I.M. van Oort

Relationship between Apparent Diffusion Coefficients at 3.0-T MR Imaging and Gleason Grade in Peripheral Zone Prostate Cancer

PURPOSE To retrospectively determine the relationship between apparent diffusion coefficients (ADCs) obtained with 3.0-T diffusion-weighted (DW) magnetic resonance (MR) imaging and Gleason grades in peripheral zone prostate cancer. MATERIALS AND METHODS The requirement to obtain institutional review board approval was waived. Fifty-one patients with prostate cancer underwent MR imaging before prostatectomy, including DW MR imaging with b values of 0, 50, 500, and 800 sec/mm(2). In prostatectomy specimens, separate slice-by-slice determinations of Gleason grade groups were performed according to primary, secondary, and tertiary Gleason grades. In addition, tumors were classified into qualitative grade groups (low-, intermediate-, or high-grade tumors). ADC maps were aligned to step-sections and regions of interest annotated for each tumor slice. The median ADC of tumors was related to qualitative grade groups with linear mixed-model regression analysis. The accuracy of the median ADC in the most aggressive tumor component in the differentiation of low- from combined intermediate- and high-grade tumors was summarized by using the area under the receiver operating characteristic (ROC) curve (A(z)). RESULTS In 51 prostatectomy specimens, 62 different tumors and 251 step-section tumor lesions were identified. The median ADC in the tumors showed a negative relationship with Gleason grade group, and differences among the three qualitative grade groups were statistically significant (P < .001). Overall, with an increase of one qualitative grade group, the median ADC (±standard deviation) decreased 0.18 × 10(-3) mm(2)/sec ± 0.02. Low-, intermediate-, and high-grade tumors had a median ADC of 1.30 × 10(-3) mm(2)/sec ± 0.30, 1.07 × 10(-3) mm(2)/sec ± 0.30, and 0.94 × 10(-3) mm(2)/sec ± 0.30, respectively. ROC analysis showed a discriminatory performance of A(z) = 0.90 in discerning low-grade from combined intermediate- and high-grade lesions. CONCLUSION ADCs at 3.0 T showed an inverse relationship to Gleason grades in peripheral zone prostate cancer. A high discriminatory performance was achieved in the differentiation of low-, intermediate-, and high-grade cancer.

Genetic correction of PSA values using sequence variants associated with PSA levels.

Sequence variants in the human genome are associated with serum levels of prostate-specific antigen. SNPping Away at Prostate Cancer Measuring prostate-specific antigen (PSA) in serum is the only diagnostic test for prostate cancer and is used as a screening tool for deciding whether to perform a biopsy. Yet, this diagnostic test is far from ideal, with more than a third of men with serum PSA levels of 10 ng/ml or greater having no evidence of prostate cancer at biopsy, and some men with very low PSA levels (less than the lower threshold of 2.5 ng/ml), who are not given a biopsy but yet end up having prostate cancer. The lack of specificity and sensitivity of the PSA test and the many confounding factors that influence the test result, including medications, inflammation, and, of course, genotype, have reduced the value of this screening tool. As with most cancers, early detection of prostate cancer leads to a greatly improved chance of survival, so improving the predictive accuracy of this test is of paramount importance. In an effort to investigate whether genome sequence variants can be used to make the PSA test more sensitive, Gudmundsson and colleagues have undertaken a genome-wide association study in 15,757 Icelandic men and 454 British men not yet diagnosed with prostate cancer to see whether they can tie sequence variants [single-nucleotide polymorphisms (SNPs)] to serum PSA levels. The authors identify six loci with SNPs that correlate with PSA levels. They then probed these data more deeply. They looked at these loci in 3834 men who underwent subsequent biopsy of the prostate and demonstrate that three of these loci (10q26, 12q24, and 19q13.33) are associated not only with higher PSA levels but also with a higher probability of a negative biopsy result. The authors suggest that this genotype information should be used to calculate a personalized “cutoff” value for serum PSA levels in each individual to improve the predictive accuracy of the test and to ensure that only men who need a prostate biopsy are subjected to this procedure. Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with Pcombined <3 × 10−10. Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.

Value of 3-T multiparametric magnetic resonance imaging and magnetic resonance-guided biopsy for early risk restratification in active surveillance of low-risk prostate cancer: a prospective multicenter cohort study

ObjectivesThe objective of this study was to evaluate the role of 3-T multiparametric magnetic resonance imaging (MP-MRI) and magnetic resonance–guided biopsy (MRGB) in early risk restratification of patients on active surveillance at 3 and 12 months of follow-up. Materials and MethodsWithin 4 hospitals participating in a large active surveillance trial, a side study was initiated. Pelvic magnetic resonance imaging, prostate MP-MRI, and MRGB were performed at 3 and 12 months (latter prostate MP-MRI and MRGB only) after prostate cancer diagnosis in 1 of the 4 participating hospitals. Cancer-suspicious regions (CSRs) were defined on prostate MP-MRI using Prostate Imaging Reporting And Data System (PI-RADS) scores.Risk restratification criteria for active surveillance discontinuance were (1) histopathologically proven magnetic resonance imaging suspicion of node/bone metastases and/or (2) a Gleason growth pattern (GGP) 4 and/or 5 and/or cancer multifocality (≥3 foci) in MRGB specimens of a CSR on MP-MRI. ResultsFrom 2009 to 2012, a total of 64 of 82 patients were consecutively and prospectively included and underwent MP-MRI and a subsequent MRGB. At 3 and 12 months of follow-up, 14% (9/64) and 10% (3/30) of the patients were risk-restratified on the basis of MP-MRI and MRGB. An overall CSR PI-RADS score of 1 or 2 had a negative predictive value of 84% (38/45) for detection of any prostate cancer and 100% (45/45) for detection of a GGP 4 or 5 containing cancer upon MRGB, respectively. A CSR PI-RADS score of 4 or higher had a sensitivity of 92% (11/12) for detection of a GGP 4 or 5 containing cancer upon MRGB. ConclusionsApplication of MP-MRI and MRGB in active surveillance may contribute in early identification of patients with GGP 4 or 5 containing cancers at 3 months of follow-up. If, during further follow-up, a PI-RADS score of 1 or 2 continues to have a negative predictive value for GGP 4 or 5 containing cancers, a PI-RADS standardized reported MP-MRI may be a promising tool for the selection of prostate cancer patients suitable for active surveillance.

Initial experience with identifying high-grade prostate cancer using diffusion-weighted MR imaging (DWI) in patients with a Gleason score </= 3 + 3 = 6 upon schematic TRUS-guided biopsy: a radical prostatectomy correlated series.

Introduction:Diffusion-weighted magnetic resonance (MR) imaging (DWI) might be able to fulfill the need to accurately identify high-grade prostate carcinoma, in patients initially selected for active surveillance in the Prostate Specific Antigen (PSA) screening era based on transrectal ultrasound-guided biopsy Gleason score. We aimed to determine whether DWI is able to correctly identify those patients with a biopsy Gleason score of ⩽3 + 3 = 6, but harboring Gleason 4 and/or 5 components in their radical prostatectomy (RP) specimen. Materials and Methods:Whole-mount RP specimens were used to identify regions of interest corresponding with tumor on the DWI-derived apparent diffusion coefficient (ADC) maps in 23 patients with a Gleason ⩽3 + 3 = 6 on biopsy. ADC values were correlated with RP Gleason grades. Statistical analysis was performed by calculating area under the receiver operating characteristic curve for identification of prostate cancer with Gleason 4 and/or 5 components using DWI, and Mann-Whitney U testing was performed to detect differences in median ADC values for tumors with presence of Gleason grade 4 and/or 5 versus a highest Gleason grade of ⩽3 on RP. Results:A diagnostic accuracy of median ADC values for identifying patients subject to transrectal ultrasound-guided biopsy undergrading with an area under the receiver operating characteristic curve of 0.88 was established using RP Gleason score as a reference. In patients harboring a Gleason 4 and/or 5 component, the median ADC was 0.86 × 10(−3) mm2/s (standard deviation ± 0.21), whereas patients harboring no Gleason 4 and/or 5 component displayed a median ADC of 1.16 × 10(−3) mm2/s (standard deviation ± 0.19) for the single tumor slice with the lowest median ADC (P < 0.002). Conclusions:DWI is able to predict the presence of high-grade tumor in patients with a Gleason ⩽3 + 3 = 6 on biopsy, providing important information for treatment decisions.

Evaluation of diffusion-weighted MR imaging at inclusion in an active surveillance protocol for low-risk prostate cancer

PurposeWe aimed to determine whether diffusion-weighted magnetic resonance imaging, by means of the apparent diffusion coefficient (ADC), is able to guide magnetic resonance–guided biopsy in patients fit for active surveillance (AS) and identify patients harboring high-grade Gleason components not suitable for AS. Materials and MethodsOur study was approved by the institutional review board of all participating hospitals, and all patients signed informed consent at inclusion. Fifty-four consecutive patients with low-risk prostate cancer (PCa) underwent multiparametric magnetic resonance imaging (MP-MRI) at inclusion for AS. Cancer-suspicious regions (CSRs) upon 3-T MP-MRI were identified in all patients, and magnetic resonance–guided biopsy was performed in all CSRs to obtain histopathological verification. For all CSRs, a median ADC (mADC) was calculated. Wilcoxon signed ranks and Mann-Whitney tests was performed to detect differences between the groups. We used the area under the receiver operating characteristic curve to evaluate the accuracy of mADC to predict the presence of PCa in a CSR. Level of statistical significance was set at P < 0.05. ResultsMean mADC in the CSRs with PCa was 1.04 × 10−3 mm2/s (SD, 0.29), whereas the CSRs with no PCa displayed a mean mADC of 1.26 × 10−3 mm2/s (SD, 0.25; P < 0.001). Cancer-suspicious regions with a high-grade Gleason component displayed a mean mADC of 0.84 × 10−3 mm2/s (SD, 0.35) vs a mean mADC for the low-grade CSRs of 1.09 × 10−3 mm2/s (SD, 0.25; P < 0.05). A diagnostic accuracy of mADC for predicting the presence of PCa in a CSR with an area under the receiver operating characteristic curve of 0.73 was established (95% confidence interval, 0.61–0.84). ConclusionsMedian ADC is able to predict the presence and grade of PCa in CSRs identified by MP-MRI.

Body mass index as a prognostic marker for biochemical recurrence in Dutch men treated with radical prostatectomy

To investigate whether body mass index (BMI) is a prognostic factor for biochemical recurrence (BCR) in Dutch men after radical prostatectomy (RP), as although epidemiological studies of obesity in relation to prostate cancer have provided conflicting results, recent studies from the USA suggest that a higher BMI is a risk factor for progression of prostate cancer.

Comparative analysis of prostate cancer specific biomarkers PCA3 and ERG in whole urine, urinary sediments and exosomes.

Abstract Background: PCA3 and ERG are mRNA-based prostate cancer (PCa) specific biomarkers that can be detected in urine. However, urine is a complex substrate that can be separated in several fractions. In this study we compared the levels of PCa-specific biomarkers (PCA3 and ERG) and KLK3 as prostate-specific reference gene in three urine substrates–whole urine, urinary sediment (cell pellet) and exosomes–and evaluated the influence of performing a digital rectal examination (DRE) prior to urine sampling. Methods: First-voided urine samples were prospectively obtained before and after DRE from 29 men undergoing prostate biopsies. The urine was separated in whole urine, cell pellet and exosomes and the biomarker levels were measured with RT-qPCR. Results: PCa was identified in 52% (15/29) of men. In several samples the mRNA levels were below the analytical limit of detection (BDL). The biomarker levels were highest in whole urine and significantly higher after DRE in all substrates. In PCa patients higher levels of PCA3 and ERG were found in all urine substrates after DRE compared to non-PCa patients. Conclusions: This is the first study in which urinary PCa-specific biomarker levels were compared directly in three separate urine fractions. These results suggest that whole urine could be the urine substrate of choice for PCa-diagnostics based on analytical sensitivity, which is reflected directly in the high informative rate. Moreover, the significant positive effect of performing a DRE prior to urine sampling is confirmed. These findings could be of influence in the development of PCa-diagnostic urine tests.

Fear of cancer recurrence in prostate cancer survivors

Abstract Background High fear of cancer recurrence (FCR) is an understudied topic in prostate cancer (PCa) survivors. This study aimed to detect the prevalence, consequences and characteristics associated with high FCR in PCa survivors. Material and methods This cross-sectional study included patients diagnosed with localized PCa and treated with curative radical prostatectomy between 1992 and 2012. We administered the Cancer Worry Scale (CWS) to assess FCR severity (primary outcome measure). Secondary outcomes included distress, quality of life (QOL), post-traumatic symptoms, and multidimensional aspects of FCR. χ2-tests, t-tests and Pearson’s correlations examined the relationship between FCR and medical/demographic characteristics. MANOVA analyses and χ2-tests identified differences between PCa survivors with high and low FCR. Results Two hundred eighty-three PCa survivors (median age of 70.0 years) completed the questionnaires a median time of 7.1 years after surgery. About a third (36%) of all PCa survivors experienced high FCR. High FCR was associated with lower QOL, more physical problems, higher distress and more post-traumatic stress symptoms. PCa survivors with high FCR reported disease-related triggers (especially medical examinations), felt helpless and experienced problems in social relationships. High FCR was associated with a younger age and having received adjuvant radiotherapy. Conclusions Results illustrate that FCR is a significant problem in PCa survivors. Younger men and those treated with adjuvant radiotherapy are especially at risk. Those with high FCR experience worse QOL and higher symptom burden. Health care providers should pay specific attention to this problem and provide appropriate psychosocial care when needed.

A single institution experience with biochemical recurrence after radical prostatectomy for tumors that on pathology are of small volume or “insignificant”

OBJECTIVE Small volume prostate cancers (<0.5 cc, svPC), and insignificant prostate cancers (<0.5 cc and Gleason scores <7, InsigPC) are considered clinically insignificant by some investigators. The aim of this study is to determine the biochemical recurrence rate (BCR) of svPC and InsigPC in prostatectomy specimens. METHODS In total, 502 patients with prostate cancer, treated with radical prostatectomy (RP) between 1992 and 2005 and with detailed pathological classification, were included in the present study. Patients were postoperatively followed for a median period of 39.5 months (0.6-150). A total of 82 specimens (16.3%) with svPC including 64 (12.8%) with InsigPC were identified. BCR was defined as 2 consecutive PSA levels >0.10 ng/ml. RESULTS In the total group, the median age at the time of surgery was 62.7 years (42.4-73.4) and the median preoperative PSA level was 8.0 ng/ml. Patients with InsigPC had Gleason scores of 4 in 7%, 5 in 37%, and 6 in 56%. Positive surgical margins were identified in 13 (15.9%) svPC and in 8 (12.7%) InsigPC specimens. The 5-year risk of BCR for the svPC group and the insigPC group was 10% (95% CI 2-18%, 7 and 5 patients, respectively) vs. 35% (95% CI 29-41%) in the rest of the cohort (log rank P = 0.001). CONCLUSION Patients with svPC and patients with InsigPC have a significantly lower risk of BCR. However, even in this seemingly very favorable patient group, 1 in 10 patients will develop a BCR after RP. Therefore, new studies are needed to examine what the prognostic relevance is of small-volume tumors.

The oncologic role of local treatment in primary metastatic prostate cancer

PurposeTo determine the oncologic benefit or otherwise of local treatment of the prostate in patients with primary metastatic prostate cancer.MethodsA review of the literature was performed in April 2014 using the Medline/PubMed database. Studies were identified using the search terms “prostate cancer,” “metastatic,” “metastasis,” “high risk,” “radiation therapy,” “radiotherapy” and “prostatectomy” from 1990 until April, 2014. Articles were also identified through searches of references of these articles.ResultsRetrospective series and population-based data suggest that the use of local treatment of the prostate in patients with primary metastatic prostate cancer may improve cancer-specific survival and overall survival compared with treating these patients with androgen deprivation therapy alone. The clinical outcome in metastatic prostate cancer is largely determined by the extent of lymph node involvement and overall metastatic burden. Contemporary data are lacking to recommend one alternative of local therapy (radiotherapy or radical prostatectomy) over the other. The primary limitation of this literature review is the lack of published randomized trial assessing the role of local treatment in addition to systemic therapy.ConclusionsLocal treatment appears to improve oncologic outcomes in metastatic prostate cancer patients. Nevertheless, due to the lack of high-quality evidence, its role needs to be confirmed in future prospective trials. The selection of ideal candidates and optimal treatment alternative (radiotherapy, radical prostatectomy or other) warrants further investigation.