Maarten Grootendorst

Cerenkov luminescence imaging (CLI) for image-guided cancer surgery

Cerenkov luminescence imaging (CLI) is a novel molecular optical imaging technique based on the detection of optical Cerenkov photons emitted by positron emission tomography (PET) imaging agents. The ability to use clinically approved tumour-targeted tracers in combination with small-sized imaging equipment makes CLI a particularly interesting technique for image-guided cancer surgery. The past few years have witnessed a rapid increase in proof-of-concept preclinical studies in this field, and several clinical trials are currently underway. This article provides an overview of the basic principles of Cerenkov radiation and outlines the challenges of CLI-guided surgery for clinical use. The preclinical and clinical trial literature is examined including applications focussed on image-guided lymph node detection and Cerenkov luminescence endoscopy, and the ongoing clinical studies and technological developments are highlighted. By intraoperatively guiding the oncosurgeon towards more accurate and complete resections, CLI has the potential to transform current surgical practice, and improve oncological and cosmetic outcomes for patients.

Intraoperative assessment of tumor resection margins in breast-conserving surgery using 18F-FDG cerenkov luminescence imaging: A first-in-human feasibility study

In early-stage breast cancer, the primary treatment option for most women is breast-conserving surgery (BCS). There is a clear need for more accurate techniques to assess resection margins intraoperatively, because on average 20% of patients require further surgery to achieve clear margins. Cerenkov luminescence imaging (CLI) combines optical and molecular imaging by detecting light emitted by 18F-FDG. Its high-resolution and small size imaging equipment make CLI a promising technology for intraoperative margin assessment. A first-in-human study was conducted to evaluate the feasibility of 18F-FDG CLI for intraoperative assessment of tumor margins in BCS. Methods: Twenty-two patients with invasive breast cancer received 18F-FDG (5 MBq/kg) 45–60 min before surgery. Sentinel lymph node biopsy was performed using an increased 99mTc-nanocolloid activity of 150 MBq to facilitate nodal detection against the γ-probe background signal (cross-talk) from 18F-FDG. The cross-talk and 99mTc dose required was evaluated in 2 lead-in studies. Immediately after excision, specimens were imaged intraoperatively in an investigational CLI system. The first 10 patients were used to optimize the imaging protocol; the remaining 12 patients were included in the analysis dataset. Cerenkov luminescence images from incised BCS specimens were analyzed postoperatively by 2 surgeons blinded to the histopathology results, and mean radiance and margin distance were measured. The agreement between margin distance on CLI and histopathology was assessed. Radiation doses to staff were measured. Results: Ten of the 12 patients had an elevated tumor radiance on CLI. Mean radiance and tumor-to-background ratio were 560 ± 160 photons/s/cm2/sr and 2.41 ± 0.54, respectively. All 15 assessable margins were clear on CLI and histopathology. The agreement in margin distance and interrater agreement was good (κ = 0.81 and 0.912, respectively). Sentinel lymph nodes were successfully detected in all patients. The radiation dose to staff was low; surgeons received a mean dose of 34 ± 15 μSv per procedure. Conclusion: Intraoperative 18F-FDG CLI is a promising, low-risk technique for intraoperative assessment of tumor margins in BCS. A randomized controlled trial will evaluate the impact of this technique on reexcision rates.

Pre-operative sentinel lymph node localization in breast cancer with superparamagnetic iron oxide MRI: the SentiMAG Multicentre Trial imaging subprotocol

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.

Adjuvant taxanes and the development of breast cancer-related arm lymphoedema

Despite affecting approximately one‐quarter of all patients undergoing axillary lymph node dissection, the pathophysiology of breast cancer‐related lymphoedema (BCRL) remains poorly understood. More extensive locoregional treatment and higher body mass index have long been identified as major risk factors. This study aimed to identify risk factors for BCRL with a specific focus on the potential impact of chemotherapy on the risk of BCRL.

Use of a handheld terahertz pulsed imaging device to differentiate benign and malignant breast tissue

Since nearly 20% of breast-conserving surgeries (BCS) require re-operation, there is a clear need for developing new techniques to more accurately assess tumor resection margins intraoperatively. This study evaluates the diagnostic accuracy of a handheld terahertz pulsed imaging (TPI) system to discriminate benign from malignant breast tissue ex vivo. Forty six freshly excised breast cancer samples were scanned with a TPI handheld probe system, and histology was obtained for comparison. The image pixels on TPI were classified using (1) parameters in combination with support vector machine (SVM) and (2) Gaussian wavelet deconvolution in combination with Bayesian classification. The results were an accuracy, sensitivity, specificity of 75%, 86%, 66% for method 1, and 69%, 87%, 54% for method 2 respectively. This demonstrates the probe can discriminate invasive breast cancer from benign breast tissue with an encouraging degree of accuracy, warranting further study.

Flexible scintillator autoradiography for tumor margin inspection using 18F-FDG

Autoradiography potentially offers high molecular sensitivity and spatial resolution for tumor margin estimation. However, conventional autoradiography requires sectioning the sample which is destructive and labor-intensive. Here we describe a novel autoradiography technique that uses a flexible ultra-thin scintillator which conforms to the sample surface. Imaging with the flexible scintillator enables direct, high-resolution and high-sensitivity imaging of beta particle emissions from targeted radiotracers. The technique has the potential to identify positive tumor margins in fresh unsectioned samples during surgery, eliminating the processing time demands of conventional autoradiography. We demonstrate the feasibility of the flexible autoradiography approach to directly image the beta emissions from radiopharmaceuticals using lab experiments and GEANT-4 simulations to determine i) the specificity for 18F compared to 99mTc-labeled tracers ii) the sensitivity to detect signal from various depths within the tissue. We found that an image resolution of 1.5 mm was achievable with a scattering background and we estimate a minimum detectable activity concentration of 0.9 kBq/ml for 18F. We show that the flexible autoradiography approach has high potential as a technique for molecular imaging of tumor margins using 18F-FDG in a tumor xenograft mouse model imaged with a radiation-shielded EMCCD camera. Due to the advantage of conforming to the specimen, the flexible scintillator showed significantly better image quality in terms of tumor signal to whole-body background noise compared to rigid and optimally thick CaF2:Eu and BC400. The sensitivity of the technique means it is suitable for clinical translation.

Intra-operative terahertz probe for detection of breast cancer

A handheld THz probe has been developed by TeraView with the goal to assess tumor resection margins intra-operatively in breast-conserving surgery (BCS) specimens and metastatic status of sentinel lymph nodes (SLNs), with a view to reduce re-operation rates. The utility of this probe for this purpose has already been shown in an ex vivo setting. Further work carried out by Teraview Ltd together with the breast surgical team at Kings College London (KCL)/Guys and St Thomass NHS Foundation Trust (GSTT) is confirming promise of this technique, with focus on the in vivo application of the handheld THz probe for real-time assessment of tumor resection margins in BCS. In particualr, the probe is designed to acquire THz images during breast cancer surgery to distinguish between normal and malignant breast tissue, thus assisting complete surgical excision of cancers. Findings of this study leading to in-vivo testing are discussed in this paper.