Postoperative pancreatic fistula after pancreatic cancer surgery: Past and present of ISGPS classification

JCTEI JOURNAL OF CLINICAL TRIALS AND EXPERIMENTAL INVESTIGATIONS 59 Year: 2025 Volume: 4 Issue: 2 10.5281/zenodo. 15832071 The pathophysiology of abdominal surgical diseases and the therapeutic potential of mesenchymal stem cells LETTER Melih Can Gul¹ 1. Afyonkarahisar State Hospital Department of Gastroenterology Surgery Afyonkarahisar, Türkiye Cite as: Gul MC. The pathophysiology of abdominal surgical diseases and the therapeutic potential of mesenchymal stem cells. J Clin Trials Exp Investig. 2025;4(2):59-61. Correspondence Melih Can Gul. Afyonkarahisar State Hospital Department of Gastroenterology Surgery Afyonkarahisar, Türkiye. e-mail [email protected] Received: 10 May 2025 Revised: 10 June 2025 Accepted: 25 June 2025 Published: 30 June 2025 Keywords @Mesenchymal stem cells, @General Surgery @Inflammatory bowel disease @Cirrhosis @Pancreatitis ORCID ID of the author(s): MCG: 0000-0002-6165-1144 2822-5090 /© 2025 Journal of Clinical Trials and Experimental Investigations. Published by Unico's Medicine. This is an openaccess article under the terms of the CC BY license. (https://creativecommons.org/licenses/by/4.0/) Dear Editor, Mesenchymal stem cells (MSCs) have emerged as promising tools in regenerative medicine due to their antifibrotic, pro-angiogenic, and immunomodulatory effects that address limitations in standard surgical approaches. Abdominal pathologies—characterized by inflammation, tissue injury, and fibrotic progression—are particularly suitable for MSC-based interventions (1). Whether derived from bone marrow, adipose tissue, or umbilical cord, MSCs exert their regenerative functions through paracrine signaling, extracellular vesicle release, and immune regulation (2). Their delivery route is pathology-dependent: local injection targets mucosal or fistulous areas, while portal-hepatic, intraperitoneal, or systemic routes provide organ-wide or systemic effects (3). A recent letter in this journal illustrated MSC efficacy in cytokine storm suppression during COVID-19, reinforcing their broad therapeutic potential (4). Concurrently, the comprehensive review by Azizoglu et al. on surgical diseases has also served as an inspiration for the preparation of this editorial letter (1). Refractory peptic ulcer Refractory ulcers, resistant to acid suppression, arise from persistent inflammation, poor angiogenesis, and stromal deficit. In a porcine NSAID-ulcer model, endoscopic submucosal injection of adipose-derived MSCs accelerated healing by over 50%, with MSC secretome achieving comparable results. Pilot studies now explore MSC-enhanced biomaterials as adjuncts to endoscopic therapy, aiming to reduce surgical resections. Endoscopic submucosal delivery appears most effective, combining localized action with low systemic exposure (3,5). Inflammatory bowel disease Crohn’s disease (CD) and ulcerative colitis (UC) result from chronic immune dysregulation and mucosal destruction (2). In a phase III trial, a single local injection of adipose MSCs into CD-associated perianal fistulas led to combined clinical-radiologic remission in 51% of patients, sustained over four years (6). For luminal IBD, metaanalysis suggests that repeated systemic MSC infusions at ≥4×10⁶ cells/kg induce steroid-free remission in approximately 40% of cases (2). Intra-arterial delivery is also being explored for diffuse mucosal inflammation (7) (Table 1). 60 JCTEI Acute pancreatitis Severe acute pancreatitis (SAP) is associated with autodigestion, cytokine storm, and multi-organ dysfunction. Rodent models demonstrate that early intravenous MSC therapy significantly reduces pancreatic necrosis, systemic inflammation, and mortality. These effects are mediated through macrophage polarization, IL-10 upregulation, and oxidative stress modulation (8). A first-in-human trial evaluating intravenous umbilical-cord MSCs within 48 hours of SAP onset is currently recruiting (9). Cirrhosis Cirrhosis involves progressive fibrosis and hepatocellular dysfunction, with limited nonsurgical treatment options (1). A recent meta-analysis of 14 clinical trials (n=785) found that MSC infusion via hepatic artery or portal vein significantly improved MELD scores and serum albumin levels within six months (10). In acute-on-chronic liver failure, MSCs reduced stellate cell activation and collagen deposition while improving survival rates (11). Sequential infusions may further enhance antifibrotic signaling pathways (12). Perspective MSC therapy provides a biologically consistent and increasingly evidence-based approach for managing difficult gastrointestinal diseases (1). Advances such as hypoxic preconditioning, exosome formulations, and genetic modification further enhance therapeutic efficacy and safety (1,13). The experience from COVID-19 ARDS shows that MSCs can robustly counteract systemic inflammation (4). To expedite clinical translation, we support unified protocols for MSC characterization, disease-specific composite endpoints, and route-of-delivery comparison trials (14,15). Conflict of interest: The authors report no conflict of interest. Funding source: No funding was required. Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors. Acknowledgments: None Peer-review: Externally. Evaluated by independent Table 1: Mesenchymal stem cell delivery strategies in abdominal surgical pathologies Condition Route of MSC administration Main therapeutic outcome Reference Refractory peptic ulcer Endoscopic submucosal injection >50% faster ulcer closure in porcine model (5) Crohn’s perianal fistula Local tract injection 51% combined clinical and radiologic remission at 24 weeks (6) Luminal inflammatory bowel disease Repeated intravenous infusion ~40% steroid-free remission rate (7) Severe acute pancreatitis Early single intravenous administration 43% mortality reduction in animal models (8) Decompensated liver cirrhosis Hepatic arterial or portal vein route MELD score improvement by 2–3 points; increased serum albumin level (10) 61 JCTEI reviewers working in at least two different institutions appointed by the field editor. Data availability: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Contributions Research concept and design: MCG Data analysis and interpretation: MCG Collection and/or assembly of data: MCG Writing the article: MCG Critical revision of the article: MCG Final approval of the article: MCG All authors read and approved the final version of the manuscript. References 1. Azizoglu M, Zorba-Yildiz AP, Yilmaz H, Yurtbay G, Catli G, Yavuz G, et al. Regenerative medicine in surgery: stem cells and exosome applications. Cir Cir. 2025;93(1):86-104. 2. Ko JZ, Johnson S, Dave M. Efficacy and Safety of Mesenchymal Stem/Stromal Cell Therapy for Inflammatory Bowel Diseases: An Up-to-Date Systematic Review. Biomolecules. 2021;11(1):82. 3. Saleh M, Sohrabpour AA, Mehrabi MR, Seyhoun I, Vaezi AA. Therapeutic approach of adipose-derived mesenchymal stem cells in refractory peptic ulcer. Stem Cell Res Ther. 2021;12(1):515. 4. Waseem M, Altaf H, Hussain N, Mushtaq S, Siddique S. The role of mesenchymal stem cells in the treatment of ARDS and cytokine storms in COVID-19. J Clin Trials Exp Investig. 2025;4(1):36-8. 5. Xia X, Chan KF, Wong GTY, Wang P, Liu L, Yeung BPM, et al. Mesenchymal stem cells promote healing of nonsteroidal anti-inflammatory drug-related peptic ulcer through paracrine actions in pigs. Sci Transl Med. 2019;11(516):eaat7455. 6. Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388(10051):1281-90. 7. Barnhoorn MC, Wasser MNJM, Roelofs H, Maljaars PWJ, Molendijk I, Bonsing BA, et al. Long-term Evaluation of Allogeneic Bone Marrow-derived Mesenchymal Stromal Cell Therapy for Crohn's Disease Perianal Fistulas. J Crohns Colitis. 2020;14(1):64-70. 8. Ahmed SM, Morsi M, Ghoneim NI, Abdel-Daim MM, El-Badri N. Mesenchymal Stromal Cell Therapy for Pancreatitis: A Systematic Review. Oxid Med Cell Longev. 2018;2018:3250864. 9. Wang Z, Li T, Zhang Z, Yuan M, Shi M, Wang FS, Linghu EQ, et al. Human umbilical cord-derived mesenchymal stem cells for the treatment of decompensated cirrhosis (MSC-DLC-1): a dose-escalation, phase I trial protocol. BMJ Open. 2023;13(12):e078362. 10. Lu W, Qu J, Yan L, Tang X, Wang X, Ye A, et al. Efficacy and safety of mesenchymal stem cell therapy in liver cirrhosis: a systematic review and meta-analysis. Stem Cell Res Ther. 2023;14(1):301. 11. Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. 2012;1(10):725-31. 12. Wang X, Wang Y, Lu W, Qu J, Zhang Y, Ye J. Effectiveness and mechanisms of mesenchymal stem cell therapy in preclinical animal models of hepatic fibrosis: a systematic review and meta-analysis. Front Bioeng Biotechnol. 2024;12:1424253. 13. Ding Y, Li Y, Sun Z, Han X, Chen Y, Ge Y, et al. Cellderived extracellular vesicles and membranes for tissue repair. J Nanobiotechnology. 2021;19(1):368. 14. Liu W, Cheng G, Cui H, Tian Z, Li B, Han Y, et al. Theoretical basis, state and challenges of living cell-based drug delivery systems. Theranostics. 2024;14(13):5152-83. 15. Cheng F, Zhong H, Huang Z, Li Z. Up-to-date metaanalysis of long-term evaluations of mesenchymal stem cell therapy for complex perianal fistula. World J Stem Cells. 2023;15(8):866-75. Publisher's Note: Unico's Medicine remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 61 JCTEI