Contrast-enhanced ultrasound predicts surgical margin positivity in patients with breast cancer who underwent partial mastectomy

Contrast-enhanced ultrasound predicts surgical margin positivity in patients with breast cancer who underwent partial mastectomy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Contrast-enhanced ultrasound predicts surgical margin positivity in patients with breast cancer who underwent partial mastectomy Hiroaki Shima, Fukino Satomi, Yuta Kondo, Noriko Nishikawa, Satoko Uno, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4212506/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The clinical disadvantage of positive margins in partial mastectomy for patients with operable breast cancer is clear and must be avoided; however, there is still room for improvement. The usefulness of contrast-enhanced ultrasound (CEUS) in diagnosing spread is currently well known. The CEUS-enhanced area for breast cancer tends to be wider than that observed in B-mode and probably includes cancer cells. This study aimed to analyze the correlation between characteristic findings and positive for margins in order to ultimately prove potential usefulness of CEUS in making the surgical margin negative. Methods We retrospectively evaluated the data of 142 patients with breast cancer who underwent partial mastectomy to explore the effect on positive margins when the CEUS staining area was smaller than the B-mode visualized mass (CEUS-B ≤ 0). Results CEUS-B ≤ 0 was associated with significantly more positive margins (p = 0.0467). CEUS-B was also extracted as an independent predictor on multivariate analysis. Conclusions The findings of no enhancement outside the area of visible tumor on CEUS but not visualized outside the area of visible tumor on B-mode might be a risk factor for a positive surgical margins. breast cancer partial mastectomy contrast-enhanced ultrasound surgical margin Figures Figure 1 Figure 2 Figure 3 Introduction Partial mastectomy is a standard procedure in breast cancer surgery; however, studies have demonstrated that the local recurrence rate is approximately twice as high in patients with cancer positive for margins as that in patients with negative margins [1–2]. Therefore, the guidelines recommend ensuring negative margins [3–4]. Another meta-analysis suggested that surgeons should aim to achieve a clear margin of at least 1 mm of invasive breast cancer [5]. Hence, margin clearance remains a definitely important issue for breast surgeons. The current standard diagnosis for the extent of disease is a comprehensive diagnosis based on imaging obtained from magnetic resonance imaging (MRI), mammography, and ultrasonography; however, unfortunately, the rate of positive margins has not reached zero. Several new complementary imaging techniques have been reported as useful modalities in the preoperative spread diagnosis of breast cancer, such as positron emission mammography and contrast-enhanced spectral mammography [6–7]. Positron emission mammography has been reported to have almost a similar diagnostic performance as that of MRI, which is inferior to that of MRI in terms of sensitivity but superior in terms of specificity [8]. The advantage of contrast-enhanced spectral mammography is that its detection ability is comparable to that of MRI, and it is reported to exhibit higher specificity and fewer false positive results than MRI [9]. Because both modalities require imaging in a different position from the surgical position, there are still some issues to be addressed. Despite the advantages and disadvantages of each modality, contrast-enhanced ultrasound (CEUS) is a promising modality among those that are expected to be practical. A study reported that CEUS is potentially useful in the diagnosis of spread, as the enhanced area of CEUS tends to be wider than that of the usual B-mode and closer to the maximum diameter for pathological diagnosis [10]. In the same study, although exploratory, approximately half of the patients exhibited the range of enhancement outside the area of visible tumor on CEUS, but it was not visualized outside the area of visible tumor in cancer cells observed on B-mode pathologically [10]. It might be considered reasonable to include the range of surgically resected specimens. Nevertheless, there are some cases in which the range of enhancement is not wider than the area of visible tumor on B-mode, and it is not clear how this should be interpreted. Because MRI allows the localization of lesions of the entire breast, mapping and resection area settings are often based on this image. Nevertheless, because MRI is often performed in a different body position from the surgical position, misalignment between the images and findings has been a concern in clinical practice [11–15]. This study was designed to explore what aspects of preoperative diagnosis of cancer spread to determine the extent of resection in the breast might be useful in reducing the number of positive margins in partial mastectomy. We focused on patients in whom CEUS did not demonstrate an unusual enhancement when used as additional information to MRI. Patients and Methods Procedures This was a single-center, retrospective observational study conducted to investigate the surgical margin positive rate for patients with breast cancer, who underwent partial mastectomy, using CEUS in addition to B-mode and MRI. Key inclusion criteria were breast cancer diagnosed pathologically, patients who underwent partial mastectomy, and patients who underwent examination for the extent of the cancerous lesion to be added to the resection area using CEUS and B-mode. Typically, the patient was positioned on the operating table rotated to elevate the affected side and the head erect position as the surgical position under anesthesia in the operating room. Patients were excluded if they met any of the following criteria: patients undergoing any preoperative systemic therapy, patients undergoing preoperative irradiation, and patients who had requested not to participate in this study by written regretted opt-out. MRI and ultrasound (US) were performed to evaluate the extent of the cancerous lesion before surgery. In the operating room, a comprehensive evaluation was conducted with reference to the MRI and US already taken, and then the CEUS and B-mode was performed in the surgical position to confirm the details of the spread. To evaluate the primary breast tumor, MRI was performed with frequency-selective fat suppression (e-THRIVE) and maximum intensity projection imaging, and the contrast effect range was judged as a viable lesion (Ingenia 3.0T Omega HP release 5.41, Philips Healthcare). US was performed by laboratory technicians who reported the imaging data in clinical documents using Aplio 700, Aplio a550 (Canon), and LOGIQ E9 (GE Healthcare Japan). The technique for partial mastectomy involves resection of a 1.5 cm safety margin in all lateral directions centered on the area to be enhanced by CEUS, with reference to the MRI and US already performed. Furthermore, on the chest wall side, the pectoralis major fascia included a layer for resection, whereas the pectoralis major muscle was preserved. Xeroradiography was performed in a routine manner on the excised specimens to confirm that they had been appropriately resected, and intraoperative histological examination of the three transected margins was also performed to ensure that they were appropriately resected. Pathological findings included the diameter of the remnant lesions in the surgical pathology report prepared by pathologists. The excised specimens were sectioned in the nipple–tumor orthogonal direction into 5- to 7-mm sections. The extent of the lesions on the sections was evaluated by pathologists. The specimens were photographed side by side in sequence and mapped by a pathologist based on the corresponding pathological spread of the cancer. Positive margins were defined as proximity of the in situ lesion to the margins within 2 mm or exposure of invasive cancer [3–4]. We analyzed how the relationship between the maximum transverse diameter of the CEUS-enhanced area and the maximum transverse diameter of the B-mode is involved in causing positive margins. The study protocol was approved by the Clinical Trial Center of Sapporo Medical University, Japan, and was conducted according to the Declaration of Helsinki and the Ethical Principles for Medical Research Involving Human Subjects (Ministry of Health, Labour and Welfare). This study was also approved by the Clinical Research Review Committee of the hospital and by the hospital director and is registered with UMIN-CTR (UMIN000053287). Statistical analysis To explore whether the CEUS-enhanced area was smaller or larger than visible on B-mode might be related to the surgical positive rate, a χ 2 square test was performed for the surgical positive rate in patients with and without CEUS-B ≤ 0. A χ 2 test was also conducted for MRI-B ≤ 0 in the same manner. Two-sided P < 0.05 was considered statistically significant. Odds ratios and 95% confidence intervals for surgical margin positivity for each clinicopathological factor, including CEUS-B ≤ 0 and MRI-B ≤ 0, were calculated by nominal logistic analysis. All statistical analyses were conducted using JMP 16.0 (SAS Institute Inc., Cary NC, USA). The receiver operating characteristic (ROC) curve, which indicates the accuracy of the CEUS diagnosis for a positive margin, was obtained by varying the cutoff according to the US findings. Results Study design Patients with breast cancer who underwent partial mastectomy were enrolled in this study from October 2014 to July 2021. A final sample of 142 patients was analyzed, who had been evaluated by CEUS in operating rooms, who had not undergone previous systemic therapy, and who had not been examined by CEUS (Fig. 1 ). Patient characteristics Table 1 lists the patients’ characteristics. The mean age was 55 years. The maximum preoperative tumor diameter on B-mode US was 29 mm. The largest number of diagnoses histologically was invasive ductal carcinoma (n = 124) followed by ductal carcinoma in situ (n = 9). Regarding the special type, patients were diagnosed with four invasive lobular carcinomas, two mucinous carcinomas, two invasive micropapillary carcinomas, and one apocrine carcinoma. Excluding the nine ductal carcinoma in situ cases, the most common subtype was ER+/HER2 − with 101 cases (71.1%). Frequency of positive margins and details Positive surgical margins were observed in 14 patients, whereas negative margins were observed in 128 patients. Of the 14 positive cases, 8 were within 2 mm of the surgical margin, and all these 8 were in situ lesions. In contrast, six cases were exposed, five were in situ lesions, and one was lobular carcinoma in situ, as demonstrated in Table 2. Figure 2 illustrates a plot of subtracting the maximum diameter of the B-mode from the maximum diameter of the CEUS (the range of enhancement outside the area of visible tumor on CEUS but was not visualized outside the area of visible tumor on B-mode; the x-axis) and the distance to the lateral transection (the y-axis). The black circles indicate cases positive for surgical margin, which tended to be distributed in the range where CEUS-B is < 0. CEUS-B was ≤ 0 in 66 of 142 patients; of these 66 patients, 10 showed positive margins, whereas the remaining 76 showed CEUS-B < 0, and 4 showed positive margins (p = 0.0467). In contrast, 55 of 142 patients had an MRI-B reading of ≤ 0. Of these 55 patients, 4 had positive margins, whereas the remaining 87 showed CEUS-B < 0, and 10 showed positive margins (p = 0.4024). Factors associated with risk for positive disconnections Table 3 shows the results of univariate and multivariate analyses for positive margins. In the univariate analysis, the only significant risk factor for surgical margin positivity was CEUS-B ≤ 0, but not MRI-B and other clinicopathological factors. In terms of B-mode-based imaging diagnosis of tumor extension in operating rooms, a multivariate analysis was performed to compare CEUS and MRI for surgical margin positivity, which indicated CEUS as an independent factor. CEUS-B is a possible predictor of positive surgical margins The ROC curve revealed that a 0.9-mm CEUS-B cutoff of CEUS best served as a surrogate for positive surgical margins, with the area under the curve being 0.7037. Because 0.9 mm may not be clinically meaningful, a sensitivity of 0.7143 and a specificity of 0.4375 were obtained when 0 mm was used as the cutoff (Fig. 3 ). Discussion This study was conducted to explore the usefulness of CEUS in the preoperative diagnosis of breast cancer spread to reduce the number of positive margins in partial mastectomy. In particular, our focus was on unusual enhancement patterns in CEUS. We found a characteristic tendency for patients who did not demonstrate enhancement. When the CEUS-enhanced area was smaller than the range visible on B-mode (CEUS-B ≤ 0), it was the only statistically significant risk factor for positive margins in the univariate analysis. This is also a relatively good area under the curve even for ROC curves, and it might be a predictor of a positive margin. In contrast, when the enhanced area as identified by MRI was smaller than that on the B-mode, it was not a risk factor. It was also extracted as a statistically significant risk factor for positive margins in the multivariate analysis of both. A possible reason for this is the difference in contrast agents. CEUS is a modality that can evaluate lesions and the surrounding hemodynamics in real time [10]. Sonazoid is a second-generation US contrast agent with excellent in vivo stability and resistance to US sound pressure. It is composed primarily of microbubbles and perflubutane gas encapsulated in a film of sodium hydrogenated egg yolk phosphatidylserine [9,16], with a small average particle size of 2–3 µm, and unlike the water-soluble contrast agents used in breast MRI, sonazoid does not leak out of the blood vessel [1, 8–10]. In other words, one reason why MRI did not correlate with positive margins may be that MRI contrast agents cause extravascular seepage and pooling, resulting in a disadvantage when evaluating noncontrasted areas. MRI has previously been reported to be more sensitive and less specific, which may be associated with the abovementioned findings [17]. Using MRI of the liver as an example, negative contrast due to phagocytosis by Kupffer cells is well known. However, in US, the concept or significance of negative contrast remains unclear. For instance, a heterogeneous staining effect is found in a breast cancer mass, but the pathological significance of the nonstaining area is not strictly clear. The advantage of the nonenhanced areas of microbubbles in CEUS is that they do not leak outside the blood vessel, and they may well be negative findings on MRI in areas that are enhanced and masked by extravascular leakage and pooling. Further investigation is warranted for contrast-effective areas on MRI but negative on CEUS. Currently, it is known that it is difficult to achieve enhancement when cardiac output is low, but the effect of the problem is considered to exert a minor impact because the time when the contrast effect is highest was observed in this study. Although some unclear points that require further investigation remain, the lack of enhancement by CEUS, which generally exerts a broad staining effect, may be a vital finding, and more detailed verification is required. Blood flow imaging-based imaging studies suggest that increased blood flow indicates the presence of cancer, but patterns that are not detected by these studies may indicate a spreading condition that does not exhibit increased blood flow. There are several limitations in this study. First, this was a small observational study and bias cannot be eliminated. Second, it is difficult to obtain a perfect match between the imaging plane of each modality. CEUS and B-mode comparisons were performed with both probes fixed at the same site, allowing evaluation of the potentially same imaging plane, whereas the comparison between MRI and B-mode cannot exclude the possibility that positional information differs from imaging derived from other imaging planes. Third, although the difficulty of matching imaging planes also exerts an impact, pathological findings that are not contrasted by CEUS have not been clarified because the situation may be completely different when the slice is changed for pathological verification. Therefore, the rationale for why a noncontrast pattern would result in positive margins must be investigated differently. Conclusion The findings of no enhancement outside the area of visible tumor on CEUS but not visualized outside the area of visible tumor on B-mode might be a risk factor for positive margins, in which the enhancement by CEUS is smaller than that by B-mode. Further details are warranted. Declarations Author contributions: Conceptualization and Methodology: Hiroaki Shima; Formal analysis and investigation: Fukino Satomi, Yuta Kondo, Noriko Nishikawa, Satoko Uno, Asaka Wada and Ai Noda; Writing - original draft preparation: Hiroaki Shima; Writing - review and editing: Daisuke Kyuno, Hidekazu Kameshima and Tosei Ohmura; Resources: Shintaro Sugita, Naoya Yama; Supervision: Ichiro Takemasa. Compliance with Ethical Standards Disclosure of potential conflicts of interest The authors declare no conflicts of interest. Statement of human rights This study adhered to the ethical tenets of the Declaration of Helsinki and Ethical Principles for Medical Research Involving Human Subjects. Itwas approved by the Clinical Trial Center of Sapporo Medical University, Japan, and is registered with UMIN-CTR (UMIN000059628). Informed consent The consent documents approved by the review committee were given to the subjects (352-115), and the need for informed consent was waived in view of the retrospective and observational nature of the study. An opt-out consent process was used, and disclosures were made on the University’s website (https://sapmed-surg1.jp/gairai/optout/). Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. References Shah C, Hobbs BP, Vicini F, Al-Hilli Z, Manyam BV, Verma V, et al. The diminishing impact of margin definitions and width on local recurrence rates following breast-conserving therapy for early-stage invasive cancer: A meta-analysis. Ann Surg Oncol 2020;27:4628-36. Houssami N, Macaskill P, Marinovich ML, Morrow M. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol 2014;21:717-30. Buchholz TA, Somerfield MR, Griggs JJ, El-Eid S, Hammond ME, Lyman GH, et al. Margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer: American Society of Clinical Oncology endorsement of the Society of Surgical Oncology/American Society for Radiation Oncology consensus guideline. J Clin Oncol 2014;32:1502-6. Marinovich ML, Azizi L, Macaskill P, Irwig L, Morrow M, Solin LJ, et al. The association of surgical margins and local recurrence in women with ductal carcinoma in situ treated with breast-conserving therapy: A meta-analysis. Ann Surg Oncol 2016;23:3811-21. Bundred JR, Michael S, Stuart B, Cutress RI, Beckmann K, Holleczek B, et al. Margin status and survival outcomes after breast cancer conservation surgery: prospectively registered systematic review and meta-analysis. BMJ 2022;378:e070346. Liu Q, Wang C, Li P, Liu J, Huang G, Song S. The role of (18)F-FDG PET/CT and MRI in assessing pathological complete response to neoadjuvant chemotherapy in patients with breast cancer: A systematic review and meta-analysis. BioMed Res Int 2016;2016:3746232. Caldarella C, Treglia G, Giordano A. Diagnostic performance of dedicated positron emission mammography using fluorine-18-fluorodeoxyglucose in women with suspicious breast lesions: a meta-analysis. Clin Breast Cancer 2014;14:241-8. Schilling K, Narayanan D, Kalinyak JE, The J, Velasquez MV, Kahn S, et al. Positron emission mammography in breast cancer presurgical planning: comparisons with magnetic resonance imaging. Eur J Nucl Med Mol Imaging 2011;38:23-36. Ali-Mucheru M, Pockaj B, Patel B, Pizzitola V, Wasif N, Stucky CC, et al. Contrast-enhanced digital mammography in the surgical management of breast cancer. Ann Surg Oncol 2016;23(suppl 5):649-55. Shima H, Okuno T, Nakamura T, Noro A, Noma M, Sato M, et al. Comparing the extent of breast cancer tumors through contrast-enhanced ultrasound vs B-mode, opposed with pathology: evergreen study. Breast Cancer 2021;28:405-13. Turnbull L, Brown S, Harvey I, Olivier C, Drew P, Napp V, et al. Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial. Lancet 2010;375:563-71. Sung JS, Li J, Da Costa G, Patil S, Van Zee KJ, Dershaw DD, et al . Preoperative breast MRI for early-stage breast cancer: effect on surgical and long-term outcomes. AJR Am J Roentgenol 2014;202:1376-82. Balleyguier C, Dunant A, Ceugnart L, Kandel M, Chauvet MP, Chérel P, et al. Preoperative breast magnetic resonance imaging in women with local ductal carcinoma in situ to optimize surgical outcomes: results from the randomized Phase III trial IRCIS. J Clin Oncol 2019;37:885-92. Houssami N, Turner RM, Morrow M. Meta-analysis of pre-operative magnetic resonance imaging (MRI) and surgical treatment for breast cancer. Breast Cancer Res Treat 2017;165:273-83. Houssami N, Turner R, Morrow M. Preoperative magnetic resonance imaging in breast cancer: meta-analysis of surgical outcomes. Ann Surg 2013;257:249-55. Miyamoto Y, Ito T, Takada E, Omoto K, Hirai T, Moriyasu F. Efficacy of sonazoid (perflubutane) for contrast-enhanced ultrasound in the differentiation of focal breast lesions: phase 3 multicenter clinical trial. AJR Am J Roentgenol 2014;202:W400-7. Medeiros LR, Duarte CS, Rosa DD, Edelweiss MI, Edelweiss M, Silva FR, et al. Accuracy of magnetic resonance in suspicious breast lesions: a systematic quantitative review and meta-analysis. Breast Cancer Res Treat 2011;126(2):273-85. Tables Tables are available in the Supplementary Files section. Supplementary Files Table1.xlsx Table 1: Patient background data Table2.xlsx Table 2: Pathological margin status of the tumor Table3.xlsx Table 3: Univariate and multivariate analyses of positive margin status Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4212506","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":290001779,"identity":"bccdf283-abef-4ec3-b6ad-c46e0b8b0c5b","order_by":0,"name":"Hiroaki 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17:55:30","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":9557,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e: Pathological margin status of the tumor\u003c/p\u003e","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4212506/v1/8165aaf1d38ab72d4d65ba06.xlsx"},{"id":54995933,"identity":"d960aa1a-49d9-4795-a33b-7ab3ed47d03c","added_by":"auto","created_at":"2024-04-19 17:55:30","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":11071,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e: Univariate and multivariate analyses of positive margin status\u003c/p\u003e","description":"","filename":"Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4212506/v1/14645e98ab79a7f03854aa80.xlsx"}],"financialInterests":"","formattedTitle":"Contrast-enhanced ultrasound predicts surgical margin positivity in patients with breast cancer who underwent partial mastectomy","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePartial mastectomy is a standard procedure in breast cancer surgery; however, studies have demonstrated that the local recurrence rate is approximately twice as high in patients with cancer positive for margins as that in patients with negative margins [1\u0026ndash;2]. Therefore, the guidelines recommend ensuring negative margins [3\u0026ndash;4]. Another meta-analysis suggested that surgeons should aim to achieve a clear margin of at least 1 mm of invasive breast cancer [5]. Hence, margin clearance remains a definitely important issue for breast surgeons. The current standard diagnosis for the extent of disease is a comprehensive diagnosis based on imaging obtained from magnetic resonance imaging (MRI), mammography, and ultrasonography; however, unfortunately, the rate of positive margins has not reached zero. Several new complementary imaging techniques have been reported as useful modalities in the preoperative spread diagnosis of breast cancer, such as positron emission mammography and contrast-enhanced spectral mammography [6\u0026ndash;7]. Positron emission mammography has been reported to have almost a similar diagnostic performance as that of MRI, which is inferior to that of MRI in terms of sensitivity but superior in terms of specificity [8]. The advantage of contrast-enhanced spectral mammography is that its detection ability is comparable to that of MRI, and it is reported to exhibit higher specificity and fewer false positive results than MRI [9]. Because both modalities require imaging in a different position from the surgical position, there are still some issues to be addressed. Despite the advantages and disadvantages of each modality, contrast-enhanced ultrasound (CEUS) is a promising modality among those that are expected to be practical.\u003c/p\u003e \u003cp\u003eA study reported that CEUS is potentially useful in the diagnosis of spread, as the enhanced area of CEUS tends to be wider than that of the usual B-mode and closer to the maximum diameter for pathological diagnosis [10]. In the same study, although exploratory, approximately half of the patients exhibited the range of enhancement outside the area of visible tumor on CEUS, but it was not visualized outside the area of visible tumor in cancer cells observed on B-mode pathologically [10]. It might be considered reasonable to include the range of surgically resected specimens. Nevertheless, there are some cases in which the range of enhancement is not wider than the area of visible tumor on B-mode, and it is not clear how this should be interpreted.\u003c/p\u003e \u003cp\u003eBecause MRI allows the localization of lesions of the entire breast, mapping and resection area settings are often based on this image. Nevertheless, because MRI is often performed in a different body position from the surgical position, misalignment between the images and findings has been a concern in clinical practice [11\u0026ndash;15].\u003c/p\u003e \u003cp\u003eThis study was designed to explore what aspects of preoperative diagnosis of cancer spread to determine the extent of resection in the breast might be useful in reducing the number of positive margins in partial mastectomy. We focused on patients in whom CEUS did not demonstrate an unusual enhancement when used as additional information to MRI.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eProcedures\u003c/h2\u003e \u003cp\u003eThis was a single-center, retrospective observational study conducted to investigate the surgical margin positive rate for patients with breast cancer, who underwent partial mastectomy, using CEUS in addition to B-mode and MRI. Key inclusion criteria were breast cancer diagnosed pathologically, patients who underwent partial mastectomy, and patients who underwent examination for the extent of the cancerous lesion to be added to the resection area using CEUS and B-mode. Typically, the patient was positioned on the operating table rotated to elevate the affected side and the head erect position as the surgical position under anesthesia in the operating room. Patients were excluded if they met any of the following criteria: patients undergoing any preoperative systemic therapy, patients undergoing preoperative irradiation, and patients who had requested not to participate in this study by written regretted opt-out.\u003c/p\u003e \u003cp\u003eMRI and ultrasound (US) were performed to evaluate the extent of the cancerous lesion before surgery. In the operating room, a comprehensive evaluation was conducted with reference to the MRI and US already taken, and then the CEUS and B-mode was performed in the surgical position to confirm the details of the spread. To evaluate the primary breast tumor, MRI was performed with frequency-selective fat suppression (e-THRIVE) and maximum intensity projection imaging, and the contrast effect range was judged as a viable lesion (Ingenia 3.0T Omega HP release 5.41, Philips Healthcare). US was performed by laboratory technicians who reported the imaging data in clinical documents using Aplio 700, Aplio a550 (Canon), and LOGIQ E9 (GE Healthcare Japan).\u003c/p\u003e \u003cp\u003eThe technique for partial mastectomy involves resection of a 1.5 cm safety margin in all lateral directions centered on the area to be enhanced by CEUS, with reference to the MRI and US already performed.\u003c/p\u003e \u003cp\u003eFurthermore, on the chest wall side, the pectoralis major fascia included a layer for resection, whereas the pectoralis major muscle was preserved. Xeroradiography was performed in a routine manner on the excised specimens to confirm that they had been appropriately resected, and intraoperative histological examination of the three transected margins was also performed to ensure that they were appropriately resected.\u003c/p\u003e \u003cp\u003ePathological findings included the diameter of the remnant lesions in the surgical pathology report prepared by pathologists. The excised specimens were sectioned in the nipple\u0026ndash;tumor orthogonal direction into 5- to 7-mm sections. The extent of the lesions on the sections was evaluated by pathologists. The specimens were photographed side by side in sequence and mapped by a pathologist based on the corresponding pathological spread of the cancer. Positive margins were defined as proximity of the in situ lesion to the margins within 2 mm or exposure of invasive cancer [3\u0026ndash;4]. We analyzed how the relationship between the maximum transverse diameter of the CEUS-enhanced area and the maximum transverse diameter of the B-mode is involved in causing positive margins.\u003c/p\u003e \u003cp\u003e The study protocol was approved by the Clinical Trial Center of Sapporo Medical University, Japan, and was conducted according to the Declaration of Helsinki and the Ethical Principles for Medical Research Involving Human Subjects (Ministry of Health, Labour and Welfare). This study was also approved by the Clinical Research Review Committee of the hospital and by the hospital director and is registered with UMIN-CTR (UMIN000053287).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eTo explore whether the CEUS-enhanced area was smaller or larger than visible on B-mode might be related to the surgical positive rate, a χ\u003csup\u003e2\u003c/sup\u003e square test was performed for the surgical positive rate in patients with and without CEUS-B\u0026thinsp;\u0026le;\u0026thinsp;0. A χ\u003csup\u003e2\u003c/sup\u003e test was also conducted for MRI-B\u0026thinsp;\u0026le;\u0026thinsp;0 in the same manner. Two-sided P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Odds ratios and 95% confidence intervals for surgical margin positivity for each clinicopathological factor, including CEUS-B\u0026thinsp;\u0026le;\u0026thinsp;0 and MRI-B\u0026thinsp;\u0026le;\u0026thinsp;0, were calculated by nominal logistic analysis. All statistical analyses were conducted using JMP 16.0 (SAS Institute Inc., Cary NC, USA). The receiver operating characteristic (ROC) curve, which indicates the accuracy of the CEUS diagnosis for a positive margin, was obtained by varying the cutoff according to the US findings.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003ePatients with breast cancer who underwent partial mastectomy were enrolled in this study from October 2014 to July 2021. A final sample of 142 patients was analyzed, who had been evaluated by CEUS in operating rooms, who had not undergone previous systemic therapy, and who had not been examined by CEUS (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;1 lists the patients\u0026rsquo; characteristics. The mean age was 55 years. The maximum preoperative tumor diameter on B-mode US was 29 mm. The largest number of diagnoses histologically was invasive ductal carcinoma (n\u0026thinsp;=\u0026thinsp;124) followed by ductal carcinoma in situ (n\u0026thinsp;=\u0026thinsp;9). Regarding the special type, patients were diagnosed with four invasive lobular carcinomas, two mucinous carcinomas, two invasive micropapillary carcinomas, and one apocrine carcinoma. Excluding the nine ductal carcinoma in situ cases, the most common subtype was ER+/HER2\u0026thinsp;\u0026minus;\u0026thinsp;with 101 cases (71.1%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eFrequency of positive margins and details\u003c/h2\u003e \u003cp\u003ePositive surgical margins were observed in 14 patients, whereas negative margins were observed in 128 patients. Of the 14 positive cases, 8 were within 2 mm of the surgical margin, and all these 8 were in situ lesions. In contrast, six cases were exposed, five were in situ lesions, and one was lobular carcinoma in situ, as demonstrated in Table\u0026nbsp;2.\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates a plot of subtracting the maximum diameter of the B-mode from the maximum diameter of the CEUS (the range of enhancement outside the area of visible tumor on CEUS but was not visualized outside the area of visible tumor on B-mode; the x-axis) and the distance to the lateral transection (the y-axis). The black circles indicate cases positive for surgical margin, which tended to be distributed in the range where CEUS-B is \u0026lt;\u0026thinsp;0. CEUS-B was \u0026le;\u0026thinsp;0 in 66 of 142 patients; of these 66 patients, 10 showed positive margins, whereas the remaining 76 showed CEUS-B\u0026thinsp;\u0026lt;\u0026thinsp;0, and 4 showed positive margins (p\u0026thinsp;=\u0026thinsp;0.0467). In contrast, 55 of 142 patients had an MRI-B reading of \u0026le;\u0026thinsp;0. Of these 55 patients, 4 had positive margins, whereas the remaining 87 showed CEUS-B\u0026thinsp;\u0026lt;\u0026thinsp;0, and 10 showed positive margins (p\u0026thinsp;=\u0026thinsp;0.4024).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eFactors associated with risk for positive disconnections\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;3 shows the results of univariate and multivariate analyses for positive margins. In the univariate analysis, the only significant risk factor for surgical margin positivity was CEUS-B\u0026thinsp;\u0026le;\u0026thinsp;0, but not MRI-B and other clinicopathological factors. In terms of B-mode-based imaging diagnosis of tumor extension in operating rooms, a multivariate analysis was performed to compare CEUS and MRI for surgical margin positivity, which indicated CEUS as an independent factor.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCEUS-B is a possible predictor of positive surgical margins\u003c/h2\u003e \u003cp\u003eThe ROC curve revealed that a 0.9-mm CEUS-B cutoff of CEUS best served as a surrogate for positive surgical margins, with the area under the curve being 0.7037. Because 0.9 mm may not be clinically meaningful, a sensitivity of 0.7143 and a specificity of 0.4375 were obtained when 0 mm was used as the cutoff (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study was conducted to explore the usefulness of CEUS in the preoperative diagnosis of breast cancer spread to reduce the number of positive margins in partial mastectomy. In particular, our focus was on unusual enhancement patterns in CEUS. We found a characteristic tendency for patients who did not demonstrate enhancement.\u003c/p\u003e \u003cp\u003eWhen the CEUS-enhanced area was smaller than the range visible on B-mode (CEUS-B\u0026thinsp;\u0026le;\u0026thinsp;0), it was the only statistically significant risk factor for positive margins in the univariate analysis. This is also a relatively good area under the curve even for ROC curves, and it might be a predictor of a positive margin. In contrast, when the enhanced area as identified by MRI was smaller than that on the B-mode, it was not a risk factor. It was also extracted as a statistically significant risk factor for positive margins in the multivariate analysis of both. A possible reason for this is the difference in contrast agents. CEUS is a modality that can evaluate lesions and the surrounding hemodynamics in real time [10]. Sonazoid is a second-generation US contrast agent with excellent in vivo stability and resistance to US sound pressure. It is composed primarily of microbubbles and perflubutane gas encapsulated in a film of sodium hydrogenated egg yolk phosphatidylserine [9,16], with a small average particle size of 2\u0026ndash;3 \u0026micro;m, and unlike the water-soluble contrast agents used in breast MRI, sonazoid does not leak out of the blood vessel [1, 8\u0026ndash;10]. In other words, one reason why MRI did not correlate with positive margins may be that MRI contrast agents cause extravascular seepage and pooling, resulting in a disadvantage when evaluating noncontrasted areas. MRI has previously been reported to be more sensitive and less specific, which may be associated with the abovementioned findings [17].\u003c/p\u003e \u003cp\u003eUsing MRI of the liver as an example, negative contrast due to phagocytosis by Kupffer cells is well known. However, in US, the concept or significance of negative contrast remains unclear. For instance, a heterogeneous staining effect is found in a breast cancer mass, but the pathological significance of the nonstaining area is not strictly clear. The advantage of the nonenhanced areas of microbubbles in CEUS is that they do not leak outside the blood vessel, and they may well be negative findings on MRI in areas that are enhanced and masked by extravascular leakage and pooling. Further investigation is warranted for contrast-effective areas on MRI but negative on CEUS.\u003c/p\u003e \u003cp\u003eCurrently, it is known that it is difficult to achieve enhancement when cardiac output is low, but the effect of the problem is considered to exert a minor impact because the time when the contrast effect is highest was observed in this study. Although some unclear points that require further investigation remain, the lack of enhancement by CEUS, which generally exerts a broad staining effect, may be a vital finding, and more detailed verification is required.\u003c/p\u003e \u003cp\u003eBlood flow imaging-based imaging studies suggest that increased blood flow indicates the presence of cancer, but patterns that are not detected by these studies may indicate a spreading condition that does not exhibit increased blood flow.\u003c/p\u003e \u003cp\u003eThere are several limitations in this study. First, this was a small observational study and bias cannot be eliminated. Second, it is difficult to obtain a perfect match between the imaging plane of each modality. CEUS and B-mode comparisons were performed with both probes fixed at the same site, allowing evaluation of the potentially same imaging plane, whereas the comparison between MRI and B-mode cannot exclude the possibility that positional information differs from imaging derived from other imaging planes. Third, although the difficulty of matching imaging planes also exerts an impact, pathological findings that are not contrasted by CEUS have not been clarified because the situation may be completely different when the slice is changed for pathological verification. Therefore, the rationale for why a noncontrast pattern would result in positive margins must be investigated differently.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe findings of no enhancement outside the area of visible tumor on CEUS but not visualized outside the area of visible tumor on B-mode might be a risk factor for positive margins, in which the enhancement by CEUS is smaller than that by B-mode. Further details are warranted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eConceptualization and\u0026nbsp;Methodology: Hiroaki Shima; Formal analysis and investigation: Fukino Satomi, Yuta Kondo, Noriko Nishikawa, Satoko Uno, Asaka Wada and Ai Noda; Writing - original draft preparation: Hiroaki Shima; Writing - review and editing: Daisuke Kyuno, Hidekazu Kameshima and Tosei Ohmura; Resources: Shintaro Sugita, Naoya Yama; Supervision: Ichiro Takemasa.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of potential conflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of human rights\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study adhered to the ethical tenets of the Declaration of Helsinki and Ethical Principles for Medical Research Involving Human Subjects. Itwas approved by the Clinical Trial Center of Sapporo Medical University, Japan, and is registered with UMIN-CTR (UMIN000059628).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe consent documents approved by the review committee were given to the subjects (352-115), and the need for informed consent was waived in view of the retrospective and observational nature of the study. An opt-out consent process was used, and disclosures were made on the University\u0026rsquo;s website (https://sapmed-surg1.jp/gairai/optout/).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShah C, Hobbs BP, Vicini F, Al-Hilli Z, Manyam BV, Verma V, et al. The diminishing impact of margin definitions and width on local recurrence rates following breast-conserving therapy for early-stage invasive cancer: A meta-analysis. Ann Surg Oncol 2020;27:4628-36.\u003c/li\u003e\n\u003cli\u003eHoussami N, Macaskill P, Marinovich ML, Morrow M. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol 2014;21:717-30.\u003c/li\u003e\n\u003cli\u003eBuchholz TA, Somerfield MR, Griggs JJ, El-Eid S, Hammond ME, Lyman GH, et al. Margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer: American Society of Clinical Oncology endorsement of the Society of Surgical Oncology/American Society for Radiation Oncology consensus guideline. J Clin Oncol 2014;32:1502-6. \u003c/li\u003e\n\u003cli\u003eMarinovich ML, Azizi L, Macaskill P, Irwig L, Morrow M, Solin LJ, et al. The association of surgical margins and local recurrence in women with ductal carcinoma in situ treated with breast-conserving therapy: A meta-analysis. Ann Surg Oncol 2016;23:3811-21. \u003c/li\u003e\n\u003cli\u003eBundred JR, Michael S, Stuart B, Cutress RI, Beckmann K, Holleczek B, et al. Margin status and survival outcomes after breast cancer conservation surgery: prospectively registered systematic review and meta-analysis. BMJ 2022;378:e070346.\u003c/li\u003e\n\u003cli\u003eLiu Q, Wang C, Li P, Liu J, Huang G, Song S. The role of (18)F-FDG PET/CT and MRI in assessing pathological complete response to neoadjuvant chemotherapy in patients with breast cancer: A systematic review and meta-analysis. BioMed Res Int 2016;2016:3746232. \u003c/li\u003e\n\u003cli\u003eCaldarella C, Treglia G, Giordano A. Diagnostic performance of dedicated positron emission mammography using fluorine-18-fluorodeoxyglucose in women with suspicious breast lesions: a meta-analysis. Clin Breast Cancer 2014;14:241-8.\u003c/li\u003e\n\u003cli\u003eSchilling K, Narayanan D, Kalinyak JE, The J, Velasquez MV, Kahn S, et al. Positron emission mammography in breast cancer presurgical planning: comparisons with magnetic resonance imaging. Eur J Nucl Med Mol Imaging 2011;38:23-36. \u003c/li\u003e\n\u003cli\u003eAli-Mucheru M, Pockaj B, Patel B, Pizzitola V, Wasif N, Stucky CC, et al. Contrast-enhanced digital mammography in the surgical management of breast cancer. Ann Surg Oncol 2016;23(suppl 5):649-55.\u003c/li\u003e\n\u003cli\u003eShima H, Okuno T, Nakamura T, Noro A, Noma M, Sato M, et al. Comparing the extent of breast cancer tumors through contrast-enhanced ultrasound vs B-mode, opposed with pathology: evergreen study. Breast Cancer 2021;28:405-13.\u003c/li\u003e\n\u003cli\u003eTurnbull L, Brown S, Harvey I, Olivier C, Drew P, Napp V, et al. Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial. Lancet 2010;375:563-71. \u003c/li\u003e\n\u003cli\u003eSung JS, Li J, Da Costa G, Patil S, Van Zee KJ, Dershaw DD, et al\u003cem\u003e.\u003c/em\u003e Preoperative breast MRI for early-stage breast cancer: effect on surgical and long-term outcomes. AJR Am J Roentgenol 2014;202:1376-82. \u003c/li\u003e\n\u003cli\u003eBalleyguier C, Dunant A, Ceugnart L, Kandel M, Chauvet MP, Ch\u0026eacute;rel P, et al. Preoperative breast magnetic resonance imaging in women with local ductal carcinoma in situ to optimize surgical outcomes: results from the randomized Phase III trial IRCIS. J Clin Oncol 2019;37:885-92. \u003c/li\u003e\n\u003cli\u003eHoussami N, Turner RM, Morrow M. Meta-analysis of pre-operative magnetic resonance imaging (MRI) and surgical treatment for breast cancer. Breast Cancer Res Treat 2017;165:273-83. \u003c/li\u003e\n\u003cli\u003eHoussami N, Turner R, Morrow M. Preoperative magnetic resonance imaging in breast cancer: meta-analysis of surgical outcomes. Ann Surg 2013;257:249-55. \u003c/li\u003e\n\u003cli\u003eMiyamoto Y, Ito T, Takada E, Omoto K, Hirai T, Moriyasu F. Efficacy of sonazoid (perflubutane) for contrast-enhanced ultrasound in the differentiation of focal breast lesions: phase 3 multicenter clinical trial. AJR Am J Roentgenol 2014;202:W400-7.\u003c/li\u003e\n\u003cli\u003eMedeiros LR, Duarte CS, Rosa DD, Edelweiss MI, Edelweiss M, Silva FR, et al. Accuracy of magnetic resonance in suspicious breast lesions: a systematic quantitative review and meta-analysis. Breast Cancer Res Treat 2011;126(2):273-85.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"breast cancer, partial mastectomy, contrast-enhanced ultrasound, surgical margin","lastPublishedDoi":"10.21203/rs.3.rs-4212506/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4212506/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe clinical disadvantage of positive margins in partial mastectomy for patients with operable breast cancer is clear and must be avoided; however, there is still room for improvement. The usefulness of contrast-enhanced ultrasound (CEUS) in diagnosing spread is currently well known. The CEUS-enhanced area for breast cancer tends to be wider than that observed in B-mode and probably includes cancer cells. This study aimed to analyze the correlation between characteristic findings and positive for margins in order to ultimately prove potential usefulness of CEUS in making the surgical margin negative.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively evaluated the data of 142 patients with breast cancer who underwent partial mastectomy to explore the effect on positive margins when the CEUS staining area was smaller than the B-mode visualized mass (CEUS-B\u0026thinsp;\u0026le;\u0026thinsp;0).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eCEUS-B\u0026thinsp;\u0026le;\u0026thinsp;0 was associated with significantly more positive margins (p\u0026thinsp;=\u0026thinsp;0.0467). CEUS-B was also extracted as an independent predictor on multivariate analysis.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe findings of no enhancement outside the area of visible tumor on CEUS but not visualized outside the area of visible tumor on B-mode might be a risk factor for a positive surgical margins.\u003c/p\u003e","manuscriptTitle":"Contrast-enhanced ultrasound predicts surgical margin positivity in patients with breast cancer who underwent partial mastectomy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 17:55:25","doi":"10.21203/rs.3.rs-4212506/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"001778bc-eecb-4b56-b8fa-e8755c9d967b","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-10T09:44:02+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-19 17:55:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4212506","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4212506","identity":"rs-4212506","version":["v1"]},"buildId":"zQwnuV7TCBrMSSSToR1PI","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}