medRxiv - Pathology最新文献

{"title":"The Concept of Stroma AReactive Invasion Front Areas (SARIFA) as a New Prognostic Biomarker for Lipid-driven Cancers Holds True in Pancreatic Ductal Adenocarcinoma","authors":"Przemyslaw Grochowski, Bianca Grosser, Florian Sommer, Andreas Probst, Johanna Waidhauser, Gerhard Schenkirsch, Nic Gabriel Reitsam, Bruno Maerkl","doi":"10.1101/2024.01.22.24301622","DOIUrl":"https://doi.org/10.1101/2024.01.22.24301622","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) is a difficult-to-treat entity. To forecast its prognosis, we introduced a new biomarker, SARIFA (stroma areactive invasion front areas), which are an area at the tumour invasion front lacking desmoplastic stroma reaction upon malignant invasion in the surrounding tissue, leading to direct contact between tumour cells and adipocytes. SARIFA showed its significance in gastric and colorectal carcinoma, revealing lipid metabolism alternations that promote tumour progression. Methods: We reviewed the SARIFA status of 174 PDAC cases on all available H&E-stained tumour slides from archival Whipple-resection specimens. SARIFA positivity was defined as SARIFA detection in at least 66% of the available slides. To investigate alterations in tumour metabolism and microenvironment, we performed immunohistochemical staining for FABP4, CD36 and CD68. To verify and quantify a supposed delipidation of adipocytes, adipose tissue was digitally morphometrised.\u0000Results: In total, 54 cases (31%) were classified as SARIFA positive and 120 (69%) as SARIFA negative. Patients with SARIFA-positive PDAC showed a significantly worse overall survival compared with SARIFA-negative cases (median overall survival: 9.9 months vs. 18.0 months, HR: 1.558 (1.081-2.247), 95% CI, p = 0.018), which was independent from other prognostic markers (p = 0.014). At the invasion front of SARIFA-positive PDAC, we observed significantly higher expression of FABP4 (p<0.0001) and higher concentrations of CD68+ macrophages (p=0.031) related to a higher risk of tumour progression. CD36 staining showed no significant expression differences. The adipocyte areas at the invasion front were significantly smaller, with mean values of 4021 +/- 1058 um2 and 1812 +/- 1008 um2 for the SARIFA-positive and -negative cases, respectively. The area differences between the SARIFA-positive invasion front area and the other three parameters were highly significant (p < 0.001)\u0000Conclusions: SARIFA is a promising prognostic biomarker for PDAC. Its assessment is characterised by simplicity and low effort. The mechanisms behind SARIFA suggest a tumour-promoting increased lipid metabolism and altered immune background, both showing new therapeutic avenues.","PeriodicalId":501528,"journal":{"name":"medRxiv - Pathology","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139553936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Label-free virtual peritoneal lavage cytology via deep-learning-assisted single-color stimulated Raman scattering microscopy","authors":"Tinghe Fang, Zhouqiao Wu, Xun Chen, Luxin Tan, Zhongwu Li, Jiafu Ji, Yubo Fan, Ziyu Li, Shuhua Yue","doi":"10.1101/2024.01.17.24301416","DOIUrl":"https://doi.org/10.1101/2024.01.17.24301416","url":null,"abstract":"Clinical guidelines for gastric cancer treatment recommend intraoperative peritoneal lavage cytology to detect free cancer cells. Patients with positive cytology require neoadjuvant chemotherapy instead of instant resection and conversion to negative cytology results in improved survival. However, the accuracy of cytological diagnosis by pathologists or artificial intelligence is disturbed by manually-produced, unstandardized slides. In addition, the elaborate infrastructure makes cytology accessible to a limited number of medical institutes. Here, we developed CellGAN, a deep learning method that enables label-free virtual peritoneal lavage cytology by producing virtual hematoxylin-eosin-stained images with single-color stimulated Raman scattering microscopy. A structural similarity loss was introduced to overcome the challenge of existing unsupervised virtual pathology techniques unable to present cellular structures accurately. This method achieved a structural similarity of 0.820±0.041 and a nucleus area consistency of 0.698±0.102, indicating the staining fidelity outperforming the state-of-the-art method. Diagnosis using virtually stained cells reached 93.8% accuracy and substantial consistency with conventional staining. Single-cell detection and classification on virtual slides achieved a mean average precision of 0.924 and an area under the receiver operating characteristic curve of 0.906, respectively. Collectively, this method achieves standardized and accurate virtual peritoneal lavage cytology and holds great potential for clinical translation.","PeriodicalId":501528,"journal":{"name":"medRxiv - Pathology","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139499471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expansion of Artemisinin Partial Resistance Mutations and Lack of Histidine Rich Protein-2 and -3 Deletions in Plasmodium falciparum infections from Rukara, Rwanda","authors":"Cecile Schreidah, David Giesbrecht, Pierre Gashema, Neeva Young, Tharcisse Munyaneza, Claude Mambo Muvunyi, Kyaw Lay Thwai, Jean-Baptiste Mazarati, Jeffrey A Bailey, Jonathan J Juliano, Corine Karema","doi":"10.1101/2023.12.17.23300081","DOIUrl":"https://doi.org/10.1101/2023.12.17.23300081","url":null,"abstract":"Background\u0000Emerging artemisinin resistance and diagnostic resistance are a threat to malaria control in Africa. Plasmodium falciparum kelch13 (K13) propeller-domain mutations that confer artemisinin partial resistance have emerged in Africa. K13-561H was initially described at a frequency of 7.4% from Masaka in 2014-2015 but not present in nearby Rukara. By 2018, 19.6% of isolates in Masaka and 22% of isolates in Rukara contained the mutation. Longitudinal monitoring is essential to inform control efforts. In Rukara, we sought to assess recent K13-561H prevalence changes, as well as for other key mutations. Prevalence of hrp2/3 deletions was also assessed. Methods\u0000We genotyped samples collected in Rukara in 2021 for key artemisinin and partner drug resistance mutations using molecular inversion probe assays and for hrp2/3 deletions using qPCR. Results\u0000Clinically validated K13 artemisinin partial resistance mutations continue to increase in prevalence with the overall level of artemisinin resistance mutant infections reaching 32% in Rwanda. The increase appears to be due to the rapid emergence of K13-675V (6.4%, 6/94 infections), previously not observed, rather than continued expansion of 561H (23.5% 20/85). Mutations to partner drugs and other antimalarials were variable, with high levels of multidrug resistance 1 (MDR1) N86 (95.5%) associated with lumefantrine resistance and dihydrofolate reductase (DHFR) 164L (24.7%) associated with antifolate resistance, but low levels of amodiaquine resistance polymorphisms with chloroquine resistance transporter (CRT) 76T: at 6.1% prevalence. No hrp2 or hrp3 gene deletions associated with diagnostic resistance were found. Conclusions\u0000Increasing prevalence of artemisinin partial resistance due to K13-561H and the rapid expansion of K13-675V is concerning for the longevity of artemisinin effectiveness in the region. False negative mRDT results do not appear to be an issue with no hrp2 or hpr3 deletions detected. Continued molecular surveillance in this region and surrounding areas is needed to follow artemisinin resistance and provide early detection of partner drug resistance, which would likely compromise control and increase malaria morbidity and mortality in East Africa.","PeriodicalId":501528,"journal":{"name":"medRxiv - Pathology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138744874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Presence Of Focal Usual Interstitial Pneumonia Is A Key Prognostic Factor In Progressive Pulmonary Fibrosis","authors":"Yukio Tsushima, Ethan N. Okoshi, Sousuke Ishijima, Andrey Bychkov, Kris Lami, Shimpei Morimoto, Yasuhiko Yamano, Kensuke Kataoka, Takeshi Johkoh, Yasuhiro Kondoh, Junya Fukuoka","doi":"10.1101/2023.12.07.23298650","DOIUrl":"https://doi.org/10.1101/2023.12.07.23298650","url":null,"abstract":"Progressive pulmonary fibrosis (PPF) is a newly recognized clinical phenotype of interstitial lung diseases in the 2022 interstitial pulmonary fibrosis (IPF) guidelines. This category is based entirely on clinical and radiological factors, and the background histopathology is unknown. Our objective was to investigate the histopathological characteristics of PPF and to examine the correlation between usual interstitial pneumonia (UIP) and prognosis in this new disease type. We hypothesized that the presence of UIP-like fibrosis predicts patients’ survival in PPF cases.","PeriodicalId":501528,"journal":{"name":"medRxiv - Pathology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138575353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual T-cell constant β chain (TRBC)1 and TRBC2 staining for the identification of T-cell neoplasms by flow cytometry","authors":"Pedro Horna, Matthew J Weybright, Mathieu Ferrari, Dennis Jungherz, YaYi Peng, Zulaikha Akbar, F Tudor Ilca, Gregory E Otteson, Jansen N Seheult, Janosch Ortmann, Min Shi, Paul M Maciocia, Marco Herling, Martin A Pule, Horatiu Olteanu","doi":"10.1101/2023.12.01.23299254","DOIUrl":"https://doi.org/10.1101/2023.12.01.23299254","url":null,"abstract":"The diagnosis of leukemic T-cell malignancies is often challenging, due to overlapping features with reactive T-cells and limitations of currently available T-cell clonality assays. Recently developed therapeutic antibodies specific for the mutually exclusive T-cell receptor constant β chain (TRBC)1 and TRBC2 isoforms provide a unique opportunity to assess for TRBC-restriction as a surrogate of clonality in the flow cytometric analysis of T-cell neoplasms. To demonstrate the diagnostic utility of this approach, we studied 135 clinical specimens with (50) or without (85) T-cell neoplasia, in addition to 29 blood samples from healthy donors. Dual TRBC1 and TRBC2 expression was studied within a comprehensive T-cell panel, in a fashion similar to the routine evaluation of kappa and lambda immunoglobulin light chains for the detection of clonal B-cells. Polytypic TRBC expression was demonstrated on total, CD4⁺ and CD8⁺ T-cells from all healthy donors; and by intracellular staining on benign T-cell precursors. All neoplastic T-cells were TRBC-restricted, except for 5 cases (10%) lacking TRBC expression. T-cell clones of uncertain significance were identified in 15 samples without T-cell malignancy (13%), and accounted for smaller subsets than neoplastic clones (median: 4.7% vs. 73% of lymphocytes, p<0.0001). Single staining for TRBC1 produced spurious TRBC1-dim subsets in 21 clinical specimens (16%), all of which resolved with dual TRBC1/2 staining. Assessment of TRBC restriction by flow cytometry provides a rapid diagnostic method to detect clonal T-cells, and to accurately determine the targetable TRBC isoform expressed by T-cell malignancies.","PeriodicalId":501528,"journal":{"name":"medRxiv - Pathology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of a high-throughput qPCR platform for the detection of soil-transmitted helminth infections","authors":"Nils Pilotte, Victor Omballa, Monica Voss, Leah Padgett, Malathi Manuel, Jeanne L. Goodman, Tim Littlewood, Zayina Zondervenni Manoharan, Lisette van Lieshout, Jaco Verweij, Manigandan Sekar, Ajith Kumar Muthukumar, Gretchen Walch, Andrew Gonzalez, Sean R Galagan, Sitara Swarna Rao Ajjampur, Moudachirou Ibikounlé, Steven A Williams, Doug Rains, Ushashi Dadwal, Judd L Walson","doi":"10.1101/2023.11.27.23299079","DOIUrl":"https://doi.org/10.1101/2023.11.27.23299079","url":null,"abstract":"<strong>Background</strong> Historically, soil-transmitted helminth (STH) control and prevention strategies have relied on mass drug administration efforts targeting preschool and school-aged children. While these efforts have succeeded in reducing morbidity associated with STH infection, recent modeling efforts have suggested that expanding intervention to treatment of the entire community could achieve transmission interruption in some settings. Testing the feasibility of such an approach requires large-scale clinical trials, such as the DeWorm3 cluster randomized trial. In addition, accurate interpretation of trial outcomes will require diagnostic platforms capable of accurately determining infection prevalence, particularly as infection intensity is reduced, at large population scale and with significant throughput. Here, we describe the development and validation of a multi-site, high-throughput molecular testing platform.","PeriodicalId":501528,"journal":{"name":"medRxiv - Pathology","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generating synthetic data in digital pathology through diffusion models: a multifaceted approach to evaluation","authors":"Matteo Pozzi, Shahryar Noei, Erich Robbi, Luca Cima, Monica Moroni, Enrico Munari, Evelin Torresani, Giuseppe Jurman","doi":"10.1101/2023.11.21.23298808","DOIUrl":"https://doi.org/10.1101/2023.11.21.23298808","url":null,"abstract":"Synthetic data has recently risen as a new precious item in the computational pathologist’s toolbox, supporting several tasks such as helping with data scarcity or augmenting training set in deep learning. Nonetheless, the use of such novel resources requires a carefully planned construction and evaluation, to avoid pitfalls such as the generation of clinically meaningless artifacts.","PeriodicalId":501528,"journal":{"name":"medRxiv - Pathology","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myelin pathology in ataxia-telangiectasia is the cell autonomous effect of ATM deficiency in oligodendrocytes","authors":"Kai-Hei Tse, Aifang Cheng, Sunny Hoi-Sang Yeung, Jia-Nian Ng, Gerald Wai-Yeung Cheng, Beika Zhu, Qingyang Wang, Yong Cui, Liwen Jiang, Julia Kofler, Karl Herrup","doi":"10.1101/2021.01.22.20245217","DOIUrl":"https://doi.org/10.1101/2021.01.22.20245217","url":null,"abstract":"Ataxia-telangiectasia (A-T) is a rare genetic disease caused by mutations in the gene encoding the ATM (ataxia-telangiectasia mutated) protein. Although neuronal degeneration in the cerebellum remains the most prominent sign in A-T pathology, neuroimaging studies reveal myelin abnormalities as early comorbidities. We hypothesize that these myelin defects are the direct consequence of ATM deficiencies in the oligodendrocytes (OL) lineage. We examined samples from ten A-T brains in which the ATM mutations had been mapped by targeted genomic sequencing and from Atm-/- mice. In healthy human cerebellum, we confirmed the presence of ATM in white matter OLs. In A-T, a significant reduction in OL density was found along with a massive astrogliosis. This white matter pathology was recapitulated in Atm-/- mice in an age- and gene dose-dependent fashion. Activated ATM was found expressed both in the nucleus and cytoplasm of OL progenitor cells (OPC) and myelinating mature OL. Its presence in the OL lineage is associated with novel OL-specific functions of the ATM protein affecting all stages of the OL life cycle. Blockage of ATM activity with KU-60019 or inducing DNA damage induced with etoposide altered the cell cycle in self-renewing OPC and triggered ectopic cell cycle re-entry in mature OL in vitro. Further, the differentiation program of OPC is highly sensitive to DNA damage either induced directly or by blocking DNA repair. As much of the impact of ATM deficiency in OL is independent of neuronal loss, our findings have important implications for the complex neurological symptoms of human A-T.","PeriodicalId":501528,"journal":{"name":"medRxiv - Pathology","volume":"94 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using an Anomaly Detection Approach for the Segmentation of Colorectal Cancer Tumors in Whole Slide Images","authors":"Qiangqiang Gu, Chady Meroueh, Jacob G. Levernier, Trynda N. Kroneman, Thomas J. Flotte, Steven N Hart","doi":"10.1101/2023.07.17.23292768","DOIUrl":"https://doi.org/10.1101/2023.07.17.23292768","url":null,"abstract":"Colorectal cancer (CRC) is the 2nd most commonly diagnosed cancer in the United States. Genetic testing is critical in assisting in the early detection of CRC and selection of individualized treatment plans, which have shown to improve the survival rate of CRC patients. The tissue slides review (TSR), a tumor tissue macro-dissection procedure, is a required pre-analytical step to perform genetic testing. Due to the subjective nature of the process, major discrepancies in CRC diagnostics by pathologists are reported, and metrics for quality are often only qualitative. Progressive context encoder anomaly detection (P-CEAD) is an anomaly detection approach to detect tumor tissue from Whole Slide Images (WSIs), since tumor tissue is by its nature, an anomaly. P-CEAD-based CRC tumor segmentation achieves a 71% ± 26% sensitivity, 92% ± 7% specificity, and 63% ± 23% F1 score. The proposed approach provides an automated CRC tumor segmentation pipeline with a quantitatively reproducible quality compared with the conventional manual tumor segmentation procedure.","PeriodicalId":501528,"journal":{"name":"medRxiv - Pathology","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}