Julia Oto1, Álvaro Fernández-Pardo1, Marta Roca2, Emma Plana1,3, Fernando Cana1, Raquel Herranz1, Javier Pérez-Ardavín4, César David Vera-Donoso4, Manuel Martínez-Sarmiento4, Pilar Medina5,6. 1. Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe, Av. Fernando Abril Martorell 106, 46026, Valencia, Spain. 2. Analytical Unit Platform, Medical Research Institute Hospital La Fe, Valencia, Spain. 3. Angiology and Vascular Surgery Service, La Fe University and Polytechnic Hospital, Av. Fernando Abril Martorell 106, 46026, Valencia, Spain. 4. Urology Service, La Fe University and Polytechnic Hospital, Av. Fernando Abril Martorell 106, 46026, Valencia, Spain. 5. Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe, Av. Fernando Abril Martorell 106, 46026, Valencia, Spain. medina_pil@gva.es. 6. IIS La Fe-Hospital Universitario y Politécnico La Fe, Torre A, 5ª Planta, Lab. 5-09, Av. Fernando Abril Martorell 106, 46026, Valencia, Spain. medina_pil@gva.es.
Abstract
PURPOSE: Bladder cancer (BC) is among the most frequent malignancies worldwide. Novel non-invasive markers are needed to diagnose and stage BC with more accuracy than invasive procedures like cystoscopy. To date, no study has identified urine metabolites characteristic of all BC stages. To discover novel urine metabolomic profiles to diagnose and stage non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) patients using mass spectrometry-based metabolomics. METHODS: We prospectively recruited 198 BC patients and 98 age- and sex-matched healthy volunteers without evidence of renal or bladder condition confirmed by ultrasound, from whom we collected a first morning urine sample (before surgery in patients). In a discovery stage, an untargeted metabolomic analysis was conducted in urine samples of a selection of 64 BC patients (19 TaG1, 11 TaG3, 20 T1G3, 12 T2G3, 1 T2G2, 1 T3G3) and 20 controls to identify dysregulated metabolites. Next, after exhaustive multivariate analysis, confirmed dysregulated metabolites were validated in an independent cohort of 134 BC patients (19 TaG1, 62 TaG2, 9 TaG3, 15 T1G2, 16 T1G3, 4 T2G2, 9 T2G3) and 78 controls. RESULTS: We validated p-cresol glucuronide as potential diagnostic biomarker for BC patients compared to controls (AUC = 0.79). For NMIBC, p-cresol glucuronide was valuable as staging biomarker (AUC = 0.803). And among NMIBCs, p-coumaric acid may be a potential specific staging biomarker for the TaG1 NMIBC; however, future validation experiments should be conducted once the precise version of the standard is commercially available. Remarkably, for MIBC we validated spermine as potential specific staging biomarker (AUC = 0.882). CONCLUSION: Ours is the first metabolomics study conducted in urine of a thoroughly characterized cohort comprising all stages of NMIBC, MIBC and healthy controls in which we identified non-invasive diagnostic and staging biomarkers. These may improve BC management, thus reducing the use of current harmful diagnostic techniques.
PURPOSE: Bladder cancer (BC) is among the most frequent malignancies worldwide. Novel non-invasive markers are needed to diagnose and stage BC with more accuracy than invasive procedures like cystoscopy. To date, no study has identified urine metabolites characteristic of all BC stages. To discover novel urine metabolomic profiles to diagnose and stage non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) patients using mass spectrometry-based metabolomics. METHODS: We prospectively recruited 198 BC patients and 98 age- and sex-matched healthy volunteers without evidence of renal or bladder condition confirmed by ultrasound, from whom we collected a first morning urine sample (before surgery in patients). In a discovery stage, an untargeted metabolomic analysis was conducted in urine samples of a selection of 64 BC patients (19 TaG1, 11 TaG3, 20 T1G3, 12 T2G3, 1 T2G2, 1 T3G3) and 20 controls to identify dysregulated metabolites. Next, after exhaustive multivariate analysis, confirmed dysregulated metabolites were validated in an independent cohort of 134 BC patients (19 TaG1, 62 TaG2, 9 TaG3, 15 T1G2, 16 T1G3, 4 T2G2, 9 T2G3) and 78 controls. RESULTS: We validated p-cresol glucuronide as potential diagnostic biomarker for BC patients compared to controls (AUC = 0.79). For NMIBC, p-cresol glucuronide was valuable as staging biomarker (AUC = 0.803). And among NMIBCs, p-coumaric acid may be a potential specific staging biomarker for the TaG1 NMIBC; however, future validation experiments should be conducted once the precise version of the standard is commercially available. Remarkably, for MIBC we validated spermine as potential specific staging biomarker (AUC = 0.882). CONCLUSION: Ours is the first metabolomics study conducted in urine of a thoroughly characterized cohort comprising all stages of NMIBC, MIBC and healthy controls in which we identified non-invasive diagnostic and staging biomarkers. These may improve BC management, thus reducing the use of current harmful diagnostic techniques.
Authors: Robert S Svatek; Brent K Hollenbeck; Sten Holmäng; Richard Lee; Simon P Kim; Arnulf Stenzl; Yair Lotan Journal: Eur Urol Date: 2014-01-21 Impact factor: 20.096
Authors: Ekaterina Laukhtina; Sung Ryul Shim; Keiichiro Mori; David D'Andrea; Francesco Soria; Pawel Rajwa; Hadi Mostafaei; Eva Compérat; Alessia Cimadamore; Marco Moschini; Jeremy Yuen-Chun Teoh; Dmitry Enikeev; Evanguelos Xylinas; Yair Lotan; Juan Palou; Paolo Gontero; Marko Babjuk; J Alfred Witjes; Ashish M Kamat; Morgan Roupret; Shahrokh F Shariat; Benjamin Pradere Journal: Eur Urol Oncol Date: 2021-11-06
Authors: Bryan M Wittmann; Steven M Stirdivant; Matthew W Mitchell; Jacob E Wulff; Jonathan E McDunn; Zhen Li; Aphrihl Dennis-Barrie; Bruce P Neri; Michael V Milburn; Yair Lotan; Robert L Wolfert Journal: PLoS One Date: 2014-12-26 Impact factor: 3.240