Prostate cancer epidemiology in a rural area of North Western Greece.

Epirus is a rural area of North-Western Greece. We reviewed data from 4 hospitals for 4.975 patients who underwent prostate biopsy in Epirus in the twelve year period from 1999 to 2010. Two six-year periods were compared (1999-2004 and 2004-2010). All cases of prostate cancer confirmed by biopsy were recorded and age-standardized incidence rates per 100,000 males were calculated. We also recorded the clinical stage for patients diagnosed in our hospital and correlated this with PSA and Gleason scores. Percentage of positive prostate biopsies was also calculated. There were a total of 1714 new cases during 1999-2010 and the mean annual age-adjusted incidence was 34/100,000. The mean incidences during 1999-2004 and 2005-2010 were 26/100,000 and 42/100,000, respectively. The mean age at diagnosis was 74. The most common Gleason score was 6 and the prevalent clinical stage was T2. Median PSA at diagnosis was 10.8 ng/ml. There was a significant difference between stage cT4 and all other stages regarding PSA value (p=0.000). A positive correlation was found between Gleason score and PSA (p=0.013). These results are in accordance with the incidence rise recorded in neighboring countries of South-East Europe. However we should keep in mind the risk of overdiagnosis and the detection of low-risk cancers that would not have caused morbidity or death during a man's lifetime anyway.

Prognostic significance of thymidine phosphorylase in superficial bladder carcinoma.

OBJECTIVE: We investigated the expression of thymidine phosphorylase (TP) in bladder carcinomas and assessed its prognostic significance in superficial bladder cancer samples. PATIENTS AND METHODS: We studied 142 primary bladder cancer samples immunohistochemically for nuclear thymidine phosphorylase (TPN), cytoplasmic (TPC) and stromal (TPSTR) expression. We correlated them with standard clinicopathological features (grade, stage, concurrent in situ, multiplicity, primary or recurrent status), as well with recurrence and progression. We examined also the relationship between TP and tumor microvessel density. RESULTS: The level of all types of TP correlated well with stage, while grade correlated well only with TPSTR and the presence of carcinoma in situ only with TPN. Patients with low levels of TPN had a longer tumor free interval, during a 38.6 months mean follow up time. Regarding the association between TP count and microvessel density we found the strongest association with TPSTR (p=0.003), a borderline statistical significance with TPC (p=0.049) and no relationship with TPN (p=0.072). CONCLUSIONS: We suggest that the assessment of TPN might be useful for predicting recurrence in superficial bladder cancer. We propose also that TP may stimulate angiogenesis.

Prognostic significance of angiogenesis in superficial bladder cancer.

OBJECTIVE: To assess the prognostic significance of angiogenesis parameters such as microvessel density (MVD) and vascular endothelial growth factor (VEGF) in superficial bladder cancer. PATIENTS AND METHODS: We studied 127 superficial bladder cancer samples immunohistochemically for the above factors. We compared them with standard clinicopathological features (grade, stage, concurrent in situ, multifocality, primary or recurrent status) as well as with p53 expression, recurrence and progression to muscle infiltrating disease. RESULTS: During a 36 months median follow up of 109 patients with superficial primary tumors (min. 3, max. 69 months), 80 of them recurred (73.4%), while 8 patients (7.3%) progressed to muscle invading disease. A significant correlation was noted between MVD and VEGF in all 127 samples (p = 0.019). No association was noted between MVD or VEGF with the other clinicopathological features, recurrence or progression. Although progression free survival rates of categorized microvessel density (up to and higher than median value) differed significantly only in grade 3 patients, no independent prognostic significance could be attributed to MVD. No correlation was observed between MVD or VEGF with p53 protein. CONCLUSIONS: Based on our data we suggest that VEGF is not useful for predicting recurrence or progression in superficial bladder cancer. Microvessel density determination may help to predict progression of grade 3 patients to muscle invasive disease but not as an independent prognostic factor.

Expression patterns of cyclins D1, E and cyclin-dependent kinase inhibitors p21(Waf1/Cip1) and p27(Kip1) in urothelial carcinoma: correlation with other cell-cycle-related proteins (Rb, p53, Ki-67 and PCNA) and clinicopathological features.

INTRODUCTION: The expression pattern of cyclins D1 and E, as well as cyclin-dependent kinase inhibitors p21(Wa1/Cip1) and p27(Kip1) and their relationship to tumour behaviour and patients' prognosis was examined in 142 urothelial cell carcinomas. The expression of these proteins was also analyzed along with other cell-cycle-related proteins such as: p53, pRb and the proliferation-associated indices Ki-67 and proliferating cell nuclear antigen (PCNA). PATIENTS AND METHODS: These molecule markers were localized immunochemically using the monoclonal antibodies anti-cyclin D1 (DCS-6), anti-cyclin E (13A3), anti-p21 (4D10), and anti-p27 (1B4) in 142 patients with urothelial cell carcinoma. RESULTS: Focal positivity (<10% of tumour cells) or the absence of cyclin D1 immunostaining was observed in 105/142 (73.9%) of the tumours. Cyclin D1 expression was correlated with tumour grade and stage as well as with the existence of in situ component. In addition, cyclin D1 expression was positively correlated with p21(Waf1/Cip1) and p27(Kip1) and inversely with the Ki-67 score. Focal positivity (<20% of tumour cells) or the absence of cyclin E immunoreactivity was observed in 105/142 (73.9%) in all cases. Cyclin E expression was correlated with tumour stage. A positive relationship between cyclin E expression and the two associated proliferating indices Ki-67 and PCNA, as well as with p53 and p27(Kip1) proteins expression was noted. Absence or focal positivity (<5% of tumour cells) of p21(Waf1/Cip1) was detected in 88/142 (62%) of the carcinomas. p21(Waf1/Cip1) expression was correlated with tumour grade and stage. A positive relationship of its expression cyclin D1, cyclin E, p27 and pRb expression was observed. Absence or focal immunostaining (<20% of tumour cells) of p27 protein was detected in 55/141 (39%) in all cases. p27(Kip1) expression was correlated with tumour grade as well as with cyclins D1 and E. The prognostic significance of cyclins D1, E and cyclin-dependent kinase inhibitors p21(Waf1/Cip1), p27(Kip1) in determining the risk of recurrence and progression with both univariate (log rank test) and multivariate (Cox regression) methods of analysis showed no statistically significance differences. CONCLUSION: These findings suggest that the level of the cell cycle regulators studied does not seem to have a clinical value in terms of predicting the risk of early recurrence and progression. In addition the interrelationship probably means their contribution to the regulation of cell growth through different pathways in bladder carcinogenesis.

Simultaneous adenomectomy and preperitoneal repair of inguinal hernias by a single incision with the application of polypropylene mesh.

Preperitoneal inguinal herniorraphy in conjuction with other pelvic procedures has been described in the literature, but it has not gained wide popularity mainly due to the high recurrence rate. Recently, there has been a resurgence of interest in the preperitoneal repair of inguinal hernias with the application of mesh on the deficiency of the inguinal wall using the method commonly known as the Stoppa procedure. We evaluated the results and complications of 22 patients who underwent open surgical prostatectomy (adenomectomy) and simultaneous preperitoneal application of polypropylene mesh. Nineteen (86.4%) patients suffered from unilateral inguinal hernia whereas the remaining 3 (13.6%) had bilateral protrusions. Primary hernias only and not recurrences were included in our series. The median clinical follow-up was 20.4 months (range 9-50 months). The hernioplasty itself prolonged the whole procedure for only a few minutes and it did not affect the patients' hospitalization time (mean 6.7 days). Wound infection with subsequent development of cutaneous fistula occurred in one patient (4.5%) and treated conservatively. During follow-up one recurrence (4.5%) at the side of the previous repair of the left inguinal hernia was recorded; the protrusion was insignificant and left untreated. In all but one patient (21/22, 95.5%), the surgical results were excellent. In our experience, simultaneous transvesical adenomectomy and mesh preperitoneal hernioplasty is a convenient and safe procedure which can easily be performed by urologists in just a few minutes. The procedure which is both cost and time effective for the surgeon, achieves long-lasting beneficial results for the vast majority of patients.

Intravesical instillations of interferon gamma in the prophylaxis of high risk superficial bladder cancer--results of a controlled prospective study.

OBJECTIVE: To determine if intravesically administered recombinant interferon (IFN) gamma may serve as adjuvant first line treatment in prophylaxis of superficial bladder cancer by reducing its risk for recurrence, in the short term. MATERIAL AND METHODS: A total of 54 patients (43 males and 11 females) with superficial bladder tumours (Ta/T1) initially treated with transurethral resection for their tumors were randomized into two groups: Twenty-eight patients were left untreated after the transurethral resection (controls) whereas 26 patients received intravesical IFN gamma adjuvantly, at a dosage of 0.7 mg per week for 8 weeks. Patients with G1 tumors and carcinoma in situ were excluded. The follow up had a mean time of 12.1 months. Recurrence or progression, as terminal events of the study, were recorded. The comparison of the recurrences between the two groups was performed by estimating: (a) the simple recurrence rate, and (b) the interval to tumor recurrence in each group. RESULTS: Tumor recurrence was detected in 24 controls (86%) and in 16 (62%) patients of the IFN gamma group (p = 0.043). The comparison of the Kaplan-Meier disease-free survival curves between the two groups of patients indicated that intravesical instillations of IFN gamma exerted a continuous protective effect to those who received the agent, in the follow up period (p = 0.0237). No serious side-effects were noted. CONCLUSIONS: Intravesically administered IFN gamma has a demonstrable protective role as first line adjuvant treatment in superficial bladder cancer. This role is mainly focused on prevention of recurrences in the short term. Further prospective studies with longer follow up are required, in order to define the exact place of the drug in the urologist's armamentarium.

Varicocele in schoolboys.

This study was conducted to examine the effect of height and weight on the incidence of varicocele in schoolboys aged 5-16 years and the impact of varicocele on testicular size. Genital stage, height, weight, varicocele grade, and testicular size were recorded for 3047 school boys who were clinically examined while standing by a specialist in urology. Left varicocele was detected in 98 of the boys who were all aged 9-16 years. The mean weight of boys with and without varicocele was 42 kg (95% confidence interval [CI] 40-44 kg) and 47 (95% CI 47-47 kg), respectively (p =.00). There was no difference in mean height between the two groups nor in left and right testicular volume. Although 6 boys with varicocele had a left testicular volume > or =2 mL less than right, there were also 7 boys of comparable age who had a left testicular volume > or =2 mL larger than right. The incidence of varicocele in Greek adolescents is low. Boys with varicocele weighed significantly less but there were no significant differences in height or left versus right testicular volumes. In the light of these observations, the use of left testicular hypotrophy (> or =2 mL compared with the right testicle) should be reconsidered as an indicator for varicocele-induced damage of the testicle in this age group.

Tumor markers in stage P1 bladder cancer.

BACKGROUND: The infiltration of muscularis mucosa in superficial bladder cancer has been reported to be predictive of an unfavourable course of the disease. MATERIALS AND METHODS: We studied immunohistochemically Ki-67, PCNA and p53 tumour markers in 68 P1a and Pib bladder tumours. RESULTS: A statistically significant difference (p = 0.01) was found in the distribution of grades between stages P1a and P1b, with more grade 3 and less grade 2 tumours in the latter category. Univariate analysis revealed a strong association of Ki-67 (p = 0.001) and PCNA (p = 0.032) only with stage. P53 protein expression did not have any significant association with either stage or grade. In 60 patients entered into the multivariate analysis a clearly predominant, significant effect of stage on Ki-67 (p = 0.000) was shown. CONCLUSION: Increased proliferative activity when compared to P1a is present in P1b bladder tumours, as detected by the increased expression of Ki-67 proliferating antigen. The immunohistochemical study of Ki-67 antigen may help in predicting stage P1 tumours' behaviour, even in cases where pathological distinction of P1a and P1b substages is difficult.

CD44 standard form expression as a predictor of progression in high risk superficial bladder tumors.

OBJECTIVE: The purpose of this study was to assess the significance of the standard CD44 adhesion molecule expression in predicting progression of high risk superficial bladder carcinoma in the short term. METHODS: Sixty-six patients (51 males and 15 females, aged 27 to 89 years (mean 64.75 years) with primary superficial transitional cell bladder cancer initially treated with transurethral resection (TURBT) were enrolled in the study. Only pTa/pT1 grade 2 multiple tumors as well as all grade 3 tumors were included in this study. All tumor samples obtained after the resection were immunohistochemically evaluated for the expression of the CD44 standard molecule. Fifty eight patients remained during the follow up period which ranged from 3 to 36 months (mean 11.8 months). Tumor progression in the short term was considered as the critical end point of interest in this study. The prognostic significance of tumor stage, grade, presence of carcinoma-in-situ (CIS) and expression of CD44 in determining the risk for progression, was studied with both univariate (log rank test) and multivariate (Cox proportional hazards) methods of analysis. RESULTS: Kaplan-Meier survival curves indicated that a shorter median progression-free survival is expected for those patients with G3 bladder tumors (p = 0.0055), concomitant CIS (p = 0.0051), and loss of expression of CD44 (p = 0.0015), whereas a similar association with stage was not detected (p = 0.5793). The cox regression multivariate analysis did not yield a significant result for any of the studied parameters therefore no one of the factors taken into account can serve as an independent predictor of progression in superficial bladder cancer in the short term. CONCLUSION: The immunohistochemically detectable loss of the expression of CD44 standard form from superficial bladder tumor samples may be, complementary to the established prognostic factors, a useful predictor of tumor progression in the short term.

Antiproliferative activity of interferon gamma in superficial bladder cancer.

BACKGROUND: Although the antiproliferative activity of interferon gamma has been reported in various tumours, this has not been studied in bladder cancer. Proliferative cell nuclear antigen and Ki67 growth fractions were estimated in this study in superficial bladder cancer, as a measure of the antiproliferative effect of interferon gamma. MATERIALS AND METHODS: Superficial bladder cancer samples before and after four weekly intravesical instillations of 0.7 mg IFN gamma were studied immunohistochemically for proliferative cell nuclear (PCNA) and Ki67 antigens in 25 evaluable patients. RESULTS: Ki67 growth fraction decreased from median 5% preoperatively to 1% postoperatively (p = 0.0015) and proliferating cell nuclear antigen from 20% to 5% respectively (p = 0.0001). Net reductions of both indices after the interferon instillations were significantly higher in T1 than in Ta tumours (p = 0.0431 for Ki67, and p = 0.0350 for PCNA). CONCLUSIONS: The intravesical instillations of the present dose of interferon gamma have a significant cytostatic effect on superficial bladder cancer cells as this is evidenced by the significant decrease of the growth fractions measured by means of the proliferating cell nuclear and the Ki67 antigens.

Lymphocyte subsets in superficial bladder cancer: correlation with biological activity of the tumours.

BACKGROUND: The investigation of relationship of tumour biological activity and the degree of tissue infiltrating lymphocytes (T4, T8, T6) and macrophages in bladder cancer was the purpose of this study. MATERIALS AND METHODS: Tumour specimens and near and distant biopsies from 26 patients suffering from superficial bladder cancer and bladder biopsies from 6 controls were studied. Monoclonal antibodies against T helper/inducer, (CD4), T suppressor/cytotoxic (CD8), Langerhans cells (CD1a) and Monocytes/Histiocytes (LeuM5) were used for the detection of lymphocyte subpopulations. Ki67 growth fractions and recurrence rate per 100 patients-months were used for the definition of the biological activity of the tumours. RESULTS: The degree of tissue infiltrating lymphocytes differed significantly between controls and both groups. Larger (but not significantly different) numbers were noticed in the non recurrence compared to the recurrence group of patients. CONCLUSIONS: We conclude that the host's immune defence mechanism against malignant cells does not seem to produce significantly different numbers of tissue infiltrating lymphocytes in tumours of low and high aggressiveness. On the other hand the degree of lymphocyte infiltration in bladder cancer is not marked compared to controls of controls of matching age.

Growth fractions in bladder cancer defined by Ki67: association with cancer grade, category and recurrence rate of superficial lesions.

Predicting future tumour behaviour has always been a major task when treating bladder cancer. Ki67 monoclonal antibody has been reported to be a good marker of proliferative activity in a variety of tumours. We have studied the association of growth fractions defined by the monoclonal antibody with tumour grade, category and recurrence rate of superficial lesions in 34 patients with bladder cancer and 15 normal controls. Mean Ki67 indexes (% stained cells) were 0.07 +/- 0.02% in normal urothelium, 1.27 +/- 1.55% in grade 1, 12.23 +/- 8.32% in grade 2 and 16.42 +/- 11.82% in grade 3 tumours, while the values were 5.45 +/- 5.87%, 12.66 +/- 9.81% and 17.18 +/- 12.41% in categories pTa, pT1 and T2-T3 respectively. Recurrence and non-recurrence groups of patients showed indexes of 13.29 +/- 9.49% and 4.15 +/- 5.0% respectively. Statistically significant differences in Ki67 values between normal urothelium and tumour, between tumours of different grades and categories as well as between recurrence and non-recurrence groups of patients led to the conclusion that Ki67 monoclonal antibody is a good tool in defining tumour behaviour in bladder cancer.