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Purpose: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).
Methods: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.
Results: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.
Conclusions: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI–TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.
Bacterial porin disrupts mitochondrial membrane potential and sensitizes host cells to apoptosis
(2009)
The bacterial PorB porin, an ATP-binding beta-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (delta psi m). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of beta-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of delta psi m. The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce delta psi m loss and apoptosis, demonstrating that dissipation of delta psi m is a requirement for cell death caused by neisserial infection.
Background: To compare severe infectious complication rates after transrectal prostate biopsies between cephalosporins and fluoroquinolones for antibiotic monoprophylaxis.
Material and Methods: In the multi-institutional cohort, between November 2014 and July 2020 patients received either cefotaxime (single dose intravenously), cefpodoxime (multiple doses orally) or fluoroquinolones (multiple-doses orally or single dose intravenously) for transrectal prostate biopsy prophylaxis. Data were prospectively acquired and retrospectively analyzed. Severe infectious complications were evaluated within 30 days after biopsy. Logistic regression models predicted biopsy-related infectious complications according to antibiotic prophylaxis, application type and patient- and procedure-related risk factors.
Results: Of 793 patients, 132 (16.6%) received a single dose of intravenous cefotaxime and were compared to 119 (15%) who received multiple doses of oral cefpodoxime and 542 (68.3%) who received fluoroquinolones as monoprophylaxis. The overall incidence of severe infectious complications was 1.0% (n=8). No significant differences were observed between the three compared groups (0.8% vs. 0.8% vs. 1.1%, p=0.9). The overall rate of urosepsis was 0.3% and did not significantly differ between the three compared groups as well.
Conclusion: Monoprophylaxis with third generation cephalosporins was efficient in preventing severe infectious complications after prostate biopsy. Single intravenous dose of cefotaxime and multiday regimen of oral cefpodoxime showed a low incidence of infectious complications <1%. No differences were observed in comparison to fluoroquinolones.
Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34+-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3+, CD3+CD4+, and CD3+CD8+ T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34+-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3+CD4+ helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34+-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.
After myocardial infarction in the adult heart the remaining, non-infarcted tissue adapts to compensate the loss of functional tissue. This adaptation requires changes in gene expression networks, which are mostly controlled by transcription regulating proteins. Long non-coding transcripts (lncRNAs) are now recognized for taking part in fine-tuning such gene programs. We identified and characterized the cardiomyocyte specific lncRNA Sweetheart RNA (Swhtr), an approximately 10 kb long transcript divergently expressed from the cardiac core transcription factor coding gene Nkx2-5. We show that Swhtr is dispensable for normal heart development and function, but becomes essential for the tissue adaptation process after myocardial infarction. Re-expressing Swhtr from an exogenous locus rescues the Swhtr null phenotype. Genes depending on Swhtr after cardiac stress are significantly occupied, and therefore most likely regulated by NKX2-5. Our results indicate a synergistic role for Swhtr and the developmentally essential transcription factor NKX2-5 in tissue adaptation after myocardial injury.
Background: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. Methods: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. Results: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict “survival”. Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients’ age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. Conclusions: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration “ClinicalTrials” (clinicaltrials.gov) under NCT04455451.
Background: The development of robotic systems has provided an alternative to frame-based stereotactic procedures. The aim of this experimental phantom study was to compare the mechanical accuracy of the Robotic Surgery Assistant (ROSA) and the Leksell stereotactic frame by reducing clinical and procedural factors to a minimum.
Methods: To precisely compare mechanical accuracy, a stereotactic system was chosen as reference for both methods. A thin layer CT scan with an acrylic phantom fixed to the frame and a localizer enabling the software to recognize the coordinate system was performed. For each of the five phantom targets, two different trajectories were planned, resulting in 10 trajectories. A series of five repetitions was performed, each time based on a new CT scan. Hence, 50 trajectories were analyzed for each method. X-rays of the final cannula position were fused with the planning data. The coordinates of the target point and the endpoint of the robot- or frame-guided probe were visually determined using the robotic software. The target point error (TPE) was calculated applying the Euclidian distance. The depth deviation along the trajectory and the lateral deviation were separately calculated.
Results: Robotics was significantly more accurate, with an arithmetic TPE mean of 0.53 mm (95% CI 0.41–0.55 mm) compared to 0.72 mm (95% CI 0.63–0.8 mm) in stereotaxy (p < 0.05). In robotics, the mean depth deviation along the trajectory was −0.22 mm (95% CI −0.25 to −0.14 mm). The mean lateral deviation was 0.43 mm (95% CI 0.32–0.49 mm). In frame-based stereotaxy, the mean depth deviation amounted to −0.20 mm (95% CI −0.26 to −0.14 mm), the mean lateral deviation to 0.65 mm (95% CI 0.55–0.74 mm).
Conclusion: Both the robotic and frame-based approach proved accurate. The robotic procedure showed significantly higher accuracy. For both methods, procedural factors occurring during surgery might have a more relevant impact on overall accuracy.
Background: IL28B gene polymorphism is the best baseline predictor of response to interferon alfa-based antiviral therapies in chronic hepatitis C. Recently, a new IFN-L4 polymorphism was identified as first potential functional variant for induction of IL28B expression. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources.
Methods: Optimization of treatment outcome prediction was assessed by combination of different IL28B and IFN-L4 polymorphisms in patients with chronic HCV genotype 1 (n = 385), 2/3 (n = 267), and 4 (n = 220) infection treated with pegylated interferon alfa (PEG-IFN) and ribavirin with (n = 79) or without telaprevir. Healthy people from Germany (n = 283) and Egypt (n = 96) served as controls.
Results: Frequencies of beneficial IL28B rs12979860 C/C genotypes were lower in HCV genotype 1/4 infected patients in comparison to controls (20–35% vs. 46–47%) this was also true for ss469415590 TT/TT (20–35% vs. 45–47%). Single interferon-lambda SNPs (rs12979860, rs8099917, ss469415590) correlated with sustained virologic response (SVR) in genotype 1, 3, and 4 infected patients while no association was observed for genotype 2. Interestingly, in genotype 3 infected patients, best SVR prediction was based on IFN-L4 genotype. Prediction of SVR with high accuracy (71–96%) was possible in genotype 1, 2, 3 and 4 infected patients who received PEG-IFN/ribavirin combination therapy by selection of beneficial IL28B rs12979860 C/C and/or ss469415590 TT/TT genotypes (p<0.001). For triple therapy with first generation protease inhibitors (PIs) (boceprevir, telaprevir) prediction of high SVR (90%) rates was based on the presence of at least one beneficial genotype of the 3 IFN-lambda SNPs.
Conclusion: IFN-L4 seems to be the best single predictor of SVR in genotype 3 infected patients. For optimized prediction of SVR by treatment with dual combination or first generation PI triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71–96%.
Triple therapy of chronic hepatitis C virus (HCV) infection with boceprevir (BOC) or telaprevir (TVR) leads to virologic failure in many patients which is often associated with the selection of resistance-associated variants (RAVs). These resistance profiles are of importance for the selection of potential rescue treatment options. In this study, we sequenced baseline NS3 RAVs population-based and investigated the sensitivity of NS3 phenotypes in an HCV replicon assay together with clinical factors for a prediction of treatment response in a cohort of 165 German and Swiss patients treated with a BOC or TVR-based triple therapy. Overall, the prevalence of baseline RAVs was low, although the frequency of RAVs was higher in patients with virologic failure compared to those who achieved a sustained virologic response (SVR) (7% versus 1%, P = 0.06). The occurrence of RAVs was associated with a resistant NS3 quasispecies phenotype (P<0.001), but the sensitivity of phenotypes was not associated with treatment outcome (P = 0.2). The majority of single viral and host predictors of SVR was only weakly associated with treatment response. In multivariate analyses, low AST levels, female sex and an IFNL4 CC genotype were independently associated with SVR. However, a combined analysis of negative predictors revealed a significantly lower overall number of negative predictors in patients with SVR in comparison to individuals with virologic failure (P<0.0001) and the presence of 2 or less negative predictors was indicative for SVR. These results demonstrate that most single baseline viral and host parameters have a weak influence on the response to triple therapy, whereas the overall number of negative predictors has a high predictive value for SVR.
Explosive volcanism affects weather and climate. Primary volcanic ash particles which act as ice nuclei (IN) can modify the phase and properties of cold tropospheric clouds. During the Eyjafjallajökull volcanic eruption we have measured the highest ice nucleus number concentrations (>600 L) in our record of 2 years of daily IN measurements in central Germany. Even in Israel, located about 5000 km away from Iceland, IN were as high as otherwise only during desert dust storms. These measurements are the only ones available on the properties of IN in the Eyjafjallajökull plume. The measured high concentrations and high activation temperature (−8 °C) point to an important impact of volcanic ash on microphysical and radiative properties of clouds through enhanced glaciation.