Positronium as a biomarker of hypoxia

In this review article, we present arguments demonstrating that the advent of high sensitivity total-body PET systems and the invention of the method of positronium imaging, open realistic perspectives for the application of positronium as a biomarker for in-vivo assessment of the degree of hypoxia. Hypoxia is a state or condition, in which the availability of oxygen is not sufficient to support physiological processes in tissue and organs. Positronium is a metastable atom formed from electron and positron which is copiously produced in the intramolecular spaces in the living organisms undergoing positron emission tomography (PET). Properties of positronium, such as e.g., lifetime, depend on the size of intramolecular spaces and the concentration in them of oxygen molecules. Therefore, information on the partial pressure of oxygen (pO2) in the tissue may be derived from the positronium lifetime measurement. The partial pressure of oxygen differs between healthy and cancer tissues in the range from 10 to 50 mmHg. Such differences of pO2 result in the change of ortho-positronium lifetime e.g., in water by about 2–7 ps. Thus, the application of positronium as a biomarker of hypoxia requires the determination of the mean positronium lifetime with the resolution in the order of 2 ps. We argue that such resolution is in principle achievable for organ-wise positronium imaging with the total-body PET systems.

Theranostics – present and future

Theragnostics in nuclear medicine constitute an essential element of precision medicine. This notion integrates radionuclide diagnostics procedures and radionuclide therapies using appropriate radiopharmaceutics and treatment targeting specific biological pathways or receptors. The term theragnostics should also include another aspect of treatment: not only whether a given radioisotopic drug can be used, but also in what dose it ought to be used. Theragnostic procedures also allow predicting the effects of treatment based on the assessment of specific receptor density or the metabolic profile of neoplastic cells. The future of theragnostics depends not only on the use of new radiopharmaceuticals, but also on new gamma cameras. Modern theragnostics already require unambiguous pharmacokinetic and pharmacodynamic measurements based on absolute values. Only dynamic studies provide such a possibility. The introduction of the dynamic total-body PET-CT will enable this type of measurements characterizing metabolic processes and receptor expression on the basis of Patlak plot.

Radioactive nuclei for β + γ PET and theranostics: selected candidates

Positron emission tomography (PET) is an established medical diagnostic imaging method. Continuous improvements are aimed at refining image reconstruction, reducing the amount of radioactive tracer and combining with targeted therapy. Time-of-flight (TOF)-PET provides the localization of the tracer through improved time resolution, nuclear physics may contribute to this goal via selection of radioactive nuclei emitting additional γ-rays. This additional radiation, when properly detected, localizes the decay of the tracer at the line of response (LoR) determined by two detected 511 keV quanta. Selected candidates are presented. Some are particularly interesting, as they are strong candidates for theranostic applications.

Novel biomarker and drug delivery systems for theranostics – extracellular vesicles

Extracellular vesicles (EVs) are nano- and micro-sized double-layered membrane entities derived from most cell types and released into biological fluids. Biological properties (cell-uptake, biocompatibility), and chemical (composition, structure) or physical (size, density) characteristics make EVs a good candidate for drug delivery systems (DDS). Recent advances in the field of EVs (e.g., scaling-up production, purification) and developments of new imaging methods (total-body positron emission tomography [PET]) revealed benefits of radiolabeled EVs in diagnostic and interventional medicine as a potential DDs in theranostics.

Perspectives of brain imaging with PET systems

In this partial review and partial attempt at vision of what may be the future of dedicated brain PET scanners, the key implementations of the PET technique, we postulate that we are still on a development path and there is still a lot to be done in order to develop optimal brain imagers. Optimized for particular imaging tasks and protocols, and also mobile, that can be used outside the PET center, in addition to the expected improvements in sensitivity and resolution. For this multi-application concept to be more practical, flexible, adaptable designs are preferred. This task is greatly facilitated by the improved TOF performance that allows for more open, adjustable, limited angular coverage geometries without creating image artifacts. As achieving uniform very high resolution in the whole body is not practical due to technological limits and high costs, hybrid systems using a moderate-resolution total body scanner (such as J-PET) combined with a very high performing brain imager could be a very attractive approach. As well, as using magnification inserts in the total body or long-axial length imagers to visualize selected targets with higher resolution. In addition, multigamma imagers combining PET with Compton imaging should be developed to enable multitracer imaging.

Progress and perspectives in total body PET systems instrumentation

Total body positron emission tomography (PET) systems are being developed by different groups worldwide. These systems have potential to change the number of applications in which molecular imaging is used. The change from a short axial field of view (FOV) to a longer one is however associated with a linear increase in the cost of these systems. This may limit their application to a small number of centers (capable of obtaining sufficient research funding). Therefore it remains interesting to see if lower cost systems can be developed and bring total body PET to the clinic for an acceptable budget. The wider availability of this low cost system can also enable more researchers to further optimize and explore the full potential of total body PET.

Unparalleled and revolutionary impact of PET imaging on research and day to day practice of medicine

Positron emission tomography (PET) imaging is the most quantitative modality for assessing disease activity at the molecular and cellular levels, and therefore, it allows monitoring its course and determining the efficacy of various therapeutic interventions. In this scientific communication, we describe the unparalleled and revolutionary impact of PET imaging on research and day to day practice of medicine. We emphasize the critical importance of the development and synthesis of novel radiotracers (starting from the enormous impact of F-Fluorodeouxyglucose (FDG) introduced by investigators at the University of Pennsylvania (PENN)) and PET instrumentation. These innovations have led to the total-body PET systems enabling dynamic and parametric molecular imaging of all organs in the body simultaneously. We also present our perspectives for future development of molecular imaging by multiphoton PET systems that will enable users to extract substantial information (owing to the evolving role of positronium imaging) about the related molecular and biological bases of various disorders, which are unachievable by the current PET imaging techniques.

Combined BNCT and PET for theranostics

This short review summarizes the issue of boron distribution monitoring in boron neutron capture therapy (BNCT), which remains a serious drawback of this powerful oncological treatment. Here we present the monitoring methods that are presently used with particular emphasis on the positron emission tomography (PET) which has the highest potential to be used for the real-time monitoring of boron biodistribution. We discuss the possibility of using present PET scanners to determine the boron uptake in vivo before the BNCT treatment with the use of p-boronphenylalanine (BPA) labeled with 18F isotope. Several examples of preclinical studies and clinical trials performed with the use of [18F]FBPA are shown. We also discuss shortly the perspectives of using other radiotracers and boron carriers which may significantly improve the boron imaging with the use of the state-of-the-art Total-Body PET scanners providing a theranostic approach in the BNCT.

Peptide receptor radionuclide therapy as a tool for the treatment of severe hypoglycemia in patients with primary inoperable insulinoma

Objectives Severe hypoglycemia in a course of inoperable insulinoma may be life-threating and often it is not well controlled, even by high doses of diazoxide requiring second line treatment. Among available methods PRRT is characterized by relatively low toxicity and is connected with favorable antitumor effect. The aim of the study was an evaluation of the PRRT effectiveness in control of hypoglycemia in patients with primary inoperable insulinoma. Methods Three patients (female with metastatic insulinoma, male with primary inoperable pancreatic tumor, female with MEN1 syndrome and hepatic metastases) were treated with PRRT due to severe hypoglycemia poorly controlled by diazoxide in course of primary inoperable insulinoma. Results Patient 1 baseline fasting glucose concentration increased from 2.4 mmol/L [3.30–5.60] to 5.9 mmol/L after PRRT. In patient 2 fasting glucose level 2.30 mmol/L increased after PRRT to 7.0 mmol/L, while baseline insulin level initially 31.15 uU/mL [2.6–24.9] decreased to 15.4 uU/mL. In patients 3, baseline fasting glucose level 2.5 mmol/L increased after PRRT to 7.9 mmol/L, and insulin decreased from 57.9 uU/mL to 6.3 uU/mL. In imaging there was partial response (PR) in patient 1 and 2 and stabilization of the tumor size in patient 3. In patient 2 reduction of tumor infiltration let for curative surgery performed 4 months after PPRT. Conclusions PRRT may be effective as a first or second line treatment in management of hypoglycemia for patients with hormonally active inoperable insulinoma.