Dynamic contrast enhanced ultrasound in gastrointestinal diseases: A current trend or an indispensable tool?

Table 1 Dynamic contrast-enhanced ultrasound parameters in time-intensity curve

Abbreviation	Parameter	Definition	Unit
AT	Arrival time	Time from administration of UCA to the beginning of the curve	s
AUC or WiWoAUC	Area under the curve or wash-in and wash-out area under the curve	Total area under the curve	AIU
FT	Fall time	Time from PE to point where tangent of descending curve across x-axis	s
IMAX or MI	Maximum intensity	Maximum intensity of the curve	AIU
MTT	Mean transit time	Mean time taken by contrast to pass through the ROI	s
PE	Peak enhancement	Maximum intensity of the curve	AIU
PI	Peak intensity	Maximum intensity of the curve	AIU
Pw	Slope coefficient of wash-in	Coefficient of the enhancement wash-in slope	AIU × s
RT	Rise time	Time from PE to point where tangent of ascending curve across x-axis	s
TPI or TTP or TP	Time to peak	Time from the beginning of the curve to peak	s
WiAUC	Wash-in area under the curve	AUC from the beginning of the curve to PE	AIU × s
WoAUC	Wash-out area under the curve	AUC from the PE to the end of the curve	AIU × s
WiR	Wash-in rate	Tangent at the ascending part of the curve	AIU × s
WoR	Wash-out rate	Tangent at the descending part of the curve	AIU × s

AIU: Absolute intensity unit; ROI: Region of interest; UCA: Ultrasound contrast agent.

Table 2 Dynamic contrast-enhanced ultrasound and liver diseases

Ref.	Study design/number of patients	Object of D-CEUS	Population/groups	Machine/UCA/software	Significant results (P < 0.05)
Wildner et al[31], 2022	Prospective/17	Melanoma liver metastasis	Patients with melanoma liver metastasis treated with sorafenib/Responders’ vs non-responders	Sequoia 512/SonoVue/Qontrast	Increase of MTT and TTP is associated with response to treatment and prognosis
Gu et al[30], 2022	Retrospective/97	HCC	Patients with HCC underwent thermal ablation	Acuson Sequoia, Phillip EpiQ7/SonoVue/VueBox	WiAUC, WoAUC, and WiWoAUC ratios between HCC and surrounding parenchyma before ablation were predictors of survival
Huang et al[18], 2022	Prospective/120	HCC	Patients with HCC underwent biopsy/Low-Ki-67 vs high-Ki-67	Logiq E9/Sonazoid/NovoUltrasound Kit	PE difference between HCC and distal liver parenchyma was different in the Kupffer phase
Li et al[22], 2022	Retrospective/31	HCC	Patients with HCC underwent surgery/MVI-positive vs MVI-negative	Phillip EpiQ7/Sonazoid/built-in auto contrast software	None of the D-CEUS parameters was related to MVI
Zocco et al[28], 2013	Prospective/46	Liver parenchyma	Cirrhotic patient underwent HVPG/clinically significant portal hypertension vs severe portal hypertension	iU22/SonoVue/QLAB	Negative correlation between PI, Pw and HVPG. Positive correlation with MTT. AUROC of 1.00 for PI < 23.3 AIU to predict clinically significant portal hypertension
Dong et al[21], 2021	Retrospective/16	HCC	Patients with HCC underwent surgery/MVI-positive vs MVI-negative	Acuson Oxana, Logiq E9, Siemens Acuson Sequoia/SonoVue, Lumason/VueBox	WiAUC and WoAUC were higher in MVI positive group
Schwarz et al[24], 2021	Retrospective/139	Focal liver lesion	Patients with diagnosed focal liver lesion/malignant versus benign	Acuson Sequoia, S2000 or S3000 and Phillip EpiQ7/SonoVue/VueBox	RT and late phase ratio were different between malignant and benign liver lesion
Xuan et al[19], 2021	Retrospective/128	HCC	Patients with HCC underwent biopsy or surgery/highly-differentiated vs moderate-differentiated vs poorly-differentiated	-/SonoVue/-	RT and MTT increased from poorly- to moderate- to highly-differentiated. Enhancement rates decreased from poorly- to moderate- to highly-differentiated
Amadori et al[32], 2018	Prospective/37	CRC Liver metastasis	Patients underwent chemotherapy/chemotherapy vs chemotherapy plus bevacizumab	iU22 vision 2008/SonoVue/QLAB	Reduction of PI and AUC and increase of TPI correlated with higher PFS in chemotherapy plus bevacizumab group
Wildner et al[25], 2019	Prospective/148	Focal liver lesion	Patients with focal liver lesion and subsequent final diagnosis/HCC, CCC, PCA, CRC, BC, MM, FNH	Sequoia 512/SonoVue/VueBox	Higher PE and WiWoAUC in HCC than CRC. Lower Relative intensity signal for PCA and CRC compared to HCC at 30 and 120 s after PE
Mogensen et al[33], 2017	Prospective/12	CRC liver metastasis	Patients underwent chemotherapy/chemotherapy vs chemotherapy plus bevacizumab	Logiq E9/SonoVue/VueBox	Early changes of PE correlate with tumor shrinkage at CT scan
Zocco et al[28], 2013	Prospective/28	HCC	Patients treated with sorafenib/Responders’ vs non-responders	iU22/SonoVue/QLAB	PI, Pw and AUC 10% decrease correlate with response to therapy. AUC 10% decrease and increased/unchanged TPI and MTT are associated with longer survival. Decrease of Pw is associated with PFS
Zhan et al[20], 2019	Prospective/35	HCC	Patients with HCC underwent microwaves ablation	Acuson Sequia/Sonovue/SonoLiver	Positive correlation between MVD, VEGF and IMAX; negative correlation between MVD and TTP. TTP was an independent predictor of OS
Wildner et al[26], 2014	Prospective/43	HCC, ICC	Patient with proven HCC and ICC	Acuson Sequoia 512/SonoVue/VueBox	FT and MTT were lower in ICC than HCC. Relative signal intensity was lower in ICC than HCC in all time point after PE
Frampas et al[69], 2013	Prospective/19	HCC	Patients with HCC treated with sorafenib or sunitinib/RECIST progressor vs non-progressor	Aplio XV/SonoVue/Vascular Recognition Imaging” mode	AUC decrease ≥ 40% correlated with RECIST non-progression
Lassau et al[29], 2011	Prospective/42	HCC	Patients with HCC treated with Bevacizumab	Aplio scanner/SonoVue/Contrast Harmonic Imaging-Quantification software	AUC, WiAUC, WoAUC and TPI decrease correlate with tumor response. TPI decrese correlate with PFS. AUC and WoAC decrease correlate with OS

AIU: Arbitrary intensity unit; AUC: Area under the curve; AUROC: Area under the receiver operating characteristic; BC: Breast cancer; CCC: Cholangiocarcinoma; CRC: Colorectal cancer; CT: Computed tomography; D-CEUS: Dynamic contrast-enhanced ultrasound; FNH: Focal nodular hyperplasia; HCC: Hepatocellular carcinoma; HVPG: Hepatic vein portal pressure; MM: Malignant melanoma; MTT: Mean transit time; MVD: Microvascular density; MVI: Microvascular invasion; OS: Overall survival; PCA: Pancreatic adenocarcinoma; PE: Peak enhancement; PFS: Progression free survival; PI: Peak intensity; Pw: Slope coefficient of wash-in; RECIST: Response evaluation criteria in solid tumors; RT: Rise time; TPI: Time to peak intensity; TTP: Time to peak; UCA: Ultrasound contrast agent; WiAUC: Wash-in area under the curve; WoAUC: Wash-out area under the curve; WiWoAUC: Wash-in and wash-out area under the curve.

Table 3 Dynamic contrast-enhanced ultrasound and pancreatic diseases

Ref.	Study design/number of patients	Object of D-CEUS	Population/groups	Machine/UCA/Software	Significant results (P < 0.05)
Yang et al[47], 2023	Retrospective/42	pNET	Patients with histopathologically proved pNET/G1, G2, G3, pNEC	Acuson Sequoia, Acuson Oxana2/SonoVue/VueBox	rPE, rMTT and rAUC were higher in pNETs G1/G2 than G3/pNECs
Zhang et al[45], 2020	Prospective/11	LAPC	Patient with LAPC underwent chemoradiotherapy	Acuson Oxana2/SonoVue/SonoLiver	MI decreased after chemoradiotherapy
Vitali et al[43], 2015	Prospective/20	PC, focal AIP	Patients with diagnosis of AIP vs histologically proved PC	Acuson Sequoia 512, S200/SonoVue/VueBox	The difference in PE (dPE) between lesion and surrounding parenchyma in AIP was lower compared to dPE in PC
D’Onofrio et al[40], 2014	Prospective/10	Suspected PDAC	Patients with suspected and then histologically proved PDAC	Acuson S2000/SonoVue/VueBox	PE and ascending curve values were different between lesion and adjacent parenchyma
Kersting et al[42], 2009	Prospective/60	Undefined pancreatic lesion	Patients with undefined pancreatic lesion underwent biopsy/PDAC vs CP	Sonoline Elegra/SonoVue/Axius ACQ	TTP and AT were longer in PDAC compared to focal masses in CP

AIP: Autoimmune pancreatitis; AT: Arrival time; CP: Chronic pancreatitis; D-CEUS: Dynamic contrast-enhanced ultrasound; LAPC: Local advanced pancreatic cancer; MI: Maximum intensity; PC: Pancreatic cancer; PDAC: Pancreatic ductal adenocarcinoma; PE: Peak enhancement; pNET: Pancreatic neuroendocrine tumor; pNEC: Pancreatic neuroendocrine carcinoma; rAUC: Relative area under the curve; rMTT: Relative mean transit time; rPE: Relative peak enhancement; TTP: Time to peak; UCA: Ultrasound contrast agent.

Table 4 Dynamic contrast-enhanced ultrasound and inflammatory bowel diseases

Ref.	Study design/number of patients	Object of D-CEUS	Population/groups	Machine/UCA/Software	Significant results (P < 0.05)
Laterza et al[60], 2021	Prospective/44	CD	Patients with CD treated with anti-TNFα/responders vs non-responders	iU22/SonoVue/QLAB	Correlation between decrease in PI, AUC, Pw, and MTT and response to therapy
Goertz et al[57], 2018	Prospective/18	CD and UC	Patients with CD or UC treated with vedolizumab/responders vs non-responders	Acuson S2000/SonoVue/VueBox	WiR was lower in responders’ group after 14 wk
Wilkens et al[56], 2018	Retrospective/104	CD	Patients with severe CD underwent CEUS/normal vs atypical intensity decline on CEUS	iU22/Definity/QLAB	AUC, wash-out time, and intensity at 60s and 120s were higher in atypical decline group and this correlated with bad outcomes
Quaia et al[53], 2017	Prospective/65	CD	Patients with CD with terminal ileal loop stricture histologically characterized/inflammatory vs fibrostenotic disease	iU22/SonoVue/VueBox	PE, WiR, WiPI, AUC, WiAUC and WoAUC were higher in inflammatory group compared to fibrostenotic gruoup. TTP was not different between the two groups
Medellin-Kowalewski et al[55], 2016	Retrospective/127	CD	Patients with CD underwent US and CEUS	iU22/Definity/QLAB	PE correlate with wall thickness
Quaia et al[61], 2016	Prospective/50	CD	Patient with CD underwent medical treatment/responders vs non-responders	iU22/SonoVue/VueBox	Changes in PE, WiR, WoR, WiPI, AUC, WiAUC, and WoAUC from baseline to six weeks after therapy differed between responders and non-responses
Socaciu et al[58], 2015	Prospective/38	CD and UC	Patients with CD or CU candidate for medical treatment	Logiq 7/SonoVue/SonoLiver	Logarithm of AUC correlated with endoscopic improvement in both diseases
Saevik et al[59], 2014	Prospective/14	CD	Patients with CD started medical treatment/remission vs treatment failure	Logiq E9/SonoVue/VueBox	PE, WiR, WoR, and WiAUC were different between two groups at 1 mo of treatment
Romanini et al[50], 2014	Prospective/33	CD	Patients with CD undergoing colonoscopy and biopsy	Sequoia 512/SonoVue/Qontrast	Correlation between high vascular density and Peak% and regional blood flow
Ripollés et al[51], 2013	Prospective/25	CD	Patients with CD undergoing elective bowel resection/inflammatory vs fibrostenotic disease	Aplio 80/SonoVue/Software in Aplio 80 system	The percentage of increase in contrast enhancement of the bowel wall in inflammatory lesions was greater than fibrotic lesions
Nylund et al[52], 2013	Prospective/33	CD	Patient with CD underwent surgery or medical treatment/inflammatory vs fibrostenotic disease	Logiq E9/SonoVue/Custom software	Blood flow and blood volume were higher in the medical group compared to surgery group
Girlich et al[54], 2012	Prospective/11	UC	Patients with UC undergoing endoscopy	Logiq E9/SonoVue/Qontrast	Negative correlation between TTP/Peak% and histopathological score
Girlich et al[49], 2011	Prospective/20	CD	Patients with planned bowel surgery due to CD	Logiq 9/SonoVue/Qontrast	Negative correlation between TTP and histopathological score. Positive correlation with single items of the score
Girlich et al[48], 2009	Prospective/20	CD	Patients with active CD vs healthy volunteers	Logiq 9/SonoVue/Qontrast	Higher PE and regional blood volume and shorter TTP in CD

AUC: Area under the curve; CD: Crohn’s disease; CEUS: Contrast-enhanced ultrasound; D-CEUS: Dynamic contrast-enhanced ultrasound; MTT: Mean transit time; PE: Peak enhancement; PI: Peak intensity; Pw: Slope coefficient of wash-in; TNF-α: Tumor necrosis factor-α; TTP: Time to peak; UC: Ulcerative colitis; UCA: Ultrasound contrast agent; US: Ultrasound; WiAUC: Wash-in area under the curve; WiPi: Wash-in ratio index; WiR: Wash-in rate; WoR: Wash-out rate.