68Ga-PSMA-11 PET Represents the Tumoricidal Effect of 223Ra in a Patient With Castrate-Resistant Metastatic Prostate Cancer.

A 64-year-old man with prostate cancer and an increasing prostate-specific antigen (PSA) level under therapy with abiraterone acetate underwent a therapy with Ra. Before the first therapy and 4 weeks after the last cycle, the patient underwent Ga-PSMA PET, which showed a clear response of bone metastases.

Evaluation of Global Histone Acetylation Levels in Bladder Cancer Patients.

BACKGROUND/AIM: Alterations of global histone modification levels have been identified in various tumor entities, including bladder cancer (BCA). Our study was designed to investigate the value of global histone acetylation levels as diagnostic and prognostic biomarker for BCA patients. MATERIALS AND METHODS: A tissue microarray with formalin-fixed paraffin-embedded tissues (271 BCA and 29 normal urothelial samples) was used to determine global histone acetylation levels (histone H3 acetylation (H3Ac); histone H3 lysine 18 acetylation (H3K18Ac); histone H4 acetylation (H4Ac)). RESULTS: Global H3Ac levels were decreased in BCA patients, whereas H3K18Ac and H4Ac levels were similar in both groups. All studied histone acetylation markers were lower in muscle-invasive BCA compared to non-muscle invasive BCA and normal urothelial tissue, thereby indicating a possible prognostic relevance. CONCLUSION: Global histone acetylation levels undergo quantitative alterations during bladder cancer progression and could be helpful to identify patients at risk for early cancer recurrence.

Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer.

Prostate-specific membrane antigen (PSMA) is highly expressed on prostate epithelial cells and strongly up-regulated in prostate cancer (PC), making it an optimal target for the treatment of metastasized PC. Radioligand therapy (RLT) with 177Lu-PSMA-DKFZ-617 (Lu-PSMA) is a targeted therapy for metastatic PC. In this study, we retrospectively analyzed the side effects and the response rate of 24 hormone and/or chemorefractory PC patients with a mean age of 75.2 years (range: 64-82) with distant metastases and progressive disease according to the PSA level, who were treated with Lu-PSMA. Median PSA was 522 ng/ml (range: 17-2360). Forty-six cycles of Lu-PSMA were performed. Of the 24 patients, 22 received two cycles. Eight weeks after the first cycle of Lu-PSMA therapy 79.1% experienced a decline in PSA level. Eight weeks after the second cycle of Lu-PSMA therapy 68.2% experienced a decline in PSA relative to the baseline value. Apart from two cases of grade 3 anemia, there was no relevant hemato- or nephrotoxicity (grade 3 or 4). These results confirmed that Lu-PSMA is a safe treatment option for metastatic PC patients and has a low toxicity profile. A positive response to therapy in terms of decline in PSA occurs in about 70% of patients.

Early side effects and first results of radioligand therapy with (177)Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre study.

BACKGROUND: Radioligand therapy (RLT) with (177)Lu-DKFZ-617 PSMA (Lu-PSMA) (prostate-specific membrane antigen) is a novel targeted therapy of metastatic prostate cancer. We analysed retrospectively the early side effects and the response rate in the first patients, who received a therapy with Lu-PSMA in our departments. METHODS: RLT was performed in ten hormone- and/or chemo-refractory patients with distant metastases and progressive disease (mean age 73.5 years). (68)Ga-PSMA HBED-CC PET/CT was performed in all patients prior to RLT. The median PSA level prior to the therapy was 298.5 ng/ml (range 5-853 ng/ml). All patients received CBC, renal and liver function tests the day before and 2 days after application (mean administered activity 5.6 GBq, range 4.1-6.1 GBq), followed by further tests every 2 weeks. All patients were contacted by telephone every week regarding side effects or any positive and negative changes. RESULTS: Eight weeks after the therapy, seven patients (70 %) experienced a PSA decline, of whom six experienced more than 30 % and five more than 50 %. Three patients showed a progressive disease according to the PSA increase. No patient experienced any side effects immediately after injection of Lu-PSMA. Relevant hematotoxicity (grade 3 or 4) occurred 7 weeks after the administration in just one patient. The same patient showed a leucopenia grade 2. Two patients showed a disturbance of only 1 hematologic cell line, whereas one patient showed a reduction of grades 1 and 2 in leucocytes and thrombocytes, respectively. Six patients did not show any hematotoxicity during the 8 weeks after therapy. There was no relevant nephrotoxicity (grade 3 or 4). CONCLUSIONS: Our initial results indicate that RLT with Lu-PSMA is safe and seems to have low early side-effect profile. A relevant PSA decline was detected in 70 % of patients.

Matched-pair analysis of dendritic cell versus targeted-therapy in patients with metastatic renal cell carcinoma.

BACKGROUND/AIM: Although targeted-therapy (TT) for patients with metastatic renal cell cancer (mRCC) has shown an improved outcome, their prognosis is still very poor. Immunotherapy with dendritic cells (DC) as one promising new treatment tries to fight cancer by boosting the patient's own immune system. The present analysis matches two different methods of treatment against mRCC, namely sequential TT versus DC vaccine therapy, by comparison of long-term overall survival (OS). PATIENTS AND METHODS: Data of patients treated with DC vaccines (N=30) in three clinical phase I/II trials (1999-2003) and patients treated with clinical standard targeted-therapy (N=30) at the University Hospital of Bonn (2010-2013) were analyzed regarding their OS, as well as specific characteristics such as number and localization of metastatic sites. RESULTS: The mean OS from the first treatment was significantly higher in the TT than in the DC group (48 versus 21 months, range=3-85 months versus 1-57 months, respectively; p=0.0002). Patients with one (p=0.036) or two metastases (p=0.037) and especially patients with bone metastases (52 versus 12 months; p<0.0001) benefited significantly from TT. However, there was no significant difference between therapy types in patients with lung (p=0.147) or liver (p=0.745) metastases, or in patients with more than two metastatic sites (p=0.074). CONCLUSION: Targeted therapy is an effective treatment against mRCC, but is limited due to common adverse events and a higher toxicity when combinations of different-targeted agents are used. Immunotherapy with DC vaccines seems to be a potent and well-tolerated therapy against mRCC, possibly showing higher benefit for patients with specific sites of metastasis, and should be investigated as a co-treatment with TT in further studies.

Alterations of global histone H3K9 and H3K27 methylation levels in bladder cancer.

BACKGROUND: Epigenetic alterations, including histone modifications, play an important role during carcinogenesis. This study was designed to systematically investigate histone H3K9 and H3K27 methylation levels in bladder cancer (BCa) tissue. METHODS: A tissue microarray with urothelial BCa (150 non-muscle-invasive BCa, NMIBC; 121 muscle-invasive BCa, MIBC; 31 metastatic BCa, MET) and normal urothelium (29, CTRL) specimen was used to determine the global levels of H3K9 and H3K27 mono-, di- and tri-methylation. RESULTS: Global levels of H3K9 and H3K27 methylation were significantly higher in CTRL than in BCa, and levels in NMIBC were higher compared to MIBC. Histone methylation levels of MET resembled MIBC. We observed furthermore a correlation of histone methylation levels with pT stage (H3K9me1, H3K9me2, H3K9me3, H3K27me1, H3K27me3) and grade (H3K9me2, H3K9me3, H3K27me1) in NMIBC. H3K9me1, H3K9me3, H3K27me1 and H3K27me3 levels were also correlated with pT stage in MIBC. Histone modifications were not associated with recurrence-free or cancer-specific survival. CONCLUSIONS: Global histone H3K9 and H3K27 methylation levels are altered in BCa.

Diagnostic meaning of urodynamic studies in pouch incontinence: results of a small series.

INTRODUCTION: To evaluate the meaning of urodynamic parameters in patients with pouch incontinence. MATERIALS AND METHODS: Thirteen urodynamic studies in patients with an ileal nipple as the efferent segment of an ileocecal pouch or ileum/ileocecal-augmented bladder were performed. The recorded parameters included pouch capacity, leak point pressure/volume, maximum pouch pressure, compliance, static and dynamic closure pressure, and functional length. Three patients suffered from urinary incontinence. RESULTS: In all cases of incontinent patients, no functional length or static or dynamic closure pressure could be revealed. In 8 of 10 cases of continent patients, a positive functional length as well as static and/or dynamic closure pressure were measured (mean value in continent patients: 15.9 mm, 14.5 cm H2O and 26.5 cm H2O, respectively). In 2 of 3 cases of incontinent patients, the pouch compliance was restricted (21 and 37 ml/cm H2O). The pouch capacity of continent patients was greater than the capacity of incontinent patients (377.4 vs. 185.7 ml). CONCLUSIONS: Positive functional length, static and dynamic closure pressures, and a high pouch capacity with an unrestricted compliance are predictive for pouch continence. They may individually not determine continence, but combining them can. However, the meaning of urodynamic studies in pouch incontinence is not the same as with the urinary bladder.

Histone methylation defines an epigenetic entity in penile squamous cell carcinoma.

PURPOSE: Earlier studies indicate that epigenetics contribute to the pathogenesis of penile squamous cell carcinoma. Histone methylation patterns are frequently altered during carcinogenesis. Therefore, we investigated the methylation pattern of the histones H3K4, H3K9 and H3K27 in penile carcinoma and normal tissue. MATERIALS AND METHODS: A tissue microarray was constructed with 65 penile carcinomas, 6 metastatic lesions and 30 control tissues. Global histone methylation was assessed using immunohistochemistry. RESULTS: Global levels of H3K4me1, H3K9me1, H3K9me2, H3K27me2 and H3K27me3 were decreased, whereas H3K9me3 was increased in penile carcinoma. Histone methylation levels defined an epigenetic entity that allowed accurate differentiation of cancer and normal samples. We observed no correlation of histone methylation levels with clinicopathological parameters or patient outcome. CONCLUSIONS: The description of a definite epigenetic entity in penile carcinoma provides a rationale for testing epigenetic agents in patients with metastatic disease.

Cabazitaxel plus prednisone for metastatic castration-resistant prostate cancer progressing after docetaxel: results from the German compassionate-use programme.

BACKGROUND: Cabazitaxel (Cbz) is an approved second-line treatment in metastatic castration-resistant prostate cancer (mCRPC) following docetaxel therapy with a significant survival benefit compared with mitoxantrone. However, grade 3/4 toxicities were reported in 82% of patients. OBJECTIVE: To report on the safety results of mCRPC patients treated within a compassionate-use programme in Germany. DESIGN, SETTING, AND PARTICIPANTS: A total of 111 patients with a mean age of 67.9 yr (range: 49-81 yr) and progressive mCRPC were included. Patients had received a mean number of 12.7 ± 10.8 cycles (range: 6-69 cycles) of docetaxel with a mean cumulative dose of 970.9 mg/m(2); mean time from last docetaxel application to progression was 6.95 mo (range: 2-54 mo). Of the patients, 31.5% progressed by prostate-specific antigen (PSA) increase only; the remainder had a combination of PSA increase and clinical progression. INTERVENTION: Cbz at a dosage of 25mg/m(2) intravenously every 3 wk combined with 5mg of oral prednisone twice a day. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Treatment-associated toxicity was the primary study end point; progression-free and overall survival were secondary end points. A descriptive statistical analysis was performed. RESULTS AND LIMITATIONS: Patients received a mean number of 6.5 ± 2.2 cycles of Cbz and a mean cumulative dose of 160.3 ± 51.5mg/m(2). Grade 3 and 4 treatment-emergent adverse events were recorded in 34 patients (30.6%) and 18 patients (16.2%), respectively. Grade 3/4 anaemia, neutropenia, and thrombocytopenia were reported in 4.5%, 7.2%, and 0.9% of the patients, respectively. Neutropenic fever was reported in 1.8% of the patients. Grade 3/4 gastrointestinal toxicity was identified in 4.5% of the patients. Three patients died because of Cbz-related toxicity. Granulocyte colony-stimulating growth factors were used in 17.1% of patients. The limitations are due to the nonrandomised nature of the trial. CONCLUSIONS: Treatment with Cbz is tolerable and is associated with a low incidence of serious adverse events in a real-world patient population with CRPC. The outcome of serious adverse events can be minimised with proactive treatment management and conscientious monitoring.

Urological surgery in patients with hemorrhagic bleeding disorders Hemophilia A, Hemophilia B, von Willebrand disease: a retrospective study with matched pairs analysis.

PURPOSE: To determine retrospectively the perioperative management and outcome of transurethral prostate/bladder surgery (TURP, TURB) and transrectal prostate biopsy in hemophiliacs. METHODS: Thirty-seven hemophilic patients underwent TURP (12 patients), TURB (13 patients), or transrectal prostate biopsy (12 patients) with proactive hemostaseological management (i.e., factor supply, close meshed hemostaseological analysis). Thirty-seven non-hemophiliac patients served as matched pairs who matched for age, gender, accompanying diseases, and the type of surgical procedure. The resulting pairs were analyzed for duration of surgery, hospital stay, and complications. RESULTS: Average TURP length in hemophiliacs was 77.92 min, in the matched pairs group TURP 67.08 min (p = 0.487). Mean TURB length in hemophiliacs was 43.46 min versus 35.38 min in controls (p = 0.678). More important, the length of hospital stay was significant longer in the hemophiliacs undergoing TURP compared to non-hemophiliac control group (12.08 days vs. 5.83 days; p < 0.001). In TURB patients, similar results were found (11.15 days hemophiliacs vs. 6.15 controls; p = 0.018). Regarding complications (bleeding, hemorrhage, readmission), no significant difference between the groups was obtained. CONCLUSION: Urological interventions in hemophiliac patients with factor supply have the same risk for postoperative complications as in non-hemophiliacs. The only significant difference between hemophiliacs and non-hemophiliacs was the length of hospital stay.

Clinical studies applying cytokine-induced killer cells for the treatment of renal cell carcinoma.

Metastatic renal cell carcinoma (RCC) seems to be resistant to conventional chemo- and radiotherapy and the general treatment regimen of cytokine therapy produces only modest responses while inducing severe side effects. Nowadays standard of care is the treatment with VEGF-inhibiting agents or mTOR inhibition; nevertheless, immunotherapy can induce complete remissions and long-term survival in selected patients. Among different adoptive lymphocyte therapies, cytokine-induced killer (CIK) cells have a particularly advantageous profile as these cells are easily available, have a high proliferative rate, and exhibit a high antitumor activity. Here, we reviewed clinical studies applying CIK cells, either alone or with standard therapies, for the treatment of RCC. The adverse events in all studies were mild, transient, and easily controllable. In vitro studies revealed an increased antitumor activity of peripheral lymphocytes of participants after CIK cell treatment and CIK cell therapy was able to induce complete clinical responses in RCC patients. The combination of CIK cell therapy and standard therapy was superior to standard therapy alone. These studies suggest that CIK cell immunotherapy is a safe and competent treatment strategy for RCC patients and further studies should investigate different treatment combinations and schedules for optimal application of CIK cells.

Enhanced expression of peroxisome proliferate-activated receptor gamma (PPAR-γ) in advanced prostate cancer.

BACKGROUND: Recent studies have underlined the role of nuclear receptors in the involvement of prostate cancer signalling pathways. PATIENTS AND METHODS: A total of 84 benign prostate hyperplasia (BPH), 84 low risk prostate cancer (LPC) and 64 advanced disease (APC) cases were sampled on a tissue microarray (TMA) and stained for retinoic acid receptor (RAR)-α, retionoid X receptor (RXR)-α, liver X receptor (LXR)-α, farnesoid X receptor (FXR) and proliferate-activated receptor gamma (PPAR)-γ and the (pro)-inflammatory molecules cyclooxygenase 2 (COX2), tumor necrosis factor (TNF)-α and inducible Nitric oxide synthase (iNOS) immunohistochemically. RESULTS: PPAR-γ expression in APC tissues was found to be significantly higher than that in LPC and BPH specimens (p<0.001). In contrast, RXR-a expression was significantly lower (p<0.001). COX2 staining demonstrated a trend towards overexpression in APC (p=0.025). No significant differences were found for RAR-α, iNOS and TNF-α expression. Staining of FXR and LXR was seen diffusely in the cytoplasm as well as in the nucleus, preventing sufficient evaluation by definition. CONCLUSION: This study provides the basis for applying PPAR-γ ligands clinically in treatment of APC.

Thulium laser (Revolix) vapoenucleation of the prostate is a safe procedure in patients with an increased risk of hemorrhage.

PURPOSE: To evaluate the feasibility and safety of thulium:yttrium-aluminium-garnet laser vapoenucleation of the prostate (ThuVEP) in patients with chronic anticoagulation and bleeding disorders. METHODS: We retrospectively analyzed the clinical data (transfusion rate, hemoglobin changes, residual urine, bleeding complications, complications and residual urine) of patients with chronic anticoagulation and bleeding disorders treated with ThuVEP. Anticoagulation was not paused for surgery. RESULTS: We identified 39 patients who fulfilled the inclusion criteria (32 with chronic anticoagulation, 3 with bleeding disorder, and 4 with both). Mean preoperative hemoglobin was 12.9 g/l; the postoperative hemoglobin was 11.7 g/l. One patient received a blood transfusion. Mean residual urine was 166 ml preoperatively and 47 ml postoperatively, respectively; spontaneous voiding postoperatively was feasible in 36 patients. During follow-up, 5 patients suffered from gross hematuria, which was treated conservatively. CONCLUSIONS: ThuVEP is a safe procedure in patients with therapeutic anticoagulation, bleeding disorders and platelet aggregation inhibitor medication.

Decreased levels of histone H3K9me1 indicate poor prognosis in patients with renal cell carcinoma.

BACKGROUND/AIM: To determine the role of global histone H3K9 and H4K20 methylation levels as prognostic parameters in patients with renal cell cancer (RCC). MATERIAL AND METHODS: Global histone methylation levels were investigated in 193 RCC (including 142 clear cell (cc), 31 papillary (p), 10 chromophobe (ch) and 10 sarcomatoid (s) RCC), 10 oncocytomas and 30 benign renal specimens. RESULTS: Histone modifications were mostly similar in the different histological subtypes (p>0.05); significant differences were observed for ccRCC vs. pRCC and pRCC vs. sRCC. Comparing the global H3K9 methylation levels of benign renal tissue with RCC H3K9me1 (histone H3 lysine 9 mono-methylation) (p<0.001), H3K9me2 (histone H3 lysine 9 di-methylation) (p=0.001) and H3K9me3 (histone H3 lysine 9 tri-methylation) (p<0.001) was significantly over-expressed in benign renal tissue. H3K9 and H4K20 methylation levels were positively correlated to pT-stage (p<0.005) and grading (p<0.05). In localized RCC (n=144), H3K9me1 levels showed a significant correlation with progression-free survival in the univariate model (p=0.034). CONCLUSION: Global histone methylation levels may help to identify RCC patients with poor prognosis.

Alterations of global histone H4K20 methylation during prostate carcinogenesis.

BACKGROUND: Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3) at different stages of prostate cancer (PCA) carcinogenesis. METHODS: Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113), non-malignant prostate disease (n = 27), metastatic hormone-naive PCA (mPCA, n = 30) and castration-resistant PCA (CRPC, n = 34). Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. RESULTS: Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. CONCLUSIONS: H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.

Global histone H3 lysine 27 (H3K27) methylation levels and their prognostic relevance in renal cell carcinoma.

OBJECTIVE: To evaluate if histone H3 lysine 27 (H3K27) methylation plays a role in renal cell carcinoma (RCC) tissue and whether its expression is a predictor of cancer recurrence in RCC. MATERIALS AND METHODS: A tissue microarray (TMA) with 193 RCC specimens (comprising 142 clear-cell, 31 papillary, 10 chromophobe and 10 sarcomatoid RCC), 10 oncocytoma tissue specimens and a TMA with 30 benign renal tissue samples were stained with antibodies against H3K27-monomethyl (H3K27me1), H3K27-dimethyl (H3K27me2) and H3K27-trimethyl (H3K27me3). Sections were scored according to staining intensity and the proportion of epithelial cells showing nuclear staining. H3K27 methylation levels were correlated with established clinical-pathological variables (tumour-node-metastasis [TNM] stage, Fuhrman grade) and progression-free/cancer-specific survival. RESULTS: H3K27me1/-me2/-me3 staining was significantly more intense in papillary RCC then in clear-cell RCC. H3K27me3 levels were higher in oncocytoma than in RCC. H3K27me1/-me2/-me3 methylation levels were inversely correlated with Fuhrman grading and pT-stage. Global H3K27me1/-me2/-me3 methylation levels were always higher in benign renal tissue than in RCC with tumour relapse (H3K27me1 P < 0.001, H3K27me2 P= 0.032, H3K27me3 P= 0.004). Progression-free survival was shorter in patients with lower levels of H3K27me1 and H3K27me3 in the univariate analysis. The newly created H3K27me score (combining the staining levels of the single modifications) was a significant and independent predictor of RCC progression-free survival. CONCLUSION: The present study on H3K27-methylation supports the hypothesis that global histone modifications are potential markers of cancer prognosis in RCC. One reason could be that decreased H3K27 indicates transcriptional activation and therefore predicts cancer activation.

Global histone H3K27 methylation levels are different in localized and metastatic prostate cancer.

Global histone modification patterns have been shown to be a predictive factor of recurrence in various cancers. We analyzed global histone-3-lysine-27 (H3K27) methylation in prostate cancer (PCA) tissues. H3K27 mono-, di-, and tri-methylation patterns were different in nonmalignant prostate tissue, localized PCA, metastatic PCA, and castration-resistant PCA. H3K27 mono-methylation was correlated with pT-stage, capsular penetration, seminal vesicle infiltration, and Gleason score in localized PCA and may therefore indicate adverse prognosis.

Genes differentially expressed in the peripheral zone compared to the transitional zone of the normal human prostate and their potential regulation by ETS factors.

Prostate cancer (PCa) is a clinically heterogeneous and multifocal disease with a clinical outcome that is difficult to predict. Notably, predisposition to develop prostate cancer is different among the prostate zones, with the peripheral zone (PZ) or prostate proper as the most frequent site compared to the transitional zone (TZ). Translocations between the TMPRSS2 gene and a number of members of the ETS family are frequently found in PCa. Here, we examined expression differences among the two zones by laser microdissection of normal tissues from PCa patients to separate glands from stroma, and investigated the gene expression differences in the glands of the PZ compared to those of the TZ using microarray analysis. We identified 9 genes involved in the so-called metastatic cascade, to be highly differentially expressed in the normal glands of the PZ compared to those of the TZ. The genes which were found to be up-regulated in the PZ compared to the TZ are commonly up-regulated in tumors. These findings may explain the lower susceptibility for PCa of the TZ compared to the PZ. According to bioinformatic analysis, 8/9 of these genes may be potentially regulated by ETS transcription factors.

The peripheral zone of the prostate is more prone to tumor development than the transitional zone: is the ETS family the key?

Predisposition to develop prostate cancer (PCA) varies among the prostate zones, with the peripheral zone (PZ) more prone to tumor development than the transitional zone (TZ). In view of the fact that molecular differences between the zones may explain this difference, combined with the findings that translocations between TMPRSS2 and several ETS members are frequently observed in PCA, we hypothesized that the ETS family may be crucial to explaining this difference. Normal tissues from the PZ and the TZ of 20 PCA patients were laser microdissected to separate glands from stroma. Two oligo microarrays were performed in order to investigate the variation in ETS family gene expression between the glands and the stroma of the two zones. The ETS members, ELF-3, ELF-5, ERG, ETV-1, ETV-4, ETV-5, ETV-7 and FEV, were found to be differentially expressed. A striking observation was that ERG and ETV-1 were found to be up-regulated in the glands of the PZ compared to the TZ, particularly when considering that ERG and ETV-1 fusions account for 50-80% and 20% of PCA occurrences, respectively. These results indicate that the glands and stroma of the two zones display distinct molecular differences and zonal-specific expression of ETS members. Furthermore, ETS members up-regulated in PCA are already overexpressed in the normal PZ, suggesting that these members play a role in the development and progression of PCA.