Potential for contrast-enhanced intraoperative ultrasonography with the Kupffer phase to improve and guide therapeutic strategies for hepatocellular carcinoma
Introduction
Hepatocellular carcinoma (HCC) is one of the most common malignancies and is a principal cause of cancer-related morbidity and mortality worldwide (1). In China, hepatitis B virus infection has been identified as the main cause of HCC and cirrhosis (2). Surgical resection is the first choice of treatment for HCC, affording long-term survival. Radiofrequency ablation (RFA) is a widely used minimally invasive procedure and an alternative to surgery. Numerous surgeons prefer RFA to surgical resection for small HCC lesions to preserve a considerable portion of the surrounding liver parenchyma and ensure a high quality of life (3). However, the imprecise placement of the needle owing to inadequate targeting of the image could lead to rapid local recurrence after RFA (4).
Intraoperative ultrasound (IOUS) plays an important role during the surgical treatment of HCC in identifying new lesions that cannot be detected by preoperative contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI). It is mandatory to decide how to resect malignant lesions or follow up benign lesions (5). However, IOUS fails to distinguish between benign and malignant tumors directly. Contrast-enhanced IOUS (CE-IOUS) is an effective technique for detecting and characterizing occulting liver lesions and is widely employed to navigate surgical RFA (6,7).
The purpose of our study was to evaluate the performance of CE-IOUS during hepatic surgery in detecting and characterizing focal liver lesions (FLL). Regenerative nodules (RN) and dysplastic nodules (DN) with cirrhosis are considered premalignant lesions of HCC and can be difficult to distinguish from early-stage HCC (8). Therefore, not all tumors detected by CE-IOUS, especially in HCC patients with cirrhosis, are malignant. Accordingly, distinguishing occult lesions by CE-IOUS during surgery could facilitate optimized treatment strategies, such as intraoperative RFA, precise hepatectomy, and follow-up. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-671/rc).
Methods
This retrospective study was approved by the Ethics Committee of Beijing Hospital (ethical approval No. 2021BJYYEC-190-02) and informed consent was provided by all the included patients. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). We enrolled 25 patients who were consecutively scheduled to undergo surgery for HCC in the Department of General Surgery of Beijing Hospital from November 2019 to July 2022. The inclusion criteria were as follows: (I) patients with a suspected diagnosis of HCC; (II) complete medical information available. The exclusion criteria were as follows: (I) absence of CEUS or IOUS or CE-IOUS; (II) incomplete clinical information; (III) contraindication for the use of the Sonazoid contrast agent (GE Healthcare, Oslo, Norway), including a history of allergies to active substances or any excipients such as sucrose, perfluorobutane, and hydrogenated egg phosphatidylserine sodium. The clinical characteristics of patients were collected, including age, sex, type of hepatitis, background liver, alpha-fetoprotein (AFP) values, and pathology of liver tumors.
Scan techniques
CEUS technique
All patients underwent ultrasound and CEUS. A Canon Aplio 500 (Canon, Honshu, Japan) diagnostic ultrasound instrument (6C1 convex array probe, frequency 1–6 MHz and 11L4 linear array probe, frequency 4–11 MHz) and a Canon Aplio i800 (Canon, Japan) diagnostic ultrasound instrument (PVI-475BX convex array probe, frequency 1–8 MHz and 11L4 linear array probe, frequency 4–11 MHz) were used. The mechanical index was 0.20–0.22. Sonazoid (perfluorobutane) was used as the contrast agent. All CEUS was performed by two sonographers with five years of experience in liver CEUS.
Sonazoid (0.015 mL/kg body weight by bolus) was administered intravenously, followed by 5 mL of normal saline flush. The vascular phase (arterial phase, portal phase, and delayed phase) and the post-vascular phase image (Kupffer phase) of the lesions were observed and recorded. During the Kupffer phase, the whole liver was scanned. In all patients, if defects were identified that could not be detected in B-mode, Sonazoid was reinjected to confirm the diagnosis by manifestation in the vascular phase. The typical dynamic enhancement patterns of HCC were hyperenhancement in the arterial phase, followed by iso/hypovascular in the portal phase, and defects in the Kupffer phase. DNs exhibit inhomogeneous and reticular patterns of hypervascularity in the early arterial phase, followed by isoenhancement or slight hypoenhancement in the portal phase to Kupffer phase. RNs exhibited iso/hypoenhancing appearance in the vascular phase with no apparent Kupffer cell defect (9).
MRI technique
All patients underwent an MRI examination. A 3.0T whole body scanner (Signa Pioneer; GE Healthcare, Milwaukee, USA) was used to obtain T1-weighted images (T1WI), T2-weighted images (T2WI), and diffusion-weighted images (DWI). Dynamic MRI was obtained in a series of phases after intravenous injection of gadolinium diamine (0.2 mL/kg of body weight).
IOUS and CE-IOUS
All patients underwent IOUS and CE-IOUS examinations. An Arietta 70 (Hitachi Aloka, Tokyo, Japan) diagnostic ultrasound instrument (L44LA laparoscopic probe, frequency 2–13 MHz and C42T microconvex probe, frequency 3–10 MHz) was used. A bolus of intravenous Sonazoid was administered via the central venous vein, with administration repeated if necessary. IOUS and CE-IOUS were performed by the same surgeon.
During intraoperative examination, IOUS and CE-IOUS were performed for lesion characterization and detection of new nodules. If new lesions were detected on IOUS, we attempted to identify HCC and other kinds of lesions using the vascular phase of CE-IOUS.
Two radiologists decided the diagnostic results of preoperative MRI and CEUS. The surgical treatment of all cases was discussed and formulated by a multidisciplinary team (MDT). The radiologists and the surgeon producing IOUS were blinded to the lesion information. Subsequently, CEUS, MRI, IOUS, and CE-IOUS imaging data were compared. Every modification in the therapeutic strategy during the operation was recorded.
The final diagnosis of all lesions considered malignant via CE-IOUS was performed by histopathological examination of surgically resected specimens or puncture biopsy tissues.
Statistical analysis
For the different radiologic imaging methods, the sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), 95% confidence interval (95% CI), and Youden index (Y) of the HCC lesion assessment were calculated using receiver operating characteristic (ROC) analysis. We applied the χ2 test to compare independent groups. The nonparametric Cochran Q-test was applied to confirm the differences in capacities to detect HCC lesions among the four imaging methods. If statistical significance was detected, we used the McNemar test to identify the differences in performance for multiple comparisons. Data analyses were performed using MedCalc Statistical Software version 19.3.1 (MedCalc Software Ltd., Ostend, Belgium). A two-tailed P<0.05 was considered significantly different.
Results
A total of 72 lesions were detected in 25 patients. Considering the detected lesions, 57 were diagnosed as HCC, and 15 were diagnosed as others. As presented in Table 1, the other 15 were classified as follows: no cancer (n=3), RN (n=5), DN (n=5), hemangioma (n=1), and focal nodular hyperplasia (n=1) (Table 1).
Table 1
| Characteristics | All (n=25) |
|---|---|
| Age (years) (mean ± SD) | 60.9±6.7 |
| <60 | 11 |
| ≥60 | 14 |
| Type of hepatitis | |
| HB | 19 |
| HC | 2 |
| HB + HC | 2 |
| Neither HB or HC | 2 |
| Background liver | |
| Fatty liver | 1 |
| Chronic hepatitis | 10 |
| Liver cirrhosis | 14 |
| AFP (μg/L) | |
| <20 | 16 |
| 20–400 | 6 |
| >400 | 3 |
| Gender | |
| Male | 22 |
| Female | 3 |
| Liver tumors | 72 |
| Hepatocellular carcinoma/others | 57 |
| Others | 15 |
| No cancer | 3 |
| Regenerative nodules | 5 |
| Dysplastic nodules | 5 |
| Hemangioma | 1 |
| FNH | 1 |
SD, standard deviation; HB, hepatitis B; HC, hepatitis C; AFP, alpha-fetoprotein; FNH, focal nodular hyperplasia.
Figure 1 presents the ROC curves of the four imaging methods. The related parameters are shown in Table 2. According to a pairwise comparison of ROC curves, CE-IOUS showed the highest sensitivity in the assessment of HCC, although not statistically significant when compared with MRI and CEUS (CE-IOUS vs. MRI P=0.946, CE-IOU vs. CEUS P=0.649, all P>0.05). The four imaging methods had significantly different sensitivities in detecting HCC lesions (Cochran’s Q 27.826, P<0.05). Based on multiple comparison results, the difference between the CE-IOUS results and those of MRI, CEUS, and IOUS was statistically significant.
Table 2
| Diagnosis performance | MRI | CEUS | IOUS | CE-IOUS |
|---|---|---|---|---|
| Sensitivity (%) | 75.4 (43/57) | 82.5 (47/57) | 75.4 (43/57) | 96.5 (55/57) |
| PPV (%) | 95.6 (43/45) | 92.2 (47/51) | 76.8 (43/56) | 91.7 (55/60) |
| Specificity (%) | 86.7 (13/15) | 73.3 (11/15) | 13.3 (1/13) | 66.7 (10/15) |
| NPV (%) | 48.1 (13/27) | 52.4 (11/21) | 12.5 (2/16) | 83.3 (10/12) |
| Accuracy (%) | 77.8 (56/72) | 80.6 (58/72) | 62.5 (45/72) | 90.3 (65/72) |
| Y | 0.621 | 0.556 | 0.112 | 0.632 |
| AUC (95% CI) | 0.811 (0.701–0.893) | 0.779 (0.666–0.868) | 0.556 (0.434–0.673) | 0.816 (0.707–0.897) |
MRI, magnetic resonance imaging; CEUS, contrast-enhanced ultrasonography; IOUS, intraoperative ultrasonography; CE-IOUS, contrast-enhanced intraoperative ultrasonography; PPV, positive predictive value; NPV, negative predictive value; Y, Youden index; AUC, area under the curve; CI, confidence interval.
Of the 25 patients, IOUS and CE-IOUS detected occult nodules in eight patients. In these eight patients, 13 nodules were detected on MRI, 18 on CEUS, 19 on IOUS, and 28 on CE-IOUS. A total of 15 occult nodules were identified by CE-IOUS.
In patient No. 2, a nodule, 4 mm in diameter and located in segment 3, was diagnosed as a cyst by MRI, whereas preoperative CEUS and CE-IOUS confirmed the lesion as HCC. The nodule was eliminated by open RFA and histopathologically confirmed as HCC.
In patient No. 3, MRI, preoperative CEUS, and IOUS failed to detect a nodule with a 6 mm diameter located at segment 8. Meanwhile, the Kupffer phase exhibited a nodule with a clear edge. Laparoscopic RFA was used to ablate the lesion, which was confirmed as HCC by histopathology (Figures 2,3).
In patient No. 10, CEUS identified three lesions, approximately 1 cm in diameter, in segments 3, 6, and 8, whereas MRI and IOUS could not be performed. CE-IOUS detected an additional lesion with a 6 mm diameter located in segment 8. Laparoscopic RFA was used to ablate the additional lesion, which was histopathologically confirmed as HCC.
In patient No. 12, two new lesions in segments 6 and 7 were identified by CE-IOUS during surgery and were considered suspicious DNs and RNs, whereas preoperative examinations failed to detect these lesions. Laparoscopic RFA was performed to ablate the two lesions, which were histopathologically confirmed as HCC at segment 6 and RN at segment 7.
In patient No. 16, IOUS and CE-IOUS detected a nodule located in segment 7, which was diagnosed as an RN; MRI and CEUS had failed to detect this nodule. Although a new lesion was detected and considered a benign lesion, the findings did not alter the course of planned management.
In patient No. 21, CEUS detected an isoechoic lesion with a 9 mm diameter at segment 4, which was considered suspicious RN. During surgery, two new lesions were detected in segments 3 and 4 by IOUS and CE-IOUS, confirmed as HCC by CE-IOUS. Three patients with HCC and two additional patients with HCC underwent laparoscopic RFA and laparoscopic hepatectomy, respectively.
In patient No. 22, a nodule located in segment 7 was identified as suspicious HCC by CEUS but not MRI. Both IOUS and CE-IOUS detected the lesion, which was confirmed as HCC. The new discovery-modified scheduled strategy and percutaneous RFA at segment 7 were used to ablate the additional nodule, which was histopathologically confirmed as HCC.
In patient No. 25, IOUS and CE-IOUS detected four extra nodules located in segments 4 and 8, which were considered HCC by CE-IOUS. Two new lesions in segments 6 and 7 were detected using CE-IOUS, and were confirmed as DN. One HCC nodule was detected by MRI and CEUS; four extra HCC nodules were detected by IOUS and CE-IOUS; and two additional DN nodules were detected by CE-IOUS. The six new nodules were ablated by laparotomy RFA.
Discussion
Multiple and complex nodules are frequently detected in the background of cirrhosis with HCC. Therefore, accurate identification of multiple nodules is crucial, given that the planned management needs to be immediately modified following nodule detection. The new FLL may be invisible with routine imaging approaches during the canceration course of HCC (10). Compared with computed tomography and MRI, IOUS has a high spatial resolution, achieved through a high-frequency linear array probe, and has a sensitivity for detecting FLL. The echogenicity of lesions is generally altered, especially after operation, embolization, or RFA, making it difficult to identify typical signs of HCC nodules. CE-IOUS has a high spatial resolution, and the visualization of blood flow through microbubbles has unique characteristics (11,12). As a second generation medium, Sonazoid allows postvascular phase imaging (Kupffer phase) because the microbubbles of Sonazoid that are taken up by Kupffer cells last up to 60 minutes, providing enough time to detect invisible lesions, whereas other kinds of contrast mediums such as SonoVue probably cannot enable such imaging. Therefore, CE-IOUS using Sonazoid seems to be the best choice to investigate a whole liver with the aim of clearly depicting liver tumors and identifying new tumors that could not be detected at preoperative imaging, as well as guiding needle biopsy and tumor ablation (13). Owing to defects in Kupffer cells in malignant tumors, the Kupffer phase with CE-IOUS exhibits a high contrast between malignant tumors and hepatic tissue (14,15). Therefore, the characteristics of the Kupffer phase of CE-IOUS with Sonazoid can contribute to the identification of occult and small nodules and influence the surgical strategy (13,16,17). Meanwhile, CE-IOUS does not easily visualize certain areas of the whole liver, such as subdiaphragmatic segment VIII, especially through laparoscopic CEUS. In addition, experienced inspectors are required to obtain high-quality CEUS scans. Sonazoid CE-CEUS can effectively guide HCC ablation due to continuous demonstration of the Kupffer phase that is not depicted on IOUS, whereas MRI cannot achieve this aim (18).
In the current study, six of the 25 patients had 10 occult HCC nodules newly detected upon CE-IOUS. Three of the 25 patients had 2 RN and 3 DN lesions newly detected following CE-IOUS. The preoperatively scheduled surgical strategies were modified owing to these newly detected lesions. The treatment strategies were altered in seven of eight patients, including five removals by laparoscopic RFA, one removal performed using open RFA, and one percutaneous RFA. Of the eight patients, one patient had a single RN lesion, and the preoperatively planned surgery for this patient was maintained. CE-IOUS impacted the planned surgical approach in 32% (8/25) of patients with tumors. Finally, CE-IOUS altered the surgical strategy in 28% (7/25) of patients owing to the detection of new lesions, which was consistent with the rate reported previously (13,19-21).
Typically, HCC has irregular hyperenhancement in the arterial phase, increasing washout in the portal phase, and hypoenhancement in the Kupffer phase (22,23). Depending on the typical HCC, a diagnostic accuracy of up to 100% can be achieved, whereas an accuracy of ≥80% can be achieved in most patients with HCC (24,25). Among the seven nodules detected by IOUS, six were diagnosed as HCC, and one nodule was verified as an RN by CE-IOUS. Among the 10 extra occult nodules discovered in the Kupffer phase, eight were diagnosed as HCC and two as DN. One lesion (<1 cm) misdiagnosed as DN by CE-IOUS was histopathologically confirmed as HCC and two lesions misdiagnosed as HCC by CE-IOUS were histopathologically confirmed as not cancerous and DN. The imaging characteristics of small lesions for HCC are atypical and difficult to detect in the background of liver cirrhosis. For example, the classification of DN, atypical hemangiomas, and small RNs in the background of cirrhosis can be challenging (18,26). In addition, differentiating between high-grade DN and early HCC with imaging is a challenging, even when using Sonazoid CEUS (9).
Based on our findings, CE-IOUS exhibited the highest sensitivity for assessing HCC, albeit not statistically superior to MRI and CEUS. For detecting HCC lesions, CE-IOUS showed statistically significant differences when compared with the other three imaging methods. Kupffer phase imaging for HCC detection, which depends on the tumor hemodynamics, may be superior to the other three imaging methods (27). Given that the duration of the Kupffer phase was substantially longer than that of the arterial phase, an overall evaluation of the whole hepatic tissue was needed by the Kupffer phase (20). Hypo-enhanced nodules in the Kupffer phase were recommended for surgical resection. Therefore, CE-IOUS was more sensitive for detecting HCC lesions, even very small tumors with a diameter of 2 mm, than other kinds of imaging methods in the complex background of cirrhosis, which occurred prior to metastatic liver tumors (13). Collectively, our findings suggest that the Kupffer phase of CE-IOUS may be sufficient for the preoperative assessment of patients with HCC.
The limitations of our study are as follows: first, the number of cases in our study was relatively small. Although our sample included only 25 patients, we evaluated 72 lesions and obtained positive results, which is meaningful for patients with HCC. Second, our study was a retrospective study with a single-center design. Third, CEUS and CE-IOUS have inherent drawbacks, such as a short arterial phase, potential effects on tumor location, and motion artifacts. Therefore, additional multicenter studies with larger samples are needed to establish the impact of tumor size on observed results.
Conclusions
CE-IOUS may be superior to other imaging methods in detecting HCC lesions in cirrhosis. The Kupffer phase of CE-IOUS demonstrated high sensitivity for intraoperatively identifying occult lesions, especially HCC lesions. Thus, it can be used as an essential tool for patients with HCC to guide and modify surgical strategies.
Acknowledgments
Funding: This study was supported by
Footnote
Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-671/rc
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-671/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This retrospective study was approved by the Ethics Committee of Beijing Hospital (ethical approval No. 2021BJYYEC-190-02) and informed consent was provided by all the included patients. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Villanueva A. Hepatocellular Carcinoma. N Engl J Med 2019;380:1450-62. [Crossref] [PubMed]
- Hao XS, Wang PP, Chen KX, Li Q, He M, Yu SB, Guo ZY, Perruccio A, Rohan T. Twenty-year trends of primary liver cancer incidence rates in an urban Chinese population. Eur J Cancer Prev 2003;12:273-9. [Crossref] [PubMed]
- da Silva NPB, Beyer LP, Hottenrott MC, Hackl C, Schlitt HJ, Stroszczynski C, Wiggermann P, Jung EM. Efficiency of contrast enhanced ultrasound for immediate assessment of ablation status after intraoperative radiofrequency ablation of hepatic malignancies. Clin Hemorheol Microcirc 2017;66:357-68. [Crossref] [PubMed]
- Minami T, Minami Y, Chishina H, Arizumi T, Takita M, Kitai S, Yada N, Inoue T, Hagiwara S, Ueshima K, Nishida N, Kudo M. Combination guidance of contrast-enhanced US and fusion imaging in radiofrequency ablation for hepatocellular carcinoma with poor conspicuity on contrast-enhanced US/fusion imaging. Oncology 2014;87:55-62. [Crossref] [PubMed]
- Donadon M, Costa G, Torzilli G. State of the art of intraoperative ultrasound in liver surgery: current use for staging and resection guidance. Ultraschall Med 2014;35:500-11; quiz 512-3. [Crossref] [PubMed]
- Sato K, Tanaka S, Mitsunori Y, Mogushi K, Yasen M, Aihara A, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Tanaka H, Arii S. Contrast-enhanced intraoperative ultrasonography for vascular imaging of hepatocellular carcinoma: clinical and biological significance. Hepatology 2013;57:1436-47. [Crossref] [PubMed]
- Joo I. The role of intraoperative ultrasonography in the diagnosis and management of focal hepatic lesions. Ultrasonography 2015;34:246-57. [Crossref] [PubMed]
- Terminology of nodular hepatocellular lesions. Hepatology 1995;22:983-93. [Crossref] [PubMed]
- Claudon M, Dietrich CF, Choi BI, Cosgrove DO, Kudo M, Nolsøe CP, et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver--update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultraschall Med 2013;34:11-29. [Crossref] [PubMed]
- Gaiani S, Celli N, Piscaglia F, Cecilioni L, Losinno F, Giangregorio F, Mancini M, Pini P, Fornari F, Bolondi L. Usefulness of contrast-enhanced perfusional sonography in the assessment of hepatocellular carcinoma hypervascular at spiral computed tomography. J Hepatol 2004;41:421-6. [Crossref] [PubMed]
- Torzilli G, Palmisano A, Del Fabbro D, Marconi M, Donadon M, Spinelli A, Bianchi PP, Montorsi M. Contrast-enhanced intraoperative ultrasonography during surgery for hepatocellular carcinoma in liver cirrhosis: is it useful or useless? A prospective cohort study of our experience. Ann Surg Oncol 2007;14:1347-55. [Crossref] [PubMed]
- Nakano H, Ishida Y, Hatakeyama T, Sakuraba K, Hayashi M, Sakurai O, Hataya K. Contrast-enhanced intraoperative ultrasonography equipped with late Kupffer-phase image obtained by sonazoid in patients with colorectal liver metastases. World J Gastroenterol 2008;14:3207-11. [Crossref] [PubMed]
- Li C, Liu Y, Xu J, Song J, Wu M, Chen J. Contrast-Enhanced Intraoperative Ultrasonography with Kupffer Phase May Change Treatment Strategy of Metastatic Liver Tumors - A Single-Centre Prospective Study. Ther Clin Risk Manag 2021;17:789-96. [Crossref] [PubMed]
- Elsayes KM, Kielar AZ, Agrons MM, Szklaruk J, Tang A, Bashir MR, Mitchell DG, Do RK, Fowler KJ, Chernyak V, Sirlin CB. Liver Imaging Reporting and Data System: an expert consensus statement. J Hepatocell Carcinoma 2017;4:29-39. [Crossref] [PubMed]
- Tanaka M, Nakashima O, Wada Y, Kage M, Kojiro M. Pathomorphological study of Kupffer cells in hepatocellular carcinoma and hyperplastic nodular lesions in the liver. Hepatology 1996;24:807-12. [Crossref] [PubMed]
- Maruyama H, Sekimoto T, Yokosuka O. Role of contrast-enhanced ultrasonography with Sonazoid for hepatocellular carcinoma: evidence from a 10-year experience. J Gastroenterol 2016;51:421-33. [Crossref] [PubMed]
- Xu J, Liu Y, Wu M, Song J, Li C. Role of Sonazoid enhanced ultrasound assistant laparoscopic radiofrequency ablation in treating liver malignancy-A single-center retrospective cohort study. Cancer Med 2023;12:9075-84. [Crossref] [PubMed]
- Pace C, Nardone V, Roma S, Chegai F, Toti L, Manzia TM, Tisone G, Orlacchio A. Evaluation of Contrast-Enhanced Intraoperative Ultrasound in the Detection and Management of Liver Lesions in Patients with Hepatocellular Carcinoma. J Oncol 2019;2019:6089340. [Crossref] [PubMed]
- Ellsmere J, Kane R, Grinbaum R, Edwards M, Schneider B, Jones D. Intraoperative ultrasonography during planned liver resections: why are we still performing it? Surg Endosc 2007;21:1280-3. [Crossref] [PubMed]
- Lu Q, Luo Y, Yuan CX, Zeng Y, Wu H, Lei Z, Zhong Y, Fan YT, Wang HH, Luo Y. Value of contrast-enhanced intraoperative ultrasound for cirrhotic patients with hepatocellular carcinoma: a report of 20 cases. World J Gastroenterol 2008;14:4005-10. [Crossref] [PubMed]
- Gong NM, Yin HH, Cai WH, Li QW, Wang JX, Gu CY, Wang YF, Wu J, Zhang YF. IOUS and CE-IOUS during hepatic resection for patients with hepatocellular carcinoma in liver cirrhosis1. Clin Hemorheol Microcirc 2019;71:483-98. [Crossref] [PubMed]
- Quaia E, Calliada F, Bertolotto M, Rossi S, Garioni L, Rosa L, Pozzi-Mucelli R. Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic performance and confidence. Radiology 2004;232:420-30. [Crossref] [PubMed]
- Nicolau C, Vilana R, Catalá V, Bianchi L, Gilabert R, García A, Brú C. Importance of evaluating all vascular phases on contrast-enhanced sonography in the differentiation of benign from malignant focal liver lesions. AJR Am J Roentgenol 2006;186:158-67. [Crossref] [PubMed]
- Seitz K, Bernatik T, Strobel D, Blank W, Friedrich-Rust M, Strunk H, Greis C, Kratzer W, Schuler A. Contrast-enhanced ultrasound (CEUS) for the characterization of focal liver lesions in clinical practice (DEGUM Multicenter Trial): CEUS vs. MRI--a prospective comparison in 269 patients. Ultraschall Med 2010;31:492-9. [Crossref] [PubMed]
- Strobel D, Bernatik T, Blank W, Schuler A, Greis C, Dietrich CF, Seitz K. Diagnostic accuracy of CEUS in the differential diagnosis of small (≤ 20 mm) and subcentimetric (≤ 10 mm) focal liver lesions in comparison with histology. Results of the DEGUM multicenter trial. Ultraschall Med 2011;32:593-7. [Crossref] [PubMed]
- Wu W, Chen M, Yan K, Dai Y, Yin S, Yang W, Fan Z. Evaluation of contrast-enhanced ultrasound for diagnosis of dysplastic nodules with a focus of hepatocellular carcinoma in liver cirrhosis patients. Chin J Cancer Res 2015;27:83-9. [Crossref] [PubMed]
- Mitsunori Y, Tanaka S, Nakamura N, Ban D, Irie T, Noguchi N, Kudo A, Iijima H, Arii S. Contrast-enhanced intraoperative ultrasound for hepatocellular carcinoma: high sensitivity of diagnosis and therapeutic impact. J Hepatobiliary Pancreat Sci 2013;20:234-42. [Crossref] [PubMed]
