Anders Angelsen

Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial.

BACKGROUND Several studies have shown the efficacy of endocrine therapy in combination with radiotherapy in high-risk prostate cancer. To assess the effect of radiotherapy, we did an open phase III study comparing endocrine therapy with and without local radiotherapy, followed by castration on progression. METHODS This randomised trial included men from 47 centres in Norway, Sweden, and Denmark. Between February, 1996, and December, 2002, 875 patients with locally advanced prostate cancer (T3; 78%; PSA<70; N0; M0) were centrally randomly assigned by computer to endocrine treatment alone (3 months of total androgen blockade followed by continuous endocrine treatment using flutamide; 439 patients), or to the same endocrine treatment combined with radiotherapy (436 patients). The primary endpoint was prostate-cancer-specific survival, and analysis was by intention to treat. This study is registered as an international standard randomised controlled trial, number ISRCTN01534787. FINDINGS After a median follow-up of 7.6 years, 79 men in the endocrine alone group and 37 men in the endocrine plus radiotherapy group had died of prostate cancer. The cumulative incidence at 10 years for prostate-cancer-specific mortality was 23.9% in the endocrine alone group and 11.9% in the endocrine plus radiotherapy group (difference 12.0%, 95% CI 4.9-19.1%), for a relative risk of 0.44 (0.30-0.66). At 10 years, the cumulative incidence for overall mortality was 39.4% in the endocrine alone group and 29.6% in the endocrine plus radiotherapy group (difference 9.8%, 0.8-18.8%), for a relative risk of 0.68 (0.52-0.89). Cumulative incidence at 10 years for PSA recurrence was substantially higher in men in the endocrine-alone group (74.7%vs 25.9%, p<0.0001; HR 0.16; 0.12-0.20). After 5 years, urinary, rectal, and sexual problems were slightly more frequent in the endocrine plus radiotherapy group. INTERPRETATION In patients with locally advanced or high-risk local prostate cancer, addition of local radiotherapy to endocrine treatment halved the 10-year prostate-cancer-specific mortality, and substantially decreased overall mortality with fully acceptable risk of side-effects compared with endocrine treatment alone. In the light of these data, endocrine treatment plus radiotherapy should be the new standard.

Neuroendocrine differentiation in carcinomas of the prostate. Do neuroendocrine serum markers reflect immunohistochemical findings

The aim of the present study was to examine the correlation between the immunohistochemical findings and the serum markers for neuroendocrine (NE) cells in patients with carcinoma of the prostate. Preoperative serum values of chromogranin A (CgA), chromogranin B (CgB), pancreastatin (Pst), neuron‐specific enolase (NSE), and prostatic specific antigen (PSA) were determined in 22 patients. The tissue specimens were obtained by a palliative transurethral resection of the prostate (TURP) because of urinary outflow obstruction. Immunohistochemistry was performed by using antibodies against CgA, CgB, NSE, serotonin, thyroid‐stimulating hormone (TSH), and somatostatin. Tumor cells with NE differentiation were found in 91% of the cases. No patient had elevated serum values of NSE, despite the presence of NSE‐positive tumor cells in 77% of the tumors. Neither did CgB in serum correlate with the immunohistochemical findings. Elevated serum values of CgA were found in 59% of patients. A positive correlation between the number of CgA‐staining cells and the serum values of CgA was found, as seven out of eight patients with groups of CgA‐positive tumor cells had elevated serum values of CgA. We conclude that CgA, in contrast to NSE, CgB, and Pst, seems to be a useful serum marker in predicting the extent of NE differentiation in prostatic tumors. Prostate 30:1–6, 1997

Frequency of lymphoceles after open and laparoscopic pelvic lymph node dissection in patients with prostate cancer.

OBJECTIVE To compare the frequencies of pelvic lymphocele formation after laparoscopic and open pelvic lymph node dissection in patients with prostate cancer. MATERIAL AND METHODS A total of 132 patients operated on with pelvic lymph node dissection (PLND) underwent CT scanning of the abdomen and pelvis at a median of 29 days postoperatively. Open pelvic lymph node dissection (OPLND) was performed in 94 patients (71%) and 38 patients (29%) were operated on using a laparoscopic technique (LPLND). The frequency and size of pelvic lymphoceles were registered. Lymphoceles with a horizontal diameter of </=4.9 cm were classified as small and those with a horizontal diameter of >/=5.0 cm were classified as large. RESULTS The overall frequency of lymphoceles was 54%. The frequencies in the OPLND and LPLND groups were 61% and 37%, respectively. A total of 27% of the OPLND patients had large lymphoceles, compared to 8% of the LPLND patients. Three patients (2.3%), all in the OPLND group, had clinically significant lymphoceles. CONCLUSIONS Although the overall frequency of lymphocele formation was high, clinically significant lymphoceles were scarce. LPLND was associated with a statistically significant lower frequency of lymphocele formation compared to OPLND.

Does Physiotherapist-Guided Pelvic Floor Muscle Training Reduce Urinary Incontinence After Radical Prostatectomy?: A Randomised Controlled Trial

BACKGROUND Urinary incontinence after radical prostatectomy (RP) is a common problem and may lead to reduced quality of life. OBJECTIVE To assess the effects of guided pelvic floor muscle training on continence status and perceived problems with urinary function after RP. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomised controlled trial at St. Olavs Hospital/Trondheim University Hospital in Norway between September 2005 and December 2007. All men with clinically localised prostate cancer who underwent surgery with open RP were invited to participate, until 85 participants were included. Dropout rate was 6%. INTERVENTION Two intervention groups (A and B). Both groups received instructions in correct pelvic floor muscle contractions and were encouraged to train the pelvic floor muscles. Group A was offered additional follow-up training instructions by a physiotherapist throughout the 1-yr period. MEASUREMENTS Primary outcome was continence (0 pads) status, and secondary outcomes were perceived problems with urinary function 6 wk and 3, 6, and 12 mo postoperatively. RESULTS No statistically significant difference in continence status between groups was found at 3 mo; 46% were continent in group A versus 43% in group B (p=0.73). In group A, 97% reported no or only mild problems with urinary function compared to 78% in group B (p=0.010). After 6 mo there was a clinically relevant difference in continence status between groups: 79% were continent in group A and 58% in group B (p=0.061). Twelve months postsurgery the difference was clinically and statistically significant (p=0.028) in favour of group A; 92% were continent in group A and 72% in group B. CONCLUSIONS Continence rates were similar 3 mo after RP in groups performing intensive pelvic floor muscle training with or without follow-up instructions by a physiotherapist. However, in the following period up to 1 yr, the group receiving physiotherapist-guided training reduced urinary incontinence significantly more compared to patients training on their own.

Spermine and Citrate as Metabolic Biomarkers for Assessing Prostate Cancer Aggressiveness

Separating indolent from aggressive prostate cancer is an important clinical challenge for identifying patients eligible for active surveillance, thereby reducing the risk of overtreatment. The purpose of this study was to assess prostate cancer aggressiveness by metabolic profiling of prostatectomy tissue and to identify specific metabolites as biomarkers for aggressiveness. Prostate tissue samples (n = 158, 48 patients) with a high cancer content (mean: 61.8%) were obtained using a new harvesting method, and metabolic profiles of samples representing different Gleason scores (GS) were acquired by high resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS). Multivariate analysis (PLS, PLS-DA) and absolute quantification (LCModel) were used to examine the ability to predict cancer aggressiveness by comparing low grade (GS = 6, n = 30) and high grade (GS≥7, n = 81) cancer with normal adjacent tissue (n = 47). High grade cancer tissue was distinguished from low grade cancer tissue by decreased concentrations of spermine (p = 0.0044) and citrate (p = 7.73·10−4), and an increase in the clinically applied (total choline+creatine+polyamines)/citrate (CCP/C) ratio (p = 2.17·10−4). The metabolic profiles were significantly correlated to the GS obtained from each tissue sample (r = 0.71), and cancer tissue could be distinguished from normal tissue with sensitivity 86.9% and specificity 85.2%. Overall, our findings show that metabolic profiling can separate aggressive from indolent prostate cancer. This holds promise for the benefit of applying in vivo magnetic resonance spectroscopy (MRS) within clinical MR imaging investigations, and HR-MAS analysis of transrectal ultrasound-guided biopsies has a potential as an additional diagnostic tool.

Peripheral zone prostate cancer localization by multiparametric magnetic resonance at 3 T: unbiased cancer identification by matching to histopathology.

ObjectivesThe aim of this study was to assess the diagnostic accuracy of peripheral zone prostate cancer localization by multiparametric magnetic resonance (MR) at 3 T using segmental matching of histopathology and MR images to avoid bias by image features in selection of cancer and noncancer regions. Materials and MethodsForty-eight patients underwent multiparametric MR imaging (MRI) on a 3 T system using a phased array body coil and spine coil elements for signal detection before prostatectomy. The examination included T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), dynamic contrast-enhanced imaging (DCE-MRI), and MR spectroscopic imaging (MRSI). Histopathology slides were correlated to T2W images and a stringent matching procedure was performed to define cancer and noncancer areas of the peripheral zone without influence of the MR image appearance. Mean T2W signal intensity, apparent diffusion coefficient, area under the enhancement curve, and choline + creatine-to-citrate signal ratio were calculated for cancer and noncancer areas. Receiver operating characteristic (ROC) analysis was performed on MR-derived parameters from the selected areas. Logistic regression was used to create models based on best combination of parameters. A simplified approach assigning a parametric score to each segment based on cutoff values from ROC analysis was also explored. ResultsBy using the stringent matching procedure, 138 noncancer and 41 cancer segments were selected in the T2W images and transferred to the images of the other MR methods. A significant difference between mean values in cancer and noncancer segments was observed for all MR parameters analyzed (P < 0.001). Apparent diffusion coefficient was the best performing single parameter, with an area under the ROC curve Az,DWI of 0.90 for prostate cancer detection. Any combination of T2WI, DWI, and DCE-MRI was significantly better than T2WI alone in separating cancer from noncancer segments (Az,T2WI + DWI + DCE-MRI = 0.94, Az,T2WI + DWI = 0.92, Az,T2WI + DCE-MRI = 0.91, Az,T2WI = 0.85). The combination of T2WI and MRSI was also better than T2WI alone (Az, T2WI + MRSI = 0.90); however, the logistic regression models including MRSI did not have significant parameters. The simplified approach combining all parameters gave similar results to logistic regression combining all parameters (Az = 0.95 and 0.97, respectively). ConclusionBy selecting histopathology defined cancer and noncancer areas without influence of image contrast, this study objectively reveals that all investigated MR parameters have the ability to separate cancer from noncancer areas in the peripheral zone individually and that any combination is better than T2WI alone.

Use of neuroendocrine serum markers in the follow‐up of patients with cancer of the prostate

Neuroendocrine (NE) differentiation of prostatic adenocarcinomas has received increasing attention in recent years as a result of possible implications on prognosis and therapy. The incidence of NE cells in tumors has been reported from 10% up to 100%. Several studies have shown chromogranin A (CgA) to be the most reliable serum marker of NE differentiation. We have followed 22 patients with prostatic adenocarcinoma over a 2‐year period. The patients underwent a palliative transurethral resection of the prostate (TURP) because of urinary outflow obstruction. The prostatic tissue specimens were stained immunohistochemically using antibodies against CgA, chromogranin B (CgB), neuron‐specific enolase (NSE), thyroid‐stimulating hormone (TSH), serotonin, and somatostatin. In addition, each specimen was stained with hematoxylin & eosin (H & E), and saffran for tumor grading. Blood samples were taken preoperatively and after 1, 3, 6, and 24 months. The serum values of CgA, CgB, pancreastatin (Pst), NSE, and prostate‐specific antigen (PSA) were determined from each sample. Carcinomas with groups of CgA‐positive cells had higher serum levels of CgA compared to carcinomas with no or only scattered CgA‐positive NE cells. During the 2‐year period, there were no statistical significant variations in serum levels of CgA, NSE, Pst, and PSA. However, there was a significant increase in serum levels of CgB during the same period. P = 0.002, possibly due to an increase in number of NE cells in tumor or to a relative increase in production of CgB in the NE cells. Prostate 31:110–117, 1997.

Changes in Gene Transcription Underlying the Aberrant Citrate and Choline Metabolism in Human Prostate Cancer Samples

Purpose: Low concentrations of citrate and high concentrations of choline-containing compounds (ChoCC) are metabolic characteristics observed by magnetic resonance spectroscopy of prostate cancer tissue. The objective was to investigate the gene expression changes underlying these metabolic aberrations to find regulatory genes with potential for targeted therapies. Experimental design: Fresh frozen samples (n = 133) from 41 patients undergoing radical prostatectomy were included. Histopathologic evaluation was carried out for each sample before a metabolic profile was obtained with high-resolution magic angle spinning (HR-MAS) spectroscopy. Following the HR-MAS, RNA was extracted from the same sample and quality controlled before carrying out microarray gene expression profiling. A partial least square statistical model was used to integrate the data sets to identify genes whose expression show significant covariance with citrate and ChoCC levels. Results: Samples were classified as benign, n = 35; cancer of low grade (Gleason score 6), n = 24; intermediate grade (Gleason score 7), n = 41; or high grade (Gleason score ≥8), n = 33. RNA quality was high with a mean RNA Integrity Number score of 9.1 (SD 1.2). Gene products predicting significantly a reduced citrate level were acetyl citrate lyase (ACLY, P = 0.003) and m-aconitase (ACON, P < 0.001). The two genes whose expression most closely accompanied the increase in ChoCC were those of phospholipase A2 group VII (PLA2G7, P < 0.001) and choline kinase α (CHKA, P = 0.002). Conclusions: By integrating histologic, transcriptomic, and metabolic data, our study has contributed to an expanded understanding of the mechanisms underlying aberrant citrate and ChoCC levels in prostate cancer. Clin Cancer Res; 18(12); 3261–9. ©2012 AACR.

Neuroendocrine cells in the prostate of the rat, guinea pig, cat, and dog

The neuroendocrine (NE) cells in the human prostate gland probably have a local regulatory role in both prostatic growth and differentiation as well as in the exocrine secretory process. Moreover, NE cells may be involved in the pathogenesis of both prostatic cancer and hyperplasia. To enhance the knowledge of the physiological and pathophysiological role of NE cells in the prostate gland, we wanted to establish an experimental animal model.

A New Method to Provide a Fresh Frozen Prostate Slice Suitable for Gene Expression Study and MR Spectroscopy

Fresh frozen tissue from radical prostatectomy specimens is highly valuable material for research on gene expression and cellular metabolites. The purpose of this study was to develop a standardized method to provide a representative high quality research sample from radical prostatectomy specimens without interfering with the routine histopathological procedure.