Title



TitlePharmacokinetic modelling of multislice dynamic contrast enhanced MRI in normal healing radial fractures; a pilot study.Mark Lewis FRCR1, Darren Ebreo MRCS2, Paul N Malcolm FRCR1, Richard Greenwood MSc1, Amratlal D Patel FRCS (Orth)2, Bahman Kasmai MSc1, Glyn Johnson PhD3, Andoni P Toms FRCR PhD1.1Norfolk and Norwich University Hospitals NHS TrustDepartment of Radiology2Norfolk and Norwich University Hospitals NHS TrustDepartment of Orthopaedics and Trauma3University of East Anglia, School of Medicine, United KingdomPrincipal investigator and corresponding author:Dr Mark Lewis FRCRNorfolk and Norwich University Hospitals NHS TrustDepartment of Radiologymark.lewis@nnuh.nhs.ukNorwich Radiology AcademyCotman CentreColney LaneNORWICHNR4 7UBAcknowledgements / Grant support:This work was supported by a charitable grant from the British Society of Skeletal RadiologyRunning titleDCE-MRI of healing fractures.AbstractPurpose DCE MRI (Dynamic contrast-enhanced MRI) is an established technique for characterising abnormal tissue microvasculature within solid tumours, but has also shown promise for assessing bone and bone marrow. This study aims to define the range of quantitative pharmacokinetic parameters in normal healing bone with dynamic contrast enhanced MRI. Materials and Methods In this study ethical approval for 8 patients was obtained. Inclusion criteria were an extra-articular distal radial fracture in patients aged 20-50 years which had united by 6 weeks in plaster cast. This was assessed by an experienced orthopaedic surgeon. DCE-MRI was performed at 1.5T 6 weeks after initial injury. The Ktrans, Kep and IAUC values for the fracture site and adjacent marrow were obtained for each patient.Results The mean T1, Ktrans, Keρ and IAUC at the fracture site were 1713 (SD 645), 0.09 (SD 0.07), 0.17 (SD 0.17) and 4.9 (SD 4.4). The relative standard deviation (RSD) for the fracture site ranged from 0.38 to 0.97 and for the adjacent marrow ranged from 0.95–3.88. Within each patient the range of RSDs was 0.04–0.42 for T1, 0.26–0.91 for Ktrans, 0.14–1.06 for Keρ and 0.35–0.96 for the IAUC.Conclusion: Pharmacokinetic measures of perfusion can be obtained from healing fractures using DCE-MRI with “excellent” intraclass correlation coefficients for inter and intra-rater reliability. The use of these perfusion parameters is limited by wide patient-to-patient variation and slice-to-slice variation within patients. KeywordsDCE_MRIFractureRadiusReliabilityIntroductionFracture healing relies on adequate bone perfusion, as well as many other factors, in order to achieve union. A poor or absent blood supply can lead to abnormal or incomplete healing ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"24oojfedmn","properties":{"formattedCitation":"(1)","plainCitation":"(1)"},"citationItems":[{"id":381,"uris":[""],"uri":[""],"itemData":{"id":381,"type":"chapter","title":"Fracture Healing","container-title":"Radiology of Skeletal Trauma","publisher":"Churchill Livingstone","publisher-place":"New York","page":"197-221","volume":"1","edition":"2","event-place":"New York","author":[{"literal":"Rogers LF, Hendrix RW"}],"issued":{"date-parts":[["1992"]]}}}],"schema":""} (1), which may lead to significant morbidity or necessitate surgical procedures to correct. Dynamic Contrast Enhanced MRI (DCE-MRI) has been used for the non-invasive evaluation of the perfusion of bone ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1r0dti8025","properties":{"formattedCitation":"{\\rtf (2\\uc0\\u8211{}4)}","plainCitation":"(2–4)"},"citationItems":[{"id":286,"uris":[""],"uri":[""],"itemData":{"id":286,"type":"article-journal","title":"Determining and optimizing the precision of quantitative measurements of perfusion from dynamic contrast enhanced MRI","container-title":"Journal of Magnetic Resonance Imaging: JMRI","page":"575-584","volume":"18","issue":"5","source":"NCBI PubMed","abstract":"PURPOSE\n\nTo examine the sensitivity of quantitative dynamic contrast enhanced MRI (DCE-MRI) perfusion maps to errors in the various source images and to determine optimal imaging parameters for reducing this sensitivity.\n\n\nMATERIALS AND METHODS\n\nA detailed analysis of the precision of a DCE-MRI protocol was performed using the \"propagation of errors\" technique to investigate the effect of errors in the source images on errors in K(trans). Optimal parameter values and interactions between parameters were examined. The propagation of errors analysis was validated by Monte-Carlo simulations.\n\n\nRESULTS\n\nThe precision of K(trans) was found to be most sensitive to artifacts in the tissue portion of the baseline images and least sensitive to noise in the arterial portion of the dynamic images. The tip-angle strongly affected the precision, with the optimum being a function of tissue T1(0).\n\n\nCONCLUSION\n\nProtocol optimization requires matching the tip-angle to the anticipated T1(0) of the tissue of interest; however such optimization yields a relatively small improvement. Future developmental efforts would be most productively focused on minimizing the artifact level.","DOI":"10.1002/jmri.10399","ISSN":"1053-1807","note":"PMID: 14579401","journalAbbreviation":"J Magn Reson Imaging","author":[{"family":"Dale","given":"Brian M"},{"family":"Jesberger","given":"John A"},{"family":"Lewin","given":"Jonathan S"},{"family":"Hillenbrand","given":"Claudia M"},{"family":"Duerk","given":"Jeffrey L"}],"issued":{"date-parts":[["2003",11]]},"PMID":"14579401"}},{"id":234,"uris":[""],"uri":[""],"itemData":{"id":234,"type":"article-journal","title":"Blood perfusion of vertebral lesions evaluated with gadolinium-enhanced dynamic MRI: in comparison with compression fracture and metastasis","container-title":"Journal of Magnetic Resonance Imaging: JMRI","page":"308-314","volume":"15","issue":"3","source":"NCBI PubMed","abstract":"PURPOSE\n\nTo investigate blood perfusion of vertebral lesions using dynamic Gd-DTPA-enhanced MRI.\n\n\nMATERIALS AND METHODS\n\nDynamic MR studies were performed for cases of acute compression fracture, chronic compression fracture, metastatic vertebral lesions with or without compression fracture. A total of 42 patients (71 vertebral segments) were included. Five types of time-intensity curves (TICs) were defined as: nearly no enhancement (type A), slow enhancement (type B), a rapid contrast wash-in followed by an equilibrium phase (type C), a rapid contrast wash-in followed by early wash-out (type D), and a rapid contrast wash-in with a second slower-rising slope (type E).\n\n\nRESULTS\n\nMetastatic vertebral lesions with or without fracture had a higher peak enhancement percentage and steeper enhancement slope than those of chronic compression fracture, but had no difference as compared to those of acute compression fracture. The type D curve had high positive predictive value for metastatic group (100%), and the type E curve had high positive predictive value for benign compression fracture (85.7%).\n\n\nCONCLUSION\n\nType D and E curves are valuable in the differentiation of benign and malignant vertebral lesions.","ISSN":"1053-1807","note":"PMID: 11891976","shortTitle":"Blood perfusion of vertebral lesions evaluated with gadolinium-enhanced dynamic MRI","journalAbbreviation":"J Magn Reson Imaging","author":[{"family":"Chen","given":"Wei-Tsung"},{"family":"Shih","given":"Tiffany Ting-Fang"},{"family":"Chen","given":"Ran-Chou"},{"family":"Lo","given":"Hsin-Yen"},{"family":"Chou","given":"Chen-Te"},{"family":"Lee","given":"Jiunn-Ming"},{"family":"Tu","given":"Hsing-Yang"}],"issued":{"date-parts":[["2002",3]]},"PMID":"11891976"}},{"id":22,"uris":[""],"uri":[""],"itemData":{"id":22,"type":"article-journal","title":"Acute fracture of the neck of the femur. An assessment of perfusion of the head by dynamic MRI","container-title":"The Journal of Bone and Joint Surgery. British Volume","page":"596-599","volume":"81","issue":"4","source":"NCBI PubMed","abstract":"We performed dynamic MRI of the femoral head within 48 hours of injury on 22 patients with subcapital fracture of the neck of the femur and on a control group of 20 of whom ten were healthy subjects and ten were patients with an intertrochanteric fracture. Three MRI patterns emerged when the results between the fractured side and the contralateral femoral head were compared. In all of the control group and in those patients who had undisplaced fractures (Garden stages I and II), perfusion of the femoral head was considered to be at the same level as on the unaffected side. In patients with displaced fractures (Garden stages III and IV) almost all the femoral heads on the fractured side were impaired or totally avascular, although some had the same level of perfusion as the unaffected side. We conclude that dynamic MRI, a new non-invasive imaging technique, is useful for evaluating the perfusion of the femoral head.","ISSN":"0301-620X","note":"PMID: 10463727","journalAbbreviation":"J Bone Joint Surg Br","author":[{"family":"Konishiike","given":"T"},{"family":"Makihata","given":"E"},{"family":"Tago","given":"H"},{"family":"Sato","given":"T"},{"family":"Inoue","given":"H"}],"issued":{"date-parts":[["1999",7]]},"PMID":"10463727"}}],"schema":""} (2–4) and to assess fracture fragment viability prior to surgical intervention ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"iqrtccvmj","properties":{"formattedCitation":"(5)","plainCitation":"(5)"},"citationItems":[{"id":71,"uris":[""],"uri":[""],"itemData":{"id":71,"type":"article-journal","title":"Is dynamic contrast-enhanced MRI useful for assessing proximal fragment vascularity in scaphoid fracture delayed and non-union?","container-title":"Skeletal radiology","page":"983-992","volume":"42","issue":"7","source":"NCBI PubMed","abstract":"OBJECTIVE: To assess dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) as a measure of vascularity in scaphoid delayed-union or non-union.\nMATERIALS AND METHODS: Thirty-five patients (34 male, one female; mean age, 27.4 ± 9.4 years; range, 16-51 years) with scaphoid delayed-union and non-union who underwent DCE MRI of the scaphoid between September 2002 and October 2012 were retrospectively reviewed. Proximal fragment vascularity was classified as good, fair, or poor on unenhanced MRI, contrast-enhanced MRI, and DCE MRI. For DCE MRI, enhancement slope, Eslope comparison of proximal and distal fragments was used to classify the proximal fragment as good, fair, or poor vascularity. Proximal fragment vascularity was similarly graded at surgery in all patients. Paired t test and McNemar test were used for data comparison. Kappa value was used to assess level of agreement between MRI findings and surgical findings.\nRESULTS: Twenty-five (71 %) of 35 patients had good vascularity, four (11 %) had fair vascularity, and six (17 %) had poor vascularity of the proximal scaphoid fragment at surgery. DCE MRI parameters had the highest correlation with surgical findings (kappa = 0.57). Proximal scaphoid fragments with surgical poor vascularity had a significantly lower Emax and Eslope than those with good vascularity (p = 0.0043 and 0.027). The sensitivity, specificity, positive and negative predictive value and accuracy of DCE MRI in predicting impaired vascularity was 67, 86, 67, 86, and 80 %, respectively, which was better than that seen with unenhanced and post-contrast MRI. Flattened time intensity curves in both proximal and distal fragments were a feature of protracted non-union with a mean time interval of 101.6 ± 95.5 months between injury and MRI.\nCONCLUSIONS: DCE MRI has a higher diagnostic accuracy than either non-enhanced MRI or contrast enhanced MRI for assessing proximal fragment vascularity in scaphoid delayed-union and non-union. For proper interpretation of contrast-enhanced studies in scaphoid vascularity, one needs to incorporate the time frame between injury and MRI.","DOI":"10.1007/s00256-013-1627-2","ISSN":"1432-2161","note":"PMID: 23653220","journalAbbreviation":"Skeletal Radiol.","language":"eng","author":[{"family":"Ng","given":"Alex W H"},{"family":"Griffith","given":"James F"},{"family":"Taljanovic","given":"Mihra S"},{"family":"Li","given":"Alvin"},{"family":"Tse","given":"W L"},{"family":"Ho","given":"P C"}],"issued":{"date-parts":[["2013",7]]},"PMID":"23653220"}}],"schema":""} (5). DCE-MRI has been shown to have a higher diagnostic accuracy for bone viability than either unenhanced MRI or contrast-enhanced MRI ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"47r3r52p2","properties":{"formattedCitation":"(5)","plainCitation":"(5)"},"citationItems":[{"id":71,"uris":[""],"uri":[""],"itemData":{"id":71,"type":"article-journal","title":"Is dynamic contrast-enhanced MRI useful for assessing proximal fragment vascularity in scaphoid fracture delayed and non-union?","container-title":"Skeletal radiology","page":"983-992","volume":"42","issue":"7","source":"NCBI PubMed","abstract":"OBJECTIVE: To assess dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) as a measure of vascularity in scaphoid delayed-union or non-union.\nMATERIALS AND METHODS: Thirty-five patients (34 male, one female; mean age, 27.4 ± 9.4 years; range, 16-51 years) with scaphoid delayed-union and non-union who underwent DCE MRI of the scaphoid between September 2002 and October 2012 were retrospectively reviewed. Proximal fragment vascularity was classified as good, fair, or poor on unenhanced MRI, contrast-enhanced MRI, and DCE MRI. For DCE MRI, enhancement slope, Eslope comparison of proximal and distal fragments was used to classify the proximal fragment as good, fair, or poor vascularity. Proximal fragment vascularity was similarly graded at surgery in all patients. Paired t test and McNemar test were used for data comparison. Kappa value was used to assess level of agreement between MRI findings and surgical findings.\nRESULTS: Twenty-five (71 %) of 35 patients had good vascularity, four (11 %) had fair vascularity, and six (17 %) had poor vascularity of the proximal scaphoid fragment at surgery. DCE MRI parameters had the highest correlation with surgical findings (kappa = 0.57). Proximal scaphoid fragments with surgical poor vascularity had a significantly lower Emax and Eslope than those with good vascularity (p = 0.0043 and 0.027). The sensitivity, specificity, positive and negative predictive value and accuracy of DCE MRI in predicting impaired vascularity was 67, 86, 67, 86, and 80 %, respectively, which was better than that seen with unenhanced and post-contrast MRI. Flattened time intensity curves in both proximal and distal fragments were a feature of protracted non-union with a mean time interval of 101.6 ± 95.5 months between injury and MRI.\nCONCLUSIONS: DCE MRI has a higher diagnostic accuracy than either non-enhanced MRI or contrast enhanced MRI for assessing proximal fragment vascularity in scaphoid delayed-union and non-union. For proper interpretation of contrast-enhanced studies in scaphoid vascularity, one needs to incorporate the time frame between injury and MRI.","DOI":"10.1007/s00256-013-1627-2","ISSN":"1432-2161","note":"PMID: 23653220","journalAbbreviation":"Skeletal Radiol.","language":"eng","author":[{"family":"Ng","given":"Alex W H"},{"family":"Griffith","given":"James F"},{"family":"Taljanovic","given":"Mihra S"},{"family":"Li","given":"Alvin"},{"family":"Tse","given":"W L"},{"family":"Ho","given":"P C"}],"issued":{"date-parts":[["2013",7]]},"PMID":"23653220"}}],"schema":""} (5).Fracture non-union is a clinically important entity, which can be associated with significant morbidity. Currently there are no available non-invasive diagnostic tests, which can be used to identify fractures at increased risk of non-union. DCE-MRI can be used to measure and describe the perfusion at the fracture site and potentially identify abnormalities in perfusion at an early stage and allow for earlier intervention, which could range from further manipulation of the fracture site to complex revascularization procedures.The purpose of this study is to observe and describe the properties of normal healing fractures with DCE-MRI using extra-articular fractures of the distal radius as a model. Extra-articular, non-displaced fractures of the distal radius are inherently stable at six week follow-up and are very unlikely to result in any symptomatic malunion12. The primary aim is to provide reference measurements derived from pharmacokinetic modelling of normal healing bone. The secondary aim is to measure the inter- and intra-rater reliability of these measurements.MethodsPatientsNational ethics committee review was obtained for a total of eight patients. To recruit a population with normal healing bone, patients aged between 20 and 50 were included into the study. Patients were identified by a regular PACS search and were provided with the study literature at their first fracture clinic appointment. Patients with an extra-articular fracture of the distal radius deemed suitable for conservative management and without any of the exclusion criteria (table 1) were enrolled. Patients were reviewed in an orthopaedic clinic by an orthopaedic surgeon of 23 years (AP) experience at six weeks following the injury and plain radiography was performed to assess for evidence of cortical union. All imaging was performed on the same day as the clinic appointment. Clinical evidence of union was accepted as the absence of pain or movement at the fracture site on direct palpation combined with pain-free flexion and extension of the wrist joint after a period of six weeks immobilisation in cast ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2qoti1kqod","properties":{"formattedCitation":"(6)","plainCitation":"(6)"},"citationItems":[{"id":331,"uris":[""],"uri":[""],"itemData":{"id":331,"type":"article-journal","title":"Nonunion of distal radius fractures","container-title":"Clinical Orthopaedics and Related Research","page":"51-56","issue":"419","source":"PubMed","abstract":"Nonunion of a distal radius fracture is extremely uncommon. Healing problems in the distal radius seem to be related to unstable situations, such as concomitant fracture of the distal radius and ulna, and to an inadequate period of immobilization. Nonunion should be suspected if there is continuing pain after remobilization of the wrist in combination with a progressing deformity. The diagnosis may be confirmed by showing movement at the fracture site on lateral radiographs of the wrist in flexion and extension. Because of the rarity of distal radius fracture nonunion, it is not surprising that there is no consensus on the optimum mode of operative treatment. Based on our experience with reconstruction surgery in 23 patients, we think that most nonunions of the distal radius are amenable to attempts to re-align and heal the fracture even when the distal fragment is small. Therefore, surgeons should try to preserve even a small amount of wrist motion and reserve wrist fusion as a final resort.","ISSN":"0009-921X","note":"PMID: 15021131","journalAbbreviation":"Clin. Orthop. Relat. Res.","language":"eng","author":[{"family":"Prommersberger","given":"Karl-Josef"},{"family":"Fernandez","given":"Diego L."}],"issued":{"date-parts":[["2004",2]]},"PMID":"15021131"}}],"schema":""} (6) .MRI protocolAll MRI examinations were performed on a 1.5T system (GE Signa HDxt, GE Healthcare, Bucks, UK) using a phased array wrist coil. The wrist was examined in a prone positon with the arm extended above the head. An HD wrist coil was used (Invivo, Gainsville, FL., USA.), The MRI protocol consisted of coronal T1 and T2 weighted anatomical images and 5 coronal T1 weighted images of variable flip angles (5°,8°, 15°, 20°, 30°). A 3D gradient echo, T1 weighted coronal acquisition with a matrix size of 48 x 48 was used for the dynamic acquisition. Six slices (thickness 5mm) were used to cover the wrist in antero-posterior plane were made for the first two patients. This was increased to eight (5mm slice thickness) after the second patient following review of the first two datasets to see if it was possible to capture an artery on the edge slices. The dynamic images were acquired with a temporal resolution of 1 second for 10 minutes after the injection of 0.1mg/kg gadobutrol (Gadovist, Bayer Healthcare) at 2ml per second using an MR compatible pump and subsequently flushed with 20ml normal saline. A summary of the pulse sequence variables is provided in Table 2.Image AnalysisDICOM data were imported into a software programme written in MatLab (7.8, The MathWorks Inc., Natick, MA, 2000) by one of the authors (BK) which separated each slice of the dynamic data acquisition into separate datasets. The accuracy of the pre-contrast T1 measurements using the in-house Matlab program was validated using the Eurospin Test Object TO5 phantom (Diagnostic Sonar, Livingstone, UK). ROIs were drawn over the fracture site by two readers: a radiologist with 12 years’ experience in MSK radiology (APT) and a radiology fellow (ML). ROIs were drawn directly on to the DCE images with a registered T1 anatomical image adjacent for accuracy (Figure 1). ROI measurements were then analysed in ClearCanvas ? (ClearCanvas, Ontario, Canada) using the DCE Tool plug-in. Maps of pre-contrast T1 (T10) were first calculated from the variable flip angle T1 weighted images. T10 values were then used to calculate contrast agent concentration from the changes in signal intensity during the dynamic acquisition ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"md6eijrot","properties":{"formattedCitation":"(7)","plainCitation":"(7)"},"citationItems":[{"id":89,"uris":[""],"uri":[""],"itemData":{"id":89,"type":"article-journal","title":"Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols","container-title":"Journal of Magnetic Resonance Imaging: JMRI","page":"223-232","volume":"10","issue":"3","source":"NCBI PubMed","abstract":"We describe a standard set of quantity names and symbols related to the estimation of kinetic parameters from dynamic contrast-enhanced T(1)-weighted magnetic resonance imaging data, using diffusable agents such as gadopentetate dimeglumine (Gd-DTPA). These include a) the volume transfer constant K(trans) (min(-1)); b) the volume of extravascular extracellular space (EES) per unit volume of tissue v(e) (0 < v(e) < 1); and c) the flux rate constant between EES and plasma k(ep) (min(-1)). The rate constant is the ratio of the transfer constant to the EES (k(ep) = K(trans)/v(e)). Under flow-limited conditions K(trans) equals the blood plasma flow per unit volume of tissue; under permeability-limited conditions K(trans) equals the permeability surface area product per unit volume of tissue. We relate these quantities to previously published work from our groups; our future publications will refer to these standardized terms, and we propose that these be adopted as international standards.","ISSN":"1053-1807","note":"PMID: 10508281","shortTitle":"Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer","journalAbbreviation":"J Magn Reson Imaging","author":[{"family":"Tofts","given":"P S"},{"family":"Brix","given":"G"},{"family":"Buckley","given":"D L"},{"family":"Evelhoch","given":"J L"},{"family":"Henderson","given":"E"},{"family":"Knopp","given":"M V"},{"family":"Larsson","given":"H B"},{"family":"Lee","given":"T Y"},{"family":"Mayr","given":"N A"},{"family":"Parker","given":"G J"},{"family":"Port","given":"R E"},{"family":"Taylor","given":"J"},{"family":"Weisskoff","given":"R M"}],"issued":{"date-parts":[["1999",9]]},"PMID":"10508281"}}],"schema":""} (7). The transfer constant, Ktrans, and transfer rate, kep were then estimated by fitting the standard Tofts model to the concentration time curves ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1kh23livud","properties":{"formattedCitation":"(8)","plainCitation":"(8)"},"citationItems":[{"id":47,"uris":[""],"uri":[""],"itemData":{"id":47,"type":"article-journal","title":"Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts","container-title":"Magnetic Resonance in Medicine","page":"357-367","volume":"17","issue":"2","source":"PubMed","abstract":"Leakage of Gd-DTPA through a defective blood-brain barrier is measured quantitatively using dynamic MRI scanning, in which repeated scans are made after a bolus injection. Image registration artifacts are minimized; a dose of 0.1 mM/kg and an IR sequence enable enhancement to be measured quantitatively. The triexponential enhancement curve is fitted to a theoretical model based on compartmental analysis. The transfer constant, or permeability surface area product per unit volume of tissue (k), and leakage space per unit volume of tissue (v1) are measured. Estimates for a quickly enhancing multiple sclerosis lesion are k = 0.050 min-1, v1 = 21%; for a slow one k = 0.013 min-1, v1 = 49%. This implies permeability in the range 4-17 x 10(-6) cm s-1, in broad agreement with other physiological methods. The method is noninvasive and can be used to make serial measurements in patients and in experimental animal models. The time course of pathological aspects of diseases with blood-brain barrier breakdown, such as multiple sclerosis, tumors, and infections (e.g., HIV) can be studied, along with their response to therapy. The measurements are of physiological variables and are therefore independent of imaging equipment and field.","ISSN":"0740-3194","note":"PMID: 2062210","journalAbbreviation":"Magn Reson Med","language":"eng","author":[{"family":"Tofts","given":"P. S."},{"family":"Kermode","given":"A. G."}],"issued":{"date-parts":[["1991",2]]},"PMID":"2062210"}}],"schema":""} (8). Since reliable arterial signals could not be obtained due to the positioning of the dynamic scans, the arterial input function, AIF, was obtained from population values ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8ojahqpck","properties":{"formattedCitation":"(9)","plainCitation":"(9)"},"citationItems":[{"id":"Euzs14O0/1o64jwKE","uris":[""],"uri":[""],"itemData":{"id":"Euzs14O0/1o64jwKE","type":"article-journal","title":"Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI","container-title":"Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine","page":"993-1000","volume":"56","issue":"5","source":"NCBI PubMed","abstract":"Rapid T(1)-weighted 3D spoiled gradient-echo (GRE) data sets were acquired in the abdomen of 23 cancer patients during a total of 113 separate visits to allow dynamic contrast-enhanced MRI (DCE-MRI) analysis of tumor microvasculature. The arterial input function (AIF) was measured in each patient at each visit using an automated AIF extraction method following a standardized bolus administration of gadodiamide. The AIFs for each patient were combined to obtain a mean AIF that is representative for any individual. The functional form of this general AIF may be useful for studies in which AIF measurements are not possible. Improvements in the reproducibility of DCE-MRI model parameters (K(trans), v(e), and v(p)) were observed when this new, high-temporal-resolution population AIF was used, indicating the potential for increased sensitivity to therapy-induced change.","DOI":"10.1002/mrm.21066","ISSN":"0740-3194","note":"PMID: 17036301","journalAbbreviation":"Magn Reson Med","language":"eng","author":[{"family":"Parker","given":"Geoff J. M."},{"family":"Roberts","given":"Caleb"},{"family":"Macdonald","given":"Andrew"},{"family":"Buonaccorsi","given":"Giovanni A."},{"family":"Cheung","given":"Sue"},{"family":"Buckley","given":"David L."},{"family":"Jackson","given":"Alan"},{"family":"Watson","given":"Yvonne"},{"family":"Davies","given":"Karen"},{"family":"Jayson","given":"Gordon C."}],"issued":{"year":2006,"month":11},"PMID":"17036301","page-first":"993","container-title-short":"Magn Reson Med"}}],"schema":""} (9). Values of the semi-quantitative parameter, the initial area under the curve (IAUC), were also calculated by summing the concentration values from the time of arrival of the bolus, estimated visually, to 60 seconds afterwards.Signal intensities were converted to gadolinium (Gd) concentrations using standard algorithms described in the Clear Canvas DCE Tool website (). Briefly, Gd concentration is given by where R1 is the relaxation rate, 1/T1, R10 is the pre-contrast relaxation rate and k is a constant related to Gd relaxivity. R1 can be calculated from signal intensity, S, bywhere TR is the repetition time, S0 is the pre-contrast signal and α is the flip angle.StatisticsDescriptive statistics were used to describe the radiological output variables. All but one of the pharmacokinetic parameters at the fracture site met the criteria for parametrically distributed data according to the D’Agostino-Pearson test whereas all but one parameter for the adjacent marrow failed the test for normally distributed data.Mixed two-way intra-class correlation coefficients using average measures for consistency were used to assess reliability along with Bland-Altman plots to assess the 95% limits of variation between observations. ResultsThirty-three patients were identified as having suitable fractures for study inclusion. Twenty-five were excluded; 6 for a history of current cigarette smoking, 8 as they underwent open reduction and internal fixation following a failure of conservative management, 3 as they were from out of area and would not be followed up locally, 2 as they failed to attend follow up, 1 who was unable to consent and 1 patient who was claustrophobic. The average age of the participants was 31 (range 20-41 years). The group was comprised of six females and two males. The average time from injury to MRI scan was 42.75 days (range 39-48 days). Eight complete datasets were obtained. The mean T1 intensity values, Ktrans, Kep and IAUC at the fracture site were 1713 (SD 645), 0.09 (SD 0.07), 0.17 (SD 0.17) and 4.9 (SD 4.4). The median T1, Ktrans, kep and IAUC in the adjacent marrow were 428.7 (IQR 224–330), 0.09 (IQR 0.02–0.14), 3.86 (IQR 0.02–0.27) and 4.28 (IQR 0.97–7.5) (Table 2). The relative standard deviation (RSD) for the fracture site ranged from 0.38 to 0.97 and for the adjacent marrow ranged from 0.95–3.88. Within each patient the range of RSDs was 0.04–0.42 for T1, 0.26–0.91 for Ktrans, 0.14–1.06 for kep and 0.35–0.96 for the IAUC. The full results are provided in Tables 3 and 4.Representative spatial maps of the fracture site and bone marrow were created from the ROIs for Ktrans and Kep (Figure 2).The intraclass correlation coefficients for all parameters were “excellent” ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1mmtufiqm8","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":107,"uris":[""],"uri":[""],"itemData":{"id":107,"type":"article-journal","title":"A general methodology for the analysis of experiments with repeated measurement of categorical data","container-title":"Biometrics","page":"133-158","volume":"33","issue":"1","source":"NCBI PubMed","abstract":"This paper is concerned with the analysis of multivariate categorical data which are obtained from repeated measurement experiments. An expository discussion of pertinent hypotheses for such situations is given, and appropriate test statistics are developed through the application of weighted least squares methods. Special consideration is given to computational problems associated with the manipulation of large tables including the treatment of empty cells. Three applications of the methodology are provided.","ISSN":"0006-341X","note":"PMID: 843570","journalAbbreviation":"Biometrics","author":[{"family":"Koch","given":"G G"},{"family":"Landis","given":"J R"},{"family":"Freeman","given":"J L"},{"family":"Freeman","given":"D H","suffix":"Jr"},{"family":"Lehnen","given":"R C"}],"issued":{"date-parts":[["1977",3]]},"PMID":"843570"}}],"schema":""} (10) with ICC ranging from 0.8–0.99. Bland-Altman mean-difference plots demonstrated no funnelling to suggest a correlation between variation and magnitude of the measurements (Figures 5 and 6). The 95% limits of agreement were in the same order of magnitude as the mean pharmacokinetic measures (Tables 4 and 5).DiscussionDCE-MRI is an established technique for the assessment of malignant tumours and their response to treatment where the increased permeability and uptake of contrast correlates to tumour activity and prognosis ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qgvu5754h","properties":{"formattedCitation":"(11, 12)","plainCitation":"(11, 12)"},"citationItems":[{"id":268,"uris":[""],"uri":[""],"itemData":{"id":268,"type":"article-journal","title":"Changes in tumor perfusion induced by chemotherapy in bone sarcomas: color Doppler flow imaging compared with contrast-enhanced MR imaging and three-phase bone scintigraphy","container-title":"Radiology","page":"421-431","volume":"191","issue":"2","source":"NCBI PubMed","abstract":"PURPOSE: To prospectively evaluate color Doppler flow imaging (CDFI) with spectral analysis versus dynamic gadolinium-enhanced magnetic resonance (MR) imaging and three-phase bone scintigraphy in monitoring the effect of chemotherapy on bone sarcomas.\nMATERIALS AND METHODS: Seventeen osteosarcomas and five Ewing sarcomas were examined with these imaging techniques before and after chemotherapy. Results were compared with the histopathologic response.\nRESULTS: Before chemotherapy, high systolic Doppler frequency shifts (DFSs) and/or low-impedance Doppler signals were found in all but one tumor. Resistive indexes (RIs) in tumor-feeding arteries were substantially lower than in contralateral normal arteries. After chemotherapy, DFSs disappeared in five of seven good respondents and remained substantial in all but one poor respondent. RIs increased substantially in all good respondents and decreased or showed minor changes only in all but one poor respondent.\nCONCLUSION: CDFI with spectral analysis has an advantage over the other two techniques in monitoring the efficacy of chemotherapy in bone sarcomas because of its superior accuracy, noninvasive nature, availability, and low cost.","DOI":"10.1148/radiology.191.2.8153316","ISSN":"0033-8419","note":"PMID: 8153316","shortTitle":"Changes in tumor perfusion induced by chemotherapy in bone sarcomas","journalAbbreviation":"Radiology","language":"eng","author":[{"family":"van der Woude","given":"H. J."},{"family":"Bloem","given":"J. L."},{"family":"Schipper","given":"J."},{"family":"Hermans","given":"J."},{"family":"van Eck-Smit","given":"B. L."},{"family":"van Oostayen","given":"J."},{"family":"Nooy","given":"M. A."},{"family":"Taminiau","given":"A. H."},{"family":"Holscher","given":"H. C."},{"family":"Hogendoorn","given":"P. C."}],"issued":{"date-parts":[["1994",5]]},"PMID":"8153316"}},{"id":270,"uris":[""],"uri":[""],"itemData":{"id":270,"type":"article-journal","title":"Osteosarcoma and Ewing's sarcoma after neoadjuvant chemotherapy: value of dynamic MR imaging in detecting viable tumor before surgery","container-title":"AJR. American journal of roentgenology","page":"593-598","volume":"165","issue":"3","source":"NCBI PubMed","abstract":"OBJECTIVE: This study analyzed the value of dynamic contrast-enhanced and subtraction MR images in detecting residual viable tumor before surgery, with emphasis on timing of enhancement, in patients with high-grade osteosarcoma and Ewing's sarcoma after neoadjuvant chemotherapy.\nSUBJECTS AND METHODS: Twenty-one patients with proved osteosarcoma or Ewing's sarcoma were treated with neoadjuvant chemotherapy followed by surgery. After IV administration of gadopentetate dimeglumine, dynamic enhancement patterns on preoperative MR images were compared with corresponding areas on histologic sections of the resected specimens. On dynamic subtraction images obtained with high temporal resolution (1.5-3 sec), the interval between arrival of the bolus of contrast agent in an artery and start of tumoral enhancement was used to distinguish residual viable tumor. Early enhancing foci (interval artery-tumor < 6 sec) and late or nonenhancing areas seen on MR images were correlated with the histopathologic findings in these areas of the resected specimens.\nRESULTS: Early and progressively enhancing structures seen on MR images corresponded to feeding arteries, physeal vessels, or residual viable tumor at specific preferential sites on corresponding histologic sections of the resected specimens. Tumor foci as small as 3-5 mm2 could be detected on dynamic MR images. Remnant viable tumor was often located subperiosteally and at the margins of the tumor. Occasionally, active periosteal reaction without presence of viable tumor contributed to early enhancement. Late and gradually enhancing or nonenhancing areas corresponded histopathologically to regions of chemotherapy-induced necrosis, mucomyxoid degeneration, or fibrosis. Alternatively, late or nonenhancing areas were associated with reactive changes such as edema, hemorrhage, or osteomyelitis or with tumor-related extracellular matrices such as abundant osteoid or chondroid. Viable tumor areas with scarce formation of matrix on microscopy, such as small cell osteosarcoma areas or Ewing's sarcoma, showed early enhancement with rapid washout of contrast agent on the dynamic MR images.\nCONCLUSION: Fast dynamic contrast-enhanced sequences are essential for identifying residual tumor before surgery. A short time interval of less than 6 sec between arterial enhancement and tumoral enhancement strongly correlates with presence of viable tumor. Both therapy-related alterations of tissue and tumor-related matrices must be considered when late or lack of enhancement is noted on dynamic MR images.","DOI":"10.2214/ajr.165.3.7645476","ISSN":"0361-803X","note":"PMID: 7645476","shortTitle":"Osteosarcoma and Ewing's sarcoma after neoadjuvant chemotherapy","journalAbbreviation":"AJR Am J Roentgenol","language":"eng","author":[{"family":"van der Woude","given":"H. J."},{"family":"Bloem","given":"J. L."},{"family":"Verstraete","given":"K. L."},{"family":"Taminiau","given":"A. H."},{"family":"Nooy","given":"M. A."},{"family":"Hogendoorn","given":"P. C."}],"issued":{"date-parts":[["1995",9]]},"PMID":"7645476"}}],"schema":""} (11,12). This aim of this study was to use DCE-MRI to define a reference range of pharmacokinetic measures in normal healing bone against which patients at risk of non-union could then be compared. However the variability demonstrated in pharmacokinetic outcome measures means that is has not been possible to produce a useful reference range from this dataset. It has however been possible to assess aspects of the reliability of DCE-MRI in the assessment of perfusion associated with fracture healing.This study demonstrates that it is technically feasible to perform pharmacokinetic modelling of DCE-MRI in healing fractures. Endpoint measures of perfusion can be calculated with a high degree of inter and intra-rater reliability measured by ICCs. However there is considerable variation in the perfusion measures across this relatively small but clearly defined population sample, targeting a relatively simple fracture with tightly controlled exclusion criteria. The relative standard deviation suggests large differences in Ktrans, kep and IAUC between patients. Even within patients there is significant variability between adjacent MR slices. There are a number of possible reasons for this variability. The “excellent” inter-rater reliability suggests that most of this variability is either dependent on the fracture, the patient, or both, but not the observers. The variability within each patient may by caused by heterogeneous fracture morphology that contribute to the within-patient slice-to-slice variability. The variability between patients may also be caused by differences in the severity and surface area of the fracture as well as chronological variations in fracture healing between patients. More complex patterns of fracture and associated soft tissue injury may take longer to heal than simple transverse fractures. There may also be patient-dependent variation in their ability to mount a repair response that could contribute to these findings. Other authors have also described local variability in the pharmacokinetic modelling of growing bone, with significant variability seen between the periosteum, metaphyseal spongiosa and the metaphyseal marrow ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"18h18trr1g","properties":{"formattedCitation":"(13)","plainCitation":"(13)"},"citationItems":[{"id":250,"uris":[""],"uri":[""],"itemData":{"id":250,"type":"article-journal","title":"Dynamic gadolinium-enhanced MRI of the proximal femur: preliminary experience in healthy children","container-title":"AJR. American journal of roentgenology","page":"W440-446","volume":"203","issue":"4","source":"PubMed","abstract":"OBJECTIVE: The purpose of this study is to use dynamic contrast-enhanced MRI to evaluate the perfusion characteristics of the proximal femur in the growing skeleton.\nMATERIALS AND METHODS: We evaluated 159 subjects (mean age, 5.67 years) who underwent a well-controlled protocol of contrast-enhanced MRI of the abdomen and hips. Perfusion and permeability parameters (enhancement ratio peak, AUC, time to peak, and rate of extraction) for six regions of the proximal femur were calculated.\nRESULTS: A decrease with age was found for all contrast kinetics parameters in all regions (p < 0.001). Perfusion parameters differed between the regions (p < 0.001). The highest perfusion and permeability parameters were found in the metaphyseal spongiosa, metaphyseal marrow, and periosteum. The metaphyseal spongiosa had a highly vascular pattern of enhancement and showed the highest enhancement ratio peak, AUC, and rate of extraction and the lowest time to peak. The metaphyseal marrow showed a vascular pattern of enhancement with a lower peak compared with the metaphyseal spongiosa. The periosteum showed prompt nonvascular contrast enhancement that reached a plateau that remained elevated.\nCONCLUSION: The highest enhancement was seen in areas involved with growth: the metaphyseal spongiosa, which is related to endochondral ossification, and the periosteal cambium, which is related to membranous ossification. The enhancement characteristics are radically different: in the spongiosa; enhancement is brisk and declines, with a vascular pattern, whereas contrast uptake increases with time in the periosteum. Recognition of normal enhancement patterns of the proximal femur is important for distinguishing normal development from pathologic processes.","DOI":"10.2214/AJR.13.12341","ISSN":"1546-3141","note":"PMID: 25247974","shortTitle":"Dynamic gadolinium-enhanced MRI of the proximal femur","journalAbbreviation":"AJR Am J Roentgenol","language":"eng","author":[{"family":"Bedoya","given":"Maria A."},{"family":"Jaimes","given":"Camilo"},{"family":"Khrichenko","given":"D'mitry"},{"family":"Delgado","given":"Jorge"},{"family":"Dardzinski","given":"Bernard J."},{"family":"Jaramillo","given":"Diego"}],"issued":{"date-parts":[["2014",10]]},"PMID":"25247974"}}],"schema":""} (13) and also between red and yellow bone marrow ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ggnd47ojn","properties":{"formattedCitation":"(14)","plainCitation":"(14)"},"citationItems":[{"id":598,"uris":[""],"uri":[""],"itemData":{"id":598,"type":"article-journal","title":"Study of proximal femoral bone perfusion with 3D T1 dynamic contrast-enhanced MRI: a feasibility study","container-title":"European Radiology","page":"3217-3223","volume":"24","issue":"12","source":"PubMed","abstract":"OBJECTIVE: The objective of this study was to compare measurements of semi-quantitative and pharmacokinetic parameters in areas of red (RBM) and yellow bone marrow (YBM) of the hip, using an in-house high-resolution DCE T1 sequence, and to assess intra- and inter-observer reproducibility of these measurements.\nMETHODS: The right hips of 21 adult patients under 50 years of age were studied. Spatial resolution was 1.8?×?1.8?×?1.8 mm(3), and temporal resolution was 13.5 seconds. Two musculoskeletal radiologists independently processed DCE images and measured semi-quantitative and pharmacokinetic parameters in areas of YBM and RBM. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated. Intra- and inter-observer reproducibility was assessed.\nRESULTS: Area under the curve (AUC) and initial slope (IS) were significantly greater for RBM than for YBM (p?<?0.05). K(trans) and kep were also significantly greater for RBM (p?<?0.05). There was no significant difference in time to peak between the regions (p?<?0.05). SNR, CNR, and intra- and inter-observer reproducibility were all good.\nCONCLUSIONS: DCE study of the whole hip is feasible with high spatial resolution using a 3D T1 sequence. Measures were possible even in low vascularized areas of the femoral head. K(trans), kep, AUC, and IS values were significantly different between red and yellow marrow, whereas TTP values were not.\nKEY POINTS: High-spatial-resolution dynamic contrast-enhanced MRI of hip structures is feasible. Intra- and inter-observer reproducibility is good. Red and yellow bone marrow have different perfusion patterns.","DOI":"10.1007/s00330-014-3340-5","ISSN":"1432-1084","note":"PMID: 25120203","shortTitle":"Study of proximal femoral bone perfusion with 3D T1 dynamic contrast-enhanced MRI","journalAbbreviation":"Eur Radiol","language":"eng","author":[{"family":"Budzik","given":"Jean-Fran?ois"},{"family":"Lefebvre","given":"Guillaume"},{"family":"Forzy","given":"Gerard"},{"family":"Rafei","given":"Mazen","dropping-particle":"El"},{"family":"Chechin","given":"David"},{"family":"Cotten","given":"Anne"}],"issued":{"date-parts":[["2014",12]]},"PMID":"25120203"}}],"schema":""} (14). The variation in T1 values may also indicate different stages of healing, with a greater calcium matrix providing a lower T1 further complicating the analysis. It may be that an earlier DCE-MRI could be more useful in assessment of fracture perfusion as changes in the enhancement patterns (e.g. lower than expected Ktrans) may be more obvious prior to union and may reflect lower than ideal vascularity or perfusion. None of the time intensity curves demonstrated an obvious vascular phase during initial passage of the contrast bolus. We therefore chose to use the unmodified Toft’s model rather than the modified model since the latter is unreliable in the absence of an obvious vascular phase. The lack of a vascular phase may be due to the peripheral fracture site, which probably has a very different AIF compared to that used in this study, which was calculated from AIFs taken from the abdominal aorta ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8f37tqmoc","properties":{"formattedCitation":"(9)","plainCitation":"(9)"},"citationItems":[{"id":266,"uris":[""],"uri":[""],"itemData":{"id":266,"type":"article-journal","title":"Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI","container-title":"Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine","page":"993-1000","volume":"56","issue":"5","source":"NCBI PubMed","abstract":"Rapid T(1)-weighted 3D spoiled gradient-echo (GRE) data sets were acquired in the abdomen of 23 cancer patients during a total of 113 separate visits to allow dynamic contrast-enhanced MRI (DCE-MRI) analysis of tumor microvasculature. The arterial input function (AIF) was measured in each patient at each visit using an automated AIF extraction method following a standardized bolus administration of gadodiamide. The AIFs for each patient were combined to obtain a mean AIF that is representative for any individual. The functional form of this general AIF may be useful for studies in which AIF measurements are not possible. Improvements in the reproducibility of DCE-MRI model parameters (K(trans), v(e), and v(p)) were observed when this new, high-temporal-resolution population AIF was used, indicating the potential for increased sensitivity to therapy-induced change.","DOI":"10.1002/mrm.21066","ISSN":"0740-3194","note":"PMID: 17036301","journalAbbreviation":"Magn Reson Med","language":"eng","author":[{"family":"Parker","given":"Geoff J. M."},{"family":"Roberts","given":"Caleb"},{"family":"Macdonald","given":"Andrew"},{"family":"Buonaccorsi","given":"Giovanni A."},{"family":"Cheung","given":"Sue"},{"family":"Buckley","given":"David L."},{"family":"Jackson","given":"Alan"},{"family":"Watson","given":"Yvonne"},{"family":"Davies","given":"Karen"},{"family":"Jayson","given":"Gordon C."}],"issued":{"date-parts":[["2006",11]]},"PMID":"17036301"}}],"schema":""} (9). Attempts to measure the actual AIF on each patient proved too difficult due to the absence of large vessels in the imaged area and in part due to the coronal orientation, which was chosen to maximise the assessment of the fracture site. An axial acquisition would have optimised imaging of the radial artery but not the radial fracture.There are limitations to this study. The first is that the use of population based AIFs has been shown to cause discrepancies in Ktrans values, although it is not clear to what extent this affects our data, and any discrepancy would be applied to the whole dataset. Therefore this would not affect the variation demonstrated in the results. The second is that the sample size of this study is small. It is clear from the results of this study that the variability between patients requires a larger sample to define a reference range with confidence. It also provides measures that could be used in further sample size calculations. A third possible limitation is that a history of manipulation of the fracture was not recorded. Extra-articular fractures which do not require reduction are more likely to progress to union before those that are displaced ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"17cup802gh","properties":{"formattedCitation":"(15)","plainCitation":"(15)"},"citationItems":[{"id":253,"uris":[""],"uri":[""],"itemData":{"id":253,"type":"article-journal","title":"Early displacement of distal radius fracture","container-title":"Acta Orthopaedica Scandinavica","page":"229-231","volume":"57","issue":"3","source":"PubMed","abstract":"In a retrospective series of 269 patients with distal radius fracture, initially undisplaced fractures (Older Type 1) had a good radiographical prognosis, whereas the more comminuted fractures showed increasing shortening until union, averaging 8 mm. Secondary displacement most often occurred during the first 2 weeks of immobilization, indicating that the radiographical control should be performed at that time. Reduction and fixation with plaster of the severely displaced Type 3 and 4 fractures never led to a satisfying radiographical end-result. Therefore, alternative methods of fixation should be considered in these fractures.","ISSN":"0001-6470","note":"PMID: 3739663","journalAbbreviation":"Acta Orthop Scand","language":"eng","author":[{"family":"Solgaard","given":"S."}],"issued":{"date-parts":[["1986",6]]},"PMID":"3739663"}}],"schema":""} (15) and a fully healed fracture is unlikely to demonstrate high capillary permeability ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"22nh7escia","properties":{"formattedCitation":"(16)","plainCitation":"(16)"},"citationItems":[{"id":28,"uris":[""],"uri":[""],"itemData":{"id":28,"type":"article-journal","title":"Evaluating automated dynamic contrast enhanced wrist 3T MRI in healthy volunteers: one-year longitudinal observational study","container-title":"European journal of radiology","page":"1286-1291","volume":"82","issue":"8","source":"NCBI PubMed","abstract":"RATIONAL AND OBJECTIVE: Dynamic contrast enhanced (DCE)-MRI has great potential to provide quantitative measure of inflammatory activity in rheumatoid arthritis. There is no current benchmark to establish the stability of signal in the joints of healthy subjects when imaged with DCE-MRI longitudinally, which is crucial so as to differentiate changes induced by treatment from the inherent variability of perfusion measures. The objective of this study was to test a pixel-by-pixel parametric map based approach for analysis of DCE-MRI (Dynamika) and to investigate the variability in signal characteristics over time in healthy controls using longitudinally acquired images.\nMATERIALS AND METHODS: 10 healthy volunteers enrolled, dominant wrists were imaged with contrast enhanced 3T MRI at baseline, week 12, 24 and 52 and scored with RAMRIS, DCE-MRI was analysed using a novel quantification parametric map based approach. Radiographs were obtained at baseline and week 52 and scored using modified Sharp van der Heidje method. RAMRIS scores and dynamic MRI measures were correlated.\nRESULTS: No erosions were seen on radiographs, whereas MRI showed erosion-like changes, low grade bone marrow oedema and low-moderate synovial enhancement. The DCE-MRI parameters were stable (baseline scores, variability) (mean±st.dev); in whole wrist analysis, MEmean (1.3±0.07, -0.08±0.1 at week 24) and IREmean (0.008±0.004, -0.002±0.005 at week 12 and 24). In the rough wrist ROI, MEmean (1.2±0.07, 0.04±0.02 at week 52) and IREmean (0.001±0.0008, 0.0006±0.0009 at week 52) and precise wrist ROI, MEmean (1.2±0.09, 0.04±0.04 at week 52) and IREmean (0.001±0.0008, 0.0008±0.001 at week 24 and 52). The Dynamic parameters obtained using fully automated analysis demonstrated strong, statistically significant correlations with RAMRIS synovitis scores.\nCONCLUSION: The study demonstrated that contrast enhancement does occur in healthy volunteers but the inherent variability of perfusion measures obtained with quantitative DCE-MRI method is low and stable, suggesting its suitability for longitudinal studies of inflammatory arthritis. These results also provide important information regarding potential cut-off levels for imaging remission goals in patients with RA using both RAMRIS and DCE-MRI extracted parametric parameters.","DOI":"10.1016/j.ejrad.2013.02.041","ISSN":"1872-7727","note":"PMID: 23562303","shortTitle":"Evaluating automated dynamic contrast enhanced wrist 3T MRI in healthy volunteers","journalAbbreviation":"Eur J Radiol","language":"eng","author":[{"family":"Rastogi","given":"Anshul"},{"family":"Kubassova","given":"Olga"},{"family":"Krasnosselskaia","given":"Lada V"},{"family":"Lim","given":"Adrian K P"},{"family":"Satchithananda","given":"Keshthra"},{"family":"Boesen","given":"Mikael"},{"family":"Binks","given":"Michael"},{"family":"Hajnal","given":"Joseph V"},{"family":"Taylor","given":"Peter C"}],"issued":{"date-parts":[["2013",8]]},"PMID":"23562303"}}],"schema":""} (16). Further, the MR signal is unlikely to reach equilibrium in 48 excitations. If this has affected the results then all subjects should be affected equally. Therefore although absolute values of DCE parameters might be affected, the relative values between subjects will be unaffected.?Overall this study demonstrates that pharmacokinetic measures of perfusion can be obtained from peripheral fracture sites with encouraging reliability. The 95% limits of agreement between raters are relatively broad but this may be a reflection of the relatively small sample size. T1 and perfusion measures are highly variable between and within patients. Even within a tightly controlled group of patients with a simple fracture the heterogeneity of outcome measures was higher than anticipated. While there is a predictable sequence of neoangiogenesis in uncomplicated fractures there appear to be causes of variation that are outside the observers calculating the outcome measures. Some of these causes may be related to fracture specific variations and others may be patient related factors such as cardiovascular function, nutrition and co-morbidities. Two approaches to addressing this might be to use larger samples with subset analysis of patient related factors and fracture morphology or to apply DCE-MRI earlier on in the healing process when the pharmacokinetics of perfusion might be more homogeneous. References ADDIN ZOTERO_BIBL {"custom":[]} CSL_BIBLIOGRAPHY 1. Rogers LF, Hendrix RW: Fracture Healing. In Radiology of Skeletal Trauma. Volume 1. 2nd edition. New York: Churchill Livingstone; 1992:197–221.2. Dale BM, Jesberger JA, Lewin JS, Hillenbrand CM, Duerk JL: Determining and optimizing the precision of quantitative measurements of perfusion from dynamic contrast enhanced MRI. J Magn Reson Imaging 2003; 18:575–584.3. Chen W-T, Shih TT-F, Chen R-C, et al.: Blood perfusion of vertebral lesions evaluated with gadolinium-enhanced dynamic MRI: in comparison with compression fracture and metastasis. J Magn Reson Imaging 2002; 15:308–314.4. Konishiike T, Makihata E, Tago H, Sato T, Inoue H: Acute fracture of the neck of the femur. An assessment of perfusion of the head by dynamic MRI. J Bone Joint Surg Br 1999; 81:596–599.5. Ng AWH, Griffith JF, Taljanovic MS, Li A, Tse WL, Ho PC: Is dynamic contrast-enhanced MRI useful for assessing proximal fragment vascularity in scaphoid fracture delayed and non-union? Skeletal Radiol 2013; 42:983–992.6. Prommersberger K-J, Fernandez DL: Nonunion of distal radius fractures. Clin Orthop Relat Res 2004:51–56.7. Tofts PS, Brix G, Buckley DL, et al.: Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J Magn Reson Imaging 1999; 10:223–232.8. Tofts PS, Kermode AG: Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn Reson Med 1991; 17:357–367.9. Parker GJM, Roberts C, Macdonald A, et al.: Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI. Magn Reson Med 2006; 56:993–1000.10. Koch GG, Landis JR, Freeman JL, Freeman DH Jr, Lehnen RC: A general methodology for the analysis of experiments with repeated measurement of categorical data. Biometrics 1977; 33:133–158.11. van der Woude HJ, Bloem JL, Schipper J, et al.: Changes in tumor perfusion induced by chemotherapy in bone sarcomas: color Doppler flow imaging compared with contrast-enhanced MR imaging and three-phase bone scintigraphy. Radiology 1994; 191:421–431.12. van der Woude HJ, Bloem JL, Verstraete KL, Taminiau AH, Nooy MA, Hogendoorn PC: Osteosarcoma and Ewing’s sarcoma after neoadjuvant chemotherapy: value of dynamic MR imaging in detecting viable tumor before surgery. AJR Am J Roentgenol 1995; 165:593–598.13. Bedoya MA, Jaimes C, Khrichenko D, Delgado J, Dardzinski BJ, Jaramillo D: Dynamic gadolinium-enhanced MRI of the proximal femur: preliminary experience in healthy children. AJR Am J Roentgenol 2014; 203:W440–446.14. Budzik J-F, Lefebvre G, Forzy G, Rafei M El, Chechin D, Cotten A: Study of proximal femoral bone perfusion with 3D T1 dynamic contrast-enhanced MRI: a feasibility study. Eur Radiol 2014; 24:3217–3223.15. Solgaard S: Early displacement of distal radius fracture. Acta Orthop Scand 1986; 57:229–231.16. Rastogi A, Kubassova O, Krasnosselskaia LV, et al.: Evaluating automated dynamic contrast enhanced wrist 3T MRI in healthy volunteers: one-year longitudinal observational study. Eur J Radiol 2013; 82:1286–1291.TablesTable 1Exclusion criteriaDiabetes MellitusPeripheral vascular diseaseHeart or renal failureMetabolic syndrome.VasculitisInflammatory arthritisLong-term steroid usersSmokersPatients unable to consentPrevious contrast medium reactionContraindication to MRIOpen injuries Table 2MRI Sequence ParameterValueTE0.94TR2.28Flip Angle30Number of excitations (NEX)1Matrix48x48Thickness5mmGap0mmFOV34cmSlices8Table 3?T1KtransKepIAUCFractureMean (95% CI)1713.7(1441–1986)0.09(0.06-0.12)0.17(0.10-0.25)4.9(3.07-6.75)SD6450.080.174.36Median (95% CI)1740(1267–1854)0.09(0.03–0.12)0.13(0.05–0.26)4.48(1.63–6.83)Interquartile Range1255–20330.02–0.140.02–0.270.97–7.5Relative Standard Deviation0.380.830.970.89D’Agostino-Pearson0.05730.390.040.05Metaphyseal MarrowMean (95% CI)428.7(178–678)0.09(0.03–0.15)0.11(0.05–0.17)4.28(1.5–6.8)SD5090.110.125.2Median (95% CI)260(227–328)0.04(0.02–0.11)0.06(0.03–0.17)1.79(0.9–6.0)Interquartile Range224–3300.02–0.130.03–0.160.8–6.7Relative Standard Deviation1.191.291.071.22D’Agostino-Pearson<0.00010.017<0.00010.09Table 4ReliabilityMeasureT1KtransKepIAUCInter-raterDifference*-3.38(-254.02–247.27)-0.03(-0.13–0.08)0.01(-0.05–0.08)-0.062(-8.41–7.17)ICC?0.96(0.81–0.99)0.98(0.92–0.99)0.95(0.79–0.99)0.89(0.42–0.98)Intra-raterDifference*151.71(-698–1002.1)0.0(-0.05–0.05)0.0(-0.22–0.22)-0.27(-3.26–2.72)ICC?0.8(0.55–0.91)0.97(0.93–0.99)0.87(0.69–0.94)0.97(0.92–0.99)*Mean difference between observations and 95% limits of agreement.?Intraclass correlation coefficient two-way random measures for consistency.Table 5T1KtranskepIAUCCaseMeanSDRSD (%)MeanSDRSD (%)MeanSDRSD (%)MeanSDRSD (%)1198726913.50.020.0291.20.030.04105.61.140.6960.72236798541.60.0030.000514.40.0030.000514.400.150.0746.331304513.90.170.0846.40.330.261.811.225.2346.54991545.40.140.0426.20.20.0313.67.242.5134.6523791737.20.030.0272.80.040.0498.31.431.3795.96211752324.70.110.0431.10.30.0515.96.553.5954.77140629821.20.170.0634.20.390.1950.67.562.8537.78115721218.30.080.0339.90.10.0441.34.012.1653.8Mean171332117.00.090.0342.70.170.0748.44.912.3153.8SD56130712.50.070.0328.20.150.0838.93.871.6519.1LegendsTable 1Table listing the exclusion criteria including comorbidities that might influence the pharmacokinetics of fracture perfusion.Table 2 Pulse sequence parameters for the DCE-MRI sequenceTable 3Table summarising the descriptive statistics of pharmacokinetic modelling parameters in normal healing fractures.Table 4Table summarising reliability measurements for inter and intra-rater reliability.Table 5Table demonstrating range of pharmacokinetic modelling parameters within each patientFigure 1Side by side images of the 3D T1 gradient echo dynamic sequence and the T1 coronal anatomical images showing ROI placement for the DCE analysis.Figure 2Representative spatial maps of Ktrans and Kep of the fracture site and bone marrow for patients 2 and 7. Figure 3Individual signal vs time-enhancement graphs for each of the studied patients demonstrating heterogeneous enhancement characteristics. Some fractures have typical arterial wash-in and wash-out enhancement of MR signal but others have gradual continuous enhancement curves that do not reach equilibrium.Figure 4Dot-plots demonstrating the variability of pharmacokinetic parameters between patients and between slices in the same patient. Figure 5Bland-Altman plots demonstrating the mean differences in observations between the two raters plotted against the average of the observation for T1, Ktrans, Kep and IAUC. Figure 6Bland-Altman plots demonstrating the mean differences in observations between first and second observations for rater 1 plotted against the average of the observation for T1, Ktrans, Kep and IAUC. ................
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