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.

PD-L1 expression in tumor and inflammatory cells is associated with favorable tumor features and favorable prognosis in muscle-invasive urothelial carcinoma of the bladder not treated by immune checkpoint inhibitors.

BACKGROUND: A high level of PD-L1 expression is the most relevant predictive parameter for response to immune checkpoint inhibitor (CPI) therapy in urinary bladder cancer. Existing data on the relationship between PD-L1 expression and the natural course of disease are controversial and sparse. METHODS: To expand our understanding of the relationship between PD-L1 expression and parameters of cancer aggressiveness, PD-L1 was analyzed on tissue microarrays containing 2710 urothelial bladder carcinomas including 512 patients with follow-up data who underwent radical cystectomy and follow-up therapies in the pre-immune checkpoint inhibitor therapy era. RESULTS: Tumor cell positivity in ≥10% of cells were seen in 513 (20%) and an immune cell positivity occurred in 872 (34%) of 2566 interpretable cancers. PD-L1 positivity in tumor cells increased from pTaG2 low grade (0.9% positive) to pTaG3 high grade (4.1%; p = 0.0255) and was even higher in muscle-invasive (pT2-4) carcinomas (29.3%; p < 0.0001). However, within pT2-4 carcinomas, PD-L1 positivity was linked to low pT stage (p = 0.0028), pN0 (p < 0.0001), L0 status (p = 0.0005), and a better prognosis within 512 patients with cystectomy who never received CPIs (p = 0.0073 for tumor cells and p = 0.0086 for inflammatory cells). PD-L1 staining in inflammatory cells was significantly linked to PD-L1 staining in tumor cells (p < 0.0001) and both were linked to a positive p53 immunostaining (p < 0.0001). CONCLUSION: It cannot be fully excluded that the strong statistical link between PD-L1 status and favorable histological tumor features as well as better prognosis could influence the outcome of studies evaluating CPIs in muscle-invasive urothelial carcinoma.

Interactive Explainable Deep Learning Model Informs Prostate Cancer Diagnosis at MRI.

Background Clinically significant prostate cancer (PCa) diagnosis at MRI requires accurate and efficient radiologic interpretation. Although artificial intelligence may assist in this task, lack of transparency has limited clinical translation. Purpose To develop an explainable artificial intelligence (XAI) model for clinically significant PCa diagnosis at biparametric MRI using Prostate Imaging Reporting and Data System (PI-RADS) features for classification justification. Materials and Methods This retrospective study included consecutive patients with histopathologic analysis-proven prostatic lesions who underwent biparametric MRI and biopsy between January 2012 and December 2017. After image annotation by two radiologists, a deep learning model was trained to detect the index lesion; classify PCa, clinically significant PCa (Gleason score ≥ 7), and benign lesions (eg, prostatitis); and justify classifications using PI-RADS features. Lesion- and patient-based performance were assessed using fivefold cross validation and areas under the receiver operating characteristic curve. Clinical feasibility was tested in a multireader study and by using the external PROSTATEx data set. Statistical evaluation of the multireader study included Mann-Whitney U and exact Fisher-Yates test. Results Overall, 1224 men (median age, 67 years; IQR, 62-73 years) had 3260 prostatic lesions (372 lesions with Gleason score of 6; 743 lesions with Gleason score of ≥ 7; 2145 benign lesions). XAI reliably detected clinically significant PCa in internal (area under the receiver operating characteristic curve, 0.89) and external test sets (area under the receiver operating characteristic curve, 0.87) with a sensitivity of 93% (95% CI: 87, 98) and an average of one false-positive finding per patient. Accuracy of the visual and textual explanations of XAI classifications was 80% (1080 of 1352), confirmed by experts. XAI-assisted readings improved the confidence (4.1 vs 3.4 on a five-point Likert scale; P = .007) of nonexperts in assessing PI-RADS 3 lesions, reducing reading time by 58 seconds (P = .009). Conclusion The explainable AI model reliably detected and classified clinically significant prostate cancer and improved the confidence and reading time of nonexperts while providing visual and textual explanations using well-established imaging features. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Chapiro in this issue.

Cytokeratin 20 expression is linked to stage progression and to poor prognosis in advanced (pT4) urothelial carcinoma of the bladder.

Cytokeratin 20 (CK20) expression is limited to umbrella cells in the normal urothelium. Since CK20 is often upregulated in neoplastic urothelial cells including dysplasia and carcinoma in situ, immunohistochemical CK20 analysis is often used for the assessment of bladder biopsies. CK20 expression is a feature of luminal bladder cancer subtype, but its prognostic relevance is disputed. In this study, we investigated CK20 on >2700 urothelial bladder carcinomas in a tissue microarray format by immunohistochemistry. Cytoplasmic and membranous CK20 staining was seen in 1319 (51.8%) cancers. The fraction of CK20 positive and especially strongly positive cases increased from pTaG2 low grade (44.5% strongly positive) and pTaG2 high grade (57.7%) to pTaG3 high grade (62.3%; p = 0.0006) but was lower in muscle-invasive (pT2-4) carcinomas (51.1% in all pTa vs. 29.6% in pT2-4; p < 0.0001). Within pT2-4 carcinomas, CK20 positivity was linked to nodal metastasis and lymphatic vessel invasion (p < 0.0001 each) and to venous invasion (p = 0.0177). CK20 staining was unrelated to overall patient survival if all 605 pT2-4 carcinomas were jointly analyzed but subgroup analyses revealed a significant association of CK20 positivity with favorable prognosis in 129 pT4 carcinomas (p = 0.0005). CK20 positivity was strongly linked to the expression of GATA3 (p < 0.0001), another feature of luminal bladder cancer. The combined analysis of both parameters showed best prognosis for luminal A (CK20+/GATA3+, CK20+/GATA3-) and worst outcome for luminal B (CK20-/GATA3+) and basal/squamous (CK20-/GATA3-) in pT4 urothelial carcinomas (p = 0.0005). In summary, the results of our study demonstrate a complex role of CK20 expression in urothelial neoplasms including neoexpression in pTa tumors, a subsequent loss of CK20 expression in a subset of tumors progressing to muscle-invasion, and a stage dependent prognostic role in muscle-invasive cancers.

Altered p53/p16 expression is linked to urothelial carcinoma progression but largely unrelated to prognosis in muscle-invasive tumors.

BACKGROUND: Most inactivating p53 mutations result in a nuclear p53 accumulation - detectable by immunohistochemistry (IHC). p53 alterations leading to a complete lack of p53 protein and absence of immunostaining do also occur - not easily detectable by IHC. p16 is upregulated in p53 inactivated cells. We hypothesized that a positive p16 IHC may help to distinguish p53 inactivation in IHC negative cases. MATERIAL AND METHODS: We investigated p53 and p16 immunostaining on 2710 urothelial bladder carcinomas in a tissue microarray format to understand their impact in relation to clinicopathological parameters of disease progression and patient outcome. RESULTS: p16 immunostaining was absent in normal urothelium but occurred in 63.5% (30.4% strong) of cancers. p16 strongly positive cases increased from pTaG2 low-grade (9.6%) to pTaG3 high-grade tumors (46.5%, p < .0001) but decreased from pTaG3 to pT4 (33.3%; p = .0030). Among pT2-4 carcinomas, p16 positivity was linked to high-grade (p = .0005) but unrelated to overall survival. p53 staining was negative in 8.4%, very weak in 15.4%, weak in 55.3%, strong in 4.7%, and very strong in 16.2% cancers. p53 negative (potentially p53 null phenotype), strong, and very strong p53 positivity increased from pTaG2 low-grade to pTaG3 high-grade tumors (p < .0001) and from pTaG3 to pT2-4 cancers (p = .0007). p53 staining was largely unrelated to histopathological parameters or patient prognosis among pT2-4 carcinomas, except of p53 strong/very strong immunostaining. p16 expression predominated in tumors with very strong, strong, and negative p53 staining and the combination of p53 negative/p16 strongly positive cancers was linked to features of tumor aggressiveness. CONCLUSION: Aberrant p53 and p16 immunostaining increases during grade and stage progression although p53 negative and p16 positive immunostaining lack prognostic significance in pT2-4 carcinomas. Potential diagnostic features are that high level p16 expression is limited to neoplastic urothelium and p53 null phenotype to aggressive cancers (grade 3 and invasive).

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.

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.

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.

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.

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.

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.

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.

Tiam1/Rac1 signals contribute to the proliferation and chemoresistance, but not motility, of chronic lymphocytic leukemia cells.

Signals from the tumor microenvironment promote the migration, survival, and proliferation of chronic lymphocytic leukemia (CLL) cells. Rho GTPases control various signaling pathways downstream of microenvironmental cues. Here, we analyze the function of Rac1 in the motility and proliferation of CLL cells. We found decreased transcription of the Rac guanine nucleotide exchange factors Tiam1 and Vav1 in unstimulated peripheral blood CLL cells with almost complete loss of Tiam1 but increased transcription of the potential Rac antagonist RhoH. Consistently, stimulation of CLL cells with the chemokine CXCL12 induced RhoA but not Rac1 activation, whereas chemokine-induced CLL cell motility was Rac1-independent. Coculture of CLL cells with activated T cells induced their activation and subsequent proliferation. Here, Tiam1 expression was induced in the malignant cells in line with increased Ki-67 and c-Myc expression. Rac1 or Tiam1 knockdown using siRNA or treatment with the Tiam1/Rac inhibitor NSC-23766 attenuated c-Myc transcription. Furthermore, treatment of CLL cells with NSC-23766 reduced their proliferation. Rac inhibition also antagonized the chemoresistance of activated CLL cells toward fludarabine. Collectively, our data suggest a dynamic regulation of Rac1 function in the CLL microenvironment. Rac inhibition could be of clinical use by selectively interfering with CLL cell proliferation and chemoresistance.

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.

Preoperative serum cholesterol is an independent prognostic factor for patients with renal cell carcinoma (RCC).

OBJECTIVE: To assess the prognostic role of preoperative serum cholesterol in patients with renal cell carcinoma (RCC), as increasing evidence suggests that alterations in the lipid profile are associated with the development, progression and prognosis of various cancers. PATIENTS AND METHODS: We analysed 867 patients, who underwent radical or partial nephrectomy for RCC between 2002 and 2012. Preoperative total cholesterol levels were determined in serum using colorimetric analysis (CHOD-PAP method). The association with cancer-specific survival (CSS) was assessed with Cox models. Discrimination was quantified with the C-index. The median follow-up was 52 months. RESULTS: The median (interquartile range) serum cholesterol was 195 (166-232) mg/dL. Decreasing serum cholesterol was associated with more advanced T, N and M stages (P < 0.001), higher grades (P = 0.001) and presence of tumour necrosis (P = 0.002). Continuously coded cholesterol was associated with CSS in both univariable (hazard ratio [HR] 0.87, P < 0.001) and multivariable analyses (HR 0.93, P = 0.001). The discrimination of a multivariable base model increased significantly from 88.3% to 89.2% following inclusion of cholesterol (P = 0.006). In patients with clinically localised disease (T1-3N0/+M0), cholesterol remained associated with CSS in multivariable analysis (HR 0.90, P = 0.002) and increased the discrimination from 74.6% to 76.9% (P = 0.002). CONCLUSIONS: Preoperative serum cholesterol is an independent prognostic factor for patients with RCC, with lower levels being associated with worse survival. Its use increases the discrimination of established prognostic factors. As cholesterol is a broadly available routine marker, its use may provide a meaningful adjunct in clinical practice. The biological rationale underlying this association remains to be clarified.

The role of adjuvant chemotherapy for lymph node-positive upper tract urothelial carcinoma following radical nephroureterectomy: a retrospective study.

OBJECTIVE: To evaluate the effect of adjuvant chemotherapy (AC) on mortality after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) with positive lymph nodes (LNs) and to identify patient subgroups that are most likely to benefit from AC. PATIENTS AND METHODS: We retrospectively analysed data of 263 patients with LN-positive UTUC, who underwent full surgical resection. In all, 107 patients (41%) received three to six cycles of AC, while 156 (59.3%) were treated with RNU alone. UTUC-related mortality was evaluated using competing-risks regression models. RESULTS: In all patients (T(all) N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3-4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019). The absolute difference in mortality was 10% after the first year and increased to 23% after 5 years. On multivariable analysis, administration of AC was associated with significantly reduced UTUC-related mortality (subhazard ratio 0.67, P = 0.022). Limitations of this study are the retrospective non-randomised design, selection bias, absence of a central pathological review and different AC protocols. CONCLUSIONS: AC seems to reduce mortality in patients with pT3-4 LN-positive UTUC after RNU. This subgroup of LN-positive patients could serve as target population for an AC prospective randomised trial.

Adjuvant cisplatin-based combined chemotherapy for lymph node (LN)-positive urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC): a retrospective international study of >1500 patients.

OBJECTIVE: To compare outcomes of patients with lymph node (LN)-positive urothelial carcinoma of the bladder (UCB) treated with or without cisplatin-based combined adjuvant chemotherapy (AC) after radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively analysed 1523 patients with LN-positive UCB, who underwent RC with bilateral pelvic LN dissection. All patients had no evidence of disease after RC. AC was administered within 3 months. Competing-risks models were applied to compare UCB-related mortality. RESULTS: Of the 1523 patients, 874 (57.4%) received AC. The cumulative 1-, 2- and 5-year UCB-related mortality rates for all patients were 16%, 36% and 56%, respectively. Administration of AC was associated with an 18% relative reduction in the risk of UCB-related death (subhazard ratio 0.82, P = 0.005). The absolute reduction in mortality was 3.5% at 5 years. The positive effect of AC was detectable in patients aged ≤70 years, in women, in pT3-4 disease, and in those with a higher LN density and lymphovascular invasion. This study is limited by its retrospective and non-randomised design, selection bias, the absence of central pathological review and lack in standardisation of LN dissection and cisplatin-based protocols. CONCLUSION: AC seems to reduce UCB-related mortality in patients with LN-positive UCB after RC. Younger patients, women and those with high-risk features such as pT3-4 disease, a higher LN density and lymphovascular invasion appear to benefit most. Appropriately powered prospective randomised trials are necessary to confirm these findings.

Outcomes of minimally invasive simple prostatectomy for benign prostatic hyperplasia: a systematic review and meta-analysis.

PURPOSE: (1) To assess the outcomes of minimally invasive simple prostatectomy (MISP) for the treatment of symptomatic benign prostatic hyperplasia in men with large prostates and (2) to compare them with open simple prostatectomy (OSP). METHODS: A systematic review of outcomes of MISP for benign prostatic hyperplasia with meta-analysis was conducted. The article selection process was conducted according to the PRISMA guidelines. RESULTS: Twenty-seven observational studies with 764 patients were analyzed. The mean prostate volume was 113.5 ml (95 % CI 106-121). The mean increase in Qmax was 14.3 ml/s (95 % CI 13.1-15.6), and the mean improvement in IPSS was 17.2 (95 % CI 15.2-19.2). Mean duration of operation was 141 min (95 % CI 124-159), and the mean intraoperative blood loss was 284 ml (95 % CI 243-325). One hundred and four patients (13.6 %) developed a surgical complication. In comparative studies, length of hospital stay (WMD -1.6 days, p = 0.02), length of catheter use (WMD -1.3 days, p = 0.04) and estimated blood loss (WMD -187 ml, p = 0.015) were significantly lower in the MISP group, while the duration of operation was longer than in OSP (WMD 37.8 min, p < 0.0001). There were no differences in improvements in Qmax, IPSS and perioperative complications between both procedures. The small study sizes, publication bias, lack of systematic complication reporting and short follow-up are limitations. CONCLUSIONS: MISP seems an effective and safe treatment option. It provides similar improvements in Qmax and IPSS as OSP. Despite taking longer, it results in less blood loss and shorter hospital stay. Prospective randomized studies comparing OSP, MISP and laser enucleation are needed to define the standard surgical treatment for large prostates.

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.