Non-Invasive Three-Dimensional Breast Tumor Positioning Before Neoadjuvant Systemic Therapy as Promissing Alternative to the Invasive Tumor Marking – Technique Description and Feasibility

Non-Invasive Three-Dimensional Breast Tumor Positioning Before Neoadjuvant Systemic Therapy as Promissing Alternative to the Invasive Tumor Marking – Technique Description and Feasibility | 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Method Article Non-Invasive Three-Dimensional Breast Tumor Positioning Before Neoadjuvant Systemic Therapy as Promissing Alternative to the Invasive Tumor Marking – Technique Description and Feasibility Dragana Bjelica, Natasa Colakovic, Svetlana Opric, Darko Zdravkovic, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4064076/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 : Surgical excision of the lodge of the tumor that has completely clinically regressed after neoadjuvant systemic therapy (NAST) is a necessary part of the treatment of early breast cancer. However, it is significantly hampered by the lack of a spatial landmark concerning the location of the pre-existing tumor in the breast. Standard surgical techniques of targeted excision of the pre-existing tumor bed generally rely on invasive insertion of various markers into or around the tumor before starting NAST. Invasive marking techniques are burdened by the disadvantages of technical complexity, invasiveness of procedures, and insufficient precision. Methods : In this paper authors present an original technique of non-invasive determining of the tumor position in the breast in three dimensions before starting NAST, with intention to overcome the disadvantages of invasive tumor marking. Tumor positioning is performed by ultrasound measurements – detailed description of the technique is given in the main text. The feasibility and precision of the technique was tested by the histological parameters of the adequacy and rationality of excision of the tumor bed, after complete clinical regression of the tumor after NAST, on a pilot series of patients. Results : A pilot series of 33 patients underwent a non-invasive breast tumor positioning technique before starting NAST. Twelve patients with complete clinical regression after NAST have been operated using a non-invasive tumor positioning technique, so far. In all cases, histological signs of tumor regression were verified in the specimen of the excised tumor bed. The ratio of the resected specimen volume to the volume of the tumor before NAST was on average 0,91, which is in favor of the rationality of excision and a good aesthetic effect. Conclusion : The initial results of a pilot series of treated patients imply that a non-invasive three-dimensional tumor positioning technique is feasible, with a satisfactory level of oncological safety and aesthetic effects of surgery. Performing a randomised clinical trial comparing this technique with standard techniques of invasive tumor marking is justified. early breast cancer neoadjuvant systemic therapy patological complete response surgical excision marking techniques tumor positioning ultrasound Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Background Neoadjuvant systemic therapy (NAST) of breast cancer has produced a special kind of challenge for surgeons: adequate excision of the tumor bed after significant regression or complete disappearance of tumor tissue in the breast, when the area of pre-existing tumor cannot be identified radiologically or by palpation. Surgical excision of the tumor bed is necessary for the histological verification of the degree of regression or complete pathohistological response (pCR). The lack of orientation regarding the location of the pre-existing tumor often leads surgeons to decide to perform a mastectomy [ 1 ], which is something paradoxical in relation to one of the main goals of NAST - enabling breast conservative surgery (BCS). Along with the increasing therapeutic efficiency of NAST and the increased percentage of achieved pCR, tumor marking techniques before the start of therapy gradually gained importance, to enable precise excision of the tumor bed after complete tumor regression. So far, several pre-NAST marking techniques have been described in the literature: tattoos on the skin in the projection of the tumor tissue [ 2 , 3 ] placement of radiopaque clip in the center of the tumor [ 1 , 4 – 7 ], tumor marking with radioactive seed [ 8 – 12 ], ROLL [ 12 , 13 ], silver wire around the tumor (bracketing) [ 14 , 15 ], radiopaque coil insertion [ 16 ], hydrogel markers [ 17 ], radiofrequency tag [ 18 ]. The abundance of techniques indicates in itself that none of the above marking techniques is ideal. That is, each of the listed techniques has its own drawbacks, regardless of their intensity and frequency: lack of a third dimension (tattoo on the skin); the ideal positioning of markers is not always achievable in practice (all techniques); additional requirements and inconveniences of working with radioactive material (ROLL and radioactive seed); objective limitations in the orientation with regard to the place and extent of excision based on an individual punctiform marker; migration of markers during NAST; difficult visibility of markers after NAST [ 19 , 20 ]. Different patterns of tumor regression during NAST (concentric or non-concentric) limit the accuracy of excision of the tumor bed, regardless of the way of marking. Bracketing marking is more reliable than central marking, but it is technically more demanding and requires a wider excision than a potentially sufficient one. All the techniques except tattoo imply an invasive approach with possible complications. In some cases, preoperative WNL marking of the marker itself is necessary. Invasive markings require specially educated staff, additional technical equipment, and financial expenses for equipment and markers. A recent meta-analysis reviewing published studies on different tumor marking techniques prior to NAST concludes: „There is limited evidence that tumor marking before neoadjuvant chemotherapy improves the rate of unsatisfactory margins or survival outcomes in a patient undergoing BCS after NAST“[ 21 ]. Methods As part of a prospective clinical study on the clinical significance of intensive and frequent monitoring of the therapeutic effects of NAST, which is currently being carried out, the diagnostic and surgical team of the UHMC "Bezanijska kosa" created its original technique of non-invasive three-dimensional positioning of the tumor in the breast by ultrasound before starting NAST, with repeated positioning of the tumor in regression during NAST, in order to optimize the surgical excision of the tumor bed after complete clinical regression. The essential difference compared to the standard techniques of pre-NAST tumor marking is the absence of any marker that would serve as a guide in post-NAST surgery, but rather a record of the three-dimensional spatial position of the tumor in the breast before and during NAST is used as a guide. In this text, we present a description of the technique and initial results. Radiologically (by ultrasound) visible or palpable residual tumor tissue is itself an adequate marker of the site of the tumor and of the extent of excision. Therefore, our target group includes only the patients in whom complete clinical tumor regression (CCR) (non-visible and non-palpable residues) occurred during NAST. The initial test of the oncological reliability of the procedure consists of histological reports on the presence of histological indicators of a pre-existing tumor in the excised specimen (edema, necrosis, vascularized hyalinization, foamy macrophages, lymphocytes, hemosiderin-laden macrophages, absence of normal ductal and lobular structures) or microscopic tumor residues, and histological margin status [ 22 ]. An intermediate test of the functionality and aesthetic effects of surgery is the ratio of the volume of the pre-NAST tumor to the volume of the resected tissue specimen. A delayed (prolonged) test of the oncological reliability of the procedure will be the local control of the disease - the frequency of local recurrences. Technique Description The three-dimensional position of the tumor in the breast is determined and recorded in measurement units relative to known landmarks: 1) the projection of the central point of the tumor on the skin, 2) the distance of the superficial margin of the tumor from the skin, 3) the distance of the deepest margin of the tumor from the pectoral fascia. Initially, a coordinate system of horizontal and vertical axes is drawn on the skin of the breast, which intersect at the nipple. Figure 1 illustrates drawing of the horizontal and vertical axis on the skin of the breast. The patient is positioned as being on the operating table, with her arms outstretched at right angles to the body axis. The central point of the tumor is determined by placing the ultrasound probe orthogonally to the surface of the skin above the tumor, in such a way that the largest section of the tumor is in the center of the ultrasound screen. Figure 2 shows position of the ultrasound probe above the central point of the tumor. Then, the distance from the center of the ultrasound probe to the corresponding axis drawn on the skin is measured with a ruler and this dimension is recorded. This procedure is performed in two directions, carnio-caudal and medio-lateral, requiring the probe to be absolutely parallel, first with the "x" and then with the "y" axis. Figures 3 and 4 illustrates determining the projection of the tumor central point on the skin. The distance of the center of the probe from the "x" axis represents the coordinate of the central point of the tumor on the "y" axis (the numerical values for tumors localized in the upper quadrants are positive, and the numerical values for tumors localized lower than the nipple negative). The distance of the center of the probe from the "y" axis represents the coordinate of the central point of the tumor on the "x" axis (the numerical values for tumors localized to the right of the nipple are positive, and the numerical values for tumors localized to the left of the nipple negative). During these measurements, the ultrasound dimensions of the largest diameters of the tumor in the craniocaudal and mediolateral direction are determined, as well as its vertical dimension (skin-fascia direction), the distance from the superficial margin of the tumor to the skin, the distance from the deepest margin of the tumor to the fascia. All these values are recorded. Figure 5 shows the ultrasound measurements. At the end of the procedure, we have the following dimensions: the largest diameter of the tumor in the craniocaudal and mediolateral direction, the vertical dimension of the tumor, the distance from the superficial margin of the tumor to the skin, the distance from the deepest margin of the tumor to the fascia, the coordinates of the central point of the tumor in relation to the coordinate system drawn on breast skin. These numerical values fully define the three-dimensional position of the tumor in the breast. (Table 1 ). Table 1 Standard record of performed tumor positioning – example of the tumor located in the lower inner quadrant of the right breast Name and Surname: Status of Neoadjuvant therapy: Before starting therapy ● After ________________ cycles of NAHT Breast : Right ● Left ○ Date of examination : Tumor dimensions : 1. cranio-caudal : 22mm 2. medio-lateral : 18mm 3. vertical : 28mm Distance between superficial margin of the tumor and the skin : 6mm Distance between deepest margin of the tumor and pectoral fascia : 0 mm Coordinates of tumor’s central point on the skin : X ossis + 32 mm Y ossis -22 mm The entire procedure is repeated on average every 6 weeks during NAST, in order to observe the way of tumor regression and possible spatial movements of the tumor caused by regression. With each ultrasound positioning a breast MRI is performed to check the ultrasound assessments and to evaluate more reliably the pattern of tumor regression – concentric or non-concentric (fragmentation or honeycomb pattern of tumor regression) [ 23 ]. The using of MRI does not aim to position the tumor in the breast, because of the different position of the patient during the US and MRI examinations. Important note: during positioning, the ultrasound probe must always be placed orthogonally to the skin surface and with the lightest possible pressure applied to the breast tissue, in order to avoid spatial deformations due to bending of the breast tissue. Before performing surgery, on the operating table, the procedure of drawing the coordinate system on the skin is repeated. The central point of the tumor is marked on the skin based on previously determined coordinates, and the cranio-caudal and medio-lateral margins of the tumor are marked on the skin based on the dimensions obtained during positioning. Figure 6 illustrates planning of the surgical excision of the tumor bed, based on the tumor positioning records. The skin incision is planned in view of the projection of the tumor on the skin, which is obtained by previously described measurements/techniques. Depending on the initial distance of the superficial margin of the tumor from the skin, a simple incision or excision of the part of the skin above the tumor is performed (if the distance of the superficial margin of the tumor from the skin is less than 10 mm]. Figure 7 shows planning of the skin incision line. Surgical resection of the tumor bed is performed with maximal avoidance of excessive traction and tissue bending, with frequently repeated observations and measurements of spatial relationships during the operation. The extent of resection depends on the pre-NAST size of the tumor and the way of tumor regression during therapy. For tumors smaller than 3 cm in the largest diameter before NAST, the resection of the tumor bed is performed a few millimeters "outside" the projected margins of the initial tumor. For tumors that before NAST had more than 3cm in the largest diameter and, established on MRI, had concentrical regression, resection of the lodge follows the projected margins of the last tumor residue as seen by ultrasound during NAST, in the same way as for tumors smaller than 3cm. In the case when the honeycomb pattern of tumor regression was evaluated by MRI, the resection of the lodge follows the projected margins of the initial tumor, regardless of the tissue defect. The specimen of the resected tissue is spatially oriented and delivered to the pathologist. The surgical resection adequacy is assessed by histologically verified residual tumor cells or secondary histological indicators of a pre-existing tumor that has completely regressed, as well as by the presence of histologically unchanged breast tissue in all directions around the target focus (margin status). The rationality of surgical excision (indirectly – aesthetic effect) is assessed with respect to the ratio of the resected specimen volume to the pre-NAST volume of the tumor. Results – Feasibility of the technique Of the 33 patients who underwent the pre-NAST three-dimensional positioning procedure and were finally operated on, two underwent surgery before completing NAST due to disease progression. In 19 patients, there were clinically detectable residues after the end of NAST, which is why the positioning technique was not used during the operation (Table 2 ). Table 2 Initial results of applying our original technique Total number of patients 63 Inadequate ultrasound visualization of the tumor 13 Adequately visualized tumors – technique applied 50 No of patients who completed NAST 33 No of patients in whom NAST was inerrupted due to disease progression 2 No of patients in whom the tehnique hasn’t been used due to the detectable residual tumor 19 No of patients with CCR and successfully applied technique 12 Type of operation in patients with CCR and successfully applied technique Mastectomy 2 BCS 10 pCR or residual tumor in patients with mastectomy pCR 2 Residual tumor 0 pCR or residual tumor in patients with BCS pCR 6 Residual tumor 4 The ratio of the resected specimen volume to the volume of the pre-NAST tumor 0,91 (0,1–2,38) Successfully performed excisions of tumor bed, based on histological parameters 12/12 Out of 12 patients with CCR (complete clinical regression), mastectomy was performed in two, due to the patient's wish or the surgeon's attitude. In these two cases, the position of the pre-existing tumor was marked in a mastectomy specimen, based on the initial positioning. Targeted histological processing of marked foci verified the signs of complete histological tumor regression (fibrosis, necrosis, stromal edema - pCR was achieved in both patients). These signs did not exist in the breast tisue outside the marked foci, which indirectly indicates the satisfactory precision of the three-dimensional positioning of the tumor before NAST. BCS was performed in 10 patients with CCR. In 6 of these 10 patients pCR was histologically verified, with the presence of histological signs of tumor regression in the excised specimen. In 4 patients there were microscopic foci of residual tumor cells in the excised specimen, with a negative margin status in all 4 cases. Fragmented tumor regression (honeycomb pattern) assessed by repeated MRI examinations was verified in 2/4 patients with microscopic residues and in 2/6 patients with pCR. Both mastectomy patients had a concentric pattern of tumor regression. The ratio of the resected specimen volume to the volume of the pre-NAST tumor (obtained as the product of three orthogonal dimensions of the specimen and the pre-NAST tumor) was on average 0,91 (from 0.1 to 2,38). Values less than 1 were achieved for tumors in which excision of the tumor bed was performed based on the positioning of the last residue visible by ultrasound during NAST (three cases). Discussion The main goal of our paper is to present the original technique of pre-NAST breast tumor positioning and post-NAST surgery based on that positioning, after complete clinical tumor regression. The secondary goal is to present theoretical assumptions concerning the possible advantages of the non-invasive positioning technique over standard tumor marking techniques. The initial results serve as an illustration of the feasibility of the technique and their purpose is not to form definitive conclusions about its validity. The need to specify the location of the tumor in the breast before NAST stems from the fact that a significant proportion of well-responsive tumors become clinically (palpatory and radiologically) undetectable after NAST. The lack of a precise orientation about the location of the pre-existing tumor in the breast prevents the surgeon from performing an oncologically adequate breast-conserving excision of the tumor site. Thus, one of the goals of NAST – enabling breast-conserving surgery in locally advanced tumors initially suitable only for mastectomy - loses its meaning, because the surgeon, in the abscence of orientation about the part of the breast to be excised, has no other choice but to perform a mastectomy. Oncologically adequate surgery still represents the conditio sine qua non of successful breast cancer treatment, therefore more important than the aesthetic effects of surgery. The appearance of local-regional recurrence, which is most often a consequence of inadequate or insufficient surgery, reduces the fifteen-year survival rate by as much as 25% [ 24 ]. Paradoxically, the effect of NAST on local control of disease is negative, probably for subjective reasons: tumor reduction after NAST motivates surgeons to perform breast sparing surgery in a significantly higher percentage than in primarily operated patients of the same initial stage; in the same time, post-NAST patients have a significantly higher percentage of local-regional recurrences compared to the same initial stage patients primarily treated surgically [ 25 ]. Obviously, the macroscopic impression is not the same as the microscopic fact. Clinical complete response (tumor undetectable by palpation and radiology) does not always correlate with pCR, and even achieved pCR is not a guarantee that there will be no local-regional recurrence or systemic disease progression. All these facts more than clearly indicate the importance of adequate surgical treatment after NAST. Clinically detectable residues of tumor tissue, or products of its decomposition after NAST, represent the most precise landmark about the position of the tumor before NAST and about the place and extent of excision [ 26 ]. Marking of the tumor position before NAST helps the accuracy of surgery only in the absence of these clinically detectable landmarks. Therefore, we tested the clinical benefit and precision of our marking technique only in patients with CCR, that is, in patients who do not have palpable and radiologically detectable manifestations of a pre-existing tumor. In our study, the percentage of utilization of prior and during NAST marking is 39% of all tumors that had partial or complete regression, that is, this proportion of tumors were clinically undetectable after NAST. In a recent systematic review of pre-NAST tumor marking techniques, the authors use margin status as the primary outcome mesure in assessing the advantage of tumor marking [ 21 ]. Patients with pCR are even excluded from analyzes of margin status, in order to obtain the “adjusted unsatisfactory margin”, since „patients with pCR cannot have an unsatisfactory margin“. This is in a sense opposed to our concept, which starts from the fact that the usefulness of pre-NAST tumor marking increases proportionally if there is less residual tumor tissue in the tumor bed, because residual tumor tissue is a satisfactory marker in itself. In cases of achieved pCR, there is the least amount of residual tissue that would serve as a marker, so then an alternative marker is most needed and its usefulness is most clearly observed in such cases. The verification of the clinical benefit of marking, i.e. the precision of surgery based only on the prior and during NAST marked tumor position, in our paper primarily rely on histological parameters that confirm that the lodge of the pre-existing tumor was successfully excised: histologically verified residual tumor cells or secondary histological indicators of a pre- existing tumor that has completely regressed. Margin status, defined as the presence of histologically unchanged breast tissue in all directions around the target focus, as well as the volume ratio of the pre-NAST tumor and the excised specimen, represent secondary parameters of surgical precision. The definitive test of the quality of surgical excision based on prior and during NAST marking will be local control of disease, based on five-year follow-up [ 4 ]. For some reason, at the very beginning of facing the serious clinical problem of marking the position of the tumor in the breast before NAST, a solution was sought in the techniques of invasive tumor marking. A non-invasive skin tumor projection tattoo technique before NAST, described by Lannin et al [ 2 ], was compared with a metal clip marking technique in a study by Espinosa-Bravo et al [ 3 ]. This study showed that operations guided by the tattoo technique lead to a significantly larger volume of excised tissue, adding no benefits to surgical margins. Our original technique of defining the three-dimensional tumor position in the breast before and during NAST is also non-invasive. Compared to the skin tattoo technique, it has two advantages: 1) determining the position of the tumor in three dimensions, and 2) dynamic monitoring of possible displacements of the tumor position due to regression during NAST. Successive monitoring of the regression pattern during NAST by MRI, which we recommend, further contributes to the precision of the technique. Dynamic monitoring of tumor regression during NAST represents a general advantage over one-time marking before NAST, which includes all invasive marking techniques. The disadvantages of invasive marking techniques mentioned in the introduction of our paper are described in the studies that deal with the results of their application. Their frequency, the statistical significance of that frequency, their clinical implications and other details... have no significance in terms of quantitatively comparing those disadvantages with our technique, because in our technique of non-invasive three-dimensional tumor positioning none of those disadvantages exist. If our technique shows non-inferiority in local disease control compared to invasive marking techniques, the absolute absence of the mentioned disadvantages would indicate its absolute advantage in clinical use compared to invasive marking techniques. Limitations of the Presented Technique Standard limitations of our technique are common to ultrasound-guided tumor marking techniques and pertain to the difficult ultrasound visualization of the tumor. Specific difficulties in performing positioning and later surgical excision originate from the consistency of the breast tissue, which bends and changes spatial relationships under the pressure of the ultrasound probe or during surgical work. This is especially pronounced with voluminous breasts. Inaccuracies that have this kind of origin can be avoided by extremely gentle manipulations during positioning and surgical excision, as emphasized in the technique description. Spatial orientation and positioning of the positive axillary lymph nodes are not covered by this text, but it is possible to apply the technique to axillary lymph nodes with a precise recording of the place and angle at which the ultrasound probe lies on the skin while visualizing a positive lymph node. Frequent MRI examinations somewhat complicate the procedure and make it more expensive; they are not necessary but contribute to the precision and reliability of the technique. Advantages of the Presented Technique The advantages of our technique over standard tumor marking procedures stem from overcoming and neutralizing the shortcomings of standard pre-NAST tumor marking techniques: 1) the presence of the third dimension and the absence of complications following invasive marking procedures; 2) the irrelevance of imprecise marker placement (missing the center of the tumor); 3) the absence of marker migration problems during NAST; 4) the absence of the poor marker visibility problem at the time of surgery; 5) no need for preoperative WNL marking; 6) more precise excision of the tumor bed in the case of eccentric or honeycomb tumor regression during NAST; 7) simplicity – the positioning technique can be applied by a radiologist or surgeon not trained in invasive marking techniques; it can be applied in health centers that do not have marking equipment; 8) more favorable cost-benefit ratio. Conclusion The paper presents a detailed description of an original technique for non-invasive three-dimensional positioning of the tumor in the breast before starting NAST, with the aim of optimizing the surgery after complete clinical regression of the tumor. Based on the initial results, the described technique of stereotaxic pre-NAST tumor positioning is feasible and shows a satisfactory level of oncological reliability and satisfactory aesthetic results of surgery, overcoming the shortcomings of standard pre-NAST tumor marking procedures. The follow-up period, as well as the number of performed procedures, is not sufficient for a definitive conclusions about its validity. The initial results of the feasibility of our technique justify the continuation of research and the performance of a prospective study comparing our technique with standard techniques of invasive tumor marking, in terms of five-year outcome (local disease free survival and overall survival ). Abbreviations NAST Neoadjuvant systemic therapy EBC early breast cancer pCR complete pathohistological response BCS Breast conservative surgery CCR Complete clinical regression ROLL radioguided ocult lesion localization WNL wire needle localization Declarations Ethics approval and consent to participate This study received approval from the institutional review and ethics board of the University Medical Hospital Center “Bezanijska kosa” (6042/1 from September 21 st ,2022) and patients provided informed consent for participation and sharing their data. Consent for publication All subjects provided written informed consent for their data to be used in publications. Availability of data and materials The data that support the findings of this study are available from the corresponding authors upon reasonable request . Competing interest The authors declare that they have no competing interests. Funding The authors state that this work has not received any funding. Authors contributions NI and DB designed the study; DB, BL, SP, SO, ZS, MG, OZ and KZ collected data; NI, DB and NC composed and translated the manuscript, DZ modified the manuscript, NC prepared the manuscript and figures for publication and submitted the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable Author information Dragana Bjelica and Natasa Colakovic contributed equaly. Authors and affiliations Department of Radiology, University Hospital Medical Center “Bežanijska kosa“, Zorza Matea bb, 11070 Belgrade, Serbia Dragana Bjelica Department of Surgical Oncology, University Hospital Medical Center “Bežanijska kosa“, Zorza Matea bb, 11070 Belgrade, Serbia Nebojsa Ivanovic, Natasa Colakovic, Darko Zdravkovic, Simona Petricevic, Barbara Loboda, Milan Gojgic, Zlatko Skuric Faculty of Medicine, University of Belgrade, dr Subotica 8, 11000 Belgrade, Serbia Nebojsa Ivanovic, Darko Zdravkovic, Natasa Colakovic, Simona Petricevic Department of pathology, University Hospital Medical Center “Bežanijska kosa“, Zorza Matea bb, 11070 Belgrade, Serbia Faculty of Dentistry Pancevo, Zarka Zrenjanina 179, 26000 Pancevo, Serbia Svetlana Opric Department of General Surgery, University Hospital Medical Center “Bežanijska kosa“, Zorza Matea bb, 11070 Belgrade, Serbia Ognjen Zecic Clinic for Gynecology and Obstetrics, Clinical Center of Serbia, Visegradska 26, 11000 Belgrade, Serbia Katarina Zecic References Minella C, Villasco A, D’Alonzo M, Cellini L, Accomasso F, Actis S et al. Surgery after Neoadjuvant Chemotherapy: A Clip-Based Technique to Improve Surgical Outcomes, a Single-Center Experience. Cancers 2022;14[ 9]:2229. Lannin DR, Grube B, Black DS, Ponn T. Breast tattoos for planning surgery following neoadjuvant chemotherapy. Am J Surg 2007;194[ 4]:518 – 20. Espinosa-Bravo M, Sao Avilés A, Esgueva A, Córdoba O, Rodriguez J, Cortadellas T et al. Breast conservative surgery after neoadjuvant chemotherapy in breast cancer patients: Comparison of two tumor localization methods. Eur J Surg Oncol. 2011;37[ 12]:1038–43. Oh JL, Nguyen G, Whitman GJ, Hunt KK, Yu TK, Woodward WA et al. Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy and breast conservation therapy. Cancer. 2007;110[ 11]:2420–7. Cha C, Lee J, Kim D, Park S, Bae SJ, Eun NL et al. Comparison of resection margin status after single or double radiopaque marker insertion for tumor localization in breast cancer patients receiving neoadjuvant chemotherapy. Breast Cancer Res Treat. 2020;184[ 3]:797–803. Alonso-Bartolome P, Ortega Garcia E, Garijo Ayensa F, de Juan Ferre A, Vega Bolivar A. Utility of the tumor bed marker in patients with breast cancer receiving induction chemotherapy. Acta Radiol. 2002;43[ 1]:29–33. Ramos M, Díez JC, Ramos T, Ruano R, Sancho M, González-Orús JM. Intraoperative ultrasound in conservative surgery for non-palpable breast cancer after neoadjuvant chemotherapy. Int J Surg. 2014;12[ 6]:572–7. Janssen NNY, Nijkamp J, Alderliesten T, Loo CE, Rutgers EJTh, Sonke JJ, et al. Radioactive seed localization in breast cancer treatment. Br J Surg. 2015;103:70–80. Van Riet YEA, Maaskant AJG, Creemers GJ, Van Warmerdam LJC, Jansen FH, Van de Veldeet CJH et al. Identification of residual breast tumour localization after neo-adjuvant chemotherapy using a radioactive 125 Iodine seed. Eur J Surg Oncol. 2010;36[ 2]:164–9. Alderliesten T, Loo CE, Pengel KE, Rutgers EJT, Gilhuijs KGA, Vrancken Peeters MJTFD. Radioactive Seed Localization of Breast Lesions: An Adequate Localization Method without Seed Migration. Breast J 2011;17[ 6]:594–601. Gobardhan PD, de Wall LL, Van der Laan L, ten Tije AJ, Van der Meer DCH, Tetteroo E et al. The role of radioactive iodine-125 seed localization in breast-conserving therapy following neoadjuvant chemotherapy. Ann Oncol. 2013;24[ 3]:668–73. Donker M, Drukker CA, Valdés Olmos RA, Rutgers EJTh, Loo CE, Sonke GS et al. Guiding Breast-Conserving Surgery in Patients After Neoadjuvant Systemic Therapy for Breast Cancer: A Comparison of Radioactive Seed Localization with the ROLL Technique. Ann Surg Oncol. 2013;20[ 8]:2569–75. Donker M, Straver ME, Rutgers EJTh RA, Loo CE, Sonke GS et al. Radioguided occult lesion localisation [ ROLL] in breast-conserving surgery after neoadjuvant chemotherapy. Eur J Surg Oncol. 2012;38[ 12]:1218–24. Aggarwal V, Agarwal G, Lal P, Krishnani N, Mishra A, Verma AK et al. Feasibility Study of Safe Breast Conservation in Large and Locally Advanced Cancers with Use of Radiopaque Markers to Mark Pre-Neoadjuvant Chemotherapy Tumor Margins. World J Surg. 2007;32[ 12]:2562–9. Hossam A, El-Badrawy A, Khater A, Setit A, Roshdy S, Abdelwahab K et al. The Evaluation of a Cost-Effective Method for Tumour Marking Prior to Neo-Adjuvant Chemotherapy Using Silver Rods. Eur J Breast Health. 2022;19[ 1]:99–105. Sever AR, O’Brien MER, Humphreys S, Singh I, Jones SE, Jones PA. Radiopaque coil insertion into breast cancers prior to neoadjuvant chemotherapy. Breast. 2005;14:108–17. Rubio IT, Esgueva-Colmenarejo A, Espinosa-Bravo M, Salazar JP, Miranda I, Peg V. Intraoperative Ultrasound-Guided Lumpectomy Versus Mammographic Wire Localization for Breast Cancer Patients After Neoadjuvant Treatment. Ann Surg Oncol. 2015;23[ 1]:38–43. Almalki H, Rankin AC, Juette A, Youssef MMG. Radio-frequency identification [ RFID] tag localisation of non-palpable breast lesions a single centre experience. Breast. 2023;69:417–21. Thomassin-Naggara I, Lalonde L, David J, Darai E, Uzan S, Trop I. A plea for the biopsy marker: how, why and why not clipping after breast biopsy? Breast Cancer Res Treat. 2011;132[ 3]:881–93. Green RT, Weiser R, Golan O, Menes TS. In Search of the Lost Clip: Outcome of Women After Needle-Guided Lumpectomy of a Marking Clip. Ann Surg Oncol. 2021;28:4974–80. Jha CK, Johri G, Singh PK, Yadav SK, Sinha U. Does Tumor Marking Before Neoadjuvant Chemotherapy Helps Achieve Better Outcomes in Patients Undergoing Breast Conservative Surgery? A Systematic Review. Indian J Surg Oncol. 2021;12[ 3]:624–31. Fusco N, Rizzo A, Costarelli L, Santinelli A, Cerbelli B, Scatena C et al. Pathological examination of breast cancer samples before and after neoadjuvant therapy: recommendations from the Italian Group for the Study of Breast Pathology - Italian Society of Pathology [ GIPaM-SIAPeC]. Pathologica 2022;114[ 2]:104–10. Bi Z, Qiu PF, Yang T, Chen P, Song XR, Zhao T, et al. The modified shrinkage classification modes could help to guide breast conserving surgery after neoadjuvant therapy in breast cancer. Front Oncol. 2022;12:982011. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet. 2005;365:1687–717. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018;19:27–39. Nebojsa Ivanovic D, Bjelica B, Loboda M, Bogdanovski N, Colakovic S, Petricevic M, Gojgic O, Zecic. Katarina Zecic, Darko Zdravkovic. Changing the role of pCR in breast cancer treatment - an unjustifiable interpretation of a good prognosticfactor as a factor for a good prognosis. Front Oncol, 18 July 2023, Sec. Breast Cancer.13–2023. Additional Declarations No competing interests reported. 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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-4064076","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Method Article","associatedPublications":[],"authors":[{"id":278479370,"identity":"65d01a0a-1209-45c1-99ed-c2c87bbc5d6e","order_by":0,"name":"Dragana Bjelica","email":"","orcid":"","institution":"University Hospital Medical Center “Bežanijska kosa“","correspondingAuthor":false,"prefix":"","firstName":"Dragana","middleName":"","lastName":"Bjelica","suffix":""},{"id":278479371,"identity":"8e0ae4b0-6d6b-43d1-85e7-967248397146","order_by":1,"name":"Natasa 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10:18:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4064076/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4064076/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52623179,"identity":"631f6b5a-60c8-4161-a4aa-bd54b9b5eee8","added_by":"auto","created_at":"2024-03-13 17:18:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1073826,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-4064076/v1/f269ca29fb17592dc595f259.png"},{"id":52623180,"identity":"23c94de7-b14d-456a-9779-40a645863254","added_by":"auto","created_at":"2024-03-13 17:18:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":36447,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure 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legend\u003c/p\u003e","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-4064076/v1/de88ac9cac207b60dca08415.png"},{"id":52623183,"identity":"7f12004e-ab28-479e-8227-b197773f5afc","added_by":"auto","created_at":"2024-03-13 17:18:27","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":952051,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-4064076/v1/2d3b19889426d3e1dd532d4c.png"},{"id":52623184,"identity":"4b2ed990-be4a-49b7-98d2-06812b282ef5","added_by":"auto","created_at":"2024-03-13 17:18:27","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1013354,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig.6.png","url":"https://assets-eu.researchsquare.com/files/rs-4064076/v1/bf81bd85f2a0df6d339c2bf3.png"},{"id":52623182,"identity":"ba6352ed-65a6-4392-b458-1d3543326e92","added_by":"auto","created_at":"2024-03-13 17:18:27","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":898945,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig.7.png","url":"https://assets-eu.researchsquare.com/files/rs-4064076/v1/dffe8e2aef8fd4f31f6c613a.png"},{"id":54625630,"identity":"599c3c99-3c85-4eb3-b595-d28f472d6c11","added_by":"auto","created_at":"2024-04-13 14:01:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4868052,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4064076/v1/06574700-c954-4ee1-a0e8-d909ffebf515.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Non-Invasive Three-Dimensional Breast Tumor Positioning Before Neoadjuvant Systemic Therapy as Promissing Alternative to the Invasive Tumor Marking – Technique Description and Feasibility","fulltext":[{"header":"Background","content":"\u003cp\u003eNeoadjuvant systemic therapy (NAST) of breast cancer has produced a special kind of challenge for surgeons: adequate excision of the tumor bed after significant regression or complete disappearance of tumor tissue in the breast, when the area of pre-existing tumor cannot be identified radiologically or by palpation. Surgical excision of the tumor bed is necessary for the histological verification of the degree of regression or complete pathohistological response (pCR). The lack of orientation regarding the location of the pre-existing tumor often leads surgeons to decide to perform a mastectomy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], which is something paradoxical in relation to one of the main goals of NAST - enabling breast conservative surgery (BCS).\u003c/p\u003e \u003cp\u003eAlong with the increasing therapeutic efficiency of NAST and the increased percentage of achieved pCR, tumor marking techniques before the start of therapy gradually gained importance, to enable precise excision of the tumor bed after complete tumor regression.\u003c/p\u003e \u003cp\u003eSo far, several pre-NAST marking techniques have been described in the literature: tattoos on the skin in the projection of the tumor tissue [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] placement of radiopaque clip in the center of the tumor [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], tumor marking with radioactive seed [\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], ROLL [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], silver wire around the tumor (bracketing) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], radiopaque coil insertion [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], hydrogel markers [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], radiofrequency tag [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe abundance of techniques indicates in itself that none of the above marking techniques is ideal. That is, each of the listed techniques has its own drawbacks, regardless of their intensity and frequency: lack of a third dimension (tattoo on the skin); the ideal positioning of markers is not always achievable in practice (all techniques); additional requirements and inconveniences of working with radioactive material (ROLL and radioactive seed); objective limitations in the orientation with regard to the place and extent of excision based on an individual punctiform marker; migration of markers during NAST; difficult visibility of markers after NAST [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Different patterns of tumor regression during NAST (concentric or non-concentric) limit the accuracy of excision of the tumor bed, regardless of the way of marking. Bracketing marking is more reliable than central marking, but it is technically more demanding and requires a wider excision than a potentially sufficient one. All the techniques except tattoo imply an invasive approach with possible complications. In some cases, preoperative WNL marking of the marker itself is necessary. Invasive markings require specially educated staff, additional technical equipment, and financial expenses for equipment and markers.\u003c/p\u003e \u003cp\u003eA recent meta-analysis reviewing published studies on different tumor marking techniques prior to NAST concludes: \u0026bdquo;There is limited evidence that tumor marking before neoadjuvant chemotherapy improves the rate of unsatisfactory margins or survival outcomes in a patient undergoing BCS after NAST\u0026ldquo;[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eAs part of a prospective clinical study on the clinical significance of intensive and frequent monitoring of the therapeutic effects of NAST, which is currently being carried out, the diagnostic and surgical team of the UHMC \"Bezanijska kosa\" created its original technique of non-invasive three-dimensional positioning of the tumor in the breast by ultrasound before starting NAST, with repeated positioning of the tumor in regression during NAST, in order to optimize the surgical excision of the tumor bed after complete clinical regression. The essential difference compared to the standard techniques of pre-NAST tumor marking is the absence of any marker that would serve as a guide in post-NAST surgery, but rather a record of the three-dimensional spatial position of the tumor in the breast before and during NAST is used as a guide. In this text, we present a description of the technique and initial results.\u003c/p\u003e \u003cp\u003eRadiologically (by ultrasound) visible or palpable residual tumor tissue is itself an adequate marker of the site of the tumor and of the extent of excision. Therefore, our target group includes only the patients in whom complete clinical tumor regression (CCR) (non-visible and non-palpable residues) occurred during NAST.\u003c/p\u003e \u003cp\u003eThe initial test of the oncological reliability of the procedure consists of histological reports on the presence of histological indicators of a pre-existing tumor in the excised specimen (edema, necrosis, vascularized hyalinization, foamy macrophages, lymphocytes, hemosiderin-laden macrophages, absence of normal ductal and lobular structures) or microscopic tumor residues, and histological margin status [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. An intermediate test of the functionality and aesthetic effects of surgery is the ratio of the volume of the pre-NAST tumor to the volume of the resected tissue specimen. A delayed (prolonged) test of the oncological reliability of the procedure will be the local control of the disease - the frequency of local recurrences.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTechnique Description\u003c/h2\u003e \u003cp\u003eThe three-dimensional position of the tumor in the breast is determined and recorded in measurement units relative to known landmarks: 1) the projection of the central point of the tumor on the skin, 2) the distance of the superficial margin of the tumor from the skin, 3) the distance of the deepest margin of the tumor from the pectoral fascia.\u003c/p\u003e \u003cp\u003eInitially, a coordinate system of horizontal and vertical axes is drawn on the skin of the breast, which intersect at the nipple. Figure\u0026nbsp;1 illustrates drawing of the horizontal and vertical axis on the skin of the breast. The patient is positioned as being on the operating table, with her arms outstretched at right angles to the body axis.\u003c/p\u003e \u003cp\u003eThe central point of the tumor is determined by placing the ultrasound probe orthogonally to the surface of the skin above the tumor, in such a way that the largest section of the tumor is in the center of the ultrasound screen. Figure\u0026nbsp;2 shows position of the ultrasound probe above the central point of the tumor.\u003c/p\u003e \u003cp\u003eThen, the distance from the center of the ultrasound probe to the corresponding axis drawn on the skin is measured with a ruler and this dimension is recorded. This procedure is performed in two directions, carnio-caudal and medio-lateral, requiring the probe to be absolutely parallel, first with the \"x\" and then with the \"y\" axis. Figures\u0026nbsp;3 and 4 illustrates determining the projection of the tumor central point on the skin.\u003c/p\u003e \u003cp\u003eThe distance of the center of the probe from the \"x\" axis represents the coordinate of the central point of the tumor on the \"y\" axis (the numerical values for tumors localized in the upper quadrants are positive, and the numerical values for tumors localized lower than the nipple negative). The distance of the center of the probe from the \"y\" axis represents the coordinate of the central point of the tumor on the \"x\" axis (the numerical values for tumors localized to the right of the nipple are positive, and the numerical values for tumors localized to the left of the nipple negative).\u003c/p\u003e \u003cp\u003eDuring these measurements, the ultrasound dimensions of the largest diameters of the tumor in the craniocaudal and mediolateral direction are determined, as well as its vertical dimension (skin-fascia direction), the distance from the superficial margin of the tumor to the skin, the distance from the deepest margin of the tumor to the fascia. All these values are recorded. Figure\u0026nbsp;5 shows the ultrasound measurements.\u003c/p\u003e \u003cp\u003eAt the end of the procedure, we have the following dimensions: the largest diameter of the tumor in the craniocaudal and mediolateral direction, the vertical dimension of the tumor, the distance from the superficial margin of the tumor to the skin, the distance from the deepest margin of the tumor to the fascia, the coordinates of the central point of the tumor in relation to the coordinate system drawn on breast skin. These numerical values fully define the three-dimensional position of the tumor in the breast. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStandard record of performed tumor positioning \u0026ndash; example of the tumor located in the lower inner quadrant of the right breast\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eName and Surname:\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatus of Neoadjuvant therapy:\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eBefore starting therapy ●\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAfter ________________ cycles of NAHT\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBreast\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eRight ●\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eLeft ○\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDate of examination\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor dimensions\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1. cranio-caudal\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22mm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2. medio-lateral\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18mm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3. vertical\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28mm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDistance between superficial margin of the tumor and the skin\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e6mm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDistance between deepest margin of the tumor and pectoral fascia\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0 mm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCoordinates of tumor\u0026rsquo;s central point on the skin\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eX ossis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;32 mm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eY ossis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-22 mm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe entire procedure is repeated on average every 6 weeks during NAST, in order to observe the way of tumor regression and possible spatial movements of the tumor caused by regression. With each ultrasound positioning a breast MRI is performed to check the ultrasound assessments and to evaluate more reliably the pattern of tumor regression \u0026ndash; concentric or non-concentric (fragmentation or honeycomb pattern of tumor regression) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The using of MRI does not aim to position the tumor in the breast, because of the different position of the patient during the US and MRI examinations.\u003c/p\u003e \u003cp\u003eImportant note: during positioning, the ultrasound probe must always be placed orthogonally to the skin surface and with the lightest possible pressure applied to the breast tissue, in order to avoid spatial deformations due to bending of the breast tissue.\u003c/p\u003e \u003cp\u003eBefore performing surgery, on the operating table, the procedure of drawing the coordinate system on the skin is repeated. The central point of the tumor is marked on the skin based on previously determined coordinates, and the cranio-caudal and medio-lateral margins of the tumor are marked on the skin based on the dimensions obtained during positioning. Figure\u0026nbsp;6 illustrates planning of the surgical excision of the tumor bed, based on the tumor positioning records.\u003c/p\u003e \u003cp\u003eThe skin incision is planned in view of the projection of the tumor on the skin, which is obtained by previously described measurements/techniques. Depending on the initial distance of the superficial margin of the tumor from the skin, a simple incision or excision of the part of the skin above the tumor is performed (if the distance of the superficial margin of the tumor from the skin is less than 10 mm]. Figure\u0026nbsp;7 shows planning of the skin incision line.\u003c/p\u003e \u003cp\u003eSurgical resection of the tumor bed is performed with maximal avoidance of excessive traction and tissue bending, with frequently repeated observations and measurements of spatial relationships during the operation.\u003c/p\u003e \u003cp\u003eThe extent of resection depends on the pre-NAST size of the tumor and the way of tumor regression during therapy. For tumors smaller than 3 cm in the largest diameter before NAST, the resection of the tumor bed is performed a few millimeters \"outside\" the projected margins of the initial tumor. For tumors that before NAST had more than 3cm in the largest diameter and, established on MRI, had concentrical regression, resection of the lodge follows the projected margins of the last tumor residue as seen by ultrasound during NAST, in the same way as for tumors smaller than 3cm. In the case when the honeycomb pattern of tumor regression was evaluated by MRI, the resection of the lodge follows the projected margins of the initial tumor, regardless of the tissue defect.\u003c/p\u003e \u003cp\u003eThe specimen of the resected tissue is spatially oriented and delivered to the pathologist.\u003c/p\u003e \u003cp\u003eThe surgical resection adequacy is assessed by histologically verified residual tumor cells or secondary histological indicators of a pre-existing tumor that has completely regressed, as well as by the presence of histologically unchanged breast tissue in all directions around the target focus (margin status).\u003c/p\u003e \u003cp\u003eThe rationality of surgical excision (indirectly \u0026ndash; aesthetic effect) is assessed with respect to the ratio of the resected specimen volume to the pre-NAST volume of the tumor.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results – Feasibility of the technique","content":" \u003cp\u003eOf the 33 patients who underwent the pre-NAST three-dimensional positioning procedure and were finally operated on, two underwent surgery before completing NAST due to disease progression. In 19 patients, there were clinically detectable residues after the end of NAST, which is why the positioning technique was not used during the operation (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInitial results of applying our original technique\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal number of patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInadequate ultrasound visualization of the tumor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAdequately visualized tumors \u0026ndash; technique applied\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo of patients who completed NAST\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo of patients in whom NAST was inerrupted due to disease progression\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo of patients in whom the tehnique hasn\u0026rsquo;t been used due to the detectable residual tumor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo of patients with CCR and successfully applied technique\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType of operation in patients with CCR and successfully applied technique\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003epCR or residual tumor in patients with mastectomy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eResidual tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003epCR or residual tumor in patients with BCS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eResidual tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThe ratio of the resected specimen volume to the volume of the pre-NAST tumor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e0,91 (0,1\u0026ndash;2,38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSuccessfully performed excisions of tumor bed, based on histological parameters\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e12/12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOut of 12 patients with CCR (complete clinical regression), mastectomy was performed in two, due to the patient's wish or the surgeon's attitude. In these two cases, the position of the pre-existing tumor was marked in a mastectomy specimen, based on the initial positioning. Targeted histological processing of marked foci verified the signs of complete histological tumor regression (fibrosis, necrosis, stromal edema - pCR was achieved in both patients). These signs did not exist in the breast tisue outside the marked foci, which indirectly indicates the satisfactory precision of the three-dimensional positioning of the tumor before NAST.\u003c/p\u003e \u003cp\u003eBCS was performed in 10 patients with CCR. In 6 of these 10 patients pCR was histologically verified, with the presence of histological signs of tumor regression in the excised specimen. In 4 patients there were microscopic foci of residual tumor cells in the excised specimen, with a negative margin status in all 4 cases.\u003c/p\u003e \u003cp\u003eFragmented tumor regression (honeycomb pattern) assessed by repeated MRI examinations was verified in 2/4 patients with microscopic residues and in 2/6 patients with pCR. Both mastectomy patients had a concentric pattern of tumor regression.\u003c/p\u003e \u003cp\u003eThe ratio of the resected specimen volume to the volume of the pre-NAST tumor (obtained as the product of three orthogonal dimensions of the specimen and the pre-NAST tumor) was on average 0,91 (from 0.1 to 2,38). Values less than 1 were achieved for tumors in which excision of the tumor bed was performed based on the positioning of the last residue visible by ultrasound during NAST (three cases).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe main goal of our paper is to present the original technique of pre-NAST breast tumor positioning and post-NAST surgery based on that positioning, after complete clinical tumor regression. The secondary goal is to present theoretical assumptions concerning the possible advantages of the non-invasive positioning technique over standard tumor marking techniques. The initial results serve as an illustration of the feasibility of the technique and their purpose is not to form definitive conclusions about its validity.\u003c/p\u003e \u003cp\u003eThe need to specify the location of the tumor in the breast before NAST stems from the fact that a significant proportion of well-responsive tumors become clinically (palpatory and radiologically) undetectable after NAST. The lack of a precise orientation about the location of the pre-existing tumor in the breast prevents the surgeon from performing an oncologically adequate breast-conserving excision of the tumor site. Thus, one of the goals of NAST \u0026ndash; enabling breast-conserving surgery in locally advanced tumors initially suitable only for mastectomy - loses its meaning, because the surgeon, in the abscence of orientation about the part of the breast to be excised, has no other choice but to perform a mastectomy.\u003c/p\u003e \u003cp\u003eOncologically adequate surgery still represents the conditio sine qua non of successful breast cancer treatment, therefore more important than the aesthetic effects of surgery. The appearance of local-regional recurrence, which is most often a consequence of inadequate or insufficient surgery, reduces the fifteen-year survival rate by as much as 25% [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Paradoxically, the effect of NAST on local control of disease is negative, probably for subjective reasons: tumor reduction after NAST motivates surgeons to perform breast sparing surgery in a significantly higher percentage than in primarily operated patients of the same initial stage; in the same time, post-NAST patients have a significantly higher percentage of local-regional recurrences compared to the same initial stage patients primarily treated surgically [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Obviously, the macroscopic impression is not the same as the microscopic fact. Clinical complete response (tumor undetectable by palpation and radiology) does not always correlate with pCR, and even achieved pCR is not a guarantee that there will be no local-regional recurrence or systemic disease progression. All these facts more than clearly indicate the importance of adequate surgical treatment after NAST.\u003c/p\u003e \u003cp\u003eClinically detectable residues of tumor tissue, or products of its decomposition after NAST, represent the most precise landmark about the position of the tumor before NAST and about the place and extent of excision [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Marking of the tumor position before NAST helps the accuracy of surgery only in the absence of these clinically detectable landmarks. Therefore, we tested the clinical benefit and precision of our marking technique only in patients with CCR, that is, in patients who do not have palpable and radiologically detectable manifestations of a pre-existing tumor. In our study, the percentage of utilization of prior and during NAST marking is 39% of all tumors that had partial or complete regression, that is, this proportion of tumors were clinically undetectable after NAST.\u003c/p\u003e \u003cp\u003eIn a recent systematic review of pre-NAST tumor marking techniques, the authors use margin status as the primary outcome mesure in assessing the advantage of tumor marking [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Patients with pCR are even excluded from analyzes of margin status, in order to obtain the \u0026ldquo;adjusted unsatisfactory margin\u0026rdquo;, since \u0026bdquo;patients with pCR cannot have an unsatisfactory margin\u0026ldquo;. This is in a sense opposed to our concept, which starts from the fact that the usefulness of pre-NAST tumor marking increases proportionally if there is less residual tumor tissue in the tumor bed, because residual tumor tissue is a satisfactory marker in itself. In cases of achieved pCR, there is the least amount of residual tissue that would serve as a marker, so then an alternative marker is most needed and its usefulness is most clearly observed in such cases.\u003c/p\u003e \u003cp\u003eThe verification of the clinical benefit of marking, i.e. the precision of surgery based only on the prior and during NAST marked tumor position, in our paper primarily rely on histological parameters that confirm that the lodge of the pre-existing tumor was successfully excised: histologically verified residual tumor cells or secondary histological indicators of a pre- existing tumor that has completely regressed. Margin status, defined as the presence of histologically unchanged breast tissue in all directions around the target focus, as well as the volume ratio of the pre-NAST tumor and the excised specimen, represent secondary parameters of surgical precision. The definitive test of the quality of surgical excision based on prior and during NAST marking will be local control of disease, based on five-year follow-up [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor some reason, at the very beginning of facing the serious clinical problem of marking the position of the tumor in the breast before NAST, a solution was sought in the techniques of invasive tumor marking. A non-invasive skin tumor projection tattoo technique before NAST, described by Lannin et al [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], was compared with a metal clip marking technique in a study by Espinosa-Bravo et al [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This study showed that operations guided by the tattoo technique lead to a significantly larger volume of excised tissue, adding no benefits to surgical margins. Our original technique of defining the three-dimensional tumor position in the breast before and during NAST is also non-invasive. Compared to the skin tattoo technique, it has two advantages: 1) determining the position of the tumor in three dimensions, and 2) dynamic monitoring of possible displacements of the tumor position due to regression during NAST. Successive monitoring of the regression pattern during NAST by MRI, which we recommend, further contributes to the precision of the technique. Dynamic monitoring of tumor regression during NAST represents a general advantage over one-time marking before NAST, which includes all invasive marking techniques.\u003c/p\u003e \u003cp\u003eThe disadvantages of invasive marking techniques mentioned in the introduction of our paper are described in the studies that deal with the results of their application. Their frequency, the statistical significance of that frequency, their clinical implications and other details... have no significance in terms of quantitatively comparing those disadvantages with our technique, because in our technique of non-invasive three-dimensional tumor positioning none of those disadvantages exist. If our technique shows non-inferiority in local disease control compared to invasive marking techniques, the absolute absence of the mentioned disadvantages would indicate its absolute advantage in clinical use compared to invasive marking techniques.\u003c/p\u003e\n\u003ch3\u003eLimitations of the Presented Technique\u003c/h3\u003e\n\u003cp\u003eStandard limitations of our technique are common to ultrasound-guided tumor marking techniques and pertain to the difficult ultrasound visualization of the tumor. Specific difficulties in performing positioning and later surgical excision originate from the consistency of the breast tissue, which bends and changes spatial relationships under the pressure of the ultrasound probe or during surgical work. This is especially pronounced with voluminous breasts. Inaccuracies that have this kind of origin can be avoided by extremely gentle manipulations during positioning and surgical excision, as emphasized in the technique description.\u003c/p\u003e \u003cp\u003eSpatial orientation and positioning of the positive axillary lymph nodes are not covered by this text, but it is possible to apply the technique to axillary lymph nodes with a precise recording of the place and angle at which the ultrasound probe lies on the skin while visualizing a positive lymph node.\u003c/p\u003e \u003cp\u003eFrequent MRI examinations somewhat complicate the procedure and make it more expensive; they are not necessary but contribute to the precision and reliability of the technique.\u003c/p\u003e\n\u003ch3\u003eAdvantages of the Presented Technique\u003c/h3\u003e\n\u003cp\u003eThe advantages of our technique over standard tumor marking procedures stem from overcoming and neutralizing the shortcomings of standard pre-NAST tumor marking techniques: 1) the presence of the third dimension and the absence of complications following invasive marking procedures; 2) the irrelevance of imprecise marker placement (missing the center of the tumor); 3) the absence of marker migration problems during NAST; 4) the absence of the poor marker visibility problem at the time of surgery; 5) no need for preoperative WNL marking; 6) more precise excision of the tumor bed in the case of eccentric or honeycomb tumor regression during NAST; 7) simplicity \u0026ndash; the positioning technique can be applied by a radiologist or surgeon not trained in invasive marking techniques; it can be applied in health centers that do not have marking equipment; 8) more favorable cost-benefit ratio.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe paper presents a detailed description of an original technique for non-invasive three-dimensional positioning of the tumor in the breast before starting NAST, with the aim of optimizing the surgery after complete clinical regression of the tumor. Based on the initial results, the described technique of stereotaxic pre-NAST tumor positioning is feasible and shows a satisfactory level of oncological reliability and satisfactory aesthetic results of surgery, overcoming the shortcomings of standard pre-NAST tumor marking procedures. The follow-up period, as well as the number of performed procedures, is not sufficient for a definitive conclusions about its validity.\u003c/p\u003e \u003cp\u003eThe initial results of the feasibility of our technique justify the continuation of research and the performance of a prospective study comparing our technique with standard techniques of invasive tumor marking, in terms of five-year outcome (local disease free survival and overall survival ).\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eNAST\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNeoadjuvant systemic therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eEBC\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eearly breast cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003epCR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomplete pathohistological response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eBCS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBreast conservative surgery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCCR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComplete clinical regression\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eROLL\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eradioguided ocult lesion localization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eWNL\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ewire needle localization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received approval from the institutional review and ethics board of the University Medical Hospital Center \u0026ldquo;Bezanijska kosa\u0026rdquo; (6042/1 from September 21\u003csup\u003est\u003c/sup\u003e,2022) and patients provided informed consent for participation and sharing their data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll subjects\u0026nbsp;provided\u0026nbsp;written\u0026nbsp;informed consent for\u0026nbsp;their data to be used in publications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding authors upon reasonable request\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors state that this work has not received any funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Authors contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;NI and DB designed the study; DB, BL, SP, SO, ZS, MG, OZ and KZ collected data; NI, DB \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; and NC composed and translated the manuscript, DZ modified the manuscript, NC prepared the manuscript and figures for publication and submitted the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDragana Bjelica and Natasa Colakovic \u0026nbsp;contributed equaly.\u003c/p\u003e\n\u003cp\u003eAuthors and affiliations\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDepartment of Radiology, University Hospital Medical Center \u0026ldquo;Bežanijska kosa\u0026ldquo;, Zorza Matea bb, \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;11070 Belgrade, Serbia\u003c/p\u003e\n\u003cp\u003eDragana Bjelica\u003c/p\u003e\n\u003cp\u003eDepartment of Surgical Oncology, University Hospital Medical Center \u0026ldquo;Bežanijska kosa\u0026ldquo;, Zorza Matea bb, 11070 Belgrade, Serbia\u003c/p\u003e\n\u003cp\u003eNebojsa Ivanovic, Natasa Colakovic, Darko Zdravkovic, Simona Petricevic, Barbara Loboda, Milan Gojgic, Zlatko Skuric\u003c/p\u003e\n\u003cp\u003eFaculty of Medicine, University of Belgrade, dr Subotica 8, 11000 Belgrade, Serbia\u003c/p\u003e\n\u003cp\u003eNebojsa Ivanovic, Darko Zdravkovic, Natasa Colakovic, Simona Petricevic\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDepartment of pathology, University Hospital Medical Center \u0026ldquo;Bežanijska kosa\u0026ldquo;, Zorza Matea bb, 11070 Belgrade, Serbia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFaculty of Dentistry Pancevo, Zarka Zrenjanina 179, 26000 Pancevo, Serbia\u003c/p\u003e\n\u003cp\u003eSvetlana Opric\u003c/p\u003e\n\u003cp\u003eDepartment of General Surgery, University Hospital Medical Center \u0026ldquo;Bežanijska kosa\u0026ldquo;, Zorza Matea bb, 11070 Belgrade, Serbia\u003c/p\u003e\n\u003cp\u003eOgnjen Zecic\u003c/p\u003e\n\u003cp\u003eClinic for Gynecology and Obstetrics, Clinical Center of Serbia, Visegradska 26, 11000 Belgrade, Serbia\u003c/p\u003e\n\u003cp\u003eKatarina Zecic\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMinella C, Villasco A, D\u0026rsquo;Alonzo M, Cellini L, Accomasso F, Actis S et al. Surgery after Neoadjuvant Chemotherapy: A Clip-Based Technique to Improve Surgical Outcomes, a Single-Center Experience. Cancers 2022;14[ 9]:2229.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLannin DR, Grube B, Black DS, Ponn T. Breast tattoos for planning surgery following neoadjuvant chemotherapy. Am J Surg 2007;194[ 4]:518\u0026thinsp;\u0026ndash;\u0026thinsp;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEspinosa-Bravo M, Sao Avil\u0026eacute;s A, Esgueva A, C\u0026oacute;rdoba O, Rodriguez J, Cortadellas T et al. Breast conservative surgery after neoadjuvant chemotherapy in breast cancer patients: Comparison of two tumor localization methods. Eur J Surg Oncol. 2011;37[ 12]:1038\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOh JL, Nguyen G, Whitman GJ, Hunt KK, Yu TK, Woodward WA et al. Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy and breast conservation therapy. Cancer. 2007;110[ 11]:2420\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCha C, Lee J, Kim D, Park S, Bae SJ, Eun NL et al. Comparison of resection margin status after single or double radiopaque marker insertion for tumor localization in breast cancer patients receiving neoadjuvant chemotherapy. Breast Cancer Res Treat. 2020;184[ 3]:797\u0026ndash;803.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlonso-Bartolome P, Ortega Garcia E, Garijo Ayensa F, de Juan Ferre A, Vega Bolivar A. Utility of the tumor bed marker in patients with breast cancer receiving induction chemotherapy. Acta Radiol. 2002;43[ 1]:29\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamos M, D\u0026iacute;ez JC, Ramos T, Ruano R, Sancho M, Gonz\u0026aacute;lez-Or\u0026uacute;s JM. Intraoperative ultrasound in conservative surgery for non-palpable breast cancer after neoadjuvant chemotherapy. Int J Surg. 2014;12[ 6]:572\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJanssen NNY, Nijkamp J, Alderliesten T, Loo CE, Rutgers EJTh, Sonke JJ, et al. Radioactive seed localization in breast cancer treatment. Br J Surg. 2015;103:70\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Riet YEA, Maaskant AJG, Creemers GJ, Van Warmerdam LJC, Jansen FH, Van de Veldeet CJH et al. Identification of residual breast tumour localization after neo-adjuvant chemotherapy using a radioactive 125 Iodine seed. Eur J Surg Oncol. 2010;36[ 2]:164\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlderliesten T, Loo CE, Pengel KE, Rutgers EJT, Gilhuijs KGA, Vrancken Peeters MJTFD. Radioactive Seed Localization of Breast Lesions: An Adequate Localization Method without Seed Migration. Breast J 2011;17[ 6]:594\u0026ndash;601.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGobardhan PD, de Wall LL, Van der Laan L, ten Tije AJ, Van der Meer DCH, Tetteroo E et al. The role of radioactive iodine-125 seed localization in breast-conserving therapy following neoadjuvant chemotherapy. Ann Oncol. 2013;24[ 3]:668\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDonker M, Drukker CA, Vald\u0026eacute;s Olmos RA, Rutgers EJTh, Loo CE, Sonke GS et al. Guiding Breast-Conserving Surgery in Patients After Neoadjuvant Systemic Therapy for Breast Cancer: A Comparison of Radioactive Seed Localization with the ROLL Technique. Ann Surg Oncol. 2013;20[ 8]:2569\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDonker M, Straver ME, Rutgers EJTh RA, Loo CE, Sonke GS et al. Radioguided occult lesion localisation [ ROLL] in breast-conserving surgery after neoadjuvant chemotherapy. Eur J Surg Oncol. 2012;38[ 12]:1218\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAggarwal V, Agarwal G, Lal P, Krishnani N, Mishra A, Verma AK et al. Feasibility Study of Safe Breast Conservation in Large and Locally Advanced Cancers with Use of Radiopaque Markers to Mark Pre-Neoadjuvant Chemotherapy Tumor Margins. World J Surg. 2007;32[ 12]:2562\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHossam A, El-Badrawy A, Khater A, Setit A, Roshdy S, Abdelwahab K et al. The Evaluation of a Cost-Effective Method for Tumour Marking Prior to Neo-Adjuvant Chemotherapy Using Silver Rods. Eur J Breast Health. 2022;19[ 1]:99\u0026ndash;105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSever AR, O\u0026rsquo;Brien MER, Humphreys S, Singh I, Jones SE, Jones PA. Radiopaque coil insertion into breast cancers prior to neoadjuvant chemotherapy. Breast. 2005;14:108\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRubio IT, Esgueva-Colmenarejo A, Espinosa-Bravo M, Salazar JP, Miranda I, Peg V. Intraoperative Ultrasound-Guided Lumpectomy Versus Mammographic Wire Localization for Breast Cancer Patients After Neoadjuvant Treatment. Ann Surg Oncol. 2015;23[ 1]:38\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlmalki H, Rankin AC, Juette A, Youssef MMG. Radio-frequency identification [ RFID] tag localisation of non-palpable breast lesions a single centre experience. Breast. 2023;69:417\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomassin-Naggara I, Lalonde L, David J, Darai E, Uzan S, Trop I. A plea for the biopsy marker: how, why and why not clipping after breast biopsy? Breast Cancer Res Treat. 2011;132[ 3]:881\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreen RT, Weiser R, Golan O, Menes TS. In Search of the Lost Clip: Outcome of Women After Needle-Guided Lumpectomy of a Marking Clip. Ann Surg Oncol. 2021;28:4974\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJha CK, Johri G, Singh PK, Yadav SK, Sinha U. Does Tumor Marking Before Neoadjuvant Chemotherapy Helps Achieve Better Outcomes in Patients Undergoing Breast Conservative Surgery? A Systematic Review. Indian J Surg Oncol. 2021;12[ 3]:624\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFusco N, Rizzo A, Costarelli L, Santinelli A, Cerbelli B, Scatena C et al. Pathological examination of breast cancer samples before and after neoadjuvant therapy: recommendations from the Italian Group for the Study of Breast Pathology - Italian Society of Pathology [ GIPaM-SIAPeC]. Pathologica 2022;114[ 2]:104\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBi Z, Qiu PF, Yang T, Chen P, Song XR, Zhao T, et al. The modified shrinkage classification modes could help to guide breast conserving surgery after neoadjuvant therapy in breast cancer. Front Oncol. 2022;12:982011.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEarly Breast Cancer Trialists\u0026rsquo; Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet. 2005;365:1687\u0026ndash;717.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEarly Breast Cancer Trialists\u0026rsquo; Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018;19:27\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNebojsa Ivanovic D, Bjelica B, Loboda M, Bogdanovski N, Colakovic S, Petricevic M, Gojgic O, Zecic. Katarina Zecic, Darko Zdravkovic. Changing the role of pCR in breast cancer treatment - an unjustifiable interpretation of a good prognosticfactor as a factor for a good prognosis. Front Oncol, 18 July 2023, Sec. Breast Cancer.13\u0026ndash;2023.\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"early breast cancer, neoadjuvant systemic therapy, patological complete response, surgical excision, marking techniques, tumor positioning, ultrasound","lastPublishedDoi":"10.21203/rs.3.rs-4064076/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4064076/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Surgical excision of the lodge of the tumor that has completely clinically regressed after neoadjuvant systemic therapy (NAST) is a necessary part of the treatment of early breast cancer. However, it is significantly hampered by the lack of a spatial landmark concerning the location of the pre-existing tumor in the breast. Standard surgical techniques of targeted excision of the pre-existing tumor bed generally rely on invasive insertion of various markers into or around the tumor before starting NAST. Invasive marking techniques are burdened by the disadvantages of technical complexity, invasiveness of procedures, and insufficient precision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: In this paper authors present an original technique of non-invasive determining of the tumor position in the breast in three dimensions before starting NAST, with intention to overcome the disadvantages of invasive tumor marking. Tumor positioning is performed by ultrasound measurements – detailed description of the technique is given in the main text. The feasibility and precision of the technique was tested by the histological parameters of the adequacy and rationality of excision of the tumor bed, after complete clinical regression of the tumor after NAST, on a pilot series of patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A pilot series of 33 patients underwent a non-invasive breast tumor positioning technique before starting NAST. Twelve patients with complete clinical regression after NAST have been operated using a non-invasive tumor positioning technique, so far. In all cases, histological signs of tumor regression were verified in the specimen of the excised tumor bed. The ratio of the resected specimen volume to the volume of the tumor before NAST was on average 0,91, which is in favor of the rationality of excision and a good aesthetic effect.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: The initial results of a pilot series of treated patients imply that a non-invasive three-dimensional tumor positioning technique is feasible, with a satisfactory level of oncological safety and aesthetic effects of surgery. Performing a randomised clinical trial comparing this technique with standard techniques of invasive tumor marking is justified.\u003c/p\u003e","manuscriptTitle":"Non-Invasive Three-Dimensional Breast Tumor Positioning Before Neoadjuvant Systemic Therapy as Promissing Alternative to the Invasive Tumor Marking – Technique Description and Feasibility","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-13 17:18:22","doi":"10.21203/rs.3.rs-4064076/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":"29dab702-8a4a-4211-bb9a-89a60d64f9d6","owner":[],"postedDate":"March 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-13T13:52:53+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-13 17:18:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4064076","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4064076","identity":"rs-4064076","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}