High-risk Urothelial Carcinoma Research Articles

Efficacy and safety of adjuvant nivolumab after radical surgery for high-risk urothelial carcinoma: a preliminary report of real-world data from a single institution.

The phase 3 CheckMate 274 trial demonstrated superiority of adjuvant nivolumab over placebo after radical surgery in patients with high-risk urothelial carcinoma (UC). However, real-world data on the efficacy and safety profile of adjuvant nivolumab in Japan have not been reported. This retrospective study enrolled patients with high-risk UC who received adjuvant nivolumab therapy following radical surgery between 2022 and 2024 at our institution. We evaluated immune-related adverse events (irAEs) according to the Common Terminology Criteria for Adverse Events, version 5.0. Kaplan-Meier curves were used to assess disease-free survival (DFS) and overall survival (OS). Thirty-three patients with high-risk UC receiving adjuvant nivolumab therapy following radical surgery were identified, and median follow-up was 11months. Three patients experienced grade 3 irAEs, and 8 discontinued adjuvant nivolumab therapy due to irAEs. No grade 4 or 5 irAEs were observed. Eight patients have completed 1year of treatment, and nine are currently on treatment. Nine patients had recurrences and one died of cancer. Of the nine patients with recurrences, six relapsed while on adjuvant nivolumab therapy, two relapsed after completing 1year of treatment, and one relapsed after discontinuation of irAE. The 1- and 2-year OS rates were 100% and 90%, respectively, and median OS was not reached. The 1- and 2-year DFS rates were 70% and 60%, respectively, and median DFS was 26months. Adjuvant nivolumab appears to have some efficacy in Japanese patients. Since this is a postoperative adjuvant therapy, careful patient selection is warranted.

A Retrospective Single-Center Comparative Study Between Robot-Assisted and Laparoscopic Radical Nephroureterectomy for Upper-Tract Urothelial Carcinoma on Perioperative Results, Overall Survival, and Recurrence Rate.

Introduction Patients with localized high-risk urothelial carcinoma of the upper urinary tract are advised radical nephroureterectomy, the surgical removal of the kidney and ureter, utilizing robot-assisted versus laparoscopic methods. This study aims to compare the surgical and oncological results of robot-assisted and laparoscopic radical nephroureterectomy for upper-tract urothelial carcinoma. Methods An observational retrospective cohort study compared 14 patients who had robotic-assisted nephroureterctomy (RAN) to 16 patients who had laparoscopic assisted nephroureterctomy (LAN). Results There was no significant difference in age, sex, glomerular filtration rate (GFR), creatinine, Charlson comorbidity score, length of hospital stays, or the need to convert to an open approach. However, there was a statistical difference between the two procedures in terms of lymph dissection (p-value of 0.037) and the length of the procedure (p-value of 0.09). Conclusions The robotic approach has significantly higher use for lymph node dissection, while laparoscopic radical nephroureterectomy has a shorter operation time.

Overview, Diagnosis, and Perioperative Systemic Therapy of Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma comprises 5-10% of all urothelial carcinoma cases. This disease tends to have a more aggressive course than its lower urinary tract counterpart, with 60% of patients presenting with invasive disease and 30% of patients presenting with metastatic disease at diagnosis. The diagnostic workup of UTUC involves imaging with CT urogram, urine cytology, and direct visualization and biopsy of suspected lesions via ureteroscopy. Standard treatment of high-grade UTUC involves radical nephroureterectomy (RNU) and excision of the ipsilateral bladder cuff. Both the NCCN and EAU Guidelines include neoadjuvant chemotherapy as a treatment option for select patients with UTUC; however, there are no strict guidelines. Much of the rationale for neoadjuvant chemotherapy is based on extrapolation from data from muscle-invasive bladder cancer, which has demonstrated a 5-year OS benefit of 5-8%. Retrospective studies evaluating the use of NACT in urothelial carcinoma have yielded pathologic objective response rates of 48% in UTUC cohorts. The randomized Phase III POUT study noted a DFS advantage with adjuvant platinum-based chemotherapy, compared with surveillance in UTUC, of 70% vs. 51% at 2 years. Though not the standard of care, multiple studies have explored the use of perioperative immunotherapy or chemoimmunotherapy in the management of invasive urothelial carcinoma. The PURE-02 study explored the use of neoadjuvant pembrolizumab in patients with high-risk UTUC. A small study of 10 patients, it showed no significant signals of activity with neoadjuvant pembrolizumab. Another Phase II study of neoadjuvant ipilimumab and nivolumab in cisplatin-ineligible UTUC yielded more promising findings, with 3/9 patients attaining a pathologic CR and the remaining six pathologically downstaged. The ABACUS trial found a 31% pathologic complete response rate amongst cisplatin-ineligible MIBC patients treated with neoadjuvant atezolizumab. The use of adjuvant immunotherapy has been explored over three phase III trials. The CheckMate-274 trial found a DFS benefit with the addition of one year of adjuvant nivolumab in patients with high-risk urothelial carcinoma. The IMvigor-010 study of adjuvant atezolizumab was a negative study. The AMBASSADOR trial of adjuvant pembrolizumab is pending results. With the FDA approval of erdafitinib in metastatic urothelial carcinoma, similar targets have been explored for use in perioperative use in invasive urothelial carcinoma, as with adjuvant infigratinib in the PROOF-302 trial. As the treatment paradigm for urothelial carcinoma evolves, further prospective studies are needed to expand the perioperative treatment landscape of UTUC.

Germline mutational profile in metastatic urothelial malignancy.

550 Background: 24% of patients with high-risk urothelial carcinoma have pathogenic germline mutations (Nassar, Genetics in Medicine 2020). In that study, demographics, metachronous/synchronous tumors, and family history did not differ between germline and sporadic cases of bladder cancer. We report herein the prevalence of actionable mutations and de novo metastatic disease in patients with germline mutations who developed metastatic urothelial carcinoma. Methods: We retrospectively analyzed a database of 90 patients with metastatic urothelial carcinoma (urethral, bladder, and upper tract disease) at our institution who had genetic testing performed on tumor specimens. T-student test was performed to calculate statistical significance for the distribution of age, while Chi-square test evaluated the frequency distribution of gender, actionable mutations, and de novo metastatic disease. Patients’ tumors were sequenced by a 700 gene panel for both somatic and germline mutations. Comprehensive chart review was performed to extract clinical data. Results: Out of the 90 patients reviewed, 11 (11.1%) had germline mutations. Of these patients, 5 had upper tract urothelial carcinoma, 5 had bladder cancer, and 1 had urethral cancer. Nine patients had pathogenic germline mutations: MUTYH, BRCA2 (each representing 1.8% of patients); APC, BRCA1, CDKN2A, FH, MSH2 (each representing 0.9% of patients). Two patients had germline mutations of unknown significance ( APC, CHEK2). Age (T-value 1.62053, p=1.08453), gender (Chi-square 0.0024, p=0.961037) or de novo metastatic presentation (Chi-square 0.5, p=0.4795) were not statistically significant between patients with germline and sporadic mutations. Somatic actionable mutations included ATR, BRCA2, BRAF, CDK12, ERBB2, FBXW7, FGFR3, HRAS, MTAP, and PIK3CA. Microsatellite instability high (MSI-H) status was only present in the patient with germline MSH2 mutation. PD-L1 expression was high (CPS ≥10) in 4 patients with germline mutations. Tumor mutational burden ranged from 1.1 to 28.4 mutations per Megabase. Conclusions: Our findings further define the clinical and genomic characteristics of patients with metastatic urothelial carcinoma and germline mutations in a tertiary center. Further investigation is warranted to validate these findings in national sequencing databases.

Oncological outcomes of distal ureterectomy for high risk urothelial carcinoma: A multicenter study

Oncological outcomes of distal ureterectomy for high risk urothelial carcinoma: A multicenter study

Replacement of long-segment ureteral defect with tapered demucosalized ileum: medium-term outcomes of 4 patients

PurposeRepair of long-segment ureteral defect (LSUD) is challenging. Currently available procedures carry some potential complications. We modified the ileal graft by tapering the wall and stripping the mucosa to combat associated pitfalls and first reported the medium-term outcomes of 4 patients.Material and methodsFrom September 2019 to October 2020, tapered demucosalized ileum (TDI) was used for LSUD reconstruction in 4 patients on the right (2 males and 2 females). Two patients were with panureteral avulsion and 2 with high-risk urothelial carcinoma in the distal ureter. TDI was made by tapering 1/2–2/3 of the antimesenteric ileal wall and stripping the mucosa with a blunt/blunt operating scissor. Follow-up modalities included serum creatinine, electrolytes, ultrasonography, CT urogram, renal scintigraphy, and ureteroscopy.ResultsMean operation time was 443 min (range 360–550) and blood loss was negligible. The mean follow-up period was 29 months (range 23–36). Vesicoureteral reflux and related pyelonephritis occurred in 1 patient, necessitating a repair operation (Clavien-Dindo grade IIIb). No strictures, obstructions, metabolic disorders, or electrolyte imbalances were observed in the remaining patients. In carcinoma patients, ureteroscopy in month 18 post-operation revealed ileal mucosal regrowth in the form of dwarf isolated islands. All renal units maintained adequate drainage and function during the follow-up.ConclusionsIleal wall tapering and mucosa stripping confined to the muscularis mucosae level will not result in shrinkage, fibrosis, or stricture formation of the ileal ureter. The present work provides evidence for further application of TDI in the replacement of LSUD in patients.

Oncological Outcomes of Distal Ureterectomy for High-Risk Urothelial Carcinoma: A Multicenter Study by The French Bladder Cancer Committee.

Upper urinary tract urothelial carcinoma (UTUC) is an uncommon disease and its gold-standard treatment is radical nephroureterectomy (RNU). Distal ureterectomy (DU) might be an alternative for tumors of the distal ureter but its indications remain unclear. Here, we aimed to evaluate the oncological outcomes of DU for UTUC of the pelvic ureter. We performed a multicenter retrospective analysis of patients with UTUC who underwent DU. The primary endpoint was 5-year cancer-specific survival (CSS), followed by overall survival (OS), intravesical recurrence-free (IVR) and homolateral urinary tract recurrence-free (HUR) survivals as secondary endpoints. Univariate and multivariate Cox regressions were performed to assess factors associated with outcomes. 155 patients were included, 91% of which were high-risk. 5-year CSS was 84.4%, OS was 71.9%, IVR-free survival was 43.6% and HUR-free survival was 74.4%. Multifocality, high grade and tumor size were the most significant predictors of survival endpoints. Of note, neither hydronephrosis nor pre-operative diagnostic ureteroscopy/JJ stent were associated with any of the endpoints. Perioperative morbidity was minimal. In conclusion, DU stands as a possible alternative to RNU for UTUC of the pelvic ureter. Close monitoring is mandatory due to the high risk of recurrence in the remaining urinary tract.

Urothelkarzinom des oberen Harntraktes: aktuelle Behandlungsstrategien

BackgroundThe treatment spectrum of urothelial carcinoma of the upper urinary tract is broad and depends largely on the individual risk constellation. The diagnosis and diagnostics of spreading need to be as accurate as possible for the classification into the low-risk or high-risk group.ObjectivePresentation of new achievements in diagnostics and treatment options as well as the differentiated treatment strategies for localized urothelial carcinoma of the upper urinary tract.Material and methodsA selective literature search was carried out in PubMed on the topic of urothelial carcinoma of the upper urinary tract, diagnostics, organ-preserving strategies, radical nephroureterectomy and multimodal treatment concepts.ResultsAdvances in imaging and endoscopic techniques, in particular, have increased the diagnostic certainty and reduced understaging. An accurate stratification as possible into the low-risk or high-risk group simplifies clinical decision making. Kidney-preserving procedures, such as endoscopic laser-guided tumor ablation or ureteral segmental resection, can be used in certain constellations. Radical nephroureterectomy remains the gold standard for high-risk urothelial carcinoma of the upper urinary tract due to the high risk of progression and metastases. For clinical stage ≥cT3 tumors an open approach is favored over a laparoscopic approach. Adjuvant platinum-based chemotherapy should be performed in a pathological tumor stage ≥pT2 and/or pN+ following radical nephroureterectomy.DiscussionNew algorithms meanwhile provide the possibility to reduce treatment-induced morbidity and to improve the oncological outcome, particularly through more effective multimodal concepts.

Effect of Levofloxacin on the Efficacy and Adverse Events in Intravesical Bacillus Calmette-Guerin Treatment for Bladder Cancer: Results of a Randomized, Prospective, Multicenter Study

BackgroundAlthough bacillus Calmette-Guerin (BCG) is a standard treatment for high-risk non–muscle-invasive bladder cancer (NMIBC), a high rate of adverse events with a variety of grades remains a difficulty. ObjectiveIn this randomized, prospective, multicenter study, we examined whether levofloxacin, given after each intravesical instillation of BCG, could improve its tolerance in patients with intermediate- to high-risk urothelial carcinoma of the bladder without compromising its efficacy. Design, setting, and participantsOverall, 106 Japanese patients (85 men and 21 women; age: median, 69.5 yr) with primary or recurrent NMIBC were randomized after transurethral resection to induce treatment with intravesical BCG plus levofloxacin (group 1) or BCG alone (group 2). InterventionPatients who underwent intravesical instillation of BCG were randomized with or without levofloxacin administration. Outcome measurements and statistical analysisAdverse events were assessed using the National Cancer Institute-Common Toxicity Criteria version 3.0. Cumulative incidence functions and Kaplan-Meier methods were applied to estimate survival outcomes. Results and limitationsThere was no significant difference in baseline characteristics between the groups. The completion rate of group 1 (85.5%) was not significantly lower than that of group 2 (76.5%; p = 0.321). There was no significant difference in the completion rate of patients with pollakisuria, painful micturition, gross hematuria, fever elevation, and others between the groups. The incidence of adverse events in patients with high-grade pollakisuria (7.3% vs 25.4%, p = 0.041) and fever (0% vs 9.1%, p = 0.034) was significantly lower in group 1. The 5-yr progression-free and cancer-specific survival rates were significantly better in group 1. ConclusionsProphylactic levofloxacin administration may reduce the severity of adverse events and contribute to better outcomes from BCG intravesical therapy in patients with NMIBC. Patient summaryLevofloxacin administration seems to be a safe and effective therapy for non–muscle-invasive bladder cancer patients treated with bacillus Calmette-Guerin intravesical therapy.

MP42-18 SOCIAL AND ENVIRONMENTAL RISK FACTORS FOR UNDERGOING RADICAL CYSTECTOMY FOR UROTHELIAL CARCINOMA IN RHODE ISLAND: 2000-2020

You have accessJournal of UrologyCME1 May 2022MP42-18 SOCIAL AND ENVIRONMENTAL RISK FACTORS FOR UNDERGOING RADICAL CYSTECTOMY FOR UROTHELIAL CARCINOMA IN RHODE ISLAND: 2000-2020 Borivoj Golijanin, Sarah Andrea, Justin Bessette, Rebecca Ortiz, Philip Caffery, Timothy O'Rourke, Christopher Tucci, Ali Amin, and Dragan Golijanin Borivoj GolijaninBorivoj Golijanin More articles by this author , Sarah AndreaSarah Andrea More articles by this author , Justin BessetteJustin Bessette More articles by this author , Rebecca OrtizRebecca Ortiz More articles by this author , Philip CafferyPhilip Caffery More articles by this author , Timothy O'RourkeTimothy O'Rourke More articles by this author , Christopher TucciChristopher Tucci More articles by this author , Ali AminAli Amin More articles by this author , and Dragan GolijaninDragan Golijanin More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002608.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Development of urothelial carcinoma (UC) has well documented risk factors including tobacco smoking and occupational exposure. Potentially upstream neighborhood-level factors are underexplored. We examined the association between sociodemographic and pollution composition and incidence of UC treated by radical cystectomy (RC) and overall survival (OS) in Rhode Island. METHODS: 484 patients underwent RC from 1/2000 to 12/2020 at Brown University affiliated hospitals. Patient addresses were linked to census tract level data on neighborhood sociodemographic composition and locations of leaking underground storage tanks, superfund sites, sanitary waste sites, and active solid waste facilities. Using Poisson and Cox proportional hazards models, we assessed incidence of RC and OS as a function of neighborhood pollution, area deprivation index (ADI), poverty, and racial composition quartiles in separate models adjusted for year and age at time of RC. RESULTS: Average age was 68 years, 73% men, and 90% white, with clinical stage T2 in 32%, Tis in 5%, Tx in 8%, and 3% had no information. Likelihood of RC positively correlated with greater neighborhood pollution (RR for 4th vs 1st quartile:1.39, 95% CI:1.08,1.79), predominance of white population (RR for 4th vs. 1st quartile:1.94, 95% CI:1.41,2.66) and negatively with greater poverty (RR for 4th vs. 1st quartile: 0.44, 95% CI:0.33, 0.58). Five-year OS rate was 56%, in neighborhoods with highest poverty rates (Q4) was 45%, and in neighborhoods with lowest rates of poverty (Q1) was 62%. Compared with Q1, the hazard ratio for those in Q4 poverty neighborhoods was 1.72 (95% CI:1.16,2.55). CONCLUSIONS: Inequalities in social determinants of health influence incidence and outcomes of UC patients undergoing RC. Patients undergoing RC were more likely to be white and living in affluent neighborhoods, however, this could be an artifact of selective survival. Those living in neighborhoods with greater number of pollutants underwent RC at greater rates. Risk of death in the first five years following RC was greatest for those living in neighborhoods with low socioeconomic status. Further research is needed to study contextual factors defining the differences in RC use and OS of patients with UC. Health policies and screening programs can target these high-risk UC hot-spots in order to improve earlier detection and patient outcomes. Source of Funding: Funded in part by DG and the Rhode Island Foundation © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e739 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Borivoj Golijanin More articles by this author Sarah Andrea More articles by this author Justin Bessette More articles by this author Rebecca Ortiz More articles by this author Philip Caffery More articles by this author Timothy O'Rourke More articles by this author Christopher Tucci More articles by this author Ali Amin More articles by this author Dragan Golijanin More articles by this author Expand All Advertisement PDF DownloadLoading ...

Nivolumab Nearly Doubles DFS in High-Risk Urothelial Carcinoma

Nivolumab Nearly Doubles DFS in High-Risk Urothelial Carcinoma

Combined immune checkpoint inhibition for high-risk urothelial carcinoma.

Combined immune checkpoint inhibition for high-risk urothelial carcinoma.

Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma

PurposeTo date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC). MethodsWe evaluated the frequency of germline pathogenic and likely pathogenic variants in 1038 patients with high-risk UC who underwent targeted clinical germline testing. Case–control enrichment analysis was performed to screen for pathogenic variant enrichment in 17 DNA repair genes in 1038 UC patients relative to cancer-free individuals. ResultsAmong 1038 patients with UC, the cumulative frequency of patients with pathogenic variants was 24%; 18.6% of patients harbored ≥1 actionable germline variant with preventive or therapeutic utility. MSH2 (34/969, 3.5%) and BRCA1/2 (38/867, 4.4%) germline variants had the highest frequency. Germline variants in DNA damage repair genes accounted for 78% of pathogenic germline variants. Compared to the cancer-free cohort, UC patients had significant variant enrichment in MSH2 (odds ratio [OR]: 15.4, 95% confidence interval [CI]: 7.1–32.7, p < 0.0001), MLH1 (OR: 15.9, 95% CI: 4.4–67.7, p < 0.0001), BRCA2 (OR: 5.7, 95% CI: 3.2–9.6, p < 0.0001), and ATM (OR: 3.8, 95% CI: 1.8–8.3, p = 0.02). ConclusionIn this study, 24% of UC patients harbored pathogenic germline variants and 18.6% had clinically actionable variants. MLH1 and MSH2 were validated as UC risk genes while ATM and BRCA2 were highlighted as potential UC predisposition genes. This work emphasizes the utility of germline testing in selected high-risk UC cohorts.

PD03-06 EFFECTS OF LEVOFLOXACIN ON BACILLUS CALMETTE-GUERIN-INDUCED TOXICITY IN PATIENTS WITH NONMUSCLE INVASIVE BLADDER CANCER: RESULTS OF A RANDOMIZED, PROSPECTIVE, MULTICENTER STUDY

You have accessJournal of UrologyBladder Cancer: Non-invasive I (PD03)1 Apr 2020PD03-06 EFFECTS OF LEVOFLOXACIN ON BACILLUS CALMETTE-GUERIN-INDUCED TOXICITY IN PATIENTS WITH NONMUSCLE INVASIVE BLADDER CANCER: RESULTS OF A RANDOMIZED, PROSPECTIVE, MULTICENTER STUDY Kazuyuki Numakura*, Mizuki Kobayashi, Toshiya Ishida, Katsumi Okane, Kazumasa Suzuki, Naotake Shimoda, Takehiro Suzuki, Teruaki Kumazawa, Ryusei Sasaki, Hisami Fukuda, Taketoshi Nara, Sohei Kanda, Huang Mingguo, Mitsuru Saito, Shintaro Narita, Takamitsu Inoue, Norihiko Tsuchiya, and Tomonori Habuchi Kazuyuki Numakura*Kazuyuki Numakura* More articles by this author , Mizuki KobayashiMizuki Kobayashi More articles by this author , Toshiya IshidaToshiya Ishida More articles by this author , Katsumi OkaneKatsumi Okane More articles by this author , Kazumasa SuzukiKazumasa Suzuki More articles by this author , Naotake ShimodaNaotake Shimoda More articles by this author , Takehiro SuzukiTakehiro Suzuki More articles by this author , Teruaki KumazawaTeruaki Kumazawa More articles by this author , Ryusei SasakiRyusei Sasaki More articles by this author , Hisami Fukuda Hisami Fukuda More articles by this author , Taketoshi Nara Taketoshi Nara More articles by this author , Sohei KandaSohei Kanda More articles by this author , Huang MingguoHuang Mingguo More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Norihiko Tsuchiya Norihiko Tsuchiya More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000823.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although bacillus Calmette-Guerin (BCG) is a standard of care for especially high-risk nonmuscle-invasive bladder cancer (NMIBC), a high rate of adverse events (AEs) remains a major problem. In this randomized, prospective, multicenter study, we examined whether levofloxacin (LVFX) given after each intravesical instillation of BCG could improve its tolerance in patients with intermediate- to high-risk urothelial carcinoma of the bladder. We also investigated the impact of LVFX on the antitumor efficacy of BCG. METHODS: In this study, 100 patients with primary or recurrent NMIBC (Ta/T1, CIS, G1-G3) were randomized to induction treatment with intravesical BCG plus LVFX in group 1 (n=52) or BCG alone in group 2 (n=48). AEs were assessed using a National Cancer Institute-Common Toxicity Criteria Version 3.0. The median patient ages were 69.5 years (46 – 80) and the median follow up period was 36 months (12 – 128). All patients were Japanese, consisting of 80 men and 20 women. RESULTS: There was no significant difference in baseline characteristics and symptoms between the groups. Overall, there were no significant differences decreases in the rate of patients having with pollakisuria, miction pain, gross hematuria, fever elevation, and others between the group 1 and group 2. The rate of BCG discontinuation was not different between the groups (24.5% vs 13.7%, p = 0.207). However, the incidence of AEs with grade II or more pollakisuria and fever elevation was significantly lower (5.9% vs 28.2%, p = 0.016; 0% vs 8.2%, p=0.034) in the group 1 (Table 1). The 5-year progression-free and cancer-specific survival rates were better in the group I (HR 0.26, 95%CI 0.57-0.81, p = 0.011; 1 HR 0.13, 95%CI 0.01-0.74, p = 0.006) (Figure 1). CONCLUSIONS: Prophylactic LVFX may reduce the severity of AEs and can contribute to better outcomes from BCG intravesical therapy in patients with NMIBC, improving compliance with the BCG course. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e74-e74 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kazuyuki Numakura* More articles by this author Mizuki Kobayashi More articles by this author Toshiya Ishida More articles by this author Katsumi Okane More articles by this author Kazumasa Suzuki More articles by this author Naotake Shimoda More articles by this author Takehiro Suzuki More articles by this author Teruaki Kumazawa More articles by this author Ryusei Sasaki More articles by this author Hisami Fukuda More articles by this author Taketoshi Nara More articles by this author Sohei Kanda More articles by this author Huang Mingguo More articles by this author Mitsuru Saito More articles by this author Shintaro Narita More articles by this author Takamitsu Inoue More articles by this author Norihiko Tsuchiya More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement PDF downloadLoading ...

TGFBI Protein Is Increased in the Urine of Patients with High-Grade Urothelial Carcinomas, and Promotes Cell Proliferation and Migration.

Here, we discovered TGFBI as a new urinary biomarker for muscle invasive and high-grade urothelial carcinoma (UC). After biomarker identification using antibody arrays, results were verified in urine samples from a study population consisting of 303 patients with UC, and 128 urological and 58 population controls. The analyses of possible modifying factors (age, sex, smoking status, urinary leukocytes and erythrocytes, and history of UC) were calculated by multiple logistic regression. Additionally, we performed knockdown experiments with TGFBI siRNA in bladder cancer cells and investigated the effects on proliferation and migration by wound closure assays and BrdU cell cycle analysis. TGFBI concentrations in urine are generally increased in patients with UC when compared to urological and population controls (1321.0 versus 701.3 and 475.6 pg/mg creatinine, respectively). However, significantly increased TGFBI was predominantly found in muscle invasive (14,411.7 pg/mg creatinine), high-grade (8190.7 pg/mg) and de novo UC (1856.7 pg/mg; all p < 0.0001). Knockdown experiments in vitro led to a significant decline of cell proliferation and migration. In summary, our results suggest a critical role of TGFBI in UC tumorigenesis and particularly in high-risk UC patients with poor prognosis and an elevated risk of progression on the molecular level.

Impact of Aurora kinase A and B expression on response to neoadjuvant chemotherapy and patient outcome in muscle-invasive bladder cancer (MIBC).

393 Background: Identification of robust biomarkers that predict likelihood of benefit from neoadjuvant chemotherapy (NAC) in patients with MIBC remains an unmet need. Previous studies have implicated tumor overexpression of aurora kinases A (AURKA) and B (AURKB) as a mechanism of chemo-resistance. Because overexpression of AURKA has also emerged as a potential biomarker for detection of high-risk urothelial carcinoma, we sought to characterize the expression of AURKA, AURKB with clinical outcomes in MIBC patients who received NAC and to test the hypothesis that tumor overexpression of AURKA and AURKB would predict for residual MIBC. Methods: 47 patients with MIBC who received NAC prior to cystectomy were retrospectively identified. Immunohistochemistry for AURKA and AURKB was performed on pre-treatment diagnostic transurethral resection of bladder tumors and matched cystectomy specimens. Logistic regression models were estimated to determine the impact of pre-NAC expression on pathologic staging at cystectomy. Receiver Operator Characteristic curves (ROC) were calculated to assess diagnostic predictive ability of AURKA and AURKB. AURKA and AURKB were assessed for association with relapse-free survival (RFS) and overall survival (OS) using Kaplan-Meier techniques and Cox proportional hazards models. Results: 22 of 47 [46.8%] patients had residual muscle-invasive (ypT2-4) urothelial carcinoma after NAC. Neither baseline tumor expression of AURKA (ROC = 0.54, p = 0.71) nor AURKB (ROC = 0.46, p = 0.98) predicted for ypT2-4 status. However, baseline expression of AURKA above the 75th percentile for this cohort, determined by the percentage of tumor cells positive, was associated with an inferior RFS, [HR = 3.79, [1.40, 10.26] p = 0.005] and OS, [HR = 5.84, [2.14, 15.98], p &lt; 0.001]. Similar trends for worse survival outcomes were also observed for high AURKB levels. Conclusions: Although baseline tumor AURKA and AURKB expression did not predict for pathologic residual MIBC after NAC, high expression of AURKA and AURKB predicted for inferior RFS and OS. Further evaluation of AURKA and AURKB as potential biomarkers and therapeutic targets in MIBC is warranted.

Prognostic value of nutritional indices and body composition parameters including sarcopenia in patients treated with radiotherapy for urothelial carcinoma of the bladder

PurposeTo assess the prognostic importance of sarcopenia in survival in patients with high-risk urothelial carcinoma of the bladder (UCB) who were unfit for radical cystectomy or systemic chemotherapy and were, therefore, treated with radiotherapy only. MethodsWe evaluated 94 patients treated with transurethral resection of the bladder and radiotherapy for UCB. Sarcopenia, identified from pretreatment computed tomography scans, was defined as a skeletal muscle index of <39 cm2/m2 for women and <55 cm2/m2 for men. Body mass index -adjusted definition of sarcopenia was used to evaluate for sarcopenic obesity. Univariate models were used to assess the association between body composition and nutritional parameters with survival outcomes. ResultsOverall, 68 patients were eligible for the final analysis, and 49 (72%) patients were sarcopenic. After body mass index adjustment of the definition of sarcopenia, its prevalence changed to 53.8% in women and 52.7% in men. Median age was 82 (interquartile range [IQR] 75–86) years, with a median, age-adjusted comorbidity index of 7.5 (IQR 6–10). The median time of follow-up was 12.5 (IQR 5.1–23.5) months. There were 42 (61.7%) patients who died of any cause and 19 (45.2%) who died because of UCB during the study period. Of all the body composition and nutritional parameters investigated, sarcopenic obesity was associated with cancer-specific survival (hazard ratio 5.0, 95% confidence interval 1.4–16.7, P = 0.01) and a low prognostic nutritional index was associated with overall survival (hazard ratio 0.46, 95% confidence interval 0.2–0.9, P = 0.02). ConclusionIn patients who are too high risk for the standard treatment of UCB, sarcopenia is highly prevalent, but not prognostic of survival. Nevertheless, sarcopenic obesity and the prognostic nutritional index might act as prognostic markers for patients with UCB undergoing radiotherapy.

923TiP - A phase III study of INCB054828 as adjuvant therapy in patients (pts) with high-risk urothelial carcinoma (UC) harboring fibroblast growth factor receptor 3 (FGFR3) genomic alterations

Background: After neoadjuvant chemotherapy (NAC), about 20% of pts with muscle-invasive UC are found to have advanced pT-stage or lymph node involvement and 5-year overall survival (OS) of them is < 30%. Tumor samples from these pts may provide information about chemotherapy resistance, and may predict for the activity of new drugs given postoperatively. Alterations of FGFR3 gene represent a therapeutic target in UC and FGFR3 mutations/fusions are enriched in UC Luminal-1 subtype. The pan-FGFR inhibitor INCB054828 has shown promising results in chemotherapy-treated patients with genomic alterations of FGFR3 in tumor tissue and is currently being evaluated in an international phase 2 study (fight-201, NCT02872714). Our study aims to assess the safety and efficacy of adjuvant INCB054828 in pts with FGFR3 mutations/fusions. Trial design: This is an open-label, single-arm, phase 2 study. Subjects will receive INCB054828 at a once-daily (QD) dose of 13.5 mg on a 2-weeks-on and 1-week-off schedule. Treatment should start within 60 days of surgery and will continue until 12 months, or until the evidence of disease recurrence or unacceptable toxicity onset. Key inclusion criteria are predominant UC histology, FGFR3 mutations/fusions (FoundationOne), bladder or upper tract UC, previous radical cystectomy or nephroureterectomy, previous administration ≥3 cycles of CDDP-based NAC, pT3-4 and/or pN1-3 stage. Relapse-free survival (RFS) is the primary endpoint, assessed every 9 weeks until disease recurrence or death. No interim analyses are planned. It is expected that about 30% of the total screened pts will harbor FGFR3 aberrations. In a single-stage design, with 90% power and one-sided alpha at 0.10, the total enrolled pts will be 56 (H0: 2-y RFS: 30%; H1: 2-y RFS: 45%). Translational research on tissue samples will include associations of immune-inflamed phenotype with next-generation sequencing results and outcome of treatment, and response to any subsequent immunotherapy. The study is sponsored by the EAU-Research Foundation and will involve 15 centers in Europe (EudraCT number 2017-004426-15). Clinical trial identification: EudraCT: 2017-004426-15. (Less)

Extraperitoneal Laparoscopic Radical Nephroureterectomy and Lymph Node Dissection in Modified Supine Position

To explore the feasibility of extraperitoneal laparoscopic radical nephroureterectomy (EL-RNU) and lymph node dissection in a modified supine position for managing urothelial carcinomas in the renal pelvis or in the upper two-thirds of the ureter. Consecutively from January 2014 to October 2015, 15 patients with high-risk urothelial carcinoma in the renal pelvis or in the upper two-thirds of the ureter underwent EL-RNU and extraperitoneal laparoscopic lymph node dissection (EL-LND). Clinical and pathologic data, histologic nodal status, perioperative complications, and recurrence data were collected. All of the 15 patients were treated with EL-RNU and EL-LND in a modified supine position, and none was converted to open surgery. The mean operation time was 178 ± 18 minutes. The mean estimated blood loss was 140 ± 40 mL. The mean postoperative intestinal function recovery time was 2 days. The mean postoperative hospitalization was 7 ± 1 days. Pathologic studies revealed positive lymph nodes in 3 patients (20%). The mean number of harvested lymph nodes was 12 ± 3. No local recurrence and distant metastasis were found after a median follow-up of 14.4 months (7-23 months). EL-RNU and EL-LND in the modified supine position are mini-invasive and feasible for patients with urothelial carcinoma in the renal pelvis or in the upper two-thirds of the ureter. Good exposure and dissection of the abdominal aorta and inferior vena cava and the integrity of the peritoneum are key to the operational success of this approach.

The utility of neutrophil-to-lymphocyte ratio in determining survival outcomes in patients treated with neoadjuvant chemotherapy and radical cystectomy for high-risk bladder cancer.

419 Background: Pre-operative neutrophil-to-lymphocyte ratio (NLR) has been found to be associated with adverse pathological results and poor long-term outcomes in patients treated with radical cystectomy (RC) for urothelial carcinoma (UC). We aimed to evaluate the predictive utility of NLR in patients treated with neoadjuvant chemotherapy (NAC) and RC for high-risk UC. Methods: We reviewed the records of 585 patients treated with NAC and RC at our institution from 2000-2013. We calculated NLR before initiation of NAC (pre-chemo NLR) and during the recovery window between NAC and RC (post-chemo NLR).. We excluded patients with concomitant infection, blood disorder, or second malignancy. We used univariate and multivariate CART models to determine the optimal NLR cut-off for survival outcomes. We estimated disease-specific (DSS) and overall survival (OS) using the Kaplan-Meier method. We used Cox proportional hazards regression to explore the association of NLR with DSS and OS. Results: 584 patients had NLR information in our cohort. The median follow-up among survivors was 4.9 years (IQR 2.4 – 8.8 years). We identified optimal NLR cut-points of 7.1 for pre-chemo, 4.9 for post-chemo, and 1.9 for change in NLR [(post-chemo) – (pre-chemo)]. Post-chemo NLR showed the strongest association with OS and DSS. Patients with a post-chemo NLR ≥ 4.9 (n = 103) had a 5-yr DSS and OS of 42% and 33% respectively, compared to 69% and 58% for patients with an NLR &lt; 4.9 (n = 481). In the multivariable analysis, post-chemo NLR ≥ 4.9 was an independent predictor of DSS (HR = 2.5 [95% CI:1.8, 3.6] p &lt; 0.001 ), and OS (HR = 2.1 [95% CI:1.6, 2.8] p &lt; 0.001). Conclusions: A post-chemo NLR ≥ 4.9 is associated with poor DSS and OS in patients treated with NAC and RC. These findings may help guide treatment planning for adjuvant therapy following RC in patients with high-risk clinically localized bladder cancer.