Real-world performance of Uromonitor® in urothelial bladder cancer detection: a multicentric trial.

OBJECTIVES: To compare Uromonitor® (U-Monitor Lda, Porto, Portugal), a multitarget DNA assay that detects mutated proto-oncogenes (telomerase reverse transcriptase [TERT], fibroblast growth factor receptor 3 [FGFR-3], Kirsten rat sarcoma viral oncogene homologue [KRAS]), with urine cytology in the urine-based diagnosis of urothelial carcinoma of the bladder (UCB) within a multicentre real-world setting. PATIENTS AND METHODS: This multicentre, prospective, double-blind study was conducted across four German urological centres from 2019 to 2024. We evaluated the diagnostic performance of Uromonitor compared to urine cytology in a cohort of patients with UCB and in healthy controls within a real-world setting. Sensitivity, specificity, positive-predictive value (PPV), negative-predictive value (NPV), and accuracy of the tests were measured, in addition to multivariate analyses to assess the ability of individual proto-oncogene mutations in detecting UCB. The biometric sample size was designed to achieve a 10% difference in sensitivity. RESULTS: Patients with UCB comprised 63.7% (339/532) of the study group. Uromonitor showed a sensitivity, specificity, PPV, NPV, accuracy, and an area-under-the-curve of 49.3%, 93.3%, 92.8%, 51.1%, 65.2%, and 0.713%, respectively. These metrics did not demonstrate statistical superiority over urine cytology in terms of sensitivity (44.6%; P = 0.316). Moreover, the comparison of additional test parameters, as well as the comparison within various sensitivity analyses, yielded no significant disparity between the two urinary tests. Multivariate logistic regression underscored the significant predictive value of a positive Uromonitor for detecting UCB (odds ratio [OR] 9.03; P < 0.001). Furthermore, mutations in TERT and FGFR-3 were independently associated with high odds of UCB detection (OR 13.30 and 7.04, respectively), while KRAS mutations did not exhibit predictive capability. CONCLUSION: Despite its innovative approach, Uromonitor fell short of confirming the superior results anticipated from previous studies in this real-world setting. The search for an optimal urine-based biomarker for detecting and monitoring UCB remains ongoing. Results from this study highlight the complexity of developing non-invasive diagnostic tools and emphasise the importance of continued research efforts to refine these technologies.

Transplant nephrectomy: indication, surgical approach and complications-experiences from a single transplantation center.

PURPOSE: Management of a failed kidney allograft, and the question whether it should be removed is a challenging task for clinicians. The reported risks for transplant nephrectomy (TN) vary, and there is no clear recommendation on indications or surgical approach that should be used. This study gives an overview of indications, compares surgical techniques, and identifies risk factors for higher morbidity. METHODS: Retrospective analysis was conducted on all transplant nephrectomies performed between 2005 and 2020 at Charité Hospital Berlin, Department of Urology. Patient demographics, laboratory parameters, graft survival data, indication for TN, and surgical complications were extracted from medical reports. RESULTS: A total of 195 TN were performed, with graft intolerance syndrome being the most common indication in 52 patients (26.7%), acute rejection in 36 (18.5%), acute infection in 30 (15.4%), and other reasons to stop immunosuppression in 26 patients (13.3%). Rare indications were vascular complications in 16 (8.2%) and malignancies in the allograft in six (3.1%) cases. Extracapsular surgical approach was significantly more often used in cases of vascular complications and earlier allograft removal, but there was no difference in complication rates between extra- and intracapsular approach. Acute infection was identified as an independent risk factor for a complication grade IIIb or higher according to Clavien-Dindo classification, with a HR of 12.3 (CI 2.2-67.7; p = 0.004). CONCLUSION: Transplant nephrectomy should only be performed when there is a good indication, and non-elective surgery should be avoided, when possible, as it increases morbidity.

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-Guérin (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.

Follow-up of men with a PI-RADS 4/5 lesion after negative MRI/Ultrasound fusion biopsy.

Magnetic resonance imaging/Ultrasound (MRI/US) fusion targeted biopsy (TB) in combination with a systematic biopsy (SB) improves cancer detection but limited data is available how to manage patients with a Prostate Imaging-Reporting and Data System (PI-RADS) ≥ 4 lesion and a negative biopsy. We evaluate the real-world management and the rate of clinically significant Prostate Cancer (csPCa) during follow-up. 1546 patients with a multi-parametric MRI (mpMRI) and a PI-RADS ≥ 3 who underwent SB and TB between January 2012 and May 2017 were retrospectively analyzed. 222 men with a PI-RADS ≥ 4 and a negative biopsy were included until 2019. For 177/222 (80%) complete follow-up data was obtained. 66/84 (78%) had an initial PI-RADS 4 and 18 (22%) a PI-RADS 5 lesion. 48% (84/177) received a repeat mpMRI; in the follow-up mpMRI, 39/84 (46%) lesions were downgraded to PI-RADS 2 and 11 (13%) to PI-RADS 3; three cases were upgraded and 28 lesions remained consistent. 18% (32/177) men underwent repeated TB and csPCa was detected in 44% (14/32). Our study presents real world data on the management of men with a negative TB biopsy. Men with a positive mpMRI and lesions with high suspicion (PI-RADS4/5) and a negative targeted biopsy should be critically reviewed and considered for repeat biopsy or strict surveillance. The optimal clinical risk assessment remains to be further evaluated.

A non-inferiority comparative analysis of micro-ultrasonography and MRI-targeted biopsy in men at risk of prostate cancer.

OBJECTIVE: To compare the efficacy of multiparametric magnetic resonance imaging (mpMRI)-directed and micro-ultrasonography (micro-US)-directed biopsy for detecting clinically significant (Grade Group >1) prostate cancer (csPCa). MATERIALS AND METHODS: A total of 203 patients were prospectively enrolled at three institutions across Germany and Austria in the period from January 2019 to December 2019. During each biopsy, the urologist was blinded to the mpMRI report until after the micro-US targets had been assessed. After unblinding, targets were then sampled using software-assisted fusion, followed by systematic samples. The primary outcome measure was non-inferiority of micro-US to detect csPCa, with a detection ratio of at least 80% that of mpMRI. RESULTS: A total of 79 csPCa cases were detected overall (39%). Micro-US-targeted biopsy detected 58/79 cases (73%), while mpMRI-targeted biopsy detected 60/79 (76%) and non-targeted (completion sampling) samples detected 45/79 cases (57%). mpMRI-targeted samples alone detected 7/79 (9%) csPCa cases which were missed by micro-US-targeted and non-targeted samples. Three of these seven were anterior lesions with 2/7 in the transition zone. Micro-US-targeted samples alone detected 5/79 (6%) and completion sampling alone detected 4/79 cases (5%). Micro-US was non-inferior to mpMRI and detected 97% of the csPCa cases detected by mpMRI-targeted biopsy (95% CI 80-116%; P = 0.023). CONCLUSIONS: This is the first multicentre prospective study comparing micro-US-targeted biopsy with mpMRI-targeted biopsy. The study provides further evidence that micro-US can reliably detect cancer lesions and suggests that micro-US biopsy might be as effective as mpMRI for detection of csPCA. This result has significant implications for increasing accessibility, reducing costs and expediting diagnosis.

Urinary expression of genes involved in DNA methylation and histone modification for diagnosis of bladder cancer in patients with asymptomatic microscopic haematuria.

The aim of the present study was to identify and test a urine marker panel of genes involved in DNA methylation and histone modification for the detection of urothelial carcinoma of the bladder (UCB). RNA samples obtained from the voided urine of 227 patients with asymptomatic microscopic haematuria (AMH) were analysed. Gene array analysis was performed on 18 randomly selected cDNA samples, which revealed that histone deacetylase 9 (HDAC9), HDAC3, tRNA (cytosine-5-)-methyltransferase1 and DNA methyltransferase 1 were differentially expressed between patients with UCB and control subjects. Subsequently, reverse transcription-quantitative polymerase chain reaction analysis was employed to test the performance of the identified four-gene panel on the remaining 209 cDNA samples. In this targeted discovery cohort, all four genes were significantly associated with UCB on univariable analyses [each odds ratio (OR) >2, P<0.05], but only HDAC3 was significant following multivariable analysis (OR=2.8, P=0.011). The addition of HDAC3 to a base risk factor model improved its accuracy by 1.4%. These data suggest that urinary HDAC3 is associated with the presence of UCB in patients with AMH; however, HDAC3 improved the accuracy of the established risk factors only to a marginal extent.

A urinary microRNA (miR) signature for diagnosis of bladder cancer.

INTRODUCTION: Bladder cancer (BC) is diagnosed by cystoscopy, which is invasive, costly and causes considerable patient discomfort. MicroRNAs (miR) are dysregulated in BC and may serve as non-invasive urine markers for primary diagnostics and monitoring. The purpose of this study was to identify a urinary miR signature that predicts the presence of BC. METHODS: For the detection of potential urinary miR markers, expression of 384 different miRs was analyzed in 16 urine samples from BC patients and controls using a Taqman™ Human MicroRNA Array (training set). The identified candidate gene signature was subsequently validated in an independent cohort of 202 urine samples of patients with BC and controls with microscopic hematuria. The final miR signature was developed from a multivariable logistic regression model. RESULTS: Analysis of the training set identified 14 candidate miRs for further analysis within the validation set. Using backward stepwise elimination, we identified a subset of 6 miRs (let-7c, miR-135a, miR-135b, miR-148a, miR-204, miR-345) that distinguished BC from controls with an area under the curve of 88.3%. The signature was most accurate in diagnosing high-grade non-muscle invasive BC (area under the curve = 92.9%), but was capable to identify both low-grade and high-grade disease as well as non-muscle and muscle-invasive BC with high accuracies. CONCLUSIONS: We identified a 6-gene miR signature that can accurately predict the presence of BC from urine samples, independent of stage and grade. This signature represents a simple urine assay that may help reducing costs and morbidity associated with invasive diagnostics.

Validation of Prostate Imaging Reporting and Data System Version 2 for the Detection of Prostate Cancer.

PURPOSE: The second version of the PI-RADS™ (Prostate Imaging Reporting and Data System) was introduced in 2015 to standardize the interpretation and reporting of prostate multiparametric magnetic resonance imaging. Recently low cancer detection rates were reported for PI-RADS version 2 category 4 lesions. Therefore the aim of the study was to evaluate the cancer detection rate of PI-RADS version 2 in a large prospective cohort. MATERIALS AND METHODS: The study included 704 consecutive men with primary or prior negative biopsies who underwent magnetic resonance imaging/ultrasound fusion guided targeted biopsy and 10-core systematic prostate biopsy between September 2015 and May 2017. All lesions were rated according to PI-RADS version 2 and lesions with PI-RADS version 2 category 3 or greater were biopsied. An ISUP (International Society of Urological Pathology) score of 2 or greater (ie Gleason 3 + 4 or greater) was defined as clinically significant prostate cancer. RESULTS: The overall cancer detection rate of PI-RADS version 2 categories 3, 4 and 5 was 39%, 72% and 91% for all prostate cancer, and 23%, 49% and 77% for all clinically significant prostate cancer, respectively. If only targeted biopsy had been performed, 59 clinically significant tumors (16%) would have been missed. The PI-RADS version 2 score was significantly associated with the presence of prostate cancer (p <0.001), the presence of clinically significant prostate cancer (p <0.001) and the ISUP grade (p <0.001). CONCLUSIONS: PI-RADS version 2 is significantly associated with the presence of clinically significant prostate cancer. The cancer detection rate of PI-RADS version 2 category 4 lesions was considerably higher than previously reported. When performing targeted biopsy, the combination with systematic biopsy still provides the highest detection of clinically significant prostate cancer.

Acceptance of Adjuvant and Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer in Germany: A Survey of Current Practice.

BACKGROUND: Guidelines support the use of neoadjuvant (NAC) and adjuvant (AC) chemotherapy in muscle-invasive bladder cancer. However, data from North America reported the underutilization of NAC in favor of AC despite the lower level of scientific evidence supporting AC. We aimed to assess current practice patterns of NAC and AC in -Germany. METHODS: A 15-question online survey was developed and sent via email newsletters to members of the -German Association of Urology and of the German Society of Residents in Urology in October 2016 to analyze current practice patterns. RESULTS: The survey yielded 141 individual responses from 61 different German urology departments. Eighty-nine (69.0%) and 119 (93.0%) participants were stated to regularly use NAC and AC respectively. The number of participants who were stated to use NAC and AC regularly was not associated with the type of institution (academic vs. nonacademic), number of hospital beds, and number of cystectomies performed annually. Gemcitabine/cisplatin combination chemotherapy was named as the primarily used NAC regimen by 80 (95%) respondents. The median number of administered cycles was 3 for NAC and 4 for AC. In the case of cisplatin ineligibility, combination chemotherapy with gemcitabine/carboplatin was the most common regimen. Respondents stated that chemotherapy was generally administered by urologists (81% for NAC and 85% for AC). CONCLUSIONS: Our survey of current practice shows a high acceptance rate of NAC in Germany, which was independent of the type of institution. Although the scientific level of evidence for AC is lower, it still seems to be more widely accepted than NAC. NAC and AC were generally administered by urologists.

Primary magnetic resonance imaging/ultrasonography fusion-guided biopsy of the prostate.

OBJECTIVE: To examine the performance of a primary magnetic resonance imaging (MRI)/ultrasonography (US) fusion-guided targeted biopsy (TB), and in combination with an added systematic biopsy (SB). PATIENTS AND METHODS: Analysis of 318 consecutive biopsy-naïve men with suspicious multiparametric MRI (mpMRI; Prostate Imaging Reporting and Data System [PI-RADS] score ≥3) undergoing transrectal TB and 10-core SB between January 2012 and December 2016. The indication for performing mpMRI was based on clinical parameters and decided by the treating urologist before admission. TB was performed with a sensor-based MRI/US fusion-guided platform. Clinically significant prostate cancer was defined as Gleason score ≥4 + 3 = 7 (International Society of Urological Pathology Grade [ISUP] grade 3) or maximum cancer core length of ≥6 mm. RESULTS: A median (interquartile range) of 14 (13-14) biopsies per case were taken. The overall cancer detection rate (CDR) was 77% (245/318). The TB alone detected 67% of prostate cancers and the SB alone detected 70%. The PI-RADS dependent CDR for the combination of TB/SB were 38% (21/55), 78% (120/154) and 95% (104/109) for PI-RADS scores of 3/4/5, respectively. Clinically significant prostate cancer was diagnosed by the combination of TB and SB in 195 men (61%) and by TB alone in 163 cases (51%). The number of missed or underestimated prostate cancers with a Gleason score ≥8 for TB alone was 31 (10%, P < 0.001) and 21 (7%, P < 0.001) for SB alone in comparison with the results of the combination of TB and SB. The rate of insignificant prostate cancer was comparable for the combination of TB and SB and TB alone (50/318, 16% vs 50/318, 16%). CONCLUSIONS: Pre-biopsy mpMRI is of incremental value in increasing the detection of clinically significant prostate cancer in biopsy-naïve patients with suspicion of prostate cancer. Combining TB with SB further improved the diagnostic accuracy without increasing the rate of insignificant prostate cancer.

Development of a Preoperative Nomogram Incorporating Biomarkers of Systemic Inflammatory Response to Predict Nonorgan-confined Urothelial Carcinoma of the Bladder at Radical Cystectomy.

OBJECTIVE: To develop a preoperative multivariable decision-making tool to predict nonorgan-confined urothelial carcinoma of the bladder (NOC-UCB) using standard clinical and pathological factors as well as biomarkers of systemic inflammatory response. MATERIALS AND METHODS: We retrospectively analyzed a prospectively maintained single-institutional database comprising 310 patients with clinically N0 M0 UCB who underwent radical cystectomy (RC) with pelvic lymph node dissection without neoadjuvant cisplatin-based chemotherapy (NAC). NOC-UCB was defined as pT3-4/Nany or pTany/N + disease. A predictive nomogram was built based on significant variables in a bootstrap-corrected multivariable logistic regression model. The accuracy was measured by the area under the curve. Decision-curve analysis was used to evaluate the clinical net benefit. RESULTS: NOC-UCB was found in 147 (47%) of the 310 patients. On multivariable analysis, T stage at transurethral resection of the bladder, lymphovascular invasion, abnormal imaging, and Glasgow prognostic score (GPS) were all independent predictors of NOC-UCB and formed the basis of the nomogram. By adding the GPS, the accuracy of the nomogram improved by 4.7% to 81.7%. The decision curve analysis showed a net benefit of this model compared with the Green model and the strategies of treating all patients or no patient with NAC. Limitations include the retrospective design and the lack of a validation cohort. CONCLUSION: NOC-UCB at radical cystectomy can be accurately predicted. The accuracy of preoperative models can be improved by adding biomarkers of systemic inflammatory response, such as the GPS. The use of this nomogram may help physicians to accurately identify patients with NOC-UCB who may benefit from NAC.

Dynamic Prognostication Using Conditional Recurrence and Progression Estimates for Patients with Nonmuscle Invasive Bladder Cancer.

PURPOSE: Conditional estimates provide a dynamic prediction of outcomes but to our knowledge there are no data on nonmuscle invasive bladder cancer. We assessed changes in conditional recurrence and progression rates after transurethral resection of the bladder and explored the prognostic impact of established factors and risk groups with time. MATERIALS AND METHODS: We retrospectively analyzed data on 1,292 consecutive patients with newly diagnosed Ta/T1 bladder cancer who underwent transurethral resection of the bladder. Study end points were time to first recurrence and time to progression. RESULTS: The 2-year recurrence rate at baseline was 36%, which improved as a function of the time that patients were free of disease recurrence. After 6, 12, 24, 36 and 48 months the 2-year conditional recurrence rate improved to 31% (14% improvement vs baseline), 22% (39% improvement), 16% (56% improvement), 13% (64% improvement) and 11% (69% improvement), respectively. Comparably, conditional progression rates improved with increasing followup, although relative differences were less distinct. The prognostic impact of established factors and nonmuscle invasive bladder cancer risk groups progressively decreased with time and finally disappeared. However, bacillus Calmette-Guérin had a protective effect on progression even after 3 years. We provide tables with dynamic prognostic information at all analyzed time points. CONCLUSIONS: In patients with primary Ta/T1 bladder cancer recurrence and progression rates improve with time. The prognostic impact of established factors and risk groups decreases and finally disappears. The effect of bacillus Calmette-Guérin on progression is long-lasting. Conditional outcome estimates may improve patient counseling and individualize surveillance planning.

The Moreau Strain of Bacillus Calmette-Guerin (BCG) for High-Risk Non-Muscle Invasive Bladder Cancer: An Alternative during Worldwide BCG Shortage?

BACKGROUND: Bacillus Calmette-Guerin (BCG) is the standard of care for adjuvant intravesical instillation therapy for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) after complete transurethral resection. Increasing evidence suggests that there are marked differences in outcomes according to BCG substrains. BCG-Moreau was recently introduced to the European market to cover the issue of BCG shortage, but there are little data regarding the oncologic efficacy. METHODS: We retrospectively analyzed 295 consecutive patients, who received adjuvant intravesical instillation therapy with BCG-Moreau for intermediate- and high-risk NMIBC between October 2007 and April 2013 at a single institution. The end points of this study were time to first recurrence and progression to muscle-invasive disease. RESULTS: Median age was 66 years (interquartile range 59-74, mean 65.9 years). According to the EAU risk group, 76 patients presented with intermediate-risk and 219 patients with high-risk NMIBC. The 5-year recurrence-free survival and progression-free survival rate was 64.8% (95% CI 52.8-74.4) and 81.4% (95% CI 65.2-90.2), respectively. CONCLUSIONS: BCG-Moreau is an effective substrain for adjuvant instillation therapies of NMIBC, and outcomes appear to be comparable to series using other substrains. During worldwide shortage of BCG-TICE, Connaught and RIVM, BCG-Moreau may serve as an equally effective alternative.

Association of human telomerase reverse transcriptase gene polymorphisms, serum levels, and telomere length with renal cell carcinoma risk and pathology.

Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of the human telomerase and plays a key role in telomere restitution and gene regulation. Evidence suggests that hTERT is linked with the risk and progression of several malignancies, but there are no comprehensive data in renal cell carcinoma (RCC). In this case-control study, we assessed seven polymorphic hTERT gene variants (MNS16A, rs2736100, rs2736098, rs7726159, rs2853677, rs13172201, and rs10069690), hTERT serum levels, and the telomere length of 663 individuals, including 243 with clear cell RCC and 420 age- and gender-matched healthy controls. The SL and SS genotypes of MNS16A were associated with a decreased risk for RCC on the multivariable logistic regression analysis (SL-OR 0.72, SS-OR 0.37, P < 0.001). The GG genotype of rs2736098 was associated with a decreased risk for RCC compared with AA (OR 0.18, P < 0.001). Both telomere length and hTERT serum levels increased with every G allele in rs2736098 (P = 0.008). Pretherapeutic hTERT serum levels were higher in patients with advanced tumor stages (P = 0.037) and distant metastases (P = 0.006). Rs2736100, rs7726159, rs2853677, rs13172201, and rs10069690 were not linked with RCC risk, and none of the polymorphisms was associated with RCC pathology. In conclusion, the polymorphic number of tandem repeats in hTERT (MNS16A) and rs2736098 may be linked with the risk for RCC. Rs2736098 may have an important role in telomere length restitution and serum hTERT levels may represent a novel biomarker for RCC. © 2015 Wiley Periodicals, Inc.

Serum Adiponectin Predicts Cancer-specific Survival of Patients with Renal Cell Carcinoma.

BACKGROUND: Prediction of outcomes in patients with renal cell carcinoma (RCC) is crucial for clinical decision-making. The limited accuracy of conventional prognostic factors such as stage and grade may be increased by the use of biomarkers. OBJECTIVE: To evaluate the association of serum adiponectin and leptin and polymorphisms in the leptin and leptin receptor genes with RCC histopathology and prognosis. DESIGN, SETTING, AND PARTICIPANTS: Adiponectin and leptin levels were measured in preoperative serum samples from 131 consecutive patients with sporadic unilateral RCC. The polymorphisms G-2548A (rs7799039) in the leptin gene (LEP) and Gln223Arg (Q223R, A668G, rs1137101) in the leptin receptor gene (LEPR) were genotyped in 233 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable associations with RCC-specific survival were analyzed using Cox models. RESULTS AND LIMITATIONS: Median preoperative serum adiponectin was 15.8µg/ml (interquartile range 10.0-23.1). Adiponectin was lower in patients with distant metastases (p=0.017) or histologic tumor necrosis (p=0.015). On multivariable analysis adjusted for the effects of variables in the Karakiewicz nomogram, each 1-µg/ml increase in adiponectin was associated with a 8% decrease in the hazard of death from RCC (hazard ratio 0.92, 95% confidence interval 0.86-0.98; p=0.007). The discrimination of the Karakiewicz nomogram increased by 0.6% on inclusion of adiponectin. Leptin levels, LEP G-2548A and LEPR Q223R were not associated with either RCC pathology or outcomes. Limitations include the retrospective study design, the low numbers of patients, and a lack of standardized follow-up. CONCLUSIONS: This study suggests that lower preoperative serum adiponectin is associated with features of biologically aggressive RCC, metastasis, and survival. PATIENT SUMMARY: We assessed the relationship between outcomes and blood levels of adiponectin and leptin and genetic changes in leptin and leptin receptor genes. We found that patients with lower adiponectin levels have more aggressive tumors and poorer survival.

Monocyte subset distribution in patients with stable atherosclerosis and elevated levels of lipoprotein(a).

BACKGROUND: Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein currently established as an independent risk factor for the development of atherosclerotic disease and as a predictor for acute thrombotic complications. In addition, Lp(a) is the major carrier of proinflammatory oxidized phospholipids (OxPL). Today, atherosclerosis is considered to be an inflammatory disease of the vessel wall in which monocytes and monocyte-derived macrophages are crucially involved. Circulating monocytes can be divided according to their surface expression pattern of CD14 and CD16 into at least 3 subsets with distinct inflammatory and atherogenic potential. OBJECTIVE: The aim of this study was to examine whether elevated levels of Lp(a) and OxPL on apolipoprotein B-100-containing lipoproteins (OxPL/apoB) are associated with changes in monocyte subset distribution. METHODS: We included 90 patients with stable coronary artery disease. Lp(a) and OxPL/apoB were measured, and monocyte subsets were identified as classical monocytes (CMs; CD14++CD16-), intermediate monocytes (IMs; CD14++CD16+), and nonclassical monocytes (NCMs; CD14+CD16++) by flow cytometry. RESULTS: In patients with elevated levels of Lp(a) (>50 mg/dL), monocyte subset distribution was skewed toward an increase in the proportion of IM (7.0 ± 3.8% vs 5.2 ± 3.0%; P = .026), whereas CM (82.6 ± 6.5% vs 82.0 ± 6.8%; P = .73) and NCM (10.5 ± 5.3 vs 12.8 ± 6.0; P = .10) were not significantly different. This association was independent of clinical risk factors, choice of statin treatment regime, and inflammatory markers. In addition, OxPL/apoB was higher in patients with elevated Lp(a) and correlated with IM but not CM and NCM. CONCLUSIONS: In conclusion, we provide a potential link between elevated levels of Lp(a) and a proatherogenic distribution of monocyte subtypes in patients with stable atherosclerotic disease.

Histopathology and prognosis of de novo bladder tumors following solid organ transplantation.

BACKGROUND: Patients following solid organ transplantation have an increased risk of developing de novo bladder tumors, but their biology is poorly characterized. METHODS: We studied 1743 patients who underwent a transurethral resection of a newly diagnosed bladder tumor at a single institution. The histopathology, treatment, recurrence-free survival and overall survival were evaluated and compared between transplant and non-transplant patients. RESULTS: We identified 74 transplant patients who developed a de novo bladder tumor after a median post-transplantation interval of 62 months. The tumor was malignant in 29 patients (39 %). The most common benign lesion was nephrogenic adenoma (84 %), which neither coexisted with nor developed into malignant tumors during follow-up. Compared with non-transplant patients (n = 1669), transplant patients were significantly younger (median 55 vs 69 years, P < 0.001) and had a 9.0-fold higher odds of benign tumors (P < 0.001), while there were no differences in pathology among patients with urothelial carcinoma of the bladder (UCB). In a multivariable analysis for non-muscle-invasive UCB that was adjusted for the risk group, patients with a transplant had a 1.8-fold increased risk of recurrence (P = 0.048). Four of five transplant patients did not respond to Bacillus Calmette-Guérin instillations. There were no differences in overall survival after radical cystectomy (P = 0.87). CONCLUSIONS: The majority of bladder tumors in transplant patients are benign, and they neither coexist with nor develop into malignant tumors. Transplant patients with non-muscle-invasive UCB show an increased risk of disease recurrence, while those treated with radical cystectomy have similar outcomes to patients without a transplant.

Comparison of the prognostic value of pretreatment measurements of systemic inflammatory response in patients undergoing curative resection of clear cell renal cell carcinoma.

PURPOSE: Pretreatment measurements of systemic inflammatory response, including the Glasgow prognostic score (GPS), the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), the platelet-to-lymphocyte ratio (PLR) and the prognostic nutritional index (PNI) have been recognized as prognostic factors in clear cell renal cell carcinoma (CCRCC), but there is at present no study that compared these markers. METHODS: We evaluated the pretreatment GPS, NLR, MLR, PLR and PNI in 430 patients, who underwent surgery for clinically localized CCRCC (pT1-3N0M0). Associations with disease-free survival were assessed with Cox models. Discrimination was measured with the C-index, and a decision curve analysis was used to evaluate the clinical net benefit. RESULTS: On multivariable analyses, all measures of systemic inflammatory response were significant prognostic factors. The increase in discrimination compared with the stage, size, grade and necrosis (SSIGN) score alone was 5.8 % for the GPS, 1.1-1.4 % for the NLR, 2.9-3.4 % for the MLR, 2.0-3.3 % for the PLR and 1.4-3.0 % for the PNI. On the simultaneous multivariable analysis of all candidate measures, the final multivariable model contained the SSIGN score (HR 1.40, P < 0.001), the GPS (HR 2.32, P < 0.001) and the MLR (HR 5.78, P = 0.003) as significant variables. Adding both the GPS and the MLR increased the discrimination of the SSIGN score by 6.2 % and improved the clinical net benefit. CONCLUSIONS: In patients with clinically localized CCRCC, the GPS and the MLR appear to be the most relevant prognostic measures of systemic inflammatory response. They may be used as an adjunct for patient counseling, tailoring management and clinical trial design.

Association of small dense LDL serum levels and circulating monocyte subsets in stable coronary artery disease.

OBJECTIVE: Atherosclerosis is considered to be an inflammatory disease in which monocytes and monocyte-derived macrophages play a key role. Circulating monocytes can be divided into three distinct subtypes, namely in classical monocytes (CM; CD14++CD16-), intermediate monocytes (IM; CD14++CD16+) and non-classical monocytes (NCM; CD14+CD16++). Low density lipoprotein particles are heterogeneous in size and density, with small, dense LDL (sdLDL) crucially implicated in atherogenesis. The aim of this study was to examine whether monocyte subsets are associated with sdLDL serum levels. METHODS: We included 90 patients with angiographically documented stable coronary artery disease and determined monocyte subtypes by flow cytometry. sdLDL was measured by an electrophoresis method on polyacrylamide gel. RESULTS: Patients with sdLDL levels in the highest tertile (sdLDL≥4mg/dL;T3) showed the highest levels of pro-inflammatory NCM (15.2±7% vs. 11.4±6% and 10.9±4%, respectively; p<0.01) when compared with patients in the middle (sdLDL=2-3mg/dL;T2) and lowest tertile (sdLDL=0-1mg/dL;T1). Furthermore, patients in the highest sdLDL tertile showed lower CM levels than patients in the middle and lowest tertile (79.2±8% vs. 83.9±7% and 82.7±5%; p<0.01 for T3 vs. T2+T1). Levels of IM were not related to sdLDL levels (5.6±4% vs. 4.6±3% vs. 6.4±3% for T3, T2 and T1, respectively). In contrast to monocyte subset distribution, levels of circulating pro- and anti-inflammatory markers were not associated with sdLDL levels. CONCLUSION: The atherogenic lipoprotein fraction sdLDL is associated with an increase of NCM and a decrease of CM. This could be a new link between lipid metabolism dysregulation, innate immunity and atherosclerosis.

The T309G murine double minute 2 gene polymorphism is an independent prognostic factor for patients with renal cell carcinoma.

The purpose of this study was to evaluate the association of the T309G MDM2 gene polymorphism with renal cell carcinoma (RCC) risk, pathology, and cancer-specific survival (CSS). T309G MDM2 was genotyped in 449 Caucasians, including 240 with RCC and 209 cancer-free controls. The T309G MDM2 genotype was TT in 174 (38.8%), GT in 214 (47.7%), and GG in 61 (13.6%) subjects, without any significant differences between cases and controls on both univariable (p=0.58) and multivariable logistic regression (each p>0.25). Furthermore, T309G MDM2 was not linked with T stage (p=0.75), N stage (p=0.37), M stage (p=0.94), grade (p=0.21), and subtype (p=0.55). There was, however, a statistically significant association of T309G MDM2 with CSS (p=0.022): patients with TT had significantly worse survival than GG/GT (p=0.009), while those with GT and GG had similar outcomes (p=0.92). The 5-year survival rate for patients with TT, GT, and GG was 69.5%, 84.5%, and 89.7%, respectively. On the multivariable analysis, T309G was identified as an independent prognostic factor. The T309G MDM2 polymorphism is an independent prognostic factor for patients with RCC, with the TT genotype being associated with worse prognosis. In this study, there were no significant associations with RCC risk and pathology.