A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron.

Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8+ T cell response, and triggers macrophage 'nutritional immunity' to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into 'oncobiotics' for a multi-layered approach to cancer therapy.

Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy. The effects of erdafitinib in patients with FGFR-altered metastatic urothelial carcinoma who have progression during or after treatment with checkpoint inhibitors (anti-programmed cell death protein 1 [PD-1] or anti-programmed death ligand 1 [PD-L1] agents) are unclear. METHODS: We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible FGFR3/2 alterations who had progression after one or two previous treatments that included an anti-PD-1 or anti-PD-L1. Patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator's choice of chemotherapy (docetaxel or vinflunine). The primary end point was overall survival. RESULTS: A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients). CONCLUSIONS: Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR alterations after previous anti-PD-1 or anti-PD-L1 treatment. (Funded by Janssen Research and Development; THOR ClinicalTrials.gov number, NCT03390504.).

Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma.

BACKGROUND: No new agent has improved overall survival in patients with unresectable or metastatic urothelial carcinoma when added to first-line cisplatin-based chemotherapy. METHODS: In this phase 3, multinational, open-label trial, we randomly assigned patients with previously untreated unresectable or metastatic urothelial carcinoma either to receive intravenous nivolumab (at a dose of 360 mg) plus gemcitabine-cisplatin (nivolumab combination) every 3 weeks for up to six cycles, followed by nivolumab (at a dose of 480 mg) every 4 weeks for a maximum of 2 years, or to receive gemcitabine-cisplatin alone every 3 weeks for up to six cycles. The primary outcomes were overall and progression-free survival. The objective response and safety were exploratory outcomes. RESULTS: A total of 608 patients underwent randomization (304 to each group). At a median follow-up of 33.6 months, overall survival was longer with nivolumab-combination therapy than with gemcitabine-cisplatin alone (hazard ratio for death, 0.78; 95% confidence interval [CI], 0.63 to 0.96; P = 0.02); the median survival was 21.7 months (95% CI, 18.6 to 26.4) as compared with 18.9 months (95% CI, 14.7 to 22.4), respectively. Progression-free survival was also longer with nivolumab-combination therapy than with gemcitabine-cisplatin alone (hazard ratio for progression or death, 0.72; 95% CI, 0.59 to 0.88; P = 0.001). The median progression-free survival was 7.9 months and 7.6 months, respectively. At 12 months, progression-free survival was 34.2% and 21.8%, respectively. The overall objective response was 57.6% (complete response, 21.7%) with nivolumab-combination therapy and 43.1% (complete response, 11.8%) with gemcitabine-cisplatin alone. The median duration of complete response was 37.1 months with nivolumab-combination therapy and 13.2 months with gemcitabine-cisplatin alone. Grade 3 or higher adverse events occurred in 61.8% and 51.7% of the patients, respectively. CONCLUSIONS: Combination therapy with nivolumab plus gemcitabine-cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma than gemcitabine-cisplatin alone. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 901 ClinicalTrials.gov number, NCT03036098.).

Creation of bladder assembloids mimicking tissue regeneration and cancer.

Current organoid models are limited by their inability to mimic mature organ architecture and associated tissue microenvironments1,2. Here we create multilayer bladder 'assembloids' by reconstituting tissue stem cells with stromal components to represent an organized architecture with an epithelium surrounding stroma and an outer muscle layer. These assembloids exhibit characteristics of mature adult bladders in cell composition and gene expression at the single-cell transcriptome level, and recapitulate in vivo tissue dynamics of regenerative responses to injury. We also develop malignant counterpart tumour assembloids to recapitulate the in vivo pathophysiological features of urothelial carcinoma. Using the genetically manipulated tumour-assembloid platform, we identify tumoural FOXA1, induced by stromal bone morphogenetic protein (BMP), as a master pioneer factor that drives enhancer reprogramming for the determination of tumour phenotype, suggesting the importance of the FOXA1-BMP-hedgehog signalling feedback axis between tumour and stroma in the control of tumour plasticity.

CREST: phase III study of sasanlimab and Bacillus Calmette-Guérin for patients with Bacillus Calmette-Guérin-naïve high-risk non-muscle-invasive bladder cancer.

Bacillus Calmette-Guérin (BCG) is the standard of care for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG in combination with programmed cell death-1 (PD-1) inhibitors may yield greater anti-tumor activity compared with either agent alone. CREST is a phase III study evaluating the efficacy and safety of the subcutaneous PD-1 inhibitor sasanlimab in combination with BCG for patients with BCG-naive high-risk NMIBC. Eligible participants are randomized to receive sasanlimab plus BCG (induction ± maintenance) or BCG alone for up to 25 cycles within 12 weeks of TURBT. The primary outcome is event-free survival. Secondary outcomes include additional efficacy end points and safety. The target sample size is around 1000 participants.

Non-muscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer. Most people have surgery to remove the cancer cells while leaving the rest of the bladder intact. This is called transurethral resection of a bladder tumor (TURBT). For people with high-risk NMIBC, a medicine called Bacillus Calmette-Guérin (BCG) is placed directly inside the bladder after TURBT. A 'high risk' classification means that the cancer is more likely to spread or come back after treatment. Some people's cancer does not respond to BCG or returns after BCG treatment. Researchers are currently looking at whether BCG combined with other immunotherapies may prevent cancer growth more than BCG on its own. Immunotherapy helps the immune system recognize and kill cancer cells. Sasanlimab is an immunotherapy medicine that is not yet approved to treat people with NMIBC. It is given as an injection under the skin. In this CREST study, researchers are looking at how safe and effective sasanlimab plus BCG is for people with high-risk NMIBC. Around 1000 people are taking part in CREST. They must have had TURBT 12 weeks or less before joining the study. Researchers want to know how long people live without certain events occurring, such as bladder cancer cells returning. A plain language summary of this article can be found as Supplementary Material. Clinical Trial Registration: NCT04165317; 2019-003375-19 (EudraCT) (ClinicalTrials.gov).

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.

Tubular damage marker as a predictive factor for pathologically upstaged renal cell carcinoma.

PURPOSE: To investigate if increased tubular damage biomarker can predict pathologically upstaged renal cell carcinoma (RCC), which may possess sub-radiologic invasive behavior, leading to surrounding tubular damage. MATERIALS AND METHODS: We examined 1563 patients with surgically resected RCC between March 2016 and June 2021 from the prospective database SUPER-RCC-Nx. Exclusion criteria were cancer not originating from the kidneys, benign renal tumor, and end-stage renal disease. RESULTS: Of 1297 patients, 131 had a clinically high T stage (T3-4), whereas 1166 had a low one. Patients with a clinically low T stage were subgrouped into identical-stage (n = 1041) and upstaged (n = 125) groups, who were confirmed as a pathologically high T stage. The upstaged group had older age (p = 0.003), larger tumor size (5.72 ± 3.24 vs. 3.12 ± 2.08, p < 0.001), higher Fuhrman grade (grades 3-4) (57.3% vs. 47.1%, p = 0.032), and higher urine N-acetyl-beta-D-glucosaminidase/creatinine (NAG/Cr) (5.13 ± 4.78 vs. 4.05 ± 2.84, p = 0.026). Tumor size (> 4 cm; odds ratio = 10.2, p < 0.001) and urine NAG/Cr (odds ratio = 1.16, p = 0.003) were independently associated with pathological upstaging in patients with normal renal function, while age and tumor size were significant risk factors in those with decreased renal function. The receiver operating characteristic curve analysis showed that the model using tumor size and urine NAG/Cr strongly predicted pathological upstaging (area under the curve, 0.84). CONCLUSION: Urine NAG/Cr may be a useful biomarker predicting pathologically upstaged RCC. Clinicians should be prudent in making management decisions when a large RCC is accompanied by an increased urine NAG/Cr.

Clinical features and Surgical Outcome of Clear Cell Papillary Renal Cell Tumor: result from a prospective cohort.

BACKGROUND: Clear cell papillary renal cell tumor (CCPRCT) was first reported in 2006 a patient with end stage renal disease. After that it was discovered in the kidney without end stage renal disease in the 2010s and started to be mentioned in pathology and urology. The incidence of CCPRCT is low and most of it is discovered incidentally, so there is a lack of reports on clinical characteristics and surgical outcome. METHODS: This study used clinical data from the Seoul National University Prospectively Enrolled Registry for Renal Cell Carcinoma-Nephrectomy (SUPER-RCC-Nx). Between August 2016 and July 2022, patients who underwent radical or partial nephrectomy with clear cell papillary RCC with pathological finding were included in this study. All patients' pathologic reports were reviewed by 1 pathologist. Clinical characteristics and surgical outcomes were presented through descriptive statistics, and Kaplan-Meier curve used for survival analysis. RESULTS: Of the 2057 patients, CCPRCT was reported in 36 patients (1.8%). The median follow up period was 26.8 months. The median age was 67 years, and there were 10 females and 26 males. The median tumor size was 1.2 cm. Twenty-nine patients underwent partial nephrectomy. Seven patients with end-stage renal disease underwent radical nephrectomy. The median operative time for patients who underwent partial nephrectomy was 97.5 min and the estimated blood loss was 100 cc. The median hospital days was 4 and 30-day complications were 2 cases with clavien-dindo classification III or higher. During the follow-up period, there was no recurrence and cancer specific mortality. CONCLUSIONS: The size of CCPRCT was small and there was no advanced stage at that time of diagnosis. There was no recurrence or cancer specific mortality during the follow-up period. A multi-center study with a large scale is needed in the future. TRIAL REGISTRATION: Seoul National University Hospital (SNUH) Institutional Review Board (IRB) (approval number: 2210-126-1371).

The effect of goal-directed hemodynamic therapy on clinical outcomes in patients undergoing radical cystectomy: a randomized controlled trial.

BACKGROUND: This study investigated the effects of intraoperative goal-directed hemodynamic therapy (GDHT) on postoperative outcomes in patients undergoing open radical cystectomy. METHODS: This prospective, single-center, randomized controlled trial included 82 patients scheduled for open radical cystectomy between September 2018 and November 2021. The GDHT group (n = 39) received the stroke volume index- and cardiac index-based hemodynamic management using advanced hemodynamic monitoring, while the control group (n = 36) received the standard care under the discretion of attending anesthesiologists during surgery. The primary outcome was the incidence of a composite of in-hospital postoperative complications during hospital stays. RESULTS: A total of 75 patients were included in the final analysis. There was no significant difference in the incidence of in-hospital postoperative complications (28/39 [71.8%] vs. 30/36 [83.3%], risk difference [95% CI], -0.12 [-0.30 to 0.07], P = 0.359) between the groups. The amounts of intraoperative fluid administered were similar between the groups (2700 [2175-3250] vs. 2900 [1950-3700] ml, median difference [95% CI] -200 [-875 to 825], P = 0.714). The secondary outcomes, including the incidence of seven major postoperative complications, duration of hospital stay, duration of intensive care unit stay, and grade of complications, were comparable between the two groups. Trends in postoperative estimated glomerular filtration rate, serum creatinine, and C-reactive protein did not differ significantly between the two groups. CONCLUSIONS: Intraoperative GDHT did not reduce the incidence of postoperative in-hospital complications during the hospital stay in patients who underwent open radical cystectomy. TRIAL REGISTRATION: This study was registered at http://www. CLINICALTRIALS: gov (Registration number: NCT03505112; date of registration: 23/04/2018).

Clinical determinants of recurrence in pTa bladder cancer following transurethral resection of bladder tumor.

BACKGROUND: Non-muscle invasive bladder cancer can be controlled by transurethral resection of bladder (TURB), but suffers from frequent recurrences in 60-70% of cases. Although, recurrence interval after TURB influences treatment course and prognosis, its implication and risk factors have not been fully elucidated. We evaluated the risk factors of early (within 1 yr) and late (after 1 yr) recurrence of pTa bladder cancer and clinical significance of recurrence interval on disease progression and overall survival. METHODS: In this study, pTa bladder cancer patients enrolled in prospective patient registry system of Seoul National University, SUPER-UC, were retrospectively examined to determine the clinical risk factors for recurrence and its significance regarding to recurrence interval. A total of 1067 bladder cancer patients who underwent TURB between March 20 and June 2021 were included and classified into three groups of no recurrence, early, or late recurrence to be comparatively analyzed. RESULTS: Early recurrence was associated with poorer cystectomy-free survival and overall survival than late recurrence. Risk factors for early recurrence included a high number of previous TURB, tumor multiplicity, tumor location, tumor shape, incompleteness of TURB, and high tumor grade. Otherwise, late recurrence was associated with low-grade tumors with insufficient TURB depth. CONCLUSION: Patients with risk factors for early recurrence should be closely followed up with special cautions.

Association between decreased ipsilateral renal function and aggressive behavior in renal cell carcinoma.

BACKGROUND: To assess prognostic value of pre-operative ipsilateral split renal function (SRF) on disease-free survival (DFS) and its association with aggressive pathological features in renal cell carcinoma (RCC) patients.  METHODS: We examined patients registered in SNUG-RCC-Nx who underwent partial or radical nephrectomy at Seoul National University Hospital between January 1, 2010 and December 31, 2020. Patients with the following criteria were excluded from the study. 1) non-kidney origin cancer or benign renal tumor, 2) no pre-operative Tc 99 m-DTPA renal scan, 3) single kidney status or previous partial or radical nephrectomy, and 4) bilateral renal mass. Finally, 1,078 patients were included. RESULTS: Among 1,078 patients, 899 (83.4%) showed maintained ipsilateral SRF on DTPA renal scan; 179 patients (16.6%) showed decreased SRF. The decreased SRF group showed significantly large tumor size (maintained vs. decreased SRF; 3.31 ± 2.15 vs. 6.85 ± 3.25, p < 0.001), high Fuhrman grade (grade 3-4) (41.7% vs. 55.6%, p < 0.001), and high T stage (T stage 3-4) (9.0% vs. 20.1%, p < 0.001). Pathological invasive features, including invasion of the renal capsule, perirenal fat, renal sinus fat, vein, and collecting duct system, were associated with low SRF of the ipsilateral kidney. Univariate Cox regression analysis identified higher SSIGN (The stage, size, grade, and necrosis) score and decreased ipsilateral SRF as significant risk factors, while multivariate analysis showed SSIGN (5-7) (hazard ratio [HR] 11.9, p < 0.001) and SSIGN (8-10) (HR 69.2, p < 0.001) were significantly associated with shortened DFS, while decreased ipsilateral SRF (HR 1.75, p = 0.065) showed borderline significance. Kaplan-Meier analysis showed that decreased ipsilateral SRF (< 45%) group had shorter DFS than the other group (median DFS: 90.3 months vs. not reached, p < 0.001). CONCLUSIONS: Among unilateral RCC patients, those with low ipsilateral SRF showed poor prognosis with pathologically invasive features. Our novel approach may facilitate risk stratification in RCC patients, helping formulate a treatment strategy.

Efficacy of the Treatment of Intraperitoneal Bladder Perforation during Transurethral Resection of Bladder Tumor with the Urethral Catheter Alone: Retrospective Analysis of over 15 Years Using the Clinical Data Warehouse System.

INTRODUCTION: We investigated the efficacy of a urethral catheter alone for intraperitoneal perforation during transurethral resection of bladder tumor (TURBT). PATIENTS AND METHODS: We retrospectively evaluated the medical records of 4,543 patients who underwent TURBT from January 2000 to December 2017 using the Clinical Data Warehouse system. The clinicopathologic characteristics, recurrence-free survival, and progression-free survival were compared between the patient groups with intraperitoneal perforation treated with the Foley catheter alone, extraperitoneal perforation, and matched control TURBT. RESULTS: Intraperitoneal perforation and extraperitoneal perforation were observed in 16 (35.6%) and 29 (64.4%) patients, respectively. In the intraperitoneal perforation group, 11 (68.8%), 2 (12.5%), and 3 (18.8%) patients were treated with the Foley catheter alone, additional percutaneous drainage, and delayed open surgery, respectively. The use of the Foley catheter alone in patients with intraperitoneal perforation of smaller size than the cystoscope or no pelvic radiotherapy history showed improved efficacy without sequelae or therapeutic delay. One of the 2 patients with the size of the intraperitoneal perforation larger than the cystoscope was successfully treated with the Foley catheter alone, whereas the other patient underwent delayed surgical repair. There was no difference in recurrence-free survival and progression-free survival of the intraperitoneal perforation treated with the Foley catheter alone compared to those of the matched control TURBT (p = 0.909, p = 0.518) and the extraperitoneal perforation (p = 0.458, p = 0.699). CONCLUSIONS: Intraperitoneal perforation rarely occurred during TURBT. In the case of intraperitoneal perforation of size smaller than cystoscopy or without pelvic radiotherapy history, treatment with the Foley alone showed successful improvement and safe oncological results. Therefore, treatment with the urethral catheter alone can be carefully considered when an intraperitoneal perforation smaller than the cystoscope size or without pelvic radiotherapy history occurs.

Predicting factor analysis of postoperative complications after robot-assisted radical cystectomy: Multicenter KORARC database study.

OBJECTIVES: To evaluate postoperative complications following robot-assisted radical cystectomy in patients diagnosed with bladder cancer and reveal if there are predictors for postoperative complications. METHODS: Prospectively collected medical records of 730 robot-assisted radical cystectomy patients between 2007/04 and 2019/05 in 13 tertiary referral centers were reviewed. Perioperative outcomes were compared between two groups by postoperative complications (complication vs non-complication). We assessed recurrence-free survival, cancer-specific survival, and overall survival between groups. Regression analyses were implemented to identify factors associated with postoperative complications. RESULTS: Any total and high-grade complication (Clavien-Dindo grade ≥3) rates were 57.8% and 21.1%, respectively. Patients in complication group had significantly higher proportion of diabetes mellitus (P = 0.048), chronic kidney disease (P = 0.011), dyslipidemia (P < 0.001), longer operation time (P = 0.001), more estimated blood loss (P = 0.001), and larger intraoperative fluid volume (P < 0.001). There was a significant difference in cancer-specific survival (log-rank P = 0.038, median cancer-specific survival: both groups not reached). Dyslipidemia (odds ratio 2.59, P = 0.002) and intraoperative fluid volume (odds ratio 1.0002, P = 0.040) were significantly associated with high-grade postoperative complications. Diabetes mellitus (odds ratio 1.97, P = 0.028), chronic kidney disease (odds ratio 1.89, P = 0.046), dyslipidemia (odds ratio 5.94, P = 0.007), and intraoperative fluid volume (odds ratio 1.0002, P = 0.009) were significantly associated with any postoperative complications. CONCLUSIONS: Patients with diabetes mellitus, chronic kidney disease, dyslipidemia, or a relatively large intraoperatively infused fluid volume are more likely to develop postoperative complications. Patients with postoperative complications might have a possibility of lower cancer-specific survival rate.

Oncological outcome according to attainment of pentafecta after robot-assisted radical cystectomy in patients with bladder cancer included in the multicentre KORARC database.

OBJECTIVES: To investigate the oncological significance of a robot-assisted radical cystectomy (RARC)-related pentafecta in patients with bladder cancer. PATIENTS AND METHODS: Using the KORARC database, which includes data from 12 centres, data from 730 patients who underwent RARC between April 2007 and May 2019 were prospectively collected and retrospectively analysed. Pentafecta was achieved if patients met all of the following criteria: (i) negative soft tissue surgical margin; (ii) ≥16 lymph nodes removed; (iii) no major complications (Clavien-Dindo grade 3-5) within 90 days; (iv) no clinical recurrence within the first 12 months; and (v) no ureteroenteric stricture. Patients were divided into two groups according to pentafecta attainment, and a comparison of overall survival (OS) and cancer-specific survival (CSS) using multivariate Cox proportional analysis was then carried out. RESULTS: Of the 730 patients included in this analysis, 208 (28.5%) attained the RARC pentafecta; the remaining 522 (71.5%) did not. The mean age of the patients was 64.67 years, 85.1% were men, 53.6% received a conduit, 37.7% received orthotopic neobladders and the total complication rate was 57.8%. Those who attained the pentafecta received more neobladders (P = 0.039), were more likely to be treated with the intracorporeal technique (P < 0.001), had longer operating times (P = 0.020) and had longer console time (P = 0.021) compared with those who did not attain the pentafecta. Over a mean of 31.1 months of follow-up, the pentafecta attainment group had significantly higher OS and CSS rates compared with the non-attainment group (10-year OS 70.4% vs 58.1%, respectively [P = 0.016]; 10-year CSS 87.8% vs 70.0%, respectively [P = 0.036]). Multivariate analysis showed that the RARC pentafecta was a significant predictor of overall mortality (hazard ratio 0.561; P = 0.038). CONCLUSIONS: Patients who attained the RARC pentafecta had significantly better survival outcomes compared with those who did not. These criteria could be used to standardize assessment of the surgical quality of RARC. In the future, a similar study using an independent cohort is warranted to confirm our results.

Role of multiparametric magnetic resonance imaging to predict postoperative Gleason score upgrading in prostate cancer with Gleason score 3 + 4.

BACKGROUND: To evaluate the role of multiparametric magnetic resonance imaging (mpMRI) in Gleason score (GS) 3 + 4 prostate cancer (PCa) and evaluate independent factors in mpMRI that can predict GS upgrading, we compared the outcomes of GS upgrading group and GS non-upgrading group. PATIENTS AND METHODS: We analyzed the data of 539 patients undergoing radical prostatectomy (RP) for biopsy GS 3 + 4 PCa from two tertiary referral centers. Univariate and multivariate analyses were performed to determine significant predictors of GS upgrading. GS upgrading, the study outcome, was defined as GS ≥ 4 + 3 at definitive pathology at RP specimen. RESULTS: GS upgrading rate was 35.3% and biochemical recurrence (BCR) rate was 8.0%. GS upgrading group was significantly older (p = 0.015), had significantly higher prebiopsy serum prostate-specific antigen (PSA) level (p = 0.001) and PSA density (p = 0.003), had a higher number of prostate biopsy (p = 0.026). There were 413 lesions (76.6%) of PI-RADS lesion ≥ 4, 236 (57.1%) for PI-RADS 4 and 177 (42.9%) for PI-RADS 5 lesion. Multivariate logistic regression analysis revealed that age (p = 0.045), initial prebiopsy PSA level (p = 0.002) and presence of PI-RADS lesion ≥ 4 (p = 0.044) are independent predictors of GS upgrading. CONCLUSION: MpMRI can predict postoperative Gleason score upgrading in prostate cancer with Gleason score 3 + 4. Especially, presence of clinically significant PI-RADS lesion ≥ 4, the significant predictor of GS upgrading, in preoperative mpMRI needs to be paid attention and can be helpful for patient counseling on prostate cancer treatment.

Prognostic Implication of Body Mass Index on Survival Outcomes in Surgically Treated Nonmetastatic Renal Cell Carcinoma: A Single-Institutional Retrospective Analysis of a Large Cohort.

PURPOSE: Obesity is a well-known risk factor for renal cell carcinoma (RCC). However, the prognostic role of obesity in RCC has not been clearly established thus far. We aim to assess the effect of preoperative body mass index (BMI) on survival outcomes in nonmetastatic RCC patients. PATIENTS AND METHODS: We retrospectively analyzed data on 2329 patients who underwent curative surgery for RCC between 2000 and 2014 in a single institution. Patients were divided into normal (< 23 kg/m2), overweight (23-24.9 kg/m2), and obese (≥ 25 kg/m2) groups depending on cutoffs for Asian population. Kaplan-Meier analysis with log-rank test was used to estimate and compare survival outcomes, including recurrence-free, overall, and cancer-specific survival, among each BMI group. The influence of BMI on each survival outcome was evaluated using multivariate Cox regression analyses. RESULTS: Obese patients presented favorable 5-year recurrent-free (90.7% vs 84.9%, p < 0.001), overall (91.8% vs 86.8%, p = 0.002), and cancer-specific (94.8% vs 89.4%, p = 0.002) survival rates than the normal group. Multivariate analyses revealed that increasing BMI was an independent predictor of favorable survival outcomes (all p values < 0.05). In particular, overweight (p = 0.009) and obese (p = 0.009) patients showed better cancer-specific survival compared with normal patients. CONCLUSIONS: Our data suggest that overweight and obesity defined based on BMI are generally related to favorable survival outcomes after surgery for RCC. Additional basic research is required to find out the biological mechanisms explaining the correlation between BMI and survival outcomes.

Sharing the initial experience of pan-cancer panel analysis in high-risk renal cell carcinoma in the Korean population.

BACKGROUND: This study aimed to assess the feasibility of a pan-cancer panel assay for high-risk renal cell carcinoma (RCC) in the Korean population. We also analyzed the clinical and genetic factors contributing to metastasis in clear cell RCC. METHODS: Thirty-one patients with advanced RCC who underwent radical nephrectomy were analyzed. A 1.8 Mb multi-cancer panel (including 25 RCC-related genes, such as VHL, PBRM1, SETD2, and MET), comprising 181 target genes, 23 fusion genes, and 45 drug target lesions developed by Seoul National University Hospital, was used for this study. RESULTS: We extracted DNA from 30 of the 31 (96.7%) RCC specimens. Twenty-one patients (average age 63.3 ± 11.3 years) with clear cell RCC, 5 with papillary RCC, 3 with chromophobe RCC, and one patient, each with MiT family translocation carcinoma RCC and succinate dehydrogenase deficiency RCC, were analyzed. The sequencing depth was 430.8 ± 206.6 and 97 mutations (7.3 ± 2.7 mutations per patient) were detected. The most commonly mutated genes were VHL (46%), PBRM1 (30%), and BAP1, NOTCH4, and POLQ (23.33% each). Compared with TNM stage matched data from TCGA of clear cell RCC, VHL and PBRM1 are most common in both cohorts. Univariate and multivariate analyses revealed that tumor size (Hazard ratio = 2.47, p = 0.04) and PBRM1 (Hazard ratio = 28.69, p = 0.05) were related to metastasis in clear cell RCC. CONCLUSION: The pan-cancer panel comprised of RCC-related genes is a feasible and promising tool to evaluate genetic alterations in advanced RCC. However, large-scale studies and a focus on the clinical utility of this cancer panels is needed.

Patients with Biopsy Gleason Score 3 + 4 Are Not Appropriate Candidates for Active Surveillance.

OBJECTIVE: The aim of this study was to evaluate the feasibility of including patients with biopsy Gleason score (bGS) 3 + 4 prostate cancer in an active surveillance (AS) protocol. METHODS: A total of 615 patients underwent a radical prostatectomy and satisfied the following requirements: prostate-specific antigen ≤10 ng/dL, clinical stage T1c or T2a, 2 or fewer positive biopsy cores, and bGS 6 or 3 + 4 prostate cancer. The patients were divided into two groups according to their bGS (bGS 6 group, n =534; bGS 3 + 4 group, n = 81). RESULTS: The adverse pathological features were significantly higher in the bGS 3 + 4 group (16.7 vs. 49.4%, p< 0.001). Biochemical recurrence (BCR)-free survival was also significantly lower in this group (p < 0.001). In a multivariate analysis, clinical stage (odds ratio [OR] 2.026, p =0.007), maximum percentage of biopsy core involvement (OR 1.015, p = 0.014), and bGS (OR 1.913, p = 0.030) were independent risk factors for adverse pathological features. However, the bGS was the only variable to forecast BCR (hazard ratio 3.567, p < 0.001). CONCLUSIONS: A bGS 3 + 4 was the leading risk factor for a worse postoperative prognosis. Therefore, patients with a bGS 3 + 4 are not appropriate candidates for AS.

Histone Demethylase KDM7A Regulates Androgen Receptor Activity, and Its Chemical Inhibitor TC-E 5002 Overcomes Cisplatin-Resistance in Bladder Cancer Cells.

Histone demethylase KDM7A regulates many biological processes, including differentiation, development, and the growth of several cancer cells. Here, we have focused on the role of KDM7A in bladder cancer cells, especially under drug-resistant conditions. When the KDM7A gene was knocked down, bladder cancer cell lines showed impaired cell growth, increased cell death, and reduced rates of cell migration. Biochemical studies revealed that KDM7A knockdown in the bladder cancer cells repressed the activity of androgen receptor (AR) through epigenetic regulation. When we developed a cisplatin-resistant bladder cancer cell line, we found that AR expression was highly elevated. Upon treatment with TC-E 5002, a chemical inhibitor of KDM7A, the cisplatin-resistant bladder cancer cells, showed decreased cell proliferation. In the mouse xenograft model, KDM7A knockdown or treatment with its inhibitor reduced the growth of the bladder tumor. We also observed the upregulation of KDM7A expression in patients with bladder cancer. The findings suggest that histone demethylase KDM7A mediates the growth of bladder cancer. Moreover, our findings highlight the therapeutic potential of the KMD7A inhibitor, TC-E 5002, in patients with cisplatin-resistant bladder cancer.