Serious immune-related upper gastrointestinal toxicity of immune checkpoint inhibitors: a multicenter case series.

BACKGROUND: Immune checkpoint inhibitors (ICI) improve the prognosis of many cancers but cause immune-related adverse events (IrAEs). Limited data are available on upper gastrointestinal (UGI) IrAEs. We describe the clinical characteristics, prognosis, and efficacy of medical therapy in patients with UGI IrAEs. METHODS: This is a retrospective, multicenter cohort study of patients with UGI symptoms and moderate to severe endoscopic UGI lesions, occurring after ICI. Efficacy of induction medical therapy and at the most recent follow-up was assessed. RESULTS: Forty patients were included; of these, 34 (85%) received anti-PD(L)1, either alone (n = 24) or combined with anti CTLA-4 (n = 10). Eighteen patients (45%) had concomitant enterocolitis. All patients had severe endoscopic lesions (erosions, ulcerations, hemorrhage, or necrotic lesions). Three patients who received an inefficient initial medical treatment had a complicated course: One patient died of enterocolitis, one had a pneumomediastinum, and one developed an ulcerated stricture of the pylorus. Thirty-five patients (88%) were treated with corticosteroids; 28 patients (80%) responded, and 20 (57%) reached clinical remission. Eight patients were treated with infliximab, and six responded (75%). After a median follow-up of 11 months, 36 patients (90%) were in corticosteroid-free clinical remission for their UGI symptoms. Endoscopic lesions persisted in 68% of patients. CONCLUSIONS: ICI cause severe UGI IrAEs, which are associated with enterocolitis in approximately half of the patients. Most patients with UGI IrAEs respond to corticosteroids or infliximab. These data support the recommendation to treat these patients without delay and in the same way as those with enterocolitis.

Revisiting medial preoptic area plasticity induced in male mice by sexual experience.

Sexual experience in male rodents, induced by a first exposure to a receptive female, improves efficiency of following copulations. In mice, the mechanisms supporting this improvement are poorly understood. We characterized molecular modifications of the mouse hypothalamic medial preoptic area (mPOA), the main integrative structure for male sexual behaviour, after a single mating event. This paradigm induced long-lasting behavioural improvements and mPOA morphological changes, evidenced by dendritic spine maturation and an increase in the acetylated and tri-methylated forms of histone H3. Ejaculation affected testosterone, progesterone and corticosterone levels in both naive and experienced mice, but sexual experience did not modify basal plasma or hypothalamic levels of steroids. In contrast to studies carried out in rats, no changes were observed, either in the nitrergic system, or in sex steroid receptor levels. However, levels of glutamate- and calcium-associated proteins, including PSD-95, calbindin and the GluN1 subunit of the NMDA receptor, were increased in sexually experienced male mice. The Iba-1 microglial marker was up-regulated in these animals suggesting multicellular interactions induced within the mPOA by sexual experience. In conclusion, plasticity mechanisms induced by sexual experience differ between rat and mouse, even if in both cases they converge to potentiation of the mPOA network.