Intestinal mucosal barrier dysfunction caused by disease and/or chemotherapy lacks an effective treatment, which highlights a strong medical need. Our group has previously demonstrated the potential of melatonin and misoprostol to treat increases in intestinal mucosal permeability induced by 15-min luminal exposure to a surfactant, sodium dodecyl sulfate (SDS). However, it is not known which luminal melatonin and misoprostol concentrations are effective, and whether they are effective for a longer SDS exposure time. The objective of this single-pass intestinal perfusion study in rats was to investigate the concentration-dependent effect of melatonin and misoprostol on an increase in intestinal permeability induced by 60-min luminal SDS exposure. The cytoprotective effect was investigated by evaluating the intestinal clearance of 51Cr-labeled EDTA in response to luminal SDS as well as a histological evaluation of the exposed tissue. Melatonin at both 10 and 100 µM reduced SDS-induced increase in permeability by 50%. Misoprostol at 1 and 10 µM reduced the permeability by 50 and 75%, respectively. Combination of the two drugs at their respective highest concentrations had no additive protective effect. These in vivo results support further investigations of melatonin and misoprostol for oral treatments of a dysfunctional intestinal barrier.

Background: Colorectal signet ring cell (SRC) carcinoma with ≥50% SRCs (SRC ≥ 50) has a poor prognosis, but the prognostic role of SRCs < 50% (SRC < 50) is unclear. The aim of this study was to provide a clinicopathological characterization of SRC colorectal and appendiceal tumours and analyse the importance of the SRC component size. Methods: All patients in the Swedish Colorectal Cancer Registry diagnosed with colorectal or appendiceal cancer in 2009–2020 at Uppsala University Hospital, Sweden, were included. The SRCs were verified, and the components estimated by a gastrointestinal pathologist. Results: Of the 2229 colorectal cancers, 51 (2.3%) had SRCs, with a median component size of 30% (interquartile range of 12.5–40) and 10 (0.45%) had SRC ≥ 50. The SRC tumours were primarily localized in the right colon (59%) and appendix (16%). No patients with SRCs had stage I disease, and 26 (51%) had stage IV, of whom, 18 (69%) had peritoneal metastases. The SRC tumours were often high grade with perineural and vascular invasion. The 5-year overall survival (OS) rate for patients with SRC ≥ 50 were 20% (95% confidence interval (CI) 6–70), for SRC < 50, 39% (95% CI 24–61); and for non-SRCs, 55% (95% CI 55–60). Among the patients with SRC < 50 and <50% extracellular mucin, the 5-year OS was 34% (95% CI 19–61), while those with ≥50% extracellular mucin had an OS of 50% (95% CI 25–99). The 5-year recurrence-free survival rates were 51% (95% CI 13–83) for patients with SRC tumours, as compared to 83% (95% CI 77–89) and 81% (95% CI 79–84) for mucinous and non-mucinous adenocarcinoma, respectively. Conclusions: The presence of SRCs was strongly associated with aggressive clinicopathological features, peritoneal metastases, and poor prognosis, also when they make up <50% of a tumour.