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Prospective testing of clinical Cerenkov luminescence imaging against standard-of-care nuclear imaging for tumour location

Abstract

In oncology, the feasibility of Cerenkov luminescence imaging (CLI) has been assessed by imaging superficial lymph nodes in a few patients undergoing diagnostic 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). However, the weak luminescence signal requires the removal of ambient light. Here we report the development of a clinical CLI fiberscope with a lightproof enclosure, and the clinical testing of the setup using five different radiotracers. In an observational prospective trial (ClinicalTrials.gov identifier NCT03484884) involving 96 patients with existing or suspected tumours, scheduled for routine clinical FDG PET or 131I therapy, the level of agreement of CLI with standard-of-care imaging (PET or planar single-photon emission CT) for tumour location was ‘acceptable’ or higher (≥3 in the 1–5 Likert scale) for 90% of the patients. CLI correlated with the concentration of radioactive activity, and captured therapeutically relevant information from patients undergoing targeted radiotherapy or receiving the alpha emitter 223Ra, which cannot be feasibly imaged clinically. CLI could supplement radiological scans, especially when scanner capacity is limited.

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Fig. 1: Clinical Cerenkov fiberscope setup with lightproof enclosure for patient imaging.
Fig. 2: Representative patients by isotope for fiberscope Cerenkov luminescence imaging.
Fig. 3: CLI improved with filtering wavelengths above 600 nm.
Fig. 4: CLI for monitoring therapy over successive imaging sessions.
Fig. 5: CL intensity analysis of patient images.

Data availability

The data generated and analysed during the study were de-identified and can be made available by the corresponding author on reasonable request. The code used to process and overlay Cerenkov images is available from Zenodo at https://doi.org/10.5281/zenodo.6261583.

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Acknowledgements

We thank the 96 patients who gave their time (some of them repeatedly) in moments of considerable stress to support our study; Lightpoint Medical, Ltd for the assembly of the CL camera and enclosure; MSKCC’s Molecular Imaging and Therapy Service, particularly the service chief H. Schöder for the support; R. Teng, R. Min, F. Avalone and N. Shahid for consenting and managing patients for NCT03484884; A. Platzman, L. Carter and S. Hellman in the Department of Medical Physics for their phantom, fiberscope arm and angular-dependence holder designs; and P. Zanzonico and V. Longo in the MSKCC Small Animal Imaging Core for their help with preclinical studies. This study is dedicated to Dr Sanjiv Sam Gambhir, who encouraged us to think outside the box and continue in our endeavours in this field. J.G. and D.T. were funded by NIH R01 CA18395305. This research was also funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

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Authors and Affiliations

Authors

Contributions

E.C.P., M.S., B.M.L., S.D., P.C.-A. and J.G. imaged patients, analysed the data and wrote the manuscript. D.T. and K.V. designed and constructed the fiberscope camera and enclosure, and wrote the manuscript. C.R. read patient data and identified patients for consent in addition to P.C., J.G., A.A. and P.S., who graded Cerenkov luminescence images with Likert scores and wrote the manuscript.

Corresponding author

Correspondence to Jan Grimm.

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Competing interests

D.T. and K.V. are employees of and have equity in Lightpoint Medical. The other authors declare no competing interests.

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Nature Biomedical Engineering thanks Lesley Jarvis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Clinical Cerenkov imaging system based on the Lightpoint fiberscope design.

a) The Cerenkov camera (Andor iXon Ultra 897 EMCCD, Andor Technology Ltd., Belfast, UK) enclosed in a lead shielded box (background) with a connecting fiberscope to a preclinical enclosure (foreground). b) Clinical enclosure (Lightpoint Medical Ltd., Chesham, UK) containing a reclining chair for patient imaging. The fiberscope (Lightpoint Medical Ltd., Chesham, UK) is installed through the rear of the enclosure opposite the dual track shroud system (red box inset). The fiberscope is held in place via a three-axis articulating arm containing a cerrobend baffle to reduce gamma and beta strikes to the fiber (green box inset). A 17 mm C-mount lens with an f# of 0.95 was used to collect CL (Xenon 0.95/17, Jos. Schneider Optische Werke GmbH, Bad Kreuznach, GM) c) Example of both shrouds deployed to prevent ambient light from reaching the patient during CLI.

Extended Data Fig. 2 Additional patient images by isotope showing the versatility of CCLI reflect the employed tracer and patient imaging location.

a) Top, 68Ga-DOTATATE CLI image shows three lesions on the posterior agree with the PET/CT, the presence on the posterior of a superficial lesion near the ribcage, directly above the spleen. Lesion discrepancy between PET and CLI is likely due to rib bone absorption. Bottom, a second patient has a prominent spot on their head in the CLI image which aligns with a lesion seen in the PET/CT in the occipital bone near the lamboid suture. b) Top, 177Lu-DOTATATE CL image shows a patient with the brightest spot below the liver with a secondary area near the patient midline below the Xiphoid Process. The main focal spot is in agreement with the planar scan the patient received prior showing one main lesion in a cluster of four below the liver near the patient midline. Bottom, CL image of a second patient showing a focal region just above the Xiphoid Process with a secondary focal area to the patient’s right abdomen in line with the navel. The corresponding planar image shows two sets of lesions, one in the top of the right lobe as well as two lesions in the bottom of the right lobe of the liver. c) Top, 18F-FDG CL image shows a vertical focal signal in the cheek and not near the applied bandage. The corresponding PET image shows the most avid region by the zygomatic bone and nearly vertical with the patient. The physiologic uptake in the brain is not seen as it is both less intense and attenuated by the skull. Bottom, a second 18F-FDG patient CL image shows three clusters at the base of the jaw and around the ear. The corresponding PET scan shows three sets of avid tissue in the region in agreement with the CL image, with the brightest lesion buried in the submandibular triangle. e) Top, 223RaCl2 (Xofigo) CL image shown from the patients back that the main CLI intensity is to the left of the spine, near the liver. A prior 18F scan from the previous month shows extensive uptake in the spine, suggesting the CLI intensity seen is the distribution of 223RaCl2 through the liver and not appreciable bone uptake. Bottom, CL image showing a patient’s right posterior to the left of the scapula from an elevated angle above the patient with three focal regions seen. The prior 18F bone scan from the previous month show uptake in the 4th and 5th ribs, alongside two focal lesions on either side. Here the CL image shows potential agreement with the 18F scan, though physiologic distribution via stomach and gastrointestinal tract confounds agreement.

Extended Data Fig. 3 Additional patient images with alternate CLI projections.

131I-Iodine patients were imaged head on and from the side. Example 1 shows images from two angles with CLI focal intensity in the patients left neck before the muscular triangle with corresponding SPECT image showing uptake near the submental triangle. In Example 2 CL images show intensity regions below the submental triangle and before the submandibular triangle while the corresponding SPECT scan shows the iodine uptake to be located deeper in the neck below the submandibular triangle adjacent to the trachea. In Example 3, two focal regions of CL are seen between projections with the reduction of the upper CL region in View 2. The corresponding SPECT scan shows three lesions with the brightest lesion to the right of the patient midline and below the submental triangle. Here CLI shows in example 3 the most avid lesion in the midline, though the upper CL spot appears to be an artifact that dissipated in the second view. Overall, the most iodine avid region in the field of view was where the most intense CLI signal was seen, with the exception of the artifact seen in View 1 of Example 3 which dissipated in View 2. Possible sources of artifact light include insufficient time (< 5 minutes) to let the light from the patient and enclosure dissipate along with residual charge on the sensor, as well as patient movement.

Extended Data Fig. 4 Additional patient images imaged with filters.

(Top) Complete optical filter set of patient in Fig. 3. Here a representative patient has multiple nodes in the subclavian vein, which cannot be completely separated with the installed short-pass and bandpass optical filters. The major lesions denoted as 1 and 3 can be seen in each filter but without the corresponding PET or CT the difference in CLI intensity does not meaningfully infer depth. (Middle) A patient with two thyroid nodules was imaged with each filter after receiving an adjuvant therapy dose of iodine-131, where the open and each filter image shows one main nodule towards the base of the neck. The upper thyroid nodule in the submandibular triangle is barely visible until the 600 nm bandpass filter, with little differentiation of CLI images with the 500 nm short-pass and band pass filters compared to the open filter image. (Bottom) In the 177Lu-DOTATATE filter example a large multicomponent liver metastasis is seen in the planar image, yet a high degree of CLI intensity is seen on the patients’ clothing though centered over the liver. The brightest CLI spot in the open and 500 nm short-pass filter images are not avid areas in the planar scan, however the longer bandpass filters, and especially the 600 nm long pass filter best represent the planar scan. Together the filtering of light from CLI in patients is useful above 600 nm where shorter wavelength filtering is troubled by a lack of definition between filters as well as high tissue absorption and scattering of any emitted CL.

Extended Data Fig. 5 Cerenkov luminescence images of 68Ga/177Lu-DOTATATE therapy with lower minimum CLI intensity to identify residual disease.

Post therapy images show reduced uptake in the abdomen, though most intense regions remain where disease is present. Artifact light can be seen on clothing.

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Pratt, E.C., Skubal, M., Mc Larney, B. et al. Prospective testing of clinical Cerenkov luminescence imaging against standard-of-care nuclear imaging for tumour location. Nat. Biomed. Eng 6, 559–568 (2022). https://doi.org/10.1038/s41551-022-00876-4

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