Table 1.
Study characteristics
| Study | Country | Study design | Study time period | # Patient (M/F) | # Nodules | Age (mean) | Tumor diameter (cm) | Locoregional treatment |
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| Ainora 2020 | Italy | Prospective | 12/2014–4/2016 | 94 (79/15) | 104 | 68 ± 9 | 1.0–7.0 (2.7) | PEI/RFA, TACE, combined |
| Cao 2018 | China | Prospective | 7/2016–10/2017 | 42 (31/11) | 42 | 24–71 (52.1 ± 13.1) | 1.4–4.8 (2.8 ± 1.0) | RFA |
| Cho 2015 | South Korea | Prospective | 11/2011–11/2012 | 12 (10/2) | 12 | 21–81 (63.9 ± 15.3) | 1.5–5 (3.2 ± 1.1) | TACE |
| Choi 2000 | South Korea | Prospective | 4/1999–10/1999 | 40 (31/9) | 45 | 35–82 (57) | 1.0–3.8 (2.7) | RFA |
| Choi 2003 | South Korea | Retrospective | 5/2000–12/2001 | 75 (63/12) | 81 | 31–72 (57) | 1.3–4.8 (2.5) | RFA |
| Cioni 2000 | Italy | Prospective | 10/1997–3/1999 | 47 (35/12) | 65 | 53–74 (65.7 ± 5.6) | 1.8–9.5 (4.3 ± 1.7) | TACE |
| Cioni 2001 | Italy | Prospective | – | 50 (39/11) | 61 | 45–78 (61.5) | 1.0–5.0 (2.5) | RFA |
| Dill-Macky 2006 | Canada | Prospective | 12/2002–2/2004 | 19 (15/4) | 21 | 43–83 (64) | 1.5–3.7 | RFA |
| Ding 2001 | China | Prospective | – | 26 (24/2) | 30 | 48–55 (66) | 1.0–6.0 (2.5 ± 1.4) | TACE, RFA, combined |
| Du 2015 | China | Prospective | 9/2011–1/2013 | 63 (55/8) | 78 | 41–67 (55 ± 7) | 0.8–2.9 (1.5 ± 0.4) | RFA |
| Gallotti 2009 | Italy | Prospective | 12/2005–12/2007 | 69 (44/14) | 90 | 28–89 (69) | 0.5–4.9 (2.6) | PEI/RFTA |
| Hirai 2002 | Japan | Prospective | 1/2000–3/2001 | 28 | 37 | 52–84 (68.8) | 1.0–8.0 (2.7) | TACE/RFA |
| Kim 2005 | Korea | Retrospective | 7/2002–7/2003 | 90 (66/24) | 94 | 35–90 (51) | 1.0–5.0 (2.1–1.3) | RFA |
| Kim 2006 | Canada | Prospective | – | 29 (19/10) | 31 | 36–74 (58) | 0.6–12.0 (2.5) | TACE |
| Kisaka 2006 | Japan | Retrospective | 3/2004–9/2004 | 29 (22/7) | 26 | 54–80 (68.6 ± 8.08) | 1.0–2.9 (1.6 ± 0.6) | RFA |
| Kono 2007 | USA | Prospective | – | 33 (21/12) | 33 | – | 1–10 (4.7) | TACE |
| Liu 2015 | China | Retrospective | 6/2007–12/2013 | 130 (122/8) | 130 | 17–80 (53 ± 12) | 1.0–21.4 (4.4 ± 4.1) | TACE |
| Lu 2007 | China | Prospective | 5/2004–3/2005 | 118 | 118 | 25–80 (56 ± 12) | 2.7 ± 12.0 | RFA/MWA |
| Luo 2010 | China | Prospective | 2/2007–11/2007 | 63 (38/25) | 63 | 53–80 (70) | 1.0–3.0 (2.2) | RFA |
| Meloni 2001 | Italy | Retrospective | 10/1999–2/2000 | 35 (24/11) | 43 | 47–75 (64) | 1.2–5.8 (3.6 ± 1.1) | RFA |
| Minami 2003 | Japan | Prospective | 3/1999–6/2001 | 17 | 19 | 52–87 (67.7) | 1.5–11 (3.9 ± 2.0) | TACE |
| Morimoto 2003 | Japan | Retrospective | 12/1999–3/2001 | 29 (17/12) | 29 | 58–79 (69.9) | – | TACE |
| Morimoto 2005 | Japan | Prospective | 1/2000–3/2002 | 48 | 72 | 52–79 (64.2) | 0.7–3.0 (2.1 ± 0.7) | RFA |
| Moschorius 2014 | Greece | Retrospective | 3/2008–4/2012 | 47 (37/10) | 80 | 51–84 (67.5 ± 8.5) | 2.3–16.3 (7.3) | TACE |
| Numata 2010 | Japan | Retrospective | 7/2007–10/2008 | 21 (12/9) | 21 | 65–80 (73) | 1.0–2.6 (16.3 ± 3.6) | HIFUA |
| Paul 2017 | India | Prospective | 2/2010–6/2015 | 42 | 57 | 24–72 (53.3 ± 12.5) | 1.0–15 (4.9 ± 2.9) | TACE |
| Pompili 2005 | Italy | Prospective | 3/2002–12/2003 | 47 (36/11) | 56 | 48–83 (70.8 ± 7.8) | 1.0–7.5 (3.3 ± 1.5) | PEI, RFA, TACE, combined |
| Pregler 2016 | Germany | Retrospective | 1/2014–1/2016 | 30 (25/5) | 30 | 54–73 (64) | (0.3 ± 0.7) x (3.2 ± 0.7) | MWA |
| Ricci 2009 | Italy | Prospective | 1/2001–5/2004 | 100 (65/35) | 100 | 62–76 | 2.6–4.8 (3.7 ± 1.1) | RFA |
| Shalvaggio 2010 | Italy | Prospective | 2/2005–12/2007 | 139 | 148 | 43–75 (59 ± 8.4) | – | RFA + TACE |
| Shaw 2015 | USA | Prospective | 2/2013–10/2013 | 14 (12/3) | 16 | 50–75 (62 ± 6) | 1.2–4.5 (2.5 ± 0.8) | TACE |
| Shima 2005 | Japan | Prospective | 4/2001–3/2004 | 51 (34/17) | 63 | 32–87 (70) | 1.0–9.0 (2.8) | TACE |
| Shimizu 2004 | Japan | Prospective | 10/2000–6/2001 | 40 (28/12) | 64 | 50–85 (66.3) | 1.0–6.0 | RFA |
| Shiozawa 2010 | Japan | Retrospective | 5/2002–10/2008 | 71 (51/20) | 87 | 46–86 (70 ± 8) | 0.8–6.5 (2.0 ± 1.0) | RFA, TACE, combined |
| Takizawa 2013 | Japan | Prospective | 9/2011–4/2012 | 32 (24/8) | 59 | 51–83 (70 ± 7) | 1.0–7.3 (2.9 ± 1.2) | TACE |
| Vilana 2003 | Spain | Prospective | 2/1999–4/2000 | 31 (22/9) | 31 | 67.87.7 | 1.5–5.0 (2.7 ± 0.8) | RFA + PEI |
| Vilana 2006 | Spain | Prospective | 7/2002–5/2003 | 41 (25/16) | 41 | 64.6 ± 11 | 1.3–4.1 (2.4 ± 0.7) | PEI, RFA |
| Wang 2016 | China | Retrospective | 7/2011–2/2013 | 75 (48/27) | 89 | 29–84 (57.5 ± 13.5) | 1.2–5.0 (3.7 ± 1.3) | RFA |
| Watanabe 2020 | Japan | Retrospective | 4/2014–6/2016 | 70 (43/27) | 89 | 44–87 (70 + 9.5) | 1.8 ± 1.1 | TACE |
| Wen 2003 | China | Prospective | 11/1999–3/2001 | 67 (47/20) | 91 | 43–85 (66) | 1.0–5.0 (2.4 ± 1.0) | RFA |
| Xia 2008 | China | Retrospective | 1/2007–8/2008 | 28 (24/4) | 43 | 60–85 (73.3) | 0.9–10.0 (2.9 ± 1.8) | TACE |
| Xu 2014 | China | Prospective | 5/2010–12/2011 | 72 | 83 | – | 2.4 ± 0.5 | RFA |
| Zheng 2013 | China | Prospective | 5/2007–5/2011 | 141 (132/9) | 266 | 21–87 (53.4 ± 12.1) | 0.6–5.7 (2.4 ± 1.0) | RFA/MWA |
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| Study | CEUS mode | Contrast agent and dosage | Time of post-treatment CEUS | CEUS criteria for residual disease | CEUS Binary TR Criteria | Reference standard | Time for reference standard | |
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| Ainora 2020 | CEUS | 2.4 ml SonoVue | 48 h | APHE | APHE | Helical CECT | 1 month | |
| Cao 2018 | 2D and 3D CEUS | 2.4 ml SonoVue | 1 month | Nodular arterially hyperenhancement area within of along the edge | APHE | CEMR | No more than 3 days after CEUS | |
| Cho 2015 | CEUS with low MI | 2.4 ml SonoVue | 4 weeks and 8 weeks | Partial or entire enhancement | Any enhancesment | Dynamic CEMRI | 12 weeks | |
| Choi 2000 | CEPD | 12.5 ml Levovist | 12–23 h | Presence of signal within the tumor | Any enhancement | CECT | 30 min | |
| Choi 2003 | CEUS with CHA | 4 g Levovist | Within 24 h | Nodular crescentic enhancing foci at the margins | Any enhancement | CECT | 1 month | |
| Cioni 2000 | CEPD | 2.5 g Levovist, 300 mg/ml | 3–4 weeks | Intratumoral blood flow signals | Any enhancement | CECT/CEMR | 3–4 weeks | |
| Cioni 2001 | CEPD | 2.5 g Levovist, 300 mg/ml | 3–7 days | Persistent intratumoral enhancement | Any enhancement | Dual-phase helical CT | 4–24 months | |
| Dill-Macky 2006 | PIH CEUS | 1.3 ml Definity | Within 1 h | APHE at the ablation margin or adjacent to the ablation zone | APHE | CT/MRI | 2 weeks to 1 month | |
| Ding 2001 | Pulse subtraction CHI | 2.5 g Levovist, 300 mg/ml | 6–10 days | Tumor perfusion flow same or higher than surroundings | Any enhancement | CECT | 6–10 days | |
| Du 2015 | CEUS with CPI | 1.5 ml SonoVue | 20–30 min | Persistent APHE | APHE | CEMR | 1 month | |
| Gallotti 2009 | CEUS nonlinear | 2.4 ml SonoVue | Immediately | Presence of residual enhancement | Any enhancement | CECT | 1 month | |
| Hirai 2002 | CEUS with CHA | 2.1 g Levovist, 300 mg/ml | 5–10 days | Residual intratumoral blood flow or residual tumor stain | Any enhancement | Dynamic CT | 3 months | |
| Kim 2005 | CEUS with ADI | 4 g Levovist, 300 mg/ml | Within 24 h | Focal areas with irregular peripheral enhancement | Any enhancement | Four-phase helical CT | 1 month | |
| Kim 2006 | CEUS with ADI | Levovist, 300 mg/ml | – | Intratumoral enhancement | Any enhancement | Angiography | – | |
| Kisaka 2006 | CEUS with VUS | Levovist, 300 mg/ml | 3 days | Distance measured on CEUS was not longer than measurement on VUS | Any enhancement | CECT | 3–5 days | |
| Kono 2007 | CEUS | 0.5–2 ml Optison and Imagent | 1–30 days | Flow present within the tumor including the rim | Any enhancement | Angiography/ CECT/CEMR | 1 month (CT), 3 months (MR) | |
| Liu 2015 | CEUS | 2.4 ml SonoVue | 0.5–3 months | mRECIST/ APHE | APHE | Histology/angiography | 0.5–3 months | |
| Lu 2007 | CEUS with low MI | 2.4 ml SonoVue | 1 month | APHE | APHE | CECT/CEMRI | 1 month | |
| Luo 2010 | 3D CEUS | 2 ml Sonazoid | 1 day | APHE | APHE | 3D CECT | 1 month | |
| Meloni 2001 | CEPD and PIH CEUS | Levovist, 300 mg/ml | 4 months | APHE | APHE | Dual-phase CECT | 4 months | |
| Minami 2003 | Coded phase harmonic sonography | 2.5 g Levovist, 400 g/l | 4–8 days | APHE | APHE | CECT | 2 months | |
| Morimoto 2003 | CEUS | Levovist, 300 mg/ml | 7 days | APHE and portal phase hypoenhancement | APHE | Histology | 7 days | |
| Morimoto 2005 | CEUS | Levovist, 300 mg/ml | 1 month | APHE | APHE | Histology | 4 weeks | |
| Moschorius 2014 | CEUS | 2.4 or 4.8 ml SonoVue | 7 days | mRECIST and diameters of viable lesions compared to baseline | Any enhancement | CT/MRI | 1 month | |
| Numata 2010 | 3D CEUS with CHA | 2 ml Sonazoid | Immediately, 1 week, and 1 month | APHE, homogenous enhancement (middle phase), and hypoechoic (late phase) | APHE | CECT/CEMR | 1 month | |
| Paul 2017 | CEUS | 2.4 ml SonoVue | 1 month | APHE and hypoenhancement during portal/ delayed phase | APHE | MRI | 1 month | |
| Pompili 2005 | Gray-scale harmonic CEUS | 2.4 ml SonoVue | Within 1 month | APHE | APHE | Multi-phasic spiral CT | 1 month | |
| Pregler 2016 | Dynamic CEUS | 2.4 ml SonoVue | 1 day | Irregular APHE and washout in the portal venous phase | APHE | CEMR | 6 weeks | |
| Ricci 2009 | CEUS with low MI | 2.4 ml SonoVue | 1 month | APHE | APHE | Spiral CT | 1 month | |
| Shalvaggio 2010 | PIH CEUS with MI | 2.4 ml SonoVue low | 1 month | Positive enhancement | Any enhancement | MDCT/angiography | 1 month | |
| Shaw 2015 | CEUS | 0.6–0.7 ml Definity | 1–2 weeks and 1 month | Tumor enhancement | Any enhancement | CT/MRI | 1 month | |
| Shima 2005 | CEPD | 7 ml Levovist, 300 mg/ml | 1 week | Enhancement in the arterial/portal phase or no ovalshaped perfusion defect the portal phase | Any enhancement | Histology/angiography | – | |
| Shimizu 2004 | CEUS with ADI | Levovist, 300 mg/ml | 1 day and 7 days | Residual vascularity in arterial phase and a defect in the post vascular phase in the delayed phase | Any enhancement | Dynamic CT | – | |
| Shiozawa 2010 | Pulse subtraction CHI | Sonazoid, 0.015 ml/kg | 34–1882 days (mean 267 days) | Nodular or crescent shaped APHE at the margins with a defect in the post vascular phase | APHE | Dynamic CT | 34–1882 days (median 267 days) | |
| Takizawa 2013 | CEUS with CHA | 2 ml Sonazoid | 1 day | Arterial and portal phase hypervascular enhancement | APHE | DSA/CECT | 2–6 months | |
| Vilana 2003 | CEPD | 2.5 g Levovist, 300 mg/ml | 1 month | APHE | APHE | Helical CT | 1 month | |
| Vilana 2006 | CEUS with CCI | 2.4 ml SonoVue | Within 24 h and 1 month | Persistence of contrast enhancement | Any enhancement | CT | 1 month | |
| Wang 2016 | Dynamic 3D CEUS | 1–1.5 ml SonoVue | 1 month | Nodular/crescent shaped APHE with portal venous phase subsiding | APHE | CECT | 1 month | |
| Watanabe 2020 | CEUS | 0.5 ml of Sonazoid | 1–2 days | Nodular enhancement | Any enhancement | CECT/angiography/CTHA | 4–16 weeks | |
| Wen 2003 | CEUS with CHA | Levovist, 400 mg/ml | 5–7 days | Safety margin detectability and hypervascularity | APHE | Dynamic CT | 5–7 days | |
| Xia 2008 | CEUS | Sonazoid, 0.01–0.02 ml/kg | 4–9 days | Intratumoral enhancement | Any enhancement | Dynamic CT | 5–9 days (median 7 days) | |
| Xu 2014 | Dynamic CEUS | 2.4 ml SonoVue | 20–40 days | Interior or rim APHE with portal phase subsiding | APHE | CECT/CEMRI | 1 month | |
| Zheng 2013 | CEUS | 2.4 ml SonoVue | 1 month | Lack of nonenhancement | Any enhancement | CECT | 1 month | |
TACE transarterial chemoembolization, RFA radiofrequency ablation, HIFUA high-intensity focused ultrasound ablation, PEI percutaneous ethanol injection, RFTA radiofrequency thermal ablation, MWA microwave ablation, CEUS contrast-enhanced ultrasound, MI mechanical index, PIH pulse inversion harmonics, CHA coded harmonic angio, VUS virtual ultrasonography, CHI contrast harmonic imaging, ADI agent detection imaging, CEPD contrast-enhanced power Doppler, CCI charge contrast imaging, APHE arterial phase hyperenhancement, CT computed tomography, MRI magnetic resonance imaging, CEMRI contrast-enhanced magnetic resonance imaging, CECT contrast-enhanced computed tomography, DSA digital subtraction angiography