Objective: to assess the expression and prognostic value of vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2) and their receptors VEGFR-1, -2; FGFR-1, -2, as well as platelet-derived growth factor receptors (PDGFR-α, PDGFR-β) in paired samples of primary tumors and tumor thrombi in renal cell carcinoma (RCC). Materials and methods. Expression of VEGF-A, FGF-2, VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β was studied in paired surgical samples of primary tumors and tumor thrombi in 25 patients with clear cell RCC pT3a–T4N0–1M0–1 and tumor venous thrombosis by immunohistochemical assay using the appropriate Abcam/Santa Cruz Biotech antibodies from the immunohistochemical staining kit Invitrogen. Expression levels were evaluated by a semi-quantitative method (H-score). The analysis of the correlation between expression levels of VEGF-A, FGF-2, VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β and RCC characteristics, as well as evaluation of their influence on the outcome of RCC were performed. Results. VEGF-A, FGF-2, as well as VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β were expressed in the cytoplasm and on the membrane of the primary tumor and tumor thrombus cells in RCC patients. Tumor thrombus cells were characterized by lower expression of VEGFR-1, VEGFR-2, PDGFR-α (p <0.05 for all) and tendency to lower expression of VEGF-A (p = 0.060), FGF-2 (p = 0.046), FGFR-1 (p = 0.077) and FGFR-2 (p = 0.090) compared with primary tumor cells. RCC Furman grade correlated with the expression levels of VEGFR-1 (p = 0.035) and FGFR-1 (p = 0.022) in the primary tumor cells, tumor invasion into venous wall correlated with the expression levels of VEGFR-1 (p = 0.023) and FGFR-2 (p = 0.005) on the thrombus cells. VEGFR-2 overexpression in the primary tumor cells was associated with significant decrease of overall survival (OS) rate (p = 0.011). There was a tendency to OS deterioration in cases with overexpression of VEGFR-2 (p = 0.093) and VEGF-A (p = 0.095) in the tumor thrombus cells. One-year OS in patients with ³ 2 identified risk factors was 27.3 %, <2 risk factors – 87.5 % (p = 0.004). Conclusion. T umor thrombus cells in RCC patients expressed VEGF-A, FGF-2, VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β less active than the cells of the primary tumor. Overexpression of growth factors and tyrosine kinases correlated with RCC Furman grade and tumor venous wall invasion. Overexpression of VEGFR-2 in both primary tumor and thrombus cells in combination with hypoexpression of VEGF-A in the thrombus negatively influenced on OS.

Purpose. The heterogeneity of target receptors expression may cause different responses of the primary tumor and metastases of renal cell carcinoma (RCC) on tyrosine kinase inhibitors therapy. The aim of the study was to investigate expression and prognostic value of vascular endothelial growth factor (VEGFA) and fibroblast growth factor (FGF2) and their receptors VEGFR-1–3, FGFR-1–2, as well as platelet-derived growth factor receptors (PDGFR-α , -β) on the tumor cells of paired samples of the primary tumor and metastases in patients with RCC. Materials and methods. Immunohistochemical analysis with primary antibodies to VEGFA and FGF2 and receptor tyrosine kinases VEGFR-1-3, FGFR-1-2 and PDGFR-α, -β was performed on surgical specimens of kidney tumor and adrenal metastases from 21 patients with RCC. Results. Cells of RCC adrenal metastases are characterized by lower expression level of VEGFA and FGF2, as well as VEGFR-1 and VEGFR-3 compared with the primary tumor. Overexpression of growth factors and their receptors by tumor cells is associated with unfavorable morphological signs of the tumor and poor prognosis in RCC patients. Conclusions. The expression of growth factors and their tyrosine kinase receptors in the cells of the primary tumor and metastases is heterogeneous. Overexpression of the studied markers in RCC cells of any localization is associated with an unfavorable prognosis.

Objective : to assess safety of left renal vein (LRV) ligation during circular resection of the inferior vena cava in right-side kidney carcinoma with tumor venous thrombosis. Materials and methods . We selected medical data of 63 renal cell carcinoma patients with tumor venous invasion undergone nephrectomy, thrombectomy, IVC resection with LRV ligation (Group 1; n = 29 (46.0 %)) or preservation of venous outflow from the contralateral kidney (Group 2; n = 34 (54.0 %)). Median age of study participants was 56.0 + 8.8 years (range: 32—72 years); a male to female ratio was 1:1.9. Such parameters as age, gender, median glomerular filtration rate (GFR), stages of chronic kidney disease (CKD), blood loss, and duration of surgery were comparable across the two groups ( р >0.05 for all parameters). Median follow-up was 32.8 months (range: 1—226 months). Results. We observed no significant changes in median GFR in the late postoperative period compared to baseline among patients with ligated LRV (65.7 vs 71.2 mL/min/1.73 m2; р >0.05) and patients with preserved venous outflow from the contralateral kidney (60.6 vs 68.4 mL/min/1.73 m2; р >0.5). Patients that underwent LRV ligation were less likely to have reduced GFR compared to those with normal contralateral renal venous outflow (34.5 % vs 44.1 %; p >0.05). However, participants with ligated LRV had CKD upstaging (from stage 0—I to stage I—II) more frequently than participants with preserved venous outflow (27.6 % vs 5.9 %; р = 0.022). None of the patients developed stage III CKD after LRV ligation. Conclusion . LRV ligation during circular resection of the IVC in right-side renal cell carcinoma patients with tumor venous thrombosis does not lead to a clinically significant decrease in long-term deterioration of renal function.

Until now selection of the 1st line therapy for advanced clear-cell renal cell carcinoma was determined by patients distribution into favorable/ intermediate or poor prognosis groups. In the favorable/ intermediate prognostic groups agents of choice included antiangiogenic substances such as bevacizumab (in combination with interferon-alpha), sunitinib, andpazopanib, which had demonstrated only progression-free survival benefit comparing with interferon-alpha in registration studies; in the poor prognosis group the only treatment option was mammalian target of rapamycin inhibitor temsirolimus which had improved overall survival comparing with interferon-alpha. However about 75 % of advanced renal cell carcinoma patients have intermediate or poor prognosis. Only 2 randomized trials investigated systemic therapy in this cohort of patients, CABOSUN and CheckMate 214. The results of the randomized phase III study CheckMate 214 have demonstrated a significant advantage of overall survival and objective response rate in previously untreated patients of intermediate/poor prognostic groups who were randomizedfor combined immunotherapy with nivolumab and ipilimumab comparing with sunitinib independently of PD-L1 expression level. Owing to the achieved data combined immunotherapy became a new standard of the first-line therapy in advanced renal-cell carcinoma patients with intermediate and poor prognosis.

Objective. To evaluate short-term and long-term results of nephrectomy, thrombectomy, circular inferior vena cava (IVC) resection in patients with renal cell carcinoma (RCC) and advanced IVC tumor invasion. Materials and methods . Medical data of 49 patients with RCC and level II–IV tumor venous thrombus with advanced IVC wall tumor invasion were analyzed. All the patients underwent nephrectomy, thrombectomy, circular IVC resection (radical – 35 (71.0 %), cytoreductive, in M+ cases – 14 (28.6 %)). Circular resection of the infrarenal IVC segment was performed in 25 (51.0 %) patients; resection of the infrarenal, perirenal and retrohepatic IVC segments with a ligation of the left renal vein (RV) – in 24 (49.0 %) patients. Perirenal IVC prosthesis was used in 2 (4.1 %) patients with initially preserved IVC blood flow, in other cases replacement of the removed IVC segment wasn’t performed due to presence of a network of venous collaterals duplicating the IVC. Patients with metastases received systemic antitumor treatment after nephrectomy, thrombectomy. Results . Median operative time was 260 (135–580) minutes, median blood loss was 8750 (3000–27 000) ml. Severe intraoperative complications were observed in 2 (4.0 %) patients, 1 (2.0 %) patient died on the operating table due to hypovolemic shock. Postoperative complications were observed in 26 (53.2 %) cases (grade III–V in 22 (45.8 %) patients). Five-year overall and cancer-specific survival of all patients was 54.6 and 67.8 %, respectively, relapse-free survival of 35 patients with M0 category was 49.4 %. Both IVC prostheses were patent 12 months after the surgery. Function of the left kidney after ligation of the left RV was preserved at the preoperative level in all 24 patients in a median of 12 (2–120) months. Conclusion. Nephrectomy, segmental/subtotal cavectomy with preservation of the main renal venous entries is an effective treatment method in RCC patients with advanced tumor IVC invasion. The method allows to achieve satisfactory long-term survival rates and functional results.

Objective – to evaluate efficacy and safety of everolimus in Russian population of unselected patients with advanced renal cell carcinoma progressing after at least 1 line of anti-angiogenic targeted therapy. Materials and methods . In observational multicenter study CRAD001LRU03 from 17.01.2012 to 31.03.2015 in 43 centers 226 patients with advanced renal cell carcinoma with documented progression on the background or after at least 1 line of anti-angiogenic targeted therapy were included. The survey was conducted on all patients according to the practice, everolimus therapy was administered in accordance with instructions to the drug. Results. Objective response rate was 10 %, tumor control was achieved on 69.2 % of patients. Progression-free survival median – 7.8 months. Adverse events occurred in 44.7 % of patients, reached the III–IV severity of 9.3 %, were the reason for the cancellation of everolimus therapy in 2.2 % of cases. The most frequent complications of treatment were pneumonitis (n = 5 (2.2 %)) and anemia (n = 3 (1.3 %)). Conclusion. The observational study confirms efficacy and favorable safety profile of everolimus mTOR inhibitor in the Russian unselected patients with advanced renal cell carcinoma with progression or intolerable toxicity against background of anti-angiogenic therapy.

Objective: to assess the role of palliative nephrectomy in disseminated kidney cancer patients planned to undergo targeted antiangiogenic treatment. Subjects and methods . The investigation included data on 83 patients with T1-4N0 / +M1 disseminated renal cell carcinoma (RCC) who had received at least 2 targeted therapy cycles in 2009 to 2011. In 48 (57.8 %) patients, the treatment was preceded by palliative nephrectomy that was not carried out in 35 (42.2 %). Before starting targeted therapy, all the cases were confirmed to be diagnosed with clear cell RCC, with a sarcomatoid component being in 7 (8.4 %) patients. The median follow-up of all the patients was 21 (12–36) months. Results. The unremoved affected kidney in disseminated kidney cancer patients receiving targeted antiangiogenic therapy is an independent factor for the poor prognosis of progression-free (odds ratio (OR), 2.4; 95 % confidence interval (CI), 1.2–4.7) and overall (OR, 2.8; 95 % CI, 1.3–6.3) survival. Palliative nephrectomy does not improve the prognosis in patients with a low somatic status, the N+ category, and metastases into the bones and nonregional lymph nodes. Conclusion. Palliative nephrectomy in the selected patients with disseminated kidney cancer on targeted antiangiogenic therapy increases progression-free and overall survival.

Purpose . The primary end-points of the study were overall response rate, progressive-free and overall survival in patients received Gemcytabin (Cytogem®) and Cisplatin as first-line therapy for transitional-cell bladder cancer. Secondary end-points were toxicity and safty of the regimen. Material. From February 2005 to March 2007 25 patients with morphologically verified inoperable locally advanced and metastatic transitional-cell bladder cancer were recruited. Men-to-women ratio was 3:1. Median age of the patients was 66,5±6,8 years. All the patients received Cytogem® 1000 mg/m2 days 1, 8, 15, cisplatin 70 mg/m2 on day 2; every 28 days. No more than 6 cycles were allowed if the evidence of disease progression and unacceptable toxicity were not registered. Median follow-up was 36,2±12,1 months. Results. Complete response was observed in 2 (8%), partial — in 11 (44%), stabilization — in 10 (40%), progression — in 2 (8%) of 25 patients. Twelve- and 24-month overall survival was — 51,3% and 22,4% (median 13,4±3,5 (95% CI: 6,6—20,4) months), progressive- free survival — 26% and 13% respectively (median 8,8±1 (95% CI: 6,6—10,6) months). Toxicity was evaluated in 24 patients and occurred in all cases (grade I—II — 16 (67%), grade III—IV — 8 (33%)). The main regimen-related toxicity was hematological (neutropenia — 16 (67%) (grade I—II — 8 (33%), grade III—IV — 8 (33%)), thrombocytopenia — 14 (58%) (grade I—II — 10 (41,5%), grade III—IV — 4 (16,5%)), anemia — 7 (29%) (grade I—II — 5 (21%), grade III—IV — 2 (8%))). Hematological toxicity was not associated with com- plications in any case. Non-hematological side-effects were nausea and vomiting in 21 (88%) (grade I—II — 67%, grade III — 21%), alopecia — in 11 (44%) patients. The regimen-related toxicity was considerable and reversible. No side-effect demanded blood transfusion, antibiotic and/or growth factors administration, and hospital admission. Conclusion. Gemcytabin (Cytogem®) and Cisplatin as first-line therapy for advanced transitional-cell bladder cancer have demonstrated satisfactory efficacy and acceptable toxicity. The regimen can be recommended for the clinical practice.

Background and objective. The division of patients with disseminated prostate cancer (PC) into prognostic groups may be potentially used for a differential approach to choosing the hormonal therapy (HT) option and regimen. This study was conducted to identify factors influencing survival, as well as prognostic groups in this category of patients. Subjects. The study enrolled 113 patients with verified cT2b–4N0–1M0–1 stage PC. Their median age was 70.0 ± 7.3 years. The median pretreatment prostate-specific antigen (PSA) concentration was 309.8 ng/ml. The stage cT2 was diagnosed in 12 (10.6 %) patients; cT3 was in 85 (75.2 %); cT4 in 16 (14.2 %); cN+ in 32 (28.3 %); М+ in 74 (65.5 %). The median baseline Gleason score was 3.0± 0.8 ± 4.0± 0.9 =7.0± 1.6. All the patients received emergency HT: castration was carried out in 2 (1.8 %) patients; maximum androgenic block and antiandrogen monotherapy were performed in 96 (85.0 %) and 15 (13.3 %), patients, respectively. The median follow-up was 31.9± 17.7 months. Results. Five-year progression-free, hormone-refractory prostate cancer-free, specific, and overall survivals (OS) were 29.7, 31.8, 39.3, and 26.0 %, respectively. Multivariate analysis has shown that OS is negatively influenced by the following factors: bone pain, stages cT4, М+, a nadir of PSA of  4 ng/ml (p < 0.05) and its baseline level of  100 ng/ml (р = 0.057). Good (no bone pain, a PSA level of < 100 ng/ml, сТ < T4, and М0) and poor (bone pain and/or a PSA level of  100 ng/ml, and/or stages cT4 and/or М+) prognostic groups were identified. The median OS in the groups was 39.8± 3.9 and 29.8± 4.2 months, respectively (р = 0.048). Conclusion. In disseminated PC, bone pain, a PSA level of 100 ng/ml, cT4 and M+, and a PSA nadir of  4 ng/ml are poor predictors of OS. The patients without these indicators belong to a good prognostic group; those have one sign or more do to a poor prognostic one.

Objective: to compare the results of continuous and intermittent hormone therapy (HT) in unselected patients with disseminated prostate cancer (PC). Subjects and methods. The study enrolled 113 patients with verified stage cT2b–4N0–1M0–1 PC. The median age of the patients was 70 ± 7.3 years. The median pretreatment concentration of prostate-specific antigen (PSA) was 309.8 ng/ml. The cT2 category was diagnosed in 12 (10.6 %) patients, сТ3 in 85 (75.2 %), сТ4 in 16 (14.2 %), сN+ in 32 (28.3 %), and М+ in 74 (65.5 %). At baseline, the median Gleason grade was (3.0 ± 0.8) + (4.0 ± 0.9) = 7.0 ± 1.7. All the patients received immediate HT: castration therapy was performed in 2 (1.8 %) patients, maximal androgen blockade in 96 (85 %), and antiandrogen monotherapy in 15 (13.3 %). Continuous and intermittent treatment regimens were used in 100 (70.8 %) and 33 (29.2 %) cases, respectively. The median follow-up was 31.9 ± 17.7 months. Results. The intermittent HT regimen was associated with a significant increase in overall survival versus that during continuous treatment (medians 57.8 ± 11.6 and 25.2 ± 2.8 months, respectively; p = 0.031). Overall survival benefit remained in the poor prognosis (bone pain and/or a PSA of  100 ng/ml and/or сТ4 and/or М+) group. The HT regimen failed to affect survival in the good prognosis (no bone pain, a PSA of < 100 ng/ml, сТ < T4, М0) group. Impotence was less common during intermittent treatment than during continuous ablation (68.2 and 96.2 %, respectively; p = 0.002). No relationship was found between the incidence of other complications and the HT regimen. There was no significant difference between the groups in quality-of-life indicators before and during treatment. The average cost of an intermittent course of therapy per year was significantly lower than that of a continuous course (50586.7 and 72996.0 rubles, respectively; p < 0.0001). Conclusions. Intermittent HT fails to result in a clinically relevant worsening of the quality of life, promotes better sexual function, and is economically expedient. In the poor prognosis group, intermittent treatment causes a significant increase in the time to hormone refractoriness and in overall survival rates as compared with these indicators when the continuous regimen is used. Intermittent therapy is as good as continuous ablation for overall survival among the good prognosis patients.

Degarelix (Firmagon) (Ferring Pharmaceuticals) is a new gonadotropin-releasing hormone (GnRH) antagonist permitted and approved for use in the treatment of hormone-dependent prostate cancer. It is recommended to administer the drug subcutaneously in the abdomen in a starting dose of 240 mg, followed by monthly maintenance doses of 80 mg. The Phase III randomized trial demonstrated that degarelix had advantages over the GnRH agonist leuprorelin in the reduction rates for testosterone to castration levels and for prostate-specific antigen (PSA) levels and in the absence of the initial increase and variations of androgen concentrations during treatment. A one-year follow-up showed that the risk of PSA recurrence and death with leuprorelin was significantly higher than that with degarelix. There was a significant reduction in the risk of PSA recurrence in patients switched from leuproprorelin to degarelix. The rates of adverse reactions and treatment discontinuation in the degarelix treatment group do not differ from that in the leuprorelin group. Long-term follow-up studies are required to draw final conclusions.