Ischemia reperfusion injury (IRI) is a form of sterile inflammation whose severity determines short- and long-term graft fates in kidney transplantation. Neutrophils are now recognized as a key cell type mediating early graft injury, which activates further innate immune responses and intensifies acquired immunity and alloimmunity. Since the macrolide Bryostatin-1 has been shown to block neutrophil transmigration, we aimed to determine whether these findings could be translated to the field of kidney transplantation. To study the effects of Bryostatin-1 on ischemia-elicited neutrophil transmigration, an in vitro model of hypoxia and normoxia was equipped with human endothelial cells and neutrophils. To translate these findings, a porcine renal autotransplantation model with eight hours of reperfusion was used to study neutrophil infiltration in vivo. Graft-specific treatment using Bryostatin-1 (100 nM) was applied during static cold storage. Bryostatin-1 dose-dependently blocked neutrophil activation and transmigration over ischemically challenged endothelial cell monolayers. When applied to porcine renal autografts, Bryostatin-1 reduced neutrophil graft infiltration, attenuated histological and ultrastructural damage, and improved renal function. Our novel findings demonstrate that Bryostatin-1 is a promising pharmacological candidate for graft-specific treatment in kidney transplantation, as it provides protection by blocking neutrophil infiltration and attenuating functional graft injury.
Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study was to evaluate whether preoperative assessment of molecular subtype as well as FGFR target gene expression is predictive for therapeutic outcome—rate of ypT0 status—to justify subsequent prospective validation within the “BladderBRIDGister”. Formalin-fixed paraffin-embedded (FFPE) tissue specimens from transurethral bladder tumor resections (TUR) prior to neoadjuvant chemotherapy and corresponding radical cystectomy samples after chemotherapy of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, Relative gene expression of subtyping markers (e.g., KRT5, KRT20) and target genes (FGFR1, FGFR3) was analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, Kruskal–Wallis, Mann–Whitney and sensitivity/specificity tests were performed by JMP 9.0.0 (SAS software). The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being node-negative during radical cystectomy after 1 to 4 cycles of NAC. When comparing pretreatment with post-treatment samples, the median expression of KRT20 dropped most significantly from DCT 37.38 to 30.65, which compares with a 128-fold decrease. The reduction in gene expression was modest for other luminal marker genes (GATA3 6.8-fold, ERBB2 6.3-fold). In contrast, FGFR1 mRNA expression increased from 33.28 to 35.88 (~6.8-fold increase). Spearman correlation revealed positive association of pretreatment KRT20 mRNA levels with achieving pCR (r = 0.3072: p = 0.0684), whereas pretreatment FGFR1 mRNA was associated with resistance to chemotherapy (r = −0.6418: p < 0.0001). Hierarchical clustering identified luminal tumors of high KRT20 mRNA expression being associated with high pCR rate (10/16; 63%), while the double-negative subgroup with high FGFR1 expression did not respond with pCR (0/9; 0%). Molecular subtyping distinguishes patients with high probability of response from tumors as resistant to neoadjuvant chemotherapy. Targeting FGFR1 in less-differentiated bladder cancer subgroups may sensitize tumors for adopted treatments or subsequent chemotherapy.
Purpose of reviewLocal treatment in oligometastatic prostate cancer patients is associated with improved survival. Nevertheless, in term of surgery, cytoreductive radical prostatectomy has no level of evidence 1 and is an individual treatment approach. We reviewed the recent literature to highlight parameters for selecting patients for a surgical approach. Recent findingsRetrospective data on oncologic outcome for cytoreductive prostatectomy are confirmed. We identified several parameters that help to select patients for surgery. Patients with a favorable prostate-specific antigen (PSA) decline after androgen deprivation therapy (ADT) have excellent oncologic long-term control. Circulating tumor cells (CTC's) are frequently analyzed in more advanced prostate cancer. In case of C-reactive protein (CRP) at least a longer interval to develop castration resistant prostate cancer (CRPC) is shown in case of low CTC count at time of surgery. Nutrition status analyzed as the hemoglobin, albumin, lymphocyte, and platelet (HALP)-score is of significant value in demonstrating an effect of CRP.
Background: Accurate staging and identification of optimal candidates for local salvage therapy, such as salvage radical prostatectomy (SRP), is necessary to ensure optimal care in patients with radiorecurrent prostate cancer (PCa). We aimed to analyze performance of magnetic resonance imaging (MRI) and prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)/computed tomography (CT) for predicting pathologic nonorgan confined disease (pT3) and lymph node involvement (pN+) in patients treated with SRP for radiorecurrent PCa. Methods:We retrospectively reviewed the institutional database to identify patients who underwent MRI or 68 Ga-PSMA-PET/CT before SRP for radiorecurrent PCa. The diagnostic estimates of MRI and PSMA-PET/CT for pT3 and pN+, were calculated. Results:We identified 113 patients with radiorecurrent PCa who underwent preoperative MRI followed by SRP; 53 had preoperative 68 Ga-PSMA-PET/CT. For the detection of pT3 disease, the overall accuracy of MRI was 70% (95% confidence interval[CI] 61−78), sensitivity 40% (95% CI 26−55) and specificity 94% (95% CI 85−98); PSMA-PET/CT had slightly higher accuracy of 77% (95% CI 64−88), and higher sensitivity of 90% (95% CI 68−99), but lower specificity of 70% (95% CI 51−84). For pN+ disease, MRI had poor sensitivity of 14% (95% CI 3−36), specificity of 50 (95% CI 39−61) and total accuracy of 43% (95% CI 34−53); PSMA-PET/CT had an accuracy of 85% (95% CI 72−93), sensitivity of 27% (95% CI 6−61), and specificity of 100% (95% CI 92−100). Conclusion:In patients with radiorecurrent PCa, both, MRI, and 68 Ga-PSMA PET/CT are valuable tools for the pre-SRP staging and should be integrated into the standard workup.For lymph node metastases, 68 Ga-PSMA PET/CT is a strong rule-in test with nearly perfect specificity; in contrast MRI had a low accuracy for lymph node metastases.
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