The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells. An ...increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma (RCC), but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete.Here we present a molecular profiling of the KEAP1 and NFE2L2 genes in five different Renal Cell Carcinoma histotypes by analysing 89 tumor/normal paired tissues (clear cell Renal Carcinoma, ccRCCs; Oncocytomas; Papillary Renal Cell Carcinoma Type 1, PRCC1; Papillary Renal Cell Carcinoma Type 2, PRCC2; and Chromophobe Cell Carcinoma).A tumor-specific DNA methylation of the KEAP1 gene promoter region was found as a specific feature of the ccRCC subtype (18/37, 48.6%) and a direct correlation with mRNA levels was confirmed by in vitro 5-azacytidine treatment. Analysis of an independent data set of 481 ccRCC and 265 PRCC tumors corroborates our results and multivariate analysis reveals a significant correlation among ccRCCs epigenetic KEAP1 silencing and staging, grading and overall survival.Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.
Urine analysis via an electronic nose provides volatile organic compounds easily usable in the diagnosis of urological diseases. Although challenging and highly expensive for health systems ...worldwide, no useful markers are available in clinical practice that aim to anticipate prostate cancer (PCa) diagnosis in the early stages in the context of wide population screening. Some previous works suggested that dogs trained to smell urine could recognize several types of cancers with various success rates. We hypothesized that urinary volatilome profiling may distinguish PCa patients from healthy controls. In this study, 272 individuals, 133 patients, and 139 healthy controls participated. Urine samples were collected, stabilized at 37 °C, and analyzed using a commercially available electronic nose (Cyranose C320). Statistical analysis of the sensor responses was performed off-line using principal component (PCA) analyses, discriminant analysis (CDA), and ROC curves. Principal components best discriminating groups were identified with univariable ANOVA analysis. groups were identified with univariable ANOVA analysis. Here, 110/133 and 123/139 cases were correctly identified in the PCa and healthy control cohorts, respectively (sensitivity 82.7%, specificity 88.5%; positive predictive value 87.3%, negative predictive value 84.2%). The Cross Validated Accuracy (CVA 85.3%, p < 0.001) was calculated. Using ROC analysis, the area under the curve was 0.9. Urine volatilome profiling via an electronic nose seems a promising non-invasive diagnostic tool.
Objectives
To assess the accuracy of Koelis fusion biopsy for the detection of prostate cancer and clinically significant prostate cancer in the everyday practice.
Methods
We retrospectively enrolled ...2115 patients from 15 institutions in four European countries undergoing transrectal Koelis fusion biopsy from 2010 to 2017. A variable number of target (usually 2–4) and random cores (usually 10–14) were carried out, depending on the clinical case and institution habits. The overall and clinically significant prostate cancer detection rates were assessed, evaluating the diagnostic role of additional random biopsies. The cancer detection rate was correlated to multiparametric magnetic resonance imaging features and clinical variables.
Results
The mean number of targeted and random cores taken were 3.9 (standard deviation 2.1) and 10.5 (standard deviation 5.0), respectively. The cancer detection rate of Koelis biopsies was 58% for all cancers and 43% for clinically significant prostate cancer. The performance of additional, random cores improved the cancer detection rate of 13% for all cancers (P < 0.001) and 9% for clinically significant prostate cancer (P < 0.001). Prostate cancer was detected in 31%, 66% and 89% of patients with lesions scored as Prostate Imaging Reporting and Data System 3, 4 and 5, respectively. Clinical stage and Prostate Imaging Reporting and Data System score were predictors of prostate cancer detection in multivariate analyses. Prostate‐specific antigen was associated with prostate cancer detection only for clinically significant prostate cancer.
Conclusions
Koelis fusion biopsy offers a good cancer detection rate, which is increased in patients with a high Prostate Imaging Reporting and Data System score and clinical stage. The performance of additional, random cores seems unavoidable for correct sampling. In our experience, the Prostate Imaging Reporting and Data System score and clinical stage are predictors of prostate cancer and clinically significant prostate cancer detection; prostate‐specific antigen is associated only with clinically significant prostate cancer detection, and a higher number of biopsy cores are not associated with a higher cancer detection rate.
To compare outcomes of sutureless (SL) vs. renorrhaphy (RR) off-clamp robotic partial nephrectomy (ocRPN), we retrospectively analyzed procedures performed at our center, from January 2017 to April ...2021, for cT1-2N0M0 renal masses. All the patients with a minimum follow-up < 1 month were excluded from the analysis. The trifecta rate defined surgical quality. Any worsening from chronic kidney disease (CKD) I-II to ≧ IIIa (from IIIa to ≧ IIIb, and from IIIb to ≧ IV) was considered as significant stage migration (sCKDsm). A 1:1 propensity score-matched (PSM) analysis minimized baseline imbalances between SL and RR cohorts in terms of age, gender, ASA score, baseline estimated glomerular filtration rate (eGFR), tumor size, and RENAL score. Logistic regression analyses identified predictors of trifecta achievement. Kaplan-Meier (KM) analysis assessed the impact of RR on significant chronic kidney disease sCKDsm-free survival (SMFS), while Cox regression analyses identified its predictors. Overall, 531 patients were included, with a median tumor size of 3.5 cm (IQR: 2.7-5); 70 (13%) presented with a cT2 mass. An SL approach was pursued in 180 cases, but 10 needed conversion to RR. After PSM analysis, patients receiving SL showed a higher trifecta rate (94% vs. 84%;
= 0.007). SMFS probabilities were comparable at KM analysis (log-rank = 0.69). Age (OR: 0.97; 95%CI: 0.95-0.99;
= 0.01), a RENAL score ≧ 10 (OR: 0.29; 95%CI: 0.15-0.57;
< 0.001), and RR (OR: 0.34; 95%CI: 0.17-0.67;
= 0.002) were independent predictors of trifecta achievement. Age (OR: 1.04; 95%CI: 1.003-1.07;
= 0.03) and baseline eGFR (OR: 0.99; 95%CI: 0.97-0.99;
= 0.05) independently predicted sCKDsm. Compared to RR, our experience seems to show that the SL approach significantly increased the probabilities of achieving the trifecta in the observed group of cases.
To evaluate the differences between the old and the new Gleason score classification systems in upgrading and downgrading rates.
Between 2012 and 2015, we identified 9703 patients treated with ...retropubic radical prostatectomy (RP) in four tertiary centers. Biopsy specimens as well as radical prostatectomy specimens were graded according to both 2005 Gleason and 2014 ISUP five-tier Gleason grading system (five-tier GG system). Upgrading and downgrading rates on radical prostatectomy were first recorded for both classifications and then compared. The accuracy of the biopsy for each histological classification was determined by using the kappa coefficient of agreement and by assessing sensitivity, specificity, positive and negative predictive value.
The five-tier GG system presented a lower clinically significant upgrading rate (1895/9703: 19,5% vs 2332/9703:24.0%; p = .001) and a similar clinically significant downgrading rate (756/9703: 7,7% vs 779/9703: 8%; p = .267) when compared to the 2005 ISUP classification. When evaluating their accuracy, the new five-tier GG system presented a better specificity (91% vs 83%) and a better negative predictive value (78% vs 60%). The kappa-statistics measures of agreement between needle biopsy and radical prostatectomy specimens were poor and good respectively for the five-tier GG system and for the 2005 Gleason score (k = 0.360 ± 0.007 vs k = 0.426 ± 0.007).
The new Epstein classification significantly reduces upgrading events. The implementation of this new classification could better define prostate cancer aggressiveness with important clinical implications, particularly in prostate cancer management.
Abstract
Extracellular vesicles (EVs) and their cargo represent an intriguing source of cancer biomarkers for developing robust and sensitive molecular tests by liquid biopsy. Prostate cancer (PCa) ...is still one of the most frequent and deadly tumor in men and analysis of EVs from biological fluids of PCa patients has proven the feasibility and the unprecedented potential of such an approach. Here, we exploited an antibody-based proteomic technology, i.e. the Reverse-Phase Protein microArrays (RPPA), to measure key antigens and activated signaling in EVs isolated from sera of PCa patients. Notably, we found tumor-specific protein profiles associated with clinical settings as well as candidate markers for EV-based tumor diagnosis. Among others, PD-L1, ERG, Integrin-β5, Survivin, TGF-β, phosphorylated-TSC2 as well as partners of the MAP-kinase and mTOR pathways emerged as differentially expressed endpoints in tumor-derived EVs. In addition, the retrospective analysis of EVs from a 15-year follow-up cohort generated a protein signature with prognostic significance. Our results confirm that serum-derived EV cargo may be exploited to improve the current diagnostic procedures while providing potential prognostic and predictive information. The approach proposed here has been already applied to tumor entities other than PCa, thus proving its value in translational medicine and paving the way to innovative, clinically meaningful tools.
Few data are available on survival outcomes of partial nephrectomy performed for cystic renal tumors. We present the first long-term oncological outcomes of cystic (cystRCC) versus pure clear cell ...renal cell carcinoma (ccRCC) in a propensity score-matched (PSM) analysis. Our “renal cancer” prospectively maintained database was queried for “cystRCC” or “ccRCC” and “off-clamp robotic partial nephrectomy” (off-C RPN). The two groups were compared for age, gender, tumor size, pT stage, and Fuhrman grade. A 1:3 PSM analysis was applied to reduce covariate imbalance to <10% and two homogeneous populations were generated. Student t- and Chi-square tests were used for continuous and categorical variables, respectively. Ten-year oncological outcomes were compared between the two cohorts using log-rank test. Univariable Cox regression analysis was used to identify predictors of disease progression after RPN. Out of 859 off-C RPNs included, 85 cases were cystRCC and 774 were ccRCC at histologic evaluation. After applying the PSM analysis, two cohorts were selected, including 64 cystRCC and 170 ccRCC. Comparable 10-year cancer-specific survival probability (95.3% versus 100%, p = 0.146) was found between the two cohorts. Conversely, 10-year disease-free survival probability (DFS) was less favorable for pure ccRCC than cystRCC (66.69% versus 90.1%, p = 0.035). At univariable regression analysis, ccRCC histology was the only independent predictor of DFS probability (HR 2.96 95% CI 1.03–8.47, p = 0.044). At the 10-year evaluation, cystRCC showed favorable oncological outcomes after off-C RPN. Pure clear cell variant histology displayed a higher rate of disease recurrence than cystic lesions.
Renal cell carcinoma (RCC) represents around 3% of all cancers, within which clear cell RCC (ccRCC) are the most common type (70–75%). The RCC disease regularly progresses asymptomatically and upon ...presentation is recurrently metastatic, therefore, an early method of detection is necessary. The identification of one or more specific biomarkers measurable in biofluids (i.e., urine) by combined approaches could surely be appropriate for this kind of cancer, especially due to easy obtainability by noninvasive method. OLR1 is a metabolic gene that encodes for the Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), implicated in inflammation, atherosclerosis, ROS, and metabolic disorder-associated carcinogenesis. Specifically, LOX-1 is clearly involved in tumor insurgence and progression of different human cancers. This work reports for the first time the presence of LOX-1 protein in ccRCC urine and its peculiar distribution in tumoral tissues. The urine samples headspace has also been analyzed for the presence of the volatile compounds (VOCs) by SPME-GC/MS and gas sensor array. In particular, it was found by GC/MS analysis that 2-Cyclohexen-1-one,3-methyl-6-(1-methylethyl)- correlates with LOX-1 concentration in urine. The combined approach of VOCs analysis and protein quantification could lead to promising results in terms of diagnostic and prognostic potential for ccRCC tumors.
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