Results of a prospective randomized study assessing the efficacy of fluorescent cystoscopy-assisted transurethral resection and single instillation of doxorubicin in patients with non-muscle-invasive bladder cancer.

OBJECTIVES: To assess the efficacy of two treatment options for non-muscle-invasive bladder cancer (NMIBC): (1) transurethral resection (TUR) guided by fluorescence cystoscopy (FC) with the use of 5-aminolevulinic acid (5-ALA) and (2) single early instillation of doxorubicin in a single-center open-label prospective randomized study with a 2 × 2 factorial design. PATIENTS AND METHODS: Patients with clinical suspicion of primary or recurrent NMIBC were randomized into four study arms: FC-assisted TUR with 5-ALA and single instillation of doxorubicin, FC-assisted TUR without instillation, TUR in white light (WL) with single instillation of doxorubicin, and WL-TUR only. The study was designed to assess recurrence-free survival in arms with and without any of two interventions. RESULTS: Of 525 patients included, 377 (72 %) were eligible for primary outcome assessment. The median follow-up was 54.8 months. FC statistically significantly decreased the risk of disease recurrence and progression with hazard ratio (HR) 0.56 (95 % CI 0.39-0.80, p = 0.001) and 0.33 (95 % CI 0.12-0.91, p = 0.031), respectively. The HRs for recurrence and progression for single instillation of doxorubicin were 0.76 (95 % CI 0.54-1.07, p = 0.11) and 0.65 (95 % CI 0.28-1.52, p = 0.32), respectively. The overall and cancer-specific survival rates did not differ significantly based on the therapeutic interventions. CONCLUSIONS: In patients with NMIBC, FC-assisted TUR with 5-ALA results in a substantial recurrence and progression risk reduction as compared to WL-TUR. The single early postoperative instillation of doxorubicin did not have a statistically significant impact on recurrence and progression risks.

Polymorphism of DNA repair genes OGG1, XRCC1, XPD and ERCC6 in bladder cancer in Belarus.

CONTEXT: The study of DNA base and nucleotide excision repair gene polymorphisms in bladder cancer seems to have a predictive value because of the evident relationship between the DNA damage response induced by environmental mutagens and cancer predisposition. OBJECTIVE: The objective was to determine OGG1 Ser326Cys, XRCC1 Arg399Gln, XPD Asp312Asn, and ERCC6 Met1097Val polymorphisms in bladder cancer patients as compared to controls. METHODS: Both groups were predominantly represented by Belarusians and Eastern Slavs. DNA samples from 336 patients and 370 controls were genotyped using a PCR-RFLP method. RESULTS: The genotype distributions were in agreement with the Hardy-Weinberg equilibrium. The minor allele frequencies in the control population were in the range of those in Caucasians in contrast to Asians. The OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes were inversely associated with cancer risk (OR [95% CI] = 0.69 [0.50-0.95] and 1.35 [1.0-1.82], respectively). The contrasting effects of these genotypes were potentiated due to their interactions with smoking habit or age. CONCLUSIONS: Among four DNA repair gene polymorphisms, the OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes might be recognized as potential genetic markers modifying susceptibility to bladder cancer in Belarus.

Low Survival in Poor Prognosis Metastatic Germ Cell Cancer in Belarus.

PURPOSE: Since the development of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification in a 1997 study, high-income countries have reported a significant increase in survival for poor prognosis patients. There are scant data on IGCCCG risk-stratified survival from low- and middle-income countries. We assessed the progression-free survival (PFS) and overall survival (OS) rates in a contemporary cohort of Belarusian patients with advanced germ cell cancer (GCC) stratified by the IGCCCG prognostic classification and analyzed prognostic factors for survival. MATERIALS AND METHODS: The consecutive cohort of patients with clinical stage IIb-III testicular GCC or extragonadal germ cell tumors who received treatment or consultation in our two centers between 2010 and 2015 was included. All patients underwent primary chemotherapy. The patients were divided into seminoma and nonseminomatous germ cell carcinoma (NSGCC) subgroups. The Kaplan-Meier method was used to estimate 5-year PFS and OS. RESULTS: This study included 111 patients with a median age of 32 years, 95% of whom were diagnosed with testicular cancer. Seminoma and NSGCC were identified in 32 (29%) and 79 (71%) patients, respectively. The median follow-up was 6.1 years. The 5-year PFS and OS rates for the entire cohort were 70% and 77%, respectively. In patients with good prognosis seminoma and good, intermediate, and poor prognosis NSGCC, the estimated PFS rates were 76%, 88%, 74%, and 39% and those for OS were 83%, 97%, 83%, and 38%, respectively. CONCLUSION: In our cohort of Belarusian patients with advanced germ cell tumors, we failed to demonstrate an improvement in PFS and OS compared with the 1997 IGCCCG study. Moreover, survival in poor prognosis group is inferior to that in IGCCCG and all contemporary series from high-income countries.

Overall survival in patients with metastatic renal cell carcinoma in Russia, Kazakhstan, and Belarus: a report from the RENSUR3 registry.

BACKGROUND: Real-world data describing outcomes of treatment among metastatic renal cell carcinoma (mRCC) patients are limited and heterogeneous. AIM: RENSUR3 registry study assessed real-world data on the use of therapies in mRCC and overall survival (OS) in Russia, Kazakhstan, and Belarus. METHODS: Patients were included in the retrospective multicenter registry study. To be eligible, patients were required to have mRCC diagnosed from January 2015 to January 2016. Anonymized data were collected through an online registry. The outcomes of interest were patient characteristics, treatment patterns, and OS. RESULTS: 1094 mRCC patients were identified. Mean age was 62.3 (SD, 11.2) years. Four hundred and forty-four (41%) patients were 65 years and older. Primary tumor has not been removed in 503 (46%) patients. Subtype of RCC based on WHO classification (clear-cell or other) has been reported in 402 (37%) patients. In total, 595 (54.4%) patients received systemic therapy for metastatic disease. 58% of elderly patients (≥65) were not treated compared to 37% of younger patients. Cytokines and targeted therapy were used in 298 (50.1%) and 297 (49.9%) of 595 treated patients, respectively. Median OS was 11.9 months (95% CI 10.9-12.9). The 1- and 3-year OS rates were 49.6% and 19.3%. CONCLUSIONS: Half of patients received no systemic therapy or had only cytokines for mRCC in Russia, Kazakhstan, and Belarus, which doubtless negatively affected OS in this population. Novel therapies should be considered as life prolonging and a priority.

Long-term results of a single-center prospective randomized trial assessing efficacy of a shortened course of adjuvant chemotherapy after radical cystectomy in patients with locally advanced bladder cancer.

INTRODUCTION: This study assesses the efficacy and tolerability of two cycles of adjuvant chemotherapy (AC) with gemcitabine and cisplatin after radical cystectomy in patients with a high risk of progression of muscle-invasive urothelial bladder cancer as compared to chemotherapy at relapse, in a prospective randomized study. MATERIAL AND METHODS: From 2008 to 2013, all patients after radical cystectomy at our institution for primary or recurrent urothelial bladder cancer with stage pT3-4 and/or pN+ on histopathology and without contraindications to combination cisplatin-based chemotherapy, were randomized either to two cycles of gemcitabine and cisplatin chemotherapy or to follow-up and chemotherapy at the time of relapse. The study endpoints were overall, cancer-specific, and disease-free survival. RESULTS: The study included 100 patients, of whom 53 received AC and the other 47 were assigned to the control arm. Out of 53 allocated to AC arm, 16 patients did not start chemotherapy or received only one cycle of AC. The median follow-up for patients in the AC and control arms was 88 and 86 months, respectively. In the AC arm the hazard ratio for death from any cause, death from bladder cancer, and disease relapse were 0.70 (95% CI 0.45-1.11; p = 0.13), 0.84 (95% CI 0.50-1.41; p = 0.51), and 0.77 (95% CI 0.46-1.28; p = 0.31), respectively. CONCLUSIONS: Two cycles of AC with gemcitabine and cisplatin in patients with high-risk urothelial bladder cancer after radical cystectomy does not improve overall, cancer-specific, and disease-free survival. Only 53% of patients randomized to AC received the entire planned treatment.

Efficacy of fluorescent cystoscopy-assisted transurethral resection in patients with non-muscle invasive bladder cancer and quality of surgery: post-hoc analysis of а prospective randomized study.

INTRODUCTION: This paper aims to evaluate the influence of quality of transurethral resection in patients with non-muscle invasive bladder cancer on the benefit of fluorescent cystoscopy-assisted transurethral resection in the post hoc analysis of the single-center randomized controlled trial. MATERIAL AND METHODS: We retrospectively analyzed the results of the prospective randomized study assessing the efficacy of fluorescent cystoscopy-assisted transurethral resection. The quality of transurethral resection was defined on the basis of a separate retrospective study estimating the variability in recurrence risk for the individual surgeon. The subgroup analysis of fluorescent cystoscopy-assisted transurethral resection efficacy depending on surgical experience was performed. RESULTS: Of 377 eligible patients, transurethral resection was performed in 365 (97%) by surgeons with available grading information. Two 'experienced' surgeons performed 238 (63%) of all transurethral resections and three 'less experienced' surgeons completed 127 (34%) surgeries. The two surgical groups were comparable with respect to basic prognostic factors and subsequent therapy. The median follow-up was 56 months.In the total cohort of patients, fluorescent cystoscopy significantly decreased the risk of recurrence with hazard ratio 0.58 (p = 0.004). In the 'experienced surgeons' subgroup the benefit of fluorescent cystoscopy was not significant (hazard ratio 0.81, p = 0.34), whereas the 'less experienced' subgroup showed a marked difference in favor of fluorescent cystoscopy-assisted transurethral resection (hazard ratio 0.31, p = 0.001), with a P-value for interaction of 0.021. CONCLUSIONS: Baseline quality of surgery may be a significant interacting factor affecting the magnitude of the benefit of fluorescent cystoscopy-assisted transurethral resection in patients with non-muscle invasive bladder cancer.

Trends in incidence, mortality and survival of testicular cancer patients in Belarus.

INTRODUCTION: The objective of this study was to assess recent trends in incidence, mortality and relative survival (RS) in testicular cancer (TC) patients in Belarus and to provide international comparisons of our figures. MATERIAL AND METHODS: We surveyed the Belarusian Cancer Registry for all male cases diagnosed with International Classification of Diseases for Oncology, third edition (ICD-O-3) topography code C62 between 1990 and 2015. Trends for incidence and mortality rates per 100,000 of the world standard population and annual percentage changes (APCs) were calculated. We also estimated the 1- and 5-year RS rates for the 1990-1998, 1999-2007 and 2008-2015 periods according to the Ederer II method. The RS estimates for the 2008-2015 period were age-standardized and compared with the published EUROCARE-5 data and SEER-18 database analysis. RESULTS: A total of 2,500 and 2,439 cases were included into incidence and survival analyses, respectively. We found a significant increase in the TC age-standardized incidence rate (APC 2.6%) and a decline in the age-standardized mortality (APC -3.0%) over the study period. RS significantly increased in all patients` strata; a relative increase was more pronounced in advanced stages of seminoma and younger age groups. Nevertheless, the most recent figures of age-standardized RS including stage-specific estimates were generally worse than the European and SEER data. CONCLUSIONS: We have found a significant increase in TC incidence in Belarus in recent years. Mortality has significantly declined with a corresponding increase in RS which, however, did not reach European or North American figures. Continued effort is required to improve the quality of management of TC patients in our country.

The Involvement of ERCC2/XPD and ERCC6/CSB Wild Type Alleles in Protection Against Aging and Cancer.

BACKGROUND: DNA helicases maintain genome stability, and their deficiency is associated with disorders resembling premature aging as well as contributes to carcinogenesis. Their functions are determined by the respective genes encoding nucleotide excision repair initiating proteins, e.g. XPD and CSB. OBJECTIVE: The present study aimed to investigate the influence of genetic variations in ERCC2/XPD (rs1799793, rs13181) and ERCC6/CSB (rs2228526, rs2228528) loci on lifespan and developing age-related bladder cancer focusing on homozygous wild type alleles. METHOD: The allelic variants were identified in 354 clinically healthy controls and 418 bladder cancer patients using the PCR-RFLP method. RESULTS: The age-depended increase in frequencies of homozygous carriers of wild-type XPD 312Asp and XPD 751Lys alleles was observed among controls, especially among subjects over 80 years (r = 0.67, p = 0.012). The statistically significant correlation was also found between the frequency of homozygous wild type alleles at all tested loci and age in healthy population over 60 years (r = 0.35, p = 0.046) suggesting the relationship between lifespan and longevity, on one hand, and normal functioning of these genes and their products, on the other hand. Homozygous carriers of wild type alleles were less susceptible to bladder cancer, tumor invasion, increase in grade of malignancy and recurrence, but their effects were specific with respect to clinicopathological and lifestyle characteristics. CONCLUSION: Homozygous wild type alleles encoding XPD and CSB proteins with optimal properties were shown to affect human lifespan, risk of developing bladder cancer, its progression and recurrence under certain conditions.

Simultaneous or staged surgery in patients with kidney tumors and concomitant cardiac disease.

INTRODUCTION: To evaluate outcomes of simultaneous and staged surgery in patients with kidney tumors and concomitant cardiac disease. MATERIAL AND METHODS: Between October 2001 and October 2015, fifteen patients (Group 1) underwent simultaneous surgery and fourteen patients (Group 2) underwent staged surgery. 89.7% were males (26/29), and the mean age was 60.8 ±1.16 years. Locally advanced cancers (Stage III) were registered in the two groups in 11 vs. 3 patients (p = 0.016) and localized (Stage I) disease in 2 vs. 10 (p = 0.007), respectively. 18 patients (62%) were operated for coronary heart disease, while 10 patients (35%) underwent surgery for valvular heart disease. Nephrectomy was performed in 14rs 5 patients respectively (p = 0.003) while partial nephrectomy in 1rs 7 patients (p = 0.005). RESULTS: In the two groups, the 30-day mortality was 13% (2 cases) and 7% (1 case), p = 1.0, and major hospital complications were observed in 3 (20%) and 2 (14%) cases, respectively, p = 0.53. The median follow-up in Group 1 and Group 2 was 87 months (range, 23.3 to 146.8 months) and 39 months (range, 3.9 to 98 months), respectively, p = 0.001. Three-year overall survival was 73.3 ±11.4% (95% CI 50.5-96.1) and 77.9 ±11.3%, respectively, p = 0.70, and three-year disease-free survival was 83.9 ±10.4% and 75.0 ±21.7%, respectively, p = 0.91. CONCLUSIONS: Simultaneous and staged surgery for kidney tumors and concomitant cardiac disease are feasible procedures. Patients with advanced tumors and complicated disease course can benefit from early intervention and consequently a simultaneous approach can be a preferred option for them. For localized renal tumors, staged surgery should be used.

Surgeon has a major impact on long-term recurrence risk in patients with non-muscle invasive bladder cancer.

INTRODUCTION: One of the factors responsible for the risk of recurrence after complete transurethral resection of the bladder tumor (TURBT) in patients with non-muscle invasive bladder cancer (NMIBC) is the quality of surgery that may vary between individual surgeons. The aim of the study was to evaluate the impact of the surgeon on recurrence-free survival in patients with NMIBC. MATERIAL AND METHODS: The long-term results of a series of consecutive TURBTs performed by five staff urologists at a single institution were retrospectively analyzed. A total of 949 cases of organ-preserving treatment in 784 patients with NMIBC were included in the analysis. RESULTS: With the median follow-up of 64.3 months (3-124 months), the 5-year recurrence-free survival rates according to the surgeon were 62.9% (95% CI 56.2-69.7%), 53.6% (95% CI 47.4-59.9%), 51.0% (95% CI 39.6-62.4%), 46.2% (95% CI 36.4-56.0%), and 44.2% (95% CI 36.8-51.7%), respectively (p <0.0001). In the multivariate analysis including all potential risk factors, the individual surgeon was associated with a risk of recurrence with a high degree of statistical significance (p = 0.0013). The between-surgeon differences in the recurrence risk were not that pronounced in less extensive tumors. CONCLUSIONS: A surgeon has a significant impact on the risk of recurrence after curative treatment of patients with NMIBC. This effect was observed despite the relatively extensive experience in bladder endoscopic surgery of all of the surgeons and practicing in a setting of one specialized center. These findings should be taken into account while performing and evaluating the results of comparative studies.

The Cellular Response to Oxidatively Induced DNA Damage and Polymorphism of Some DNA Repair Genes Associated with Clinicopathological Features of Bladder Cancer.

Genome instability and impaired DNA repair are hallmarks of carcinogenesis. The study was aimed at evaluating the DNA damage response in H2O2-treated lymphocytes using the alkaline comet assay in bladder cancer (BC) patients as compared to clinically healthy controls, elderly persons, and individuals with chronic inflammations. Polymorphism in DNA repair genes involved in nucleotide excision repair (NER) and base excision repair (BER) was studied using the PCR-RFLP method in the Belarusian population to elucidate the possible association of their variations with both bladder cancer risk and clinicopathological features of tumors. The increased level of H2O2-induced DNA damage and a higher proportion of individuals sensitive to oxidative stress were found among BC patients as compared to other groups under study. Heterozygosity in the XPD gene (codon 751) increased cancer risk: OR (95% CI) = 1.36 (1.03-1.81), p = 0.031. The frequency of the XPD 312Asn allele was significantly higher in T ≥ 2 high grade than in T ≥ 2 low grade tumors (p = 0.036); the ERCC6 1097Val/Val genotype was strongly associated with muscle-invasive tumors. Combinations of homozygous wild type alleles occurred with the increased frequency in patients with non-muscle-invasive tumors suggesting that the maintenance of normal DNA repair activity may prevent cancer progression.