This prospective randomized controlled study was conducted over a period of two years from April 2018 to April 2020. Minimal sample size needed for each group was calculated to be 76. The calculation was based on α of 0.05, power of 0.80, confidence level 95%, assumed incidence of complications to be 4% [15], and odds ratio 6. It was calculated by using the Epi Info [16] program, developed by the Centers for Disease Control and Prevention.
The study included female patients with breast cancer whose NAC was required for their management. Patients who refused NAC or did not complete the course were excluded from the study. Also, patients who did not undergo ultrasonography after they finished NAC were excluded from the study. All patients underwent complete blood picture (CBC), bleeding profile (INR, PT and PTT) within a week from the procedure. Careful medical and medication history were obtained. None of them had an absolute contraindication to the procedure according to ACR guideline [17].
A total of 160 patients were randomly allocated using closed envelop technique into 2 groups; group I (80 patients), who were subjected to the insertion of the small vascular surgical clips, and Group II (80 patients), who were subjected to the insertion of the dedicated breast clips (UltraClips ®). Two sets of opaque envelops were prepared (I and II) each containing 80 envelops. They were closed and shuffled. An assistant nurse with no relation to the research was asked to choose an envelope just before the procedure and to inform the radiologists about the type of the procedure.
Technique of clips application
Both techniques used in the study were applied by the same team of expert interventional radiologists with an experience of 15–19 years. All procedures were performed under a completely aseptic technique.
Group I
Ligating vascular clip (small Titanium Ligating EUROCLIPS. Ackermann instrumente GmbH. EisenbahnStrasse Wellheim. Made in Germany) was taken by the clip dedicated applier (VITALITEC ® stainless PJ 120-EB small Manufactured by Peters Surgical CE 2018-11) and was bent manually using a needle holder. The stylet of a disposable 18 Gauge spinal needle (Sterile single use S.Q Introducer Needle with Trocar. Q for plastic Industries. Land Plot #25, 1st Industrial Zone. Badr City 11,829, Cairo, Egypt) was withdrawn for one cm and the bent clip was inserted within the outlet of the spinal needle (Fig. 1). Spinal needles (3 US $) were chosen rather than coaxial needles (35 US $) as they were cheaper with same effectiveness, and achieve the target of having a cost-effective technique.
The patient lied down in the proper position either supine or oblique according to the tumor site and the breast was prepared with antiseptics. At the selected site for skin incision, the skin was infiltrated with xylocaine to form a bulla. With the ultrasound-guidance more xylocaine infiltration was performed through the course of needle to the mass. A puncture in the skin was done using a scalpel (size 11) then the ultrasound-guided spinal needle was introduced until its tip was immediately related to the center of the mass. The stylet was advanced to push the bent clip into the mass center or the desired location then the whole spinal needle was withdrawn smoothly (Fig. 2).
Group II
UltraClips® (Bard BIOPSY SYSTEMS. Bard Peripheral Vascular, Inc. 1625 West 3rd street. Tempe, AZ 85,281. USA) were used as tissue markers in group II. Insertion of the UltraClips® had the same preparations of the patient and the site of insertion as in group I. Ultrasound-guided advancement of the needle was performed till reaching above the center of the mass. Then, the firing button was pressed and kept in the pressed position while retracting the needle.
The position of the clip[s] was/were assessed by ultrasound (Fig. 3) and mammography (MLO and CC views) in all patients to ensure proper localization (Figs. 4, 5). Non-deployment and mal-deployment (when the marker deployed initially ≥ 1 cm away from the accurate location) were detected and reapplication of other clips was performed (Fig. 6). In case of multifocal lesions, either the clips were inserted in the center of each mass or bracketing technique was performed (Fig. 7). After assuring successful marking of the tissues, patients received their neoadjuvant chemotherapy.
All patients had MRI before the NAC and after finishing their NAC for assessment of the post-NAC response (Fig. 8). Patients were subjected to another mammography preoperatively for detection of late complications, such as migration of the clips.
Outcomes
Primary endpoints
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Assessment of the feasibility of the application of the vascular surgical clips as markers for breast cancer prior to NAC by determination of the success rate of its application.
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Detection of the complications of the vascular surgical clips as markers for breast cancer prior to NAC compared to the UltraClip® commercial clips by the radiologists immediately after performing the procedure and through follow-up radiological studies.
Statistical analysis
The statistical analysis of the data was done using the Statistical Package for Social Sciences (SPSS version 25; SPSS Inc., Chicago, Illinois, USA). Descriptive statistics were applied (frequency and percentage for categorical variables, mean and SD for quantitative variables). To test significance of differences between the studied groups, independent sample t-test was applied for quantitative data, whereas the χ2-test was applied for qualitative data. A statistically significant P value was considered at P less than 0.05.
Ethical approval
The study was approved by the Institutional Research Board of the Medical Research Institute, Alexandria University (IORG#0,008,812). All precautions were taken to conceal the identity of the patients.
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Written informed consents were obtained from all patients participating in this study regarding the steps of the procedures, potential complications, and participation in the study.