Personalized management of prostate cancer: from molecular and imaging markers to radiogenomics.

PURPOSE: Prostate cancer (PCa) is the second most common cancer in men. The urge to guide treatment tactics based on personal clinical risk factors has evolved in the era of human genome sequencing. To date, personalized approaches to managing PCa patients have not yet been developed. Radiogenomics is a relatively new term, used to refer to the study of genetic variation associated with imaging features of the tumour in order to improve the prognostication of the disease course. MATERIAL AND METHODS: The study is a review of recent knowledge regarding potential clinical applications of radiogenomics in personalized treatment of PCa. RESULTS: Recent investigations have proven that by combining data on individual genetic tumour features, and radiomic profiling (radiologic-molecular correlation), with traditional staging procedures in order to personalize treatment of PCa, an improved prognostication of PCa course can be performed, and overtreatment of indolent cancer can be avoided. It was found that a combination of multiparametric MRI and gene expression data allowed the detection of radiomic features of PCa, which correlated with a number of gene signatures associated with adverse outcomes. It was revealed that several molecular markers may drive tumour upstaging, allowed the distinction between the PCa stages, and correlated with aggressiveness-related radiomic features. CONCLUSIONS: The radiogenomics of PCa is not a comprehensively investigated area of oncourology. The combination of genomics and radiomics as integrative parts of precision medicine in the future has the potential to become the foundation for a personalized approach to the management of PCa.

Local recurrence of renal cell carcinoma after partial nephrectomy: applicability of the apparent diffusion coefficient of MRI as an imaging marker - a multicentre study.

Purpose: The goal of the study was an assessment of the diagnostic performance of diffusion-weighted images (DWI) and apparent diffusion coefficient (ADC) of magnetic resonance imaging (MRI) in distinguishing local recurrence (LR) of renal cell carcinoma (RCC) from benign conditions after partial nephrectomy. Material and methods: Thirty-nine patients after partial nephrectomy for solid RCC were enrolled in the study. Patients were followed up using MRI, which included DWI sequence (b = 800 s/mm2). All patients with MRI features of LR were included in the main group (n = 14) and patients without such features - into the group of comparison (n = 25). Apparent diffusion coefficient (ADC) values of suspicious lesions were recorded. In all patients with signs of locally recurrent RCC, surgical treatment was performed followed by pathologic analysis. Results: The mean ADC values of recurrent RCC demonstrated significantly higher numbers compared to benign fibrous tissues and were 1.64 ± 0.15 × 10-3 mm2/s vs. 1.02 ± 0.26 × 10-3 mm2/s (p < 0.001). The mean ADC values of RCCs' LR and benign post-op changes in renal scar substantially differed from mean ADC values of healthy kidneys' parenchyma; the latter was 2.58 ± 0.05 × 10-3 mm2/s (p < 0.001). In ROC analysis, the use of ADC with a threshold value of 1.28 × 10-3 mm2/s allowed us to differentiate local recurrence of RCC from benign postoperative changes with 100% sensitivity, 80% specificity, and accuracy: AUC = 0.980 (p < 0.001). Conclusions: The apparent diffusion coefficient of DWI of MRI can be used as a potential imaging marker for the diagnosis of local recurrence of RCC.

METASTATIC CHORIOCARCINOMA PRESENTING AS RENAL COLIC AND SKIN LESION - CASE REPORT.

OBJECTIVE: Choriocarcinoma is a rare malignant disease that is usually associated with a gestational event. Kidney metastasis might be misdiagnosed as renal cell carcinoma or kidney abscess. To the best of our knowledge, only 13 cases of cutaneous metastasis of choriocarcinoma have been reported in the literature so far. We report a case of choriocarcinoma that manifested with multiple metastases to the lung, skin, kidney and brain. Case report: We reported a case of a 37-year-old woman with a history of hydatiform mole, with symptoms of renal colic and abnormal findings on the skin. Chest X-ray revealed visible focal change 80 mm in diameter, located in the left lung area. The CT exposed in both kidneys multiple hypodense foci, 32 mm in size, suggesting multifocal abscesses with disruptions and perforation to paranephric area. Due to the presence of and temporary loss of vision in the right eye head CT was performed revealing metastatic changes in the brain. The diferential diagnosis between renal cancer, lung carcinoma and choriocarcinoma was achieved only after surgical removal skin lesion. This was the first time in our experience with choriocarcinoma. Immunohistochemically, the analysis was positive for beta hCG, cytokeratin AE1/AE, CK 8/18, CD10, EMA, alfa 1-inhibin and negative for protein 63, CD30 and CD117. Serum hCG level was 394590,0 mIU/mL. CONCLUSION: Conclusions: Choriocarcinoma should be taken into consideration when associated symptoms and significantly elevated blood levels of ß-hCG were identified.

Value of the diffusion-weighted MRI in the differential diagnostics of malignant and benign kidney neoplasms - our clinical experience.

BACKGROUND: Diffusion-weighted imaging (DWI) is an MRI modality using strong bipolar gradients to create a sensitivity of the signal to the thermally-induced Brownian motions of water molecules and in vivo measurement of molecular diffusion. The apparent diffusion coefficient (ADC) is a quantitative parameter calculated from DWI images which is used as a measure of diffusion. DWI allows to obtain comprehensive information on morphological and functional state of the kidney during a single examination without contrast medium administration. The purpose of the study was to evaluate the value of DWI in differentiating benign and malignant solid kidney tumors based on the initial stage of the study. MATERIAL/METHODS: The study included 19 adult patients with pathologically verified renal tumors: 9 patients with clear cell subtype of the renal cell carcinoma, 5 patients with oncocytoma and 5 patients with angiomyolipoma (AML). In addition, 5 healthy volunteers with completely normal findings according to kidney ultrasound were included into this study and set as reference. All patients underwent renal MR imaging which included DWI with subsequent ADC measurement. MR imaging was performed with a 1.5 T body scanner using an eight-channel phased-array body coil. RESULTS: The mean ADC value of ccRCC was significantly lower than that of normal renal parenchyma (2.11±0.25×10(-3) mm(2)/s vs. 3.36±0.41×10(-3) mm(2)/s, p<0.01). There was a significant difference in ADC between the malignant and benign renal lesions: in patients with angiomyolipoma the ADC value was 2.36±0.32×10(-3) mm(2)/s vs. 2.11±0.25×10(-3) mm(2)/s; p<0.05 and in patients with oncocytoma - 2.75±0.27×10(-3) mm(2)/s vs. 2.11±0.25×10(-3) mm(2)/s; p<0.05. The difference in ADC values in patients with high and low ccRCC grades was observed. CONCLUSIONS: DWI can be used to characterize renal lesions; the ADC of a renal lesion can be potentially used as an additional parameter to help determine the appropriate clinical management.

The performance and limitations of PCA3, TMPRSS2:ERG, HOXC6 and DLX1 urinary markers combined in the improvement of prostate cancer diagnostics.

BACKGROUND: Prostate cancer (PCa) is the second most commonly diagnosed cancer in men. To date, the role of the combined application of long non-coding RNAs (PCA3, DLX1, HOXC6, TMPRSS2:ERG) for obtaining the most accurate method of detection of PCa has not yet been comprehensively investigated. METHODS: In total 240 persons were included in the retrospective study. Among them were 150 patients with confirmed PCa, 30 patients with benign prostatic hyperplasia, 30 patients with active chronic prostatitis and 30 healthy volunteers. In all patients, the urine samples were collected prior to biopsy or treatment. Polymerase chain reaction with reverse transcription was performed to detect the expression level of PCA3, HOXC6, DLX1 and the presence of the TMPRSS2:ERG transcript. RESULTS: PCA3 was detected in urine samples in all cases. Using a PCA3 score of 56 allowed the differentiation between PCa and all other cases with a sensitivity of 61% and specificity of 96% (p < 0.001) while a PCA3 score threshold value of 50 resulted in a differentiation between clinically significant PCa (ISUP grades 2-5) and all other cases with a sensitivity of 93% and specificity of 93% (p < 0.001). The TMPRSS2:ERG expression in urine was detected exclusively in the group of patients with PCa and only in 16% of all cases. CONCLUSIONS: PCA3 score detected in urine demonstrated moderate sensitivity and good specificity in differentiation between PCa and non-PCa and high sensitivity and specificity in differentiation between clinically significant PCa and non-PCa.

Systemic treatment of the metastatic renal cell carcinoma: usefulness of the apparent diffusion coefficient of diffusion-weighted MRI in prediction of early therapeutic response.

Accurate prediction of early treatment response to systemic therapy (ST) with tyrosine kinase inhibitors (TKI) in patients with metastatic renal cell carcinoma (mRCC) could help avoid ineffective and expensive treatment with serious side effects. Neither RECIST v.1.1 nor Choi criteria successfully discriminate between patients with mRCC who received ST having a short or long time to progression (TTP). There is no biomarker, which is able to predict early therapeutic response to TKIs application in patients with mRCC. The goal of our study was to investigate the potential of apparent diffusion coefficient (ADC) of diffusion-weighted imaging (DWI) of MRI in prediction of early therapeutic response to ST with pazopanib in patients with mRCC. The retrospective study enrolled 32 adult patients with conventional mRCC who received pazopanib (mean duration-7.5 ± 3.45). The mean duration of follow-up was 11.85 ± 4.34 months. In all patients as baseline examination and 1 month after treatment, 1.5T MRI including DWI sequence was performed followed by ADC measurement of the main renal lesion. For assessment of the therapeutic response, RECIST 1.1 is used. Partial response (PR), stable disease (SD) and progressive disease (PD) were observed in 12 (37.50%), 10 (31.25%) and 10 (31.25%) cases with mean TTP of 10.33 ± 2.06 months (95% confidence interval, CI = 9.05-11.61), 7.40 ± 2.50 months (95% CI = 5.61-9.19) and 4.20 ± 1.99 months (95% CI = 2.78-5.62) accordingly (p < 0.05). There was no difference in change of main lesions' longest size 1 month after ST in patients with PR, SD and PD. Comparison of mean ADC values before and 1 month after systemic treatment showed significant decrease by 19.11 ± 10.64% (95% CI = 12.35-25.87) and by 7.66 ± 6.72% (95% CI = 2.86-12.47) in subgroups with PR and SD, respectively (p < 0.05). There was shorter TTP in patients with mRCC if ADC of the main renal lesion 1 month after the ST increased from the baseline less than 1.73% compared to patients with ADC levels above this threshold: 5.29 ± 3.45 versus 9.50 ± 2.04 months accordingly (p < 0.001). Overall, our findings highlighted the use of ADC as a predictive biomarker for early therapeutic response assessment. Use of ADC will be effective and useful for reliable prediction of responders and non-responders to systemic treatment with pazopanib.

MicroRNA-15a tissue expression is a prognostic marker for survival in patients with clear cell renal cell carcinoma.

None of the currently investigated molecular markers demonstrated sufficient accuracy in prognostication of the renal cell carcinoma (RCC) oncologic outcomes; thus, none of them has been recommended for the application in the routine clinical practice. The role of miR-15a as a potential prognostic marker for RCC is still not unveiled. The aim of our study was to assess the expression of miR-15a in tumor tissues of the patients with RCC and to evaluate the possibility of its usage as a prognostic molecular biomarker of this disease. The retrospective included 64 adult patients with clear cell RCC (ccRCC) in whom radical or partial nephrectomy was conducted. After deparaffinization of formalin-fixed paraffin-embedded (FFPE) ccRCC specimens, the tissue expression of miR-15a was measured using the reverse transcription and quantitative polymerase chain reaction in the real time. For the reference, the expression of miR-15a was estimated in 15 FFPE tissue specimens of the normal renal parenchyma. Survival analysis involved all cases of non-metastatic RCCs (n = 57). Five-year cancer-specific survival (CSS) was estimated by means of the Kaplan-Meier method and was calculated from the date of surgery to the date of death. Patients with the RCC were characterized by significantly upregulated tumor tissue mean levels of miR-15a compared to the healthy controls: 0.10 ± 2.62 relative units (RU) versus 4.84E - 03 ± 3.11E - 03 RU (p < 0.001). Overexpression of miR-15a was strongly associated with poor histologic prognostic features of ccRCC. Poorly differentiated tumors tend to have more pronounced upregulation of miR-15a compared to highly differentiated lesions: Mean expression values were 4.57 ± 3.19 RU for Fuhrman grade 4 versus 0.02 ± 0.01 RU for Fuhrman grade 1 (p < 0.001). The metastatic involvement of the regional lymphatic nodules (N +) was associated with significantly upregulated miRNA-15a in comparison with N - cases: Mean expression values were 4.92 ± 2.80 RU versus 1.10 ± 2.29 RU, respectively (p < 0.001). In patients with miR-15a expression in RCC tissues ≤ 0.10 RU, mean 5-year CSS was significantly longer compared to patients with expression levels above this threshold: 92.31% (mean duration of survival-59.88 ± 0.12 months) versus 54.8% (mean duration of survival-49.74 ± 2.16 months), respectively (p < 0.001). The tissue expression of miR-15a could be used as a potential prognostic molecular biomarker for conventional RCC.

Potential clinical applications of microRNAs as biomarkers for renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) accounts for 3% of adult malignancies and more than 90% of kidney neoplasms. High rates of undiagnostic percutaneous kidney biopsies and difficulties in reliable pre-operative differentiation between malignant and benign renal tumors using contemporary imaging techniques result in large numbers of redundant surgeries. Absence of specific biomarkers for early detection and monitoring complicates on-time diagnosis of the disease and relapse. For the patients followed up after having a nephrectomy, a noninvasive and sensitive biomarker enabling early detection of disease relapse would be extremely useful. MATERIAL AND METHODS: The study is a review of recent knowledge regarding potential clinical applications of microRNAs (miRNAs) as biomarkers of RCC. RESULTS: MicroRNAs are essential regulators of various processes such as cell proliferation, differentiation, development and death; they have been implicated in diverse biological and pathological processes in RCC. There is a class of miRNAs that promote RCC development (oncomirs) and a class of miRNAs that negatively regulate oncogenes, suppress tumor growth and invasion, and thus could be considered treatment agents (anti-oncomirs). Separate miRNAs and specific miRNAs expression profiles have been identified, enabling early detection of the disease, prediction of response to systemic therapy, or prognostication of biological behavior of the disease. CONCLUSIONS: The miRNA network analysis and gene profiling may help to identify the most sensible molecular signatures of RCC that can be used for diagnostic purposes, as well as poor prognosis signatures and poor therapeutic response signatures in patients who undergo systemic therapy.

MicroRNA-15a expression measured in urine samples as a potential biomarker of renal cell carcinoma.

INTRODUCTION: Currently, there is no accurate diagnostic molecular biomarker for renal cell carcinoma (RCC). The aim of this study was to assess the expression of microRNA-15a (miR-15a) in urine of patients with RCC and to evaluate its potential as a diagnostic molecular biomarker. MATERIALS AND METHODS: In total, 67 patients with solid renal tumors were enrolled: clear-cell RCC (ccRCC, n = 22), papillary RCC (pRCC, n = 16), chromophobe RCC (chRCC, n = 14), oncocytoma (n = 8), papillary adenoma (n = 2) and angiomyolipoma (n = 5). MiRNA-15a expression levels measurement in urine were performed using qPCR. Urine of 15 healthy volunteers without kidney pathology was used as control. RESULTS: We observed a difference in mean miR-15a expression values in groups of pre-operative patients with RCC, benign renal tumors and healthy persons (2.50E-01 ± 2.72E-01 vs 1.32E-03 ± 3.90E-03 vs 3.36E-07 ± 1.04E-07 RFU, respectively, p < 0.01). There was no difference in miR-15a expression between ccRCC, pRCC and chRCC (p > 0.05). Direct association between RCC size and miR-15a expression values was obtained (Pearson correlation coefficient-0.873). On the 8th day after nephrectomy, mean expression value in patients with RCC decreased by 99.53% (p < 0.01). MiR-15a expression differentiated RCC from benign renal tumors with 98.1% specificity, 100% sensitivity at a cut-off value of 5.00E-06 RFU, with AUC-0.955. CONCLUSIONS: MiR-15a expression measured in urine may be used as diagnostic molecular biomarker for RCC.

Differential diagnosis of the small renal masses: role of the apparent diffusion coefficient of the diffusion-weighted MRI.

INTRODUCTION: Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and more than 90% of neoplasms arising from the kidney. Uninformative percutaneous kidney biopsies vary from 10 to 23%. As a result, 7.5-33.6% of partial nephrectomies in patients with small renal masses (SRM) are performed on benign renal tumors. The aim of this study was to assess the feasibility of the apparent diffusion coefficient (ADC) of the diffusion-weighted imaging (DWI) of MRI, as RCC imaging biomarker for differentiation of SRM. METHOD: Adult patients (n = 158) with 170 SRM were enrolled into this study. The control group were healthy volunteers with normal clinical and radiologic findings (n = 15). All participants underwent MRI with DWI sequence included. RESULTS: Mean ADC values of solid RCC (1.65 ± 0.38 × 10-3 mm2/s) were lower than healthy renal parenchyma (2.47 ± 0.12 × 10-3 mm2/s, p < 0.05). There was no difference between mean ADC values of ccRCC, pRCC and chRCC (1.82 ± 0.22 × 10-3 vs 1.61 ± 0.07 × 10-3 vs 1.46 ± 0.09 × 10-3 mm2/s, respectively, p = ns). An inverse relationship between mean ADC values and Fuhrman grade of nuclear atypia of solid ccRCCs was observed: grade I-1.92 ± 0.11 × 10-3 mm2/s, grade II-1.84 ± 0.14 × 10-3 mm2/s, grade III-1.79 ± 0.10 × 10-3 mm2/s, grade IV-1.72 ± 0.06 × 10-3 mm2/s. This was significant (p < 0.05) only between tumors of I and IV grades. Significant difference (p < 0.05) between mean ADC values of solid RCCs, benign renal tumors and renal cysts was observed (1.65 ± 0.38 × 10-3 vs 2.23 ± 0.18 × 10-3 vs 3.15 ± 0.51 × 10-3 mm2/s, respectively). In addition, there was a significant difference (p < 0.05) in mean ADC values between benign cysts and cystic RCC (3.36 ± 0.35 × 10-3 vs 2.83 ± 0.21 × 10-3 mm2/s, respectively). CONCLUSION: ADC maps with b values of 0 and 800 s/mm2 can be used as an imaging biomarker, to differentiate benign SRM from malignant SRM. Using ADC value threshold of 1.75 × 10-3 mm2/s allows to differentiate solid RCC from solid benign kidney tumors with 91% sensitivity and 89% specificity; ADC value threshold of 2.96 × 10-3 mm2/s distinguishes cystic RCC from benign renal cysts with 90% sensitivity and 88% specificity. However, the possibility of differentiation between ccRCC histologic subtypes and grades, utilizing ADC values, is limited.

Renal cell carcinoma: applicability of the apparent coefficient of the diffusion-weighted estimated by MRI for improving their differential diagnosis, histologic subtyping, and differentiation grade.

BACKGROUND: Renal cell carcinoma (RCC) represents the most common malignant epithelial neoplasm of the kidney. Accurate assessment of the renal masses, defining the histologic subtype and the grade of differentiation of the tumor, is vital to ensure an adequate case management as well as for staging and prognosis. Recently, diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) tends to be increasingly appealing for the clinicians as an imaging procedure of choice for the diagnosis and staging of the RCC, which is predetermined by several advantages over CT. The goal of the survey was to assess the applicability of the apparent diffusion coefficient (ADC) of the DWI MRI for the differential diagnostics, histologic subtyping, and defining the grade of differentiation of the RCC. METHODS: The study enrolled 288 adult patients with renal lesions: 188 patients with solid RCC-126 patients with clear cell subtype (ccRCC), 32 patients with papillary RCC (pRCC), 30 patients with chromophobe RCC (chRCC); 27 patient with cystic form or RCC (Bosniak cyst, category IV); 32 patients with renal angiomyolipoma (AML); 25 patients with renal oncocytoma (OC); and 16 patients with the renal abscess (AB). In total, 245 lesions were pathologically verified. As a reference, 19 healthy volunteers were included into the study. All patients underwent MRI of the kidneys, involving DWI with subsequent evaluation of the ADC. RESULTS: There was a reliable difference (p < 0.05) in mean ADC values between the normal renal parenchyma (NRP), solid RCC of different histologic subtypes and grades, cystic RCC, and benign renal lesions. The mean ADC values obtained in the result of the study were (×10-3 mm2/s): 2.47 ± 0.12 in NRP, 1.63 ± 0.29 in all solid RCCs, 1.82 ± 0.22 in solid ccRCC (1.92 ± 0.11-Fuhrman grade I, 1.84 ± 0.14-Fuhrman grade II, 1.79 ± 0.10-Fuhrman grade III, 1.72 ± 0.06-Fuhrman grade IV), 1.61 ± 0.07 in pRCC, 1.46 ± 0.09 in chRCC, 2.68 ± 0.11 in cystic RCC, 2.13 ± 0.08 in AML, 2.26 ± 0.06 in OC, and 3.30 ± 0.07 in AB. CONCLUSION: The data received in our study demonstrate a substantial restriction of diffusion of hydrogen molecules in tissues of ccRCC in comparison with the healthy renal parenchyma preconditioned by the greater density of tumor. A statistically significant difference in mean ADC values of ccRCC with different grades of nuclear pleomorphism by Fuhrman was observed: Low-grade tumors showed higher mean ADC values compared to high-grade tumors. The modality of the MRI DWI along with ADC measurement allows to reliably differentiate between the solid RCC of main histologic subtypes and grades, cystic RCC, and the benign renal lesions.