The Polymorphisms in GSTO Genes (GSTO1 rs4925, GSTO2 rs156697, and GSTO2 rs2297235) Affect the Risk for Testicular Germ Cell Tumor Development: A Pilot Study.

Members of the omega class of glutathione transferases (GSTs), GSTO1, and GSTO2, catalyze a range of reduction reactions as a part of the antioxidant defense system. Polymorphisms of genes encoding antioxidant proteins and the resultant altered redox profile have already been associated with the increased risk for testicular germ cell cancer (GCT) development. The aim of this pilot study was to assess the individual, combined, haplotype, and cumulative effect of GSTO1rs4925, GSTO2rs156697, and GSTO2rs2297235 polymorphisms with the risk for testicular GCT development, in 88 patients and 96 matched controls, through logistic regression models. We found that carriers of the GSTO1*C/A*C/C genotype exhibited an increased risk for testicular GCT development. Significant association with increased risk of testicular GCT was observed in carriers of GSTO2rs2297235*A/G*G/G genotype, and in carriers of combined GSTO2rs156697*A/G*G/G and GSTO2rs2297235*A/G*G/G genotypes. Haplotype H7 (GSTO1rs4925*C/GSTO2rs2297235*G/GSTO2rs156697*G) exhibited higher risk of testicular GCT, however, without significant association (p > 0.05). Finally, 51% of testicular GCT patients were the carriers of all three risk-associated genotypes, with 2.5-fold increased cumulative risk. In conclusion, the results of this pilot study suggest that GSTO polymorphisms might affect the protective antioxidant activity of GSTO isoenzymes, therefore predisposing susceptible individuals toward higher risk for testicular GCT development.

Interplay between Comprehensive Inflammation Indices and Redox Biomarkers in Testicular Germ-Cell Tumors.

Sustained and dysregulated inflammation, concurrent tumor-induced immune suppression, and oxidative stress are profoundly involved in cancer initiation, presentation, and perpetuation. Within this prospective study, we simultaneously analyzed the preoperative indices of systemic inflammatory response and the representative byproducts of oxidative DNA, protein, and lipid damage with the aim of evaluating their clinical relevance among patients diagnosed with testicular germ-cell tumors (GCT). In the analytical cohort (n = 88, median age 34 years), neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and C-reactive protein (CRP) were significantly altered in patients with a higher tumor stage (p < 0.05). Highly suggestive correlations were found between NLR, dNLR, and SII and modified nucleoside 8-OHdG. CRP and albumin-to-globulin ratio (AGR) significantly correlated with thiols group level and maximal tumor dimension (p < 0.05). Based on receiver operating characteristic (ROC) curve analyses, all the evaluated pre-orchiectomy inflammation markers demonstrated strong performance in predicting metastatic disease; optimal cut-off points were determined for each indicator. Although further large-scale studies are warranted, inflammatory and redox indices may both complement the established tumor markers and standard clinicopathological prognostic variables and contribute to enhanced personalized risk-assessment among testicular GCT patients.

The Polymorphisms of Genes Encoding Catalytic Antioxidant Proteins Modulate the Susceptibility and Progression of Testicular Germ Cell Tumor.

The simultaneous analysis of redox biomarkers and polymorphisms encoding for regulatory and catalytic antioxidant proteins was performed in order to evaluate their potential role in the development of testicular germ cell tumor (GCT), as well as the progression of the disease. NRF2 (rs6721961), GSTM3 (rs1332018), SOD2 (rs4880) and GPX3 (rs8177412) polymorphisms were assessed in 88 patients with testicular GCT (52 with seminoma) and 88 age-matched controls. The plasma levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), thiol groups and the plasma activity of glutathione peroxidase were measured. A significant association between variant GPX3*TC+CC genotype and risk of overall testicular GCT, as well as seminoma development, was found. Moreover, carriers of variant SOD2*TT genotype were at almost 3-fold increased risk of seminoma development. Interestingly, combined SOD2*TT/GPX3*TC+CC genotype conferred a 7-fold higher risk for testicular GCT development. Finally, variant GSTM3*AC+CC genotype was associated with a higher risk for the development of advanced diseased. The presence of assessed genetic variants was not associated with significantly higher levels of redox biomarkers in both testicular GCT patients, as well as in those diagnosed with seminoma. In conclusion, the polymorphic expression of certain antioxidant enzymes might affect susceptibility toward testicular GCT development, as well as the progression of the disease.

Prognostic value of Balkan endemic nephropathy and gender on upper tract urothelial carcinoma outcomes after radical nephroureterectomy: A cohort study.

BACKGROUND: To identify the prognostic impact of residence in a BEN-endemic area and gender on upper tract urothelial carcinoma (UTUC) outcomes in Serbian patients treated with radical nephroureterectomy (RNU). METHODS: The study included 334 consecutive patients with UTUC. Patients with permanent residence in Balkan endemic nephropathy (BEN) or non-endemic areas from their birth to the end of follow-up were included in the analysis. Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates. RESULTS: Female patients were more likely to have preoperative pyuria (P = 0.01), tumor multifocality was significantly associated with the female gender (P = 0.003). Gender was not associated with pathologic stage and grade, lymph node metastasis, lymphovascular invasion, adjuvant chemotherapy, bladder cancer history, tumor size, distribution of tumor location, preoperative anemia and demographic characteristics. A total of 107 cases recurred, with a median time to bladder recurrence of 24.5 months. History of bladder tumor (HR, 1.98; P = 0.005), tumor multifocality (HR, 3.80; P < 0.001) and residence in a BEN-endemic area (HR, 1.81; P = 0.01) were independently associated with bladder cancer recurrence. The 5-year bladder cancer RFS for the patients from areas of BEN was 77.8 % and for the patients from non-BEN areas was 64.7 %. The 5-year CSS for the men was 66.2% when compared to 66.6% for the women (P = 0.55). CONCLUSIONS: Residence in a BEN-endemic area represents an independent predictor of bladder cancer recurrence in patients who underwent RNU. Gender cannot be used to predict outcomes in a single-centre series of consecutive patients who were treated with RNU for UTUC.

Prognostic significance of tumor multifocality on outcomes in patients with upper tract urothelial carcinoma after radical nephroureterectomy: A cohort study.

To identify the prognostic impact of tumor multifocality on upper tract urothelial carcinoma (UTUC) outcomes in patients treated with radical nephroureterectomy (RNU). Study included 342 consecutive patients with UTUC. Tumor multifocality was defined as the synchronous presence of 2 or more pathologically confirmed tumors in any upper urinary tract location. Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates. Tumor multifocality was significantly associated with a history of previous non-muscle invasive bladder cancer (P < 0.001), tumor size (P < 0.001), gender (P = 0.009), tumor location (P = 0.005), and anemia (P = 0.01). The Kaplan-Meier method showed that tumor multifocality was significantly associated with worse recurrence-free survival (P < 0.001, log rank). Using multivariate analysis, tumor multifocality (HR, 2.86; 95% CI, 2.06 - 3.99; P < 0.001) was independently associated with recurrence free survival. During the follow-up, a total of 128 (37.4%) patients died, including 92 (28.2%) from UTUC. However, tumor multifocality was not associated with CSS (HR, 1.29; 95% CI, 0.89 - 1.96; P = 0.21) in univariate Cox regression analyses. Tumor stage (HR, 11.1; 95% CI, 3.64 - 33.8; P < 0.001), lymph node status (HR, 2.04, 95% CI, 1.05 - 3.94; P = 0.03) and preoperative anemia (HR, 3.50, 95% CI, 2.02 - 6.08; P < 0.001) were the only independent predictors associated with worse cancer-specific survival. Tumor multifocality is an independent prognostic factor of disease recurrence in patients treated with RNU for UTUC. Tumor multifocality is unable to predict cancer specific survival in a single-center series of consecutive patients who were treated with RNU.

Urothelial carcinoma of the upper urinary tract: preoperative pyuria is not correlated with bladder cancer recurrence and survival.

OBJECTIVE: To identify the impact of preoperative pyuria on the bladder cancer recurrence and survival of patients who were treated surgically for UTUC. PATIENTS AND METHODS: Study included 319 consecutive patients who were treated with RNU for UTUC. Cox proportional hazard regression models were used to evaluate the association of preoperative pyuria with outcome. RESULTS: Eighty patients (25.1%) had pyuria. Preoperative pyuria was associated with sex (P = 0.01), tumor focality (P = 0.01), tumor size (P = 0.05), tumor stage (P = 0.01), lymph node metastasis (P = 0.01), lymphovascular invasion (P = 0.02), and chemotherapy (P = 0.04). A total of 102 patients recurred, with a median time to bladder recurrence of 24.2 months. Bladder cancer recurrence-free survival rates for these 319 patients at 1, 3, 5, 7, and 10 years were 84.6, 72.4, 69.0, 68.3, and 68.0%, respectively. Preoperative pyuria was not independently associated with bladder cancer recurrence (HR 1.15; p = 0.5). Preoperative pyuria was associated with OS (HR 1.57; p = 0.02) and CSS (HR 1.65; p = 0.02). However, preoperative pyuria was not independently associated with OS and CSS (HR 1.07; p = 0.79). CONCLUSIONS: Preoperative pyuria is unable to predict outcomes in a single-centre series of consecutive patients who were treated with RNU.

Urothelial carcinoma: Recurrence and risk factors.

Urothelial carcinomas are malignant tumors that arise from the urothelial epithelium and may involve the lower and upper urinary tract. They are characterized by multiple, multifocal recurrences throughout the genitourinary tract. Bladder tumors account for 90-95% of urothelial carcinomas and are the most common malignancies of the urinary tract. Upper urinary tract urothelial carcinomas (UTUC) are relatively rare, accounting for 5% of urothelial tumors. The incidence of subsequent bladder cancer after surgical treatment for UTUC is approximately 15-50%. In contrast, patients with a primary tumor of the bladder have a low risk (2-6%) the development of UTUC. Identification of prognostic factors and early detection of recurrent disease provide a better strategy for postoperative monitoring, surveillance, and potentially improve patient outcomes. In this review study we discuss the main risk factors for UTUC recurrence after radical cystectomy, and risk factors for intravesical recurrence after radical nephroureterectomy.

Prognostic Impact of Preoperative Anemia on Urothelial and Extraurothelial Recurrence in Patients With Upper Tract Urothelial Carcinoma.

BACKGROUND: To investigate the prognostic impact of preoperative anemia on urothelial and extraurothelial recurrence after radical nephroureterectomy. METHODS: A single-center series of 238 consecutive patients who were treated with radical nephroureterectomy for upper tract urothelial carcinoma was evaluated. We categorized patients on the basis of hemoglobin level into 2 groups, including normal or anemia. Survival was estimated using the Kaplan-Meier method. Cox proportional hazard regression models were used to evaluate the association of preoperative anemia with outcome, controlling for clinicopathologic variables. RESULTS: Ninety-seven patients (40.8%) had anemia (median hemoglobin level, 143 vs. 107 g/L). Preoperative anemia was associated with history of bladder cancer (P = .01), tumor multifocality (P = .03), lymphovascular invasion (P = .05), and adjuvant chemotherapy (P = .01). Higher tumor stage and grade, and lymph node metastasis were significantly associated with preoperative anemia. Preoperative anemia was independently associated with extraurothelial recurrence (hazard ratio, 1.95; 95% confidence interval, 1.14-3.34; P = .01) in multivariate Cox regression analyses. Only a history of bladder tumor (hazard ratio, 2.07; P = .009) and tumor multifocality (hazard ratio, 3.97; 95% confidence interval, 2.37-6.67; P < .001) were independently associated with urothelial recurrence. The 5-year cancer-specific survival for patients with normal hemoglobin level was 82.1% and for patients with preoperative anemia was 54.2%. CONCLUSION: Patients with preoperative anemia had a greater probability of having upper tract urothelial carcinoma with higher tumor stages, higher tumor grades, and lymph node metastasis (pN+). Preoperative anemia was statistically significantly associated with worse cancer-specific survival and extraurothelial recurrence in patients who underwent radical nephroureterectomy.

Extraurothelial recurrence after radical nephroureterectomy: preoperative predictors and survival.

OBJECTIVE: To identify the preoperative predictors of extraurothelial recurrence (EUR) after radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC). METHODS: A single-center series of 238 consecutive patients who were treated with RNU for UTUC was evaluated. Recurrence-free probabilities and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Multivariate Cox proportional hazards regression models were used to evaluate the association between various clinicopathological factors and EUR. RESULTS: The median time to EUR was 17.6 months (range 3-73 months). EUR-free survival rates at 1, 3, 5, and 7 years were 87.8, 75.2, 73.5, and 72.6%, respectively. In multivariate Cox regression analyses, tumor stage (HR 27.4; 95% CI 7.83-95.8; p = 0.0001) and lymphovascular invasion (LVI) (HR 1.53; 95% CI 1.22-3.12; p = 0.01) were independently associated with EUR. In patients with EUR, 5-year CSS estimate was 29.2%. Tumor stage (HR 14.3; 95% CI 4.55-45.2; p < 0.001) and EUR (HR 2.7; 95% CI 1.54-4.73; p = 0.001) were the only independent predictors associated with worse CSS. CONCLUSIONS: EUR significantly affected the prognosis in patients with UTUC managed by RNU. Patient with EUR had a greater probability of having higher tumor stages, higher tumor grades, and positive LVI. Tumor stage and LVI were independently associated with a worse EUR-free survival.

Evaluation of free-to-total prostate specific antigen (F/T PSA), prostate specific antigen density (PSAD) and (F/T)/PSAD sensitivity on reduction of unnecessary prostate biopsies for patients with PSA in gray zone.

AIM: We evaluated the influence of ratio between free-to-total prostate specific antigen (F/T PSA) and prostate specific antigen density (PSAD)-(F/T)/PSAD on reduction of unnecessary prostate biopsies in grey zone (prostate specific antigen (psa) value 4.0-10.0 ng/ml). METHODS: The study included 108 patients. For all patients serum total PSA (T PSA), free PSA (F PSA), F/T PSA and PSAD were analyzed. The group was divided due to the prostate volume into: entire group (regardless the prostate VOL-Group 1) and group with prostate VOL<40 (Group 2). RESULTS: Seventy five patients were diagnosed with benign prostatic hyperplasia (BPH) and 33 with prostate cancer (CaP). F/T PSA and (F/T)/PSAD showed significantly lower values in patients with CaP versus those with BPH, while PSAD had significantly higher values. For the cutoff values of 1.12 for (F/T)/PSAD, we found sensitivity to be 67% and specificity 60%, and the (AUC) 0.701. For patients with VOL<40, statistical significance remained with AUC of 0.732 (p=0.003), cutoff was 0.82, and with sensitivity 77% and specificity 68%. CONCLUSIONS: Most significant prostate carcinoma predictors were PSAD and (F/T)/PSAD, where we proposed that patients with (F/T)/PSAD values below 1.49 ± 0.94 and PSAD values above 0.17±0.06 should be included for biopsy.

Complications associated with percutaneous nephrolitholapaxy (PCNL)--our experience and literature review.

BACKGROUND: PCNL is safe procedure which is well tolerated, but as with any other surgical procedure, it is associated with a specific set of complications. There is a marked heterogeneity in reporting complication rates in literature, and this problem was highlighted in Ad Hoc EAU guidelines panel who recommended urgent creation of uniform and reproducible quality system. Modified Dindo-Clavien grading system today is the most utilized classification for complications in urology, and standard in reporting complications for PCNL. AIM(S): To analyze the complication rate for PCNL using the modified Dindo-Clavien grading system in our patients and literature review. METHODS: In our institution, with few breaks, PCNL was performed since mid 2010. Complication rate in 63 patients was analyzed retrospectively. Modified Dindo-Clavien grading system that is validated for PCNL has been accepted for classification of complication for PCNL, and literature review was performed. We have summarized the most significant factors which may affect the complication rate during and after PCNL. RESULTS: Overall complication rate was 30% in our study population. The most common complications observed were: postoperative fever Grade 1-2 (9.52%) and bleeding Grade l (7.9%), Grade 2 (3.17%), Grade 3a (4.76%) and Grade 3b (1.58%). Nephrostomy tube leakage was not found in our sample, mostly due to specific postoperative utilizing of auxiliary procedures. CONCLUSION: Reporting of complication for PCNL should be uniform, and modified Dindo-Clavien grading system that is validated for PCNL should be accepted to be a standard in urology. Surgeons training and experience are the most important to ensure the efficacy of procedure, therefore we suggest that learning of percutaneous renal access should be mandatory in residents trainee program.

New and experimental techniques in the treatment of benign prostatic diseases.

BACKGROUND: Benign prostatic hyperplasia (BPH) and chronic prostatitis (CP) are disorders with high prevalence and have a great impact on overall morbidity in men. The patients that do not respond to medical therapy for lower urinary tract symptoms (LUTS) related to BPH are candidates for surgery. However, the number of men with BPH/LUTS seeking for non-surgical, or for less invasive treatment is growing. AIM: To present the basic information about minimally invasive treatment modalities for BPH and CP: intraprostatic injections, urethral lift procedures, modifications of transurethral microwave thermotherapy (TUMT), prostatic artery embolization etc. CONCLUSION: The majority of these techniques is still in experimental phase and not widely accepted. However, it is very likely that new, safe and minimally invasive techniques will appear in the near future.