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Summary Background Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer. Methods We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0–2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961 , and is ongoing. Findings Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0–40·7). 39 (41%; 95% CI 30·7–51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related. Interpretation Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population. Funding Merck Sharp & Dohme.

Intravesical bacillus Calmette–Guérin (BCG) immunotherapy has been the gold standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG immunotherapy prevents disease recurrence and progression to muscle-invasive disease following TURBT. Although most patients initially respond well to intravesical BCG, considerable concern has been raised for patients with BCG failure who are refractory or recur in 6 months after their last BCG, which implies ‘BCG-unresponsiveness’. Based on current clinical guidelines, early radical cystectomy (RC) is recommended to treat BCG-unresponsive NMIBC. However, due to the high risk of morbidity and mortality of RC and patients' desire to preserve their own bladder, there is a critical unmet need for alternative conservative treatments as bladder-sparing strategies in BCG-unresponsive patients. Trials for effective bladder-sparing treatments are ongoing, and several novel agents have been recently tested in the NMIBC setting. The goal of this review is to introduce and summarize recently reported novel and emerging drugs and ongoing clinical trials for BCG-unresponsive NMIBC., Graphical Abstract

Over the past few decades, platinum-based combination chemotherapy (PBCC) has been the preferred initial therapy for metastatic urothelial cancer (mUC). However, despite a response rate of approximately 50%, a small proportion of patients with distant metastases may be cured by cisplatin-based combination chemotherapy (CBCC). In addition, up to 50% of patients are not eligible for CBCC due to age or comorbidities. Furthermore, adverse effects from PBCC are a major concern. The emergence of check-point inhibitors (CPIs), particularly those with antibodies directed against programmed cell death 1 protein (PD-1) or its ligand (PD-L1), advanced the treatment of mUC. Avelumab switch-maintenance therapy is recommended in patients with locally advanced or mUC who did not progress on initial PBCC. With the recent advances in tumor molecular biology and the discovery of actionable therapeutic targets, the clinical application of targeted therapy is now being explored for mUC. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown positive outcomes in patients with advanced UC with FGFR alterations. Another recent technological development is antibody-drug conjugates (ADCs), which are complex molecules composed of an antibody linked to a biologically active cytotoxic drug (payload) that targets and kills tumor cells while sparing healthy cells. Enfortumab vedotin, a monoclonal antibody targeting nectin-4 conjugated to monomethyl auristatin E, has demonstrated clinically significant efficacy in patients who do not respond to both cytotoxic chemotherapy and CPIs. In this review, we describe switch-maintenance therapies using CPI, various targeted agents, and ADCs that have been investigated for mUC treatment.

Background Upper urinary tract urothelial carcinomas are relatively rare and have a cancer-specific survival rate of 20%–30%. The current gold standard treatment for nonmetastatic high-grade urinary tract urothelial carcinoma is radical nephroureterectomy with bladder cuff resection. Objective This study aimed to compare conditional cancer-specific survival between open radical nephroureterectomy and laparoscopic radical nephroureterectomy in patients with nonmetastatic stage pT3-4 or TxN(+) locally advanced urinary tract urothelial carcinoma from five tertiary centers. Methods The medical records of 723 patients were retrospectively reviewed. The patients had locally advanced and nodal staged tumors and had undergone open radical nephroureterectomy (n = 388) or laparoscopic radical nephroureterectomy (n = 260) at five tertiary Korean institutions from January 2000 and December 2012. To control for heterogenic baseline differences between the two modalities, propensity score matching and subgroup analysis were conducted. Conditional survival analysis was also conducted to determine survival outcome and to overcome differences in follow-up duration between the groups. Results During the median 50.8-month follow up, 255 deaths occurred. In univariate analysis, significant factors affecting cancer-specific survival (e.g., age, history of bladder cancer, American Society of Anesthesiologists score, pathological N stage, and presence of lymphovascular invasion and carcinoma in situ) differed in each subsequent year. The cancer-specific survival between patients treated with open radical nephroureterectomy and laparoscopic radical nephroureterectomy was not different between patients with and without a history of bladder cancer. After adjusting baseline differences between the two groups by using propensity score matching, both groups still had no significant differences in cancer-specific survival. Conclusion The two surgical modalities showed no significant differences in the 5-year cancer-specific survival in patients with locally advanced urinary tract urothelial carcinoma.

Purpose This study aimed to identify prognostic factors for outcomes after radical nephroureterectomy among patients with upper urinary tract urothelial carcinoma (UTUC). Materials and methods We retrospectively reviewed 184 nonmetastatic cases of UTUC after radical nephroureterectomy, bladder cuffing, and/or partial cystectomy (2004-2016). Bladder recurrence-free survival (BRFS), disease progression-free survival (DPFS), and cancer-specific survival (CSS) were estimated. The prognostic values of clinicopathologic parameters were evaluated by using Cox logistic regression analysis. Results The median BRFS, DPFS, and CSS values were 19.0 months, 38.5 months, and 67.0 months, respectively. We identified cases of bladder recurrence (64 cases, 34.8%), disease progression (54 cases, 29.3%), and cancer-specific death (23 cases, 12.5%). BRFS was independently associated with lymphovascular invasion (hazard ratio [HR], 0.421); DPFS was associated with intravesical instillation (HR, 0.290), active smoking (HR, 0.367), synchronous bladder lesions (HR, 2.355), and pT2 (HR, 5.199) and pT3 and pT4 (HR, 13.281) stages; and CSS was associated with alkaline phosphatase levels (HR, 0.966). Among 123 cases without previous bladder cancer, DPFS was associated with intravesical instillation (HR, 0.264), multifocal ureteral tumors (HR, 4.823), and pT3 and pT4 stages (HR, 10.899), whereas CSS was associated with pTis (HR, 32.071). Conclusions Patients with the factors we identified should receive adjuvant intravesical/systemic chemotherapy and intensive surveillance.

Purpose The lower incidence of bladder cancer among women has led to a lack of information on female radical cystectomy (RC). This study aimed to analyze the characteristics related with female RC in a cohort from multiple academic institutions. Materials and methods This was a retrospective review of 384 female patients who underwent RC for bladder cancer. Epidemiologic, perioperative variables including urologic referral periodwith consequent pathologic stage distributions were assessed. The changes in surgical techniques over time were illustrated. Also, we evaluated recurrence-free survival (RFS) at 2 and 5 years and overall survival (OS) at 5 years with stage-specific analyses using the Kaplan-Meier method. Results The mean follow-up time was 35 months (interquartile rage [IQR], 9 to 55). The average time to urologic referral with initial symptoms was 5.5 (IQR, 1 to 6) months and over 20% of patients visited clinics after 6 months. In subsequent stage distributions according to referral period, T2 or higher stage distributions were abruptly increased after 1 year. Overall 2-year/5-year RFS rates were 0.72/0.57 and 5-year OS was 0.61. Notable surgical descriptions were as follows: 91% of patients underwent open RC; 80% of patients underwent an ileal conduit; and 83% of patients received anterior exenteration. However, the proportions of robotic surgery, orthotopic neobladder and organ sparing cystectomy have increased recen-tly. Conclusion We identified the general characteristics and changes in pattern of female RC. Our results also suggest that women are susceptible to delays in referral to an urologist and are at greater risk for worse prognosis.

Purpose The purpose of this study was to determine whether histologic inflammation (HI) in initial and repeat prostate biopsy specimens was significantly associated with the detection of prostate cancer. Materials and Methods Between 2005 and 2017, the clinicopathological records of patients with high prostatespecific antigen (PSA) levels who underwent initial and repeat prostate biopsies were retrospectively reviewed. The presence of HI and its degree in each biopsied specimen were interpreted by one uropathologist with 20 years of experience. The association between HI and cancer diagnosis was statistically assessed, with p < 0.05 considered significant, and the cancer and non-cancer groups were compared. Results Among the 522 patients with a median PSA levels of 6.5 ng/dL, including 258 (49.4%) whose cancer was diagnosed following repeat biopsy, the median degrees of HI in the initial and repeat biopsies were 25.0% and 41.7%, respectively. Furthermore, 211 (40.4%) and 247 (47.3%) patients had HI (> 0%) on biopsied specimens, respectively. Comparison of the cancer and noncancer groups revealed that a greater rate of HI specimens in the initial biopsy was associated with fewer prostate cancer diagnoses following repeat biopsy (p < 0.001). Other comparisons between the cancer and non-cancer groups showed that the cancer group had a significantly higher rate of hypertension, whereas those non-cancer group had a significantly higher rate of benign prostatic hyperplasia and prostatitis (p < 0.05). Conclusion A finding of a lesser degree of HI in the initial and a greater degree of HI in the repeat biopsied specimens was associated with the higher probability of cancer diagnosis in patients with high PSA levels.

Purpose The purpose of this study was to compare oncologic outcomes between open nephroureterectomy (ONU) and laparoscopic nephroureterectomy (LNU) in patients with upper tract urothelial carcinoma. Materials and Methods The medical records of consecutive ONU and LNU cases from five tertiary institutions were retrospectively analyzed between 2000 and 2012. The propensity-score matching methodology was used to compare the two surgical approaches in terms of age, body mass index, American Society of Anesthesiologists score, tumor location, grade, pathologic T and N categories, the presence of lymphovascular invasion, and follow-up duration. The Kaplan-Meier with log-rank tests and clustered Cox regression were used to compare the estimated rates of survival for each surgical approach and to investigate the effect of the surgical approach on each prognostic outcome. Results Six hundred thirty-eight propensity-score matching pairs (n=1,276) were compared; LNU was significantly better than ONU in all types of survival, including intravesical recurrence-free survival (IVRFS), disease-free survival, overall survival (OS), and cancer-specific survival (CSS) (p < 0.05). The 3-year OS and CSS rates were significantly higher with LNU than with ONU (p < 0.05). Compared with ONU, LNU had significantly better 3-year OS and CSS rates (82.9% and 86.2% vs. 78.3% and 81.8%); there were no differences at 5 years. In subgroup analysis of the early-staged group, advanced-stage group, lymph node–positive group, and lymph node–negative group, the two approaches did not significantly affect prognostic outcomes, except LNU improved the IVRFS in the lymph node–negative or no history of previous bladder cancer group. Conclusion LNU had a significantly better prognostic outcome than ONU after propensity-score matching.

Background In this study, we aimed to propose a validated prediction model for disease‐free survival (DFS) after radical nephroureterectomy (RNU) in a Korean population with upper urinary tract urothelial carcinoma (UTUC). Methods We performed a retrospective review of 1561 cases of UTUC who underwent either open RNU (ONU, n = 906) or laparoscopic RNU (LNU, n = 615) from five tertiary Korean institutions between January 2000 and December 2012. Data were used to develop a prediction model using the Cox proportional hazards model. Prognostic factors were selected using the backward variable selection method. The prediction model performance was investigated using Harrell's concordance index (C‐index) and Hosmer‐Lemeshow type 2 statistics. Internal validation was performed using a bootstrap approach, and the National Cancer Center data set (n = 128) was used for external validation. Results A best‐fitting prediction model with seven significant factors was developed. The C‐index and two Hosmer‐Lemeshow type statistics of the prediction model were 0.785 (95% CI, 0.755‐0.815), 4.810 (P = 0.8506), and 5.285 (P = 0.8088). The optimism‐corrected estimate through the internal validation was 0.774 (95% CI, 0.744‐0.804) and the optimism‐corrected calibration curve was close to the ideal line with mean absolute error = 0.012. In external validation, the discrimination was 0.657 (95% CI, 0.560‐0.755) and the two calibration statistics were 0.790 (P = 0.9397) and 3.103 (P = 0.5408), respectively. Conclusion A validated prediction model based on a large Korean RNU cohort was developed with acceptable performance to estimate DFS in patients with UTUC.

PURPOSE The purpose of this study was to identify prognostic tissue markers for several survival outcomes after radical nephroureterectomy among patients with upper urinary tract urothelial carcinoma using tissue microarray and immunohistochemistry. Materials and Methods Retrospectively, data of 162 non-metastatic patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy between 2004 and 2016 were reviewed to determine intravesical recurrence-free survival (IVRFS), disease-free survival (DFS), and overall survival (OS). The expression of 27 tissue markers on a tissue microarray of radical nephroureterectomy samples and prognostic values of clinicopathological parameters were evaluated using immunohistochemistry and Cox proportional hazard models after adjusting for significant prognostic clinicopathological variables. The expression of all tissue markers was categorized into a binary group with continuous H-scores (0-300). RESULTS Median follow-up was 53.4 months (range, 3.6 to 176.5 months); and, 58 (35.8%), 48 (29.6%), and 19 (11.7%) bladder recurrence, disease progression, and all cause death, respectively, were identified. After adjusting for significant clinicopathological factors including intravesical instillation for bladder recurrence-free survival, pathologic T category and intravesical instillation for disease progression-free survival , and pathologic T category for OS (p < 0.05), IVRFS was associated with epithelial cadherin (hazard ratio [HR], 0.49), epidermal growth factor receptor/erythroblastosis oncogene B (c-erb) (HR, 2.59), and retinoblastoma protein loss (HR, 1.85); DFS was associated with cyclin D1 (HR, 2.16) and high-molecular-weight cytokeratin (HR, 0.42); OS was associated with E-cadherin (HR, 0.34) and programmed cell death 1 ligand (HR, 13.42) (p < 0.05). CONCLUSION Several significant tissue markers were associated with survival outcomes in upper urinary tract urothelial carcinoma patients treated with radical nephroureterectomy.

AimThis study evaluated the prognosis and survival predictors for bladder urachal carcinoma (UC), based on large scale multicenter cohort with long term follow-up database.MethodsA total 203 patients with bladder UC treated at 19 hospitals were enrolled. Clinical parameters on carcinoma presentation, diagnosis, and therapeutic methods were reviewed for the primary cancer and for all subsequent recurrences. The stage of UC was stratified by Mayo and Sheldon pathological staging system. Oncological outcomes and the possible clinicopathological parameters associated with survival outcomes were investigated.ResultsThe mean age of the patients was 54.2 years. Among the total of 203 patients, stages I, II, III, and IV (Mayo stage) were 48 (23.8%), 108 (53.5%), 23 (11.4%), and 23 (11.4%), respectively. Gross hematuria and bladder irritation symptoms were the two most common initial symptoms. The mean follow-up period was 65 months, and 5-year overall survival rates (OS), cancer-specific survival rates (CSS), and recurrence-free survival rates (RFS) were 88.3, 83.1, and 63.9%, respectively. For the patients with Mayo stage ≥III, OS, CSS, and RFS were significantly decreased to 38.0, 35.2, and 28.4%, respectively. The higher pathological stage (Mayo stage ≥III, Sheldon stage ≥IIIc), positive surgical margin (PSM), and positive lymphovascular invasion (PLM) were independent predictors of shorter OS, CSS, and RFS.ConclusionThe pathological stage, PSM, and PLM were significantly associated with the survival of UC patients, emphasizing an importance of the complete surgical resection of tumor lesion.

BACKGROUND: Limited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1) negative patients receiving immunotherapy. Final results from these trials are unknown. OBJECTIVE: To compare survival in cisplatin-ineligible mUC patients receiving first-line immunotherapy versus carboplatin-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective cohort study of 2,017 mUC patients receiving first-line carboplatin-based chemotherapy (n=1,530) or immunotherapy (n=487) from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record-derived database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was overall survival (OS), comparing 12- and 36-month OS, and hazard ratios before and after 12 months. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression model estimates of comparative effectiveness. RESULTS AND LIMITATIONS: IPTW-adjusted OS rates in the immunotherapy group were lower at 12 months (39.6% [95% CI 34.0-45.3%] versus 46.1% [95% CI 43.4-48.8%]) but higher at 36 months (28.3% [95% CI 21.8-34.7%] versus 13.3% [95% CI 11.1-15.5%]) relative to the chemotherapy group. Immunotherapy treatment demonstrated inferior OS during the first 12 months relative to carboplatin-based chemotherapy (IPTW-adjusted HR 1.37, 95% CI 1.15-1.62), but superior OS beyond 12 months (IPTW-adjusted HR 0.50, 95% CI 0.30-0.85). Limitations include retrospective design and potential unmeasured confounding. CONCLUSIONS: In the setting of mUC, clinicians and patients should carefully consider how to balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy. PATIENT SUMMARY: To determine the optimal first-line therapy for metastatic bladder cancer patients who are unfit for cisplatin, we compared carboplatin-based chemotherapy versus immunotherapy using real-world data. Survival in the first year of treatment was lower with immunotherapy relative to chemotherapy, but for patients surviving beyond the first year, immunotherapy was superior.

ObjectiveTo investigate the association between antibiotic therapy and the efficacy of intravesical BCG therapy in patients with high-risk non-muscle invasive bladder cancer (NMIBC).MethodsThis study involved the retrospective review of medical records of patients who underwent transurethral resection of bladder tumors for high-risk NMIBC followed by intravesical BCG therapy between 2008 and 2017. Patients were categorized as none, short- (2-6 days), and long-course use (≥7 days) based on the duration of antibiotic treatment concurrent with or initiated ≤30 days before BCG therapy. Oncologic outcomes, including recurrence-free survival and progression-free survival, were analyzed.ResultsOf the 276 patients enrolled in the study, 162 (58.7%) had pathologic T1 disease and 206 (80.2%) had high-grade disease. Concurrently with or prior to BCG therapy, 114 patients had (41.3%) received short-course antibiotic therapy, and 96 (34.8%) patients had received long-course antibiotics. The 5-year recurrence-free survival (62.2% vs 26.9%; log rank, p ConclusionLong-course antibiotic treatment concurrently with or prior to intravesical BCG adversely influenced disease recurrence and progression outcomes in patients with high-risk NMIBC. Careful use of antibiotics may be required to enhance the efficacy of intravesical BCG therapy. Further mechanistic and prospective studies are warranted.

Purpose: To investigate programmed cell death-ligand 1 (PD-L1) expression status and the clinical and pathological factors related to its expression in urothelial carcinoma (UC) patients.Materials and Methods: Data from 761 UC patients who underwent testing for PD-L1 expression using the VENTANA (SP-142 immunohistochemistry assay) for measuring PD-L1 expression according to the manufacturer's protocol between February 2016 and July 2019 were retrospectively reviewed. Patients were categorized into three groups based on the percentage of tumor area covered by PD-L1-expressing tumor-infiltrating immune cells (ICs) as follows: IC0 (

INTRODUCTION AND OBJECTIVE:Incontinence after radical prostatectomy is poorly understood. Preoperative factors such as age and membranous urethral length (MUL) have been shown to correlate with pos...

INTRODUCTION AND OBJECTIVE:Preoperative chronic kidney disease (CKD) status may affect disease outcomes in patients with upper tract urothelial carcinoma (UTUC). We evaluated the impact of preopera...

Clear cell papillary renal cell carcinoma (ccpRCC) was recently established as a distinct type of epithelial neoplasm by the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia. Here, we report a case of partial nephrectomy for a ccpRCC detected during the routine follow-up of a previously treated liposarcoma in a 70-year-old male patient. The patient was referred to the urology department for a right-sided renal mass (size: 2 cm) detected during routine annual imaging follow-up for a malignant right inguinal fibrous histocytoma and liposarcoma that had been diagnosed 6 and 4 years earlier, respectively, and treated with surgery and adjuvant radiation therapy. Following partial nephrectomy, the renal mass was pathologically diagnosed as ccpRCC, and immunohistochemistry revealed carbonic anhydrase 9 (CA9) expression. No recurrences or metastases were detected on follow-up imaging for 6 months. This is the first report of partial nephrectomy for incidentally discovered CA9-positive ccpRCC.

Urothelial carcinoma (UC), originating in the bladder or upper urinary tract, is the most common histological type of cancer. Currently, platinum-based cytotoxic chemotherapy is the standard treatment for metastatic UC (mUC) and the preferred treatment option in the perioperative (neoadjuvant and/or adjuvant) setting of muscle invasive bladder cancer (MIBC). In addition, intravesical bacillus Calmette-Guerin immunotherapy or chemotherapy is applied as the adjuvant therapeutic option in non-muscle invasive bladder cancer (NMIBC) after transurethral resection, to prevent recurrence and progression. In recent years, with an increased understanding of cancer immunobiology, systemic immunotherapies targeting immune checkpoint inhibition has been explored and clinically used in the area of UC. The programmed cell death 1 receptor (PD-1) and its ligand (PD-L1) are important negative regulators of immune activity, preventing the destruction of normal tissues and autoimmunity. To date, five immune checkpoint inhibitors blocking PD-1 (pembrolizumab, nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved by the United States Food and Drug Administration (US-FDA) for first- or second-line use in mUC, based on durable therapeutic response and manageable safety profiles observed in relevant clinical trials. In addition, the clinical use of several immune checkpoint inhibitors is currently being tested for MIBC and NMIBC. In this article, we review the current and ongoing clinical trials, regarding immune checkpoint inhibitors, being conducted in various clinical settings of UC, including mUC, MIBC, and NMIBC.

// Yoon Seok Suh 1, * , Jae Young Joung 1, * , Sung Han Kim 1 , Jeong Eun Kim 1 , Moon Kyung Choi 2 , Weon Seo Park 2 , Sang-Jin Lee 3 , Ho Kyung Seo 1 , Jinsoo Chung 1 and Kang Hyun Lee 1 1 Department of Urology, Center for Prostate Cancer, Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea 2 Department of Pathology, Center for Prostate Cancer, Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea 3 Immunotherapeutics Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea * These authors contributed equally to this work Correspondence to: Kang Hyun Lee, email: uroonco@ncc.re.kr Keywords: prostate stem cell antigen; prostate cancer; biochemical recurrence; survival Received: September 04, 2017 Accepted: March 13, 2018 Published: May 29, 2018 ABSTRACT Objectives: To investigate whether the preoperative detection of prostate stem cell antigen (PSCA) mRNA in blood has predictive value for biochemical recurrence, overall survival, and cancer-specific survival after radical prostatectomy in patients with high-risk prostate cancer. Results: Median age was 67 years (interquartile range: 63-71), and median follow-up was 41 months (interquartile range: 25–65). PSCA mRNA was detected in 151 patients (51.1%). Biochemical recurrence was developed in 101 patients (34.2%), and all-cause mortality and prostate cancer-specific mortality occurred in 17 (5.7%) and 8 (2.7%) patients, respectively. Kaplan–Meier analysis revealed significant differences in biochemical recurrence, overall survival, and cancer-specific survival according to PSCA mRNA positivity. Cox regression hazards model analysis showed that PSCA mRNA positivity was an independent predictor of biochemical recurrence, overall survival, and cancer-specific survival. Conclusions: PSCA mRNA in the peripheral blood was related to poor prognosis. Detection of PSCA mRNA by polymerase chain reaction in peripheral blood can be used to predict survival after radical prostatectomy in patients with high-risk prostate cancer. Future study with larger cohort and long-term follow-up is required to confirm this finding. Materials and methods: A total of 295 patients with high-risk prostate cancer scheduled to undergo radical prostatectomy were prospectively enrolled from 2008 to 2016. Nested reverse transcription polymerase chain reaction was used to detect cells with PSCA mRNA in peripheral blood. The predicting ability of PSCA mRNA positivity for biochemical recurrence, overall survival, and cancer-specific survival after radical prostatectomy was evaluated.

Urothelial bladder cancer (UBC) is one of the most prevalent and aggressive malignancies. Recent evidence indicates that the tumor microenvironment (TME), including a variety of immune cells, is a critical modulator of tumor initiation, progression, evolution, and treatment resistance. Mast cells (MCs) in UBC are possibly involved in tumor angiogenesis, tissue remodeling, and immunomodulation. Moreover, tumor-infiltration by MCs has been reported in early-stage UBC patients. This infiltration is linked with a favorable or unfavorable prognosis depending on the tumor type and location. Despite the discrepancy of MC function in tumor progression, MCs can modify the TME to regulate the immunity and infiltration of tumors by producing an array of mediators. Nonetheless, the precise role of MCs in UBC tumor progression and evolution remains unknown. Thus, this review discusses some critical roles of MCs in UBC. Patients with UBC are treated at both early and late stages by immunotherapeutic methods, including intravenous bacillus Calmette–Guérin instillation and immune checkpoint blockade. An understanding of the patient response and resistance mechanisms in UBC is required to unlock the complete potential of immunotherapy. Since MCs are pivotal to understand the underlying processes and predictors of therapeutic responses in UBC, our review also focuses on possible immunotherapeutic treatments that involve MCs.

Locally advanced or metastatic urothelial bladder cancer (a/m UBC) is currently treated using platinum-based combination chemotherapy. Immune checkpoint inhibitors (ICIs) are the preferred second-line treatment options for cisplatin-eligible a/m UBC patients and as first-line options in cisplatin-ineligible settings. However, the response rates for ICI monotherapy are modest (~20%), which necessitates the exploration of alternative strategies. Dysregulated activation of fibroblast growth factor receptor (FGFR) signaling enhances tumor proliferation, survival, invasion, angiogenesis, and immune evasion. The recent U.S. Food and Drug Administration approval of erdafitinib and the emergence of other potent and selective FGFR inhibitors (FGFRis) have shifted the treatment paradigm for patients with a/m UBC harboring actionable FGFR2 or FGFR3 genomic alterations, who often have a minimal-to-modest response to ICIs. FGFRi–ICI combinations are therefore worth exploring, and their preliminary response rates and safety profiles are promising. In the present review, we summarize the impact of altered FGFR signaling on a/m UBC tumor evolution, the clinical development of FGFRis, the rationale for FGFRi–ICI combinations, current trials, and prospective research directions.

Objective: Often a sick or an anxious person can experience pain or anxiety relief if another person holds his or her hand. In this study, we conducted investigations to determine whether hand-holding during cystoscopy decreases patient anxiety, pain, and dissatisfaction while at the same time increasing patient comfort and tolerance during the procedure. Patients and Methods: Eighty-six male patients who underwent flexible cystoscopy between November 2015 and March 2017 were randomized as follows: hand-holding (group I, n = 43) or non-hand-holding (group II, n = 43) during the procedure. Before flexible cystoscopy, lidocaine gel was instilled in the urethra. Patients’ anxiety levels were quantified using the State-Trait Anxiety Inventory. A visual analog scale (0–10) was used for self-assessment of satisfaction, discomfort, and willingness to undergo repeat cystoscopy. Results: Demographic characteristics, mean age, procedure duration, procedure indications, and preprocedural analyses did not differ significantly between the 2 groups. In group I, the postprocedural mean anxiety level, pain score, heart rate, and systolic blood pressure were significantly lower compared with those in group II (p = 0.009, p = 0.003, p = 0.022, and p = 0.014, respectively). In group I, postprocedural mean satisfaction score were higher, and patients were more likely to undergo a repeat cystoscopy, compared with those in group II (p = 0.001 and p = 0.004, respectively). Conclusions: Hand-holding during cystoscopy significantly reduced patients’ feelings of anxiety, pain, discomfort, and dissatisfaction. Hand-holding served as a simple, inexpensive, and effective adjunct to sedation during cystoscopy.

// Ho Kyung Seo 1, 2, * , Sung Han Kim 1, 3, * , Kyung-Ohk Ahn 3 , Sang-Jin Lee 4 , Weon Seo Park 5 , Sohee Kim 6 , Sang-Hyun Hwang 7 , Do Hoon Lee 8 , Jae Young Joung 1 , Jinsoo Chung 1 , Jungnam Joo 6 and Kyung-Chae Jeong 3 1 Department of Urology, Center for Prostate Cancer, Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea 2 Biomarker Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea 3 Translational Research Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea 4 Immunotherapeutics Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea 5 Department of Pathology, Center for Prostate Cancer, Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea 6 Biometrics Research Branch, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea 7 Department of Laboratory Medicine, Center for Diagnostic Oncology, National Cancer Center, Goyang-si, Korea 8 Department of Laboratory Medicine and Hematologic Malignancy Branch, Research Institute and Hospital of National Cancer Center, Goyang-si, Korea * These authors have contributed equally to this work Correspondence to: Kyung-Chae Jeong, email: jeongkc@ncc.re.kr Keywords: administration; intravesical therapy; mitomycin C; neoplasm; urinary bladder Received: March 17, 2017 Accepted: June 30, 2017 Published: October 09, 2017 ABSTRACT Objective: Sodium bicarbonate has been reported to maximize the efficacy of intravesical instillation of mitomycin-C (IVI-MMC) therapy by urine alkalinization in non-muscle-invasive bladder cancer (NMIBC). This study aimed to analyze the changes in MMC concentration according to urinary pH and evaluate the efficacy of sodium bicarbonate to maintain the concentration of active form of MMC during IVI-MMC. Methods: We prospectively enrolled 26 patients with NMIBC after transurethral resection of bladder tumor. Patients with very high-risk and low-risk NMIBC were excluded. Urinary creatinine, volume, pH, and concentrations of MMC and its degraded form were measured immediately before and after IVI-MMC. The patients were administered 1.5 g of oral sodium bicarbonate during the preceding evening, in the morning, and immediately before the fourth cycle of the six-cycle IVI-MMC. The correlation between MMC concentration and urinary pH changes was explored with or without oral bicarbonate therapy. Results: Recurrence without progression to muscle-invasive disease was noted in 4 of 26 patients in a 23.7-month follow-up. The mean urinary pH before and after the therapy increased from 6.03 to 6.50, and 6.46 to 7.24, without or with oral SB therapy, respectively. Despite this increase, the concentration of active form of MMC did not change significantly. No correlation was found between urinary pH and MMC concentration. Urine alkalinization by SB administration did not maintain the high concentration of urinary MMC. Conclusions: Urine alkalinization by sodium bicarbonate administration for IVI-MMC did not maintain the high concentration of active urinary MMC in NMIBC.

Objective The present study aimed to determine the effect of an increasing number of predisposing atheroembolic risk factors on the development of chronic kidney disease (CKD) after partial nephrectomy (PN) in patients with T1-stage renal cell carcinoma (RCC). Methods The study included 147 patients with T1-stage RCC with a normal contralateral kidney and without preoperative CKD, who underwent open (OPN, N = 83, 56.5%) or laparoscopic PN (LPN, N = 64, 43.5%) between 2003 and 2014. Postoperative CKD was defined as an estimated glomerular filtration rate

// Sung Han Kim 1, * , Jung Kwon Kim 1, * , Boram Park 2 , Jungnam Joo 2 , Jae Young Joung 1 , Ho Kyung Seo 1 , Kang Hyun Lee 1 and Jinsoo Chung 1 1 Department of Urology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, Goyang, Korea 2 Biometrics Research Branch, Division of Cancer Epidemiology and Prevention, Research Institute and Hospital of National Cancer Center, Goyang, Korea * These authors contributed equally to this work Correspondence to: Jinsoo Chung, email: cjs5225@ncc.re.kr Keywords: renal cell carcinoma, metastasis, synchronous, embolization, nephrectomy Received: December 28, 2016 Accepted: May 03, 2017 Published: May 15, 2017 ABSTRACT Objective: To compare survival outcomes for renal embolization (RE) to cytoreductive nephrectomy (CN) and no primary renal treatment (NT) among patients with synchronous metastatic renal cell carcinoma (mRCC) treated using either targeted therapy (TT) or immunotherapy (IT). Results: The median follow-up duration was 81.3 months, with a duration of first-line treatment of 3.5 months. Among the 211 patients, the median PFS and OS were 4.4 and 10.6 months. Specifically for patients receiving TT (124 patients), the PFS and OS were 5.5 and 12.0 months. An intervention effect was identified only for OS, with a median OS of 20.1, 8.8 and 9.3 months for CN, RE and NT, respectively. After stratification by risk classification, CN provided a significant benefit on OS, compared to RE and NT, for patients with an intermediate risk (MSKCC). For those with a poor risk (Heng criteria), NT provided better survival than PFS ( p =0.003), and a comparable survival to RE ( p > 0.05). Materials and Methods: Retrospective analysis of 211 patients, 87 treated with IT and 124 with TT, retrieved from our RCC database. Patients' risk factors for survival was evaluated using the Heng and MSKCC criteria, with only patients with an intermediate or poor survival risk included in the analysis. Between-group comparisons were evaluated with respect to progression-free survival (PFS) and overall survival (OS). Conclusions: The differential effect of CN and RE on OS appears to be modulated by risk classification. In patients with a poor risk, RE should be implemented after careful consideration of comorbidities and life expectancy.

PURPOSE Secondary primary cancers (SPCs) commonly arise in patients with renal cell carcinoma (RCC). We designed the present study to estimate the SPC incidence in Korean patients with RCC. MATERIALS AND METHODS The study cohort was population-based and consisted of 40,347 individuals from the Korean Central Cancer Registry who were diagnosed with primary renal cancer between 1993 and 2013. Standardized incidence ratios (SIRs) for SPCs were estimated for different ages at diagnosis, latencies, diagnostic periods, and treatments. RESULTS For patients with primary RCC, the risk of developing a SPC was higher than the risk of developing cancer in the general population (SIR, 1.13; 95% confidence interval, 1.08 to 1.18). Most cancer types showed higher incidences in patients with RCC than in the general population. However, the relative incidence of gastric cancer as an SPC varied by age. Gastric cancer incidence was elevated in young patients (< 30 years) with RCC, but reduced in older (≥ 30) patients with RCC. Patients with advanced RCC died prematurely, regardless of SPC development. In contrast, those with early-stage RCC survived for longer periods, although SPC development affected their post-RCC survival. After SPC development, women had better survival than men. CONCLUSION In Korean patients with primary RCC, the incidence of SPC was 13% higher than the incidence of cancer in the general population. These findings may play important roles in the conduct of follow-up evaluations and education for patients with RCC.

In the present study we examined the effect of the Prognostic Nutritional Index (PNI) on the overall survival (OS) and progression-free survival (PFS) of patients with metastatic renal cell carcinoma (RCC) treated with targeted therapy.The study included 125 patients with metastatic RCC. Pretreatment PNI was calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mmThe median follow-up time was 45.3 months (interquartile range, 23.7-77.3 months). Decreased PNI was significantly associated with older female patients, poor Eastern Cooperative Oncology Group performance status, types of initial drug, and increased Memorial Sloan Kettering Cancer Center (MSKCC) and Heng risk score (P .05). An increase in the PNI of 1 unit was associated with a 10% decrease in the risk of death from RCC (hazard ratio, 0.90; P .001). In the multivariable analysis, the PNI was an independent prognostic factor for OS (P .001). In intermediate-risk patients according to MSKCC and Heng risk criteria, OS was better in the high PNI group than in the low PNI group (P = .0136 and P = .0009, respectively).PNI is an independent prognostic factor in patients with metastatic RCC treated with targeted therapy. When used as an adjunct, it increases the prognostic accuracy of established factors and could be a valuable tool for tailoring surveillance, patient counseling, and clinical trial design.

Background Docetaxel is the preferred chemotherapeutic agent for hormone-refractory prostate cancer (PC) patients. However, patients eventually develop docetaxel resistance, and no effective treatment options are available for them. Objective We aimed to establish docetaxel resistance in castration-resistant prostate cancer (CRPC) cell lines (DU145/TXR, PC-3/TXR, and CWR22/TXR) and characterized transcriptional changes upon acquiring resistance to the docetaxel. Methods Human PC cells (DU145, PC-3, CWR22) and all docetaxel-resistant cells were maintained in Roswell Park Memorial Institute Medium (RPMI) 1640 media supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. ABCB1 was detected by using both parental and docetaxel-resistant CRPCs prepared for flow cytometry. For the evaluation of tumor-suppressive effects under each chemotherapeutic agent, subcutaneous xenografts of DU145 or DU145/TXR were implanted at the mouse flank. Results The P-glycoprotein-encoding gene ABCB1 was distinctively upregulated in the resistant cells, and its overexpression played an essential role in docetaxel resistance in CRPC. When tested for the cytotoxicity of gemcitabine, another option for chemotherapy, the docetaxel-resistant cells were shown to become sensitive to the drug, implying additional phenotypic transformation in the docetaxel-resistant cells. Studies using xenograft animal models demonstrated that the growth of tumors composed of both docetaxel-sensitive and docetaxel-resistant cells was deterred most profoundly when docetaxel and gemcitabine were administered together. Conclusion This study suggests that when a drug develops therapeutic resistance, sensitivity tests could be another option, ultimately providing insight into a novel alternative clinical strategy.

Background The differences in progression-free survival (PFS) and cancer-specific survival (CSS) of metastatic renal cell carcinoma (mRCC) patients according to treatment, type of metastasis, and Heng criteria risk are unclear. In this study, we compared survival according to various such parameters. Methods Between 2000 to 2014, 214 mRCC patients, of whom 171 (79.9%) were intermediate-risk and 43 (20.1%) were poor-risk, were retrospectively selected; 126 (58.9%) patients were treated with immunotherapy (IT) and 88 (41.1%) with targeted therapy (TT). Moreover, 144 patients had synchronous mRCCs (67.3%, SM) and 70 had metachronous mRCCs (32.7%, MM). The Kaplan-Meier method and log-rank test were used to compare progression-free survival (PFS) and CSS. Results During a median 4.2 (1.0–70.4) months of systemic treatment and 98.3 (4.8–147.6) months of follow-up, the median PFS and CSS were 4.7 (95% confidence interval [CI]: 3.8–5.5) and 13.8 (95% CI, 9.8–18.3) months, respectively. The PFS and CSS were significantly better in the MM (5.9 and 21.3 months) and intermediate-risk groups (5.2 and 18.3 months) than those in the SM (4.4 and 9.6 months) and poor-risk groups (2.7 and 5.8 months), respectively (p 0.05). Conclusion Dividing patients into specific subcategories helps to better predict therapeutic outcomes. Electronic supplementary material The online version of this article (10.1186/s12885-019-5900-1) contains supplementary material, which is available to authorized users.

INTRODUCTION AND OBJECTIVES:Most patients with non-muscle invasive bladder cancer (NMIBC) who receive standard-of-care TURBT and Bacillus Calmette-Guerin (BCG) experience recurrence. For BCG-unresp...

Purpose. This study aimed to evaluate the statuses of P16INK4A expression and human papillomavirus (HPV) infection among patients with penile cancer at a single Korean institution. Patients and Methods. Fourteen patients with penile cancer at our center were retrospectively identified and their clinicopathological data were analyzed. The patients’ HPV and P16INK4A expression status (a known tumor suppressor protein) were tested using genotyping with a DNA chip assay and immunohistochemical staining, respectively. The results regarding HPV status were compared to those from another Asian study. Results. The mean age at diagnosis was 60 years (range: 34–86 years). The median tumor size was 3.0 cm (range: 0.6–4.7 cm). Ten tumors were located on the penile glans. Five patients tested positive for HPV DNA (5/14, 36%) and all cases involved HPV type 16 (5/5, 100%). Positive expression of P16INK4A was observed in 6 cases (6/14, 43%). Among the HPV positive cases, 80% of cases (4/5) were also positive for P16INK4A. The prevalence of HPV infection in our study (36%) was higher than in a previous Asian study (23%). Conclusions. This is the first study to evaluate the prevalence of HPV infection and P16INK4A expression among patients with penile cancer at a single Korean institution. The prevalence of HPV (36%) was slightly higher than the results from a previous Asian study. Additional multi-center studies are needed to better understand penile cancer in Korea and to identify biomarkers that can determine high-risk cases and predict their prognosis.

Purpose We aimed to evaluate the efficacy and safety of the use of docetaxel plus androgen deprivation therapy (ADT) for metastatic hormone-sensitive prostate cancer (mHSPC) in Korean patients. Materials and methods This study was conducted retrospectively. In total, 61 Korean patients with mHSPC who used docetaxel plus ADT were identified from medical records. Patients received docetaxel plus ADT at a dose of 75 mg/m2 every 3 weeks for 6 cycles. We evaluated prostate-specific antigen (PSA) response, PSA progression, progression to castration-resistant prostate cancer (CRPC), clinical progression, and adverse events. Results Most of the patients had high volume disease (98.3%) and 83.6% had a Gleason score of 8 or higher. The median PSA level at the start of ADT was 131.4 ng/mL. The percentage of patients whose PSA levels decreased to less than 0.2 ng/mL at 3, 6, and 12 months were 28.3%, 41.0%, and 45.0%, respectively. During a median of 12.0 months after treatment, PSA progression occurred in 13.3% of patients. Clinical progression and progression to CRPC were observed in 15.1% and 14.8%, respectively. Neutropenia grade ≥3 and febrile neutropenia occurred in 63.5% and 11.5%, respectively. Conclusions Comparing our findings with those of the prior chemohormonal therapy versus androgen ablation randomized trial for extensive disease in prostate cancer (CHAARTED) study, in Korean patients, the use of docetaxel plus ADT for mHSPC showed similar results for early oncologic outcomes including PSA response and time to clinical progression. However, we observed a higher rate of adverse events, which should be considered seriously.