PURPOSE: To evaluate the prognostic value and the clinical impact of preoperative serum cholinesterase (ChoE) levels on decision-making in patients treated with radical nephroureterectomy (RNU) for clinically non-metastatic upper tract urothelial cancer (UTUC). METHODS: A retrospective review of an established multi-institutional UTUC database was performed. We evaluated preoperative ChoE as a continuous and dichotomized variable using a visual assessment of the functional form of the association of ChoE with cancer-specific survival (CSS). We used univariable and multivariable Cox regression models to establish its association with recurrence-free survival (RFS), CSS, and overall survival (OS). Discrimination was evaluated using Harrell's concordance index. Decision curve analysis (DCA) was used to assess the impact on clinical decision-making of preoperative ChoE. RESULTS: A total of 748 patients were available for analysis. Within a median follow-up of 34 months (IQR 15-64), 191 patients experienced disease recurrence, and 257 died, with 165 dying of UTUC. The optimal ChoE cutoff identified was 5.8 U/l. ChoE as continuous variable was significantly associated with RFS (p < 0.001), OS (p < 0.001), and CSS (p < 0.001) on univariable and multivariable analyses. The concordance index improved by 8%, 4.4%, and 7% for RFS, OS, and CSS, respectively. On DCA, including ChoE did not improve the net benefit of standard prognostic models. CONCLUSION: Despite its independent association with RFS, OS, and CSS, preoperative serum ChoE has no impact on clinical decision-making. In future studies, ChoE should be investigated as part of the tumor microenvironment and assessed as part of predictive and prognostic models, specifically in the setting of immune checkpoint-inhibitor therapy.

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal Canada

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Comprehensive Cancer Center Vienna General Hospital Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria

Department of Urology Hillel Yaffe Medical Center Hadera Israel

Department of Urology Jagiellonian University Cracow Poland

Department of Urology La Croix Du Sud Hospital Quint Fonsegrives France

Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Hospital Salzburg Paracelsus Medical University Salzburg Austria

Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

Department of Urology Urological Research Institute Vita Salute University San Raffaele Scientific Institute Milan Italy

Department of Urology Weill Cornell Medical College New York NY USA

Departments of Urology and Oncology The James Buchanan Brady Urological Institute Johns Hopkins University School of Medicine Baltimore MD USA

Division of Urology Department of Surgical Sciences San Giovanni Battista Hospital University of Studies of Torino Turin Italy

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

S H Ho Urology Centre Department of Surgery Prince of Wales Hospital The Chinese University of Hong Kong Hong Kong China

Sorbonne University GRC 5 Predictive Onco Uro AP HP Urology Pitie Salpetriere Hospital Paris France

Zobrazit více v PubMed

Rouprêt M, Seisen T, Birtle AJ, Capoun O, Compérat E, Dominguez-Escrig JL, et al. EAU guidelines on upper urinary tract urothelial carcinoma. Eur Urol. 2022 doi: 10.1016/j.eururo.2023.03.013. PubMed DOI

Rink M, Sjoberg D, Comploj E, Margulis V, Xylinas E, Lee RK, et al. Risk of cancer-specific mortality following recurrence after radical nephroureterectomy. Ann Surg Oncol. 2012;19(13):4337–4344. doi: 10.1245/s10434-012-2499-8. PubMed DOI PMC

Margulis V, Shariat SF, Matin SF, Kamat AM, Zigeuner R, Kikuchi E, et al. Outcomes of radical nephroureterectomy: a series from the upper tract urothelial carcinoma collaboration. Cancer. 2009;115(6):1224–1233. doi: 10.1002/cncr.24135. PubMed DOI

Mbeutcha A, Rouprêt M, Kamat AM, Karakiewicz PI, Lawrentschuk N, Novara G, et al. Prognostic factors and predictive tools for upper tract urothelial carcinoma: a systematic review. World J Urol. 2017;35(3):337–353. doi: 10.1007/s00345-016-1826-2. PubMed DOI

Mori K, Janisch F, Mostafaei H, et al. Prognostic value of preoperative blood-based biomarkers in upper tract urothelial carcinoma treated with nephroureterectomy: a systematic review and meta-analysis. Urol Oncol Semin Orig Investig. 2020;38(5):315. PubMed

Shariat SF, Lotan Y, Vickers A, Karakiewicz PI, Schmitz-Dräger BJ, Goebell PJ, et al. Statistical consideration for clinical biomarker research in bladder cancer. Urol Oncol Semin Orig Investig. 2010;28(4):389–400. PubMed PMC

Lampón N, Hermida-Cadahia EF, Riveiro A, Tutor JC. Association between butyrylcholinesterase activity and low-grade systemic inflammation. Ann Hepatol. 2012;11(3):356–363. doi: 10.1016/S1665-2681(19)30932-9. PubMed DOI

Gu SZ, Zhao XH, Ping Q, Bin LS, Pan BR. Alterations of serum cholinesterase in patients with gastric cancer. World J Gastroenterol. 2005;11(29):4604–4606. doi: 10.3748/wjg.v11.i29.4604. PubMed DOI PMC

Mitsunaga S, Kinoshita T, Hasebe T, Nakagohri T, Konishi M, Takahashi S, et al. Low serum level of cholinesterase at recurrence of pancreatic cancer is a poor prognostic factor and relates to systemic disorder and nerve plexus invasion. Pancreas. 2008;36(3):241–248. doi: 10.1097/MPA.0b013e31815b6b2b. PubMed DOI

Santarpia L, Grandone I, Contaldo F, Pasanisi F. Butyrylcholinesterase as a prognostic marker: a review of the literature. J Cachexia Sarcopenia Muscle. 2013;4(1):31–39. doi: 10.1007/s13539-012-0083-5. PubMed DOI PMC

Kimura S, Soria F, D’Andrea D, Foerster B, Abufaraj M, Vartolomei MD, et al. Prognostic value of serum cholinesterase in non-muscle-invasive bladder cancer. Clin Genitourin Cancer. 2018;16(6):e1123–e1132. doi: 10.1016/j.clgc.2018.07.002. PubMed DOI

D’Andrea D, Soria F, Abufaraj M, Gust K, Foerster B, Vartolomei MD, et al. Clinical value of cholinesterase in the prediction of biochemical recurrence after radical prostatectomy. Urol Oncol Semin Orig Investig. 2018;36(12):528.e7–528.e13. PubMed

Vartolomei MD, D’Andrea D, Chade DC, Soria F, Kimura S, Foerster B, et al. Role of serum cholinesterase in patients treated with salvage radical prostatectomy. Urol Oncol Semin Orig Investig. 2019;37(2):123–129. PubMed

Koie T, Ohyama C, Yamamoto H, Hatakeyama S, Imai A, Yoneyama T, et al. Significance of preoperative butyrylcholinesterase as an independent predictor of survival in patients with muscle-invasive bladder cancer treated with radical cystectomy. Urol Oncol Semin Orig Investig. 2014;32(6):820–825. PubMed

Vidal CJ. Expression of cholinesterases in brain and non-brain tumours. Chem Biol Interact. 2005;157–158:227–232. doi: 10.1016/j.cbi.2005.10.035. PubMed DOI

Battisti V, Bagatini MD, Maders LDK, Chiesa J, Santos KF, Gonçalves JF, et al. Cholinesterase activities and biochemical determinations in patients with prostate cancer: Influence of Gleason score, treatment and bone metastasis. Biomed Pharmacother. 2012;66(4):249–255. doi: 10.1016/j.biopha.2011.11.005. PubMed DOI

Robitzki A, Mack A, Hoppe U, Chatonnet A, Layer PG. Butyrylcholinesterase antisense transfection increases apoptosis in differentiating retinal reaggregates of the chick embryo. J Neurochem. 1998;71(4):1413–1420. doi: 10.1046/j.1471-4159.1998.71041413.x. PubMed DOI

Zhang B, Shen C, Jin J, Song Y, Zhao Z, Zhang X. Pretreatment serum pseudocholinesterase level as a novel prognostic biomarker for upper tract urothelial carcinoma. Int Urol Nephrol. 2016;48(12):1993–1999. doi: 10.1007/s11255-016-1401-1. PubMed DOI

Noro D, Koie T, Hashimoto Y, Tanaka T, Ohyama C, Tobisawa Y, et al. Significance of preoperative butyrylcholinesterase level as an independent predictor of survival in patients with upper urinary tract urothelial carcinoma treated with nephroureterectomy. Jpn J Clin Oncol. 2018;48(2):184–189. doi: 10.1093/jjco/hyx168. PubMed DOI

Remzi M, Haitel A, Margulis V, Karakiewizc P, Montorsi F, Kikuchi E, et al. Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int. 2008;103(3):307–311. doi: 10.1111/j.1464-410X.2008.08003.x. PubMed DOI

Zigeuner R, Shariat SF, Margulis V, Karakiewicz PI, Roscigno M, Weizer A, et al. Tumour necrosis is an indicator of aggressive biology in patients with urothelial carcinoma of the upper urinary tract. Eur Urol. 2010;57(4):575–581. doi: 10.1016/j.eururo.2009.11.035. PubMed DOI

Rink M, Fajkovic H, Cha EK, Gupta A, Karakiewicz PI, Chun FK, et al. Death certificates are valid for the determination of cause of death in patients with upper and lower tract urothelial carcinoma. Eur Urol. 2012;61(4):854–855. doi: 10.1016/j.eururo.2011.12.055. PubMed DOI

Schuettfort VM, D’Andrea D, Quhal F, Mostafaei H, Laukhtina E, Mori K, et al. A panel of systemic inflammatory response biomarkers for outcome prediction in patients treated with radical cystectomy for urothelial carcinoma. BJU Int. 2022;129(2):182–193. doi: 10.1111/bju.15379. PubMed DOI PMC

Pallauf M, König F, Andrea DD, Laukhtina E, Mostafaei H, Motlagh RS, et al. A systematic review and meta-analysis of prognostic nomograms after UTUC surgery. Front Oncol. 2022;12:1–12. doi: 10.3389/fonc.2022.907975. PubMed DOI PMC

Rosas-Ballina M, Tracey KJ. Cholinergic control of inflammation. J Intern Med. 2009;265(6):663–679. doi: 10.1111/j.1365-2796.2009.02098.x. PubMed DOI PMC

Hu G, Xu F, Zhong K, Wang S, Xu Q, Huang L, et al. The prognostic role of preoperative circulating neutrophil–lymphocyte ratio in primary bladder cancer patients undergoing radical cystectomy: a meta-analysis. World J Urol. 2019;37(9):1817–1825. doi: 10.1007/s00345-018-2593-z. PubMed DOI

Fornarini G, Rebuzzi SE, Banna GL, Calabrò F, Scandurra G, De Giorgi U, et al. Immune-inflammatory biomarkers as prognostic factors for immunotherapy in pretreated advanced urinary tract cancer patients: an analysis of the Italian SAUL cohort. ESMO Open. 2021;6(3):1–9. doi: 10.1016/j.esmoop.2021.100118. PubMed DOI PMC