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Item Best Practices in Liver Biopsy Histologic Assessment for Nonalcoholic Steatohepatitis Clinical Trials: Expert Opinion(Wiley, 2022) Filozof, Claudia M.; Lackner, Carolin; Romero-Gómez, Manuel; Imperial, Joanne C.; McGee, Robert; Dimick-Santos, Lara; Cummings, Oscar; Behling, Cynthia; Johnson, Troy; Sanyal, Arun; Pathology and Laboratory Medicine, School of MedicineBackground: In most clinical trials focusing on precirrhotic nonalcoholic steatohepatitis (NASH), a liver biopsy is required for confirmation of diagnosis, staging fibrosis, and grading steatohepatitis activity. Reliance on the biopsy, both as a requisite for study entry, as well as for a primary endpoint in clinical trials, poses several challenges that need to be overcome: patient reluctance to undergo the procedure; potential sampling error; concern regarding the handling, processing and shipping of the biopsy of the biopsy material to the central reader(s); and the degree of pathologists’ intra- and interobserver variability in biopsy interpretation. Aims: To provide recommendations for improving the liver biopsy process in order to maximize the accuracy of its histological interpretation in NASH clinical trials. Methods and Results: These recommendations were created by an expert panel of participants from the United States and European Union who met multiple times and reached alignment through review of available data and their individual clinical experiences. The recommendations include the methodology for biopsy procedure, central lab and pathology processing of the specimen, and recommendations to minimize the intra- and intersubject variability. Finally, we are discussing digital pathology technology and machine learning applications as important additions to enhance liver biopsy interpretation. Conclusions: Liver biopsy poses multiple challenges in clinical trials in NASH, and there is a need to standardize the processes to maximize accuracy and minimize variability. Many questions remained unanswered due to limited available data. New evolving modalities may help in the future, but generation of robust data is warranted.Item Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia(Oxford University Press, 2024-07-22) Madut, Deng B.; Chemaly, Roy F.; Dadwal, Sanjeet S.; Hill, Joshua A.; Lee, Yeon Joo; Haidar, Ghady; Luk, Alfred; Drelick, Alexander; Chin-Hong, Peter V.; Benamu, Esther; Khawaja, Fareed; Nanayakkara, Deepa; Papanicolaou, Genovefa A.; Butkus Small, Catherine; Fung, Monica; Barron, Michelle; Davis, Thomas; McClain, Micah T.; Maziarz, Eileen K.; Bedoya, Armando D.; Gilstrap, Daniel L.; Todd, Jamie L.; Barkauskas, Christina E.; Heldman, Madeleine R.; Bigelow, Robert; Leimberger, Jeffrey D.; Tsalik, Ephraim L.; Wolf, Olivia; Mughar, Mona; Lau, Constance; Noll, Nicholas; Hollemon, Desiree; Duttagupta, Radha; Lupu, Daniel S.; Bercovici, Sivan; Perkins, Bradley A.; Blauwkamp, Timothy A.; Fowler, Vance G., Jr.; Holland, Thomas L.; Bergin, Stephen P.; Pathology and Laboratory Medicine, School of MedicineBackground: Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit. Methods: We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies. This is a secondary analysis of an expanded cohort that evaluated the clinical utility of plasma mcfDNA sequencing across prespecified and adjudicated outcomes. We examined the percentage of participants for whom plasma mcfDNA sequencing identified a probable cause of pneumonia or clinically relevant nonpneumonia infection. We then assessed potential changes in antimicrobial therapy based on plasma mcfDNA sequencing results and the potential for early mcfDNA testing to avoid bronchoscopy and its associated adverse events. Results: Of 223 participants, at least 1 microbial detection by plasma mcfDNA sequencing was adjudicated as a probable cause of pneumonia in 57 (25.6%) and a clinically relevant nonpneumonia infection in 88 (39.5%). A probable cause of pneumonia was exclusively identified by plasma mcfDNA sequencing in 23 (10.3%) participants. Antimicrobial therapy would have changed for 41 (18.4%) participants had plasma mcfDNA results been available in real time. Among the 57 participants with a probable cause of pneumonia identified by plasma mcfDNA sequencing, bronchoscopy identified no additional probable cause of pneumonia in 52 (91.2%). Conclusions: Plasma mcfDNA sequencing could improve management of both pneumonia and other concurrent infections in immunocompromised patients with suspected pneumonia.Item Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy(Springer Nature, 2024-08-16) Wang, Hui; Chang, Timothy S.; Dombroski, Beth A.; Cheng, Po-Liang; Patil, Vishakha; Valiente-Banuet, Leopoldo; Farrell, Kurt; Mclean, Catriona; Molina-Porcel, Laura; Rajput, Alex; De Deyn, Peter Paul; Le Bastard, Nathalie; Gearing, Marla; Donker Kaat, Laura; Van Swieten, John C.; Dopper, Elise; Ghetti, Bernardino F.; Newell, Kathy L.; Troakes, Claire; de Yébenes, Justo G.; Rábano-Gutierrez, Alberto; Meller, Tina; Oertel, Wolfgang H.; Respondek, Gesine; Stamelou, Maria; Arzberger, Thomas; Roeber, Sigrun; Müller, Ulrich; Hopfner, Franziska; Pastor, Pau; Brice, Alexis; Durr, Alexandra; Le Ber, Isabelle; Beach, Thomas G.; Serrano, Geidy E.; Hazrati, Lili-Naz; Litvan, Irene; Rademakers, Rosa; Ross, Owen A.; Galasko, Douglas; Boxer, Adam L.; Miller, Bruce L.; Seeley, Willian W.; Van Deerlin, Vivanna M.; Lee, Edward B.; White, Charles L., III; Morris, Huw; de Silva, Rohan; Crary, John F.; Goate, Alison M.; Friedman, Jeffrey S.; Leung, Yuk Yee; Coppola, Giovanni; Naj, Adam C.; Wang, Li-San; P. S. P. genetics study group; Dalgard, Clifton; Dickson, Dennis W.; Höglinger, Günter U.; Schellenberg, Gerard D.; Geschwind, Daniel H.; Lee, Wan-Ping; Pathology and Laboratory Medicine, School of MedicineBackground: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.Item Extraskeletal Ewing Sarcoma of the Gastrointestinal and Hepatobiliary Tract: Deceptive Immunophenotype Commonly Leads to Misdiagnosis(Wolters Kluwer, 2024) Shiyanbola, Oyewale; Nigdelioglu, Recep; Dhall, Deepti; González, Iván A.; Warmke, Laura M.; Schechter, Shula; Choi, Won-Tak; Hu, Shaomin; Voltaggio, Lysandra; Zhang, Yujie; Liang, Tom Z.; Ko, Huaibin M.; Charville, Greg W.; Longacre, Teri A.; Pathology and Laboratory Medicine, School of MedicineEwing sarcoma (ES) is an uncommon mesenchymal neoplasm that typically develops as a bone mass, although up to 30% arise in extraskeletal sites. ES of the gastrointestinal (GI) and hepatobiliary tract is rare and may be misdiagnosed as other, more common neoplasms that occur in these sites. However, the correct classification of extraskeletal ES is important for timely clinical management and prognostication. We reviewed our experience of ES in the GI and hepatobiliary tract in order to further highlight the clinicopathologic features of these neoplasms and document the potential for misdiagnosis in this setting. The archives and consultation files of 6 academic institutions were retrospectively queried for cases of ES occurring in the GI and hepatobiliary tract. The histologic slides and ancillary studies were reviewed and clinical data were retrieved for each case through the electronic medical records, when available. Twenty-three patients with ES in the GI and/or hepatobiliary tract were identified from 2000 to 2022. Of these, 11 were women and 12 were men with a median age of 38 years (range, 2 to 64). Tumor locations included the pancreas (n=5), liver (n=2), stomach (n=3), colorectum (n=3), and small intestine (n=5), as well as tumors involving multiple organs, pelvis and retroperitoneum (n=5). Tumor size varied between 2 cm and 18 cm. Twenty were primary and 3 were metastases. Of the 23 cases, only 17% were initially diagnosed as ES. The most common misdiagnoses involved various forms of neuroendocrine neoplasia due to expression of synaptophysin and other neuroendocrine markers (22%). A wide variety of diagnoses including GI stromal tumor was considered due to aberrant CD117 expression (4%). The diagnosis of ES was ultimately confirmed by detection of the EWSR1 rearrangement in 22 cases. The remaining case was diagnosed using traditional immunohistochemistry. Follow-up information was available in 20 cases, with follow-up time varying between 2 and 256 months. Six patients with follow-up died of disease between 6 and 60 months following initial presentation. Our data indicate ES in the GI and hepatobiliary tract is commonly misdiagnosed leading to a delay in therapy. In light of the attendant therapeutic and prognostic implications, ES should be considered in the differential diagnosis of any GI or hepatobiliary tumor with epithelioid and/or small round cell morphology.Item Correction: Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems(Springer Nature, 2024-08-14) Bacioglu, Mehtap; Gray, Derrick; Lövestam, Sofia; Katsinelos, Taxiarchis; Quaegebeur, Annelies; van Swieten, John; Jaunmuktane, Zane; Davies, Stephen W.; Scheres, Sjors H. W.; Goedert, Michel; Ghetti, Bernardino; Grazia Spillantini, Maria; Pathology and Laboratory Medicine, School of MedicineCorrection: Acta Neuropathologica Communications (2024) 12:99 10.1186/s40478-024-01813-z Following publication of the original article [1], the sentence “It remains to be determined if the formation of TMEM106B filaments can influence the risk of developing neurodegenerative diseases” in the paragraph starting with “Abundant filaments made of residues” under Discussion heading gives the relevant meaning of the previous sentence. The author wants to delete the sentence. The original article has been corrected.Item Novel tau filament folds in individuals with MAPT mutations P301L and P301T(bioRxiv, 2024-08-17) Schweighauser, Manuel; Shi, Yang; Murzin, Alexey G.; Garringer, Holly J.; Vidal, Ruben; Murrell, Jill R.; Erro, M. Elena; Seelaar, Harro; Ferrer, Isidro; van Swieten, John C.; Ghetti, Bernardino; Scheres, Sjors H. W.; Goedert, Michel; Pathology and Laboratory Medicine, School of MedicineMutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with abundant filamentous tau inclusions in brain cells. Individuals with pathological MAPT variants exhibit behavioural changes, cognitive impairment and signs of parkinsonism. Missense mutations of residue P301, which are the most common MAPT mutations associated with FTDP-17, give rise to the assembly of mutant four-repeat tau into filamentous inclusions, in the absence of extracellular deposits. Here we report the cryo-EM structures of tau filaments from five individuals belonging to three unrelated families with mutation P301L and from one individual belonging to a family with mutation P301T. A novel three-lobed tau fold resembling the two-layered tau fold of Pick's disease was present in all cases with the P301L tau mutation. Two different tau folds were found in the case with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease. These findings suggest that FTDP-17 with mutations in P301 should be considered distinct inherited tauopathies and that model systems with these mutations should be used with caution in the study of sporadic tauopathies.Item VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma(MDPI, 2024-07-24) Muñoz Perez, Natalia; Pensabene, Juliana M.; Galbo, Phillip M., Jr.; Sadeghipour, Negar; Xiu, Joanne; Moziak, Kirsten; Yazejian, Rita M.; Welch, Rachel L.; Bell, W. Robert; Sengupta, Soma; Aulakh, Sonikpreet; Eberhart, Charles G.; Loeb, David M.; Eskandar, Emad; Zheng, Deyou; Zang, Xingxing; Martin, Allison M.; Pathology and Laboratory Medicine, School of MedicineBackground: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor-cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA-VSIG axis to enhance anti-tumor responses.Item Metrics reloaded: recommendations for image analysis validation(Springer Nature, 2024) Maier-Hein, Lena; Reinke, Annika; Godau, Patrick; Tizabi, Minu D.; Buettner, Florian; Christodoulou, Evangelia; Glocker, Ben; Isensee, Fabian; Kleesiek, Jens; Kozubek, Michal; Reyes, Mauricio; Riegler, Michael A.; Wiesenfarth, Manuel; Kavur, A. Emre; Sudre, Carole H.; Baumgartner, Michael; Eisenmann, Matthias; Heckmann-Nötzel, Doreen; Rädsch, Tim; Acion, Laura; Antonelli, Michela; Arbel, Tal; Bakas, Spyridon; Benis, Arriel; Blaschko, Matthew B.; Cardoso, M. Jorge; Cheplygina, Veronika; Cimini, Beth A.; Collins, Gary S.; Farahani, Keyvan; Ferrer, Luciana; Galdran, Adrian; van Ginneken, Bram; Haase, Robert; Hashimoto, Daniel A.; Hoffman, Michael M.; Huisman, Merel; Jannin, Pierre; Kahn, Charles E.; Kainmueller, Dagmar; Kainz, Bernhard; Karargyris, Alexandros; Karthikesalingam, Alan; Kofler, Florian; Kopp-Schneider, Annette; Kreshuk, Anna; Kurc, Tahsin; Landman, Bennett A.; Litjens, Geert; Madani, Amin; Maier-Hein, Klaus; Martel, Anne L.; Mattson, Peter; Meijering, Erik; Menze, Bjoern; Moons, Karel G. M.; Müller, Henning; Nichyporuk, Brennan; Nickel, Felix; Petersen, Jens; Rajpoot, Nasir; Rieke, Nicola; Saez-Rodriguez, Julio; Sánchez, Clara I.; Shetty, Shravya; van Smeden, Maarten; Summers, Ronald M.; Taha, Abdel A.; Tiulpin, Aleksei; Tsaftaris, Sotirios A.; Van Calster, Ben; Varoquaux, Gaël; Jäger, Paul F.; Pathology and Laboratory Medicine, School of MedicineIncreasing evidence shows that flaws in machine learning (ML) algorithm validation are an underestimated global problem. In biomedical image analysis, chosen performance metrics often do not reflect the domain interest, and thus fail to adequately measure scientific progress and hinder translation of ML techniques into practice. To overcome this, we created Metrics Reloaded, a comprehensive framework guiding researchers in the problem-aware selection of metrics. Developed by a large international consortium in a multistage Delphi process, it is based on the novel concept of a problem fingerprint-a structured representation of the given problem that captures all aspects that are relevant for metric selection, from the domain interest to the properties of the target structure(s), dataset and algorithm output. On the basis of the problem fingerprint, users are guided through the process of choosing and applying appropriate validation metrics while being made aware of potential pitfalls. Metrics Reloaded targets image analysis problems that can be interpreted as classification tasks at image, object or pixel level, namely image-level classification, object detection, semantic segmentation and instance segmentation tasks. To improve the user experience, we implemented the framework in the Metrics Reloaded online tool. Following the convergence of ML methodology across application domains, Metrics Reloaded fosters the convergence of validation methodology. Its applicability is demonstrated for various biomedical use cases.Item Best practices to evaluate the impact of biomedical research software-metric collection beyond citations(Oxford University Press, 2024) Afiaz, Awan; Ivanov, Andrey A.; Chamberlin, John; Hanauer, David; Savonen, Candace L.; Goldman, Mary J.; Morgan, Martin; Reich, Michael; Getka, Alexander; Holmes, Aaron; Pati, Sarthak; Knight, Dan; Boutros, Paul C.; Bakas, Spyridon; Caporaso, J. Gregory; Del Fiol, Guilherme; Hochheiser, Harry; Haas, Brian; Schloss, Patrick D.; Eddy, James A.; Albrecht, Jake; Fedorov, Andrey; Waldron, Levi; Hoffman, Ava M.; Bradshaw, Richard L.; Leek, Jeffrey T.; Wright, Carrie; Pathology and Laboratory Medicine, School of MedicineMotivation: Software is vital for the advancement of biology and medicine. Impact evaluations of scientific software have primarily emphasized traditional citation metrics of associated papers, despite these metrics inadequately capturing the dynamic picture of impact and despite challenges with improper citation. Results: To understand how software developers evaluate their tools, we conducted a survey of participants in the Informatics Technology for Cancer Research (ITCR) program funded by the National Cancer Institute (NCI). We found that although developers realize the value of more extensive metric collection, they find a lack of funding and time hindering. We also investigated software among this community for how often infrastructure that supports more nontraditional metrics were implemented and how this impacted rates of papers describing usage of the software. We found that infrastructure such as social media presence, more in-depth documentation, the presence of software health metrics, and clear information on how to contact developers seemed to be associated with increased mention rates. Analysing more diverse metrics can enable developers to better understand user engagement, justify continued funding, identify novel use cases, pinpoint improvement areas, and ultimately amplify their software's impact. Challenges are associated, including distorted or misleading metrics, as well as ethical and security concerns. More attention to nuances involved in capturing impact across the spectrum of biomedical software is needed. For funders and developers, we outline guidance based on experience from our community. By considering how we evaluate software, we can empower developers to create tools that more effectively accelerate biological and medical research progress. Availability and implementation: More information about the analysis, as well as access to data and code is available at https://github.com/fhdsl/ITCR_Metrics_manuscript_website.Item Cryo-EM structures of cotton wool plaques' amyloid β and of tau filaments in dominantly inherited Alzheimer disease(Springer, 2024-08-15) Hoq, Md Rejaul; Fernandez, Anllely; Vago, Frank S.; Hallinan, Grace I.; Bharath, Sakshibeedu R.; Li, Daoyi; Ozcan, Kadir A.; Garringer, Holly J.; Jiang, Wen; Vidal, Ruben; Ghetti, Bernardino; Pathology and Laboratory Medicine, School of MedicineCotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-β (Aβ) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aβ peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aβ and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aβ filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aβ filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aβ filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.