Outcomes of a Bladder Cancer Screening Program Using Home Hematuria Testing and Molecular Markers

Background

We previously reported the preliminary findings from a feasibility study of bladder cancer (BCa) screening with urinary molecular markers (Bladder Cancer Urine Marker Project [BLU-P]) that has now been terminated.

Objective

To report the final results from BLU-P to determine whether mass screening for BCa is feasible and useful.

Design, setting, and participants

BLU-P was a Dutch population-based study initiated in 2008 to evaluate BCa screening. A total of 6500 men were invited to participate in the study, 1984 (30.5%) agreed, and 1747 (88.1%) men completed the protocol and were followed for 2 yr.

Intervention

The screening protocol included home hematuria testing followed by molecular markers—nuclear matrix protein 22 (NMP22), microsatellite analysis (MA), fibroblast growth factor receptor 3 (FGFR3) mutation snapshot assay, and a custom methylation-specific (MLPA) test—to determine the need for cystoscopy.

Outcome measurements and statistical analysis

Outcomes included the number of cystoscopies and the cancer detection rate within and outside the protocol, as determined by linkage to national registries.

Results and limitations

Overall, 409 men (23.4%) tested positive for hematuria and underwent molecular testing. Current smokers (n = 295 [17%]) and past smokers (n = 998 [58%]) were significantly more likely to test positive for hematuria than nonsmokers. Seventy-one of 75 men (94.6%) with positive molecular markers underwent the recommended cystoscopy. Four BCas and one kidney tumor were detected through this sequential protocol, whereas one BCa and one kidney tumor were missed through the screening program. Limitations include the possibility of healthy subject bias.

Conclusions

For BCa screening, use of a sequential protocol with home hematuria testing followed by molecular markers substantially reduced the number of cystoscopy recommendations compared with dipstick testing alone. A sequential screening approach may help minimize unnecessary invasive follow-up testing, with very few missed cancers. Nevertheless, this mass screening program had a very low diagnostic yield in an unselected asymptomatic European male population.     

HYAL-1 Hyaluronidase: A Potential Prognostic Indicator for Progression to Muscle Invasion and Recurrence in Bladder Cancer

Background

For bladder cancer (BCa) patients undergoing bladder-sparing treatments, molecular markers may aid in accurately predicting progression to muscle invasion and recurrence. Hyaluronic acid (HA) is a glycosaminoglycan that promotes tumor metastasis. Hyaluronoglucosaminidase 1 (HYAL-1)–type hyaluronidase (HAase) promotes tumor growth, invasion, and angiogenesis. Urinary HA and HAase levels are diagnostic markers for BCa.

Objective

We evaluated whether HA and HYAL-1 can predict progression to muscle invasion and recurrence among patients with non–muscle-invasive BCa.

Design, setting, and participants

: Based on tissue availability, tissue microarrays were prepared from a cohort of 178 BCa specimens (144 non–muscle invasive, 34 muscle invasive). Follow-up information was available on 111 patients with non–muscle-invasive BCa (mean follow-up: 69.5 mo); 58 patients recurred and 25 progressed to muscle invasion (mean time to progress: 22.3 mo).

Measurements

HA and HYAL-1 expression was evaluated by immunohistochemistry and graded for intensity and area of staining. Association of HA and HYAL-1 staining with BCa recurrence and muscle invasion was evaluated by univariate and multivariate models.

Results and limitations

HA and HYAL-1 expression correlated with tumor grade, stage, and multifocality (p < 0.05). In non–muscle-invasive BCa specimens, HYAL-1 staining was higher (234.3 ± 52.2; 200.6 ± 61.4) if patients experienced progression to muscle invasion or recurrence when compared with no progression or recurrence (164.1 ± 48.2; 172.1 ± 57; p < 0.001). HA staining correlated with muscle invasion (p < 0.001). In univariate analysis, age (p = 0.014), multifocality (p = 0.023), and HYAL-1 staining (p < 0.001) correlated with muscle invasion, whereas only HYAL-1 correlated with recurrence (p = 0.013). In multivariate analysis, HYAL-1 significantly associated with muscle invasion (p < 0.001; 76.8% accuracy) and recurrence (p = 0.01; 67.8% accuracy).

Conclusions

HYAL-1 is a potential prognostic marker for predicting progression to muscle invasion and recurrence.     

The Application of Artificial Intelligence to Microarray Data: Identification of a Novel Gene Signature to Identify Bladder Cancer Progression

Background

New methods for identifying bladder cancer (BCa) progression are required. Gene expression microarrays can reveal insights into disease biology and identify novel biomarkers. However, these experiments produce large datasets that are difficult to interpret.

Objective

To develop a novel method of microarray analysis combining two forms of artificial intelligence (AI): neurofuzzy modelling (NFM) and artificial neural networks (ANN) and validate it in a BCa cohort.

Design, setting, and participants

We used AI and statistical analyses to identify progression-related genes in a microarray dataset (n = 66 tumours, n = 2800 genes). The AI-selected genes were then investigated in a second cohort (n = 262 tumours) using immunohistochemistry.

Measurements

We compared the accuracy of AI and statistical approaches to identify tumour progression.

Results and limitations

AI identified 11 progression-associated genes (odds ratio [OR]: 0.70; 95% confidence interval [CI], 0.56–0.87; p = 0.0004), and these were more discriminate than genes chosen using statistical analyses (OR: 1.24; 95% CI, 0.96–1.60; p = 0.09). The expression of six AI-selected genes (LIG3, FAS, KRT18, ICAM1, DSG2, and BRCA2) was determined using commercial antibodies and successfully identified tumour progression (concordance index: 0.66; log-rank test: p = 0.01). AI-selected genes were more discriminate than pathologic criteria at determining progression (Cox multivariate analysis: p = 0.01). Limitations include the use of statistical correlation to identify 200 genes for AI analysis and that we did not compare regression identified genes with immunohistochemistry.

Conclusions

AI and statistical analyses use different techniques of inference to determine gene–phenotype associations and identify distinct prognostic gene signatures that are equally valid. We have identified a prognostic gene signature whose members reflect a variety of carcinogenic pathways that could identify progression in non–muscle-invasive BCa.     

Insulin-like Growth Factor Messenger RNA-binding Protein 3 Expression Helps Prognostication in Patients with Upper Tract Urothelial Carcinoma

Background

Upper tract urothelial carcinoma (UTUC) is a clinically heterogeneous disease that lacks high-quality trials that provide definitive prognostic markers. Insulin-like growth factor messenger RNA binding protein 3 (IMP3) has been associated with outcomes in urothelial carcinoma of the bladder but was not yet studied in UTUC.

Objective

To evaluate the association of the oncofetal protein IMP3 with oncologic outcomes in patients with UTUC treated with radical nephroureterectomy (RNU).

Design, setting, and participants

We investigated the expression of IMP3 and its association with clinical outcomes using tissue microarrays constructed from 622 patients treated with RNU at seven international institutions between 1991 and 2008.

Intervention

All patients were diagnosed with UTUC and underwent RNU.

Outcome measurement and statistical analysis

Uni- and multivariable Cox regression analyses evaluated the association of IMP3 protein expression with disease recurrence, cancer-specific mortality, and all-cause mortality.

Results and limitations

IMP3 was expressed in 12.2% of patients with UTUC (n = 76). The expression was tumor specific and correlated with higher stages/grades. Within a median follow-up of 27 mo (interquartile range [IQR]: 12–53), 191 patients (25.4%) experienced disease recurrence, and 165 (21.9%) died of the disease. Patients with IMP3 demonstrated significantly worse recurrence-free survival (27.4% vs 75.1%; p < 0.01), cancer-specific survival (34.5% vs 78.9%; p < 0.01), and overall survival (15.6% vs 64.8%; p < 0.01) at 5 yr compared with those without IMP3. In multivariable Cox regression analyses, which adjusted for the effects of standard clinicopathologic features, IMP3expression was independently associated with disease recurrence (hazard ratio [HR]: 1.87; p < 0.01), cancer-specific mortality (HR: 2.15; p < 0.01), and all-cause mortality (HR: 2.07; p < 0.01). Major limitations include the retrospective design and relatively short follow-up time.

Conclusions

IMP3 expression is independently associated with disease recurrence, cancer-specific mortality, and all-cause mortality in UTUC. IMP3 may help improve risk stratification and prognostication of UTUC patients treated with RNU.     

Molecular Grade (FGFR3/MIB-1) and EORTC Risk Scores Are Predictive in Primary Non–Muscle-Invasive Bladder Cancer

Background

The European Organization for Research and Treatment of Cancer (EORTC) risk scores are not validated in an independent patient population. Molecular grade (mG) based on fibroblast growth factor receptor 3 (FGFR3) gene mutation status and MIB-1 expression was proposed as an alternative to pathologic grade in bladder cancer (BCa) [1].

Objective

To validate the EORTC risk score and to determine its relation to mG in a series with long-term follow-up as well as to determine reproducibility of pathologic grade and mG.

Design, setting, and participants

In this multicenter study, we included 230 patients with primary non–muscle-invasive BCa (NMIBC).

Measurements

Four uropathologists reviewed the slides. FGFR3 mutation status was examined by two assays. MIB-1 was assessed by immunohistochemistry. The EORTC risk scores for recurrence and progression were determined. Multivariable analyses were used to find prognostic factors.

Results and limitations

Median follow-up was 8.62 yr (interquartile range: 6.6–11.8). FGFR3 mutations were significantly related to favorable disease parameters, whereas altered MIB-1 was frequently seen with pT1, high grade, and high EORTC risk scores. EORTC risk scores were significant in multivariable analyses for recurrence and progression. In multivariable analyses for progression and disease-specific survival, the mG had independent significance. The addition of mG to the multivariable model for progression increased the predictive accuracy from 74.9% to 81.7% (p < 0.001; Mantel-Haenszel test). The mG (89%) was more reproducible than the pathologic grade (41–74%).

Conclusions

We validated the EORTC risk scores for primary NMIBC in a clinical and biomarker setting. Next to EORTC risk score, mG proved highly reproducible and predictive. Our long-term results justify an independent prospective analysis of mG and EORTC risk scores.     

The Effect of Tumor Location on Prognosis in Patients Treated with Radical Nephroureterectomy at Memorial Sloan-Kettering Cancer Center

Background

The prognostic impact of primary tumor location on outcomes for patients with upper-tract urothelial carcinoma (UTUC) is still contentious.

Objective

To test the association between tumor location and disease recurrence and cancer-specific survival (CSS) in patients treated with radical nephroureterectomy (RNU) for UTUC.

Design, setting, and participants

Prospectively collected data were retrospectively reviewed from 324 consecutive patients treated with RNU between 1995 and 2008 at a single tertiary referral center. Patients who had previous radical cystectomy, preoperative chemotherapy, previous contralateral UTUC, or metastatic disease at presentation were excluded. This left 253 patients for analysis. Tumor location was categorized as renal pelvis or ureter based on the location of the dominant tumor. Recurrences in the bladder only, in nonbladder sites, and in any site were analyzed.

Intervention

All patients were treated with RNU.

Measurements

Recurrence-free survival and CSS probabilities were estimated using Kaplan-Meier and Cox regression analyses.

Results and limitations

Median follow-up for survivors was 48 mo. The 5-yr recurrence-free probability (including bladder recurrence) and CSS estimates were 32% and 78%, respectively. On multivariable analysis, pathologic stage was the only predictor for disease recurrence (p = 0.01). Tumor location was not an independent predictor for recurrence (hazard ratio: 1.19; p = 0.3), and there was no difference in the probability of disease recurrence between ureteral and renal pelvic tumors (p = 0.18). On survival analysis, we also found no differences between ureteral and renal pelvic tumors on probability of CSS (p = 0.2). On multivariate analysis, pathologic stage (p < 0.0001) and nodal status (p = 0.01) were associated with worse CSS. This study is limited by its retrospective nature.

Conclusions

Our study did not show any differences in recurrence and CSS rates between patients with ureteral and renal pelvic tumors treated with RNU.     

Childbearing and the Risk of Bladder Cancer: A Nationwide Population-based Cohort Study

Background

The incidence of bladder cancer (BCa) is substantially lower in women than in men, a difference that cannot be fully explained by established risk factors. Several studies suggest that hormonal and reproductive factors play a role in the development of BCa.

Objective

To examine possible associations between patterns of childbearing and the risk of BCa.

Design, setting, and participants

This cohort study encompassed >2 million women for whom information on reproductive history and BCa incidence was retrieved from Swedish population-based registers.

Outcome measurements and statistical analysis

Incidence rate ratios (IRRs) of BCa were estimated using Cox proportional hazards modelling. The exposures under investigation were parity and age at first birth, adjusted for education and history of chronic obstructive lung disease (COLD).

Results and limitations

Among 2 009 811 women in the cohort, 2860 incident cases of BCa were identified. Parous women had lower incidence of BCa compared with nulliparous women (adjusted IRR: 0.80; 95% confidence interval [CI], 0.72–0.89). Moreover, the incidence was 15% lower in women with two children and 24% lower in women with three or more children compared with uniparous women. Compared with women aged 20–24 at first childbirth, the incidence was elevated in women with a first birth before age 20 (adjusted IRR: 1.16; 95% CI, 1.05–1.29). The risk of BCa was elevated in women with low education and among women with a history of COLD. Absence of data on menstrual history, use of exogenous hormones, and smoking was a limitation of the study.

Conclusions

The incidence of BCa decreased with increasing parity and older age at first birth. Although smoking habits may partly explain some of the associations, our findings provide support for yet-to-be-identified protective mechanisms associated with childbearing, possibly mediated by hormonal or structural changes following pregnancy.     

The Impact of Perioperative Blood Transfusion on Cancer Recurrence and Survival Following Radical Cystectomy

Background

While the receipt of a perioperative blood transfusion (PBT) has been associated with an increased risk of mortality for a number of malignancies, the relationship between PBT and survival following radical cystectomy (RC) for bladder cancer (BCa) has not been well established.

Objective

To evaluate the association of PBT with disease recurrence and mortality following RC.

Design, setting, and participants

We identified 2060 patients who underwent RC at the Mayo Clinic between 1980 and 2005. PBT was defined as transfusion of allogenic red blood cells during RC or postoperative hospitalization.

Outcome measurements and statistical analysis

Survival was estimated using the Kaplan-Meier method and was compared with the log-rank test. Cox proportional hazard regression models were used to evaluate the association of PBT with outcome, controlling for clinicopathologic variables.

Results and limitations

A total of 1279 patients (62%) received PBT. The median number of units transfused was 2 (interquartile range [IQR]: 2–4). Patients receiving PBT were significantly older (median: 69 yr vs 66 yr; p < 0.0001), had a worse Eastern Cooperative Oncology Group performance status (p < 0.0001), and were more likely to have muscle-invasive tumors (56% vs 49%; p = 0.004). Median postoperative follow-up was 10.9 yr (IQR: 7.9–15.7). Receipt of PBT was associated with significantly worse 5-yr recurrence-free survival (58% vs 64%; p = 0.01), cancer-specific survival (59% vs 72%; p < 0.001), and overall survival (45% vs 63%; p < 0.001). On multivariate analyses, PBT remained associated with significantly increased risks of postoperative tumor recurrence (hazard ratio [HR]: 1.20; p = 0.04), death from BCa (HR: 1.31; p = 0.003), and all-cause mortality (HR: 1.27; p = 0.0002). Among patients who received PBT, an increasing number of units transfused was independently associated with increased cancer-specific mortality (HR: 1.07; p < 0.0001) and all-cause mortality (HR: 1.05; p < 0.0001). Limitations include selection bias and lack of standardized transfusion criteria.

Conclusions

We found that PBT is associated with significantly increased risks of cancer recurrence and mortality following RC. While external validation is required, continued efforts to reduce the use of blood products in these patients are warranted.     

Robotic and Laparoscopic Radical Cystectomy for Bladder Cancer: Long-term Oncologic Outcomes

Background

Extended oncologic outcomes after minimally invasive cystectomy have not been previously reported.

Objective

To report outcomes of robot-assisted radical cystectomy (RARC) and laparoscopic radical cystectomy (LRC) for bladder cancer (BCa) at up to 12-yr follow-up.

Design, setting, and participants

All 121 patients undergoing RARC or LRC for BCa between December 1999 and September 2008 at a tertiary referral center were retrospectively evaluated from a prospectively maintained database.

Intervention

RARC or LRC.

Outcome measurements and statistical analysis

Primary end points were overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) calculated using Kaplan-Meier curves. Secondary end points were survival analysis by number of lymph nodes (LNs) and type of procedure. Surgical outcomes, including complications, were analyzed.

Results and limitations

Most tumors were muscle invasive (≥pT2; n = 81; 67%) urothelial carcinomas (n = 102; 84%). Extended LN dissection was performed in 98 patients (81%), with a median of 14 nodes removed (interquartile range [IQR]: 8–18). Twenty-four patients (20%) had node-positive disease (N1: 10 [8%]; N2: 14 [12%]). Eight patients (6.6%) had positive soft tissue margins. Median follow-up was 5.5 yr (mean: 5.9; IQR: 4.2–8.2; range: 0.13–12.1). At last follow-up, 58 patients (48%) had no evidence of disease, 3 (2%) were alive with recurrence, 59 (49%) had died, and status was unknown in 1. Twenty-eight patients (23%) died from cancer-specific causes, 20 (17%) from unrelated causes, and 11 (9%) from unknown causes. The 10-yr actuarial OS, CSS, and RFS rates were 35%, 63%, and 54%, respectively. At last follow-up, OS for pT0, pTis/a, pT1, pT2, and pT3 versus pT4 was 67%, 73%, 53%, 50%, and 16% versus 0%, respectively (p = 0.02). At last follow-up, CSS for pT0, pTis/a, pT1, pT2, and pT3 versus pT4 was 100%, 91%, 74%, 77%, and 56% versus 0%, respectively (p = 0.03).

Conclusions

The longest oncologic outcomes following RARC and LRC for BCa reported demonstrates results similar to those reported for open RC. Continued analysis and direct randomized comparison between techniques is necessary.     

A Systematic Review and Meta-analysis of Adjuvant and Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma

Context

The role of adjuvant chemotherapy (AC) or neoadjuvant chemotherapy (NC) remains poorly defined for the management of upper tract urothelial carcinoma (UTUC), although some studies suggest a benefit.

Objective

To update the current evidence on the role of NC and AC for UTUC patients.

Evidence acquisition

We searched for all studies investigating NC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings prior to February 2014. A systematic review and meta-analysis were performed.

Evidence synthesis

No randomized trials investigated the role of AC for UTUC. There was one prospective study (n = 36) investigating adjuvant carboplatin–paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin–based AC after nephroureterectomy (NU) and 1300 patients receiving NU alone. Across three cisplatin-based studies, the pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21–0.89; p = 0.023) compared with those who received surgery alone. For disease-free survival (DFS), the pooled HR across two studies was 0.49 (95% CI, 0.24–0.99; p = 0.048). Benefit was not seen for non-cisplatin–based regimens. For NC, two phase 2 trials demonstrated favorable pathologic downstaging rates, with 3-yr OS and disease-specific survival (DSS) ≤93%. Across two retrospective studies investigating NC, there was a DSS benefit, with a pooled HR of 0.41 (95% CI, 0.22–0.76; p = 0.005).

Conclusions

There appears to be an OS and DFS benefit for cisplatin-based AC in UTUC. This evidence is limited by the retrospective nature of studies and their relatively small sample size. NC appears to be promising, but more trials are needed to confirm its utility.

Patient summary

After a comprehensive search of studies examining the role of chemotherapy for upper tract urothelial cancer, the pooled evidence shows that cisplatin-based adjuvant chemotherapy was beneficial for prolonging survival.     

Impact of Tumor Location on Prognosis for Patients with Upper Tract Urothelial Carcinoma Managed by Radical Nephroureterectomy

Background

There is a lack of consensus regarding the prognostic significance of ureteral versus renal pelvic upper tract urothelial carcinoma (UTUC).

Objective

To investigate the association of tumor location on outcomes for UTUC in an international cohort of patients managed by radical nephroureterectomy (RNU).

Design, setting, and participants

A retrospective review of institutional databases from 10 institutions worldwide identified patients with UTUC.

Intervention

The 1249 patients in the study underwent RNU with ipsilateral bladder cuff resection between 1987 and 2007.

Measurements

Data accrued included age, gender, race, surgical approach (open vs laparoscopic), tumor pathology (stage, grade, lymph node status), tumor location, use of perioperative chemotherapy, prior endoscopic therapy, urothelial carcinoma recurrence, and mortality from urothelial carcinoma. Tumor location was divided into two groups (renal pelvis and ureter) based on the location of the dominant tumor.

Results and limitations

The 5-yr recurrence-free and cancer-specific survival estimates for this cohort were 75% and 78%, respectively. On multivariate analysis, only pathologic tumor (pT) classification (p < 0.001), grade (p < 0.02), and lymph node status (p < 0.001) were associated with disease recurrence and cancer-specific survival. When adjusting for these variables, there was no difference in the probability of disease recurrence (hazard ratio [HR]: 1.22; p = 0.133) or cancer death (HR: 1.23; p = 0.25) between ureteral and renal pelvic tumors. Adding tumor location to a base prognostic model for disease recurrence and cancer death that included pT stage, tumor grade, and lymph node status only improved the predictive accuracy of this model by 0.1%. This study is limited by biases associated with its retrospective design.

Conclusions

There is no difference in outcomes between patients with renal pelvic tumors and with ureteral tumors following nephroureterectomy. These data support the current TNM staging system, whereby renal pelvic and ureteral carcinomas are classified as one integral group of tumors.     

Comparison of Oncologic Outcomes for Open and Laparoscopic Nephroureterectomy: A Multi-Institutional Analysis of 1249 Cases

Background

Data regarding the oncologic efficacy of laparoscopic nephroureterectomy (LNU) compared to open nephroureterectomy (ONU) are scarce.

Objective

We compared recurrence and cause-specific mortality rates of ONU and LNU.

Design, setting, and participants

Thirteen centers from three continents contributed data on 1249 patients with nonmetastatic upper tract urothelial carcinoma (UTUC).

Measurements

Univariable and multivariable survival models tested the effect of procedure type (ONU [n = 979] vs LNU [n = 270]) on cancer recurrence and cancer-specific mortality. Covariables consisted of institution, age, Eastern Cooperative Oncology Group (ECOG) performance status score, pT stage, pN stage, tumor grade, lymphovascular invasion, tumor location, concomitant carcinoma in situ, ureteral cuff management, previous urothelial bladder cancer, and previous endoscopic treatment.

Results and limitations

Median follow-up for censored cases was 49 mo (mean: 62). Relative to ONU, LNU patients had more favorable pathologic stages (pT0/Ta/Tis: 38.1% vs 20.8%, p < 0.001) and less lymphovascular invasion (14.8% vs 21.3%, p = 0.02) and less frequently had tumors located in the ureter (64.5 vs 71.1%, p = 0.04). In univariable recurrence and cancer-specific mortality models, ONU was associated with higher cancer recurrence and mortality rates compared to LNU (hazard ratio [HR]: 2.1 [p < 0.001] and 2.0 [p = 0.008], respectively). After adjustment for all covariates, ONU and LNU had no residual effect on cancer recurrence and mortality (p = 0.1 for both).

Conclusions

Short-term oncologic data on LNU are comparable to ONU. Since LNU was selectively performed in favorable-risk patients, we cannot state with certainty that ONU and LNU have the same oncologic efficacy in poor-risk patients. Long-term follow-up data and morbidity data are necessary before LNU can be considered as the standard of care in patients with muscle-invasive or high-grade UTUC.     

Lymphadenectomy for Bladder Cancer at the Time of Radical Cystectomy

Context

Although the importance of lymphadenectomy during radical cystectomy (RC) in high-risk non–muscle-invasive and muscle-invasive bladder cancer (BCa) is well accepted, the optimal extent of lymphadenectomy, number of lymph nodes (LNs) to be retrieved, and prognostic and therapeutic role of lymphadenectomy remain debated issues.

Objective

In this review, we summarize the existing data on the value of lymphadenectomy for staging and outcome of BCa patients undergoing RC and lymphadenectomy.

Evidence acquisition

A systematic Medline/PubMed literature search of peer-reviewed scientific articles published from 1998 and 2012, concerning the role of lymphadenectomy in BCa patients, was carried out. The terms and permutations used were lymphadenectomy, bladder cancer/carcinoma, urothelial carcinomas, radical cystectomy, lymph node metastasis, lymph node dissection, bladder, recurrence, and survival. Selective older articles were included.

Evidence synthesis

Bilateral pelvic lymphadenectomy is an integral part of RC for BCa. The literature regarding the role of lymphadenectomy in BCa patients in general is retrospective, nonstandardized, and of low-level quality in regard to evidence. Prospective randomized trials designed to define the optimal template of lymphadenectomy and its impact on oncologic outcome are advocated. Some of these studies are ongoing, and their completion and analyses are necessary to resolve controversies.

Conclusions

Many consistent and concordant observations, although of low level of evidence, document that the extent of lymphadenectomy may influence disease-free survival after RC independent of the status of LNs and the pathologic stage of BCa. Lymphadenectomy standardization at the time of RC to create evidence-based guidelines is essential for further improvement of surgical quality and BCa patient survival.     

Comparative Outcomes of Primary,Recurrent, and Progressive High-risk Non–muscle-invasive Bladder Cancer

Background

The treatment of high-risk non–muscle-invasive bladder cancer (BCa) is problematic given the variable natural history of the disease. Few reports have compared outcomes for primary high-risk tumours with those that develop following previous BCas (relapses). The latter represent a self-selected cohort, having failed previous treatments.

Objective

To compare outcomes in patients with primary, progressive, and recurrent high-risk non–muscle-invasive BCa.

Design, setting, and participants

We identified all patients with primary and relapsing high-risk BCa tumours at our institution since 1994. Relapses were divided into progressive (previous low- or intermediate-risk disease) and recurrent (previous high-risk disease) cancers.

Outcome measurements and statistical analysis

Relationships with outcome analysed using multivariable Cox regression and log-rank analysis.

Results and limitations

We identified 699 primary, 110 progressive, and 494 recurrent high-risk BCa tumours in 809 patients (average follow-up: 59 mo [interquartile range: 6–190]). Muscle invasion occurred most commonly in recurrent (23%) tumours, when compared to progressive (20%) and primary (14.6%) cohorts (log rank p < 0.001). Disease-specific mortality (DSM) occurred more frequently in patients with recurrent (25.5%) and progressive (24.6%) tumours compared to primary disease (19.2%; log rank p = 0.006). Other-cause mortality was similar in all groups (log rank p = 0.57), and overall mortality was highest in the progressive cohort (62%) compared with the recurrent (58%) and primary groups (54%; log rank p < 0.001). In multivariable analysis, progression and DSM were predicted by tumour grouping (hazard ratio [HR]: >1.15; p < 0.026), stage (HR: >1.30; p < 0.001), and patient age and sex (HR: >1.03; p < 0.037). Carcinoma in situ was only predictive of outcome in primary tumors. Limitations include retrospective design and limited details regarding bacillus Camille-Guérin use.

Conclusions

Patients with relapsing, high-risk, BCa tumors have higher progression, DSM, and overall mortality rates than those with primary cancers. The use of bladder-sparing strategies in these patients should approached cautiously. Carcinoma in situ has little predicative role in relapsing, high-risk, BCa tumors.     

The impact of tumor multifocality on outcomes in patients treated with radical nephroureterectomy

Background

The prognostic impact of multifocal upper-tract urothelial carcinoma (UTUC) is poorly understood.

Objective

To investigate the association between tumor multifocality and clinicopathologic features and outcomes of UTUC in patients managed by radical nephroureterectomy (RNU).

Design, setting, and participants

The study included 2492 patients treated with either open or laparoscopic RNU. Tumor and patient characteristics included tumor stage, tumor grade, lymph node status, lymphovascular invasion (LVI), tumor architecture, tumor location, unifocal or multifocal disease, gender, age, history of bladder cancer (BCa), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adjuvant chemotherapy. tumor multifocality of UTUC was defined as the synchronous presence of multiple tumors in the renal pelvis or ureter.

Intervention

All patients were treated with either open or laparoscopic RNU.

Measurements

Univariable and multivariable models tested the effect of tumor multifocality on disease progression and cancer-specific mortality.

Results and limitations

Five hundred ninety patients (23.7%) had tumor multifocality at the time of RNU. The median follow-up was 45 mo (interquartile range [IQR]: 0-101). Tumor multifocality was significantly associated with a history of previous BCa (p = 0.032), lymph node involvement (p = 0.036), tumor location in the ureter (p = 0.003), higher tumor stage (p < 0.001), higher tumor grade (p < 0.001), sessile tumor architecture (p = 0.003), and LVI (p = 0.001). In organ-confined patients, tumor multifocality was an independent predictor of both disease progression (hazard ratio [HR]: 1.43; p = 0.019) and cancer-specific mortality (HR: 1.46; p = 0.027). When assessed in all patients, tumor multifocality was associated with both disease progression and cancer-specific mortality in univariable (p = 0.005 and p = 0.006, respectively) but not in multivariable analyses (p = 0.468 and p = 0.798, respectively). The main limitation is the retrospective design of the study.

Conclusions

Tumor multifocality is an independent prognosticator of disease progression and cancer-specific mortality in patients with organ-confined UTUC treated with RNU. Multifocal organ-confined patients with UTUC may need closer follow-up. Integration of tumor multifocality with other factors may help identify those patients who would benefit from multimodal therapy.     

Prognostic Role of Lymphovascular Invasion in Patients with Urothelial Carcinoma of the Upper Urinary Tract: An International Validation Study

Background

Lymphovascular invasion (LVI) identified following pathologic slide review has been shown to be an independent predictor of recurrence-free survival (RFS) and cancer-specific survival (CSS) in a multicenter series of patients undergoing radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). However, the validity of LVI in everyday practice, where pathologic re-review of all slides is uncommon, has not been assessed.

Objective

Our aim was to evaluate the prognostic role of LVI in an international cohort of patients treated with RNU for UTUC without pathologic slide review.

Design, setting, and participants

Data from 762 patients treated with RNU for UTUC without neoadjuvant chemotherapy were collected at nine centers located in Europe, Asia, and Canada.

Measurements

We evaluated patients’ characteristics, RFS, and CSS.

Results and limitations

LVI was present in 148 patients (19.4%). At a median follow-up of 34 mo, 23.5% of the patients developed disease recurrence and 19.8% died of UTUC. The 5-yr RFS and CSS rates were 79.3% and 82.1%, respectively, in the absence of LVI compared with 45.1% and 45.8%, respectively, in the presence of LVI (p values <0.0001). On multivariable Cox regression analyses, LVI was an independent predictor of RFS (hazard ratio [HR]: 3.3; p = 0.005) and CSS (HR: 5.9; p < 0.0001). Similarly, among patients with pN0/Nx disease, LVI was an independent predictor of RFS (HR: 2.1; p = 0.001) and CSS (HR: 2.3; p < 0.0001).

Conclusions

In a large multicenter series of patients treated with RNU for UTUC and for which no pathologic slide review was performed, LVI was present in approximately 20% and was an independent predictor of both RFS and CSS. LVI status should always be included in the pathologic report of RNU specimens, and patients with LVI should be considered for adjuvant therapy studies.     

Identification and Validation of the Methylated TWIST1 and NID2 Genes through Real-Time Methylation-Specific Polymerase Chain Reaction Assays for the Noninvasive Detection of Primary Bladder Cancer in Urine Samples

Background

Accumulating evidence suggests that DNA methylation markers could serve as sensitive and specific cancer biomarkers.

Objective

To determine whether a panel of methylated genes would have the potential to identify primary bladder cancer (BCa) in voided urine samples.

Design, setting, and participants

A pharmacologic unmasking reexpression analysis in BCa cell lines was initially undertaken to unveil candidate methylated genes, which were then evaluated in methylation-specific polymerase chain reaction (MSP) assays performed on DNA extracted from noncancerous and cancerous bladder tissues. The most frequently methylated genes in cancerous tissues, with 100% specificity, were retained for subsequent MSP analysis in DNA extracted from urine samples to build and validate a panel of potential methylated gene markers. Urine samples were prospectively collected at three urologic centres from patients with histologically proven BCa and processed for use in real-time MSP and cytologic analysis. Patients with nonmalignant urologic disorders were included as controls.

Measurements

A urine sample was classified as valid when ≥10 copies of the gene encoding ß-actin were measured in the urine sediment genomic DNA. Sensitivity, specificity, and predictive values of the MSP and cytology tests were assessed and compared.

Results and limitations

MSP assays performed on 466 of the 496 (94%) valid urine samples identified two genes, TWIST1 and NID2, that were frequently methylated in urine samples collected from BCa patients, including those with early-stage and low-grade disease. The sensitivity of this two-gene panel (90%) was significantly better than that of cytology (48%), with comparable specificity (93% and 96%, respectively). The positive predictive value and negative predictive value of the two-gene panel was 86% and 95%, respectively.

Conclusions

Detection of the methylated TWIST1 and NID2 genes in urine sediments using MSP provides a highly (≥90%) sensitive and specific, noninvasive approach for detecting primary BCa.

Trial registration

BlCa-001 study – EudraCt 2006-003303-40.     

Prevalence and clinicopathologic/molecular characteristics of mismatch repair-deficient colorectal cancer in the under-50-year-old Japanese population

Purpose

To clarify the prevalence and clinicopathologic/molecular characteristics of mismatch repair (MMR)-deficient colorectal cancer in the young Japanese population.

Methods

Immunohistochemical analyses for MMR proteins (MLH1, MSH2, MSH6, and PMS2) were performed in formalin-fixed paraffin-embedded sections prepared from the resected CRC specimens of 119 consecutive patients aged <50 years old, who underwent resection of the primary tumor at our institution between 1996 and 2015. Analyses for somatic BRAF V600E mutation, somatic hypermethylation of the MLH1 promoter, and germline MMR gene mutations were undertaken where indicated.

Results

MMR protein loss was found in 10 patients (8.4%), 7 (5.9%) of whom were subsequently identified to have Lynch syndrome (LS). The remaining 3 patients were categorized as having sporadic MMR-deficient CRC (n?=?2) or “possible LS (n?=?1)”. In multivariate logistic regression analysis, the presence of tumor-infiltrating lymphocytes (P?<?0.01), right-sided location of the tumor (P?=?0.01), and a history of LS-associated tumors in the first-degree relatives (P?<?0.01) were identified as independent factors predictive of MMR-deficient CRC.

Conclusion

These results are of value in the clinical management of patients with the early onset CRC under circumstances where universal tumor screening approaches for LS are still not available, like in Japan.

     

Comparative Effectiveness of External-Beam Radiation Approaches for Prostate Cancer

Background

Intensity-modulated radiotherapy (IMRT) is increasingly used to treat localized prostate cancer. Although allowing for the delivery of higher doses of radiation to the prostate, its effectiveness compared with the prior standard three-dimensional conformal therapy (3D-CRT) is uncertain.

Objective

To examine the comparative effectiveness of IMRT relative to 3D-CRT.

Design, setting, and participants

We performed a population-based cohort study using Surveillance, Epidemiology, and End Results-Medicare data to identify men diagnosed with prostate cancer between 2001 and 2007 who underwent either 3D-CRT (n = 6976) or IMRT (n = 11 039).

Outcome measurements and statistical analysis

We assessed our main outcomes (ie, the adjusted use of salvage therapy with androgen-deprivation therapy [ADT] and risk of a complication requiring an intervention) using Cox proportional hazards models.

Results and limitations

The percentage of men receiving IMRT increased from 9% in 2001 to 93% in 2007. Compared with those treated with 3D-CRT, low-risk patients treated with IMRT had similar likelihoods of using salvage therapy with ADT and similar risks of having a complication requiring an intervention (all p > 0.05). Conversely, a subset of higher risk patients treated with IMRT who did not receive concurrent ADT were less likely to use salvage therapy (p = 0.02) while maintaining similar complication rates. Because our cohort includes Medicare beneficiaries, our findings may not be generalizable to younger patients.

Conclusions

For a subset of higher risk patients, IMRT appears to show a benefit in terms of reduced salvage therapy without an increase in complications. For other patients, the risks of salvage therapy and complications are comparable between the two modalities.     

Gonadotropin-releasing Hormone Agonists and Acute Kidney Injury in Patients with Prostate Cancer

Background

Androgen deprivation therapy (ADT) might increase the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa).

Objective

To examine the impact of ADT on AKI in a large contemporary cohort of patients with nonmetastatic PCa representing the US population.

Design, setting, and participants

Overall, 69 292 patients diagnosed with nonmetastatic PCa between 1995 and 2009 were abstracted from the Surveillance Epidemiology and End Results–Medicare database.

Outcomes measurements and statistical analyses

Patient in both treatment arms (ADT vs no ADT) were matched using propensity-score methodology. Ten-year AKI rates were estimated. Competing-risks regression analyses tested the association between ADT and AKI, after adjusting for the risk of death during follow-up.

Results and limitations

Overall, the 10-yr AKI rates were 24.9% versus 30.7% for ADT-naive patients versus those treated with ADT, respectively (p < 0.001). When patients were stratified according to the type of ADT, the 10-yr AKI rates were 31.1% versus 26.0% for men treated with gonadotropin-releasing hormone (GnRH) agonists and bilateral orchiectomy, respectively (p < 0.001). In multivariable analyses, the administration of GnRH agonists (hazard ratio [HR]: 1.24; 95% confidence interval [CI], 1.18–1.31; p < 0.001), but not bilateral orchiectomy (HR: 1.11; 95% CI, 0.96–1.29; p = 0.1), was associated with the risk of experiencing AKI. Our study is limited by its retrospective design.

Conclusions

ADT is associated with an increased risk of AKI in patients with nonmetastatic PCa. In particular, the administration of GnRH agonists, but not surgical castration, may substantially increase the risk of experiencing AKI. These observations should help provide physicians with better patient selection to reduce the risk of AKI.

Patient summary

The administration of gonadotropin-releasing hormone agonists, but not bilateral orchiectomy, increases the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa). These observations should help provide physicians with better patient selection to reduce the risk of AKI in PCa patients.