Efficacy and cost-effectiveness of Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis: protocol for a randomised placebo-controlled trial (the SCUlpTOR trial).

INTRODUCTION: Knee osteoarthritis (KOA) is a highly prevalent disabling joint disease. Intra-articular stem cell therapy is increasingly being used for treating KOA with little high-quality evidence to support its use. The aim of this study is to investigate the efficacy, safety and cost-effectiveness of allogeneic mesenchymal stem cells (Cymerus MSCs) for treating symptomatic tibiofemoral KOA and improving knee structure over 24 months. METHODS AND ANALYSIS: The Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis study is a phase III, multi-centre, parallel, superiority, randomised, double-blind, placebo-controlled trial, which will be conducted in Sydney and Hobart, Australia. 440 participants (220 per arm) aged over 40 years with painful KOA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) with medial minimum joint space width between 1 and 4 mm in the study knee will be recruited from the community and randomly allocated to receive either intra-articular MSCs or saline at baseline, week 3 and week 52. The coprimary outcomes will be the proportion of participants achieving patient-acceptable symptom state for knee pain at 24 months and quantitative central medial femorotibial compartment cartilage thickness change from baseline to 24 months. Main secondary outcomes include change in knee pain, Patient Global Assessment, physical function, quality of life and other structural changes. Additional data for cost-effectiveness analysis will also be recorded. Adverse events will be monitored throughout the study. The primary analysis will be conducted using modified intention-to-treat. ETHICS AND DISSEMINATION: This protocol has been approved by The University of Sydney (USYD) Human Research Ethics Committee (HREC) #: 2020/119 and The University of Tasmania (UTAS) HREC #: H0021868. All participants will be required to provide informed consent. Dissemination will occur through conferences, social media, and scientific publications. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trials Registry (ACTRN12620000870954); U1111-1234-4897.

Impact of Diabetes Mellitus on Knee Osteoarthritis Pain and Physical and Mental Status: Data From the Osteoarthritis Initiative.

OBJECTIVE: Diabetes mellitus (DM) appears to increase osteoarthritic knee pain, which may be related to greater adiposity and more advanced disease status often observed in individuals with osteoarthritis (OA) and DM. We aimed to assess whether OA knee pain and health status are worse in individuals with OA and DM, independent of these potential confounders. METHODS: We included 202 OA participants with DM and 2,279 without DM from the Osteoarthritis Initiative. Knee pain was evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and a numeric rating scale (NRS). Physical and mental status were assessed by the Medical Outcomes Study Short Form 12 (SF-12) questionnaire, physical component summary (PCS) score and mental component summary (MCS) score, and by the Center for Epidemiologic Studies Depression Scale (CES-D). Linear regression models assessed the influence of DM, adjusted for age, sex, body mass index (BMI), and radiographic severity. RESULTS: OA participants with DM reported worse knee pain and greater physical and mental issues compared with participants without DM. Individuals with DM had worse KOOS pain (ß = -4.72 [95% confidence interval (95% CI) -7.22, -2.23]) and worse NRS pain (ß = 0.42 [95% CI 0.04, 0.80]) independent of BMI, OA severity, age, and sex. The negative influence of DM was also apparent for SF-12 PCS (ß = -3.49 [95% CI -4.73, -2.25]), SF-12 MCS (ß = -1.42 [95% CI -2.57, -0.26]), and CES-D (ß = 1.08 [95% CI 0.08, 2.08]). CONCLUSION: Individuals with knee OA experience on average higher pain intensity and a worse physical and mental health status if they have DM. Linear regression models show that DM is a risk factor for higher pain, in addition to and independent of greater BMI and radiographic OA severity.

Dynamic Volume Assessment of Hepatocellular Carcinoma in Rat Livers Using a Clinical 3T MRI and Novel Segmentation.

PURPOSE: In vivo liver cancer research commonly uses rodent models. One of the limitations of such models is the lack of accurate and reproducible endpoints for a dynamic assessment of growing tumor nodules. The aim of this study was to validate a noninvasive, true volume segmentation method using two rat hepatocellular carcinoma (HCC) models, correlating magnetic resonance imaging (MRI) with histological volume measurement, and with blood levels of α-fetoprotein. MATERIALS AND METHODS: We used 3T clinical MRI to quantify tumor volume with follow-up over time. Using two distinct rat HCC models, calculated MRI tumor volumes were correlated with volumes from histological sections, or with blood levels of α-fetoprotein. Eleven rats, comprising six Buffalo rats (n = 9 scans) and five Fischer rats (n = 14 tumors), were injected in the portal vein with 2.5 × 105 and 2.0 × 106 syngeneic HCC cells, respectively. Longitudinal (T1) relaxation time- and transverse (T2) relaxation time-weighted MR images were acquired. RESULTS: The three-dimensional (3D) T1-weighted gradient echo had 0.35-mm isotropic resolution allowing accurate semi-automatic volume segmentation. 2D T2-weighted imaging provided high tumor contrast. Segmentation of combined 3D gradient echo T1-weighted images and 2D turbo spin echo T2-weighted images provided excellent correlation with histology (y = 0.866x + 0.034, R² = 0.997 p < .0001) and with α-fetoprotein (y = 0.736x + 1.077, R² = 0.976, p < .0001). There was robust inter- and intra-observer reproducibility (intra-class correlation coefficient > 0.998, p < .0001). CONCLUSIONS: We have developed a novel, noninvasive contrast imaging protocol which enables semi-automatic 3D volume quantification to analyze nonspherical tumor nodules and to follow up the growth of tumor nodules over time.

Five-minute knee MRI for simultaneous morphometry and T2 relaxometry of cartilage and meniscus and for semiquantitative radiological assessment using double-echo in steady-state at 3T.

BACKGROUND: Biomarkers for assessing osteoarthritis activity necessitate multiple MRI sequences with long acquisition times. PURPOSE: To perform 5-minute simultaneous morphometry (thickness/volume measurements) and T2 relaxometry of both cartilage and meniscus, and semiquantitative MRI Osteoarthritis Knee Scoring (MOAKS). STUDY TYPE: Prospective. SUBJECTS: Fifteen healthy volunteers for morphometry and T2 measurements, and 15 patients (five each Kellgren-Lawrence grades 0/2/3) for MOAKS assessment. FIELD STRENGTH/SEQUENCE: A 5-minute double-echo steady-state (DESS) sequence was evaluated for generating quantitative and semiquantitative osteoarthritis biomarkers at 3T. ASSESSMENT: Flip angle simulations evaluated tissue signals and sensitivity of T2 measurements. Morphometry and T2 reproducibility was compared against morphometry-optimized and relaxometry-optimized sequences. Repeatability was assessed by scanning five volunteers twice. MOAKS reproducibility was compared to MOAKS derived from a clinical knee MRI protocol by two readers. STATISTICAL TESTS: Coefficients of variation (CVs), concordance confidence intervals (CCI), and Wilcoxon signed-rank tests compared morphometry and relaxometry measurements with their reference standards. DESS MOAKS positive percent agreement (PPA), negative percentage agreement (NPA), and interreader agreement was calculated using the clinical protocol as a reference. Biomarker variations between Kellgren-Lawrence groups were evaluated using Wilcoxon rank-sum tests. RESULTS: Cartilage thickness (P = 0.65), cartilage T2 (P = 0.69), and meniscus T2 (P = 0.06) did not significantly differ from their reference standard (with a 20° DESS flip angle). DESS slightly overestimated meniscus volume (P < 0.001). Accuracy and repeatability CVs were <3.3%, except the meniscus T2 accuracy (7.6%). DESS MOAKS had substantial interreader agreement and high PPA/NPA values of 87%/90%. Bone marrow lesions and menisci had slightly lower PPAs. Cartilage and meniscus T2 , and MOAKS (cartilage surface area, osteophytes, cysts, and total score) was higher in Kellgren-Lawrence groups 2 and 3 than group 0 (P < 0.05). DATA CONCLUSION: The 5-minute DESS sequence permits MOAKS assessment for a majority of tissues, along with repeatable and reproducible simultaneous cartilage and meniscus T2 relaxometry and morphometry measurements. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1328-1341.

Contralateral knee effect on self-reported knee-specific function and global functional assessment: data from the Osteoarthritis Initiative.

OBJECTIVE: To analyze the effect of contralateral knee pain on sensitivity of patient-reported outcomes and objectively measured functional performance tests in subjects with knee osteoarthritis (OA). METHODS: Subjects with discordant knee pain status (i.e., 1 knee being painful [≥4 on a numeric pain rating scale (NPRS)], with the contralateral knee being pain free [NPRS 0]) were selected from the Osteoarthritis Initiative and matched to subjects with bilaterally pain-free and painful knees by age, sex, body mass index, and radiographic knee OA. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function score, the global Physical Activity Scale for the Elderly (PASE), and objective functional performance tests were cross-sectionally compared in a matched case-control design. RESULTS: A total of 378 subjects with discordant knee pain status were matched to 359 controls with bilaterally pain-free knees and to 323 controls with bilaterally painful knees. WOMAC scores in pain-free knees of discordant knee pain cases significantly differed compared to scores of bilaterally pain-free knees (P = 0.003). Likewise, scores in painful knees of discordant knee pain cases significantly differed compared to scores of bilaterally painful knees (P < 0.001). PASE levels between these groups were not significantly different (P > 0.68). Functional performance tests differed in subjects with discordant knee pain compared to subjects with bilaterally pain-free knees and when compared to subjects with bilaterally painful knees, with the chair stand test showing the strongest effect size (standardized response mean 0.28 and 0.33, respectively). CONCLUSION: The WOMAC physical function score, although knee specific, is impacted by the contralateral knee pain status. The repeated chair stand test appears to be the most sensitive assessment in differentiation between groups with different status of knee pain.

Effect of exercise intervention on thigh muscle volume and anatomical cross-sectional areas--quantitative assessment using MRI.

The objective of this study was to evaluate the location-specific magnitudes of an exercise intervention on thigh muscle volume and anatomical cross-sectional area, using MRI. Forty one untrained women participated in strength, endurance, or autogenic training for 12 weeks. Axial MR images of the thigh were acquired before and after the intervention, using a T1-weighted turbo-spin-echo sequence (10 mm sections, 0.78 mm in-plane resolution). The extensor, flexor, adductor, and sartorius muscles were segmented between the femoral neck and the rectus femoris tendon. Muscle volumes were determined, and anatomical cross-sectional areas were derived from 3D reconstructions at 10% (proximal-to-distal) intervals. With strength training, the volume of the extensors (+3.1%), flexors (+3.5%), and adductors (+3.9%) increased significantly (P < 0.05) between baseline and follow-up, and with endurance training, the volume of the extensor (+3.7%) and sartorius (+5.1%) increased significantly (P < 0.05). No relevant or statistically significant change was observed with autogenic training. The greatest standardized response means were observed for the anatomical cross-sectional area in the proximal aspect (10-30%) of the thigh and generally exceeded those for muscle volumes. The study shows that MRI can be used to monitor location-specific effects of exercise intervention on muscle cross-sectional areas, with the proximal aspect of the thigh muscles being most responsive.

Accuracy and precision of quantitative assessment of cartilage morphology by magnetic resonance imaging at 3.0T.

OBJECTIVE: Quantitative magnetic resonance imaging (MRI) of articular cartilage represents a powerful tool in osteoarthritis (OA) research, but has so far been confined to a field strength of 1.5T. The aim of this study was to evaluate the precision of quantitative MRI assessments of human cartilage morphology at 3.0T and to correlate the measurements at 3.0T with validated measurements at 1.5T. METHODS: MR images of the knee of 15 participants with OA and 15 healthy control subjects were acquired using Siemens 1.5T and 3.0T scanners. Double oblique coronal scans were obtained at 1.5T with a 1.5-mm partition thickness, at 3.0T with a 1.5-mm partition thickness, and at 3.0T with a 1.0-mm partition thickness. Cartilage volume, thickness, and surface area of the femorotibial cartilage plates were quantified using proprietary software. RESULTS: For 1.5-mm partition thickness at 1.5T, the precision error was 3.0% and 2.6% for cartilage volume and cartilage thickness, respectively. The error was smaller for a 1.5-mm partition thickness at 3.0T (2.6% and 2.5%) and still smaller for a 1.0-mm partition thickness at 3.0T (2.1% and 2.0%). Correlation coefficients between values obtained at 3.0T and 1.5T were high (r > or = 0.96), with no significant deviation between the two field strengths. CONCLUSION: Quantitative MRI measurement of cartilage morphology at 3.0T (partition thickness 1 mm) was found to be accurate and tended to be more reproducible than at 1.5T (partition thickness 1.5 mm). Imaging at 3.0T may therefore provide superior ability to detect changes in cartilage status over time and to determine responses to treatment with structure-modifying drugs.