Steffen Rausch

Survival Prediction of Clear Cell Renal Cell Carcinoma Based on Gene Expression Similarity to the Proximal Tubule of the Nephron

UNLABELLED There is evidence that molecular features support subclassification of tumours, thereby improving prediction of patient outcome. Currently, two gene expression signatures (ccA/ccB and ClearCode34) have been established to classify clear cell renal cell carcinoma (ccRCC). Because RCC arises from nephron cell types, we aimed to explore its heterogeneity on a molecular level by comparing gene expression between tumour tissue and nephron regions. Based on genes that differ in expression between nephron regions, expression data of 479 ccRCCs and 212 papillary and 66 chromophobe RCCs from The Cancer Genome Atlas were correlated to those of nephron cell types. Cancer-specific survival (CSS) of ccRCC patients was significantly associated with gene expression similarity to the proximal tubules. Subsequently, a ccRCC risk score (S3-score) was established. Survival analyses indicated that the S3-score was significantly associated with CSS considering all cases of ccRCC, as well as metastatic and nonmetastatic ccRCC. Results could be validated in an independent cohort. The S3-score significantly improved the predictive ability of the ccA/ccB and ClearCode34 signatures, and the clinicopathologic-based stage, size, grade, and necrosis score (p [chi-square] = 1.56E-04). Intratumour heterogeneity of the S3-score was observed in 6 of 10 ccRCCs. In summary, the nephron-based S3-score enables prognostic risk stratification for ccRCC. Further studies are needed to evaluate its clinical utility. PATIENT SUMMARY We developed a novel risk score for clear cell renal cell carcinoma to identify patients at risk of worse outcome that may improve patient care in the future.

Impaired estimated glomerular filtration rate is a significant predictor for non-muscle-invasive bladder cancer recurrence and progression—Introducing a novel prognostic model for bladder cancer recurrence

PURPOSE To evaluate the influence of preoperative patient-associated parameters and comorbidities, with special focus on preoperative renal function on non-muscle-invasive bladder carcinoma (NMIBC) recurrence and progression. PATIENTS AND METHODS Medical records of 192 patients with first diagnosis of NMIBC from 1996 to 2006 treated at our department were reviewed for tumor stage and grade, comorbidities, and putative preoperative risk factors (diabetes mellitus, smoking habits, C-reactive protein levels, estimated glomerular filtration rate [eGFR] by chronic kidney disease-epidemiology collaboration formula, patient age, and sex). RESULTS Median follow-up was 80 months. Tumor recurrence was observed in 104 patients (54%); progression to higher pT category or grade was found in 43 patients (22%). Overall, 20 (10%) patients had progression to category pT2, with a median time to progression of 11 months (95% CI: 3.16-55.77). Overall, median time to recurrence was 11.91 months (8.00-14.94), while median time to progression to higher category/grade was 15 months (8.60-36.95). Cancer-specific death was recorded for 12 patients (6%). Univariate analysis revealed category, grade, and eGFR < 60 ml/min as significant predictive determinants for recurrence, overall progression, and progression to pT2-category disease. Based on the results of multivariate analysis, a risk factor model was created to classify patients with high and low risk of recurrence. CONCLUSIONS eGFR is a significant predictive variable of NMIBC recurrence and progression. Integrating eGFR into NMIBC risk calculation helped to discriminate individuals with high and low risk of cancer recurrence. Confirmatory studies and external validation are needed to corroborate these findings. Furthermore, the role of tumor multifocality and size should be analyzed for the proposed prediction model.

Analysis of Early Morbidity and Functional Outcome of Thulium: Yttrium-Aluminum-Garnet Laser Enucleation for Benign Prostate Enlargement: Patient Age and Prostate Size Determine Adverse Surgical Outcome

OBJECTIVE To evaluate complications and functional outcome and to identify patient-associated risk factors, we analyzed consecutive patients undergoing thulium:yttrium-aluminum-garnet laser enucleation of the prostate (ThuLEP) in our department. METHODS A total of 234 patients were prospectively analyzed. Preoperative data, postoperative complications, and outcome at 6, 12, and 24 months were recorded. Individual risk factors for complications and treatment failure were assessed by univariate and multivariate analyses. RESULTS Mean age at surgery was 72.88 ± 7.83 years. Mean preoperative prostate size was 84.8 ± 34.9 mL. Thirty-day complication rate was 19.7%. Functional treatment failure occurred in 9.0% of all patients. Decline of mean International Prostate Symptom Score was -75%, quality of life index -76%, and postvoid residual -86% at 24 months. Maximum urine flow at 24 months was improved at +231%. In univariate analysis, age >80 years and prostate size <50 mL were significant predictors of complications, which was confirmed by multivariate analysis (P = .0277 and .0409, respectively). Age >80 years, prostate size <80 mL or <50 mL, and American Society of Anesthesiologists classification were significant predictors of functional treatment failure in univariate analysis. Prostate size <80 mL or <50 mL was significantly associated with treatment failure (P < .001) in multivariate analysis. CONCLUSION ThuLEP is a safe and efficient surgical procedure, even in a patient cohort with high prostate volumes, age, and comorbidities. However, high patient age and small prostate size were significant determinants of adverse outcomes after surgery. To address the question of optimal therapy selection for patients with prostates smaller than 80 mL, further prospective randomized evaluation of ThuLEP and alternative surgical interventions is needed.

Methylomes of renal cell lines and tumors or metastases differ significantly with impact on pharmacogenes

Current therapies for metastatic clear cell renal cell carcinoma (ccRCC) show limited efficacy. Drug efficacy, typically investigated in preclinical cell line models during drug development, is influenced by pharmacogenes involved in targeting and disposition of drugs. Here we show through genome-wide DNA methylation profiling, that methylation patterns are concordant between primary ccRCC and macro-metastases irrespective of metastatic sites (rs ≥ 0.92). However, 195,038 (41%) of all investigated CpG sites, including sites within pharmacogenes, were differentially methylated (adjusted P < 0.05) in five established RCC cell lines compared to primary tumors, resulting in altered transcriptional expression. Exemplarily, gene-specific analyses of DNA methylation, mRNA and protein expression demonstrate lack of expression of the clinically important drug transporter OCT2 (encoded by SLC22A2) in cell lines due to hypermethylation compared to tumors or metastases. Our findings provide evidence that RCC cell lines are of limited benefit for prediction of drug effects due to epigenetic alterations. Similar epigenetic landscape of ccRCC-metastases and tumors opens new avenue for future therapeutic strategies.

mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer

Among currently available vaccine strategies for cancer, nucleotide-based vaccination is an appealing treatment modality. Curevacs’ mRNA containing vaccines (RNActive®) combine the beneficial properties of sufficient antigen-expression, autologous immune-stimulation and a high flexibility with respect to production and application. CV9103 and CV9104 are novel RNActive®-derived anticancer vaccines for the treatment of patients with prostate cancer. After successful phase I/II studies with documentation of good tolerability and favorable immune-activation of CV9103, the vaccine CV9104 is currently undergoing clinical testing in specific clinical settings such as castration resistant prostate cancer and as a neoadjuvant agent in men with high risk prostate cancer prior to surgery. This review discusses the available preclinical and clinical data on the anticancer vaccination treatment with RNActive®-derived anticancer-vaccines CV9103 and CV9104.

Robot-assisted radical cystectomy and intracorporeal neobladder formation: on the way to a standardized procedure

BackgroundRobot-assisted radical cystectomy (RARC) with intracorporeal diversion has been shown to be feasible in a few centers of excellence worldwide, with promising functional and oncologic outcomes. However, it remains unknown whether the complexity of the procedure allows its duplication in other non-pioneer centers. We attempt to address this issue by presenting our cumulative experience with RARC and intracorporeal neobladder formation.MethodsWe retrospectively identified 62 RARCs in 50 men and 12 women (mean age 63.6 years) in two tertiary centers. Intracorporeal Studer neobladders were created, duplicating the steps of standard open surgery. Perioperative and postoperative variables and complications were analyzed using standardized tools. Functional and oncological results were assessed.ResultsThe mean operative time was 476.9 min (range, 310 to 690) and blood loss was 385 ml (200 to 800). The mean hospital stay was 16.7 (12 to 62) days with no open conversion. Perioperative complications were grade II in 15, grade III in 11, and grade IV in 5 patients. The mean nodal yield was 22.9 (8 to 46). Positive margins were found in in 6.4%. The 90- and 180-day mortality rates were 0% and 3.3%. The average follow-up was 37.3 months (3 to 52). Continence was achieved in 88% of patients. The cancer-specific survival rate and overall survival rate were 84% and 71%, respectively.ConclusionsA RARC with intracorporeal neobladder creation is safe and reproducible in ‘non-pioneer’ tertiary centers with robotic expertise with acceptable operative time and complications. Further standardization of RARC with intracorporeal diversion is a prerequisite for its widespread use.

MCT4 surpasses the prognostic relevance of the ancillary protein CD147 in clear cell renal cell carcinoma

Cluster of differentiation 147 (CD147/BSG) is a transmembrane glycoprotein mediating oncogenic processes partly through its role as binding partner for monocarboxylate transporter MCT4/SLC16A3. As demonstrated for MCT4, CD147 is proposed to be associated with progression in clear cell renal cell carcinoma (ccRCC). In this study, we evaluated the prognostic relevance of CD147 in comparison to MCT4/SLC16A3 expression and DNA methylation. Methods CD147 protein expression was assessed in two independent ccRCC-cohorts (n = 186, n = 59) by immunohistochemical staining of tissue microarrays and subsequent manual as well as automated software-supported scoring (Tissue Studio, Definien sAG). Epigenetic regulation of CD147 was investigated using RNAseq and DNA methylation data of The Cancer Genome Atlas. These results were validated in our cohort. Relevance of prognostic models for cancer-specific survival, comprising CD147 and MCT4 expression or SLC16A3 DNA methylation, was compared using chi-square statistics. Results CD147 protein expression generated with Tissue Studio correlated significantly with those from manual scoring (P < 0.0001, rS = 0.85), indicating feasibility of software-based evaluation exemplarily for the membrane protein CD147 in ccRCC. Association of CD147 expression with patient outcome differed between cohorts. DNA methylation in the CD147/BSG promoter was not associated with expression. Comparison of prognostic relevance of CD147/BSG and MCT4/SLC16A3, showed higher significance for MCT4 expression and superior prognostic power for DNA methylation at specific CpG-sites in the SLC16A3 promoter (e.g. CD147 protein: P = 0.7780, Harrells c-index = 53.7% vs. DNA methylation: P = 0.0076, Harrells c-index = 80.0%). Conclusions Prognostic significance of CD147 protein expression could not surpass that of MCT4, especially of SLC16A3 DNA methylation, corroborating the role of MCT4 as prognostic biomarker for ccRCC.

Totally intracorporeal replacement of the ureter using whole-mount ileum.

Ileal ureter is a suitable treatment option for patients with long ureteral strictures. Minimally invasive techniques have been shown to be as safe as open technique and superior in terms of postoperative recovery. We report the first case of laparoscopic totally intracorporeal replacement of ureter using whole-mount ileum in a patient with right-sided long ureteral stricture. The operative time was 150 minutes, and there were no complications. We have demonstrated the safety and feasibility of laparoscopic intracorporeal ileal ureter with possible advantage of shorter operative time compared with the robotic-assisted technique reported recently.

IMA901 for metastatic renal cell carcinoma in the context of new approaches to immunotherapy

The promising option of immunotherapy for metastatic renal cell carcinoma has evolved from rather unspecific approaches to a specific activation of an anti-tumor T-cell response. The latest step is a synthetic peptide vaccine called IMA901, which demonstrated a clear association between a provoked T-cell response and a prolonged overall survival. The results of IMA901 for the treatment of metastatic renal cell carcinoma are discussed together with new approaches to immunotherapy, such as local and systemic immunomodulation with adjuvants, checkpoint inhibitors, classical chemotherapeutics, such as cyclophosphamide or tyrosine kinase inhibitors. The capability of theses substances to modulate leukocytes subsets, such as myeloid-derived suppressor cells, Tregs or Th17 cells, are outlined together with the possibility to combine them with tumor vaccination strategies to achieve a higher cancer specificity and immunogenicity.

Intracorporeal ileal ureter replacement using laparoscopy and robotics.

Introduction Ileal ureter is a suitable treatment option for patients with long ureteric strictures. Minimally invasive techniques have been shown to be as safe as open techniques but superior in terms of post–operative recovery. We report our experience using minimally invasive techniques for total intracorporeal ureteral replacement. Material and methods A chart review revealed five patients who underwent intracorporeal ileal ureter using minimally invasive techniques in the preceding 5 years. 4 patients underwent conventional laparoscopic surgery and 1 patient underwent robotic–assisted surgery. Patients characteristics, perioperative data and functional outcomes as well as a detailed description of surgical technique are reported. In all 5 of these patients, the ileal ureter was performed completely intracorporeally. Results The median age of our patients is 61 (range 42–73). The median operative time was 250 minutes (range 150–320) and median blood loss was 100 ml (range 50–200). The median hospital stay was 8 days (range 6–10) and there were no major perioperative complications reported. At median follow up of 22 months (range 4–38), there were no recurrences of strictures or any other complications. Conclusions We have demonstrated the safety and feasibility of minimally invasive intracorporeal ileal ureter. Numbers are still small but its application is likely to grow further.