Functional liver imaging Bernard Van Beers

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1 Functional liver imaging Bernard Van Beers Department of Radiology Beaujon University Hospital Paris Nord Laboratory of Imaging biomarkers UMR 1149 Inserm - University Paris Diderot France

2 Functional imaging Morphological imaging Based on size, shape and signal intensity Often qualitative Functional imaging Based on function Perfusion Diffusion Elastography Often quantitative: imaging biomarkers Rationale Provide information that can not been easily observed Biomarkers Definition Working Group, 2001

3 Imaging biomarkers: RECIST criteria RECIST: response evaluation criteria in solid tumors Measurement of tumor diameter at CT Complete response: disappearance of the lesions Objective response: decrease 30% Stable disease Progressive disease: increase 20% Used since more than 10 years to assess response to treatment in drug development studies Therasse P et al. JNCI 2000; 92: Jain RK et al. J Clin Oncol 2013; 266:

4 Limitations of RECIST criteria RECIST : semi-quantitative score with arbitrary cutoffs Decrease in size is not always observed because tumor tissue may be completely replaced with necrosis or fibrosis, especially when targeted treatments are used Colorectal liver metastases treated with chemotherapy and bevazucimab Chun YS et al. JAMA 2009; 302:

5 Size criteria in HCC treated with sorafenib Ronot M et al. Oncologist 2014; 19:

6 Size criteria in HCC treated with sorafenib Ronot M et al. Oncologist 2014; 19:

7 Limitations of mrecist/easl 2D measurements in very heterogeneous tumors March April June

8 Beyond RECIST Functional biomarkers FDG PET: metabolism Dynamic contrast-enhanced CT/MRI: angiogenesis Diffusion MRI: cellularity MR elastography: visco-elasticity Hanahan D et al. Cell 2011; 144:

9 Response to treatment: volumetric assessment of ADC and enhancement Bonekamp S et al: Radiology 2013; 268:

10 HCC after TACE Volumetric ADC increase 25% and portal venous enhancement decrease 65% 3 4 weeks after TACE are better predictors of survival than RECIST, mrecist and EASL criteria Bonekamp S et al: Radiology 2013; 268:

11 Improvement of diagnostic performance with functional MRI relative to RECIST Shift from morphological to functional parameters Shift from manual one-dimensional to automatic three-dimensional approach Tumor heterogeneity is taken into account: texture analysis Reproducibility is improved Multiparametric approach Bonekamp D et al. Eur J Radiol 2014

12 Early diffusion and perfusion changes after TACE of HCC Diffusion and perfusion changes are already observed at MR imaging one week after TACE Boustany G et al. 2015

13 Pharmacokinetic modeling for liver perfusion Enhancement depends on local perfusion/ permeability but also on arterial input function Pharmacokinetic modeling improves the assessment of results between patients and in longitudinal studies BUT Long acquisition times: respiratory artefacts Specific image acquisition scheme that is suboptimal for morphological analysis

14 Hepatic perfusion: kinetic model Cartery (t) C vein (t) Endothelium k 1a k 2 k 1p Intravascular Space C tissue (t) v d Liver Parenchyma Liver: one-compartment model and dual input with delays k 1a the hepatic artery inflow k 1p the portal vein inflow k 2 the reflux rate v d =k 2 /(k 1a +k 1p ) the distribution volume T c =1/k 2 the mean transit time C tissue t k 1aCarterial ( u a ) k1 pc portal ( u p ) ( t) 0 e k 2 ( t u) du Annet, Radiology 2003

15 Tumor: kinetic model Endothelium Kety : one-compartment model C plasma (t) Intravascular Space K trans C tissue (t) v e Extravascular Extracellular Space C tissue K trans reflects the blood flow and/or the endothelial permeability depending on whether the perfusion is flow- or permeability-limited dc tissue (t) / dt = K trans C plasma - k C tissue ( t) trans K Cplasma( t) e K v trans e t Tofts, J Magn Reson Imaging 1999 Leach, Brit J Cancer 2005

16 Perfusion MRI changes after treatment in liver metastases Improvement of disease free survival in patients with liver colorectal metastases treated with chemotherapy and bevacuzimab when perfusion increase < 40% after one week and perfusion decrease > 40% after 10 weeks De Bruyne S et al. Br J Cancer 2012

17 ADC: distinction between benign and malignant lesions High ADC in benign lesions with high fluid content such as hemangiomas No significant difference in ADC between benign hepatocellular lesions and malignant tumors Doblas S et al. Invest Radiol 2013;48:

18 Visco-elastic properties Garteiser P. et al. Eur Radiol 2012; 22:

19 Areas under ROC curves AUROC ADC = 0.71 AUROC Gl = 0.76 AUROC malignancy index = 0.84

20 Imaging of liver chronic liver disease Inflammation and fibrosis: microscopic findings Changes Stiffness Diffusion Perfusion and hepatocyte transport T1 relaxation time Susceptibility

21 Dynamic elastography Mechanical waves captured by sequence sensitive to movement Wavelength depends on elasticity Attenuation depends on viscosity

22 Elastography TE Elastography: most established method to stage liver fibrosis Three techniques with increasing diagnostic performance Transient elastography Shear wave elastography MR elastography SSI Sandrin L et al. IEEE Trans Ultrason Ferro Freq Contr 2002 Huwart L et al. NMR Biomed 2006 Bavu E. et al. Ultrasound Med Biol D MRE

23 MR elastography

24 Elastography: reliability and reproducibility Reliability Transient elastography 85% of patients with BMI < 30 kg/m 2 71% of patients with BMI 30 kg/m 2 Shear wave elastography 90 % of patients with BMI < 30 kg/m 2 73% of patients with BMI 30 kg/m 2 MR elastography 95%, can be performed in obese patients and patients with ascites Reproducibility Ultrasound elastography: interobserver agreement: 85% MR elastography: better reproducibility than ultrasound elastography Van Beers BE et al. Semin Liv Dis; in press

25 Ultrasound elastography: accuracy Meta analyses and comparative studies Transient elastography AUROC 0.84 for F2 AUROC 0.94 for F4 Shear wave elastography Two-dimensional shear wave elastography: better results for F2 F 2 Bavu E. et al. Ultrasound Med Biol 2011

26 MR elastography: accuracy MR elastography AUROCs > 0.9 for F2, F3 and F4 Higher accuracy than transient and shear wave elastography Huwart et al. Gastroenterology 2008 Cui et al. Hepatology 2016 Imajo K et al. Gastroenterology 2016 Joon JH et al. Radiology 2014

27 Prognostic biomarker and cost-effectiveness Patients with high baseline stiffness values but also patients with increasing values during follow-up have impaired prognosis and survival Ultrasound elastography is cost-effective in patients with chronic HCV and HBV infection and NAFLD to diagnose advanced fibrosis and cirrhosis F1 MR elastography is more cost-effective than liver biopsy to confirm advanced fibrosis F4 Corpechot C et al. Gastroenterology 2014 Tapper EB et al. Am J Gastroenterol 2015 Zhang E et al. Eur Radiol 2015

28 Potential indications for MR elastography Discordant results between ultrasound elastography and serum biomarkers Follow-up after treatment Assessment of cirrhosis severity and portal hypertension Diagnosis of non-alcoholic steatohepatitis: NASH F1 F3

29 Loomba et al. Hepatology 2015; 61:

30 Cirrhosis and portal hypertension Portal hypertension: HPVG, endoscopy Elastography is an non-invasive alternative to HVPG measurements Feasibility of ultrasound elastography often limited, especially > 10 mm Hg MR elastography is promising Garcia-Tsao G et al. Hepatology 2010 Ronot M et al. Eur Radiol 2012 Procopet B et al. J Hepatol 2015

31 MR elastography of portal hypertension Viscosity (Gl) of the spleen is a marker of portal hypertension Sensitivity % G* 56 Hz Gd 56 Hz Gl 56 Hz 20 G* 84 Hz Gd 84 Hz Gl 84 Hz Specificity % Ronot M et al. Eur Radiol 2014

32 Baveno VI consensus workshop on portal hypertension Stiffness > 15 kpa: compensated advanced chronic liver disease Stiffness > 20 kpa: significant portal hypertension (HVPG 10 mm Hg) Stiffness < 20 kpa associated with platelet count > 150,000 can safely avoid screening of esophageal varices by endoscopy de Franchis R et al. J Hepatol 2015

33 Increase in liver stiffness is non specific Fibrosis Portal hypertension Liver congestion Bile duct obstruction Inflammation Acute flares in hepatitis B virus infection NASH de Franchis R et al. J Hepatol 2015

34 Diagnosis of NASH Liver ultrasound showing steatosis Elevated aminotransferase levels Liver biopsy Diagnosis of NASH Diagnosis of F3 fibrosis: advanced fibrosis, best prognostic factor Angulo P et al. Gastroenterology 2015

35 Alternatives to diagnose liver fibrosis: DW-MRI Decrease of ADC with increasing stage of fibrosis Diagnostic performance > MRE DW-MRI is influenced by steatosis and perfusion changes Lewin M et al. Hepatology 2007 Wang QB et al. hepatology 2012 Leitao H et al. Radiology 2016

36 Gadoxetic acid-enhanced MR imaging Hepatocyte uptake through OATP1B1/B3, biliary efflux through MRP2, sinusoidal backflux through MRP3 In NASH and liver fibrosis : decrease of OATP1B1/B3 et MRP2, increase of MRP3 Van Beers BE et al. J Hepatol 2012 Giraudeau C et al. Eur Radiol 2016

37 Gadoxetic acid-enhanced MR imaging F0 F2 F4 Decrease of signal intensity in NASH and liver fibrosis AUROCs of gadoxetic acid-enhanced MRI in fibrosis: AUROC > 0.9 Feier D et al. Radiology 2013 Choi YR et al. Invest Radiol 2013

38 Gadoxetic acid-enhanced MR imaging Texture analysis of signal enhancement during the hepatobiliary phase AUROC > 0.9 F0 F2 F4 Leporq B et al. 2016

39 Dynamic gadoxetic acid-enhanced MRI Lagadec M. et al. Radiology 2015 Giraudeau C. et al. Eur Radiol 2016 Leporq B et al. ISMRM 2015

40 Conclusions Functional imaging may add important quantitative information Liver tumors Predictive of tumor aggressiveness and response to treatment Diffusion and perfusion measurements Taking whole tumor volume and its heterogeneity into account Multiparametric Chronic liver disease Predictive of disease stage and response to treatment Elastography and perfusion/hepatocyte transport measurements