RESUMO
BACKGROUND: Sodium level is an important clinical predictor of complex biliary disease. Hyponatremia has been observed in conjunction with biliary disease, however the nature of this association remains unclear. AIM: To investigate the association between serum sodium and severe biliary disease. METHODS: Of 920 patients with gallstone disease treated at the SFVA Hospital from 1989-2019 were studied. We conducted multivariate analyses of correlation between sodium level and biliary disease severity, the presence/location of biliary bacteria, and other factors. Minimum sodium level pre-intervention was collected. Gallstones, bile, and blood (as relevant) were cultured. Illness severity was characterized: (1) None (no infectious manifestations); (2) Systemic inflammatory response syndrome; (3) Severe illness (gangrenous cholecystitis, cholangitis, necrotizing pancreatitis); and (4) Multiple organ dysfunction syndrome (bacteremia, hypotension, organ failure). Comorbidity was defined using the Charlson Comorbidity Index (CCI). RESULTS: Decreased sodium level significantly correlated with worsening illness severity, ascending bacterial infection, gangrenous changes, elevated CCI score, increasing age, male sex, and glucose. On multivariate analysis, all factors, except age, gender and glucose, independently correlated with sodium level and factors were additive. CONCLUSION: This unique study is the first to explore, with such granularity, the relationship between biliary disease and sodium. No prior studies have examined specific culture and clinical data. It illustrates an inverse, independent correlation between illness severity and sodium. Culture data demonstrate that sodium decreases as infection ascends from gallstone colonization to bactibilia to bacteremia. Patient comorbidity and gangrenous changes also independently correlate with sodium on multivariate analysis. Sodium level is an important clinical indicator of disease severity for patients with biliary disease.
RESUMO
BACKGROUND: Immunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not been evaluated when initiated before primary tumor removal. Using a surgical mouse model of human NB, we examined if initiating dinutuximab plus ex vivo-activated natural killer (aNK) cells before resection of the primary tumor improves survival. METHODS: In vitro, human NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc) were treated with dinutuximab and/or aNK cells and cytotoxicity was measured. In vivo, NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc, or COG-N-415x PDX) were injected into the kidney of NOD-scid gamma mice. Mice received eight intravenous infusions of aNK cells plus dinutuximab beginning either 12 days before or 2 days after resection of primary tumors. Tumors in control mice were treated by resection alone or with immunotherapy alone. Disease was quantified by bioluminescent imaging and survival was monitored. aNK cell infiltration into primary tumors was quantified by flow cytometry and immunohistochemistry at varying timepoints. RESULTS: In vitro, aNK cells and dinutuximab were more cytotoxic than either treatment alone. In vivo, treatment with aNK cells plus dinutuximab prior to resection of the primary tumor was most effective in limiting metastatic disease and prolonging survival. aNK cell infiltration into xenograft tumors was observed after 1 day and peaked at 5 days following injection. CONCLUSION: Dinutuximab plus aNK cell immunotherapy initiated before resection of primary tumors decreases disease burden and prolongs survival in an experimental mouse model of NB. These findings support the clinical investigation of this treatment strategy during induction therapy in patients with high-risk NB.