Comprehensive tissue deconvolution of cell-free DNA by deep learning for disease diagnosis and monitoring.

Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of diseases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the largest comprehensive and high-resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the first supervised tissue deconvolution approach, a deep-learning-powered model, cfSort, for sensitive and accurate tissue deconvolution in cfDNA. On the benchmarking data, cfSort showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical utilities of cfSort with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from cfSort reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and cfSort enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring.

Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer.

Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow.

Efficacy of 3T Multiparametric MR Imaging followed by 3T in-Bore MR-Guided Biopsy for Detection of Clinically Significant Prostate Cancer Based on PIRADSv2.1 Score.

PURPOSE: To evaluate the diagnostic yield of 3T in-Bore magnetic resonance-guided biopsy (3T IB-MRGB) for detection of clinically significant prostate cancer (csPCa), based on assessment using the Prostate Imaging Reporting and Data System version 2.1 (PIRADSv2.1). MATERIALS AND METHODS: This single-center study examined individuals who underwent 3T multiparametric prostate magnetic resonance (MR) imaging and subsequent 3T IB-MRGB. The final study cohort included 379 men (with 475 targets) divided into 3 subcohorts: biopsy-naïve men (n = 123), individuals with a history of negative trans-rectal-ultrasonography (TRUS) biopsy results (n = 106), and men with low-grade PCa under active surveillance (n = 150). csPCa was defined as having a Gleason score (GS) ≥3+4. RESULTS: 3T IB-MRGB detected PCa and csPCa in 69.1% (262 of 379) and 50.3% (193 of 379) of patients, respectively. The PCa and csPCa detection rates per target were 64.2% (305 of 475) and 43.8% (208 of 475), respectively. The rate of urosepsis, treated with intravenous antibiotics, was 1% (4 patients). In TRUS biopsy negative results and biopsy-naïve subcohorts, csPCa was found in 36.8% (39 of 106) and 52.8% (65 of 123), respectively. In 50.7% (76 of 150) of the active surveillance subcohort, 3T IB-MRGB upgraded the GS assigned in prior TRUS biopsies. Positive predictive values of PIRADSv2.1 categories 3, 4, and 5 for csPCa detection were 24.8%, 44.4%, and 67.1%, respectively. Higher PIRADSv2.1 categories were significantly associated with PCa (odds ratio [OR], 3.97; 95% confidence interval [CI], 2.98-5.28) and csPCa (OR, 1.41; 95% CI, 1.03-1.94) detection. Of 137 PIRADSv2 category 3 lesions, 28 were downgraded to PIRADSv2.1 category 2, in which there were no occurrences of csPCa in histology. CONCLUSIONS: Use of 3T IB-MRGB resulted in detection of csPCa in 50.9% of individuals. 3T IB-MRGB has a high diagnostic yield in individuals with negative TRUS biopsy results and those under active surveillance. The PIRADSv2.1 category is a strong predictor of PCa and csPCa detection.

3-T Multiparametric MRI Followed by In-Bore MR-Guided Biopsy for Detecting Clinically Significant Prostate Cancer After Prior Negative Transrectal Ultrasound-Guided Biopsy.

OBJECTIVE. The purpose of this study was to evaluate the rate of detection of clinically significant prostate cancer (csPCa), as assessed on the basis of Prostate Imaging Reporting and Data System version 2.1 (PI-RADSv2.1) guidelines, using 3-T in-bore MR-guided biopsy (MRGB) for a cohort of patients suspected of having csPCa despite having a history of recent negative transrectal ultrasound-guided biopsy results. MATERIALS AND METHODS. The cohort in this retrospective, single-center study was derived from a database of 330 patients who underwent multiparametric MRI (mpMRI) followed by in-bore transrectal 3-T MRGB. Seventy-nine patients (mean [± SD] age, 64.1 ± 8.6 years) with prior negative transrectal ultrasound-guided biopsy results and positive pre-MRGB mpMRI results (PI-RADS score ≥ 3) composed the final cohort. The rate of detection of PCa and csPCa (the latter of which was defined by a Gleason score of 3 + 4 or higher) was stratified according to updated PI-RADSv2.1 assessment. RESULTS. MRGB detected PCa in 36 patients (45.6%), 30 (83.3%) of whom had csPCa. The PI-RADSv2.1 score was a strong predictor (odds ratio, 3.97; 95% CI, 1.93-7.47) of csPCa detection. We found two benign transition zone target lesions that were downgraded from PI-RADSv2 category 3 to PI-RADSv2.1 category 2. PCa was detected in 18.4% (7/38), 65.2% (15/23), and 87.5% (14/16) of individuals with PI-RADSv2.1 category 3, 4, and 5 lesions, respectively, with 85.7% (6/7), 86.7% (13/15), and 78.6% (11/14) of these cases found to be csPCa, respectively. Of the seven PI-RADSv2.1 category 3 csPCa lesions, six had prostate-specific antigen density greater than 0.10 ng/mL/cc. CONCLUSION. With the use of 3-T in-bore MRGB, csPCa was detected in 38% of individuals with prior negative transrectal ultrasound-guided biopsy results. PI-RADSv2.1 was a strong predictor of csPCa detection. On the basis of our results, patients with PI-RADSv2.1 category 4 or 5 lesions and patients with PI-RADSv2.1 category 3 lesions and a prostate-specific antigen density greater than or equal to 0.10 ng/mL/cc may benefit from in-bore MRGB.

Influence of the Location and Zone of Tumor in Prostate Cancer Detection and Localization on 3-T Multiparametric MRI Based on PI-RADS Version 2.

OBJECTIVE. The objective of our study was to determine the performance of 3-T multiparametric MRI (mpMRI) for prostate cancer (PCa) detection and localization, stratified by anatomic zone and level, using Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) and whole-mount histopathology (WMHP) as reference. MATERIALS AND METHODS. Multiparametric MRI examinations of 415 consecutive men were compared with thin-section WMHP results. A genitourinary radiologist and pathologist collectively determined concordance. Two radiologists assigned PI-RADSv2 scores and sector location to all detected foci by consensus. Tumor detection rates were calculated for clinical and pathologic (tumor location and zone) variables. Both rigid and adjusted sector-matching models were used to account for fixation-related issues. RESULTS. Of 863 PCa foci in 16,185 prostate sectors, the detection of overall and index PCa lesions in the midgland, base, and apex was 54.9% and 83.1%, 42.1% and 64.0% (p = 0.04, p = 0.02), and 41.9% and 71.4% (p = 0.001, p = 0.006), respectively. Tumor localization sensitivity was highest in the midgland compared with the base and apex using an adjusted match compared with a rigid match (index lesions, 71.3% vs 43.7%; all lesions, 70.8% vs 36.0%) and was greater in the peripheral zone (PZ) than in the transition zone. Three-Tesla mpMRI had similarly high specificity (range, 93.8-98.3%) for overall and index tumor localization when using both rigid and adjusted sector-matching approaches. CONCLUSION. For 3-T mpMRI, the highest sensitivity (83.1%) for detection of index PCa lesions was in the midgland, with 98.3% specificity. Multiparametric MRI performance for sectoral localization of PCa within the prostate was moderate and was best for index lesions in the PZ using an adjusted model.

Detection and Localization of Prostate Cancer at 3-T Multiparametric MRI Using PI-RADS Segmentation.

OBJECTIVE. The purpose of this study is to determine the overall and sector-based performance of 3-T multiparametric MRI for prostate cancer (PCa) detection and localization by using Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2) scoring and segmentation compared with whole-mount histopathologic analysis. MATERIALS AND METHODS. Multiparametric 3-T MRI examinations of 415 consecutive men were compared with thin-section whole-mount histopathologic analysis. A genitourinary radiologist and pathologist collectively determined concordance. Two radiologists assigned PI-RADSv2 categories and sectoral location to all detected foci by consensus. Tumor detection rates were calculated for clinical and pathologic (Gleason score) variables. Both rigid and adjusted sector-matching models were used to account for fixation-related issues. RESULTS. The 415 patients had 863 PCa foci (52.7% had a Gleason score ≥ 7, 61.9% were ≥ 1 cm, and 90.4% (375/415) of index lesions were ≥ 1 cm) and 16,185 prostate sectors. Multiparametric MRI enabled greater detection of PCa lesions 1 cm or larger (all lesions vs index lesions, 61.6% vs 81.6%), lesions with Gleason score greater than or equal to 7 (all lesions vs index lesions, 71.4% vs 80.9%), and index lesions with both Gleason score greater than or equal to 7 and size 1 cm or larger (83.3%). Higher sensitivity was obtained for adjusted versus rigid tumor localization for all lesions (56.0% vs 28.5%), index lesions (55.4% vs 34.3%), lesions with Gleason score greater than or equal to 7 (55.7% vs 36.0%), and index lesions 1 cm or larger (56.1% vs 35.0%). Multiparametric 3-T MRI had similarly high specificity (96.0-97.9%) for overall and index tumor localization with adjusted and rigid sector-matching approaches. CONCLUSION. Using 3-T multiparametric MRI and PI-RADSv2, we achieved the highest sensitivity (83.3%) for the detection of lesions 1 cm or larger with Gleason score greater than or equal to 7. Sectoral localization of PCa within the prostate was moderate and was better with an adjusted model than with a rigid model.

The effect of tumor size and location on efficacy and safety of US- and CT- guided percutaneous microwave ablation in renal cell carcinomas.

PURPOSE: To evaluate the effect of size and central location of the tumor on safety and efficacy of percutaneous CEUS- and CT-guided MWA in biopsy-proven renal cell carcinomas (RCCs). MATERIALS AND METHODS: In this IRB-approved retrospective study, 69 biopsy-proven renal tumors in 56 patients, who underwent MWA in our institution from January 2013 to March 2017, were evaluated. Data collection included demographics, tumor characteristics, procedural protocols, and follow-up visits within 6 months post procedure. Primary outcomes were assessed by technical success (TS), local tumor progression (LTP), and complications. The Kaplan-Meier analysis was used for survival rate. RESULTS: Overall technical success was achieved for all 69 lesions (92.8% primary TS, 100% overall). Median nephrometry score was 8 (4-11) and median tumor size was 2.5 cm (0.8-7). Five lesions which required second ablation had significantly higher median tumor size 4 cm (P = 0.039) with the same nephrometry score. Renal function remained stable with no significant change in eGFR before or after ablation. The LTP rate was 5.8%. The most recurrent tumors were clear cell (50%) followed by papillary tumors (25%). The complication rate was 5.8% with minor complications (hematoma and pain) and no major issues. There was no significant association between nephrometry score and technical success, recurrence, or complication rates. Overall and tumor-specific survival rates were 96.7% and 100% at 11.9 months. CONCLUSIONS: Image-guided MWA appears to be a safe and effective treatment regardless of nephrometry score and tumor location with high technical success, low recurrence, and complication rates.

Molecular Hallmarks of Multiparametric Magnetic Resonance Imaging Visibility in Prostate Cancer.

Multiparametric magnetic resonance imaging (mpMRI) has transformed the management of localized prostate cancer by improving identification of clinically significant disease at diagnosis. Approximately 20% of primary prostate tumors are invisible to mpMRI, and we hypothesize that this invisibility reflects fundamental molecular properties of the tumor. We therefore profiled the genomes and transcriptomes of 40 International Society of Urological Pathology grade 2 tumors: 20 mpMRI-invisible (Prostate Imaging-Reporting and Data System [PI-RADS] v2 <3) and 20 mpMRI-visible (PI-RADS v2 5) tumors. mpMRI-visible tumors were enriched in hallmarks of nimbosus, an aggressive pathological, molecular, and microenvironmental phenomenon in prostate cancer. These hallmarks included genomes with increased mutation density, a higher prevalence of intraductal carcinoma/cribriform architecture pathology, and altered abundance of 102 transcripts, including overexpression of noncoding RNAs such as SCHLAP1. Multiple small nucleolar RNAs (snoRNAs) were identified, and a snoRNA signature synergized with nimbosus hallmarks to discriminate visible from invisible tumors. These data suggest a confluence of aggressive molecular and microenvironmental phenomena underlie mpMRI visibility of localized prostate cancer. PATIENT SUMMARY: We examined the correlation between tumor biology and magnetic resonance imaging (MRI) visibility in a group of patients with low- intermediate-risk prostate cancer. We observed that MRI findings are associated with biological features of aggressive prostate cancer.

A system using patient-specific 3D-printed molds to spatially align in vivo MRI with ex vivo MRI and whole-mount histopathology for prostate cancer research.

BACKGROUND: Patient-specific 3D-printed molds and ex vivo MRI of the resected prostate have been two important strategies to align MRI with whole-mount histopathology (WMHP) for prostate cancer (PCa) research, but the combination of these two strategies has not been systematically evaluated. PURPOSE: To develop and evaluate a system that combines patient-specific 3D-printed molds with ex vivo MRI (ExV) to spatially align in vivo MRI (InV), ExV, and WMHP in PCa patients. STUDY TYPE: Prospective cohort study. POPULATION: Seventeen PCa patients who underwent 3T MRI and robotic-assisted laparoscopic radical prostatectomy (RALP). FIELD STRENGTH/SEQUENCES: T2 -weighted turbo spin-echo sequences at 3T. ASSESSMENT: Immediately after RALP, the fresh whole prostate specimens were imaged in patient-specific 3D-printed molds by 3T MRI and then sectioned to create WMHP slides. The time required for ExV was measured to assess impact on workflow. InV, ExV, and WMHP images were registered. Spatial alignment was evaluated using: slide offset (mm) between ExV slice locations and WMHP slides; overlap of the 3D prostate contour on InV versus ExV using Dice's coefficient (0 to 1); and 2D target registration error (TRE, mm) between corresponding landmarks on InV, ExV, and WMHP. Data are reported as mean ± standard deviation (SD). STATISTICAL TESTING: Differences in 2D TRE before versus after registration were compared using the Wilcoxon signed-rank test (P < 0.05 considered significant). RESULTS: ExV (duration 115 ± 15 min) was successfully incorporated into the workflow for all cases. Absolute slide offset was 1.58 ± 1.57 mm. Dice's coefficient was 0.865 ± 0.035. 2D TRE was significantly reduced after registration (P < 0.01) with mean (±SD of per patient means) of 1.9 ± 0.6 mm for InV versus ExV, 1.4 ± 0.5 mm for WMHP versus ExV, and 2.0 ± 0.5 mm for WMHP versus InV. DATA CONCLUSION: The proposed system combines patient-specific 3D-printed molds with ExV to achieve spatial alignment between InV, ExV, and WMHP with mean 2D TRE of 1-2 mm. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:270-279.

Detection of Individual Prostate Cancer Foci via Multiparametric Magnetic Resonance Imaging.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) undoubtedly affects the diagnosis and treatment of localized prostate cancer (CaP). However, clinicians need a better understanding of its accuracy and limitations in detecting individual CaP foci to optimize management. OBJECTIVE: To determine the per-lesion detection rate for CaP foci by mpMRI and identify predictors of tumor detection. DESIGN, SETTING, AND PARTICIPANTS: We carried out a retrospective analysis of a prospectively managed database correlating lesion-specific results from mpMRI co-registered with whole-mount pathology (WMP) prostatectomy specimens from June 2010 to February 2018. Participants include 588 consecutive patients with biopsy-proven CaP undergoing 3-T mpMRI before radical prostatectomy at a single tertiary institution. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured mpMRI sensitivity in detecting individual CaP and clinically significant (any Gleason score ≥7) CaP foci and predictors of tumor detection using multivariate analysis. RESULTS AND LIMITATIONS: The final analysis included 1213 pathologically confirmed tumor foci in 588 patients with primarily intermediate- (75%) or high-risk (12%) CaP. mpMRI detected 45% of all lesions (95% confidence interval [CI] 42-47%), including 65% of clinically significant lesions (95% CI 61-69%) and nearly 80% of high-grade tumors. Some 74% and 31% of missed solitary and multifocal tumors, respectively, were clinically significant. The majority of missed lesions were small (61.1% ≤1cm); 28.3% were between 1 and 2cm, and 10.4% were >2cm. mpMRI missed at least one clinically significant focus in 34% of patients overall, and in 45% of men with multifocal lesions. On multivariate analysis, smaller, low-grade, multifocal, nonindex tumors with lower prostate-specific antigen density were more likely to be missed. Limitations include selection bias in a prostatectomy cohort, lack of specificity data, an imperfect co-registration process, and uncertain clinical significance for undetected lesions. CONCLUSIONS: mpMRI detects less than half of all and less than two-thirds of clinically significant CaP foci. The moderate per-lesion sensitivity and significant proportion of men with undetected tumor foci demonstrate the current limitations of mpMRI. PATIENT SUMMARY: Magnetic resonance imaging of the prostate before surgical removal for prostate cancer finds less than half of all individual prostate cancer tumors. Large, solitary, aggressive tumors are more likely to be visualized on imaging.

PI-RADS Version 2 Category on 3 Tesla Multiparametric Prostate Magnetic Resonance Imaging Predicts Oncologic Outcomes in Gleason 3 + 4 Prostate Cancer on Biopsy.

PURPOSE: Three Tesla multiparametric magnetic resonance imaging with PI-RADS™ (Prostate Imaging Reporting and Data System) version 2 scoring is a common tool in prostate cancer diagnosis which informs the likelihood of a cancerous lesion. We investigated whether PI-RADS version 2 also predicts adverse pathology features mainly in patients with biopsy Gleason score 3 + 4 disease. MATERIALS AND METHODS: We reviewed the records of 326 consecutive men with a preoperative template and/or magnetic resonance imaging-ultrasound fusion biopsy Gleason score of 6-7 from a prospectively maintained database of men who underwent robotic radical prostatectomy. The primary analysis was done in patients with biopsy Gleason score 3 + 4 to assess the primary outcome of adverse pathology features on univariate and multivariate logistic regression. The secondary outcome was biochemical recurrence-free survival using the Kaplan-Meier method. Similar analysis was done in patients with a biopsy Gleason score of 6-7. RESULTS: Of men with Gleason score 3 + 4 findings 27%, 15%, 36% and 23% showed a PI-RADS version 2 score of 0-2, 3, 4 and 5, respectively. On univariate analysis PI-RADS version 2 category 5 predicted adverse pathology features vs categories 0-2 (OR 10.7, 95% CI 3.7-31, p ≤0.001). On multivariate analysis the PI-RADS version 2 category 5 was associated with adverse pathology when adjusting for preoperative magnetic resonance imaging targeted biopsy (OR 11.4, 95% CI 3.7-35, p ≤0.0001). In men with a targeted biopsy Gleason score of 3 + 4 prostate cancer PI-RADS version 2 category 5 was associated with adverse pathology (OR 14.7, 95% CI 1.5-146.9, p = 0.02). Of men with biopsy Gleason score 3 + 4 disease 92% and 58% with a PI-RADS version 2 score of 4 and 5, respectively, had 2-year biochemical recurrence-free survival. CONCLUSIONS: A PI-RADS version 2 category 5 lesion in patients with a biopsy Gleason score 3 + 4 lesion predicted adverse pathology features and biochemical recurrence-free survival. These findings suggest that preoperative 3 Tesla multiparametric magnetic resonance imaging may serve as a prognostic marker of treatment outcomes independently of biopsy Gleason score or biopsy type.

Three Tesla Multiparametric Magnetic Resonance Imaging: Comparison of Performance with and without Endorectal Coil for Prostate Cancer Detection, PI-RADS™ version 2 Category and Staging with Whole Mount Histopathology Correlation.

PURPOSE: We investigated the performance of 3 Tesla multiparametric magnetic resonance imaging with and without an endorectal coil to detect prostate cancer with a whole mount histopathology reference. MATERIALS AND METHODS: This retrospective HIPAA (Health Insurance Portability and Accountability Act) compliant, institutional review board approved, case-control study included patients who underwent 3 Tesla multiparametric magnetic resonance imaging with and without an endorectal coil from July 2009 to December 2016 prior to prostatectomy. The tumor detection rate was calculated for total and index lesions. Lesion magnetic resonance imaging and histopathology features were compared between the 2 groups. Using SPSS®, version 24 p <0.05 was considered significant. RESULTS: A total of 871 whole mount histopathology lesions in 429 patients with a mean ± SD age of 61.8 ± 7 years were included in analysis. The subcohorts with and without an endorectal coil comprised 260 and 169 patients with a total of 529 and 342 lesions, respectively. The overall tumor detection rates in all patients, and in the endorectal coil and nonendorectal coil subcohorts were 49.6% (432 of 871 patients), 50.5% (267 of 529) and 48.2% (165 of 342), respectively. The index tumor detection rates overall, and in the endorectal coil and nonendorectal coil subcohorts were 77.6% (333 of 429 patients), 78.5% (204 of 260) and 76.3% (129 of 169), respectively. In the endorectal coil and nonendorectal coil subcohorts we detected 35.9% (66 of 184) and 48.4% (76 of 157) of anterior lesions (p = 0.019), 58% (200 of 345) and 48.1% (89 of 185) of posterior lesions (p = 0.025), 37.3% (41 of 110) and 54.4% (62 of 114) of transition zone lesions (p = 0.010), and 53.7% (225 of 419) and 45.2% (103 of 228) of peripheral lesions (p = 0.033), respectively. After adjusting for clinical and pathological factors the endorectal coil group only showed higher detection of peripheral and posterior prostate cancer. CONCLUSIONS: We found that 3 Tesla multiparametric magnetic resonance imaging with and without an endorectal coil had similar detection of overall and index prostate cancer. However, the endorectal coil subcohort had significantly higher detection of posterior and peripheral prostate cancer, and lower detection of anterior and transition zone prostate cancer.

Characteristics of missed prostate cancer lesions on 3T multiparametric-MRI in 518 patients: based on PI-RADSv2 and using whole-mount histopathology reference.

PURPOSE: To determine the characteristics of missed prostate cancer (PCa) lesions on 3T multiparametric-MRI (mpMRI) based on PI-RADSv2 with whole-mount histopathology (WMHP) correlation. MATERIALS AND METHODS: This IRB-approved, HIPAA-compliant study, included 614 consecutive men with 3T mpMRI prior to prostatectomy at a single tertiary center between 12/2009 and 4/2017. Clinical, mpMRI, and pathologic features were obtained. PI-RADSv2-based MRI detected lesions were matched with previously finalized WMHP by a genitourinary (GU) radiologist and a GU pathologist. Patients with no mpMRI detected PCa lesion, but with at least one lesion ≥ 1 cm on WMHP, were reviewed retrospectively and assigned a PI-RADSv2 score. Tumor characteristics were compared between missed and detected lesions. RESULT: The final cohort included 518 patients with 1085 WMHP lesions. 51.9% (563/1085) of lesions were missed on 3T mpMRI. 71.4% (402/563), 21.7% (122/563), 4.4% (25/563), and 2.5% (14/563) of the missed lesions were Gleason scores (GS) 3 + 3, 3 + 4, 4 + 3, and 8 - 10, respectively. Missed PCa lesions had significantly lower proportion of GS ≥ 7 (p < 0.001) and smaller size for overall (p < 0.001) and index subcohorts (p < 0.001), as compared to detected lesions. 34.5% (194) of overall and 71.2% (79) index missed lesions were larger than 1 cm. In 13.7% (71/518) of patients without MR detected PCa, 149 lesions were detected on WMHP, with 70 (47%) lesions ≥ 1 cm. In retrospective review of these lesions, 42.9% (30), 18.6% (13), 21.5% (15), 10% (7), and 7% (5) were PI-RADSv2 1, 2, 3, 4, and 5, respectively. CONCLUSION: 3T mpMRI has an excellent per patients diagnostic performance for PCa and majority of missed lesions are clinically nonsignificant.

PI-RADS Version 2 Category on 3 Tesla Multiparametric Prostate Magnetic Resonance Imaging Predicts Oncologic Outcomes in Gleason 3 + 4 Prostate Cancer on Biopsy.

PURPOSE: Three Tesla multiparametric magnetic resonance imaging with PI-RADS™ (Prostate Imaging Reporting and Data System) version 2 scoring is a common tool in prostate cancer diagnosis which informs the likelihood of a cancerous lesion. We investigated whether PI-RADS version 2 also predicts adverse pathology features mainly in patients with biopsy Gleason score 3 + 4 disease. MATERIALS AND METHODS: We reviewed the records of 326 consecutive men with a preoperative template and/or magnetic resonance imaging-ultrasound fusion biopsy Gleason score of 6-7 from a prospectively maintained database of men who underwent robotic radical prostatectomy. The primary analysis was done in patients with biopsy Gleason score 3 + 4 to assess the primary outcome of adverse pathology features on univariate and multivariate logistic regression. The secondary outcome was biochemical recurrence-free survival using the Kaplan-Meier method. Similar analysis was done in patients with a biopsy Gleason score of 6-7. RESULTS: Of men with Gleason score 3 + 4 findings 27%, 15%, 36% and 23% showed a PI-RADS version 2 score of 0-2, 3, 4 and 5, respectively. On univariate analysis PI-RADS version 2 category 5 predicted adverse pathology features vs categories 0-2 (OR 10.7, 95% CI 3.7-31, p ≤0.001). On multivariate analysis the PI-RADS version 2 category 5 was associated with adverse pathology when adjusting for preoperative magnetic resonance imaging targeted biopsy (OR 11.4, 95% CI 3.7-35, p ≤0.0001). In men with a targeted biopsy Gleason score of 3 + 4 prostate cancer PI-RADS version 2 category 5 was associated with adverse pathology (OR 14.7, 95% CI 1.5-146.9, p = 0.02). Of men with biopsy Gleason score 3 + 4 disease 92% and 58% with a PI-RADS version 2 score of 4 and 5, respectively, had 2-year biochemical recurrence-free survival. CONCLUSIONS: A PI-RADS version 2 category 5 lesion in patients with a biopsy Gleason score 3 + 4 lesion predicted adverse pathology features and biochemical recurrence-free survival. These findings suggest that preoperative 3 Tesla multiparametric magnetic resonance imaging may serve as a prognostic marker of treatment outcomes independently of biopsy Gleason score or biopsy type.

Building a high-resolution T2-weighted MR-based probabilistic model of tumor occurrence in the prostate.

PURPOSE: We present a method for generating a T2 MR-based probabilistic model of tumor occurrence in the prostate to guide the selection of anatomical sites for targeted biopsies and serve as a diagnostic tool to aid radiological evaluation of prostate cancer. MATERIALS AND METHODS: In our study, the prostate and any radiological findings within were segmented retrospectively on 3D T2-weighted MR images of 266 subjects who underwent radical prostatectomy. Subsequent histopathological analysis determined both the ground truth and the Gleason grade of the tumors. A randomly chosen subset of 19 subjects was used to generate a multi-subject-derived prostate template. Subsequently, a cascading registration algorithm involving both affine and non-rigid B-spline transforms was used to register the prostate of every subject to the template. Corresponding transformation of radiological findings yielded a population-based probabilistic model of tumor occurrence. The quality of our probabilistic model building approach was statistically evaluated by measuring the proportion of correct placements of tumors in the prostate template, i.e., the number of tumors that maintained their anatomical location within the prostate after their transformation into the prostate template space. RESULTS: Probabilistic model built with tumors deemed clinically significant demonstrated a heterogeneous distribution of tumors, with higher likelihood of tumor occurrence at the mid-gland anterior transition zone and the base-to-mid-gland posterior peripheral zones. Of 250 MR lesions analyzed, 248 maintained their original anatomical location with respect to the prostate zones after transformation to the prostate. CONCLUSION: We present a robust method for generating a probabilistic model of tumor occurrence in the prostate that could aid clinical decision making, such as selection of anatomical sites for MR-guided prostate biopsies.

Divergent mitochondrial biogenesis responses in human cardiomyopathy.

BACKGROUND: Mitochondria are key players in the development and progression of heart failure (HF). Mitochondrial (mt) dysfunction leads to diminished energy production and increased cell death contributing to the progression of left ventricular failure. The fundamental mechanisms that underlie mt dysfunction in HF have not been fully elucidated. METHODS AND RESULTS: To characterize mt morphology, biogenesis, and genomic integrity in human HF, we investigated left ventricular tissue from nonfailing hearts and end-stage ischemic (ICM) or dilated (DCM) cardiomyopathic hearts. Although mt dysfunction was present in both types of cardiomyopathy, mt were smaller and increased in number in DCM compared with ICM or nonfailing hearts. mt volume density and mtDNA copy number was increased by ≈2-fold (P<0.001) in DCM hearts in comparison with ICM hearts. These changes were accompanied by an increase in the expression of mtDNA-encoded genes in DCM versus no change in ICM. mtDNA repair and antioxidant genes were reduced in failing hearts, suggestive of a defective repair and protection system, which may account for the 4.1-fold increase in mtDNA deletion mutations in DCM (P<0.05 versus nonfailing hearts, P<0.05 versus ICM). CONCLUSIONS: In DCM, mt dysfunction is associated with mtDNA damage and deletions, which could be a consequence of mutating stress coupled with a peroxisome proliferator-activated receptor γ coactivator 1α-dependent stimulus for mt biogenesis. However, this maladaptive compensatory response contributes to additional oxidative damage. Thus, our findings support further investigations into novel mechanisms and therapeutic strategies for mt dysfunction in DCM.

Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration.

Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic mithramycin prolongs survival of mouse models of Huntington's disease in vivo and inhibits oxidative stress-induced death in cortical neurons in vitro. We had correlated protection by mithramycin with its ability to bind to GC-rich DNA and globally displace Sp1 family transcription factors. To understand how antitumor drugs prevent neurodegeneration, here we use structure-activity relationships of mithramycin analogs to discover that selective DNA-binding inhibition of the drug is necessary for its neuroprotective effect. We identify several genes (Myc, c-Src, Hif1α, and p21(waf1/cip1)) involved in neoplastic transformation, whose altered expression correlates with protective doses of mithramycin or its analogs. Most interestingly, inhibition of one these genes, Myc, is neuroprotective, whereas forced expression of Myc induces Rattus norvegicus neuronal cell death. These results support a model in which cancer cell transformation shares key genetic components with neurodegeneration.

Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice.

In the adult heart, regulation of fatty acid oxidation and mitochondrial genes is controlled by the PPARgamma coactivator-1 (PGC-1) family of transcriptional coactivators. However, in response to pathological stressors such as hemodynamic load or ischemia, cardiac myocytes downregulate PGC-1 activity and fatty acid oxidation genes in preference for glucose metabolism pathways. Interestingly, despite the reduced PGC-1 activity, these pathological stressors are associated with mitochondrial biogenesis, at least initially. The transcription factors that regulate these changes in the setting of reduced PGC-1 are unknown, but Myc can regulate glucose metabolism and mitochondrial biogenesis during cell proliferation and tumorigenesis in cancer cells. Here we have demonstrated that Myc activation in the myocardium of adult mice increases glucose uptake and utilization, downregulates fatty acid oxidation by reducing PGC-1alpha levels, and induces mitochondrial biogenesis. Inactivation of Myc in the adult myocardium attenuated hypertrophic growth and decreased the expression of glycolytic and mitochondrial biogenesis genes in response to hemodynamic load. Surprisingly, the Myc-orchestrated metabolic alterations were associated with preserved cardiac function and improved recovery from ischemia. Our data suggest that Myc directly regulates glucose metabolism and mitochondrial biogenesis in cardiac myocytes and is an important regulator of energy metabolism in the heart in response to pathologic stress.

Essential role of developmentally activated hypoxia-inducible factor 1alpha for cardiac morphogenesis and function.

Development of the mammalian heart is governed by precisely orchestrated interactions between signaling pathways integrating environmental cues and a core cardiac transcriptional network that directs differentiation, growth and morphogenesis. Here we report that in mice, at about embryonic day (E)8.5 to E10.0, cardiac development proceeds in an environment that is hypoxic and characterized by high levels of hypoxia-inducible factor (HIF)1alpha protein. Mice lacking HIF1alpha in ventricular cardiomyocytes exhibit aborted development at looping morphogenesis and embryonic lethality between E11.0 to E12.0. Intriguingly, HIF1alpha-deficient hearts display reduced expression of the core cardiac transcription factors Mef2C and Tbx5 and of titin, a giant protein that serves as a template for the assembly and organization of the sarcomere. Chromatin immunoprecipitation experiments revealed that Mef2C, Tbx5, and titin are direct target genes of HIF1alpha in vivo. Thus, hypoxia signaling controls cardiac development through HIF1alpha-mediated transcriptional regulation of key components of myofibrillogenesis and the cardiac transcription factor network, thereby providing a mechanistic basis of how heart development, morphogenesis, and function is coupled to low oxygen tension during early embryogenesis.