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.

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.

[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.

[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.

Multiple cutaneous metastases as the first sign of lung cancer in a patient with well-differentiated papillary transitional cell carcinoma of the urinary bladder.

A case of multiple, cutaneous metastases as the first sign of lung cancer in a patient with well-differentiated, papillary, transitional cell carcinoma of the urinary bladder is presented. In the left clavicular region were two, sharply demarcated, dark red tumors measuring 3 and 2 cm in diameter with a history of rapid growth and intermittent spontaneous bleeding. Thorough examination of the patient revealed 16 additional skin lesions, which were dark red macules and papules, 2-3 mm in diameter, situated on the left side of the chest. The skin biopsy material (tumors, macular and papular lesions) was studied using histological and immunohistochemical techniques and showed intact epidermis and massive dermal and subcutaneous metastatic involvement by a small cell carcinoma with neuroendocrine differentiation most likely originating in the lung.

A new approach in radionuclide imaging to ureteric peristalsis using 99Tcm-MAG 3 and condensed images.

A new method for the evaluation of ureteric peristalsis is described. Standard, dynamic renal scintigraphy was carried out using 99Tcm-MAG 3 in 59 patients. Time-activity curves and condensed images over the ureter area were created simultaneously. A six-grade scale (O-V) was chosen for the classification of ureteral function. The results obtained were compared with parameters of renographic curves and other clinical findings. In a group of 13 patients, two different renal radiopharmaceuticals were used: 131I-OIH and 99Tcm-DTPA. The results show that the new method is suitable for the assessment of ureteral disorders, and has some advantages compared with previously described methods. 99Tcm-MAG 3, with a better target-to-background ratio compared to 131I-OIH and 99Tcm-DTPA, is the most suitable radiopharmaceutical for this purpose.

Urovaginal fistulas: experience with the management of 41 cases.

In a retrospective analysis the authors have evaluated their experience with the management of urovaginal fistulas in 41 patients. Of them 34 had vesicovaginal, 3 ureterovaginal, 2 urethrovaginal, 1 ureterovesicovaginal and 1 ileovasicorectovaginal fistula. Fistulas occurred most frequently after gynaecological operations for benign and malignant diseases and after radiotherapy. Reconstructive operations were performed in 37 patients, mostly from the vaginal approach. Primary repair of fistulas was successful in 35 patients. In 2 patients reoperation was required. Due to good experience the authors recommend the transvaginal approach, which in their opinion is suitable for repair of the prevailing part of vesicovaginal fistulas.

Surgical management of vesicoureteral reflux by modified Gil-Vernet method.

Modified antireflux Gil-Vernet technique was used in the surgical management of primary vesicoureteral reflux grades II and III in 62 patients (60 children, 2 adults). Reflux has been eliminated in 90.3% of the patients. In patients with persisting reflux it was of lower grade than before surgery and showed a tendency to spontaneous disappearance when treated conservatively. Taking into consideration also the late results of elimination of the reflux, the success rate is comparable to that in other antireflux methods. In none of our patients has obstruction or other more serious complication occurred. Advantages of this technique are stressed, first of all its simplicity, preservation of musculature of terminal ureters, possibility of management of both ureters and absence of complications, mostly of obstructive character.

X-ray changes in the kidneys of children with orthostatic proteinuria.

In 38 patients with orthostatic proteinuria (O.P.) and in 31 children of the control group (C) roentgenograms of excretory urography have been compared, made in the standing erect and in the lying down posture. In children with O.P. significantly more frequent and more expressive ptosis of the kidneys during orthostasis was found than in the controls. In children with O.P. disturbed urine outflow was found in 36.8%, while in children of the control group only in 3.2%. On the basis of the results obtained relations between haemodynamic changes in ptosis of the kidneys, disturbed urine outflow and the origin of O.P. are analysed.

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.

Carcinoma of the colon after ureterosigmoidostomy and trigonosigmoidostomy for exstrophy of the bladder.

Two cases of adenocarcinoma of the colon developing 28 and 33 years after ureterosigmoidostomy and trigonosigmoidostomy are described. The mechanisms of neoplastic transformation and the clinical implications are discussed.

Isolation of Neisseria gonorrheae and concomitant bacterial microflora from urine obtained by suprapubic bladder puncture in women with gonococcal urethritis.

The authors examined 38 non-pregnant women with gonococcal urethritis. Thirty-three (86.8%) of them suffered also from endocervical gonorrhea. Neisseria gonorrheae (N. go) was isolated from the midstream of urine in a quantity of 1 x 10(2) to 9 x 10(8) in 1 ml of urine with an average of 5.08 x 10(4) N. go per 1 ml of urine and S. E. M. +/- 3.85 x 10(4) N. go per 1 ml of urine. On the basis of suprapubic puncture ascendent propagation of bacteria to the bladder was observed by cultivation in 13 (34.2%) patients, with isolation of N. go in 5 cases.

Squamous cell carcinoma of the penis. Analysis of 24 cases.

The authors evaluated retrospectively 24 cases of spinocellular carcinoma of the penis, trying to detect aetiological carcinogenic factors of the disease. Phimosis persisting since childhood was reported by ten men, whereby in five of them circumcision was performed during puberty. The duration of symptoms up to the time of biopsy and histological verification of differentiated spinocellular carcinoma of the penis varied from one month to thirteen years. Eight patients (33.3%) belonged to category T1, 8 (33.3%) to T2 and 8 (33.3%) to T3. Fifteen tumours (62.5%) were G1, 5 (20.8%) G2 and 4 (16.7%) G3. In 5 men print cytology was negative.

[Submicroscopic changes in ciliated cells of the epithelium of the oviduct in cows during the estrus cycle]. / Submikroskopické zmeny ciliárnych buniek epitelu vajcovodu kravy pocas pohlavného cyklu.

The submicroscopic changes in the ciliary cells of the ampullar part of oviduct are of qualitative as well as quantitative nature. The mitochondria are mainly located in the supranuclear region. They are small, having densely arranged lamelliform cristae and dense matrix. They have the largest volume in metoestrus and the highest number and the largest surface already during oestrus. The volume and surface of granular endoplasmic reticulum culminates already during pro-oestrus. The reticulum occurs mainly over the nucleus where it produces tubuli densely covered with ribosomes which begin to dilate already during pro-oestrus. The Golgi apparatus and the membranes of smooth reticulum are poorly developed and their quantitative changes during the cycle are not significant. Various forms of lysosomes, whose volume reaches its maximum in dioestrus and during pro-oestrus, constitute a constant component of cytoplasm. Secretory granules occur only rarely in these cells. Kinocilia grow from the basal corpuscles and are more frequent on cells with a light cytoplasm. Higher-density cells have more micro-villi between kinocilia. Deciliation with the disintegration of membrane, filaments and often also the basal corpuscles is observed during metoestrus and at the beginning of dioestrus. Reciliation begins with the formation of basal corpuscles and their replication at the end of dioestrus and in pro-oestrus. The frequency of ciliary regeneration is comparatively small.