TY - JOUR
AU - Kokudo, N
AB - Abstract Background Intraoperative ultrasonography (IOUS) is considered the standard for the identification of liver metastases. Use of lipid-stabilized perfluorobutane microbubbles as an ultrasound contrast agent may improve this. The value of contrast-enhanced IOUS (CE-IOUS) in enumerating colorectal liver metastases was studied here. Methods CE-IOUS was performed in consecutive resections for colorectal liver metastases in 2007–2010. All patients underwent preoperative computed tomography. Magnetic resonance imaging was not carried out routinely. Conventional intraoperative examination including IOUS, and CE-IOUS with peripherally injected contrast were performed. The histopathological findings and 6-month follow-up images were used as the reference standard. Results The study group of 102 patients had a total of 315 lesions identified on preoperative imaging (2·4 lesions per operation; 129 operations). Conventional intraoperative examination including IOUS identified 350 lesions (2·7 per operation). CE-IOUS identified 370 lesions (2·9 per operation). The sensitivity, specificity and accuracy of CE-IOUS were 97·1, 59·1 and 93·2 per cent respectively. The CE-IOUS findings altered the surgical plan in 19 operations (14·7 per cent). Conclusion CE-IOUS provided additional information to that obtained using contemporary preoperative imaging and conventional intraoperative examinations. Introduction The liver remnant is the most frequent site of recurrence following resection of colorectal liver metastases (CLMs)1. These recurrent foci may have been present but undetected at surgery because of their small size. Intraoperative ultrasonography (IOUS) may identify at least one additional malignant lesion in 10 per cent of patients2. Furthermore, the preoperative surgical plan may be changed in one-fifth to one-third based on the IOUS findings3,4. Therefore, IOUS is considered the standard for the final detection and enumeration of liver metastases5–7. Second-generation contrast agents have further improved the sensitivity of contrast-enhanced IOUS (CE- IOUS)8,9. Two widely used contrast agents for ultrasound imaging, perfluoropropane microbubbles (Definity®; Lantheus Medical Imaging, Billerica, Massachusetts, USA) and sulphur-hexafluoride microbubbles (SonoVue®; Bracco, Milan, Italy), are both pure intravascular contrast agents. Perfluorobutane microbubbles (Sonazoid®; GE Healthcare, Oslo, Norway) represent a second-generation contrast agent that has the peculiarity of accumulating in hepatic Kupffer cells, thereby providing a parenchyma-specific image10. There have been reports of CE-IOUS using this agent in the clarification of CLM anatomy11–13. The present study tested the utility of this approach. Methods This prospective study examined consecutive hepatic resections for CLMs in the Hepato-Biliary-Pancreatic Surgery Division of the University of Tokyo between 2007 and 2010. Conventional abdominal ultrasonography from the body surface and computed tomography (CT) were performed in all patients. Contrast-enhanced ultrasonography from the body surface was not performed routinely. Magnetic resonance imaging (MRI) was carried out mainly in patients who were allergic to iodinated contrast medium. All preoperative imaging was performed within 6 weeks of surgery. Written informed consent was obtained from all patients, and the data analysis was approved by the institutional review board. This study was registered with the Clinical Trials Registry managed by the University Hospital Medical Information Network in Japan (registration ID: UMIN000001053). Preoperative imaging Preoperative abdominal ultrasonography was performed using the ultrasound system Prosound α10 (Hitachi-Aloka Medical, Tokyo, Japan). CT was performed using equipment with 64 detector rows (Aquilion 64, Toshiba Medical, Tokyo, Japan; LightSpeed VCT, GE Medical Systems, Milwaukee, Wisconsin, USA). The collimation, pitch factor, rotation time and tube voltage were 32 × 1 mm and 64 × 0·65 mm, 0·656 and 0·984, both 0·5 s and both 120 kV, for Aquilion 64 and LightSpeed VCT respectively. Scanned images were obtained in 2–2·5-mm sections. An injection of non-ionic contrast material at 2 ml per kg bodyweight was given for enhanced imaging. MRI was performed using a 1·5-T system (Signa HDX 1·5 T; GE Medical Systems). The dynamic study was performed using the liver acquisition with volume acceleration (LAVA) sequence. During the dynamic study, patients received 25 mol/kg (0·1 ml/kg) gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA). After the dynamic study, hepatobiliary phase imaging was obtained using the LAVA sequence 20 min after the injection. Conventional intraoperative examination and contrast-enhanced intraoperative ultrasonography Conventional intraoperative examinations consisted of surgical inspection, palpation and IOUS. The fundamental B-mode IOUS and CE-IOUS examinations were performed using the ultrasound system Prosound α10. UST-9132 (Aloka), a microconvex probe with a frequency of 3·75 MHz, was used for IOUS, and UST-9133 for CE-IOUS. After laparotomy, abdominal and pelvic explorations were carried out to confirm the absence of distant metastases. Next, the liver was mobilized for inspection and palpation. IOUS was then used to confirm the preoperative diagnosis and to search for new tumours. Perfluorobutane microbubbles were injected at a dose of 0·12 µl microbubbles per kg bodyweight through a peripheral vein. The vascularity of one lesion was examined for approximately 1 min after the injection (vascular phase). Approximately 15 min later, ultrasonic observation of the whole liver was performed; this period was defined as the ‘Kupffer phase’. Perfluorobutane microbubbles were taken up by the Kupffer cells and enhanced the contrast of the liver parenchyma. Therefore, tumours lacking Kupffer cells became visible as hypoechoic, regardless of the tumour pattern observed by IOUS. During the pause after the vascular phase, surgical procedures that would not influence the subsequent CE-IOUS examination were allowed. The contrast effect lasted for at least 30 min, unlike the effect of sulphur-hexafluoride microbubbles and perfluoropropane microbubbles10. A real-time B-mode image was displayed simultaneously next to the CE-IOUS image (Fig. 1). All ultrasound procedures were done by one of three investigators who each had over 10 years of experience with IOUS. Investigators were aware of information from preoperative imaging and conventional intraoperative examinations including IOUS. Fig. 1 Open in new tabDownload slide Images obtained during contrast-enhanced intraoperative ultrasonography (CE-IOUS): a normal mode, b harmonic mode; both images were obtained simultaneously. The lesion was clearly detected using CE-IOUS The reference standard consisted of histopathological findings for resected specimens and the results of follow-up studies using CT and/or MRI carried out within 3–6 months after operation. Tumours of uncertain nature were followed up for 6 months after surgery. A final diagnosis of malignancy was made only for tumours that had apparently grown during this interval. All the detected tumours were counted, and the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the preoperative imaging studies, conventional intraoperative examinations and CE-IOUS were compared. The impact of CE-IOUS on surgical decision-making was evaluated with special emphasis on the effect of preceding MRI. Statistical analysis Statistical analyses were performed using the Wilcoxon rank sum test. The McNemar test was used to compare diagnostic abilities between two imaging examinations. Calculations were done using JMP® 8.0 computer software (SAS Institute, Cary, North Carolina, USA). Results A total of 129 operations in 102 patients (median age 63·0 (range 36–88) years; 67 men and 35 women) were included in the study. During the preoperative evaluation, staging was done with CT alone before 66 operations (51·2 per cent), MRI alone before three (2·3 per cent), and with both CT and MRI before 60 procedures (46·5 per cent). Gd-EOB-DTPA MRI was used before 55 operations (42·6 per cent), supraparamagnetic iron oxide-based MRI before six, and gadolinium-enhanced MRI before two procedures. Preoperative chemotherapy had been administered before 50 operations (38·8 per cent). Some 381 lesions (mean(s.d.) 3·0(2·7) per operation) were diagnosed as malignant based on the reference standards. Preoperative imaging correctly identified 315 lesions (2·4(2·0) per operation), conventional intraoperative examinations identified 350 (2·7(2·5) per operation) and CE-IOUS identified 370 (2·9(2·5) per operation) (Fig. 2). A statistically significant increase was observed between sequential groups (CE-IOUS versus conventional intraoperative examination, P < 0·001; conventional intra- operative examination versus preoperative imaging, P < 0·001). The diagnostic performance of each examination is summarized in Table 1. The accuracy of CE-IOUS was significantly greater than that of conventional intraoperative examination (93·2 versus 87·3 per cent; odds ratio 11·0, 95 per cent confidence interval 2·7 to 96·5; P < 0·001). Fig. 2 Open in new tabDownload slide Relationships between identified lesions and each examination, including preoperative imaging, conventional intraoperative examination, contrast-enhanced intraoperative ultrasonography (CE-IOUS) and the reference standard, analysed on a lesion-by-lesion basis Table 1 Diagnostic performance of preoperative imaging, conventional intraoperative examination and contrast-enhanced intraoperative ultrasonography . Preoperative imaging* . Conventional intraoperative imaging . CE-IOUS . Sensitivity (%) 82·7 (315 of 381) 91·9 (350 of 381) 97·1 (370 of 381) Specificity (%) 59·1 (26 of 44) 47·7 (21 of 44) 59·1 (26 of 44) Positive predictive value (%) 94·6 (315 of 333) 93·8 (350 of 373) 95·4 (370 of 388) Negative predictive value (%) 28·3 (26 of 92) 40·4 (21 of 52) 70·3 (26 of 37) Accuracy (%) 80·2 (341 of 425) 87·3 (371 of 425) 93·2 (396 of 425) . Preoperative imaging* . Conventional intraoperative imaging . CE-IOUS . Sensitivity (%) 82·7 (315 of 381) 91·9 (350 of 381) 97·1 (370 of 381) Specificity (%) 59·1 (26 of 44) 47·7 (21 of 44) 59·1 (26 of 44) Positive predictive value (%) 94·6 (315 of 333) 93·8 (350 of 373) 95·4 (370 of 388) Negative predictive value (%) 28·3 (26 of 92) 40·4 (21 of 52) 70·3 (26 of 37) Accuracy (%) 80·2 (341 of 425) 87·3 (371 of 425) 93·2 (396 of 425) * Computed tomography in all patients and magnetic resonance imaging in 48·8 per cent. CE-IOUS, contrast-enhanced intraoperative ultrasonography. Open in new tab Table 1 Diagnostic performance of preoperative imaging, conventional intraoperative examination and contrast-enhanced intraoperative ultrasonography . Preoperative imaging* . Conventional intraoperative imaging . CE-IOUS . Sensitivity (%) 82·7 (315 of 381) 91·9 (350 of 381) 97·1 (370 of 381) Specificity (%) 59·1 (26 of 44) 47·7 (21 of 44) 59·1 (26 of 44) Positive predictive value (%) 94·6 (315 of 333) 93·8 (350 of 373) 95·4 (370 of 388) Negative predictive value (%) 28·3 (26 of 92) 40·4 (21 of 52) 70·3 (26 of 37) Accuracy (%) 80·2 (341 of 425) 87·3 (371 of 425) 93·2 (396 of 425) . Preoperative imaging* . Conventional intraoperative imaging . CE-IOUS . Sensitivity (%) 82·7 (315 of 381) 91·9 (350 of 381) 97·1 (370 of 381) Specificity (%) 59·1 (26 of 44) 47·7 (21 of 44) 59·1 (26 of 44) Positive predictive value (%) 94·6 (315 of 333) 93·8 (350 of 373) 95·4 (370 of 388) Negative predictive value (%) 28·3 (26 of 92) 40·4 (21 of 52) 70·3 (26 of 37) Accuracy (%) 80·2 (341 of 425) 87·3 (371 of 425) 93·2 (396 of 425) * Computed tomography in all patients and magnetic resonance imaging in 48·8 per cent. CE-IOUS, contrast-enhanced intraoperative ultrasonography. Open in new tab Only CE-IOUS correctly diagnosed 21 lesions in 15 operations (11·6 per cent): 19 malignant lesions in 13 operations (10·1 per cent) and two benign lesions in two operations (1·6 per cent). CE-IOUS identified all but two of the tumours detected by conventional intraoperative examination. In addition, CE-IOUS was able to detect three malignant lesions in two operations (2·3 per cent) that were detected using preoperative imaging but not by conventional intraoperative examination. The total number of tumours in patients with new tumour detected by CE-IOUS alone was significantly higher than in the remaining patients (mean 5·2 versus 2·7; P = 0·002). Non-anatomical limited resections were performed in 84 operations (65·1 per cent), anatomical plus partial limited resections in 28 (21·7 per cent) and anatomical resections in 17 (13·2 per cent). None of the patients underwent local ablation therapy. Only CE-IOUS altered the intended surgery. The plan changed in 19 operations (14·7 per cent); an additional hepatic resection was performed in seven operations, the planned resection was cancelled because tumours had been misdiagnosed as malignant based on preoperative imaging in five operations, and the planned resection lines were altered in seven operations. CE-IOUS enabled better visualization of the tumour margins in all patients, even after preoperative chemotherapy (Figs 3 and 4). The surgical plans were altered more often in patients who received preoperative chemotherapy than in those who did not: 11 (22 per cent) of 50 operations versus eight (10 per cent) of 79 (P = 0·071). Fig. 3 Open in new tabDownload slide Ultrasonograms of a metastatic focus after chemotherapy. a The tumour (T) appeared to be located close to the left hepatic vein (LHV) when observed using fundamental B-mode imaging because of an unclear border. b Harmonic mode imaging clearly demonstrated a sufficient distance between the tumour border and the LHV Fig. 4 Open in new tabDownload slide Ultrasonograms of a metastatic focus after chemotherapy. a The tumour (T) was not clearly visualized using fundamental B-mode imaging. b Harmonic mode imaging clearly demonstrated tumour invasion of the right hepatic vein (RHV), which was subsequently divided In relation to MRI findings, the rate of detection of tumours by CE-IOUS alone tended to be lower for operations preceded by Gd-EOB-DTPA MRI: three (5 per cent) of 55 versus ten (14 per cent) of 74 procedures with and without preoperative MRI respectively (P = 0·153). The rate of alteration of the planned surgical procedure resulting from CE-IOUS findings showed the same tendency: five (9 per cent) of 55 versus 14 (19 per cent) of 74 (P = 0·139). All tumours detected by MRI were identified by CE-IOUS. No severe adverse events occurred during or after the administration of perfluorobutane microbubbles. The additional cost of using one vial of this agent was € 120 (US $ 160). Discussion CE-IOUS using perfluorobutane microbubbles was more sensitive for diagnosing CLMs than most imaging modalities and conventional intraoperative examinations including IOUS. Improved contrast between the tumour and the surrounding parenchyma was an important advantage9,14. A policy of resecting multiple hepatic metastases with a minimal margin has been widely accepted15. In the present study only CE-IOUS altered planned resection lines, mainly because of visualization of the presence or absence of vascular invasion. This feature is very important for multiple non-anatomical limited liver resections, in which most of the major intrahepatic vessels are preserved. The more CLMs present, the more tumours detected only by CE-IOUS, as in earlier reports7,9. In the present study, CE-IOUS altered 22 per cent of the surgical plans after preoperative chemotherapy. The side-effects of preoperative chemotherapy include modification of the hepatic parenchymal structure, such as sinusoidal injury and steatohepatitis. These alterations reduce the echogenicity difference between the lesion and the surrounding parenchyma16. Benoist and colleagues17 reported that 83 per cent of liver metastases with a complete response after neoadjuvant chemotherapy were subsequently involved in residual disease or early recurrence, even after IOUS. The increasing use of preoperative chemotherapy18,19 may widen the role of CE-IOUS. The number of newly detected metastases was slightly lower in the present study than reported by Leen and co-workers8 in 2006. These differences may be due to recent advances in diagnostic modalities. In a report by Torzilli and colleagues9, published in 2008, additional metastases were detected in only four patients (8·5 per cent). MRI is now considered the most useful modality for detecting CLM20–23. In the present study the number of new lesions detected only by CE-IOUS and the impact of such imaging on the surgical procedure were decreased if MRI had been carried out before surgery. However, the difference was not statistically significant and all tumours detected by MRI were identified by CE-IOUS. Of note, information gained from these two examinations was not exclusive, but additive. Positron emission tomography (PET)/CT may also be useful for CLM diagnosis24. The authors understand that routine PET/CT would have been better for accurate evaluation of the diagnostic ability of CE-IOUS, but this was not possible in practice because of high medical costs and limitations of the Japanese insurance system. It was expected that CE-IOUS would achieve a higher detection rate than preoperative imaging and conventional IOUS, because the investigators knew the results of the preceding investigations when they performed CE-IOUS. In theory, a true comparison in terms of diagnostic accuracy could be achieved only by blinding the investigators to the previous imaging results. However, this would have been unacceptable ethically, because tumours detected during earlier imaging might have been overlooked by CE-IOUS. Acknowledgements This work was supported by a grants-in-aid of the Public Trust Fund For Clinical Cancer Research. Disclosure: No author has financial interest in the company producing or selling Sonazoid®. 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
TI - Contrast-enhanced intraoperative ultrasonography using perfluorobutane microbubbles for the enumeration of colorectal liver metastases
JO - British Journal of Surgery
DO - 10.1002/bjs.8844
DA - 2012-08-02
UR - https://www.deepdyve.com/lp/oxford-university-press/contrast-enhanced-intraoperative-ultrasonography-using-perfluorobutane-MrLclxNA4D
SP - 1271
EP - 1277
VL - 99
IS - 9
DP - DeepDyve
ER -