Single versus multiple renal arteries in living donor kidney transplantation: A systematic review and patient-level meta-analysis.

INTRODUCTION: Grafts with multiple renal arteries (MRAs) were historically considered a relative contraindication to transplantation due to the higher risk of vascular and urologic complications. This study aimed to evaluate graft and patient survival between single renal artery (SRA) and MRA living-donor kidney transplants. METHODS: An electronic literature search was conducted on PubMed, EMBASE, and Scopus for prospective or retrospective studies comparing SRA versus MRA in living donor renal transplantation, with the provision of Kaplan-Meier curves for recipient overall survival (OS) or graft survival (GS). A graphical reconstructive algorithm was used to obtain OS and GS of individual patients, which was then pooled under random-effects individual patient data (IPD) meta-analysis using Cox-models to determine hazard ratios (HRs) and 95% confidence intervals (CIs). Meta-regression of baseline covariates versus HRs of OS and GS was performed for variables reported in 10 or more studies. RESULTS: Fourteen studies were retrieved, of which 13 (8400 patients) reported OS and 9 (6912 patients) reported GS. There were no significant differences in OS (shared-frailty HR = .94, 95%CI = .85-1.03, p = .172) or GS (shared-frailty HR = .95, 95%CI = .83-1.08, p = .419) between SRA and MRA. This comparison remained non-significant even when restricted to open- or laparoscopic-only studies. Meta-regression yielded no significant associations of GS with donor age, recipient age, and percentage of double renal arteries within the MRA arm. CONCLUSIONS: The similar rates of GS and OS between MRA and SRA grafts suggest that there is no need for discrimination between the two when evaluating donors for nephrectomy.

Evolving trends in the surgical management of renal masses over the past two decades: A contemporary picture from a large prospectively-maintained database.

OBJECTIVES: To investigate the trends in the presentation and surgical management of renal tumors at Singapore General Hospital, Singapore. METHODS: We accessed our uro-oncological registry to extract the clinicopathological data of patients with renal tumors who underwent nephrectomy from 2000 to 2015. Binary logistic regression was used to identify predictors of nephron-sparing surgery utilization, Clavien-Dindo grade ≥III complications and progression to stage ≥3 chronic kidney disease. Cox regression models were created to evaluate the proportional hazards of the risk factors for overall survival and cancer-specific survival. RESULTS: A total of 1208 cases of nephrectomy were carried out between 2000 and 2015. The proportion of cT1a tumors increased from 2000-2004 to 2010-2015, which was accompanied by the doubling of utilization rates of nephron-sparing surgery and minimally invasive surgery. Charlson Comorbidity Index score <2, asymptomatic presentation, clinical T1a tumors and having an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 were all independent predictors of nephron-sparing surgery utilization. Age, symptomatic presentation and nephron-sparing surgery utilization were all significantly associated with greater odds of having Clavien-Dindo grade ≥III complications, whereas minimally invasive surgery was associated with decreased risk. The utilization of partial nephrectomy and minimally invasive surgery was significantly associated with a decreased risk of developing postoperative stage ≥3 chronic kidney disease. Both overall survival and cancer-specific survival were not significantly affected by whether nephron-sparing surgery was utilized. CONCLUSIONS: There has been an increasing proportion of small renal masses diagnosed incidentally with a shift towards nephron-sparing surgery for clinically localized tumors. With the adoption of nephron-sparing surgery, progression to stage 3 chronic kidney disease has decreased, without any compromise in oncological and survival outcomes.

Tumor size and Fuhrman grade further enhance the prognostic impact of perinephric fat invasion and renal vein extension in T3a staging of renal cell carcinoma.

OBJECTIVE: To evaluate the prognostic values of perinephric fat invasion and renal vein invasion in pT3a renal cell carcinoma, as stand-alone factors and in combination with tumor size and Fuhrman grade. METHODS: Survival data of pT1 and pT2 renal cell carcinomas were analyzed alongside pT3a tumors of similar size bands (pT1 vs pT3a <7 cm, pT2 vs pT3a >7 cm). Patients with adjuvant therapy, positive surgical margins, metastasis or pT3b-pT4 tumors were excluded. RESULTS: No significant baseline demographic differences existed between the groups. Patients with renal vein invasion had larger tumors (median, 7.2 ± 3.0 cm vs 5.5 ± 3.6 cm, P = 0.039), and were more symptomatic (90.0% vs 61.7%, P = 0.028) compared with patients with perinephric fat invasion alone. Patients with perinephric fat invasion alone appeared to have better disease-free survival compared with those with renal vein invasion (P = 0.009). Having both perinephric fat invasion and renal vein invasion did not result in a poorer disease-free survival. pT3a (perinephric fat invasion) tumors <4 cm and 4-7 cm have significantly worse disease-free survival compared with pT1a and pT1b tumors (P < 0.001). Similarly, pT3a (perinephric fat invasion) tumors measuring ≥7 show a trend of poorer disease-free survival compared with pT2a and pT2b tumors (P = 0.267). Disease-free survival correlated with Fuhrman grading for patients with perinephric fat invasion (P = 0.008). In multivariate analysis, the survival curve of pT3a perinephric fat invasion group closely approximates that of pT2 group, whereas survival of the renal vein invasion group was significantly worse than the pT2 and perinephric fat invasion groups (P = 0.001). CONCLUSION: pT3a tumors with perinephric fat invasion appear to have better prognosis than those with renal vein invasion. Further stratification of pT3a renal cell carcinomas with regard to tumor size and Fuhrman grade further enhances the prognostic value in this group.

Graft retrieval incisions in minimally invasive donor nephrectomy: Systematic review and network meta-analysis.

BACKGROUND: Various incisions are employed for graft extraction during minimally invasive donor nephrectomy, but an overarching synthesis of associated short-term donor outcomes is lacking. METHODS: An electronic literature search was conducted on PubMed, EMBASE and Scopus for studies comparing ≥2 graft extraction incisions in laparoscopic or robotic donor nephrectomy with ≥10 patients per arm. Eligible study designs included randomized trials, case-control, and cohort studies. Primary outcomes were donor length of stay (LOS); in-hospital analgesic requirement; and postoperative complications. Secondary outcomes were warm ischemia time (WIT), total operation time (TOT), and estimated blood loss (EBL). Random-effects Frequentist network meta-analyses were conducted for all outcomes. RESULTS: Twenty-nine studies (4702 patients) were shortlisted. Six incisions were analyzed: iliac, Pfannenstiel, midline hand-assisted laparoscopic (HAL), midline umbilical, flank and transvaginal natural orifice transluminal endoscopic surgery (NOTES). The flank incision had significantly longer LOS than all other incisions. LOS was significantly longer in Pfannenstiel than iliac incision (mean difference [MD] = 0.29, 95%CI = 0.002-0.58 days). Midline HAL had significantly shorter TOT than most other incisions. Midline umbilical incisions had significantly higher WIT than midline HAL and Pfannenstiel incisions. Midline HAL had shorter WIT than transvaginal NOTES (MD = 0.80, 95%CI = 0.05-1.56 min). No major differences were seen in analgesia requirement, postoperative complications and EBL. CONCLUSION: Six different incisions for graft retrieval are broadly comparable across most short-term outcomes although long-term outcomes remain to be elucidated. Iliac and Pfannenstiel incisions yielded similar outcomes besides marginally lower LOS for the former. Midline incision for HAL may be associated with shorter TOT, and transvaginal NOTES is an effective technique for selected female donors. TRIAL REGISTRATION: PROSPERO CRD42023445407.

Radiomics in Kidney Transplantation: A Scoping Review of Current Applications, Limitations, and Future Directions.

Radiomics is increasingly applied to the diagnosis, management, and outcome prediction of various urological conditions. The purpose of this scoping review is to evaluate the current evidence of the application of radiomics in kidney transplantation, especially its utility in diagnostics and therapeutics. An electronic literature search on radiomics in the setting of transplantation was conducted on PubMed, EMBASE, and Scopus from inception to September 23, 2022. A total of 16 studies were included. The most widely studied clinical utility of radiomics in kidney transplantation is its use as an adjunct to diagnose rejection, potentially reducing the need for unnecessary biopsies or guiding decisions for earlier biopsies to optimize graft survival. Technology such as optical coherence tomography is a noninvasive procedure to build high-resolution optical cross-section images of the kidney cortex in situ and in real time, which can provide histopathological information of donor kidney candidates for transplantation, and to predict posttransplant function. This review shows that, although radiomics in kidney transplants is still in its infancy, it has the potential for large-scale implementation. Its greatest potential lies in the correlation with conventional established diagnostic evaluation for living donors and potential in predicting and detecting rejection postoperatively.

Development and Validation of a Deep Learning System for Sound-based Prediction of Urinary Flow.

BACKGROUND: Uroflowmetry remains an important tool for the assessment of patients with lower urinary tract symptoms (LUTS), but accuracy can be limited by within-subject variation of urinary flow rates. Voiding acoustics appear to correlate well with conventional uroflowmetry and show promise as a convenient home-based alternative for the monitoring of urinary flows. OBJECTIVE: To evaluate the ability of a sound-based deep learning algorithm (Audioflow) to predict uroflowmetry parameters and identify abnormal urinary flow patterns. DESIGN, SETTING, AND PARTICIPANTS: In this prospective open-label study, 534 male participants recruited at Singapore General Hospital between December 1, 2017 and July 1, 2019 voided into a uroflowmetry machine, and voiding acoustics were recorded using a smartphone in close proximity. The Audioflow algorithm consisted of two models-the first model for the prediction of flow parameters including maximum flow rate (Qmax), average flow rate (Qave), and voided volume (VV) was trained and validated using leave-one-out cross-validation procedures; the second model for discrimination of normal and abnormal urinary flows was trained based on a reference standard created by three senior urologists. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Lin's correlation coefficient was used to evaluate the agreement between Audioflow predictions and conventional uroflowmetry for Qmax, Qave, and VV. Accuracy of the Audioflow algorithm in the identification of abnormal urinary flows was assessed with sensitivity analyses and the area under the receiver operating curve (AUC); this algorithm was compared with an external panel of graders comprising six urology residents/general practitioners who separately graded flow patterns in the validation dataset. RESULTS AND LIMITATIONS: A total of 331 patients were included for analysis. Agreement between Audioflow and conventional uroflowmetry for Qmax, Qave, and VV was 0.77 (95% confidence interval [CI], 0.72-0.80), 0.85 (95% CI, 0.82-0.88) and 0.84 (95% CI, 0.80-0.87), respectively. For the identification of abnormal flows, Audioflow achieved a high rate of agreement of 83.8% (95% CI, 77.5-90.1%) with the reference standard, and was comparable with an external panel of six residents/general practitioners. AUC was 0.892 (95% CI, 0.834-0.951), with high sensitivity of 87.3% (95% CI, 76.8-93.7%) and specificity of 77.5% (95% CI, 61.1-88.6%). CONCLUSIONS: The results of this study suggest that a deep learning algorithm can predict uroflowmetry parameters and identify abnormal urinary voids based on voiding sounds, and shows promise as a simple home-based alternative to uroflowmetry in the management of patients with LUTS. PATIENT SUMMARY: In this study, we trained a deep learning-based algorithm to measure urinary flow rates and identify abnormal flow patterns based on voiding sounds. This may provide a convenient, home-based alternative to conventional uroflowmetry for the assessment and monitoring of patients with lower urinary tract symptoms.

Intravesical Bacillus Calmette-Guerin and its complications: 12 years of learning experience in a single local institution.

INTRODUCTION: Intravesical Bacillus Calmette-Guerin (BCG) therapy is the standard adjuvant treatment for non-muscle-invasive bladder carcinoma (NMIBC) with carcinoma in situ, in addition to tumour resection. We aimed to study BCG complications that preclude adequate treatment of NMIBC in an Asian population. METHODS: This retrospective study was conducted using a large, prospectively maintained bladder cancer database. 336 patients received intravesical BCG therapy for bladder cancer in our institution between 2004 and 2016, with an average follow-up duration of 63 months. RESULTS: The study included 258 (76.8%) male and 78 (23.2%) female patients. The median age of the patients at diagnosis of bladder cancer was 69 (range 17-94) years, and the median number of BCG instillations was 6 (range 1-27). 52 (15.5%) patients received maintenance therapy. The most common complications included urinary tract infection with/without sepsis (n = 18, 5.4%), haematuria (n = 9, 2.7%) and acute urinary retention (n = 4, 1.2%). 93.3% of the patients with complications presented early, within one month of completion of therapy. 22 out of 30 complications were Clavien-Dindo grade ≤ 2. 10 (33.3%) patients were admitted to hospital because of BCG-related adverse effects. The most common reasons for termination were urosepsis (2/30, 6.7%) and acute urinary retention (2/30, 6.7%). Patients aged ≥ 80 years at diagnosis were at higher risk of developing BCG-related complications (19.0% vs. 7.5%, p = 0.01). CONCLUSION: This retrospective cohort and subgroup study showed that intravesical BCG therapy is well tolerated and has a low incidence of complications even in the elderly and patients with multiple comorbidities.

Primary resection of oligometastatic recurrent prostatic carcinoma in the urethra.

A man in his 70s presented to the emergency department with acute urinary retention following a 2-day history of gross haematuria with blood clots. He had a significant medical history of intermediate-risk prostate adenocarcinoma (grade group 2, prostate-specific antigen (PSA) 14.9 ng/mL) for which he underwent a robotic-assisted laparoscopic radical prostatectomy (RARP) 13 years ago. PSA nadir was achieved (<0.03 ng/mL). Three years after RARP, he had biochemical recurrence with PSA rising to 0.06 ng/mL. Salvage radiotherapy was performed with good PSA response back to nadir. Workup for gross haematuria included a flexible cystoscopy which revealed a lobulated fleshy lesion occupying the mid-penile urethra. Staging imaging showed no local recurrence at prostatectomy site or lymphadenopathy. PSA was 4.2 ng/mL. Surgical resection with primary repair of the urethra was performed. Postoperative recovery was good with PSA achieving nadir. Histology revealed an upgraded metastatic prostate adenocarcinoma, grade group 5.

A Systemic Review and Meta-analysis of Transabdominal Intravesical Prostatic Protrusion Assessment in Determining Bladder Outlet Obstruction and Unsuccessful Trial Without Catheter.

CONTEXT: Urodynamic study (UDS) provides the most objective assessment of bladder outlet obstruction (BOO) but is impractical to be recommended routinely in outpatient services. Intravesical prostatic protrusion (IPP) had been described to obstruct urinary flow by creating an anatomical ball-valve effect, but there remains a lack of pooled evidence that can objectively correlate with BOO in benign prostatic hyperplasia. OBJECTIVE: To update the current evidence on the predictive role of IPP in determining BOO and unsuccessful trial without catheter (TWOC). EVIDENCE ACQUISITION: A comprehensive literature search was performed to identify studies that evaluated IPP in diagnosing UDS-determined BOO and TWOC. The search included the PubMed/MEDLINE, EMBASE, and Cochrane Library up to January 2021. An updated systemic review and meta-analysis was performed. EVIDENCE SYNTHESIS: A total of 18 studies with 4128 patients were examined. Eleven studies with 1478 patients examined the role of IPP in UDS-determined BOO. The pooled area under the curve (AUC) was 0.83 (95% confidence interval [CI]: 0.79-0.86), and at a cut-off of >10 mm, the sensitivity (Sn) and specificity (Sp) were 0.71 (95% CI: 0.61-0.78) and 0.77 (95% CI: 0.68-0.84), respectively. The probability-modifying plot revealed positive and negative likelihood ratios of 3.34 (95% CI: 2.56-4.36) and 0.35 (95% CI: 0.26-0.45), respectively. Seven studies with 2650 patients examined IPP in predicting unsuccessful TWOC, with a pooled AUC of 0.74 (95% CI: 0.70-0.84), with Sn of 0.51 (95% CI: 0.43-0.60) and Sp of 0.79 (95% CI: 0.73-0.84) at an IPP cut-off of >10 mm. Five studies compared prostate volume (PV) and IPP and revealed a lower AUC of PV at 0.71 (95% CI: 0.67-0.75), which was an inferior parameter in diagnosing BOO (p < 0.001). CONCLUSIONS: This systemic review provided evidence that IPP is a reliable clinical parameter that correlates strongly with underlying BOO and unsuccessful TWOC. PATIENT SUMMARY: In this review, we comprehensively reviewed all the literature to date on evaluating the clinical utility of intravesical prostatic protrusion (IPP). We have demonstrated that IPP correlates strongly with urodynamic study (UDS)-determined bladder outlet obstruction and failure of trial without catheter (TWOC). Outpatient IPP measurement is a quick, inexpensive, and reproducible clinical parameter that can determine the severity of benign prostatic hyperplasia. The clinical role of IPP in predicting failure of TWOC selects patients who are best treated with aggressive surgical approaches rather than conservative medical therapies. More importantly, IPP can facilitate the discriminatory use of invasive UDS, reserved for patients with a strong suspicion of concomitant detrusor abnormalities.

Botulinum toxin and benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a clinical condition where lower urinary tract symptoms are caused by both a physically obstructing prostate as well as tight smooth muscles around the bladder outlet. Treatment of this condition with botulinum toxin has been used since 2003, but this interest has somewhat died down after two large randomized controlled trials (RCTs) showing equivalence of results between their treatment and placebo arms. However, with review of animal studies and unexplained exaggerated effect of the placebo arms of the two RCTs, together with recent data of sustained benefits after 18 months of treatment, the place of botulinum toxin in the BPH field is probably still present.

Automating the Renal Cell Carcinoma Registry in Singapore: A Case Study on the Integration of the Research Electronic Data Capture System with the Enterprise Data Warehouse.

The renal cell carcinoma registry (RCCR) at the Singapore General Hospital was established in the 1980s. In 2012, the registry transited to a partially automated system using Research Electronic Data Capture (REDCap) and Oracle Business Intelligence Enterprise Edition (OBIEE), which is a platform for retrieval of electronic data from the Electronic Health Intelligence System (eHIntS). A committee was formed of experts from the department of urology and the health services research center, as well as an information technology (IT) team to evaluate the efficacy of the partially automated system. In the 5 years after the new system was implemented, 1,751 cases were recorded in the RCCR. The casefinding completeness increased by 1.9%, the data accuracy rate was 97%, and the efficiency increased by 12%. Strengths of the new system after partial automation were: (1) secure access to the registry via the hospital Web, (2) direct access to REDCap via the electronic medical records system, (3) automated and timely data extraction, and (4) visual presentation of data. On the other hand, we also encountered several challenges in the process of automating the registry, including limited IT support, limited expertise in matching data variables from RCCR and eHIntS, and limited availability and accessibility of eHIntS information for import into REDCap. In summary, despite these challenges, partial automation was achieved with the REDCap/OBIEE system, enhancing efficiency, data security, and data quality.

A 3D Printed Implantable Device for Voiding the Bladder Using Shape Memory Alloy (SMA) Actuators.

Underactive bladder or detrusor underactivity (DU) is defined as a reduction of contraction strength or duration of the bladder wall. Despite the serious healthcare implications of DU, there are limited solutions for affected individuals. A flexible 3D printed implantable device driven by shape memory alloys (SMA) actuators is presented here for the first time to physically contract the bladder to restore voluntary control of the bladder for individuals suffering from DU. This approach is used initially in benchtop experiments with a rubber balloon acting as a model for the rat bladder to verify its potential for voiding, and that the operating temperatures are safe for the eventual implantation of the device in a rat. The device is then implanted and tested on an anesthetized rat, and a voiding volume of more than 8% is successfully achieved for the SMA-based device without any surgical intervention or drug injection to relax the external sphincter.

Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2.

Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in KDM6A-mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in KDM6A-null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that KDM6A-null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in KDM6A-null cell lines. EZH2 inhibition delayed tumor onset in KDM6A-null cells and caused regression of KDM6A-null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of KDM6A, which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2.

Metformin Use in Relation With Survival Outcomes of Patients With Renal Cell Carcinoma.

PURPOSE: To examine the effect of metformin use on survival outcomes in patients with renal cell carcinoma (RCC). METHODS: Retrospective analysis of 1528 RCC patients from 2 centers between 1992 and 2012 was conducted. A total of 390 diabetics with confirmed metformin use were included in the final analysis, with a median follow-up of 43.1 months. Primary outcomes were disease-free survival (DFS) and cancer-specific survival (CSS). Cox regression models were performed to evaluate the effects of potential predictors on DFS and CSS, following stratification of patients into local and metastatic disease. RESULTS: We identified 290 diabetics with localized and 100 with metastatic RCC. There were no clinicopathologic differences in the profiles of metformin users and non-metformin users. For patients with localized RCC, metformin users had significantly better DFS (hazard ratio, 0.47; P < .01) and CSS (hazard ratio, 0.21; P < .01) than non-users. There was no difference in CSS between metformin users and non-metformin users in diabetics with metastatic RCC (hazard ratio, 0.78; P = .286). Limitations include retrospective design and lack of data on metformin dosage and duration of use. CONCLUSIONS: Metformin use is correlated with improved survival in patients with localized RCC, but not in metastatic RCC. Future studies should focus on its potential mechanisms and clinical utility.

The clinical presentation and diagnosis of ketamine-associated urinary tract dysfunction in Singapore.

Ketamine is a short-acting anaesthetic agent that has gained popularity as a 'club drug' due to its hallucinogenic effects. Substance abuse should be considered in young adult patients who present with severe debilitating symptoms such as lower urinary tract symptoms, even though the use of controlled substances is rare in Singapore. Although the natural history of disease varies from person to person, a relationship between symptom severity and frequency/dosage of abuse has been established. It is important to be aware of this condition and have a high degree of clinical suspicion to enable early diagnosis and immediate initiation of multidisciplinary and holistic treatment. A delayed diagnosis can lead to irreversible pathological changes and increased morbidity among ketamine abusers.

Heart failure as the first manifestation of renal cell carcinoma.

We report the rare case of a patient with advanced renal cell carcinoma (RCC) who initially presented to the hospital with symptoms of cardiac failure. Preoperative cardiac studies did not reveal any underlying ischemia. After resection of a large 14-cm left renal tumor, cardiac function was noted to improve dramatically. We discuss this case of concomitant RCC and nonischemic cardiomyopathy.

A multigene assay identifying distinct prognostic subtypes of clear cell renal cell carcinoma with differential response to tyrosine kinase inhibition.

Patients with clear cell renal cell carcinoma (ccRCC) have divergent survival outcomes and therapeutic responses, which may be determined by underlying molecular diversity. We aimed to develop a practical molecular assay that can identify subtypes with differential prognosis and response to targeted therapy. Whole-genome expression analysis of formalin-fixed paraffin-embedded (FFPE) material from 55 ccRCC patients was performed and two molecular subtypes with differential clinical outcomes were identified by hierarchical clustering. An eight-gene quantitative polymerase chain reaction assay for classification into two subtypes was developed for FFPE material. The primary objective was to assess assay performance by correlating ccRCC prognostic subtypes to cancer-specific survival (CSS) and, for patients receiving targeted therapy, radiologic response. In three validation cohorts, patients could be distinguished into prognostic subtypes with differential CSS (Singapore General Hospital FFPE cohort: n = 224; p = 1.48 × 10(-8); the Cancer Genome Atlas RNA-Sequencing cohort: n = 419; p = 3.06 × 10(-7); Van Andel Research Institute microarray cohort: n=174; p=0.00743). For 48 patients receiving tyrosine kinase inhibitor (TKI) treatment, the prognostic classification was associated with radiologic response to treatment (p = 5.96 × 10(-4)) and prolonged survival on TKI treatment (p=0.019). The multigene assay can classify ccRCCs into clinical prognostic subtypes, which may be predictive of response in patients receiving TKI therapy.

Mutation signatures implicate aristolochic acid in bladder cancer development.

BACKGROUND: Aristolochic acid (AA) is a natural compound found in many plants of the Aristolochia genus, and these plants are widely used in traditional medicines for numerous conditions and for weight loss. Previous work has connected AA-mutagenesis to upper-tract urothelial cell carcinomas and hepatocellular carcinomas. We hypothesize that AA may also contribute to bladder cancer. METHODS: Here, we investigated the involvement of AA-mutagenesis in bladder cancer by sequencing bladder tumor genomes from two patients with known exposure to AA. After detecting strong mutational signatures of AA exposure in these tumors, we exome-sequenced and analyzed an additional 11 bladder tumors and analyzed publicly available somatic mutation data from a further 336 bladder tumors. RESULTS: The somatic mutations in the bladder tumors from the two patients with known AA exposure showed overwhelming AA signatures. We also detected evidence of AA exposure in 1 out of 11 bladder tumors from Singapore and in 3 out of 99 bladder tumors from China. In addition, 1 out of 194 bladder tumors from North America showed a pattern of mutations that might have resulted from exposure to an unknown mutagen with a heretofore undescribed pattern of A > T mutations. Besides the signature of AA exposure, the bladder tumors also showed the CpG > TpG and activated-APOBEC signatures, which have been previously reported in bladder cancer. CONCLUSIONS: This study demonstrates the utility of inferring mutagenic exposures from somatic mutation spectra. Moreover, AA exposure in bladder cancer appears to be more pervasive in the East, where traditional herbal medicine is more widely used. More broadly, our results suggest that AA exposure is more extensive than previously thought both in terms of populations at risk and in terms of types of cancers involved. This appears to be an important public health issue that should be addressed by further investigation and by primary prevention through regulation and education. In addition to opportunities for primary prevention, knowledge of AA exposure would provide opportunities for secondary prevention in the form of intensified screening of patients with known or suspected AA exposure.