Publications by authors named "Hannu J Aronen"

64 Publications

Computer extracted gland features from H&E predicts prostate cancer recurrence comparably to a genomic companion diagnostic test: a large multi-site study.

NPJ Precis Oncol 2021 May 3;5(1):35. Epub 2021 May 3.

Department of Urology, Case Western Reserve University, Cleveland, OH, USA.

Existing tools for post-radical prostatectomy (RP) prostate cancer biochemical recurrence (BCR) prognosis rely on human pathologist-derived parameters such as tumor grade, with the resulting inter-reviewer variability. Genomic companion diagnostic tests such as Decipher tend to be tissue destructive, expensive, and not routinely available in most centers. We present a tissue non-destructive method for automated BCR prognosis, termed "Histotyping", that employs computational image analysis of morphologic patterns of prostate tissue from a single, routinely acquired hematoxylin and eosin slide. Patients from two institutions (n = 214) were used to train Histotyping for identifying high-risk patients based on six features of glandular morphology extracted from RP specimens. Histotyping was validated for post-RP BCR prognosis on a separate set of n = 675 patients from five institutions and compared against Decipher on n = 167 patients. Histotyping was prognostic of BCR in the validation set (p < 0.001, univariable hazard ratio [HR] = 2.83, 95% confidence interval [CI]: 2.03-3.93, concordance index [c-index] = 0.68, median years-to-BCR: 1.7). Histotyping was also prognostic in clinically stratified subsets, such as patients with Gleason grade group 3 (HR = 4.09) and negative surgical margins (HR = 3.26). Histotyping was prognostic independent of grade group, margin status, pathological stage, and preoperative prostate-specific antigen (PSA) (multivariable p < 0.001, HR = 2.09, 95% CI: 1.40-3.10, n = 648). The combination of Histotyping, grade group, and preoperative PSA outperformed Decipher (c-index = 0.75 vs. 0.70, n = 167). These results suggest that a prognostic classifier for prostate cancer based on digital images could serve as an alternative or complement to molecular-based companion diagnostic tests.
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http://dx.doi.org/10.1038/s41698-021-00174-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093226PMC
May 2021

Prospective comparison of F-PSMA-1007 PET/CT, whole-body MRI and CT in primary nodal staging of unfavourable intermediate- and high-risk prostate cancer.

Eur J Nucl Med Mol Imaging 2021 Mar 13. Epub 2021 Mar 13.

Department of Urology, University of Turku and Turku University Hospital, Turku, Finland.

Purpose: To prospectively compare F-prostate-specific membrane antigen (PSMA)-1007 positron emission tomography (PET)/CT, whole-body magnetic resonance imaging (WBMRI) including diffusion-weighted imaging (DWI) and standard computed tomography (CT), in primary nodal staging of prostate cancer (PCa).

Methods: Men with newly diagnosed unfavourable intermediate- or high-risk PCa prospectively underwent F-PSMA-1007 PET/CT, WBMRI with DWI and contrast-enhanced CT within a median of 8 days. Six readers (two for each modality) independently reported pelvic lymph nodes as malignant, equivocal or benign while blinded to the other imaging modalities. Sensitivity, specificity and accuracy were reported according to optimistic (equivocal lesions interpreted as benign) and pessimistic (equivocal lesions interpreted as malignant) analyses. The reference standard diagnosis was based on multidisciplinary consensus meetings where available histopathology, clinical and follow-up data were used.

Results: Seventy-nine patients completed all the imaging modalities, except for one case of interrupted WBMRI. Thirty-one (39%) patients had pelvic lymph node metastases, which were detected in 27/31 (87%), 14/31 (45%) and 8/31 (26%) patients by F-PSMA-1007 PET/CT, WBMRI with DWI and CT, respectively (optimistic analysis). In 8/31 (26%) patients, only F-PSMA-1007 PET/CT detected malignant lymph nodes, while the other two imaging modalities were reported as negative. At the patient level, sensitivity and specificity values for F-PSMA-1007 PET/CT, WBMRI with DWI and CT in optimistic analysis were 0.87 (95%CI 0.71-0.95) and 0.98 (95%CI 0.89-1.00), 0.37 (95%CI 0.22-0.55) and 0.98 (95%CI 0.89-1.00) and 0.26 (95%CI 0.14-0.43) and 1.00 (95%CI 0.93-1.00), respectively.

Conclusion: F-PSMA-1007 PET/CT showed significantly greater sensitivity in nodal staging of primary PCa than did WBMRI with DWI or CT, while maintaining high specificity.

Clinical Trial Registration: Clinicaltrials.gov ID: NCT03537391.
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http://dx.doi.org/10.1007/s00259-021-05296-1DOI Listing
March 2021

Whole Brain Adiabatic T and Relaxation Along a Fictitious Field Imaging in Healthy Volunteers and Patients With Multiple Sclerosis: Initial Findings.

J Magn Reson Imaging 2021 Mar 6. Epub 2021 Mar 6.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Background: In preclinical models of multiple sclerosis (MS), both adiabatic T (T ) and relaxation along a fictitious field (RAFF) imaging have demonstrated potential to noninvasively characterize MS.

Purpose: To evaluate the feasibility of whole brain T and RAFF imaging in healthy volunteers and patients with MS.

Study Type: Single institutional clinical trial.

Subjects: 38 healthy volunteers (24-69 years) and 21 patients (26-59 years) with MS. Five healthy volunteers underwent a second MR examination performed within 8 days. Clinical disease severity (The Expanded Disability Status Scale [EDSS] and The Multiple Sclerosis Severity Score [MSSS]) was evaluated at baseline and 1-year follow-up (FU).

Field Strength/sequence: RAFF in second rotating frame of reference (RAFF2) was performed at 3 T using 3D-fast-field echo with magnetization preparation, RF amplitude of 11.74 μT while the corresponding value for T was 13.50 μT. T -, T -, and FLAIR-weighted images were acquired with reconstruction voxel size 1.0 × 1.0 × 1.0 mm .

Assessment: The parametric maps of T and RAFF2 (T ) were calculated using a monoexponential model. Semi-automatic segmentation of MS lesions, white matter (WM), and gray matter (GM), and WM tracks was performed using T -, T -, and FLAIR-weighted images.

Statistical Tests: Regression analysis was used to evaluate correlation of T and T with age and disease severity while a Friedman test followed by Wilcoxon Signed Rank test for differences between tissue types. Short-term repeatability was evaluated on voxel level.

Results: Both T and T demonstrated good short-term repeatability with relative differences on voxel level in the range of 6.1%-11.9%. Differences in T and T between the tissue types in MS patients were significant (P < 0.05). T and T correlated (P < 0.001) with baseline EDSS/MSSM and disease progression at FU (P < 0.001).

Data Conclusion: Whole brain T and T at 3 T was feasible with significant differences in T and T values between tissues types and correlation with disease severity.

Evidence Level: 1 TECHNICAL EFFICACY: Stage 1.
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http://dx.doi.org/10.1002/jmri.27586DOI Listing
March 2021

Combined Use of Prostate-specific Antigen Density and Magnetic Resonance Imaging for Prostate Biopsy Decision Planning: A Retrospective Multi-institutional Study Using the Prostate Magnetic Resonance Imaging Outcome Database (PROMOD).

Eur Urol Oncol 2020 Sep 21. Epub 2020 Sep 21.

Department of Urology and Organ Transplantation, University of Foggia, Foggia, Italy.

Background: Previous studies suggested that prostate-specific antigen (PSA) density (PSAd) combined with magnetic resonance imaging (MRI) may help avoid unnecessary prostate biopsy (PB) with a limited risk of missing clinically significant prostate cancer (csPCa; Gleason grade group [GGG] >1).

Objective: To define optimal diagnostic strategies based on the combined use of PSAd and MRI in patients at risk of prostate cancer (PCa).

Design, Setting, And Participants: A retrospective analysis of the international multicenter Prostate MRI Outcome Database (PROMOD), including 2512 men having undergone PSAd and prostate MRI before PB between 2013 and 2019, was performed.

Outcome Measurements And Statistical Analysis: Rates of avoided PB, missed GGG 1, and csPCa according to 10 strategies based on PSAd values and MRI reporting scores (Prostate Imaging Reporting and Data System [PI-RADS]/Likert/IMPROD biparametric prostate MRI Likert). Decision curve analysis (DCA) was used to statistically compare the net benefit of each strategy. Combined systematic and targeted biopsies were used for reference.

Results And Limitations: According to DCA, the best strategy in biopsy-naive patients was #7 (PI-RADS/Likert 4-5 or PI-RADS/Likert 3 if PSAd >0.2), which avoided 41.2% PBs while missed 44% of GGG 1 and 10.9% of csPCa cases. From a clinical standpoint, however, strategies with a lower risk of missing csPCa included #10 (PI-RADS/Likert 4-5 or PI-RADS 3 if PSAd >0.10 or PSAd >0.2), which avoided 27% PBs while missing 24.4% GGG 1 and 4% csPCa cases, or #5 (PI-RADS/Likert 3-5 or PSAd>0.15), which avoided 14.7% PBs while missing 9.3% GGG 1 and 1.7% csPCa cases. Similar results were found in patients with a previous negative biopsy. This study is limited by its retrospective nature, and no central review of MRI and histopathological findings.

Conclusions: Combined PSAd and MRI findings allows individualization of the decision to perform PB on the basis of the risk of missing PCa that both patients and clinicians are ready to accept to avoid this procedure.

Patient Summary: We compared several biopsy strategies based on a combination of prostate magnetic resonance imaging findings and prostate-specific antigen density, providing a readily available tool for each center and practicing urologist to counsel patients about their individual risk of significant prostate cancer.
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http://dx.doi.org/10.1016/j.euo.2020.08.014DOI Listing
September 2020

Added value of systematic biopsy in men with a clinical suspicion of prostate cancer undergoing biparametric MRI-targeted biopsy: multi-institutional external validation study.

World J Urol 2020 Aug 10. Epub 2020 Aug 10.

Department of Urology, University of Turku and Turku University Hospital, Turku, Finland.

Purpose: We aimed to develop and externally validate a nomogram based on MRI volumetric parameters and clinical information for deciding when SBx should be performed in addition to TBx in man with suspicious prostate MRI.

Materials And Methods: Retrospective analyses of single (IMPROD, NCT01864135) and multi-institution (MULTI-IMPROD, NCT02241122) clinical trials. All men underwent a unique rapid biparametric magnetic resonance imaging (IMPROD bpMRI) consisting of T2-weighted imaging and three separate DWI acquisitions. Men with IMPROD bpMRI Likert scores of 3-5 were included. Logistic regression models were developed using IMPROD trial (n = 122) and validated using MULTI-IMPROD trial (n = 262) data. The model's performance was evaluated in the terms of PCa detection with Gleason Grade Group 1 (clinically insignificant prostate cancer, iPCa) and > 1 (clinically significant prostate cancer, csPCa). Net benefits and decision curve analyses (DCA) were compared. Combined biopsies were used for reference.

Results: The developed nomogram included age, PSA, prostate volume, MRI suspicion score (IMPROD bpMRI Likert or PIRADsv2.1 score), MRI-suspicion lesion volume percentage, and lesion location. All these variables were significant predictors of csPCa in SBx in multivariable analysis. In the validation cohort (n = 262) using different nomogram cutoffs, 19-43% of men would have avoided SBx while missing 1-4% of csPCa and avoiding detection of 9-20% of iPCa. Similar performance was found for nomograms using IMPROD bpMRI Likert score or v2.1.

Conclusions: The developed nomogram demonstrated potential to select men with a clinical suspicion of PCa who would benefit from performing SBx in addition to TBx. Public access to the nomogram is provided at: https://petiv.utu.fi/multiimprod/ .
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http://dx.doi.org/10.1007/s00345-020-03393-8DOI Listing
August 2020

Test-retest repeatability of a deep learning architecture in detecting and segmenting clinically significant prostate cancer on apparent diffusion coefficient (ADC) maps.

Eur Radiol 2021 Jan 23;31(1):379-391. Epub 2020 Jul 23.

Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.

Objectives: To evaluate short-term test-retest repeatability of a deep learning architecture (U-Net) in slice- and lesion-level detection and segmentation of clinically significant prostate cancer (csPCa: Gleason grade group > 1) using diffusion-weighted imaging fitted with monoexponential function, ADC.

Methods: One hundred twelve patients with prostate cancer (PCa) underwent 2 prostate MRI examinations on the same day. PCa areas were annotated using whole mount prostatectomy sections. Two U-Net-based convolutional neural networks were trained on three different ADC b value settings for (a) slice- and (b) lesion-level detection and (c) segmentation of csPCa. Short-term test-retest repeatability was estimated using intra-class correlation coefficient (ICC(3,1)), proportionate agreement, and dice similarity coefficient (DSC). A 3-fold cross-validation was performed on training set (N = 78 patients) and evaluated for performance and repeatability on testing data (N = 34 patients).

Results: For the three ADC b value settings, repeatability of mean ADC of csPCa lesions was ICC(3,1) = 0.86-0.98. Two CNNs with U-Net-based architecture demonstrated ICC(3,1) in the range of 0.80-0.83, agreement of 66-72%, and DSC of 0.68-0.72 for slice- and lesion-level detection and segmentation of csPCa. Bland-Altman plots suggest that there is no systematic bias in agreement between inter-scan ground truth segmentation repeatability and segmentation repeatability of the networks.

Conclusions: For the three ADC b value settings, two CNNs with U-Net-based architecture were repeatable for the problem of detection of csPCa at the slice-level. The network repeatability in segmenting csPCa lesions is affected by inter-scan variability and ground truth segmentation repeatability and may thus improve with better inter-scan reproducibility.

Key Points: • For the three ADC b value settings, two CNNs with U-Net-based architecture were repeatable for the problem of detection of csPCa at the slice-level. • The network repeatability in segmenting csPCa lesions is affected by inter-scan variability and ground truth segmentation repeatability and may thus improve with better inter-scan reproducibility.
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http://dx.doi.org/10.1007/s00330-020-07065-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821380PMC
January 2021

A Prospective Comparison of F-prostate-specific Membrane Antigen-1007 Positron Emission Tomography Computed Tomography, Whole-body 1.5 T Magnetic Resonance Imaging with Diffusion-weighted Imaging, and Single-photon Emission Computed Tomography/Computed Tomography with Traditional Imaging in Primary Distant Metastasis Staging of Prostate Cancer (PROSTAGE).

Eur Urol Oncol 2020 Jul 13. Epub 2020 Jul 13.

Department of Urology, University of Turku and Turku University Hospital, Turku, Finland.

Background: Computed tomography (CT) and bone scintigraphy (BS) are the imaging modalities currently used for distant metastasis staging of prostate cancer (PCa).

Objective: To compare standard staging modalities with newer and potentially more accurate imaging modalities.

Design, Setting, And Participants: This prospective, single-centre trial (NCT03537391) enrolled 80 patients with newly diagnosed high-risk PCa (International Society of Urological Pathology grade group ≥3 and/or prostate-specific antigen [PSA] ≥20 and/or cT ≥ T3; March 2018-June 2019) to undergo primary metastasis staging with two standard and three advanced imaging modalities.

Outcome Measurements And Statistical Analysis: The participants underwent the following five imaging examinations within 2 wk of enrolment and without a prespecified sequence: BS, CT, Tc-hydroxymethylene diphosphonate (Tc-HMDP) single-photon emission computed tomography (SPECT)-CT, 1.5 T whole-body magnetic resonance imaging (WBMRI) using diffusion-weighted imaging, and F-prostate-specific membrane antigen-1007 (F-PSMA-1007) positron emission tomography(PET)-CT. Each modality was reviewed by two independent experts blinded to the results of the prior studies, who classified lesions as benign, equivocal, or malignant. Pessimistic and optimistic analyses were performed to resolve each equivocal diagnosis. The reference standard diagnosis was defined using all available information accrued during at least 12 mo of clinical follow-up. Patients with equivocal reference standard diagnoses underwent MRI and/or CT to search for the development of anatomical correspondence. PSMA PET-avid lesions without histopathological verification were rated to be malignant only if there was a corresponding anatomical finding suspicious for malignancy at the primary or follow-up imaging.

Results And Limitations: Seventy-nine men underwent all imaging modalities except for one case of interrupted MRI. The median interval per patient between the first and the last imaging study was 8 d (interquartile range [IQR]: 6-9). The mean age was 70 yr (standard deviation: 7) and median PSA 12 ng/mL (IQR:7-23). The median follow-up was 435 d (IQR: 378-557). Metastatic disease was detected in 20 (25%) patients. The imaging modality F-PSMA-1007 PET-CT had superior sensitivity and highest inter-reader agreement. The area under the receiver-operating characteristic curve (AUC) values for bone metastasis detection with PSMA PET-CT were 0.90 (95% confidence interval [CI]: 0.85-0.95) and 0.91 (95% CI: 0.87-0.96) for readers 1 and 2, respectively, while the AUC values for BS, CT, SPECT-CT, and WBMRI were 0.71 (95% CI: 0.58-0.84) and 0.8 (95% CI: 0.67-0.92), 0.53 (95% CI: 0.39-0.67) and 0.66 (95% CI: 0.54-0.77), 0.77 (95% CI: 0.65-0.89) and 0.75 (95% CI: 0.62-0.88), and 0.85 (95% CI: 0.74-0.96) and 0.67 (95% CI: 0.54-0.80), respectively, for the other four pairs of readers. The imaging method F-PSMA-1007 PET-CT detected metastatic disease in 11/20 patients in whom standard imaging was negative and influenced clinical decision making in 14/79 (18%) patients. In 12/79 cases, false positive bone disease was reported only by PSMA PET-CT. Limitations included a nonrandomised study setting and few histopathologically validated suspicious lesions.

Conclusions: Despite the risk of false positive bone lesions, F-PSMA-1007 PET-CT outperformed all other imaging methods studied for the detection of primary distant metastasis in high-risk PCa.

Patient Summary: In this report, we compared the diagnostic performance of conventional and advanced imaging. It was found that F-prostate-specific membrane antigen-1007 positron emission tomography/computed tomography (F-PSMA-1007 PET-CT) was superior to the other imaging modalities studied for the detection of distant metastasis at the time of initial diagnosis of high-risk prostate cancer. PSMA PET-CT also appears to detect some nonmetastatic bone lesions.
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http://dx.doi.org/10.1016/j.euo.2020.06.012DOI Listing
July 2020

Negative Predictive Value of Biparametric Prostate Magnetic Resonance Imaging in Excluding Significant Prostate Cancer: A Pooled Data Analysis Based on Clinical Data from Four Prospective, Registered Studies.

Eur Urol Focus 2020 May 14. Epub 2020 May 14.

Department of Urology, University of Turku and Turku University hospital, Turku, Finland.

Background: Multiparametric prostate magnetic resonance imaging (mpMRI) can be considered the gold standard in prostate magnetic resonance imaging (MRI). Biparametric prostate MRI (bpMRI) is faster and could be a feasible alternative to mpMRI.

Objective: To determine the negative predictive value (NPV) of Improved Prostate Cancer Diagnosis (IMPROD) bpMRI as a whole and in clinical subgroups in primary diagnostics of clinically significant prostate cancer (CSPCa).

Design, Setting, And Participants: This is a pooled data analysis of four prospective, registered clinical trials investigating prebiopsy IMPROD bpMRI. Men with a clinical suspicion of prostate cancer (PCa) were included.

Intervention: Prebiopsy IMPROD bpMRI was performed, and an IMPROD bpMRI Likert scoring system was used. If suspicious lesions (IMPROD bpMRI Likert score 3-5) were visible, targeted biopsies in addition to systematic biopsies were taken.

Outcome Measurements And Statistical Analysis: Performance measures of IMPROD bpMRI in CSPCa diagnostics were evaluated. NPV was also evaluated in clinical subgroups. Gleason grade ≥3 + 4 in any biopsy core taken was defined as CSPCa.

Results And Limitations: A total of 639 men were included in the analysis. The mean age was 64 yr, mean prostate-specific antigen level was 8.9 ng/ml, and CSPCa prevalence was 48%. NPVs of IMPROD bpMRI Likert scores 3-5 and 4-5 for CSPCa were 0.932 and 0.909, respectively, and the corresponding positive predictive values were 0.589 and 0.720. Only nine of 132 (7%) men with IMPROD bpMRI Likert score 1-2 had CSPCa and none with Gleason score >7. Thus, 132 of 639 (21%) study patients could have avoided biopsies without missing a single Gleason >7 cancer in the study biopsies. In the subgroup analysis, no clear outlier was present. The limitation is uncertainty of the true CSPCa prevalence.

Conclusions: IMPROD bpMRI demonstrated a high NPV to rule out CSPCa. IMPROD bpMRI Likert score 1-2 excludes Gleason >7 PCa in the study biopsies.

Patient Summary: We investigated the feasibility of prostate magnetic resonance imaging (MRI) with the Improved Prostate Cancer Diagnosis (IMPROD) biparametric MRI (bpMRI) protocol in excluding significant prostate cancer. In this study, highly aggressive prostate cancer was excluded using the publicly available IMPROD bpMRI protocol (http://petiv.utu.fi/multiimprod/).
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http://dx.doi.org/10.1016/j.euf.2020.04.007DOI Listing
May 2020

Impact of biparametric prebiopsy prostate magnetic resonance imaging on the diagnostics of clinically significant prostate cancer in biopsy naïve men.

Scand J Urol 2020 Feb 9;54(1):7-13. Epub 2020 Jan 9.

Department of Urology, University of Turku and Turku University Hospital, Turku, Finland.

The objective of this study was to compare the prevalence of clinically significant prostate cancer (CSPCa) in men with biparametric prebiopsy prostate magnetic resonance imaging (MRI) and lesion-targeted biopsies (TBs) to the group of men without prebiopsy MRI in an initial biopsy session. The MRI group consists of men enrolled into four prospective clinical trials investigating a biparametric MRI (bpMRI) and TB while the non-MRI group was a retrospective cohort of men collected from an era prior to a clinical use of a prostate MRI. All men had standard biopsies (SBs). In the MRI group, men had additional TBs from potential cancer-suspicious lesions. CSPCa was defined as Gleason score ≥3 + 4 in any biopsy core taken. All the patients were prostate biopsy naïve. The MRI group consists of 507 while the non-MRI group 379 men. Mean age and prostate specific antigen (PSA) level differed significantly ( < 0.05) between the groups: In the MRI group, 64 years and 7.6 ng/ml, respectively, and in the non-MRI group 68 years and 8.2 ng/ml, respectively. Significantly ( < 0.05) more CSPCa was diagnosed with initial biopsies in the MRI group (48%) compared to non-MRI group (34%). In men with no CSPCa diagnosed during the initial biopsies, significantly fewer ( < 0.05) men had upgrading re-biopsies in the MRI group (5%) than in the non-MRI group (19%) during the follow up. Prebiopsy bpMRI with TBs combined with SBs could lead to earlier diagnoses of CSPCa compared with men without prebiopsy prostate MRI used in initial PCa diagnostics.
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http://dx.doi.org/10.1080/21681805.2019.1711161DOI Listing
February 2020

Qualitative and Quantitative Reporting of a Unique Biparametric MRI: Towards Biparametric MRI-Based Nomograms for Prediction of Prostate Biopsy Outcome in Men With a Clinical Suspicion of Prostate Cancer (IMPROD and MULTI-IMPROD Trials).

J Magn Reson Imaging 2020 05 21;51(5):1556-1567. Epub 2019 Nov 21.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Background: Multiparametric MRI of the prostate has been shown to improve the risk stratification of men with an elevated prostate-specific antigen (PSA). However, long acquisition time, high cost, and inter-center/reader variability of a routine prostate multiparametric MRI limit its wider adoption.

Purpose: To develop and validate nomograms based on unique rapid biparametric MRI (bpMRI) qualitative and quantitative derived variables for prediction of clinically significant cancer (SPCa).

Study Type: Retrospective analyses of single (IMPROD, NCT01864135) and multiinstitution trials (MULTI-IMPROD, NCT02241122).

Population: 161 and 338 prospectively enrolled men who completed the IMPROD and MULTI-IMPROD trials, respectively.

Field Strength/sequence: IMPROD bpMRI: 3T/1.5T, T -weighted imaging, three separate diffusion-weighted imaging (DWI) acquisitions: 1) b-values 0, 100, 200, 300, 500 s/mm ; 2) b values 0, 1500 s/mm ; 3) values 0, 2000 s/mm .

Assessment: The primary endpoint of the combined trial analysis was the diagnostic accuracy of the combination of IMPROD bpMRI and clinical variables for detection of SPCa.

Statistical Tests: Logistic regression models were developed using IMPROD trial data and validated using MULTI-IMPROD trial data. The model's performance was expressed as the area under the curve (AUC) values for the detection of SPCa, defined as ISUP Gleason Grade Group ≥2.

Results: A model incorporating clinical variables had an AUC (95% confidence interval) of 0.83 (0.77-0.89) and 0.80 (0.75-0.85) in the development and validation cohorts, respectively. The corresponding values for a model using IMPROD bpMRI findings were 0.93 (0.89-0.97), and 0.88 (0.84-0.92), respectively. Further addition of the quantitative DWI-based score did not improve AUC values (P < 0.05).

Data Conclusion: A prediction model using qualitative IMPROD bpMRI findings demonstrated high accuracy for predicting SPCa in men with an elevated PSA. Online risk calculator: http://petiv.utu.fi/multiimprod/ Level of Evidence: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1556-1567.
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http://dx.doi.org/10.1002/jmri.26975DOI Listing
May 2020

Repeatability of radiomics and machine learning for DWI: Short-term repeatability study of 112 patients with prostate cancer.

Magn Reson Med 2020 06 8;83(6):2293-2309. Epub 2019 Nov 8.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Purpose: To evaluate repeatability of prostate DWI-derived radiomics and machine learning methods for prostate cancer (PCa) characterization.

Methods: A total of 112 patients with diagnosed PCa underwent 2 prostate MRI examinations (Scan1 and Scan2) performed on the same day. DWI was performed using 12 b-values (0-2000 s/mm ), post-processed using kurtosis function, and PCa areas were annotated using whole mount prostatectomy sections. A total of 1694 radiomic features including Sobel, Kirch, Gradient, Zernike Moments, Gabor, Haralick, CoLIAGe, Haar wavelet coefficients, 3D analogue to Laws features, 2D contours, and corner detectors were calculated. Radiomics and 4 feature pruning methods (area under the receiver operator characteristic curve, maximum relevance minimum redundancy, Spearman's ρ, Wilcoxon rank-sum) were evaluated in terms of Scan1-Scan2 repeatability using intraclass correlation coefficient (ICC)(3,1). Classification performance for clinically significant and insignificant PCa with Gleason grade groups 1 versus >1 was evaluated by area under the receiver operator characteristic curve in unseen random 30% data split.

Results: The ICC(3,1) values for conventional radiomics and feature pruning methods were in the range of 0.28-0.90. The machine learning classifications varied between Scan1 and Scan2 with % of same class labels between Scan1 and Scan2 in the range of 61-81%. Surface-to-volume ratio and corner detector-based features were among the most represented features with high repeatability, ICC(3,1) >0.75, consistently high ranking using all 4 feature pruning methods, and classification performance with area under the receiver operator characteristic curve >0.70.

Conclusion: Surface-to-volume ratio and corner detectors for prostate DWI led to good classification of unseen data and performed similarly in Scan1 and Scan2 in contrast to multiple conventional radiomic features.
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http://dx.doi.org/10.1002/mrm.28058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047644PMC
June 2020

Prostate Cancer Risk Stratification in Men With a Clinical Suspicion of Prostate Cancer Using a Unique Biparametric MRI and Expression of 11 Genes in Apparently Benign Tissue: Evaluation Using Machine-Learning Techniques.

J Magn Reson Imaging 2020 05 6;51(5):1540-1553. Epub 2019 Oct 6.

Institute of Biomedicine, University of Turku and Department of Pathology, Turku University Hospital, Turku, Finland.

Background: Accurate risk stratification of men with a clinical suspicion of prostate cancer (cSPCa) remains challenging despite the increasing use of MRI.

Purpose: To evaluate the diagnostic accuracy of a unique biparametric MRI protocol (IMPROD bpMRI) combined with clinical and molecular markers in men with cSPCa.

Study Type: Prospective single-institutional clinical trial (NCT01864135).

Subjects: Eighty men with cSPCa.

Field Strength/sequence: 3T, surface array coils. Two T -weighted and three diffusion-weighted imaging (DWI) acquisitions: 1) b-values 0, 100, 200, 300, 500 s/mm ; 2) b-values 0,1500 s/mm ; 3) b-values 0, 2000 s/mm .

Assessment: IMPROD bpMRI examinations were qualitatively (IMPROD bpMRI Likert score) and quantitatively (DWI-based Gleason grade score) prospectively reported. Men with IMPROD bpMRI Likert 3-5 had two targeted biopsies followed by 12-core systematic biopsies (SB); those with IMPROD bpMRI Likert 1-2 had only SB. Additionally, 2-core from normal-appearing prostate areas were obtained for the mRNA expression of ACSM1, AMACR, CACNA1D, DLX1, PCA3, PLA2G7, RHOU, SPINK1, SPON2, TMPRSS2-ERG, and TDRD1 measured by quantitative reverse-transcription polymerase chain reaction.

Statistical Tests: Univariate and multivariate analysis using regularized least-squares, feature selection and tournament leave-pair-out cross-validation (TLPOCV), as well as 10 random splits of the data in training-testing sets, were used to evaluate the mRNA, clinical and IMPROD bpMRI parameters in detecting clinically significant prostate cancer (SPCa) defined as Gleason score ≥ 3 + 4. The evaluation metric was the area under the curve (AUC).

Results: IMPROD bpMRI Likert demonstrated the highest TLPOCV AUC of 0.92. The tested clinical variables had AUC 0.56-0.73, while the mRNA and additional IMPROD bpMRI parameters had AUC 0.50-0.67 and 0.65-0.89 respectively. The combination of clinical and mRNA biomarkers produced TLPOCV AUC of 0.87, the highest TLPOCV performance without including IMPROD bpMRI Likert.

Data Conclusion: The qualitative IMPROD bpMRI Likert score demonstrated the highest accuracy for SPCa detection compared with the tested clinical variables and mRNA biomarkers.

Level Of Evidence: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1540-1553.
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http://dx.doi.org/10.1002/jmri.26945DOI Listing
May 2020

Prebiopsy IMPROD Biparametric Magnetic Resonance Imaging Combined with Prostate-Specific Antigen Density in the Diagnosis of Prostate Cancer: An External Validation Study.

Eur Urol Oncol 2020 10 6;3(5):648-656. Epub 2019 Sep 6.

Department of Urology, University of Turku and Turku University Hospital, Turku, Finland.

Background: Biparametric magnetic resonance imaging (bpMRI) combined with prostate-specific antigen density (PSAd) may be an effective strategy for selecting men for prostate biopsy. It has been shown that performing biopsy only for men with bpMRI Likert scores of 4-5 or PSAd ≥0.15 ng/ml/cm is the most efficient strategy.

Objective: To externally validate previously published biopsy strategies using two prospective bpMRI trial cohorts.

Design, Setting, And Participants: After IMPROD bpMRI, 499 men had systematic transrectal prostate biopsies and men with IMPROD bpMRI Likert scores of 3-5 had an additional two to four targeted biopsies.

Outcome Measurements And Statistical Analysis: Various IMPROD bpMRI Likert score and PSAd thresholds were assessed using detection rates for significant prostate cancer (sPCa; Gleason score ≥3 + 4), predictive values, and proportion of biopsies avoided. Net benefits and decision curve analyses (DCA) were compared with the aim of finding an optimal strategy for sPCa detection. Combined biopsies were used for reference.

Results And Limitations: The negative predictive value (NPV) for sPCa in IMPROD bpMRI Likert 3-5 and 4-5 score groups was 93% and 92%, respectively, while the corresponding positive predictive value (PPV) was 57% and 72%, respectively. In DCA, the optimal combination was IMPROD bpMRI Likert score 4-5 or Likert 3 with PSAd ≥0.20 ng/ml/cm, which had NPV of 93% and PPV of 67%. Using this combination, 35% of the study patients would have avoided biopsies and 13 sPCas (6%, 13/229, of all sPCas diagnosed) would have been missed.

Conclusions: IMPROD bpMRI demonstrated a good NPV for sPCa. PSAd improved the NPV mainly among men with equivocal suspicion on IMPROD bpMRI. However, the additional value of PSAd was marginal: the NPV and PPV for IMPROD bpMRI Likert 4-5 score group were 92% and 72%, respectively, while the corresponding values for the best combination strategy were 93% and 67%.

Patient Summary: We investigated a rapid prostate magnetic resonance imaging protocol (IMPROD bpMRI) combined with prostate-specific antigen (PSA) density for detection of significant prostate cancer. Our results show that IMPROD bpMRI is a good diagnostic tool, but the additional value provided by PSA density is marginal.
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http://dx.doi.org/10.1016/j.euo.2019.08.008DOI Listing
October 2020

Radiomics and machine learning of multisequence multiparametric prostate MRI: Towards improved non-invasive prostate cancer characterization.

PLoS One 2019 8;14(7):e0217702. Epub 2019 Jul 8.

Dept. of Diagnostic Radiology, University of Turku, Turku, Finland.

Purpose: To develop and validate a classifier system for prediction of prostate cancer (PCa) Gleason score (GS) using radiomics and texture features of T2-weighted imaging (T2w), diffusion weighted imaging (DWI) acquired using high b values, and T2-mapping (T2).

Methods: T2w, DWI (12 b values, 0-2000 s/mm2), and T2 data sets of 62 patients with histologically confirmed PCa were acquired at 3T using surface array coils. The DWI data sets were post-processed using monoexponential and kurtosis models, while T2w was standardized to a common scale. Local statistics and 8 different radiomics/texture descriptors were utilized at different configurations to extract a total of 7105 unique per-tumor features. Regularized logistic regression with implicit feature selection and leave pair out cross validation was used to discriminate tumors with 3+3 vs >3+3 GS.

Results: In total, 100 PCa lesions were analysed, of those 20 and 80 had GS of 3+3 and >3+3, respectively. The best model performance was obtained by selecting the top 1% features of T2w, ADCm and K with ROC AUC of 0.88 (95% CI of 0.82-0.95). Features from T2 mapping provided little added value. The most useful texture features were based on the gray-level co-occurrence matrix, Gabor transform, and Zernike moments.

Conclusion: Texture feature analysis of DWI, post-processed using monoexponential and kurtosis models, and T2w demonstrated good classification performance for GS of PCa. In multisequence setting, the optimal radiomics based texture extraction methods and parameters differed between different image types.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217702PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613688PMC
February 2020

Validation of IMPROD biparametric MRI in men with clinically suspected prostate cancer: A prospective multi-institutional trial.

PLoS Med 2019 06 3;16(6):e1002813. Epub 2019 Jun 3.

Department of Urology, University of Turku and Turku University Hospital, Turku, Finland.

Background: Magnetic resonance imaging (MRI) combined with targeted biopsy (TB) is increasingly used in men with clinically suspected prostate cancer (PCa), but the long acquisition times, high costs, and inter-center/reader variability of routine multiparametric prostate MRI limit its wider adoption.

Methods And Findings: The aim was to validate a previously developed unique MRI acquisition and reporting protocol, IMPROD biparametric MRI (bpMRI) (NCT01864135), in men with a clinical suspicion of PCa in a multi-institutional trial (NCT02241122). IMPROD bpMRI has average acquisition time of 15 minutes (no endorectal coil, no intravenous contrast use) and consists of T2-weighted imaging and 3 separate diffusion-weighed imaging acquisitions. Between February 1, 2015, and March 31, 2017, 364 men with a clinical suspicion of PCa were enrolled at 4 institutions in Finland. Men with an equivocal to high suspicion (IMPROD bpMRI Likert score 3-5) of PCa had 2 TBs of up to 2 lesions followed by a systematic biopsy (SB). Men with a low to very low suspicion (IMPROD bpMRI Likert score 1-2) had only SB. All data and protocols are freely available. The primary outcome of the trial was diagnostic accuracy-including overall accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value-of IMPROD bpMRI for clinically significant PCa (SPCa), which was defined as a Gleason score ≥ 3 + 4 (Gleason grade group 2 or higher). In total, 338 (338/364, 93%) prospectively enrolled men completed the trial. The accuracy and NPV of IMPROD bpMRI for SPCa were 70% (113/161) and 95% (71/75) (95% CI 87%-98%), respectively. Restricting the biopsy to men with equivocal to highly suspicious IMPROD bpMRI findings would have resulted in a 22% (75/338) reduction in the number of men undergoing biopsy while missing 4 (3%, 4/146) men with SPCa. The main limitation is uncertainty about the true PCa prevalence in the study cohort, since some of the men may have PCa despite having negative biopsy findings.

Conclusions: IMPROD bpMRI demonstrated a high NPV for SPCa in men with a clinical suspicion of PCa in this prospective multi-institutional clinical trial.

Trial Registration: ClinicalTrials.gov NCT02241122.
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http://dx.doi.org/10.1371/journal.pmed.1002813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546206PMC
June 2019

IMPROD biparametric MRI in men with a clinical suspicion of prostate cancer (IMPROD Trial): Sensitivity for prostate cancer detection in correlation with whole-mount prostatectomy sections and implications for focal therapy.

J Magn Reson Imaging 2019 11 22;50(5):1641-1650. Epub 2019 Mar 22.

Institute of Biomedicine, University of Turku and Department of Pathology, Turku University Hospital, Turku, Finland.

Background: Prostate MRI is increasingly being used in men with a clinical suspicion of prostate cancer (PCa). However, development and validation of methods for focal therapy planning are still lagging.

Purpose: To evaluate the diagnostic accuracy on lesion, region-of-interest (ROI), and voxel level of IMPROD biparametric prostate MRI (bpMRI) for PCa detection in men with a clinical suspicion of PCa who subsequently underwent radical prostatectomy.

Study Type: Prospective single-institution clinical trial (NCT01864135).

Population: Sixty-four men who underwent radical prostatectomy after IMPROD bpMRI performed in prebiopsy settings.

Field Strength/sequence: IMPROD bpMRI consisted of T -weighted imaging (T w) and three separate diffusion-weighted imaging acquisitions with an average acquisition time of 15 minutes.

Assessment: The diagnostic accuracy of prospectively reported manual cancer delineations and regions increased with 3D dilation were evaluated on the voxel level (volume of 1.17 mm , 1 mm , 125 mm ) as well as the 36 ROI level. Only PCa lesions with a diameter ≥ 5 mm or any Gleason Grade 4 were analyzed. All data and protocols are freely available at: http://petiv.utu.fi/improd STATISTICAL TESTS: Sensitivity, specificity, accuracy.

Results: In total, 99 PCa lesions were identified. Forty (40%, 40/99) had a Gleason score (GS) of >3 + 4. Twenty-eight PCa lesions (28%, 28/99) were missed by IMPROD bpMRI, three (7.5%, 3/40) with GS >3 + 4. 3D dilation of manual cancer delineations in all directions by ~10-12 mm (corresponding to the Hausdorff distance) was needed to achieve sensitivity approaching 100% on a voxel level.

Data Conclusion: IMPROD bpMRI had a high sensitivity on lesion level for PCa with GS >3 + 4. Increasing 3D lesion delineations by ~10-12 mm (corresponding to the Hausdorff distance) was needed to achieve high sensitivity on the voxel level. Such information may help in planning ablation therapies.

Level Of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1641-1650.
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http://dx.doi.org/10.1002/jmri.26727DOI Listing
November 2019

Prospective evaluation of F-FACBC PET/CT and PET/MRI versus multiparametric MRI in intermediate- to high-risk prostate cancer patients (FLUCIPRO trial).

Eur J Nucl Med Mol Imaging 2018 03 16;45(3):355-364. Epub 2017 Nov 16.

Turku PET Centre, Turku, Finland.

Purpose: The purpose of this study was to evaluate F-FACBC PET/CT, PET/MRI, and multiparametric MRI (mpMRI) in detection of primary prostate cancer (PCa).

Methods: Twenty-six men with histologically confirmed PCa underwent PET/CT immediately after injection of 369 ± 10 MBq F-FACBC (fluciclovine) followed by PET/MRI started 55 ± 7 min from injection. Maximum standardized uptake values (SUV) were measured for both hybrid PET acquisitions. A separate mpMRI was acquired within a week of the PET scans. Logan plots were used to calculate volume of distribution (V). The presence of PCa was estimated in 12 regions with radical prostatectomy findings as ground truth. For each imaging modality, area under the curve (AUC) for detection of PCa was determined to predict diagnostic performance. The clinical trial registration number is NCT02002455.

Results: In the visual analysis, 164/312 (53%) regions contained PCa, and 41 tumor foci were identified. PET/CT demonstrated the highest sensitivity at 87% while its specificity was low at 56%. The AUC of both PET/MRI and mpMRI significantly (p < 0.01) outperformed that of PET/CT while no differences were detected between PET/MRI and mpMRI. SUV and V of Gleason score (GS) >3 + 4 tumors were significantly (p < 0.05) higher than those for GS 3 + 3 and benign hyperplasia. A total of 442 lymph nodes were evaluable for staging, and PET/CT and PET/MRI demonstrated true-positive findings in only 1/7 patients with metastatic lymph nodes.

Conclusions: Quantitative F-FACBC imaging significantly correlated with GS but failed to outperform MRI in lesion detection. F-FACBC may assist in targeted biopsies in the setting of hybrid imaging with MRI.
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http://dx.doi.org/10.1007/s00259-017-3875-1DOI Listing
March 2018

Novel biparametric MRI and targeted biopsy improves risk stratification in men with a clinical suspicion of prostate cancer (IMPROD Trial).

J Magn Reson Imaging 2017 10 6;46(4):1089-1095. Epub 2017 Feb 6.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Purpose: To evaluate the role of a 3T biparametric magnetic resonance imaging (bpMRI), T -weighted imaging, and three separate diffusion-weighted imaging acquisitions combined with targeted biopsy (TB) for improving risk stratification of men with elevated prostate-specific antigen (PSA).

Materials And Methods: Between March 2013 and February 2015, 175 men with a clinical suspicion of prostate cancer (PCa) were offered bpMRI (NCT01864135) based on a suspicion of PCa (two repeated PSA measurements in the range 2.5-20.0 ng/ml and/or abnormal digital rectal examination). Men with an equivocal to high suspicion of PCa had two TBs of the dominant lesion using cognitive ultrasound guidance, followed by systematic biopsy (SB). Men with a low to very low suspicion had only SB. In total, 161 (161/175, 92%) prospectively enrolled men completed the trial and were included in the final analyses. The primary endpoint of the trial was the cancer detection rate (CDR) of TB and SB. Clinically significant cancer (SPCa) was defined as Gleason score ≥3 + 4.

Results: TB compared with SB had higher CDR for SPCa (45%, 72/161 vs. 39%, 63/161, respectively; P > 0.05) and a lower CDR for Gleason score 3 + 3 (8%, 15/161 vs. 16%, 30/161; P < 0.05). Restricting biopsy to men with equivocal to highly suspicious bpMRI findings would have resulted in a 24% (38/161) reduction in the number of men undergoing biopsy, while missing 4 (2%) with SPCa. All anonymized datasets, including bpMRI reports and follow up information, are freely available on the trial server.

Conclusion: Prebiopsy bpMRI and TB in men with a clinical suspicion of PCa improved risk stratification.

Level Of Evidence: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:1089-1095.
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http://dx.doi.org/10.1002/jmri.25641DOI Listing
October 2017

Radiomic features for prostate cancer detection on MRI differ between the transition and peripheral zones: Preliminary findings from a multi-institutional study.

J Magn Reson Imaging 2017 07 19;46(1):184-193. Epub 2016 Dec 19.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA.

Purpose: To evaluate in a multi-institutional study whether radiomic features useful for prostate cancer (PCa) detection from 3 Tesla (T) multi-parametric MRI (mpMRI) in the transition zone (TZ) differ from those in the peripheral zone (PZ).

Materials And Methods: 3T mpMRI, including T2-weighted (T2w), apparent diffusion coefficient (ADC) maps, and dynamic contrast-enhanced MRI (DCE-MRI), were retrospectively obtained from 80 patients at three institutions. This study was approved by the institutional review board of each participating institution. First-order statistical, co-occurrence, and wavelet features were extracted from T2w MRI and ADC maps, and contrast kinetic features were extracted from DCE-MRI. Feature selection was performed to identify 10 features for PCa detection in the TZ and PZ, respectively. Two logistic regression classifiers used these features to detect PCa and were evaluated by area under the receiver-operating characteristic curve (AUC). Classifier performance was compared with a zone-ignorant classifier.

Results: Radiomic features that were identified as useful for PCa detection differed between TZ and PZ. When classification was performed on a per-voxel basis, a PZ-specific classifier detected PZ tumors on an independent test set with significantly higher accuracy (AUC = 0.61-0.71) than a zone-ignorant classifier trained to detect cancer throughout the entire prostate (P < 0.05). When classifiers were evaluated on MRI data from multiple institutions, statistically similar AUC values (P > 0.14) were obtained for all institutions.

Conclusion: A zone-aware classifier significantly improves the accuracy of cancer detection in the PZ.

Level Of Evidence: 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:184-193.
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http://dx.doi.org/10.1002/jmri.25562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464994PMC
July 2017

Patient-specific pharmacokinetic parameter estimation on dynamic contrast-enhanced MRI of prostate: Preliminary evaluation of a novel AIF-free estimation method.

J Magn Reson Imaging 2016 12 10;44(6):1405-1414. Epub 2016 Jun 10.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA.

Purpose: To develop and evaluate a prostate-based method (PBM) for estimating pharmacokinetic parameters on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) by leveraging inherent differences in pharmacokinetic characteristics between the peripheral zone (PZ) and transition zone (TZ).

Materials And Methods: This retrospective study, approved by the Institutional Review Board, included 40 patients who underwent a multiparametric 3T MRI examination and subsequent radical prostatectomy. A two-step PBM for estimating pharmacokinetic parameters exploited the inherent differences in pharmacokinetic characteristics associated with the TZ and PZ. First, the reference region model was implemented to estimate ratios of K between normal TZ and PZ. Subsequently, the reference region model was leveraged again to estimate values for K and v for every prostate voxel. The parameters of PBM were compared with those estimated using an arterial input function (AIF) derived from the femoral arteries. The ability of the parameters to differentiate prostate cancer (PCa) from benign tissue was evaluated on a voxel and lesion level. Additionally, the effect of temporal downsampling of the DCE MRI data was assessed.

Results: Significant differences (P < 0.05) in PBM K between PCa lesions and benign tissue were found in 26/27 patients with TZ lesions and in 33/38 patients with PZ lesions; significant differences in AIF-based K occurred in 26/27 and 30/38 patients, respectively. The 75 and 100 percentiles of K and v estimated using PBM positively correlated with lesion size (P < 0.05).

Conclusion: Pharmacokinetic parameters estimated via PBM outperformed AIF-based parameters in PCa detection. J. Magn. Reson. Imaging 2016;44:1405-1414.
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http://dx.doi.org/10.1002/jmri.25330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559229PMC
December 2016

Fitting methods for intravoxel incoherent motion imaging of prostate cancer on region of interest level: Repeatability and gleason score prediction.

Magn Reson Med 2017 03 28;77(3):1249-1264. Epub 2016 Feb 28.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Purpose: To evaluate different fitting methods for intravoxel incoherent motion (IVIM) imaging of prostate cancer in the terms of repeatability and Gleason score prediction.

Methods: Eighty-one patients with histologically confirmed prostate cancer underwent two repeated 3 Tesla diffusion-weighted imaging (DWI) examinations performed using 14 b-values in the range of 0-500 s/mm and diffusion time of 19.004 ms. Mean signal intensities of regions-of-interest were fitted using five different fitting methods for IVIM as well as monoexponential, kurtosis, and stretched exponential models. The fitting methods and models were evaluated in the terms of fitting quality [Akaike information criteria (AIC)], repeatability, and Gleason score prediction. Tumors were classified into three groups (3 + 3, 3 + 4, > 3 + 4). Machine learning algorithms were used to evaluate the performance of the combined use of the parameters. Simulation studies were performed to evaluate robustness of the fitting methods against noise.

Results: Monoexponential model was preferred over IVIM based on AIC. The "pseudodiffusion" parameters demonstrated low repeatability and clinical value. Median "pseudodiffusion" fraction values were below 8.00%. Combined use of the parameters did not outperform the monoexponential model.

Conclusion: Monoexponential model demonstrated the highest repeatability and clinical values in the regions-of-interest based analysis of prostate cancer DWI, b-values in the range of 0-500 s/mm . Magn Reson Med 77:1249-1264, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
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http://dx.doi.org/10.1002/mrm.26169DOI Listing
March 2017

Diffusion-weighted imaging of prostate cancer: effect of b-value distribution on repeatability and cancer characterization.

Magn Reson Imaging 2015 Dec 26;33(10):1212-1218. Epub 2015 Jul 26.

Department of Diagnostic Radiology, University of Turku, Turku, Finland. Electronic address:

Purpose: To evaluate the effect of b-value distribution on the repeatability and Gleason score (GS) prediction of prostate cancer (PCa).

Methods: Fifty PCa patients underwent two repeated 3T diffusion-weighted imaging (DWI) examinations using 12 b values in the range from 0 to 2000s/mm(2) and diffusion time of 20.3ms. Mean signal intensities of regions of interest, placed in PCa using whole mount prostatectomy sections as the reference, were fitted using monoexponential, kurtosis, stretched exponential, and biexponential models. In total, 4083 different b-value combinations consisting of 2 to 12 b values were evaluated. Repeatability was assessed by intraclass correlation coefficient, ICC(3,1), and coefficient of repeatability (CoR). Areas under receiver operating characteristic curve (AUCs) for PCa characterization were estimated while the correlation of the fitted values with GS groups (3+3, 3+4, >3+4) was evaluated by using the Spearman correlation coefficient (ρ).

Results: The parameters of monoexponential, kurtosis, and stretched exponential models estimated using only 4-5, 5-7, 5-7 b values, respectively, had similar ICC(3,1), CoR, AUC, and ρ values as the parameters estimated using all 12 b values. Optimized b-value distributions demonstrated improved ICC(3,1) and CoR values but failed to improve AUC and ρ values. The parameters of biexponential model demonstrated the worst repeatability and diagnostic performance.

Conclusion: B-value distribution influences mainly the repeatability of DWI-derived parameters rather than the diagnostic performance.
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http://dx.doi.org/10.1016/j.mri.2015.07.004DOI Listing
December 2015

Relaxation along fictitious field, diffusion-weighted imaging, and T2 mapping of prostate cancer: Prediction of cancer aggressiveness.

Magn Reson Med 2016 May 22;75(5):2130-40. Epub 2015 Jun 22.

Department of Radiology, University of Turku, Turku, Finland.

Purpose: To evaluate the performance of relaxation along a fictitious field (RAFF) relaxation time (TRAFF ), diffusion-weighted imaging (DWI)-derived parameters, and T2 relaxation time values for prostate cancer (PCa) detection and characterization.

Methods: Fifty patients underwent 3T MR examination using surface array coils before prostatectomy. DWI was performed using 14 and 12 b values in the ranges of 0-500 s/mm(2) and 0-2000 s/mm(2) , respectively. Repeated MR examination was performed in 16 patients. TRAFF , DWI-derived parameters (monoexponential, kurtosis, biexponential models), and T2 values were measured and averaged over regions of interest placed in PCa and normal tissue. Repeatability of TRAFF and DWI-derived parameters were assessed by coefficient of repeatability and intraclass correlation coefficient ICC(3,1). Areas under the receiver operating characteristic curve (AUCs) for PCa detection and Gleason score classification were estimated. The parameters were correlated with Gleason score groups using Spearman correlation coefficient (ρ).

Results: ICC(3,1) values for TRAFF were in the range of 0.82-0.92. TRAFF values had higher AUC values for Gleason score classification compared with DWI-derived parameters and T2 . The RAFF method demonstrated the highest ρ value (-0.65).

Conclusion: In a quantitative region of interest-based analysis, RAFF outperformed DWI ("low" and "high" b values) and T2 mapping in the characterization of PCa.
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http://dx.doi.org/10.1002/mrm.25808DOI Listing
May 2016

Prospective evaluation of planar bone scintigraphy, SPECT, SPECT/CT, 18F-NaF PET/CT and whole body 1.5T MRI, including DWI, for the detection of bone metastases in high risk breast and prostate cancer patients: SKELETA clinical trial.

Acta Oncol 2016 2;55(1):59-67. Epub 2015 Apr 2.

d Turku PET Centre , Turku , Finland.

Purpose: Detection of bone metastases in breast and prostate cancer patients remains a major clinical challenge. The aim of the current trial was to compare the diagnostic accuracy of (99m)Tc-hydroxymethane diphosphonate ((99m)Tc-HDP) planar bone scintigraphy (BS), (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and whole body 1.5 Tesla magnetic resonance imaging (MRI), including diffusion weighted imaging, (wbMRI+DWI) for the detection of bone metastases in high risk breast and prostate cancer patients.

Material And Methods: Twenty-six breast and 27 prostate cancer patients at high risk of bone metastases underwent (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and wbMRI+DWI. Five independent reviewers interpreted each individual modality without the knowledge of other imaging findings. The final metastatic status was based on the consensus reading, clinical and imaging follow-up (minimal and maximal follow-up time was 6, and 32 months, respectively). The bone findings were compared on patient-, region-, and lesion-level.

Results: (99m)Tc-HDP BS was false negative in four patients. In the region-based analysis, sensitivity values for (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT, and wbMRI+DWI were 62%, 74%, 85%, 93%, and 91%, respectively. The number of equivocal findings for (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and wbMRI+DWI was 50, 44, 5, 6, and 4, respectively.

Conclusion: wbMRI+DWI showed similar diagnostic accuracy to (18)F-NaF PET/CT and outperformed (99m)Tc-HDP SPECT/CT, and (99m)Tc-HDP BS.
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http://dx.doi.org/10.3109/0284186X.2015.1027411DOI Listing
December 2016

Rotating frame relaxation imaging of prostate cancer: Repeatability, cancer detection, and Gleason score prediction.

Magn Reson Med 2016 Jan 2;75(1):337-44. Epub 2015 Mar 2.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Purpose: To investigate relaxation along a fictitious field (RAFF) and continuous wave (cw) T1ρ imaging of prostate cancer (PCa) in the terms of repeatability, PCa detection, and characterization.

Methods: Thirty-six patients (PSA 11.6 ± 7.6 ng/mL, mean ± standard deviation) with histologically confirmed PCa underwent two repeated 3T MR examinations using surface array coils before prostatectomy. Relaxation along fictitious field, cw T1ρ, and T2 relaxation times (TRAFF, T1ρcw, T2) were measured and averaged over regions of interest placed in PCa, normal peripheral zone (PZ), and normal central gland (CG) positioned using whole-mount prostatectomy sections and anatomical T2-weighted images. Receiver operating characteristic curve analysis with area under the curve (AUC) was calculated to distinguish PCa from PZ/CG and PCa with Gleason score (GS) of 3+3 from GS of 3+4/≥ 3+4.

Results: TRAFF and T1ρcw relaxation times were repeatable with coefficients of repeatability as a percentage of median value in the range of 7.8-23.2%. AUC (mean, 95% confidence interval) in the differentiation of PCa with GS of 3+3 from PCa with CS of ≥ 3+4 were 0.88 (0.72-0.99), 0.69 (0.46-0.90), and 0.68 (0.45-0.88), for TRAFF, T1ρcw, and T2, respectively.

Conclusion: In quantitative region of interest based analysis, TRAFF outperformed T1ρcw and T2 in PCa detection and characterization.
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http://dx.doi.org/10.1002/mrm.25647DOI Listing
January 2016

Mathematical models for diffusion-weighted imaging of prostate cancer using b values up to 2000 s/mm(2) : correlation with Gleason score and repeatability of region of interest analysis.

Magn Reson Med 2015 Oct 20;74(4):1116-24. Epub 2014 Oct 20.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Purpose: To evaluate four mathematical models for diffusion weighted imaging (DWI) of prostate cancer (PCa) in terms of PCa detection and characterization.

Methods: Fifty patients with histologically confirmed PCa underwent two repeated 3 Tesla DWI examinations using 12 equally distributed b values, the highest b value of 2000 s/mm(2) . Normalized mean signal intensities of regions-of-interest were fitted using monoexponential, kurtosis, stretched exponential, and biexponential models. Tumors were classified into low, intermediate, and high Gleason score groups. Areas under receiver operating characteristic curve (AUCs) were estimated to evaluate performance in PCa detection and Gleason score classifications. The fitted parameters were correlated with Gleason score groups by using the Spearman correlation coefficient (ρ). Coefficient of repeatability and intraclass correlation coefficient [specifically ICC(3,1)], were calculated to evaluate repeatability of the fitted parameters.

Results: The AUC and ρ values were similar between parameters of monoexponential, kurtosis, and stretched exponential (with the exception of the α parameter) models. The absolute ρ values for ADCm , ADCk , K, and ADCs were in the range from 0.31 to 0.53 (P < 0.01). Parameters of the biexponential model demonstrated low repeatability.

Conclusion: In region-of-interest based analysis, the monoexponential model for DWI of PCa using b values up to 2000 s/mm(2) was sufficient for PCa detection and characterization.
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http://dx.doi.org/10.1002/mrm.25482DOI Listing
October 2015

Evaluation of different mathematical models for diffusion-weighted imaging of normal prostate and prostate cancer using high b-values: a repeatability study.

Magn Reson Med 2015 May 12;73(5):1988-98. Epub 2014 Jul 12.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Purpose: To evaluate monoexponential, stretched exponential, kurtosis, and biexponential models for diffusion-weighted imaging (DWI) of normal prostate and prostate cancer (PCa), using b-values up to 2000 s/mm(2) , in terms of fitting quality and repeatability.

Methods: Eight healthy volunteers and 16 PCa patients underwent a total of four repeated 3T DWI examinations using 16 and 12 b-values, respectively. The highest b-value was 2000 s/mm(2) . The normalized mean signal intensities of regions of interest, placed in normal tissue and PCa using anatomical images and prostatectomy sections, were fitted using the four models. The fitting quality was evaluated using Akaike information criteria and F-ratio. Repeatability of the fitted parameters was evaluated using intraclass correlation coefficient ICC(3,1).

Results: The biexponential model provided the best fit to normal prostate and PCa DWI data. The parameters of the monoexponential, kurtosis, and stretched exponential (with the exception of the α parameter) models had higher ICC(3,1) values compared with the biexponential model. The kurtosis model provided a better fit to DWI data of normal prostate and PCa than the monoexponential model, whereas these models had comparable reliability and repeatability based on ICC(3,1) values.

Conclusion: Considering the model fit and repeatability, the kurtosis model seems to be the preferred model for characterization of normal prostate and PCa DWI using b-values up to 2000 s/mm(2) .
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http://dx.doi.org/10.1002/mrm.25323DOI Listing
May 2015

Prebiopsy multiparametric 3T prostate MRI in patients with elevated PSA, normal digital rectal examination, and no previous biopsy.

J Magn Reson Imaging 2015 May 23;41(5):1394-404. Epub 2014 Jun 23.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Purpose: To find the diagnostic accuracy of 3T multiparametric magnetic resonance imaging (mpMRI) and mpMRI targeted transrectal ultrasound (TRUS)-guided biopsy using visual coregistration (TB) in patients with elevated prostate-specific antigen (PSA), normal digital rectal examination, and no previous biopsy.

Materials And Methods: Fifty-five patients at two institutions underwent mpMRI, consisting of anatomical T2 -weighted imaging (T2 W), diffusion-weighted imaging (DWI), proton magnetic resonance spectroscopy ((1) H-MRS), and dynamic contrast-enhanced MRI (DCE-MRI), followed by TB in addition to 12 core systematic TRUS-guided biopsy (SB). Histopathological scorings of biopsy (n = 38) and prostatectomy (n = 17) specimens were used as the reference standard for calculation of diagnostic accuracy values. Clinically significant prostate cancer (SPCa) was defined as 3 mm core length of Gleason score 3+3 or any Gleason grade 4.

Results: The sensitivity, specificity, accuracy, and area under the curve (AUC) values for the detection of SPCa on the sextant level for T2 W+DWI+(1) H-MRS+DCE-MRI were 72%, 89%, 85%, and 0.81, respectively. The corresponding values for T2 wi+DWI were 61%, 96%, 87%, and 0.79, respectively. The overall PCa detection rate per core in 53 patients was 21% (138 of 648 cores) for SB and 43% (33 of 77 cores) for TB (P < 0.001).

Conclusion: Prebiopsy mpMRI is an accurate tool for PCa detection and biopsy targeting in patients with elevated PSA.
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http://dx.doi.org/10.1002/jmri.24682DOI Listing
May 2015

Optimization of b-value distribution for biexponential diffusion-weighted MR imaging of normal prostate.

J Magn Reson Imaging 2014 May 11;39(5):1213-22. Epub 2013 Oct 11.

Department of Diagnostic Radiology, University of Turku, Turku, Finland; 2nd Department of Radiology, Comenius University and St. Elisabeth Oncology Institute, Bratislava, Slovakia.

Purpose: To determine the optimal b-value distribution for biexponential diffusion-weighted imaging (DWI) of normal prostate using both a computer modeling approach and in vivo measurements.

Materials And Methods: Optimal b-value distributions for the fit of three parameters (fast diffusion Df, slow diffusion Ds, and fraction of fast diffusion f) were determined using Monte-Carlo simulations. The optimal b-value distribution was calculated using four individual optimization methods. Eight healthy volunteers underwent four repeated 3 Tesla prostate DWI scans using both 16 equally distributed b-values and an optimized b-value distribution obtained from the simulations. The b-value distributions were compared in terms of measurement reliability and repeatability using Shrout-Fleiss analysis.

Results: Using low noise levels, the optimal b-value distribution formed three separate clusters at low (0-400 s/mm2), mid-range (650-1200 s/mm2), and high b-values (1700-2000 s/mm2). Higher noise levels resulted into less pronounced clustering of b-values. The clustered optimized b-value distribution demonstrated better measurement reliability and repeatability in Shrout-Fleiss analysis compared with 16 equally distributed b-values.

Conclusion: The optimal b-value distribution was found to be a clustered distribution with b-values concentrated in the low, mid, and high ranges and was shown to improve the estimation quality of biexponential DWI parameters of in vivo experiments.
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http://dx.doi.org/10.1002/jmri.24271DOI Listing
May 2014

Cavum septum pellucidum and psychopathy.

Br J Psychiatry 2013 Aug;203(2):152-3

Vanha Vaasa Hospital, Vaasa, Finland.

The presence of cavum septum pellucidum (CSP) has been reported to be a neurodevelopmental marker of psychopathy. We scanned 26 violent offenders and 25 controls; 2 offenders and 2 controls had CSP (8% in both groups). Thus, the presence of CSP is not a common or a unique feature of antisocial personality disorder or psychopathy.
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http://dx.doi.org/10.1192/bjp.bp.112.123844DOI Listing
August 2013