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Purpose: To evaluate the efficacy of intravesical (IVe) Bacillus Calmette-Guerin (BCG) to treat non-muscle invasive bladder cancer (NMIBC) recurrences in patients who have previously undergone nephroureterectomy for upper tract urothelial carcinoma (UTUC)., Methods: We performed a single institution retrospective review of patients who underwent nephroureterectomy for UTUC from 2009 to 2021. Patients who subsequently developed NMIBC treated with transurethral resection followed by IVe BCG were included in the study group. A control cohort was formed by retrospective review of patents with primary NMIBC treated with BCG during the same period. Patients in the control cohort were matched by stage of bladder cancer at a 2:1 ratio of control to study subjects. Demographic data, pathology of bladder tumors prior to and following BCG, use of maintenance BCG (mBCG), time to recurrence, time to progression, progression to cystectomy, and progression to metastatic disease were collected on all patients. Descriptive statistics were utilized to compare the 2 groups. The primary outcome was progression to muscle invasive disease. Secondary outcomes included intravesical recurrence free survival, disease free survival, and progression to metastatic disease. Univariable and multivariable logistic regression analysis was performed to elucidate independent variables associated with bladder tumor recurrence. Multivariable Cox regression analysis was used to assess the impact of prior UTUC on time to bladder tumor recurrence., Results: One-hundred and ninety-one patients underwent nephroureterectomy at our institution from 2009 to 2021 for UTUC. Twenty-five patients were identified to have subsequently developed NMIBC recurrences treated with inductions BCG. The control group was comprised of 50 patients with primary NMIBC matched by stage of bladder cancer for which BCG was indicated in the study group. Median (interquartile range [IQR]) follow-up was significantly longer in the control group relative to the study group (64.8 [50.1-85.6] vs 25 months [17-35]; P = 0.001). There were no significant differences in demographics between the study and control groups. The rate of progression to muscle invasive disease was 17% vs 0% in the study group and control group respectively (P = 0.0521). History of UTUC was associated with increased risk of intravesical bladder tumor recurrence post BCG on multivariable analysis (HR 2.5; P = 0.017) and Kaplan Meier survival analysis (P = 0.039). The mean time to bladder tumor recurrence after treatment with BCG was significantly worse in the study group at (7.9 vs. 23.9 months; P = 0.0322). Similarly, the rate of progression to metastatic disease was worse in the study group (24% vs 2%; P = 0.0047). Overall disease-free survival was also noted to be significantly worse on Kaplan Meier survival analysis in the study group (P = 0.0074). No statistically significant differences in the stage grade of bladder tumor recurrence, grade of bladder tumor recurrence, or rate of progression to cystectomy were identified., Conclusions: Our study suggests reduced efficacy of BCG for NMIBC in patients with a history of UTUC. Patients in this population should be counseled accordingly. Research into alternative treatments for bladder tumor recurrence and more aggressive prophylactic regimens after nephroureterectomy for prevention of bladder tumor recurrence in this population is encouraged., Competing Interests: Declaration of competing interest None of the authors have a conflict of interest with the submitted research. There were no funding sources for the research submitted. All listed authors have contributed significantly to the published research and reviewed the above manuscript. There was no use of artificial intelligence software in the writing or editing of the submitted research., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: We aimed to assess the effectiveness of early single intravesical administration of epirubicin in preventing intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma., Materials and Methods: Patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy between November 2018 and May 2022 were retrospectively reviewed. Intravesical epirubicin was administered within 48 hours if no evidence of leakage was observed. Epirubicin (50 mg) in 50 mL normal saline solution was introduced into the bladder via a catheter and maintained for 60 minutes. The severity of adverse events was graded using the Clavien-Dindo classification. We compared intravesical recurrence rate between the two groups. Multivariate analyses were performed to identify the independent predictors of bladder recurrence following radical nephroureterectomy., Results: Epirubicin (n=55) and control (n=116) groups were included in the analysis. No grade 1 or higher bladder symptoms have been reported. A statistically significant difference in the intravesical recurrence rate was observed between the two groups (11.8% at 1 year in the epirubicin group vs. 28.4% at 1 year in the control group; log-rank p=0.039). In multivariate analysis, epirubicin instillation (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.20 to 0.93; p=0.033) and adjuvant chemotherapy (HR, 0.29; 95% CI, 0.13 to 0.65; p=0.003) were independently predictive of a reduced incidence of bladder recurrence., Conclusion: This retrospective review revealed that a single immediate intravesical instillation of epirubicin is safe and can reduce the incidence of intravesical recurrence after radical nephroureterectomy. However, further prospective trials are required to confirm these findings.

Purpose: The aim of this retrospective study was to evaluate the efficacy of adjuvant cisplatin-based chemotherapy in patients with locally advanced upper tract urothelial carcinoma (UTUC), administered following radical nephroureterectomy., Materials and Methods: Patients with UTUC, arising from renal pelvis or ureter, staged pT3/T4 or N+ were treated with adjuvant chemotherapy following surgery. The chemotherapy consisted of gemcitabine 1,000 mg/m2 on days 1 and 8, cisplatin 70 mg/m2 on day 1. Treatment was repeated every 3 weeks for up to 4 cycles. Endpoints included disease-free survival (DFS), metastasis-free survival (MFS), and safety., Results: Among 89 eligible patients, 85 (95.5%) completed at least 3 cycles of adjuvant chemotherapy. Chemotherapy was well tolerated, the main toxicities being mild-to-moderate gastrointestinal toxic effects and pruritus. With a median follow-up of 37 months, median DFS was 30 months (95% confidence interval, 22 to 39), and the median MFS was not reached. The 3-year DFS and MFS were 44% and 56%, respectively. Multivariate analyses revealed that the main factor associated with DFS and MFS was the lymph node involvement, whereas age, T category, grade, or the primary site of UTUC were not significantly associated with DFS or MFS., Conclusion: Adjuvant cisplatin-based chemotherapy after radical surgery of pT3/T4 or N+ UTUC was feasible and may demonstrate benefits in DFS and MFS. Whether novel agents added to the chemotherapy regimen, as a concurrent combination or maintenance, impacts on survival or reduces the development of metastases remains to be studied.

Purpose: We initiated a biomarker-informed preoperative study of infigratinib, a fibroblast growth factor receptor (FGFR) inhibitor, in patients with localized upper tract urothelial carcinoma (UTUC), a population with high unmet needs and tumor with a high frequency of FGFR3 alterations., Materials and Methods: Patients with localized UTUC undergoing ureteroscopy or nephroureterectomy/ureterectomy were enrolled on a phase 1b trial (NCT04228042). Once-daily infigratinib 125 mg by mouth × 21 days (28-day cycle) was given for 2 cycles. Tolerability was monitored by Bayesian design and predefined stopping boundaries. The primary endpoint was tolerability, and the secondary endpoint was objective response based on tumor mapping, done after endoscopic biopsy and post-trial surgery. Total planned enrollment: 20 patients. Targeted sequencing performed using a NovaSeq 6000 solid tumor panel., Results: From May 2021 to November 2022, 14 patients were enrolled, at which point the trial was closed due to termination of all infigratinib oncology trials. Two patients (14.3%) had treatment-terminating toxicities, well below the stopping threshold. Responses occurred in 6 (66.7%) of 9 patients with FGFR3 alterations. Responders had median tumor size reduction of 67%, with 3 of 5 patients initially planned for nephroureterectomy/ureterectomy converted to ureteroscopy. Median follow-up in responders was 24.7 months (14.9-28.9)., Conclusions: In this first trial of targeted therapy for localized UTUC, FGFR inhibition was well tolerated and had significant activity in FGFR3 altered tumors. Renal preservation was enabled in a substantial proportion of participants. These data support the design of a biomarker-driven phase 2 trial of FGFR3 inhibition in this population with significant unmet clinical needs.

Objective: The European POUT III randomized controlled trial provided level-one evidence that adjuvant platinum-based chemotherapy is the standard of care following nephroureterectomy (RNU) for locally invasive or node-positive upper tract urothelial carcinoma. We aim to assess this European randomized controlled trial's generalizability (external validity) to a North American cohort, using a nationwide database., Materials and Methods: To compare trial patients with those seen in real-world practice, we simulated the trial inclusion criteria using data from the National Cancer Database (NCDB). We identified patients with histologically confirmed transitional cell carcinoma who underwent RNU. The available demographic characteristics of the NCDB cohort were compared with the POUT III trial cohort using Chi-squared test., Results: The NCDB cohort (n = 3,380) had a significantly higher proportion of older patients (age ≥ 80: 23.5% vs. 5%), and more males (68% vs. 56.2%) than the POUT cohort (Table 1, both p < 0.001). Additionally, the rate of advanced nodal disease was higher in the NCDB (N1 9.6%, N2 9.3%) than in the POUT (N1 6%, N2 3%) cohort (p < 0.001). A more extensive lymph node dissection was performed in NCDB vs. POUT patients (node≥10 10.9% vs. 3%, p < 0.001). Sensitivity analysis removing all subjects with a Charlson Comorbidity Index > 0 did not change the significance of any results., Conclusions: While the primary disease stage was similar, the rate of advanced nodal disease was significantly higher in NCDB, which might be explained partially by the more extensive lymph node dissection performed in the latter. These differences warrant caution when applying the POUT III findings to North American patients., Competing Interests: Declaration of competing interest The authors did not receive support from any organization for the submitted work. All authors have no relevant financial or non-financial interests to disclose. No funding was received to assist with the preparation of this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. POUT was a phase III, randomized, open-label trial, including 261 patients with muscle-invasive or lymph node-positive, nonmetastatic upper tract urothelial cancer (UTUC) randomly assigned after radical nephroureterectomy to platinum-based chemotherapy (132) or surveillance (129). Primary outcome analysis demonstrated that chemotherapy improved disease-free survival (DFS). At that time, the planned secondary outcome analysis of overall survival (OS) was immature. By February 2022, 50 and 67 DFS events had occurred in the chemotherapy and surveillance groups, respectively, at a median follow-up of 65 months. The 5-year DFS was 62% versus 45%, univariable hazard ratio (HR), 0.55 (95% CI, 0.38 to 0.80, P = .001). The restricted mean survival time (RMST) was 18 months longer (95% CI, 6 to 30) in the chemotherapy arm. There were 46 and 60 deaths in the chemotherapy and control arms, respectively. The 5-year OS was 66% versus 57%, with univariable HR, 0.68 (95% CI, 0.46 to 1.00, P = .049) and RMST difference 11 months (95% CI, 1 to 21). Treatment effects were consistent across chemotherapy regimens (carboplatin or cisplatin) and disease stage. Toxicities were similar to those previously reported, and there were no clinically relevant differences in quality of life between arms. In summary, although OS was not the primary outcome measure, the updated results add further support for the use of adjuvant chemotherapy in patients with UTUC, suggesting long-term benefits.

Objective: To date, there have been few studies examining the prognostic implications of histological subtypes in ureteral cancer. And chemotherapy plays a crucial role in the treatment of ureteral cancer, while many factors influence the efficacy of chemotherapy. This study aimed to utilize the Surveillance, Epidemiology and End Results database to assess the impact of histological type on ureteral cancer prognostic outcomes and discovered how histological type and T-stage influence the efficacy of chemotherapy., Methods: Based on Surveillance, Epidemiology, and End Results Program, we reviewed 8915 records of patients with primary ureteral cancer from 18 centers between 2000 and 2018. We focused on the overall survival and cancer-specific survival of the records and used Kaplan‒Meier method to calculate survival curves., Results: In the comparison of prognostic outcomes, atypical subtypes exhibited a less favorable prognosis compared to typical ureteral carcinoma. Notably, patients diagnosed with papillary urothelial carcinoma demonstrated the most favorable overall survival (p = 0.005). Statistically significant benefits were observed in the prognosis of patients with non-papillary urothelial carcinoma who received chemotherapy (HR = 0.860, 95% CI 0.764-0.966, p = 0.011), while chemotherapy did not yield a statistically significant effect on the prognosis of patients with papillary urothelial carcinoma (HR = 1.055, 95% CI 0.906-1.228, p = 0.493). Chemotherapy had an adverse impact on the prognosis of patients with T1 ureteral cancer (HR = 1.235, 95% CI 1.016-1.502, p = 0.034), whereas it exhibited a positive prognostic effect for T3/T4 cases (HR = 0.739, 95% CI 0.654-0.835, p < 0.001)., Conclusions: Histological type affects the prognosis of ureteral cancer. And evaluation of cancer histological type and T stage in ureteral cancer patients prior to chemotherapy is mandatory., (© 2024. The Author(s).)

Purpose: To retrospectively investigate the safety and efficacy of radiotherapy combined with chemotherapy for recurrent metastatic renal pelvic and ureteral carcinoma., Methods: 109 patients were enrolled in this study, including 44 patients in the radiochemotherapy group and 65 patients in the chemotherapy group. Propensity score matching (PSM) was used to balance the baseline characteristics of the two groups by 1:1 matching. Kaplan-Meier method was used to calculate PFS and OS. Cox regression model was used for multivariate analysis. The side effects were evaluated by CTCAE v5.0 RESULTS: The median follow-up time was 14.5 months. Multivariate analysis showed that radiotherapy was a good independent prognostic factor for OS (HR: 0.327, 95% CI 0.157-0.680, P = 0.003). After matching, there were 40 patients in both groups, and the median PFS and OS in the radiochemotherapy group were longer than those in the chemotherapy group (PFS: 10.4 vs. 6.7 months, P = 0.035; OS: 43.5 vs. 18.8 months, P < 0.001). In addition, in the radiochemotherapy group, patients treated with radiotherapy before first-line chemotherapy failure had a longer PFS than those treated with radiotherapy after chemotherapy failure (median PFS: 15.7 vs. 6 months, P = 0.003). There was no significant difference in the incidence of grade 3-4 toxicities between the two groups (52.3% vs. 50.8%, P = 0.878)., Conclusion: For patients with recurrent metastatic renal pelvic and ureteral carcinoma, radiotherapy combined with chemotherapy is well tolerable and expected to bring long-term survival benefits, and the benefits of early interventional radiotherapy may be more obvious., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The objective of this study was to determine effects of adjuvant chemotherapy (AC) on survival outcomes compared to surgery alone without AC for upper tract urothelial carcinoma (UTUC) patients with variant histology (VH)., Methods: We conducted a systematic review and meta-analysis of studies investigating AC for UTUC in Medline, Embase, the Cochrane Library up to January 2023. Population, intervention, comparator, and outcome were UTUC patients with VH, radical nephroureterectomy with AC, radical nephroureterectomy only, and oncological survival, respectively., Results: Four retrospective studies were included. Regarding overall survival (OS), the pooled hazard ratio was 0.61 (95% confidence interval: 0.42-0.87; p = 0.007) across two studies. Regarding cancer-specific survival (CSS), the pooled hazard ratio was 0.46 (95% confidence interval: 0.25-0.84; p = 0.01) across three studies. All included studies had a high quality based on the Newcastle-Ottawa Scale. Certainty of evidence for OS was low. Certainty of evidence for CSS was moderate due to a strong association (hazard ratio &lt;0.5). Publication bias was not significant for any studies., Conclusion: In UTUC patients with VH, administration of AC after surgery might have better survival outcomes than surgery alone. Our study provides evidence for decision-making of clinicians who treat UTUC patients with VH., (© 2024 S. Karger AG, Basel.)

Purpose: There is an unmet need for effective renal sparing treatments for upper tract urothelial carcinoma (UTUC). Gemcitabine/Docetaxel (Gem/Doce) has shown favorable efficacy in nonmuscle invasive bladder cancer. We report the outcomes of patients treated with endoluminal Gem/Doce for noninvasive high-grade UTUC., Methods: A retrospective review of patients treated with Gem/Doce for clinically noninvasive high-grade UTUC with no radiographic or endoscopically visible disease, either at diagnosis or following ablation, was performed. Treatment was instilled via nephrostomy or retrograde ureteral catheter. Induction instillations were performed weekly for 6 weeks, followed by 6 monthly instillations if disease-free. Recurrence was defined as biopsy-proven disease or high-grade (HG) cytology. Progression was defined by development of muscle invasion, metastases, or death due to cancer. Survival was assessed with the Kaplan-Meier method., Results: The final cohort included 31 patients with 41 upper tract units, 51% of which would have been dialysis dependent with nephroureterectomy. Median (IQR) age was 74 years (68-81). Median follow-up was 29 months (IQR 20-58). Prior to treatment, 37 (90%) units presented with a localizing HG cytology (presumed occult CIS), and 4 (9.8%) with HG biopsy-proven disease. Sixteen (52%) patients reported any side effects; 5 were Grade 3 and 1 was Grade 5. Recurrence-free survival was 76%, 54%, and 40% at 1, 2, and 3 years, respectively. Five patients died from urothelial carcinoma. The 3-year progression-free and overall survival were 75% and 75%, respectively., Conclusions: Gem/Doce demonstrates promising safety and efficacy as a renal-sparing treatment option for high-grade UTUC in appropriately selected patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Intracavitary chemotherapy is one of the current treatment options for kidney-sparing treatment of upper tract urothelial carcinoma (UTUC). The purpose of this meta-analysis was to assess the efficacy and safety of intracavitary perfusion., Methods: We carefully selected publications for study from four databases (Embase, PubMed, Web of Science, and Scopus) up to January 2023. The R 4.0.4 software was used to calculate the pooled ratio and its 95% confidence intervals (95% CIs). The I2 score was used to test heterogeneity, and the funnel plot was used to estimate the publication bias., Results: Thirty-four studies with a total of 788 patients were included in this study. The overall survival at a median follow-up of 26.3 months was 87.2% (95% CI 0.80-0.93). The cancer-specific survival at a median follow-up of 30 months was 94.1% (95% CI 0.89-0.98). At a median follow-up of 30 months, the recurrence rate of UTUC was 27.5% (95% CI 0.21-0.34). By subgroup analysis, we found that the recurrence rate in patients with T1 / Ta stage was 35.1% and CIS stage 29.0%. The recurrence rates of BCG, Mitomycin C, and Mitomycin Gel (UGN101) were 31.2%, 41.3% and 12.9%, respectively. The recurrence rates for anterograde and retrograde perfusion were 28.5% and 21.8%, respectively., Conclusion: With the advent of new drugs, including UGN101, patients with UTUC have a better prognosis. Therefore, kidney preservation therapy for patients with UTUC would be promising.

Background: Multiple studies have demonstrated the effectiveness of neoadjuvant chemotherapy and adjuvant chemotherapy in patients with upper tract urothelial carcinoma compared with surgery alone. However, no clinical trial has established the superiority of neoadjuvant chemotherapy or adjuvant chemotherapy in terms of perioperative outcomes., Methods: We conducted a retrospective analysis encompassing 164 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy and received perioperative chemotherapy. Of these patients, 65 (39.6%) and 99 (60.4%) received neoadjuvant chemotherapy and adjuvant chemotherapy, respectively. Recurrence-free survival and cancer-specific survival were computed using the Kaplan-Meier method. Additionally, we conducted Cox regression analyses to evaluate the risk factors for recurrence-free survival and cancer-specific survival., Results: Pathological downstaging was seen in 37% of the neoadjuvant chemotherapy group. However, no pathological complete response was observed in this cohort. The Kaplan-Meier curves demonstrated significantly lower recurrence-free survival and cancer-specific survival in patients who received adjuvant chemotherapy. Multivariate Cox regression analysis revealed patients treated with adjuvant chemotherapy exhibited a marked association with inferior recurrence-free survival and cancer-specific survival., Conclusion: Our study has suggested that neoadjuvant chemotherapy would be more effective in high-risk upper tract urothelial carcinoma patients compared with adjuvant chemotherapy., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Upper urinary tract urothelial carcinoma (UTUC) is often locally advanced at initial diagnosis and is associated with high recurrence and mortality rates after radical nephroureterectomy (RNU). Adjuvant platinum-based chemotherapy has shown a recurrence-free survival benefit in a randomised phase III trial, while neoadjuvant treatment seems promising in retrospective series. On the contrary, little is known about the role of perioperative immunotherapy and its combination with chemotherapy for UTUC patients, although initial positive results have been published for muscle-invasive bladder cancer., Study Design and Endpoints: Against this backdrop, we are running a multi-centre single-arm phase 2 trial of neoadjuvant Durvalumab, a monoclonal antibody targeting programmed cell death ligand 1, combined with Gemcitabine and Cisplatin or Carboplatin for high-risk UTUC patients. The primary outcome is pathological complete response rate at RNU. Secondary endpoints include the partial pathological response rate, safety, as well as disease-free and overall survival. A biomarker analysis is also planned., Patients and Interventions: Included patients must have a good performance status and harbour a non-metastatic UTUC, considered at high risk of progression, defined as either biopsy-proven high-grade disease or invasive features at imaging with or, more recently, without high-grade cytology at the multidisciplinary team discretion, as specified in the latest amendment. Enrolled patients receive 3 cycles of neoadjuvant immuno-chemotherapy before RNU, and the standard of care thereafter. The trial is registered as NCT04617756 and is supervised by an independent data monitoring committee., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To summarize evidence regarding the use of neoadjuvant (NAC) and adjuvant chemotherapy (AC) among patients treated with radical nephroureterectomy (RNU)., Methods: A comprehensive literature search of PubMed (MEDLINE), EMBASE and the Cochrane library was performed to identify any original or review article on the role of perioperative chemotherapy for UTUC patients treated with RNU., Results: With regards to NAC, retrospective studies consistently suggested that it may be associated with better pathological downstaging (pDS) ranging from 10.8 to 80% and complete response (pCR) ranging from 4.3 to 15%, while decreasing the risk of recurrence and death as compared to RNU alone. Even higher pDS ranging from 58 to 75% and pCR ranging from 14 to 38% were observed in single-arm phase II trials. With regards to AC, retrospective studies provided conflicting results although the largest report from the National Cancer Database suggested an overall survival benefit in pT3-T4 and/or pN + patients. In addition, a phase III randomized controlled trial showed that the use of AC was associated with a disease-free survival benefit (HR = 0.45; 95% CI = [0.30-0.68]; p = 0.0001) in pT2-T4 and/or pN + patients with acceptable toxicity profile. This benefit was consistent in all subgroups analyzed., Conclusions: Perioperative chemotherapy improves oncological outcomes associated with RNU. Given the impact of RNU on renal function, the rational is stronger for the use of NAC which impacts final pathology and potentially prolongs survival. However, the level of evidence is stronger for the use of AC that has been proven to decrease the risk of recurrence after RNU with a potential survival benefit., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Assess the real-world ablative effect of mitomycin reverse thermal gel for low-grade upper tract urothelial carcinoma (UTUC) in patients who undergo biopsy only or partial ablation and evaluate utility of complete ablation prior to UGN-101., Material and Methods: We retrospectively reviewed low-grade UTUC patients treated with UGN-101 from 15 high-volume centers. Patients were categorized based on initial endoscopic ablation (biopsy only, partial ablation, or complete ablation) and by size of remaining tumor (complete ablation, <1cm, 1-3cm, or >3cm) prior to UGN-101. The primary outcome was rendered disease free (RDF) rate at first post-UGN-101 ureteroscopy (URS), defined as complete response or partial response with minimal mechanical ablation to endoscopically clear the upper tract of visible disease., Results: One hundred and sixteen patients were included for analysis after excluding those with high-grade disease. At first post-UGN-101 URS, there were no differences in RDF rates between those who at initial URS (pre-UGN-101) had complete ablation (RDF 77.0%), partial ablation (RDF 55.9%) or biopsy only (RDF 66.7%) (P = 0.14). Similarly, a complimentary analysis focusing on tumor size (completely ablated, <1cm, 1-3cm or >3cm) prior to UGN-101 induction did not demonstrate significant differences in RDF rates (P = 0.17)., Conclusion: The results of the early real-world experience suggest that UGN-101 may play a role in initial chemo-ablative cytoreduction of larger volume low-grade tumors that may not initially appear to be amenable to renal preservation. Further studies will help to better quantify the chemo-ablative effect and to identify clinical factors for patient selection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: A recovery period between surgery and initiation of adjuvant chemotherapy (AC) is common in patients with upper tract urothelial carcinoma (UTUC), which can progress after a relatively long time. Therefore, the efficacy of AC initiated within 90 days after radical nephroureterectomy (RNU) was evaluated in UTUC patients at stage ≥pT2 (N0-3M0), in addition to the effect of delayed AC initiation on survival outcomes., Methods: Clinical data for 428 UTUC patients diagnosed with transitional cell carcinoma with postoperatively confirmed pathological stages, muscle-invasive or greater-stage (pT2-4) disease, any nodal status, and metastasis-free (M0) disease were retrospectively analyzed. All patients who received AC were treated within 90 days after RNU and underwent at least 4 cycles of the AC procedure. Then, patients receiving AC were divided into the "within 45 days" and "45 to 90 days" groups according to the time interval between RNU and AC initiation. Their clinicopathological characteristics were evaluated and the survival outcomes of the 2 groups were compared. Any adverse events that occurred during the AC process were also recorded., Results: A total of 428 patients were analyzed in the study, including 132 individuals who underwent the AC procedure with platinum in combination with gemcitabine within 90 days after RNU and 296 patients who failed to initiate AC within 90 days. The median age of all patients was 68 years (mean 67, range 28-90 years), and the median follow-up was 25 months (mean 36, range 1-129 months). There were no significant differences in age, sex, lymph node metastasis, tumor location, hydronephrosis status, hematuria status, cancer grade, or multifocality between the 2 groups. Individuals undergoing AC initiated within 90 days of RNU showed a significantly decreased mortality relative to those patients who did not receive AC. Shorter intervals between RNU and AC initiation within 45 days vs. 45-90 days did not improve patient OS and cancer-specific survival (CSS) and may have increased the incidence of adverse events., Conclusion: The present study data supported the finding that a platinum-based combination with gemcitabine regimen initiated postoperatively significantly improved OS and CSS in patients with UTUC at stages ≥pT2 (N0-3M0). Furthermore, no survival benefit was evident in patients who started AC within 45 days after RNU compared to those who received AC within 45 to 90 days., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Upper tract urothelial carcinoma (UTUC) are rare tumors with a poor prognosis. The standard treatment for localized disease is based on total nephroureterectomy (NUT) followed by platinum-based adjuvant chemotherapy for eligible patients at risk of recurrence. However, many patients have renal failure after surgery preventing chemotherapy. Thus, the place of preoperative chemotherapy (POC) is questioned with little information available about renal toxicity and efficacity., Methods: A single center retrospective study was performed on patients with UTUC who received POC., Results: In all, 24 patients with localized UTUC were treated with POC between 2013 and 2022. Twenty-one (91%) had secondarily NUT. In this cohort, POC did not result in degradation of median renal function (pre-POC median GFR: 70mL/min, post-POC median GFR: 77mL/min, P=0.79), unlike NUT (post-NUT median GFR: 51.5mL/min, P<0.001). In addition, the rate of complete pathological response to pathological examination was 29%. After a median follow-up of 27.4 months, the overall survival rate was 74% and the recurrence-free survival rate was 46%., Conclusion: POC for UTUC shows a very reassuring renal toxicity profile and encouraging histological results. These data encourage prospective studies assessing its place for UTUC management., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Objective: The purpose of this study was to evaluate the efficacy of postoperative adjuvant radiotherapy for patients with upper tract urothelial carcinoma (UTUC) who underwent kidney-sparing surgery (KSS)., Methods: We retrospectively reviewed the clinical records of 31 patients with primary UTUC who underwent kidney-sparing surgery (KSS) and who were treated with adjuvant radiotherapy at our center between October 1998 and May 2017. Statistical analyses were performed with SPSS 23.0. The primary endpoints of this study included overall survival (OS) and local recurrence-free survival (LRFS); the secondary endpoints were disease-free survival (DFS) and treatment-related toxicity., Results: The median follow-up was 58.4 months (range, 12.7-185.3 months), and the median local recurrence time was 59.0 months (range, 7.0-185 months). All of the patients completed radiotherapy on schedule, and no grade 3-4 late-stage reaction was observed. The estimated 5-year and 10-year OS, DFS and LRFS rates of the patients were 64.0%, 61.1%, 69.6% and 48.0%, 40.9%, 64.6%, respectively. Univariate analysis showed that age (χ2 = 4.224, P = 0.040), R0 resection (χ2 = 3.949, P = 0.047), and early stage (I + II) (χ2 = 6.515, P = 0.011) were associated with good OS; DFS benefit in early stage patients (χ2 = 6.151, P = 0.013) and age<70 years old (χ2 = 5.091, P = 0.024). Patients with distal ureteral segments had better LRFS than patients with proximal ureteral cancer (χ2 = 5.248, P = 0.022). However, multivariate analysis showed that age was the only factor of OS (χ2 = 4.099, P = 0.043)., Conclusion: Adjuvant radiotherapy is safe and tolerated, and LRFS was superior in middle and distal ureteral cancer than in proximal ureteral cancer., (© 2023. The Author(s).)

Purpose: We describe a novel application of the reverse thermal polymer gel of mitomycin C (UGN-101) as adjuvant therapy after complete endoscopic ablation of upper tract urothelial carcinoma., Materials and Methods: We retrospectively reviewed patients treated with UGN-101 from 15 high-volume centers. Adjuvant therapy was defined as treatment administered following visually complete endoscopic ablation. Response at primary endoscopic evaluation was defined as no visual tumor or negative biopsy. Ipsilateral disease-free and progression-free survival were estimated by the Kaplan-Meier method. Ureteral stenosis and other adverse events were abstracted from the medical records. Ureteral stenosis was defined as a condition requiring ureteral stent or nephrostomy, or that would typically warrant stent or nephrostomy., Results: Adjuvant UGN-101 after complete endoscopic ablation was used in 52 of 115 (45%) renal units in the oncologic analysis. At first endoscopic evaluation, 36/52 (69%) were without visible disease. At 6.8 months' median follow-up, the ipsilateral disease-free rate was 63%. Recurrence after adjuvant UGN-101 therapy was more likely in multifocal tumors compared to unifocal (HR 3.3, 95% CI 1.07-9.91). Compared with UGN-101 treatment for chemoablation of measurable disease, there were significantly fewer disease detections with adjuvant therapy ( P < .001). Ureteral stenosis after UGN-101 was diagnosed in 10 patients (19%) undergoing adjuvant therapy compared to 17 (29%) undergoing chemoablative therapy ( P = .28)., Conclusions: In patients being considered for UGN-101, maximal endoscopic ablation prior to UGN-101 treatment may result in fewer patients with disease at first endoscopy and possibly fewer adverse events than primary chemoablative therapy. Longer follow-up is needed to determine if UGN-101 after complete endoscopic ablation will lead to durable disease-free interval.

Background/aim: There are few reports confirming the relationship between the therapeutic effects of adjuvant systemic chemotherapy and intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma. We aimed to evaluate the benefits of adjuvant systemic chemotherapy on intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma., Patients and Methods: We retrospectively reviewed the medical records of 133 patients with pathological T stage ≥3 upper urinary tract urothelial carcinoma or lymph node metastasis who underwent radical nephroureterectomy between January 2010 and September 2020 at our hospital and other satellite hospitals. In total, 60 patients received adjuvant systemic chemotherapy, and 73 did not. The Student's t-test and chi-square (χ 2 ) test were used to compare between-group differences. The log-rank test was utilized to compare differences in intravesical recurrence between patients with or without adjuvant systemic chemotherapy. Cox proportional hazards regression analysis was performed to identify the predictive factors of intravesical recurrence., Results: The median follow-up period was 25 months. Forty (30.1%) patients presented with intravesical recurrence. The 1-year intravesical recurrence-free survival rates of patients with and without adjuvant systemic chemotherapy were 86.0% and 70.2%, respectively (p=0.046). Multivariate analysis showed that adjuvant systemic chemotherapy was significantly associated with a lower risk of intravesical recurrence (p=0.032)., Conclusion: Patients with pathological T stage ≥3 upper urinary tract urothelial carcinoma or lymph node metastasis can have a satisfactory intravesical recurrence-free survival rate with adjuvant systemic chemotherapy., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: To assess the safety profile of antegrade mitomycin gel instillation through a percutaneous nephrostomy tube (PCNT) for upper tract urothelial carcinoma (UTUC) with the aim of decreasing morbidity associated with therapy., Patients and Methods: Patients undergoing antegrade administration of mitomycin gel via PCNT were retrospectively included for analysis from four tertiary referral centres between 2020 and 2022. The primary outcome was safety profile, as graded by Common Terminology Criteria for Adverse Events (v5.0). Post-therapy disease burden was assessed by primary disease evaluation (PDE) via ureteroscopy., Results: Thirty-two patients received at least one dose of mitomycin gel via PCNT for UTUC, 29 of whom completed induction and underwent PDE. Thirteen patients (41%) had residual tumour present prior to induction therapy. At a median of 15.0 months following first dose of induction therapy, ureteric stenosis occurred in three patients (9%), all of whom were treated without later recurrence or chronic stenosis. Other adverse events included fatigue (27%), flank pain (19%), urinary tract infection (12%), sepsis (8%) and haematuria (8%). No patients had impaired renal function during follow-up and there were no treatment-related deaths. Seventeen patients (59%) had no evidence of disease at PDE and have not experienced recurrence at a median follow-up of 13.0 months post induction., Conclusions: Administration of mitomycin gel via a PCNT offers a low rate of ureteric stenosis, demonstrates a favourable safety profile, and is administered without general anaesthesia., (© 2022 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Ureteric carcinoma is the rarest of all urothelial malignancies, and little attention has been given to it. Palliation in these groups of patients is a dilemma in the clinics. Use of chemotherapeutic agents in ureteric carcinoma is a double edged sword, as these patients had already impaired renal function due to post-renal failure and nephrotoxic nature of most of the chemotherapeutic agents can further deteriorate the renal function, making the management approach, a relatively visionary task. Here, we present a case of a 77-year-old female with metastatic ureteric carcinoma locally complicated with hydroureteronephrosis, coming to us with gross haematuria, lower abdominal pain along with cough. Apart from age factor of the lady, presence of hydroureteronephrosis and pulmonary metastases was another challenge for us. Paclitaxel remains the mainstay of our treatment., Keywords: carcinoma; case reports; metastasis; paclitaxel.

Objective: To establish a prognostic nomogram among UTUC patients who received chemotherapy., Methods: 1195 UTUC patients who received chemotherapy were extracted from the Surveillance, Epidemiology, and End Results (SEER) database for the period between 2004 and 2015. Patients were randomly divided into a training and a validation set. Nomogram was constructed to predict 1-, 3-, and 5-year overall survival (OS) in those patients. Receiver-operating characteristic curves (ROCs), calibration plots, and Decision curve analysis (DCA) were applied to assess and compare the discrimination, accuracy, and practicability of the nomogram with 8th American Joint Committee on Cancer (AJCC) tumor node metastasis (TNM) staging system., Results: Six clinical parameters were identified as independent prognostic factors for UTUC patients' OS, including age, marital status, TNM stage, and surgical methods of the primary site. The ROC curves showed a satisfactory discrimination capacity of the nomogram, with 1-, 3-, and 5-year area under curve (AUC) values of 0.789, 0.772, and 0.763 in the training set and 0.772, 0.822, and 0.814 in the validation set, respectively. Calibration curves indicated a good agreement between actual observation and nomogram prediction. ROC and DCA curves showed our nomograms exhibited larger benefits than the 8th AJCC-TNM staging system., Conclusions: A prognostic nomogram was established and validated to present individual predictions of OS among chemotherapeutic UTUC patients. This nomogram may assist clinicians in accurate survival prognostication, treatment decision-making, and design of future clinical trials., (© 2023. The Author(s).)

A 77-year-old man complaining of gross hematuria was referred to our hospital for further examination and treatment. The contrast-enhanced computed tomographic (CT) scan revealed a left ureteral tumor, multiple bladder tumors, para-aortic lymph node metastasis, left supraclavicular lymph node metastasis, multiple liver metastases, and multiple lung metastases. Transurethral resection was performed. One of the multiple bladder tumors, located at the bladder neck, was pathologically diagnosed as urothelial carcinoma, pT1, high grade, G2．We diagnosed the patient with metastatic ureteral cancer (T4N2M1, stage IV). We stated gemcitabine, cisplatin (GC) therapy, but stopped after the first course due to gemcitabine drug eruption. We changed the regimen to methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy and the cycle was completed without complications. However, CT scan showed disease progression. After palliative irradiation of the primary lesion, we administered pembrolizumab. Although he was asymptomatic, we diagnosed him with ocular myasthenia gravis because of a high level of serum anti-acetylcholine receptor antibodies and a temporary ptosis in his past history. In spite of the possibility of relapse of myasthenia gravis, treatment with pembrolizumab was continued with his consent since there were no other treatment options. After two courses of pembrolizumab, he was hospitalized due to disease progression and died about three weeks after admission. Myasthenia gravis is a possible immune-related adverse event of pembrolizumab, However, there have been few reports on the successful treatment with this agent in patients with previously diagnosed myasthenia gravis. We report, here, a case of metastatic ureteral carcinoma safely treated with pembrolizumab without relapse of ocular myasthenia gravis.

Purpose: Renal function dictates sequencing and eligibility for definitive therapy in upper tract urothelial carcinoma. We investigated longitudinal glomerular filtration rate (GFR) changes after neoadjuvant chemotherapy (NAC) and nephroureterectomy (RNU)., Materials and Methods: Patients treated with ≥3 cycles of chemotherapy prior to RNU for UTUC from 2000 to 2019 were included. GFR was calculated by CKD-Epi before chemotherapy, before RNU, 1 to 3 months, and 12 months post-RNU. Pathologic stage and overall survival were compared in those with stable GFR (+/-10% of baseline) to the rest of the cohort., Results: One hundred and fifty-two patients received ≥3 cycles of NAC, with 121 (79%) receiving at least 1 cycle of cisplatin. Renal function dropped by mean of 22.3 ml/min/1.73 m 2 from the beginning of chemotherapy to 1-year post-surgery. In patients receiving cisplatin, a mean decline of 26.2 ml/min/1.73 m 2 was observed vs. 8.8 ml/min/1.73 m 2 without cisplatin-based NAC (P < 0.01). GFR after RNU was unchanged between 3 and 12 months postoperatively. At 1 to 3 months after RNU, 19% of patients had GFR<30 ml/min/1.73m 2 . Improvement in GFR during NAC was associated with invasive final pathologic stage (P = 0.018) and worse overall survival (P = 0.049)., Conclusions: In patients managed with NAC prior to RNU, renal function stabilizes at 1 to 3 months post-operatively and remains clinically similar for cisplatin or non-cisplatin-based therapy. Improvement in GFR during NAC was associated with higher pathologic stage and poorer survival, especially in those receiving non-cisplatin-based therapy, an observation that requires further investigation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Perioperative intravesical chemotherapy (IVC) at or around the time of radical nephroureterectomy (RNU) reduces the risk of intravesical recurrence. Guidelines since 2013 have recommended its use. The objective of this study is to examine IVC utilization and determine predictors of its administration within a large international consortium., Methods and Materials: Data was collected from 17 academic centers on patients who underwent robotic/laparoscopic RNU between 2006 and 2020. Patients who underwent concomitant radical cystectomy and cases in which IVC administration details were unknown were excluded. Univariate and multivariate analyses were utilized to determine predictors of IVC administration. A Joinpoint regression was performed to evaluate utilization by year., Results: Six hundred and fifty-nine patients were included. A total of 512 (78%) did not receive IVC while 147 (22%) did. Non-IVC patients were older (P < 0.001), had higher ECOG scores (P = 0.003), and had more multifocal disease (23% vs. 12%, P = 0.005). Those in the IVC group were more likely to have higher clinical T stage disease (P = 0.008), undergone laparoscopic RNU (83% vs. 68%, P < 0.001), undergone endoscopic management of the bladder cuff (20% vs. 4%, P = 0.008). Multivariable regression showed that decreased age (OR 0.940, P < 0.001), laparoscopic approach (OR 2.403, P = 0.008), and endoscopic management of the bladder cuff (OR 7.619, P < 0.001) were significant predictors favoring IVC administration. Treatment at a European center was associated with lower IVC use (OR 0.278, P = 0.018). Overall utilization of IVC after the 2013 European Association of Urology (EAU) guideline was 24% vs. 0% prior to 2013 (P < 0.001). Limitations include limited data regarding IVC timing/agent and inclusion of minimally invasive RNU patients only., Conclusions: While IVC use has increased since being added to the EAU UTUC guidelines, its use remains low at academic centers, particularly within Europe., Competing Interests: Conflict of interest The authors have no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose of Review: This article aimed to investigate the efficacy of drug instillation therapy in preventing the recurrence of postsurgical upper urinary tract urothelial carcinoma (UTUC) by reviewing recently published research articles., Recent Findings: Several clinical trials have shown new potential forms of postsurgical intracavitary and intravesical drug instillation methodologies with better efficacy and less toxicity for use in UTUC. With the improvement of endoscopic imaging techniques and laser sciences, diverse attempts in drug instillation have shown an improved recurrence rate after kidney-sparing surgery in low-grade, low-tumor burden cancers in the upper urinary tract. A gel-form type of mitomycin-C in intracavitary instillation further reduced recurrence rates in UTUC. Other studies have compared different drug instillation methodologies with varying initiation times and timed instillation. They have shown that early instillation with multiple rounds resulted in better protective effects for recurrence rates before, during, and after surgery., Summary: A new gel-form of intracavitary instillation of mitomycin-C, the timing of drug instillation, and refining techniques can result in better recurrence-free survival of patients with UTUC after surgery. Further large-scale prospective clinical trials are needed to validate these new forms of drugs and methodologies to change the therapeutic guidelines of UTUC., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: UGN-101 (mitomycin for pyelocalyceal solution) is a recently approved chemoablative treatment for low-grade (LG) upper tract urothelial carcinoma (UTUC). While approved for retrograde or antegrade administration, previous reports discuss only patients treated by retrograde approach. We report our techniques for antegrade administration along with early outcomes from our cohort of patients who have undergone UGN-101 administration via nephrostomy., Materials and Methods: UGN-101 is administered as 6 weekly instillations in patients who have undergone endoscopic ablation of LG UTUC. We outline our approach in patients thought to have LG UTUC from initial ureteroscopy to nephrostomy placement, UGN-101 administration and eventual nephrostomy removal. We discuss early durability of response along with adverse events with special attention to ureteral strictures., Results: Eight patients underwent antegrade UGN-101 administration during the study period, all of whom underwent followup ureteroscopy with complete response in 4 patients. Three patients reported 5 adverse events-3 grade 1, 1 grade 2 requiring 1 week delay of treatment and 1 asymptomatic ureteral stricture. Median followup was 7 months., Conclusions: We outline our approach for antegrade administration of UGN-101 and discuss early results along with adverse events. Future studies should evaluate our method's potential to increase patient comfort, improve logistics and decrease risk of adverse events.

A 72-year-old man, who had received pembrolizumab of immune checkpoint inhibitor (ICI) over 6 months for ureter cancer, developed progressive skeletal muscle weakness, dysarthria, dyspnea, and consciousness disturbance over the past two weeks. The systemic work-up tests documented an encephalitis, myopathy, and myocarditis. Multiple autoimmune antibodies of anti-Tr, anti-titin, anti-kv1.4, anti-GM1 and anti-GD1a were positive in the serum. Although myopathy and myocarditis responded to high-dose steroid pulse therapy, encephalopathy deteriorated. Electroencephalogram showed a fluctuated pattern of rhythmic delta activity with fast waves, and a rapid response to intravenous diazepam revealed a condition of nonconvulsive status epileptics (NCSE). The patient had an uneventful course after anti-epileptic medication. The ICIs therapy may trigger a broader activation of multiple autoimmune mechanisms. When an encephalitis by immune-related adverse events does not respond to standard immunotherapy, NCSE may be a main pathophysiological mechanism, thereby anti-epileptics being an alternative treatment option.

Background: Emerging data suggests improved outcomes in patients receiving neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU) for high-risk upper tract urothelial carcinoma. In one of the largest single-center experiences to date, we provide an updated analysis of outcomes of patients receiving NAC followed by RNU., Patients and Methods: A retrospective review of patients with high-risk UTUC who received NAC followed by surgery between 2004 to 2017 was conducted. 126 patients were evaluated as part of the analysis. Kaplan-Meier method was used to estimate survival probabilities. Multivariable Cox modeling was used to evaluate for association with outcomes, and the cumulative incidence factor was used for competing risk analysis., Results: Median OS time was 106 months. 14.3% of patients had a pathologic complete response and 60% were down-staged to ypT0-1 ypN0. The estimated 5 and 10-year DSS rates were 89.8% and 80.6%, respectively. The estimated 5 and 10-year metastasis-free survival rates were 81% and 75.4%, respectively. The estimated 5 and 10-year OS rates were 73.7% and 35.9 %, respectively. Recurrences mainly occurred in lymph nodes and lung at a median time of 15.5 months (IQR 8.9-27). The estimated 5 and 10-year cumulative incidence factor for death from UTUC was 9.5% and 16.1%, respectively. Limitations include retrospective nature and challenge of accurate pre-surgical staging., Conclusions: NAC prior to RNU in high-risk UTUC shows durable 5 and 10-year OS and DSS rates in a large single-institution series, confirming prior findings in prospective trials and retrospective studies., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The indications of neoadjuvant chemotherapy (NAC) for lymph node-positive upper tract urothelial carcinoma (UTUC) have not been investigated regarding improved survival outcomes. Our specific aim was to compare the clinical outcomes of clinically node-positive UTUC patients who were treated by NAC followed by radical nephroureterectomy (RNU) or upfront RNU followed by adjuvant chemotherapy (AC)., Materials and Methods: Among 966 UTUC patients, we identified 89 with clinical nodal involvement who received either NAC before RNU nor AC after upfront RNU. Cox proportional hazard models were employed to evaluate the impact of chemotherapy modality on the oncological outcomes., Results: Of the patient cohort, 36 (40.4%) received NAC followed by RNU, whereas 53 (59.6%) underwent RNU followed by AC. Multivariate analysis revealed that tumor size ≥3 cm, clinical T4, and gemcitabine and cisplatin regimen were independent risk factors for disease recurrence, whereas NAC followed by RNU was an independent factor for favorable RFS. Furthermore, regarding cancer-specific survival (CSS), NAC followed by RNU remained an independent factor for favorable CSS. According to Kaplan-Meier analysis, the 1-year and 2-year RFS were 67.9% and 47.0%, respectively, in the NAC+RNU group, which were significantly higher than those in the RNU+AC group (43.9% and 24.6%, respectively, P = 0.006). Moreover, the 1-year and 2-year CSS were 80.5% and 64.2%, respectively, in the NAC+RNU group, which were higher than those in the RNU+AC group (68.6% and 48.2%, respectively, P = 0.016)., Conclusion: For node-positive UTUC patients, NAC followed by RNU was more clinically beneficial than RNU followed by AC., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Advances in neoadjuvant therapy for patients with localized, nonmetastatic, upper tract urothelial carcinoma (UTUC) is needed., Patients and Methods: PURE-02 was a feasibility study enrolling individuals with UTUC, at clinical stage N0M0, with high-risk features according to the modified European Association of Urology definition, based on the presence of either: high-grade disease, multifocality, tumor size ≥2 cm, and/or hydronephrosis. The treatment consisted of 3 courses of 200 mg pembrolizumab, intravenously, every 3 weeks, followed by radical nephroureterectomy (RNU). The endpoints were to assess the safety, pathological responses, and biomarkers., Results: Ten patients were enrolled between August 2018 and November 2020, 9 (90%) completed the neoadjuvant course. One treatment-related death occurred as a complication of severe myocarditis, myasthenia gravis, hepatitis and myositis. One (14.3%) patient achieved a clinical complete response and refused to undergo RNU. Two (20%) had disease progression and received subsequent chemotherapy, prior to RNU. Overall, 7 patients underwent RNU: one (14.3%) achieved an ypT1N0 response, although this patient was reported to have a cT1 tumor at baseline imaging. The remaining patients were nonresponders. Circulating tumor DNA assay did not identify patients likely to achieve a complete pathologic response., Conclusion: Single-agent neoadjuvant pembrolizumab did not appear to be a promising treatment strategy for patients with biomarker-unselected, high-risk localized UTUC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate temporal trends in neoadjuvant chemotherapy (NAC) utilisation and outcomes in patients with locally advanced upper tract urothelial carcinoma (UTUC)., Patients and Methods: We included 289 patients from seven hospitals who underwent radical nephroureterectomy (RNU) for locally advanced UTUC (≥cT3 or cN+) between 2000 and 2020. These patients received RNU alone or two to four courses of NAC with either a cisplatin- or carboplatin-based regimen. We evaluated the temporal changes in NAC use and compared the visceral recurrence-free, cancer-specific, and overall survival rates. The effect of NAC on oncological outcomes was examined using multivariate Cox regression analysis with inverse probability of treatment weighting (IPTW) models., Results: Of 289 patients, 144 underwent NAC followed by RNU (NAC group) and 145 underwent RNU alone (Control [Ctrl] group). NAC use increased significantly from 19% (2006-2010), 58% (2011-2015), to 79% (2016-2020). Pathological downstaging was significantly higher in the NAC group than in the Ctrl group. The IPTW-adjusted multivariable analyses showed that NAC significantly improved the oncological outcomes in the NAC group compared with the Ctrl group. Moreover, carboplatin-based NAC significantly improved the oncological outcomes in the NAC group compared with the Ctrl group among patients with chronic kidney disease Stage ≥3. There were no significant differences in oncological outcomes between the cisplatin- and carboplatin-based regimens., Conclusions: The use of NAC for high-risk UTUC increased significantly after 2010. Platinum-based short-term NAC followed by immediate RNU may not impede and potentially improves oncological outcomes., (© 2021 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Objective: To analyze utilization and outcomes of cytoreductive surgery (CRS) after systemic chemotherapy in select patients with metastatic upper tract urothelial carcinoma (UTUC)., Material and Methods: We identified 1,73 patients with cM1 UTUC from the National Cancer Database who were treated with first-line multiagent chemotherapy from 2004 to 2015. Patients considered surgical candidates based on Charlon-Deyo performance score were stratified into nonsurgical versus surgical arms based on receipt of CRS after systemic therapy. Those receiving radiation, immunotherapy, or other types of treatment were excluded. Cox proportional hazard models were used to analyze prognostic factors for overall survival (OS). Propensity-score matching and inverse probability of treatment weighting-adjusted regression models were used to compare OS., Results: A total of 1182 patients were included of which 349 (29.5%) were treated with definitive surgery. Median follow-up was 64 months (95% confidence interval:49.8-79.4) for chemotherapy+surgery versus 61.2 (52.2-78.7) for the chemotherapy-alone arms (P = .09). Patients treated with surgery were younger and more commonly treated at academic facilities. Patients who received CRS had improved median-OS versus those treated with chemotherapy alone (13.7 vs 10.8 months, log-rank P-value <.001). Predictors of OS were performance score, treatment at academic facility, and performance of CRS. Furthermore, in propensity-score and inverse probability of treatment weighting-adjusted Cox regression analyses, CRS was associated with significant OS benefit (hazard ratios = 0.61, 95% confidence interval:0.49-0.77, and 0.63;0.55-0.72; respectively)., Conclusion: We provide a contemporary report on the survival benefit of CRS after treatment with systemic therapy for M1 UTUC patients. Longitudinal studies are needed to evaluate the role of surgery, when feasible, within multidisciplinary approaches for this relatively, rare disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Context: To improve the prognosis of upper tract urothelial carcinoma (UTUC), clinicians have used neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (AC) before or after radical nephroureterectomy (RNU). Despite some new data, the evidence remains mixed on their efficacy., Objective: To update the current evidence on the role of NAC and AC for UTUC., Evidence Acquisition: We searched for all studies investigating NAC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings up to February 2020. A systematic review and meta-analysis was performed., Evidence Synthesis: For NAC, the pooled pathologic complete response rate (≤ypT0N0M0) was 11% (n = 811) and pathologic partial response rate (≤ypT1N0M0) was 43% (n = 869), both across 14 studies. Across six studies, the pooled hazard ratios (HRs) were 0.44 (95% confidence interval [CI]: 0.32-0.59, p <  0.001) for overall survival (OS) and 0.38 (95% CI: 0.24-0.61, p <  0.001) for cancer-specific survival (CSS) in favor of NAC. The evidence for NAC is at best level 2. As for AC, there was a benefit in OS (pooled HR 0.77; 95% CI: 0.64-0.92, p =  0.004 across 14 studies and 7983 patients), CSS (pooled HR 0.79; 95% CI: 0.69-0.91, p =  0.001 across 18 studies and 5659 patients), and disease-free survival (DFS; pooled HR 0.52; 95% CI: 0.38-0.70 across four studies and 602 patients). While most studies were retrospective (level 2 evidence), there were two prospective randomized trials providing level 1 evidence. There are currently four phase 2 trials on neoadjuvant immunotherapy and three phase 2 trials on adjuvant immunotherapy for UTUC., Conclusions: NAC for UTUC confers a favorable pathologic response and tumor downstaging rate, and an OS and CSS benefit compared with RNU alone. AC confers an OS, CSS, and DFS benefit compared with RNU alone. Currently, the evidence for AC appears stronger (with positive level 1 evidence) than that for NAC (at best level 2 evidence). Limited data are available for chemoimmunotherapy approaches, but preliminary data support an active research investment., Patient Summary: After a comprehensive search of the latest studies examining the role of neoadjuvant and adjuvant chemotherapy for upper tract urothelial cancer, the pooled evidence shows that perioperative chemotherapy was beneficial for prolonging survival; however, the evidence for adjuvant chemotherapy was stronger than that for neoadjuvant chemotherapy., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Immunotherapy is changing the way we think about and treat urothelial carcinoma (UC). The PD-1/PD-L1 pathway inhibition has shown robust efficacy, associated with an acceptable toxicity profile, in patients with locally advanced and metastatic unresectable disease, addressing a high decades-old unmet medical need., Material and Methods: Using the Pubmed database, we conducted a literature review for English written published articles up to June 2020. The highest available evidence for the immunotherapy treatment of UC with ICIs were evaluated. The leading phase one, two and three clinical trials were considered for inclusion (n = 12). Patient's data were extracted from studies depicting the UTUC subpopulation., Results: Two monoclonal antibodies targeting PD-1 (pembrolizumab and nivolumab) and three to its ligand PD-L1 (atezolizumab, avelumab, and durvalumab) have obtained US FDA and EMA approval for the second-line treatment of platinum-pretreated patients, between 2016 and 2019. Atezolizumab and Pembrolizumab are even currently approved in the first-line setting for cisplatin ineligible patients, with PD-L1- positive tumor. The neoadjuvant scenario in localized high-risk disease is still evolving, with the first data available to date limited to the muscle-invasive bladder carcinoma. The management of patients with upper tract urothelial carcinoma (UTUC: renal pelvis and ureters) is complicated by the lack of specific high-level evidence, due to the rarity of the disease. No published studies addressing immunotherapy in UTUC patients only are available. The largest clinical trials aimed at UC patients, regardless of the upper or lower location of the primary tumor, have enrolled a minority of patients with UTUC, providing the data on which our current knowledge is based. However, targeted scientific efforts are needed to improve our level of care., Conclusions: This review summarizes the main currently available evidence on the use of the PD-1/PD-L1 pathway inhibition with reference to patients presenting with UTUC.

Background: The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown., Materials and Methods: We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells., Results: Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months; p = 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemotherapy arm [46/57 (81%) vs 44/74 (59%)]., Conclusion: Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab.

Introduction: Patients with upper-tract carcinoma in situ (UT-CIS) that have failed treatment with BCG are recommended for radical nephroureterectomy (RNU). We describe a cohort of patients with BCG-refractory UT-CIS that were treated with docetaxel, a novel agent in the approach to topical therapy., Methods: Patients with pathologically proven UT-CIS from 2012 to 2020 with an imperative indication for organ preservation and history of BCG-refractory disease were included. Each patient underwent ureteroscopy with biopsy and selective cytology pre- and postinduction, and after each maintenance course. Complete response (CR) was defined as the absence of visualized lesions on ureteroscopy, negative selective cytology, and absence of clinical progression. No response (NR) was defined as persistence of lesions after induction or absence of visualized lesions with persistently positive cytology., Results: Seven patients and 10 renal units were treated. Six of the 10 renal units had initial CR (60%). Three patients with NR went on to have RNU, one of which subsequently died due to cancer-specific mortality. One patient with bilateral disease had NR in 10 renal unit and cure in the other. This patient subsequently developed recurrence in his remaining renal unit. A second patient had CR in both kidneys for 6 years, but 1 year after finishing maintenance regimen developed HG disease in 1 ureter. Average follow-up was 33 months., Conclusion: This study demonstrates efficacy of docetaxel as a treatment option for patients with UT-CIS with a contraindication to RNU after failing BCG. Response rates of 60% appear to be similar to those of BCG-refractory bladder CIS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Upper tract urothelial carcinoma (UTUC) is clinically understudied, and there are no definitive recommendations regarding timing of perioperative chemotherapy. The objective of this study was to compare 3 treatment pathways in UTUC: nephroureterectomy (NU) alone, neoadjuvant chemotherapy (NAC), and adjuvant chemotherapy (AC) using a microsimulation model., Patients and Methods: An individual-level state transition model was constructed using TreeAgePro software to compare treatment strategies for patients with newly diagnosed UTUC. The base case was that of a 70-year-old patient with a radiographically localized upper tract tumor. Primary outcome was quality-adjusted life expectancy. Secondary outcomes included crude overall survival, rates of adverse events, and bladder cancer diagnoses., Results: A total of 100,000 patients were simulated. NAC was preferred, with an estimated quality-adjusted life expectancy of 7.50 years versus 6.79 years with NU alone and 7.23 years with AC. Median crude overall survival was 123 months with NAC, 96 months with NU only, and 111 months with AC. Overall, 40.0% of patients in the AC group with invasive pathology completed chemotherapy. In the NAC group, 83.3% of patients completed chemotherapy. In the NAC group, 37.5% of patients experienced an adverse chemotherapy event compared to 15.1% of patients in the AC group. Bladder cancer recurrence rates were 64.9%, 65.9%, and 67.4% over the patient's lifetime for the NU, NAC, and AC strategies, respectively., Conclusion: This study supports the increased use of NAC in UTUC until robust randomized trials are completed. The ultimate choice should be based on patient and tumor factors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Intensified treatment such as extended lymph node dissection (LND) and/or perioperative chemotherapy in addition to radical nephroureterectomy (RNU) has been suggested for high-risk cases of upper tract urothelial carcinoma (UTUC). We aimed to identify preoperative predictors of tumour stage and prognosis in the diagnostic work-up before RNU. Further to evaluate if our findings could be used in selecting patients for intensified treatment., Patients and Methods: A total of 179 patients treated with RNU for UTUC at Haukeland University Hospital (HUS) and Vestfold Hospital Trust (VHT) during 2005-2017 were included in this retrospective study. All relevant preoperative variables regarding the patient, the CT and the ureteroscopy (URS) were registered and analysed regarding their ability to predict non-organ confined disease (NOCD, pT3+ and/or N+) at final pathology after RNU. The prognosis was assessed calculating survival for the cohort and stratified by preoperative variables., Results: Local invasion and pathological lymph nodes at CT predicted NOCD in uni and multivariate regression analyses (OR 3.36, p =.004 and OR 6.21, p =.03, respectively). Reactive oedema surrounding the tumour (OR 2.55, p =.02), tumour size (4.8 vs. 3.9 cm, p =.006) and high-grade tumour at URS biopsy (OR 3.59, p =.04) predicted NOCD at univariate regression analyses. The 5-year CSS and OS for the entire cohort was 79% and 60%. ECOG, local invasion, pathological lymph nodes and reactive oedema surrounding the tumour at CT predicted CSS., Conclusions: Several variables at the CT predicted both stage and survival. Local invasion at CT seems the most promising feature for selecting patients for intensified treatment.

Background: Intravesical instillation of chemo- or immunotherapy is commonly used in bladder cancer. Upper tract urothelial carcinoma (UTUC) shares similar pathological features, but current formulations are not suitable for direct instillation to the upper urinary tract., Objective: To evaluate in vivo applicability, characteristics and toxicity of ST-UC, a mucoadhesive polymeric paste formulation of gemcitabine, for upper urinary tract instillation., Material and Methods: Three pigs received 10 ml of ST-UC (100 mg/ml gemcitabine) retrogradely into 1 renal pelvis for pharmacokinetic studies. Four days later, a second injection into the contralateral renal pelvis was followed by serial euthanasia of the pigs and nephroureterectomy after 1, 3, and 6 hours. Adverse effects were monitored. Urine, serum, and tissue gemcitabine concentrations were measured, along with histologic examination of the upper urinary tract., Results: Retrograde instillation of ST-UC was well tolerated with mild, completely receding hydronephrosis. Urine gemcitabine concentrations were highest in the first 3-hour collection interval. Hundred percent of gemcitabine was recovered in the urine within 24 hours. Serum peak concentrations (c max ) of gemcitabine were low at 5.5 µg/ml compared to the 10 to 30 µg/ml levels observed after a single intravenous dose of 1,000 mg/m 2 gemcitabine. The formulation was still traceable after one hour and gemcitabine tissue concentrations are supportive of this extended drug exposure. No major histopathological changes were observed. The main limitation of this study is the lack of antitumor activity data., Conclusion: This preclinical evaluation of ST-UC demonstrated feasible instillation in the renal pelvis, no significant safety concerns, and sustained release of gemcitabine., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: To evaluate the efficacy and safety of RC48-ADC, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E, in patients with HER2 + locally advanced or metastatic urothelial carcinoma (mUC) refractory to standard therapies., Patients and Methods: This was a phase II, open-label, multicenter, single-arm study of patients with HER2 + (IHC status 3+ or 2+) locally advanced or mUC who previously failed at least one line of systemic chemotherapy. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee (BIRC). The secondary endpoint included progression-free survival (PFS), disease control rate, duration of response, overall survival (OS), and safety., Results: Forty-three patients were enrolled. The median follow-up was 20.3 months. The overall confirmed ORR as assessed by the BIRC was 51.2% [95% confidence interval (CI), 35.5%-66.7%]. Similar responses were observed in prespecified subgroups, such as those with liver metastasis and those previously treated with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies. The median PFS and OS were 6.9 months (95% CI, 5.6-8.9) and 13.9 months (95% CI, 9.1-NE), respectively. The most common treatment-related adverse events (TRAE) were hypoesthesia (60.5%), alopecia (55.8%), and leukopenia (55.8%). Twenty-five (58%) patients experienced grade 3 TRAEs, including hypoesthesia (23.3%) and neutropenia (14.0%). No grade 4 or grade 5 TRAEs occurred., Conclusions: RC48-ADC demonstrated a promising efficacy with a manageable safety profile in patients with HER2 + locally advanced or mUC who had failed at least one line of systemic chemotherapy., (©2020 American Association for Cancer Research.)

Objectives: The aim of the study was to examine the effectiveness of a modified-short hydration gemcitabine and cisplatin (m-shGC) regimen for patients with metastatic urothelial carcinoma (mUC) and to assess the efficacy of a geriatric nutritional risk index (GNRI) with regard to prognosis., Patients and Methods: From January 2016 to July 2020, 68 patients with mUC underwent first-line m-shGC therapy with 70 mg/m2 cisplatin and 1,000 mg/m2 gemcitabine (days 1, 8, and 15), with 2,050 mL fluid replaced on the first day of each 28-day cycle. Prior to the start of treatment, the serum neutrophil-to-lymphocyte ratio (NLR), and levels of albumin and C-reactive protein (CRP) in serum, as well as body heights and weights were measured. Patients were grouped according to GNRI <92 (low) or ≥92 (high). The analysis of data was done retrospectively., Results: Median follow-up was found to be 12.9 (range 1.7-50.2) months and the objective response rate (ORR) was 54.4% after m-shGC treatment. The ORR was significantly different when high and low-GNRI groups were compared (ORR: 28.0 vs. 69.8% in low- vs. high-GNRI groups). Median overall survival (OS) was calculated as 8.6 (95% confidence interval [CI]: 5.4-21.3) and 34.5 (95% CI: 20.5-NA) months for low- and high-GNRI groups, respectively (p < 0.0001). Unlike for NLR and CRP, univariate and multivariate analyses revealed that low GNRI and visceral metastases were significant prognostic factors for short OS., Conclusions: First-line m-shGC showed a survival benefit for mUC, with GNRI a useful prognostic biomarker., (© 2021 S. Karger AG, Basel.)

Objective: Whether adjuvant chemotherapy (AC) for patients with upper tract urothelial carcinoma (UTUC) offers survival benefit is still controversial. To explore the impact of AC on overall survival (OS) of cN0M0 UTUC patients, we conducted a propensity score-matched analysis using the regression model, including pathologic features such as lymphatic and vascular invasion., Methods: A multi-institutional cohort of 413 UTUC patient record was used. Propensity score matching was performed to reduce bias by potential confounding factors for survival, including pathologic features from the specimen of radical nephroureterectomy (RNU), RESULTS: Ninety-eight patients were identified as pair-matched groups (49 patients in RNU and 49 patients in RNU + AC). Kaplan-Meier curves demonstrated that a 5-year OS rate of 72.7% for patients treated with RNU + AC was significantly higher than 51.6% for those treated with RNU (p = 0.0156). On multivariate analysis, pathologic vascular invasion (HR 3.41, 95% CI 1.24-10.66, p = 0.0166) and administration of AC (HR 0.45, 95% CI 0.19-0.98, p = 0.0438) still remained as the significant predictors for OS. In patients with pathologic vascular invasion (51 of 98 patients), a significantly longer OS in RNU + AC groups was observed (median OS of 30 and 70 months in RNU and RNU + AC groups, respectively: p = 0.0432), whereas there was no significant difference in the OS between RNU (median OS: not reached) and RNU + AC (median OS: not reached) groups in patients without the invasion (p = 0.4549)., Conclusion: The result indicates a significant benefit for OS by the administration of AC, and pathologic vascular invasion in the specimen of RNU could help the patient selection to better predict the effect of AC.

Objective: Whether pathologic stage at radical nephroureterectomy (RNU) can serve as an appropriate surrogate for oncologic outcomes in patients with high-grade (HG) upper tract urothelial carcinoma (UTUC) treated with neoadjuvant chemotherapy (NAC) is not defined. We sought to determine whether patients who achieve pathologically non-muscle-invasive (ypT0, ypTa, ypT1, ypTis) HG UTUC after receipt of NAC exhibit oncologic outcomes comparable to those who are inherently low stage without chemotherapy., Methods: We identified 647 UTUC patients who underwent RNU among 3 institutions from 1993to2016. Patients with low or unknown grade, pathologic muscle invasion, or receipt of adjuvant chemotherapy were excluded. We compared clinicopathologic data and oncologic outcomes between pT0-1 and ypT0-1 patients. Kaplan-Meier analysis was used to assess overall (OS), cancer-specific (CSS), and systemic recurrence-free (RFS) survival. Predictors of these endpoints were identified using Cox regression., Results: 234 (43 ypT0-1, 191 pT0-1) patients with HG UTUC were included. Two patients exhibited pathologic complete response after NAC. OS (P = 0.055), CSS (P = 0.152), and RFS (P = 0.098) were similar between ypT0-1 and pT0-1 patients. Predictors of worse outcomes included African-American race (RFS, CSS, and OS), Charlson score (OS), and systemic recurrence (OS and CSS)., Conclusions: Patients with HG UTUC who achieve ypT0-1 stage after NAC exhibit favorable oncologic outcomes comparable to those inherently non-muscle-invasive who do not receive chemotherapy. Improvements in clinical staging will play an important role in better defining candidacy for NAC in treating HG UTUC while minimizing overtreatment. Furthermore, pathologic stage may serve as an appropriate early surrogate for oncologic endpoints in designing clinical trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)