Protocol for a Randomized Phase II Trial for Mesh Optimization by Autologous Plasma Coating in Prolapse Repair: IDEAL Stage 3

Introduction: Mesh-related complications especially after vaginal implantation have raised awareness lately because of severe adverse reactions and legal aspects. About 20% of patients suffer from complications after mesh insertion in the anterior vaginal wall. Autologous plasma coating of meshes prior to implantation has shown potential to improve the biocompatibility of meshes in vivo and in vitro. This innovative approach has been developed according to the IDEAL recommendations for surgical innovations. The method has still to be assessed at stage 3 accordingly. Methods: A protocol is developed for a prospective single-blinded randomized controlled phase II trial for biocompatibility optimization of anterior vaginal meshes for prolapse repair by autologous plasma coating versus non-coated meshes. Results: The protocol aims at fulfilling the requirements for stage 3 (assessment) according to IDEAL. Eligible for inclusion are women with primary cystocele, requiring a surgical procedure, suitable for randomization, and willing to be randomized. Participants will be followed up by postal questionnaires (6 months post surgery and 12 months post randomization) and will also be reviewed in clinic 12 and 24 months post surgery. Primary endpoint is the assessment of mesh-related complications following the Clavien–Dindo classifications. QoL, sexual function assessment, efficacy, and validation of an already developed long-term register are considered secondary endpoints. To afford a calculated 10% reduction of postoperative complications through plasma-coated meshes vs. non-coated meshes at 1-year follow-up, a total 214 women in each arm will be necessary to achieve 80% power at a significance level of 5%. Conclusion: The protocol for this randomized clinical trial represents the conditions to assess the surgical innovation of plasma coating of meshes in order to improve the meshes’ biocompatibility at stage 3 according to the IDEAL recommendations. © 2017 Springer Healthcar

Fibronectin 1 mRNA expression correlates with advanced disease in renal cancer

<p>Abstract</p> <p>Background</p> <p>Fibronectin 1 (<it>FN1</it>) is a glycoprotein involved in cellular adhesion and migration processes. The aim of this study was to elucidate the role of <it>FN1 </it>in development of renal cell cancer (RCC) and to determine a prognostic relevance for optimal clinical management.</p> <p>Methods</p> <p>212 renal tissue samples (109 RCC, 86 corresponding tissues from adjacent normal renal tissue and 17 oncocytomas) were collected from patients undergoing surgery for renal tumors and subjected to total RNA extraction. Detection of <it>FN1 </it>mRNA expression was performed using quantitative real time PCR, three endogenous controls, renal proximal tubular epithelial cells (RPTEC) as biological control and the ΔΔCt method for calculation of relative quantities.</p> <p>Results</p> <p>Mean tissue specific <it>FN1 </it>mRNA expression was found to be increased approximately seven fold comparing RCC and corresponding kidney control tissues (p < 0.001; ANOVA). Furthermore, tissue specific mean <it>FN1 </it>expression was increased approx. 11 fold in clear cell compared to papillary RCC (p = 9×10^-5; Wilcoxon rank sum test). Patients with advanced disease had higher <it>FN1 </it>expression when compared to organ-confined disease (p < 0.001; Wilcoxon rank sum test). Applying subgroup analysis we found a significantly higher <it>FN1 </it>mRNA expression between organ-confined and advanced disease in the papillary and not in the clear cell RCC group (p = 0.02 vs. p = 0.2; Wilcoxon rank sum test). There was an increased expression in RCC compared to oncocytoma (p = 0.016; ANOVA).</p> <p>Conclusions</p> <p>To our knowledge, this is the first study to show that <it>FN1 </it>mRNA expression is higher in RCC compared to normal renal tissue. <it>FN1 </it>mRNA expression might serve as a marker for RCC aggressiveness, indicating early systemic progression particularly for patients with papillary RCC.</p

Gain-of-function mutation in ubiquitin ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues

The start codon c.1A>G mutation in KLHL24, encoding ubiquitin ligase KLHL24, results in the loss of 28 N-terminal amino acids (KLHL24-ΔN28) by skipping the initial start codon. In skin, KLHL24-ΔN28 leads to gain of function, excessively targeting intermediate filament keratin-14 for proteasomal degradation and ultimately causing epidermolysis bullosa simplex (EBS). The majority of patients with EBS are also diagnosed with dilated cardiomyopathy (DCM), but the pathological mechanism in the heart is unknown. As desmin is the cardiac homolog of keratin-14, we hypothesized that KLHL24-ΔN28 leads to excessive degradation of desmin, resulting in DCM. Dynamically loaded engineered heart tissues (dyn-EHTs) were generated from human-induced pluripotent stem cell–derived (hiPSC-derived) cardiomyocytes from 2 patients and 3 nonfamilial controls. Ten-fold lower desmin protein levels were observed in patient-derived dyn-EHTs, in line with diminished desmin levels detected in patients’ explanted heart. This was accompanied by tissue dilatation, impaired mitochondrial function, decreased force values, and increased cardiomyocyte stress. HEK293 transfection studies confirmed KLHL24-mediated desmin degradation. KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs. To conclude, presence of KLHL24-ΔN28 in cardiomyocytes leads to excessive degradation of desmin, affecting tissue morphology and function, which can be prevented by restoring desmin protein levels

Discrepancy between German S3 Guideline Recommendations and Daily Urologic Practice in the Management of Nonmuscle Invasive Bladder Cancer: Results of a Binational Survey

Introduction: Guideline recommendations are meant to help minimize morbidity and to improve the care of nonmuscle invasive bladder cancer (NMIBC) patients but studies have suggested an underuse of guideline-recommended care. The aim of this study was to evaluate the level of adherence of German and Austrian urologists to German guideline recommendations. Methods: A survey of 27 items evaluating diagnostic and therapeutic recommendations (15 cases of strong consensus and 6 cases of consensus) for NMIBC was administered among 14 urologic training courses. Survey construction and realization followed the checklist for reporting results of internet e-surveys and was approved by an internal review board. Results: Between January 2018 and June 2019, a total of 307 urologists responded to the questionnaire, with a mean response rate of 71%. The data showed a weak role of urine cytology (54%) for initial diagnostics although it is strongly recommended by the guideline. The most frequently used supporting diagnostic tool during transurethral resection of the bladder was hexaminolevulinate (95%). Contrary to the guideline recommendation, 38% of the participants performed a second resection in the case of pTa low-grade NMIBC. Correct monitoring of Bacille Calmette-Guerin (BCG) response with cystoscopy and cytology was performed by only 34% of the urologists. Conclusions: We found a discrepancy between certain guideline recommendations and daily routine practice concerning the use of urine cytology for initial diagnostics, instillation therapy with a low monitoring rate of BCG response, and follow-up care with unnecessary second resection after pTa low-grade NMIBC in particular. Our survey showed a moderate overall adherence rate of 73%. These results demonstrate the need for sharpening awareness of German guideline recommendations by promoting more intense education of urologists to optimize NMIBC care thus decreasing morbidity and mortality rates

Nomograms including the UBC® Rapid test to detect primary bladder cancer based on a multicentre dataset

Objectives: To evaluate the clinical utility of the urinary bladder cancer antigen test UBC Rapid for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high risk of primary BC. Patients and Methods: Data from 1787 patients from 13 participating centres, who were tested between 2012 and 2020, including 763 patients with BC, were analysed. Urine samples were analysed with the UBC Rapid test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC Rapid test was evaluated using receiver-operating characteristic curve analysis. Brier scores and calibration curves were chosen for the validation. Biopsy-proven BC was predicted using multivariate logistic regression. Results: The sensitivity, specificity, and area under the curve for the UBC Rapid test were 46.4%, 75.5% and 0.61 (95% confidence interval [CI] 0.58–0.64) for low-grade (LG) BC, and 70.5%, 75.5% and 0.73 (95% CI 0.70–0.76) for high-grade (HG) BC, respectively. Age, UBC Rapid test results, smoking status and haematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in areas under the curve of 0.79 (95% CI 0.72–0.87) and 0.95 (95% CI: 0.92–0.98) for predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC Rapid test alone for low and medium risk levels in decision curve analysis. The R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. Conclusion: The UBC Rapid test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status and haematuria provides a fast, highly accurate and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC

P1‐349: Advancing Clinical And Biomarker Research In Ad: The Lead Study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152716/1/alzjjalz201906904.pd

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN