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5 must read articles that changed the molecular imaging space

Prof. G.M. van Dam, MD, PhD

Over the last two decades, targeted optical and nuclear imaging has a major impact on the diagnostic and therapeutic trajectory for a variety of diseases, especially for solid tumors. There are a few key land-mark papers which drove growth of or will change our view on molecular imaging. Each paper discusses a different modality related to these novel imaging techniques.

1. Surgical optical imaging – the first in-human study.

Article: Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Van Dam et al. Nature Medicine, 2011

Takeaway: tumor-specific fluorescence imaging can increase visualization of solid tumors and paves the way for adequate margin assessment using optical imaging.

Fluorescence-guided surgery using the FDA-approved fluorophore indocyanine green (ICG) for assessment of vascularization and the detection of liver metastasis has been used for multiple decades. However, the first study assessing the feasibility of intra-operative tumor-targeted fluorescence imaging real-time during surgery was published in 2011. In this phase 1 study, folate-receptor-alfa conjugated to fluorescein isothiocyanate (folate-FITC) was used as a targeted fluorescence imaging agent to detect ovarian cancer and its possible peritoneal metastases.

This study showed that in vivo imaging was feasible with a mean in vivo tumor-to-background ratio of 3.1 (0.8 SD). Additionally, it indicated that optical imaging showed the potential to improve cytoreductive surgery, by increasing discrimination between benign and fluorescent malignant tissue. To date, this study set the stage for tumor-specific fluorescence imaging to increase visualization of solid tumors real-time during surgery. Furthermore, it paved the way for adequate margin assessment using optical imaging in subsequent clinical studies. Nowadays, a majority of clinical trials are investigating the clinical benefit of intra-operative imaging using fluorophore-labeled antibodies, peptides and activatable nanoprobes to increase surgical success. For example, in head- and neck cancer, colorectal cancer and breast cancer, among others.

However, as we reach a point of real clinical implementation of optical imaging nowadays, standardization of imaging agents and imaging techniques are necessary to implement optical imaging into the standard of care (SOC). The next paper discusses the need for international standardization to implement imaging into standard of care worldwide.

2. Standardization – a standardized imaging platform.

Article: Tackling standardization in fluorescence molecular imaging. Koch et al. Nature Photonics, 2018

Takeaway: Adaptation of standardized imaging methods, the use of phantoms to calculate all imaging parameters prior to optical imaging and the clear reflection of those parameters in this manuscript is needed to reach a broad implementation of fluorescence imaging worldwide.

In the last few years, the use of targeted optical imaging, especially tumor-targeted fluorescence imaging, has grown exponentially worldwide. However, there are major differences in the used imaging methodologies by different imaging groups, especially during intra-operative imaging. There are various (commercial) camera systems and operating procedures which make adequate comparison between study results difficult. In this paper by Koch et al, multiple parameters are discussed which influence fluorescence intensity, and therefore, accuracy during optical imaging.

The authors advocate for standardization of imaging procedures in medical research, as different parameters like the distance of the camera to the tissue, the field of view, the depth of focus and the camera sensitivity have major influence on the initial imaging result. This combination of parameters may result in different outcomes of fluorochrome concentration in tissue. As a result, it could therefore give an unrealistic and irreproducible imaging outcome. Due to a lack of standardization, imaging results are potentially misleading.

The directive of this paper is to adopt standardized imaging methods and the broad use of tissue simulating phantoms to calculate all imaging parameters prior to an actual in situ optical imaging procedure. Furthermore, all these variables should be mentioned in the researchers’ manuscript to inform colleagues about the applied methodology. To share this information with peers is crucial to eventually allow broad clinical implementation and reliable reproduction of targeted fluorescence imaging worldwide.

3. Nuclear molecular imaging.

Article: 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Bensch et al. Nature Medicine, 2018

Takeaway:  nuclear imaging allows for quick assessment of biodistribution and pharmacokinetics and a response-measure of therapy success in innovative immunotherapy in oncology

The use of nuclear imaging to improve therapeutic possibilities for cancer patients is a well-known phenomenon. In immunotherapy, a new treatment area, therapy assessment and spatiotemporal monitoring is crucial to identify the right therapy for the right cancer type and individual patient. Moreover, with the support of quantitative imaging data, a quick decision can be made on the potential therapeutic effect of immunotherapy in a personalized tailor-made manner. The introduction of immune-check points blockades, such as PD-1/PDL-1 blockade which induces cell death, has been extensively investigated. Nuclear molecular imaging by labeling a therapeutic compound allows for non-invasive visualization of drug, distribution, pharmacokinetic data, patient stratification and treatment monitoring.

In the paper by Bensch et al. the immune checkpoint inhibitor atezolizumab was labelled with zirconium-89. This was used to deliver biodistribution and pharmacokinetic data and monitor therapy response in patients with three different tumor types. The first PET/CT with zirconium-89-atezolizumab was made prior to the start of the actual unlabeled atezolizumab therapy. The imaging process was repeated three times during therapy. Promising results showed that by measuring the SUVmax of the tracer in the tumor is a strong predictor of therapy response in overall survival.

In summary, the paper showed that therapeutic evaluation, efficacy and monitoring using nuclear imaging is possible in a non-invasive setting. In the future, potentially an earlier switch in therapy can be made if no therapeutic effect is visualized during imaging or when the target of interest is not presented by the imaging data in the individual patient.

4. A new imaging method – optoacoustic imaging.

Article: Detection of various types of collagen by multispectral optoacoustic tomography as an imaging biomarker for Duchenne muscular dystrophy. Regensburger et al. Nature Medicine, 2019

Takeaway:  optoacoustic imaging is a highly potential non-invasive imaging modality, without the use of ionizing radiation, to collect endogenous and exogenous disease characteristics.

Optoacoustic imaging is a novel non-invasive in vivo imaging technique which uses pulsed laser light. The imaging technique allows for visualization of endo- and exogenous chromophores in human tissue. After illumination of laser light in multiple wavelengths, molecules absorb the laser pulses and undergo thermoelastic expansion. Sequentially, they emit piezoelectric waves in a specific wavelength which can be detected by specific transducers. Endogenous chromophores like fat, melanin and collagen all have a specific absorption spectrum. In this study, optoacoustic imaging was performed in patients with the muscular disease Duchenne. In Duchenne disease, collagen is overexpressed as a manifestation of fibrosis. The study showed the feasibility of optoacoustic imaging first in disease-presenting pigs and thereafter in human pediatric patients. The latter allowed for quantification of collagen in the functional status of the patients.

The study conducted by Regensburger et al. paved the way for the introduction of non-invasive optoacoustic imaging into medical research. Optoacoustic imaging is non-invasive and non-ionizing and allows for visualization of endogenous disease-specific characteristics and endogenous tracer visualization. This combination can be crucial in the upcoming years in diagnostic and treatment monitoring trajectory.

5. Implementation of molecular imaging in standard care.

Article: Clinical translation and implementation of optical imaging agents for precision image-guided cancer surgery. Achterberg et al. European Journal of Nuclear Medicine and Molecular Imaging, 2020

Takeaway: A multidisciplinary and (inter)national solid framework is needed to make molecular imaging, particularly optical imaging, standard of care.

All the above-mentioned novel imaging techniques are extensively described in literature. Nuclear imaging modalities are already part of our standard of care imaging workflow. However, both optical and optoacoustic imaging needs a standardized model to evaluate the impact on patient outcome and patient benefit in upcoming clinical trials. In this review, Achterberg et al. discuss all parameters needed to introduce optical imaging not only in a research setting, but also in non-academic centers without expertise in optical imaging. In summary, this requires motivational teamwork with intense training programs and streamlining of imaging cameras and procedures. Furthermore, it needs adequate identifications of clinical applications. This multidisciplinary framework, which has also been applied by nuclear imaging techniques, such as PET/CT and SPECT imaging, will hopefully eventually lead to an improved patient outcome in a variety of diseases.

Would you like to read more about relevant molecular imaging studies? We put a list of relevant articles together for you.


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