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The result of a kidney transplantation may be affected by certain congenital or acquired urological diseases that need to be addressed before, during or after the kidney transplant. Complications accompanying kidney transplantation are not fundamentally different from the events that accompany other difficult surgical procedures. However, their course is usually modified by adverse circumstances in the recipient - uremia, dialysis treatment, immunosuppression. The incidence of urological complications is reported in the range of 1 to 30 % of the transplants, and they represent up to one half of all surgical complications. They can cause a significant morbidity and mortality and can lead to a delayed onset of the function and even to a loss of the transplanted kidney.Urological complications that need to be addressed before kidney transplantation include anomalies or pathological changes in the lower urinary tract, pelvic involvement in atherosclerosis or previous kidney transplants, infectious foci in lithiasis or pyonephrosis, large polycystic kidneys and malignancies. During the kidney transplantation itself, vascular complications, and complications connected with the reconstruction of the lower urinary tract can occur. Other complications are bacterial and viral infections and malignancies. All these complications require a rapid and accurate diagnosis and subsequent targeted treatment with intention to maintain a functional kidney transplant (Fig. 11, Ref. 36). Text in PDF www.elis.sk Keywords: kidney transplantation, urological, vascular, infectious, bleeding, complications.

Recurrence of the primary disease is one of the most common causes of graft failure in the first decade after kidney transplantation. We present a case of a patient with an unusually rapid recurrence of focal segmental glomerulonephritis in the graft, the recognition of its occurrence was hampered by the primary graft affection and oligoanuria and by insignificant histological changes in the first two biopsy samples in the early post-transplant period, as well as by unawareness of the disease leading to terminal renal failure, as no renal biopsy was performed due to grade 3 obesity. Only worsening of hypoalbuminemia and finding of massive proteinuria despite oligoanuria were crucial for further management. Disease recurrence in the graft was confirmed by electron microscopy. However, complex targeted therapy did not result in restoration of graft function and decrease in proteinuria. This case history was aimed to draw attention to the knowledge of the importance of the primary disease confirmed by renal biopsy and early (so called pre-emptive) treatment in case of diseases with a high potential of recurrence (Fig. 7, Ref. 10). Text in PDF www.elis.sk Keywords: kidney transplantation, recurrence, minimal changes in glomeruli, focal segmental glomerulosclerosis.

The aim of this study was to measure the impact of innovative pelvic floor muscle training (iPFMT) on Quality-Adjusted Life Years (QALYs) in women with stress urinary incontinence (SUI) treated by duloxetine.This analysis is part of the DULOXING study conducted between February 2019 and 2020. The control group received oral duloxetine treatment (40 mg BID), and the experimental group received oral duloxetine treatment (40 mg BID) and iPFMT with lumbopelvic stabilization. SUI was analysed at baseline and in the final period according to the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF). The QALYs gained were calculated by multiplying life expectancy (LE) by a weighting factor (QALYs = LE * WF).The study included 158 women, of whom 129 were fully analysed (81.6%). The mean life expectancy was 26.3 ± 11.8 years for the control group and 29.0 ± 11.7 years for the experimental group. The mean baseline ICIQ-UI SF scores were 15.2 ± 1.7 vs 15.1 ± 1.5, and the final ICIQ-UI SF scores were 9.8 ± 4.2 vs 8.3 ± 3.8, in the control vs the experimental group, respectively (p 0.05). The mean baseline WF was 0.27 ± 0.08 vs 0.28 ± 0.07, and the final WF was 0.53 ± 0.20 vs 0.60 ± 0.18, in the control vs the experimental group, respectively (p 0.05). Before treatment, the number of QALYs during life expectancy in the control vs the experimental group was 7.53 ± 4.24 vs 8.30 ± 4.01. The number of QALYs during life expectancy in control vs the experimental group increased following treatment: 15.03 ± 7.63 vs 17.90 ± 7.86 (p 0.05).Combination treatment with duloxetine and iPFMT statistically significantly increased the number of QALYs and reduced the degree of urinary incontinence in women with stress urinary incontinence.

Genetic nephrotic syndrome is caused by pathogenic variants in genes encoding proteins necessary for the stability and functionality of the glomerular filtration barrier. To date, more than 70 genes associated with steroid-resistant nephrotic syndrome have been identified. We review the clinical and molecular aspects of genetic nephrotic syndrome with a particular focus on genes associated with slit membrane and podocyte cytoskeleton defects. Sanger sequencing and next-generation sequencing are widely used in the identification of novel gene variants and help us gain a better understanding of the disease. Despite these findings, therapy is mainly supportive and focused on the reduction of proteinuria and management of chronic kidney disease with an unfavorable outcome for a significant proportion of cases. Positive therapeutic effects of immunosuppressive drugs have been reported in some patients; however, their long-time administration cannot be generally recommended.Personalized treatment based on understanding the distinct disease pathogenesis is needed. With this, it will be possible to avoid harmful immunosuppressive therapy and improve outcomes and quality of life for pediatric patients suffering from genetic nephrotic syndrome.

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The aim of our analysis was to evaluate the impact of the COVID-19 pandemic on the procurement program and kidney transplantation in Slovakia and to identify the risk factors for a severe course of COVID-19 disease, as well as the risk factors for COVID-19 fatalities, with the focus on the parameters preceding the infection. We compared morbidity and mortality from COVID-19 before and after the spread of the alpha variant of the virus and the same among transplant (KTRs) and haemodialysis patients in Slovakia.305 KTRs (68.8 % males) with confirmed SARS-CoV-2 positivity were included in the multicentric retrospective analysis. The patients were split into subgroups based on the time of falling ill and their clinical course.The procurement program and kidney transplants in Slovakia dropped in the observed period by 28.6 % (p0.0001) and by 33.5 % (p0.0001) respectively. Age over 59 years (p=0.0088) and diabetes mellitus (p=0.0106) were identified as independent risk factors for severe course of the disease. Risk factors for death were the age over 59 years (p=0.0003) and graft dysfunction with CKD-EPI0.5 mL/s (p=0.0029). The prevalence of the alpha variant in Slovakia was associated with a severe course in KTRs treated with corticoids (p=0.0273) and in graft dysfunction with CKD-EPI0.5 mL/s (p=0.0076); the risk of death was higher in KTRs over 59 years (p=0.0173) and again with CKD-EPI0.5 mL/s (p=0.0393). KTRs had a 3.7 times lower risk of infection compared to the haemodialysis patients (p0.0001), with mortality of 9.8 % vs 30 % (p0.0001).The procurement and transplant program is sustainable even during a pandemic, provided that measures are set up quickly. Morbidity and mortality from COVID-19 in KTRs was comparable to the situation in EU countries. Patients in the haemodialysis program had a worse prognosis (Tab. 5, Fig. 1, Ref. 21) Keywords: COVID-19, kidney transplantation, dialysis, immunosuppression, obesity, diabetes mellitus.

The aim of this study was to evaluate the potential of supportive therapy by natural polyphenols combined with vitamins C and E on kidney function and risk factors of cardiovascular diseases in renal transplant recipients (RTR).Transplant patients have an altered lipid profile associated with the development of cardiovascular disease, which is a major cause of graft loss and mortality in patients.The study included 29 renal transplant recipients with mean graft function levels. The lipoprotein (atherogenic and non-atherogenic) subfractions were identified and quantified in plasma by polyacrylamide gel electrophoresis.After supplementation, glomerular filtration rate (GFR) was increased by 8 %, serum creatinine was decreased by 6.7 % and significant changes were found in atherogenic LDL subfractions. The effect of supplementation was observed in arylesterase and lactonase activities of paraoxonase 1 which increased by 9.3 % and 8.1 %, respectively. In addition, significantly decreased levels of neopterin (by 16 %) and asymmetric dimethylarginine (ADMA) (by 7.9 %) were found.We could summarize that supportive therapy improves the renal function (GFR, serum creatinine), and reduces the risk of cardiovascular disease by affecting important risk markers of atherosclerosis (lipid profile, paraoxonase 1 activity, neopterin and ADMA) in RTR (Tab. 4, Fig. 1, Ref. 53).

The aim of our study was to evaluate the effect of a combination of innovative pelvic floor muscle training (iPFMT) and duloxetine compared with the use of duloxetine alone on women with stress urinary incontinence (SUI) after 12 weeks of treatment. We conducted a parallel multicentre study with randomized intervention in 45 national urological outpatient clinics. Patients with an enrolment ratio of 1:1 were divided into the experimental and control groups. The following were used for evaluation: incontinence episode frequency (IEF)/week, the International Consultation on Incontinence Questionnaire (ICIQ-SF), the Urinary Incontinence Quality of Life Scale (I-QoL) and the Patient Global Impression of Improvement (PGI-I). The experimental group received oral treatment with duloxetine (a daily dose of 40 mg BID) and innovative pelvic floor muscle training (iPFMT). The control group received only oral treatment with duloxetine at a daily dose of 40 mg BID. The number of women who were evaluated was 158. The control group comprised 79 women with an average age of 56.8 ± 13.8 years and the experimental group comprised 79 women with an average age of 53.4 ± 11.9 years. There were no significant differences in pre-treatment parameters. For the intent-to-treat analysis after 12 weeks’ treatment, significant differences were observed between the experimental vs. control group (p

Erectile dysfunction (ED) and diabetes mellitus (DM) share common pathophysiological risk factors including endothelial dysfunction which together with hyperglycemia contribute to the increased oxidative/glycooxidative stress. A reduced NO concentration is insufficient for relaxation processes in the penis. Chronic inflammation and endoglin are involved in the regulation of endothelial function. Adiponectin from the adipose tissue has anti-inflammatory effects. Our study aimed to investigate the relation between erectile function in patients with and without DM and the oxidative stress, hormone adiponectin, and endothelial dysfunction marker endoglin. Men (n=32) with ED evaluated by the International Index of Erectile function (IIEF-5) questionnaire (17 without DM (NDM); 15 with type 2 diabetes mellitus (DM)) and 31 controls were included. Advanced glycation end products (AGEs), 8-isoprostanes (8-isoP), protein carbonyls, antioxidant capacity, adiponectin and endoglin were determined in the blood. DM patients compared to NDM patients and controls, had increased levels of glucose, C-reactive protein, triacylglycerols, 8-isoP, AGEs, endoglin and BMI. IIEF-5 score, NO and adiponectin levels were decreased. We are the first to find out that endoglin shows a negative correlation with erectile function in NDM, but not in DM patients. Endoglin can be considered as endothelial dysfunction marker in nondiabetic men suffering from ED.

Objectives Erectile dysfunction (ED) is characterised as the inability to achieve or maintain an erection to complete sexual intercourse. ED may be considered as an early complication of diabetes mellitus (DM). The aim of this study was to assess the effect of registered food supplement, natural polyphenolic extract from the French maritime pine bark, Pycnogenol (PYC) on erectile function and lipid profile in ED patients. Methods 53 patients with ED were divided into two groups (32 with DM, 21 non-DM) in randomised, blinded and placebo-controlled study. During 3-month intervention with PYC or placebo and one month after the end of the intervention patients were investigated for ED with validated questionnaire International Index of Erectile Function-5 (IIEF-5); lipid profile, glycaemia was analysed in each group. Results In a randomised, blinded and placebo-controlled study, we found that natural polyphenolic extract, Pycnogenol improved erectile function in DM group by 45 % compared to the NDM group, where the improvement was also significant, but only by 22 %. Total cholesterol, LDL-cholesterol and glucose level was lowered by PYC in patients with DM. Glucose level was not affected by PYC in non-DM. Placebo showed no effect on monitored parameters in both groups. Conclusion Administration of Pycnogenol leads in improvement of erectile function in patients with ED and diabetes (DM group) by 45 %, in NDM group by 22 %, in lowering of total-, LDL-cholesterol by 20 % and 21 % and glycaemia by 22 % in DM (Tab. 2, Fig. 2, Ref. 19).

Malignancies are one of the three major causes of renal recipient´s death with a functioning graft after cardiovascular diseases and infections. Among the variety of risk factors, including conventional and specific to transplant recipients, the duration of immunosuppressive therapy, the intensity of therapy, and the type of immunosuppressive agent all have an impact on development of post-transplant malignancy. The aim of our retrospective study was to document the incidence, the type of malignancies, the patient/graft survival in the group of kidney transplant recipients in Slovak Republic, and to identify the factors which influenced the outcome. We analyzed the data of 1421 patients who underwent renal transplantation from deceased or living donors in the period from 2007 to 2015 in the Slovak transplant centers. The incidence of malignant tumors was 6%, the malignancy was diagnosed in 85 patients at the age of 54.1 ± 9.8 years, more frequently in men (68.2 %; P < 0.0001). The mean time of malignancy occurrence was 45 months after transplantation. The most frequent malignancies were skin cancers- basal cell carcinoma (BCC) in 17.6%, squamous cell carcinoma (SCC) in 8.2%, and malignant melanoma (MM) in 2.4% of patients, followed by non-skin tumors such as renal cell carcinoma (RCC) in 16.5%, cancer of colon in 12.9%, prostatic cancer in 9.4%, breast cancer in 9.4%, cancer of lung in 7.1%, post-transplant lymphoproliferative disease (PTLD) in 2.4%, cancer of urine bladder in 2.4%, and cancer of sublingual gland in 1.17% of patients. Surgical treatment was used in 40% of patients, chemotherapy in 7.1%, radiotherapy in 2.4%, treatment with biological agents in 15.3%, combined therapy in 29.4% and palliative treatment in 5.9% of patients. 55.3% of patients underwent conversion from other immunosuppressive agents into mTORi at the time of malignancy occurrence. The remission was achieved in 48.2% of patients, 28.2% of patients were in the oncology treatment in the end of the year 2015, and 23.5% of patients died. There was no difference in the kidney function at the time of malignancy occurrence (s-creat 133.7 ± 59.8 µmol/l) and one year later (s-creat 131.1 ± 47.9 µmol/l) (P = 0.7768). The patients after successful treatment more frequently suffered from BCC (P = 0.0140), did not undergo palliative treatment (P = 0.0033), but were more frequently treated surgically (P < 0.0001).

The aim of the current study was to investigate the influence of different grades of abdominal obesity (AO) on the prevalence of testosterone deficiency syndrome (TDS), erectile dysfunction (ED), and metabolic syndrome (MetS). In a cross-sectional descriptive study, a total of 216 males underwent a complete urological, internal, and hormonal evaluation. Males were divided according to waist circumference into five groups: less than 94 cm (Grade [G] 0), 94 to 101 cm (G1), 102 to 109 cm (G2), 110 to 119 cm (G3), and more than 120 cm (G4). Incidence of ED, TDS, and MetS was compared in these groups and in participants without AO. Some degree of ED was identified in 74.7% of males with AO. In G1, there were 61% of males with ED, in G2 68%, in G3 83%, and in G4 87%. A strong correlation between testosterone (TST) level and AO was identified. Ninety-eight out of 198 (49.5%) males with AO and 1/18 (5.5%) males without AO had TDS. There were significant differences between individual groups. In the group of males with AO G4 (more than 120 cm), 87.1% had TDS. MetS was diagnosed in 105/198 (53.0%) males with AO, but in G4, 83.9% of males with AO had MetS. Males older than 40 years of age with AO have a higher incidence of ED, TDS, and MetS. Dividing males into five groups according to waist circumference seems to be reasonable. With growing AO, there were significantly more males with ED, TDS, and MetS.

We have investigated the vasoactive effects of the coupled nitro-sulfide signaling pathway in lobar arteries (LAs) isolated from the nephrectomized kidneys of cancer patients: normotensive patients (NT) and patients with arterial hypertension (AH). LAs of patients with AH revealed endothelial dysfunction, which was associated with an increased response to the exogenous NO donor, nitrosoglutathione (GSNO). The interaction of GSNO with the H2S donor triggered a specific vasoactive response. Unlike in normotensive patients, in patients with AH, the starting and returning of the vasorelaxation induced by the end-products of the H2S-GSNO interaction (S/GSNO) was significantly faster, however, without the potentiation of the maximum. Moreover, increasing glycemia shortened the time required to reach 50% of the maximum vasorelaxant response induced by S/GSNO products so modulating their final effect. Moreover, we found out that, unlike K+ channel activation, cGMP pathway and HNO as probable mediator could be involved in mechanisms of S/GSNO action. For the first time, we demonstrated the expression of genes coding H2S-producing enzymes in perivascular adipose tissue and we showed the localization of these enzymes in LAs of normotensive patients and in patients with AH. Our study confirmed that the heterogeneity of specific nitroso-sulfide vasoactive signaling exists depending on the occurrence of hypertension associated with increased plasma glucose level. Endogenous H2S and the end-products of the H2S-GSNO interaction could represent prospective pharmacological targets to modulate the vasoactive properties of human intrarenal arteries.

Although the involvement of type 1 (IP3R1) and type 2 (IP3R2) inositol 1,4,5-trisphosphate receptors in apoptosis induction has been well documented in different cancer cells and tissues, the function of type 3 IP3R (IP3R3) is still elusive. Therefore, in this work we focused on the role of IP3R3 in tumor cells in vitro and in vivo. We determined increased expression of this receptor in clear cell renal cell carcinoma compared to matched unaffected part of the kidney from the same patient. Thus, we hypothesized about different functions of IP3R3 compared to IP3R1 and IP3R2 in tumor cells. Silencing of IP3R1 prevented apoptosis induction in colorectal cancer DLD1 cells, ovarian cancer A2780 cells, and clear cell renal cell carcinoma RCC4 cells, compared to apoptosis in cells treated with scrambled siRNA. As expected, silencing of IP3R3 and subsequent apoptosis induction resulted in increased levels of apoptosis in all these cells. Further, we prepared a DLD1/IP3R3_del cell line using CRISPR/Cas9 gene editing method. These cells were injected into nude mice and tumor's volume was compared with tumors induced by DLD1 cells. Lower volume of tumors originated from DLD1/IP3R3_del cells was observed after 12 days, compared to wild type DLD1 cells. Also, the migration of these cells was lesser compared to wild type DLD1 cells. Apoptosis under hypoxic conditions was more pronounced in DLD1/IP3R3_del cells than in DLD1 cells. These results clearly show that IP3R3 has proliferative and anti-apoptotic effect in tumor cells, on contrary to the pro-apoptotic effect of IP3R1.

BACKGROUND:Adjuvant sunitinib significantly improved disease-free survival (DFS) versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98; p=0.03).OBJECTIVE:To report the relationship between baseline factors and DFS, pattern of recurrence, and updated overall survival (OS).DESIGN, SETTING, AND PARTICIPANTS:Data for 615 patients randomized to sunitinib (n=309) or placebo (n=306) in the S-TRAC trial.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Subgroup DFS analyses by baseline risk factors were conducted using a Cox proportional hazards model. Baseline risk factors included: modified University of California Los Angeles integrated staging system criteria, age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), weight, neutrophil-to-lymphocyte ratio (NLR), and Fuhrman grade.RESULTS AND LIMITATIONS:Of 615 patients, 97 and 122 in the sunitinib and placebo arms developed metastatic disease, with the most common sites of distant recurrence being lung (40 and 49), lymph node (21 and 26), and liver (11 and 14), respectively. A benefit of adjuvant sunitinib over placebo was observed across subgroups, including: higher risk (T3, no or undetermined nodal involvement, Fuhrman grade ≥2, ECOG PS ≥1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55-0.99; p=0.04), NLR ≤3 (HR 0.72, 95% CI 0.54-0.95; p=0.02), and Fuhrman grade 3/4 (HR 0.73, 95% CI 0.55-0.98; p=0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66-1.28; p=0.6); 67 and 74 patients died in the sunitinib and placebo arms, respectively.CONCLUSIONS:A benefit of adjuvant sunitinib over placebo was observed across subgroups. The results are consistent with the primary analysis, which showed a benefit for adjuvant sunitinib in patients at high risk of recurrent RCC after nephrectomy.PATIENT SUMMARY:Most subgroups of patients at high risk of recurrent renal cell carcinoma after nephrectomy experienced a clinical benefit with adjuvant sunitinib.TRIAL REGISTRATION:ClinicalTrials.gov NCT00375674. BACKGROUND: Adjuvant sunitinib significantly improved disease-free survival (DFS) versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98; p=0.03).OBJECTIVE: To report the relationship between baseline factors and DFS, pattern of recurrence, and updated overall survival (OS).DESIGN, SETTING, AND PARTICIPANTS: Data for 615 patients randomized to sunitinib (n=309) or placebo (n=306) in the S-TRAC trial.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Subgroup DFS analyses by baseline risk factors were conducted using a Cox proportional hazards model. Baseline risk factors included: modified University of California Los Angeles integrated staging system criteria, age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), weight, neutrophil-to-lymphocyte ratio (NLR), and Fuhrman grade.RESULTS AND LIMITATIONS: Of 615 patients, 97 and 122 in the sunitinib and placebo arms developed metastatic disease, with the most common sites of distant recurrence being lung (40 and 49), lymph node (21 and 26), and liver (11 and 14), respectively. A benefit of adjuvant sunitinib over placebo was observed across subgroups, including: higher risk (T3, no or undetermined nodal involvement, Fuhrman grade ≥2, ECOG PS ≥1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55-0.99; p=0.04), NLR ≤3 (HR 0.72, 95% CI 0.54-0.95; p=0.02), and Fuhrman grade 3/4 (HR 0.73, 95% CI 0.55-0.98; p=0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66-1.28; p=0.6); 67 and 74 patients died in the sunitinib and placebo arms, respectively.CONCLUSIONS: A benefit of adjuvant sunitinib over placebo was observed across subgroups. The results are consistent with the primary analysis, which showed a benefit for adjuvant sunitinib in patients at high risk of recurrent RCC after nephrectomy.PATIENT SUMMARY: Most subgroups of patients at high risk of recurrent renal cell carcinoma after nephrectomy experienced a clinical benefit with adjuvant sunitinib.TRIAL REGISTRATION: ClinicalTrials.gov NCT00375674.

INTRODUCTION TRT in men with testosterone deficiency syndrome (TDS) had multiple positive effects and restore a quality of life of affected men. Polyglobulia is the most common dose-limiting adverse effect of TRT, but the mechanisms of TRT-mediated erythropoesis remain unclear. In this study, we evaluated long term haematological side effects of TRT: polyglobulia, elevated hemoglobin (Hb) and haematocrit (Ht). METHODS In a cross-sectional descriptive study, the authors treated 69 men with TDS and the average age 59 years and the follow-up period 81.32 months. The men were treated with three-month i.m. injections of 1000 mg testosterone undecanoate. The elevated values were: Hb above 176 g/l, Ht above 0.52 and erythrocytes (Ery) above 6.0 mil/mcl. RESULTS 21 out of 69 patients (30.43 %) had an increased Hb, Ht or Ery during treatment. The interesting fact was that only five men (7.24 %) had increased the number of Ery (true polyglobulia). No men with elevated level of Hb, Ht or Ery had other side effects (like thrombosis). CONCLUSION It is still not clear, why in some men on TRT the feedback does not work and bone marrow production of red blood cells continues even if the upper limit is reached. Authors expect that only 7% of men had true polyglobulia, other men had elevated Hb or Ht. Based on our own experience we recommend a regular check of men on TRT on order to avoid possible serious side-effects (Tab. 1, Fig. 2, Ref. 25).

In normotensive conditions, it has been confirmed that S-nitrosothiols, as a source of NO, interact with hydrogen sulfide (H2S) and create new substance/s with specific vasoactive effects. This interaction could represent new regulator pathway also in hypertension. The aim of the study was to investigate the vasoactive effects of H2S, GSNO, and products of H2S/GSNO interaction in lobar arteries isolated from kidney after nephrectomy of patients suffering from arterial hypertension. Changes in isometric tension after pre-contraction were evaluated. Acetylcholine- induced vasorelaxation was significantly reduced compared to the effect induced by exogenous NO donor, sodium nitroprusside, probably suggesting an endothelium dysfunction. While 1 μmol/l Na2S had a minimal effect on the vascular tone, 20 μmol/l evoked a slight vasorelaxation. GSNO at 0.1 μmol/l induced vasorelaxation which was significantly smaller compared to the effect induced by 1μmol/l. The mixture of GSNO (0.1 μmol/l) and Na2S (1 μmol/l) induced significantly higher vasorelaxation compared to GSNO (0.1 μmol/l) alone only in 5th minute without the differences in the speed. On the other hand, the mixture prepared from higher concentrations of GSNO (1 μmol/l) and Na2S (10 μmol/l) induced a significantly higher (in 1st, 2nd, 5th, 10th minute) and faster vasorelaxation compared to the effect induced by GSNO (1 μmol/l) alone. In conditions of arterial hypertension H2S in interaction with GSNO regulated a vasoconstrictor-increased arterial tone towards of more pronounced vasorelaxation compared to GSNO alone. We confirmed for the first time that specific vasoactive effects of coupled nitroso-sulfide signalization were triggered also in human arterial tissue.

Background The HLA-G molecule has a high potential to modulate immune response towards the improvement of graft survival after transplantation. In this work, we have analyzed the total HLA-G mRNA expression in graft tissues of dysfunctional transplanted kidneys. Material and methods We examined 84 kidney biopsy samples obtained from 65 renal transplant recipients with dysfunctional graft (50 males, 15 females; average age 46.8 ± 11.9 years). 52 specimens were with signs of acute rejection and 32 without any rejection characteristics (diagnosed as glomerulonephritis, ATN and IFTA). Patients with acute rejection were divided into three groups: antibody-mediated rejection (AMR; n = 23), T cell-mediated rejection (TCMR; n = 16) and combined antibody and T cell-mediated rejection (AMR + TCMR; n = 13). The biopsy samples were taken from a dysfunctional graft at different time periods after kidney transplantation. The relative expression of total HLA-G mRNA in biopsy specimens was determined by real time RT-PCR. The correlation between HLA-G mRNA expression and dysfunctional graft state was investigated. The impact of different factors (post-transplantation interval, gender, mismatch, induction therapy and cold ischemia time) on relative expression of total HLA-G mRNA was also studied. Results We have found that the levels of HLA-G transcripts in kidneys with rejection were higher than those in non-rejected but dysfunctional grafts (P = 0.0003). The highest levels of HLA-G mRNA were detected at combined AMR + TCMR rejection (P = 0.005). The time-course analysis of total HLA-G mRNA expression was also studied. In both dysfunctional graft groups (rejected and non-rejected) the lower levels of HLA-G transcripts were detected during early post-transplant period (1–3 months), however a substantial increase of HLA-G mRNA expression was observed after an extended period of time (> 3 months). It was also revealed that antibody induction therapy may reduce HLA-G expression (P = 0.0004) and in female samples were higher levels of HLA-G transcripts than those in male recipients (P = 0.003). It was found no significant impact of age, cold ischemic time, PRA (Panel Reactive Antibody) score, and a number of HLA-mismatches on HLA-G mRNA expression. Conclusions We have demonstrated that the expression of total HLA-G mRNA in renal grafts can be influenced by different factors such as clinical state of transplanted kidney, elapsed time after transplantation, gender and antibody induction therapy. We have proved that HLA-G mRNA expression was significantly higher in recipients with acute rejection in comparison to patients with dysfunctional but non-rejected grafts.

Background. Renal cell carcinoma (RCC) is a urologic malignancy with a steady rise in incidence and high mortality rate. Between 60 to 70% of patients with renal cell carcinoma can only be cured with surgery but despite advances in early diagnostis, in around 20-30% of cases there is metastasis. For these patients, chemotherapy and radiotherapy are ineffective and hence the prognosis is poor. Retinoids are biologically active compounds of either natural or synthetic origin that are involved in complex physiological and developmental processes in many tissues including cell proliferation and activation of tumour suppression genes. This article reviews the role of retinoids and their cognate nuclear retinoid/rexinoid receptors in relation to renal cell carcinoma. Methods. A literature search using ScienceDirect and Medline with a focus on the relationship between renal cell carcinoma and nuclear retinoid/rexinoid receptors. Results. Use of retinoids/rexinoids in the treatment of locally advanced and metastatic RCC significantly prolongs median time of tumour progression and overall survival of patients. Combination therapy with other preparations has greater efficacy than treatment with retinoids alone. Patient survival can be predicted on the basis of the expression of different all-trans retinoic acid receptor (RAR) and 9-cis retinoic acid receptor (RXR) subtypes. Conclusions. Since nuclear retinoid receptors play a crucial role as ligand-activated, DNA binding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes, retinoids might be an alternative approach for the treatment of renal cell carcinoma.

INTRODUCTION Malignant mesothelioma of tunica vaginalis testis is an extremely rare tumour. It is often caused by exposition to asbestos, however, more often its occurrence is sporadic. The diagnosis is usually set secondarily during hydrocele surgery. This type of tumour should be considered in cases with with atypical hydrocele, especially haematocele or atypical shape of seminal covering. RESULTS A case of an asbestos-exposed patient with described disease and long-term hydrocele is presented. The number of patients is so small that the guidelines are limited due to low statistical power (Fig. 2, Ref. 14).

Optimizing immunosuppressive treatment in the early posttransplant period is important for achieving long-term graft function and survival.There were 205 renal transplant recipients involved in this study. Patients were divided into groups according to the induction therapy (no induction vs basiliximab/daclizumab vs rabbit antithymocyte globulin), maintenance therapy at the time of transplantation (tacrolimus [TAC] vs cyclosporine), the average trough TAC levels in months 4 to 6 after TO and serum creatinine 5 years after renal transplantation.The incidence of acute rejection was significantly higher in cyclosporine than in TAC group of patients (P = .0364). The average TAC levels on elapsed time after transplantation significantly decreased (P .0001). Five years after renal transplantation, there were higher TAC levels (5.6 ± 0.7 ng/mL) in the group with "zero" low levels than in the group with "zero" high levels (4.6 ± 1.1 ng/mL), which was statistically significant (P .0001). We did not find any difference in graft and patient survival in posttransplant years 2 to 5 according to TAC levels or the induction treatment.In our study, we have confirmed that better graft function 5 years after transplantation was connected with higher trough tacrolimus levels on elapsed time after renal transplantation.

Carbonic anhydrase IX (CA IX) is regarded as one of the most prominent markers of tumor hypoxia with potential to serve as a diagnostic biomarker, prognostic indicator as well as tumor therapeutic target. The aim of the present study was to perform an in-depth analysis of CA IX expression in blood and tissue samples and to evaluate the significance of CA IX status for different renal cell carcinomas (RCCs). The expression of CA IX was determined in blood and tissue samples from 74 kidney cancer patients using reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), Western blotting (WB) and immunohistochemistry (IHC). The CA IX status was correlated with RCC type and tumor stage. IHC and WB provided evidence for a significantly higher expression of CA IX in clear cell RCC (CCRCC) specimens compared to other RCCs. RT-PCR assay revealed that 32.42% of all RCC patients possess CA9-positive cells in peripheral blood and three-quarters of CA9-positive patients were diagnosed with CCRCC. When the patients were subdivided according to tumor stage, decreased positivity was observed with higher tumor stage (50% in T1 vs. 17% in T3). Serum CA IX levels determined by ELISA were significantly higher in CCRCC patients than in non-CCRCC. A significant association between s-CA IX and CCRCC tumor stage was also determined (T1-87.51 vs. T3-341.98 pg/ml, p=0.046). We demonstrated that the CA IX expression profiles in blood and tissue samples from 74 kidney cancer patients are closely correlated with their histological subtypes. This is the first study reporting CA IX expression in blood and tissue samples from kidney cancer patients determined by four different methods.

Mutations of succinate dehydrogenase subunit B (SDHB) play a crucial role in the pathogenesis of the most aggressive and metastatic pheochromocytomas (PHEOs) and paragangliomas (PGLs). Although a variety of missense mutations in the coding sequence of the SDHB gene have been found in PHEOs and PGLs, it has been unclear whether these mutations impair mRNA expression, protein stability, subcellular localization, or intrinsic protein function. RT-PCR and Western blot analysis of SDHB mRNA and protein expression from SDHB-related PHEOs and PGLs demonstrated intact mRNA expression but significantly reduced protein expression compared to non-SDHB PHEOs and PGLs. A pulse-chase assay of common SDHB missense mutations in transfected HeLa cell lines demonstrated that the loss of SDHB function was due to a reduction in mutant protein half-life, whereas colocalization of SDHB with mitochondria and immunoprecipitation with SDHA demonstrated intact subcellular localization and complex formation. The half-life of the SDHB protein increased after treatment with histone deacetylase inhibitors (HDACis), implicating the protein quality control machinery in the degradation of mutant SDHB protein. These findings provide the first direct mechanism of functional loss resulting from SDHB mutations and suggest that reducing protein degradation with HDACis may serve as a novel therapeutic paradigm for preventing the development of SDHB-related tumors.—Yang, C., Matro, J. C., Huntoon, K. M., Ye, D. Y., Huynh, T. T., Fliedner, S. M. J., Breza, J., Zhuang, Z., Pacak, K. Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function.

The aim of this study was to determine the prevalence of erectile dysfunction (ED), testosterone deficiency syndrome (TDS), and metabolic syndrome in patients with abdominal obesity (AO) and the prevalence of morbidity at different levels of testosterone (TST).Male sex hormones play an important role in ED and variety of TDS and may have influence on the development of metabolic syndrome. The number of men with AO which constitutes a serious health risk is continuously growing. Currently, there are different views that TST levels are already insufficient, and the patient should benefit from treatment.This study examined the association between ED, testosterone level and metabolic syndrome in men with AO.The study was carried out in an outpatient urology center of Urology Clinic and Obesity Center of the Clinic of Internal Medicine. There were 167 participants—men with AO which were examined as part of preventive examination.Hormonal, a complete urological and internal evaluation was carried out in every patient.We found some degree of ED in 73% (122/167) in men with AO. The TST levels below 14 nmol/l had of these 122 patients 84 patients (68.9%) and 49 patients (40.2%) below 10 nmol/l. In this group of patients, we found 103/167 patients (61.7%) with metabolic syndrome. When we compared TST level and morbidity, we found significantly more patients with diabetes mellitus (DM), hypertension and dyslipidemia in group with TST below 10 nmol/l. We also found difference in the levels of HDL cholesterol and triglycerides in the group of patients with TST 10–14 and over 14 nmol/l.Patients over 40 years of age with AO and ED should also be examined for TDS and metabolic syndrome. In this group of patients we found that 113/167 patients (67.6%) had total TST below 14 nmol/l, and sufficient level of TST seems to be above this level.

Tubulocystic renal carcinoma (TCRC) is a recently described neoplastic entity. To date, clinicopathological features on less than hundred cases of these rare tumours have been characterized exclusively in the pathological literature. Herein, we present five additional cases emphasizing clinical aspects on these rare renal neoplasms. Cases diagnosed as TCRC were retrieved and reviewed from the routine and consultation files of the Pilsen tumour registry comprising over 20,000 cases of renal tumours. All patients were men, mean age 56 years (range 29–70). Features on computed tomography (CT) were in two cases Bosniak III, one IV and two were solid tumours. In four patients, nephrectomy was performed, and one patient underwent resection. At the time of surgery, two patients had metastases. In one case, both primary tumour and metastases were active on FDG positron emission tomography (PET)/CT. Both patients with metastatic disease were treated with sunitinib with partial response. One patient died 26 months postoperatively and the other patient is alive 5 months after surgery. Three patients with localized tumours are without evidence of disease 31, 28 and 7 months after surgery. In one case, the resected tumour was histologically combined with a papillary renal cell carcinoma (PRCC). TCRC occurs predominantly in men with a wide age range. TCRC frequently displays a cystic component which may render a radiological classification of Bosniak III or IV. FDG PET/CT is helpful in the detection of metastases. TCRC has definitive malignant potential. Our findings support a possible relationship to PRCC. The tyrosine kinase inhibitor sunitinib may be used a therapeutical agent with partial response and temporary effect.

There are often problems in differentiating between benign and malignant adrenal gland tumors by imaging and histopathology. Fine-needle biopsy is possible but not used owing to problems in histopathological differentiation. On account of considerable differences in the therapy and aftercare of benign and malignant adrenal tumors, correct classification of tumor type is of greatest importance. The purpose of this study was to define specific genetic alterations differentiating between adenomas and carcinomas.DNA was isolated from tumor areas in paraffin sections and amplified by a modified protocol for DOP-PCR. After labeling of tumor-DNA and normal DNA with biotin-dUTP and digoxigenin-dUTP, respectively, comparative genomic hybridization (CGH) was carried out according to standard protocols. Retrospectively, 26 (16 adenomas and 10 carcinomas) tumors of the adrenal cortex were analyzed.Genetic alterations were found in 5/16 adenomas (31.25%) and in all adrenocortical carcinomas. The mean number of genetic changes per tumor was 8.7 (range 6-12) in carcinomas. The benign cortical tumors present 1.6 changes (range 0-3) per tumor. Only a moderate correlation between number of alterations and size of tumor was seen. Furthermore, specific chromosomal alterations of carcinomas were identified.Genetic evaluation facilitates differentiation between adrenal gland tumors. Genetic tests should be used in routine diagnostics of adrenal specimens. Potentially, fine-needle biopsy can be established as standard diagnostics of adrenal tumors with unknown genesis.

576 Background: In the phase III S-TRAC trial, adjuvant sunitinib (SU) prolonged disease-free survival (DFS) vs placebo (PBO) in patients with locoregional renal cell carcinoma at high risk of recurrence after nephrectomy (median 6.8 vs 5.6 y; hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59–0.98; P= 0.03). An exploratory analysis evaluated associations between single nucleotide polymorphisms (SNPs) in angiogenesis-related genes and clinical outcomes in S-TRAC. Methods: Prospectively collected blood samples were genotyped for 10 SNPs and 1 insertion/deletion mutation with TaqMan assays. DFS was compared with a log-rank test for each SNP genotype in SU vs PBO arms and between SNP genotypes within each arm. P-values are unadjusted for multiplicity comparison. Results: Of 615 patients, 286 (142 SU; 144 PBO) were analyzed. There were generally no genotype frequency deviations from the Hardy-Weinberg equilibrium, but linkage disequilibrium was seen between VEGFA rs699947 and rs833061 on chromosome 6 (D′ = 1.000, r2 = 0.979). Longer DFS was observed with SU vs PBO for VEGFR1 rs9554320 C/C (median: not reached [NR] vs 5.56 y; HR 0.44, 95% CI 0.21–0.91; P= 0.023), VEGFR2 rs2071559 T/T (median: NR vs 4.47 y; HR 0.46, 95% CI 0.23–0.90; P= 0.020), and eNOS rs2070744 T/T (median: 7.07 vs 3.44 y; HR 0.53, 95% CI 0.30–0.94; P= 0.028), with a trend for VEGFR1 rs9582036 A/A (median: NR in both arms; P= 0.054) and SH3GL2 rs10963287 C/T (median: NR vs 5.35 y; P= 0.088). Shorter DFS was observed for VEGFR1 rs9582036 C/A vs C/C in the SU, PBO, and combined arms ( P< 0.05); for A/A vs common, the association was only seen in the SU arm ( P= 0.022). VEGFR1 rs9554320 A/C was associated with shorter DFS vs A/A in the PBO ( P= 0.038) and combined arm ( P= 0.006), with a trend in the SU arm ( P= 0.051). VEGFR2 rs1870377 T/T was associated with longer DFS vs A/A in the combined arms, but not in the PBO arm (n = 7 with A/A genotype in the SU arm precluded statistical tests). Conclusions: Correlations between common VEGFR1 and VEGFR2 SNPs and longer DFS with SU suggest germline SNPs are predictive of improved outcomes with adjuvant SU. Due to the exploratory nature of this analysis, prospective validation studies are needed to confirm these findings. Clinical trial information: NCT00375674.

Clear cell renal cell carcinoma (ccRCC) is the most frequent type of kidney cancer. In order to better understand the biology of ccRCC, we accomplished the gene profiling of fresh tissue specimens from 11 patients with the renal tumors (9 ccRCCs, 1 oncocytoma and 1 renal B-lymphoma), in which the tumor-related data were compared to the paired healthy kidney tissues from the same patients. All ccRCCs exhibited a considerably elevated transcription of the gene coding for carbonic anhydrase IX (CAIX). Moreover, the ccRCC tumors consistently displayed increased expression of genes encoding the glycolytic pathway enzymes, e.g. hexokinase II (HK2) and lactate dehydrogenase A (LDHA) and a decreased expression of genes for the mitochondrial electron transport chain components, indicating an overall reprogramming of the energetic metabolism in this tumor type. This appears to be accompanied by altered expression of the genes of the pH regulating machinery, including ion and lactate transporters. Immunohistochemical staining of tumor tissue sections confirmed the increased expression of CAIX, HK2 and LDHA in ccRCC, validating the microarray data and supporting their potential as the energetic metabolism-related biomarkers of the ccRCC.

Contains fulltext : 49933.pdf (Publisher’s version ) (Closed access) There are currently no reliable diagnostic and prognostic markers or effective treatments for malignant pheochromocytoma. This study used oligonucleotide microarrays to examine gene expression profiles in pheochromocytomas from 90 patients, including 20 with malignant tumors, the latter including metastases and primary tumors from which metastases developed. Other subgroups of tumors included those defined by tissue norepinephrine compared to epinephrine contents (i.e., noradrenergic versus adrenergic phenotypes), adrenal versus extra-adrenal locations, and presence of germline mutations of genes predisposing to the tumor. Correcting for the confounding influence of noradrenergic versus adrenergic catecholamine phenotype by the analysis of variance revealed a larger and more accurate number of genes that discriminated benign from malignant pheochromocytomas than when the confounding influence of catecholamine phenotype was not considered. Seventy percent of these genes were underexpressed in malignant compared to benign tumors. Similarly, 89% of genes were underexpressed in malignant primary tumors compared to benign tumors, suggesting that malignant potential is largely characterized by a less-differentiated pattern of gene expression. The present database of differentially expressed genes provides a unique resource for mapping the pathways leading to malignancy and for establishing new targets for treatment and diagnostic and prognostic markers of malignant disease. The database may also be useful for examining mechanisms of tumorigenesis and genotype-phenotype relationships. Further progress on the basis of this database can be made from follow-up confirmatory studies, application of bioinformatics approaches for data mining and pathway analyses, testing in pheochromocytoma cell culture and animal model systems, and retrospective and prospective studies of diagnostic markers.

There is no reliable method currently available to predict malignant potential of pheochromocytoma based on conventional histology or genetic, molecular or immunohistochemical markers. Metastasis suppressor genes affect the spread of several cancers and, therefore, may provide promise as prognostic markers or therapeutic targets for malignant pheochromocytoma. We hypothesized that the downregulation of metastasis suppressor genes in malignant pheochromocytoma may play a role in malignant behavior. We applied quantitative real-time polymerase chain reaction (QRT-PCR) to 11 metastasis suppressor genes. These genes are known to be involved in the regulation of important cancer-related cellular events, such as cell growth regulation and apoptosis (nm23-H1, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TXNIP and CRSP-3), cell-cell communication (BRMS-1), invasion (CRMP-1) and cell adhesion (E-Cad and KiSS1). The study included 15 benign and 10 malignant pheochromocytomas. Six metastasis suppressor genes (nm23-H1, TIMP-4, BRMS-1, TXNIP, CRSP-3 and E-Cad) were downregulated significantly in malignant compared to benign pheochromocytoma (p < 0.05, Mann-Whitney U-test). We applied a non-linear rule using median malignant value (MMV) as a threshold to use metastasis suppressor genes to distinguish malignant from benign samples. After cross-validation, the non-linear rule produced no errors in 10 malignant samples and 3 errors in the 15 benign samples, with an overall error rate of 12%. These results suggest that downregulation of metastasis suppressor genes reflect malignant pheochromocytoma with a high degree of sensitivity. Thus, we conclude that altered function of these metastasis suppressor gene pathways may play an important role in the malignant behavior of pheochromocytoma.

The effect of Pycnogenol® (PYC) (extract from the bark of the French maritime pine, Pinus pinaster) and placebo on lipid metabolism, antioxidant status and erectile function was investigated in 21 patients suffering from erectile dysfunction (ED). The patients were treated with PYC (120 mg/day) or placebo for three months in a double-blind study. After three months of administration, PYC significantly improved ED (p < 0.05) from moderate to mild stage determined with International Index of Erectile Function (IIEF-5). Simultaneously, a significant increase of plasma antioxidant activity (p < 0.01) was observed. Three months after PYC administration, the level of total cholesterol decreased from 5.41 to 4.98 mmol/L and LDL-cholesterol from 3.44 to 2.78 mmol/L. Placebo had no effect. The levels of HDL-cholesterol and TAGs were not changed. Pycnogenol® seems to have a beneficial effect on treatment of erectile dysfunction.

The authors publish probably the first biopsy case of signet ring carcinoma of female prostate in a 76-year-old woman. Tumorous tissue infiltrating orifice of the urethra and its surroundings, with periurethral propagation in the urethrovaginal septum and the anterior vaginal wall, produced increasing painful dysuria in the patient. Histologically, the tumor was composed of large cells with characteristics of neoplastic signet ring cells with diastase-resistant PAS positivity of cumulated mucin in cytoplasm. Smaller anaplastic tumor cells with large nucleus and rudimentary glandular carcinoma structures were also present. All neoplastic cells expressed prostate specific antigen (PSA), cytokeratins, vimentin, most of them also carcinoembryonic antigen (CEA) and some also the prostate specific acid phosphatase (PSAP). Electron microscopy of signet ring cells disclosed numerous mucin granules of different sizes and dense lysosome-like particles with the character of cytosegresomes containing residues of mito...

Background: Adjuvant therapy with sunitinib (SU) compared with placebo (PBO) prolonged disease-free survival (DFS) in patients (pts) with loco-regional high-risk renal cell carcinoma (HR=0.76, 95% CI: 0.59-0.98; P=0.03; median[m] DFS, 6.8 vs 5.6 years). Here, we report the results of a retrospective exploratory molecular biomarker analysis using nephrectomy biospecimens from the S-TRAC trial. Materials and Methods: Formalin-fixed paraffin-embedded tumor tissue blocks from patients who provided informed consent were used for immunohistochemistry (IHC) staining of PD-L1, CD4, CD8, and CD68. Biomarker quantification was done by automated image analysis of the regions of interest (ROI). The analysis algorithm utilized an immunoscore approach applied to ROI, reflecting assessment of both the center and invasive margin of tumors (for PD-L1 and CD8 staining). DFS was compared between biomarker stratum by < median vs ≥ median values of a particular IHC parameter using Kaplan-Meier (K-M) analysis. Receiver Operating Characteristics (ROC) curves were generated to further assess the potential clinical utility of biomarkers for which significant (P < 0.05) results were obtained in K-M analysis. Results: In total, 191/615 (101, SU and 90, PBO) pts in the intent-to-treat population were included for IHC analysis. Baseline characteristics were similar in the subpopulations with and without IHC data. Shorter DFS was observed in the PBO group for pts with PD-L1+ vs PD-L1- tumors, although not statistically significant (HR=1.75; 95% CI: 0.89-3.46; P=0.103). In pts with PD-L1+ tumors, DFS was numerically longer for SU vs PBO (mDFS=6.17 vs 2.67 years) (HR=0.58; 95% CI: 0.26-1.29; P=0.175). In the SU group, pts with CD8+ T-cell density ≥ median (cutoff=269.5 CD8+ cells/mm2) had longer DFS (mDFS=not reached [NR]; 95% CI: 6.83-NR) than pts with CD8+ T-cell density < median (mDFS=3.47 years; 95% CI: 1.73-NR), and the difference was statistically significant (HR=0.40, 95% CI: 0.20-0.81; P=0.009), while CD8+ T-cell density showed no significant difference in DFS for PBO pts (HR=0.80, 95% CI: 0.42-1.50; P=0.484). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively, and the optimal cutoff was 222.22 cells/mm2 with an area under ROC curve of 0.622. Conclusions: Increased density of CD8+ T-cells in tumor tissue was associated with longer DFS in SU-randomized pts but not PBO, suggesting this may be predictive of treatment effect. Further validation in an independent cohort is warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk non-metastatic RCC should be further explored. Citation Format: Daniel J. George, Jean-Francois Martini, Yen-Hwa Chang, Michael Staehler, Jan Breza, Jean-Jacques Patard, Robert J. Motzer, Ahmed Magheli, Bernard Escudier, Giacomo Carteni, Paola Gerletti, Sherry Li, Michelle Casey, Brigitte Laguerre, Hardev S. Pandha, Allan J. Pantuck, Anup Patel, Maria Lechuga, Alain Ravaud. Phase 3 trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma: exploratory molecular analysis of tumor biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1771. doi:10.1158/1538-7445.AM2017-1771

4508 Background: Adjuvant therapy with sunitinib (SU) compared with placebo (PBO) prolonged disease-free survival (DFS) in 615 patients (pts) with high-risk RCC (hazard ratio [HR] 0.76; P= 0.03) in the S-TRAC trial. The 16-gene Recurrence Score (RS) was developed and validated to predict risk of recurrence of RCC after nephrectomy in 2 cohorts of stage I–III pts (Rini et al., Lancet Oncol 2015;16:676-85). We present further validation of RS results in high-risk stage III pts from S-TRAC. Methods: The study was prospectively designed with prespecified genes, algorithm, endpoints, analytical methods, and analysis plan using primary RCC tissues from 212 evaluable pts with informed consent. Gene expression was quantitated by RT-PCR; primary analysis focused on stage III (n = 193 pts). Time to recurrence (TTR) and DFS were analyzed using Cox proportional hazard regression. Results: Baseline characteristics were similar in SU and PBO arms and in pts with and without gene expression data; effect of SU was numerically similar to that in the entire trial (DFS HR 0.78, 95% CI 0.48–1.24; P= 0.29). RS predicted TTR and DFS in both treatment arms with the strongest results observed in PBO arm where high RS group had significantly higher risk (Table). Interaction of RS with treatment was not significant (TTR P= 0.192; DFS P= 0.219); however, the number of events was relatively low. Conclusions: The prognostic value of the 16-gene assay was confirmed in S-TRAC. RS is now validated with consistent results in 2 separate studies (level IB evidence). RS results may help identify patients at high risk who could derive higher absolute benefit from adjuvant treatment. The predictive value of RS to select patients for adjuvant SU requires further investigation in independent adjuvant trials. [Table: see text]

Introduction. Seborrheic keratoses are very common benign epidermal tumors. Despite the high frequency, the pathogenesis is still unknown. They are extremely rare in the genital area. The participation of human papilloma viruses (HPVs) in pathogenesis of seborrheic keratoses is being discussed. Aims. The aims of this case report are to inform about extremely rare lesion in genital area in a young man and evaluate the association of HPVs in the development of seborrheic keratoses. Methods. We used histopathological examination to establish the correct diagnosis, which revealed signs of sebor- rheic keratosis. The real-time polymerase chain reaction method confirmed low-risk HPV 6 from the lesions. Main Outcome Measures. HPVs may play a role in pathogenesis of seborrheic keratoses. Results. The patient was successfully treated with shave excision under spinal anesthesia. Six-month follow-up was without any recurrence. We suggest that HPVs can be considered as etiologic factor in creation of seborrheic keratosis. Conclusions. Seborrheic keratoses are very common on sun-exposed skin, but they are rare in the genital area, such as on the shaft of penis. This localization may lead to misdiagnosis. Seborrheic keratoses in genital area might negatively influence the sexual life of the patient. Containing HPV 6 low-risk virus, they never lead to malignant transformation. Part M, Svecova D, Brezova D, and Breza J. Giant seborrheic keratoses on penis. J Sex Med 2014;11:3119-3122.