Increased mediator complex subunit CDK19 expression associates with aggressive prostate cancer.

The Mediator complex is a transcriptional regulator interacting with transcription factors and RNA-polymerase-II. Recently, we identified its subunit CDK19 to be specifically expressed in prostate cancer (PCa) and to be functionally implicated in PCa aggressiveness. Aim of our study was to comprehensively characterize the protein expression of CDK19 and its paralog CDK8 in PCa. We performed immunohistochemistry (IHC) for CDK19/CDK8 on a large cohort including needle biopsies from 202 patients, 799 primary tumor foci of radical prostatectomy specimens from 415 patients, 120 locally advanced tumor foci obtained by palliative transurethral resection, 140 lymph node metastases, 67 distant metastases and 82 benigns. Primary tumors were stained for the proliferation marker Ki67, androgen receptor (AR) and ERG. For 376 patients, clinic-pathologic data were available. Primary endpoint was disease-recurrence-free survival (DFS). Nuclear CDK19 and CDK8 expression increases during progression showing the highest intensity in metastatic and castration-resistant tumors. High CDK19 expression on primary tumors correlates with DFS independently from Gleason grade and PSA. Five-year-DFS rates of patients with primary tumors expressing no, moderate and high CDK19 are 73.7, 56.9 and 30.4%, respectively. CDK19 correlates with Gleason grade, T-stage, Ki67 proliferation-index, nuclear AR expression and ERG-status. Therapeutic options for metastatic and castration-resistant PCa remain limited. In the current study, we confirmed an important role of the Mediator subunit CDK19 in advanced PCa supporting current developments to target CDK19 and its paralog CDK8. Furthermore, CDK19 protein expression has the potential to predict disease recurrence independently from established biomarkers thus contributing to individual management for PCa patients.

Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status.

Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.

Up-regulation of POM121 is linked to prostate cancer aggressiveness and serves as a prognostic biomarker.

PURPOSE: Nucleoporins as components of the nuclear pore complex (NCP) are known for regulating nuclear-cytoplasmatic transport. Recently, the nucleoporin POM121 was found to have an important impact on intranuclear translocation of prostate cancer (PCa)-specific tumor drivers including the androgen receptor (AR). The aim of our study was to assess the potential of POM121 as a prognostic biomarker. METHODS: Therefore, we performed immunohistochemistry (IHC) for POM121 on a large clinically, well characterized PCa tissue cohort comprising benign prostatic samples, radical prostatectomy (RPE) samples, lymph node metastases, local recurrent tumors and distant metastases of 289 patients. Using a semi automated tissue image analysis software we evaluated POM121 protein expression level based on IHC. RESULTS: We could show that POM121 expression increases during tumor progression. Expression levels were significantly higher in primary tumors compared to benign samples (P = 0.001), and substantially higher in advanced tumors (P < 0.001) and in distant metastases (P = 0.006) compared to primary tumors. Furthermore, POM121 expression predicts biochemical recurrence free survival (BFS) after surgery independent of the WHO group and other clinicopathological markers. 5-years BFS with primary tumors lacking POM121 and expressing POM121 was 88.8% and 68.9%, respectively. CONCLUSION: Our study reveals the potential of POM121 as a potential biomarker for PCa, predicting BFS independent of other common clinicopathological parameters. Furthermore, POM121 might be a new targetable structure for patients suffering from advanced PCa.

Relevance of cohort design for studying the frequency of the ERG rearrangement in prostate cancer.

AIMS: ERG rearrangements, mostly resulting in TMPRSS2-ERG fusions, are frequent alterations in prostate cancer (PCa), with a frequency ranging from 15% to 78%. As the reason for this variability is unknown, our aim was to investigate the ERG rearrangement frequency with a cohort design. METHODS AND RESULTS: We assessed three well-defined cohorts for ERG rearrangements, using fluorescence in situ hybridization (FISH). The first cohort comprised 119 prostatectomy specimens. The second and third cohorts included incidentally diagnosed PCa [71 cystoprostatectomy specimens, and 105 transurethral resection of the prostate (TURP) specimens]. Seventy of 119 (59%) cases of the prostatectomy cohort harboured ERG rearrangements. Regarding zonal origin, 2/11 (18%) transition zone (TZ) foci and 75/145 (52%) peripheral zone (PZ) foci harboured ERG rearrangements. Within the cystoprostatectomies, 24/71 (34%) cases harboured ERG rearrangements. Regarding zonal origin, 2/9 (22%) TZ foci and 26/86 (30%) PZ foci harboured ERG rearrangements. PCa incidentally identified by TURP harboured ERG rearrangements in 31/105 (29%) cases. CONCLUSIONS: ERG rearrangements occur in TZ PCa, although at a lower frequency than in PZ PCa. We confirmed that approximately half of all prostatectomies harbour ERG rearrangements. However, the frequency in incidentally diagnosed PCa cohorts was significantly lower, even if multifocality was considered. Consequently, zonal origin and cohort design are key for studying the clinical implications of ERG rearrangements.

POU5F1P1, a putative cancer susceptibility gene, is overexpressed in prostatic carcinoma.

BACKGROUND: Association between genetic variants located on human chromosome 8q24.21 with an increased risk for prostatic carcinoma has been well established. POU5F1P1, a processed pseudogene homologous to the pluripotency factor OCT4, is the only sequence with coding capacity in this region. The objective of this study was to investigate the POU5F1P1 expression in prostatic carcinoma and carcinoma surrounding prostatic tissue. METHODS: RT-PCR and real-time PCR was used to measure the expression of POU5F1P1 relative to the expression of HPRT1 in cell lines, prostatic carcinoma and carcinoma surrounding prostatic tissue. The structure of the POU5F1P1 mRNA and the promoter sequence were elucidated by 5'-RACE experiments. The POU5F1P1 protein was shown with immunohistochemistry on prostate tissue. RESULTS: POU5F1P1 was found to be the only member of the POU5F1 family to be expressed in prostate with over-expression in prostatic carcinoma compared to surrounding prostatic tissue probably because of an increased density of expressing cells. The POU5F1P1 expression is driven by a variety of promoter structures scattered over a genomic region of 860 kB. CONCLUSIONS: The over-expression of POU5F1P1 in prostatic carcinoma in addition to its genomic location and the putative function of its gene product render POU5F1P1 a good candidate to harbour functional genetic variants which modulate prostatic cancer susceptibility.

ERG rearrangement is specific to prostate cancer and does not occur in any other common tumor.

Identification of specific somatic gene alterations is crucial for the insight into the development, progression, and clinical behavior of individual cancer types. The recently discovered recurrent ERG rearrangement in prostate cancer might represent a prostate cancer-specific alteration that has not been systematically assessed in tumors other than prostate cancer. Aim of this study was to assess, whether the ERG rearrangement and the distinct deletion site between TMPRSS2 and ERG, both predominantly resulting in a TMPRSS2-ERG fusion, occur in tumors other than prostate cancer. We assessed 54 different tumor types (2942 samples in total) for their ERG rearrangement status by fluorescence in situ hybridization (FISH). To calibrate, we analyzed 285 prostate cancer samples for the ERG rearrangement frequency. Additionally, we interrogated a high-resolution single nucleotide polymorphism (SNP) data set across 3131 cancer specimens (26 tumor types) for copy number alterations. None of the 54 different tumor types assessed by FISH harbored an ERG rearrangement, whereas the prostate cancer samples revealed an ERG rearrangement in 49.5% of cases. Furthermore, within the 26 tumor types assessed for copy number alterations by SNP, the distinct deletion site between TMPRSS2 and ERG (21q22.2-3) was detectable exclusively in prostate cancer. Although Ewing's sarcoma and AML have known rearrangements rarely involving ERG, we hypothesize that the ERG rearrangement as well as the distinct deletion site on 21q22.2-3 between TMPRSS2 and ERG are prostate-cancer-specific genomic alterations. These observations provide further insight into the oncogenesis of prostate cancer and might be critical for the development of ERG rearrangement assessment as a clinical tool.

Distinct genomic aberrations associated with ERG rearranged prostate cancer.

Emerging molecular and clinical data suggest that ETS fusion prostate cancer represents a distinct molecular subclass, driven most commonly by a hormonally regulated promoter and characterized by an aggressive natural history. The study of the genomic landscape of prostate cancer in the light of ETS fusion events is required to understand the foundation of this molecularly and clinically distinct subtype. We performed genome-wide profiling of 49 primary prostate cancers and identified 20 recurrent chromosomal copy number aberrations, mainly occurring as genomic losses. Co-occurring events included losses at 19q13.32 and 1p22.1. We discovered three genomic events associated with ERG rearranged prostate cancer, affecting 6q, 7q, and 16q. 6q loss in nonrearranged prostate cancer is accompanied by gene expression deregulation in an independent dataset and by protein deregulation of MYO6. To analyze copy number alterations within the ETS genes, we performed a comprehensive analysis of all 27 ETS genes and of the 3 Mbp genomic area between ERG and TMPRSS2 (21q) with an unprecedented resolution (30 bp). We demonstrate that high-resolution tiling arrays can be used to pin-point breakpoints leading to fusion events. This study provides further support to define a distinct molecular subtype of prostate cancer based on the presence of ETS gene rearrangements.

Oncological followup after radical cystectomy for bladder cancer-is there any benefit?

PURPOSE: Tumor recurrence after radical cystectomy for bladder cancer can be detected in an asymptomatic patient by regular followup or in a symptomatic patient by symptom guided examination. To our knowledge it is still unknown whether detecting tumor recurrence at an asymptomatic stage offers a better survival rate. MATERIALS AND METHODS: A total of 1,270 radical cystectomies for bladder cancer were performed at a single institution between January 1, 1986 and December 2006. All patients had regular followup examinations with chest x-ray and abdominal ultrasound every 3 months, computerized tomography of the abdomen every 6 months, and bone scan and excretory urography every 12 months. Additional examinations were required for symptomatic disease. We analyzed the first site and date of tumor recurrence. Survival was compared using the log rank test. RESULTS: The 20-year recurrence rate was 48.6% in the complete series. Tumor recurrence developed in 444 patients, including 154 asymptomatic and 290 symptomatic patients, with a mean time after radical cystectomy of 20 and 17.5 months, respectively. The most frequent symptoms were pain, ileus, acute urinary retention, hydronephrosis with flank pain, hematuria, neurological symptoms and a palpable mass. Of the 444 patients 182 (41%) had local recurrence and 324 (73%) had distant failure at the time of first recurrence. The overall survival rate 1, 2 and 5 years after first recurrence was 22.5%, 10.1% and 5.5% in asymptomatic patients, and 18.9%, 8.2% and 2.9% in symptomatic patients, respectively (log rank not significant). CONCLUSIONS: This study fails to demonstrate a survival benefit for detecting tumor recurrence early at an asymptomatic stage by regular followup examinations. These data show that symptom guided followup examinations may provide similar results at lower cost.

Upper urinary tract recurrence after radical cystectomy for bladder cancer--who is at risk?

PURPOSE: Patients who underwent radical cystectomy for bladder cancer are at risk for upper urinary tract recurrence. We identified subgroups of patients at increased risk for upper urinary tract recurrence. MATERIALS AND METHODS: All 1,420 patients who underwent radical cystectomy for bladder cancer at our center between January 1986 and October 2008 were included in the study. Negative frozen sections of the ureteral margins were obtained from all patients. Data analysis included preoperative tumor history, pathological findings of the cystectomy specimen and complete followup. Survival was calculated using the Kaplan-Meier method. RESULTS: Until October 2008, 25 cases of upper urinary tract recurrence were observed. The overall rate of upper urinary tract recurrence at 5, 10 and 15 years was 2.4%, 3.9% and 4.9%, respectively. Of the patients 3 had superficial tumors of the renal pelvis and 22 had invasive upper tract transitional cell carcinoma. Upper urinary tract recurrence did not develop in any patients with nontransitional cell carcinoma. Four risk factors for upper urinary tract recurrence were identified including history of carcinoma in situ (RR 2.3), history of recurrent bladder cancer (RR 2.6), cystectomy for nonmuscle invasive bladder cancer (RR 3.8) and tumor involvement of the distal ureter in the cystectomy specimen (RR 2.7). Patients with transitional cell carcinoma who had none of these risk factors had an upper urinary tract recurrence rate of only 0.8% at 15 years. This rate increased with the number of positive risk factors, ie 8.4% in patients with 1 to 2 risk factors and 13.5% in those with 3 to 4 risk factors. CONCLUSIONS: Patients who underwent cystectomy for transitional cell carcinoma and with at least 1 risk factor for upper urinary tract recurrence should have closer followup regimens than those with nontransitional cell carcinoma or without any of these risk factors.

TRIM24 as an independent prognostic biomarker for prostate cancer.

INTRODUCTION: Simply applicable biomarkers for prostate cancer patients predicting the clinical course are urgently needed. Recently, TRIM24 has been identified to promote androgen receptor signaling and to correlate with an aggressive prostate cancer phenotype. Based on these data, we proofed TRIM24 as a prognostic biomarker for risk stratification. MATERIALS AND METHODS: We performed TRIM24 immunohistochemistry on 2 independent cohorts including a total of 806 primary tumors, 26 locally advanced/recurrent tumors, 30 lymph node metastases, 30 distant metastases, and 129 benign prostatic samples from 497 patients as well as on 246 prostate needle biopsies. Expression data were correlated with clinic-pathological data including biochemical recurrence-free survival (bRFS) as endpoint. RESULTS: Benign samples show no or low TRIM24 expression in 94%, while tumor tissues demonstrate significant higher levels. Strongest expression is observed in advanced and metastatic tumors. In multivariate analyses, TRIM24 up-regulation on radical prostatectomy specimens correlates with shorter bRFS independent of other prognostic parameters. 5-(10-) year bRFS rates for TRIM24 negative, low, medium and high expressing tumors are 93.1(93.1)%, 75.4(68.5)%, 54.9(47.5)% and 43.1(32.3)%, respectively. Of interest, tumors diagnosed as indolent disease, TRIM24 expression stratifies patients into specific risk groups. Increased TRIM24 expression associates with higher grade group, positive nodal status and extraprostatic tumor growth. TRIM24 assessment on prostate needle biopsies taken prior to treatment decision at time of initial diagnosis significantly correlates with recurrence after surgery. CONCLUSION: Using 2 large independent radical prostatectomy specimen cohorts, we found that TRIM24 expression predicts patients' risk to develop disease recurrence with high accuracy and independent from other established biomarkers. Further, this is the first study exploring TRIM24 expression on prostate needle biopsies which represents the clinically relevant tissue type on which biomarkers guide treatment decisions. Thus, we strongly suggest introducing TRIM24 evaluation in prostate needle biopsies in clinical routine as an inexpensive and simple immunohistochemical test.

Multiple novel prostate cancer predisposition loci confirmed by an international study: the PRACTICAL Consortium.

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10(-17)). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction.

Expression changes of CAV1 and EZH2, located on 7q31 approximately q36, are rarely related to genomic alterations in primary prostate carcinoma.

The chromosomal region 7q was repeatedly found to be rearranged in prostate carcinoma. It harbors several well described candidate tumor suppressor and oncogenes. We addressed two genes with opposite roles in cancer; CAV1, a putative tumor suppressor gene at 7q31, and EZH2 at 7q36, which is believed to promote tumor progression. Our primary aim was to assess their expression changes in primary tumors, and then to elucidate the underlying mechanism, assuming that genomic alterations of either locus could affect the other gene as well. In 35 prostate tumor samples, compared with adjacent tissues, CAV1 was overall downregulated (P < 10(-06)), whereas EZH2 was significantly overexpressed (P < 10(-06)). The observed dysregulations were coincident in nearly 70% of the cases. Copy number changes occurred in few tumors. Loss of CAV1 DNA was only marginally associated with reduced expression (P = 0.07), however, and genomic amplification of EZH2 could not explain its upregulation. Through bisulfite sequencing of four tumor samples, CpG-hypermethylation was verified as an alternative mechanism for CAV1 silencing, as reported previously. Moreover, it could also be involved in the reactivation of EZH2.

Intensifying the saturation biopsy technique for detecting prostate cancer after previous negative biopsies: a step in the wrong direction.

OBJECTIVE: To report the results using an extensive saturation biopsy in men with negative prostate biopsies but in whom there is still a clinical suspicion for carcinoma. PATIENTS AND METHODS: Between February 1999 and October 2004 we offered 40 patients (median age 63 years) an extensive saturation biopsy if there was clinical suspicion of prostate cancer after previous negative prostate biopsies. The median (range) number of cores taken was 64 (39-139) and was adjusted to the size of the prostate. All patients received general or spinal anaesthesia. RESULTS: Of the 40 patients, 18 (45%) had carcinoma in at least one core; 16 had a radical prostatectomy, which showed pT2a, pT2b, pT2c, pT3a and pT3b adenocarcinoma of the prostate in three, four, six, two and one patients, respectively. Brachytherapy and external radiation were the therapies of choice in the other patients. Sixteen patients had marked haematuria after the biopsy procedure. CONCLUSION: There is no significant increase in the cancer detection rate in an extensive saturation-biopsy regimen compared to published series with fewer cores, but the morbidity increased.

5-aza-2'-deoxycytidine delays androgen-independent disease and improves survival in the transgenic adenocarcinoma of the mouse prostate mouse model of prostate cancer.

PURPOSE: We have previously shown that 5-aza-2'-deoxycytidine (5-aza) is an effective chemopreventive agent capable of preventing early disease progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The purpose of this study was to determine the effect of 5-aza on preexisting TRAMP prostate cancers and prevention of androgen-independent prostate cancer. EXPERIMENTAL DESIGN: TRAMP mice with established prostate cancers were treated with 5-aza, castration, castration + 5-aza, or vehicle control (PBS). One cohort of 22 mice per treatment was euthanized after 10 weeks of treatment, whereas a second cohort of 14 mice per group was followed until death to determine survival. Histologic sections of prostate, pelvic lymph nodes, lung, and liver were blinded and analyzed by a certified genitourinary pathologist (K.J.W.). RESULTS: Combined treatment (castration + 5-aza) provided significant survival benefits over either single treatment (combined versus castration P = 0.029, combined versus 5-aza P = 0.036). At 24 weeks of age, 86% of mice within the PBS cohort exhibited histologic evidence of prostate cancer, whereas only 47% of the combined cohort exhibited malignant disease (P < 0.0001). Additionally, whereas 43% of the PBS treatment group exhibited lymph node metastases, these were only observed in 21% of the combined treatment mice. CONCLUSIONS: This is the first study to examine the effect of 5-aza and combined castration + 5-aza on preexisting prostate cancer in an animal model. Based on these preclinical findings, we suggest that 5-aza treatment may prolong the time to an androgen-independent status and thus survival in a hormone-deprived setting in prostate cancer.

Collagen XXIII expression is associated with prostate cancer recurrence and distant metastases.

PURPOSE: We had previously identified a new transmembrane collagen, type XXIII, in metastatic rat prostate carcinoma cells. The purpose of this study was to determine the expression of collagen XXIII in human prostate cancer and investigate its relationship with disease progression. EXPERIMENTAL DESIGN: We investigated collagen XXIII expression in prostate cancer tissue and did a retrospective analysis of association with prostate-specific antigen (PSA)-defined disease recurrence. The presence of collagen XXIII in prostate cancer patient urine was also assessed before and after prostatectomy. RESULTS: Collagen XXIII protein was detected at very low levels in benign prostate tissue and was significantly increased in prostate cancer. Distant metastases exhibited significantly higher collagen XXIII levels compared with either localized prostate cancer or regional (lymph node) metastases. Patients with high collagen XXIII levels had a 2.8-fold higher risk of PSA failure with median time to failure of 8.1 months, compared with low collagen XXIII patients with a median time to failure of 5 years. Multivariate Cox regression showed that the presence of collagen XXIII was significantly associated with time to PSA recurrence, independent of other clinical variables. Collagen XXIII was also detected in prostate cancer patient urine, with reduced levels after prostatectomy, indicating potential as a noninvasive fluid biomarker. CONCLUSIONS: We present the first report demonstrating increased collagen XXIII expression in prostate cancer tissue. We show that collagen XXIII level is a significant independent predictor of PSA-defined disease recurrence, suggesting a potential role as a molecular biomarker of prostate cancer progression and metastasis.

Nosocomial bacteriuria in patients with indwelling catheter after radical retropubic prostatectomy for prostate cancer.

INTRODUCTION: Patients with prolonged catheter drainage following pelvic surgery are at increased risk for bacteriuria that may have an impact on the clinical course. MATERIALS AND METHODS: We retrieved all urine analyses from 148 consecutive patients that underwent open retropubic radical prostatectomy at our institution in 2002. The following data were generated: number of bacteriuria with day of onset, used antibiotics, microbiological analysis, resistogram, day of catheter removal and clinical postoperative course. RESULTS: 44.6% of the investigated patients presented with bacteriuria. The highest incidence of bacteriuria was between day 13-15 (40.4%). The most common bacteria detected over the hospital stay were Staphylococcus spp. (24.3%). The most common used antibiotic was trimethoprim/sulfamethoxazole (44.6%). The highest susceptibility was found for levofloxacin (62.4%). No difference in time period of catheter drainage was noticeable in patients with bacteriuria compared to patients without bacteriuria. CONCLUSIONS: Bacteriuria is common after radical prostatectomy. To minor the risk of complications related to bacterial infection, the catheter should be removed 7-10 days after surgery. In case of the necessity of longer catheter drainage, an empiric antibiotic therapy seems rational.

[11C]Choline PET/CT for targeted salvage lymph node dissection in patients with biochemical recurrence after primary curative therapy for prostate cancer. Preliminary results of a prospective study.

INTRODUCTION: In this prospective study we set out to investigate the diagnostic value of [(11)C]choline-PET/CT in patients with suspected lymph node metastases before salvage lymph node dissection. PATIENTS AND METHODS: 15 consecutive patients with rising PSA underwent [(11)C]choline-PET/CT and consecutive open salvage pelvic/retroperitoneal extended lymph node dissection due to uptake of [(11)C]choline in at least 1 lymph node. Mean age was 62.1 (range 53-73). RESULTS: [(11)C]choline-PET/CT results were compared with the histopathology reports and clinical follow-up (mean 13.7 months, range 6-24). Mean time to progression was 23.6 months (range 4-81). [(11)C]choline uptake was observed in nodes along the external and internal and common iliac arteries and in the paraaortic region. A positive histology was reported in 8/15 patients. Only one patient had a PSA nadir of <0.1 ng/ml after salvage surgery. Another patient had stable disease with a PSA of 0.5 ng/ml. Three patients developed bone metastases during follow-up. CONCLUSIONS: This interim analysis indicates that [(11)C]choline-PET/CT may be a useful technique in detection of lymph node metastases when rising PSA occurs after definite prostate cancer therapy. The presented cohort is limited in size, but there is still strong evidence that the patients benefit from [(11)C]choline-PET/CT and consecutive salvage lymph node dissection is rather small.

Elevated E2F1 inhibits transcription of the androgen receptor in metastatic hormone-resistant prostate cancer.

Activation of E2F transcription factors, through disruption of the retinoblastoma (Rb) tumor-suppressor gene, is a key event in the development of many human cancers. Previously, we showed that homozygous deletion of Rb in a prostate tissue recombination model exhibits increased E2F activity, activation of E2F-target genes, and increased susceptibility to hormonal carcinogenesis. In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis. We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-naïve patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006). In contrast, strong AR expression was detected in benign prostate (83%), localized prostate cancer (100%), and lymph node metastasis (80%), but decreased to 40% in metastatic hormone-resistant prostate cancer (P = 0.004). Semiquantitative reverse transcription-PCR analysis showed elevated E2F1 mRNA levels and increased levels of the E2F-target genes dihyrofolate reductase and proliferating cell nuclear antigen in metastatic hormone-independent prostate cancer cases compared with benign tissues. To identify a role of E2F1 in hormone-independent prostate cancer, we examined whether E2F1 can regulate AR expression. We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells. E2F1 also inhibited an AR promoter-luciferase construct that was dependent on the transactivation domain of E2F1. Furthermore, using chromatin immunoprecipitation assays, we show that E2F1 and the pocket protein family members p107 and p130 bind to the AR promoter in vivo. Taken together, these results show that elevated E2F1, through its ability to repress AR transcription, may contribute to the progression of hormone-independent prostate cancer.

Expression of Prostate-Specific Membrane Antigen (PSMA) on Biopsies Is an Independent Risk Stratifier of Prostate Cancer Patients at Time of Initial Diagnosis.

Background: Stratifying prostate cancer (PCa) patients into risk groups at time of initial diagnosis enabling a risk-adapted disease management is still a major clinical challenge. Existing studies evaluating the prognostic potential of PSMA (prostate-specific membrane antigen) for PCa were performed on radical prostatectomy specimens (RPE), i.e., decision making for disease management was already completed at time of sample analysis. Aim of our study was to assess the prognostic value of PSMA expression for PCa patients on biopsies at time of initial diagnosis. Methods: PSMA expression was assessed by immunohistochemistry on 294 prostate biopsies with corresponding RPE, 621 primary tumor foci from 242 RPE, 43 locally advanced or recurrent tumors, 34 lymph node metastases, 78 distant metastases and 52 benign prostatic samples. PSMA expression was correlated with clinico-pathologic features. Primary endpoint was recurrence free survival. Other clinicopathologic features included WHO/ISUP grade groups, PSA serum level, TNM-stage, and R-status. Chi-square test, ANOVA-analyses, Cox-regression, and log-rank tests were performed for statistical analyses. Results: High PSMA expression on both biopsy and RPE significantly associates with a higher risk of disease recurrence following curative surgery. The 5-year-recurrence free survival rates were 88.2, 74.2, 67.7 and 26.8% for patients exhibiting no, low, medium, or high PSMA expression on biopsy, respectively. High PSMA expression on biopsy was significant in multivariate analysis predicting a 4-fold increased risk of disease recurrence independently from established prognostic markers. PSMA significantly increases during PCa progression. Conclusion: PSMA is an independent prognostic marker on biopsies at time of initial diagnosis and can predict disease recurrence following curative therapy for PCa. Our study proposes the application of the routinely used IHC marker PSMA for outcome prediction and decision making in risk-adapted PCa management on biopsies at time of initial diagnosis.

Prostate-specific membrane antigen expression as a predictor of prostate cancer progression.

Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, because current therapy may lead to overtreatment of men with limited disease. The prostate-specific membrane antigen (PSMA) is a membrane-bound glycoprotein that is highly restricted to the prostate. Previously, studies analyzing the expression of PSMA have found an up-regulation in correlation with prostate cancer, particularly in advanced cancer. This association is ideal for an application as a prognostic marker. In the current study, we characterized PSMA expression in a high-risk cohort and evaluated its potential use as predictive marker of prostate-specific antigen (PSA) recurrence. PSMA expression was analyzed by immunohistochemistry using tissue microarrays composed of tumor samples from 450 patients. Protein intensity was recorded using a semiautomated quantitative microscope system (ACIS II; Clarient Chromavision Medical Systems, San Juan Capistrano, CA). PSMA expression levels differed significantly (P < .001) between benign prostatic tissue, localized prostate cancer, and lymph node metastases. Dividing the cohort into high- and low-PSMA expressing cancers based on the median area of positive staining, we found that high PSMA levels were associated with significant increase of PSA recurrence (P = .004). This was independent of clinical parameters such as lymph node tumor burden (lymph node density, >20%; P < .001), extraprostatic extension (P = .017), seminal vesicle invasion (P < .001), and high Gleason score (8-10, P = .006). In a multivariate model, PSMA expression and metastases to pelvic lymph nodes were significantly associated with time to PSA recurrence (HR, 1.4; 95% confidence interval, 1.1-2.8, P = .017; and hazard ratio, 5; 95% confidence interval, 2.6-9.7, P < .001, respectively). In summary, PSMA is independently associated with PSA recurrence in a high-risk cohort and thus might provide insight into the additional use of adjuvant therapy. Validation on other cohorts is required.