Steven D Forsythe1,2,3, Shyama Sasikumar1,2, Omeed Moaven4,5, Hemamylammal Sivakumar6,7, Perry Shen4,5, Edward A Levine4,5, Shay Soker1,2,3, Aleksander Skardal6,7, Konstantinos I Votanopoulos8,9,10,11. 1. Wake Forest Organoid Research Center (WFORCE), Wake Forest School of Medicine, Winston-Salem, NC, USA. 2. Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. 3. Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA. 4. Comprehensive Cancer Center at Wake Forest Baptist Medical, Winston-Salem, NC, USA. 5. Department of Surgery - Surgical Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA. 6. Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA. 7. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. 8. Wake Forest Organoid Research Center (WFORCE), Wake Forest School of Medicine, Winston-Salem, NC, USA. kvotanop@wakehealth.edu. 9. Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. kvotanop@wakehealth.edu. 10. Comprehensive Cancer Center at Wake Forest Baptist Medical, Winston-Salem, NC, USA. kvotanop@wakehealth.edu. 11. Department of Surgery - Surgical Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA. kvotanop@wakehealth.edu.
Abstract
BACKGROUND: Chemotherapy dosing duration and perfusion temperature vary significantly in HIPEC protocols. This study investigates patient-derived tumor organoids as a platform to identify the most efficacious perfusion protocol in a personalized approach. PATIENTS AND METHODS: Peritoneal tumor tissue from 15 appendiceal and 8 colon cancer patients who underwent CRS/HIPEC were used for personalized organoid development. Organoids were perfused in parallel at 37 and 42 °C with low- and high-dose oxaliplatin (200 mg/m2 over 2 h vs. 460 mg/m2 over 30 min) and MMC (40 mg/3L over 2 h). Viability assays were performed and pooled for statistical analysis. RESULTS: An adequate organoid number was generated for 75% (6/8) of colon and 73% (11/15) of appendiceal patients. All 42 °C treatments displayed lower viability than 37 °C treatments. On pooled analysis, MMC and 200 mg/m2 oxaliplatin displayed no treatment difference for either appendiceal or colon organoids (19% vs. 25%, p = 0.22 and 27% vs. 31%, p = 0.55, respectively), whereas heated MMC was superior to 460 mg/m2 oxaliplatin in both primaries (19% vs. 54%, p < 0.001 and 27% vs. 53%, p = 0.002, respectively). In both appendiceal and colon tumor organoids, heated 200 mg/m2 oxaliplatin displayed increased cytotoxicity as compared with 460 mg/m2 oxaliplatin (25% vs. 54%, p < 0.001 and 31% vs. 53%, p = 0.008, respectively). CONCLUSIONS: Organoids treated with MMC or 200 mg/m2 heated oxaliplatin for 2 h displayed increased susceptibility in comparison with 30-min 460 mg/m2 oxaliplatin. Optimal perfusion protocol varies among patients, and organoid technology may offer a platform for tailoring HIPEC conditions to the individual patient level.
BACKGROUND: Chemotherapy dosing duration and perfusion temperature vary significantly in HIPEC protocols. This study investigates patient-derived tumor organoids as a platform to identify the most efficacious perfusion protocol in a personalized approach. PATIENTS AND METHODS: Peritoneal tumor tissue from 15 appendiceal and 8 colon cancerpatients who underwent CRS/HIPEC were used for personalized organoid development. Organoids were perfused in parallel at 37 and 42 °C with low- and high-dose oxaliplatin (200 mg/m2 over 2 h vs. 460 mg/m2 over 30 min) and MMC (40 mg/3L over 2 h). Viability assays were performed and pooled for statistical analysis. RESULTS: An adequate organoid number was generated for 75% (6/8) of colon and 73% (11/15) of appendiceal patients. All 42 °C treatments displayed lower viability than 37 °C treatments. On pooled analysis, MMC and 200 mg/m2 oxaliplatin displayed no treatment difference for either appendiceal or colon organoids (19% vs. 25%, p = 0.22 and 27% vs. 31%, p = 0.55, respectively), whereas heated MMC was superior to 460 mg/m2 oxaliplatin in both primaries (19% vs. 54%, p < 0.001 and 27% vs. 53%, p = 0.002, respectively). In both appendiceal and colon tumor organoids, heated 200 mg/m2 oxaliplatin displayed increased cytotoxicity as compared with 460 mg/m2 oxaliplatin (25% vs. 54%, p < 0.001 and 31% vs. 53%, p = 0.008, respectively). CONCLUSIONS: Organoids treated with MMC or 200 mg/m2 heated oxaliplatin for 2 h displayed increased susceptibility in comparison with 30-min 460 mg/m2 oxaliplatin. Optimal perfusion protocol varies among patients, and organoid technology may offer a platform for tailoring HIPEC conditions to the individual patient level.
Authors: Michael Flood; Vignesh Narasimhan; Kasmira Wilson; Wei Mou Lim; Robert Ramsay; Michael Michael; Alexander Heriot Journal: Ann Surg Oncol Date: 2021-10-01 Impact factor: 5.344
Authors: Steven D Forsythe; Hemamylammal Sivakumar; Richard A Erali; Nadeem Wajih; Wencheng Li; Perry Shen; Edward A Levine; Katherine E Miller; Aleksander Skardal; Konstantinos I Votanopoulos Journal: Ann Surg Oncol Date: 2022-07-03 Impact factor: 4.339
Authors: Anthony J Dominijanni; Mahesh Devarasetty; Steven D Forsythe; Konstantinos I Votanopoulos; Shay Soker Journal: Tissue Eng Part C Methods Date: 2021-07 Impact factor: 3.273
Authors: Nick Seyfried; Can Yurttas; Markus Burkard; Benedikt Oswald; Alexander Tolios; Franziska Herster; Joseph Kauer; Tarkan Jäger; Ingmar Königsrainer; Karolin Thiel; Markus Quante; Hans-Georg Rammensee; Sascha Venturelli; Matthias Schwab; Alfred Königsrainer; Stefan Beckert; Markus W Löffler Journal: Cancers (Basel) Date: 2022-02-24 Impact factor: 6.639
Authors: Steven D Forsythe; Richard A Erali; Preston Laney; Hemamylammal Sivakumar; Wencheng Li; Aleksander Skardal; Shay Soker; Konstantinos I Votanopoulos Journal: Sci Rep Date: 2022-08-16 Impact factor: 4.996
Authors: Steven D Forsythe; Richard A Erali; Shyama Sasikumar; Preston Laney; Ethan Shelkey; Ralph D'Agostino; Lance D Miller; Perry Shen; Edward A Levine; Shay Soker; Konstantinos I Votanopoulos Journal: Clin Cancer Res Date: 2021-07-01 Impact factor: 13.801