A reliable transcriptomic risk-score applicable to formalin-fixed paraffin-embedded biopsies improves outcome prediction in localized prostate cancer.

BACKGROUND: Clinical manifestation of prostate cancer (PCa) is highly variable. Aggressive tumors require radical treatment while clinically non-significant ones may be suitable for active surveillance. We previously developed the prognostic ProstaTrend RNA signature based on transcriptome-wide microarray and RNA-sequencing (RNA-Seq) analyses, primarily of prostatectomy specimens. An RNA-Seq study of formalin-fixed paraffin-embedded (FFPE) tumor biopsies has now allowed us to use this test as a basis for the development of a novel test that is applicable to FFPE biopsies as a tool for early routine PCa diagnostics. METHODS: All patients of the FFPE biopsy cohort were treated by radical prostatectomy and median follow-up for biochemical recurrence (BCR) was 9 years. Based on the transcriptome data of 176 FFPE biopsies, we filtered ProstaTrend for genes susceptible to FFPE-associated degradation via regression analysis. ProstaTrend was additionally restricted to genes with concordant prognostic effects in the RNA-Seq TCGA prostate adenocarcinoma (PRAD) cohort to ensure robust and broad applicability. The prognostic relevance of the refined Transcriptomic Risk Score (TRS) was analyzed by Kaplan-Meier curves and Cox-regression models in our FFPE-biopsy cohort and 9 other public datasets from PCa patients with BCR as primary endpoint. In addition, we developed a prostate single-cell atlas of 41 PCa patients from 5 publicly available studies to analyze gene expression of ProstaTrend genes in different cell compartments. RESULTS: Validation of the TRS using the original ProstaTrend signature in the cohort of FFPE biopsies revealed a relevant impact of FFPE-associated degradation on gene expression and consequently no significant association with prognosis (Cox-regression, p-value > 0.05) in FFPE tissue. However, the TRS based on the new version of the ProstaTrend-ffpe signature, which included 204 genes (of originally 1396 genes), was significantly associated with BCR in the FFPE biopsy cohort (Cox-regression p-value < 0.001) and retained prognostic relevance when adjusted for Gleason Grade Groups. We confirmed a significant association with BCR in 9 independent cohorts including 1109 patients. Comparison of the prognostic performance of the TRS with 17 other prognostically relevant PCa panels revealed that ProstaTrend-ffpe was among the best-ranked panels. We generated a PCa cell atlas to associate ProstaTrend genes with cell lineages or cell types. Tumor-specific luminal cells have a significantly higher TRS than normal luminal cells in all analyzed datasets. In addition, TRS of epithelial and luminal cells was correlated with increased Gleason score in 3 studies. CONCLUSIONS: We developed a prognostic gene-expression signature for PCa that can be applied to FFPE biopsies and may be suitable to support clinical decision-making.

Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is one of the most prevalent cancers worldwide. The clinical manifestations and molecular characteristics of PCa are highly variable. Aggressive types require radical treatment, whereas indolent ones may be suitable for active surveillance or organ-preserving focal therapies. Patient stratification by clinical or pathological risk categories still lacks sufficient precision. Incorporating molecular biomarkers, such as transcriptome-wide expression signatures, improves patient stratification but so far excludes chromosomal rearrangements. In this study, we investigated gene fusions in PCa, characterized potential novel candidates, and explored their role as prognostic markers for PCa progression. METHODS: We analyzed 630 patients in four cohorts with varying traits regarding sequencing protocols, sample conservation, and PCa risk group. The datasets included transcriptome-wide expression and matched clinical follow-up data to detect and characterize gene fusions in PCa. With the fusion calling software Arriba, we computationally predicted gene fusions. Following detection, we annotated the gene fusions using published databases for gene fusions in cancer. To relate the occurrence of gene fusions to Gleason Grading Groups and disease prognosis, we performed survival analyses using the Kaplan-Meier estimator, log-rank test, and Cox regression. RESULTS: Our analyses identified two potential novel gene fusions, MBTTPS2,L0XNC01::SMS and AMACR::AMACR. These fusions were detected in all four studied cohorts, providing compelling evidence for the validity of these fusions and their relevance in PCa. We also found that the number of gene fusions detected in a patient sample was significantly associated with the time to biochemical recurrence in two of the four cohorts (log-rank test, p-value < 0.05 for both cohorts). This was also confirmed after adjusting the prognostic model for Gleason Grading Groups (Cox regression, p-values < 0.05). CONCLUSIONS: Our gene fusion characterization workflow revealed two potential novel fusions specific for PCa. We found evidence that the number of gene fusions was associated with the prognosis of PCa. However, as the quantitative correlations were only moderately strong, further validation and assessment of clinical value is required before potential application.

Acceptance and efficacy of recommended adjuvant radiotherapy in patients with positive lymph nodes at radical prostatectomy: a preference-based study.

PURPOSE: To investigate acceptance and efficacy of recommended adjuvant radiotherapy in patients with positive lymph nodes at radical prostatectomy. METHODS: Among 495 patients with positive lymph nodes who consecutively underwent radical prostatectomy between 2007 and 2017, we investigated 347 patients who were recommended to undergo adjuvant radiotherapy by a multidisciplinary post-therapeutic tumor board and in whom information whether such treatment was eventually given was available. The median follow-up for censored patients was 5.4 years. Univariate analyses were performed using Kaplan-Meier curves, Mantel-Haenszel hazard ratios and log rank tests. Proportional hazard models for competing risks were used for multivariable analyses. RESULTS: Adjuvant radiotherapy was independently associated with lower overall mortality and in high-risk patients (Gleason score 8-10 or three or more involved lymph nodes) also with lower prostate cancer-specific mortality. In patients with a Gleason score of 8-10 or three or more involved lymph nodes, the hazard ratio for adjuvant radiotherapy was 0.455 (95% confidence interval 0.257-0.806, p = 0.0069) for overall and 0.426 (95% confidence interval 0.201-0.902, p = 0.0259) for prostate cancer-specific mortality. Among patients receiving adjuvant radiotherapy, there was a trend to lower mortality when such treatment was combined with adjuvant androgen deprivation. CONCLUSION: Adjuvant radiotherapy decreased mortality in patients with positive lymph nodes at radical prostatectomy with further disease factors but not in patients with low-risk disease. Simultaneous androgen deprivation might increase efficacy. Multidisciplinary recommendations may possibly increase the use of adjuvant radiotherapy in this setting.

The Clinical Complexity of Penile Cancer: Current Clinical-Epidemiological Data from the Database of the Free State of Saxony/Germany.

OBJECTIVES: The aim of this study was to assess penile cancer incidence, clinical characteristics, treatment options, transparency of clinical quality, and relative survival based on data from the clinical cancer registry. SUBJECTS AND METHODS: A total of 898 patients with tumours of the penis were diagnosed and analysed in the period from 2000 to 2018; they were documented in the 4 regional clinical cancer registries and summarized in the Command Office of these 4 registries. RESULTS: The standardized incidence rate increased from 0.86 in 2000 to 2.67 in 2018. Most tumours were located at the glans (42.9%) followed by the prepuce (19.5%) and corpus penis (6.9%); they were classified into pT1a/pT1b (20.0%/7.0%), pT2 (23.5%), pT3 (12.4%), and pT4 (0.8%). In only 32.0% of all documented cases, a stage-related lymphadenectomy (LND) was carried out. Negative surgical margins were found in only 70% and the Rx status in 15.1%. Primary metastasis was detected in pN1 (5.1%), pN2 (3.9%), pN3 (3.1%), and M1 status in 3.0%, respectively. The predominant therapy was surgery in 78.3%. The proportion of penile partial resections was significantly (p = 0.0045) regredient over the control period. Adjuvant chemotherapy was performed in 4.7%, adjuvant external-beam radiotherapy in 3.0%. The 5-year relative overall survival rate was 74.7% and ranged from 108.0% (stage 0) to 17.1% (stage IV). A total of 29 hospitals performed tumour operations. CONCLUSIONS: The multitude of clinical and epidemiological variables available in clinical cancer registries allows a safe assessment of tumour dynamics themselves, as well as good quality of transparency and broadly acceptable guideline adherence. Deviations from the accepted level of evidence were found in the grading definition, in the high quota of positive surgical margins, in the defensive indication position to the glans resurfacing/reconstruction and diagnostical LND. Based on these relevant findings in the database combined with the low frequency of the tumour in area/clinics/year, we recommended establishing SCCP reference clinics. This work is the first time that European standardized rate-based cancer registry data on penile cancer from Germany has been communicated.

Anti-Biofilm Effect of Octenidine and Polyhexanide on Uropathogenic Biofilm-Producing Bacteria.

BACKGROUND: A catheter allowing a release of antibacterial substances such as antiseptics into the bladder could be a new way of preventing biofilm formation and subsequent catheter-associated urinary tract infections. METHODS: Minimal inhibitory and bactericidal concentration (MIC/MBC) determinations in cation-adjusted Mueller-Hinton broth and artificial urine were performed for 4 antiseptics against 3 uropathogenic biofilm producers, Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis. Furthermore, effects of octenidine and polyhexanide against catheter biofilm formation were determined by quantification of biofilm-producing bacteria. RESULTS: Sodium hypochlorite showed MIC/MBC values between 200 and 800 mg/L for all strains tested. Triclosan was efficient against E. coli and P. mirabilis (MIC ≤2.98 mg/L) but ineffective against P. aeruginosa. Octenidine and polyhexanide showed antibacterial activity against all 3 species tested (MIC 1.95-7.8 and 3.9-31.25 mg/L). Both octenidine and polyhexanide were able to prevent biofilm formation on catheter segments in a concentration dependent manner. Furthermore, adding 250 mg/L of each biocide disrupted biofilms formed by E. coli and P. mirabilis, whereas even 500 mg/L was not sufficient to completely destroy P. aeruginosa biofilms. CONCLUSION: Octenidine- and polyhexanide-containing antiseptics showed a broad effect against typical uropathogenic biofilm producers even in high dilutions. This study provides a basis for further investigation of the potential of octenidine and polyhexanide as prophylaxis or treatment of catheter biofilms.

Neuropilin-2 is an independent prognostic factor for shorter cancer-specific survival in patients with acinar adenocarcinoma of the prostate.

Neuropilin-2 (NRP2) is a member of the neuropilin receptor family and known to regulate autophagy and mTORC2 signaling in prostate cancer (PCa). Our study investigated the association of immunohistochemical NRP2 expression with clinicopathological data in PCa patients. For this purpose, we generated a tissue microarray with prostate tissue specimens from 400 PCa patients treated by radical prostatectomy. We focused on patients with high-risk factors such as extraprostatic extension (pT ≥ 3), Gleason score ≥8 and/or the presence of regional lymph node metastases (pN1). Protein levels of NRP2, the vascular endothelial growth factor C (VEGFC) and oncogenic v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) gene as an indicator for TMPRSS2-ERG fusion was assessed in relation to the patients' outcome. NRP2 emerged as an independent prognostic factor for cancer-specific survival (CSS) (hazard ratio 2.360, 95% confidence interval = 1.2-4.8; p = 0.016). Moreover, the association between NRP2 expression and shorter CSS was also especially pronounced in patients at high risk for progression (log-rank test: p = 0.010). We evaluated the association between NRP2 and the TMPRSS2-ERG gene fusion status assessed by immunohistochemical nuclear ERG staining. However, ERG staining alone did not show any prognostic significance. NRP2 immunostaining is significantly associated with shorter CSS in ERG-negative tumors (log-rank test: p = 0.012). No prognostic impact of NRP2 expression on CSS was observed in ERG-positive tumors (log-rank test: p = 0.153). Our study identifies NRP2 as an important prognostic marker for a worse clinical outcome especially in patients with a high-risk PCa and in patients with ERG-negative PCa.

Which comorbidity classification is best suited to identify patients at risk for 90-day and long-term non-bladder cancer mortality after radical cystectomy?

PURPOSE: There is no consensus on the best comorbidity measure in candidates for radical cystectomy. The aim of this study was to identify tool best suited to identify patients at risk for 90-day or premature long-term non-bladder cancer mortality. METHODS: We studied 1268 patients who underwent radical cystectomy to identify patients at risk for 90-day and later-than-90-day mortality, respectively. Six classifications were investigated as possible predictors of both types of mortality. Multivariable models including age as continuous variable and each classification separately were calculated. A heuristic ranking was based on the evaluation of the hazard ratios, p values, Akaike's information criteria, and concerning the logit models also the areas under the curve. RESULTS: The median follow-up was 5.7 years. Within 90 days after surgery, the mortality rate was 4.2%. The greatest independent contribution concerning the prediction of 90-day mortality was seen with the American Society of Anesthesiologists (ASA) physical status classification (classes 3-4 versus 1-2: hazard ratio 7.98, 95% confidence interval 3.54-18.01, p < 0.0001). In the longer term, countable diseases (Canadian Cardiovascular Society classification of angina pectoris, conditions contributing the Charlson score) were of greater importance. The results of heuristic ranking were confirmed by multivariate analyses including age and all classifications together. CONCLUSIONS: Besides to chronological age, clinicians should pay particular attention to the ASA classification to identify patients at risk for 90-day mortality after radical cystectomy, whereas long-term mortality is more determined by countable comorbid diseases.

External validation of a postoperative nomogram for the prediction of disease-specific survival in patients with papillary renal cell carcinoma using a large multicenter database.

PURPOSE: Based on data retrieved from a comprehensive multicenter database, we externally validated a published postoperative nomogram for the prediction of disease-specific survival (DSS) in patients with papillary renal cell carcinoma (papRCC). METHODS: A multicenter database containing data of 2325 patients with surgically treated papRCC was used as validation cohort. After exclusion of patients with missing data and patients included in the development cohort, 1372 patients were included in the final analysis. DSS-probabilities according to the nomogram were calculated and compared to actual DSS-probabilities. Subsequently, calibration plots and decision curve analyses were applied. RESULTS: The median follow-up was 38 months (IQR 11.8-80.7). Median DSS was not reached. The c-index of the nomogram was 0.71 (95% CI 0.60-0.83). A sensitivity analysis including only patients operated after 1998 delivered a c-index of 0.84 (95% CI 0.77-0.92). Calibration plots showed slight underestimation of nomogram-predicted DSS in probability ranges below 90%: median nomogram-predicted 5-year DSS in the range below 90% was 55% (IQR 20-80), but the median actual 5-year DSS in the same group was 58% (95% CI 52-65). Decision-curve analysis showed a positive net-benefit for probability ranges between a DSS probability of 5% and 85%. CONCLUSIONS: The nomogram performance was satisfactory for almost all DSS probabilities; hence it can be recommended for application in clinical routine and for counseling of patients with papRCC.

Validation of a Questionnaire-Suitable Comorbidity Index in Patients Undergoing Radical Cystectomy.

OBJECTIVE: To investigate the capability of a modified self-administrable comorbidity index recommended in the standard sets for neoplastic diseases published by the International Consortium for Health Outcomes Measurement (ICHOM) to predict 90-day and long-term mortality after radical cystectomy. METHODS: A single-center series of 1,337 consecutive patients who underwent radical cystectomy for muscle-invasive or high-risk non-muscle-invasive urothelial or undifferentiated bladder cancer were stratified by the modified self-administrable comorbidity index and Charlson score, respectively. Multivariate logit models (for 90-day mortality) and proportional-hazards models (for overall and non-bladder cancer mortality) were used for statistical workup. RESULTS: Considering 90-day mortality, both comorbidity indexes contributed independent information when analyzed together with age (p < 0.0001). The Charlson score performed slightly better (area under the curve [AUC] 0.74 vs. 0.72 for the ICHOM-recommended comorbidity index). Considering 5-year overall mortality in 727 patients with complete observation, the performance of both measures was similar (AUC 0.63 vs. 0.62, including age AUC 0.66 for both indexes). With 6-sided stratifications, the modified self-administrable comorbidity index separated the risk groups slightly better (p values for directly neighboring curves: 0.0068-0.1043 vs. 0.0001-0.8100). CONCLUSION: The ICHOM-recommended modified self-administrable comorbidity index is capable of predicting 90-day mortality and long-term non-bladder cancer mortality after radical cystectomy similarly to the commonly used Charlson score.

Socioeconomic Status-Related Parameters as Predictors of Competing (Non-Bladder Cancer) Mortality after Radical Cystectomy.

OBJECTIVE: To investigate the impact of socioeconomic status-related parameters on competing (non-bladder cancer) mortality after radical cystectomy. PATIENTS AND METHODS: A total of 1,268 consecutive patients who underwent radical cystectomy for urothelial or undifferentiated bladder cancer at our institution between 1993 and 2016 with a mean age of 69 years (median 70 years) were studied. The mean -follow-up of the censored patients was 7.2 years (median 5.7 years). Proportional hazard models for competing risk were used to identify predictors of non-bladder cancer (competing) mortality. The following parameters were included into multivariate analyses: age, American Society of Anesthesiologists physical status classification, Charlson score, gender, level of education, smoking status, marital status, local tumour stage, lymph node status, adjuvant and neoadjuvant chemotherapy. RESULTS: Besides age and both comorbidity classifications, the socioeconomic status-related parameters gender (female versus male, hazard ratio [HR] 0.58, 95% CI 0.40-0.84, p = 0.0042), level of education (university degree or master craftsman versus others, HR 0.76, 95% CI 0.56-0.1.03, p = 0.0801), smoking status (current smoking versus others, HR 1.47, 95% CI 1.10-1.96, p = 0.0085) and marital status (married versus others, HR 0.68, 95% CI 0.50-0.92, p = 0.0133) were independent predictors of competing mortality after radical cystectomy. If considered in combination (multiplication of HRs), the prognostic impact of socioeconomic parameters superseded that of the investigated comorbidity classifications. CONCLUSION: Socioeconomic status-related parameters may provide important information on the long-term competing mortality risk after radical cystectomy supplementary to chronological age and comorbidity.

Urinary MicroRNAs as Potential Markers for Non-Invasive Diagnosis of Bladder Cancer.

Currently, voided urine cytology (VUC) serves as the gold standard for the detection of bladder cancer (BCa) in urine. Despite its high specificity, VUC has shortcomings in terms of sensitivity. Therefore, alternative biomarkers are being searched, which might overcome these disadvantages as a useful adjunct to VUC. The aim of this study was to evaluate the diagnostic potential of the urinary levels of selected microRNAs (miRs), which might represent such alternative biomarkers due to their BCa-specific expression. Expression levels of nine BCa-associated microRNAs (miR-21, -96, -125b, -126, -145, -183, -205, -210, -221) were assessed by quantitative PCR in urine sediments from 104 patients with primary BCa and 46 control subjects. Receiver operating characteristic (ROC) curve analyses revealed a diagnostic potential for miR-96, -125b, -126, -145, -183, and -221 with area under the curve (AUC) values between 0.605 and 0.772. The combination of the four best candidates resulted in sensitivity, specificity, positive and negative predictive values (NPV), and accuracy of 73.1%, 95.7%, 97.4%, 61.1%, and 80.0%, respectively. Combined with VUC, sensitivity and NPV could be increased by nearly 8%, each surpassing the performance of VUC alone. The present findings suggested a diagnostic potential of miR-125b, -145, -183, and -221 in combination with VUC for non-invasive detection of BCa in urine.

ITIH5 and ECRG4 DNA Methylation Biomarker Test (EI-BLA) for Urine-Based Non-Invasive Detection of Bladder Cancer.

Bladder cancer is one of the more common malignancies in humans and the most expensive tumor for treating in the Unites States (US) and Europe due to the need for lifelong surveillance. Non-invasive tests approved by the FDA have not been widely adopted in routine diagnosis so far. Therefore, we aimed to characterize the two putative tumor suppressor genes ECRG4 and ITIH5 as novel urinary DNA methylation biomarkers that are suitable for non-invasive detection of bladder cancer. While assessing the analytical performance, a spiking experiment was performed by determining the limit of RT112 tumor cell detection (range: 100-10,000 cells) in the urine of healthy donors in dependency of the processing protocols of the RWTH cBMB. Clinically, urine sediments of 474 patients were analyzed by using quantitative methylation-specific PCR (qMSP) and Methylation Sensitive Restriction Enzyme (MSRE) qPCR techniques. Overall, ECRG4-ITIH5 showed a sensitivity of 64% to 70% with a specificity ranging between 80% and 92%, i.e., discriminating healthy, benign lesions, and/or inflammatory diseases from bladder tumors. When comparing single biomarkers, ECRG4 achieved a sensitivity of 73%, which was increased by combination with the known biomarker candidate NID2 up to 76% at a specificity of 97%. Hence, ITIH5 and, in particular, ECRG4 might be promising candidates for further optimizing current bladder cancer biomarker panels and platforms.

Radium-223 in asymptomatic patients with castration-resistant prostate cancer and bone metastases treated in an international early access program.

BACKGROUND: Radium-223, a targeted alpha therapy, is used to treat symptomatic patients with castration-resistant prostate cancer (CRPC) and bone metastases. Data for radium-223 in asymptomatic CRPC patients with bone metastases are lacking. METHODS: This was a prospective, single-arm phase 3b study. Patients with metastatic CRPC (malignant lymphadenopathy not exceeding 6 cm was allowed, visceral disease was excluded) received radium-223, 55 kBq/kg intravenously, every 4 weeks for up to 6 cycles. Co-primary endpoints were safety and overall survival. Post hoc analyses were performed according to baseline asymptomatic or symptomatic disease status. Asymptomatic status was defined as no pain and no opioid use at baseline. RESULTS: Seven hundred eight patients received ≥1 radium-223 injection: 548 (77%) were symptomatic to various degrees, and 135 (19%) were asymptomatic. Asymptomatic patients had more favorable baseline disease characteristics than symptomatic. A lower proportion of asymptomatic versus symptomatic patients had received prior abiraterone (25% vs 35%) and prior docetaxel (52% vs 62%). A higher proportion of asymptomatic (71%) versus symptomatic (55%) patients completed radium-223 treatment. Overall survival (hazard ratio [HR] 0.486), time to disease progression (HR 0.722) and time to first symptomatic skeletal event (HR 0.328) were better in asymptomatic than symptomatic patients. Alkaline phosphatase (ALP) response rates were similar (46% vs 47%), and ALP normalization (44% vs 25%) and prostate-specific antigen response rates (21% vs 13%) were higher in asymptomatic than symptomatic patients. A lower proportion of asymptomatic patients reported treatment-emergent adverse events (TEAEs, 61% vs 79%), grade 3-4 TEAEs (29% vs 40%) and drug-related TEAEs (28% vs 44%). There were two treatment-related deaths, both in patients with baseline symptomatic disease. CONCLUSIONS: Using radium-223 earlier in the disease course, when patients are asymptomatic or minimally symptomatic, may enable patients to complete treatment and optimize treatment outcome compared to symptomatic patients, and therefore may allow sequencing with other life-prolonging therapies. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov , number NCT01618370 on June 13, 2012 and the European Union Clinical Trials Register, EudraCT number 2012-000075-16 on April 4, 2012.

Incidence and survival outcomes in patients with upper urinary tract urothelial carcinoma diagnosed with variant histology and treated with nephroureterectomy.

OBJECTIVE: To evaluate the incidence and survival outcomes of histological variants of upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). MATERIALS AND METHODS: We retrospectively analysed data from 1610 patients treated with RNU for clinically non-metastatic UTUC between 1990 and 2016 in several centres participating in the UTUC Collaboration. Histological variants were classified as micropapillary, squamous, sarcomatoid and other, including other rare variants (<10 cases for each). Multivariable competing risk analyses were conducted to assess the effect of variant histology on overall recurrence and cancer-specific mortality (CSM). RESULTS: Overall, 1460 patients (91%) had pure urothelial carcinoma (PUC), whereas 150 (9%) were diagnosed with a variant histology, including 89 (5.0%), 41 (2.0%), 10 (1.0%) and 10 (1.0%) cases of micropapillary, squamous, sarcomatoid and other tumours, respectively. Variant histology was associated with the presence of adverse pathological features compared with PUC, including non-organ-confined disease (59% vs 38%; P < 0.001), lymph node invasion (28% vs 24%; P = 0.02), high-grade disease (88% vs 71%; P < 0.001), tumour necrosis (28% vs 16%; P = 0.001) and positive surgical margins (15% vs 8%; P = 0.01). In competing risk analysis, micropapillary variant was the only factor associated with worse recurrence (sub-hazard ratio [SHR] 2.27, 95% confidence interval [CI] 1.25-4.79; P = 0.02) whereas sarcomatoid variant was associated with worse CSM (SHR 16.8, 95% CI 6.86-41.17; P < 0.001). CONCLUSION: We found that one out of 10 patients with UTUC treated with RNU had variant histology. Only micropapillary and sarcomatoid variants were associated with poorer oncological outcomes after adjusting for available confounding factors.

Online support groups offer low-threshold backing for family and friends of patients with prostate cancer.

A prostate cancer diagnosis affects not only the patients but also their family and friends. We performed a secondary analysis of a survey of users of the largest German online support group (OSG) for prostate cancer. We collected socio-demographic, psychological and disease-related data over a three-month period in 2013. Among 769 participants with a complete questionnaire, 686 were patients, and 83 were family members and friends of other patients. The family and friends group comprised 33% spouses, 31% children and 36% people with other relationships to the patient ("others"). Compared to the patient group, the family and friends group showed higher scores for anxiety and depression and described a higher rate of metastatic disease in the patients with whom they had a relationship. The children of patients showed the highest psychological burden based on their scores for anxiety and depression. Only 7% of spouses and none of the children attended face-to-face support groups, compared to 70% of people in the "others" group. OSGs offer low-threshold support for family members and friends; specifically, they meet the needs of spouses and children who do not attend face-to-face support groups. To improve counselling efforts, physicians should be aware of this online resource.

Leiomyosarcoma of the Urinary Bladder in Adult Patients: A Systematic Review of the Literature and Meta-Analysis.

PURPOSE: Leiomyosarcoma of the urinary bladder is exceedingly rare. Most clinicians come across only a few cases during their career, and information regarding treatment and outcome is scattered in the scientific literature. Interested clinicians and patients have to undertake troublesome search for treatment and outcome information. MATERIAL AND METHODS: We performed a systematic review of the literature using the PubMed and Web of Science databases and included all identified cases published in English language between 1970 and June 2018 into a meta-analysis. Prior to the literature search, key questions were formulated and with the data obtained, answers to these questions should be derived. RESULTS: We analyzed clinical data of 210 cases of urinary bladder leiomyosarcoma revealed by this review and seen in our institution. The mean age of patients was 52 years. The majority (75%) of the tumors was classified as high-grade sarcomas. We found no report of a prior radiation therapy to the pelvic organs, but some authors suggested an association between cyclophosphamide treatment and the development of bladder leiomyosarcoma, especially in patients with retinoblastoma. For the whole sample, we determined 5- and 10-year cancer-specific cumulative mortality rates of 38 and 50%. Patients with high-grade sarcomas had a trend toward a higher mortality compared with low-grade tumors (p = 0.0280). The most promising treatment option seems to be surgery (radical or partial cystectomy) with negative resection margins, possibly supplemented by chemotherapy or radiation. CONCLUSION: About half of patients with bladder leiomyosarcoma survived on the long run. Low-grade tumors may have a better outcome with, nevertheless, countable long-term mortality. For better assessment of that rare bladder tumor, its best treatment options, and the influence of neoadjuvant or adjuvant therapies on the outcome of patients, a larger series with long-term survival data is required.

In-Hospital Outcomes after Radical Cystectomy for Bladder Cancer: Comparing National Trends in the United States and Germany from 2006 to 2014.

BACKGROUND: Radical cystectomy (RC) still poses a significant risk for mortality and morbidity. OBJECTIVES: We compared in-hospital outcomes after RC in the United States and -Germany using population-based data. METHODS: We compared data from the US Nationwide Inpatient Sample to the German hospital billing database. Mortality and transfusion during hospital stay and length of stay (LOS) were evaluated. RESULTS: In all, 17,711 (the United States) and 60,447 (-Germany) cases were included. The share of robot-assisted RC increased to 20.5% in the United States vs. 2.3% in Germany (p < 0.001). In-hospital mortality was 1.9% (the United States) vs. 4.6% (Germany), transfusion rates were 34.2% (the United States) vs. 58.7% (Germany), and LOS was 10.7 (the United States) vs. 25.1 days (Germany; all p < 0.001). On multivariate analysis, higher patient age and lower annual hospital caseload were associated with increased mortality and longer LOS. Minimal-invasive surgery was associated with less blood transfusion and shorter LOS in the United States vs. hospital caseload and choice of urinary diversion in Germany. CONCLUSIONS: Healthcare systems might exert a relevant impact on outcomes of oncologic surgery. Increased in-hospital mortality rates in Germany seem to be partly explained by much longer LOS compared to those in the United States. Annual caseload seems to be influential on in-hospital outcomes raising the question of centralization of RC.

Long-Term Mortality in Patients with Positive Lymph Nodes at the Time of Radical Prostatectomy.

BACKGROUND: The aim of this study was to determine prognostic factors and to provide long-term mortality data in patients with positive lymph nodes at the time of radical prostatectomy in a sample with long-term follow-up. METHODS: A total of 527 patients with complete data sets treated in the years 1992-2014 were studied. The median follow-up was 7.2 years. The median number of removed lymph nodes was 15. Age, year of surgery, Gleason score, local tumor stage, prostate-specific antigen level, lymph node density, lymph node count and the number of positive lymph nodes were included in multivariable competing risk analyses with prostate cancer mortality as endpoint. RESULTS: After 20 years, 28% of patients (95% CI 20-36%) died from non-prostate cancer (competing) causes, whereas 29% (95% CI 23-36%) died from prostate cancer. Only lymph node density (stratified by the median of 11.1%; hazard ratio [HR] 1.66, 95% CI 1.04-2.64, p = 0.0340) and Gleason score (8-10 vs. <8: HR 5.97, 95% CI 3.18-11.23, p < 0.0001) were independent predictors of prostate cancer mortality. Patients with a Gleason score <8 and a lymph node density < median had a 20-year prostate cancer mortality of only 5% (95% CI 0-10%), whereas this rate in patients with Gleason score 8-10 and a lymph node density ≥ median was 44% (95% CI 32-56%), p < 0.0001. CONCLUSIONS: Mortality in patients with positive lymph nodes was determined by tumor aggressiveness and the relative extent of spread; neither the year of surgery nor the number of removed lymph nodes was associated with outcome. Patients with a lymph node density of <11.1% and a Gleason score <8 had an excellent long-term outcome.

Evaluation of Transperineal Magnetic Resonance Imaging/Ultrasound-Fusion Biopsy Compared to Transrectal Systematic Biopsy in the Prediction of Tumour Aggressiveness in Patients with Previously Negative Biopsy.

OBJECTIVES: We compared the transperineal MRI/ultrasound-fusion biopsy (fusPbx) to transrectal systematic biopsy (sysPbx) in patients with previously negative biopsy and investigated the prediction of tumour aggressiveness with regard to radical prostatectomy (RP) specimen. MATERIAL AND METHODS: A total of 710 patients underwent multiparametric magnetic resonance imaging (mpMRI), which was evaluated in accordance with Prostate Imaging Reporting and Data System (PI-RADS). The maximum PI-RADS (maxPI-RADS) was defined as the highest PI-RADS of all lesions detected in mpMRI. In case of proven prostate cancer (PCa) and performed RP, tumour grading of the biopsy specimen was compared to that of the RP. Significant PCa (csPCa) was defined according to Epstein criteria. RESULTS: Overall, scPCa was detected in 40% of patients. The detection rate of scPCa was 33% for fusPbx and 25% for sysPbx alone (p < 0.005). Patients with a maxPI-RADS ≥3 and a prostate specific antigen (PSA)-density ≥0.2 ng/mL2 harboured more csPCa than those with a PSA-density < 0.2 ng/mL2 (41% [33/81] vs. 20% [48/248]; p < 0.001). Compared to the RP specimen (n = 140), the concordance of tumour grading was 48% (γ = 0.57), 36% (γ = 0.31) and 54% (γ = 0.6) in fusPbx, sysPbx and comPbx, respectively. CONCLUSIONS: The combination of fusPbx and sysPbx outperforms both biopsy modalities in patients with re-biopsy. Additionally, the PSA-density may represent a predictor for csPCa in patients with maxPI-RADS ≥3.

Urinary Diversion After Radical Cystectomy for Bladder Cancer: Comparing Trends in the US and Germany from 2006 to 2014.

OBJECTIVE: Our aim was to assess and compare trends of urinary diversion (UD) for patients receiving radical cystectomy for the treatment of bladder cancer in the US and Germany, and to investigate decisive predictors for the choice of UD. METHODS: We analyzed the nationwide German hospital billing database and the Nationwide Inpatient Sample (NIS) from 2006 to 2014. Cases with a bladder cancer diagnosis combined with RC were included, and trends in the choice of UD, transfusion rates, length of stay, and mortality were assessed. RESULTS: From 2006 to 2014, the total number of RCs recorded within the NIS were 17,711, with a varying annual caseload of 1666-2009, while RC numbers increased from 5627 to 7390 in Germany (p < 0.001 for trends), with a total of 60,447 cases. The share of incontinent UD in the US remained stable at 93%, while increasing from 63.2 to 70.8% in Germany. Multivariate models indicated age and sex were the most important factors associated with the choice of UD in both countries, while hospital caseload and teaching status were less relevant factors in the US. In-hospital mortality was lower in the US compared with Germany (1.9% vs. 4.6%; p < 0.001), with significantly shorter hospital stays (10.7 days in the US vs. 25.1 days in Germany; p < 0.001). CONCLUSIONS: The increasing age of patients with presumably higher comorbidity in recent years led to increased use of incontinent UD in Germany, while continent UD appears to be underused in the US. Mortality and transfusion rates were significantly lower in the US within a shorter hospital stay.