Cribriform growth is highly predictive for postoperative metastasis and disease-specific death in Gleason score 7 prostate cancer.

Patients with Gleason score 7 prostate cancer on radical prostatectomy demonstrate a wide range in clinical outcome. Gleason grade 4 prostate cancer encompasses a heterogeneous group of tumor growth patterns including fused, ill-defined, cribriform, and glomeruloid glandular structures. Our objective was to determine the prognostic value of different Gleason grade 4 growth patterns. We performed a nested case-control study among 535 patients with Gleason score 7 prostate cancer at radical prostatectomy, treated between March 1985 and July 2013 at a university hospital in the Netherlands. We analyzed 52 cases (with metastasis, disease-specific mortality or both) and 109 controls, matched for age, PSA level, and pT stage. Presence of the following Gleason grade 4 patterns was recorded: fused, ill-defined, cribriform, and glomeruloid. Intraductal carcinoma of the prostate and tertiary Gleason grade 5 were additionally assessed. Outcomes were metastasis-free survival and disease-specific survival. We used Cox proportional hazards regression to determine the predictive value of Gleason grade 4 patterns for survival time. The overall prevalence of Gleason grade 4 patterns was as follows: fused 75% (n=121), ill-defined 64% (n=102), cribriform 48% (n=83), and glomeruloid 25% (n=40). Cribriform pattern was the only pattern with an unequal distribution between cases and controls. Forty-two out of 52 cases (81%) had cribriform growth pattern versus 41/109 controls (38%). In multivariate analysis, presence of cribriform growth was an adverse independent predictor for distant metastasis-free survival (HR 8.0, 95% CI 3.0-21; P<0.001) and disease-specific survival (HR 5.4, 95% CI 2.0-15, P=0.001). In conclusion, cribriform growth in Gleason grade 4 is a strong prognostic marker for distant metastasis and disease-specific death in patients with Gleason score 7 prostate cancer at radical prostatectomy.

Disease-specific death and metastasis do not occur in patients with Gleason score ≤6 at radical prostatectomy.

OBJECTIVES: To assess the metastasis-free survival (MFS) and disease-specific survival (DSS) in men with Gleason score ≤6 prostate cancer at radical prostatectomy (RP). PATIENTS AND METHODS: We included 1101 consecutive RP patients operated between March 1985 to July 2013 at a single institution. The outcome variables were MFS and DSS. The postoperative survival was estimated by the Kaplan-Meier method. RESULTS: The Gleason score distribution of the study population (1101 patients) was Gleason score ≤6 (449, 41%), Gleason score 3 + 4 = 7 (436, 40%), Gleason score 4 + 3 = 7 (99, 9%) and Gleason score 8-10 (117, 11%). The median (interquartile range) postoperative follow-up was 100 (48-150) months. During follow-up 197 men (18%) died, of whom 42 (3.8%) died from prostate cancer-related causes. In all, 19/1101 patients (1.7%) had documented lymph node metastasis at the time of RP: none with Gleason score ≤6, seven with Gleason score 3 + 4 = 7 (1.6%), six with Gleason score 4 + 3 = 7 (6.1%) and six with Gleason score 8-10 (5.1%). Distant metastasis occurred in 56/1101 patients (5.1%): none with Gleason score ≤6, 23 with Gleason score 3 + 4 = 7 (5.3%), 17 with Gleason score 4 + 3 = 7 (17%) and 16 with Gleason score 8-10 (14%). Disease-specific death, stratified per Gleason-score group was: none in ≤6, 16 (3.7%) in 3 + 4 = 7, 16 (16%) in 4 + 3 = 7 and 10 (8.5%) in 8-10 group. CONCLUSION: No metastasis or disease-specific death were seen in men with Gleason score ≤6 prostate cancer at RP, showing the negligible potential to metastasise in this large subgroup of patients with prostate cancer.

Validation of the Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7) in a Dutch population.

AIMS: The Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7) assess symptom distress and the impact on daily life of urinary incontinence. The UDI-6 has not been validated before in males. Our aim was to validate the UDI-6 and IIQ-7 in Dutch men and women. METHODS: The translation to Dutch followed standardized procedures. We validated the IIQ-7 with and without an additional gender-neutral item (IIQ-SF). Adults with urinary incontinence for at least 3 months, completed the measures at inclusion; 1-week after inclusion to evaluate the test-retest reproducibility; and 6 months after inclusion with the addition of the RAND-36 health transition item to assess responsiveness and interpretability. To assess the discriminate ability, a reference population was enrolled. To assess construct validity, the urodynamic diagnosis was used. RESULTS: Questionnaire data of 160 patients were analyzed. Patients reported more symptoms and bother than the reference population (P < 0.001). The internal consistency was good in the IIQ-SF baseline scores (Cronbach's alphas 0.86-0.92), though moderate in the UDI-6 (Cronbach's alphas 0.44-0.66). Both measures showed good reproducibility at the test-retest (Intraclass Correlations Coefficients 0.75-0.85). Construct was adequate with 75% confirmed hypotheses of urodynamic data with measure scores. The measures were responsive after treatment with smaller measurement errors than the minimal important change. No floor or ceiling effects were observed in baseline data. CONCLUSIONS: The Dutch UDI-6 and IIQ-7 are reliable, valid, and responsive instruments for assessing symptom distress of urinary incontinence and its impact on daily life in both men and women.

Validation of stem cell markers in clinical prostate cancer: α6-integrin is predictive for non-aggressive disease.

BACKGROUND: Stem cells are postulated to mediate prostate cancer progression, and represent a small fraction of the entire tumor. Various proteins (α2-integrin, α6-integrin, CD117, CD133, EZH2, OCT3/4) are associated with a prostate cancer stem cell phenotype in cell lines and xenografts. Our objective was to investigate expression of stem cell markers in clinical prostate cancer in relation to outcome. METHODS: We validated immunohistochemical expression of stem cell markers in 481 prostate cancer patients and correlated expression with clinicopathologic parameters. RESULTS: Sporadic expression of α2-integrin was present in a fraction of tumor cells (<5%) in 94.7% of tumors and associated with PSA > 10 ng/ml (P = 0.04). α6-Integrin expression (<5%) occurred in 28.4% patients, while ≥5% α6-integrin expression was associated with PSA≤10 ng/ml (P = 0.01), Gleason score <7 (P < 0.01) and pT2-disease (P = 0.02). α6-integrin was predictive for biochemical recurrence (P < 0.01), local recurrence (P = 0.03) and disease specific death (P = 0.03). EZH2 expression was generally low with 2.6% of tumors showing ≥1% positive cells. EZH2 was associated with Gleason score ≥7 (P = 0.01) and biochemical recurrence (P = 0.01). We did not identify expression of CD117, CD133, and OCT3/4 in prostate cancer samples. CONCLUSIONS: Expression of α2-integrin and EZH2 in a small fraction of prostate cancer cells is supportive for their role as stem cell marker. Although α6-integrin was not a unique stem cell marker, it was predictive for prostate cancer biochemical and local recurrence, and disease specific death. The validity of CD117, CD133, and OCT3/4 as prostate cancer stem cell marker is questionable since these proteins were not expressed in clinical prostate cancer.

Serum levels of arachidonic acid metabolites change during prostate cancer progression.

BACKGROUND: Arachidonic acid (AA) pathway has been shown to play a role in the development and progression of prostate cancer (PCa). In this study we aimed to assess the changes in concentrations of hydroxyeicosatetraenoic acids (HETEs) in serum samples from patients diagnosed with PCa compared to controls. METHODS: HETEs were determined using ultrahigh pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). RESULTS: Elevated concentrations of 5-HETE, 8-HETE, 11-HETE and 15-HETE were observed in 6 out of 20 patients diagnosed with PCa; no statistical differences with controls were observed for 12-HETE and AA in the discovery set. An independent validation set composed of 222 samples divided in five groups ranging from subjects with low PSA and no PCa, to patients with advanced PCa was included. In 30% of the patients in the advanced PCa group, up to ten times higher concentrations of the same set of HETEs were observed with a significant concomitant decrease of the concentration of AA. Logistic regression and Kaplan-Meier curves illustrate that a decreased concentration of AA is a predictor of PCa biochemical recurrence after radical prostatectomy (RP). CONCLUSIONS: From the present study we conclude that a significant association between AA and AA metabolites in serum and PCa progression exists, although serum concentrations of HETEs exhibited low sensitivity toward the diagnosis of PCa.

Intermittent versus continuous cyproterone acetate in bone metastatic prostate cancer: results of a randomized trial.

BACKGROUND: To compare intermittent treatment (IT) versus continuous treatment (CT) using cyproterone acetate (CPA) in bone metastatic prostate cancer patients, we conducted an open-label, multicenter randomized trial. Continuous androgen deprivation therapy is the standard treatment in metastatic prostate cancer. Intermittent treatment might maintain efficacy while toxicity and costs are reduced. METHODS: Patients received CPA 100 mg tid in the prephase. Patients with a PSA decline of ≥ 90 % or PSA <4 ng/ml were randomized. If patients were progressive, LHRH analogues were added. Primary end point was time to PSA progression. RESULTS: A total of 366 patients were recruited; 258 reached a good response after 3 or 6 months and were randomized. A total of 131 patients randomized to IT and 127 to CT. Patients on IT had an average of 1.7 episodes on CPA, before LHRH analogues were started. The mean time without treatment in IT was 463 days versus 422 days on treatment. There were statistical significant differences between IT and CT in 3 of the 5 functional scales of EORTC QLQ C 30; however, the clinical relevance of this finding appears modest. Symptom and potency scales showed significant advantages for IT. There were no differences in time to PSA progression on CPA, time to PSA and/or clinical progression on LHRH analogues and time to cancer-specific and overall survival. CONCLUSIONS: IT by CPA is associated with less symptoms and modest advantages in QOL domains. There were no differences in time to PSA progression, clinical progression or survival.

Lymph node count at inguinofemoral lymphadenectomy and groin recurrences in vulvar cancer.

OBJECTIVE: The objective of the study is to determine the risk factors for groin recurrence (GR) in patients with primary vulvar squamous cell carcinoma (SCC) after inguinofemoral lymphadenectomy (IFL) without lymph node metastases and/or adjuvant chemoradiotherapy. METHODS: The study is a multicenter retrospective review of clinical and histopathological data of patients with lymph node-negative vulvar SCC who underwent an IFL. Patients with and without GRs were compared to identify risk factors. RESULTS: In 134 patients, 252 groins were eligible for the analyses--16 patients underwent ipsilateral IFL and 118 patients underwent bilateral IFL. Groin recurrences occurred in 4 (1.6%) of the 252 dissected groins. Besides, 1 patient who underwent ipsilateral IFL had a recurrence in the nonoperated contralateral groin; this groin was left out of analysis. The median number of dissected nodes per groin was 9.8 (range, 1-38) in all patients and 6.5 (range, 5-8) in patients with GR. Multivariate analyses showed that GR was related to poor differentiation (P = 0.04), and node count less than 9 (P = 0.04), no association with age, tumor localization, tumor diameter, focality, invasion depth, or stage was found. Nineteen patients with both low node count and poor differentiation had 19% GRs. Survival analyses showed less favorable survival in patients with poor differentiation. CONCLUSIONS: The overall risk of developing GR after negative IFL in patients with vulvar SCC is low (1.6% per groin) but significantly higher in patients with tumors with a poor differentiation and lymph node count less than 9 at IFL. A large well-designed prospective study is needed to evaluate closer surveillance in patients at risk.

Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate.

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 × 10(6) to 44.4 × 10(6), 4.8 × 10(6)/ml to 14.3 × 10(6)/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.

Dietary vitamin A intake below the recommended daily intake during pregnancy and the risk of congenital diaphragmatic hernia in the offspring.

BACKGROUND: Vitamin A has been related to the etiology of congenital diaphragmatic hernia (CDH). We performed a case-control study to investigate whether maternal dietary vitamin A intake is related to CDH in the offspring. METHODS: Thirty-one pregnancies diagnosed with CDH and 46 control pregnancies were included during the study. After CDH diagnosis and inclusion of controls by risk set sampling, maternal vitamin A intake was investigated with a food frequency questionnaire. Serum retinol and retinol-binding protein were determined. Univariable and multivariable logistic regression models were used to calculate risk estimates with adjustment for potential confounders. RESULTS: We found no significant differences in the overall nutrient and vitamin A intake between case and control mothers. After stratification in body mass index (BMI) categories, case mothers with normal weight showed a lower energy adjusted vitamin A intake (685 vs. 843 µg retinol activity equivalents [RAEs] / day; p = 0.04) and a slightly lower serum retinol (1.58 vs. 1.67 µmol/L; p = 0.08) than control mothers. Vitamin A intake <800 µg retinol activity equivalents (recommended daily intake) in normal weight mothers was associated with a significantly increased CDH risk (odds ratio [OR], 7.2; 95% confidence interval [CI], 1.5-34.4; p = 0.01). Associations were not significantly different in underweight and overweight mothers. CONCLUSIONS: In normal-weight mothers, dietary vitamin A intake during pregnancy below the recommended daily intake is significantly associated with an increased risk of a child with CDH. This finding supports the retinoid hypothesis in human CDH, but warrants further investigation in larger study populations. Birth Defects Research (Part A), 2013. © 2013 Wiley Periodicals, Inc.

ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer.

In prostate cancer genomic rearrangements involving genes encoding ETS transcription factors are commonly present, with androgen-regulated transmembrane protease, serine 2 (TMPRSS2)-v-ets erythroblastosis virus E26 oncogen homologue (ERG) gene fusion occurring in 40-70%. Studies on the predictive value of ERG rearrangement as detected by in-situ hybridization or polymerase chain reaction have resulted in varying outcomes. The objective of this study was to correlate immunohistochemical ERG protein expression with clinico-pathological parameters at radical prostatectomy specimens, and to determine its predictive value for postoperative disease recurrence and progression in a prostate cancer screening cohort. Since androgen receptor is downregulated by ERG in cell lines, we also compared the expression of respective proteins. We selected 481 participants from the European Randomized Study of Screening for Prostate Cancer treated by radical prostatectomy for prostate adenocarcinoma. A tissue microarray was constructed containing representative cores of all prostate cancer specimens as well as 22 xenografts and seven cell lines. Immunohistochemical expression of ERG and androgen receptor was correlated with prostate-specific antigen (PSA), Gleason sum, pT-stage, surgical margins, biochemical recurrence, local recurrence, overall death and disease-specific death. ERG expression was detected in 284 patients (65%). Expression occurred significantly more frequent in patients with PSA ≤10 ng/ml (P=0.024). There was no significant association between ERG and Gleason sum, pT-stage or surgical margin status. PSA (P=0.011), Gleason sum (P=0.003), pT-stage (P=0.001) and surgical margin status (P<0.001) all had independent value for postoperative biochemical recurrence, while positive surgical margin (P=0.021) was the only independent predictor for local recurrence. ERG protein expression did not have prognostic value for the clinical end points in uni- and multivariate analyses. A positive correlation existed between ERG and androgen receptor expression in single tissue cores (P<0.001). In conclusion, immunohistochemical ERG expression has no predictive value for prostate cancer recurrence or progression after radical prostatectomy. Increasing ERG levels are associated with the upregulation of androgen receptor expression in clinical specimens.

Congenital heart defects and parental occupational exposure to chemicals.

BACKGROUND: Congenital heart defects (CHDs) are the most common major malformations in newborns. In this study we examined the associations between the occurrence of CHDs in children and periconceptional occupational parental exposures to chemicals. METHODS: In an age-matched case-control study with standardized data collection at c. 15 months after birth, 424 mothers and 421 fathers of a child with CHD and 480 mothers and 477 fathers of a non-malformed child, filled out questionnaires on periconceptional general and job characteristics. A job exposure matrix, which links the information on job title and a description of work tasks to an expert judgement on exposure to chemicals in the workplace, was used. RESULTS: The overall prevalence of occupational exposure to chemicals was 5.0 in cases and 6.2% in controls for mothers [odds ratio (OR) adjusted = 0.92; 95% confidence interval (CI): 0.26-3.25], while 22.3 and 15.9% for fathers, respectively (OR adjusted = 1.23; 95% CI: 0.39-3.91). No association of maternal occupational exposure to chemicals with risk of CHDs was found. Paternal exposure to phthalates was associated with a higher incidence of CHDs in general (OR adjusted = 2.08; 95% CI: 1.27-3.40). Paternal exposure to phthalates was associated with perimembranous ventricular septal defect (OR adjusted = 2.84; 95% CI: 1.37-5.92), to polychlorinated compounds with atrioventricular septal defect (OR adjusted = 4.22; 95% CI: 1.23-14.42) and to alkylphenolic compounds with coarctation of the aorta (OR adjusted = 3.85; 95% CI: 1.17-12.67). CONCLUSIONS: Periconceptional paternal (but not maternal) occupational exposure to certain chemicals is associated with an increased risk of CHDs in children. The results, however, must be interpreted cautiously as exposure probabilities are a crude measure of exposure.

Urodynamic quantification of decrease in sphincter function after radical prostatectomy: relation to postoperative continence status and the effect of intensive pelvic floor muscle exercises.

AIMS: We analyzed the impact of radical retropubic prostatectomy (RRP) on the urethral sphincter function as assessed by urethral pressure profilometry (UPP) and its relation to post-radical prostatectomy continence status. Furthermore, we analyzed the effect of intensive pelvic floor muscle exercises (PFME) on the urethral sphincter function. METHODS: Sixty-six patients were included in the study. UPP was performed before RRP and 26 weeks after catheter removal. All patients were instructed in PFME, however, the intensity of PFME varied between instructions based on an information folder only (F-PFME) and intensive guidance by a physiotherapist, in addition to the folder (PG-PFME). RESULTS: In 66 patients, pre- as well as postoperative UPP was evaluable. After surgery, the functional profile length and the maximum urethral closure pressure (MUCP) showed a median decrease of 64% and 41%, respectively. For men who had regained continence after 6 months the median MUCP was significantly higher both before and after operation as compared to men who were still incontinent. In multivariate analysis, non-nerve sparing approach was a prognostic factors for a higher relative decrease of the MUCP after RRP. Comparing the PG-PFME group with the F-PFME group there were no significant differences in changes in UPP parameters. CONCLUSIONS: A poor preoperative MUCP seems to be an important prognostic factor for persistent incontinence after RRP. Non-nerve sparing approach seems to be an important prognostic factor for impairment of the urethral sphincter function as measured by UPP. More intensive physiotherapy seems to have no additional effect on the postoperative urethral sphincter function as measured by UPP.

Congenital heart defects and biomarkers of methylation in children: a case-control study.

BACKGROUND: 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.

Medical methods for mid-trimester termination of pregnancy.

BACKGROUND: With the improvement of ultrasound technology, the likelihood of detection of major fetal structural anomalies in mid-pregnancy has increased considerably. Upon the detection of serious anomalies, women typically are offered the option of pregnancy termination. Additionally, there are still many reasons other than fetal anomalies why women seek abortion in the mid-trimester. OBJECTIVES: To compare different methods of second trimester medical termination of pregnancy for their efficacy and side-effects. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, Popline and reference lists of retrieved papers and other sources. SELECTION CRITERIA: All randomised controlled trials (RCTs) examining medical regimens for termination of pregnancy of a singleton living fetus between 12-28 weeks' gestation were analysed. The outcome measures were the induction to abortion interval, abortion rate within 24 hours, need for surgical evacuation, blood loss, uterine rupture, pain, and side-effects.Trials including >20% fetal death, multiple pregnancies, previous uterine scars and regimens which involved cervical preparation were excluded. DATA COLLECTION AND ANALYSIS: Two authors selected the trials and three authors extracted data. MAIN RESULTS: Fourty RCTs were included, addressing various agents for pregnancy termination and methods of administration. When used alone, misoprostol was an effective inductive agent, though it appeared to be more effective in combination with mifepristone. However, the evidence from RCTs is limited.Misoprostol was preferably administered vaginally, although among multiparous women sublingual administration appeared equally effective. A range of doses of vaginally administered misoprostol has been used. No randomised trials comparing doses of misoprostol were identified; however low doses of misoprostol appear to be associated with fewer side-effects while moderate doses appear to be more efficient in completing abortion. Four RCTs showed that the induction to abortion interval with 3-hourly vaginal administration of prostaglandins is shorter than 6-hourly administration without an increase in side-effects.Many studies reported the need for surgical evacuation. Indications for surgical evacuation include retained products of the placenta and heavy vaginal bleeding. Fewer women required surgical evacuation when misoprostol was administrated vaginally compared with women receiving intra-amniotical PGF(2a) . Mild, self-limiting diarrhoea was more common among women who received misoprostol compared to other agents. AUTHORS' CONCLUSIONS: Medical abortion in the second trimester using the combination of mifepristone and misoprostol appeared to have the highest efficacy and shortest abortion time interval. Where mifepristone is not available, misoprostol alone is a reasonable alternative. The optimal route for administering misoprostol is vaginally, preferably using tablets at 3-hourly intervals. Apart from pain, the side-effects of vaginal misoprostol are usually mild and self limiting. Conclusions from this review are limited by the gestational age ranges and variable medical regimens, including dosing, administrative routes and intervals of medication, of the included trials.

Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate.

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 x 10(6) to 44.4 x 10(6), 4.8 x 10(6)/ml to 14.3 x 10(6)/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.

Prognostic factors for and outcome of locally advanced prostate cancer after radical prostatectomy.

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.

The association of daily physical activity and birth outcome: a population-based cohort study.

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.

Body mass index as a prognostic marker for biochemical recurrence in Dutch men treated with radical prostatectomy.

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/m(2)) classes were defined as normal (<25), overweight (25-30) and obese (> or =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.

Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies.

BACKGROUND: Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer. PURPOSE: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer. DATA SOURCES: Studies identified in PubMed, Web of Science, and CancerLit. STUDY SELECTION: The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate. DATA EXTRACTION: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom. DATA SYNTHESIS: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake. LIMITATIONS: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies. CONCLUSION: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.

Homocysteine metabolism in the pre-ovulatory follicle during ovarian stimulation.

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