The Impact of Histologic Subtypes on Clinical Outcomes After Radiation-Based Therapy for Muscle-Invasive Bladder Cancer.

PURPOSE: Outcomes of radiation-based therapy (RT) for muscle-invasive bladder cancer (MIBC) with histologic subtypes of urothelial cancer (HS-UC) are lacking. Our objective was to compare survival outcomes of pure urothelial carcinoma (PUC) to HS-UC after RT. MATERIALS AND METHODS: A multicenter retrospective study of 864 patients with MIBC who underwent curative-intent RT to the bladder for MIBC (clinical T2-T4aN0-2M0) between 2001 and 2018 was conducted. Regression models were used to test the association between HS-UC and complete response (CR) and survival outcomes after RT. RESULTS: In total, 122 patients (14%) had HS-UC. Seventy-five (61%) had HS-UC with squamous and/or glandular differentiation. A CR was confirmed in 69% of patients with PUC and 63% with HS-UC. There were 207 (28%) and 31 (25%) patients who died of metastatic bladder cancer in the PUC and HS-UC groups, respectively. There were 361 (49%) and 58 (48%) patients who died of any cause in the PUC and HS-UC groups, respectively. Survival outcomes were not statistically different between the groups. The HS-UC status was not associated with survival outcomes in multivariable Cox regression analyses. CONCLUSIONS: In our study, HS-UC responded to RT with no significant difference in CR and survival outcomes compared to PUC. The presence of HS-UC in MIBC does not seem to confer resistance to RT, and patients should not be withheld from bladder preservation therapy options. Due to low numbers, definitive conclusions cannot be drawn for particular histologic subtypes.

Radiation-based Therapy for Muscle-invasive Bladder Cancer: Contemporary Outcomes Across Tertiary Centers.

BACKGROUND: Radiation therapy (RT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To analyze predictors of complete response (CR) and survival after RT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter retrospective study of 864 patients with nonmetastatic MIBC who underwent curative-intent RT from 2002 to 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Regression models were used to explore prognostic factors associated with CR, cancer-specific survival (CSS), and overall survival (OS). RESULTS AND LIMITATIONS: The median patient age was 77 yr and median follow-up was 34 mo. Disease stage was cT2 in 675 patients (78%) and cN0 in 766 (89%). Neoadjuvant chemotherapy (NAC) was given to 147 patients (17%) and concurrent chemotherapy to 542 (63%). A CR was experienced by 592 patients (78%). cT3-4 stage (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29-0.63; p < 0.001) and hydronephrosis (OR 0.50, 95% CI 034-0.74; p = 0.001) were significantly associated with lower CR. The 5-yr survival rates were 63% for CSS and 49% for OS. Higher cT stage (HR 1.93, 95% CI 1.46-2.56; p < 0.001), carcinoma in situ (HR 2.10, 95% CI 1.25-3.53; p = 0.005), hydronephrosis (HR 2.36, 95% CI 1.79-3.10; p < 0.001), NAC use (HR 0.66, 95% CI 0.46-0.95; p = 0.025), and whole-pelvis RT (HR 0.66, 95% CI 0.51-0.86; p = 0.002) were independently associated with CSS; advanced age (HR 1.03, 95% CI 1.01-1.05; p = 0.001), worse performance status (HR 1.73, 95% CI 1.34-2.22; p < 0.001), hydronephrosis (HR 1.50, 95% CI 1.17-1.91; p = 0.001), NAC use (HR 0.69, 95% CI 0.49-0.97; p = 0.033), whole-pelvis RT (HR 0.64, 95% CI 0.51-0.80; p < 0.001), and being surgically unfit (HR 1.42, 95% CI 1.12-1.80; p = 0.004) were associated with OS. The study is limited by the heterogeneity of different treatment protocols. CONCLUSIONS: RT for MIBC yields a CR in most patients who elect for curative-intent bladder preservation. The benefit of NAC and whole-pelvis RT require prospective trial validation. PATIENT SUMMARY: We investigated outcomes for patients with muscle-invasive bladder cancer treated with curative-intent radiation therapy as an alternative to surgical removal of the bladder. The benefit of chemotherapy before radiotherapy and whole-pelvis radiation (bladder plus the pelvis lymph nodes) needs further study.

A Population-Based Cohort Study of the Impact of Infectious Complications Requiring Hospitalization after Prostate Biopsy on Radical Prostatectomy Surgical Outcomes.

OBJECTIVE: To compare radical prostatectomy outcomes in men with and without exposure to a major infectious event within 30-days of a prior TRUS-biopsy. MATERIALS AND METHODS: This retrospective cohort study included men who underwent radical prostatectomy from 2002 to 2013 in Ontario, Canada. Several linked administrative databases were used. Exposure was defined as hospitalization with evidence of a urinary tract infection or sepsis during the first 30-days after a prostate biopsy. The primary outcome was a composite of procedures indicative of a likely serious complication of radical prostectomy within the first 12 months after surgery. Secondary outcomes included oncological, functional, and hospital related events within 2 years of radical prostatectomy. RESULTS: A total of 26,254 patients were included in this study and 530 (2.02%) had a post-TRUS-biopsy infection. A similar proportion of patients with and without a post-TRUS-biopsy infectious event experienced the composite primary outcome (1.7% vs 1.1%; odds ratio [OR] 1.61, 95% confidence interval [CI] 0.82-3.14; P = .16). However, exposed patients had significantly higher odds of perioperative blood transfusion (OR 1.61, 95% CI 1.30-2.00; P <.001), bladder neck contracture (OR 1.35, 95% CI 1.12-1.63; P = .002), and 30-day hospital readmission (OR 2.08, 95% CI 1.47-2.95; P <.001), and a small but significant increase in length of hospital stay (P = 0.005). No other significant differences were observed. CONCLUSION: Although prior infectious events are associated with increased risk of blood transfusion, bladder neck contracture, and hospital readmission following radical prostatectomy, results from this study suggest that major surgical complications, are not adversely affected by TRUS-biopsy related infections.

The Impact of Multiple Prostate Biopsies on Risk for Major Complications Following Radical Prostatectomy: A Population-based Cohort Study.

OBJECTIVE: To evaluate the impact of multiple transrectal ultrasound-guided prostate biopsies (TRUS-Bx) before radical prostatectomy (RP) on surgical outcomes. MATERIALS AND METHODS: Administrative databases were used to identify all patients who had a RP performed in the province of Ontario from April 1, 2002, to March 31, 2013. TRUS-Bx prior to RP were identified and patients were categorized as having one or more than one prior TRUS-Bx. The primary end point was a composite index of serious surgical complications. Secondary outcomes included oncological interventions, functional-related events, and general health service-related outcomes. RESULTS: Among 27,637 patients, 4780 (17.3%) had ≥2 biopsies performed before RP. The proportion of patients who experienced the composite end point was similar between those with one TRUS-Bx compared to those with ≥2 TRUS-Bx (1.05% vs 1.19%, OR 1.14, 95% CI 0.85-1.52). Patients with ≥2 biopsies were more likely to have a perioperative blood transfusion compared to patients with only 1 biopsy (15.5% vs 12.8%, OR 1.25, 95% CI 1.15-1.37), while readmission rate and 30-day mortality were similar. The need for radiotherapy and androgen deprivation therapy within the first year after RP was higher in patients with a single biopsy. Patients with multiple TRUS-Bx were more likely to require post-RP urodynamic evaluation and bladder neck contracture-related interventions but were not at increased odds of surgery for incontinence or erectile dysfunction. CONCLUSION: Perioperative outcomes after RP are similar between men with single or multiple TRUS-Bx, although multiple TRUS-Bx were associated with an increased odds of perioperative blood transfusion.

Comparison of prostate MRI-3D transrectal ultrasound fusion biopsy for first-time and repeat biopsy patients with previous atypical small acinar proliferation.

INTRODUCTION: This study evaluates the clinical benefit of magnetic resonance-transrectal ultrasound (MR-TRUS) fusion biopsy over systematic biopsy between first-time and repeat prostate biopsy patients with prior atypical small acinar proliferation (ASAP). MATERIALS: 100 patients were enrolled in a single-centre prospective cohort study: 50 for first biopsy, 50 for repeat biopsy with prior ASAP. Multiparameteric magnetic resonance imaging (MP-MRI) and standard 12-core ultrasound biopsy (Std-Bx) were performed on all patients. Targeted biopsy using MRI-TRUS fusion (Fn-Bx) was performed f suspicious lesions were identified on the pre-biopsy MP-MRI. Classification of clinically significant disease was assessed independently for the Std-Bx vs. Fn-Bx cores to compare the two approaches. RESULTS: Adenocarcinoma was detected in 49/100 patients (26 first biopsy, 23 ASAP biopsy), with 25 having significant disease (17 first, 8 ASAP). Fn-Bx demonstrated significantly higher per-core cancer detection rates, cancer involvement, and Gleason scores for first-time and ASAP patients. However, Fn-Bx was significantly more likely to detect significant cancer missed on Std-Bx for ASAP patients than first-time biopsy patients. The addition of Fn-Bx to Std-Bx for ASAP patients had a 166.7% relative risk reduction for missing Gleason ≥ 3 + 4 disease (number needed to image with MP-MRI=10 patients) compared to 6.3% for first biopsy (number to image=50 patients). Negative predictive value of MP-MRI for negative biopsy was 79% for first-time and 100% for ASAP patients, with median followup of 32.1 ± 15.5 months. CONCLUSIONS: MR-TRUS Fn-Bx has a greater clinical impact for repeat biopsy patients with prior ASAP than biopsy-naïve patients by detecting more significant cancers that are missed on Std-Bx.

Prostate extracellular vesicles in patient plasma as a liquid biopsy platform for prostate cancer using nanoscale flow cytometry.

BACKGROUND: Extracellular vesicles released by prostate cancer present in seminal fluid, urine, and blood may represent a non-invasive means to identify and prioritize patients with intermediate risk and high risk of prostate cancer. We hypothesize that enumeration of circulating prostate microparticles (PMPs), a type of extracellular vesicle (EV), can identify patients with Gleason Score≥4+4 prostate cancer (PCa) in a manner independent of PSA. PATIENTS AND METHODS: Plasmas from healthy volunteers, benign prostatic hyperplasia patients, and PCa patients with various Gleason score patterns were analyzed for PMPs. We used nanoscale flow cytometry to enumerate PMPs which were defined as submicron events (100-1000nm) immunoreactive to anti-PSMA mAb when compared to isotype control labeled samples. Levels of PMPs (counts/µL of plasma) were also compared to CellSearch CTC Subclasses in various PCa metastatic disease subtypes (treatment naïve, castration resistant prostate cancer) and in serially collected plasma sets from patients undergoing radical prostatectomy. RESULTS: PMP levels in plasma as enumerated by nanoscale flow cytometry are effective in distinguishing PCa patients with Gleason Score≥8 disease, a high-risk prognostic factor, from patients with Gleason Score≤7 PCa, which carries an intermediate risk of PCa recurrence. PMP levels were independent of PSA and significantly decreased after surgical resection of the prostate, demonstrating its prognostic potential for clinical follow-up. CTC subclasses did not decrease after prostatectomy and were not effective in distinguishing localized PCa patients from metastatic PCa patients. CONCLUSIONS: PMP enumeration was able to identify patients with Gleason Score ≥8 PCa but not patients with Gleason Score 4+3 PCa, but offers greater confidence than CTC counts in identifying patients with metastatic prostate cancer. CTC Subclass analysis was also not effective for post-prostatectomy follow up and for distinguishing metastatic PCa and localized PCa patients. Nanoscale flow cytometry of PMPs presents an emerging biomarker platform for various stages of prostate cancer.

Ileal conduit: standard urinary diversion for elderly patients undergoing radical cystectomy.

PURPOSE: Ileal conduit (IC) is the most frequent urinary diversion (UD) performed after radical cystectomy (RC). We reviewed the literature to investigate the factors influencing the choice of this diversion and its complications. METHODS: A literature search (PubMed) was performed for all English language publications on UDs performed for treatment of bladder cancer from 1950 to 2015. The literature review was focused on studies reporting outcome of IC and its comparison with other types of UDs. RESULTS: IC is the most common UD performed in elderly patients undergoing RC for bladder cancer. Long-term studies looking at the change in renal function after UD report a universal decline in the glomerular filtration rate; however, this decline in renal function is the least for IC. There is a significant morbidity of RC (20-56 %), which can be attributed to patient factors, surgical technique and hospital volume. Modern concepts of bowel preparation, postoperative nutrition, early enteral feeding and involvement of stoma therapists have helped improve the outcomes. The quality of life is preserved, and in many including elderly, it may be improved with IC UD. CONCLUSIONS: IC is the most commonly performed UD following radical cystectomy. It is associated with acceptable morbidity and has the lowest reoperation rates as compared to continent diversion. It is also the procedure of choice for most patients' elderly patients as well as patients with limited dexterity, poor motivation, anatomical restrictions and poor renal function. Studies measuring HRQOL report excellent patient acceptability, especially in the elderly population.

Systematic methods for measuring outcomes: How they may be used to improve outcomes after Radical cystectomy.

In the era of managed healthcare, the measuring and reporting of surgical outcomes is a universal mandate. The outcomes should be monitored and reported in a timely manner. Methods for measuring surgical outcomes should be continuous, free of bias and accommodate variations in patient factors. The traditional methods of surgical audits are periodic, resource-intensive and have a potential for bias. These audits are typically annual and therefore there is a long time lag before any effective remedial action could be taken. To reduce this delay the manufacturing industry has long used statistical control-chart monitoring systems, as they offer continuous monitoring and are better suited to monitoring outcomes systematically and promptly. The healthcare industry is now embracing such systematic methods. Radical cystectomy (RC) is one of the most complex surgical procedures. Systematic methods for measuring outcomes after RC can identify areas of improvements on an ongoing basis, which can be used to initiate timely corrective measures. We review the available methods to improve the outcomes. Cumulative summation charts have the potential to be a robust method which can prompt early warnings and thus initiate an analysis of root causes. This early-warning system might help to resolve the issue promptly with no need to wait for the report of annual audits. This system can also be helpful for monitoring learning curves for individuals, both in training or when learning a new technology.

Evaluation of MRI-TRUS fusion versus cognitive registration accuracy for MRI-targeted, TRUS-guided prostate biopsy.

OBJECTIVE: The purpose of this article is to compare transrectal ultrasound (TRUS) biopsy accuracies of operators with different levels of prostate MRI experience using cognitive registration versus MRI-TRUS fusion to assess the preferred method of TRUS prostate biopsy for MRI-identified lesions. SUBJECTS AND METHODS; One hundred patients from a prospective prostate MRI-TRUS fusion biopsy study were reviewed to identify all patients with clinically significant prostate adenocarcinoma (PCA) detected on MRI-targeted biopsy. Twenty-five PCA tumors were incorporated into a validated TRUS prostate biopsy simulator. Three prostate biopsy experts, each with different levels of experience in prostate MRI and MRI-TRUS fusion biopsy, performed a total of 225 simulated targeted biopsies on the MRI lesions as well as regional biopsy targets. Simulated biopsies performed using cognitive registration with 2D TRUS and 3D TRUS were compared with biopsies performed under MRI-TRUS fusion. RESULTS: Two-dimensional and 3D TRUS sampled only 48% and 45% of clinically significant PCA MRI lesions, respectively, compared with 100% with MRI-TRUS fusion. Lesion sampling accuracy did not statistically significantly vary according to operator experience or tumor volume. MRI-TRUS fusion-naïve operators showed consistent errors in targeting of the apex, midgland, and anterior targets, suggesting that there is biased error in cognitive registration. The MRI-TRUS fusion expert correctly targeted the prostate apex; however, his midgland and anterior mistargeting was similar to that of the less-experienced operators. CONCLUSION: MRI-targeted TRUS-guided prostate biopsy using cognitive registration appears to be inferior to MRI-TRUS fusion, with fewer than 50% of clinically significant PCA lesions successfully sampled. No statistically significant difference in biopsy accuracy was seen according to operator experience with prostate MRI or MRI-TRUS fusion.

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

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

Female gender is associated with a worse survival after radical cystectomy for urothelial carcinoma of the bladder: a competing risk analysis.

OBJECTIVE: To determine the association of gender with outcome after radical cystectomy for patients with bladder cancer. METHODS: An observational cohort study was conducted using retrospectively collected data from 11 centers on patients with advanced bladder cancer treated with radical cystectomy. The association of gender with disease recurrence and cancer-specific mortality was examined using a competing risk analysis. RESULTS: The study comprised 4296 patients, including 890 women (21%). The median follow-up duration was 31.5 months for all patients. Disease recurred in 1430 patients (33.9%) (36.8% of women and 33.1% of men) at a median of 11 months after surgery. Death from any cause was observed in 46.0% of men and 50.1% of women. Cancer-specific death was observed in 33.0% of women and 27.2% of men. Multivariable regression with competing risk found that female gender was associated with an increased risk for disease recurrence and cancer-specific mortality (hazard ratio, 1.27; 95% confidence interval, 1.108-1.465; P = .007) compared with male gender. Important limitations include the inability to account for additional potential confounders, such as differences in environmental exposures, treatment selection, and histologic subtypes between men and women. CONCLUSION: Our analysis identified female gender as a poor-risk feature for patients undergoing radical cystectomy. This adverse prognostic factor was independent of standard clinical and pathologic features and competing risk from non-cancer-related death.

Effect of body mass index on the outcomes of patients with upper and lower urinary tract cancers treated by radical surgery: results from a Canadian multicenter collaboration.

OBJECTIVE: To evaluate the effect of body mass index (BMI) on the outcomes of patients with urinary tract carcinoma treated with radical surgery. MATERIALS AND METHODS: Data were collected from 10 Canadian centers on patients who underwent radical cystectomy (RC) (1998-2008) or radical nephroureterectomy (RNU) (1990-2010). Various parameters among subsets of patients (BMI < 25, 25 ≤ BMI < 30, and BMI ≥ 30 kg/m(2)) were analyzed. Kaplan-Meier and multivariate analyses were performed to assess the effect of BMI on overall survival, disease-specific survival, and recurrence-free survival (RFS). RESULTS: Among the 847 RC and 664 RNU patients, there was no difference in histology, stage, grade, and margin status among the 3 patient subsets undergoing either surgery. However, RC patients with lower BMIs (< 25 kg/m(2)) were significantly older (P = 0.004), had more nodal metastasis (P = 0.03), and trended toward higher stage (P = 0.052). RNU patients with lower BMIs (< 25 kg/m(2)) were significantly older (P = 0.0004) and fewer received adjuvant chemotherapy (P = 0.04) compared with those with BMI ≥ 30 kg/m(2); however, there was no difference in tumor location (P = 0.20), stage (P = 0.48), and management of distal ureter among the groups (P = 0.30). On multivariate analysis, BMI was not prognostic for overall survival, disease-specific survival, and RFS in the RC group. However, BMI ≥ 30 kg/m(2) was associated with more bladder cancer recurrences and worse RFS in the RNU group (HR = 1.588; 95% CI: 1.148-2.196; P = 0.0052). CONCLUSIONS: Increased BMI did not influence survival among RC patients. BMI ≥ 30 kg/m(2) is associated with worse bladder cancer recurrences among RNU patients; whether this is related to difficulty in obtaining adequate bladder cuff in patients with obesity requires further evaluation.

Comparison of the clonality of urothelial carcinoma developing in the upper urinary tract and those developing in the bladder.

PURPOSE: To identify the origin of synchronous and metachronous urothelial carcinoma (UC) of the bladder and upper urinary tract to get a better understanding of the basic mechanism behind the multifocality of UC, which may provide a sound bases for the future development of new strategies for detection, prevention and therapy. METHODS: Six patients with UC of the bladder and synchronous or metachronous UC of the upper urinary tract were studied. Genetic analysis involving the study of loss of heterozygosity (LOH) has been evaluated on their tumours using well characterised and new markers of UC (D9S171, D9S177, D9S303 and TP53). RESULTS: Five of the six patients demonstrated informative results. Four of five (80%) of patients had synchronous or metacharonous UC tumour and showed patterns of LOH consistent with tumorigenesis from monoclonal tumour origin. One of five (20%) patients exhibited a LOH consistent with oligoclonal tumorigenesis. CONCLUSION: These findings suggest that both the monoclonal and field cancerization theory of tumorigenesis may play a role in tumors of the urothelial tract. However, more data is needed.

Perineural invasion and TRUS findings are complementary in predicting prostate cancer biology.

INTRODUCTION: Clinical variables with more accuracy to predict biologically insignificant prostate cancer are needed. We evaluated the combination of transrectal ultrasound-guided biopsy of the prostate (TRUSBx) pathologic and radiologic findings in their ability to predict the biologic potential of each prostate cancer. MATERIALS AND METHODS: A total of 1043 consecutive patients who underwent TRUSBx were reviewed. Using pathologic criteria, patients with prostate cancer (n = 529) and those treated with radical prostatectomy (RP) (n = 147) were grouped as: "insignificant" (Gleason score ≤ 6, prostate-specific antigen (PSA) density ≤ 0.15 ng/ml, tumor in ≤ 50% of any single core, and < 33% positive cores) and "significant" prostate cancer. TRUSBx imaging and pathology results were compared with the RP specimen to identify factors predictive of "insignificant" prostate cancer. RESULTS: TRUSBx pathology results demonstrated perineural invasion in 36.4% of "significant" versus 5.4% of "insignificant" prostate cancers (p < 0.01) and pathologic invasion of periprostatic tissue in 7% of significant versus 0% of insignificant prostate cancers (p < 0.01). TRUS findings concerning for neoplasia were associated with significant tumors (p < 0.01). Multivariable analysis demonstrated perineural invasion in the biopsy specimen (p = 0.03), PSA density (p = 0.02) and maximum tumor volume of any core (p = 0.02) were independently predictive of a significant prostate cancer. CONCLUSIONS: TRUS findings concerning for measurable tumor and perineural invasion in TRUSBx specimens appear to be complementary to Epstein's pathologic criteria and should be considered to aid in the determination whether a prostate cancer is organ-confined and more likely to be biologically insignificant.