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Updated classification of urothelial cell cancer differentiates low-grade and high-grade cancers, which determines potential clinical outcome. Substantial interobserver variability necessitates new biomarkers to ensure classification. Claudins’ specific expression pattern characterizes normal tissues, different tumor types, and defined grades of tumor differentiation. The aim of this study was to examine the expression pattern of claudins and proliferation marker Ki-67 in low-grade and high-grade urothelial cell cancers compared with independent control samples of non-tumorous urothelium, as well as to reveal the predictive usefulness of claudins. The expression of claudins-1, -2, -3, -4, -5, -7, and -10 and Ki-67 was studied with quantitative immunohistochemistry and real-time RT-PCR with relative quantification in 103 samples: 86 urothelial cell cancers (27 low grade, 59 high grade) and 17 non-tumorous urothelia. Results were analyzed regarding overall survival and recurrence-free period as well. High-grade tumors overall showed significantly higher claudin-4 and Ki-67 and significantly lower claudin-7 expression when compared with low-grade ones. High-grade tumors revealed significantly shorter overall survival in Kaplan-Meier analysis. Claudin-4, claudin-7, and Ki-67 might be used as potential markers to differentiate low-grade and high-grade urothelial cell cancers, thereby possibly enhancing accuracy of pathological diagnosis and adding further information to clinical outcome.

The members of the claudin family are major integral transmembrane protein constituents of tight junctions. Normal and neoplastic tissues can be characterized by unique qualitative and quantitative distribution of claudin subtypes, which may be related to clinicopathological features. Differential diagnosis and prognosis of nonmuscle invasive tumor entities of urinary bladder epithelium are often challenging. The aim was to investigate the expression profile of claudins in inverted urothelial papillomas (IUPs), urothelial papillomas (UPs), papillary urothelial neoplasms of low malignant potential (PUNLMPs), and intraepithelial (Ta), low-grade urothelial cell carcinomas (LG-UCCs) in order to reveal potential prognostic and differential diagnostic values of certain claudins. Claudin-1, -2, -4, and -7 protein expressions detected by immunohistochemistry and clinical data were analyzed in 15 IUPs, 20 UPs, 20 PUNLMPs, and 20 LG-UCCs. UPs, PUNLMPs, and LG-UCCs showed significantly decreased claudin-1 expression in comparison to IUPs. LG-UCCs expressing claudin-4 over the median were associated with significantly shorter recurrence-free survival. PUNLMPs expressing claudin-1 over the median revealed significantly longer recurrence-free survival. High claudin-1 protein expression might help to differentiate IUP from UPs, PUNLMPs, and LG-UCCs. High claudin-4 expression may determine an unfavorable clinical course of LG-UCCs, while high claudin-1 expression in PUNLMP was associated with markedly better clinical outcome.

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.

Abstract: In our retrospective study the pathological and clinical factors, influencing the survival of 65 renal clear cell carcinoma patients operated for bone metastasis between 1990 and 2008 were examined. Based on Kaplan-Meier curves age, gender, clinical symptoms, pathological fracture, progression to the soft tissues, localization and size of the metastasis, whether the occurrence of multiplex metastases is multiorganic or only located to the skeletal system and the stage and grade of primary renal cancer did not influence the survival. The survival significantly improved if the bone metastases were solitary, low Fuhrman grade, late onset; and radical surgery was performed. Based on Cox regression analysis, survival after bone surgery was influenced by the multiplicity and grade of metastasis and by the radicality of the surgery, whereas survival after nephrectomy was significantly influenced by onset time and grade of metastasis. When the solitary metastasis was radically removed, 75.0% of the patients survived the first, and 35.5% the fifth postoperative year. If the metastasis was multiple or the surgery was not radical, no patient survived the fifth year. This is the first report on the prognostic significance of the Fuhrman grade of bone metastasis of renal cell cancer. While the Fuhrman grade of the primary tumour did not influence the survival, the lower grade of metastasis was associated with a significant longer survival. Therefore in cases of solitary, operable, late onset metastases with low Fuhrman grade radical removal is recommended, since this way in 35.5% of cases 5 year survival can be expected.

Abstract: The aim of our study was to find the cause of urinary incontinence and voiding dysfunction in patients undergoing radical cystectomy and orthotopic bladder replacement with modified ileal neobladder (Reddy). Twenty-eight incontinent patients (operated on between 1988 and 2004) were involved in our examination. Based on the complaints of the patients, continence status was evaluated and divided into two groups: group I: partially incontinent (only night-time incontinence) n = 11 (39.3%) and group II: totally incontinent (night-time and daytime incontinence) n = 17 (60.7%). Detailed urodynamic examination (enterocystometry and urethral pressure profile) in addition to involuntary neobladder contractions and capacity detection were carried out on all patients. Furthermore resting pressure and maximal voluntary contraction ability of the sphincter were determined and statistically analyzed in both groups. Significant difference was noticed in resting pressure and maximal voluntary contraction ability of the sphincter among the partially incontinent and totally incontinent patients. Frequency, intensity and duration of involuntary neobladder contractions also showed significant differences between the two groups. Incontinence of neobladder depends not only on the destruction of resting and contraction capability of the urethral sphincter, but also on the presence or absence of involuntary contractions in the wall of the neobladder and decreased capacity of the neobladder.

Abstract: Angiogenesis plays a critical role in tumor growth. VEGF, angiopoietins (Ang-1, Ang-2) and their tyrosine kinase receptor Tie2 are major regulators of angiogenesis. The aim of this study was to evaluate the prognostic value of the serum levels of these factors in bladder cancer. We analyzed the serum samples of 117 bladder cancer patients and 64 healthy volunteers by enzyme linked immunosorbent assay (ELISA) for Ang-1, Ang-2, VEGF and the extracellular domain of Tie2. The statistical evaluation of the obtained data was performed via Kaplan–Meier log-rank test, univariate Cox analyses as well as Cox proportional hazards regression model. Serum Ang-1 levels of bladder cancer patients were significantly higher (p < 0.001), while soluble Ang-2 and Tie2 levels were significantly lower (p = 0.016 and p = 0.001 respectively) in patients than those in controls. Cox univariate analysis revealed high sTie2 serum level as a risk factor for metastasis and as a borderline significant risk factor for disease related death (p = 0.022 and p = 0.081 respectively). These correlations were independent from tumor stage and grade in a Cox multivariate model (p = 0.016 and p = 0.069). These data indicate that the serum levels of analyzed angiogenic factors do change characteristically in bladder cancer. The soluble extracellular serum level of Tie2 may provide a stage and grade independent diagnostic tool to select a high risk group of bladder cancer patients.

Abstract: Altered CD24, c-myc and phospholipase 2a expression was reported in different cancers. Our aim was to measure the expression of these genes in prostate cancer tissues, and compare it to non-cancerous samples. Prostate tissue samples were collected by needle biopsy from 20 prostate cancer (PCA) and 11 benign prostate hyperplasic (BPH) patients. RNA was isolated; cDNA synthetized, CD24, c-myc and phospholipase 2A (PL2A) expressions were determined by quantitative real-time PCR method. The expression of β-globin gene was measured for normalization of the gene expression results. Serum prostate specific antigen (PSA) levels were determined by microparticle enzyme immunoassay (MEIA) method. PSA levels were significantly different between the PCA and BPH groups, 252.37 ± 308.33 ng/ml vs. 3.5 ± 2.14 ng/ml (p = 0.001), respectively. CD24 expression was 988.86 ± 3041 ng/μl in prostate tumor and 4.00 ± 4.25 ng/μl in the BPH group (p = 0.035). The c-myc expression was 88.32 ± 11.93 ng/μl in the prostate tumor and 17.08 ± 21.75 ng/μl in the BPH group (p = 0.02), and the PL2A 31.36 ± 67.02 ng/μl was in PCA and 5.56 ± 14.08 ng/μl in BPH (p = 0.025). Gleason’s scores showed correlation with c-myc (p = 0.019) and PSA (p = 0.033) levels. Overexpression of PL2A, CD24 and c-myc was observed in prostate cancer samples using quantitative real-time PCR method.

Abstract: The aim of this study was to investigate the expression of p21waf1/cip1, p27kip1, 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 (p21waf1/cip1 and p27kip1), 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 p21waf1/cip1 proteins detected in normal basal cell nuclei were lost in all but one studied tumors respectively. P27kip1 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 p27kip1 results. The low to high grade dedifferentiation of prostate adenocarcinoma is accompanied with the down-regulation of p27kip1 protein, which may be an important molecular sign of the lost cell cycle control.

The molecular mechanism playing a role in the development of prostate cancer (PCA) is not well defined. We decided to determine the changes in gene expression in PCA tissues and to compare them to those in noncancerous samples. Prostate tissue samples were collected by needle biopsy from 21 PCA and 10 benign prostate hyperplasic (BPH) patients. Total RNA was isolated, cDNA was synthesized, and gene expression levels were determined by microarray method. In the progression to PCA, 738 up-regulated and 515 downregulated genes were detected in samples. Analysis using Ingenuity Pathway Analysis (IPA) software revealed that 466 network and 423 functions-pathways eligible genes were up-regulated, and 363 network and 342 functions-pathways eligible genes were down-regulated. Up-regulated networks were identified around IL-1ß and insulin-like growth factor-1 (IGF-1) genes. The NFKB gene was centered around two upand down-regulated networks. Up-regulated canonical pathways were assigned and four of them were evaluated in detail: acute phase response, hepatic fibrosis, actin cytoskeleton, and coagulation pathways. Axonal guidance signaling was the most significant down-regulated canonical pathway. Our data provide not only networks between the genes for understanding the biologic properties of PCA but also useful pathway maps for future understanding of disease and the construction of new therapeutic targets.

Abstract: The authors report on their first experiences with the UroVysion fluorescencein situ hybridization (FISH) kit developed for the detection of bladder cancer. This new non-invasive diagnostic application of the FISH technique in the field of urology was elaborated to replace cystoscopy. The special urine examination method detects genetic alterations of the urothelial cells found in the urine, using fluorescent directlabeled DNA probes binding to the peri-centromeric regions of chromosomes 3, 7 and 17 as well as on the 9p21 locus. We aimed to evaluate the utility of UroVysion test in the light of the histological diagnosis. Urine samples from 43 bladder cancer patients and 12 patients with no or benign alterations were studied using a new application of FISH technique: the UroVysion reagent kit. The obtained FISH results were compared with the histological findings of the transurethral surgical resection specimens. The study rated the specificity and sensitivity of the technique 100% and 87%, respectively. Therefore, the technique could well fit into the diagnostic process of bladder carcinomas. Statistical analyses showed significant correlation between tumor progression and the severity of the genetic alterations detected by this FISH technique. Furthermore, positive correlation was found between tumor grade and the proportion of tumor cells showing genetic abnormality. The noninvasiveness, the robustness of evaluation and the high specificity/sensitivity are all in favor of this technique. The disadvantages are the higher costs of the technical background and the required future clinical studies to determine whether this technique can replace cystoscopy.

Abstract: The authors analyzed the expression of E-cadherin, one of the most important cell adhesion molecules, on paraffin sections of tumors of bladder cancer patients. The aim of the study was to see whether there is any association between E-cadherin expression and tumor grade, stage, age and gender of the patients, number of recurrences, or overall survival. The samples were examined in 51 primary bladder transitional cell carcinomas (TCC) of 50 patients, resected by transurethral resection (TUR) between January 1, 1996 and January 1, 1997. Immunoreactions were performed with monoclonal anti-human E-cadherin antibody. Forty of the fifty patients could be clinically followed. The analysis of the results on these forty patients was performed by contingency analysis and significance was assessed by Ξ2 test. No significant association between E-cadherin expression and tumor grade, stage, age or gender of the patients, the number of recurrences, or overall survival could be seen. (Pathology Oncology Research Vol 12, No 2, 73–77)

AbstractThe aim of this study was to estimate the prevalence of chromosome abnormalities in patients with azoospermia, in our material. Preoperative evaluation included routine andrological investigations with 2 semen analysis, ultrasound, hormonal and genetic examinations. In the last three years, 73 biopsies were performed for testicular sperm extraction in 71 patients. Non-obstructive azoospermia was diagnosed in 53 patients (79%). Karyotyping was performed on lymphocyte preparations of 36 men with diagnosis of infertility. In order to obtain exact diagnosis, cytogenetic methods (QFQ-, GTG-, CBG-band and FISH analysis) were complemented with molecular genetic techniques. Patients were included in the assisted reproduction programme on the base of their genetic results. The most characteristic cases were sex numerical deviations, such as XXY (3 cases), XYY (2 cases) and mosaic X0 syndromes (1 case).

In this prospective study we evaluate the effect of combined transurethral resection of early muscle invasive bladder cancer and immunotherapy with bacillus Calmette-Guerin (BCG) in patients unfit for radical cystectomy or refusing more aggressive therapies.

Systematic random rectal ultrasound directed mapbiopsy of the prostate was performed in 77 RDE (rectal digital examination) positive and 25 RDE negative cases, if applicable. Hypoechoic areas were found in 30% of RDE positive and in 16% of RDE negative cases. The score for carcinoma in the hypoechoic areas was 6.5% in RDE positive and 0% in RDE negative cases, whereas systematic “map” biopsy detected 62% carcinomas in RDE positive, and 16% carcinomas in RDE negative patients. The probability of positive diagnosis of prostate carcinoma increased in parallel with the number of biopsy samples/case. The importance of systematic map biopsy is emphasized.

Abstract: Authors report on a 75-year-old man with bilateral testicular lymphoma. He complained of painless right testicular enlargement. Orchidectomy was indicated by ultrasound examination and the diagnosis (large cell, non-Hodgkin lymphoma B-cell origin) was established by histology and immunohistochemistry. Two months later, the left testis enlarged, orchidectomy was performed, and a lymphoma with identical histology was found. PET revealed retroperitoneal spread of the tumor. Irradiation (18 Gy) was applied. Three months later, because of gastric metastases of the lymphoma the patient underwent CVP and CAVP (Cyclophosphamide, Adriablastin, Vincristin, Prednisolone) chemotherapy. Despite of the repeated courses, eleven months after the primary diagnosis the patient died due to of multiple metastases.

A total of 102 (66 untreated and 36 hormone-treated) prostate cancers were examined histologically in order to determine their histological grade and the percentage of apoptotic tumor cells. The less differentiated the tumors were, the higher the spontaneous apoptotic activity was. Hormone therapy increased the apoptotic index in the prostate cancers. The increase was of greater significance in grade I than in grade II and grade III tumors. The therapeutic consequences of these findings and the possibility of different oncogene-expressions in various histological types of prostate cancer are discussed.

We report a case of bilateral renal cell carcinoma in a horseshoe kidney. To the best of our knowledge this is the second reported case in the international literature. We performed different radiological examinations preoperatively to identify of blood supply, because correct preoperative location of vessels is mandatory.