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Background: Acute and chronic pre-traumatic cigarette smoke exposure increases morbidity and mortality after trauma and hemorrhage. In mice with a genetic deletion of the H2S-producing enzyme cystathione-γ-lyase (CSE−/−), providing exogenous H2S using sodium thiosulfate (Na2S2O3) improved organ function after chest trauma and hemorrhagic shock. Therefore, we evaluated the effect of Na2S2O3 during resuscitation from blunt chest trauma and hemorrhagic shock on CSE−/− mice with pre-traumatic cigarette smoke (CS) exposure. Since H2S is well established as being able to modify energy metabolism, a specific focus was placed on whole-body metabolic pathways and mitochondrial respiratory activity. Methods: Following CS exposure, the CSE−/− mice underwent anesthesia, surgical instrumentation, blunt chest trauma, hemorrhagic shock for over 1 h (target mean arterial pressure (MAP) ≈ 35 ± 5 mmHg), and resuscitation for up to 8 h comprising lung-protective mechanical ventilation, the re-transfusion of shed blood, fluid resuscitation, and continuous i.v. noradrenaline (NoA) to maintain an MAP ≥ 55 mmHg. At the start of the resuscitation, the mice randomly received either i.v. Na2S2O3 (0.45 mg/gbodyweight; n = 14) or the vehicle (NaCl 0.9%; n = 11). In addition to the hemodynamics, lung mechanics, gas exchange, acid–base status, and organ function, we quantified the parameters of carbohydrate, lipid, and protein metabolism using a primed continuous infusion of stable, non-radioactive, isotope-labeled substrates (gas chromatography/mass spectrometry) and the post-mortem tissue mitochondrial respiratory activity (“high-resolution respirometry”). Results: While the hemodynamics and NoA infusion rates did not differ, Na2S2O3 was associated with a trend towards lower static lung compliance (p = 0.071) and arterial PO2 (p = 0.089) at the end of the experiment. The direct, aerobic glucose oxidation rate was higher (p = 0.041) in the Na2S2O3-treated mice, which resulted in lower glycemia levels (p = 0.050) and a higher whole-body CO2 production rate (p = 0.065). The mitochondrial respiration in the heart, kidney, and liver tissue did not differ. While the kidney function was comparable, the Na2S2O3-treated mice showed a trend towards a shorter survival time (p = 0.068). Conclusions: During resuscitation from blunt chest trauma and hemorrhagic shock in CSE−/− mice with pre-traumatic CS exposure, Na2S2O3 was associated with increased direct, aerobic glucose oxidation, suggesting a switch in energy metabolism towards preferential carbohydrate utilization. Nevertheless, treatment with Na2S2O3 coincided with a trend towards worsened lung mechanics and gas exchange, and, ultimately, shorter survival.

Background: A biochemical recurrence (BCR) risk model was created based on pretest prostate specific antigen (PSA) and groupings by restaging prostate specific membrane antigen (PSMA) PET/CT. Methods: A cohort of 1216 BCR patients were analyzed for overall survival (OS) according to the PSA threshold and restaging PSMA PET/CT. A Cox regression analysis of OS was carried out to detect significant clinical characteristics. Results: In the cohort, 271 patients had a pretest PSA of 5 positive sites. In the Cox regression analysis, four variables significantly predicted OS: treatment center, International Society of Urologic Pathology (ISUP) grade, pretest PSA threshold, and the grouping of positive sites on the restaging PSMA PET/CT. Conclusions: The pretest PSA and PSMA PET/CT were important for the OS of the BCR patients. The findings argue for the new BCR risk model and serve as framework for ongoing trials.

In this systematic review and network meta-analysis (NMA), we aimed to assess the benefits and harms of third-line (L3) treatments in randomized controlled trials (RCTs) of patients with metastatic castration-resistant prostate cancer (mCRPC). Two reviewers searched for publications from 1 January 2006 to 30 June 2021. The review analyzed seven RCTs that included 3958 patients and eight treatments. Treatment with prostate-specific membrane antigen (PSMA)-based radioligand therapy (PRLT) resulted in a 1.3-times-higher rate of median PSA decline ≥50% than treatment with abiraterone, enzalutamide, mitoxantrone, or cabazitaxel (p = 0.00001). The likelihood was 97.6% for PRLT to bring about the best PSA response, out of the examined treatments. PRLT resulted in a 1.1-times-higher six-month rate of median radiographic progression-free survival. Treatment with PRLT in the VISION trial resulted in 1.05-times-higher twelve-month median overall survival than L3 treatment with cabazitaxel in other RCTs. PRLT more often resulted in severe thrombocytopenia and less often in severe leukopenia than did cabazitaxel. In conclusion, for patients with mCRPC, L3 treatment with PRLT is highly effective and safe.