337 Summary, general discussion and future perspectives work revealed that intraperitoneal administration of a supramolecular hydrogel loaded with mitomycin (MMC) resulted in extended peritoneal exposure and led to a clinically significant improvement in survival compared to treatment with just free MMC in rats with colorectal PM 93. Therefore, our research team believed it was interesting to see if such a minimal invasive treatment is safe to use during colorectal surgery after primary resection of (e.g. BRAF-mutated) tumors as a preventive intervention. Chapter 13 assessed the impact of intraperitoneal hydrogel administration in a colorectal surgery setting, especially on anastomotic healing. Forty-two healthy Wistar rats underwent a colonic end-to-end anastomosis, with subsequent intraperitoneal injections administered to 6 animals with saline, 18 with unloaded hydrogel, and 18 with mitomycin (MMC)-loaded hydrogel. After a 7-day period, the animals were euthanized, and primary outcomes, including anastomotic adhesion and leakage scores, were measured. Secondary outcomes encompassed bursting pressure, histological anastomosis evaluation, and changes in body weight. Twenty-two rats completed the follow-up (saline: n = 6, unloaded hydrogel: n = 10, MMC-loaded hydrogel: n = 6) and were included in the analysis. After multiple-comparison correction, a trend toward significance was observed for the AL score between rats receiving saline and those receiving unloaded hydrogel (p = 0.020, α = 0.0167). However, no significant differences were noted for all other outcomes. The primary reason for drop-out in this study was intestinal blood loss (n = 16), which only occurred in intervention animals. While the preliminary results suggest that MMC-loaded or unloaded hydrogel may not affect anastomotic healing, the observed intestinal blood loss in a substantial number of animals receiving both types of hydrogel indicates that the injection of the hydrogel under the studied conditions is not safe in the current rodent model. This underscores the need for further optimization of the hydrogel before it can be considered as a preventive strategy. The promising results of applying a cytostatic loaded supramolecular hydrogel as a minimal invasive preventive treatment, turned out to be disappointing in chapter 13. Besides, as the strength of a good clinical biomarker lies in its ability to accurately and reliably predict a particular biological or clinical outcome, which is metachronous peritoneal spread in this case, the evidence found in chapter 11 and 12 is not strong enough to guide personalized therapeutic interventions that are more invasive. As we cannot offer the patients any treatment options, standard clinical screening for BRAF mutations in all primary colorectal tumors might feel too early. On the other hand, a stricter follow-up in this population may be clinically beneficial. While current international guidelines recommend the first follow-up CT scan 12 months after primary surgery, a BRAF-mutated population may warrant earlier imaging and increased clinical monitoring for PM development. Prospective research, including validation of BRAF mutations in relation to metachronous PM development, particularly through methods like liquid biopsies, is essential to support this proposal. Additionally, future research should focus on minimal invasive preventive strategies, whether it is optimizing the drug delivery system in our study or new innovations. 14
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