A Review of Recent and Emerging Approaches for the Clinical Application of Cerenkov Luminescence Imaging

Cerenkov luminescence is a blue-weighted emission of light produced by a vast array of clinically approved radioisotopes and LINAC accelerators. When β particles (emitted during the decay of radioisotopes) are present in a medium such as water or tissue, they are able to travel faster than the speed of light in that medium and in doing so polarize the molecules around them. Once the particle has left the local area, the polarized molecules relax and return to their baseline state releasing the additional energy as light (luminescence). This blue glow has commonly been used to determine the output of nuclear power plant cores and, in recent years, has found traction in the preclinical and clinical imaging field. This brief review will discuss the technology which has enabled the emergence of the biomedical Cerenkov imaging field, recent pre-clinical studies with potential clinical translation of Cerenkov luminescence imaging and the current clinical implementations of the method. Finally, an outlook is given as to the direction in which the field is heading.

In-vitro Study for Cerenkov Luminescence Imaging Application in Hepatic Metastasectomy

Cerenkov luminescence imaging (CLI) has been recently proposed as a method to visualize surgical margins in the operating theater, immediately after resection, to allow refining surgery in a single procedure. Our group is preparing a pilot clinical study to evaluate the impact of CLI during hepatic metastasectomy, using 18F-FDG and 68Ga-DOTATOC. Currently, we are optimizing the clinical protocol in terms of patient inclusion criteria, activity to inject, maximum allowed delay for imaging, and radiation monitoring. This paper describes a preliminary study we have performed to define the clinical protocol. The study is composed of two branches: 1) an in-vitro study to predict the typical signals and optical attenuation in the liver with 18F and 68Ga, 2) an analysis of clinical PET/CT data to determine typical values of relevant parameters, such as uptake and lesion dimension. The combined information by these two branches gives us an indication of the feasibility of CLI for margin assessment in liver metastasectomy. For 68Ga, we obtained detection limits ranging from 0.55 to 3.5 kBq/cc, to be compared with minimum and mean clinical uptakes of 1.6 and 7 kBq/cc, respectively. For 18F, the detection limits ranged from 12 to 145 kBq/cc, and the minimum and mean clinical uptakes were 5 and 11 kBq/cc, respectively. From these values, we expect CLI with 68Ga to be able to detect surgical margins in most patients, while with 18F the activities to inject for sufficient signal-to-noise ratio should be larger than standards, or the time delay between injection and imaging largely reduced. The results reported here can be useful also more in general, for studies dedicated to other CLI applications in the liver.

Cerenkov Luminescence Imaging in the Development and Production of Radiopharmaceuticals

Over the past several years there has been an explosion of interest in exploiting Cerenkov radiation to enable in vivo and intraoperative optical imaging of subjects injected with trace amounts of radiopharmaceuticals. At the same time, Cerenkov luminescence imaging (CLI) also has been serving as a critical tool in radiochemistry, especially for the development of novel microfluidic devices for producing radiopharmaceuticals. By enabling microfluidic processes to be monitored non-destructively in situ, CLI has made it possible to literally watch the activity distribution as the synthesis occurs, and to quantitatively measure activity propagation and losses at each step of synthesis, paving the way for significant strides forward in performance and robustness of those devices. In some cases, CLI has enabled detection and resolution of unexpected problems not observable via standard optical methods. CLI is also being used in analytical radiochemistry to increase the reliability of radio-thin layer chromatography (radio-TLC) assays. Rapid and high-resolution Cerenkov imaging of radio-TLC plates enables detection of issues in the spotting or separation process, improves chromatographic resolution (and/or allows reduced separation distance and time), and enables increased throughput by allowing multiple samples to be spotted side-by-side on a single TLC plate for parallel separation and readout. In combination with new multi-reaction microfluidic chips, this is creating a new possibility for high-throughput optimization in radiochemistry. In this mini review, we provide an overview of the role that CLI has played to date in the radiochemistry side of radiopharmaceuticals.