This abstract presents how RGI can be used in drug development for pharmacodynamic and pharmacokinetic assessment of cellular, gene, oncolytic viral and immunotherapeutic approaches using MRI, PET, SPECT, Ultrasound, Bioluminescence and Fluoroscence. Some of the teaching points include further insight into RGI imaging probes that can be direct, indirect or activable; range from enzymes, protein receptors and cell membrane transporters and how RGI qualitatively and quantitatively assesses cell targeting, transfection, protein expression and intracellular processes.
Imaging Considerations
The Role of Advanced MRI in the Development of Treat-to-Target Therapeutic Strategies, Patient Stratification and Phenotyping in Rheumatoid Arthritis
In this commentary we discuss the potential of advanced imaging, particularly Dynamic Contrast Enhanced (DCE) magnetic resonance imaging (MRI) for the objective assessment of disease progression in rheumatoid arthritis (RA). We emphasise the potential DCE-MRI in advancing the field and exploring new areas of research and development in RA. We believe that different grades of bone marrow edema (BME) and synovitis in RA can be examined and monitored in a more sensitive manner with DCE-MRI. Future treatments for RA will be significantly improved by enhanced imaging of BMEs and synovitis. DCE-MRI will also facilitate enhanced stratification and phenotyping of patients enrolled in clinical trials.
Multi-Parametric MRI As Supplement to mRANO Criteria for Response Assessment to MDNA55 in Adults with Recurrent or Progressive Glioblastoma.
Copyright © 2019 by American Society of Clinical Oncology
Journal of Clinical Oncology May 2019; 37(15)_suppl DOI: 10.1200/JCO.2019.37.15_suppl.e13559
Abstract
BACKGROUND:
Modified response assessment in neuro-oncology (mRANO) criteria are widely used in GBM but seem insufficient to capture Pseudoprogression (PsP), which occurs due to extensive inflammatory infiltration, increased vascular permeability, tumor necrosis and edema. mRANO criteria recommend volumetric response evaluation using contrast-enhanced T1 subtraction maps for identifying PsP. Our approach incorporates multi-parametric MRI biomarkers to unravel the true PsP from recurrence or distinguish Pseudo Response (PsR) – following anti-VEGF agents – from delayed (immuno)response.
METHODS:
Multiple time-points MRI (18-24h after convection-enhance delivery of the anti-IL4-R agent MDNA55, then at 30-day intervals) was utilized to determine response. Multi-parametric MRI biomarkers analyzed included (1) 3D-FLAIR-T2-based tumor volume assessment reflecting edema, necrosis and tumor infiltration; (2) 3D-gadolinium-enhanced-based tumor volume estimation reflecting active tumor infiltration, neo-angiogenesis and disrupted blood brain barrier; (3) Dynamic susceptibility contrast-based relative cerebral blood volume (rCBV) measurements for estimation of the vascular tumour properties; and (4) Diffusion weighted imaging – Apparent diffusion coefficient measurements that assess interstitial edema, tumor cellularity and ischemic injury.
RESULTS:
We demonstrate similar imaging phenotypes on conventional FLAIR-T2- and enhanced T1- MR images among different disease states (PsP vs true progression, PsR vs and immuno-response) and describe the perfusion and diffusion MRI biomarkers that improve response staging including PsP masking true progression, PsP masking clinical response, early progression with delayed response, and differentiation between true and PsR. The results are compared with the mRANO-based assessments for concurrence.
CONCLUSION:
Incorporating multi-parametric MRI measurements to determine the complex underlying tissue processes enables a better assessment of PsP, PsR and delayed tumour response, and can supplement mRANO-based response assessments in GBM patients undergoing novel immunotherapies.
Decision Making in Surveillance of High-Grade Gliomas Using Perfusion MRI as Adjunct to conventional MRI and Artificial Intelligence.
IAG & UCL poster for the 2019 ASCO Annual Meeting
Abstract
BACKGROUND:
Surveillance of High-Grade Gliomas (HGGs) remains a major challenge in clinical neurooncology. Histopathological validation is not an option during the course of disease and imaging surveillance suffers from ambiguous features of both disease progression and treatment related changes. This study aimed to differentiate between Pseudoprogression (PsP) and Progressive Disease (PD) using an artificial intelligence (support vector machine – SVM) classification algorithm.
METHODS:
Two groups of patients with histologically proven HGGs were analysed, a group with a single time point DSC perfusion MRI (45 patients) and a group with multiple time point DSC perfusion MRI (19 patients). Both groups included conventional MRI studies prior and after each perfusion MRI. This study design aimed to replicate decision making in clinical practice including multiple previous studies for each patient. SVM training was performed with all available MRI studies for each group and classification was based on different feature datasets from a single or multiple (subtracted features) time points. Classification accuracy comparisons were performed by calculating prediction error rates for different feature datasets and different time point analyses.
RESULTS:
Our results indicate that the addition of multiple time point perfusion MRI combined with structural (conventional with gadolinium-enhanced sequences) MRI features results in optimal classification performance (median error rate: 0.016, lowest value dispersion). Subtracted feature datasets improved classification performance, more prominently when the final and first perfusion studies were included in the analysis. On the contrary, in the single time point group analysis, structural feature-based classification performed best (median error rate: 0.012).
CONCLUSION:
Validation of our results with a larger patient cohort may have significant clinical importance in optimising imaging surveillance and clinical decision making for patients with HGG.
Development of a Multi-Modality Imaging Approach to evaluate Lupus Nephritis and initial results.
© Author(s) (or their employer(s)) 2019. Published by BMJ.
Annals of the Rheumatic Diseases. 2019 June;78(2)
Abstract
BACKGROUND:
Lupus nephritis (LN) remains a significant cause of morbidity and mortality in subjects with Systemic Lupus Erythematosus (SLE). The gold standard for evaluation of LN remains the kidney biopsy, whereas renal function is usually evaluated by eGFR and urinary protein:creatinine ratio. More effective and sensitive methodology is needed to assess LN and also the response to treatment. Functional imaging of the kidney using quantitative techniques has great potential, as it can assess kidney function and pathologic changes non-invasively by evaluating perfusion, oxygenation, cellular density and fibrosis.
OBJECTIVE:
To develop a multi-modality imaging approach for the evaluation of the spectrum of pathologic changes in LN.
METHODS:
In this multi-center study, subjects who were having a standard of care renal biopsy for LN were asked to participate in the imaging evaluation. Local Institutional Review Board approval was obtained, and subjects signed an Informed Consent Form. Dynamic contrast enhanced MRI (DCE-MRI) was employed to detect changes in vascularization and perfusion, Diffusion Weighted Imaging (DWI) to assess interstitial diffusion, T2*Map/BOLD – the tissue oxygenation and T1rho to evaluate fibrosis. The imaging scores will be compared to renal biopsy, including ISN/RPS classification of LN, activity index and chronicity index.
RESULTS:
Five patients have been evaluated to date and their imaging data assessed for quality. The initial results have demonstrated the feasibility of acquiring multi-modality imaging data, including dynamic imaging sequences, in the multi-center trial setting. Figure 1 illustrates scans from a representative patient. This study will determine whether multi-modality imaging could become an effective, non-invasive tool to assess renal function and pathology in LN.
CONCLUSION:
The initial assessment of 5 LN subjects has established the feasibility of multi-modality imaging as a tool to evaluate LN in a multi-center study. By assessing functional and structural MRI outcomes and correlating them to clinical data, this study will provide essential preliminary evidence on the value of multi-modality imaging in diagnosis and evaluating the response to treatment of LN patients.
A Phase IV, Multicenter, Single-Arm, Open-Label Study to Evaluate the Impact of Apremilast on Hand and Whole-Body MRI Outcomes in Patients with Psoriatic Arthritis (MOSAIC): Rationale, Design, and Methods.
Copyright © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ
Annals of the Rheumatic Diseases. 2019 June;78(2)_suppl. doi: 10.1136/annrheumdis-2019-eular.1368
Abstract
BACKGROUND:
Phase III clinical trials have shown apremilast (APR) reduced PsA signs/symptoms and improved physical function,but no study has addressed its impact on structural disease progression. MRI is a highly sensitive, validated tool to assess inflammatory and structural changes, as it can detect soft tissue inflammation, bone marrow edema (BME) lesions, bone erosion and proliferation in peripheral joints and axial skeleton. Whole-body (WB)-MRI, a relatively novel technique in musculoskeletal studies, allows assessment of all peripheral/axial joints and entheses in 1 examination. Recent, consensus-based and semi-quantitative scoring methods were developed and validated. This study is the first to systematically use new state-of-the-art MRI scoring methodologies to assess PsA inflammatory and structural changes in a global clinical trial.
OBJECTIVES:
To assess APR efficacy on inflammatory indices and imaging outcome measures associated with PsA structural progression by conventional static MRI and dynamic contrast-enhanced (DCE)-MRI of the most affected hand and WB-MRI.
METHODS:
The study aims to enroll 120 biologic-naïve adults with PsA for ≥3 mos to ≤5 yrs and prior treatment with ≤2 conventional DMARDs. Subjects must have ≥3 swollen and ≥3 tender joints, hand involvement (≥1 swollen joint or ≥1 dactylitis) and ≥1 active enthesitis site. After 4-wk screening, all eligible patients will receive APR 30 mg twice daily (titrated during the first 5 days) as monotherapy or in combination with methotrexate for 48 wks, with a 4-wk observational follow-up. Conventional MRI and optional DCE-MRI of the most affected hand and WB-MRI of the entire body will be performed at Wks 0, 24 and 48. The primary endpoint is change from BL to Wk 24 in OMERACT PsA MRI (PsAMRIS) composite score of BME + synovitis + tenosynovitis. Other imaging endpoints include change from BL to Wk 48 in PsAMRIS composite score (BME + synovitis + tenosynovitis) and change from BL to Wks 24 and 48 in PsAMRIS composite score (BME + synovitis), PsAMRIS composite inflammation score (BME + synovitis + tenosynovitis + periarticular inflammation), PsAMRIS total damage score (erosion + bone proliferation), WB-MRI indices (including peripheral joint inflammation index and peripheral enthesis inflammation index), hip and knee inflammation MRI scores (HIMRISS, KIMRISS), OMERACT heel enthesitis MRI indices, axial inflammation indices (SPARCC, CanDen), DEMRIQ-Volume and DEMRIQ-Inflammation and other DCE-MRI–derived parameters. Clinical parameters will include SJC/TJC, cDAPSA, SPARCC Enthesitis Index, Leeds Enthesitis Index, Leeds Dactylitis Index, PASDAS, PtGA, PhGA, Patient’s Assessment of Pain, HAQ-DI, and BASDAI and impact of disease (PsAID12). Safety and tolerability also will be assessed.
RESULTS:
The study protocol was approved by an independent ethics committee and is now enrolling in the USA. Selected countries in Europe and Russia will also participate. MRI, clinical and patient-reported outcomes will be analyzed.
CONCLUSION:
This study will provide important evidence of APR’s impact on inflammatory/structural changes by assessing all PsA musculoskeletal domains (peripheral arthritis, enthesitis, dactylitis and axial disease). Furthermore, it will yield information on use of conventional MRI–, WB-MRI– and DCE-MRI–driven outcome measures in PsA clinical trials.
Less Severe Synovitis in Patients with Knee Osteoarthritis is Associated with Higher Self-Reported Pain Intensity 12 Months After Total Knee Arthroplasty- An Exploratory Cohort Study.
Copyright © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ
Annals of the Rheumatic Diseases. 2019 June;78(2)_suppl. doi: 10.1136/annrheumdis-2019-eular.5695
Abstract
BACKGROUND:
Synovitis is a pain generator in patients with osteoarthritis and associated with upregulation of pro-inflammatory cytokines, which have been found to lead to pain sensitivity and worse self-reported pain(1).
OBJECTIVES:
This study aimed to investigate the association between pre- and perioperative synovitis from imaging and histology and self-reported pain 12 months after total knee arthroplasty (TKA).
METHODS:
Preoperative synovitis was assessed from MRI data of the knee by 11 point synovitis score a.m Guermazi (2) using contrast enhanced MRI (CE-synovitis) and heuristic time intensity curve analysis of the dynamic contrast enhanced MRI (DCE-MRI) data using the DYNAMIKA® software (Image Analysis group, London) providing Dynamic Enhanced MR Quantification (DEMRIQ) Indices (3). Perioperative synovitis was also assessed from biopsies of the synovium in 6 predefined places graded histologically a.m Krenn (4). Worst pain within the last 24-hours (visual analog scale, VAS, 0-100) was assessed before and 12 months after TKA. Patients were divided into a low-pain (VAS≤30) and a high-pain (VAS>30) group based on 12-months postoperative VAS.
RESULTS:
Twenty-six patients had full pre- and postoperative data and were analysed. The high-pain group had significantly lower CE-synovitis (P=0.03), DCE-MRI inflammation indices (DEMRIQ-inflammation) (P<0.03) and a trend towards lower histologically assessed synovitis grades (P=0.077) compared to the low-pain group at baseline. Preoperative synovitis scores were also inversely correlated with pain 12-months after TKA, CE-synovitis (R = – 0.455, P = 0.022) and DCE-MRI inflammation (R = -0.528, P = 0.007), indicating that more severe preoperative synovitis is associated with less severe pain at 12-months.
CONCLUSION:
Higher preoperative synovitis scores are associated with less postoperative pain 12-months after TKA. Further, correlation analysis revealed that less severe preoperative synovitis was associated with worse pain 12-months after TKA, suggesting that CE and DCE-MRI synovitis quantification could be used as imaging markers for prediction of good surgical outcomes.
Magnetic Resonance Imaging Tenosynovitis and Osteitis are Independent Predictors of Radiographic and MRI Damage Progression in Rheumatoid Arthritis Patients In Clincial Remission
Copyright © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ
Annals of the Rheumatic Diseases. 2019 June;78(2)_suppl. doi: 10.1136/annrheumdis-2019-eular.2006
Abstract
BACKGROUND:
Progression of structural joint damage occurs in 20-30 % of patients with rheumatoid arthritis (RA) in clinical remission1. Magnetic resonance imaging (MRI)-detected synovitis and in particular osteitis/bone marrow edema (BME) are known predictors of structural progression in both active RA and in remission, but the predictive value of adding MRI tenosynovitis assessment as potential predictor in patients in clinical remission has not been investigated.
OBJECTIVES:
To investigate the predictive value of baseline MRI inflammatory and damage parameters on 2 year MRI and X-ray damage progression in an RA cohort in clinical remission, following MRI and conventional treat-to-target (T2T) strategies.
METHODS:
200 RA patients in clinical remission (DAS28-CRP<3.2 and no swollen joints) on conventional DMARDs, included in the randomized IMAGINE-RA trial2 (conventional DAS28 + MRI-guided T2T strategy targeting absence of BME vs conventional DAS28 guided T2T strategy) had baseline and 2 years contrast-enhanced MRIs of the dominant wrist and 2nd-5th MCP joints and X-rays of hands and feet performed, which were evaluated with known chronology by two experienced readers according to the OMERACT RAMRIS scoring system and Sharp/van der Heijde method, respectively.
The following potentially predictive baseline variables: MRI BME, synovitis, tenosynovitis, MRI and X-ray erosion and joint space narrowing (JSN) score, CRP, DAS28, smoking status, gender, age and patient group were tested in univariate logistic regression analyses with 2-year progression in MRI combined damage score, Total Sharp Score (TSS), and MRI and X-ray JSN and erosion scores as dependent variables. Variables with p<0.1, age, gender and patient group were included in multivariable logistic regression analyses with backward selection.
RESULTS:
Based on univariate analyses MRI BME, synovitis, tenosynovitis, x-ray erosion and JSN, gender and age were included in subsequent multivariable analyses. Independent MRI predictors of structural progression were BME (MRI progression) and tenosynovitis (MRI and X-ray progression), MRI combined damage score: sum score of MRI erosion and JSN scores.
CONCLUSION:
This trial is the first to report that MRI tenosynovitis independently predicts both X-ray and MRI damage progression in RA patients in clinical remission. Further studies are needed to confirm MRI-determined tenosynovitis as predictor of progressive joint destruction in RA clinical remission.
Impact of a Magnetic Resonance Imaging-Guided Treat-to-Target Strategy on Disease Activity and Progression in Patients with Rheumatoid Arthritis (The IMAGINE-RA Trial): Study Protocol for a Randomized Controlled Trial.
Copyright © Author(s) (or their employer(s)) 2015.
Trials. 2015 Apr;7(178)_suppl doi: 10.1186/s13063-015-0693-2
Trial registration: http://www.ClinicalTrials.gov identifier: NCT01656278 (5 July 2012)
Abstract
BACKGROUND:
Rheumatoid arthritis (RA) is a chronic, progressive joint disease, which frequently leads to irreversible joint deformity and severe functional impairment. Although patients are treated according to existing guidelines and reach clinical remission, erosive progression still occurs. This demonstrates that additional methods for prognostication and monitoring of the disease activity are needed. Bone marrow edema (BME) detected by magnetic resonance imaging (MRI) has proved to be an independent predictor of subsequent radiographic progression. Guiding the treatment based on the presence/absence of BME may therefore be clinically beneficial. We present the design of a randomized controlled trial (RCT) aiming to evaluate whether an MRI-guided treatment strategy compared to a conventional treatment strategy in anti-CCP-positive erosive RA is better to prevent progression of erosive joint damage and increase the remission rate in patients with low disease activity or clinical remission.
METHODS/DESIGN:
The study is a non-blinded, multicenter, 2-year RCT with a parallel group design. Two hundred anti-CCP-positive, erosive RA patients characterized by low disease activity or remission, no clinically swollen joints and treatment with synthetic disease-modifying antirheumatic drugs (DMARDs) will be included. Patients will be randomized to either a treatment strategy based on conventional laboratory and clinical examinations (control group) or a treatment strategy based on conventional laboratory and clinical examinations as well as MRI (intervention group). Treatment is intensified according to a predefined treatment algorithm in case of inflammation defined as a disease activity score (DAS28) >3.2 and at least one clinically swollen joint (control and intervention groups) and/or MRI-detected BME (intervention group only). The primary outcome measures are DAS28 remission (DAS28 < 2.6) and radiographic progression (Sharp/vdHeijde score).
DISCUSSION:
The perspectives, strengths and weaknesses of this study are discussed.
Osteoarthritis Phenotypes and Novel Therapeutic Targets.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Biochemical Pharmacology. 2019 Jul;37 doi: 10.1016/j.bcp.2019.02.037. Epub 2019 Mar 1.
Abstract
The success of disease-modifying osteoarthritis drug (DMOAD) development is still elusive. While there have been successes in preclinical and early clinical studies, phase 3 clinical trials have failed so far and there is still no approved, widely available DMOAD on the market. The latest research suggests that, among other causes, poor trial outcomes might be explained by the fact that osteoarthritis (OA) is a heterogeneous disease with distinct phenotypes. OA trials might be more successful if they would address and target a specific phenotype. The increasing availability of advanced techniques to detect particular OA characteristics expands the possibilities to distinguish between such potential OA phenotypes. Magnetic resonance imaging is among the key imaging techniques to stratify and monitor patients with changes in bone, cartilage and inflammation. Biochemical markers have mainly used as secondary parameters and could further delineate phenotypes. Moreover, post-hoc analyses of trial data have suggested the existence of distinct pain phenotypes and their relevance in the design of clinical trials. Although ongoing work in the field supports the concept of OA heterogeneity, this has not yet resulted in more effective treatment options. This paper reviews the current knowledge about potential OA phenotypes and suggests that combining patient clinical data, quantitative imaging, biochemical markers and utilizing data-driven approaches in patient selection and efficacy assessment will allow for more successful development of effective DMOADs.