Should follow-up cystoscopy be performed in upper-tract urothelial carcinoma patients managed with radical nephroureterectomy after a five-year bladder tumor-free period?
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Abstract Objectives: There is disagreement on the follow-up schedule after a 5-year bladder recurrence-free period in patients with upper-tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). In this study, we aimed to clarify the risk factors for the late recurrence in UTUC patients who remained bladder recurrence-free for more than 5 years. Methods: Data from a large single-center Chinese institution were retrospectively reviewed. Among the patients with UTUC who were treated with RNU between 1999 and 2018, those who had no recurrence for more than 5 years were included in this study. The Kaplan–Meier method and Cox hazards model were used to estimate recurrence-free survival. Results: In total, 1028 patients were enrolled in this study. Of these patients, 57 patients (5.5%) experienced late recurrence. The median follow-up time was 96 years (interquartile range 6.9–11.3 years). A prior history of bladder cancer (BCa) before RNU,synchronous T1 BCa, a prior history of kidney transplantation and carcinoma in situ (CIS) were significant predictors for late recurrence, although other clinical factors including tumor grade, pathologic stage and tumor multiplicity were not associated with late recurrence. Conclusions: Late recurrence after a prolonged intravesical tumor-free period is not uncommon and can not be fully predicted by the current risk stratification system. Patients with high-risk factors including previous and synchronous BCa, CIS variants and a previous kidney transplantation require more extensive cystoscopy follow-up for 5 to 10 years after RNU to ensure effective surveillance and timely management of potential recurrences.
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Should follow-up cystoscopy be performed in upper-tract urothelial carcinoma patients managed with radical nephroureterectomy after a five-year bladder tumor-free period? | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Should follow-up cystoscopy be performed in upper-tract urothelial carcinoma patients managed with radical nephroureterectomy after a five-year bladder tumor-free period? Bao Guan, Guoli Wang, Qian Yang, Hanzhen Ren, Huifeng Zhang, Chao Cao, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4587966/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives: There is disagreement on the follow-up schedule after a 5-year bladder recurrence-free period in patients with upper-tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). In this study, we aimed to clarify the risk factors for the late recurrence in UTUC patients who remained bladder recurrence-free for more than 5 years. Methods: Data from a large single-center Chinese institution were retrospectively reviewed. Among the patients with UTUC who were treated with RNU between 1999 and 2018, those who had no recurrence for more than 5 years were included in this study. The Kaplan–Meier method and Cox hazards model were used to estimate recurrence-free survival. Results: In total, 1028 patients were enrolled in this study. Of these patients, 57 patients (5.5%) experienced late recurrence. The median follow-up time was 96 years (interquartile range 6.9–11.3 years). A prior history of bladder cancer (BCa) before RNU,synchronous T1 BCa, a prior history of kidney transplantation and carcinoma in situ (CIS) were significant predictors for late recurrence, although other clinical factors including tumor grade, pathologic stage and tumor multiplicity were not associated with late recurrence. Conclusions: Late recurrence after a prolonged intravesical tumor-free period is not uncommon and can not be fully predicted by the current risk stratification system. Patients with high-risk factors including previous and synchronous BCa, CIS variants and a previous kidney transplantation require more extensive cystoscopy follow-up for 5 to 10 years after RNU to ensure effective surveillance and timely management of potential recurrences. upper-tract urothelial carcinoma late bladder recurrence risk factor Figures Figure 1 Figure 2 Introduction Upper-tract urothelial carcinoma (UTUC) accounts for approximately 5%~10% of all urothelial cancers, and radical nephroureterectomy (RNU) combined with bladder cuff excision is the ‘gold standard’ treatment for high-risk UTUC patients[ 1 ]. After RNU, approximately 22%~47% of patients experience bladder recurrence[ 1 ]. Previous studies demonstrated that the peak period for intravesical recurrence typically falls within the first two years, emphasizing the crucial need for frequent cystoscopy follow-up to detect early recurrence[ 2 ]. Factors such as male gender, previous and synchronous bladder cancer (BCa), ureteroscopy, renal dysfunction, and tumor stage and grade are significantly related to increased bladder recurrence[ 2 , 3 ]. While these risk variables have been addressed in previous studies, there remains a gap in knowledge regarding the characteristics of bladder lesions that may emerge after a 5-year bladder recurrence-free period. In fact, these findings are primarily based on studies with relatively short-term follow-up durations[ 2 ]. Current guidelines also lack specific recommendation on the follow-up plan on late recurrence[ 1 , 4 ]. It is suggested that the intensity of follow-up can be appropriately reduced after a 4-year recurrence-free period, and that personalized follow-up plan can be made jointly by doctors and patients. In the face of such a paucity of data, we focused on the patients with UTUC who remained intravesical recurrence-free for more than 5 years and evaluated the risk of late bladder recurrence. In addition, we tried to elucidate the risk factors for the late recurrence in this very long-term follow-up study. Material and methods We relied on a retrospectively maintained database including 2456 consecutive non-metastatic UTUC patients treated with RNU from 1999 to 2018 at our high-volume medical center. Patients were excluded based on the following criteria: lost to follow-up (n = 267), prior contralateral or bilateral UTUC (n = 34), prior ≥ T2 BCa or radical cystectomy (n = 4), synchronous ≥ T2 BCa or radical cystectomy (n = 37), unclear clinical pathological information (n = 45), death within 5 years after RNU (n = 578) or bladder recurrence within 5 years after RNU (n = 463). The remaining 1028 patients with a 5-year bladder recurrence-free period were included in the final analysis (Fig. 1 ). The primary endpoint was the time to tumor recurrence. Recurrence was defined as a pathologically confirmed tumor appearing in the bladder after RNU. Surveillance frequency, programs, and indications for intravesical therapy after RNU were based on EAU instructions and urologist’s discretion. This study was approved by our institutional ethics committee. We chose variables that showed P values less than 0.05 in the univariate analyses as candidates for the multivariate model. Smoothed hazard analysis was applied to estimate the hazard of recurrence using a kernel function method. All analyses were conducted using SPSS version 20.0 (SPSS, Chicago, IL). Results The median follow-up duration was 96 (IQR: 76–126) months, during which 57 (5.5%) patients experienced late bladder relapse after a 5-year bladder recurrence-free period. The peak incidence of bladder recurrence was 70 ~ 90 months, and the recurrence over 10 years was not unusual. The Kaplan-Meier estimated risk for recurrence was 7.1% at 10 year and 14.5% at 15 year, respectively (Fig. 2 A& 2 B). Tate recurrence was significantly related to male gender, prior non-muscle invasive BCa (NMIBCa), synchronous NMIBCa, hydronephrosis and a history of ureteroscopy (Table 1 ). Conversely, there was no significant difference in late bladder recurrence between gender, age, ureteroscopy, hydronephrosis, multiple upper tract tumors, upper tract tumor architecture, tumor grade and stage. Table 1 Patients clinicopathologic data. Variable Total Without late recurrence(%) With late recurrence(%) p Patient characteristics No. (%) 1028 971(94.5%) 57(5.5%) Age (IQR), years 68 (61 ~ 74) 67 (58 ~ 72) 0.168 Male 436(42.4%) 411(42.3%) 25(43.9%) 0.820 Smoking 143(13.9%) 135(13.9%) 8(14.0%) 0.978 Prior history of NMIBCa 46(4.5%) 38(3.9%) 8(14.0%) < 0.001 Concurrent NMIBCa 47(4.6%) 42(4.3%) 5(8.8%) 0.118 T1 (concurrent NMIBCa) 30(2.9%) 25(2.6%) 5(8.8%) 0.010 Grade 2&3 (concurrent NMIBCa) 36(3.5%) 31(3.2%) 5(8.8%) 0.044 Sessile (concurrent NMIBCa) 8(0.8%) 6(0.6%) 2(3.5%) 0.068 CKD1 ~ 2 572(55.6%) 544(56.1%) 28(49.1%) 0.300 CKD3 ~ 5 454(44.2%) 425(43.9%) 29(50.9%) Prior renal transplantation 24(2.3%) 20(2.1%) 4(7.0%) 0.001 Hydronephrosis 447(43.5%) 421(43.4%) 26(45.6%) 0.738 Prior ureteroscopy 75(7.3%) 69(7.1%) 6(10.5%) 0.298 Pelvis 522(50.8%) 496(51.1%) 26(45.6%) 0.680 Ureter 430(41.8%) 403(41.5%) 27(47.4%) Pelvis + ureter 76(7.4%) 72(7.4%) 4(7.0%) Tumour characteristics, no. patients (%) Diameter, cm 3 (2 ~ 4) 3 (2 ~ 4) 2.5(2 ~ 3.5) 0.042 Multifocal upper tract tumor 172(16.7%) 162(16.7%) 10(17.5%) 0.866 Grade 1 21(2.0%) 19(2.0%) 2(3.5%) 0.717 Grade 2 651(63.3%) 615(63.3%) 36(63.2%) Grade 3 356(34.6%) 337(34.7%) 19(33.3%) Ta&T1 528(51.4%) 506(52.1%) 22(38.6%) 0.047 T2,T3&T4 500(48.6%) 465(47.9%) 35(61.4%) Positive lymph node 26(2.5%) 26(2.7%) 0 0.393 Variant Sessile tumor architecture 193(18.8%) 181(18.6%) 12(21.1%) 0.650 Lymphovascular Invasion 117(11.4%) 110(11.3%) 7(12.3%) 0.826 Carcinoma In Situ 17(1.7%) 14(1.4%) 3(5.3%) 0.028 Squamous differentiation 90(8.8%) 88(9.1%) 2(3.5%) 0.149 Adenoid differentiation 46(4.5%) 43(4.4%) 3(5.3%) 0.583 Sarcomatoid differentiation 52(5.1%) 50(5.1%) 2(3.5%) 0.583 Necrosis 146(14.2%) 138(14.2%) 8(14.0%) 0.970 IQR: Interquartile Range, CKD: Chronic kidney disease; NMIBCa: non-muscle invasive bladder cancer Univariate Cox analysis revealed that a prior previous NMIBCa, synchronous high-risk NMIBCa (T1, G2&G3 or sessile lesion), a history of kidney transplantation and upper tract tumor with carcinoma in situ (CIS) variants were risk factors of late recurrence. Multivariate Cox hazards regression analysis further identified that prior previous NMIBCa (hazard ratio (HR) 2.566 [95% confidence interval (CI) 1.142 ~ 5.765], p = 0.022), synchronous T1 BCa (HR 4.283 [95%CI 1.595 ~ 11.498], p = 0.004), prior history of kidney transplantation (HR 9.633 [95%CI 2.918 ~ 31.801], p < 0.001) and CIS variant (HR 4.147 [95%CI 1.286 ~ 13.368], p = 0.017) were independent predictors of late recurrence (Fig. 2 C and Table 2 ). We divided 1028 patients into three groups: low-risk (zero risk factors), meddle-risk (1 risk factor) and high-risk (≥ 2 risk factors). Statistically significant differences in tumor recurrence were observed among these three groups (Fig. 2 D, p < 0.001). Notably, half of the patients in the high-risk group experienced a late bladder recurrence after 5-year recurrence-free period. Interestingly, the two-thirds patients who underwent renal transplantationation had a history of aristolochic acid nephropathy ( Table S1 ). Table 2 Risk factor for late recurrence Univariable analysis Multivariable analysis Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Sex (referent: female) 0.890(0.528 ~ 1.502) 0.663 Age, years (continuous) 0.991(0.967 ~ 1.015) 0.455 Smoking (referent: no smoking) 0.881(0.417 ~ 1.860) 0.739 Prior history of NMIBCa (referent: no prior history) 3.517(1.664 ~ 7.435) 0.001 2.566(1.142 ~ 5.765) 0.022 Concurrent NMIBCa(referent: no concurrent) 2.435(0.971 ~ 6.102) 0.058 tumor stage of concurrent NMIBCa (referent: Ta or no concurrent BCa) 5.326(2.121 ~ 13.373) < 0.001 4.283(1.595 ~ 11.498) 0.004 Grade of concurrent NMIBCa (referent: G1 or no concurrent BCa) 3.031(1.209 ~ 7.594) 0.018 Architecture of concurrent NMIBCa (referent: pappilary or no concurrent BCa) 6.333(1.542 ~ 26.008) 0.010 Prior renal transplantation (referent: no) 10.342(3.196 ~ 33.463) < 0.001 9.633(2.918 ~ 31.801) < 0.001 Hydronephrosis (referent: no) 1.232(0.731 ~ 2.077) 0.433 CKD (referent: CKD1 ~ 2) 1.344(0.798 ~ 2.264) 0.266 Prior ureteroscopy (referent: no) 1.634(0.700 ~ 3.814) 0.256 Pelvis Referent Ureter 0.871(0.304 ~ 2.498) 0.797 Pelvis + ureter 1.247(0.436 ~ 3.566) 0.680 Diameter, cm (continuous) 0.845(0.706 ~ 1.011) 0.065 Multifocal upper-tract tumour(referent: focal) 1.030(0.521 ~ 2.039) 0.932 Grade 1 Referent Grade 2 1.417(0.330 ~ 6.089) 0.639 Grade 3 1.037(0.594 ~ 1.808) 0.899 Tumor stage (referent: Ta&T1) 1.616(0.948 ~ 2.757) 0.078 N status(referent: negative) 0.048(0.000 ~ 64.773) 0.408 Architecture(referent: pappilary) 1.777(0.937 ~ 3.369) 0.078 Lymphovascular Invasion (referent: absent) 1.103(0.500 ~ 2.434) 0.808 Carcinoma In Situ (referent: absent) 3.554(1.110 ~ 11.377) 0.033 4.147(1.286 ~ 13.368) 0.017 Squamous differentiation (referent: absent) 0.392(0.095 ~ 1.606) 0.193 Adenoid differentiation (referent: absent) 0.680(0.166 ~ 2.790) 0.593 Sarcomatoid differentiation (referent: absent) 0.680(0.166 ~ 2.790) 0.593 Necrosis (referent: absent) 0.959(0.454 ~ 2.026) 0.913 CKD: Chronic kidney disease; NMIBCa: non-muscle invasive bladder cancer Discussion In this study, we present the late outcomes of one of the largest single-center series of patients who underwent RNU. In our population, the 10- and 15-year bladder recurrence rates were 7.1% and 14.5%, respectively, after a 5-year bladder recurrence-free period. Comparing late recurrence between studies is difficult due to a lack of long-term follow-up data and differences in study design. Our results are lower than those reported in previous studies of NMIBCa patients treated with TURBT[5-7]. The 10- and 15-year recurrence-free survival rates after a 5-year recurrence-free period were 64.2%~91.3% and 59.6%~86%, respectively. Our analysis revealed that a prior history of NMIBCa, a noted predictive risk factor, was significantly associated with late recurrence. This result aligned with previous papers investigating late recurrence in NMIBCa patients after TURBT, which revealed a prior history of BCa was a significant factor for late bladder recurrence[6, 7]. In addition, concurrent high-risk BCa and CIS are acknowledged risk factors for disease recurrence and tumor progression within a short-term follow-up period, and they were also found to be risk factors for late recurrence[8]. Furthermore, renal transplantation has been reported to be a strong predictor of bladder recurrence by S Medani et al[9]. Long-term immunosuppressive drug intake after kidney transplantation may impair the ability of DNA damage repair and the decreased barrier function to resist viral invasion is an important cause of postoperative bladder recurrence[10]. Although aristolochic acid exposure could increase the incidence of bladder recurrence[11], but we were unable to review its impact due to the retrospective nature of our study. Nevertheless, our study demonstrated that well-known risk factors such as mutifocal upper tract tumors and a history of diagnostic ureteroscopic biopsy were not significant predictors for late recurrence. Consistent with our findings, Matsumoto et al. also demonstrated that the American Urological Association risk classification system, which includes information on multifocal tumors and ureteroscopic biopsy was not significantly related to late recurrence[7]. These results were as expected since most risk classification systems were validated using cohorts with a relatively short-term follow-up period. The current risk system is useful for predicting early recurrence; however, it may not be suitable for predicting late recurrence. Further research is needed on how best to follow UTUC patients after surgery in a clinically relevant manner, and the intravesical recurrence risks found in this study may be a positive indication for postoperative cancer surveillance. The seeding hypothesis is an explanation for bladder recurrence, which suggests that recurrent tumor originate from the primary tumor mutant clone. However, the late bladder recurrence seems more likely to be caused by persistent exposure to carcinogens in bladder tissue, which is called the field defect hypothesis. The reason for late bladder recurrence may be correlate with the latter theory. Our analysis revealed that a history of bladder cancer and synchronous bladder cancer are high-risk factors for late bladder recurrence. Li et al[12] reported that mutational signatures similar to tumor clonal differentiation were also found in tissues with pathologically normal lesions around bladder cancer, implying that the field defect theory is a potential pathogenic mechanism for intravesical recurrence in UTUC patients with a history of bladder cancer and synchronous bladder cancer. In addition, we found that smoking history was not associated with late bladder recurrence, and we failed to collect a detailed family history related to germline mutations or exposure to other carcinogens, such as aristolochic acid and other occupational exposures, which may also be associated with late recurrence; thus, further large-scale epidemiological studies are needed. This study has several limitations. Given its retrospective design and long-term observation period, certain crucial clinical information, including the intravesical instillation protocol, was unavailable for the final analysis. Moreover, our study did not include patients who underwent recent evidence-based treatments such as maintenance BCG therapy or immediate intravesical instillation. Conclusion In conclusion, our study is the first to demonstrate that the late recurrence after a prolonged intravesical tumor-free period is not uncommon and can not be fully predicted by the current risk stratification system. A prior history of NMIBCa, synchronous T1 BCa and CIS remain significant high-risk factors for late recurrence. Additionally, a previous kidney transplantation also serves as an independent predictor for late bladder recurrence. Consequently, patients with these risk factors require more extensive cystoscopy follow-up for 5 to 10 years after RNU to ensure effective surveillance and timely management of potential recurrences. Declarations Conflicts of interest: The authors have nothing to disclose. Ethics statement All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Peking University First Hospital Ethics Committee. Author Contribution B.G.: data analysis, figure and table preparationand manuscript writing.G.W.: data collection. Q.Y: data collection. H.R.: data collection . H.Z.: data collection . C.C.: data collection.K.L.: data collection.Z.L.: data collection.L. Z.: project development, and manuscript revision .X.L.: project development, and manuscript revision. Acknowledgments: This work was supported by Research Seed Fund Project of Peking University First Hospital (2023SF01). Data Availability Data is provided within the manuscript or supplementary information files References Roupret M, Seisen T, Birtle AJ et al (2023) Jul European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update. Eur Urol. : 84:49–64 Seisen T, Granger B, Colin P et al (2015) A Systematic Review and Meta-analysis of Clinicopathologic Factors Linked to Intravesical Recurrence After Radical Nephroureterectomy to Treat Upper Tract Urothelial Carcinoma. Eur Urol Jun:67:1122–1133 Sharma V, Miest TS, Juvet TS et al (2021) Sep The Impact of Upper Tract Urothelial Carcinoma Diagnostic Modality on Intravesical Recurrence after Radical Nephroureterectomy: A Single Institution Series and Updated Meta-Analysis. J Urol. : 206:558 – 67 Coleman JA, Clark PE, Bixler BR et al (2023) Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline. J Urol Jun:209:1071–1081 Golabek T, Palou J, Rodriguez O, Gaya JM, Breda A, Villavicencio H (2017) Feb Is it possible to stop follow-up of patients with primary T1G3 urothelial carcinoma of the bladder managed with intravesical bacille Calmette-Guerin immunotherapy? World J Urol. : 35:237 – 43 Holmang S, Strock V (2012) Should follow-up cystoscopy in bacillus Calmette-Guerin-treated patients continue after five tumour-free years? Eur Urol Mar:61:503–507 Matsumoto K, Kikuchi E, Horiguchi Y et al (2010) Late recurrence and progression in non-muscle-invasive bladder cancers after 5-year tumor-free periods. Urology Jun:75:1385–1390 Otto W, Shariat SF, Fritsche HM et al (2011) Aug Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients. World J Urol. : 29:487 – 94 Medani S, O'Kelly P, O'Brien KM, Mohan P, Magee C, Conlon P (2014) Dec Bladder cancer in renal allograft recipients: risk factors and outcomes. Transplant Proc. : 46:3466-73 Liu Y, Lu J, Hong K, Huang Y, Ma L (2014) Feb Independent prognostic factors for initial intravesical recurrence after laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma. Urol Oncol. : 32:146 – 52 Zhong W, Zhang L, Ma J et al (2017) Impact of aristolochic acid exposure on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. Onco Targets Ther 10:5775–5782 Li R, Du Y, Chen Z et al Macroscopic somatic clonal expansion in morphologically normal human urothelium. Sci 2020 Oct 2: 37082–37089 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4587966","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":325410717,"identity":"de7ad0f3-3de5-4658-8fec-f0660b8f3208","order_by":0,"name":"Bao 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23:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4587966/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4587966/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60614663,"identity":"d24f029e-cf34-4e85-8870-92628f9060ff","added_by":"auto","created_at":"2024-07-18 20:04:19","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1610047,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of patient inclusion\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4587966/v1/edd0aa0e29cf59f9d0f30f58.jpg"},{"id":60614664,"identity":"7c0c7c81-1d21-4a91-a8a8-0e9a892e3c84","added_by":"auto","created_at":"2024-07-18 20:04:19","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1238217,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Kaplan-Meier estimates of oncological outcomes for 1028 patients with non-metastatic upper-tract urothelial carcinoma treated with radical nephroureterectomy after a 5-year recurrence-free period. (B) The estimated hazard of late recurrence using the kernel function method. The time point 0 was the date of radical nephroureterectomy. (C) Forest plots showing the hazard ratios associated with clinical information in multivariate Cox proportional hazard models for late bladder recurrence. (D) Kaplan-Meier plot shown late bladder recurrence-free survival after surgery stratified according to the presence of high-risk disease (≥2 risk factors) and middle-risk disease (1 risk factor) versus low-risk disease (zero risk factor).\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4587966/v1/a99dd67f6bf079e482c7fc66.jpg"},{"id":62930162,"identity":"490a17ae-3213-4971-9adb-76f1058b8d79","added_by":"auto","created_at":"2024-08-21 07:38:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3388683,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4587966/v1/37b1f7c5-3933-4205-9bed-5acbdac3ee51.pdf"},{"id":60614662,"identity":"f15880ff-c185-47ec-9c51-ae818d032478","added_by":"auto","created_at":"2024-07-18 20:04:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14612,"visible":true,"origin":"","legend":"","description":"","filename":"tableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4587966/v1/e4f2311ffb70daab89e4f722.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Should follow-up cystoscopy be performed in upper-tract urothelial carcinoma patients managed with radical nephroureterectomy after a five-year bladder tumor-free period?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eUpper-tract urothelial carcinoma (UTUC) accounts for approximately 5%~10% of all urothelial cancers, and radical nephroureterectomy (RNU) combined with bladder cuff excision is the \u0026lsquo;gold standard\u0026rsquo; treatment for high-risk UTUC patients[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. After RNU, approximately 22%~47% of patients experience bladder recurrence[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Previous studies demonstrated that the peak period for intravesical recurrence typically falls within the first two years, emphasizing the crucial need for frequent cystoscopy follow-up to detect early recurrence[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Factors such as male gender, previous and synchronous bladder cancer (BCa), ureteroscopy, renal dysfunction, and tumor stage and grade are significantly related to increased bladder recurrence[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. While these risk variables have been addressed in previous studies, there remains a gap in knowledge regarding the characteristics of bladder lesions that may emerge after a 5-year bladder recurrence-free period. In fact, these findings are primarily based on studies with relatively short-term follow-up durations[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Current guidelines also lack specific recommendation on the follow-up plan on late recurrence[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. It is suggested that the intensity of follow-up can be appropriately reduced after a 4-year recurrence-free period, and that personalized follow-up plan can be made jointly by doctors and patients. In the face of such a paucity of data, we focused on the patients with UTUC who remained intravesical recurrence-free for more than 5 years and evaluated the risk of late bladder recurrence. In addition, we tried to elucidate the risk factors for the late recurrence in this very long-term follow-up study.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cp\u003eWe relied on a retrospectively maintained database including 2456 consecutive non-metastatic UTUC patients treated with RNU from 1999 to 2018 at our high-volume medical center. Patients were excluded based on the following criteria: lost to follow-up (n\u0026thinsp;=\u0026thinsp;267), prior contralateral or bilateral UTUC (n\u0026thinsp;=\u0026thinsp;34), prior\u0026thinsp;\u0026ge;\u0026thinsp;T2 BCa or radical cystectomy (n\u0026thinsp;=\u0026thinsp;4), synchronous\u0026thinsp;\u0026ge;\u0026thinsp;T2 BCa or radical cystectomy (n\u0026thinsp;=\u0026thinsp;37), unclear clinical pathological information (n\u0026thinsp;=\u0026thinsp;45), death within 5 years after RNU (n\u0026thinsp;=\u0026thinsp;578) or bladder recurrence within 5 years after RNU (n\u0026thinsp;=\u0026thinsp;463). The remaining 1028 patients with a 5-year bladder recurrence-free period were included in the final analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The primary endpoint was the time to tumor recurrence. Recurrence was defined as a pathologically confirmed tumor appearing in the bladder after RNU. Surveillance frequency, programs, and indications for intravesical therapy after RNU were based on EAU instructions and urologist\u0026rsquo;s discretion. This study was approved by our institutional ethics committee.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe chose variables that showed P values less than 0.05 in the univariate analyses as candidates for the multivariate model. Smoothed hazard analysis was applied to estimate the hazard of recurrence using a kernel function method. All analyses were conducted using SPSS version 20.0 (SPSS, Chicago, IL).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe median follow-up duration was 96 (IQR: 76\u0026ndash;126) months, during which 57 (5.5%) patients experienced late bladder relapse after a 5-year bladder recurrence-free period. The peak incidence of bladder recurrence was 70\u0026thinsp;~\u0026thinsp;90 months, and the recurrence over 10 years was not unusual. The Kaplan-Meier estimated risk for recurrence was 7.1% at 10 year and 14.5% at 15 year, respectively (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA\u0026amp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB). Tate recurrence was significantly related to male gender, prior non-muscle invasive BCa (NMIBCa), synchronous NMIBCa, hydronephrosis and a history of ureteroscopy (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Conversely, there was no significant difference in late bladder recurrence between gender, age, ureteroscopy, hydronephrosis, multiple upper tract tumors, upper tract tumor architecture, tumor grade and stage.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatients clinicopathologic data.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWithout late recurrence(%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWith late recurrence(%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e971(94.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57(5.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (IQR), years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (61\u0026thinsp;~\u0026thinsp;74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (58\u0026thinsp;~\u0026thinsp;72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.168\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e436(42.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e411(42.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25(43.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.820\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e143(13.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135(13.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(14.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.978\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior history of NMIBCa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46(4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38(3.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(14.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConcurrent NMIBCa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47(4.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42(4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5(8.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.118\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eT1 (concurrent NMIBCa)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30(2.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25(2.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5(8.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eGrade 2\u0026amp;3 (concurrent NMIBCa)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36(3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31(3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5(8.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eSessile (concurrent NMIBCa)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6(0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCKD1\u0026thinsp;~\u0026thinsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e572(55.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e544(56.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28(49.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCKD3\u0026thinsp;~\u0026thinsp;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e454(44.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e425(43.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29(50.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior renal transplantation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24(2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20(2.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4(7.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydronephrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e447(43.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e421(43.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26(45.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.738\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior ureteroscopy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75(7.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69(7.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6(10.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.298\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePelvis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e522(50.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e496(51.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26(45.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.680\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUreter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e430(41.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e403(41.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27(47.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePelvis\u0026thinsp;+\u0026thinsp;ureter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76(7.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72(7.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4(7.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumour characteristics, no. patients (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiameter, cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (2\u0026thinsp;~\u0026thinsp;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (2\u0026thinsp;~\u0026thinsp;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.5(2\u0026thinsp;~\u0026thinsp;3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultifocal upper tract tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e172(16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e162(16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(17.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.866\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21(2.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19(2.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.717\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e651(63.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e615(63.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36(63.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e356(34.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e337(34.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19(33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTa\u0026amp;T1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e528(51.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e506(52.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22(38.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT2,T3\u0026amp;T4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e500(48.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e465(47.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35(61.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26(2.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26(2.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.393\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVariant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSessile tumor architecture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e193(18.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e181(18.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12(21.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.650\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymphovascular Invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e117(11.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110(11.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7(12.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.826\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCarcinoma In Situ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17(1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous differentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90(8.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88(9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.149\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenoid differentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46(4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43(4.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.583\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSarcomatoid differentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52(5.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50(5.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.583\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNecrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e146(14.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e138(14.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(14.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.970\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eIQR: Interquartile Range, CKD: Chronic kidney disease; NMIBCa: non-muscle invasive bladder cancer\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eUnivariate Cox analysis revealed that a prior previous NMIBCa, synchronous high-risk NMIBCa (T1, G2\u0026amp;G3 or sessile lesion), a history of kidney transplantation and upper tract tumor with carcinoma in situ (CIS) variants were risk factors of late recurrence. Multivariate Cox hazards regression analysis further identified that prior previous NMIBCa (hazard ratio (HR) 2.566 [95% confidence interval (CI) 1.142\u0026thinsp;~\u0026thinsp;5.765], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022), synchronous T1 BCa (HR 4.283 [95%CI 1.595\u0026thinsp;~\u0026thinsp;11.498], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), prior history of kidney transplantation (HR 9.633 [95%CI 2.918\u0026thinsp;~\u0026thinsp;31.801], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and CIS variant (HR 4.147 [95%CI 1.286\u0026thinsp;~\u0026thinsp;13.368], \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.017) were independent predictors of late recurrence (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC \u003cstrong\u003eand\u003c/strong\u003e Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eWe divided 1028 patients into three groups: low-risk (zero risk factors), meddle-risk (1 risk factor) and high-risk (\u0026ge;\u0026thinsp;2 risk factors). Statistically significant differences in tumor recurrence were observed among these three groups (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eD, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Notably, half of the patients in the high-risk group experienced a late bladder recurrence after 5-year recurrence-free period. Interestingly, the two-thirds patients who underwent renal transplantationation had a history of aristolochic acid nephropathy (\u003cstrong\u003eTable \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/strong\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRisk factor for late recurrence\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUnivariable analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMultivariable analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex (referent: female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.890(0.528\u0026thinsp;~\u0026thinsp;1.502)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.663\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, years (continuous)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.991(0.967\u0026thinsp;~\u0026thinsp;1.015)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.455\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmoking (referent: no smoking)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.881(0.417\u0026thinsp;~\u0026thinsp;1.860)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.739\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior history of NMIBCa (referent: no prior history)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.517(1.664\u0026thinsp;~\u0026thinsp;7.435)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.566(1.142\u0026thinsp;~\u0026thinsp;5.765)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConcurrent NMIBCa(referent: no concurrent)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e2.435(0.971\u0026thinsp;~\u0026thinsp;6.102)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e0.058\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etumor stage of concurrent NMIBCa (referent: Ta or no concurrent BCa)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.326(2.121\u0026thinsp;~\u0026thinsp;13.373)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.283(1.595\u0026thinsp;~\u0026thinsp;11.498)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade of concurrent NMIBCa (referent: G1 or no concurrent BCa)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.031(1.209\u0026thinsp;~\u0026thinsp;7.594)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.018\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArchitecture of concurrent NMIBCa (referent: pappilary or no concurrent BCa)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.333(1.542\u0026thinsp;~\u0026thinsp;26.008)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.010\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior renal transplantation (referent: no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.342(3.196\u0026thinsp;~\u0026thinsp;33.463)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.633(2.918\u0026thinsp;~\u0026thinsp;31.801)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydronephrosis (referent: no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.232(0.731\u0026thinsp;~\u0026thinsp;2.077)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.433\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCKD (referent: CKD1\u0026thinsp;~\u0026thinsp;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.344(0.798\u0026thinsp;~\u0026thinsp;2.264)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.266\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior ureteroscopy (referent: no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.634(0.700\u0026thinsp;~\u0026thinsp;3.814)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.256\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePelvis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReferent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUreter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.871(0.304\u0026thinsp;~\u0026thinsp;2.498)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.797\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePelvis\u0026thinsp;+\u0026thinsp;ureter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.247(0.436\u0026thinsp;~\u0026thinsp;3.566)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.680\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiameter, cm (continuous)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.845(0.706\u0026thinsp;~\u0026thinsp;1.011)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultifocal upper-tract tumour(referent: focal)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.030(0.521\u0026thinsp;~\u0026thinsp;2.039)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReferent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.417(0.330\u0026thinsp;~\u0026thinsp;6.089)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.639\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.037(0.594\u0026thinsp;~\u0026thinsp;1.808)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.899\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor stage (referent: Ta\u0026amp;T1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.616(0.948\u0026thinsp;~\u0026thinsp;2.757)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.078\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN status(referent: negative)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.048(0.000\u0026thinsp;~\u0026thinsp;64.773)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.408\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArchitecture(referent: pappilary)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.777(0.937\u0026thinsp;~\u0026thinsp;3.369)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.078\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymphovascular Invasion (referent: absent)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.103(0.500\u0026thinsp;~\u0026thinsp;2.434)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.808\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCarcinoma In Situ (referent: absent)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.554(1.110\u0026thinsp;~\u0026thinsp;11.377)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.147(1.286\u0026thinsp;~\u0026thinsp;13.368)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous differentiation (referent: absent)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.392(0.095\u0026thinsp;~\u0026thinsp;1.606)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.193\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenoid differentiation (referent: absent)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.680(0.166\u0026thinsp;~\u0026thinsp;2.790)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.593\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSarcomatoid differentiation (referent: absent)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.680(0.166\u0026thinsp;~\u0026thinsp;2.790)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.593\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNecrosis (referent: absent)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.959(0.454\u0026thinsp;~\u0026thinsp;2.026)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.913\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eCKD: Chronic kidney disease; NMIBCa: non-muscle invasive bladder cancer\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we present the late outcomes of one of the largest single-center series of patients who underwent RNU. In our population, the 10- and 15-year bladder recurrence rates were 7.1% and 14.5%, respectively, after a 5-year bladder recurrence-free period. Comparing late recurrence between studies is difficult due to a lack of long-term follow-up data and differences in study design. Our results are lower than those reported in previous studies of NMIBCa patients treated with TURBT[5-7]. The 10- and 15-year recurrence-free survival rates after a 5-year recurrence-free period were 64.2%~91.3% and 59.6%~86%, respectively.\u003c/p\u003e\n\u003cp\u003eOur analysis revealed that a prior history of NMIBCa, a noted predictive risk factor, was significantly associated with late recurrence. This result aligned with previous papers investigating late recurrence in NMIBCa patients after TURBT, which revealed a prior history of BCa was a significant factor for late bladder recurrence[6, 7]. In addition, concurrent high-risk BCa and CIS are acknowledged risk factors for disease recurrence and tumor progression within a short-term follow-up period, and they were also found to be risk factors for late recurrence[8]. Furthermore, renal transplantation has been reported to be a strong predictor of bladder recurrence by S Medani et al[9]. Long-term immunosuppressive drug intake after kidney transplantation may impair the ability of DNA damage repair and the decreased barrier function to resist viral invasion is an important cause of postoperative bladder recurrence[10]. Although aristolochic acid exposure could increase the incidence of bladder recurrence[11], but we were unable to review its impact due to the retrospective nature of our study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNevertheless, our study demonstrated that well-known risk factors such as mutifocal upper tract tumors and a history of diagnostic ureteroscopic biopsy were not significant predictors for late recurrence. Consistent with our findings, Matsumoto et al. also demonstrated that the American Urological Association risk classification system, which includes information on multifocal tumors and ureteroscopic biopsy was not significantly related to late recurrence[7]. These results were as expected since most risk classification systems were validated using cohorts with a relatively short-term follow-up period. The current risk system is useful for predicting early recurrence; however, it may not be suitable for predicting late recurrence. Further research is needed on how best to follow UTUC patients after surgery in a clinically relevant manner, and the intravesical recurrence risks found in this study may be a positive indication for postoperative cancer surveillance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe seeding hypothesis is an explanation for bladder recurrence, which suggests that recurrent tumor originate from the primary tumor mutant clone. However, the late bladder recurrence seems more likely to be caused by persistent exposure to carcinogens in bladder tissue, which is called the field defect hypothesis. The reason for late bladder recurrence may be correlate with the latter theory. Our analysis revealed that a history of bladder cancer and synchronous bladder cancer are high-risk factors for late bladder recurrence. Li et al[12]\u0026nbsp;reported that mutational signatures similar to tumor clonal differentiation were also found in tissues with pathologically normal lesions around bladder cancer, implying that the field defect theory is a potential pathogenic mechanism for intravesical recurrence in UTUC patients with a history of bladder cancer and synchronous bladder cancer. In addition, we found that smoking history was not associated with late bladder recurrence, and we failed to collect a detailed family history related to germline mutations or exposure to other carcinogens, such as aristolochic acid and other occupational exposures, which may also be associated with late recurrence; thus, further large-scale epidemiological studies are needed.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. Given its retrospective design and long-term observation period, certain crucial clinical information, including the intravesical instillation protocol, was unavailable for the final analysis. Moreover, our study did not include patients who underwent recent evidence-based treatments such as maintenance BCG therapy or immediate intravesical instillation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study is the first to demonstrate that the late recurrence after a prolonged intravesical tumor-free period is not uncommon and can not be fully predicted by the current risk stratification system. A prior history of NMIBCa, synchronous T1 BCa and CIS remain significant high-risk factors for late recurrence. Additionally, a previous kidney transplantation also serves as an independent predictor for late bladder recurrence. Consequently, patients with these risk factors require more extensive cystoscopy follow-up for 5 to 10 years after RNU to ensure effective surveillance and timely management of potential recurrences.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflicts of interest:\u003c/h2\u003e\n\u003cp\u003eThe authors have nothing to disclose.\u003c/p\u003e\n\u003cp\u003e \u003cstrong\u003eEthics statement\u003c/strong\u003e \u003c/p\u003e\n\u003cp\u003e All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Peking University First Hospital Ethics Committee.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eB.G.: data analysis, figure and table preparationand manuscript writing.G.W.: data collection. Q.Y: data collection. H.R.: data collection . H.Z.: data collection . C.C.: data collection.K.L.: data collection.Z.L.: data collection.L. Z.: project development, and manuscript revision .X.L.: project development, and manuscript revision.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments:\u003c/h2\u003e\n\u003cp\u003eThis work was supported by Research Seed Fund Project of Peking University First Hospital (2023SF01).\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information files\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRoupret M, Seisen T, Birtle AJ et al (2023) Jul European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update. Eur Urol. : 84:49\u0026ndash;64\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeisen T, Granger B, Colin P et al (2015) A Systematic Review and Meta-analysis of Clinicopathologic Factors Linked to Intravesical Recurrence After Radical Nephroureterectomy to Treat Upper Tract Urothelial Carcinoma. Eur Urol Jun:67:1122\u0026ndash;1133\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharma V, Miest TS, Juvet TS et al (2021) Sep The Impact of Upper Tract Urothelial Carcinoma Diagnostic Modality on Intravesical Recurrence after Radical Nephroureterectomy: A Single Institution Series and Updated Meta-Analysis. J Urol. : 206:558\u0026thinsp;\u0026ndash;\u0026thinsp;67\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColeman JA, Clark PE, Bixler BR et al (2023) Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline. J Urol Jun:209:1071\u0026ndash;1081\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGolabek T, Palou J, Rodriguez O, Gaya JM, Breda A, Villavicencio H (2017) Feb Is it possible to stop follow-up of patients with primary T1G3 urothelial carcinoma of the bladder managed with intravesical bacille Calmette-Guerin immunotherapy? World J Urol. : 35:237\u0026thinsp;\u0026ndash;\u0026thinsp;43\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolmang S, Strock V (2012) Should follow-up cystoscopy in bacillus Calmette-Guerin-treated patients continue after five tumour-free years? Eur Urol Mar:61:503\u0026ndash;507\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsumoto K, Kikuchi E, Horiguchi Y et al (2010) Late recurrence and progression in non-muscle-invasive bladder cancers after 5-year tumor-free periods. Urology Jun:75:1385\u0026ndash;1390\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOtto W, Shariat SF, Fritsche HM et al (2011) Aug Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients. World J Urol. : 29:487\u0026thinsp;\u0026ndash;\u0026thinsp;94\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMedani S, O'Kelly P, O'Brien KM, Mohan P, Magee C, Conlon P (2014) Dec Bladder cancer in renal allograft recipients: risk factors and outcomes. Transplant Proc. : 46:3466-73\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Lu J, Hong K, Huang Y, Ma L (2014) Feb Independent prognostic factors for initial intravesical recurrence after laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma. Urol Oncol. : 32:146\u0026thinsp;\u0026ndash;\u0026thinsp;52\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhong W, Zhang L, Ma J et al (2017) Impact of aristolochic acid exposure on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. Onco Targets Ther 10:5775\u0026ndash;5782\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi R, Du Y, Chen Z et al Macroscopic somatic clonal expansion in morphologically normal human urothelium. Sci 2020 Oct 2: 37082\u0026ndash;37089\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"upper-tract urothelial carcinoma, late bladder recurrence, risk factor","lastPublishedDoi":"10.21203/rs.3.rs-4587966/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4587966/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives: \u003c/strong\u003eThere is disagreement on the follow-up schedule after a 5-year bladder recurrence-free period in patients with upper-tract urothelial carcinoma (UTUC) after \u0026nbsp;radical nephroureterectomy (RNU). In this study, we aimed to clarify the risk factors for the late recurrence in UTUC patients who remained bladder recurrence-free for more than 5 years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Data from a large single-center Chinese institution were retrospectively reviewed. Among the patients with UTUC who were treated with RNU between 1999 and 2018, those who had no recurrence for more than 5 years were included in this study. The Kaplan–Meier method and Cox hazards model were used to estimate recurrence-free survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e In total, 1028 patients were enrolled in this study. Of these patients, 57 patients (5.5%) experienced late recurrence. The median follow-up time was 96 years (interquartile range 6.9–11.3 years). A prior history of bladder cancer (BCa) before RNU,synchronous T1 BCa, a prior history of kidney transplantation and carcinoma in situ (CIS) were significant predictors for late recurrence, although other clinical factors including tumor grade, pathologic stage and tumor multiplicity were not associated with late recurrence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Late recurrence after a prolonged intravesical tumor-free period is not uncommon and can not be fully predicted by the current risk stratification system. Patients with high-risk factors including previous and synchronous BCa, CIS variants and a previous kidney transplantation require more extensive cystoscopy follow-up for 5 to 10 years after RNU to ensure effective surveillance and timely management of potential recurrences.\u003c/p\u003e","manuscriptTitle":"Should follow-up cystoscopy be performed in upper-tract urothelial carcinoma patients managed with radical nephroureterectomy after a five-year bladder tumor-free period?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 20:04:15","doi":"10.21203/rs.3.rs-4587966/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"30a3b4a7-2a0b-4b11-8ecb-a045cb8b7b4b","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-21T07:30:41+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-18 20:04:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4587966","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4587966","identity":"rs-4587966","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}
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