The utilization of positron emission tomography in the evaluation of renal health and disease

Purpose: Positron emission tomography (PET) is a nuclear imaging technique that uses radiotracers to visualize metabolic processes of interest across different organs, to diagnose and manage diseases, and monitor therapeutic response. This systematic review aimed to characterize the value of PET for the assessment of renal metabolism and function in subjects with non-oncological metabolic disorders. Methods: This review was conducted and reported in accordance with the PRISMA statement. Research articles reporting “kidney” or “renal” metabolism evaluated with PET imaging between 1980 and 2021 were systematically searched in Medline/PubMed, Science Direct, and the Cochrane Library. Search results were exported and stored in RefWorks, the duplicates were removed, and eligible studies were identified, evaluated, and summarized. Results: Thirty reports met the inclusion criteria. The majority of the studies were prospective (73.33%, n = 22) in nature. The most utilized PET radiotracers were 15O-labeled radio water (H215O, n = 14) and 18F-fluorodeoxyglucose (18F-FDG, n = 8). Other radiotracers used in at least one study were 14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid (18F-FTHA), 18F-Sodium Fluoride (18F-NaF), 11C-acetate, 68-Gallium (68Ga), 13N-ammonia (13N-NH3), Rubidium-82 (82Rb), radiolabeled cationic ferritin (RadioCF), 11C‐para-aminobenzoic acid (11C-PABA), Gallium-68 pentixafor (68Ga-Pentixafor), 2-deoxy-2-F-fluoro-d-sorbitol (F-FDS) and 55Co-ethylene diamine tetra acetic acid (55Co-EDTA). Conclusion: PET imaging provides an effective modality for evaluating a range of metabolic functions including glucose and fatty acid uptake, oxygen consumption and renal perfusion. Multiple positron emitting radiolabeled racers can be used for renal imaging in clinical settings. PET imaging thus holds the potential to improve the diagnosis of renal disorders, and to monitor disease progression and treatment response

Current and future perspectives on functional molecular imaging in nephro-urology: theranostics on the horizon

In recent years, a paradigm shift from single-photon-emitting radionuclide radiotracers toward positron-emission tomography (PET) radiotracers has occurred in nuclear oncology. Although PET-based molecular imaging of the kidneys is still in its infancy, such a trend has emerged in the field of functional renal radionuclide imaging. Potentially allowing for precise and thorough evaluation of renal radiotracer urodynamics, PET radionuclide imaging has numerous advantages including precise anatomical co-registration with CT images and dynamic three-dimensional imaging capability. In addition, relative to scintigraphic approaches, PET can allow for significantly reduced scan time enabling high-throughput in a busy PET practice and further reduces radiation exposure, which may have a clinical impact in pediatric populations. In recent years, multiple renal PET radiotracers labeled with C-11, Ga-68, and F-18 have been utilized in clinical studies. Beyond providing a precise non-invasive read-out of renal function, such radiotracers may also be used to assess renal inflammation. This manuscript will provide an overview of renal molecular PET imaging and will highlight the transformation of conventional scintigraphy of the kidneys toward novel, high-resolution PET imaging for assessing renal function. In addition, future applications will be introduced, e.g. by transferring the concept of molecular image-guided diagnostics and therapy (theranostics) to the field of nephrology

Studies on 68Ga-Based Agents for PET Imaging of Cancer and Inflammation

Studies on 68Ga-Based Agents for PET Imaging of Cancer and Inflammation Positron emission tomography (PET) is based on the use of radiolabeled agents and facilitates in vivo imaging of biological processes, such as cancer. Because the detection of cancer is demanding and is often obscured by inflammation, there is a demand for better PET imaging agents. The aim was to preliminarily evaluate new PET agents for imaging cancer and inflammation using experimental models. 68Ga-chloride and peptides, 68Ga-labeled through 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), targeting matrix metalloproteinase-9 (MMP-9) were tested for tumor imaging. In addition, a 68Ga-DOTA-conjugated peptide targeting vascular adhesion protein-1 (VAP-1), was tested for inflammation imaging. The 68Ga-based imaging agents described here showed potential features by passing the essential in vitro tests, proceeding further to preclinical in vivo evaluation and being able to visualize the target. The target uptake and target-to-background ratios of 68Ga-based agents were, however, not optimal. 68Ga-chloride showed slow clearance caused by its binding to blood transferrin. In the case of 68Ga-DOTA-peptides low in vivo stability and/or low lipophilicity led to too rapid blood clearance and urinary excretion. The properties of 68Ga-labeled peptides are modifiable, as shown with matrix metalloproteinase-9 targeting ligands. In the conclusion of this PhD thesis, 68Ga-based agents for PET imaging of cancer and inflammation could be applied in the development of drugs, earlier diagnostics and following-up of the efficacy of therapies.Siirretty Doriast

The utilization of positron emission tomography in the evaluation of renal health and disease

PurposePositron emission tomography (PET) is a nuclear imaging technique that uses radiotracers to visualize metabolic processes of interest across different organs, to diagnose and manage diseases, and monitor therapeutic response. This systematic review aimed to characterize the value of PET for the assessment of renal metabolism and function in subjects with non-oncological metabolic disorders.MethodsThis review was conducted and reported in accordance with the PRISMA statement. Research articles reporting “kidney” or “renal” metabolism evaluated with PET imaging between 1980 and 2021 were systematically searched in Medline/PubMed, Science Direct, and the Cochrane Library. Search results were exported and stored in RefWorks, the duplicates were removed, and eligible studies were identified, evaluated, and summarized.ResultsThirty reports met the inclusion criteria. The majority of the studies were prospective (73.33%, n = 22) in nature. The most utilized PET radiotracers were 15O-labeled radio water (H215O, n = 14) and 18F-fluorodeoxyglucose (18F-FDG, n = 8). Other radiotracers used in at least one study were 14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid (18F-FTHA), 18F-Sodium Fluoride (18F-NaF), 11C-acetate, 68-Gallium (68Ga), 13N-ammonia (13N-NH3), Rubidium-82 (82Rb), radiolabeled cationic ferritin (RadioCF), 11C‐para-aminobenzoic acid (11C-PABA), Gallium-68 pentixafor (68Ga-Pentixafor), 2-deoxy-2-F-fluoro-D-sorbitol (F-FDS) and 55Co-ethylene diamine tetra acetic acid (55Co-EDTA).ConclusionPET imaging provides an effective modality for evaluating a range of metabolic functions including glucose and fatty acid uptake, oxygen consumption and renal perfusion. Multiple positron emitting radiolabeled racers can be used for renal imaging in clinical settings. PET imaging thus holds the potential to improve the diagnosis of renal disorders, and to monitor disease progression and treatment response.</p

In vivo imaging of vascular adhesion protein 1 - preclinical studies with positron emission tomography

The golden standard in nuclear medicine imaging of inflammation is the use of radiolabeled leukocytes. Although their diagnostic accuracy is good, the preparation of the leukocytes is both laborious and potentially hazardous for laboratory personnel. Molecules involved in leukocyte migration could serve as targets for the development of inflammation imaging agents. An excellent target would be a molecule that is absent or expressed at low level in normal tissues, but is induced or up-regulated at the site of inflammation. Vascular adhesion protein-1 (VAP-1) is a very promising target for in vivo imaging, since it is translocated to the endothelial cell surface when inflammation occurs. VAP-1 functions as an endothelial adhesion molecule that participates in leukocyte recruitment to inflamed tissues. Besides being an adhesion molecule, VAP-1 also has enzymatic activity. In this thesis, the targeting of VAP-1 was studied by using Gallium-68 (68Ga) labeled peptides and an Iodine-124 (124I) labeled antibody. The peptides were designed based on molecular modelling and phage display library searches. The new imaging agents were preclinically tested in vitro, as well as in vivo in animal models. The most promising imaging agent appeared to be a peptide belonging to the VAP-1 leukocyte ligand, Siglec-9 peptide. The 68Ga-labeled Siglec-9 peptide was able to detect VAP-1 positive vasculature in rodent models of sterile skin inflammation and melanoma by positron emission tomography. In addition to peptides, the 124I-labeled antibody showed VAP-1 specific binding both in vitro and in vivo. However, the estimated human radiation dose was rather high, and thus further preclinical studies in disease models are needed to clarify the value of this imaging agent. Detection of VAP-1 on endothelium was demonstrated in these studies and this imaging approach could be used in the diagnosis of inflammatory conditions as well as melanoma. These studies provide a proof-of-concept for PET imaging of VAP-1 and further studies are warranted.Siirretty Doriast

Imaging of preclinical endometrial cancer models for monitoring tumor progression and response to targeted therapy

Endometrial cancer is the most common gynecologic malignancy in industrialized countries. Most patients are cured by surgery; however, about 15% of the patients develop recurrence with limited treatment options. Patient-derived tumor xenograft (PDX) mouse models represent useful tools for preclinical evaluation of new therapies and biomarker identification. Preclinical imaging by magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT), single-photon emission computed tomography (SPECT) and optical imaging during disease progression enables visualization and quantification of functional tumor characteristics, which may serve as imaging biomarkers guiding targeted therapies. A critical question, however, is whether the in vivo model systems mimic the disease setting in patients to such an extent that the imaging biomarkers may be translatable to the clinic. The primary objective of this review is to give an overview of current and novel preclinical imaging methods relevant for endometrial cancer animal models. Furthermore, we highlight how these advanced imaging methods depict pathogenic mechanisms important for tumor progression that represent potential targets for treatment in endometrial cancer.publishedVersio

POSTER SESSION

Matrix-PET is a novel detector solution for the Positron Emission Tomography. It is one of thetwo methods which is developed at present at the Jagiellonian University [1]. The detectoridea is a subject of a patent application

Development of novel imaging biomarkers using positron emission tomography for characterization of malignant phenotype and response evaluation

Positron emission tomography (PET) enables noninvasive tumour imaging, as changes in metabolic activity secondary to therapy can be measured before changes in tumour size are evident on standard anatomic imaging. Two imaging approaches representing proliferation dependent and independent technologies are evolving as potential methods for assessing growth signalling and, thus, treatment response: [18F]3’-deoxy-3’-fluorothymidine (FLT) and [11C]choline. The validity of the former in patients with pancreatic cancer is unproven and likewise, the role of the latter in response to androgen deprivation/radiotherapy in prostate cancer (PCa) remains unexplored. Using a variety of approaches, the aim of this thesis was to provide an understanding of the role of these tracers in lesion detection and response assessment in patients by PET/computed tomography (PET/CT). Given the high physiological hepatic localisation of FLT, a recently reported kinetic spatial filtering (KSF) algorithm was evaluated as a way to de-noise abdominal FLT-PET data from patients with advanced pancreatic cancer. Application of KSF led to improved lesion detection. FLT uptake (SUV60,max) significantly increased in mid-treatment (gemcitabine based) progressors (p=0.04). In this limited number of patients, reduction in FLT uptake did not predict overall survival. The role of [11C]choline PET/CT in lesion detection and response in prostate cancer (PCa) was also investigated using semi-quantitative and quantitative methods. As a prelude to the quantitative imaging studies, it was established that irreversible tracer uptake characterised tumour (breast cancer) [11C]choline kinetics. Similar irreversible uptake characterised PCa. An important finding was that tumour [11C]choline uptake (in 29 PCa patients) correlated with choline kinase (CHK) expression but not proliferation, as assessed by Ki67 labelling index. Immunohistochemistry of the above patients’ prostate cores with CHKα antibody demonstrated a spectrum of CHKα expression, ranging from expression in prostatic-intraepithelial-neoplasia to low to high expression in malignant cores. These findings were further corroborated in a larger cohort of 75 malignant cores derived from non-imaging studies. Having established [11C]choline as a proliferation independent marker of growth, its role in assessing treatment response was investigated. [11C]choline PET was sensitive to metabolic changes within prostate tumours following androgen deprivation and radical radiotherapy. While promising data were obtained with [11C]choline PET, the radiotracer is subject to metabolic degradation complicating data analysis. To this end, a novel metabolically stable analogue of choline ([18F]fluoromethyl-[1,2-2H4]-choline ([18F]D4FCH)) was transitioned into volunteers and patients to study its pharmacokinetics and preliminary diagnostic potential. This tracer embodies deuterium isotope substitution as a means to discourage systemic metabolism. The radiotracer had favourable dosimetry (effective-dose: 0.025mSv/MBq) and safety. Preliminary results in non-small cell lung cancer showed that the tracer is taken up in tumours. Further studies are warranted to characterise this new tracer in different tumour types. As a prelude to imaging cancer cell death in tumours, a caspase-3 specific radiotracer, [18F](S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4- difluorophenoxymethyl)-pyrrolidine-1-sulfonyl) isatin ([18F]ICMT-11) was also transitioned into volunteers. The radiotracer had favourable dosimetry (effective-dose: 0.025mSv/MBq) and safety. In summary, FLT-PET/CT combined with KSF and [11C]choline PET/CT were shown to be promising methods for imaging early treatment response in patients. Further work will be required to evaluate the clinical relevance of these data in terms of overall patient outcome. Furthermore, a new choline-based radiotracer and a caspase-3 specific radiotracer have been transitioned into humans.Open Acces

Development and assessment of estimate methods for internal dosimetry using PET/CT

The aim of this thesis was to assess and develop internal dose calculations methods in diagnostic and therapeutic nuclear medicine procedures to patients undergone PET/CT explorations. Towards this objective, the accuracy and precision of different classical methods commonly used to estimate internal dosimetry were investigated. Biodistribution studies were used in order to compare these methods. The main study aspects included region-of-interest (ROI) delineation methods, reconstruction algorithms, scatter correction and radiopharmaceutical's biokinetic. Optimization of internal dosimetry in this thesis was completed with the development of a Monte Carlo (MC) technique for estimating the patient-specific PET/CT dosimetry. The development of a mathematical model using MC techniques allowed us to have a gold standard to which compare classical techniques and study the aspects discussed previously. It was observed that effective dose (ED) estimations were sensitive to whichever delineation ROI method was applied. Furthermore, it was perceived that the biokinetics of the radioligand also influences in the ED estimation. On the other hand, similar quantitative accuracy was found regarding image reconstruction (FBP and OSEM) and scatter correction methods studied (FSC and SSC). Analysis of the impact of inter- and intra-operator variability in dose estimations revealed higher reproducibility in 3D methods in comparison with 2D planar method. The last one, showed the highest interoperator variability, which implies an overestimation of the ED. In this dissertation, specific routines were developed to be applied with the MC code PENELOPE/penEasy to perform individualized internal dosimetry estimations. Voxel-level absorbed dose maps which include self- and cross-irradiation doses were generated from the morphological and functional patient images. Further parameters such as cumulative organ dose, maximum and minimum voxel organ values, volume of the organ and dose-volume histograms of interest were reported. The model implemented was applied to a theoretical study using simulated PET images of a voxelized Zubal phantom. The results were benchmarked with the ones obtained using the OLINDA/EXM software. The comparison was in good agreement for those organs were both phantoms considered (Zubal and the reference one in OLINDA/EXM) were close. Undoubtedly, the implementation of a patient-specific internal dosimetry method not only leads to an improvement in diagnostic examinations where the risk could be quantified, but also NM therapy could become more effective in terms that patients receiving an optimal care.L'objectiu d'aquesta tesi va ser avaluar i desenvolupar mètodes de càlcul de dosis interna en procediments de diagnòstic i terapèutics de medicina nuclear per a pacients sotmesos a exploracions PET / TC. Amb aquest objectiu, es va investigar l'exactitud i la precisió dels diferents mètodes clàssics utilitzats habitualment per estimar la dosimetria interna. Es van utilitzar estudis de biodistribució per comparar aquests mètodes. Els principals aspectes d'estudi incloïen mètodes de delimitació de la regió d'interès (ROI), algoritmes de reconstrucció, correcció de dispersió i biocinètiques de radiofàrmacs. L'optimització de la dosimetria interna en aquesta tesi es va completar amb el desenvolupament d'una tècnica de Monte Carlo (MC) per a estimar la dosimetria PET / TC específica del pacient. El desenvolupament d'un model matemàtic amb tècniques de MC ens va permetre tenir una referència amb la que comparar les tècniques clàssiques i estudiar els aspectes descrits anteriorment. Es va observar que les estimacions de la dosi efectiva (DE) eren sensibles a qualsevol mètode de delimitació de la ROI aplicada. A més a més, es va percebre que la biocinètica del radiolligand també influeix en l'estimació de la DE. D'altra banda, es va trobar una exactitud quantitativament similar pel que fa a la reconstrucció d'imatges (FBP i OSEM) i els mètodes de correcció de dispersió estudiats (FSC i SSC). L'anàlisi de l'impacte de la variabilitat entre operadors i intra-operadors en les estimacions de dosis va mostrar una major reproductibilitat en els mètodes 3D en comparació amb el mètode planar 2D. Aquest últim, va mostrar la màxima variabilitat entre operadors, la qual cosa implica una sobreestimació de la DE. En aquesta tesi, es van desenvolupar rutines específiques per aplicar-les amb el codi MC PENELOPE / penEasy per a realitzar estimacions de dosimetria interna individualitzades. Es van generar mapes de dosis absorbida a nivell de voxel que incloïen dosis d? autoirradiació i irradiació creuada a partir de les imatges morfològiques i funcionals del pacient. Es van reportar altres paràmetres d?interès com la dosi d'òrgan acumulada, els valors màxims i mínims de l'òrgan i del vòxel, el volum de l'òrgan i els histogrames de dosi-volum. El model implementat es va aplicar a un estudi teòric mitjançant imatges simulades de PET d'un maniquí de Zubal voxelitzat. Els resultats es van comparar amb els obtinguts mitjançant el programa OLINDA / EXM. Es va observar un bon acord per a aquells òrgans semblants entre el maniquí de Zubal i el maniquí de referència del software OLINDA/EXM. Sens dubte, la implementació d'un mètode de dosimetria interna específic per al pacient no només condueix a una millora en les exploracions de diagnòstic on es pot quantificar el risc d?irradiació, sinó que la teràpia amb medicina nuclear podria ser més eficaç en termes que els pacients rebin un tractament òptim.Postprint (published version