{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:38:25Z","timestamp":1791581905089,"version":"4.3.4"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["JP25K17080"],"award-info":[{"award-number":["JP25K17080"]}]},{"name":"the J&amp;J MedTech Research Grant","award":["AS2024A00023600"],"award-info":[{"award-number":["AS2024A00023600"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: In malignant pleural mesothelioma, epithelioid histology is traditionally considered a favorable prognostic marker. However, it remains clinically undetermined whether the intensity of an oncogenic insult can disrupt this link. Radiation-induced cases serve as an unconfounded biological model to dissect such trajectories masked by asbestos confounding. Methods: We performed an Individual Patient Data (IPD) synthesis of 20 strictly asbestos-unexposed human cases, applying clinically established dose stratification (intermediate: 20\u201345 Gy vs. high: &gt;45 Gy). To confirm the observed pattern, we examined data from 829 dogs in the Colorado State University (CSU) Beagle Study. Results: In the intermediate-dose group (n = 13), a significant positive correlation persisted between age at radiotherapy and the latent period (\u03c1 = 0.567, p = 0.043). Conversely, high-dose exposure (&gt;45 Gy) showed a disruption of this age-dependent pattern, with a trend toward inverse correlation (\u03c1 = \u22120.754, p = 0.084). Interaction analysis confirmed a statistically significant divergence between these dose-dependent trends (p = 0.005). The CSU Beagle Study (n = 829) demonstrated the physical basis of this phenomenon: in the canine model, high-dose exposure (\u22650.74 Gy) triggered a \u201cStep-Jump\u201d in cumulative incidence (30.4% at 0.5 years), indicating instantaneous carcinogenic onset distinct from cumulative biological aging. Conclusions: This kinetic divergence points to a \u201cDiagnostic Trap.\u201d We propose a \u2018Single- to Double-Brake\u2019 framework where intermediate doses preserve age-dependent progression, whereas high doses likely trigger catastrophic genomic failure (chromothripsis) that bypasses the time required for morphological dedifferentiation. Consequently, morphologically indolent epithelioid tumors in high-dose survivors may harbor aggressive molecular profiles not predicted by histology alone, necessitating risk-stratified precision surveillance.<\/jats:p>","DOI":"10.3390\/cancers18020221","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T14:15:50Z","timestamp":1767968150000},"page":"221","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Diagnostic Trap in Radiation-Induced Mesothelioma: Kinetic-Morphological Decoupling Masks Molecular Aggression"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5004-4919","authenticated-orcid":false,"given":"Norikatsu","family":"Fujita","sequence":"first","affiliation":[{"name":"Digital Transformation of Skill Unit, The Polytechnic University of Japan, 2-32-1 Ogawa-nishimachi, Kodaira-shi, Tokyo 187-0035, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsumi","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto-shi 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironobu","family":"Osumi","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto-shi 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1826-742X","authenticated-orcid":false,"given":"Yoshiyasu","family":"Takefuji","sequence":"additional","affiliation":[{"name":"Faculty of Data Science, Musashino University, 3-3-3 Ariake, Koto-ku, Tokyo 135-8181, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.annonc.2021.11.005","article-title":"Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"33","author":"Popat","year":"2022","journal-title":"Ann. 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