Metastasis-free survival as a new endpoint in castration- -resistant prostate cancer.

INTRODUCTION: Recent breakthrough recognition of metastasis-free survival as a clinically relevant endpoint has opened a new era in the management of advanced prostate cancer. The need for new, intermediate endpoints is the logical consequence of scientific advances in prostate carcinoma. The treatment algorithms for non-metastatic castration-resistant prostate cancer (M0 CRPC) have recently been updated by adding novel anti-androgen apalutamide, and also enzalutamide for high-risk patients. OBJECTIVE: To review clinical evidence of metastasis-free survival as an efficacy endpoint used in prostate cancer studies, especially those in an advanced stage of the disease and identify its clinical benefit and correlation with overall survival. METHODS: Literature search up to October 2019  was conducted, including clinical trials and clinical practice guidelines. EVIDENCE SYNTHESIS: Metastasis-free survival (MFS) was used as the primary endpoint in the registration of clinical trials of second-generation anti-androgens. The study results have demonstrated the beneficial effect of these anti-androgens on delaying the development of metastases or death (MFS), with median MFSextended by 22‒24 months. The correlation tests have shown a positive correlation of MFS and overall survival. CONCLUSION: The metastasis-free survival can be considered a clinically significant and reliable efficacy endpoint in both localized prostate cancer patients and M0 CRPC patients being at high-risk of disease progression (Ref. 15).

Association between interleukin-18 variants and prostate cancer in Slovak population.

Interleukin-18 (IL-18), pro-inflammatory cytokine, plays important role in antitumor immunity. Polymorphisms in the IL-18 gene may lead to its altered production/activity and such modulate susceptibility to prostate cancer. The aim of this study was to evaluate the relationship between the -607 and +105 polymorphisms in the IL-18 gene and the risk of prostate cancer development and progression in Slovak population. The study was performed using 425 patients with prostate cancer, 270 patients with benign prostatic hyperplasia (BHP) and 263 healthy male controls. The statistically significant association of the -607 AC genotype (OR = 2.24; p < 0.001), CC genotype (OR = 1.86; p = 0.006), as well as C allele (OR = 1.27; p = 0.033) with the higher risk of prostate cancer development was observed. No association of the IL-18 -607 polymorphism and BHP was detected. The subset analysis revealed the significant association of the -607 AC genotype (OR = 2.01; p = 0.008) with development of higher-grade carcinomas (Gleason score ≥7) and the strong association of the -607 AC genotype (OR = 3.11; p < 0.001), CC genotype (OR = 2.96; p < 0.001) as well as C allele (OR = 1.51; p = 0.003) with the higher risk of prostate cancer development in the group of patients with PSA < 10 ng/ml. The -607 AC genotype was also connected with significantly higher IL-18 plasma concentrations. No association between the IL-18 +105 polymorphism and prostate cancer was observed. The analysis of the distribution of the -607 and +105 haplotypes showed significant association of the - 607 C/ + 105 A and - 607 C/ + 105 C haplotypes with the risk of prostate cancer. This study found that the IL-18 -607 promoter polymorphism could contribute to prostate cancer development in Slovak population. Its presence was also associated with development of higher-grade carcinomas and therefore may influences the prognosis and aggressiveness of the disease.

Alpha emitter radium-223 and survival in metastatic prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Microsomal epoxide hydrolase polymorphisms, cigarette smoking and prostate cancer risk in the Slovak population.

Polymorphisms in tobacco carcinogen metabolizing enzymes may generate interindividual variations towards the risk of developing prostate cancer. One of these enzymes is microsomal epoxide hydrolase (EPHX1) which metabolizes polycyclic aromatic hydrocarbons, or PAH, carcinogens found in cigarette smoke. The activity of this enzyme is affected by two polymorphisms, a substitution of Tyr113 by His in exon 3 and a substitution of His139 by Arg in exon 4. The aim of this study was to use a population-based case-control study to investigate whether or not such genetic polymorphisms in EPHX1 gene can modify the relationship between smoking status and the risk of developing prostate cancer. We used restriction fragment length polymorphism, or PCR-RFLP to determine EPHX1 genotypes in subjects comprising 194 patients with histologically verified prostate cancer and 305 healthy individuals as control. We found no overall association between prostate cancer risk and functional polymorphisms of EPHX1 gene in exon 3 and exon 4. We further analysed the association between the EPHX1 genotypes and smoking. Smokers carrying the exon 3 Tyr/Tyr and Tyr/His genotypes were at no significant risk compared to non-smokers with the "rapid" Tyr/Tyr genotype. By contrast, a significant interaction of smoking and the exon 4 polymorphism was present.

Prostate cancer incidence and mortality in selected countries of Central Europe.

BACKGROUNDS: This paper analyzes the incidence and mortality of prostate cancer in the Slovak (SR) and Czech (CR) Republics (as Central European countries with population-based cancer registries) before and after the introduction of PSA testing, the possible reasons for any differences disclosed, and compares the results with selected regions and countries around the world. MATERIAL, METHODS AND RESULTS: In SR, the age-adjusted incidence of prostate cancer rose from 14.6/100,000 in 1968 to 36.2/100,000 in 2005. The estimated annual increase of incidence from 1968 to 1991 (before nation-wide PSA testing) was 0.421 and 1991-2003 it reached 0.941. The mortality rates rose from 7.3/100,000 in 1968 to 14.9/100,000 in 2005. The increase in incidence occurred faster in CR than in SR, from 15.8/100,000 in 1977 to 59.5/100,000 in 2005. The estimated annual increase of incidence in CR in 1977-1991 was 0.581,while in 1991-2003 it reached 1.981. Before 1991, mortality rose more sharply in CR than in SR while after the introduction of PSA testing mortality stabilized more quickly in the CR than in SR. In SR a significant reduction of mortality was observed after 2002 and is probably affected by more factors than those associated with the increase in PSA testing. CONCLUSION: The difference in the incidence and mortality of prostate cancer in SR and in CR results from a difference in the intensity of PSA testing as well as from the earlier introduction of effective treatment in CR.

[Detection of DNA hypermethylation as a potential biomarker for prostate cancer]. / Detekcia hypermetylácie DNA ako potenciálny biomarker pre karcinóm prostaty.

Prostate cancer is one of the most common malignant diseases in men above the age of 50. A genetic predisposition and/or acquired genetic and epigenetic changes together with lifestyle contribute to the development of the disease. The most studied epigenetic modification in prostate cancer is the methylation of the cytosine located within the dinucleotide CpG of promoter regions of different genes by methylation specific PCR. The evidence of gene silencing by DNA methylation in genes like GSTP1, APC or RASF1 is a common and relatively specific event in prostate cancer. DNA methylation testing can be performed on tissue samples or urine, ejaculate or serum. Translational research is searching for new biomarkers for early detection and prognosis of prostate cancer, but because of large methodological differences in applied techniques and patient cohorts, the investigations have yielded promising, but also some controversial results. More prospective randomized trials and standardized methods are needed to assess the true value of methylation for the diagnosis and prognosis of prostate cancer.

Serum level of IGFBP3 and IGF1/IGFBP3 molar ratio in addition to PSA and single nucleotide polymorphism in PSA and CYP17 gene may contribute to early diagnostics of prostate cancer.

The aim of the paper is to determine whether IGF1, IGFBP3 and IGF1/IGFBP3 molar ratio in addition to PSA and one-nucleotide polymorphism in PSA and CYP17 gene might contribute to early diagnostics of prostate cancer (PCa). Serum level of PSA, IGF1 and IGFBP3 in the group of 158 individuals (92 PCa and 66 controls) was examined by RIA method and IGF1/IGFBP3 was calculated. PCR RLFP method was used to examine one- nucleotide polymorphism in PSA and CYP 17 gene. The results suggest that serum level of IGF1 over 95% CI did not increase relative risk of PCa development in overall group, not even regarding to particular investigated genotypes, not even if individuals with genotype AG+A1A1, AG+A1A2, GG+A1A1 and GG+A1A2 were evaluated. Serum level of IGFBP3 under 95% CI increased PCa relative risk in overall group(chi(2) = 10,03, p= 0,001, OR 3,12, 95% CI 1,44-6,93), as well as regarding to one-nucleotide polymorphism in individuals with PSA genotype AG(chi(2) = 4,72 p= 0,029, OR 2,87, 95% CI 01,09-7,49) and CYP 17 genotype A1A1(chi(2) = 3,76 p= 0,052, OR 2,57, 95% CI 0,97-6,75). The association between frequencies of occurrence of PCa and higher IGF1/IGFBP3 molar ratio was not confirmed, nor for gene polymorphism in PSA and CYP17, however OR (chi(2) = 1,58, p= 0,208, OR 1,67, 95% CI 0,75-3,71) was more than 1, nor in combination AG+A1A1,AG+ A1A2. Serum level of IGFBP3 and IGF1/IGFBP3 molar ratio in addition to PSA and gene polymorphism in PSA and CYP17 gene might contribute to early diagnostics of PCa. Further research is needed to prove, whether serum level of IGFBP3 in addition to PSA determines the prognosis and progression of PCa.

[Procedure on low extremities varicose veins using the VNUS-Closure radiofrequency ablation method]. / Operace varixu dolních koncetin radiofrekvencní ablací metodou VNUS-Closure.

From 01-06-2007 to 31-12-2008, the authors operated 334 patients with low extremities varicose veins, using the VNUS-Closure radiofrequency apparatus, in the surgical department of Príbram regional hospital (Oblastní nemocnice v Príbrami, a.s.). Their first experience is very positive, the method is very elegant, safe and miniinvasive. The mean duration of the procedure on a single lower extremity was 29 minutes, the mean duration of hospitalization was one day. Relapses were recorded in 3 patients in the operated area (0.9%), however, in all the subjects, the relaps affected a side venous branch, never the main branch. The relapses were managed with subsequent sclerotization. The method was patient- friendly, reliable and resulted in early return to work, was little painful and had favourable cosmetic outcomes. These were the factors, which made the patients choose the VNUS-Closure endoluminal radiofrequency method.

Radical prostatectomy for locally advanced prostate cancer: results of a feasibility study (EORTC 30001).

The aim of this open, non-randomised, 2-stage feasibility study was to determine whether radical prostatectomy (RP) was safe and could provide cure for good prognosis patients with clinical T3 prostate cancer, in a multicentre setting. Cure was defined as a 3 months post-operative of undetectable serum PSA in combination with the presence of pathologically negative margins in the surgical specimen. Forty patients were enrolled of whom 38 were eligible. Six patients (5 pN+ and 1 pNx) did not meet the inclusion criteria and were excluded leaving 32 evaluable pN0 patients of whom 19 (59.4%, SE=4.26) achieved a complete response (CR) and in whom only two serious toxic events (STEs) were observed. The results of the first phase of the study passed the toxicity criteria (<3 STE's) but failed on the cure rate (>20 CRs). This resulted in discontinuation of the study after the first stage. The main reason for failure was the incidence of positive margins in the resected specimen. Although the study was stopped after the first phase, 28 of the 32 pN0 patients (87.5%) had undetectable serum PSA at 3 months. We continue to believe that RP with extensive resection can be beneficial as monotherapy for T3aN0M0 prostate cancer.

Reactivity of urinary bladder smooth muscle in guinea pigs to acetylcholine and carbachol--participation of acetylcholinesterase.

The authors examined the influence of acetylcholinesterase inhibitor (neostigmine) on the in vitro reactivity of urinary bladder smooth muscle (UBSM) in guinea pigs. The aim of the present study was to determine the participation of pharmacokinetic properties of acetylcholine and carbachol in different UBSM reactivity to these mediators. In vitro method of organ baths was used and reactivity of UBSM strips to cumulative doses of acetylcholine and carbachol was tested before and after the incubation with neostigmine (10(-4) mol.l(-1)). Neostigmine caused a significant increase of UBSM reactivity to acetylcholine. The UBSM reactivity to acetylcholine was significantly higher at concentrations of 10(-5) and 10(-4) mol.l(-1) compared to carbachol at the same concentrations. These findings indicate that in addition to different mediator affinity to muscarinic receptors and to their different intrinsic activity, the pharmacokinetic properties of acetylcholine and carbachol also participate in UBSM reactivity.

Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer.

BACKGROUND: Vinorelbine (VRL) has been shown to be active in hormone-refractory prostate cancer (HRPC) in phase II studies, alone or in combination. Its moderate toxicity profile is well tolerated in elderly patients. PATIENTS AND METHODS: Patients with metastatic prostate cancer, progressive after primary hormonal therapy, were randomised to receive intravenous VRL 30 mg/m2 on days 1 and 8 every 3 weeks, and hydrocortisone 40 mg/day or hydrocortisone alone until disease progression. Centres could choose to add aminoglutethimide 1000 mg/day to hydrocortisone as second-line hormone therapy (HT) for all their patients. Randomisation was stratified by centre. Further chemotherapy was allowed after progression. The primary end point was progression-free survival (PFS). The final analysis was performed on a total of 414 patients. Reported results were all based on intention-to-treat analyses. All progressions and responses were reviewed by an independent panel. RESULTS: PFS was significantly prolonged in the VRL plus HT arm compared with the HT alone arm, according to the statistical hypothesis of the protocol (P=0.055 in the two-sided log-rank test with a pre-specified significance level of 10%). The 6-month PFS rates were 33.2% versus 22.8%, and the median durations of PFS were 3.7 versus 2.8 months. In the multivariate Cox analysis, which included age, Karnofsky performance status (PS), haemoglobin, alkaline phosphatase at study entry and number of prior hormonal treatments, the P value was decreased to 0.005. The prostate-specific antigen (PSA) response rate (> or =50% decline sustained for at least 6 weeks) was significantly higher for VRL plus HT compared with HT (30.1% versus 19.2%; P=0.01). Clinical benefit, defined as a decrease in pain intensity or analgesic consumption or an improvement of Karnofsky PS for at least 9 weeks, and at least stable assessment in the other two, was also more frequently observed in patients who received VRL plus HT versus HT alone (30.6% and 19.2%; P=0.008). There was no statistical difference in overall survival. Forty-three per cent of patients in the HT arm received at least one line of further chemotherapy after progression, compared with 28% of patients in the VRL-based arm. Aminoglutethimide did not seem to result in better efficacy for either arm. VRL plus HT was well tolerated, with a median administered relative dose intensity of 90%; grade 4 neutropenia occurred in 6.5% of patients and non-haematological toxicity was rare. CONCLUSIONS: The combination of VRL and hydrocortisone compared with hydrocortisone alone resulted in improved clinical benefit, PFS and PSA response rate. This therapeutic gain is similar to that previously reported with mitoxantrone in combination with low-dose corticosteroids. There was no gain in survival; however, the combination is well tolerated in this elderly group of patients, who often present cardiac co-morbidities, and therefore offers an active and safe therapeutic option for patients with hormone-refractory prostate cancer.

Intraprostatic ethanol chemoablation via transurethral and transperineal injection.

OBJECTIVES: To further assess the safety and feasibility of prostatic chemoablation with ethanol and to address previous concerns associated with transperineal injection using a canine model. MATERIALS AND METHODS: The study included 25 dogs; normal saline or 98% dehydrated ethanol were injected into the prostate using both routes, at volumes of 25-50% of the total prostate volume. The prostate and adjacent structures were examined grossly and histopathologically after the dogs were killed humanely at 4 h, 7 days and 12 weeks after injection. RESULTS: Transperineal injection resulted in tissue necrosis in all prostates and significant extraprostatic necrosis in two of three animals treated. With transurethral injection, the control groups showed minimal change, whereas the group injected with ethanol resulted in lesions with variable necrosis and location. CONCLUSIONS: Intraprostatic chemoablation is possible with ethanol injection both transperineally and transurethrally. Transperineal ethanol injections were associated with more extraprostatic necrosis. Transurethral injections resulted in larger amounts of necrosis in the prostatic parenchyma with minimal extraprostatic effects. However, the extent of prostatic necrosis/ablation was inconsistent and further research is warranted.

Mechanisms of reactivity of urinary bladder smooth muscle.

BACKGROUND: Mechanism of bladder smooth muscle contraction and relaxation and its pharmacological influence in various pathologic states are of incremental interest of investigators and clinicians. OBJECTIVES: The aim of our study was to assess the reactivity of urinary bladder smooth muscle in guinea pigs to two different pharmacological agents. METHODS: We compared the in vitro reactivity of smooth muscle strips of guinea pig urinary bladder to muscarinic stimulation by carbachol and acetylcholine. We prepared two kinds of strips, urothelium-denuded and with intact urothelium. Both kinds of strips were aerated under tension in Krebs-Henseleit's solution in organ-bath for 1 hour and after that cumulative concentration-response curves to carbachol (10(-9) - 10(-5) mol/l) and acetylcholine (10(-8) - 10(-3) mol/l) were constructed. RESULTS: We observed significantly higher reactivity of smooth muscle strips to carbachol, comparing to acetylcholine at the same concentrations both in strips with urothelium (at concentration 10(-5) mol/l: 22.1 g/100 mg vs 6.1 g/100 mg) and in urothelium-denuded strips (at concentration 10(-5) mol/l: 24.5 g/100 mg vs 5.1 g/100 mg). The reactivity differences between strips with and without urothelium were not significant, however, in higher concentrations of acetylcholine (10(-4) and 10(-5) mol/l) and carbachol (10(-6) and 10(-5) mol/l) we noticed no significant inhibition of contractile response of smooth muscle strips with intact urothelium. CONCLUSION: In our experiments we confirmed that carbachol was more potent constrictor than acetylcholine in detrusor smooth muscle strips of guinea pigs. The presence of urothelium did not change the reactivity significantly. (Fig. 4, Ref: 23.).

Neuromodulative treatment of overactive bladder--noninvasive tibial nerve stimulation.

BACKGROUND: Conservative treatment of overactive bladder employes behavioral or invasive neuromodulatory inhibition of miction reflex and administration of anticholinergic drugs. MAIN PURPOSE: The aim of this study was to use non-invasive stimulation of the tibial nerve with the intention to achieve desired therapeutic effects without iatrogenic nerve damage using a superficial electrostimulation. METHODS: All patients suffered from overactive bladder (OAB) without bladder outlet obstruction. OAB was examined by the Behavioral urge score BUS (0.0--the best and 1.0--the worst score), the International prostate symptom score IPSS (0--the best and 35--the worst score) and the Incontinence quality of life questionnaire IQOL (0.0--the worst and 1.0--the best index). The patients were divided into 3 groups: Group I--patients with electrode attached behind the medial ankle of the left lower extremity. The intensity of stimulation corresponded to 70% of the maximum amplitude of response from musculus abductor hallucis. Frequency of stimulation was 1 Hz and duration of the square impulse was 0.1 ms. Surface stimulation lasted 30 minutes and was repeated once a week. Group II--patients were treated by oral oxybutynin 5 mg t.i.d. Group III--patients without treatment. The BUS, IPSS, and IQOL were repeated after the treatment. RESULTS: The study included 28 females of average age 54 year (range 45 to 63). Mean IPSS was 17 (range 12 to 21), mean index of quality of life IQOL was 30 (range 12 to 78) and mean BUS score was 0.68 (range 0.50 to 0.86). Group I with stimulation did achieve statistically significant changes following the treatment: decrease of mean IPSS from 17 +/- 3 points to 6 +/- 4 points after the treatment, increase in mean IQOL from 36 +/- 10 to 68 +/- 20 and decrease of mean BUS from 0.65 +/- 0.12 to 0.43 +/- 0.16. Group II had similar statistically significant differences after the treatment of OAB. Group III noted no changes in the complaints. CONCLUSION: Noninvasive stimulation had improved subjective symptom related to overactive bladder, had no adverse events and was well tolerated. (Fig. 1, Tab. 1, Ref. 18.).

Renal Doppler ultrasonography in infants with hydronephrosis.

The objective was to evaluate the importance of obstruction in unilateral hydronephrosis by using renal Doppler ultrasonography. A total of 19 infants were examined. It was revealed that patients of group with obstruction have in the affected kidney a higher mean resistive index [RI = 0.77 +/- 0.04] than in the healthy kidney [RI = 0.69 +/- 0.02] [p < 0.001]. In patients of group with nonobstructive dilatation this difference was not observed. In infants it is not possible to evaluate only absolute changes of the resistive index. It is much more useful to compare values of RI of both kidneys using the above indices. The determination of RI, RIR and delta RI can be helpful in distinguishing obstructed from non-obstructed hydronephrosis.

[Importance of transrectal ultrasonography in the detection of local recurrence of prostatic carcinoma after radical prostatectomy]. / Význam transrektálnej ultrasonografie pri detekcii lokálnej recidívy karcinómu prostaty u pacientov po radikálnej prostatektómii.

OBJECTIVE: To assess the importance of transrectal ultrasonography in early detection of local recurrence of prostate carcinoma in patients after radical retropubic prostatectomy and compare it with digital rectal examination and the level of prostatic specific antigen. PATIENTS AND METHODS: In a group of 72 patients, at least six months after radical prostatectomy regularly after 3-6-month intervals the levels of prostatic specific antigen were monitored. When the level of specific prostatic antigen was repeatedly higher than 0.2 ng/ml or when it increased as compared with the previous examination the patient was submitted to digital rectal examination and transrectal ultrasonography of the bed after radical prostatectomy. In case of a positive sonographic finding, ultrasound-guided biopsy was performed. RESULTS: A local recurrence of the disease was confirmed by ultrasound-guided biopsy in 5 (6.9%) of 72 investigated patients on average 51 months (23-81) after radical prostatectomy. The mean preoperative value of the prostatic specific antigen was in these patients 23.4 ng/ml (10.6-33). In all patients the authors detected by transrectal ultrasonography a hypoechoic focus at the site of anastomosis. Of 5 patients with a local recurrence of the disease two (40%) had a negative digital rectal examination. CONCLUSION: The prostatic specific antigen monitored most accurately the local progression of the disease after radical prostatectomy. Transrectal ultrasonography detected a local recurrence of the disease in all five patients despite the negative digital rectal examination. Transrectal ultrasonography makes guided biopsy from the site of radical prostatectomy possible and thus increases the detection rate of local progress of the disease as compared with digital rectal examination. Elevation of the prostatic specific antigen with subsequent transrectal ultrasonographic examination makes it possible to detect as soon as possible early local recurrence of prostate carcinoma after radical prostatectomy.

[Diagnosis and treatment of functional disorders of the lower urinary tract in younger men]. / Diagnostika a liecba funkcných porúch dolných mocových ciest u mladsích muzov.

BACKGROUND: Functional disorders of the lower urinary tract can manifest by different symptoms. This could be caused by inaccurate diagnosis and non-causal treatment in young men. Urodynamics is helpful in the differential diagnosis and treatment of such cases. OBJECTIVES: Examination of lower urinary tract functions in young men and causal treatment of both bladder neck obstruction or impaired bladder. METHODS: In a prospective study, a group of 38 young men were treated at mean age of 42 years (range 19-50 yrs). Chronic abacterial prostatitis was treated in all cases unsuccessfully. Patients with positive urinary infection, previous surgery of the lower urinary tract and neurogenic bladder were excluded. Urodynamics confirmed a bladder neck obstruction or impaired bladder, the symptom score revealed subjective difficulties (maximum 35 points). Patients with the obstruction underwent transurethral incision of the bladder neck. Patients with impaired bladder were administrated with distigmine bromid (Ubretid) 5 mg for 1 year, every other day. All patients were re-examined one year following the treatment. RESULTS: Bladder neck obstruction occurred in 18 cases, and impaired bladder in 20 cases. Significant differences were found in relation to age (47 vs. 31 years, p < 0.01) and detrusor pressure at maximum flow (62 vs. 30 cmH2O, p < 0.01). There were no differences in peak flow rate (9 vs. 10 ml/s, p = 0.75), symptom score (19 vs. 18, p = 0.46), residual urine (45 vs. 100, p = 0.08) and maximum cystometric capacity (341 vs. 383 ml, p = 0.10). Transurethral bladder neck incision or distigmine administration improved the symptom score by 68.4% vs. 33.3%, peak flow rate 50.0% vs. 23.1% and residual urine 100% vs. 75%. CONCLUSIONS: Treatment of lower urinary tract disorders is successful in causal treatment of bladder neck obstruction and impaired bladder. (Tab. 2, Fig. 2, Ref. 12.)

[Diagnosis of intrinsic urethral sphincter insufficiency in women]. / Diagnostika intrinzickej nedostatocnosti uretrálneho zvieraca u zien.

OBJECTIVE: Evaluation of intrinsic sphincter deficiency (ISD) according to the urethral leak point pressure in female population with stress urinary incontinence. DESIGN: Prospective clinical study. SETTING: Department of Urology, Jessenius School of Medicine Comenius University Martin, Slovak Republic. METHODS: Study population compromise of 204 females with lower urinary tract symptoms. Exclusion criteria were neurogenic bladder and unstable bladder. Valsalva leak point pressures were evaluated (VLPP). ISD was defined if VLPP below 65 cm H2O has been occurred. Pad weighing test (PWT) was positive after leakage of 2 g per hour and more. RESULTS: Stress urinary incontinence was in 134 and continence in 70 cases (control group). The first stage of incontinence was in 83, the second stage in 45 and the third stage in 6 cases of incontinence group. ISD has been occurred in 14 cases (10.5%), 8 cases with the second stage and 6 cases with the third stage. The best correlation was between VLPP and PWT, symptoms of incontinence and age of patients. All ISD cases underwent antiincontinent surgery with urethral suspension, some years ago. CONCLUSION: ISD has been risen in the second stage (6%) and the third stage (4.5%), also, in the female population with stress urinary incontinence.

Quality of life of patients with newly diagnosed poor prognosis M1 prostate cancer undergoing orchiectomy without or with mitomycin C. Results from the EORTC Phase-III trial 30893.

OBJECTIVES: To compare the quality of life (QL) of patients with poor prognosis M1 prostate cancer treated with orchiectomy alone (ORCH) or orchiectomy combined with adjuvant mitomycin C (MMC; 15 mg/m(2) i.v. q 6 weeks: ORCH+MMC; EORTC trial 30893). METHODS: Patients with newly diagnosed M1 poor prognosis prostate cancer completed a truncated version of the EORTC QLQ-C30 (V 1.0) at randomization (baseline) and every 6-12 weeks thereafter until going off the protocol. Five ad hoc questions assessing lower urinary tract symptoms were included in the QL questionnaire. RESULTS: At least one QL form was completed by 177 of the 189 patients included in the trial, with baseline questionnaires available for 113 patients (ORCH n = 52; ORCH+MMC n = 61). In both arms, pain and urinary dysfunction improved during treatment. Compared with patients from the ORCH arm, the use of adjuvant MMC was associated with a significant reduction in global health status/QL and with impairment in 7 of 11 QL dimensions covered by the questionnaire. Some improvement in QL was observed after discontinuation of MMC. A survival benefit was not observed in the ORCH+MMC arm. CONCLUSIONS: Intravenous MMC (15 mg/m(2) q 6 weeks) cannot be recommended as adjuvant treatment in M1 poor prognosis prostate cancer due to its negative impact on QL and lack of efficacy. In general, QL assessments should be mandatory when adjuvant chemotherapy is evaluated in patients with metastatic prostate cancer.

Orchiectomy and orchiectomy plus mitomycin C for metastatic prostate cancer in patients with poor prognosis: the final results of a European Organization for Research in Cancer Therapy Genitourinary Group Trial.

PURPOSE: The outcome of patients with symptomatic metastatic prostate cancer is poor and improved treatment regimens are urgently needed. Theoretically, the combination of orchiectomy and chemotherapy could reduce androgen sensitive and insensitive cells in the prostate. This European Organization for Research in Cancer Therapy Genitourinary Group randomized, multicenter phase III trial demonstrates the outcome of orchiectomy alone versus orchiectomy followed by intravenous mitomycin C. MATERIALS AND METHODS: A total of 189 patients with metastatic prostate cancer and poor prognostic factors were randomized in this trial by 42 institutions. Of these patients 184 (97%) were eligible for study, including 90 treated with orchiectomy alone (orchiectomy only arm) and 94 treated with orchiectomy followed by 15 mg./m.2 mitomycin C in 1 week (combined treatment arm). Mitomycin C was administered every 6 weeks and treatment was continued as long as tolerance and patient compliance allowed, and no progression was observed. Objective and subjective criteria for progression were clearly defined in the protocol. RESULTS: Patient and tumor characteristics were well balanced between the 2 treatment arms. At a median followup of 4.2 years 144 patients had died, including 112 of prostate cancer. No significant differences for time to overall (p = 0.17), subjective (p = 0.25) and objective (p = 0.08) progression were found between the 2 treatment groups. For progression-free survival no difference was noted (p = 0.67) between the 2 treatment groups but a trend in favor of orchiectomy alone was observed for overall survival (p = 0.04). Mitomycin C induced considerable hematological, gastrointestinal, renal and pulmonary toxicity leading to discontinuation in 31% of patients with pulmonary toxicity and 7% with renal deterioration. In addition, the quality of life evaluation revealed significant reduction in the combined treatment arm. CONCLUSIONS: Based on the results of this randomized phase III study orchiectomy plus mitomycin C for metastatic prostate cancer in patients with poor prognostic factors cannot be recommended due to failure of improvement in survival and reduced quality of life parameters.