Identification and replication of the interplay of four genetic high-risk variants for urinary bladder cancer.

Little is known whether genetic variants identified in genome-wide association studies interact to increase bladder cancer risk. Recently, we identified two- and three-variant combinations associated with a particular increase of bladder cancer risk in a urinary bladder cancer case-control series (Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), 1501 cases, 1565 controls). In an independent case-control series (Nijmegen Bladder Cancer Study, NBCS, 1468 cases, 1720 controls) we confirmed these two- and three-variant combinations. Pooled analysis of the two studies as discovery group (IfADo-NBCS) resulted in sufficient statistical power to test up to four-variant combinations by a logistic regression approach. The New England and Spanish Bladder Cancer Studies (2080 cases and 2167 controls) were used as a replication series. Twelve previously identified risk variants were considered. The strongest four-variant combination was obtained in never smokers. The combination of rs1014971[AA] near apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A (APOBEC3A) and chromobox homolog 6 (CBX6), solute carrier family 1s4 (urea transporter), member 1 (Kidd blood group) (SLC14A1) exon single nucleotide polymorphism (SNP) rs1058396[AG, GG], UDP glucuronosyltransferase 1 family, polypeptide A complex locus (UGT1A) intron SNP rs11892031[AA] and rs8102137[CC, CT] near cyclin E1 (CCNE1) resulted in an unadjusted odds ratio (OR) of 2.59 (95% CI = 1.93-3.47; P = 1.87 × 10-10), while the individual variant ORs ranged only between 1.11 and 1.30. The combination replicated in the New England and Spanish Bladder Cancer Studies (ORunadjusted = 1.60, 95% CI = 1.10-2.33; P = 0.013). The four-variant combination is relatively frequent, with 25% in never smoking cases and 11% in never smoking controls (total study group: 19% cases, 14% controls). In conclusion, we show that four high-risk variants can statistically interact to confer increased bladder cancer risk particularly in never smokers.

Polymorphisms of xenobiotic metabolizing enzymes in bladder cancer patients of the Semmelweis University Budapest, Hungary.

Polymorphic xenobiotic metabolizing enzymes such as N-acetyltransferase 2 (NAT2) or glutathione S-transferase M1 (GSTM1) are known to modulate bladder cancer risk. As no apparent data were available from Hungary, a former member of the eastern European economic organization, a study was performed in Budapest. In total, 182 bladder cancer cases and 78 cancer-free controls were investigated by questionnaire. Genotypes of NAT2, GSTM1, GSTT1, rs1058396 and rs17674580 were determined by standard methods. Current smokers' crude odds ratio (OR) (3.43) and former smokers crude OR (2.36) displayed a significantly increased bladder cancer risk. The risk rose by a factor of 1.56 per 10 pack years. Exposure to fumes was associated with an elevated bladder cancer risk (23% cases, 13% controls). Sixty-four % of the cases and 59% of controls were slow NAT2 acetylators. It was not possible to establish a particular impact of NAT2*6A and *7B genotypes (15 cases, 8%, 5 controls, 7%). GSTT1 exerted no marked influence on bladder cancer (negative 21% cases vs. 22% controls). The portion of GSTM1 negative bladder cancer patients was increased (63% cases vs. 54% controls). The SLC14A1 SNPs rs1058396[AG/GG] and the nearby rs17674580[CT/TT] occurred more frequently in cases (79% and 68%) than controls (77% and 55%). The portion of GSTM1 negative bladder cancer patients is comparable with portions reported from other industrialized areas like Lutherstadt Wittenberg/Germany (58%), Dortmund/Germany (70%), Brescia/Italy (66%) or an occupational case-control series in Germany (56%). Data indicate that GSTM1 is a susceptibility factor for environmentally triggered bladder cancer rather than for smoking-mediated bladder cancer.

[Role of the diet in urinary stone formation and prevalence]. / Az étrend szerepe a húgyúti kövek kialakulásában és megelozésében.

In Hungary and in the developed countries urinary stones occur more often due to nutritional habits, obesity and sedentary lifestyle beside the endocrine and metabolic causes. In the daily urological and family doctor practice prevention should have an important role. Prevention is based not only on body weight control, physical exercise and medical treatment, but on proper diet as well. The nutritional components can change the consistence of urine, causing supersaturation, which is essential in stone formation. Specific nutritional components can either prevent stone formation (increased fluid intake, citrate, magnesium, fruits and vegetables) or either increase stone formation (decreased fluid intake, proteins, carbohydrates, oxalate, salt, increased calcium intake, ascorbic-acid etc). We summarized evidence-based practical dietary suggestions on the primary and secondary prevention of urinary stones. Orv Hetil. 2017; 158(22): 851-855.

Urinary bladder cancer risk in relation to a single nucleotide polymorphism (rs2854744) in the insulin-like growth factor-binding protein-3 (IGFBP3) gene.

Currently, twelve validated genetic variants have been identified that are associated with urinary bladder cancer (UBC) risk. However, those validated variants explain only 5-10% of the overall inherited risk. In addition, there are more than 100 published polymorphisms still awaiting validation or disproval. A particularly promising of the latter unconfirmed polymorphisms is rs2854744 that recently has been published to be associated with UBC risk. The [A] allele of rs2854744 has been reported to be associated with a higher promoter activity of the insulin-like growth factor-binding protein-3 (IGFBP3) gene, which may lead to increased IGFBP-3 plasma levels and cancer risk. Therefore, we investigated the association of rs2854744 with UBC in the IfADo case-control series consisting of 1,450 cases and 1,725 controls from Germany, Hungary, Venezuela and Pakistan. No significant association of rs2854744 with UBC risk was obtained (all study groups combined: unadjusted P = 0.4446; adjusted for age, gender and smoking habits P = 0.6510), besides a small effect of the [A] allele in the Pakistani study group opposed to the original findings (unadjusted P = 0.0508, odds ratio (OR) = 1.43 for the multiplicative model) that diminished after adjustment for age, gender and smoking habits (P = 0.7871; OR = 0.93). Associations of rs2854744 with occupational exposure to urinary bladder carcinogens and smoking habits were also not present. A meta-analysis of all available case-control series including the original discovery study resulted in an OR of 1.00 (P = 0.9562). In conclusion, we could not confirm the recently published hypothesis that rs2854744 in the IGFBP3 gene is associated with UBC risk.

Rs11892031[A] on chromosome 2q37 in an intronic region of the UGT1A locus is associated with urinary bladder cancer risk.

Recently, rs11892031[A] has been identified in a genome-wide association study (GWAS) to confer increased risk of urinary bladder cancer (UBC). To confirm this association and additionally study a possible relevance of exposure to urinary bladder carcinogens, we investigated the IfADo UBC study group, consisting of eight case-control series from different regions including 1,805 cases and 2,141 controls. This analysis was supplemented by a meta-analysis of all published data, including 13,395 cases and 54,876 controls. Rs11892031 A/A was significantly associated with UBC risk in the IfADo case-control series adjusted to cigarette smoking, gender, age and ethnicity (OR = 1.18; 95% CI = 1.02-1.37; P = 0.026). In the meta-analysis, a convincing association with UBC risk was obtained (OR = 1.19; 95% Cl = 1.12-1.26; P < 0.0001). Interestingly, the highest odds ratios were obtained for individual case-control series with a high degree of occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines: cases with suspected occupational UBC (OR = 1.41) and cases from the highly industrialized Ruhr area (OR = 1.98) compared with Ruhr area controls (all combined OR = 1.46). Odds ratios were lower for study groups with no or a lower degree of occupational exposure to bladder carcinogens, such as the Hungary (OR = 1.02) or the ongoing West German case-control series (OR = 1.06). However, the possible association of rs11892031[A] with exposure to bladder carcinogens still should be interpreted with caution, because in contrast to the differences between the individual study groups, interview-based data on occupational exposure were not significantly associated with rs11892031. In conclusion, the association of rs11892031[A] with UBC risk could be confirmed in independent study groups.

Genotyping NAT2 with only two SNPs (rs1041983 and rs1801280) outperforms the tagging SNP rs1495741 and is equivalent to the conventional 7-SNP NAT2 genotype.

Genotyping N-acetyltransferase 2 (NAT2) is of high relevance for individualized dosing of antituberculosis drugs and bladder cancer epidemiology. In this study we compared a recently published tagging single nucleotide polymorphism (SNP) (rs1495741) to the conventional 7-SNP genotype (G191A, C282T, T341C, C481T, G590A, A803G and G857A haplotype pairs) and systematically analysed if novel SNP combinations outperform the latter. For this purpose, we studied 3177 individuals by PCR and phenotyped 344 individuals by the caffeine test. Although the tagSNP and the 7-SNP genotype showed a high degree of correlation (R=0.933, P<0.0001) the 7-SNP genotype nevertheless outperformed the tagging SNP with respect to specificity (1.0 vs. 0.9444, P=0.0065). Considering all possible SNP combinations in a receiver operating characteristic analysis we identified a 2-SNP genotype (C282T, T341C) that outperformed the tagging SNP and was equivalent to the 7-SNP genotype. The 2-SNP genotype predicted the correct phenotype with a sensitivity of 0.8643 and a specificity of 1.0. In addition, it predicted the 7-SNP genotype with sensitivity and specificity of 0.9993 and 0.9880, respectively. The prediction of the NAT2 genotype by the 2-SNP genotype performed similar in populations of Caucasian, Venezuelan and Pakistani background. A 2-SNP genotype predicts NAT2 phenotypes with similar sensitivity and specificity as the conventional 7-SNP genotype. This procedure represents a facilitation in individualized dosing of NAT2 substrates without losing sensitivity or specificity.

Rs710521[A] on chromosome 3q28 close to TP63 is associated with increased urinary bladder cancer risk.

Single nucleotide polymorphism (SNP) rs710521[A], located near TP63 on chromosome 3q28, was identified to be significantly associated with increased bladder cancer risk. To investigate the association of rs710521[A] and bladder cancer by new data and by meta-analysis including all published data, rs710521 was studied in 1,425 bladder cancer cases and 1,740 controls that had not been included in previous studies. Blood samples were collected from 1995 to 2010 in Germany (n = 948/1,258), Hungary (n = 262/65), Venezuela (n = 112/190) and Pakistan (n = 103/227) supplemented by a meta-analysis of 5,695 cases and 40,187 controls. Detection of a A/G substitution (rs710521) on chromosome 3q28, position 191128627 was done via fast real-time polymerase chain reaction (rt-PCR). Rs710521[A] is associated with increased risk in the unadjusted analysis (OR = 1.21; 95% Cl = 1.04-1.40; P = 0.011) and in the recessive model adjusted for age, gender, smoking habits and ethnicity (OR = 1.23; 95% Cl = 1.05-1.44; P = 0.010). No difference between individuals occupationally exposed versus not occupationally exposed to urinary bladder carcinogens was observed concerning the relevance of rs710521[A]. Similarly, rs710521[A] did not confer different susceptibility in smokers and non-smokers. Performing a meta-analysis of 5,695 cases and 40,187 controls including all published studies on rs710521, a convincing association with bladder cancer risk was obtained (OR = 1.18; 95% Cl = 1.12-1.25; P < 0.0001). However, the odds ratio is relatively small.

Major Complications after Male Anti-Incontinence Procedures: Predisposing Factors, Management and Prevention.

PURPOSE: Significant post-prostatectomy incontinence (PPI) is a crippling condition and managed best through sling or artificial urinary sphincter (AUS) implantation. These procedures are often associated with complications requiring surgical intervention. The aim of our retrospective study was to evaluate the occurrence of major complications and identify risk factors. MATERIALS AND METHODS: Between 2010 and 2018 ninety-one patients have been implanted with sling (22; 24.2%) or AUS (69; 75.8%) in our department. The cases where surgical revision was needed were examined regarding the etiology (mechanical failure (MF), urethral erosion (UE), urethral atrophy (UA), surgical site infection (SSI), combined reasons (COMB) and analyzed, using 16 possible perioperative risk factors. RESULTS: Surgical intervention was carried out by 19 / 91 (20.9%) patients. (In 16 / 69 cases after AUS (23.1%), 3 / 13 after slings (23%)). The indication was in 6 (31.6%) cases MF, in 3 (15.8 %) COMB, in 4 (21.1%) UE, in 5 (26.3 %) SSI, in 1 (5.2%) UA. The type of reoperation was either explantation (12 / 19), system replacement (6 / 19), or cuff replacement (1 /19). Regarding the surgical intervention requiring complications only preoperative bacteriuria (P = .006) and postoperative surgical site oedema (P = .002) proved to be independent predictive factors. CONCLUSION: Preoperative bacteriuria and surgical site oedema seemed to be good predictors for obligate surgical revision. Patients with AUS were more prone to have major complications. In most cases it was mechanical failure, infection or erosion. By reducing the frequency of these risk factors we might be able to decrease the amount of complications.

Management of congenital penile curvature.

PURPOSE: The long-term results of the management in adulthood of congenital curvature of the penis (ventral, lateral and dorsal) without hypospadias using 3 different techniques are carefully evaluated based on our experience. MATERIALS AND METHODS: A total of 116 patients were operated on for congenital curvature of the penis without hypospadias in adulthood between January 1985 and December 2004 of whom 87 (75%) (mean age 24 years) were available for evaluation by a telephone survey. A total of 54 ventral, 28 lateral and 5 dorsal penile curvatures were operated on with a mean followup of 89 months. Bend was managed with Nesbit's procedure in 18, plication in 7 and the Heineke-Mikulitz technique in 62 men. RESULTS: There were no significant intraoperative or postoperative complications. Overall 81 of the 87 patients (93.1%) were successfully treated with 1 operation. Curvature recurrence was less common in patients treated with the Heineke-Mikulitz technique. There were no complaints of de novo erectile dysfunction, but 15 men complained of shortening of the penis and 4 experienced decreased sensation of the glans. CONCLUSIONS: Although feasible in cases of different types of congenital curvature, in our 20-year experience chordectomy always reduced the bend but patients could never completely straighten the penis by themselves. Surgical correction was reported by patients to be highly successful using the Heineke-Mikulitz technique, and statistical analysis revealed it to be significantly better than plication or the Nesbit procedure in terms of palpable nodules, recurrence and overall satisfaction.

Expression of p21(waf1/cip1), p27 (kip1), p63 and androgen receptor in low and high Gleason score prostate cancer.

The aim of this study was to investigate the expression of p21(waf1/cip1), p27(kip1), p63 and androgen receptor proteins in relation to serum prostate specific antigen levels in low and high Gleason score prostate cancers. Biopsies of patients suffering from prostate adenocarcinoma of low (3 + 3 to 3 + 4) and high (5 + 4 to 5 + 5) Gleason scores (13 cases each group) were immunostained for positive regulators of cell cycle control (p21(waf1/cip1) and p27(kip1)), and essential markers of normal prostate gland ontogeny (p63) and growth (androgen receptor) to find differentially expressed markers of malignant progression. Serum prostate specific antigen levels were also monitored at the time of biopsy and following anti-androgen therapy. All cases except one in each group were androgen receptor positive. P63 and p21(waf1/cip1) proteins detected in normal basal cell nuclei were lost in all but one studied tumors respectively. P27(kip1) protein, however, was detected in all low Gleason score prostate cancers, but it was found in only 7/13 high score cases. Prostate specific antigen levels, either pre- or post-treatment, did not show strict correlation with the p27(kip1) results. The low to high grade dedifferentiation of prostate adenocarcinoma is accompanied with the down-regulation of p27(kip1) protein, which may be an important molecular sign of the lost cell cycle control.

[Investigation of prostate specific antigen in the first decade of its use, in our clinic (1994-2004)]. / A prosztataspecifikus antigén-vizsgálat elso évtizede klinikánkon (1994-2004).

INTRODUCTION AND AIMS: Prostate cancer is the most common malignant tumor in male; its diagnostic algorithm and therapy were investigated. The goal of the study was to compare the data from the first year of clinical use of prostate specific antigen (1994) and the data of 2004. RESULTS: During the first decade, the number of prostate biopsies has increased 4.5-fold times. In 1994, 36.2%, while in 2004, 47.5% of the biopsies demonstrated cancer. The average age of the patients, who underwent biopsy, decreased from 69.7 to 62.3 years; however, the average age of patients who suffered from prostate cancer remained constant (70.8 vs. 71.3 years old). CONCLUSION: In 2004, along with the earlier used PSA level, the free-PSA and PSA-density was also involved in the diagnostic algorithm. The prostate biopsy is guided by a transrectal US, in contrast to the earlier used blind or transperineal method. Consequently, the effectiveness of the prostate biopsy has improved, but the earlier diagnosis and identification are not assured. The Gleason score of the diagnosed prostate cancer was lower; therefore, more patients were selected for curative surgery. The increased average PSA level reflected a higher number of patients at an advanced stage, which could only be treated palliatively.

[Experiences in treatment and follow up of 50 patients with penile cancer]. / Hímvesszô-daganatos betegek kezelésével szerzett tapasztalataink.

INTRODUCTION: Malignant tumour of the penis is a rare disease. Although most of the cases are squamous cell carcinoma histologically, operation is managed by the urologist because of its location. AIM AND METHOD: Experience with the treatment and attendance of penile cancer is presented by the author. Results were both retrospectively and prospectively worked up. RESULTS: Between June 1996 and June 2006 there was operation performed in 50 patients. Mean age of men was 63.1 (31-83) years. Ninety-four percent of tumours were squamous cell carcinoma, 2 (4%) verrucosus carcinoma, in one case malignant melanoma. Pathological T stadium was T1 in 23 cases (46%), T2 in 19 (38%) patients, in 6 (12%) cases T3 and in 1 (2%) T4. Differentiation was grade 1 in 12 (24%), grade 2 in 27 (54%) and grade 3 in 10 (20%) cases. One side inguinal lymph node metastases were found in 11 (22%) and both side in 8 (16%) patients. In anamnesis 4 (8%) patients underwent circumcision because of phimosis, and 25 (50%) patients had had phimosis by identification of cancer. Seventeen patients (34%) were given chemotherapy after surgical treatment. Mean survival time of all patients was 31,4 (2-114) months. CONCLUSION: Phimosis plays an important role in development of penile cancer, that's surgical treatment does not prevent the higher chance of incidence rate. The disease behaves aggressively, spreading through lymphatic vessels, where in advanced stadium, or in low differentiation cases it is already demonstrable by diagnosis. In the choice of therapy, stadium-oriented principle should be predominant. With early operation, long-term survival can be achieved.

[Lichen sclerosus in urological practice]. / Lichen sclerosus az urológiai gyakorlatban.

UNLABELLED: Lichen sclerosus in urological practice. INTRODUCTION: Lichen sclerosus is a sclerosing, inflammatory skin disease with unknown origin which causes secondary phimosis of the foreskin and stricture of the urethra. In the case of long term existence of it the prevalence of intraepithelial squamous cell neoplasia is increased. AIM: To identify the role of lichen sclerosus in adulthood phimosis and to categorize urological treatment. To define the proper therapy of lichen sclerosus, causing meatal and urethral stricture. To measure the incidence of lichen sclerosus in patients with squamous cell neoplasia. METHOD: There was looked the incidence of lichen sclerosus in patient suffering with phimosis, recurrent urethral stricture, therapeutical options and presence of lichen sclerosus in patient with penile squamous cell neoplasia. RESULTS: There were 123 foreskins sent for histological examination from 624 patients operated with circumcision in the last 5 years in the clinic. There were 76 (62%) times lichen sclerosus justified in 123 foreskins. There were lichen sclerosus found in 90% (9/10) of excised tissues of recurrent urethral strictures. There were lichen sclerosus noticed in 3 of 10 (33%) penile squamous cell carcinoma slides. CONCLUSIONS: Lichen sclerosus can be detected in significant proportion of phimosis in adulthood. Lichen sclerosus can be found very often as the cause of recurrent urethral strictures, which takes necessary to perform 2 steps reconstructive operation with complete excision of the urethra and buccal graft emplacement. In the third of our all squamous cell carcinoma cases lichen sclerosus could be histologically shown, which give good reason for the opportunity of malignant disease development of this dermatological illness.

Changes of protein expression in prostate cancer having lost its androgen sensitivity.

OBJECTIVE: The majority of prostate cancers require androgen hormones for growth, and androgen ablation is an important part of the systemic treatment of advanced prostate cancer. Nevertheless, most of these cancers eventually relapse as they become less sensitive to androgen ablation and anti-androgen treatment. Elucidating the molecular events that are responsible for the conversion of androgen-sensitive cancers to androgen-refractory tumors may reveal new therapeutic opportunities. METHODS: In the present study, we investigated nine androgen-sensitive and nine androgen-refractory prostate cancer samples to evaluate the expression levels of 10 selected proteins that have been implicated in oncogenesis and cancer progression. RESULTS: Our immunohistochemical data show that three of the investigated proteins (i.e., minichromosome maintenance-2, methylguanine-DNA methyltransferase, and androgen receptor) are expressed at significantly different levels in the androgen-refractory cancer samples than in the androgen-sensitive tumors, whereas the expression levels of the seven other studied proteins (i.e., ß-catenin, p27, p21, p16, Ki67, hypoxia-inducible factor 1 alpha, and geminin) are not significantly different regarding the two groups. CONCLUSIONS: Our data suggest that the increased expression of minichromosome maintenance-2 and decreased expression of methylguanine-DNA methyltransferase related to androgen receptor are indicative of the androgen-refractory stage in prostate cancer. Further studies are required to determine whether these expression changes play a causative role in the transition of androgen-sensitive to androgen-refractory prostate cancer.

[Summary of our clinical experience with the determination of serum prostate-specific antigen level in the first five years]. / A prosztataspecifikus antigén-szint meghatározásának elsô öt éve során szerzett tapasztalataink összefoglalása.

The authors determined serum PSA levels in combination with digital rectal examination (DRE) and evaluated their role in the differential diagnosis of prostate diseases with special reference to cancer. The possible causes of differences between the observed cut-off level of PSA and the standard level PSA were analyzed. In the last few years the PSA determination found its clinical role in the diagnosis of prostate cancer.

Penis covering and simultaneous urethral replacement by scrotal skin for severe penile and urethral necrosis.

OBJECTIVES: Penile strangulation with severe necrosis and concomitant significant tissue loss is a challenging problem for reconstructive surgery. Final reconstruction and tissue augmentation of the resected penis often require multi-step plastic reconstruction. METHODS: Severe damage of the phallus with gangrene and septic complication caused by a bronze ring were first conservatively treated to achieve dry gangrene. The glans of the penis, the whole penile skin, and distal third of the corpus spongiosum with the urethra were lost to necrosis, resulting in a missing urethral segment on the penis. Surgery was performed 3 months after removing the metal ring; a one-step skin and urethral reconstruction was done. RESULTS: Good functional and esthetic results could be achieved by mid-term follow-up. CONCLUSION: In long-lasting penile strangulation with damaged blood supply, further surgery and treatment are needed in addition to immediate decompression. Most commonly in these situations, amputation seems to be the best and easiest action to be taken. However, our case shows that even in a most severe situation, careful conservative treatment allows preserving the phallus, and subsequently reconstruction enables reaching the best functional and esthetic results.

Treatment and outcome of vaseline-induced sclerosing lipogranuloma of the penis.

OBJECTIVES: To study the treatment and short-term outcome of 16 consecutive cases of sclerosing lipogranuloma of penis developing after Vaseline inoculation for penile augmentation. METHODS: After Vaseline inoculation, patient pain was related mainly to erection and severe phimosis. At surgical reconstruction complete and radical excision of the involved penile skin was performed, followed by skin substitution from the existing, saved coat of the penis. In most cases the stored, uninvolved inner preputial skin was used; less frequently scrotal flaps and in the least-favorable cases penis embedment in the scrotum was applied for coverage of the penis. RESULTS: All 16 patients were cured, no matter how long after self-injection vaselinoma developed or which kind of surgery was performed. Histopathologic evaluation revealed different findings according to the time elapsed after Vaseline injection. CONCLUSIONS: Early detection of patients with Vaseline penile augmentation and urgent surgery are essential because the best esthetic and functional results can be achieved in the acute period; this is when granuloma does not involve the subdermal but only the subcutaneous layer and local penile flaps can most commonly be used for reconstruction.