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Joost J Pouw,1,* Muneer Ahmed,2,* Bauke Anninga,2 Kimberley Schuurman,1 Sarah E Pinder,2 Mieke Van Hemelrijck,3 Quentin A Pankhurst,4,5 Michael Douek,2 Bennie ten Haken1 1MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, the Netherlands; 2Research Oncology, Division of Cancer Studies, King’s College London, Guy’s Hospital, London, UK; 3Cancer Epidemiology Group, Division of Cancer Studies, King’s College London, London, UK; 4Healthcare Biomagnetics Laboratory, University College London, London, UK; 5Institute of Biomedical Engineering, University College London, London, UK *These authors contributed equally to this work Introduction: Breast cancer staging with sentinel lymph node biopsy relies on the use of radioisotopes, which limits the availability of the procedure worldwide. The use of a magnetic nanoparticle tracer and a handheld magnetometer provides a radiation-free alternative, which was recently evaluated in two clinical trials. The hydrodynamic particle size of the used magnetic tracer differs substantially from the radioisotope tracer and could therefore benefit from optimization. The aim of this study was to assess the performance of three different-sized magnetic nanoparticle tracers for sentinel lymph node biopsy within an in vivo porcine model.Materials and methods: Sentinel lymph node biopsy was performed within a validated porcine model using three magnetic nanoparticle tracers, approved for use in humans (ferumoxytol, with hydrodynamic diameter dH =32 nm; Sienna+®, dH =59 nm; and ferumoxide, dH =111 nm), and a handheld magnetometer. Magnetometer counts (transcutaneous and ex vivo), iron quantification (vibrating sample magnetometry), and histopathological assessments were performed on all ex vivo nodes.Results: Transcutaneous “hotspots” were present in 12/12 cases within 30 minutes of injection for the 59 nm tracer, compared to 7/12 for the 32 nm tracer and 8/12 for the 111 nm tracer, at the same time point. Ex vivo magnetometer counts were significantly greater for the 59 nm tracer than for the other tracers. Significantly more nodes per basin were excised for the 32 nm tracer compared to other tracers, indicating poor retention of the 32 nm tracer. Using the 59 nm tracer resulted in a significantly higher iron accumulation compared to the 32 nm tracer.Conclusion: The 59 nm tracer demonstrated rapid lymphatic uptake, retention in the first nodes reached, and accumulation in high concentration, making it the most suitable tracer for intraoperative sentinel lymph node localization. Keywords: superparamagnetic iron oxide, breast cancer, magnetic tracer, ferumoxytol, ferumoxide, Sienna+®

The application of nanomaterials in medicine has led to novel pharmaceuticals and medical devices that have demonstrated a strong potential for increasing the efficacy/performance and safety of therapeutic and diagnostic procedures to address a wide range of diseases. However, the successful translation of these technologies from their inception (proof-of-concept) to clinical practice has been challenged by substantial gaps in the scientific and technical capacity of R&D companies, especially SMEs, to keep up with the ever-evolving regulatory expectations in the emerging area of nanomedicine. To address these challenges, the EU Horizon 2020 project REFINE has developed a Decision Support System (DSS) to support developers of nanotechnology-enabled health products in bringing their products to the clinic. The REFINE DSS has been developed to support experts, innovators, and regulators in the implementation of intelligent testing strategies (ITS) for efficient preclinical assessment of nanotechnology-enabled health products. The DSS applies logical rules provided by REFINE experts which generate prioritized lists of assays to be performed (i.e. ITSs) for physicochemical characterisation and for immunotoxicological endpoints. The DSS has been tested against several case studies and was validated by internal project experts as well as external ones., (© 2022. The Author(s).)

Background: A procedure for sentinel lymph node biopsy (SLNB) using superparamagnetic iron-oxide (SPIO) nanoparticles and intraoperative sentinel lymph node (SLN) detection was developed to overcome drawbacks associated with the current standard-of-care SLNB. However, residual SPIO nanoparticles can result in void artefacts at follow-up magnetic resonance imaging (MRI) scans. We present a grading protocol to quantitatively assess the severity of these artefacts and offer an option to minimise the impact of SPIO nanoparticles on diagnostic imaging., Methods: Follow-up mammography and MRI of two patient groups after a magnetic SLNB were included in the study. They received a 2-mL subareolar dose of SPIO (high-dose, HD) or a 0.1-mL intratumoural dose of SPIO (low-dose, LD). Follow-up mammography and MRI after magnetic SLNB were acquired within 4 years after breast conserving surgery (BCS). Two radiologists with over 10-year experience in breast imaging assessed the images and analysed the void artefacts and their impact on diagnostic follow-up., Results: A total of 19 patients were included (HD, n = 13; LD, n = 6). In the HD group, 9/13 patients displayed an artefact on T1-weighted images up to 3.6 years after the procedure, while no impact of the SPIO remnants was observed in the LD group., Conclusions: SLNB using a 2-mL subareolar dose of magnetic tracer in patients undergoing BCS resulted in residual artefacts in the breast in the majority of patients, which may hamper follow-up MRI. This can be avoided by using a 0.1-mL intratumoural dose., (© 2021. The Author(s) under exclusive licence to European Society of Radiology.)

Objectives: To assess the feasibility and merits of a complete magnetic approach for a sentinel lymph node biopsy (SLNB) procedure in oral cancer patients., Materials and Methods: This study included ten oral cancer patients (stage cT1-T2N0M0) scheduled for elective neck dissection (END). Superparamagnetic iron oxide nanoparticles (SPIO) were administered peritumorally prior to surgery. A preoperative MRI was acquired to identify lymph nodes (LNs) with iron uptake. A magnetic detector was used to identify magnetic hotspots prior, during, and after the SLNB procedure. The resected sentinel LNs (SLNs) were evaluated using step-serial sectioning, and the neck dissection specimen was assessed by routine histopathological examination. A postoperative MRI was acquired to observe any residual iron., Results: Of ten primary tumors, eight were located in the tongue, one floor-of-mouth (FOM), and one tongue-FOM transition. SPIO injections were experienced as painful by nine patients, two of whom developed a tongue swelling. In eight patients, magnetic SLNs were successfully detected and excised during the magnetic SLNB procedure. During the END procedure, additional magnetic SLNs were identified in three patients. Histopathology confirmed iron deposits in sinuses of excised SLNs. Three SLNs were harboring metastases, of which one was identified only during the END procedure. The END specimens revealed no further metastases., Conclusion: A complete magnetic SLNB procedure was successfully performed in eight of ten patients (80% success rate), therefore the procedure seems feasible. Recommendations for further investigation are made including: use of anesthetics, magnetic tracer volume, planning preoperative MRI, comparison to conventional technique and follow-up., (Copyright © 2021. Published by Elsevier Ltd.)

Aim: Nodal status is the most important prognostic factor in colorectal cancer (CRC). Small occult metastases may remain undetected on conventional histopathological examination, potentially resulting in undertreatment. Ex vivo sentinel lymph node mapping (SLNM) can be used to improve the accuracy of nodal staging, but the currently used tracers suffer from drawbacks, which hamper implementation of the technique in routine clinical practice. Magnetic tracers are the optimal size for sentinel lymph node (SLN) retention and allow objective quantitative selection of SLNs; they therefore have great potential for SLNM in CRC. The study evaluates the feasibility of ex vivo magnetic SLNM and compares the performance of this technique with blue dye SLNM., Method: Twenty-eight ex vivo SLNM procedures were performed in 27 histological node-negative patients with CRC using a magnetic tracer and blue dye. A magnetometer was used to select magnetic SLNs after formalin fixation of the CRC specimen. Both magnetic and blue SLNs were subjected to serial sectioning and immunohistochemical staining to reveal occult metastases., Results: At least one SLN was successfully identified in 27/28 (96%) and 25/28 (89%) of the cases with the magnetic technique and blue dye. Isolated tumour cells were detected in 10 patients. This was predicted with 100% sensitivity and accuracy using the magnetic technique, and with 91% sensitivity and 96% accuracy using the blue dye technique., Conclusion: This study demonstrates that ex vivo magnetic SLNM is a feasible technique for use in routine clinical practice, improving nodal staging accuracy of CRC patients., (Colorectal Disease © 2016 The Association of Coloproctology of Great Britain and Ireland.)

Purpose: The use of a magnetic nanoparticle tracer and handheld magnetometer for sentinel lymph node biopsy (SLNB) was recently introduced to overcome drawbacks associated with the use of radioisotope tracers. Unlike the gamma probe, the used magnetometers are not only sensitive to the tracer, but also the diamagnetic human body. This potentially limits the performance of the magnetometer when used clinically., Methods: A phantom, mimicking the magnetic and mechanical properties of the human axilla, was constructed. The depth performance of two current generation magnetometers was evaluated in this phantom. LN-phantoms with tracer uptake ranging from 5 to 500μg iron were placed at clinically relevant depths of 2.5, 4 and 5.5cm. Distance-response curves were obtained to quantify the depth performance of the probes., Results: The depth performance of both probes was limited. In the absence of diamagnetic material and forces on the probe (ideal conditions) a LN-phantom with high uptake (500μg iron) could first be detected at 3.75cm distance. In the phantom, only superficially placed LNs (2.5cm) with high uptake (500μg iron) could be detected from the surface. The penetration depth was insufficient to detect LNs with lower uptake, or which were located deeper., Conclusion: The detection distance of the current generation magnetometers is limited, and does not meet the demands formulated by the European Association for Nuclear Medicine for successful transcutaneous SLN localization. Future clinical trials should evaluate whether the limited depth sensitivity is of influence to the clinical outcome of the SLNB procedure., (Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

The magnetic technique for sentinel lymph node biopsy (SLNB) has been evaluated in several clinical trials. An in vivo porcine model was developed to optimise the magnetic technique by evaluating the effect of differing volume, concentration and time of injection of magnetic tracer. A total of 60 sentinel node procedures were undertaken. There was a significant correlation between magnetometer counts and iron content of excised sentinel lymph nodes (SLNs) (r=0.82; P<0.001). Total number of SLNs increased with increasing volumes of magnetic tracer (P<0.001). Transcutaneous magnetometer counts increased with increasing time from injection of magnetic tracer (P<0.0001), plateauing within 60min. Increasing concentration resulted in higher iron content of SLNs (P=0.006). Increasing magnetic tracer volume and injecting prior to surgery improve transcutaneous 'hotspot' identification but very high volumes, increase the number of nodes excised., From the Clinical Editor: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging of breast cancer patients. Although the current gold standard technique is the combined injection of technetium-labelled nanocolloid and blue dye into the breast, the magnetic technique, using superparamagnetic carboxydextran-coated iron oxide (SPIO), has also been demonstrated as a feasible alternative. In this article, the authors set up to study factors in order to optimize the magnetic tracers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Sentinel lymph node biopsy (SLNB) with a superparamagnetic iron oxide (SPIO) tracer was shown to be non-inferior to the standard combined technique in the SentiMAG Multicentre Trial. The MRI subprotocol of this trial aimed to develop a magnetic alternative for pre-operative lymphoscintigraphy (LS). We evaluated the feasibility of using MRI following the administration of magnetic tracer for pre-operative localization of sentinel lymph nodes (SLNs) and its potential for non-invasive identification of lymph node (LN) metastases., Methods: Patients with breast cancer scheduled to undergo SLNB were recruited for pre-operative LS, single photon emission CT (SPECT)-CT and SPIO MRI. T1 weighted turbo spin echo and T2 weighted gradient echo sequences were used before and after interstitial injection of magnetic tracer into the breast. SLNs on MRI were defined as LNs with signal drop and direct lymphatic drainage from the injection site. LNs showing inhomogeneous SPIO uptake were classified as metastatic. During surgery, a handheld magnetometer was used for SLNB. Blue or radioactive nodes were also excised. The number of SLNs and MR assessment of metastatic involvement were compared with surgical and histological outcomes., Results: 11 patients were recruited. SPIO MRI successfully identified SLNs in 10 of 11 patients vs 11 of 11 patients with LS/SPECT-CT. One patient had metastatic involvement of four LNs, and this was identified in one node on pre-operative MRI., Conclusion: SPIO MRI is a feasible technique for pre-operative localization of SLNs and, in combination with intraoperative use of a handheld magnetometer, provides an entirely radioisotope-free technique for SLNB. Further research is needed for the evaluation of MRI characterization of LN involvement using subcutaneous injection of magnetic tracer., Advances in Knowledge: This study is the first to demonstrate that an interstitially administered magnetic tracer can be used both for pre-operative imaging and intraoperative SLNB, with equal performance to imaging and localization with radioisotopes.

As the first step in developing a new clinical technique for the magnetic detection of colorectal sentinel lymph nodes (SLNs), a method is developed to measure the magnetic content in intact, formalin fixated lymph nodes using a vibrating sample magnetometer (VSM). A suspension of superparamagnetic nanoparticles is injected ex vivo around the tumor in the resected colon segments. A selection of three lymph nodes is excised from the region around the tumor and is separately measured in the VSM. The iron content in the lymph nodes is quantified from the magnetic moment curve using the Langevin model for superparamagnetism and a bimodal particle size distribution. Adverse, parasitic movements of the sample were successfully reduced by tight fixation of the soft tissue and using a small vibration amplitude. Iron content in the lymph nodes is detected with 0.5 μg accuracy and ranged from 1 to 51 μg. Histological staining confirmed iron presence. The current method of measuring intact biological tissue in a VSM is suitable to show the feasibility and merit of magnetic detection of SLNs in colorectal cancer. For clinical validation of magnetic SLN selection in colorectal cancer, a new magnetometer with high specificity for superparamagnetic nanoparticles is required.