Evaluation of response to tyrosine kinase inhibitors in renal cell carcinoma patients based on expression of miR-99b, -144, -210, -222, -302а and -377 in tumor tissue.

BACKGROUND: Renal cell carcinoma (RCC) is one of the most common solid tumors in adults highly resistant to conventional therapies. The expression profile of a number of miRNAs correlates with RCC response to chemotherapeutic agents. AIM: To identify the association of tumor miRNAs expression with neoadjuvant treatment response in patients with RCC. MATERIALS AND METHODS: We analyzed the expression levels of tumor miR-99b, -144, -155, -210, -222, -302а, -377 in 93 RCC patients who received pazopanib or sunitinib in neoadjuvant regimen using RT-PCR. RNU48 was used as a reference miRNA. RESULTS: The levels of expression of miR-99b and -377 are associated with the RCC response to pazopanib, and microRNA-210 and -377 to sunitinib. The characteristic expression profile of miR-99b, -144, -222, -377, and miR-302a determined in 90% of cases was delineated in pazopanib responders as opposed to nonresponders. Similarly, the characteristic expression profile of miR-210, -222, -302a and -377 was suggested for sunitinib responders. CONCLUSIONS: Levels of miR-99b, -210 and -377 expression in RCC tumor tissue might be used as a basis for future predictive panel intended for the assessment of the sensitivity to the regimens of neoadjuvant RCC treatment.

Efficacy of Neoadjuvant Targeted Therapy in Treatment of Patients with Localised Clear-Cell Renal Cell Carcinoma.

AIM: This study aimed to evaluate the efficacy of neoadjuvant targeted therapy (TT) in patients with localised clear-cell renal cell carcinoma (RCC). MATERIALS AND METHODS: A special randomised trial was planned and conducted by the Research Department of Plastic and Reconstructive Oncology in the National Cancer Institute of Ukraine for testing the clinical efficacy of neoadjuvant TT in the treatment of clear-cell localised RCC, and the primary endpoint was tumour response evaluation after TT. The secondary endpoints included evaluation of dependence between the use of neoadjuvant TT and the probability of partial nephrectomy and the correlation between tumour size, stage, remaining functioning parenchyma volume, and response to systemic therapy. RESULTS: Overall, 118 patients met the inclusion criteria and were randomly assigned to receive combined treatment or surgery alone. The percentage of tumour regression ranged from 0% to 60%, and the median was (95% confidence interval) 20.5 ± 14.3 (16.8-24.3%). Most of the patients had a slightly positive response to TT (3%-29% decrease in tumour size); n = 44 (76.9%) cases. Partial response by the Response Evaluation Criteria in Solid Tumours, version 1.1, was observed in 14 (24.1%) patients and reached a maximum of 60% regression. Tumour reduction in the neoadjuvant TT group allowed kidney preservation in 53 (91.4%) patients. In the control group, the number of organ-sparing procedures was significantly lower (n = 20, 33.3%). The statistical difference was relevant (x 2 = 42.1; p < 0.001). CONCLUSION: The positive results of neoadjuvant TT obtained in our study indicate the clinical validity of combined treatment in patients with localised RCC.

Quality of life in patients after radical cystectomy with modified ureterocutaneostomy and Bricker urinary diversion.

BACKGROUND: Radical cystectomy (RC) has been used for over 100 years as an effective treatment of muscle invasive bladder cancer (MIBC). However, the main surgical challenge is not only to remove an affected organ but also to replace its functional component - urine diversion. The aim of our work is to study the efficacy of the modified ureterocutaneostomy technique by estimating the quality of life in post-RC patients with MIBC. MATERIALS AND METHODS: A retrospective analysis of the cases of 40 patients was provided. Two groups were delineated depending on urinary diversion: 20 patients with urinary derivation by the modified ureterocutaneostomy method, and 20 patients - with Bricker conduit. All patients were matched by mean age, gender, American Society of Anesthesiologists status, disease stage and duration. 16 (80%) and 15 (75%) patients from the study and control groups, respectively, passed 3 courses of standard preoperative polychemotherapy with gemcitabine-cisplatin. Quality of life was assessed using the health survey SF-36 form (developed at the US Medical Research Institute), adapted at the National Cancer Institute (Ukraine). RESULTS: Comparing patients after ureterocutaneostomy or Bricker surgery, no statistical discrepancy was noted before surgery and after 3 months. A statistical difference in perioperative parameters was noted only when comparing the surgery duration and length of stay in hospital. CONCLUSIONS: The modified ureterocutaneostomy technique contributes to performing surgery faster and more effectively since an intestinal stage is skipped in surgery. Our findings indicate that ureterocutaneostomy technique may be used as a standard of care for post-RC patients with MIBC.

Expression of steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion.

AIM: To analyze an expression pattern of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion; and to examine a putative correlation between gene expression and clinical characteristics, to define the molecular subtypes of prostate cancer. MATERIALS AND METHODS: The relative gene expression (RE) of 33 transcripts (27 genes) and the presence/absence of the TMPRSS2/ERG fusion were analyzed by a quantitative PCR. 37 prostate cancer tissues (T) paired with conventionally normal prostate tissue (CNT) and 21 samples of prostate adenomas were investigated. RE changes were calculated, using different protocols of statistics. RESULTS: We demonstrated differences in RE of seven genes between tumors and CNT, as was calculated, using the 2-ΔCT model and the Wilcoxon matched paired test. Five genes (ESR1, KRT18, MKI67, MMP9, PCA3) showed altered expression in adenocarcinomas, in which the TMPRSS2/ERG fusion was detected. Two genes (INSR, isoform B and HOTAIR) expressed differently in tumors without fusion. Comparison of the gene expression pattern in adenomas, CNT and adenocarcinomas demonstrated that in adenocarcinomas, bearing the TMPRSS2/ERG fusion, genes KRT18, PCA3, and SCHLAP1 expressed differently. At the same time, we detected differences in RE of AR (isoform 2), MMP9, PRLR and HOTAIR in adenocarcinomas without the TMPRSS2/ERG fusion. Two genes (ESR1 and SRD5A2) showed differences in RE in both adenocarcinoma groups. Fourteen genes, namely AR (isoforms 1 and 2), CDH1, OCLN, NKX3-1, XIAP, GCR (ins AG), INSR (isoform A), IGF1R, IGF1R tr, PRLR, PRL, VDR and SRD5A2 showed correlation between RE and tumor stage. RE of four genes (CDH2, ESR2, VDR and SRD5A2) correlated with differentiation status of tumors (Gleason score). Using the K-means clustering, we could cluster adenocarcinomas in three groups, according to gene expression profiles. A specific subtype of prostate tumors is characterized by the activated ERG signaling, due to the presence of TMPRSS2/ERG fusion, and also by high levels of the androgen receptor, prolactin, IGF, INSR and PCA3. CONCLUSIONS: We have found the specific differences in expression of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes, depending on the pre-sence/absence of the TMPRSS2/ERG fusion in prostate adenocarcinomas, CNT and adenomas. We showed three different gene expression profiles of prostate adenocarcinomas. One of them is characteristic for adenocarcinomas with the TMPRSS2/ERG fusion. Further experiments are needed to confirm these data in a larger cohort of patients.