http://repub.eur.nl/res/aut/5564/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/31112/ 2011-09-01T00:00:00Z Objective To identify maternal dietary patterns related to biomarkers of methylation and to investigate associations between these dietary patterns and the risk of congenital heart defects (CHDs) in the offspring. Design Case-control study. Setting Western part of the Netherlands, 2003-08. Population One hundred and seventy-nine mothers of children with CHD and 231 mothers of children without a congenital malformation. Methods Food intake was obtained by food frequency questionnaires. The reduced rank regression method was used to identify dietary patterns related to the biomarker concentrations of methylation in blood. Main outcome measures Dietary patterns, vitamin B and homocysteine concentrations, biomarkers of methylation (S-adenosylmethionine [SAM] and S-adenosylhomocysteine [SAH]) and the risk of CHD estimated by odds ratios and 95% confidence intervals. Results The one-carbon-poor dietary pattern, comprising a high intake of snacks, sugar-rich products and beverages, was associated with SAH (β = 0.92, P < 0.001). The one-carbon-rich dietary pattern with high fish and seafood intake was associated with SAM (β = 0.44, P < 0.001) and inversely with SAH (β = -0.08, P < 0.001). Strong adherence to this dietary pattern resulted in higher serum (P < 0.05) and red blood cell (P < 0.01) folate and a reduced risk of CHD in offspring: odds ratio, 0.3 (95% confidence interval, 0.2-0.6). Conclusions The one-carbon-rich dietary pattern, characterised by the high intake of fish and seafood, is associated with a reduced risk of CHD. This finding warrants further investigation in a randomised intervention trial. © 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology http://repub.eur.nl/res/pub/23552/ 2011-02-01T00:00:00Z Eur J Clin Invest 2011; 41 (2): 143-150Background Derangements in the maternal methylation pathway, expressed by global hypomethylation and hyperhomocysteinemia, are associated with the risk of having a child with a congenital heart defect (CHD). It is not known whether periconception exposure to these metabolic derangements contributes to chromosome segregation and metabolic programming of this pathway in the foetus.Design In a Dutch population-based case-control study of 143 children with CHD and 186 healthy children, we investigated S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), total homocysteine (tHcy), the vitamins folate and B12 and the functional single nucleotide polymorphisms in the folate gene MTHFR 677C>T and 1298A>C. Comparisons were made between cases and controls adjusting for age, medication, vitamin use and CHD family history.Results In the overall CHD group, the median concentrations of SAM (P = 0.011), folate in serum (P = 0.021) and RBC (P = 0.030) were significantly higher than in the controls. Subgroup analysis showed that this was mainly attributable to complex CHD with higher SAM (P < 0.001), SAH (P = 0.012) and serum folate (P = 0.010) independent of carriership of MTHFR polymorphisms. Highest concentrations of SAM, SAH and folate RBC were observed in complex syndromic CHD. The subgroup of children with Down syndrome, however, showed significantly higher SAH (P = 0.037) and significantly lower SAM:SAH ratio (P = 0.034) compared with other complex CHD, suggesting a state of global hypomethylation.Conclusion High concentrations of methylation biomarkers in very young children are associated with complex CHD. Down syndrome and CHD may be associated with a global hypomethylation status, which has to be confirmed in tissues and global DNA methylation in future studies. http://repub.eur.nl/res/pub/27613/ 2010-10-01T00:00:00Z Objective: To establish the diagnostic value of sperm chromatin structure assessment for the evaluation of male factor infertility, in addition to conventional andrological workup. Design: Cross-sectional controlled study. Setting: A tertiary referral andrology clinic. Patient(s): Two hundred seventy-nine male partners of infertile couples. Intervention(s): None. Main Outcome Measure(s): The DNA fragmentation index (DFI) determined by the sperm chromatin structure assay (SCSA), semen parameters, serum levels of reproductive hormones, and World Health Organization (WHO) classification of male factor subfertility. Result(s): In all patient categories, except those including patients with hypogonadotrophic hypogonadism, sperm antibodies, or normospermia, DFI was significantly higher compared with in proven fertile controls. After classification of the quality of spermatogenesis based on mean testicular volume (<10 ml vs. >15 ml), follicle stimulating hormone (FSH; > 10 U/L vs. <5 U/L), and inhibin-B (<100 nmol/L vs. >150 nmol/L), the DFI was significantly higher in patients with poor spermatogenesis (35.9%) than in patients with normal spermatogenesis (25.9%). In a multiple regression analysis, the teratozoospermia index, sperm vitality, and FSH were significant determinants of the DFI level. Male age was associated with DFI, but leukocytospermia, body mass index, and smoking were not confounders of DFI. Conclusion(s): Impaired spermatogenesis, irrespective of the WHO classification of male factor subfertility, is generally associated with an increase of sperm DNA damage. Copyright http://repub.eur.nl/res/pub/27842/ 2010-08-01T00:00:00Z Background: We assessed sperm DNA fragmentation index (DFI) in cancer patients before and after treatment to evaluate if sperm DNA integrity is compromised by cancer itself or its treatment. Methods: In a prospective study, DFI was assessed in 127 patients diagnosed with testicular germ cell tumours (TGCT), Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL) and various malignancies. The severity of cancer and tumour markers at diagnosis was recorded. Follow-up DFI after treatment was available in 52 patients who were mostly less severely affected. Results: In patients diagnosed with TGCT, HL and various malignancies, pretreatment DFI levels were not significantly different from that of proven fertile controls, but in patients with NHL an increased DFI was found. An overall significant decrease in post-treatment DFI (13.2 range 5.0-70.5) compared with pretreatment values (17.1 range 5.1-66.6) was found (P = 0.040). In TGCT patients, post-treatment DFI was significantly higher in patients who were treated with radiotherapy (16.9 range 11.5-39.9) compared with that in patients treated with chemotherapy (CT) alone (10.9 range 5.5-39.9) (P = 0.037). In HL patients, the type of treatment or number of CT cycles was not associated with DFI. Overall, post-treatment DFI in cancer patients was not significantly different from that of proven fertile controls. Conclusion: SIn this study, the presence of cancer does not seem to negatively affect the sperm DNA integrity in TGCT and HL patients; only NHL patients showed increased DFI at the time of diagnosis compared with healthy controls. Our Results: confirm previous reports that DFI decreases significantly following various anti-cancer treatments. In contrast, radiotherapy in TGCT patients is associated with an increase in DFI compared with CT treatment alone. http://repub.eur.nl/res/pub/28468/ 2010-08-01T00:00:00Z Study Type - Therapy (RCT) Level of Evidence 1b Objective: To compare the effect on the recovery of incontinence after retropubic radical prostatectomy (RRP) of intensive physiotherapist-guided pelvic floor muscle exercises (PG-PFME) in addition to an information folder, with PFME explained to patients by an information folder only (F-PFME), and to determine independent predictors of failure to regain continence after RRP. Patients and Methods: We postulated that a 10% increase in the proportion of men who regained continence at 6 months with PG-PFME compared with men treated with F-PFME only would constitute a clinically relevant effect. To show statistical significance of this difference with a power of 80%, 96 men should be randomized to each of the two arms. One day before operation, all patients received verbal instruction and an information folder on PFME. Patients randomized to the F-PFME arm received no further physiotherapist guidance, whereas those in the PG-PFME arm received a maximum of nine sessions with the physiotherapist. The men underwent a 1-h pad-test at 1, 12 and 26 weeks, and a 24-h pad-test at 1, 4, 8, 12 and 26 weeks after catheter removal. We defined 'continence' as urine loss of <1 g at the 1-h and <4 g at the 24-h pad-test. Results: During the 2-year recruitment period, the number of patients randomized fell short of the target determined by the sample size calculation, because of limitations of resources and unexpected changes in treatment preferences. Despite this, we analysed the data. Of the 82 randomized patients, 70 completed the study. Of these, 34 and 36 men had been assigned to the PG-PFME and the F-PFME group, respectively. At 6 months after RRP, 10 (30%) and nine (27%) men were completely dry on both the 1-h and 24-h pad-test in the PG-PFME and the F-PFME group, respectively (difference not significant). In a multivariate analysis the amount of urine loss at 1 week after catheter removal seemed to be an independent prognostic factor for failure to regain continence. CONCLUSION PG-PFME seems to have no beneficial effect on the recovery of continence within the first 6 months after RRP, over an instruction folder-guided approach. However, due to under-powering there is a high risk of type II error. Nevertheless, these findings add to the knowledge base for availability in meta-analyses and can serve as a starting point for the design of new randomized studies. Journal Compilation http://repub.eur.nl/res/pub/18594/ 2010-06-01T00:00:00Z Background: Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA = tPSA/fPSA) lack diagnostic specificity. Objective: To evaluate the use of prostate-specific antigen (PSA) isoforms p2PSA and benign prostatic hyperplasia-associated PSA (BPHA). Design, setting, and participants: Our study included 405 serum samples from the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer and 351 samples from the Urology Department of Innsbruck Medical University. Measurements: BPHA, tPSA, fPSA, and p2PSA levels were measured by Beckman-Coulter Access Immunoassay. In addition, the Beckman Coulter Prostate Health Index was calculated: phi = (p2PSA/fPSA) × √(tPSA). Results and limitations: The p2PSA and phi levels differed significantly between men with and without PCa. No difference in BPHA levels was observed. The highest PCa predictive value in both cohorts was achieved by phi with areas under the curve (AUCs) of 0.750 and 0.709, a significant increase compared to tPSA (AUC: 0.585 and 0.534) and %fPSA (AUC: 0.675 and 0.576). Also, %p2PSA (p2PSA/fPSA) showed significantly higher AUCs compared to tPSA and %fPSA (AUC: 0.716 and 0.695, respectively). At 95% and 90% sensitivity, the specificities of phi were 23% and 31% compared to 10% and 8% for tPSA, respectively. In both cohorts, multivariate analysis showed a significant increase in PCa predictive value after addition of p2PSA to a model consisting of tPSA and fPSA (increase in AUC from 0.675 to 0.755 and from 0.581 to 0.697, respectively). Additionally, the specificity at 95% sensitivity increased from 8% to 24% and 7% to 23%, respectively. Furthermore, %p2PSA, phi, and the model consisting of tPSA and fPSA with or without the addition of p2PSA missed the least of the tumours with a biopsy or pathologic Gleason score ≥7 at 95% and 90% sensitivity. Conclusions: This study shows significant increases in PCa predictive value and specificity of phi and %p2PSA compared to tPSA and %fPSA. p2PSA has limited additional value in identifying aggressive PCa (Gleason score ≥7). http://repub.eur.nl/res/pub/19642/ 2010-06-01T00:00:00Z Study Type - Therapy (case series) Level of Evidence 2b Objective To present the outcomes of cT3N0M0 prostate cancer after radical prostatectomy (RP) and determine the prognostic factors in biochemical progression-free survival (BPFS), clinical progression-free survival (CPFS), cancer-specific survival (CSS) and overall survival (OS) after long-term follow-up of 10 years. Patients and Methods In all, 164 patients who were assessed as clinical T3 prostate cancer by digital rectal examination (DRE), underwent RP and bilateral pelvic lymphadenectomy at Erasmus MC between 1977 and 2004 without neoadjuvant treatment. Preoperative staging computed tomography showed no signs of metastasis. Kaplan-Meier curves were constructed to show BPFS, CPFS, CSS and OS. Cox proportional hazard analysis was used to determine prognostic indicators of disease progression. Results The mean (range) follow-up was 100 (1-291) months. At 5, 10 and 15 years, BPFS was 50.4%, 43.0% and 38.3%, respectively, CPFS was 79.7%, 68.7% and 63.5%, CSS was 93.4%, 80.3% and 66.3%, and OS was 87.1%, 67.2% and 37.4%. Multivariate Cox proportional hazard analysis showed that surgical tumour grade, margin and node status were significant factors in CPFS and CSS. Surgical tumour grade, node status and preoperative PSA level were significant factors in BPFS Conclusion RP for clinically locally advanced prostate cancer may produce acceptable long-term BPFS, which is comparable with published results of radiotherapy with adjuvant endocrine therapy. Pathological tumour grade and node status were significant predicting factors in BPFS and CPFS, as well as tumour-specific survival after 100 months follow-up. http://repub.eur.nl/res/pub/21174/ 2010-06-01T00:00:00Z The potential relationship between daily physical activity and pregnancy outcome remains unclear because of the wide variation in study designs and physical activity assessment measures. We sought to prospectively quantify the potential effects of the various domains of physical activity on selected birth outcomes in a large unselected population. The sample consisted of 11,759 singleton pregnancies from the Avon longitudinal study of parents and children, United Kingdom. Information on daily physical activity was collected by postal questionnaire for self-report measures. Main outcome measures were birth weight, gestational age at delivery, preterm birth and survival. After controlling for confounders, a sedentary lifestyle and paid work during the second trimester of pregnancy were found to be associated with a lower birth weight, while 'bending and stooping' and 'working night shifts' were associated with a higher birth weight. There was no association between physical exertion and duration of gestation or survival. Repetitive boring tasks during the first trimester was weakly associated with an increased risk of preterm birth (<37 weeks) (adjusted odds ratio [OR] = 1.25, 95% CI 1.04-1.50). 'Bending and stooping' during the third trimester was associated with a reduced risk of preterm birth (adjusted OR = 0.73, 95% CI 0.63-0.84). Demanding physical activities do not have a harmful effect on the selected birth outcomes while a sedentary lifestyle is associated with a lower birth weight. In the absence of either medical or obstetric complications, pregnant women may safely continue their normal daily physical activities should they wish to do so. http://repub.eur.nl/res/pub/27945/ 2010-05-01T00:00:00Z Background: Fusion of the androgen-regulated gene transmembrane protease, serine 2, TMPRSS2, to the v-ets erythroblastosis virus E26 oncogene homolog (avian), ERG, of the erythroblast transformation-specific (ETS) family is the most common genetic alteration in prostate cancer (PCa). Objective: To determine whether expression of androgen-regulated TMPRSS2-ERG predicts response to endocrine treatment in hormone-naïve, node-positive PCa. Design, setting, and participants: Eighty-five patients with histologically confirmed, node-positive PCa who were without treatment at the moment of lymph node dissection were analysed. RNA was isolated from the paraffin-embedded lymph node metastases and complementary DNA (cDNA) was made. The quality of cDNA was tested by polymerase chain reaction (PCR) analysis of the expression of the housekeeping gene hydroxymethylbilane synthase, HMBS (formerly PBGD). TMPRSS2-ERG expression was analysed by PCR using a forward primer in TMPRSS2 exon 1 and a reverse primer in ERG exon 4. Measurements: The primary end point was time from start of endocrine therapy to the occurrence of three consecutive rises in prostate-specific antigen (PSA) that were at least 2 wk apart and resulted in two 50% increases over the PSA nadir. Secondary end points were time to PSA nadir after start of endocrine treatment and cancer-specific and overall survival. Results and limitations: TMPRSS2-ERG was expressed in 59% of the 71 patients who could be analysed. Median duration of response to endocrine therapy was 20.9 mo versus 24.1 mo for gene fusion-positive versus gene fusion-negative patients (95% confidence intervals: 18.6-23.1 vs 18.9-29.4, p = 0.70). Furthermore, no significant differences were seen between the two groups for the secondary end points. Conclusions: Expression of TMPRSS2-ERG is frequent in lymph node metastases of patients with untreated PCa; however, expression of this androgen-regulated fusion gene did not correspond with duration of response to endocrine therapy. Our results suggest that expression of TMPRSS2-ERG is not a candidate marker to select for metastatic PCa patients who will benefit more from endocrine treatment. http://repub.eur.nl/res/pub/33000/ 2010-03-01T00:00:00Z Introduction: Erectile function after radical retropubic prostatectomy (RRP) is extensively discussed in literature. However, less is known about orgasm after RRP. Aim: To analyze sexual function, in particularly orgasmic function, in men before and after RRP. Methods: Between 1977 and 2007 a RRP was performed in 1,021 men. All men were interviewed by their follow-up physician using a standardized interview about sexual function before and after RRP at regular intervals during a 2-year follow-up. The questions were related to sexual interest, sexual activity, spontaneous erections, and orgasmic function. Main Outcome Measures: Sexual function, in particularly orgasmic function, before and after RRP. Factors potentially influencing orgasmic function, such as patients age, type of operation, pathological stage and continence status were analyzed for their predictive value. Results: Information about preoperative and postoperative sexual activity and spontaneous erection was available in 596 and 698 men, respectively. Additional questions were asked on sexual interest (N = 425) and orgasmic function (N = 458).Pre-operatively, sexual interest, sexual activity, spontaneous erections and orgasmic function were normal in 99%, 82.1%, 90.0% and 90% of men, respectively. After operation these values decreased to 97.2%, 67.3%, 29.4% and 66.8%, respectively. Orgasmic function was preserved in 141 of 192 men (73.4%) after a bilateral nerve sparing procedure, in 90 out of 127 men (70.9%) after a unilateral nerve-sparing procedure and in 75 of 139 men (54.0%) after non-nerve sparing technique. Postoperatively, orgasm was present in 123 (77.4%) men below the age of 60 years and in 183 (61.2%) men of 60 years and older (P < 0.0001). Orgasmic function was significantly affected by age ≥60 years, non-nerve sparing procedure and severe incontinence (more than two pads/day). Conclusions: After RRP, orgasmic function is still present in the majority of men. A non-nerve sparing operation, age, and severe urinary incontinence are risk factors for orgasmic dysfunction after RRP. http://repub.eur.nl/res/pub/27294/ 2010-01-01T00:00:00Z Purpose: We prospectively evaluated changes in sperm chromatin structure in infertile patients before and after surgical repair of varicocele, and the impact on the pregnancy rate. Materials and Methods: Included in the study were 49 men with at least a 1-year history of infertility, a palpable varicocele and oligospermia. World Health Organization semen analysis and sperm DNA damage expressed as the DNA fragmentation index using the sperm chromatin structure assay were assessed preoperatively and postoperatively. Pregnancy (spontaneous and after assisted reproductive technique) was recorded 2 years after surgery. Results: Mean sperm count, sperm concentration and sperm progressive motility improved significantly after varicocelectomy from 18.3 × 106to 44.4 × 106, 4.8 × 106/ml to 14.3 × 106/ml and 16.7% to 26.6%, respectively (p <0.001). The DNA fragmentation index decreased significantly after surgery from 35.2% to 30.2% (p = 0.019). When the definition of greater than 50% improvement in sperm concentration after varicocelectomy was applied, 31 of 49 patients (63%) responded to varicocelectomy. After varicocelectomy 37% of the couples conceived spontaneously and 24% achieved pregnancy with assisted reproductive technique. The mean postoperative DNA fragmentation index was significantly higher in couples who did not conceive spontaneously or with assisted reproductive technique (p = 0.033). Conclusions: After varicocelectomy sperm parameters significantly improved and sperm DNA fragmentation was significantly decreased. Low DNA fragmentation index values are associated with a higher pregnancy rate (spontaneous and with assisted reproductive technique). We suggest that varicocelectomy should be considered in infertile men with palpable varicocele, abnormal semen analysis and no major female factors. http://repub.eur.nl/res/pub/24811/ 2009-08-01T00:00:00Z OBJECTIVE To investigate whether body mass index (BMI) is a prognostic factor for biochemical recurrence (BCR) in Dutch men after radical prostatectomy (RP), as although epidemiological studies of obesity in relation to prostate cancer have provided conflicting results, recent studies from the USA suggest that a higher BMI is a risk factor for progression of prostate cancer. PATIENTS AND METHODS Of the 1417 patients with prostate cancer who had RP at two University hospitals, 1302 were included in the present study. BMI (kg/m2) classes were defined as normal (<25), overweight (25-30) and obese (≥30). The median follow-up was 59 months and clinical data were obtained retrospectively from charts. BCR was defined as two consecutive prostate-specific antigen (PSA) levels of >0.1 ng/mL. RESULTS In all, 600 patients were classified as having normal weight (43.9%), 665 as overweight (48.6%) and 103 as obese (7.5%). Overall, 297 patients developed BCR after RP; the 10-year risk (95% confidence interval) of BCR was 31.9 (26.6-37.2)%, 30.5 (25.8-35.2)% and 23.9 (14.9-32.9)% for patients in the three categories, respectively (P = 0.836). Multivariable proportional hazard regression analyses of BMI and established prognostic factors for BCR did not change these results. CONCLUSION BMI appeared to have no prognostic value for BCR in Dutch patients with clinically localized prostate cancer and treated with RP. http://repub.eur.nl/res/pub/14988/ 2009-02-01T00:00:00Z Objective: To study associations between maternal dietary and supplement intake of antioxidants vitamin E, retinol and congenital heart defects (CHDs). Design: Case-control study. Setting: Erasmus MC, University Medical Center Rotterdam, the Netherlands. Population: Participants were 276 case mothers of a child with CHD and 324 control mothers with their children. Methods: Food frequency questionnaires covering the intake of the previous 4 weeks were filled out at 16 months after the index pregnancy. Data were compared between cases and controls using the Mann-Whitney U test. Risk estimates for the association between CHD and dietary intake of vitamin E and retinol were estimated in a multivariable logistic regression model. Main outcome measures: Medians (5-95th percentile) and odds ratios with 95% CI. Results: Dietary vitamin E intake was higher in case mothers than in controls, 13.3 (8.1-20.4) and 12.6 (8.5-19.8) mg/day (P = 0.05). CHD risk increased with rising dietary vitamin E intakes (P-trend = 0.01). Periconception use of vitamin E supplements in addition to a high dietary vitamin E intake above 14.9 mg/day up to nine-fold increased CHD risk. Retinol intakes were not significantly different between the groups and not associated with CHD risk. Conclusions: High maternal vitamin E by diet and supplements is associated with an increased risk of CHD offspring. http://repub.eur.nl/res/pub/14151/ 2008-12-01T00:00:00Z OBJECTIVE: To correlate the histopathological characteristics of lymph node metastases in prostate cancer with cancer-specific survival (CSS). PATIENTS AND METHODS: The histopathological slides from 142 patients who had had a pelvic lymph node dissection for node-positive prostate cancer were reviewed. For each patient we recorded the number of lymph nodes removed, the number of positive nodes, the diameter of the largest metastasis and extranodal extension (ENE). The lymph node metastases were graded according to the Gleason system. These variables were correlated with CSS. RESULTS: The mean age of the patients was 62.4 years and the mean preoperative prostate-specific antigen level was 40.2 ng/mL. The median follow-up was 77.5 months, and the median overall and CSS were 91 and 112 months, respectively. On univariable analysis the following variables correlated with poor CSS: a nodal Gleason score of >7 (hazard ratio 2.4, P < 0.001), a diameter of the largest metastasis of >3 mm (2.2, P = 0.025), more than two lymph node metastases (2.0, P = 0.003), and ENE in more than one lymph node (1.9, P = 0.014). Multivariable analysis showed only the nodal Gleason score and the diameter of the largest metastasis to be independent predictors of CSS (1.8, P = 0.021, and 2.2, P = 0.046, respectively). CONCLUSION: The histopathological characteristics of lymph node metastases in prostate cancer have predictive value for the clinical outcome. The nodal Gleason score and the diameter of the largest metastasis are independent predictors of survival. http://repub.eur.nl/res/pub/14541/ 2008-11-01T00:00:00Z BACKGROUND: Ovarian stimulation gives rise to supraphysiological estradiol levels, which may affect oocyte quality. This study aims to investigate whether ovarian stimulation deranges the homocysteine pathway thereby affecting the pre-ovulatory follicle. METHODS: Blood samples were collected on cycle day 2 and the day of hCG administration in 181 women undergoing ovarian stimulation for IVF. In each subject, the diameter of the two leading follicles was measured and the corresponding follicular fluids were collected. In blood and follicular fluid samples, total homocysteine (tHcy), folate, cobalamin and pyridoxal'5-phosphate (PLP) were determined. According to the blood folate levels, women were classified as either folic acid supplemented (n = 113) or non-supplemented (n = 32). RESULTS: Ovarian stimulation resulted in a significant decrease in blood tHcy and cobalamin levels (both P ≤ 0.001). The blood concentrations of tHcy, folate, cobalamin and PLP were significantly correlated with the corresponding follicular fluid concentrations (all P ≤ 0.001). Follicular fluid tHcy concentrations were inversely correlated with follicular diameter (P ≤ 0.05). In folic acid supplemented women, follicular fluid folate was inversely correlated with follicular diameter (P ≤ 0.05). CONCLUSIONS: Ovarian stimulation deranges blood and follicular fluid biomarkers of the homocysteine pathway. High ovarian follicular fluid tHcy and folate levels may have detrimental effects on follicular development. http://repub.eur.nl/res/pub/15866/ 2008-10-01T00:00:00Z Sexual dysfunction is common after surgery for prostate cancer. The aetiology of changes in sexual potency after radical prostatectomy is probably multifactorial, including neurogenic, vascular and psychosexual factors. A prospective study was designed to investigate haemodynamic and psychosexual changes before and after radical retropubic prostatectomy (RRP) for organ-confined prostate cancer. Penile haemodynamic evaluation and an assessment of sexual excitement were performed preoperatively and 3 months after RRP by colour Doppler ultrasonography (CDU) with visual erotic stimulation combined with a single intracavernous injection of a mixture of papaverine/phentolamine. Questionnaires on sexual function [International Index of Erectile Function (IIEF)], general health and quality of life were sent to the patients preoperative, 3 months and 5 years after operation. Forty-eight men participated in the study. Mean age was 62.6 years (range 55-69). CDU did not show any significant reduction in mean peak systolic flow velocity and mean resistance index. From the men who preoperatively had normal arterial inflow 18% developed arteriogenic insufficiency. Some form of veno-occlusive insufficiency and low resistance indices were already present in the majority of normal potent men preoperatively. Surgical technique did not influence penile arterial blood flow after the operation. Three months and 5 years postoperatively, there was a highly significant reduction in erectile function, intercourse satisfaction, overall satisfaction, orgasmic function and sexual desire. However, with respect to the outcome at 3 months there was a significant improvement of orgasmic function 5 years after operation, especially after a bilateral nerve sparing procedure. Erections sufficient for vaginal penetration (questions 3 and 4 of the IIEF, score ≥8) improved from 2% to 11% 3 months and 5 years after RRP respectively. Total IIEF score was significantly better after a bilateral nerve-sparing procedure compared with non-nerve sparing. No structural vascular changes were observed 3 months after operation. Vascular factors appear to be less important in the aetiology of ED after RRP. There seems to be a trend of a better improvement of sexual function over time, especially orgasmic function, in patients with bilateral nerve-sparing surgery. http://repub.eur.nl/res/pub/36008/ 2007-11-01T00:00:00Z Objectives: The purpose of screening for prostate cancer is to decrease the disease-specific mortality. However not every screen-detected prostate cancer is a threat to the patient's life. The risk of overdetection and subsequent overtreatment in prostate cancer has been recognised. The purpose of this investigation was to evaluate the role of tumour markers total PSA, free PSA, and hK2, and their combinations in predicting minimal prostate cancer. Methods: Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam, The Netherlands, prebiopsy serum samples were analysed for 100 selected men who underwent a radical prostatectomy for their screen-detected prostate cancer. All had a PSA value between 4 and 10 ng/ml prior to diagnosis. Minimal prostate cancer is defined as organ confined, Gleason score ≤6 (no Gleason grade 4 or 5), and tumour volume <0.5 ml. Results: Sera and tumour volumes from 91 men were available for analysis. Minimal prostate cancer was diagnosed in 16.5% of the selected cases. Mean tumour volume was 1.2 ml (range: 0.04-13.5); hK2, the algorithms hK2/fPSA, and hK2/%fPSA have significant correlations with tumour volume. Both algorithms also yielded the best test results in predicting minimal disease with an area under the receiver operator characteristics curve of 82%. Conclusions: hK2 and percent free PSA have added prognostic value for the detection of minimal prostate cancer in screen-detected cases within PSA range 4-10 ng/ml. These biomarkers can possibly be used to select less invasive treatment options like active surveillance and to prevent overtreatment. http://repub.eur.nl/res/pub/36660/ 2007-05-01T00:00:00Z Aim: To evaluate whether inhibin-B can predict the outcome of a microsurgical epidymal sperm aspiration (MESA) procedure in patients with suspected primary obstructive azoospermia (OA) and if inhibin-B can replace testicular biopsy in the diagnostic work-up of these patients. Methods: Inhibin-B levels and testicular biopsy scores were related to the outcome of MESA in 43 patients with suspected primary OA. MESA was considered to be successful when epididymal sperm could be identified during the procedure. Results: Spermatozoa were present in the epididymal aspirate in 28 out of the 43 patients (65%). Inhibin-B values were not significantly different in patients with successful or unsuccessful MESA. The modified Johnsen score, however, was significantly lower in patients with unsuccessful MESA (P=0.003). Arete testis obstruction or epididymal malfunctioning was found in 15% of patients with suspected primary OA, reflected by unsuccessful MESA despite normal inhibin-B levels and normal testicular histology. Conclusion: Inhibin-B cannot replace testicular biopsy as a diagnostic tool in the work-up of patients with suspected primary OA. Testicular biopsy is useful in identifying patients with spermatogenic arrest, who might have normal inhibin-B values. http://repub.eur.nl/res/pub/36216/ 2007-03-01T00:00:00Z Use of percent free PSA (%fPSA) and artificial neural networks (ANNs) can eliminate unnecessary prostate biopsies. In a total of 4,480 patients from five centers with PSA concentrations in the range of 2-10 ng/ml an IMMULITE PSA-based ANN (iANN) was compared with other PSA assay-adapted ANNs (nANNs) to investigate the impact of different PSA assays. ANN data were generated with PSA, fPSA (assays from Abbott, Beckman, DPC, Roche or Wallac), age, prostate volume, and DRE status. In 15 different ROC analyses, the area under the curve (AUC) in the PSA ranges 2-4, 2-10, and 4-10 ng/ml for the nANN was always significantly larger than the AUC for %fPSA or PSA. The nANN and logistic regression models mostly also performed better than the iANN. Therefore, for each patient population, PSA assay-specific ANNs should be used to optimize the ANN outcome in order to reduce the number of unnecessary biopsies. http://repub.eur.nl/res/pub/35844/ 2007-02-01T00:00:00Z Determination of sperm DNA fragmentation, as assessed by the sperm chromatin structure assay (SCSA), has become an important tool for the evaluation of semen quality. The aim of the present study was to describe the biological variation of sperm DNA fragmentation in men attending an andrology clinic and to identify clinical correlates of the biological variation of sperm DNA fragmentation. For this study, two consecutive semen samples from 100 patients attending our andrology outpatient clinic were subjected to semen analysis, performed in parallel according to WHO guidelines and by SCSA. A good agreement between pairs of samples was found for SCSA-derived variables, as indicated by a significantly lower median coefficient of variation (CV) of the DNA Fragmentation Index (DFI) and the high DNA stainability (HDS) compared with WHO semen parameters. In half of the men attending our andrology clinic, however, the individual biological variation of DFI and HDS, expressed as CV of two samples, exceeded 10%. Dysregulation of spermatogenesis, as seen as testicular insufficiency or varicocele, was not associated with increased variability of DFI or HDS. A backward multiple linear regression analysis, however, indicated that the biological variation of DFI may be more profound in men with characteristics of normal spermatogenesis. In conclusion, we confirm previous reports that sperm DNA fragmentation has a lower biological variability than classical semen parameters. We hypothesize that the sperm chromatin structure may be more influenced in patients with normal spermatogenesis, whereas in men with disturbed spermatogenesis, the chromatin structure may be already so impaired that the effect of unidentified factors leading to variability of sperm DNA fragmentation in time may not be as profound. http://repub.eur.nl/res/pub/13495/ 2004-09-01T00:00:00Z Recent studies have reported that serum IGF-I levels in the highest quartile of the normal range and IGF binding protein-3 (IGFBP-3) in the lowest quartile of the normal range are associated with an increased risk of future prostate cancer and/or presence of prostate cancer. It has also been suggested that the measurement of circulating total IGF-I concentrations might be a useful tool for the early detection of prostate cancer in men with moderately increased prostate-specific antigen (PSA) levels.To determine whether circulating free IGF-I, total IGF-I, and IGFBP-3 levels can predict future prostate cancer risk, we prospectively studied prostate cancer characteristics in a cohort of men during two rounds (mean interval, 4 yr) of a population-based screening study for prostate cancer. Two hundred one prostate cancer cases were detected at the second-round screening (aged 55-70 yr), and all these subjects were enrolled in the case group for the present study. Prostate cancer had been confirmed by biopsy in all cases. These 201 subjects were matched with the 201 nonprostate cancer cases by age, serum PSA range at the first-round screening (PSA < 2 ng/ml, n = 67; PSA = 2-3 ng/ml, n = 67; and PSA = 3-4 ng/ml, n = 67), and residence area.At baseline, total IGF-I, free IGF-I, and IGFBP-3 levels and prostate volume of cases with prostate cancer were not different from those of healthy controls. PSA velocity was significantly different between cases and controls (P < 0.001).Stepwise forward logistic regression analysis showed that only PSA levels at baseline and PSA at round 2 after 4 yr are good predictors of prostate cancer, whereas total IGF-I, free IGF-I, and IGFBP-3 did not predict the development of prostate cancer.Only one of the 201 subjects with prostate cancer had metastases. Within the subjects with prostate cancer, there were no differences of IGF-I parameters with different tumor node metastasis categories and/or Gleason scores.Our study suggests that the measurement of serum IGF-I and/or IGFBP-3 concentrations in addition to PSA does not improve the identification of men at high risk to develop early stages of prostate cancer. In addition, our results indicate that the endocrine IGF-I system is not directly involved in the growth of the early stages of prostate cancer. http://repub.eur.nl/res/pub/10086/ 2003-01-01T00:00:00Z BACKGROUND: We compared two recently developed research assays for the measurement of human kallikrein 2 (hK2) in serum: one fully automated assay (Beckman Coulter Access immunoanalyzer) and one manual assay based on the DELFIA technology. METHODS: We used two subsets of clinical specimens consisting of 48 samples from prostate cancer patients and 210 samples from participants in an ongoing screening study (ERSPC). Both subsets were measured in the Rotterdam laboratory, and the prostate cancer samples were used for analytical comparison with the originating sites for the assays: Beckman Coulter Research Department (San Diego, CA) and Turku University (Turku, Finland). RESULTS: Both the Beckman Coulter and the Turku assays performed very similarly between the Rotterdam laboratory and the originating sites: the R(2) value for both comparisons was 0.99, and the slope difference between sites was <20%. Deming regression analysis of the DELFIA (y) and Access (x) assays yielded the following: for the prostate cancer group, y = 1.17x - 0.01 (R(2) = 0.88; n = 48); and for the ERSPC group, y = 0.62x - 0.01 (R(2) = 0.77). Breakdown of the latter group into subgroups (nondiseased, benign prostatic hyperplasia, and prostate cancer samples) gave only minor differences. The Access calibrators were underrecovered by 13% in the DELFIA assay, whereas the DELFIA calibrators were overrecovered by 45% in the Access assay. CONCLUSION: The DELFIA and Access assays for hK2, which have similar analytical features, show differences that cannot be explained by calibration. http://repub.eur.nl/res/pub/9579/ 2001-01-01T00:00:00Z No objective parameters have been found so far that can predict the biological behavior of early stages of prostatic cancer, which are encountered frequently nowadays due to surveillance and screening programs. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded radical prostatectomy specimens derived from patients who participated in the European Randomized Study of Screening for Prostate Cancer. We defined a panel consisting of 36 early cancer specimens: 13 small (total tumor volume (Tv) < 0.5 ml) carcinomas and 23 intermediate (Tv between 0.5-1.0 ml) tumors. These samples were compared with a set of 16 locally advanced, large (Tv > 2.0 ml) tumor samples, not derived from the European Randomized Study of Screening for Prostate Cancer. Chromosome arms that frequently (ie, > or = 15%) showed loss in the small tumors included 13q (31%), 6q (23%), and Y (15%), whereas frequent (ie, > or = 15%) gain was seen of 20q (15%). In the intermediate cancers, loss was detected of 8p (35%), 16q (30%), 5q (26%), Y (22%), 6q, and 18q (both 17%). No consistent gains were found in this group. In the large tumors, loss was seen of 13q (69%), 8p (50%), 5q, 6q (both 31%), and Y (15%). Gains were observed of 8q (37%), 3q (25%), 7p, 7q, 9q, and Xq (all 19%). Comparison of these early, localized tumors with large adenocarcinomas showed a significant increase in the number of aberrant chromosomes per case (Rs = 0.36, P = 0.009). The same was true for the number of lost or gained chromosomes per case (Rs = 0.27, P: = 0.05; Rs = 0.48, respectively; P < 0.001). Interestingly, chromosomal alterations that were found in previous studies to be potential biomarkers for tumor aggressiveness, ie, gain of 7pq and/or 8q, were already distinguished in the small and intermediate cancers. In conclusion, our data show that chromosomal losses, more specifically of 6q and 13q, are early events in prostatic tumorigenesis, whereas chromosomal gains, especially of 8q, appear to be late events in prostatic tumor development. Finally, early localized tumors, as detected by screening programs, harbor cancers with aggressive genetic characteristics. http://repub.eur.nl/res/pub/19789/ 1999-04-07T00:00:00Z Two to six percent of all newborn children have a disorder with a genetic cause (1-3). For an increasing number of these diseases, the precise genetic cause is known and this can lead to new treatment opportunities (see Appendix A for a basic description of the mechanisms of genetic inheritance). However, for most disorders total cure is not yet possible. For example, complications in patients with cystic fibrosis can be reduced by intensive treatment, but many patients will still die of lung problems caused by the disease. For diseases for which cure is not yet possible genetic screening might be a (temporary) solution. For example, a genetic screening programme in most Western countries is the offer of amniocentesis to pregnant women of a specified age (36 years and older in The Netherlands) to detect Down syndrome. Women in whom a foetus with Down syndrome is detected can then decide to prepare for the birth of an affected child or to avoid its birth by induced abortion. A list with examples of tests to detect disorders with a genetic cause or component currently offered in The Netherlands is given in Table 1.1. Because of the increasing number of genetic diseases that can be detected early, this list will probably continue to be extended. http://repub.eur.nl/res/pub/8926/ 1998-01-01T00:00:00Z STUDY OBJECTIVE: Evaluating the costs, effects, and savings of several strategies for cystic fibrosis (CF) gene carrier screening. DESIGN: A general model for evaluating prenatal, preconceptional, school, and neonatal carrier screening was constructed. For prenatal and preconceptional screening, two strategies were evaluated: single entry and double entry two step couple screening. Firstly, the Dutch situation was evaluated prospectively; subsequently the results were generalised to other carrier frequencies. SETTING: Prospective simulation model. MAIN RESULTS: Of all screening strategies, neonatal carrier screening gives most carrier couples an informed choice concerning reproduction. If the parents of carrier newborns would not be tested however, prenatal screening detects most carrier couples. Prenatal and single entry preconceptional screening programmes have a favourable cost-savings balance in the Netherlands under a wide range of assumptions. For double entry preconceptional screening and neonatal screening, high enough values of uptake of screening, prenatal diagnosis, and induced abortion are necessary. School carrier screening does not have a favourable cost-savings balance. CONCLUSIONS: If a CF screening programme is judged to be useful on individual and social grounds, costs considerations are no obstacle for prenatal and single entry preconceptional screening.