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- Profiling of urinary extracellular vesicle protein signatures from patients with cribriform and intraductal prostate carcinoma in a cross-sectional studyPublication . Bernardino, R; Carvalho, AS; Hall, MJ; Alves, L; Leão, R; Sayyid, R; Pereira, H; Beck, HC; Campos-Pinheiro, L; Henrique, R; Fleshner, N; Matthiesen, RPrognostic tests and treatment approaches for optimized clinical care of prostatic neoplasms are an unmet need. Prostate cancer (PCa) and derived extracellular vesicles (EVs) proteome changes occur during initiation and progression of the disease. PCa tissue proteome has been previously characterized, but screening of tissue samples constitutes an invasive procedure. Consequently, we focused this study on liquid biopsies, such as urine samples. More specifically, urinary small extracellular vesicle and particles proteome profiles of 100 subjects were analyzed using liquid chromatography coupled to high-resolution mass spectrometry (LC-MS/MS). We identified 171 proteins that were differentially expressed between intraductal prostate cancer/cribriform (IDC/Crib) and non-IDC/non-Crib after correction for multiple testing. However, the strong correlation between IDC/Crib and Gleason Grade complicates the disentanglement of the underlying factors driving this association. Nevertheless, even after accounting for multiple testing and adjusting for ISUP (International Society of Urological Pathology) grading, two proteins continued to exhibit significant differential expression between IDC/Crib and non-IDC/non-Crib. Functional enrichment analysis based on cancer hallmark proteins disclosed a clear pattern of androgen response down-regulation in urinary EVs from IDC/Crib compared to non-IDC/non-Crib. Interestingly, proteome differences between IDC and cribriform were more subtle, suggesting high proteome heterogeneity. Overall, the urinary EV proteome reflected partly the prostate pathology.
- Integrated Expression of Circulating miR375 and miR371 to Identify Teratoma and Active Germ Cell Malignancy Components in Malignant Germ Cell TumorsPublication . Nappi, L; Thi, M; Adra, N; Hamilton, RJ; Leao, R; Lavoie, JM; Soleimani, M; Eigl, BJ; Chi, K; Gleave, M; So, A; Black, PC; Bell, R; Daneshmand, S; Cary, C; Masterson, T; Einhorn, L; Nichols, C; Kollmannsberger, CActive germ cell malignancies express high levels of specific circulating micro-RNAs (miRNAs), including miR-371a-3p (miR371), which is undetectable in teratoma. Teratoma markers are urgently needed for theselection of patients and treatments because of the risk of malignant transformation and growing teratoma syndrome. To assess the accuracy of plasma miR375 alone or in combination with miR371 in detecting teratoma, 100 germ cell tumor patients, divided into two cohorts, were enrolled in a prospective multi-institutional study. In the discovery cohort, patients with pure teratoma and with no/low risk of harboring teratoma were compared; the validation cohort included patients with confirmed teratoma, active germ cell malignancy, or complete response after chemotherapy. The area under the receiver operating characteristic curve values for miR375, miR371, and miR371-miR375 were, respectively, 0.93 (95% confidence interval [CI]: 0.87-0.99), 0.59 (95% CI: 0.44-0.73), and 0.95 (95% CI: 0.90-0.99) in the discovery cohort and 0.55 (95% CI: 0.36-0.74), 0.74 (95% CI: 0.58-0.91), and 0.77 (95% CI: 0.62-0.93) in the validation cohort. Our study demonstrated that the plasma miR371-miR375 integrated evaluation is highly accurate to detect teratoma. PATIENT SUMMARY: The evaluation of two micro-RNAs (miR375-miR371) in the blood of patients with germ cell tumors is promising to predict teratoma. This test could be particularly relevant to the identification of teratoma in patients with postchemotherapy residual disease.
- Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter StudyPublication . Batista, Rui; Vinagre, João; Prazeres, Hugo; Sampaio, Cristina; Peralta, Pedro; Conceição, Paulo; Sismeiro, Amílcar; Leão, Ricardo; Gomes, Andreia; Furriel, Frederico; Oliveira, Carlos; Torres, João Nuno; Eufrásio, Pedro; Azinhais, Paulo; Almeida, Fábio; Gonzalez, Edwin Romero; Bidovanets, Bohdan; Ecke, Thorsten; Stinjs, Pascal; Pascual, Álvaro Serrano; Abdelmalek, Rabehi; Villafruela, Ainara; Beardo-Villar, Pastora; Fidalgo, Nuno; Öztürk, Hakan; Gonzalez-Enguita, Carmen; Monzo, Juan; Lopes, Tomé; Álvarez-Maestro, Mario; Servan, Patricia Parra; De La Cruz, Santiago Moreno Perez; Perez, Mario Pual Sanchez; Máximo, Valdemar; Soares, PaulaBladder cancer (BC), the most frequent malignancy of the urinary system, is ranked the sixth most prevalent cancer worldwide. Of all newly diagnosed patients with BC, 70-75% will present disease confined to the mucosa or submucosa, the non-muscle-invasive BC (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to high rate of recurrence, patients are submitted to an intensive follow-up program maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different noninvasive assays (both based in serum and urine samples) have been developed in order to search genetic and protein alterations related to the development, progression, and recurrence of BC. TERT promoter mutations and FGFR3 hotspot mutations are the most frequent somatic alterations in BC and constitute the most reliable biomarkers for BC. Based on these, we developed an ultra-sensitive, urine-based assay called Uromonitor®, capable of detecting trace amounts of TERT promoter (c.1-124C > T and c.1-146C > T) and FGFR3 (p.R248C and p.S249C) hotspot mutations, in tumor cells exfoliated to urine samples. Cells present in urine were concentrated by the filtration of urine through filters where tumor cells are trapped and stored until analysis, presenting long-term stability. Detection of the alterations was achieved through a custom-made, robust, and highly sensitive multiplex competitive allele-specific discrimination PCR allowing clear interpretation of results. In this study, we validate a test for NMIBC recurrence detection, using for technical validation a total of 331 urine samples and 41 formalin-fixed paraffin-embedded tissues of the primary tumor and recurrence lesions from a large cluster of urology centers. In the clinical validation, we used 185 samples to assess sensitivity/specificity in the detection of NMIBC recurrence vs. cystoscopy/cytology and in a smaller cohort its potential as a primary diagnostic tool for NMIBC. Our results show this test to be highly sensitive (73.5%) and specific (93.2%) in detecting recurrence of BC in patients under surveillance of NMIBC.