Optimizing the treatment strategy of breast cancer
Qiu, Si-Qi
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CHAPTER 5
Micro-computed tomography (micro-CT) for
intraoperative surgical margin assessment
of breast cancer: a feasibility study in breast
conserving surgery
Si-Qi Qiu1,2,3, Monique D. Dorrius4, Steven J. de Jongh2, Liesbeth Jansen2, Jakob de Vries2, Carolien P. Schröder1, Guo-Jun Zhang5,6, Elisabeth G.E. de Vries1, Bert van der Vegt7,*, Gooitzen M. van Dam2,8,*
*contributed equally
1Department of Medical Oncology, 2Department of Surgical Oncology, 4Department of Radiology, 7Department of Pathology, 8Department of Nuclear Medicine and Molecular Imaging and Intensive Care,
University of Groningen, University Medical Center Groningen, Groninge, The Netherlands. 3The Breast
Center, Cancer Hospital, of Shantou University Medical College, Guangdong, China. 5Changjiang Scholar’s
Laboratory of Shantou University Medical College, Guangdong, China. 6The Cancer Center, Xiang’ an Hospital
of Xiamen University, Fujian, China.
Abstract
Purpose: Around 15%-30% of patients receiving breast-conserving surgery (BCS) for
invasive breast carcinoma or ductal carcinoma in situ (DCIS) need a reoperation due to tumor-positive margins at final histopathology. Currently available intraoperative surgical margin assessment modalities all have specific limitations. Therefore, we aimed to assess the feasibility and accuracy of micro-computed tomography (micro-CT) as a novel method for intraoperative margin assessment in BCS.
Methods: Lumpectomy specimens from 30 consecutive patients diagnosed with invasive
breast cancer or DCIS were imaged using a micro-CT. Margin status was assessed on micro-CT images by two investigators who were blinded to the final histopathological margin status. The micro-CT margin status was compared with the histopathological margin status.
Results: The margin status could be assessed by micro-CT in 29 out of 30 patients. Of
these, nine patients had a positive tumor margin and 20 a negative tumor margin at final histopathology. Margin status evaluation by micro-CT took always less than 15 minutes. The margin status in 25 patients was correctly predicted by micro-CT. There were four false-negative predictions. The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of micro-CT in margin status prediction were 86%, 56%, 100%, 100% and 83%, respectively. With micro-CT, the positive margin rate could potentially have been reduced from 31% to 14%.
Conclusions: Whole lumpectomy specimen micro-CT scanning is a promising technique
for intraoperative margin assessment in BCS. Intraoperative quick feedback on the margin status could potentially lead to a reduction in the number of reoperations.
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IntroductionBreast cancer is the most prevalent cancer and the leading cause of cancer-related death in females worldwide1,2. Due to national screening programs, more patients are diagnosed with smaller invasive tumors and are therefore likely to receive breast conserving surgery (BCS)3,4. The increased use of neoadjuvant chemotherapy, resulting in tumor downstaging, also leads to more patients receiving BCS5,6. Achieving tumor-free surgical margins is critical in BCS, as ipsilateral breast tumor recurrence rates double in patients with positive resection margins after BCS compared to patients with negative margins7,8. Overall, positive margins occur in 20%-40% of all patients receiving BCS, and 15%-30% undergo a reoperation to improve local control4,9–11. Repeat breast surgery has been associated with higher surgical risk, poorer cosmetic outcome and increased psychological and economic burden12.
To reduce the reoperation rate and its associated sequelae, intraoperative surgical margin assessment techniques aiming to identify involved margins and to enable immediate re-excision have been investigated. Those techniques, which include frozen section, imprint cytology, intraoperative ultrasound and specimen mammography, all have considerable limitations. Frozen section and imprint cytology have variable sensitivity and specificity depending on experience of the pathologist and both techniques are time-consuming13–17. Moreover, frozen section has a risk of sampling error because only a small amount of tissue can be sampled for analysis13,18. Imprint cytology provides no information on margin width19. Intraoperative ultrasound and specimen mammography have low sensitivity and specificity due to their inherent 2-dimensional (2D) nature20, which is unable to accurately reflect the 3-dimensional (3D) specimen. To overcome the limitations of existing techniques, several novel tools, including micro-computed tomography (micro-CT), have been developed for intraoperative margin assessment13. Micro-CT is a fully self-shielded desktop instrument that can be placed in the operation room or in the pathology department. It can be used to scan breast samples with a maximum diameter up to 14 cm and provides high quality images with spatial resolution to less than 1 µm. It provides 3D images of the sample, enabling assessment of margin status in all directions. The possibility of providing fast feedback to surgeons makes micro-CT a potential tool for intraoperative margin assessment. Several studies have demonstrated that micro-CT can distinguish malignant from benign breast tissue21,22. One study used micro-CT to evaluate the shaved cavity margin status from BCS23. However, no studies have reported on the performance of micro-CT for evaluating the margin status of the whole specimen from BCS.
surgical margin assessment of whole lumpectomy specimens from BCS.
Methods
Study population
We scanned lumpectomy specimens from consecutive series of patients who were diagnosed with invasive breast cancer or ductal carcinoma in situ (DCIS) and who received primary BCS at the University Medical Center Groningen (UMCG). Lumpectomy specimens from patients who received neoadjuvant systemic therapy, who underwent a breast re-excision surgery, or who participated in other clinical trials were not included. All patients received preoperative breast ultrasound, mammography or both. Two patients received a preoperative contrast-enhanced magnetic resonance imaging for screening of multifocal or multicentric diseases. For patients with non-palpable tumors, an iodine-125 seed or a wire was placed in the tumor for intraoperative tumor localization. This study was approved by the Medical Ethical Committee of UMCG.
Micro-CT tissue scanning and image evaluation
Lumpectomy specimens were imaged using a desktop micro-CT (SkyScan 1275, Bruker SkyScan, Kontich, Belgium) with an X-ray source voltage of 20-100 kV and a minimum spot size of 5 µm at 10 W. The resolution of this device can reach to 4-50 μm. The micro-CT system was located in the gross room of the pathology department. After excision, the whole specimens were placed in a plastic container with a diameter of 10 cm and scanned at 80 kV, 125 mA, 52 mS exposure time and 360° of rotation with incremental rotational steps of 0.3°. One or two 2D images, with 972 x 768 pixels, were obtained at each rotation step. The 2D cross-sections were then fully reconstructed using SkyScan’s NRecon program (Bruker SkyScan). In parallel with tomographic reconstruction of the micro-CT images, the breast specimens were sliced into ‘bread loaf’ slices with a thickness of around 0.5 cm by a pathology department technician. To confirm that the suspicious areas detected in the reconstructed images of the specimen were correctly embedded, the ‘bread loaf’ slices with tumor or suspicious areas found in whole specimen reconstructed images were scanned using the same protocol described above. The 2D cross sections of tissue slices were also fully reconstructed using NRecon. For radio-guided or wire-radio-guided excision, the whole specimens were imaged with mammography before imaging with micro-CT.
The SkyScan DataViewer (Bruker SkyScan) was used to view the 3D images. All the 3D images were evaluated by M.D. and S.Q.Q., who were blinded to the histopathological margin status. All the images were viewed by the two observers together in three planes (transverse, coronal and sagittal). Based on the preoperative breast ultrasound and/or mammography, the tumors were classified into three groups: tumors with solid tumor
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component only, tumors with calcification component only and tumors with both solid tumor and calcification components. The solid tumor component and calcification component detected by micro-CT were evaluated and recorded for each specimen. Radiographic indications of margin involvement were assessed. For patients with a preoperative diagnosis of invasive tumor, grouped calcifications or spiculated masses touching the margin were considered a positive margin7. For patients with a preoperative diagnosis of DCIS, grouped calcifications or spiculated masses within 2 mm of the margin were considered a positive margin8. The location of the involved margin was recorded for each patient. The results of margin status prediction by micro-CT did not influence the standard surgical procedure.
Histopathological examination
The ‘bread loaf’ sliced breast specimens were fixed in 4% formalin overnight and embedded in paraffin according to the standard grossing protocol after micro-CT scanning. We performed a standard hematoxylin and eosin (H&E) staining on 3 µm sections. Histopathological margin status was assessed by a qualified breast pathologist (B.v.d.V.). For invasive tumors, the margin was considered positive if ink was found on the invasive carcinoma or DCIS. For pure DCIS, the margin was considered positive if the tumor was within 2 mm of the inked margin’s surface. Margin status and the positive margin location assessed by micro-CT were compared with results of histopathology for each patient.
Statistical analysis
In a previous study using micro-CT to evaluate shaved cavity margin status in BCS, the accuracy of micro-CT in margin status prediction was 92%23. With a calculated sample size of 28, we could estimate a same accuracy of 92% for micro-CT margin status prediction, with a 95% confidence interval (CI) of +/- 10%. Based on this calculation, we decided to include lumpectomy specimens from 30 patients. The continuous variables were described by median and interquartile range (IQR). The categorical variables were described by percentages. The micro-CT solid tumor or calcification component detection rate was calculated as follows: the number of each component detected by micro-CT divided by the number of corresponding components detected by preoperative imaging modalities (ultrasound and/or mammography). The agreement between the location of positive margin predicted by micro-CT (hereafter, micro-CT positive margin location) and the location of histopathological positive margin (hereafter, histopathology positive margin location) were assessed by B.v.d.V. and S.Q.Q.. A true prediction of micro-CT was defined as a micro-CT positive margin location that was the same as the histopathology positive margin location. If the micro-CT positive margin location was different from the histopathology positive margin location, it was considered a false-negative prediction.
The accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of micro-CT in margin status prediction were calculated.
Results
The study was conducted at the UMCG from April 2016 to February 2017. A total of 30 lumpectomy specimens from 30 consecutive patients were scanned. Two patients presented with 2 tumors. Patients’ characteristics are shown in Table 1. For each sample 7 minutes were needed for sample scanning, 1.5 minutes for image reconstruction and 5 minutes for image evaluation. Tumor component detection by micro-CT is summarized in Table 2. Overall, the micro-CT solid tumor component detection rate was 88% (23/26), and the calcification component detection rate was 100% (14/14). All three patients with solid tumor component undetectable with micro-CT were younger than 50 years of age and had dense breast tissue as shown by preoperative mammography. These solid tumor components were also undetectable with preoperative mammography. However, two out of these three patients had a calcification component in the tumors and the calcification components were detected by both preoperative mammography and micro-CT (Table 2). Representative images of micro-CT detectable and undetectable solid tumors are shown in Figure 1.
A B C
10 mm
Figure 1. Representative images of CT tumor detection. (A) CT detectable solid tumor, (B)
micro-CT undetectable solid tumor, (C) micro-micro-CT undetectable solid tumor with detectable calcifications. Arrowhead in (A) indicates a spiculated solid tumor. Arrowhead in (C) indicates grouped calcifications.
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The resection margin status was assessed by micro-CT in 29 patients. In the remaining patient, the tumor had solid tumor component only, which was undetectable with CT. Therefore, the margin status in this patient could not be assessed by micro-CT. At final histopathology, nine patients from this group had positive surgical margins and 20 had negative margins. From the nine patients with positive margins, seven were positive for DCIS only, one patient for invasive ductal carcinoma only and one patient for
Table 1. Patient characteristics
Characteristics Patients (n=30) Age, years (median, IQR) 62 (55-69) Menopausal status (number, %)
Premenopausal Postmenopausal Unknown 5 (17) 22 (73) 3 (10) Tumor type (number, %)
IDC DCIS ILC Other 22 (74) 6 (20) 1 (3) 1 (3) Tumor localization technique (number, %)
Iodine (I125) seed Wire None 19 (63) 1 (3) 10 (34) Tumor location (number, %)
Upper outer quadrant Lower outer quadrant Lower inner quadrant Upper inner quadrant Central 18 (60) 4 (13) 1 (3) 4 (13) 3 (10) Tumor classification by preoperative breast US and MMG (number of tumors = 32)
(number, %)
Solid tumor component only Calcification component only
Solid tumor and calcification components
18 (56) 6 (19) 8 (25) DCIS, ductal carcinoma in situ; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; IQR, interquartile range; MMG, mammography; US, ultrasound
Table 2. Breast tumor detection by micro-CT
Tumor classification by preoperative US and MMG Number of tumors
Number of tumors detected by micro-CT
Solid tumor component only 18 17 Calcification component only 6 6
Solid tumor and calcification components 8 Solid tumor component: 6 Calcification component: 8 MMG, mammography; US, ultrasound
both DCIS and invasive ductal carcinoma. Micro-CT resulted in a true-positive margin status prediction in five patients (56%) and true-negative margin status prediction in 20 patients (100%). In the other four patients micro-CT resulted in a false-negative prediction (Table 3). In one out of these four patients, micro-CT predicted a positive margin status, however, the micro-CT positive margin location was different from the histopathology positive margin location. All four false-negative cases involved DCIS on margins as determined by final histopathology, in which no calcifications were visible on the micro-CT images. Of the five patients with true-positive margin prediction, the positive surgical margins were presented as DCIS in three patients, invasive ductal carcinoma in one patient and both DCIS and invasive ductal carcinoma in the remaining patient. The micro-CT images of positive margins were visible as grouped calcifications in four cases and as a spiculated solid tumor in one case. Micro-CT images of positive margins and associated histopathological pictures are shown in Figure 2. The accuracy, sensitivity, specificity, PPV and NPV of micro-CT for margin status assessment were 86% (25/29), 56% (5/9), 100% (20/20), 100% (5/5) and 83% (20/24), respectively. With the use of micro-CT, the positive margin rate could potentially have been lowered from 31% (9/29) to 14% (4/29).
Table 3. Comparison of micro-CT with histopathology in surgical margin assessment in breast cancer
Micro-CT margin status per patient Histopathological margin status per patient
Total Positive Negative Positive 5 0 5 Negative 4 20 24 Total 9 20 29 10 mm 500 µm MicroCT Histopathology MicroCT Histopathology Case 1 Case 2 Case 3 Case 4 Case 5
Figure 2. Five cases with tumor-positive resection margins. Transverse section (Case 1, 2 and 3) and
coronal section (Case 4 and 5) micro-CT images show tumor-positive resection margins on the breast lumps characterized by grouped calcifications (Case 1, 2, 4 and 5) or a spiculated mass (Case 3), as indicated by the arrowheads. Histopathological images show tumor-positive resection margins characterized by ductal carcinoma in situ (Case 1, 2, 4 and 5) or invasive tumor (Case 3). Arrowheads indicate the inked margins.
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DiscussionThis feasibility study shows that intraoperative surgical margins can be assessed with micro-CT, which provided feedback to surgeons on the margin status within 15 minutes with an overall accuracy of 86% in surgical margin status prediction.
This is the first study reporting on the clinical use of micro-CT for margin status assessment in whole specimens from patients with primary breast cancer eligible for BCS. The time from specimen scanning to informing the surgeons of the margin status in this study was less than the time reported to be needed for frozen section (mean 27.8 minutes, range: 20 to 50 minutes20) or imprint cytology (mean 16.6 minutes, range: 15 to 22.5 minutes20). Therefore, micro-CT technique would have little impact on the lumpectomy procedure and is technically feasible for intraoperative use.
Margin status predicted by micro-CT in our study was concordant with the histopathological margin status in 86% of the patients. Micro-CT margin status prediction had a sensitivity of 56%, and a specificity of 100%. This specificity is similar to that previously reported for shaved cavity margin assessment using micro-CT (94.7%23), thus indicating a consistently low false-positive prediction rate for this technique. However, the sensitivity in our study is quite low as compared to the sensitivity reported in that study (58% versus 83%23). A possible explanation for this might be a difference in the definition of a positive margin in the two studies. The radiographic definition of a positive margin was not clearly mentioned in the previously published micro-CT study. The small sample size in both studies might also account for the difference in the sensitivity in margin status prediction. The specificity of micro-CT is comparable with the reported data for frozen section and imprint cytology, but is higher than that reported for intraoperative ultrasound and specimen mammography. In a recently published systematic review and meta-analysis, the pooled specificities were 96% (95% CI: 92%-98%) for frozen section (from 9 studies), 95% (95% CI: 90%-98%) for imprint cytology (from 11 studies), 81% (95% CI: 66%-91%) for intraoperative ultrasound (from 4 studies), and 84% (95% CI: 77%-89%) for specimen mammography (from 9 studies)20. The sensitivity of micro-CT reported in our study is similar with the pooled sensitivities for intraoperative ultrasound (59%, 95%CI: 36%-79%) and for specimen mammography (53%, 95% CI: 45%-61%). However, it is lower than the pooled sensitivities for frozen section (86%, 95% CI: 78%-91%) and for imprint cytology (91%, 95% CI: 71%-97%)20. When compared with MarginProbe®, which is a US Food and Drug Administration approved device for intraoperative margin assessment, micro-CT shows a much higher specificity and a lower sensitivity. In a multicenter randomized study including 596 patients with breast cancer, the specificity and sensitivity of MarginProbe® were 46.4% (95% CI: 42.9%-49.9%) and 75.2% (95% CI: 69.4%-81.0%), respectively24. MarginProbe®
use significantly reduced the rates of positive margins and reoperations compared with standard of care in this study. However, the positive margin rate and reoperation rate of the MarginProbe® group were still as high as 30.9% and 19.8%, respectively24. Cavity-shaving after lumpectomy has also been reported to be associated with lower rates of positive margins and reoperations25. In a randomized controlled trial with 235 breast cancer patients, the positive margin rate and reoperation rate of this technique were 19% and 10%, respectively, both lower than that of the no-shave group (34% and 21%, respectively)26. The cavity-shaving was associated with a significantly larger volume of tissue excised (median, 115.1 cm3 vs 74.2 cm3)26. The reoperation rates of frozen section and imprint cytology were 10±6% and 11±4%, respectively. Both are lower than the reoperation rate of permanent section (35±3%) as demonstrated in a systematic review including 10,489 tumors25. Intraoperative specimen radiography does not clearly improve the rates of reoperations for the positive margins and therefore its routinely use is not recommended for this purpose25. In our study, five out of nine positive margins might have been predicted if the micro-CT technique had been used intraoperatively, resulting in an absolute 17% (relative 55%) reduction of positive margin rate (from 31% to 14%). The reoperation rate could be even lower because not all patients with a positive margin would need a reoperation. This would have dramatically reduced the surgical risks, patients’ psychological burden and medical costs. In contrast, none of the reported positive margins were detected by standard visual inspection and palpation. Micro-CT technique could be cost-effective. According to a premature cost effectiveness analysis based on the assumption that micro-CT is used for scanning a number of 250 lumpectomies per year, the cost of micro-CT per patient is €120 (Supplementary data). This is cheaper than the cost of frozen section (€300) in The Netherlands.
A drawback of micro-CT is the unsatisfactory solid tumor detection in young patients with dense breasts. This is due to its inherent mechanism in tissue discrimination, which is based on the difference in tissue densities on a radiographic image. The tissue densities of breast cancer and normal breast parenchyma in patients with dense breasts are similar, which hampers the use of micro-CT in this patient group. One possible solution is the use of an iodinated or nanoparticle-based contrast agent before the operation to enhance the density contrast between breast cancer and normal tissue. This technique improved
in vivo liver-to-tumor contrast in studies in mice with hepatocellular carcinoma or
metastatic liver tumor27,28. In the future, the feasibility of tumor-to-background contrast improvement using a contrast agent should be tested in animal breast tumor models and subsequently in clinical studies. However, before contrast agents are available to be used in the clinic for micro-CT, preoperative mammography could be a useful tool to select appropriate patient candidates for micro-CT margin assessment. In this study, solid
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tumors in all the three micro-CT undetectable cases were not detected by preoperative mammography. However, micro-CT detected all of the solid tumors that were detectable in preoperative mammography.
An advantage of micro-CT is the excellent calcification detection. In this study, calcification component detection rate by micro-CT was 100%. Moreover, 80% (4/5) of the true-positive margin predictions were predicted by grouped calcifications. It is relatively easy for surgeons and pathologists to recognize a solid tumor positive margin by standard visual inspection and palpation during BCS because the texture and hardness of cancerous tissue is often different from normal breast tissue. However, identification of a grouped calcifications positive margin with the naked eye or by palpation is more difficult. Micro-CT is thus a very useful technique to assist intraoperative margin assessment in tumors with calcifications shown on preoperative mammography.
In future studies, it would be interesting to determine the added value of intraoperative use of micro-CT for the standard surgical procedure regarding reduction of reoperation rate. A proposed study design is shown in Figure 3. Briefly, after lumpectomy according to standard procedure, surgeons decide whether to biopsy the surgical cavity based on gross examination of specimens. After that, the whole lumpectomy specimens or biopsy specimens are scanned by micro-CT. Subsequently, surgeons decide whether to perform re-excision (in the same operation) or not on the surgical cavity based on results from micro-CT margin status evaluation. In this study we compared primary tumor detection by micro-CT with tumor detection by preoperative ultrasound and mammography. In order to avoid the influence of neoadjuvant therapy and surgery on the primary tumor, we excluded patients with neoadjuvant therapy and patients with reoperations. In future study, it is highly recommended to include these patients to evaluate the role of micro-CT in decreasing the rates of positive margins and reoperations.
After standard lumpectomy Surgeon’s decision Cavity biopsy No cavity biopsy Biopsy specimens Lumpectomy specimens Micro-CT scanning Micro-CT intraoperative margin evaluation Re-excision No re-excision
Figure 3. A proposed flowchart for future studies to evaluate the added value of intraoperative use of micro-CT
for the standard surgical procedure regarding reduction of reoperation rate.
Conclusions
Micro-CT is a promising novel technique for intraoperative margin assessment in BCS, especially in the cases with calcifications on the resection margins. The quick feedback to surgeons on the margin status could potentially lead to efficient handling of involved margins during the same operation.
Online supplementary materials
https://doi.org/10.1016/j.ejso.2018.06.022
Acknowledgements
We would like to acknowledge the support of the Department of Pathology, University Medical Center Groningen. S.Q.Q. was funded by the Abel Tasman Talent Program (ATTP) of the University of Groningen. G.J.Z. was funded by the Major International Collaborative Research Project of NSFC (81320108015).
Role of the funding source
The study funders did not participate in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to manuscript submission.
Conflict of interest statement
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References1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87–108.
2. Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends — an update. Cancer Epidemiol Biomarkers Prev 2016; 25: 16–27. 3. Warrier S, Tapis G, Goltsman D, Beith J. An update in breast cancer screening and
management. Womens Heal 2016; 12: 229–39.
4. Pleijhuis RG, Graafland M, de Vries J, Bart J, de Jong JS, van Dam GM. Obtaining adequate surgical margins in breast-conserving therapy for patients with early-stage breast cancer: current modalities and future directions. Ann Surg Oncol 2009; 16: 2717–30.
5. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997; 15: 2483–93. 6. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative
docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer : National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2006; 24: 2019–27.
7. Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology – American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol 2014; 32: 1507–15.
8. Morrow M, Zee KJ Van, Solin LJ, et al. Society of Surgical Oncology – American Society for Radiation Oncology – American Society of Clinical Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ. J Clin Oncol 2016; 34: 4040–6.
9. Wilke LG, Czechura T, Wang C, et al. Repeat surgery after breast conservation for the treatment of stage 0 to II breast carcinoma a report from the national cancer data base, 2004-2010. JAMA Surg 2014; 149: 1296–305.
10. Isaacs AJ, Gemignani ML, Pusic A, Sedrakyan A. Association of breast conservation surgery for cancer with 90-day reoperation rates in New York State. JAMA Surg 2016; 151: 648–55.
11. Bodilsen A, Bjerre K, Offersen B V., et al. The influence of repeat surgery and residual disease on recurrence after breast-conserving surgery: A Danish Breast Cancer Cooperative Group study. Ann Surg Oncol 2015; 22: S476-485.
12. Houssami N, Morrow M. Margins in breast conservation: A clinician’s perspective and what the literature tells us. J Surg Oncol 2014; 110: 2–7.
13. Thill M, Baumann K, Barinoff J. Intraoperative assessment of margins in breast conservative surgery — still in use ? J Surg Oncol 2014; 110: 15–20.
14. Olson TP, Harter J, Munoz A, Mahvi DM, Breslin TM. Frozen section analysis for intraoperative margin assessment during breast-conserving surgery results in low rates of re-excision and local recurrence. Ann Surg Oncol 2007; 14: 2953–60. 15. Osako T, Nishimura R, Nishiyama Y, et al. Efficacy of intraoperative entire -
circumferential frozen section analysis of lumpectomy margins during breast - conserving surgery for breast cancer. Int J Clin Oncol 2015; 20: 1093–101.
16. Cendán JC, Coco D, Copeland III EM. Accuracy of intraoperative frozen-section analysis of breast cancer lumpectomy-bed margins. J Am Coll Surg 2005; 201: 194–8. 17. Noguchi M, Minami M, Earashi M, et al. Intraoperative histologic assessment of
surgical margins and lymph node metastasis in breast-conserving surgery. J Surg Oncol 1995; 60: 185–90.
18. Weber WP, Engelberger S, Viehl CT, et al. Accuracy of frozen section analysis versus specimen radiography during breast-conserving surgery for nonpalpable lesions. World J Surg 2008; 32: 2599–606.
19. Muttalib M, Tai CC, Briant-Evans T, et al. Intra-operative assessment of excision margins using breast imprint and scrape cytology. Breast 2005; 14: 42–50.
20. St John, Robert E, Al-khudairi R, Ashrafian H, et al. Diagnostic accuracy of intraoperative techniques for margin assessment in breast cancer surgery. Ann Surg 2017; 265: 300–10.
21. Gufler H, Franke FE, Wagner S, Rau WS. Fine structure of breast tissue on micro computed tomography a feasibility study. Acad Radiol 2011; 18: 230–4.
22. Gufler H, Wagner S, Franke FE. The interior structure of breast microcalcifications assessed with micro computed tomography. Acta radiol 2011; 52: 592–6.
23. Tang R, Coopey SB, Buckley JM, et al. A pilot study evaluating shaved cavity margins with micro-computed tomography: a novel method for predicting lumpectomy margin status intraoperatively. Breast J 2013; 19: 485–9.
24. Schnabel F, Boolbol SK, Gittleman M, et al. A randomized prospective study of lumpectomy margin assessment with use of marginprobe in patients with nonpalpable breast malignancies. Ann Surg Oncol 2014; 21: 1589–95.
25. Gray RJ, Pockaj BA, Garvey E, Blair S. Intraoperative margin management in breast-conserving surgery: a systematic review of the literature. Ann Surg Oncol 2018; 25: 18–27.
26. Chagpar AB, Killelea BK, Tsangaris TN, et al. A randomized, controlled trial of cavity shave margins in breast cancer. N Engl J Med 2015; 373: 503–10.
27. Rothe JH, Rudolph I, Rohwer N, et al. Time course of contrast enhancement by micro-CT with dedicated contrast agents in normal mice and mice with hepatocellular carcinoma: comparison of one iodinated and two nanoparticle-based agents. Acad Radiol 2015; 22: 169–78.
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a nanoparticulate contrast agent: a longitudinal study in mice. PLoS One 2011; 6: e25692.
