{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:12:41Z","timestamp":1788545561009,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Eleftherios Makris\u2019 NIH K12 award","award":["K12TR004931"],"award-info":[{"award-number":["K12TR004931"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignancy for which cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is central to treatment in appropriately selected patients. Recurrence remains common even after complete macroscopic cytoreduction. Current HIPEC regimens are protocolized at the institutional and population levels but are not individualized using site-specific molecular or functional tumor biology. We performed a narrative review of clinical, genomic, epigenetic, immune, microenvironmental, and patient-derived organoid evidence relevant to DMPM, CRS\/HIPEC, and treatment resistance. Recurrence is multifactorial, with plausible contributions from spatial, histologic, genomic, epigenetic, immune, stromal, and pharmacokinetic heterogeneity. Three primary reports provide direct DMPM organoid evidence, including preliminary demonstrations of patient-specific drug response and discordant responses among anatomically distinct implants. However, these platforms differ biologically, and predictive thresholds, analytical reproducibility, turnaround time, and microenvironmental modeling remain unvalidated. Multi-site organoid pharmacotyping integrated with molecular profiling is therefore a plausible strategy for studying HIPEC resistance. Translation requires a staged pathway encompassing analytical validity, blinded clinical validity, and clinical-utility testing. Precision HIPEC should presently be considered an investigational, validation-ready framework rather than a standard of care.<\/jats:p>","DOI":"10.3390\/ijms27177911","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:25:56Z","timestamp":1788542756000},"page":"7911","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Patient-Derived Organoid Models and Precision HIPEC in Diffuse Malignant Peritoneal Mesothelioma: Modeling Heterogeneity to Address Recurrence"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7496-6117","authenticated-orcid":false,"given":"Eleftherios A.","family":"Makris","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA"},{"name":"Wake Forest Organoid Research Center, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James K.","family":"Ives","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Votanopoulos","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA"},{"name":"Wake Forest Organoid Research Center, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Calthorpe, L., Romero-Hernandez, F., Miller, P., Conroy, P.C., Hirose, K., Kim, A., Kirkwood, K., Nakakura, E., Corvera, C., and Maker, A.V. (2023). Contemporary trends in malignant peritoneal mesothelioma: Incidence and survival in the United States. Cancers, 15.","DOI":"10.3390\/cancers15010229"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"599","DOI":"10.21037\/tlcr.2018.08.03","article-title":"Update on the management of malignant peritoneal mesothelioma","volume":"7","author":"Sugarbaker","year":"2018","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"36","DOI":"10.21037\/asj-22-37","article-title":"An update in malignant peritoneal mesothelioma diagnosis and treatment: A narrative review","volume":"3","author":"Newland","year":"2023","journal-title":"AME Surg. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.jamcollsurg.2013.12.013","article-title":"Intraperitoneal chemotherapy for peritoneal surface malignancy: Experience with 1,000 patients","volume":"218","author":"Levine","year":"2014","journal-title":"J. Am. Coll. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1245\/s10434-017-6293-5","article-title":"Is cytoreductive surgery with hyperthermic intraperitoneal chemotherapy justified for biphasic variants of peritoneal mesothelioma? Outcomes from the Peritoneal Surface Oncology Group International Registry","volume":"25","author":"Votanopoulos","year":"2018","journal-title":"Ann. Surg. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1245\/s10434-019-07425-5","article-title":"Effect of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on quality of life in patients with peritoneal mesothelioma","volume":"27","author":"Ali","year":"2020","journal-title":"Ann. Surg. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.2147\/CMAR.S170300","article-title":"Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma: Patient selection and special considerations","volume":"11","author":"Enomoto","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s13193-023-01728-6","article-title":"Peritoneal Mesothelioma: Systematic Review of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Protocol Outcomes","volume":"14","author":"Kepenekian","year":"2023","journal-title":"Indian J. Surg. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ejca.2016.06.002","article-title":"Diffuse malignant peritoneal mesothelioma: Evaluation of systemic chemotherapy with comprehensive treatment through the RENAPE Database: Multi-Institutional Retrospective Study","volume":"65","author":"Kepenekian","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9731","DOI":"10.1245\/s10434-025-18196-7","article-title":"Assessing the annual risk of recurrence following complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for diffuse malignant peritoneal mesothelioma patients","volume":"32","author":"Peron","year":"2025","journal-title":"Ann. Surg. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.jamcollsurg.2012.04.023","article-title":"Outcomes of repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal surface malignancy","volume":"215","author":"Votanopoulos","year":"2012","journal-title":"J. Am. Coll. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1038\/s41416-022-01979-0","article-title":"Genomic landscape of pleural and peritoneal mesothelioma tumours","volume":"127","author":"Hiltbrunner","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"a003566","DOI":"10.1101\/mcs.a003566","article-title":"Integrative genomic analysis of peritoneal malignant mesothelioma: Understanding a case with extraordinary chemotherapy response","volume":"5","author":"Nakken","year":"2019","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1038\/s41467-021-21798-w","article-title":"Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment","volume":"12","author":"Zhang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1097\/PAS.0000000000000696","article-title":"A histomorphologic grading system that predicts overall survival in diffuse malignant peritoneal mesothelioma with epithelioid subtype","volume":"40","author":"Valente","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/s41588-023-01321-1","article-title":"Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity","volume":"55","author":"Mangiante","year":"2023","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"100938","DOI":"10.1016\/j.xcrm.2023.100938","article-title":"Genomic and transcriptomic analyses identify a prognostic gene signature and predict response to therapy in pleural and peritoneal mesothelioma","volume":"4","author":"Nair","year":"2023","journal-title":"Cell Rep. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/s41416-020-01130-x","article-title":"Heterogeneity in PD-L1 expression in malignant peritoneal mesothelioma with systemic or intraperitoneal chemotherapy","volume":"124","author":"White","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"995651","DOI":"10.3389\/fonc.2022.995651","article-title":"Unraveling tumor microenvironment heterogeneity in malignant pleural mesothelioma identifies biologically distinct immune subtypes enabling prognosis determination","volume":"12","author":"Yang","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1158\/2159-8290.CD-23-0017","article-title":"Single-cell view of tumor microenvironment gradients in pleural mesothelioma","volume":"14","author":"Giotti","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2300143","DOI":"10.1183\/13993003.00143-2023","article-title":"Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma","volume":"63","author":"Obacz","year":"2024","journal-title":"Eur. Respir. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1038\/s41418-025-01639-9","article-title":"Fibroblast-like cells in mesothelioma can derive from tumor cells","volume":"33","author":"Rrapaj","year":"2026","journal-title":"Cell Death Differ."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s00109-020-01990-z","article-title":"Cancer research using organoid technology","volume":"99","author":"Kretzschmar","year":"2021","journal-title":"J. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1158\/1078-0432.CCR-20-0073","article-title":"Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases to direct personalized therapy","volume":"26","author":"Narasimhan","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kaur, H., Wright, J.A., Worthley, D.L., Murphy, E., and Woods, S.L. (2025). Precision medicine for peritoneal carcinomatosis: Current advances in organoid drug testing and clinical applicability. Organoids, 4.","DOI":"10.3390\/organoids4010002"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2886","DOI":"10.1038\/s41598-018-21200-8","article-title":"In vitro patient-derived 3D mesothelioma tumor organoids facilitate patient-centric therapeutic screening","volume":"8","author":"Mazzocchi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12943-023-01901-z","article-title":"Organoids derived from patients provide a new opportunity for research and individualized treatment of malignant peritoneal mesothelioma","volume":"23","author":"Fang","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11640","DOI":"10.1038\/s41598-023-38545-4","article-title":"Cisplatin exhibits superiority over MMC as a perfusion agent in a peritoneal mesothelioma patient specific organoid HIPEC platform","volume":"13","author":"Forsythe","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Gao, Y., Kruithof-de Julio, M., Peng, R.W., and Dorn, P. (2022). Organoids as a model for precision medicine in malignant pleural mesothelioma: Where are we today?. Cancers, 14.","DOI":"10.3390\/cancers14153758"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107542","DOI":"10.1016\/j.lungcan.2024.107542","article-title":"Establishing mesothelioma patient-derived organoid models from malignant pleural effusions","volume":"191","author":"Hocking","year":"2024","journal-title":"Lung Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Cioce, M., Gatti, V., Napolitano, F., Giorgiano, N.M., Marra, A., Portella, G., Fiorelli, A., Pentimalli, F., and Fazio, V.M. (2024). Mesothelioma-associated fibroblasts modulate the response of mesothelioma patient-derived organoids to chemotherapy via interleukin-6. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202403.1058.v1"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"L756","DOI":"10.1152\/ajplung.00078.2025","article-title":"Use of patient-derived organoids for pleural mesothelioma 3-D modeling","volume":"329","author":"Volpini","year":"2025","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Useckaite, Z., Hocking, A.J., Mortimer, L.A., Salamon, J., Lee, S., Irani, Y., Franzon, L., Arul, A.L., Prabhakaran, S., and Klebe, S. (2026). A high-fidelity patient-derived organoid platform recapitulates the dynamic metabolic landscape of cisplatin tolerance in mesothelioma. Cancers, 18.","DOI":"10.20944\/preprints202604.0904.v1"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1146\/annurev-pathol-042420-092719","article-title":"Diffuse pleural mesothelioma: Advances in molecular pathogenesis, diagnosis, and treatment","volume":"19","author":"Fanaroff","year":"2024","journal-title":"Annu. Rev. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1038\/s41591-025-03958-3","article-title":"Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: A phase 2 trial and ctDNA analyses","volume":"31","author":"Reuss","year":"2025","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1200\/JCO-24-02425","article-title":"Treatment of pleural mesothelioma: ASCO guideline update","volume":"43","author":"Kindler","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5125","DOI":"10.1245\/s10434-025-17358-x","article-title":"Consensus guideline for the management of peritoneal mesothelioma","volume":"33","author":"Brown","year":"2026","journal-title":"Ann. Surg. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"111492","DOI":"10.1016\/j.ejso.2026.111492","article-title":"Ten-year of French multicentric experience in the management of peritoneal mesothelioma with 924 patients","volume":"52","author":"Noiret","year":"2026","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7803","DOI":"10.1245\/s10434-023-13973-8","article-title":"2022 PSOGI consensus on HIPEC regimens for peritoneal malignancies: Diffuse malignant peritoneal mesothelioma","volume":"30","author":"Kepenekian","year":"2023","journal-title":"Ann. Surg. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.jtho.2020.01.012","article-title":"Sensitivity of mesothelioma cells to PARP inhibitors is not dependent on BAP1 but is enhanced by temozolomide in cells with high Schlafen 11 and low O6-methylguanine-DNA methyltransferase expression","volume":"15","author":"Rathkey","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_41","first-page":"100231","article-title":"Phase 2 study of olaparib in malignant mesothelioma and correlation of efficacy with germline or somatic mutations in BAP1 gene","volume":"2","author":"Ghafoor","year":"2021","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1200\/JCO.2018.79.0543","article-title":"Maintenance defactinib versus placebo after first-line chemotherapy in patients with merlin-stratified pleural mesothelioma: COMMAND-A double-blind, randomized, phase II study","volume":"37","author":"Fennell","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1158\/2159-8290.CD-23-0669","article-title":"MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer","volume":"13","author":"Engstrom","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1002\/pmic.200900758","article-title":"Matrigel: A complex protein mixture required for optimal growth of cell culture","volume":"10","author":"Hughes","year":"2010","journal-title":"Proteomics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/nature20168","article-title":"Designer matrices for intestinal stem cell and organoid culture","volume":"539","author":"Gjorevski","year":"2016","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature10137","article-title":"Role of YAP\/TAZ in mechanotransduction","volume":"474","author":"Dupont","year":"2011","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.ccell.2016.05.005","article-title":"YAP\/TAZ at the roots of cancer","volume":"29","author":"Zanconato","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1080\/02656730500532028","article-title":"Cell biological effects of hyperthermia alone or combined with radiation or drugs: A short introduction to newcomers in the field","volume":"22","author":"Kampinga","year":"2006","journal-title":"Int. J. Hyperth."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9851","DOI":"10.1073\/pnas.1101053108","article-title":"Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition","volume":"108","author":"Krawczyk","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s13014-015-0462-0","article-title":"Effects of hyperthermia on DNA repair pathways: One treatment to inhibit them all","volume":"10","author":"Oei","year":"2015","journal-title":"Radiat. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1016\/j.ejca.2008.07.038","article-title":"Hyperthermia adds to chemotherapy","volume":"44","author":"Issels","year":"2008","journal-title":"Eur. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"14298","DOI":"10.1073\/pnas.162491399","article-title":"Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals","volume":"99","author":"Ishida","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nrc2167","article-title":"The resurgence of platinum-based cancer chemotherapy","volume":"7","author":"Kelland","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1038\/onc.2011.384","article-title":"Molecular mechanisms of cisplatin resistance","volume":"31","author":"Galluzzi","year":"2012","journal-title":"Oncogene"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7911\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:27:29Z","timestamp":1788542849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7911"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":54,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177911"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177911","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]}}}