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574 Background: To evaluate how the location of bladder cancer recurrence after radical cystectomy (RC) affects survival and assess the role of salvage immunotherapy in this setting. Methods: On retrospective review of 4093 patients from our institutional IRB approved cystectomy database from January 1971 to December 2021, we identified 889 patients who underwent RC with curative intent and have been detected with recurrence of bladder cancer. Patients with urethral and ureteral recurrence were excluded. The data was then stratified based on the site of recurrence. Results: In this cohort of 889 patients (median age of 68, 77% male), the most common sites of metastases were widespread (48%), local (15%), lung (10%), bone (8%), retroperitoneal nodes (5.5%), liver (5%) and brain (1.5%) in order. With a median of 8.4 months, bone metastasis had shortest length from cystectomy to recurrence, while liver metastasis had shortest post recurrence survival (median of 4 months). For distant recurrence alone, only 33% survived past the first year. Salvage immunotherapy was administered in 8% of the patients and 47% received salvage chemotherapy. On multivariate analysis, liver metastasis (HR 2, 95%CI 1.4-2.9), widespread metastasis (HR 1.9, 95%CI 1.5-2.4), pathological staging>T3 (HR 1.3, 95%CI 1.1-1.6) and nodal involvement at the time of RC (HR 1.5, 95%CI 1.2-1.7) were significantly associated with worse survival after the recurrence. Salvage immunotherapy provided a significant improvement in post-recurrence survival (HR 0.2, 95% CI 0.1-0.3). Conclusions: Liver, brain, and widespread metastases predominantly showed the lowest chance of survival past one year from recurrence; however, more than half of all patients with recurrence did not live past the first year. Salvage immunotherapy may lead to a better prognosis in recurrence post-cystectomy. [Table: see text]

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a “two-bottle” as well as a “drinking in the dark” paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.