Non-muscle Invasive Urothelial Bladder Cancer Research Articles

Development and validation of competing risk nomograms for predicting cancer‑specific mortality in non-metastatic patients with non‑muscle invasive urothelial bladder cancer

We aimed to assess the cumulative incidences of cancer-specific mortality (CSM) in non-metastatic patients with non‑muscle invasive urothelial bladder cancer (NMIUBC) and establish competing risk nomograms to predict CSM. Patient data was sourced from the Surveillance, Epidemiology, and End Results database, as well as the electronic medical record system in our institution to form the external validation cohort. Sub-distribution proportional hazards model was utilized to determine independent risk factors influencing CSM in non-metastatic NMIUBC patients. Competitive risk nomograms were constructed to predict 3-year, 5-year, and 8-year cancer-specific survival (CSS) in all patients group, TURBT group and cystectomy group, respectively. The discrimination and accuracy of the model were validated through the concordance index (C-index), the area under the receiver operating characteristic curve (AUC), and calibration curves. Decision curve analysis (DCA) and a risk stratification system was employed to evaluate the clinical utility of the model. Race, age, marital status, surgery in other sites, tumor size, histological type, histological grade, T stage and N stage were identified as independent risk factors to predict CSS in all patients group. The C-index for 3-year CSS was 0.771, 0.770 and 0.846 in the training, testing and external validation sets, respectively. The ROC curves showed well discrimination and the calibration plots were well fitted and consistent. Moreover, DCA demonstrated well clinical effectiveness. Altogether, the competing risk nomogram displayed excellent discrimination and accuracy for predicting CSS in non-metastatic NMIUBC patients, which can be applied in clinical practice to help tailor treatment plans and make clinical decisions.

Intravesical thermochemotherapy in the treatment of high-risk and very high-risk non-muscle-invasive urothelial bladder cancer: a single-arm study

AimIntravesical thermochemotherapy, also known as HIVEC (Hyperthermic Intra-VEsical Chemotherapy), represents an alternative adjuvant topical treatment for non-muscle-invasive urothelial bladder cancer (NMIBC). High-risk (HR) and very HR tumors carry a substantial risk of recurrence and progression. In this study, we present our own results using HIVEC as an alternative to unavailable Bacillus Calmette–Guérin (BCG) vaccine in the treatment of such groups of patients.MethodsDuring the period of November 2014–June 2022, a total of 47 patients with HR and very HR NMIBC underwent treatment with HIVEC after transurethral resection. They were given an induction of 6 instillations with/without a maintenance. The aim was to evaluate the time to recurrence, event-free survival (recurrence or progression), as measured by Kaplan–Meier analysis, the effect of maintenance treatment and other factors on survival (log-rank test and multivariable Cox regression analysis), and complications.ResultsThe median follow-up for patients who did not experience an event was 32 months. The median time to HR (high grade and/or T1 tumor) recurrence in those who recurred was 15 months. The survival rate without HR recurrence at 12, 24, and 48 months was 84, 70, and 59%, respectively. Progression was detected in 10.6% of patients, which translated to 89% of patients living without progression after 24 months. Maintenance treatment (defined as more than six instillations) and presence of CIS significantly correlated with risk of HR recurrence (Hazard ratio 0.34 and 3.12, respectively). One female patient underwent salvage cystectomy due to contractory bladder, and 19.1% of patients experienced transient lower urinary tract symptoms.ConclusionBased on our experience, HIVEC represents an adequate and safe alternative treatment for HR and very HR NMIBC in situations where BCG is not available or radical cystectomy is not an option for the patient. However, high-quality data from prospective randomized studies are still lacking, and thus, thermochemotherapy should still be regarded as an experimental treatment modality.

Adding mitomycin (MM) to bacillus Calmette-Guérin (BCG) as adjuvant intravesical therapy for high-risk, non–muscle-invasive urothelial bladder cancer (NMIBC): BCGMM; ANZUP 1301.

TPS4617 Background: Adjuvant intravesical BCG decreases disease recurrence and progression in high-risk, NMIBC, however recurrence occurs in 30% of those affected, despite optimal therapy. Meta-analyses evaluating addition of intravesical MM to BCG showed lower rates of recurrence and cancer-specific mortality in people with NMIBC who received combination regimens. Phase 3 randomized trials to definitively test this combination are lacking. The BCGMM trial (NCT02948543) will determine the effects of adding MM to the standard BCG after resection of high-risk NMBIC. This is the largest study evaluating this approach in high-risk NMIBC, is of particular relevance given the current BCG shortage, and has the potential to change global practice. Methods: This open-label phase 3 trial is randomizing 500 participants stratified by stage, site of disease, and presence of carcinoma in-situ, in a 1:1 ratio to Arm A (BCG induction weekly x6 then monthly x10) or Arm B (BCG weeks 1, 2, 4, 5, 7, 8; months 4, 5, 7, 8 + MM weeks 3, 6, 9; months 3, 6, 9, see figure below). This provides 85% power to detect an absolute improvement of 10% in 2-year disease free survival (DFS) at 2p = 0.05. Stage 1 (n = 130) was to determine rates of treatment completion, activity reflected by cystoscopic findings at 3 months, adverse events, resource use, and health related quality of life, established feasibility. Stage 2, including an additional 370 participants, will provide information on DFS, time to recurrence and progression, overall survival, and identification of potential predictive biomarkers, is estimated to complete accrual by Q2 2023. Progress As of Jan 2023, 484 of 500 planned participants have been recruited from 16 Australian and 1 UK site. In stage 1, successful treatment completion, defined as 75% or more of planned treatment doses, was achieved by 76% in the experimental group (BCGMM) versus 60% in the control group (BCG alone). Clinical trial information: NCT02948543 .

Is Regular Radiographic Upper Urinary Tract Imaging for Surveillance of Non-Muscle Invasive Bladder Cancer Justified?

Patients with non-muscle invasive (NMI) urothelial bladder cancer (BC) are at increased risk for the development of a secondary upper-urinary-tract urothelial carcinoma (UTUC). We aimed to assess the usefulness of routine upper-tract imaging surveillance during NMIBC follow-up in a patient cohort of a tertiary academic center. All routine upper-tract-imaging scans using computerized tomography urography (CTU) between 2003 and 2016 were assessed for UTUC detection. A total of 315 patients were analyzed. Initial tumor stage was Ta in 207 patients (65.7%), T1 in 98 patients (31.1%) and pure CIS in 10 patients (3.2%). A total of 149 (47.3%) presented with low-grade (LG), and 166 (52.7%) with high-grade (HG) disease. Median follow-up was 48 months (IQR: 55). Four patients (1.2%) were diagnosed with UTUC during follow-up. All four patients presented with initial Ta HG BC. Two of the patients (50%) were diagnosed by routine upper tract imaging. The other two patients were diagnosed after development of symptoms. The 5- and 10-year UTUC-free survival was 98.5% (standard error (SE) 0.9) and 97.6% (SE 1.3), respectively. UTUCs were detected exclusively in patients with initial HG disease, indicating that upper-tract surveillance might only be necessary in these patients.

Influence of Antibiotic Administration on the Urinary Bladder Cancer Early Recurrence Rate.

Bladder cancer tends to recur, making treatment one of the most expensive in oncology. The limited efficacy and high cost of adjuvant therapies in the treatment of bladder cancer prompt research on new drugs which could replace them. In vitro studies have established that antibiotics can have a cytostatic and cytotoxic effect on urinary bladder cancer cells. The objective of the study was to investigate the influence of antibiotics on the recurrence rate of bladder cancer. In a retrospective study, we analyzed a group of 199 patients with urinary bladder cancer from four urological centers. The study groups consisted of 40 patients who received ciprofloxacin and 83 patients who received beta-lactams as perioperative antimicrobial prophylaxis. The control group included 76 patients who did not get perioperative antimicrobial prophylaxis. The groups were analyzed for risk stratification, degree of malignancy, and size of the primary tumor. The average follow-up time was 24 months. The main focus of the study was to investigate the early recurrence rate of bladder cancer among studied groups, which could correlate with the effectiveness of currently used intravesical instillations. Additionally, cancer's early progression was examined. Regardless of the division used, the highest recurrence rate was found in the ciprofloxacin group. There were no statistical differences in the recurrence rate between patients who received beta-lactams and patients who did not receive any antibiotics. In addition, there were no differences due to the progression rate between the groups. Perioperative antibiotic administration does not influence the early recurrence rate in patients with nonmuscle invasive urothelial bladder cancer.

The role of endoscopic management and adjuvant topical therapy for upper tract urothelial cancer.

Upper tract urothelial carcinoma (UTUC) has traditionally been managed with radical nephroureterectomy, and while this approach remains the gold standard for high-risk disease, endoscopic, kidney-sparing management has increasingly been adopted for low-risk disease as it preserves kidney function without compromising oncologic outcomes. Ureteroscopy and percutaneous renal access not only provide diagnoses by tumor visualization and biopsy, but also enable treatment with electrocautery or laser ablation. Several modalities exist for laser ablative treatments including thulium:YAG, neodymium:YAG, holmium:YAG, and combinations of the preceding. Furthermore, due to high recurrence rates after endoscopic management, adjuvant intracavitary instillation of various agents such as mitomycin C and bacillus Calmette-Guerin have been used given benefits seen in non-muscle invasive urothelial bladder cancer. Other formulations also being studied include gemcitabine, anthracyclines, and immunotherapies. More recently, Jelmyto, a mitomycin reverse thermal gel, has been developed to allow for adequate drug delivery time and potency since urine flow could otherwise dilute and washout topical therapy. In this article, the authors review techniques, indications, best practices, and areas of current investigation in endoscopic management and adjuvant topical therapy for UTUC.

Association of statin use and oncological outcomes in patients with first diagnosis of T1 high grade non-muscle invasive urothelial bladder cancer: results from a multicenter study.

We aimed to test the hypothesis that the immune-modulatory effect of statins may improve survival outcomes in patients with non-muscle invasive bladder cancer (NMIBC). We focused on a cohort of patients diagnosed with high risk NMIBC, that were treated with intravesical BCG immunotherapy. We included patients at first diagnosis of T1 high grade NMIBC after transurethral resection of bladder (TURB). All procedures were performed at 18 different tertiary institutions between January 2002 and December 2012. Univariable and multivariable models were used to test differences in terms of residual tumor, disease recurrence, disease progression and overall mortality (OM) rates. Overall, 1510 patients with T1 high grade NMIBC at TURB were included in our analyses. Of these, 402 (26.6%) were statin users. At multivariable analysis, statin use was associated with a higher rate of high-grade BC at re-TURB (OR: 1.37, 95%CI: 1.04-1.78; P=0.022), while at follow-up it was not independently associated with OM (HR: 0.71, 95%CI: 0.50-1.03; P=0.068) and disease progression rates (HR: 0.97, 95%CI: 0.79-1.19; P=0.753). Conversely, statin use has been shown to be independently associated with a lower risk of recurrence (HR:0.80, 95%CI: 0.67-0.95; P=0.009). The median recurrence-free survival was 47 (95%CI 40-49) months for those classified as non-statin users vs. 53 (95%CI 48-68) months in those classified as statin users. Statin daily intake do not compromise oncological outcomes in high risk NMIBC patients treated with BCG. Moreover, statin may have a beneficial effect on recurrence rates in this cohort of patients.

Association of statin use and oncological outcomes in patients with first diagnosis of T1 high grade non-muscle invasive urothelial bladder cancer: results from a multicentre study

article: Association of statin use and oncological outcomes in patients with first diagnosis of T1 high grade non-muscle invasive urothelial bladder cancer: results from a multicentre study - Minerva Urologica e Nefrologica 2021 Jan 13 - Minerva Medica - Journals

Adding mitomycin to Bacillus Calmette-Guérin as adjuvant intravesical therapy for high-risk, nonmuscle-invasive urothelial bladder cancer (BCGMM; ANZUP 1301).

TPS602 Background: Adjuvant intravesical bacillus Calmette-Guérin (BCG) decreases disease recurrence and progression in people with high-risk, non-muscle invasive urothelial bladder cancer (NMIBC), however recurrence occurs in 30% despite optimal therapy. Recent meta-analyses evaluating addition of intravesical mitomycin (MM) to BCG showed lower rates of recurrence and cancer-specific mortality in people with NMIBC who received combination regimens. Good quality randomized trials to definitively test this combination are lacking. The BCGMM trial (NCT02948543) will be the largest study to date evaluating this approach in people with high-risk NMIBC. Methods: This open-label phase 3 trial aims to randomize 500 participants, stratified by stage, site of disease, and presence of carcinoma in-situ, to Arm A (BCG induction weekly x6 then monthly x10) or Arm B (BCG + MM weekly x9 then monthly x9). This study is powered to detect a 10% improvement in 2-year disease free survival (DFS) at 5% level of significance with 85% power. Stage 1 of this study, designed to recruit 130 patients to determine rates of treatment completion, activity reflected by cystoscopic findings at 3 months, adverse events, resource use, and health related quality of life, has completed enrolment and successfully established feasibility of this trial protocol. Stage 2, aiming for a further 370 patients, will inform on additional endpoints including differences in DFS, time to recurrence and progression, overall survival, and potential predictive biomarkers, is estimated to complete accrual in December 2020. Successful treatment completion, defined as 75% or more of planned treatment doses, has been achieved in 76% of patients treated in the experimental arm of Stage 1, compared to 60% in those allocated BCG alone. Clinical trial information: NCT02948543.

Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer.

People with urothelial carcinoma of the bladder are at risk for recurrence and progression following transurethral resection of a bladder tumour (TURBT). Mitomycin C (MMC) and Bacillus Calmette-Guérin (BCG) are commonly used, competing forms of intravesical therapy for intermediate- or high-risk non-muscle invasive (Ta and T1) urothelial bladder cancer but their relative merits are somewhat uncertain. To assess the effects of BCG intravesical therapy compared to MMC intravesical therapy for treating intermediate- and high-risk Ta and T1 bladder cancer in adults. We performed a systematic literature search in multiple databases (CENTRAL, MEDLINE, Embase, Web of Science, Scopus, LILACS), as well as in two clinical trial registries. We searched reference lists of relevant publications and abstract proceedings. We applied no language restrictions. The latest search was conducted in September 2019. We included randomised controlled trials (RCTs) that compared intravesical BCG with intravesical MMC therapy for non-muscle invasive urothelial bladder cancer. Two review authors independently screened the literature, extracted data, assessed risk of bias and rated the quality of evidence according to GRADE per outcome. In the meta-analyses, we used the random-effects model. We identified 12 RCTs comparing BCG versus MMC in participants with intermediate- and high-risk non-muscle invasive bladder tumours (published from 1995 to 2013). In total, 2932 participants were randomised. Time to death from any cause: BCG may make little or no difference on time to death from any cause compared to MMC (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.79 to 1.20; participants = 1132, studies = 5; 567 participants in the BCG arm and 565 in the MMC arm; low-certainty evidence). This corresponds to 6 fewer deaths (40 fewer to 36 more) per 1000 participants treated with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Serious adverse effects: 12/577 participants treated with BCG experienced serious non-fatal adverse effects compared to 4/447 participants in the MMC group. The pooled risk ratio (RR) is 2.31 (95% CI 0.82 to 6.52; participants = 1024, studies = 5; low-certainty evidence). Therefore, BCG may increase the risk for serious adverse effects compared to MMC. This corresponds to nine more serious adverse effects (one fewer to 37 more) with BCG. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Time to recurrence: BCG may reduce the time to recurrence compared to MMC (HR 0.88, 95% CI 0.71 to 1.09; participants = 2616, studies = 11, 1273 participants in the BCG arm and 1343 in the MMC arm; low-certainty evidence). This corresponds to 41 fewer recurrences (104 fewer to 29 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations, imprecision and inconsistency. Time to progression: BCG may make little or no difference on time to progression compared to MMC (HR 0.96, 95% CI 0.73 to 1.26; participants = 1622, studies = 6; 804 participants in the BCG arm and 818 in the MMC arm; low-certainty evidence). This corresponds to four fewer progressions (29 fewer to 27 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Quality of life: we found very limited data for this outcomes and were unable to estimate an effect size. Based on our findings, BCG may reduce the risk of recurrence over time although the Confidence Intervals include the possibility of no difference. It may have no effect on either the risk of progression or risk of death from any cause over time. BCG may cause more serious adverse events although the Confidence Intervals once again include the possibility of no difference. We were unable to determine the impact on quality of life. The certainty of the evidence was consistently low, due to concerns that include possible selection bias, performance bias, given the lack of blinding in these studies, and imprecision.

703 - Systemic inflammatory markers and oncological outcomes in patients with high risk non-muscle invasive urothelial bladder cancer

703 - Systemic inflammatory markers and oncological outcomes in patients with high risk non-muscle invasive urothelial bladder cancer

1156 - Non-muscle invasive urothelial bladder cancer (NMIBC) in very elderly patients: What does affect overall survival (OS)? Clinical outcomes in a retrospective analysis

1156 - Non-muscle invasive urothelial bladder cancer (NMIBC) in very elderly patients: What does affect overall survival (OS)? Clinical outcomes in a retrospective analysis

P280 - Systemic inflammatory markers and oncological outcomes in patients with high risk non-muscle invasive urothelial bladder cancer

P280 - Systemic inflammatory markers and oncological outcomes in patients with high risk non-muscle invasive urothelial bladder cancer

Nano-BCG: A Promising Delivery System for Treatment of Human Bladder Cancer.

Mycobacterium bovis bacillus Calmette–Guerin (BCG) remains at the forefront of immunotherapy for treating bladder cancer patients. However, the incidence of recurrence and progression to invasive cancer is commonly observed. There are no established effective intravesical therapies available for patients, whose tumors recur following BCG treatment, representing an important unmet clinical need. In addition, there are very limited options for patients who do not respond to or tolerate chemotherapy due to toxicities, resulting in poor overall treatment outcomes. Within this context, nanotechnology is an emergent and promising tool for: (1) controlling drug release for extended time frames, (2) combination therapies due to the ability to encapsulate multiple drugs simultaneously, (3) reducing systemic side effects, (4) increasing bioavailability, (5) and increasing the viability of various routes of administration. Moreover, bladder cancer is often characterized by high mutation rates and over expression of tumor antigens on the tumor cell surface. Therapeutic targeting of these biomolecules may be improved by nanotechnology strategies. In this mini-review, we discuss how nanotechnology can help overcome current obstacles in bladder cancer treatment, and how nanotechnology can facilitate combination chemotherapeutic and BCG immunotherapies for the treatment of non-muscle invasive urothelial bladder cancer.

A larger detrusor wall thickness increases the risk of non muscle invasive bladder cancer recurrence and progression: result from a multicenter observational study.

Recent experimental study showed a higher incidence of bladder cancer in presence of bladder detrusor muscle thickening. The aim of this study is to assess whether a higher detrusor muscle thickness (DWT) may be a risk factor of recurrence of non-muscle invasive urothelial bladder cancer (NMIBC). Men with histologically-confirmed diagnosis of NMIBC were prospectively enrolled in 4 centers between December 2015 and April 2017. DWT was measured by ultrasound and DWT>2.5 mm was used as threshold for detrusor muscle thickening. Patients underwent to adjuvant local treatment in according to their progression and recurrence risk computed by European Organization Research and Treatment of Cancer (EORTC) Score for NMIBC. Every three months cystoscopy and urinary cytology were used to detect disease recurrence and progression. The main clinic-pathological variables were compared between patients with DWT≤2.5 mm and DWT>2.5 mm. One hundred patients (49.8%) with DWT >2.5 mm were significantly older, had larger and more tumors and experienced more prior NMIBC than 101 (50.2%) patients with a DWT≤2.5 mm. Recurrence and progression disease occurred more often and briefly in patients with a detrusor muscle thickening. At univariate analysis, DWT>2.5 was a predictive risk factors of cancer recurrence and progression, respectively: OR 4.9 (95% CI: 2.5-9.5) P=0.001 and OR 2.21 (95% CI: 1.71-4.73), P=0.001. Enclosing DWT in EORTC risk calculator significantly increased by 3% and 1% recurrence and progression risk assessment, respectively. Detrusor muscle thickening may have a role in NMIBC course with a higher recurrence rate, however further confirmatory and elucidating studies are required.

Spinal Anesthesia is Associated with Lower Recurrence Rates after Resection of Nonmuscle Invasive Bladder Cancer

We sought to determine whether anesthetic type (general vs spinal) would influence cancer recurrence following transurethral resection of bladder tumors. With institutional ethics board approval we examined the electronic medical records of all patients who underwent transurethral bladder tumor resection for nonmuscle invasive urothelial bladder cancer between 2011 and 2013 at a single tertiary care center. Followup information was gathered on all patients in December 2016. The time to first cancer recurrence and the incidence of cancer recurrence were the main outcome measures. A total of 231 patients underwent 1 or more transurethral bladder tumor resections between 2011 and 2013. Of the 231 patients 135 received spinal anesthesia and 96 received general anesthesia. On univariable analysis the 135 patients who received spinal anesthesia had a longer median time to recurrence than the 96 who received general anesthesia (42.1 vs 17.2 months, p = 0.014). As anticipated, adjuvant therapies and risk category were associated with recurrence rates (p = 0.003 and 0.042, respectively). On multivariable analyses incorporating a priori variables of nonmuscle invasive bladder cancer risk stratification and postoperative therapies the patients who received general anesthesia had a higher incidence of recurrence (OR 2.06, 95% CI 1.14-3.74, p = 0.017) and an earlier time to recurrence (HR 1.57, 95% CI 1.13-2.19, p = 0.008) than those who received spinal anesthesia. Anesthetic type was not associated with cancer progression or overall mortality. Patients who received spinal anesthesia had a lower incidence of recurrence and a delayed time to recurrence following transurethral bladder tumor resection for nonmuscle invasive bladder cancer. These findings should prompt large-scale prospective studies to confirm this association.

Is the Expression of p53, c-<italic>erb</italic>-B2 and Ki-67 Influence the Prognosis of the Non-muscle Invasive Urothelial Bladder Cancer?

Purpose The immunohistochemial markers can be used to predict prognosis more accurately for several cancers. In non-muscle invasive urothelial carcinoma, p53, c-erb-B2 and Ki-67 are applicable. We investigated a retrospective analysis of the relation between the markers and clinical prognostic factors of urothelial bladder cancer. Materials and Methods Data from 268 non-muscle invasive urothelial bladder cancer (Ta, T1) patients from one single center were collected. Immunohistochemical evaluation was carried out on 268 (p53, c-erb-B2, Ki-67) cases. Clinical prognostic factors are as follows; number of tumor, tumor invasiveness, tumor grade and recurrence. The sum of all positivity of 3 markers was made as a new factor and evaluation of correlation between this factor and prognostic factors was also done. Statistical analysis was done by chi-squares test and Pearson's correlation test. Results Through chi-square test, there were significant relations between all markers and tumor invasiveness (p<0.001), tumor grade (p<0.001). Number of tumor is significantly related with Ki-67 (p=0.043). Recurrence is related with c-erb-B2 (p=0.010) and Ki-67 (p=0.043). There was also significant correlations between the sum of the markers and prognostic factors-tumor invasiveness (p<0,001), tumor grade (p<0.001) and recurrence (p=0.007). Conclusions In this study, evaluated markers were closely related with clinical prognostic factors and may contribute to decision making on risk-assessment and management strategy for non-muscle invasive urothelial bladder cancer. Key Words: Urinary bladder neoplasms; Immunohistochemistry; Risk assessment.

Molecular Subtypes of Non-muscle Invasive Bladder Cancer

In this issue of Cancer Cell, Hedegaard etal. report a comprehensive multi-center transcriptional analysis of non-muscle invasive urothelial bladder cancer. They describe three molecular subtypes similar to those seen in other cohorts, as well as a unique CIS signature associated with risk of progression to muscle invasive cancer.

The potential effect of age on the natural behavior of bladder cancer: Does urothelial cell carcinoma progress differently in various age groups?

We aimed to evaluate the potential effect of age on the natural behavior of bladder cancer and to compare these findings between different age groups. The clinical and pathologic data of 239 patients treated at our institution between 1994 and 2014 were analyzed. The patients were classified into three groups according to age: ≤ 40 years (Group 1), 41–59 years (Group 2), and ≥ 60 years (Group 3). The following data were collected: characteristics of the patients, initial pathological findings after transurethral resection, tumor stage and grade, tumor size and multiplicity, and disease recurrence and progression. The mean age of the patients at initial diagnosis was 34.2±5.5 years, 53±5.1 years, and 71.1±7 years in Groups 1, 2, and 3, respectively. There were 207 (86.6%) patients with nonmuscle-invasive urothelial bladder cancer and 32 (13.4%) patients with muscle-invasive disease. Tumor recurrence was significantly lower in Group 1 than in Group 2 (p=0.001) and Group 3 (p=0.001). Although the time to tumor recurrence was significantly different between the three groups (p=0.001), no significant difference was noted in the time to progression (p=0.349). Patients with urothelial cancer younger than 40 years tend to have single and small tumors. The tumor recurrence rate is lower in the younger age group, but tumor progression is similar in older and younger patients. Therefore, the findings indicate that clinicians should be careful when assessing the invasiveness of urothelial tumors in younger patients and start treatment as soon as possible.

Determining the origin of synchronous multifocal bladder cancer by exome sequencing.

BackgroundSynchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours.MethodsTo better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pTa urothelial bladder cancers at a high depth, using multiple samples from three patients.ResultsPhylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated SNVs were cytosine mutations of TpC* dinucleotides (Fisher’s exact test p < 10−41), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that TpC* type mutations occurred 2-5× more often among SNVs on the ancestral branches than in the more recent private branches (p < 10−4) suggesting that TpC* mutations largely occurred early in the development of the tumour.ConclusionsThese results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1859-8) contains supplementary material, which is available to authorized users.