Biomarkers Paediatrics

The following list has been reviewed and approved by the European Society of Gastrointestinal and Abdominal Radiology (ESGAR).

PAEDIATRIC MUSCULOSKELETAL IMAGING

Paediatric

MSK

Disease

Biomarker and evidence for use

Description of imaging technique

Pathophysiological process informed by MRI biomarker

Biomarker measured

Units of measurement

Suitable for use in clinical trials

Juvenile idiopathic arthritis (JIA) -synovial inflammation  

 CE MRI1-3!

T1 fs weighted images, pre- and post Gadolinium

Key measure in grading synovitis

Inflammation score

0 - 3

Developmental dysplasia of the hip (DDH)

  US4!

Coronal section through the mid-acetabulum (standard-view)

Acetabular dysplasia

 

Alpha angle

Degrees

DDH

XR5!

Pelvic XR

Acetabular dysplasia

Acetabular Index

Sharp’s angle

Wiberg’s CE angle

FHEI, ATD, ADR

Degrees or mm

Biomarkers in development

DDH

XR5!

Pelvic XR

Acetabular dysplasia

Ogata angle

Acetabular roof angle

 

Coxarthrosis

XR5!

Pelvic XR

Coxarthrosis

Joint space width

 

  1. Damasio MB, Malattia C, Tanturri de HL, et al. MRI of the wrist in juvenile idiopathic arthritis: proposal of a paediatric synovitis score by a consensus of an international working group. Results of a multicentre reliability study. PediatrRadiol 2012;42:1047-55.
  2. Nusman CM, Ording Muller LS, Hemke R, et al. Current Status of Efforts on Standardizing Magnetic Resonance Imaging of Juvenile Idiopathic Arthritis: Report from the OMERACT MRI in JIA Working Group and Health-e-Child. J Rheumatol 2016;43:239-44.
  3. Avenarius DFM, Ording Muller LS, Rosendahl K. Joint Fluid, Bone Marrow Edemalike Changes, and Ganglion Cysts in the Pediatric Wrist: Features That May Mimic Pathologic Abnormalities-Follow-Up of a
  4. Rosendahl K, Aslaksen A, Lie RT, Markestad T. Reliability of ultrasound in the early diagnosis of developmental dysplasia of the hip. PediatrRadiol 1995;25:219-24.
  5. Engesaeter IO, Laborie LB, Lehmann TG, et al. Radiological findings for hip dysplasia at skeletal maturity. Validation of digital and manual measurement techniques. Skeletal Radiol 2012;41:775-85.

PAEDIATRIC NEURO

Neuro

Disease

Biomarker and evidence for use

Description of imaging technique

Pathophysiological process informed by MRI biomarker

Biomarker measured

Units of measurement

Suitable for use in clinical trials

Hydrocephalus

US1!

Coronal view through the 3rd ventricle

Hydrocephalus

Ventricular / SAS dimensions

mm

  1. Gravendeel J, Rosendahl K. Cerebral biometry at birth and at 4 and 8 months of age. A prospective study using US. Ped Radiol 2010 Oct;40(10):1651-6.

PHYSICAL ABUSE

 

Disease

Biomarker and evidence for use

Description of imaging technique

Pathophysiological process informed by MRI biomarker

Biomarker measured

Units of measurement

Suitable for use in clinical trials

 

 

Physical abuse

XR skeletal survey1!

High-resolution radiographs

Acute fracture of shafts of tubular bones, clavicles or ribs

Soft tissue swelling

No periosteal reaction or callus2,3!

Number

Physical abuse

XR skeletal survey 1!

High-resolution radiographs

Healing fracture of shafts of tubular bones, clavicles or ribs

Periosteal reaction, callus, or remodelling2,3!

Number

Physical abuse

XR skeletal survey1!

High-resolution radiographs

Metaphyseal fracture ≤ 2 weeks of age4!

Thickness4!

mm (≤1mm) 4

Physical abuse

XR skeletal survey1!

High-resolution radiographs

Metaphyseal fracture > 2 weeks of age4!

Thickness4!

mm (>1mm) 4

Physical abuse

CT head1!

Axial, coronal, sagittal and 3D recons (bone algorithm)1,5!

Acute skull fracture (≤14 days)

Overlying scalp swelling

Presence/absence

Abusive head injury

CT or MRI1!

RCR protocol1!

Intracranial/spinal haemorrhage, hypoxic ischaemic injury6!

Presence/absence

Presence/absence

  1. The radiological investigation of suspected physical abuse in children RCR 2017
  2. Walters MM, Forbes PW, Buonomo C, Kleinman PK Healing patterns of clavicular birth injuries as a guide to fracture dating in cases of possible infant abuse Pediatr Radiol 2014;44:1224-1229
  3. Fadell M, Miller A, Trefan L et al Radiological features of healing in newborn clavicular fractures Eur Radiol 2017;27:2180-2187
  4. Karmazyn B, Marine MB, Wanner MR et al Establishing signs for acute and healing phases of distal tibial classic metaphyseal lesions Pediatr Radiol 2020;50:715-725
  5. Choudhary A, Servaes S, Slovis TL et al Consensus statement on abusive head trauma in infants and young children Pediatr Radiol 2018 48:1048-1065
  6. Martin A, Paddock M, Johns CS et al Avoiding skull radiographs in infants with suspected inflicted injury who also undergo head CT: “A no-brainer” Eur Radiol 2020;30:1480-1487

PAEDIATRIC ONCOLOGY

Paediatric

Oncology

Disease

Biomarker and evidence for use

Description of imaging technique

Pathophysiological process informed by MRI biomarker

Biomarker measured

Units of measurement

Suitable for use in clinical trials

Neuroblastoma

ADC1-4!

Diffusion weighted imaging

Restriction of the free diffusibility correlates with histologic subtypes

Diffusion restriction

mm2/s

Nephroblastoma

ADC5-8!

Diffusion weighted imaging

Restriction of the free diffusibility correlates with histologic subtypes

Diffusion restriction

mm2/s

Hodgkin Lymphoma

Deauville Score9-11!

18F-FDG-PET/CT

18F-FDG Uptake after chemoth. correlates with outcome

Points

n.a.

Neuroblastoma

SIOPEN Score12,13!

123I-metaiodobenzylguanidine scintigraphy

Prognostic value of the SIOPEN skeletal score

Points

n.a.

Neuroblastoma

18F-FDG14-20! Uptake

18F-FDG-PET/CT

18F-FDG Uptake correlate with tumor grading

SUV

n.a.

Brain tumor

18F-FET Uptake21!

18F-FET-PET/CT

Brain tumor detection and recurrence

SUV

n.a.

Solid tumor

Tumor size22-25!

RECIST 1.1

Cross sectional imaging

Tumor dimension before and after chemotherapy correlates with outcome

1 dimensional

cm

  1. Neubauer H, Li M, Müller VR, Pabst T, Beer M. Diagnostic Value of Diffusion-Weighted MRI for Tumor Characterization, Differentiation and Monitoring in Pediatric Patients with Neuroblastic Tumors. Rofo 2017;189:640-50.
  2. Peschmann AL, Beer M, Ammann B, et al. Quantitative DWI predicts event-free survival in children with neuroblastic tumours: preliminary findings from a retrospective cohort study. Eur Radiol Exp 2019;3:6.
  3. Serin HI, Gorkem SB, Doganay S, et al. Diffusion weighted imaging in differentiating malignant and benign neuroblastic tumors. Jpn J Radiol 2016;34:620-4.
  4. Gahr N, Darge K, Hahn G, Kreher BW, von Buiren M, Uhl M. Diffusion-weighted MRI for differentiation of neuroblastoma and ganglioneuroblastoma/ganglioneuroma. Eur J Radiol 2011;79:443-6.
  5. Hales PW, Olsen Ø E, Sebire NJ, Pritchard-Jones K, Clark CA. A multi-Gaussian model for apparent diffusion coefficient histogram analysis of Wilms’ tumour subtype and response to chemotherapy. NMR Biomed 2015;28:948-57.
  6. Littooij AS, Nikkels PG, Hulsbergen-van de Kaa CA, van de Ven CP, van den Heuvel-Eibrink MM, Olsen Ø E. Apparent diffusion coefficient as it relates to histopathology findings in post-chemotherapy nephroblastoma: a feasibility study. Pediatr Radiol 2017;47:1608-14.
  7. Rogers HJ, Verhagen MV, Shelmerdine SC, Clark CA, Hales PW. An alternative approach to contrast-enhanced imaging: diffusion-weighted imaging and T(1)-weighted imaging identifies and quantifies necrosis in Wilms tumour. Eur Radiol 2019;29:4141-9.
  8. Rogers HJ, Verhagen MV, Clark CA, Hales PW. Comparison of models of diffusion in Wilms’ tumours and normal contralateral renal tissue. Magma 2020.
  9. Hasenclever D, Kurch L, Mauz-Körholz C, et al. qPET – a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma. Eur J Nucl Med Mol Imaging 2014;41:1301-8.
  10. Kluge R, Chavdarova L, Hoffmann M, et al. Inter-Reader Reliability of Early FDG-PET/CT Response Assessment Using the Deauville Scale after 2 Cycles of Intensive Chemotherapy (OEPA) in Hodgkin’s Lymphoma. PLoS One 2016;11:e0149072.
  11. Kurch L, Hasenclever D, Kluge R, et al. Only strongly enhanced residual FDG uptake in early response PET (Deauville 5 or qPET ≥ 2) is prognostic in pediatric Hodgkin lymphoma: Results of the GPOH-HD2002 trial. Pediatr Blood Cancer 2019;66:e27539.
  12. Morgenstern DA, Pötschger U, Moreno L, et al. Risk stratification of high-risk metastatic neuroblastoma: A report from the HR-NBL-1/SIOPEN study. Pediatr Blood Cancer 2018;65:e27363.
  13. Ladenstein R, Lambert B, Pötschger U, et al. Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials. Eur J Nucl Med Mol Imaging 2018;45:292-305.
  14. Kang SY, Rahim MK, Kim YI, et al. Clinical Significance of Pretreatment FDG PET/CT in MIBG-Avid Pediatric Neuroblastoma. Nucl Med Mol Imaging 2017;51:154-60.
  15. Lee JW, Cho A, Yun M, Lee JD, Lyu CJ, Kang WJ. Prognostic value of pretreatment FDG PET in pediatric neuroblastoma. Eur J Radiol 2015;84:2633-9.
  16. Li C, Huang S, Guo J, et al. Metabolic Evaluation of MYCN-Amplified Neuroblastoma by 4-[(18)F]FGln PET Imaging. Mol Imaging Biol 2019;21:1117-26.
  17. Li C, Zhang J, Chen S, et al. Prognostic value of metabolic indices and bone marrow uptake pattern on preoperative 18F-FDG PET/CT in pediatric patients with neuroblastoma. Eur J Nucl Med Mol Imaging 2018;45:306-15.
  18. Liu CJ, Lu MY, Liu YL, et al. Risk Stratification of Pediatric Patients With Neuroblastoma Using Volumetric Parameters of 18F-FDG and 18F-DOPA PET/CT. Clin Nucl Med 2017;42:e142-e8.
  19. Melzer HI, Coppenrath E, Schmid I, et al. ¹²³I-MIBG scintigraphy/SPECT versus ¹⁸F-FDG PET in paediatric neuroblastoma. Eur J Nucl Med Mol Imaging 2011;38:1648-58.
  20. Papathanasiou ND, Gaze MN, Sullivan K, et al. 18F-FDG PET/CT and 123I-metaiodobenzylguanidine imaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 2011;52:519-25.
  21. Dunkl V, Cleff C, Stoffels G, et al. The usefulness of dynamic O-(2-18F-fluoroethyl)-L-tyrosine PET in the clinical evaluation of brain tumors in children and adolescents. J Nucl Med 2015;56:88-92.
  22. Orr KE, McHugh K. The new international neuroblastoma response criteria. Pediatr Radiol 2019;49:1433-40.
  23. Park JR, Bagatell R, Cohn SL, et al. Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol 2017;35:2580-7.
  24. Guenther LM, Rowe RG, Acharya PT, et al. Response Evaluation Criteria in Solid Tumors (RECIST) following neoadjuvant chemotherapy in osteosarcoma. Pediatr Blood Cancer 2018;65.
  25. McHugh K, Kao S. Can paediatric radiologists resist RECIST (response evaluation criteria in solid tumours)? Pediatr Radiol 2003;33:739-43.

PAEDIATRIC CARDIAC IMAGING

  Paediatric

Cardiac imaging

Disease

Biomarker and evidence for use

Description of imaging technique

Pathophysiological process informed by MRI biomarker

Biomarker measured

Units of measurement

Suitable for use in clinical trials

Myocarditis

Values of T1 native, T2 mapping and ECV in CMR in pediatric patients with myocarditis.

 CMR

  Myocardial inflamation

CMR relaxation parameter T1 and T2

 

ms

Normal values in pediatric healthy population

- Normal values of diameter of Coronary Artery Diameters in pediatric population ( most of them with Congenital Heart Disease) ,  determined by Prospectively EKG- triggered coronary CT angiography (CCTA).

 

- Normal values of T1 native, T2 mapping and ECV in CMR in pediatric healthy population.

 

  CCTA

 

 

 

 

 

 

 

 

 

 

 

 CMR

 Diameter coronary arteries

 

 

 

 

 

 

 

 

 

 

 Values in healthy pediatric population

 

 Measure in orthogonal plane in coronary arteries

 

 

 

 

 

CMR relaxation parameter T1 and T2

 

 

Mm

 

 

 

 

 

 

 

 

 

 

ms

Thalassaemia Major

Value of T2* on CMR for the early identification and treatment of patients at high risk of heart failure and arrhythmia1!

CMR (direct assessment of myocardial iron concentration with CMR because iron deposits shorten T2*)

Myocardial siderosis

CMR relaxation parameter T2*

ms

Cardiac T2* values > 20 ms are considered normal

  1. Kirk P, Roughton M, Porter JB et al. Cardiac T2* Magnetic Resonance for Prediction of Cardiac Complications in Thalassemia Major. Circulation 2009;120:1961-1968

PAEDIATRIC LUNG IMAGING

Paediatric lung imaging

Disease

Biomarker and evidence for use

Description of radiology technique

Pathophysiological process informed by biomarker

Biomarker measured

Units of measurement

 

Cystic Fibrosis

Bronchiectasis and airway wall thickening

CT

 

End-inspiratory or free-breathing non-contrast enhanced CTR

Key measure in disease progression1-4!, risk of pulmonary exacerbation3,5!, lower QoL

Severity and extent of bronchiectasis

 

 

 

 

Airway Tapering

Score depends on disease and scoring system6-7!:

Semiquantitative (Bhalla, Brody, CF-CT), score range from 0-3 (mild-moderate-severe, tubular, varicose and cystic)

Intra and inter branches tapering index

Small Airways Diseases

 

CT

End-expiratory CT

Key measure in disease progression1,8,9!, reflecting small airways disease

Low Attenuation Region (LAR) (LAR/Lungvolume)*100%

Volume quantified with HU-based software or PRAGMA-CF scoring system7!

Airways – artery ratio

CT

End-inspiratory of free-breathing CT non contrast enhanced

Key measure of bronchiectasis, air wall thickening and lack of tapering

Inflammation

Automatic segmentation with software11,12, 13!

Fraction of abnormal airways per generation

PRAGMA-CF

CT

End-inspiratory and expiratory CT of free-breathing CT non contrast enhanced

Measure of key CF features, such as bronchiectasis, bronchial wall thickening, mucus plugging, consolidation, air trapping

Disease progression

Each feature is express as % of total lung volume or ml

Quantification of lung water

 MR

Half-Fourier singleshot

turbo spin-echo

Measure the severity of lung disease or pulmonary oedema.

Monitoring lung disease

Lung water density (LWD, %) is the ratio of lung to liver signal intensity multiplied by 70%, the estimated hepatic water density16!

Diaphragmatic motion disorders/Diaphragm hernia

 US/MRI

 M-mode sonography of hemidiaphragms during respiratory movements, subxiphoid and subcostal approach

 

T2- be used for clinical trials

 

Half-fourier-acqusition single-shot turbo spin-echo (HASTE) , T2- (true fast imaging with steady-state free precession) (TRUFI) at least two planes (coronal, axial or sagittal)

 Key measure in evaluation of  hemidiaphragmatic respiratory movements

 

Key measure is to identify the diaphragm defect, hernia content, mediastinal shift, associated lung abnormalities

Hemidiaphragmatic excursions, difference of excursions between the hemidiaphragms

Severity and extent of the diaphragm defect

 mm, % 14,15!

 

 

 mm, %

  1. Mott Thorax 2012 Jun;67(6):509-16.
  2. De Jong Thorax 2006, Thorax, 61(1):80-85
  3. Tepper ERJ 2013, 42: 371-379;
  4. Owens Thorax 2012 Jun;67(6):471-2
  5. Loeve Thorax 2009 Oct;64(10):876-82
  6. Tiddens Eur Respir Rev. 2018 Feb 28;27(147):170097
  7. Szczesniak J Cyst Fibros. 2017 Mar;16(2):175-185
  8. Loeve Radiology 2012 2012 Mar;262(3):969-76
  9. Loeve AJRCCM 2012 185(10):1096-103
  10. Kuo 2020, European radiol 2020 May;30(5):2703-2711
  11. Perez-Rovira Med Phys. 2016 Oct;43(10):5736
  12. Kuo Eur Radiol. 2017 Nov;27(11):4680-4689.
  13. Kuo J Cyst Fibros. 2017 Jan;16(1):116-123
  14. Urvoas E Pediatr Radiol 1994;24:564-568
  15. Epelman M, Pediatr Radiol. 2005;35(7):661-667
  16. Thompson RB  Journal of Cardiovascular Magnetic Resonance 2019; 21:58

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