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.

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.

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.

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.

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.

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.

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 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.

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 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.

Prostate-specific antigen (PSA) isoform p2PSA in combination with total PSA and free PSA improves diagnostic accuracy in prostate cancer detection.

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).

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.

Sperm chromatin structure is associated with the quality of spermatogenesis in infertile patients.

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.

Expression of the androgen-regulated fusion gene TMPRSS2-ERG does not predict response to endocrine treatment in hormone-naïve, node-positive prostate cancer.

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.

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.

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.

Histopathological characteristics of lymph node metastases predict cancer-specific survival in node-positive prostate cancer.

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.