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Pathology has benefited from the rapid progress of image-digitizing technology during the last decade. However, the application of digital whole slide images (WSI) in forensic pathology still needs to be improved. WSI validation is crucial to ensure diagnostic performance, at least equivalent to glass slides and light microscopy. The College of American Pathologists Pathology and Laboratory Quality Center recently updated internal digital pathology system validation recommendations. Following these guidelines, this pilot study aimed to validate the performance of a digital approach for forensic histopathological diagnosis. Six independent skilled forensic pathologists from different forensic medicine institutes evaluated 100 glass slides of forensic interest (80 stained with standard hematoxylin and eosin, 20 with special staining), including different organs and tissues, with light microscopy (Olympus BX51, Tokyo, Japan). Glass slides were scanned using the Aperio GT 450 DX Digital Slides Scanner (Leica Biosystems, Nussloch, Germany). After two wash-out weeks, forensic pathologists evaluated WSIs in front of a widescreen using computer devices with dedicated software (O3 viewer, O3 Enterprise, Zucchetti, Trieste, Italy). Side-by-side comparisons between diagnoses performed on tissue glass slides versus WSIs were above the threshold stated in the validation guidelines (mean concordance of 97.8%). CSUQ Version 3 questionnaire showed high satisfaction for all pathologists (mean result: 6.6/7). Our institutional digital forensic pathology system has been validated for practical casework application. This approach opens new scenarios in practical forensic casework investigations, such as sharing live histological ex-glass slides online, as well as educational and research perspectives, with improving impacts on the whole daily workflow., Competing Interests: Declarations. Conflict of interest: The authors declared no potential competing interest concerning this article’s research, authorship, and/or publication. Human ethics and consent to participate: Not applicable. Ethical approval and informed consent: This article does not contain any studies with animals. Informed consent is unnecessary in this work because only judicial–autopsy cases were considered. The report does not contain personal data. In any case, all data are covered by the Italian Law – Data Protection Authority (Official Gazette no. 72 of March 26, 2012) for scientific research purposes., (© 2025. The Author(s).)

Purpose: This study aimed to explore metabolic tumor volume (MTV) as assessed by 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) and understand its biological meaning in patients with non-small cell lung cancer (NSCLC) exposed to immune checkpoint blockers (ICB)., Experimental Design: In this study, patients with advanced NSCLC and a positive PET scan within 42 days of first-line treatment were enrolled in 11 institutions across four countries. Total MTV (tMTV) was analyzed, with a 42% maximum standardized uptake value threshold. Survival was analyzed according to high tMTV (≥median). Plasma proteomic profile, whole exome, transcriptome, and other analyses were performed on monocentric cohorts to explore its biological correlates., Results: Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. Median overall survival (OS) for patients with high tMTV treated with ICBs was 11.4 vs. 29.6 months (P < 0.0012) for those with low tMTV. In patients who received chemotherapy-ICB, tMTV did not correlate with OS (P = 0.099). In patients with programmed death-ligand 1 (PD-L1) ≥1% and high tMTV, chemotherapy-ICB combination was associated with longer OS compared with ICBs alone (20 vs. 11.4 months; P = 0.026), while no survival differences were observed in the low tMTV group. High tMTV correlated (and its detrimental effect seems to be driven) with a specific proteomic profile and increase in genomic instability., Conclusions: Our analysis indicates high tMTV is linked to an increase in systemic inflammation, specific cytokines production, and chromosomal instability. tMTV may serve as one of the biomarkers to select the best upfront strategy in patients with PD-L1-positive advanced NSCLC., (©2024 American Association for Cancer Research.)