Microvascular proliferation is associated with high tumour blood flow by mpMRI and disease progression in primary prostate cancer.

Active angiogenesis may be assessed by immunohistochemistry using Nestin, a marker of newly formed vessels, combined with Ki67 for proliferating cells. Here, we studied microvascular proliferation by Nestin-Ki67 co-expression in prostate cancer, focusing on relations to quantitative imaging parameters from anatomically matched areas obtained by preoperative mpMRI, clinico-pathological features and prognosis. Tumour slides from 67 patients (radical prostatectomies) were stained for Nestin-Ki67. Proliferative microvessel density (pMVD) and presence of glomeruloid microvascular proliferation (GMP) were recorded. From mpMRI, forward volume transfer constant (Ktrans), reverse volume transfer constant (kep), volume of EES (ve), blood flow, and apparent diffusion coefficient (ADC) were obtained. High pMVD was associated with high blood flow (p = 0.008) and low ADC (p = 0.032). High Ktrans, kep, and blood flow were associated with high Gleason score. High pMVD, GMP, and low ADC were associated with most adverse clinico-pathological factors. Regarding prognosis, high pMVD, Ktrans, kep, and low ADC were associated with reduced biochemical recurrence-free- and metastasis-free survival (p ≤ 0.044) and high blood flow with reduced time to biochemical- and clinical recurrence (p < 0.026). In multivariate analyses however, microvascular proliferation was a stronger predictor compared with blood flow. Indirect, dynamic markers of angiogenesis from mpMRI and direct, static markers of angiogenesis from immunohistochemistry may aid in the stratification and therapy planning of prostate cancer patients.

PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression.

The progression of cancer from localized to metastatic disease is the primary cause of morbidity and mortality. The interplay between the tumor and its microenvironment is the key driver in this process of tumor progression. In order for tumors to progress and metastasize they must reprogram the cells that make up the microenvironment to promote tumor growth and suppress endogenous defense systems, such as the immune and inflammatory response. We have previously demonstrated that stimulation of Tsp-1 in the tumor microenvironment (TME) potently inhibits tumor growth and progression. Here, we identify a novel tumor-mediated mechanism that represses the expression of Tsp-1 in the TME via secretion of the serine protease PRSS2. We demonstrate that PRSS2 represses Tsp-1, not via its enzymatic activity, but by binding to low-density lipoprotein receptor-related protein 1 (LRP1). These findings describe a hitherto undescribed activity for PRSS2 through binding to LRP1 and represent a potential therapeutic strategy to treat cancer by blocking the PRSS2-mediated repression of Tsp-1. Based on the ability of PRSS2 to reprogram the tumor microenvironment, this discovery could lead to the development of therapeutic agents that are indication agnostic.

The epithelial-mesenchymal transition regulators Twist, Slug, and Snail are associated with aggressive tumour features and poor outcome in prostate cancer patients.

The prognostic importance of transcription factors promoting epithelial-mesenchymal transition (EMT) and angiogenesis has not been well explored in prostate cancer patients with long follow-up, nor the interplay between these factors. The objective of this study was to assess the individual protein expression and co-expression of Twist, Slug (Snai2), Snail (Snai1), and hypoxia-inducible factor-1 alpha (Hif-1α) in prostate cancer in relation to EMT, angiogenesis, hypoxia, tumour features, disease recurrence, and patient survival. Immunohistochemical staining was performed on tissue microarray sections from 338 radical prostatectomies with long follow-up. In addition, 41 cases of prostatic hyperplasia, 33 non-skeletal metastases, 13 skeletal metastases, and 33 castration-resistant prostate carcinomas were included. Our findings were validated in external gene expression data sets. Twist was overexpressed in primary prostate cancer and markedly reduced in distant metastases (p < 0.0005). Strong expression of Twist and Slug was associated with Hif-1α in localised prostate cancer (p ≤ 0.001), and strong Twist was associated with Hif-1α in castration-resistant carcinomas (p = 0.044). Twist, Slug, and increased Snail at the tumour stromal border were associated with vascular factors (p ≤ 0.045). Each of the three EMT-regulating transcription factors were associated with aggressive tumour features and shorter time to recurrence and cancer-specific death. Notably, the co-expression of factors demonstrated an enhanced influence on outcome. In the subgroup of E-cadherinlow carcinomas, strong Slug was associated with shorter time to all end points and was an independent predictor of time to multiple end points, including cancer-specific death (hazard ratio 3.0, p = 0.041). To conclude, we demonstrate an important relation between EMT, hypoxia, and angiogenesis and a strong link between the investigated EMT regulators and aggressive tumour features and poor patient outcome in prostate cancer. Despite the retrospective nature of this long-term study, our findings could have a significant impact on the future treatment of prostate cancer, where tailored therapies might be directed simultaneously against epithelial-mesenchymal phenotypes, angiogenesis, and tumour hypoxia.

FOXC2 expression and epithelial-mesenchymal phenotypes are associated with castration resistance, metastasis and survival in prostate cancer.

Epithelial-mesenchymal transition (EMT) is important for tumour cell invasion and metastasis and is a feature of aggressive carcinomas. EMT is characterised by reduced E-cadherin and increased N-cadherin expression (EN-switch), and increased expression of the EMT-regulating transcription factor Forkhead box protein C2 (FOXC2) has been associated with progression and poor prognosis in various malignancies. FOXC2 was recently highlighted as a novel therapy target in prostate cancer, but survival data on FOXC2 are lacking. This study evaluates the expression of FOXC2, E-cadherin and N-cadherin in different prostatic tissues focusing on EMT, clinico-pathological phenotype, recurrence and patient survival. Tissue microarray sections from 338 radical prostatectomies (1986-2007) with long and complete follow-up, 33 castration resistant prostate cancers, 33 non-skeletal metastases, 13 skeletal metastases and 41 prostatic hyperplasias were stained immunohistochemically for FOXC2, E-cadherin and N-cadherin. FOXC2 was strongly expressed in primary carcinomas, including castration resistant tumours and metastatic lesions as compared to benign prostatic hyperplasia. A hybrid epithelial-mesenchymal phenotype, with co-expression of E-cadherin and N-cadherin, was found in the majority of skeletal metastases and in a substantial proportion of castration resistant tumours. In localised carcinomas, the EN-switch was associated with adverse clinico-pathological variables, such as extra-prostatic extension, high pathological stage and lymph node infiltration. In univariate survival analyses of the clinically important, large subgroup of 199 patients with Gleason score 7, high FOXC2 expression and EN-switching were significantly associated with shorter time to clinical recurrence, skeletal metastases and cancer specific death. In multivariate Cox' survival analysis, high FOXC2 and the EN-switch, together with Gleason grade group (GG3 versus GG2), were independent predictors of time to these end-points. High FOXC2 gene expression (mRNA) was also related to patient outcome, validating our immunohistochemical findings. FOXC2 and factors signifying EMT or its intermediate states may prove important as biomarkers for aggressive disease and are potential novel therapy targets in prostate cancer.

Optimising preoperative risk stratification tools for prostate cancer using mpMRI.

PURPOSE: To improve preoperative risk stratification for prostate cancer (PCa) by incorporating multiparametric MRI (mpMRI) features into risk stratification tools for PCa, CAPRA and D'Amico. METHODS: 807 consecutive patients operated on by robot-assisted radical prostatectomy at our institution during the period 2010-2015 were followed to identify biochemical recurrence (BCR). 591 patients were eligible for final analysis. We employed stepwise backward likelihood methodology and penalised Cox cross-validation to identify the most significant predictors of BCR including mpMRI features. mpMRI features were then integrated into image-adjusted (IA) risk prediction models and the two risk prediction tools were then evaluated both with and without image adjustment using receiver operating characteristics, survival and decision curve analyses. RESULTS: 37 patients suffered BCR. Apparent diffusion coefficient (ADC) and radiological extraprostatic extension (rEPE) from mpMRI were both significant predictors of BCR. Both IA prediction models reallocated more than 20% of intermediate-risk patients to the low-risk group, reducing their estimated cumulative BCR risk from approximately 5% to 1.1%. Both IA models showed improved prognostic performance with a better separation of the survival curves. CONCLUSION: Integrating ADC and rEPE from mpMRI of the prostate into risk stratification tools improves preoperative risk estimation for BCR. KEY POINTS: • MRI-derived features, ADC and EPE, improve risk stratification of biochemical recurrence. • Using mpMRI to stratify prostate cancer patients improves the differentiation between risk groups. • Using preoperative mpMRI will help urologists in selecting the most appropriate treatment.

A positive Real-Time Elastography (RTE) combined with a Prostate Cancer Gene 3 (PCA3) score above 35 convey a high probability of intermediate- or high-risk prostate cancer in patient admitted for primary prostate biopsy.

BACKGROUND: The standard of care in patients with suspected prostate cancer (PCa) is systematic prostate biopsies. This approach leads to unnecessary biopsies in patients without PCa and also to the detection of clinical insignificant PCa. Better tools are wanted. We have evaluated the performance of real-time elastography (RTE) combined with prostate cancer gene 3 (PCA3) in an initial biopsy setting with the goal of better identifying patients in need of prostate biopsies. METHODS: 127 patients were included in this study; three were excluded because of not measureable PCA3 score leading to 124 evaluable patients. A cut-off value of 35 was used for PCA3. All patients were examined with a Hitachi Preirus with an endfire probe for RTE, a maximum of five targeted biopsies were obtained from suspicious lesions detected by RTE. All patients then had a 10-core systematic biopsy performed by another urologist unaware of the RTE results. The study includes follow-up data for a minimum of three years; all available histopathological data are included in the analysis. RESULTS: There was a significant difference in PCA3 score: 26.6 for benign disease, 73.6 for cancer patients (p < 0.001). 70 patients (56 %) were diagnosed with prostate cancer in the study period, 21 (30 %) low-risk, 32 (46 %) intermediate-risk and 17 (24 %) high-risk. RTE and PCA3 were significant markers for predicting intermediate- and high-risk PCa (p = 0.001). The combination of RTE and PCA3 had a sensitivity of 96 % and a negative predictive value (NPV) of 90 % for the group of intermediate- and high-risk PCa together and a NPV for high-risk PCa of 100 %. If both parameters are positive there is a high probability of detecting intermediate- or high-risk PCa, if both parameters are negative there is only a small chance of missing prostate cancer with documented treatment benefit. CONCLUSIONS: RTE and PCA3 may be used as pre-biopsy examinations to reduce the number of prostate biopsies.

Prostate cancer antigen-3 (PCA3) and PCA3-based nomograms in the diagnosis of prostate cancer: an external validation of Hansen's nomogram on a Norwegian cohort.

OBJECTIVE: The aim of this study was to test the ability of prostate cancer antigen-3 (PCA3) and Hansen's PCA3-based nomogram to predict prostate cancer (PCa) probability in a Norwegian cohort, with the goal of reducing unnecessary biopsies. MATERIAL AND METHODS: Altogether, 127 consecutive patients were recruited to this study at Haukeland University Hospital, Norway. Prostate-specific antigen (PSA), PCA3 score, digital rectal examination (DRE), prostate volume (Pvol) and age were determined. All patients had an extended 10-core biopsy. The performance of PCA3 score and Hansen's nomogram was tested. RESULTS: There were 124 evaluable patients. Among these, 59 patients had PCa on the initial biopsies. Mean PSA, PCA3 score and age were significantly higher and Pvol was significantly lower in patients with PCa. PCA3 scores of 35 and 21 led to a sensitivity of 71% and 81% and specificity of 72% and 55%, respectively. Hansen's nomogram gave an area under the curve (AUC) of 0.806. The intraclass correlation was 0.959 (Cronbach's alpha). Applied to this material, PCa would be missed in 15.2% of patients when applying the suggested threshold probability of 30%, among whom 66.7% had high-grade PCa. With a threshold probability of 20% only one patient had PCa and this was low grade. CONCLUSIONS: Hansen's PCA3-based nomogram is valid for this cohort. A threshold probability of 20% seems more adequate than 30% for this less screened cohort. PCA3 score only affects the biopsy indication in some patients and is recommended only for this subset. The results need to be confirmed in a larger study.

1.5-T multiparametric MRI using PI-RADS: a region by region analysis to localize the index-tumor of prostate cancer in patients undergoing prostatectomy.

BACKGROUND: The use of multiparametric magnetic resonance imaging (mpMRI) to detect and localize prostate cancer has increased in recent years. In 2010, the European Society of Urogenital Radiology (ESUR) published guidelines for mpMRI and introduced the Prostate Imaging Reporting and Data System (PI-RADS) for scoring the different parameters. PURPOSE: To evaluate the reliability and diagnostic performance of endorectal 1.5-T mpMRI using the PI-RADS to localize the index tumor of prostate cancer in patients undergoing prostatectomy. MATERIAL AND METHODS: This institutional review board IRB-approved, retrospective study included 63 patients (mean age, 60.7 years, median PSA, 8.0). Three observers read mpMRI parameters (T2W, DWI, and DCE) using the PI-RADS, which were compared with the results from whole-mount histopathology that analyzed 27 regions of interest. Inter-observer agreement was calculated as well as sensitivity, specificity, positive predictive value (PPV), and negative predicted value (NPV) by dichotomizing the PI-RADS criteria scores ≥3. A receiver-operating curve (ROC) analysis was performed for the different MR parameters and overall score. RESULTS: Inter-observer agreement on the overall score was 0.41. The overall score in the peripheral zone achieved sensitivities of 0.41, 0.60, and 0.55 with an NPV of 0.80, 0.84, and 0.83, and in the transitional zone, sensitivities of 0.26, 0.15, and 0.19 with an NPV of 0.92, 0.91, and 0.92 for Observers 1, 2, and 3, respectively. The ROC analysis showed a significantly increased area under the curve (AUC) for the overall score when compared to T2W alone for two of the three observers. CONCLUSION: 1.5 T mpMRI using the PI-RADS to localize the index tumor achieved moderate reliability and diagnostic performance.

A positive real-time elastography is an independent marker for detection of high-risk prostate cancers in the primary biopsy setting.

OBJECTIVE: To evaluate the performance of real-time elastography (RTE) in an initial biopsy setting. PATIENTS AND METHODS: In the period from February 2011 to June 2012, 127 consecutive patients were included in the study. We used a Hitachi Preirus with Hi-RTE module, a prostate end-fire transrectal probe was used for RTE and for targeted biopsies, and a simultaneous biplane probe was used for the standard systematic biopsies. The peripheral zone of the prostate was divided into six regions, and each biopsy obtained was referred to a specific region. All patients were first examined with RTE and, if cancer was suspected, targeted biopsies were taken. A standard systematic 10-core biopsy was then taken in all patients. RESULTS: In all, 64 (50%) patients were diagnosed with prostate cancer in the initial biopsy setting. Three patients were diagnosed solely on RTE-targeted biopsies, 31 were found only in systematic biopsies, and 30 were correctly diagnosed with both methods. In the RTE-positive group there was a significantly higher frequency of positive cores, a lower prostate volume, a higher Gleason score, and a higher fraction of cancer tissue in each core. In a multiple regression model RTE was an independent marker for high-risk cancer. The sensitivity of 42% for all prostate cancers increased to 60% for high-grade prostate cancers. Similarly, the negative predictive value increased from 79% to 97%. An additional eight patients were diagnosed with prostate cancer during the study period. CONCLUSIONS: A positive RTE is an independent marker for detection of high-risk prostate cancer, and a negative RTE argues against such. RTE with targeted biopsies cannot replace systematic biopsies, but provides valuable additional information about the tumours.

Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1.

UNLABELLED: Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow-derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1(+) myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1(+) donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1(+) bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1(+) myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1(+) cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. SIGNIFICANCE: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow­derived Gr1+myeloid cells. A 5-amino acid peptide with Tsp-1­inducing activity was identified as a therapeutic agent against metastatic cancer.

Combination of real-time elastography and urine prostate cancer gene 3 (PCA3) detects more than 97% of significant prostate cancers.

OBJECTIVE: The prostate cancer gene 3 (PCA3) score in urine is a promising biomarker for prostate cancer. Real-time elastography (RTE) is a well-documented ultrasound modality. The objective of this study was to evaluate the ability to detect significant cancer foci in the prostate with these methods alone and in combination. MATERIAL AND METHODS: From September 2009 to September 2010, 40 patients planned for radical prostatectomy underwent a PCA3 urine test and RTE before operation. A Hitachi EUB-8500 with prostate end-fire transrectal probe was used. The PCA3 score was evaluated with a standard cut-off value of 35. RTE was evaluated in correlation with whole-mount section pathology. Three patients fulfilled the criteria for insignificant prostate cancer and were excluded from the study. RESULTS: The PCA3 score was increased in 26 patients (70%). RTE identified at least one tumour in 33 out of 37 patients (89%). RTE detected the largest tumour in 27 out of 37 patients (73%). More than one cancer was present in 29 patients and RTE identified more than one tumour in 13 of these. The RTE was false positive in four patients. The PCA3 score was increased in three out of four false-negative RTE patients. By combining both methods, 36 out of 37 patients (97%) with significant prostate cancer were detected. CONCLUSIONS: The combination of PCA3 score and RTE detected 97% of significant prostate cancers. The combinative use of RTE and PCA3 will be further investigated in an unselected series of men with suspected prostate cancer.

The expression of thrombospondin-1 and p53 in clear cell renal cell carcinoma: its relationship to angiogenesis, cell proliferation and cancer specific survival.

PURPOSE: We evaluated possible associations among thrombospondin-1, p53 expression, microvessel density, cell proliferation index, nuclear grade, tumor stage and continuously coded tumor size in clear cell renal cell carcinoma. The value of thrombospondin-1 as a prognostic marker in clear cell renal cell carcinoma was examined. MATERIALS AND METHODS: A total of 172 consecutive patients with clear cell renal cell carcinoma treated with radical nephrectomy were initially enrolled in the study. However, due to technical problems and lack of material 12 cases were excluded from analysis. A total of 68 patients (43%) died of renal cell carcinoma and 46 (29%) died of other diseases. Median followup for the surviving 42 patients (29%) was 13.8 years. The expression of thrombospondin-1, Ki-67 (proliferation index), p53 and microvessel density were analyzed without knowledge of the clinical outcome on formalin fixed, paraffin embedded tissues. RESULTS: Low expression of thrombospondin-1 was significantly associated with advanced stage (p <0.001), high nuclear grade (p = 0.001), positive p53 status (p <0.001), high proliferation index (p = 0.001), high microvessel density (p = 0.036) and tumor progression (p = 0.006). On univariate analysis thrombospondin-1, microvessel density, proliferation index, p53 over expression, TNM stage, Fuhrman nuclear grade (p <0.001) and continuously coded tumor size (p = 0.002) had a significant impact on survival. Multivariate analysis revealed TNM stage, thrombospondin-1, p53, Ki-67 (proliferation index) and microvessel density were independent predictors of cancer specific survival. CONCLUSIONS: Thrombospondin-1 expression is strongly associated with prognostic tumor features in clear cell renal cell carcinoma and is an independent prognostic factor for cancer specific survival. Our findings revealed a significant correlation among p53, proliferation index, microvessel density and thrombospondin-1 expression, and indicate that thrombospondin-1 may have an impact on angiogenesis, proliferation and tumor aggressiveness in clear cell renal cell carcinoma.

TMPRSS2:ERG fusion transcripts in urine from prostate cancer patients correlate with a less favorable prognosis.

The transcription factor ERG is highly upregulated in the majority of prostate cancers due to chromosomal fusion of the androgen responsive promoter of TMPRSS2 to the ERG reading frame. Our aim was to identify this gene fusion in urine samples from prostate cancer patients prior to radical treatment and to compare fusion status with clinicopathological variables. Urine fractions from 55 patients (with and without prior prostatic massage) were analyzed for the presence of TMPRSS2:ERG isoforms using real-time qPCR. Sixty-nine percent of urine samples following prostatic massage were positive for TMPRSS2:ERG isoforms a or b, five out of which were positive for both, vs 24% of samples obtained without prior massage. Isoform a seems to be most prevalent and some patients may be positive for more than one fusion variant, reflecting the multifocality of prostate cancer. Prostatic massage prior to sampling, analysis of pelleted urine material and detection of cDNA provided the highest sensitivity. Positive statistical correlations were identified between TMPRSS2:ERG fusion and high s-PSA, pathological stage and Gleason score. Our findings contribute to the increasing elucidation of the role of TMPRSS2:ERG in the development of prostate cancer.

Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1.

Metastatic tumors can prepare a distant site for colonization via the secretion of factors that act in a systemic manner. We hypothesized that non- or weakly metastatic human tumor cells may act in an opposite fashion by creating a microenvironment in distant tissues that is refractory to colonization. By comparing cell lines with different metastatic potential, we have identified a tumor-secreted inhibitor of metastasis, prosaposin (Psap), which functions in a paracrine and endocrine fashion by stimulating the expression of thrombospondin-1 (Tsp-1) in fibroblasts present in both primary tumors and distant organs, doing so in a p53-dependent manner. Introduction of Psap in highly metastatic cells significantly reduced the occurrence of metastases, whereas inhibition of Psap production by tumor cells was associated with increased metastatic frequency. In human prostate cancer, decreased Psap expression was significantly associated with metastatic tumors. Our findings suggest that prosaposin, or other agents that stimulate p53 activity in the tumor stroma, may be an effective therapy by inhibition of the metastatic process.

Proliferation of immature tumor vessels is a novel marker of clinical progression in prostate cancer.

Nestin (neuroepithelial stem cell protein) is expressed in immature endothelial cells, and we here introduce coexpression of Nestin and Ki-67 as a novel angiogenesis marker on tissue sections. Including vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1alpha (HIF-1alpha) expression, we studied relation to disease progression in prostate cancer. Different patient series were included. Sections from 104 radical prostatectomies with long follow-up, 33 castration-resistant prostate cancers, 28 nonskeletal metastases, 13 skeletal metastases, and 41 benign prostatic hyperplasias were immunostained for Nestin/Ki-67, VEGF-A, and HIF-1alpha. Vascular proliferation by Nestin/Ki-67-positive vessels was counted within "hotspot" areas. Median vascular proliferation counts were 4- to 5-fold higher in castration-resistant prostate cancers and metastases versus localized cancers and prostatic hyperplasias (P < 0.0005). Among localized cancers, high vascular proliferation was significantly related to adverse clinicopathologic features and was a strong and independent predictor of biochemical failure (P < 0.005), clinical recurrence (P = 0.005), and skeletal metastasis (P = 0.025) in multivariate analysis. Castration-resistant cancers were characterized by reduced VEGF-A and increased HIF-1alpha expression, and vascular proliferation was associated with reduced patient survival in this group. Thus, vascular proliferation was of independent prognostic importance among prostate cancers. When compared with localized cancers, vascular proliferation was significantly increased in castration-resistant cases and metastatic lesions. The castration-resistant tumors exhibited weak VEGF-A but strong HIF-1alpha expression. These novel data might have an effect on clinical evaluation and treatment of prostate cancer patients.

Outcome in intermediate or high risk prostate cancer patients receiving radiation dose and hormone therapy.

BACKGROUND: To analyse the impact of radiation dose escalation and hormone treatment in prostate cancer patients according to risk groups. MATERIAL AND METHODS: Totally 494 prostate cancer patients received external beam radiation therapy, with or without androgen deprivation, between January 1990 and December 1999. The patients were divided into three risk groups, where the low risk group (stage T(1c), pretreatment prostate-specific antigen (PSA) level < or =10 ng/ml and WHO Grade 1) included 26 patients, the intermediate risk group (either stage T(2), PSA 10.1-20 ng/ml or WHO Grade 2) comprised 149 patients whereas the high-risk group (either stage T(3), PSA >20 ng/ml or WHO Grade 3) included 319 patients. RESULTS: In the intermediate risk group, the 5-years bNED rate was 92%, 69% and 61% after a radiation dose of 70 Gy, 66 Gy or 64 Gy, respectively (p < 0.001). In the high-risk group, the 5-year bNED rate was 79%, 69% and 34% for the same dose levels (p < 0.001). The 5-years CSS rates were not significantly different between the dose levels in the intermediate risk group while for the high-risk group it was 93%, 92% and 80% for the three dose levels (p < 0.001). Risk group and radiation doses were independent predictors of bNED, CSS and overall survival, for bNED also hormone treatment was independent predictors. CONCLUSION: Radiation dose is important for the outcome in intermediate and high risk prostate cancer patients. A dose of 70 Gy should be considered the minimal dose for these patients.

Genome-wide profiling of histone h3 lysine 4 and lysine 27 trimethylation reveals an epigenetic signature in prostate carcinogenesis.

BACKGROUND: Increasing evidence implicates the critical roles of epigenetic regulation in cancer. Very recent reports indicate that global gene silencing in cancer is associated with specific epigenetic modifications. However, the relationship between epigenetic switches and more dynamic patterns of gene activation and repression has remained largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Genome-wide profiling of the trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) was performed using chromatin immunoprecipitation coupled with whole genome promoter microarray (ChIP-chip) techniques. Comparison of the ChIP-chip data and microarray gene expression data revealed that loss and/or gain of H3K4me3 and/or H3K27me3 were strongly associated with differential gene expression, including microRNA expression, between prostate cancer and primary cells. The most common switches were gain or loss of H3K27me3 coupled with low effect on gene expression. The least prevalent switches were between H3K4me3 and H3K27me3 coupled with much higher fractions of activated and silenced genes. Promoter patterns of H3K4me3 and H3K27me3 corresponded strongly with coordinated expression changes of regulatory gene modules, such as HOX and microRNA genes, and structural gene modules, such as desmosome and gap junction genes. A number of epigenetically switched oncogenes and tumor suppressor genes were found overexpressed and underexpressed accordingly in prostate cancer cells. CONCLUSIONS/SIGNIFICANCE: This work offers a dynamic picture of epigenetic switches in carcinogenesis and contributes to an overall understanding of coordinated regulation of gene expression in cancer. Our data indicate an H3K4me3/H3K27me3 epigenetic signature of prostate carcinogenesis.

The prognostic relevance of interactions between venous invasion, lymph node involvement and distant metastases in renal cell carcinoma after radical nephrectomy.

BACKGROUND: To investigate a possible prognostic significance of interactions between lymph node invasion (LNI), synchronous distant metastases (SDM), and venous invasion (VI) adjusted for mode of detection, Eastern Cooperative Oncology Group performance status (ECOG PS), erythrocyte sedimentation rate (ESR) and tumour size (TS) in 196 patients with renal cell carcinoma treated with radical nephrectomy. METHODS: Median follow-up was 5.5 years (mean 6.9 years; range 0.01-19.4). The mode of detection, ECOG PS, ESR and TS were obtained from the patients' records. Vena cava invasion and distant metastases were detected by preoperative imaging. The surgical specimens were examined for pathological stage, LNI and VI. RESULTS: The univariate analyses showed significant impact of VI, LNI, SDM, ESR and TS (p < 0.001), as well as mode of detection (p = 0.003) and ECOG PS (p = 0.002) on cancer specific survival. In multivariate analyses LNI was significantly associated with survival only in patients without SDM or VI (p < 0.001) with a hazard ratio of 9.0. LNI lost its prognostic significance when SDM or VI was present. CONCLUSION: Our findings underline the prognostic importance of the status of the lymph nodes. LNI, SDM, ESR, and VI were independently associated with cancer specific survival after radical nephrectomy. LNI provided the strongest prognostic information for patients without SDM or VI whereas SDM and VI had strongest impact on survival when there was no nodal involvement.

Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5.

OBJECTIVE: To compare parenteral estrogen therapy in the form of high-dose polyestradiol phosphate (PEP; Estradurin) with combined androgen deprivation (CAD) in the treatment of prostate cancer patients with skeletal metastases. The aim of the study was to compare anticancer efficacy and adverse events, especially cardiovascular events. MATERIAL AND METHODS: In total, 910 eligible patients with T0-4, NX, M1, G1-3 prostate cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were randomized to treatment with either PEP 240 mg i.m. twice a month for 2 months and thereafter monthly, or flutamide (Eulexin) 250 mg t.i.d. per os in combination with either triptorelin (Decapeptyl) 3.75 mg i.m. per month or on an optional basis bilateral orchidectomy. RESULTS: At this final evaluation of the trial 855 of the 910 patients were dead. There was no difference between the treatment groups in terms of biochemical or clinical progression-free survival or in overall or disease-specific survival. There was no difference in cardiovascular mortality, but a significant increase in non-fatal cardiovascular events in the PEP arm (p<0.05) predominantly caused by an increase in ischemic heart and heart decompensation events. There were 18 grave skeletal events in the CAD group but none in the PEP group (p=0.001). CONCLUSIONS: PEP has an anticancer efficacy equal to CAD and does not increase cardiovascular mortality in metastasized patients, but carries a significant risk of non-fatal cardiovascular events, which should be balanced against the skeletal complications in the CAD group. It is feasible to use Estradurin in the primary or secondary endocrine treatment of metastasized patients without prominent cardiac risk factors and especially those with osteoporosis.