ICRS 2019 - Conference Calendar

Displaying One Session

Georgia Special Session
Session Type
Special Session
Date
08.10.2019
Time
12:15 - 13:15
Location
Georgia
Extended Abstract (for invited Faculty only) Clinical Outcome

24.1.1 - The Knee Injury & Osteoarthritis Outcome Score (KOOS). Aspects to Consider in Assessment of Patients Undergoing Cartilage Repair

Presentation Number
24.1.1
Presentation Topic
Clinical Outcome
Lecture Time
12:15 - 12:35
Session Type
Special Session
Corresponding Author

Abstract

Introduction

The Lysholm knee scoring scale, The International Knee Documentation Committee (IKDC) and the Knee injury and Osteoarthritis Outcomes Score (KOOS) are all recommended for assessment of patient-reported outcomes in patients undergoing cartilage repair. A recent PubMed search found at least 250 publications for either of these measures when combined with the search term “articular cartilage”, indicating their frequent use in this area.

Content

Their use and interpretation are however far from straight forward. This presentation will use the Knee injury and Osteoarthritis Outcome Score (KOOS) as an example and focus on frequently asked questions users have when applying KOOS in clinical practice and when planning, conducting and interpreting the patient-reported outcomes (PROMs) from a study.

PROMs are questionnaires from which one or several scores can be calculated. It is important to calculate the score(s) according to the instructions by the developers, so as not to threaten the validity of the measure. The recommended way to report PROM scores in clinical trials is to give the mean change score with its 95% confidence interval (95% CI), outlining the uncertainty of the estimated mean change score. Measures of uncertainty (and effect sizes) are instrumental in understanding the results and in clinical decision-making. The use of p-values is discouraged by many journals.

A statistically significant difference in PROM score is not necessarily equivalent to a clinically relevant finding. To help establish clinical relevance, the concepts “minimal important change”, “patient acceptable symptom state” and “treatment failure” have been introduced. These cut-offs are applied on an individual patient level allowing for categorization of patients into those feeling better, those feeling good and those who feel that the treatment has failed.
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Extended Abstract (for invited Faculty only) Cartilage Imaging and Functional Testing

24.1.2 - Quantitative Methods

Presentation Number
24.1.2
Presentation Topic
Cartilage Imaging and Functional Testing
Lecture Time
12:35 - 12:55
Session Type
Special Session
Corresponding Author

Abstract

Introduction

The macromolecular network of normal healthy cartilage consists mainly of collagen and proteoglycans. Normally, the collagen network is highly organized, serves as the tissue’s structural framework, and is the principal source of tensile and shear strength. Glycosaminoglycans (GAGs) are repeating disaccharides with carboxyl and sulfate groups attached to the larger aggrecan molecule(proteoglycan) that is part of the extracellular matrix network of cartilage. GAG molecules possess considerable net negative charge and confer compressive strength to the cartilage. In all cartilage repair techniques the main goal is to restore this extracellular macromolecular network of collagen and GAG. Several MR imaging techniques are available that enable to selectively demonstrate and quantify the GAG components and/or the collagen fiber network of the extracellular matrix and are usually summarized as “compositional imaging” of cartilage.

Content

GAG-specific MR methods

Delayed Gadolinium enhanced MRI of Cartilage (dGEMRIC)

The dGEMRIC and sodium (23 Na) MR imaging techniques are based on similar principles, with positive sodium ions being attracted by the negatively fixed charged density of the GAG side chains. These electrostatic forces are responsible for a direct relationship between the local sodium concentration and fixed charged density with a strong correlation between fixed charged density and GAG content. dGEMRIC is based on the fact that GAGs contain negatively charged side chains, which lead to an inverse distribution of negatively charged contrast agent molecules (eg, gadolinium) with respect to GAG concentration. However, drawbacks of this technique are the need to use a double dose of a gadolinium-based contrast agent (0.2 mmol per kilogram of body weight) and the requirement for a delay between intravenous administration of the agent and the start of the MR examination (usually 60–90 minutes) to allow complete penetration of the contrast agent into the cartilage.

The so far used linear Gd-compounds such as Magnevist have been removed from the European market by the European Medical Agency (EMA) due to concerns of Gadolinium depositions in the brain. Furthermore in cartilage repair pre-and postcontrast T1 mapping which is time consuming has to be performed and T1 relaxation rates and delta T1 relaxation rates have to be calculated which makes dGEMRIC in cartilage repair analysis impractical.

Sodium imaging

The major advantage of sodium MRI in musculo-skeletal applications is that it is highly specific to GAG content and, since the sodium from surrounding structures in the joint is low (<50mM), articular cartilage can be visualized with very high contrast without the requirement for any exogenous contrast agent such as that in dGEMRIC. The major drawback ist he low sensitivity of sodium imaging which requires a 7T MR scanner to provide enough signal to noise ratio. The recent proliferation of 7T whole-body MRI scanners in clinical research centers and the recent CE certification and FDA approval of a 7T scanner offers a significant impact on sodium MRI and its potential for clinical use. Although sodium MRI has high specificity and does not require any exogenous contrast agent, it does require special hardware capabilities (multinuclear) and specialized RF coils.

In patients after matrix-associated autologous chondrocyte transplantation (MACT) sodium imaging allowed to differentiate between sodium content and hence GAG content in the transplants compared to native, healthy cartilage. In another study sodium imaging was capable to evaluate to efficacy of different cartilage repair surgery techniques to develop GAG in repair tissue.

Chemical Exchange Saturation Transfer (gagCEST)

Chemical exchange saturation transfer (CEST) imaging have recently been presented as a technique with the potential to measure GAG content in cartilage. These technique exploits the biochemical properties of GAG, i.e., the chemical exchange of labile protons with bulk water (gagCEST). It was shown that labile –NH (δ=3.2 ppm offset from the water resonance) and –OH (δ=0.9 to 1.9 ppm) protons of GAG can be used as CEST agents through selective saturation of their resonance signals. This selectivity is also the fundamental difference between gagCEST and T rho relaxation, with the latter being caused by a sum of non-distinguishable exchange effects.

Recent studies aimed mostly at general optimization of gagCEST imaging techniques, but also the feasibility of gagCEST imaging in patients was demonstrated at 7T. A strong correlation was found between gagCEST results and sodium imaging in patients after cartilage repair surgeries, which is another sensitive and highly specific method to determine cartilage GAG content at 7T. Compared to sodium imaging the specificity of gagCEST is lower, but it is proton-based and allows higher spatial resolution and shorter scan times.

Collagen specific MR methods

T2 Mapping

T2 mapping has been used to describe the composition of hyaline articular cartilage in the knee joint on the basis of collagen structure and hydration. In healthy articular cartilage, an increase in T2 values from deep to superficial cartilage layers can be observed; this is based on the anisotropy of collagen fibers running perpendicular to cortical bone in the deep layer of cartilage. Therefore, zonal evaluation of articular cartilage is important in T2 analyses. Analyses of T2 relaxation times in the knee can be performed on clinical routine MR scanners at 1.5 T and 3.0 T. In cartilage repair tissue global and zonal T2 ratios should be calculated to get rid of absolute T2 values which may be different from site to site due tio different vendor, coil and acquisition protocol. The global T2 ratio (absolute T2 values in repair tissue divided by the absolute T2 values in healthy reference cartilage) show a value close to 1 about one year after surgery. The closer the zonal T2 ratio (calculated by a division of deep T2 values by superficial T2 values) of repair tissue to healthy reference cartilage the better the reorganization of the collagen fiber network in repair tissue. It could be demonstrated that the quantification of zonal T2 was a good marker for an organization of repair tissue in the follow up after cartilage repair surgeries.

Advanced T2 mapping analysis using RADIOMICS (GLCM feature extraction)

Grey level co-occurrence matrix (GLCM) is part of a rapidly developing field in radiology – Radiomics. GLCM texture analysis of a T2 map is potentially more sensitive to cartilage degeneration than the mean T2 values of the derived ROIs. With careful parameter and feature selection, texture analysis can be used to probe the underlying structural information from the T2 relaxation maps of cartilage and the changes caused by osteoarthritis. Texture analysis is a versatile category of image processing tools based on the extraction of spatial correspondence information from digital images, such as images acquired using magnetic resonance imaging (MRI). GLCM analysis determines co-occurrence probabilities of different pixel intensities, e.g., the T2 relaxation time values, along specified offset within an image, i.e., how often intensity value i occurs adjacent to intensity value j in a specified direction, creating a co-occurrence matrix. From this matrix, various features, such as homogeneity or entropy, can be calculated and these features characterize the structural properties of the image. Characterizing the heterogeneity of T2 values by standard deviation (SD) or GLCM provides a means to quantify their distribution. SD, which evaluates the deviation of T2 values from their mean, characterizes the spread of T2 values, while GLCM texture features examine the differences in neighbouring T2 pixel values. It has been shown previously that degenerative cartilage has higher and more heterogeneous cartilage T2 values than healthy controls. And moreover, GLCM features are sensitive enough to detect the subtle changes in osteoarthritis development over the course of years. Peuna et al. have recently analyzed the whole spectrum of GLCM features and define the most relevant ones for cartilage analysis: contrast, entropy, sum of squares: variance, homogeneity, contrast, dissimilarity and energy.

In case of cartilage repair tissue, GLCM features serve as a quantitative marker for collagen fibers organization. Average T2 value from a single ROI (or several in case of more slices) provides only a global information about the tissue quality and does not reflect the local organization of collagen fibers. GLCM features, on the other hand, provide a powerful tool for analyzing the texture organization. Successful cartilage transplant development is characterized by continuous increase of tissue organization (predominantly collagen). Hence, GLCM features provide a quantitative marker for cartilage tissue maturation.

References

Shapiro EM , Borthakur A , Gougoutas A , Reddy R . 23Na MRI accurately measures fi xed charge density in articular cartilage. Magn Reson Med 2002 ; 47 ( 2 ): 284 – 291 .

Bashir A , Gray ML , Boutin RD , Burstein D . Glycosaminoglycan in articular cartilage: in vivo assessment with delayed Gd(DTPA) (2-)-enhanced MR imaging . Radiology 1997 ; 205 ( 2 ): 551 – 558 .

Zbýň S, Stelzeneder D, Welsch GH, Negrin LL, Juras V, Mayerhoefer ME, Szomolanyi P, Bogner W, Domayer SE, Weber M, Trattnig S. Evaluation of native hyaline cartilage and repair tissue after two cartilage repair surgery techniques with 23Na MR imaging at 7 T: initial experience. Osteoarthritis Cartilage. 2012 Aug;20(8):837-45.

Trattnig S, Zbýň S, Schmitt B, Friedrich K, Juras V, Szomolanyi P, Bogner W. Advanced MR methods at ultra-high field (7 Tesla) for clinical musculoskeletal applications. Eur Radiol. 2012 Nov;22(11):2338-46.

Trattnig S, Welsch GH, Juras V, Szomolanyi P, Mayerhoefer ME, Stelzeneder D, Mamisch TC, Bieri O, Scheffler K, Zbyn S. 23Na MR Imaging at 7 T after Knee Matrix-associated Autologous Chondrocyte Transplantation: Preliminary Results. Radiology. 2010 Oct;257(1):175-84. Epub 2010 Aug 16.

Krusche-Mandl I, Schmitt B, Zak L, Apprich S, Aldrian S, Juras V, Friedrich KM, Marlovits S, Weber M, Trattnig Long-term results 8 years after autologous osteochondral transplantation: 7 T gagCEST and sodium magnetic resonance imaging with morphological and clinical correlation. S. Osteoarthritis Cartilage. 2012 May;20(5):357-63.

Schmitt B, Zbyn S, Stelzender D, Jellus V, Paul D, Lauer L, Bachert P, Trattnig S. Cartilage quality assessment by using glycosaminoglycan chemical exchange saturation transfer and Na MR Imaging at 7T. Radiology 2011 Jul;260(1):257-64.

Guermazi A, Roemer FW, Alizai H, Winalski CS, Welsch G, Brittberg M, Trattnig S. State of the Art: MR Imaging after Knee Cartilage Repair Surgery. Radiology. 2015 Oct;277(1):23-43

Welsch GH, Mamisch TC, Marlovits S, Glaser C, Friedrich K, Hennig FF, Salomonowitz E, Trattnig S. Quantitative T2 mapping during follow-up after matrix-associated autologous chondrocyte transplantation (MACT): full-thickness and zonal evaluation to visualize the maturation of cartilage repair tissue. J Orthop Res. 2009 Jul;27(7):957-63.

Welsch GH, Mamisch TC, Domayer SE, Dorotka R, Kutscha-Lissberg F, Marlovits S, White LM, Trattnig S Cartilage T2 assessment at 3-T MR imaging: in vivo differentiation of normal hyaline cartilage from reparative tissue after two cartilage repair procedures--initial experience. Radiology. 2008 Apr;247(1):154-61.

Trattnig S, Ohel K, Mlynarik V, Juras V, Zbyn S, Korner A Morphological and compositional monitoring of a new cell-free cartilage repair hydrogel technology - GelrinC by MR using semi-quantitative MOCART scoring and quantitative T2 index and new zonal T2 index calculation. Osteoarthritis Cartilage. 2015 Dec;23(12):2224-2232.

Blumenkrantz G, Stahl R, Carballido-Gamio J, Zhao S, Lu Y, Munoz T, Le Graverand-Gastineau MPL, Jain SK, Link TM, Majumdar S, The feasibility of characterizing the spatial distribution of cartilage T-2 using texture analysis, Osteoarthr Cartilage, 2008; 16:584-590.

Neumann J, Heilmeier U, Joseph GB, Hofmann FC, Ashmeik W, Gersing AS, Chanchek N, Schwaiger BJ, M.C. Nevitt, McCulloch CE, Lane NE, Liux F, Lynch JA, Link TM, Texture Analysis of T2 Maps of the Cartilage Indicates Differences in Knee Cartilage Matrix in Subjects with Type 2 Diabetes: Data from the Osteoarthritis Initiative, Osteoarthr Cartilage, 2017; 25: 73-74.

Peuna A, Hekkala J, Haapea A, Podlipska J, Guermazi A, Saarakkala S, Nieminen MT, Lammentausta E, Variable angle gray level co-occurence matrix analysis of T-2 relaxation time maps reveals degenerative changes of cartilage in knee osteoarthritis: Oulu knee osteoarthritis study, J Magn Reson Imaging, 2018;47:1316-1327.

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Extended Abstract (for invited Faculty only) Others

24.1.3 - Aligning Scientists, Researchers, Payors & Policy-Makers Goals to Optimize Access to Patients for Meaningful Innovation: A Health Economist Perspective

Presentation Number
24.1.3
Presentation Topic
Others
Lecture Time
12:55 - 13:15
Session Type
Special Session
Corresponding Author

Abstract

Introduction

OA is a major source of economic burden in the 21st century and is among the leading causes of disability. Isolated cartilage injuries can cause major clinical problems and functional impairment. If left untreated, isolated cartilage lesions can lead to progressive chondropenia or global cartilage loss over time. Ultimately, this can result in the need for total knee replacement. Repair of cartilage lesions of the knee continues to be a therapeutic challenge faced by both surgeons in the operating room and basic scientists in the laboratory. Full thickness articular lesions of the knee are among the important problems in current orthopaedic surgery for which there is no definite consensus regarding the preferred surgical management, as results reported in the literature are inconsistent.

Content

Over the last 40 years, there has been significant research and a quest to optimize articular cartilage repair. Cartilage repair treatments are on the front line of innovation, with new techniques and products continually emerging. The science of cartilage repair rapidly evolving, with the emergence of innovative techniques, tissue engineering and new products. These must be evaluated in well-designed trials to evaluate their effectiveness. The resulting literature documenting these advances is prolific but generally of low evidence level.

Although OA is not life threatening, it is interesting to note that OA has been labelled a priority disease by WHO due to its unmet need and rising prevalence; where it is expected that it could double within the next 20 years. Mostly expensive alternatives are available for surgical interventions. Presently, no reasonable alternatives have shown their ability to stop or slow disease progression leading surgery. In this complex healthcare environment, decisions must respect budgets, proven efficacy, populational priorities and represent efficient (cost-effective) alternatives. Thus, with inconsistent data and the inherent uncertainties, it becomes a challenging exercise to convince governments of the importance of reimbursement for cartilage treatments, which is mostly in the young that wish to remain active by minimizing the risk of pain, grief, and multiple revisions that could lead to total knee replacement, with their deleterious impact on activities of daily living and lifelong goals. The optimal treatment for articular cartilage lesions is still a subject for debate. Due to the heightened awareness of the significant implications of failing to treat cartilage lesions, surgical treatment has increased significantly. On the one hand, bone marrow stimulation techniques are widely used as simple and cost-effective first-line of treatment. On the other hand, ACI and OCA have become popular in the last 20 years with a growing body of literature reporting favorable results. However, the high costs of these procedures raises concerns on their sustainability and cost-effectiveness and thus delays considerably time for reimbursement.

Although physician’s objective and responsibility are to offer patients a clinically relevant surgical intervention that will meet the therapeutic goal, their choices are constrained by health care pressures due to cost and population growth. Although these alternatives have received regulatory approval, it may take more than 10 years before they can be reimbursed by the public sector. This session will share the view of a health economist about the urgency of aligning scientists, researchers, payors and policymakers to optimize access to patients for meaningful innovation. The importance of bridging research to the patient bedside is beyond demonstrating clinical relevance and regulatory approval.
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