Adding a second endoscopic therapy to epinephrine injection might improve hemostatic efficacy in patients with high-risk bleeding ulcers but the optimum modality remains unknown. We aimed to estimate the comparative efficacy of different dual endoscopic therapies for the management of bleeding peptic ulcers through random-effects Bayesian network meta-analysis. Different databases were searched for controlled trials comparing dual therapy versus epinephrine monotherapy or epinephrine combined with another second modality until September, 30 2016. We estimated the ORs for rebleeding, surgery and mortality among different treatments. Adverse events were also evaluated. Seventeen eligible articles were included in the network meta-analysis. The addition of mechanical therapy (OR 0.19, 95% CrI 0.07–0.52 and OR 0.10, 95% CrI 0.01–0.50, respectively) after epinephrine injection significantly reduced the probability of rebleeding and surgery. Similarly, patients who received epinephrine plus thermal therapy showed a significantly decreased rebleeding rate (OR 0.30, 95% CrI 0.10–0.91), as well as a non-significant reduction in surgery (OR 0.47, 95% CrI 0.16–1.20). Although differing, epinephrine plus mechanical therapy did not provide a significant reduction in rebleeding (OR 0.62, 95% CrI 0.19–2.22) and surgery (OR 0.21, 95% CrI 0.03–1.73) compared to epinephrine plus thermal therapy. Sclerosant failed to confer further benefits and was ranked highest among the 5 treatments in relation to adverse events. Mechanical therapy was the most appropriate modality to add to epinephrine injection. Epinephrine plus thermal coagulation was effective for controlling high risk bleeding ulcers. There was no further benefit with sclerosants with regard to rebleeding or surgery, and sclerosants were also associated with more adverse events than any other modality.

Background: Immune checkpoint blockade (ICB) therapy demonstrates significant efficacy across multiple malignancies, yet resistance remains prevalent. Recent studies have repositioned the clinically approved antiepileptic drug stiripentol (STP) as a potent lactate dehydrogenase A inhibitor that effectively disrupts tumor metabolic reprogramming, thereby reinstating tumor control. Despite its promising antineoplastic activity, the direct impact of STP on immune cells and its potential synergy with anti-PD-1 antibodies remain unexplored. Methods: We used an orthotopic 4T1 breast cancer model to evaluate whether STP remodels the immunosuppressive tumor microenvironment and enhances anti-PD-1 efficacy. Tumor growth was monitored, and immune cell profiles in tumors and blood were analyzed by flow cytometry. Lactate levels and chemokine expression in tumor tissue were also assessed. In vitro, the effects of STP on 4T1 cell proliferation and lactate secretion, bone marrow-derived myeloid-derived suppressor cell (MDSC) differentiation and suppressive function, and macrophage polarization were evaluated. Results: The combination of STP and anti-PD-1 synergistically suppressed 4T1 tumor growth, reduced the infiltration of immunosuppressive MDSCs and M2-like tumor-associated macrophages, and reactivated CD8⁺ T cells. STP inhibited 4T1 cell proliferation and lactate secretion in a concentration-dependent manner. Furthermore, STP directly reprogrammed MDSCs by inducing MHC II⁺ cell differentiation and attenuating their T cell suppressive capacity via downregulation of immunosuppressive genes. STP also drove M2-to-M1 macrophage repolarization. Importantly, STP exhibited no direct T cell-activating effects. Conclusions: Our work establishes STP as a potent remodeler of the immunosuppressive tumor microenvironment that synergizes with anti-PD-1 therapy, providing a novel strategy to overcome ICB resistance.