The discovery and characterization of two novel structural motifs on the carboxy-terminal domain of kinetoplastid RNA editing ligases.

Parasitic protozoans of the Trypanosoma and Leishmania species have a uniquely organized mitochondrial genome, the kinetoplast. Most kinetoplast-transcribed mRNAs are cryptic and encode multiple subunits for the electron transport chain following maturation through a uridine insertion/deletion process called RNA editing. This process is achieved through an enzyme cascade by an RNA editing catalytic complex (RECC), where the final ligation step is catalyzed by the kinetoplastid RNA editing ligases, KREL1 and KREL2. While the amino-terminal domain (NTD) of these proteins is highly conserved with other DNA ligases and mRNA capping enzymes, with five recognizable motifs, the functional role of their diverged carboxy-terminal domain (CTD) has remained elusive. In this manuscript, we assayed recombinant KREL1 in vitro to unveil critical residues from its CTD to be involved in protein-protein interaction and dsRNA ligation activity. Our data show that the α-helix (H)3 of KREL1 CTD interacts with the αH1 of its editosome protein partner KREPA2. Intriguingly, the OB-fold domain and the zinc fingers on KREPA2 do not appear to influence the RNA ligation activity of KREL1. Moreover, a specific KWKE motif on the αH4 of KREL1 CTD is found to be implicated in ligase auto-adenylylation analogous to motif VI in DNA ligases. In summary, we present in the KREL1 CTD a motif VI for auto-adenylylation and a KREPA2 binding motif for RECC integration.

Hammerhead ribozyme-based U-insertion and deletion RNA editing assays for multiplexing in HTS applications.

Untranslatable mitochondrial transcripts in kinetoplastids are decrypted post-transcriptionally through an RNA editing process that entails uridine insertion/deletion. This unique stepwise process is mediated by the editosome, a multiprotein complex that is a validated drug target of considerable interest in addressing the unmet medical needs for kinetoplastid diseases. With that objective, several in vitro RNA editing assays have been developed, albeit with limited success in discovering potent inhibitors. This manuscript describes the development of three hammerhead ribozyme (HHR) FRET reporter-based RNA editing assays for precleaved deletion, insertion, and ligation assays that bypass the rate-limiting endonucleolytic cleavage step, providing information on U-deletion, U-insertion, and ligation activities. These assays exhibit higher editing efficiencies in shorter incubation times while requiring significantly less purified editosome and 10,000-fold less ATP than the previously published full round of in vitro RNA editing assay. Moreover, modifications in the reporter ribozyme sequence enable the feasibility of multiplexing a ribozyme-based insertion/deletion editing (RIDE) assay that simultaneously surveils U-insertion and deletion editing suitable for HTS. These assays can be used to find novel chemical compounds with chemotherapeutic applications or as probes for studying the editosome machinery.

Quantitative MRI in the Local Staging of Prostate Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Local staging of prostate cancer (PCa) is important for treatment planning. Radiologist interpretation using qualitative criteria is variable with high specificity but low sensitivity. Quantitative methods may be useful in the diagnosis of extracapsular extension (ECE). PURPOSE: To assess the performance of quantitative MRI markers for detecting ECE. STUDY TYPE: Systematic review and meta-analysis. SUBJECTS: 4800 patients from 28 studies with histopathologically confirmed PCa on radical prostatectomy were pooled for meta-analysis. Patients from 46 studies were included for systematic review. FIELD STRENGTH/SEQUENCE: Diffusion-weighted, T2-weighted, and dynamic contrast-enhanced MRI at 1.5 T or 3 T. ASSESSMENT: PubMed, Embase, Web of Science, Scopus, and Cochrane databases were searched to identify studies on diagnostic test accuracy or association of any quantitative MRI markers with ECE. Results extracted by two independent reviewers for tumor contact length (TCL) and mean apparent diffusion coefficient (ADC-mean) were pooled for meta-analysis, but not for other quantitative markers including radiomics due to low number of studies available. STATISTICAL TESTS: Hierarchical summary receiver operating characteristic (HSROC) curves were computed for both TCL and ADC-mean, but summary operating points were computed for TCL only. Heterogeneity was investigated by meta-regression. Results were significant if P ≤ 0.05. RESULTS: At the 10 mm threshold for TCL, summary sensitivity and specificity were 0.76 [95% confidence interval (CI) 0.71-0.81] and 0.68 [95% CI 0.63-0.73], respectively. At the 15 mm threshold, summary sensitivity and specificity were 0.70 [95% CI 0.53-0.83] and 0.74 [95% CI 0.60-0.84] respectively. The area under the HSROC curves for TCL and ADC-mean were 0.79 and 0.78, respectively. Significant sources of heterogeneity for TCL included timing of MRI relative to biopsy. DATA CONCLUSION: Both 10 mm and 15 mm thresholds for TCL may be reasonable for clinical use. From comparison of the HSROC curves, ADC-mean may be superior to TCL at higher sensitivities. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Perfusion magnetic resonance imaging in Asherman syndrome.

BACKGROUND: Microvascular scarring compromises the functionality of the endometrium, and vascular flow at the junctional zone (JZ) may be the key to understanding poor reproductive outcomes in women with Asherman syndrome (AS). AIMS: To investigate whether vascular perfusion of the uterus, measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is impaired in women with intrauterine adhesions (IUA) and AS. MATERIALS AND METHODS: A prospective observational cohort pilot study of 23 women with IUA treated with hysteroscopic synecholysis and a control group of two patients with cervix cancer were subject to DCE-MRI with gadolinium to assess uterine vascularity. Twelve regions of interest (ROIs) were allocated on the DCE-MRI image incorporating the JZ, with control ROI placed at the psoas muscle. Individual ROIs were compared to the mean total perfusion (TP) in the same uterus. Pre- and post-operative perfusion analyses were performed on five women. Receiver operator curves (ROC) were used to analyse MRI as a predictor of IUA. RESULTS: There was no significant difference in perfusion; a trend toward reduced perfusion was observed in women with IUA compared to the controls. The ROC was predictive of higher-grade and inoperable IUA. CONCLUSIONS: Reduced perfusion on DCE-MRI as assessed by ROC predicted higher-stage AS. The results of this study support further investigation of DCE-MRI as a prognostic tool for AS prior to surgical intervention to assist in providing prognostic guidance for women suffering from AS.

Comparison of Skeletal Muscle Changes at Three Vertebral Levels Following Radiotherapy in Patients With Oropharyngeal Carcinoma.

Evaluation of skeletal muscle (SM) depletion, or sarcopenia, utilizes the cross-sectional area (CSA) of computed tomography (CT) scans at the lumbar level L3. However, alternate vertebral landmarks are used in patients with head and neck cancer due to scan unavailability. Muscle changes following radiotherapy at cervical (C3) and thoracic (T2) levels were compared to L3 in patients with oropharyngeal carcinoma. Muscle density data were derived retrospectively from diagnostic PET-CT scans at C3, T2 and L3 pretreatment, and up to six months post. CSA changes were compared to L3 in scans of 33 patients (88% male, mean age 61 (SD 8.5) years). On matched pair analysis; mean L3-CSA change -12.1 cm2 (SD 9.7, 95%CI -15.5 to -8.6, and p < 0.001), T2-CSA -30.5 cm2 (SD 34.8, 95%CI -42.8 to -18.1, and p < 0.001) and C3-CSA +2.1 cm2 (SD 4.1, 95%CI 0.63 to 3.5, and p < 0.00). No difference was found in the percentage change of T2-CSA with L3-CSA (mean -2.2%, SD 10.6, 95%CI -6.0 to 1.6, and p = 0.240), however, was significantly different to C3-CSA (mean 13.2%, SD 11.6, 95%CI 9.1 to 17.3, and p < 0.001). Results suggest SM at C3 does not change proportionately and may not be a reliable representation of whole-body SM change over time.

Changes in serial multiparametric MRI and FDG-PET/CT functional imaging during radiation therapy can predict treatment response in patients with head and neck cancer.

OBJECTIVES: To test if tumour changes measured using combination of diffusion-weighted imaging (DWI) MRI and FDG-PET/CT performed serially during radiotherapy (RT) in mucosal head and neck carcinoma can predict treatment response. METHODS: Fifty-five patients from two prospective imaging biomarker studies were analysed. FDG-PET/CT was performed at baseline, during RT (week 3), and post RT (3 months). DWI was performed at baseline, during RT (weeks 2, 3, 5, 6), and post RT (1 and 3 months). The ADCmean from DWI and FDG-PET parameters SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were measured. Absolute and relative change (%∆) in DWI and PET parameters were correlated to 1-year local recurrence. Patients were categorised into favourable, mixed, and unfavourable imaging response using optimal cut-off (OC) values of DWI and FDG-PET parameters and correlated to local control. RESULTS: The 1-year local, regional, and distant recurrence rates were 18.2% (10/55), 7.3% (4/55), and 12.7% (7/55), respectively. ∆Week 3 ADCmean (AUC 0.825, p = 0.003; OC ∆ > 24.4%) and ∆MTV (AUC 0.833, p = 0.001; OC ∆ > 50.4%) were the best predictors of local recurrence. Week 3 was the optimal time point for assessing DWI imaging response. Using a combination of ∆ADCmean and ∆MTV improved the strength of correlation to local recurrence (p ≤ 0.001). In patients who underwent both week 3 MRI and FDG-PET/CT, significant differences in local recurrence rates were seen between patients with favourable (0%), mixed (17%), and unfavourable (78%) combined imaging response. CONCLUSIONS: Changes in mid-treatment DWI and FDG-PET/CT imaging can predict treatment response and could be utilised in the design of future adaptive clinical trials. CLINICAL RELEVANCE STATEMENT: Our study shows the complementary information provided by two functional imaging modalities for mid-treatment response prediction in patients with head and neck cancer. KEY POINTS: •FDG-PET/CT and DWI MRI changes in tumour during radiotherapy in head and neck cancer can predict treatment response. •Combination of FDG-PET/CT and DWI parameters improved correlation to clinical outcome. •Week 3 was the optimal time point for DWI MRI imaging response assessment.

A prediction model for skeletal muscle evaluation and computed tomography-defined sarcopenia diagnosis in a predominantly overweight cohort of patients with head and neck cancer.

PURPOSE: This study investigates the feasibility of computed tomography (CT)-defined sarcopenia assessment using a prediction model for estimating the cross-sectional area (CSA) of skeletal muscle (SM) in CT scans at the third lumbar vertebra (L3), using measures at the third cervical level (C3) in a predominantly overweight population with head and neck cancer (HNC). METHODS: Analysis was conducted on adult patients with newly diagnosed HNC who had a diagnostic positron emission tomography-CT scan. CSA of SM in CT images was measured at L3 and C3 in each patient, and a predictive formula developed using fivefold cross-validation and linear regression modelling. Correlation and agreement between measured CSA at L3 and predicted values were evaluated using intraclass correlation coefficients (ICC) and Bland-Altman plot. The model's ability to identify sarcopenia was investigated using Cohen's Kappa (k). RESULTS: A total of 109 patient scans were analysed, with 64% of the cohort being overweight or obese. The prediction model demonstrated high level of correlation between measured and predicted CSA measures (ICC 0.954, r = 0.916, p < 0.001), and skeletal muscle index (SMI) (ICC 0.939, r = 0.883, p < 0.001). Bland-Altman plot showed good agreement in SMI, with mean difference (bias) = 0.22% (SD 8.65, 95% CI - 3.35 to 3.79%), limits of agreement (- 16.74 to 17.17%). The model had a sensitivity of 80.0% and specificity of 85.0%, with moderate agreement on sarcopenia diagnosis (k = 0.565, p = 0.004). CONCLUSION: This model is effective in predicting lumbar SM CSA using measures at C3, and in identifying low SM in a predominately overweight group of patients with HNC.

Thoracic skeletal muscle index is effective for CT-defined sarcopenia evaluation in patients with head and neck cancer.

PURPOSE: Computed tomography (CT)-defined sarcopenia, as a measurement of low skeletal muscle (SM), is a poor prognostic indicator in patients with head and neck cancer (HNC), independent of weight or nutritional status. We used SM measures at the second thoracic vertebra (T2) to determine T2-SM index (SMI) thresholds for sarcopenia, and investigate the impact of low T2-SMI on overall survival (OS), and weight loss during radiotherapy (RT). METHODS: Adult patients with newly diagnosed HNC with a diagnostic PET-CT or RT planning CT scan were included. SM was analysed at T2 and a model applied to predict SM at L3. T2-SMI thresholds for sarcopenia were established with predicted measures, stratified by BMI and sex. Impact of sarcopenia and low T2-SMI on OS and weight loss during RT was investigated. RESULTS: A total of 361 scans were analysed (84% males, 54% oropharynx tumours). Sarcopenia was found in 49%, demonstrating worse OS (p = 0.037). T2-SMI cutoff values were: females-74 cm2/m2 [area under the curve (AUC): 0.89 (95%CI 0.80-0.98)], males (BMI < 25)-63 cm2/m2 [AUC 0.93 (95%CI 0.89-0.96)], males (BMI ≥ 25)-88cm2/m2 [AUC 0.86 (95%CI 0.78-0.93)]. No difference in OS with T2-SMI categories. Lowest T2-SMI quartile of < 63 cm2/m2 demonstrated worse OS (p = 0.017). Weight loss during RT was higher in patients; who were not sarcopenic (6.2% vs 4.9%, p = 0.023); with higher T2-SMI (6.3% vs 4.9%, p = 0.014) and; in the highest quartiles (3.6% vs 5.7% vs 7.2%, p < 0.001). CONCLUSIONS: These T2-SMI thresholds are effective in assessing CT-defined sarcopenia in HNC. Further assessment of clinical application is warranted.

The first Australian uterus transplantation procedure: A result of a long-term Australian-Swedish research collaboration.

AIMS: The aim is to report the results of Australia's first uterus transplantation (UTx). METHODS: Following long-standing collaboration between the Swedish and Australian teams, Human Research Ethics approval was obtained to perform six UTx procedures in a collaborative multi-site research study (Western Sydney Local District Health 2019/ETH13038), including Royal Hospital for Women, Prince of Wales Hospital, and Westmead Hospital in New Souh Wales. Surgeries were approved in both the live donor (LD) and deceased donor models in collaboration with the inaugural Swedish UTx team. RESULTS: This is the first UTx procedure to occur in Australia, involving a mother donating her uterus to her daughter. The total operative time for the donor was 9 h 54 min. Concurrently, recipient surgery was synchronised to minimise graft ischaemic time, and the total operative time for the recipient was 6 h 12 min. Surgery was by laparotomy in the LD and recipient. The total warm ischaemic time of the graft was 1 h 53 min, and the cold ischaemic time was 2 h 17 min (total ischaemic time 4 h 10 min). The patient's first menstruation occurred 33 days after the UTx procedure. CONCLUSION: Twenty-five years of Swedish and Australian collaboration has led to Australia's first successfully performed UTx surgery at The Royal Hospital for Women, Sydney, Australia.

Final Analysis of the Magnetic Resonance Imaging in Active Surveillance Trial.

PURPOSE: This study aimed to assess the medium-term oncologic outcomes of an active surveillance protocol, replacing confirmatory biopsy with serial multiparametric magnetic resonance imaging. MATERIALS AND METHODS: A total of 172 men were enrolled in this single-arm prospective trial. Men with prostate cancer (Gleason 3+3=6 or Gleason 3+4=7 with ≤10% Gleason pattern 4 overall and <2 cores Gleason pattern 4) eligible for surveillance were included in the study. Men underwent baseline multiparametric magnetic resonance imaging and template ± targeted biopsy, then multiparametric magnetic resonance imaging at years 1 and 2 with a 3-year end-of-protocol biopsy. Biopsies during the 3-year protocol period were triggered by abnormalities on multiparametric magnetic resonance imaging and/or increases in prostate specific antigen density (>0.2 ng/ml/cc). RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of multiparametric magnetic resonance imaging to detect progression to clinically significant prostate cancer were 57% (95% CI 39%-74%), 82% (95% CI 74%-89%), 50% (95% CI 38%-62%), and 86% (95% CI 81%-90%), respectively. Both multiparametric magnetic resonance imaging and prostate specific antigen density were significant predictors for progression (multiparametric magnetic resonance imaging OR 6.20, 95% CI 2.72-14.16, P < .001; prostate specific antigen density OR 6.19, 95% CI 2.14-17.92, P = .001). Only 2.3% (4/172) of patients had false-negative multiparametric magnetic resonance imaging and high-risk pathological features (pT3 or high-volume International Society of Urological Pathology >2). After a median 69 months (Q1-Q3 56-79) follow-up of all patients in the cohort, freedom from biochemical recurrence, metastasis, and prostate cancer-related death were 99.3%, 100%, and 100%, respectively. CONCLUSIONS: Final analysis of the Magnetic Resonance Imaging in Active Surveillance trial indicates that there is minimal risk to omitting 1-year confirmatory biopsy during active surveillance if baseline magnetic resonance-targeted + saturation template biopsy was performed; however, standardized 3-year systematic biopsy should be performed due to occasional magnetic resonance imaging-invisible tumors.

Interobserver and intraobserver variability of RECIST assessment in ovarian cancer.

OBJECTIVES: Measurement of Response Evaluation Criteria In Solid Tumors (RECIST) relies on reproducible unidimensional tumor measurements. This study assessed intraobserver and interobserver variability of target lesion selection and measurement, according to RECIST version 1.1 in patients with ovarian cancer. METHODS: Eight international radiologists independently viewed 47 images demonstrating malignant lesions in patients with ovarian cancer and selected and measured lesions according to RECIST V.1.1 criteria. Thirteen images were viewed twice. Interobserver variability of selection and measurement were calculated for all images. Intraobserver variability of selection and measurement were calculated for images viewed twice. Lesions were classified according to their anatomical site as pulmonary, hepatic, pelvic mass, peritoneal, lymph nodal, or other. Lesion selection variability was assessed by calculating the reproducibility rate. Lesion measurement variability was assessed with the intra-class correlation coefficient. RESULTS: From 47 images, 82 distinct lesions were identified. For lesion selection, the interobserver and intraobserver reproducibility rates were high, at 0.91 and 0.93, respectively. Interobserver selection reproducibility was highest (reproducibility rate 1) for pelvic mass and other lesions. Intraobserver selection reproducibility was highest (reproducibility rate 1) for pelvic mass, hepatic, nodal, and other lesions. Selection reproducibility was lowest for peritoneal lesions (interobserver reproducibility rate 0.76 and intraobserver reproducibility rate 0.69). For lesion measurement, the overall interobserver and intraobserver intraclass correlation coefficients showed very good concordance of 0.84 and 0.94, respectively. Interobserver intraclass correlation coefficient showed very good concordance for hepatic, pulmonary, peritoneal, and other lesions, and ranged from 0.84 to 0.97, but only moderate concordance for lymph node lesions (0.58). Intraobserver intraclass correlation coefficient showed very good concordance for all lesions, ranging from 0.82 to 0.99. In total, 85% of total measurement variability resulted from interobserver measurement difference. CONCLUSIONS: Our study showed that while selection and measurement concordance were high, there was significant interobserver and intraobserver variability. Most resulted from interobserver variability. Compared with other lesions, peritoneal lesions had the lowest selection reproducibility, and lymph node lesions had the lowest measurement concordance. These factors need consideration to improve response assessment, especially as progression free survival remains the most common endpoint in phase III trials.

The Magnetic Resonance Imaging in Active Surveillance (MRIAS) Trial: Use of Baseline Multiparametric Magnetic Resonance Imaging and Saturation Biopsy to Reduce the Frequency of Surveillance Prostate Biopsies.

PURPOSE: Prospective studies are lacking in assessing the diagnostic utility of serial multiparametric magnetic resonance imaging to predict biopsy proven progression to clinically significant prostate cancer in men on active surveillance, as well as the oncologic safety of baseline magnetic resonance imaging and saturation diagnostic biopsy in replacing early confirmatory biopsy during active surveillance. MATERIALS AND METHODS: A total of 172 men were enrolled in this single arm prospective trial. Men with cT2 or lower histologically proven prostate cancer (Gleason 3+3=6 or Gleason 3+4=7 with 10% or less Gleason pattern 4 overall and less than 2 cores Gleason pattern 4) eligible for surveillance were included in the study. Men underwent baseline multiparametric magnetic resonance imaging and saturation biopsy followed by serial annual multiparametric magnetic resonance imaging until a 3-year end point per protocol saturation biopsy. The standardized 1-year confirmatory biopsy was omitted and biopsies during the protocol were triggered based on new abnormalities on multiparametric magnetic resonance imaging and prostate specific antigen density. RESULTS: We report the prespecified interim analysis of the first 100 men at 3 years. At baseline the median age was 64.5 (IQR 57.25-69) years, prostate specific antigen was 4.7 ng/ml (IQR 3.4-6.6), 91% had Gleason 3+3=6 prostate cancer and multiparametric magnetic resonance imaging was negative (Prostate Imaging Reporting and Data System 1/2/3) in 87% of men. Within 3 years 21% experienced pathological progression. The positive predictive value, negative predictive value, sensitivity and specificity for detection of clinically significant prostate cancer by surveillance multiparametric magnetic resonance imaging was 45%, 89%, 61% and 80%, respectively. Positive surveillance magnetic resonance imaging (p=0.002) and prostate specific antigen density greater than 0.2 ng/ml (p=0.042) had significant predictive value for clinically significant prostate cancer. CONCLUSIONS: Our novel active surveillance protocol incorporating multiparametric magnetic resonance imaging detected most cases of disease progression and may enable confirmatory biopsy to be deferred, but should not replace 3-year surveillance biopsy altogether due to occasional magnetic resonance imaging invisible tumors.

Editorial for "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".

LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;51:1554-1555.

Adaptive tutorials versus web-based resources in radiology: a mixed methods analysis in junior doctors of efficacy and engagement.

BACKGROUND: Radiology education is limited in undergraduate Medicine programs. Junior doctors might not have the necessary background to effectively order and interpret diagnostic imaging investigations. Furthermore, junior doctors are often time-poor, balancing clinical commitments with ongoing learning, leadership and teaching responsibilities. Previous studies have demonstrated the efficacy of radiology-themed online adaptive tutorials for senior medical students. Such adaptive tutorials might therefore be an efficient and effective form of radiology education for junior doctors. METHODS: A randomised controlled crossover trial was performed to evaluate the impact of adaptive tutorials on learning the indications for, and interpretation of, basic imaging studies, compared with peer-reviewed web-based resources. Ninety-one volunteer junior doctors, comprising 53 postgraduate year 1 (PGY 1) and 38 postgraduate year 2 (PGY 2), were randomly allocated into two groups. In the first phase of the trial, focusing on head CT, one group accessed adaptive tutorials while the other received web-based resources. In the second phase of the trial, focusing on chest CT, the groups crossed over. Following each phase of the trial, participants completed exam-style online assessments. At the conclusion of the study, participants also completed an online questionnaire regarding perceived engagement and efficacy of each type of educational resource. RESULTS: Junior doctors completed the adaptive tutorials significantly faster than the relevant web-based resources for both head CT and chest CT (p = 0.03 and < 0.01 respectively). Mean quiz scores were higher in the groups receiving adaptive tutorials on head CT and chest CT (86.4% vs 83.5 and 77.7% vs 75% respectively). However, in contrast to previous studies in senior medical students, these differences were not statistically significant. Participants reported higher engagement and perceived value of adaptive tutorials, compared with web-based resources. CONCLUSIONS: Adaptive tutorials are more time-efficient than existing web-based resources for learning radiology by junior doctors, while both types of resources were equally effective for learning in this cohort. Junior doctors found the adaptive tutorials more engaging and were more likely to recommend these resources to their colleagues.

Radiomic features on MRI enable risk categorization of prostate cancer patients on active surveillance: Preliminary findings.

BACKGROUND: Radiomic analysis is defined as computationally extracting features from radiographic images for quantitatively characterizing disease patterns. There has been recent interest in examining the use of MRI for identifying prostate cancer (PCa) aggressiveness in patients on active surveillance (AS). PURPOSE: To evaluate the performance of MRI-based radiomic features in identifying the presence or absence of clinically significant PCa in AS patients. STUDY TYPE: Retrospective. SUBJECTS MODEL: MRI/TRUS (transperineal grid ultrasound) fusion-guided biopsy was performed for 56 PCa patients on AS who had undergone prebiopsy. FIELD STRENGTH/SEQUENCE: 3T, T2 -weighted (T2 w) and diffusion-weighted (DW) MRI. ASSESSMENT: A pathologist histopathologically defined the presence of clinically significant disease. A radiologist manually delineated lesions on T2 w-MRs. Then three radiologists assessed MRIs using PIRADS v2.0 guidelines. Tumors were categorized into four groups: MRI-negative-biopsy-negative (Group 1, N = 15), MRI-positive-biopsy-positive (Group 2, N = 16), MRI-negative-biopsy-positive (Group 3, N = 10), and MRI-positive-biopsy-negative (Group 4, N = 15). In all, 308 radiomic features (First-order statistics, Gabor, Laws Energy, and Haralick) were extracted from within the annotated lesions on T2 w images and apparent diffusion coefficient (ADC) maps. The top 10 features associated with clinically significant tumors were identified using minimum-redundancy-maximum-relevance and used to construct three machine-learning models that were independently evaluated for their ability to identify the presence and absence of clinically significant disease. STATISTICAL TESTS: Wilcoxon rank-sum tests with P < 0.05 considered statistically significant. RESULTS: Seven T2 w-based (First-order Statistics, Haralick, Laws, and Gabor) and three ADC-based radiomic features (Laws, Gradient and Sobel) exhibited statistically significant differences (P < 0.001) between malignant and normal regions in the training groups. The three constructed models yielded overall accuracy improvement of 33, 60, 80% and 30, 40, 60% for patients in testing groups, when compared to PIRADS v2.0 alone. DATA CONCLUSION: Radiomic features could help in identifying the presence and absence of clinically significant disease in AS patients when PIRADS v2.0 assessment on MRI contradicted pathology findings of MRI-TRUS prostate biopsies. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

Study protocol: multi-parametric magnetic resonance imaging for therapeutic response prediction in rectal cancer.

BACKGROUND: Response to neoadjuvant chemoradiotherapy (CRT) of rectal cancer is variable. Accurate imaging for prediction and early assessment of response would enable appropriate stratification of management to reduce treatment morbidity and improve therapeutic outcomes. Use of either diffusion weighted imaging (DWI) or dynamic contrast enhanced (DCE) imaging alone currently lacks sufficient sensitivity and specificity for clinical use to guide individualized treatment in rectal cancer. Multi-parametric MRI and analysis combining DWI and DCE may have potential to improve the accuracy of therapeutic response prediction and assessment. METHODS: This protocol describes a prospective non-interventional single-arm clinical study. Patients with locally advanced rectal cancer undergoing preoperative CRT will prospectively undergo multi-parametric MRI pre-CRT, week 3 CRT, and post-CRT. The protocol consists of DWI using a read-out segmented sequence (RESOLVE), and DCE with pre-contrast T1-weighted (VIBE) scans for T1 calculation, followed by 60 phases at high temporal resolution (TWIST) after gadoversetamide injection. A 3-dimensional voxel-by-voxel technique will be used to produce colour-coded ADC and Ktrans histograms, and data evaluated in combination using scatter plots. MRI parameters will be correlated with surgical histopathology. Histopathology analysis will be standardized, with chemoradiotherapy response defined according to AJCC 7th Edition Tumour Regression Grade (TRG) criteria. Good response will be defined as TRG 0-1, and poor response will be defined as TRG 2-3. DISCUSSION: The combination of DWI and DCE can provide information on physiological tumour factors such as cellularity and perfusion that may affect radiotherapy response. If validated, multi-parametric MRI combining DWI and DCE can be used to stratify management in rectal cancer patients. Accurate imaging prediction of patients with a complete response to CRT would enable a 'watch and wait' approach, avoiding surgical morbidity in these patients. Consistent and reliable quantitation from standardised protocols is essential in order to establish optimal thresholds of ADC and Ktrans and permit the role of multi-parametric MRI for early treatment prediction to be properly evaluated. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12616001690448 (retrospectively registered 8/12/2016).

A multiparametric magnetic resonance imaging-based risk model to determine the risk of significant prostate cancer prior to biopsy.

OBJECTIVE: To develop and externally validate a predictive model for detection of significant prostate cancer. PATIENTS AND METHODS: Development of the model was based on a prospective cohort including 393 men who underwent multiparametric magnetic resonance imaging (mpMRI) before biopsy. External validity of the model was then examined retrospectively in 198 men from a separate institution whom underwent mpMRI followed by biopsy for abnormal prostate-specific antigen (PSA) level or digital rectal examination (DRE). A model was developed with age, PSA level, DRE, prostate volume, previous biopsy, and Prostate Imaging Reporting and Data System (PIRADS) score, as predictors for significant prostate cancer (Gleason 7 with >5% grade 4, ≥20% cores positive or ≥7 mm of cancer in any core). Probability was studied via logistic regression. Discriminatory performance was quantified by concordance statistics and internally validated with bootstrap resampling. RESULTS: In all, 393 men had complete data and 149 (37.9%) had significant prostate cancer. While the variable model had good accuracy in predicting significant prostate cancer, area under the curve (AUC) of 0.80, the advanced model (incorporating mpMRI) had a significantly higher AUC of 0.88 (P < 0.001). The model was well calibrated in internal and external validation. Decision analysis showed that use of the advanced model in practice would improve biopsy outcome predictions. Clinical application of the model would reduce 28% of biopsies, whilst missing 2.6% significant prostate cancer. CONCLUSIONS: Individualised risk assessment of significant prostate cancer using a predictive model that incorporates mpMRI PIRADS score and clinical data allows a considerable reduction in unnecessary biopsies and reduction of the risk of over-detection of insignificant prostate cancer at the cost of a very small increase in the number of significant cancers missed.

Adverse diastolic remodeling after reperfused ST-elevation myocardial infarction: An important prognostic indicator.

OBJECTIVES: We sought to determine the relationship of adverse diastolic remodeling (ie, worsening diastolic or persistent restrictive filling) with infarct scar characteristics, and to evaluate its prognostic value after ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Severe diastolic dysfunction (restrictive filling) has known prognostic value post STEMI. However, ongoing left ventricular (LV) remodeling post STEMI may alter diastolic function even if less severe. METHODS AND RESULTS: There were 218 prospectively recruited STEMI patients with serial echocardiograms (transthoracic echocardiography) and cardiac magnetic resonance imaging (CMR) performed, at a median of 4 days (early) and 55 days (follow-up). LV ejection fraction and infarct characteristics were assessed by CMR, and comprehensive diastolic function assessment including a diastolic grade was evaluated on transthoracic echocardiography. 'Adverse diastolic remodeling' occurred if diastolic function grade either worsened (≥1 grade) between early and follow-up imaging, or remained as persistent restrictive filling at follow-up. Follow-up infarct scar size (IS) predicted adverse diastolic remodeling (area under the curve 0.86) and persistent restrictive filling (area under the curve 0.89). The primary endpoint of major adverse cardiovascular events (MACE) occurred in 48 patients during follow-up (mean, 710±79 days). Kaplan-Meier analysis showed that adverse diastolic remodeling (n=50) and persistent restrictive filling alone (n=33) were significant predictors of MACE (both P<.001). Multivariate Cox analysis, when adjusted for TIMI risk score and CMR IS, microvascular obstruction, and LV ejection fraction, showed adverse diastolic remodeling (HR 3.79, P<.001) was an independent predictor of MACE, as was persistent restrictive filling alone (HR 2.61, P=.019). CONCLUSIONS: Larger IS is associated with adverse diastolic remodeling. Following STEMI, adverse diastolic remodeling is a powerful prognostic marker, and identifies a larger group of 'at-risk' patients, than does persistent restrictive filling alone.