Artificial intelligence and radiologists in prostate cancer detection on MRI (PI-CAI): an international, paired, non-inferiority, confirmatory study.

BACKGROUND: Artificial intelligence (AI) systems can potentially aid the diagnostic pathway of prostate cancer by alleviating the increasing workload, preventing overdiagnosis, and reducing the dependence on experienced radiologists. We aimed to investigate the performance of AI systems at detecting clinically significant prostate cancer on MRI in comparison with radiologists using the Prostate Imaging-Reporting and Data System version 2.1 (PI-RADS 2.1) and the standard of care in multidisciplinary routine practice at scale. METHODS: In this international, paired, non-inferiority, confirmatory study, we trained and externally validated an AI system (developed within an international consortium) for detecting Gleason grade group 2 or greater cancers using a retrospective cohort of 10 207 MRI examinations from 9129 patients. Of these examinations, 9207 cases from three centres (11 sites) based in the Netherlands were used for training and tuning, and 1000 cases from four centres (12 sites) based in the Netherlands and Norway were used for testing. In parallel, we facilitated a multireader, multicase observer study with 62 radiologists (45 centres in 20 countries; median 7 [IQR 5-10] years of experience in reading prostate MRI) using PI-RADS (2.1) on 400 paired MRI examinations from the testing cohort. Primary endpoints were the sensitivity, specificity, and the area under the receiver operating characteristic curve (AUROC) of the AI system in comparison with that of all readers using PI-RADS (2.1) and in comparison with that of the historical radiology readings made during multidisciplinary routine practice (ie, the standard of care with the aid of patient history and peer consultation). Histopathology and at least 3 years (median 5 [IQR 4-6] years) of follow-up were used to establish the reference standard. The statistical analysis plan was prespecified with a primary hypothesis of non-inferiority (considering a margin of 0·05) and a secondary hypothesis of superiority towards the AI system, if non-inferiority was confirmed. This study was registered at ClinicalTrials.gov, NCT05489341. FINDINGS: Of the 10 207 examinations included from Jan 1, 2012, through Dec 31, 2021, 2440 cases had histologically confirmed Gleason grade group 2 or greater prostate cancer. In the subset of 400 testing cases in which the AI system was compared with the radiologists participating in the reader study, the AI system showed a statistically superior and non-inferior AUROC of 0·91 (95% CI 0·87-0·94; p<0·0001), in comparison to the pool of 62 radiologists with an AUROC of 0·86 (0·83-0·89), with a lower boundary of the two-sided 95% Wald CI for the difference in AUROC of 0·02. At the mean PI-RADS 3 or greater operating point of all readers, the AI system detected 6·8% more cases with Gleason grade group 2 or greater cancers at the same specificity (57·7%, 95% CI 51·6-63·3), or 50·4% fewer false-positive results and 20·0% fewer cases with Gleason grade group 1 cancers at the same sensitivity (89·4%, 95% CI 85·3-92·9). In all 1000 testing cases where the AI system was compared with the radiology readings made during multidisciplinary practice, non-inferiority was not confirmed, as the AI system showed lower specificity (68·9% [95% CI 65·3-72·4] vs 69·0% [65·5-72·5]) at the same sensitivity (96·1%, 94·0-98·2) as the PI-RADS 3 or greater operating point. The lower boundary of the two-sided 95% Wald CI for the difference in specificity (-0·04) was greater than the non-inferiority margin (-0·05) and a p value below the significance threshold was reached (p<0·001). INTERPRETATION: An AI system was superior to radiologists using PI-RADS (2.1), on average, at detecting clinically significant prostate cancer and comparable to the standard of care. Such a system shows the potential to be a supportive tool within a primary diagnostic setting, with several associated benefits for patients and radiologists. Prospective validation is needed to test clinical applicability of this system. FUNDING: Health~Holland and EU Horizon 2020.

Prostagram magnetic resonance imaging in a screening population: Prostate Imaging-Reporting and Data System or Likert?

OBJECTIVE: To compare biopsy recommendation rates and accuracy of the Prostate Imaging-Reporting and Data System, version 2 (PI-RADSv2) with the Likert scale for detection of clinically significant and insignificant prostate cancer in men screened within the Imperial Prostate 1 Prostate Cancer Screening Trial Using Imaging (IP1-PROSTAGRAM). PATIENTS AND METHODS: Men aged 50-69 years were screened with Prostagram MRI. Scans were prospectively reported using both PI-RADSv2 (excluding dynamic contrast-enhanced sequence score) and 5-point Likert scores by expert uro-radiologists. Systematic and targeted transperineal biopsy was recommended if the scan was scored ≥ 3, based on either reporting system. The proportion of patients recommended for biopsy and detection rates for Grade Groups (GGs) 1 and ≥ 2 were compared. Receiver operating characteristic (ROC) analysis was performed to compare performance. RESULTS: A total of 406 men underwent Prostagram MRI. The median (interquartile range) age and prostate-specific antigen level were 57 (53-61) years and 0.91 (0.56-1.74) ng/mL, respectively. At MRI score ≥ 3, more patients were recommended for biopsy based on Likert criteria (94/406; 23%, 95% confidence interval [CI] 19.2%-27.6%) compared to PI-RADSv2 (72/406; 18%, 95% CI 14.2%-21.9%; P = 0.03). For MRI scores ≥ 4, PI-RADSv2 and Likert scales led to 43/406 (11%, 95% CI 7.9%-14.1%) and 35/406 (9%, 95% CI 6.2%-11.9%) men recommended for biopsy (P = 0.40). For GG ≥ 2 detection, PIRADSv2 and Likert detected 22% (95% CI 11.4%-30.8%, 14/72) and 16% (95% CI 9.5%-25.3%, 15/94), respectively (P = 0.56). For GG1 cancers detection these were 11% (95% CI 4.3%-19.6%, seven of 72) vs 11% (95% CI 4.7%-17.8%, nine of 94; P = 1.00). The accuracy of PI-RADSv2 and Likert scale was similar (area under the ROC curve 0.64 vs 0.65, P = 0.95). CONCLUSIONS: In reporting non-contrast-enhanced Prostagram MRI in a screening population, the PI-RADSv2 and Likert scoring systems were equally accurate; however, Likert scale use led to more men undergoing biopsy without a subsequent increase in significant cancer detection rates. To improve reporting of Prostagram MRI, either the PI-RADSv2 or a modified Likert scale or a standalone scoring system should be developed.

Key learning on the promise and limitations of MRI in prostate cancer screening.

MRI retains its ability to reduce the harm of prostate biopsies by decreasing biopsy rates and the detection of indolent cancers in population-based screening studies aiming to find clinically significant prostate cancers. Limitations of low positive predictive values and high reader variability in diagnostic performance require optimisations in patient selection, imaging protocols, interpretation standards, diagnostic thresholds, and biopsy methods. Improvements in diagnostic accuracy could come about through emerging technologies like risk calculators and polygenic risk scores to select men for MRI. Furthermore, artificial intelligence and workflow optimisations focused on streamlining the diagnostic pathway, quality control, and assurance measures will improve MRI variability. CLINICAL RELEVANCE STATEMENT: MRI significantly reduces harm in prostate cancer screening, lowering unnecessary biopsies and minimizing the overdiagnosis of indolent cancers. MRI maintains the effective detection of high-grade cancers, thus improving the overall benefit-to-harm ratio in population-based screenings with or without using serum prostate-specific antigen (PSA) for patient selection. KEY POINTS: • The use of MRI enables the harm reduction benefits seen in individual early cancer detection to be extended to both risk-stratified and non-stratified prostate cancer screening populations. • MRI limitations include a low positive predictive value and imperfect reader variability, which require standardising interpretations, biopsy methods, and integration into a quality diagnostic pathway. • Current evidence is based on one-time point use of MRI in screening; MRI effectiveness in multiple rounds of screening is not well-documented.

Image quality of whole-body diffusion MR images comparing deep-learning accelerated and conventional sequences.

OBJECTIVES: To compare the image quality of deep learning accelerated whole-body (WB) with conventional diffusion sequences. METHODS: Fifty consecutive patients with bone marrow cancer underwent WB-MRI. Two experts compared axial b900 s/mm2 and the corresponding maximum intensity projections (MIP) of deep resolve boost (DRB) accelerated diffusion-weighted imaging (DWI) sequences (time of acquisition: 6:42 min) against conventional sequences (time of acquisition: 14 min). Readers assessed paired images for noise, artefacts, signal fat suppression, and lesion conspicuity using Likert scales, also expressing their overall subjective preference. Signal-to-noise and contrast-to-noise ratios (SNR and CNR) and the apparent diffusion coefficient (ADC) values of normal tissues and cancer lesions were statistically compared. RESULTS: Overall, radiologists preferred either axial DRB b900 and/or corresponding MIP images in almost 80% of the patients, particularly in patients with a high body-mass index (BMI > 25 kg/m2). In qualitative assessments, axial DRB images were preferred (preferred/strongly preferred) in 56-100% of cases, whereas DRB MIP images were favoured in 52-96% of cases. DRB-SNR/CNR was higher in all normal tissues (p < 0.05). For cancer lesions, the DRB-SNR was higher (p < 0.001), but the CNR was not different. DRB-ADC values were significantly higher for the brain and psoas muscles, but not for cancer lesions (mean difference: + 53 µm2/s). Inter-class correlation coefficient analysis showed good to excellent agreement (95% CI 0.75-0.93). CONCLUSION: DRB sequences produce higher-quality axial DWI, resulting in improved MIPs and significantly reduced acquisition times. However, differences in the ADC values of normal tissues need to be considered. CLINICAL RELEVANCE STATEMENT: Deep learning accelerated diffusion sequences produce high-quality axial images and MIP at reduced acquisition times. This advancement could enable the increased adoption of Whole Body-MRI for the evaluation of patients with bone marrow cancer. KEY POINTS: Deep learning reconstruction enables a more than 50% reduction in acquisition time for WB diffusion sequences. DRB images were preferred by radiologists in almost 80% of cases due to fewer artefacts, improved background signal suppression, higher signal-to-noise ratio, and increased lesion conspicuity in patients with higher body mass index. Cancer lesion diffusivity from DRB images was not different from conventional sequences.

ESR Essentials: using the right scoring system in prostate MRI-practice recommendations by ESUR.

MRI has gained prominence in the diagnostic workup of prostate cancer (PCa) patients, with the Prostate Imaging Reporting and Data System (PI-RADS) being widely used for cancer detection. Beyond PI-RADS, other MRI-based scoring tools have emerged to address broader aspects within the PCa domain. However, the multitude of available MRI-based grading systems has led to inconsistencies in their application within clinical workflows. The Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) assesses the likelihood of clinically significant radiological changes of PCa during active surveillance, and the Prostate Imaging for Local Recurrence Reporting (PI-RR) scoring system evaluates the risk of local recurrence after whole-gland therapies with curative intent. Underlying any system is the requirement to assess image quality using the Prostate Imaging Quality Scoring System (PI-QUAL). This article offers practicing radiologists a comprehensive overview of currently available scoring systems with clinical evidence supporting their use for managing PCa patients to enhance consistency in interpretation and facilitate effective communication with referring clinicians. KEY POINTS: Assessing image quality is essential for all prostate MRI interpretations and the PI-QUAL score represents  the standardized tool for this purpose. Current urological clinical guidelines for prostate cancer diagnosis and localization recommend adhering to the PI-RADS recommendations. The PRECISE and PI-RR scoring systems can be used for assessing radiological changes of prostate cancer during active surveillance and the likelihood of local recurrence after radical treatments respectively.

Reduction of false positives using zone-specific prostate-specific antigen density for prostate MRI-based biopsy decision strategies.

OBJECTIVES: To develop and test zone-specific prostate-specific antigen density (sPSAD) combined with PI-RADS to guide prostate biopsy decision strategies (BDS). METHODS: This retrospective study included consecutive patients, who underwent prostate MRI and biopsy (01/2012-10/2018). The whole gland and transition zone (TZ) were segmented at MRI using a retrained deep learning system (DLS; nnU-Net) to calculate PSAD and sPSAD, respectively. Additionally, sPSAD and PI-RADS were combined in a BDS, and diagnostic performances to detect Grade Group ≥ 2 (GG ≥ 2) prostate cancer were compared. Patient-based cancer detection using sPSAD was assessed by bootstrapping with 1000 repetitions and reported as area under the curve (AUC). Clinical utility of the BDS was tested in the hold-out test set using decision curve analysis. Statistics included nonparametric DeLong test for AUCs and Fisher-Yates test for remaining performance metrics. RESULTS: A total of 1604 patients aged 67 (interquartile range, 61-73) with 48% GG ≥ 2 prevalence (774/1604) were evaluated. By employing DLS-based prostate and TZ volumes (DICE coefficients of 0.89 (95% confidence interval, 0.80-0.97) and 0.84 (0.70-0.99)), GG ≥ 2 detection using PSAD was inferior to sPSAD (AUC, 0.71 (0.68-0.74)/0.73 (0.70-0.76); p < 0.001). Combining PI-RADS with sPSAD, GG ≥ 2 detection specificity doubled from 18% (10-20%) to 43% (30-44%; p < 0.001) with similar sensitivity (93% (89-96%)/97% (94-99%); p = 0.052), when biopsies were taken in PI-RADS 4-5 and 3 only if sPSAD was ≥ 0.42 ng/mL/cc as compared to all PI-RADS 3-5 cases. Additionally, using the sPSAD-based BDS, false positives were reduced by 25% (123 (104-142)/165 (146-185); p < 0.001). CONCLUSION: Using sPSAD to guide biopsy decisions in PI-RADS 3 lesions can reduce false positives at MRI while maintaining high sensitivity for GG ≥ 2 cancers. CLINICAL RELEVANCE STATEMENT: Transition zone-specific prostate-specific antigen density can improve the accuracy of prostate cancer detection compared to MRI assessments alone, by lowering false-positive cases without significantly missing men with ISUP GG ≥ 2 cancers. KEY POINTS: • Prostate biopsy decision strategies using PI-RADS at MRI are limited by a substantial proportion of false positives, not yielding grade group ≥ 2 prostate cancer. • PI-RADS combined with transition zone (TZ)-specific prostate-specific antigen density (PSAD) decreased the number of unproductive biopsies by 25% compared to PI-RADS only. • TZ-specific PSAD also improved the specificity of MRI-directed biopsies by 9% compared to the whole gland PSAD, while showing identical sensitivity.

PI-QUAL version 2: an update of a standardised scoring system for the assessment of image quality of prostate MRI.

Multiparametric MRI is the optimal primary investigation when prostate cancer is suspected, and its ability to rule in and rule out clinically significant disease relies on high-quality anatomical and functional images. Avenues for achieving consistent high-quality acquisitions include meticulous patient preparation, scanner setup, optimised pulse sequences, personnel training, and artificial intelligence systems. The impact of these interventions on the final images needs to be quantified. The prostate imaging quality (PI-QUAL) scoring system was the first standardised quantification method that demonstrated the potential for clinical benefit by relating image quality to cancer detection ability by MRI. We present the updated version of PI-QUAL (PI-QUAL v2) which applies to prostate MRI performed with or without intravenous contrast medium using a simplified 3-point scale focused on critical technical and qualitative image parameters. CLINICAL RELEVANCE STATEMENT: High image quality is crucial for prostate MRI, and the updated version of the PI-QUAL score (PI-QUAL v2) aims to address the limitations of version 1. It is now applicable to both multiparametric MRI and MRI without intravenous contrast medium. KEY POINTS: High-quality images are essential for prostate cancer diagnosis and management using MRI. PI-QUAL v2 simplifies image assessment and expands its applicability to prostate MRI without contrast medium. PI-QUAL v2 focuses on critical technical and qualitative image parameters and emphasises T2-WI and DWI.

PI-RADS Upgrading Rules: Impact on Prostate Cancer Detection and Biopsy Avoidance of MRI-Directed Diagnostic Pathways.

BACKGROUND. PI-RADS incorporates rules by which ancillary sequence findings upgrade a dominant score to a higher final category. Evidence on the upgrading rules' impact on diagnostic pathways remains scarce. OBJECTIVE. The purpose of this article was to evaluate the clinical net benefit of the PI-RADS upgrading rules in MRI-directed diagnostic pathways. METHODS. This study was a retrospective analysis of a prospectively maintained clinical registry. The study included patients without known prostate cancer who underwent prostate MRI followed by prostate biopsy from January 2016 to May 2020. Clinically significant prostate cancer (csPCa) was defined as International Society of Urological Pathology (ISUP) grade group 2 and higher. csPCa detection was compared between dominant (i.e., no upgrade rule applied) and upgraded lesions. Decision-curve analysis was used to compare the net benefit, considering the trade-off of csPCa detection and biopsy avoidance, of MRI-directed pathways in scenarios considering and disregarding PI-RADS upgrading rules. These included a biopsy-all pathway, MRI-focused pathway (no biopsy for PI-RADS ≤ 2), and risk-based pathway (use of PSA density ≥ 0.15 ng/mL2 to select patients with PI-RADS ≤ 3 for biopsy). RESULTS. The sample comprised 716 patients (mean age, 64.9 years; 93 with a PI-RADS ≤ 2 examination, 623 with total of 780 PI-RADS ≥ 3 lesions). Frequencies of csPCa were not significantly different between dominant and upgraded PI-RADS 3 transition zone lesions (20% vs 19%, respectively), dominant and upgraded PI-RADS 4 transition zone lesions (33% vs 26%), and dominant and upgraded PI-RADS 4 peripheral zone lesions (58% vs 45%) (p > .05). In the biopsy-all, per-guideline MRI-focused, MRI-focused disregarding upgrading rules, per-guideline risk-based, and risk-based disregarding upgrading rules pathways, csPCa frequency was 53%, 52%, 51%, 52%, and 48% and biopsy avoidance was 0%, 13%, 16%, 19%, and 25%, respectively. Disregarding upgrading rules yielded 5.5 and 1.9 biopsies avoided per missed csPCa for MRI-focused and risk-based pathways, respectively. At probability thresholds for biopsy selection of 7.5-30.0%, net benefit was highest for the per-guideline risk-based pathway. CONCLUSION. Disregarding PI-RADS upgrading rules reduced net clinical bene fit of the risk-based MRI-directed diagnostic pathway when considering trade-offs between csPCa detection and biopsy avoidance. CLINICAL IMPACT. This study supports the application of PI-RADS upgrading rules to optimize biopsy selection, particularly in risk-based pathways.

How Imaging Advances Are Defining the Future of Precision Radiation Therapy.

Radiation therapy is fundamental in the treatment of cancer. Imaging has always played a central role in radiation oncology. Integrating imaging technology into irradiation devices has increased the precision and accuracy of dose delivery and decreased the toxic effects of the treatment. Although CT has become the standard imaging modality in radiation therapy, the development of recently introduced next-generation imaging techniques has improved diagnostic and therapeutic decision making in radiation oncology. Functional and molecular imaging techniques, as well as other advanced imaging modalities such as SPECT, yield information about the anatomic and biologic characteristics of tumors for the radiation therapy workflow. In clinical practice, they can be useful for characterizing tumor phenotypes, delineating volumes, planning treatment, determining patients' prognoses, predicting toxic effects, assessing responses to therapy, and detecting tumor relapse. Next-generation imaging can enable personalization of radiation therapy based on a greater understanding of tumor biologic factors. It can be used to map tumor characteristics, such as metabolic pathways, vascularity, cellular proliferation, and hypoxia, that are known to define tumor phenotype. It can also be used to consider tumor heterogeneity by highlighting areas at risk for radiation resistance for focused biologic dose escalation, which can impact the radiation planning process and patient outcomes. The authors review the possible contributions of next-generation imaging to the treatment of patients undergoing radiation therapy. In addition, the possible roles of radio(geno)mics in radiation therapy, the limitations of these techniques, and hurdles in introducing them into clinical practice are discussed. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Potentially active aspirin derivative to release nitric oxide: In-vitro, in-vivo and in-silico approaches.

The series of newer salicylate derivatives incorporating nitroxy functionality were synthesized and evaluated for their potential effect in gastrointestinal (GI) related toxicity produced by aspirin. The synthesized compounds (5a-j) were subjected to %NO (nitric oxide) release study, in-vitro anti-inflammatory potential, % inhibition of carrageenan-induced paw edema and the obtained results were validated by in-silico studies including molecular docking, MD simulations and in-silico ADME (absorption, distribution, metabolism, and elimination) calculations. Compounds 5a (20.86 %) and 5g (18.20 %) displayed the highest percentage of NO release in all the tested compounds. Similarly, 5a and 5h were found to have (77.11 % and 79.53 %) &(78.56 % and 66.10 %) inhibition in carrageenan induced paw edema in animal mode which were relatively higher than ibuprofen (standard used). The obtained results were validated by molecular docking and MD simulations studies. The molecular docking study of 5a and 5h revealed that docking scores were also obtained in very close proximity of -8.35, -9.67 and -8.48 for ibuprofen, 5g and 5h respectively. In MD simulations studies, the calculated lower RMSD (root mean square deviation) values 2.8 Å and 5.6 Å for 5g and 5h, respectively indicated the stability of ligand-protein complexes. Similarly lower RSMF (root mean square fluctuation) values indicated the molecules remained in the active pocket throughout the entire MD simulations run. Further, in-silico ADME calculations were determined and all compounds obey the Lipinski's rule of five and it was predicted that these molecules would be orally active without any serious toxic effect.

Prostate cancer screening-stepping forward with MRI.

OBJECTIVE: To comprehensively review the literature on the integration of MRI as a diagnostic tool in prostate cancer screening and offer practical recommendations for optimising its use. METHODS: Existing research studies, clinical guidelines and expert opinions were reviewed to support the optimisation standards for MRI use in screening. Consolidated screening principles were used to make appropriate recommendations regarding the integration of MRI into the diagnostic pathway. RESULTS: To strike a balance between the potential benefits of early detection on mortality and minimising the harm of over-diagnosing indolent cancers, it is necessary to have a clear understanding of the context of MRI use. The key to optimisation is patient selections and MRI-targeted biopsies. For men at higher-than-average risk, it is essential to use screening-specific MRI protocols and establish accuracy levels and interpretation criteria. Optimisation of readings by the automation of data acquisition, image quality monitoring, post-processing, radiologist certification and deep-learning computer-aided software is needed. The optimal utilisation of MRI involves its integration into a multistep diagnostic pathway, supported by a quality-assured and cost-effective infrastructure that ensures community-wide access to imaging. CONCLUSION: MRI in the prostate cancer screening pathway can bring substantial diagnostic benefits. By carefully considering its advantages, limitations and safety concerns and integrating it into a multistep diagnostic pathway, clinicians can improve outcomes while minimising harm to screening participants. CLINICAL RELEVANCE STATEMENT: The manuscript discusses the role of MRI in prostate cancer screening, highlighting its potential to improve accuracy and reduce overdiagnosis. It emphasises the importance of optimising protocols and integrating MRI into a multistep diagnostic pathway for successfully delivering screening benefits. KEY POINTS: • Population screening for prostate cancer is a new indication for prostate MRI that allows the detection of high-risk cancers while reducing the need for biopsies and associated harm. • To optimise prostate cancer screening using MRI, it is essential to redefine MRI protocols; establish accuracy levels, reliability and interpretation criteria; and optimise reading (including post-processing, image quality, radiologist certification, and deep-learning computer-aided software). • The optimal utilisation of MRI for prostate cancer screening would involve its integration into a multistep diagnostic pathway, supported by a quality-assured and cost-effective infrastructure that ensures community-wide access to imaging.

Management of Patients With a Negative Multiparametric Prostate MRI Examination: AJR Expert Panel Narrative Review.

Multiparametric prostate MRI (mpMRI) aids risk stratification of patients with elevated PSA levels. While most clinically significant prostate cancers are detected by mpMRI, insignificant cancers are less evident. Thus, multiple international prostate cancer guidelines now endorse routine use of prostate MRI as a secondary screening test before prostate biopsy. Nonetheless, management of patients with negative mpMRI results (defined as PI-RADS category 1 or 2) remains unclear. This AJR Expert Panel Narrative Review summarizes the available literature on patients with an elevated screening PSA level and a negative prostate mpMRI, and provides guidance for these patients' management. Systematic biopsy should not be routinely performed after a negative mpMRI in patients at average risk but should be considered in patients at high risk. In patients who undergo PSA screening rather than systematic biopsy after negative mpMRI, clear triggers should be established for when to perform a repeat MRI. Patients with negative MRI followed by negative biopsy should follow their healthcare practitioners' preferred guidelines concerning subsequent PSA screening for the patient's risk level. Insufficient high-level data exist to support routine use of adjunctive serum or urine biomarkers, artificial intelligence, or PSMA PET to determine the need for prostate biopsy after negative mpMRI.

The Impact of Semicarbazide Sensitive Amine Oxidase Activity on Rat Aortic Vascular Smooth Muscle Cells.

Semicarbazide-sensitive amine oxidase (SSAO) is both a soluble- and membrane-bound transmembrane protein expressed in the vascular endothelial and in smooth muscle cells. In vascular endothelial cells, SSAO contributes to the development of atherosclerosis by mediating a leukocyte adhesion cascade; however, its contributory role in the development of atherosclerosis in VSMCs has not yet been fully explored. This study investigates SSAO enzymatic activity in VSMCs using methylamine and aminoacetone as model substrates. The study also addresses the mechanism by which SSAO catalytic activity causes vascular damage, and further evaluates the contribution of SSAO in oxidative stress formation in the vascular wall. SSAO demonstrated higher affinity for aminoacetone when compared to methylamine (Km = 12.08 µM vs. 65.35 µM). Aminoacetone- and methylamine-induced VSMCs death at concentrations of 50 & 1000 µM, and their cytotoxic effect, was reversed with 100 µM of the irreversible SSAO inhibitor MDL72527, which completely abolished cell death. Cytotoxic effects were also observed after 24 h of exposure to formaldehyde, methylglyoxal and H2O2. Enhanced cytotoxicity was detected after the simultaneous addition of formaldehyde and H2O2, as well as methylglyoxal and H2O2. The highest ROS production was observed in aminoacetone- and benzylamine-treated cells. MDL72527 abolished ROS in benzylamine-, methylamine- and aminoacetone-treated cells (**** p < 0.0001), while ßAPN demonstrated inhibitory potential only in benzylamine-treated cells (* p < 0.05). Treatment with benzylamine, methylamine and aminoacetone reduced the total GSH levels (**** p < 0.0001); the addition of MDL72527 and ßAPN failed to reverse this effect. Overall, a cytotoxic consequence of SSAO catalytic activity was observed in cultured VSMCs where SSAO was identified as a key mediator in ROS formation. These findings could potentially associate SSAO activity with the early developing stages of atherosclerosis through oxidative stress formation and vascular damage.

Topical betamethasone and systemic colchicine for treatment of recurrent aphthous stomatitis: a randomised clinical trial.

BACKGROUND: Recurrent Aphthous Stomatitis (RAS) is painful oral ulceration frequently treated with topical steroids. There is limited published evidence for the efficacy of any treatment for RAS and there remains a need for longitudinal randomised clinical trials to evaluate and compare the effectiveness of different therapies in the management of RAS. The aim of the current project was to assess the efficacy of betamethasone mouthwash and colchicine tablets, individually and combined, for the treatment of RAS, and to establish the optimum treatment period necessary for a significant reduction in the disease severity. METHODOLOGY: A randomised, prospective, parallel-group clinical trial was conducted over one year, to compare the efficacy of three therapies in RAS. One hundred and six patients were randomized into three groups; 35 received betamethasone mouthwash, 35 had colchicine tablets and 36 received both therapies. The response was evaluated quantitatively every 3 months for 1 year, using the Ulcer Severity Score (USS). RESULTS: For all three treatment regimes, the mean USS decreased by about 30% in the first 3 months (p < 0.001). Further improvement was noted for up to 9 months. At the end of the study, the mean USS had improved by 50% from 34.9 ± 7.2 before treatment to 17.5 ± 8.9 after treatment (p < 0.001). Of included participants, 86% showed significant clinical improvement by the end of the study. There were no significant differences in outcomes between the three regimes (p < 0.05). CONCLUSIONS: This clinical trial has provided evidence for the efficacy of betamethasone mouthwash and for colchicine tablets in the treatment of RAS and has shown that at least six months of treatment may be required for optimum effect. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN3267716. Date of clinical trial registration: 15/04/2018.

Diagnostic Accuracy and Observer Agreement of the MRI Prostate Imaging for Recurrence Reporting Assessment Score.

Background Prostate cancer local recurrence location and extent must be determined in an accurate and timely manner. Because of the lack of a standardized MRI approach after whole-gland treatment, a panel of international experts recently proposed the Prostate Imaging for Recurrence Reporting (PI-RR) assessment score. Purpose To determine the diagnostic accuracy of PI-RR for detecting local recurrence in patients with biochemical recurrence (BCR) after radiation therapy (RT) or radical prostatectomy (RP) and to evaluate the interreader variability of PI-RR scoring. Materials and Methods This retrospective observational study included patients who underwent multiparametric MRI between September 2016 and May 2021 for BCR after RT or RP. MRI scans were analyzed, and a PI-RR score was assigned independently by four radiologists. The reference standard was defined using histopathologic findings, follow-up imaging, or clinical response to treatment. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated to assess PI-RR performance for each reader. The intraclass correlation coefficient was used to determine interreader agreement. Results A total of 100 men were included: 48 patients after RT (median age, 76 years [IQR, 70-82 years]) and 52 patients after RP (median age, 70 years [IQR, 66-74 years]). After RT, with PI-RR of 3 or greater as a cutoff (assigned when recurrence is uncertain), diagnostic performance ranges were 71%-81% sensitivity, 74%-93% specificity, 71%-89% PPV, 79%-86% NPV, and 77%-88% accuracy across the four readers. After RP, with PI-RR of 3 or greater as a cutoff, performance ranges were 59%-83% sensitivity, 87%-100% specificity, 88%-100% PPV, 66%-80% NPV, and 75%-85% accuracy. The intraclass correlation coefficient was 0.87 across the four readers for both the RT and RP groups. Conclusion MRI scoring with the Prostate Imaging for Recurrence Reporting assessment provides structured, reproducible, and accurate evaluation of local recurrence after definitive therapy for prostate cancer. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Haider in this issue. An earlier incorrect version appeared online. This article was corrected on May 11, 2022.

Whole-body magnetic resonance imaging for prostate cancer assessment: Current status and future directions.

Over the past decade, updated definitions for the different stages of prostate cancer and risk for distant disease, along with the advent of new therapies, have remarkably changed the management of patients. The two expectations from imaging are accurate staging and appropriate assessment of disease response to therapies. Modern, next-generation imaging (NGI) modalities, including whole-body magnetic resonance imaging (WB-MRI) and nuclear medicine (most often prostate-specific membrane antigen [PSMA] positron emission tomography [PET]/computed tomography [CT]) bring added value to these imaging tasks. WB-MRI has proven its superiority over bone scintigraphy (BS) and CT for the detection of distant metastasis, also providing reliable evaluations of disease response to treatment. Comparison of the effectiveness of WB-MRI and molecular nuclear imaging techniques with regard to indications and the definition of their respective/complementary roles in clinical practice is ongoing. This paper illustrates the evolution of WB-MRI imaging protocols, defines the current state-of-the art, and highlights the latest developments and future challenges. The paper presents and discusses WB-MRI indications in the care pathway of men with prostate cancer in specific key situations: response assessment of metastatic disease, "all in one" cancer staging, and oligometastatic disease.

Balancing the benefits and harms of MRI-directed biopsy pathways.

KEY POINTS: • Before a prostate biopsy, the likely benefits and the harms emanating from true and false test MRI results need to be balanced. Prioritizing patients' preferences and their tolerance to potential harms are essential to assess.• The decision curve analysis method is an analytical framework where the net clinical benefit is plotted against a range of risk thresholds of having important cancers, helping patients and their physicians to decide between cancer averse (important cancers being detected) and biopsy averse (biopsies avoided) strategies.• The decision curve analysis method showed that the incorporation of clinical risk factors with MRI findings optimizes biopsy outcomes over a range of clinically relevant risk thresholds, compared to other biopsy strategies.

High-throughput sequencing of IgH gene in minor salivary glands from Sjögren's syndrome patients reveals dynamic B cell recirculation between ectopic lymphoid structures.

OBJECTIVES: B cells play a central role in Sjögren's syndrome (SS) whereby autoreactive B-cells populate ectopic germinal centres (GC) in SS salivary glands (SG) and undergo somatic hypermutation (SHM) and class-switch recombination of the immunoglobulin genes. However, the capacity of specific B cell clones to seed ectopic GC in different SG and undergo clonal diversification is unclear. To unravel the dynamics of B cell recirculation among minor SG biopsies, we investigated the immunoglobulin heavy chain (IgH) gene usage and the pattern of SHM using a high-throughput sequencing approach. METHODS: We generated ~166,000 reads longer than 350bp and detected 1631 clonotypes across eight samples from four different SS patients, all characterised by the presence of functional ectopic GC as demonstrated by the expression of activation-induced cytidine deaminase. RESULTS: A large number of shared clonotypes were observed among paired mSG biopsies from each patient but not across different patients. Lineage tree analysis revealed significant clonal expansion within the mSG with the identification of shared dominant B cell clones suggestive of extensive recirculation across different SG. Several shared clonotypes with high proliferating capacity displayed IgH-VH gene usage common in autoreactive B cells, including VH1-69, which is typical of rheumatoid factor+ B cells representing potential lymphoma precursors. CONCLUSIONS: The complex dynamic recirculation of B cells that we observed within ectopic GC responses linked with their ability to independently proliferate, undergo ongoing SHM and Ig class-switching within individual glands may explain the difficulty in achieving consistent eradication of ectopic GCs following B cell depleting agents reported in different studies.

The impact of SjÓ§gren's syndrome on the quality of sexual life of female patients in the UK: a controlled analysis.

Mucosal dryness and dyspareunia are symptoms that may significantly affect women with primary SjÓ§gren syndrome (pSS). We investigated whether vaginal dryness is correlated with sexual function, and the impact may have on the quality of life (QoL) and mental health well-being in pSS patients. Ethically approved comparative cross-sectional study was designed to assess sexual function using the Female Sexual Function Index (FSFI) in 65 pSS female patients vs 62 sex-matched controls. The effect of vaginal dryness and fatigue on sexual function was investigated. Vaginal dryness was correlated with oral dryness estimated by salivary flow rate and the Clinical Oral Dryness Score to investigate whether genital dryness is indicative of general mucosal dryness in pSS. Validated questionnaires were used to investigate the effect of sexual function on QoL and mental health well-being. The number of sexually active pSS participants was significantly less than in the control group (28/65 vs 42/62, p < 0.05). The sexual function was significantly impaired in the pSS group (mean FSFI = 19 vs 28.3, p < 0.05). There was no significant association between self-reported vaginal dryness and oral dryness or sexual function. The open-ended questions showed that the most troublesome symptom reported by pSS patients was oral dryness (43%, n = 28/65) followed by fatigue (31%, n = 20/65). Sexual dysfunction had a negative impact on QoL and the mental health well-being of pSS patients in all aspects, especially on the quality of social life (ß = 0.7, p = 0.02). Addressing sexual dysfunction can potentially improve the QoL of pSS patients significantly, especially their social well-being.

2-Oxothiazolidine-4-carboxylic acid inhibits vascular calcification via induction of glutathione synthesis.

Arterial medial calcification (AMC), the deposition of hydroxyapatite in the medial layer of the arteries, is a known risk factor for cardiovascular events. Oxidative stress is a known inducer of AMC and endogenous antioxidants, such as glutathione (GSH), may prevent calcification. GSH synthesis, however, can be limited by cysteine levels. Therefore, we assessed the effects of the cysteine prodrug 2-oxothiazolidine-4-carboxylic acid (OTC), on vascular smooth muscle cell (VSMC) calcification to ascertain its therapeutic potential. Human aortic VSMCs were cultured in basal or mineralising medium (1 mM calcium chloride/sodium phosphate) and treated with OTC (1-5 mM) for 7 days. Cell-based assays and western blot analysis were performed to assess cell differentiation and function. OTC inhibited calcification ≤90%, which was associated with increased ectonucleotide pyrophosphatase/phosphodiesterase activity, and reduced apoptosis. In calcifying cells, OTC downregulated protein expression of osteoblast markers (Runt-related transcription factor 2 and osteopontin), while maintaining expression of VSMC markers (smooth muscle protein 22α and α-smooth muscle actin). GSH levels were significantly reduced by 90% in VSMCs cultured in calcifying conditions, which was associated with declines in expression of gamma-glutamylcysteine synthetase and GSH synthetase. Treatment of calcifying cells with OTC blocked the reduction in expression of both enzymes and prevented the decline in GSH. This study shows OTC to be a potent and effective inhibitor of in vitro VSMC calcification. It appears to maintain GSH synthesis which may, in turn, prevent apoptosis and VSMCs gaining osteoblast-like characteristics. These findings may be of clinical relevance and raise the possibility that treatment with OTC could benefit patients susceptible to AMC.