Diagnostic Endoscopic Ultrasound in Pancreatology: Focus on Normal Variants and Pancreatic Masses.

Background: Endoscopic ultrasound (EUS) is a main tool in gastroenterology for both diagnosis and exclusion of pancreatic pathology. It allows minimally invasive assessment of various diseases or anatomic variations affecting the pancreas also with the help of new Doppler technologies, elastography, contrast-enhanced imaging including post hoc image processing with quantification analyses, three-dimensional reconstruction, and artificial intelligence. EUS also allows interventional direct access to the pancreatic parenchyma and the retroperitoneal space, to the pancreatic duct, pancreatic masses, cysts, and vascular structures. Summary: This review aimed to summarize new developments of EUS in the field of pancreatology. We highlight the role of EUS in evaluating pancreatic pathology by describing normal anatomic variants like pancreas divisum, pancreatic lipomatosis, pancreatic fibrosis in the elderly and characterizing pancreatic masses, both in the context of chronic pancreatitis and within healthy pancreatic parenchyma. EUS is considered the optimal imaging modality for pancreatic masses of uncertain dignity and allows both cytological diagnosis and histology, which is essential not only for neoplastic conditions but also for tailoring therapy for benign inflammatory conditions. Key Messages: EUS plays an indispensable role in pancreatology and the development of new diagnostic and interventional approaches to the retroperitoneal space and the pancreas exponentially increased over the last years. The development of computer-aided diagnosis and artificial intelligence algorithms hold the potential to overcome the obstacles associated with interobserver variability and will most likely support decision-making in the management of pancreatic disease.

Endoscopic Ultrasound in Pancreatology: Focus on Inflammatory Diseases and Interventions.

Background: Endoscopic ultrasound (EUS) is a main tool in pancreatology for both diagnosis and therapy. It allows minimally invasive differentiation of various diseases, with a minimal degree of inflammation or anatomic variations. EUS also enables interventional direct access to the pancreatic parenchyma and the retroperitoneal space, the pancreatic duct, the pancreatic masses, cysts, vascular structures for diagnostic and therapeutic purposes. Summary: This review aimed to summarize the new developments of EUS in the field of pancreatology, with special interest on inflammation and interventions. EUS enables way to perform pseudocyst drainage, necrosectomy, transenteral drainage and transenteric access of the main pancreatic duct, or the direct visualization or therapy of vascular structures adjacent to the pancreas. Key Messages: EUS has a deep impact on pancreatology, and the development of new diagnostic and interventional approaches to the retroperitoneal space and the pancreas has increased in the last years exponentially, allowing minimal invasive diagnostics and therapy and avoiding surgery and percutaneous therapy.

Washout appearance of hepatocellular carcinomas using standardized contrast-enhanced ultrasound (CEUS) including an extended late phase observation - Real-world data from the prospective multicentre DEGUM study.

BACKGROUND: Non-invasive diagnosis of hepatocellular carcinoma (HCC) in contrast-enhanced ultrasound (CEUS) is based on the combination of arterial phase hyperenhancement (APHE) and subsequent late (>60 seconds) and mild contrast washout (WO). Whereas APHE is seen in the majority of HCC, wash-out pattern may vary in onset and intensity. In some HCC lesions, even no washout is seen at all. OBJECTIVE: Our prospective multicentre DEGUM HCC CEUS study aimed at identifying typical and atypical washout appearance of HCC in a real-life setting. METHODS: High-risked patients for HCC with focal liver lesions upon B-mode ultrasound were recruited prospectively. In a multicentre real-life setting, a standardised CEUS examination including an extended late phase up to 6 minutes was performed. CEUS patterns of HCC were recorded, and onset and intensity of washout appearance were assessed with respect to patient and tumour characteristics. Histological findings served as reference standard. RESULTS: In 230/316 HCC (72.8%), a CEUS pattern of APHE followed by WO was observed. In 158 cases (68.7%), WO was typical (onset > 60 seconds, mild intensity). 72 cases (31.3%) showed marked and / or early WO, whereas in 41 HCCs (13%), APHE was followed by sustained isoenhancement.Atypical WO upon CEUS was associated with macroinvasion of the liver vessels, portal vein thrombosis and diffuse growth pattern, but not tumour size and histological grading. CONCLUSIONS: In a prospective multicentre real-life setting, APHE is followed by atypical washout appearance or no washout at all in almost half of the HCCs with APHE. The examiner has to bear in mind that in spite of a characteristic APHE in HCCs, washout appearance can be atypical in CEUS, especially in HCCs with macrovascular invasion or diffuse growth pattern.

HCCs lacking arterial phase hyperenhancement (APHE) on contrast-enhanced ultrasound (CEUS) - a diagnostic challenge. Findings from the prospective multicenter DEGUM CEUS HCC trial.

OBJECTIVES: Hepatocellular carcinoma (HCC) upon contrast-enhanced ultrasound (CEUS) typically shows arterial phase hyperenhancement (APHE), followed by late (> 60 seconds) and mild contrast washout (WO). Although APHE is considered as the hallmark of HCC, it can be absent in some HCCs. Thus, we explored which sonomorphological and histopathological features of HCC are associated with a lack of APHE upon CEUS. METHODS: Focal liver lesions in high-risk patients for HCC were assessed with CEUS following a standardized protocol in a prospective multi-center real-life setting. CEUS patterns in HCC were assessed, and tumour and patient characteristics were compared for HCCs with and without APHE. RESULTS: 316 patients with HCC were recruited (cirrhosis, 76.9%). APHE occurred in 271/316 HCCs (85.8%). A lack of APHE was associated with portal vein thrombosis, tumour infiltration of the liver vessels (p<0.001), larger size, multilocularity, and higher depth location upon ultrasound (p<0.01). Histological grading did not differ between HCCs with and without APHE (p=0.39). Histopathological features of HCCs without APHE included cirrhotic stromal reaction, marked tumour cell steatosis and absence of the typical surrounding dilated sinusoidal vascular channels. CONCLUSION: Correlation with histopathological findings support the fact that HCCs with a lack of APHE in CEUS are a heterogeneous group. The examiner has to be aware that particularly HCCs with portal vein thrombosis or macro-invasion of the liver vessels may lack APHE.

Increase of liver stiffness and altered bile acid metabolism after triple CFTR modulator initiation in children and young adults with cystic fibrosis.

BACKGROUND: Novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies (elexacaftor/tezacaftor/ivacaftor-ETI) promise clinically significant and sustained improvements for patients with cystic fibrosis (CF). In this study, we investigated the impact of ETI therapy on liver stiffness and bile acid metabolism in a cohort of children and young adults with CF. METHODS: A prospective observational study (NCT05576324) was conducted from September 2020 to November 2021 enrolling CF patients naive to ETI. Standard laboratory chemistry, sweat test, lung function, share wave velocity (SWV) derived by acoustic radiation force impulse imaging (ARFI) and serum bile acid profiles were assessed before and 6 months after induction of ETI therapy. RESULTS: A total of 20 patients (10 aged <20 years) completed the study. While lung function and BMI improved after ETI therapy, ARFI SWV increased in CF patients <20 years of age (from 1.27 to 1.43 m/s, p = 0.023). Bile acid (BA) profiles revealed a decrease in unconjugated (5.75 vs 1.46, p = 0.007) and increase in glycine-conjugated derivatives (GCDCA) (4.79 vs 6.64 p = 0.016). There was a positive correlation between ARFI SWV values and GCDCA (r = 0.80, p < 0.0001). Glycine-conjugated BA provided high diagnostic accuracy to predict increased ARFI measurements (AUC 0.90) and clinical (Colombo) CFLD grading (AUC 0.97). CONCLUSIONS: ARFI SWV and bile acid profiles provide evidence for early increase in liver stiffness and altered bile acid metabolism in young CF patients after initiation of ETI and may serve as synergistic measures for detection of hepatic complications during ETI therapy.

Contrast-enhanced ultrasound pattern of hepatocellular carcinoma in noncirrhotic liver - results from the prospective multicentre DEGUM CEUS HCC study.

OBJECTIVES: Contrast-enhanced ultrasound (CEUS) has a high diagnostic accuracy for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in cirrhosis. However, as HCC in noncirrhosis becomes an emerging clinical concern, our study aimed to assess the diagnostic value of CEUS and the CEUS algorithms CEUS LI-RADS and ESCULAP in noncirrhotic liver in a prospective multicentre real-life setting. METHODS: High-risk patients for HCC with focal liver lesions upon B-mode ultrasound were recruited prospectively in a multicentre real-life approach to undergo standardized CEUS. Diagnostic accuracies of CEUS and the CEUS algorithms were assessed for the sub-collective of noncirrhotic patients. Histology, MRI and CT served as the reference standard. RESULTS: In total 47/517 patients were noncirrhotic. The reference standard of the lesions showed 30 HCCs (63.8%), four intrahepatic cholangiocellular carcinomas (iCCAs), two other malignancies and 11 benign lesions. HCCs in noncirrhosis showed a tendency towards larger tumor size and better differentiation. A typical CEUS pattern of arterial phase hyperenhancement and late-onset (>60 s), mild washout occurred in 22/30 HCCs (73.3%). Very late onset of washout > 4-6 min was not seen in noncirrhotic liver. The CEUS algorithm ESCULAP showed a perfect sensitivity (100 vs. 68% with CEUS LI-RADS), whereas CEUS LI-RADS had a superior specificity (83 vs. 53%). The positive predictive value was high with both algorithms. CONCLUSION: The CEUS patterns of HCCs in noncirrhotic liver resembled those in cirrhosis. Our findings suggest that although designed for the application in cirrhosis only, the diagnostic accuracies of the CEUS algorithms in noncirrhotic liver seem comparable to the findings in cirrhosis.

Rectal Cancer Presenting with Absceding Infection Due to Fusobacterium nucleatum.

Intestinal microbiota such as Fusobacterium nucleatum play an important role in the pathogenesis of colorectal cancer. Here, we describe the case of a 47-year-old patient presenting with endophthalmitis and a liver abscess due to Fusobacterium nucleatum that prompted the diagnosis of colorectal cancer as the most likely source of infection. This case highlights that colorectal cancer needs to be considered in patients with systemic infection with Fusobacterium nucleatum and colonoscopy should be performed.

Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US).

PURPOSE: Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma. METHODS: In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria. RESULTS: Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73-0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis. CONCLUSION: An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma.

Contrast-Enhanced Ultrasound Patterns for the Non-invasive Diagnosis of Hepatocellular Carcinoma: A Prospective Multicenter Study in Histologically Proven Liver Lesions in a Real-Life Setting Demonstrating the Benefit of Extended Late Phase Observation.

The hallmark for the non-invasive diagnosis of hepatocellular carcinoma (HCC) with contrast-enhanced ultrasound (CEUS) in cirrhosis is arterial phase hyperenhancement (APHE), followed by late-onset (>60 s), mild washout. Large retrospective studies report this pattern of washout to occur in the vast majority of HCCs. However, a prospective multicenter validation of these findings is still missing. Thus, we initiated a prospective multicenter validation study assessing CEUS enhancement patterns in focal liver lesions of patients at risk for HCC. We analyzed lesions that were eventually histology proven in a real-life setting. CEUS patterns were assessed for subgroups of HCC, intrahepatic cholangiocellular carcinoma (iCCA) and non-HCC, non-iCCA lesions. The diagnosis was HCC in 316 lesions (median size: 40 mm), iCCA in 26 lesions (median size: 47.5 mm) and non-HCC, non-iCCA in 53 lesions (median size: 27 mm). Overall, 85.8% of HCCs exhibited APHE. APHE followed by washout occurred in 72.8% of HCCs and 50% of iCCAs and non-HCC, non-iCCA malignancies (p < 0.05). Early and marked washout was associated more commonly with iCCA; HCCs exhibited mostly late and mild washout (onset >4-6 min in 10% of cases). Our prospective data confirm that the typical pattern of APHE followed by late-onset, mild washout occurs in the majority of HCCs.

Bowel wall thickening and hyperemia assessed by high-frequency ultrasound indicate histological inflammation in Crohn's ileitis.

PURPOSE: We evaluated ileal bowel wall thickness and semiquantitative vascularization by ultrasound in correlation with the presence or absence of histopathological inflammation in patients with Crohn's disease (CD). METHODS: We conducted a retrospective analysis of 221 ultrasound examinations of the terminal ileum or neoterminal ileum in CD patients with biopsies of the ileum during colonoscopies within 8 weeks of the ultrasound. Ultrasound data were obtained from an inflammatory bowel disease ultrasound register from 2011 to 2017. Bowel wall ultrasound was performed by a high-frequency, linear transducer (7-12 MHz). Presence of bowel wall thickening (> 3 mm), vascularization by the Limberg score, and presence of ileal histopathological inflammation were analyzed. RESULTS: In 221 bowel wall ultrasound examinations of CD patients (128 female, 93 male, mean age 37.5 years), a thickened bowel wall was found in 140 (63.3%) and hypervascularization (corresponding to a Limberg score ≥ 2) in 96 (43.4%) cases. In 187 (84.6%) cases, ileal inflammation was confirmed by histopathology and in 34 (15.4%) cases no inflammation was shown. Bowel wall thickening showed a sensitivity of 70.1%, a negative predictive value (NPV) of 30.9%, a specificity of 73.5% and a positive predictive value (PPV) of 93.6% for the detection of histopathological ileal inflammation. Hypervasularization had a low sensitivity (49.7%) and NPV (24.8%), but high specificity (91.2%) and PPV (96.9%). CONCLUSION: In this CD subcohort of an ultrasound register, pathologic ultrasound findings were quite common. Bowel wall thickening (> 3 mm) and hypervascularization are good predictors of histopathological inflammation within the terminal ileum or neoterminal ileum. Normal ultrasound findings without bowel wall thickening and without hypervascularization do not rule out histopathological inflammation.

Alteration of contrast enhanced ultrasound (CEUS) of hepatocellular carcinoma in patients with cirrhosis and transjugular intrahepatic portosystemic shunt (TIPS).

Transjugular intrahepatic portosystemic shunt (TIPS) can treat portal hypertensive complications and modifies hepatic hemodynamics. Modification of liver perfusion can alter contrast enhancement dynamics of liver nodules. This study investigated the diagnostic performance of contrast-enhanced ultrasound (CEUS) to diagnose hepatocellular carcinoma (HCC) in cirrhosis with TIPS. In this prospective monocentric observational study, CEUS was used to characterize focal liver lesions in patients at risk for HCC with and without TIPS. Times of arterial phase hyperenhancement (APHE) und washout were quantified. Perfusion-index (PI) and resistance-index (RI) of hepatic artery and portal venous flow parameters were measured via doppler ultrasonography. Diagnostic gold standard was MRI/CT or histology. This study included 49 liver lesions [23 TIPS (11 HCC), 26 no TIPS (15 HCC)]. 26 were diagnosed as HCC by gold standard. Sensitivity and specificity of CEUS to diagnose HCC with and without TIPS were 93.3% and 100% vs. 90.9% and 93.3%, respectively. APHE appeared significantly earlier in patients with TIPS compared to patients without TIPS. TIPS significantly accentuates APHE of HCC in CEUS. CEUS has good diagnostic performance for diagnosis of HCC in patients with TIPS.

Ultrasound-Based Attenuation Imaging for the Non-Invasive Quantification of Liver Fat - A Pilot Study on Feasibility and Inter-Observer Variability.

Attenuation imaging is a novel, ultrasound-based technique to objectively detect and quantify liver steatosis. In this study, we evaluated the performance and inter-observer variability of attenuation imaging and compared it to a known quantification method of liver fat, the hepatorenal index (HRI). Two observers measured attenuation coefficients (AC) in an attenuation phantom, 20 healthy volunteers and 27 patients scheduled for biopsy for suspected diffuse liver disease. Results were compared with the HRI and histological findings. Both observers were blinded to the results of the biopsy and the measurements of the other observer. Our results showed that patients with moderate (S2, 33-66%) and severe fatty infiltration of the liver (S3, >66%) showed significantly higher ACs in comparison to patients with a liver fat fraction of less than 33% (S0/1). There was no significant difference in AC-values of patients with fatty infiltration of less than 5% (S0) and 5-32% (S1). In the Receiver Operating Characteristic (ROC)-analysis, the area under the curve (AUC)-values for the detection of moderate and severe steatosis were excellent at 0.98. Cut-off values were 0.64 dB/cm/MHz for the detection of S2- and 0.68 dB/cm/MHz for the detection of S3-steatosis. The inter-observer agreement of attenuation imaging was very good with an intraclass correlation coefficient (ICC) of 0.92 in patient and 0.96 in phantom measurements. The ICC decreased with depth in the phantom measurements. In summary, attenuation imaging showed very good inter-observer agreement and is a promising tool for the detection and quantification of moderate and severe hepatic steatosis.

Tips and Tricks in Contrast-Enhanced Ultrasound (CEUS) for the Characterization and Detection of Liver Malignancies.

Contrast-enhanced ultrasound (CEUS) has a high diagnostic accuracy in the assessment of focal liver lesions. Clinical context (presence of liver cirrhosis, history of other malignancy versus incidental finding) is crucial for the correct interpretation of CEUS findings. CEUS has to be preceded by structured anamnesis and clinical examination as well as accurate B-mode sonography. Metastases are the most common malignant liver lesions in a non-cirrhotic liver. According to their contrast enhancement in the arterial phase, metastases are categorized as hyper- and hypo-vascular metastases. A common feature of all metastatic lesions is washout of the contrast agent in the portal venous or late phase. In the context of liver cirrhosis, > 95 % of focal liver lesions are hepatocellular carcinomas (HCCs). HCCs typically show arterial phase hyperenhancement, followed by mild and gradual contrast washout occurring very late in the late phase. For intrahepatic cholangiocellular carcinoma (ICC), the pattern of contrast enhancement in the arterial phase can vary. However, all ICCs typically show early and pronounced washout. Other liver malignancies like lymphoma, angiosarcoma, epithelioid hemangioendothelioma and others are very rare. Except for the contrast washout seen in all liver malignancies, they do not display pathognomonic enhancement patterns upon CEUS. Thus, biopsy is indispensable for definite diagnosis of the tumor entity. Furthermore, CEUS is used for the detection of metastases and therapeutic monitoring after local ablative procedures. The examination procedure differs slightly depending on the specific indication (characterization, detection).

Acoustic Radiation Force Impulse (ARFI) Elastography in Autoimmune and Cholestatic Liver Diseases.

INTRODUCTION: Acoustic Radiation Force Impulse (ARFI) elastography evaluates hepatic fibrosis non-invasively and has been mainly validated in viral hepatitis. Data on rare liver diseases such as autoimmune hepatitis (AIH), overlap syndrome, primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) are sparse. MATERIAL AND METHODS: 85 patients (including 31 AIH, 26 PBC, 16 PSC and 3 PSC-and 9 PBC-AIH-overlap syndromes) were retrospectively analysed pointing at ARFI elastography of the liver and the correlation with histologic Ishak fibrosis score (F0-6). Results of shear wave velocities (m/s) were expressed as mean ± standard deviation. RESULTS: The mean shear wave velocity of all 85 patients showed 1.80 ± 0.84 m/s (0.74-3.98). The ARFI elastography values correlated with the degree of fibrosis in all patients overall and in patients with AIH, overlap syndrome and PSC, respectively. The subgroup of 26 patients with PBC (only with Ishak F > 3) revealed no correlation between ARFI and these early fibrosis stages (r = 0.019, p = 0.927). ARFI elastography correlated with bilirubin, AST, but not with patient age, body mass index or measurement depth. The cut-off of 2.04 m/s for detecting cirrhosis (Ishak F > 5) leads to a sensitivity of 90.0% and specificity of 74.7% (AUROC 87.2%). CONCLUSION: ARFI elastography can evaluate fibrosis in AIH, PSC and PSC-/PBC-AIH-overlap syndrome with good accuracy for the detection of hepatic cirrhosis. Shear wave velocities in PBC should be interpreted with caution in early stages of fibrosis.

Acoustic radiation force impulse (ARFI) shear wave elastography of the bowel wall in healthy volunteers and in ulcerative colitis.

BACKGROUND: Acoustic radiation force impulse (ARFI) elastography is a non-invasive, ultrasound-based approach of evaluation of tissue elasticity. It has not yet been systematically applied to the bowel wall. PURPOSE: To perform ARFI elastography of the bowel wall in healthy volunteers and patients with ulcerative colitis (UC). MATERIAL AND METHODS: A high-frequency ultrasound (with bowel wall thickness and vascularization score) and an ARFI elastography of the bowel wall were performed in 20 patients with UC and 13 healthy volunteers. At least 10 ARFI measurements were obtained within the terminal ileum and the ascending, transverse, descending, and sigmoid colon and correlated with results of high-frequency ultrasound. RESULTS: The UC group had mostly moderate disease activity. All patients had signs of inflammation upon B-mode ultrasound. Eight patients showed an ulcerative (ileo)pancolitis. Overall, ARFI elastography values and wall thickness were higher in the UC group than in the group of healthy volunteers (P = 0.021 and P < 0.001, respectively). ARFI velocities of the separate segments were significantly higher in the transverse (P = 0.045) and sigmoid colon (P = 0.032) in case of UC. CONCLUSION: ARFI elastography of the bowel wall of the colonic frame and the terminal ileum is feasible but shows high standard deviation. ARFI shear wave velocities appear to be slightly higher in patients with UC than in healthy volunteers, particularly in the sigmoid and transverse colon. Further studies are needed.

Differentiation of malignant liver tumors by software-based perfusion quantification with dynamic contrast-enhanced ultrasound (DCEUS).

BACKGROUNDEnhancement patterns on contrast-enhanced ultrasound (CEUS) help to distinguish different liver tumors. OBJECTIVE: Assessing the diagnostic value of dynamic contrast-enhanced ultrasound (DCEUS) for the discrimination of different malignant liver lesions. METHODS: 148 malignant focal liver lesions were assessed prospectively with DCEUS (hepatocellular carcinoma = HCC; cholangiocellular carcinoma = CCC; pancreatic adenocarcinoma = PCA; breast cancer = BC; colorectal cancer = CRC; melanoma = MM). Focal-nodular-hyperplasias (FNH) served as a reference for benign lesions. DCEUS-clips were recorded continuously over three minutes. DCEUS-values were compared between the tumor entities. For better inter-individual comparability, perfusion kinetics were analyzed considering the perfusion characteristics of the surrounding liver parenchyma (Relative Signal Intensity = RSI: lesion-liver tissue/liver tissue) at different points in time. RESULTS: Absolute signal intensity in FNH showed a tendency towards higher values compared with malignant liver lesions [Peak Enhancement(a.u.): FNH 7111.4; HCC 549.9; CCC -6654.3; PCA -7307.9; BC -4562.4; CRC -10672.9; MM -3034.1]. Washout was significantly less in FNH versus PCA and CRC, and more pronounced and earlier in PCA and CRC versus HCC [RSI 30 seconds after PE-lesion(%): FNH +52; PCA -65; CRC -76; HCC -26]. Rise Time, Fall Time and mean-Transit-Time did not differ significantly. CONCLUSIONS: DCEUS-values reflect significant differences between malignant liver lesions, especially at peak enhancement and during the washout phases.