains largely unexplored. We propose an automated pipeline for prognostication of luminal BC based on the analysis of spatial distribution of Ki67 expression in tumor cells using a large well-characterized cohort (<i>n</i> = 2,081). The proposed Ki67 colocalization (Ki67CL) score can stratify ER+/HER2− BC patients with high significance in terms of BC-specific survival (<i>p</i> &lt; 0.00001) and distant metastasis-free survival (<i>p</i> = 0.0048). Ki67CL score is shown to be highly significant compared with the standard Ki67 index. In addition, we show that the proposed Ki67CL score can help identify luminal BC patients who can potentially benefit from adjuvant chemotherapy.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49693132","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":"Identifying primary tumor site of origin for liver metastases via a combination of handcrafted and deep learning features","authors":"Chuheng Chen,&nbsp;Cheng Lu,&nbsp;Vidya Viswanathan,&nbsp;Brandon Maveal,&nbsp;Bhunesh Maheshwari,&nbsp;Joseph Willis,&nbsp;Anant Madabhushi","doi":"10.1002/cjp2.344","DOIUrl":"10.1002/cjp2.344","url":null,"abstract":"<p>Liver is one of the most common sites for metastases, which can occur on account of primary tumors from multiple sites of origin. Identifying the primary site of origin (PSO) of a metastasis can help in guiding therapeutic options for liver metastases. In this pilot study, we hypothesized that computer extracted handcrafted (HC) histomorphometric features can be utilized to identify the PSO of liver metastases. Cellular features, including tumor nuclei morphological and graph features as well as cytoplasm texture features, were extracted by computer algorithms from 175 slides (114 patients). The study comprised three experiments: (1) comparing and (2) fusing a machine learning (ML) model trained with HC pathomic features and deep learning (DL)-based classifiers to predict site of origin; (3) identifying the section of the primary tumor from which metastases were derived. For experiment 1, we divided the cohort into training sets composed of primary and matched liver metastases [60 patients, 121 whole slide images (WSIs)], and a hold-out validation set (54 patients, 54 WSIs) composed solely of liver metastases of known site of origin. Using the extracted HC features of the training set, a combination of supervised machine classifiers and unsupervised clustering was applied to identify the PSO. A random forest classifier achieved areas under the curve (AUCs) of 0.83, 0.64, 0.82, and 0.64 in classifying the metastatic tumor from colon, esophagus, breast, and pancreas on the validation set. The top features related to nuclear and peri-nuclear shape and textural attributes. We also trained a DL network to serve as a direct comparison to our method. The DL model achieved AUCs for colon: 0.94, esophagus: 0.66, breast: 0.79, and pancreas: 0.67 in identifying PSO. A decision fusion-based strategy was deployed to fuse the trained ML and DL classifiers and achieved slightly better results than ML or DL classifier alone (colon: 0.93, esophagus: 0.68, breast: 0.81, and pancreas: 0.69). For the third experiment, WSI-level attention maps were also generated using a trained DL network to generate a composite feature similarity heat map between paired primaries and their associated metastases. Our experiments revealed that epithelium-rich and moderately differentiated tumor regions of primary tumors were quantitatively similar to paired metastatic tumors. Our findings suggest that a combination of HC and DL features could potentially help identify the PSO for liver metastases while at the same time also potentially identify the spatial sites of origin for the metastases within primary tumors.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.344","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41216694","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":"Expression of B7-H3 and TIM-3 in gastric-type endocervical adenocarcinoma: prevalence, association with PD-L1 expression, and prognostic significance","authors":"Yao Sun,&nbsp;Xin Zhou,&nbsp;Elena Lucas,&nbsp;Lili Chen,&nbsp;Huijuan Zhang,&nbsp;Hao Chen,&nbsp;Feng Zhou","doi":"10.1002/cjp2.345","DOIUrl":"10.1002/cjp2.345","url":null,"abstract":"<p>Gastric-type endocervical adenocarcinoma (GEA) is the second most common subtype of endocervical adenocarcinoma and has a poor prognosis. Anti-programmed death-1 and anti-programmed death-ligand 1 (PD-L1) inhibitors have emerged as a major treatment option for GEA; however, data on the expression of other immune checkpoints in GEA are limited. We analyzed the expression of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and B7 homolog 3 protein (B7-H3) in 58 GEA and investigated their prognostic significance as well as association with PD-L1 expression and other known prognostic factors. Applying the tumor proportion score (TPS) with a cutoff of 1%, B7-H3 and TIM-3 were present in 48.3% and 17.2% of cases, respectively. Applying the combined positive score (CPS) with a cutoff of 1, TIM-3 expression was present in 70.7% of cases. Moreover, the expression of three checkpoints (B7-H3, TIM-3, and PD-L1) was incompletely overlapping. Patients with B7-H3 positive tumors (by TPS) or TIM-3 positive tumors (by TPS) had significantly worse recurrence-free survival (RFS) and overall survival (OS) (log-rank). Using CPS, patients with TIM-3 positive tumors showed significantly worse RFS (log-rank). Similarly, B7-H3 positivity (by TPS) and TIM-3 positivity (by TPS) were associated with worse RFS and OS in univariate analysis. TIM-3 positivity (by CPS) was associated with worse RFS in univariate analysis and the final Cox multivariate analysis. In conclusion, our results show that (1) B7-H3 and TIM-3 are frequently expressed in GEA and their expression overlaps incompletely with PD-L1; and (2) both B7-H3 and TIM-3 are independent negative prognostic markers in GEA.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41180307","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":"Accounting for intensity variation in image analysis of large-scale multiplexed clinical trial datasets","authors":"Anja L Frei,&nbsp;Anthony McGuigan,&nbsp;Ritik RAK Sinha,&nbsp;Mark A Glaire,&nbsp;Faiz Jabbar,&nbsp;Luciana Gneo,&nbsp;Tijana Tomasevic,&nbsp;Andrea Harkin,&nbsp;Tim J Iveson,&nbsp;Mark Saunders,&nbsp;Karin Oein,&nbsp;Noori Maka,&nbsp;Francesco Pezella,&nbsp;Leticia Campo,&nbsp;Jennifer Hay,&nbsp;Joanne Edwards,&nbsp;Owen J Sansom,&nbsp;Caroline Kelly,&nbsp;Ian Tomlinson,&nbsp;Wanja Kildal,&nbsp;Rachel S Kerr,&nbsp;David J Kerr,&nbsp;Håvard E Danielsen,&nbsp;Enric Domingo,&nbsp;TransSCOT Consortium,&nbsp;David N Church,&nbsp;Viktor H Koelzer","doi":"10.1002/cjp2.342","DOIUrl":"10.1002/cjp2.342","url":null,"abstract":"<p>Multiplex immunofluorescence (mIF) imaging can provide comprehensive quantitative and spatial information for multiple immune markers for tumour immunoprofiling. However, application at scale to clinical trial samples sourced from multiple institutions is challenging due to pre-analytical heterogeneity. This study reports an analytical approach to the largest multi-parameter immunoprofiling study of clinical trial samples to date. We analysed 12,592 tissue microarray (TMA) spots from 3,545 colorectal cancers sourced from more than 240 institutions in two clinical trials (QUASAR 2 and SCOT) stained for CD4, CD8, CD20, CD68, FoxP3, pan-cytokeratin, and DAPI by mIF. TMA slides were multi-spectrally imaged and analysed by cell-based and pixel-based marker analysis. We developed an adaptive thresholding method to account for inter- and intra-slide intensity variation in TMA analysis. Applying this method effectively ameliorated inter- and intra-slide intensity variation improving the image analysis results compared with methods using a single global threshold. Correlation of CD8 data derived by our mIF analysis approach with single-plex chromogenic immunohistochemistry CD8 data derived from subsequent sections indicates the validity of our method (Spearman's rank correlation coefficients <i>ρ</i> between 0.63 and 0.66, <i>p</i> ≪ 0.01) as compared with the current gold standard analysis approach. Evaluation of correlation between cell-based and pixel-based analysis results confirms equivalency (<i>ρ</i> &gt; 0.8, <i>p</i> ≪ 0.01, except for CD20 in the epithelial region) of both analytical approaches. These data suggest that our adaptive thresholding approach can enable analysis of mIF-stained clinical trial TMA datasets by digital pathology at scale for precision immunoprofiling.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 6","pages":"449-463"},"PeriodicalIF":4.1,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.342","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10580413","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":"Reducing the risks of nuclear war – the role of health professionals","authors":"Kamran Abbasi,&nbsp;Parveen Ali,&nbsp;Virginia Barbour,&nbsp;Kirsten Bibbins-Domingo,&nbsp;Marcel GM Olde Rikkert,&nbsp;Andy Haines,&nbsp;Ira Helfand,&nbsp;Richard Horton,&nbsp;Bob Mash,&nbsp;Arun Mitra,&nbsp;Carlos Monteiro,&nbsp;Elena N Naumova,&nbsp;Eric J Rubin,&nbsp;Tilman Ruff,&nbsp;Peush Sahni,&nbsp;James Tumwine,&nbsp;Paul Yonga,&nbsp;Chris Zielinski","doi":"10.1002/cjp2.341","DOIUrl":"10.1002/cjp2.341","url":null,"abstract":"&lt;p&gt;In January, 2023, the Science and Security Board of the Bulletin of the Atomic Scientists moved the hands of the Doomsday Clock forward to 90s before midnight, reflecting the growing risk of nuclear war [&lt;span&gt;1&lt;/span&gt;]. In August 2022, the UN Secretary-General António Guterres warned that the world is now in ‘a time of nuclear danger not seen since the height of the Cold War’ [&lt;span&gt;2&lt;/span&gt;]. The danger has been underlined by growing tensions between many nuclear-armed states [&lt;span&gt;1, 3&lt;/span&gt;]. As editors of health and medical journals worldwide, we call on health professionals to alert the public and our leaders to this major danger to public health and the essential life support systems of the planet – and urge action to prevent it.&lt;/p&gt;&lt;p&gt;Current nuclear arms control and non-proliferation efforts are inadequate to protect the world's population against the threat of nuclear war by design, error, or miscalculation. The Treaty on the Non-Proliferation of Nuclear Weapons (NPT) commits each of the 190 participating nations ‘to pursue negotiations in good faith on effective measures relating to cessation of the nuclear arms race at an early date and to nuclear disarmament, and on a treaty on general and complete disarmament under strict and effective international control’ [&lt;span&gt;4&lt;/span&gt;]. Progress has been disappointingly slow and the most recent NPT review conference in 2022 ended without an agreed statement [&lt;span&gt;5&lt;/span&gt;]. There are many examples of near disasters that have exposed the risks of depending on nuclear deterrence for the indefinite future [&lt;span&gt;6&lt;/span&gt;]. Modernisation of nuclear arsenals could increase risks: for example, hypersonic missiles decrease the time available to distinguish between an attack and a false alarm, increasing the likelihood of rapid escalation.&lt;/p&gt;&lt;p&gt;Any use of nuclear weapons would be catastrophic for humanity. Even a ‘limited’ nuclear war involving only 250 of the 13,000 nuclear weapons in the world could kill 120 million people outright and cause global climate disruption, leading to a nuclear famine, putting 2 billion people at risk [&lt;span&gt;7, 8&lt;/span&gt;]. A large-scale nuclear war between the USA and Russia could kill 200 million people or more in the near term, and potentially cause a global ‘nuclear winter’ that could kill 5–6 billion people, threatening the survival of humanity [&lt;span&gt;7, 8&lt;/span&gt;]. Once a nuclear weapon is detonated, escalation to all-out nuclear war could occur rapidly. The prevention of any use of nuclear weapons is therefore an urgent public health priority and fundamental steps must also be taken to address the root cause of the problem – by abolishing nuclear weapons.&lt;/p&gt;&lt;p&gt;The health community has had a crucial role in efforts to reduce the risk of nuclear war and must continue to do so in the future [&lt;span&gt;9&lt;/span&gt;]. In the 1980s, the efforts of health professionals, led by the International Physicians for the Prevention of Nuclear War (IPPNW), helped to end the Cold War ","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 6","pages":"439-441"},"PeriodicalIF":4.1,"publicationDate":"2023-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10173413","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}