Francesco Gatto1, Kyle A Blum2, Seyedeh Shaghayegh Hosseini1, Mazyar Ghanaat2, Mahyar Kashan2, Francesca Maccari3, Fabio Galeotti3, James J Hsieh4, Nicola Volpi3, A Ari Hakimi2, Jens Nielsen5. 1. Department of Biology and Biological Engineering, Chalmers University of Technology, Göteborg, Sweden. 2. Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3. Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. 4. Department of Medicine, Genitourinary Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 5. Department of Biology and Biological Engineering, Chalmers University of Technology, Göteborg, Sweden. Electronic address: nielsenj@chalmers.se.
Abstract
BACKGROUND: Plasma glycosaminoglycan (GAG) measurements, when aggregated into diagnostic scores, accurately distinguish metastatic clear-cell renal cell carcinoma (RCC) from healthy samples and correlate with prognosis. However, it is unknown if GAG scores can detect RCC in earlier stages or if they correlate with prognosis after surgery. OBJECTIVE: To explore the sensitivity and specificity of plasma GAGs for detection of early-stage RCC and prediction of recurrence and death after RCC surgery. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective case-control study consisting of a consecutive series of 175 RCC patients surgically treated between May 2011 and February 2014 and 19 healthy controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Plasma GAGs in preoperative and postoperative RCC and healthy samples were measured using capillary electrophoresis with laser-induced fluorescence in a single blinded laboratory. A discovery set was first analyzed to update the historical GAG score. The sensitivity of the new GAG score for RCC detection versus healthy subjects was validated using the remaining samples. The correlation of the new GAG score to histopathologic variables, overall survival, and recurrence-free survival was evaluated using nonparametric and log-rank tests and multivariable Cox regression analyses. RESULTS AND LIMITATIONS: The RCC cohort included 94 stage I, 58 stage II-III, and 22 stage IV cases. In the first discovery set (n=67), the new GAG score distinguished RCC from healthy samples with an area under the receiver operating characteristic curve (AUC) of 0.999. In the validation set (n=108), the GAG score achieved an AUC of 0.991, with 93.5% sensitivity. GAG scores were elevated in RCC compared to healthy samples, irrespective of and uncorrelated to stage, grade, histology, age, or gender. The total chondroitin sulfate concentration was an independent prognostic factor for both overall and recurrence-free survival (hazard ratios 1.51 and 1.25) with high concordance when combined with variables available at pathologic diagnosis (C-index 0.926 and 0.849) or preoperatively (C-index 0.846 and 0.736). Limitations of the study include its retrospective nature and moderate variability in GAG laboratory measurements. CONCLUSIONS: Plasma GAGs are highly sensitive diagnostic and prognostic biomarkers in surgically treated RCC independent of stage, grade, or histology. Prospective validation studies on GAG scores for early detection, prediction, and surveillance for RCC recurrence are thus warranted. PATIENT SUMMARY: In this study, we examined if a new molecular blood test can detect renal cell carcinoma in the early stages and predict if the cancer might relapse after surgery. The trial is registered on ClinicalTrial.gov as NCT03471897.
BACKGROUND: Plasma glycosaminoglycan (GAG) measurements, when aggregated into diagnostic scores, accurately distinguish metastatic clear-cell renal cell carcinoma (RCC) from healthy samples and correlate with prognosis. However, it is unknown if GAG scores can detect RCC in earlier stages or if they correlate with prognosis after surgery. OBJECTIVE: To explore the sensitivity and specificity of plasma GAGs for detection of early-stage RCC and prediction of recurrence and death after RCC surgery. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective case-control study consisting of a consecutive series of 175 RCCpatients surgically treated between May 2011 and February 2014 and 19 healthy controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Plasma GAGs in preoperative and postoperative RCC and healthy samples were measured using capillary electrophoresis with laser-induced fluorescence in a single blinded laboratory. A discovery set was first analyzed to update the historical GAG score. The sensitivity of the new GAG score for RCC detection versus healthy subjects was validated using the remaining samples. The correlation of the new GAG score to histopathologic variables, overall survival, and recurrence-free survival was evaluated using nonparametric and log-rank tests and multivariable Cox regression analyses. RESULTS AND LIMITATIONS: The RCC cohort included 94 stage I, 58 stage II-III, and 22 stage IV cases. In the first discovery set (n=67), the new GAG score distinguished RCC from healthy samples with an area under the receiver operating characteristic curve (AUC) of 0.999. In the validation set (n=108), the GAG score achieved an AUC of 0.991, with 93.5% sensitivity. GAG scores were elevated in RCC compared to healthy samples, irrespective of and uncorrelated to stage, grade, histology, age, or gender. The total chondroitin sulfate concentration was an independent prognostic factor for both overall and recurrence-free survival (hazard ratios 1.51 and 1.25) with high concordance when combined with variables available at pathologic diagnosis (C-index 0.926 and 0.849) or preoperatively (C-index 0.846 and 0.736). Limitations of the study include its retrospective nature and moderate variability in GAG laboratory measurements. CONCLUSIONS: Plasma GAGs are highly sensitive diagnostic and prognostic biomarkers in surgically treated RCC independent of stage, grade, or histology. Prospective validation studies on GAG scores for early detection, prediction, and surveillance for RCC recurrence are thus warranted. PATIENT SUMMARY: In this study, we examined if a new molecular blood test can detect renal cell carcinoma in the early stages and predict if the cancer might relapse after surgery. The trial is registered on ClinicalTrial.gov as NCT03471897.
Authors: Thomas Mandel Clausen; Gunjan Kumar; Emilie K Ibsen; Maj S Ørum-Madsen; Antonio Hurtado-Coll; Tobias Gustavsson; Mette Ø Agerbæk; Francesco Gatto; Tilman Todenhöfer; Umberto Basso; Margaret A Knowles; Marta Sanchez-Carbayo; Ali Salanti; Peter C Black; Mads Daugaard Journal: Cell Death Discov Date: 2020-07-27