Simultaneous 18F-fluciclovine Positron Emission Tomography and Magnetic Resonance Spectroscopic Imaging of Prostate Cancer

Purpose: To investigate the associations of metabolite levels derived from magnetic resonance spectroscopic imaging (MRSI) and 18F-fluciclovine positron emission tomography (PET) with prostate tissue characteristics. Methods: In a cohort of 19 high-risk prostate cancer patients that underwent simultaneous PET/MRI, we evaluated the diagnostic performance of MRSI and PET for discrimination of aggressive cancer lesions from healthy tissue and benign lesions. Data analysis comprised calculations of correlations of mean standardized uptake values (SUVmean), maximum SUV (SUVmax), and the MRSI-derived ratio of (total choline + spermine + creatine) to citrate (CSC/C). Whole-mount histopathology was used as gold standard. Results: The results showed a moderate significant correlation between both SUVmean and SUVmax with CSC/C ratio. Conclusions: We demonstrated that the simultaneous acquisition of 18F-fluciclovine PET and MRSI with an integrated PET/MRI system is feasible and a combination of these imaging modalities has potential to improve the diagnostic sensitivity and specificity of prostate cancer lesions

A comparison of Generative Adversarial Networks for automated prostate cancer detection on T2-weighted MRI

Generative Adversarial Networks (GANs) have shown potential in medical imaging. In this study, several previously developed GANs were investigated for prostate cancer (PCa) detection on T2-weighted (T2W) magnetic resonance images (MRI).T2W MRI from an in-house collected dataset (N=961) were used to train, validate, and test an automated computer-aided detection (CAD) pipeline. The open-access PROSTATEx training dataset (N=199) was used as an external test set. The CAD pipeline consisted of normalization, prostate segmentation, quality control, prostate gland cropping, and a GAN model. Six GANs (f-AnoGAN, HealthyGAN, StarGAN, StarGAN-v2, Fixed-Point-GAN and DeScarGAN) were evaluated for PCa detection on the patient-level using the area under the receiver operating characteristic curve (AUC). The best performing GAN (validation set) was trained with five different initializations and evaluated on the internal and external test sets to assess its robustness.Fixed-Point-GAN performed best (validation, AUC 0.76) and was selected for further assessment. The highest performance on the internal and external test sets were an AUC of 0.73 (95% CI: 0.68-0.79) and 0.77 (95% CI: 0.70-0.83), respectively. The average AUCs ± standard deviation across all runs corresponded to 0.71 ± 0.01 and 0.71 ± 0.04, respectively.Fixed-Point-GAN was identified as a promising GAN for the detection of PCa on T2W MRI. This model needs to be further investigated and trained on a larger dataset of multiparametric or biparametric MR images to assess its full potential as a support tool for radiologists

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

A novel non-canonical Wnt signature for prostate cancer aggressiveness

Activation of the Canonical Wnt pathway (CWP) has been linked to advanced and metastatic prostate cancer, whereas the Wnt5a-induced non-canonical Wnt pathway (NCWP) has been associated with both good and poor prognosis. A newly discovered NCWP, Wnt5/Fzd2, has been shown to induce epithelial-to-mesenchymal transition (EMT) in cancers, but has not been investigated in prostate cancer. The aim of this study was to investigate if the CWP and NCWP, in combination with EMT, are associated with metabolic alterations, aggressive disease and biochemical recurrence in prostate cancer. An initial analysis was performed using integrated transcriptomics, ex vivo and in vivo metabolomics, and histopathology of prostatectomy samples (n=129), combined with at least five-year follow-up. This analysis detected increased activation of NCWP through Wnt5a/ Fzd2 as the most common mode of Wnt activation in prostate cancer. This activation was associated with increased expression of EMT markers and higher Gleason score. The transcriptional association between NCWP and EMT was confirmed in five other publicly available patient cohorts (1519 samples in total). A novel gene expression signature of concordant activation of NCWP and EMT (NCWP-EMT) was developed, and this signature was significantly associated with metastasis and shown to be a significant predictor of biochemical recurrence. The NCWP-EMT signature was also associated with decreased concentrations of the metabolites citrate and spermine, which have previously been linked to aggressive prostate cancer. Our results demonstrate the importance of NCWP and EMT in prostate cancer aggressiveness, suggest a novel gene signature for improved risk stratification, and give new molecular insight

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

Metabolite concentrations (mmol/kg) and ratios in low grade (GS = 6) and high grade (GS≥7) prostate cancer samples and comparison between different GSs.

<p>Concentrations are reported as mmol/kg wet weight. ^a P-values from Linear mixed models corrected for multiple testing by Benjamini-Hochberg correction; * p<0.05.</p

Representative HR-MAS spectra and corresponding HES stained prostate tissue samples with different Gleason grades.

<p>Visual inspection of the spectra show decreased levels of polyamines (predominately spermine) and citrate, and increased levels of GPC, PCho, and Cho with increasing tumor grade.</p