Severe AKI is often associated with multiorgan dysfunction, but the mechanisms of this remote tissue injury are unknown. We hypothesized that renal necroinflammation releases cytotoxic molecules that may cause remote organ damage. In hypoxia-induced tubular epithelial cell necrosis , histone secretion from ischemic tubular cells primed neutrophils to form neutrophil extracellular traps. These traps induced tubular epithelial cell death and stimulated neutrophil extracellular trap formation in fresh neutrophils., ischemia-reperfusion injury in the mouse kidney induced tubular necrosis, which preceded the expansion of localized and circulating neutrophil extracellular traps and the increased expression of inflammatory and injury-related genes. Pretreatment with inhibitors of neutrophil extracellular trap formation reduced kidney injury. Dual inhibition of neutrophil trap formation and tubular cell necrosis had an additive protective effect. Moreover, pretreatment with antihistone IgG suppressed ischemia-induced neutrophil extracellular trap formation and renal injury. Renal ischemic injury also increased the levels of circulating histones, and we detected neutrophil infiltration and TUNEL-positive cells in the lungs, liver, brain, and heart along with neutrophil extracellular trap accumulation in the lungs. Inhibition of neutrophil extracellular trap formation or of circulating histones reduced these effects as well. These data suggest that tubular necrosis and neutrophil extracellular trap formation accelerate kidney damage and remote organ dysfunction through cytokine and histone release and identify novel molecular targets to limit renal necroinflammation and multiorgan failure.

OBJECTIVE: The aim of this study was to evaluate clinical features associated with benign histopathology of Prostate Imaging Reporting and Data System (PI-RADS) category 4 and 5 lesions. MATERIALS AND METHODS: Between March 2015 and November 2020, 1161 patients underwent mpMRI/Ultrasound-fusion-guided prostate biopsy (FBx) and concurrent 12-core systematic prostate biopsy (SBx) at the Department of Urology of the Ludwig-Maximilians-University of Munich, Germany. 848/ 1161 (73%) patients presented with either PI-RADS 4 or 5 index lesion and were retrospectively evaluated. Multivariate analysis was performed to evaluate clinical parameters associated with a negative outcome of PI-RADS 4 or 5 category lesions after FBx. Area under the receiver operating characteristics (ROC) curve (AUC) was conducted using ROC-analysis. RESULTS: 676/848 (79.7%) patients with either PI-RADS 4 or 5 index lesion were diagnosed with prostate cancer (PCa) by FBx and 172/848 (20.3%) patients had a negative biopsy (including the concurrent systematic prostate biopsy), respectively. Prostate volume (P-Vol) (OR 0.99, 95% CI = 0.98–1.00, p = 0.038), pre-biopsy-status (OR 0.48, 95% CI = 0.29–0.79, p = 0.004) and localization of the lesion in the transitional zone (OR 0.28, 95% CI = 0.13–0.60, p = 0.001) were independent risk factors for a negative outcome of FBx. Age (OR 1.09, 95% CI = 1.05–1.13, p < 0.001) and PSA density (PSAD) (OR 75.92, 95% CI = 1.03–5584.61, p = 0.048) increased the risk for PCa diagnosis after FBx. The multivariate logistic regression model combining all clinical characteristics achieved an AUC of 0.802 (95% CI = 0.765–0.835; p < 0.001) with a sensitivity and specificity of 66% and 85%. CONCLUSION: Lesions with high or highly likelihood of PCa on multiparametric magnetic resonance imaging (mpMRI) but subsequent negative prostate biopsy occur in a small amount of patients. Localization of the lesion in the transitional zone, prostate volume and prebiopsy were shown to be predictors for benign histopathology of category 4 or 5 lesions on mpMRI. Integration of these features into daily clinical routine could be used for risk-stratification of these patients after negative biopsy of PI-RADS 4 or 5 index lesions.

Multiparametric magnetic resonance imaging and multiparametric magnetic resonance imaging-guided biopsy in the diagnostic pathway of prostate cancer Abstract Multiparametric magnetic resonance imaging (mpMRI) of the prostate and mpMRI-guided biopsy have proved to be a valuable part of the diagnostic pathway for prostate cancer. This review reports on the current results in terms of clinical performance of these diagnostic tools and their role in clinical decision-making. Keywords Imaging • Prostatectomy • PI-RADS classification • Tissue • Clinical decisionmaking Multiparametrische Magnetresonanztomographie (mpMRT) und mpMRTgesteuerte Biopsie bei der Diagnostik des Prostatakarzinoms Zusammenfassung Die multiparametrische Magnetresonanztomographie (mpMRT) der Prostata und die mpMRT-gesteuerte Biopsie sind ein wichtiger Bestandteil der Diagnostik des Prostatakarzinoms. In dieser Übersichtsarbeit berichten wir über die aktuelle Studienlage zur klinischen Anwendung dieser diagnostischen Mittel und bewerten deren Stellenwert in der klinischen Entscheidungsfindung.

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RESULTS: MET mutations were associated with improved response to anti-VEGF therapy (50% vs 9%, p<.05). PBRM1 mutations and lack of BAP1 mutations were associated with improved TTF on anti-VEGF therapy; (12 vs 6.9 months, p[.01) and (11.0 vs 6.4 months, p[.01), respectively. Mutations in the mTOR pathway (TSC1, TSC2, MTOR) were associated with improved response to mTOR inhibitors (p[.06). TERT promoter mutations may be predictive of resistance to ICI, as one study found TERT promoter mutations to be enriched in patients with no clinical benefit in the ICI cohort (p[0.038). PBRM-1 LOF mutations were associated with increased RTT in patients receiving nivolumab monotherapy (p[.012), but decreased RTT in patients receiving atezolizumab monotherapy (p[.04). PBRM-1 LOF also was associated with improved TTF in patients receiving some anti-VEGF therapies (12 vs 6.9 months, p[.01), but not in patients receiving everolimus, sunitinib, or combination therapy (p>.05). Tumor mutational burden has not been associated with differential response to targeted, ICI, or combination therapy (p>.05).CONCLUSIONS: Mutations in MET, PBRM-1, BAP1 and the mTOR pathway may be associated with improved response to VEGF targeted therapies. Mutations in the TERT promoter may be associated with improved response to ICI, while PBRM-1 LOF shows promise for predicting response to specific ICI regimens. Very limited data exist regarding the predictive value of all biomarkers, with further study required to personalize treatment regimens.