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IPSG Preliminary MRI Data

IPSG Preliminary MRI Data. Molly McGuire October 19 th , 2018. Overview of MRI Processing. MRI Disk Processing. Do we have the physical disk? Is it uploaded into PACS and de-identified? Does the DOB on the disk match our participant data? Does the MRI study date match our MRI data?

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IPSG Preliminary MRI Data

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  1. IPSG Preliminary MRI Data Molly McGuire October 19th, 2018

  2. Overview of MRI Processing

  3. MRI Disk Processing Do we have the physical disk? Is it uploaded into PACS and de-identified? Does the DOB on the disk match our participant data? Does the MRI study date match our MRI data? Did we follow the MRI protocol? Are any sequences missing? Is the patient enrolled in the correct cohort? Does image upload properly into HIPVASC?

  4. MRI Library Overview • 215 audited MRIs for enrolled patients (by participant, not by hip) • 154 reviewed in Hipvasc • 25 with motion artifacts, poor quality, overexposure, or failed to import • 25 have not yet been reviewed by a specialist • 49 not audited MRIs for enrolled patients • Waiting for the disk or undergoing processing • Exploring digital sharing to improve processing • Ambra to roll out in early 2019

  5. Overview of MRI Metadata

  6. MRI Data Collected • Perfusion MRI only required for >6 year old, Early stage patients at time of enrollment • 296 MRIs have been submitted for required groups AND: • Children under 6 • Late Stage • Annual follow up MRIs • Non-Perfusion MRIs • Evaluation includes required MRIs only for enrolled participants • Data from October 15th, 2018 • Includes only forms marked “complete” • N=181

  7. Missing MRI Form Data • 56 forms are considered “incomplete” • Missing or discordant date of MRI • Missing data on magnet strength • Requirements for MRI missing • “Other” type of gadolinium is not described • Form not filled out

  8. Complete MRI Data, by Cohort

  9. Complete MRI data, by site

  10. MRI Data Required variables for completion of the MRI data form

  11. Number of hips with requirements for MRI (n=181)

  12. Make of MRI Scanner

  13. Magnet Strength

  14. Type of Gadolinium Use, by site

  15. Type of Gadolinium Used

  16. Current Gadolinium Use among IPSG members

  17. Safety of Gadolinium and Use of Macrocyclic Agents October 19th, 2018 Dr. Molly Dempsey Radiology, TSRH

  18. IPSG protocol for contrast subtraction (perfusion) MRI v7 Imaging subgroup, IPSG Last Updated, March 2018 Perfusion MRI How safe is perfusion MRI? BecauseGadolinium (Gd+3) as a free agent is toxic it is chelated to various chelates such as DOTA or DTPA in the various contrast agents available on the market today. The chelated complex is excreted by the kidneys so renal function should be normal in children undergoing this investigation. A history of allergy should also be sought. Most chelates are stable with a wide safety margin at appropriate doses. Recent studies have reported gadolinium deposition in various soft tissues, such as brain, following repeated administration of GBCA’s. The clinical significance is unknown, but to date the available literature suggests the likelihood of Gd3+ deposition is reduced with a macrocyclic agent such as Dotarem (gadoteratemeglumine) or Prohance (gadoteridol). These agents are among those with the highest chelate stability. All agents are similar for their risk of minor adverse reactions (taste alteration, nausea, hives). Spurious hypocalacemia has been reported with some agents, but not gadoteridol or gadoterate. Nephrogenic systemic fibrosis (NSF) is reported in association with gadolinium given to patients with renal failure (3% rate when GFR<30). There is a 5% fatality rate and it is incurable. There are 5 reported associations between gadolinium and NSF in children under 18 years of age; all had chronic kidney disease and only one had a definite history of Gadolinium exposure.Overall the adverse event rate in adults is 0.01% (9% of this severe) over 15 years and 45 million administrations. Data for young children is less abundant; gadolinium should therefore be given on a case by case basis with appropriate discussion of risks and benefits. Gadolinium

  19. Gadolinium Deposition and the New Requirements Shannon G. Farmakis,M.D. SSM Health Cardinal Glennon Children’sHospital St. Louis University School OfMedicine

  20. Introduction McDonald Radiol 2018. 1-18. Runge1989: Chapter 9 Enhanced Mag ResonImag; 108. • Gadolinium-based contrast agents (GBCAs) introduced in 1980s • Over 450 million doses have been given worldwide since 1986 • Types: linear vs. macrocyclic; nonionic vs. ionic • Safety concerns related to use of GBCAs • NSF • Gadolinium deposition • Uncertainty surrounding significance of these deposits • Greater stability of macrocyclic chelates established as early as 1989

  21. GBCA Approval in Pediatrics • Omniscan—CNS and body in patients 2-16 years • Optimark—not approved for use in pediatrics • Magnevist—CNS and body in patients 2-16 years • Multihance—CNS in term neonates and older, MRA in adults • Eovist—approved in patients with known or suspected focal liver disease • Prohance—CNS in patients over 2 years of age • Gadavist—CNS and MRA in term neonates and older • Dotarem—CNS in term neonates and older

  22. Gd deposits in brain on MRI: Summary of literature Errante Invest Radiol 2014; 49: 685-690 Quattrochi Invest Radiol 2015; 50: 470-472 Kang AJNR 2018; 39: 1597-1603 Malhotra AJR 2018; 211: 1-7 Kanda Radiol 2014; 270: 834-841. Jaulent Eur J Radiol 2018; 105: 204-208 Tamrazi Radiol 2018; 1-7 Forslin AJNR 2017; 38: 1311-1316. Patients have normal renal function Increased T1 SI in DN and GP associated with linear GBCAs, not with macrocyclic GBCAs Suggested minimum threshold of 5 or 6 CE MRIs Effects tend to be linear and cumulative with variability in dose-dependent findings Some increased SI changes initially thought to be disease-related (MS, radiation therapy) now thought to be a result of Gd deposition

  23. Summary of Publications with Increased Signal intensity in Brain Linear Macrocyclic Magnevist • MultiHance • Weberling 2015 • Ramalho 2015 • Ramalho2016 • Schneider 2017 • Eovist • Kahn 2016 • Ichikawa 2017 • Conte 2017 • Dotarem • Radbruch 2015a • Radbruch 2016 • Eisele 2016 • Bae 2017 • Radbruch 2017a • Radbruch 2017b • Tibussek 2017 • Rossi Espagnet 2017 • Lee PLOS One 2017 • Kasper 2017 • Ryu 2018 T1 SI • Kuno 2016 • Kasper 2017 • Ryu2018 • Behzadi 2018 • Malhotra 2018 • Kanda 2014 • Aidin 2015 • Kanda 2015a • Radbruch 2015a • Radbruch 2016 • Cao 2016 • Tanaka 2016 • Hu 2016 • Flood 2016 • Schlemm 2016 • Roberts 2016b No change in SI Ionic Results inconclusive/ questionable study design Thermodynamic Stblity • Omniscan • Kanda 2014 • Errante 2014 • Quattrocchi 2015 • Ramalho 2015 • Tanaka 2016 • Kasper2017 • Gadavist • Stojanov 2015 • Radbruch 2015b • Radbruch 2016 • Cao 2016 • Schlemm 2016 • Radbruch 2017 • Kasper 2017 • ProHance • Kanda 2015a • Tibussek 2017 • Ryu 2018 • Young 2018 • Guillaume 2018 • Young 2018 • Jaulent 2018 Non-ionic

  24. Effect on SI after changing GBCA • Several studies show no further increase in the SI after switching from a linear to macrocyclic agent • Other studies showed decrease in areas of increased SI over time after changing to a macrocyclic agent • Suggests possible washout effect

  25. Other sites of gadolinium Deposition Bone, skin, liver

  26. Gd deposits in bone White Invest Radiol 2006; 41:272-278 DarrahMetallomics 2009; 1: 479-488 • Hydroxyapatite incorporates metals into bone • Active incorporation • Passive ionic exchange • Bone acts as long term reservoir and stability of the GBCA influences residence time in this deep compartment • Deposits could later be mobilized and re-released into blood • Could alter fracture healing, bone metabolism, and remodeling • Increased risk in postmenopausal, pregnant, or lactating women and osteoporotic patients • Elevated risk in pro-inflammatory events/surgery • May explain skin deposits of NSF patients that have not received additional GBCAs

  27. Gd in skin Gathings JAMA Dermatol 2015; 151: 316-319. Roberts Invest Radiol 2016; 51: 280-289. Gathings (2015) reported erythematous plaques in 2 patients (one symptomatic, one not) which revealed sclerotic bodies on biopsy Roberts (2016) found intact gadolinium-chelate species on biopsy of patient with normal renal function who had received 61 CE MRIs over 11 years (Multihance, Magnevist, Omniscan, and Prohance)

  28. studies in rats Gd deposits (linear and macrocyclic agents) found in skin, liver, spleen, kidneys, brain, and bones Deposits in bones tend to be much higher>organs>brain Deposits in brain found in cortex, subcortical brain, and cerebellum Extensive renal injury with Prohance > Multihance, Gadavist, or Omniscan Liver necrosis/apoptosis (Omniscan, Dotarem)

  29. Studies in pregnant rats/mice • Erdene (2017)—Omniscan or Dotarem given to pregnant mice • Gd retention in maternal organs < organs of non-pregnant mice • Retention of Omniscan>Dotarem in pup organs of mothers given Gd • Khairinisa (2018)—Behavioral testing of offspring of pregnant mothers that received Omniscan or Dotarem • Perinatal exposure to GBCAs caused anxiety-like behavior, disrupted motor coordination, impaired memory function, stimulated tactile sensitivity, and decreased muscle strength (Omniscan>Dotarem) • Higher levels of Gd retention in mothers and pups in Omniscan group • Zheng (2013)—Exposure to lanthanums results in significant neurotoxic effects during development • Impaired spatial learning and memory in offspring of exposed mothers

  30. Potential Implications • Vague symptoms reported in survey results • Central pain, peripheral pain, headache, and bone pain • Skin thickening • Clouded mentation and headache persisted beyond 3 months in some subjects • Symptoms developed in some subjects after single exam with GBCAs Semelka Mag Reson Imag 2016; 34: 1383-1390

  31. Runge. Invest Radiol. 2018

  32. FDA Statement: December 19, 2017 • New class warning issued on GBCAs concerning Gd retention • New patient Medication Guide to be provided to every patient • Drug companies updating PIs • Requiring drug companies to conduct human and animal studies re: GBCA safety https://www.fda.gov/Drugs/DrugSafety/ucm589213.htm

  33. FDA Statement: December 19, 2017 Conclusion: Linear GBCAs result in more retention and retention for a longer time than macrocyclic GBCAS https://www.fda.gov/Drugs/DrugSafety/ucm589213.htm

  34. Example of Medication Guide

  35. Summary • Macrocylic agents are safer than linear agents, but all have been shown to leave deposits in various tissues • Standardization of research methods needed for future studies • Need unbiased study on potential neurocognitive affects • Need to start distributing the patient information sheet and medication guides • Be prepared to discuss this topic with patients and be prepared to have patients refuse contrast for their MRI • We have to consider the potential for deleterious effects • Animal studies have shown deleterious effects from exposure/deposits in organs and neurocognitive function • Consider alternative methods of imaging evaluation

  36. Future : Develop ways to assess perfusion w/o contrast “Fast” decaying term “Slow” decaying term • Echoplanar Diffusion with multiple B values + post processing IVIM (Intravoxel Incoherent Motion) IVIM effect = signal attenuation from incoherent motion of water in blood that perfuses the tissue via its capillaries • MR signal attenuation in low b-value range contains 2 fractions: • diffusion fraction (signal attenuation from diffusion effect) • perfusion fraction (signal attenuation from IVIM effect)

  37. Future • ? T1 rho • Investigational in MSK applications • “spin lock” “ro”tating frame • Decay of the locked magnetization ( from 2nd pulse applied after 90 degree pulse) to 0 = T1 rho time • Macromolecules – collagen content

  38. Future : Imaging exam upload :Ambra Web-uploader from any file path ( including CD) via link on website

  39. Future: Imaging exam upload details WIP • De-identified study can be sent • Streamlined method will require research license of Ambra • Future may be to install Ambra Gateway at sending institutions to allow direct DICOM send from institution’s PACS • 3rd Q 2019 for TSRH installation of Ambra clinical application

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  44. Thank You!

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