18F-Fluciclovine PET/MRI for preoperative lymph node staging in high-risk prostate cancer patients.

OBJECTIVE: To investigate the diagnostic potential of simultaneous 18F-fluciclovine PET/MRI for pelvic lymph node (LN) staging in patients with high-risk prostate cancer. METHODS: High-risk prostate cancer patients (n=28) underwent simultaneous 18F-fluciclovine PET/MRI prior to surgery. LNs were removed according to a predefined template of eight regions. PET and MR images were evaluated for presence of LN metastases according to these regions. Sensitivity/specificity for detection of LN metastases were calculated on patient and region basis. Sizes of LN metastases in regions with positive and negative imaging findings were compared with linear mixed models. Clinical parameters of PET-positive and -negative stage N1 patients were compared with the Mann-Whitney U test. RESULTS: Patient- and region-based sensitivity/specificity for detection of pelvic LN metastases was 40 %/87.5 % and 35 %/95.7 %, respectively, for MRI and 40 %/100 % and 30 %/100 %, respectively, for PET. LN metastases in true-positive regions were significantly larger than metastases in false-negative regions. PET-positive stage N1 patients had higher metastatic burden than PET-negative N1 patients. CONCLUSION: Simultaneous 18F-fluciclovine PET/MRI provides high specificity but low sensitivity for detection of LN metastases in high-risk prostate cancer patients. 18F-Fluciclovine PET/MRI scan positive for LN metastases indicates higher metastatic burden than negative scan. KEY POINTS: • 18F-Fluciclovine PET/MRI has high specificity for detection of lymph node metastasis. • 18F-Fluciclovine PET/MRI lacks sensitivity to replace ePLND. • 18F-Fluciclovine PET/MRI may be used to aid surgery and select adjuvant therapy. • 18F-Fluciclovine PET-positive patients have more extensive disease than PET-negative patients. • Size of metastatic lymph nodes is an important factor for detection.

Metabolic markers in blood can separate prostate cancer from benign prostatic hyperplasia.

BACKGROUND: An individualised risk-stratified screening for prostate cancer (PCa) would select the patients who will benefit from further investigations as well as therapy. Current detection methods suffer from low sensitivity and specificity, especially for separating PCa from benign prostatic conditions. We have investigated the use of metabolomics analyses of blood samples for separating PCa patients and controls with benign prostatic hyperplasia (BPH). METHODS: Blood plasma and serum samples from 29 PCa patient and 21 controls with BPH were analysed by metabolomics analysis using magnetic resonance spectroscopy, mass spectrometry and gas chromatography. Differences in blood metabolic patterns were examined by multivariate and univariate statistics. RESULTS: By combining results from different methodological platforms, PCa patients and controls were separated with a sensitivity and specificity of 81.5% and 75.2%, respectively. CONCLUSIONS: The combined analysis of serum and plasma samples by different metabolomics measurement techniques gave successful discrimination of PCa and controls, and provided metabolic markers and insight into the processes characteristic of PCa. Our results suggest changes in fatty acid (acylcarnitines), choline (glycerophospholipids) and amino acid metabolism (arginine) as markers for PCa compared with BPH.

Bilateral testicular germ cell tumors in patients treated for clinical stage I non-seminoma within two risk-adapted SWENOTECA protocols.

BACKGROUND: A contralateral tumor occurs in 3.5-5% of men diagnosed with testicular germ cell cancer (TGCC). Biopsy of the contralateral testis may detect intratubular germ cell neoplasia ITGCNU, a precursor of TGCC. Biopsy of the contralateral testis to detect ITGCNU is controversial. If adjuvant chemotherapy (ACT) protects against bilateral cancer is debated. MATERIAL AND METHODS: A total of 1003 patients with clinical stage I (CS I) non-seminomatous testicular germ cell cancer (NSGCT) were included in two prospective, population-based protocols. Fifteen patients were excluded. Treatment was either adjuvant chemotherapy (n = 494), or surveillance (n = 494). Contralateral testicular biopsy was recommended for all patients, but was performed only in 282 patients. In case of ITGCNU radiotherapy (RT) to 16 Gy was recommended. RESULTS: During a follow-up of 8.3 years, 31 (3.6%) patients developed contralateral TGCC. ITGCNU was detected in 3.2% (9/282) of biopsied patients. The incidence of bilateral TGCC was similar following ACT, 2.5% (11/494), and surveillance, 3.4% (13/494), p = 0.41. Young age was a risk factor for metachronous TGCC (HR 0.93; 95% CI 0.88-0.99, p = 0.02). In total 2.2% (6/273) of patients without ITGCNU in the biopsy developed contralateral TGCC. One irradiated patient developed contralateral cancer, and one developed contralateral tumor before RT was given. CONCLUSION: ACT did not reduce the incidence of contralateral TGCC. Young patients had the highest risk of developing contralateral TGCC. The proportion of false negatives biopsies was higher than reported in earlier trials, but this may in part be related to patient selection, single biopsies and lack of mandatory immunohistochemistry.

Identification of metabolites from 2D (1)H-(13)C HSQC NMR using peak correlation plots.

BACKGROUND: Identification of individual components in complex mixtures is an important and sometimes daunting task in several research areas like metabolomics and natural product studies. NMR spectroscopy is an excellent technique for analysis of mixtures of organic compounds and gives a detailed chemical fingerprint of most individual components above the detection limit. For the identification of individual metabolites in metabolomics, correlation or covariance between peaks in (1)H NMR spectra has previously been successfully employed. Similar correlation of 2D (1)H-(13)C Heteronuclear Single Quantum Correlation spectra was recently applied to investigate the structure of heparine. In this paper, we demonstrate how a similar approach can be used to identify metabolites in human biofluids (post-prostatic palpation urine). RESULTS: From 50 (1)H-(13)C Heteronuclear Single Quantum Correlation spectra, 23 correlation plots resembling pure metabolites were constructed. The identities of these metabolites were confirmed by comparing the correlation plots with reported NMR data, mostly from the Human Metabolome Database. CONCLUSIONS: Correlation plots prepared by statistically correlating (1)H-(13)C Heteronuclear Single Quantum Correlation spectra from human biofluids provide unambiguous identification of metabolites. The correlation plots highlight cross-peaks belonging to each individual compound, not limited by long-range magnetization transfer as conventional NMR experiments.

Disease-specific outcomes of radical prostatectomies in Northern Norway; a case for the impact of perineural infiltration and postoperative PSA-doubling time.

BACKGROUND: Prostate cancer is the most common male malignancy and a mayor cause of mortality in the western world. The impact of clinicopathological variables on disease related outcomes have mainly been reported from a few large US series, most of them not reporting on perineural infiltration. We therefore wanted to investigate relevant cancer outcomes in patients undergoing radical prostatectomy in two Norwegian health regions with an emphasis on the impact of perineural infiltration (PNI) and prostate specific antigen- doubling time (PSA-DT). METHODS: We conducted a retrospective analysis of 535 prostatectomy patients at three hospitals between 1995 and 2005 estimating biochemical failure- (BFFS), clinical failure- (CFFS) and prostate cancer death-free survival (PCDFS) with the Kaplan-Meier method. We investigated clinicopathological factors influencing risk of events using cox proportional hazard regression. RESULTS: After a median follow-up of 89 months, 170 patients (32%) experienced biochemical failure (BF), 36 (7%) experienced clinical failure and 15 (3%) had died of prostate cancer. pT-Stage (p = 0.001), preoperative PSA (p = 0.047), Gleason Score (p = 0.032), non-apical positive surgical margins (PSM) (p = 0.003) and apical PSM (p = 0.031) were all independently associated to BFFS. Gleason score (p = 0.019), PNI (p = 0.012) and non-apical PSM (p = 0.002) were all independently associated to CFFS while only PNI (P = 0.047) and subgroups of Gleason score were independently associated to PCDFS. After BF, patients with a shorter PSA-DT had independent and significant worse event-free survivals than patients with PSA-DT > 15 months (PSA-DT = 3-9 months, CFFS HR = 6.44, p < 0.001, PCDFS HR = 13.7, p = 0.020; PSA-DT < 3 months, CFFS HR = 11.2, p < 0.001, PCDFS HR = 27.5, p = 0.006). CONCLUSIONS: After prostatectomy, CFFS and PCDFS are variable, but both are strongly associated to Gleason score and PNI. In patients with BF, PSA-DT was most strongly associated to CF and PCD. Our study adds weight to the importance of PSA-DT and re-launches PNI as a strong prognosticator for clinically relevant endpoints.

Spatially matched in vivo and ex vivo MR metabolic profiles of prostate cancer -- investigation of a correlation with Gleason score.

MR metabolic profiling of the prostate is promising as an additional diagnostic approach to separate indolent from aggressive prostate cancer. The objective of this study was to assess the relationship between the Gleason score and the metabolic biomarker (choline + creatine + spermine)/citrate (CCS/C) measured by ex vivo high-resolution magic angle spinning MRS (HR-MAS MRS) and in vivo MRSI, and to evaluate the correlation between in vivo- and ex vivo-measured metabolite ratios from spatially matched prostate regions. Patients (n = 13) underwent in vivo MRSI prior to radical prostatectomy. A prostate tissue slice was snap-frozen shortly after surgery and the locations of tissue samples (n = 40) collected for ex vivo HR-MAS were matched to in vivo MRSI voxels (n = 40). In vivo MRSI was performed on a 3T clinical MR system and ex vivo HR-MAS on a 14.1T magnet. Relative metabolite concentrations were calculated by LCModel fitting of in vivo spectra and by peak integration of ex vivo spectra. Spearman's rank correlations (ρ) between CCS/C from in vivo and ex vivo MR spectra, and with their corresponding Gleason score, were calculated. There was a strong positive correlation between the Gleason score and CCS/C measured both in vivo and ex vivo (ρ = 0.77 and ρ = 0.69, respectively; p < 0.001), and between in vivo and ex vivo metabolite ratios from spatially matched regions (ρ = 0.67, p < 0.001). Our data indicate that MR metabolic profiling is a potentially useful tool for the assessment of cancer aggressiveness. Moreover, the good correlation between in vivo- and ex vivo-measured CCS/C demonstrates that our method is able to bridge MRSI and HR-MAS molecular analysis.

Does physiotherapist-guided pelvic floor muscle training increase the quality of life in patients after radical prostatectomy? A randomized clinical study.

OBJECTIVE: The aim of this study was to study the effect of postoperative physiotherapist-guided pelvic floor muscle training (PFMT) on health-related quality of life (HRQoL) parameters in patients treated with radical prostatectomy (RP). MATERIAL AND METHODS: A prospective randomized controlled trial was conducted at St. Olavs Hospital, Trondheim University Hospital, Norway. Eighty-five men were randomized into two intervention groups (A and B). patients in group A (n = 42) were offered physiotherapist-guided PFMT (in groups or by DVD) once weekly throughout the first 12 months after RP, while those in group B (n = 43) trained on their own. HRQoL data were assessed using the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI) and the Short Form-12 (SF-12) health survey. The physical component summary (PCS) and mental component summary (MCS) scores of the SF-12 plus the urinary, sexual and bowel function and bother of the UCLA-PCI make up the eight quality of life outcomes used in this study. Data were obtained preoperatively (baseline), 6 weeks, and 3, 6 and 12 months postoperatively. RESULTS: Eighty patients completed at least one follow-up assessment, 38 in group A and 42 in group B, giving a dropout rate of 5.9%. The overall response rates were 96% at baseline, 83% at 6 weeks, 90% at 3 months, 88% at 6 months and 68% at 12 months. No statistically significant difference in HRQoL was found between groups A and B. CONCLUSIONS: Even though physiotherapist-guided training of the pelvic floor muscles after RP improved postoperative urinary incontinence significantly compared to those patients receiving standard care/training, this was not reflected in better outcome in HRQoL parameters.

A new method to provide a fresh frozen prostate slice suitable for gene expression study and MR spectroscopy.

BACKGROUND: 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. METHODS: A complete transversal slice is collected and snap-frozen before formalin fixation and routine processing of the remaining gland. The freezing preserves the original geometric shape, thus allowing subsampling of specific cell populations without thawing. RNA was extracted from 53 cylindrical subsamples (diameter 3 mm, thickness 2 mm) from 16 consecutive frozen slices. The histological pattern was evaluated by microscopy of a cryosection from sample before further analysis. RESULTS: Using this novel harvesting method close to 400 slices have been collected. Whenever tumor was present in both adjacent surrounding hematoxylin-eosin sections, we found cancer in 88% of the frozen slices. The extracted RNA showed very high quality with a mean RNA integrity number of 9.16 (SD 0.53). The MR spectra showed metabolic profiles containing several resonances, which deserve further evaluation as possible biomarkers for prostate cancer. After MR analysis the RNA was still highly intact with a mean RNA integrity number of 8.40 (SD 1.53), which makes it possible to correlate transcriptomic and metabolomic profiles of the extracted samples. CONCLUSION: We present a safe and standardized method for procurement of a high quality fresh frozen prostate slice, suitable for gene expression analysis and MR spectroscopy.

Side-effects of post-treatment biopsies in prostate cancer patients treated with endocrine therapy alone or combined with radical radiotherapy in the Scandinavian Prostate Cancer Group-7 randomized trial.

OBJECTIVE: Post-treatment prostate biopsy side-effects were evaluated in patients with locally advanced prostate cancer on endocrine therapy alone or combined with radiotherapy in the Scandinavian Prostate Cancer Group-7 randomized trial. MATERIAL AND METHODS: One-hundred and twenty patients underwent transrectalultrasound-guided biopsy, and were requested to complete a questionnaire on side-effects occurring within 7 days' follow-up. RESULTS: The questionnaire was returned by 109 patients (91%) (endocrine therapy only 52%, combined endocrine therapy and radiotherapy 48%). Previous therapy had no significant influence on pain, urinary flow, haematuria or haematospermia. Pain at biopsy was reported in 63% (mild, 57%; moderate, 5.6%; severe, one patient) and pain at follow-up in 31% (mild, 27%; moderate, four patients). Haematuria (mean duration 2.2 days) was reported in 41%, and reduced urinary flow in 20% (mild, 18%; severe: four patients; no patient had urinary retention). Haematospermia was scarce. No patient reported urinary tract infection. Rectal bleeding occurred in 18% in the endocrine and 35% in the combined therapy group (p = 0.047), with a mean duration of 1.6 and 2.2 days, respectively (p = 0.031). In logistic regression analysis, a trend towards increased rectal bleeding was found in patients on combined endocrine therapy and radiotherapy (odds ratio 2.4, p = 0.050). CONCLUSION: Patient-reported post-treatment prostate biopsy side-effects were mild and self-limiting.

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.

Early pharmacokinetics of nasal fentanyl: is there a significant arterio-venous difference?

OBJECTIVE: We have investigated the arterio-venous difference in the pharmacokinetics of 50 microg fentanyl during the first hour following nasal administration and documented its tolerability in opioid-naïve middle-aged to elderly patients. METHODS: Twelve male patients (range in age 47-84 years) scheduled for transurethral resection of the prostate gland received a 100-microl dose of 50 microg fentanyl base as a fentanyl citrate formulation in one nostril. Simultaneous arterial and venous blood samples for analyses of fentanyl were drawn at baseline and at 1, 3, 5, 7, 9, 13, 15, 20, 25, 35, 45 and 60 min after drug administration. Vital signs, sedation and symptoms of local irritation were recorded. RESULTS: The arterial C(max) (maximum serum concentration) of 0.83 ng/ml was nearly twofold higher than the venous C(max) of 0.47 ng/ml, and the arterial T(max) (time to maximum serum concentration) of 7.0 min was about 5 min shorter than the venous T(max) of 11.6 min. The arterial AUC(0-60) (area under the curve from 0 to 60 min after administration) of 21 min*ng/ml was approximately 30% larger than the venous AUC(0-60) of 15 min*ng/ml (all p values < or = 0.005). Venous T(max) and C(max) did not predict the corresponding arterial values. No significant adverse events were observed. CONCLUSION: A significant arterio-venous difference was present after intranasal administration of fentanyl. The short arterial T(max) complies with its rapid onset of action. The use of venous concentrations for the prediction of onset time of analgesia should be discouraged. A 50-microg dose of nasal fentanyl was well tolerated by opioid-naïve middle-aged to elderly male patients.

Docetaxel Versus Surveillance After Radical Prostatectomy for High-risk Prostate Cancer: Results from the Prospective Randomised, Open-label Phase 3 Scandinavian Prostate Cancer Group 12 Trial.

BACKGROUND: Adjuvant chemotherapy is standard treatment for other solid tumours, but to date has not proven effective in prostate cancer. OBJECTIVE: o evaluate whether six cycles of docetaxel alone improve biochemical disease-free survival after radical prostatectomy for high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomised multinational phase 3 trial. Enrolment of 459 patients after prostatectomy. INCLUSION CRITERIA: high-risk pT2 margin positive or pT3a Gleason score ≥4+3, pT3b, or lymph node positive disease Gleason score ≥3+4. Patients assigned (1:1) to either six cycles of adjuvant docetaxel 75mg/m2 every 3 wk without daily prednisone (Arm A) or surveillance (Arm B) until endpoint was reached. Primary endpoint was prostate-specific antigen progression ≥0.5 ng/ml. INTERVENTION: Docetaxel treatment after prostatectomy. RESULTS AND LIMITATIONS: Median time to progression, death, or last follow-up was 56.8 mo. Primary endpoint was reached in 190/459 patients-the risk of progression at 5 yr being 41% (45% in Arm A and 38% in Arm B). There was evidence of nonproportional hazards in Kaplan-Meier analysis, so we used the difference in restricted mean survival time as the primary estimate of effect. Restricted mean survival time to endpoint was 43 mo in Arm A versus 46 mo in Arm B (p=0.06), a nonsignificant difference of 3.2 mo (95% confidence interval: 6.7 to -1.5 mo). A total of 116 serious adverse events were recorded in Arm A and 41 in Arm B with no treatment-related deaths. Not all patients received docetaxel by protocol. The endpoint is biochemical progression and some patients received radiation treatment before the endpoint. CONCLUSIONS: Docetaxel without hormonal therapy did not significantly improve biochemical disease-free survival after radical prostatectomy. PATIENT SUMMARY: In this randomised trial, we tested whether chemotherapy after surgery for high-risk prostate cancer decreases the risk of a rising prostate-specific antigen. We found no benefit from docetaxel given after radical prostatectomy.

Extracorporeal shockwave lithotripsy versus ureteroscopy for 5- to 10-mm stones in the proximal ureter: Prospective effectiveness patient-preference trial.

BACKGROUND: To establish the best treatment modality in our hospitals for patients with proximal-ureteral calculi 5 to 10 mm, we compared the treatment outcome in those who underwent primary ureteroscopy (URS) with that in patients who underwent primary in-situ SWL. The primary endpoints were stone-free rates at 3 weeks and 3 months and the subjective patient experience. PATIENTS AND METHODS: The study was a prospective patient-preference trial. From September 2002 to May 2005, 80 patients were included, of whom 71 could be evaluated. Thirty-three patients were treated with SWL and 38 with semirigid or flexible URS. Stone status was evaluated with excretory urography or noncontrast helical CT. The bother score of urinary-tract symptoms was recorded on a visual analog scale. RESULTS: The stone-free rate at 3 weeks was 58% and 78% (P = 0.061) and at 3 months 88% and 89% (P = 1) for SWL and URS, respectively. The percentage of patients in need of analgesics was 30% and 49% (P = 0.118) at 3 weeks and 9% and 21% (P = 0.181) at 3 months for the SWL and the URS group, respectively. The bother score regarding dysuria, hematuria, and flank pain were statistically significant in favor of SWL. CONCLUSION: Ureteroscopy tends to make patients stone free faster, but SWL is preferred by most patients because there is less discomfort after treatment.

[Curative treatment of prostatic cancer in Norway in 1998 and 2001]. / Kurativ behandling av prostatakreft i Norge i 1998 og 2001.

BACKGROUND: The two major therapeutic options for early diagnosed prostate cancer are radical prostatectomy or radiation therapy. The National Program for Prostate Cancer in Norway conducted this study in order to document the use of treatment with curative intention in five geographical regions in Norway. MATERIAL AND METHODS: The study is based on data from the Cancer Registry of Norway on patients diagnosed with prostate cancer in 1998 and 2001. The departments of oncology have provided relevant information about radiation therapy. Treatment with curative intention is defined as radical prostatectomy or radiation therapy with > or = 64 Gy. RESULTS: About one third of all patients under the age of 75 years with recently diagnosed prostate cancer were treated with curative intention in 1998 and 2001 (1998: 28%, 2001: 33%); the total number increased from 440 in 1998 to 556 in 2001. There were marked variations between the geographical regions in the use of treatment with curative intention and in the use of radical prostatectomy versus radiation therapy. INTERPRETATION: The fact that no more than one third of the patients were treated with curative intention is probably due to uncertainty about the therapeutic benefit in relation to side effects. The regional variations probably reflect different opinions on the true effect of early diagnosis and treatment.

A Balanced Tissue Composition Reveals New Metabolic and Gene Expression Markers in Prostate Cancer.

Molecular analysis of patient tissue samples is essential to characterize the in vivo variability in human cancers which are not accessible in cell-lines or animal models. This applies particularly to studies of tumor metabolism. The challenge is, however, the complex mixture of various tissue types within each sample, such as benign epithelium, stroma and cancer tissue, which can introduce systematic biases when cancers are compared to normal samples. In this study we apply a simple strategy to remove such biases using sample selections where the average content of stroma tissue is balanced between the sample groups. The strategy is applied to a prostate cancer patient cohort where data from MR spectroscopy and gene expression have been collected from and integrated on the exact same tissue samples. We reveal in vivo changes in cancer-relevant metabolic pathways which are otherwise hidden in the data due to tissue confounding. In particular, lowered levels of putrescine are connected to increased expression of SRM, reduced levels of citrate are attributed to upregulation of genes promoting fatty acid synthesis, and increased succinate levels coincide with reduced expression of SUCLA2 and SDHD. In addition, the strategy also highlights important metabolic differences between the stroma, epithelium and prostate cancer. These results show that important in vivo metabolic features of cancer can be revealed from patient data only if the heterogeneous tissue composition is properly accounted for in the analysis.

Ten- and 15-yr Prostate Cancer-specific Mortality in Patients with Nonmetastatic Locally Advanced or Aggressive Intermediate Prostate Cancer, Randomized to Lifelong Endocrine Treatment Alone or Combined with Radiotherapy: Final Results of The Scandinavian Prostate Cancer Group-7.

BACKGROUND: In high-risk prostate cancer (PCa), no study with observation times beyond 10 yr has demonstrated survival improvement after addition of prostatic radiotherapy (RAD) to endocrine treatment (ET) alone. OBJECTIVE: To compare mortality rates in patients receiving ET alone versus ET + RAD. DESIGN, SETTINGS, AND PARTICIPANTS: From 1996 to 2002, 875 Scandinavian patients with high-risk (90%) or intermediate PCa were randomized to ET or ET + RAD (The Scandinavian Prostate Cancer Group-7). After 3 mo with total androgen blockade in all patients, all individuals continued lifelong antiandrogen monotherapy. Those randomized to ET + RAD started prostate radiotherapy (70Gy) at 3 mo. OUTCOME, MEASUREMENTS AND STATISTICAL ANALYSIS: PCa-specific 15-yr mortality represented the primary endpoint. Assessment of the combination treatment effect and prognostic factors was performed in competing risk analyses and Cox proportional-hazard models. INTERVENTION: RAD added to ET. RESULTS AND LIMITATIONS: With a median observation time of 12 yr, the 15-yr PCa-specific mortality rates were 34% (95% confidence interval, 29-39%) and 17% (95% confidence interval, 13-22%) in the ET and ET + RAD arms respectively (p<0.001). Compared with the ET arm, the median overall survival in the ET + RAD arm was prolonged by 2.4 yr. Treatment with ET alone, age ≥65 yr and increasing histology grade independently increased the risk of PCa-specific and overall mortality. Limitations include nonformal evaluation of comorbidity, the inability to calculate progression-free survival, and lack of information about salvage therapy and toxicity. CONCLUSIONS: In patients with nonmetastatic locally advanced or aggressive PCa, ET + RAD reduces the absolute risk of PCa-specific death by 17% at 15 yr compared with ET alone; the comparable 15-yr PCa-specific mortality rates being 17% and 34%. The results warrant a phase 3 study comparing ET + RAD with radical prostatectomy in high-risk PCa. PATIENT SUMMARY: Adding prostatic therapy to lifelong antiandrogen therapy halves the absolute risk of death from prostate cancer from 34% to 17% 15 yr after diagnosis.

Tissue Microstructure Is Linked to MRI Parameters and Metabolite Levels in Prostate Cancer.

INTRODUCTION: Magnetic resonance imaging (MRI) can portray spatial variations in tumor heterogeneity, architecture, and its microenvironment in a non-destructive way. The objective of this study was to assess the relationship between MRI parameters measured on patients in vivo, individual metabolites measured in prostatectomy tissue ex vivo, and quantitative histopathology. MATERIALS AND METHODS: Fresh frozen tissue samples (n = 53 from 15 patients) were extracted from transversal prostate slices and linked to in vivo MR images, allowing spatially matching of ex vivo measured metabolites with in vivo MR parameters. Color-based segmentation of cryosections of each tissue sample was used to identify luminal space, stroma, and nuclei. RESULTS: Cancer samples have significantly lower area percentage of lumen and higher area percentage of nuclei than non-cancer samples (p ≤ 0.001). Apparent diffusion coefficient is significantly correlated with percentage area of lumen (ρ = 0.6, p < 0.001) and percentage area of nuclei (ρ = -0.35, p = 0.01). There is a positive correlation (ρ = 0.31, p = 0.053) between citrate and percentage area of lumen. Choline is negatively correlated with lumen (ρ = -0.38, p = 0.02) and positively correlated with percentage area of nuclei (ρ = 0.38, p = 0.02). CONCLUSION: Microstructures that are observed by histopathology are linked to MR characteristics and metabolite levels observed in prostate cancer.

Presence of TMPRSS2-ERG is associated with alterations of the metabolic profile in human prostate cancer.

TMPRSS2-ERG has been proposed to be a prognostic marker for prostate cancer. The aim of this study was to identify changes in metabolism, genes and biochemical recurrence related to TMPRSS2-ERG by using an integrated approach, combining metabolomics, transcriptomics, histopathology and clinical data in a cohort of 129 human prostate samples (41 patients). Metabolic analyses revealed lower concentrations of citrate and spermine comparing ERGhigh to ERGlow samples, suggesting an increased cancer aggressiveness of ERGhigh compared to ERGlow. These results could be validated in a separate cohort, consisting of 40 samples (40 patients), and magnetic resonance spectroscopy imaging (MRSI) indicated an in vivo translational potential. Alterations of gene expression levels associated with key enzymes in the metabolism of citrate and polyamines were in consistence with the metabolic results. Furthermore, the metabolic alterations between ERGhigh and ERGlow were more pronounced in low Gleason samples than in high Gleason samples, suggesting it as a potential tool for risk stratification. However, no significant difference in biochemical recurrence was detected, although a trend towards significance was detected for low Gleason samples. Using an integrated approach, this study suggests TMPRSS2-ERG as a potential risk stratification tool for inclusion of active surveillance patients.