Controversies in terminology associated with management of BCG-unresponsive NMIBC in Asia-Pacific.

OBJECTIVES: Examine the understanding of terminologies and management patterns of bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle invasive bladder cancer (NMIBC) in six territories in Asia-Pacific. METHODS: This study involved two phases: (1) a survey with 32 urologists and 7 medical oncologists (MOs) and (2) a factorial experiment and in-depth interviews with 23 urologists and 2 MOs. All clinicians had ≥8 years' experience managing NMIBC patients in Australia, Hong Kong, Japan, South Korea, Singapore, and Taiwan. Data from Phase 1 were summarized using descriptive statistics; content and thematic analyses applied in Phase 2. RESULTS: In phase 1, 35% of clinicians defined BCG-unresponsive as BCG-refractory, -relapse and -resistant, 6% defined it as BCG-refractory and -relapse; 22% classified BCG-failure as BCG-refractory, -relapse, -resistant, and when muscle-invasive bladder cancer is detected. If eligible and willing, 50% (interquartile range [IQR], 50%-80%) of BCG-unresponsive patients would undergo radical cystectomy (RC), and 50% (IQR 20%-50%) of RC-eligible patients would receive bladder-sparing treatment or surveillance. In phase 2, we found that 32%, 88%, and 48% of clinicians, respectively, used "BCG-unresponsive," "BCG-refractory," and "BCG-relapse" in clinical practice but with no consistent interpretation of the terms. Compared with EAU definitions, 8%-60% of clinicians appropriately classified 9 tumor types that are persistent or recurrent after adequate BCG. Fifty percent of clinicians mentioned a lack of bladder-preserving treatment that outperforms RC in quality of life as a reason to retreat BCG-unresponsive patients with BCG. CONCLUSIONS: Our study revealed varied understanding and application of BCG-unresponsive terminologies in practice. There is a need for a uniform and simple definition of BCG-unresponsive disease in Asia-Pacific.

Risk stratification and management of non-muscle-invasive bladder cancer: A physician survey in six Asia-Pacific territories.

OBJECTIVES: Multiple clinical practice guidelines, conflicting evidence, and physician perceptions result in variations in risk stratification among patients with non-muscle-invasive bladder cancer (NMIBC). This study aims to describe the extent of this variation and its impact on management approaches in the Asia-Pacific region. METHODS: We conducted a cross-sectional survey involving 32 urologists and seven medical oncologists with ≥8 years of experience managing early-stage bladder cancer patients across Australia, Hong Kong, Japan, South Korea, Singapore, and Taiwan. The physicians completed an anonymous questionnaire that assessed their risk stratification and respective management approaches, based on 19 NMIBC characteristics. For each NMIBC characteristic, they were required to select one risk group, and their most preferred management approach. RESULTS: Our results demonstrated a higher consensus on risk classification versus management approaches. More than 50% of the respondents agreed on the risk classification of all NMIBC characteristics, but 42% or fewer chose the same treatment option as their preferred choice for all but two characteristics-existence of variant histology (55%) and persistent high-grade T1 disease on repeat resection (52%). Across territories, there was the greatest variation in preferred treatment options (i.e., no treatment, intravesical chemotherapy, or Bacillus Calmette-Guérin [BCG] treatment) for intermediate-risk patients and the highest consensus on the treatment of very high-risk patients, namely radical cystectomy. CONCLUSIONS: Our study revealed considerable variation in risk stratification and management of NMIBC in the region. It is critical to develop practical algorithms to facilitate the recognition of NMIBC and standardize the treatment of NMIBC patients.

CCL5 promotes the proliferation and metastasis of bladder cancer via the JAK2/STAT3 signaling pathway.

Background: Non-muscle invasive bladder cancer (NMIBC) is one of the most common malignant tumors of the urinary system. There is an urgent need for further studies to elucidate the underlying mechanisms of bladder cancer (BC) progression. It has been observed that C-C chemokine ligand 5 (CCL5) and its receptor C-C chemokine receptor type 5 (CCR5) are expressed abnormally and activated in solid tumors and hematological malignancies, which is gaining increasing attention. However, the underlying mechanism of CCL5 in BC remains unclear. Methods: The expression levels of CCL5 were analyzed by real-time polymerase chain reaction (RT-PCR) and western blot. Proliferation analysis of cells was carried out using Cell Counting Kit-8 (CCK-8). The assessment of the migration was conducted using a wound-healing assay. A Matrigel-coated transwell chamber was used to test cell invasiveness. A subcutaneous transplantation tumor model and tail vein injection pulmonary metastasis tumor model were used to evaluate the proliferation and metastasis of BC cell in vivo. Results: This study showed that CCL5 promotes proliferative, migratory, and tumor-growing BC cells in vitro and tumor metastasizing BC cells in vivo. Moreover, we found that the tumor-promotive role of CCL5 is dependent on activation of the JAK2/STAT3 signaling pathway. Conclusions: CCL5 may play an oncogenic role in BC and may also serve as a potential diagnostic and prognostic biomarker.

Patient-reported outcomes of a phase II neoadjuvant apalutamide (ARN-509) and radical prostatectomy in treatment of intermediate- to high-risk prostate cancer (NEAR) trial.

OBJECTIVE: The NEAR trial is a single-arm phase II trial investigating the efficacy of neoadjuvant apalutamide and radical prostatectomy in the treatment of D'Amico intermediate- to high-risk prostate cancer. This publication focuses on health-related quality of life (HRQoL) during 12 weeks of neoadjuvant apalutamide treatment. METHODS: From 2017 to 2019, 30 suitable patients received neoadjuvant apalutamide 240 mg once daily for 12 weeks followed by radical prostatectomy (ClinicalTrials.gov Identifier: NCT03124433). Patient-reported quality of life outcomes was analyzed using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core Module (EORTC QLQ-C30), EORTC Quality of Life Questionnaire Prostate Module (QLQ-PR25), and Sexual Health Inventory for Men questionnaire (SHIM) at weeks 0,4,12, and 20 of the study. RESULTS: Thirty patients completed 12 weeks of apalutamide therapy and data analyzed for 29 with complete datasets. Neoadjuvant apalutamide therapy was associated with no clinically significant negative impact on patients' global health and QoL scores. Deteriorations in mean scores of functional and symptom scales of QLQ-C30 questionnaire were statistically significant (p = 0.011 and p = 0.008, respectively) but were not clinically meaningful. Patients were also affected by fatigue (p = 0.012), cognitive function (p = 0.038), reduced role functioning (p = 0.025), and lower SHIM scores (p < 0.001). Median daily step count reduced from 8228/day to 6001/day per day (p = 0.063), while BMI and body weight reduction were observed (statistically but not clinically significant). CONCLUSION: During 12 weeks of neoadjuvant apalutamide in organ-confined prostate cancer, the overall patient-reported HRQoL outcomes were maintained, but fatigue and sexual dysfunction were observed in those patients.

Adverse Pathological Findings at Radical Prostatectomy following Active Surveillance: Results from the Movember GAP3 Cohort.

Background: Little is known about the consequences of delaying radical prostatectomy (RP) after Active Surveillance (AS) according to stringent or wider entry criteria. We investigated the association between inclusion criteria and rates, and timing of adverse pathological findings (APFs) among patients in GAP3 cohorts. Methods: APFs (GG ≥ 3, pT ≥ 3, pN > 0 and positive surgical margins [R1]) were accounted for in very low-risk (VLR: grade group [GG] 1, cT1, positive cores < 3, PSA < 10 ng/mL, PSA density [PSAD] < 0.15 ng/mL/cm3) and low-risk (LR: GG1, cT1-2, PSA ≤ 10 ng/mL) patients undergoing subsequent RP. The Kaplan−Meier method and log−rank test analyzed APF-free survival. Stratified mixed effects models analyzed association. Results: Out of 21,169 patients on AS, 1742 (VLR: 721; LR: 1021) underwent delayed RP. Most (60.8%) did not have APFs. APFs occurred more frequently (44.6% vs. 31.7%; OR 1.54, p < 0.001) and earlier (median time: 40.3 vs. 62.6 months; p < 0.001) in LR patients, and consisted of pT ≥ 3 (OR 1.47, p = 0.013) or R1 (OR 1.80, p < 0.001), but not of GG ≥ 3 or node involvement. Age (OR 1.05, p < 0.001), PSAD (OR 23.21, p = 0.003), and number of positive cores (OR 1.16, p = 0.004) were independently associated with APFs. Conclusions: AS stands as a safe option for low-risk patients, and most do not have APFs at surgery. Wider entry criteria are associated with pT3 and R1. The prognostic implications remain uncertain.

Predicting perioperative outcomes of robot-assisted radical cystectomy: Data from the Asian Robot-Assisted Radical Cystectomy Consortium.

OBJECTIVES: To report the perioperative outcomes of robot-assisted radical cystectomy and elucidate their risk factors. METHODS: A review of the Asian Robot-Assisted Radical Cystectomy Consortium database from 2007 to 2020 was performed. The perioperative outcomes studied included complication rates, time to solid food intake, estimated blood loss, length of hospital stay, and 30-day readmission rates. RESULTS: Of 568 patients, the overall complication rate was 49.2%, comprising major complications in 15.6%. Preoperative hydronephrosis was associated with an increased risk of major complications (odds ratio 3.27, 95% confidence interval 1.48-7.26, P = 0.004) while neoadjuvant chemotherapy was protective (odds ratio 0.46, 95% confidence interval 0.25-0.84, P = 0.012). The median time to solid food intake was 4 days (interquartile range 3-7) and smoking was a risk factor (odds ratio 4.28, 95% confidence interval 2.36-7.79, P < 0.001) for prolonged time to solid food intake. Median length of hospital stay was 13 days (interquartile range 9-19), and diabetes mellitus (odds ratio 1.66, 95% confidence interval 1.08-2.56, P = 0.021), neoadjuvant chemotherapy (odds ratio 2.21, 95% confidence interval 1.46-3.33, P < 0.001), and orthotopic bladder substitute creation (odds ratio 2.82, 95% confidence interval 1.90-4.18, P < 0.001) were independent risk factors for prolonged length of hospital stay. The 30-day readmission rate was 23.4% and higher in those with bilateral hydronephrosis (odds ratio 4.58, 95% confidence interval 1.97-10.65, P < 0.001) and orthotopic bladder substitute creation (odds ratio 1.87, 95% confidence interval 1.16-3.02, P = 0.010). CONCLUSIONS: There are preoperative conditions which are significant risk factors for adverse perioperative outcomes in robot-assisted radical cystectomy. Most are potentially modifiable and can direct strategies to reduce surgical morbidity related to this major oncological procedure.

NEAR trial: A single-arm phase II trial of neoadjuvant apalutamide monotherapy and radical prostatectomy in intermediate- and high-risk prostate cancer.

OBJECTIVE: Treatment efficacy of androgen deprivation therapy with radical prostatectomy for intermediate- to high-risk prostate cancer is less well-studied. The NEAR trial is a single-arm, phase II investigation of neoadjuvant apalutamide monotherapy and radical prostatectomy (RP) in the treatment of D'Amico intermediate- and high-risk prostate cancer (NCT03124433). MATERIALS AND METHODS: Patients with histologically-proven, D'Amico intermediate- to high-risk prostate adenocarcinoma received apalutamide 240 mg once-daily for 12 weeks followed by RP + /-lymphadenectomy. Primary outcome was pathological complete response (pCR) rate. Secondary outcomes included rate of biochemical response (defined by PSA < 0.03 ng/mL at week 24 from starting apalutamide without subsequent PSA relapse), treatment-related adverse events, and RP complication rates. Correlative biomarker analyses were performed to examine for molecular predictors of treatment responses. RESULTS: From 2017 to 2019, 30 patients were recruited, of which 20 and 10 were high and intermediate risk, respectively; 25 completed treatment as per-protocol. We did not observe any pCR on trial; median reduction of cancer burden was 41.7% (IQR: 33.3%-60.0%). 18 out of 25 patients were classified as having a biochemical response (4 did not achieve PSA of <0.03 ng/mL at week 24 and 3 developed PSA relapse subsequently). Dry skin (N = 16; 53.3%), fatigue (N = 10; 33.3%) and skin rash (N = 9; 30.0%) were the most common adverse events, and there was no major peri-operative complication. We observed an association between tumours of low androgen receptor activity and PAM50 basal status with biochemical non-responders, albeit these molecular phenotypes were not associated with pathological response. CONCLUSIONS: A 12-week course of neoadjuvant apalutamide prior to RP did not meet the primary endpoint of pCR in this trial. Tumours with low androgen receptor activity or of the PAM50 basal subtype may have a reduced response to apalutamide.

Efficacy, toxicity, and quality-of-life outcomes of ultrahypofractionated radiotherapy in patients with localized prostate cancer: A single-arm phase 2 trial from Asia.

AIMS: Ultra-hypofractionated radiotherapy (UHF-RT) is widely utilized in men with localized prostate cancer (PCa). There are limited data in Asian cohorts. We report the outcomes of a single-arm, phase II trial of UHF-RT from an Asian center. METHODS: We recruited men with histologically confirmed, nonmetastatic localized PCa. UHF-RT regimens were 36.25 Gy (Cohort A) and 37.5 Gy (Cohort B) delivered in five fractions every other day over 1.5-2.5 weeks. Primary endpoint was physician-scored late genitourinary (GU) and gastrointestinal (GI) adverse events (AEs). Quality-of-life (QoL) was assessed by Expanded Prostate Cancer Index Composite (EPIC) at baseline, 1- and 2-year post-UHF-RT. RESULTS: Between March 2014 and August 2019, 105 men were recruited; four were subsequently excluded from analysis. Median age was 68.0 (Interquartile range (IQR): 63.8-73.0) years. 26 (24.8%) and 68 (64.8%) men had NCCN-defined low-and intermediate-risk PCa, respectively. No late ≥G3 GU or GI toxicities were reported in both cohorts. Peak incidence of acute ≥G2 GU AEs at 14 days post-UHF-RT was 23.6% (17/72) and 24.0% (6/25) in Cohorts A and B, respectively; ≥G2 GI AEs were observed in 9.7% (7/72) and 36.0% (9/25), respectively. Late ≥G2 GU and GI AEs occurred in 4.7% and 3.1% of Cohort A patients, and 5.0% in Cohort B at 12 months, with no AEs at 24 months. EPIC scores changed minimally across all domains. At a median follow-up of 44.9 months, we recorded one (1.3%) biochemical relapse by the Phoenix criteria (Cohort A). CONCLUSION: UHF-RT is well tolerated in Asian men and can be a recommended fractionation schema for localized PCa.

Perioperative Outcomes of Robot-Assisted Radical Cystectomy with Intracorporeal Versus Extracorporeal Urinary Diversion.

PURPOSE: This study was designed to investigate and compare the perioperative outcomes of intracorporeal urinary diversion (ICUD) versus extracorporeal urinary diversion (ECUD) following robotic-assisted radical cystectomy (RARC) in patients with localized bladder cancer from the Asian Robot-Assisted Radical Cystectomy (RARC) Consortium. METHODS: The Asian RARC registry was a multicenter registry involving nine centers in Asia. Consecutive patients who underwent RARC were included. Patient and disease characteristics, intraoperative details, and perioperative outcomes were reviewed and compared between the ICUD and ECUD groups. Postoperative complications were the primary outcomes, whereas secondary outcomes were the estimated blood loss and the duration of hospitalization. Multivariate regression analyses were performed to adjust potential confounders. RESULTS: From 2007 to 2020, 556 patients underwent RARC; 55.2% and 44.8% had ICUD and ECUD, respectively. ICUD group had less estimated blood loss (423.1 ± 361.1 vs. 541.3 ± 474.3 mL, p = 0.002) and a shorter hospital stay (15.7 ± 12.3 vs 17.8 ± 11.6 days, p = 0.042) than the ECUD group. Overall complication rates were similar between the two groups. Upon multivariate analysis, ICUD was associated with less estimated blood loss (Regression coefficient: - 143.06, 95% confidence interval [CI]: - 229.60 to - 56.52, p = 0.001) and a shorter hospital stay (Regression coefficient: - 2.37, 95% CI: - 4.69 to - 0.05, p = 0.046). In addition, ICUD was not associated with any increased risks of minor, major, and overall complications. CONCLUSIONS: RARC with ICUD was safe and technically feasible with similar postoperative complication rates as ECUD, with additional benefits of reduced blood loss and a shorter hospitalization.

A first step towards a global nomogram to predict disease progression for men on active surveillance.

BACKGROUND: Signs of disease progression (28%) and conversion to active treatment without evidence of disease progression (13%) are the main reasons for discontinuation of active surveillance (AS) in men with localised prostate cancer (PCa). We aimed to develop a nomogram to predict disease progression in these patients. METHODS: As a first step in the development of a nomogram, using data from Movembers' GAP3 Consortium (n=14,380), we assessed heterogeneity between centres in terms of risk of disease progression. We started with assessment of baseline hazards for disease progression based on grouping of centres according to follow-up protocols [high: yearly; intermediate: ~2 yearly; and low: at year 1, 4 & 7 (i.e., PRIAS)]. We conducted cause-specific random effect Cox proportional hazards regression to estimate risk of disease progression by centre in each group. RESULTS: Disease progression rates varied substantially between centres [median hazard ratio (MHR): 2.5]. After adjustment for various clinical factors (age, year of diagnosis, Gleason grade group, number of positive cores and PSA), substantial heterogeneity in disease progression remained between centres. CONCLUSIONS: When combining worldwide data on AS, we noted unexplained differences of disease progression rate even after adjustment for various clinical factors. This suggests that when developing a global nomogram, local adjustments for differences in risk of disease progression and competing outcomes such as conversion to active treatment need to be considered.

Limitations of overlapping cores in systematic and MRI-US fusion biopsy.

OBJECTIVES: To evaluate the clinically-significant prostate cancer (csCaP) detection rate of systematic (SBx) vs. targeted biopsy (TBx), after accounting for the overlapping systematic cores within the MRI regions of interest. MATERIALS AND METHODS: We identified 398 consecutive men who underwent both transperineal systematic and targeted biopsy between January 2015 to January 2019. We reclassified overlapping systematic cores in the MRI regions of interest as target cores. The detection rates of SBx and TBx were compared using McNemar's test. RESULTS: Detection rate of csCaP (grade group ≥2) was 42% (168/398). Median number of systematic and targeted cores were 23 (IQR 19-29) and 9 (IQR 6-12) respectively. A median of 3 (IQR 2-4) overlapping systematic cores were reclassified as targeted cores. After accounting for overlap, csPC detection rate on SBx decreased from 37% and 21% while the csCaP detection rate of TBx increased from 34% to 39% (both P < 0.001), with TBx having a better detection rate (39% vs. 21%, P < 0.001). A previous negative biopsy was associated with a lower risk of having csCaP on non-targeted SBx (OR 0.27, 95% CI: 0.12 - 0.58, P = 0.001). Only 5% (13/243) of those who had no cancer detected on TBx had csCaP on non-targeted SBx compared to 45% (70/155) of those who had csCaP on TBx (P< 0.001). CONCLUSIONS: The utility of SBx in detecting csCaP decreases after accounting for overlap into the MRI region of interest, especially in men with a prior negative biopsy. Overlapping systematic cores improve the csCaP detection rate on TBx.

Case of flank pain from ureteral injury after lumbar laminectomy.

We present a case of an iatrogenic complete left proximal ureteric injury after a lumbar 1 laminectomy and intradural tumour excision and lumbar 4/5 transforaminal lumbar interbody fusion. Initial management included a percutaneous nephrostomy for urinary diversion followed by definitive urinary reconstruction with an ileal ureter.

External validation and comparison of magnetic resonance imaging-based predictive models for clinically significant prostate cancer.

PURPOSE: Several multiparametric magnetic resonance imaging (mpMRI)-based models have been developed with significant improvements in diagnostic accuracy for clinically significant prostate cancer (csCaP), but lack proper external validation. We therefore sought to externally validate and compare all published mpMRI-based csCaP risk prediction models in an independent Asian population. PATIENTS AND METHODS: A total of 449 men undergoing combined transperineal fusion-targeted/systematic prostate biopsy at our specialist center between 2015 to 2019 were retrospectively analyzed. csCaP was defined as lesions with ISUP (International Society of Urological Pathology) grade group ≥2. The performance of 6 mpMRI-based risk models (MRI-ERSPC-3/4, Distler, Radtke, Mehralivand, van Leeuwen and He) were evaluated in terms of discrimination, calibration and clinical utility, using area under the receiver operating characteristic curve (AUC), calibration curves and decision curve analyses. RESULTS: A total of 202 (45%) subjects were diagnosed with csCaP. All models demonstrated excellent accuracy with AUCs ranging from 0.75 to 0.86, and most significantly outperformed mpMRI PIRADSv2.0 (Prostate Imaging Reporting and Data System version 2.0) alone. The models by Mehralivand and He showed good calibration to our validation population, with respective intercepts of -0.08 and -0.84. All models were nevertheless recalibrated to the csCaP prevalence in our population for analysis. Decision curve analysis showed that above a threshold probability of 10%, all mpMRI-based models demonstrated superior net benefit compared to mpMRI PIRADSv2.0 or a biopsy-all-men strategy. The van Leeuwen model had the greatest net benefit, avoiding 39% of unnecessary biopsies while missing only 4% of csCaP, at a threshold probability of 15%. CONCLUSIONS: The mpMRI-based risk models demonstrate excellent discrimination and clinical utility and are easy to apply in practice, suggesting that individualized risk-based approaches can be considered over mpMRI alone to avoid unnecessary biopsies.

Primary renal synovial sarcoma presenting with a retroperitoneal bleed.

Synovial sarcomas are most commonly localised in extremities, especially in the lower thigh and knee areas. Comprising less than 1% of all malignancies, retroperitoneal synovial sarcoma is very rare with primary synovial sarcoma of the kidney being even more infrequent and difficult to diagnose. We describe a case report of a renal synovial sarcoma in a young adult who was initially managed as a case of Wunderlich's syndrome secondary to what was believed to be a ruptured renal angiomyolipoma. After biopsy confirmation, the patient was eventually managed with neo-adjuvant chemotherapy followed by a right radical nephrectomy and right hepatectomy. Despite its rarity, synovial sarcoma should be considered as differential diagnosis of a bleeding retroperitoneal soft tissue mass detected in young adults.

Risk-Based Selection for Active Surveillance: Results of the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) Initiative.

PURPOSE: We sought to identify and validate known predictors of disease reclassification at 1 or 4 years to support risk-based selection of patients suitable for active surveillance. MATERIALS AND METHODS: An individual participant data meta-analysis using data from 25 established cohorts within the Movember Foundations GAP3 Consortium. In total 5,530 men were included. Disease reclassification was defined as any increase in Gleason grade group at biopsy at 1 and 4 years. Associations were estimated using random effect logistic regression models. The discriminative ability of combinations of predictors was assessed in an internal-external validation procedure using the AUC curve. RESULTS: Among the 5,570 men evaluated at 1 year, we found 815 reclassifications to higher Gleason grade group at biopsy (pooled reclassification rate 13%, range 0% to 31%). Important predictors were age, prostate specific antigen, prostate volume, T-stage and number of biopsy cores with prostate cancer. Among the 1,515 men evaluated at 4 years, we found 205 reclassifications (pooled reclassification rates 14%, range 3% to 40%), with similar predictors. The average areas under the receiver operating characteristic curve at internal-external validation were 0.68 and 0.61 for 1-year and 4-year reclassification, respectively. CONCLUSIONS: Disease reclassification occurs typically in 13% to 14% of biopsies at 1 and 4 years after the start of active surveillance with substantial between-study heterogeneity. Current guidelines might be extended by considering prostate volume to improve individualized selection for active surveillance. Additional predictors are needed to improve patient selection for active surveillance.