Application Of Positron Emission Tomography Research Articles

Research and application of 18F-fluorodeoxyglucose positron emission tomography/ computed tomography for the diagnosis and treatment of primary hepatocellular carcinoma

Primary hepatocellular carcinoma is a common cancer. Many patients are found with intermediate-advanced stage, rapid development, poor treatment and high mortality. 18F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18F-FDG PET/CT) can discover the early lesions and therefore plays an important role in diagnosis, treatment and prognosis of patients with hepatocellular carcinoma. It especially has obvious advantages in detecting metastasis and monitoring recurrence. However, 18F-FDG PET/CT imaging has poor quality and low diagnosis rate. Understanding the advantages and limitations of 18F-FDG PET/CT can provide better basis for clinical diagnosis and treatment for hepatocellular carcinoma patients. This article briefly introduces the research and application of 18F-FDG PET/CT in the diagnosis and treatment of hepatocellular carcinoma.

Clinical overview of the current state and future applications of positron emission tomography in bone and soft tissue sarcoma

Positron emission tomography (PET) provides a noninvasive, functional assessment providing incremental diagnostic value over magnetic resonance imaging (MRI) and computed tomography (CT) for the initial staging, restaging, response assessment, and prognosis of bone and soft tissue sarcomas. The purpose of this article is to review the current state and future applications of PET in sarcoma imaging, including the clinical roles of 18F-fluorodeoxyglucose (FDG) and other PET radiotracers as well as the use of PET with concurrent MRI. A PubMed search using the query “(‘positron emission tomography’ OR PET) AND (‘CT’ OR ‘computed tomograph*’ OR ‘MR*’ OR ‘magnetic resonance’) AND (FDG OR hypox* OR prolif*) AND sarcoma*” for PET examinations involving bone and soft tissue sarcoma studies up to February 1, 2017 were performed. Additionally, analogous Google Scholar, Scopus, and Web of Science search queries were also performed. Subsequently, references for the retrieved articles were reviewed, and the relevant publications on the subject were also included. A total of 30 studies were included in the review. FDG-PET with concurrent computed tomography (CT) can provide incremental diagnostic value relative to MRI to provide additional insight into the grading, staging, restaging, and response assessment in sarcomas, particularly when neoadjuvant therapy is an option. FDG-PET/CT can be used for noninvasive prediction of tumor grade and assess regional heterogeneity, providing guidance for tissue sampling and reducing the risk of undergrading and understaging. In addition, early clinical studies of sarcoma PET imaging using hypoxia and cellular proliferation agents suggest incremental diagnostic benefit over FDG-PET. The use of PET/MRI is under active investigation and may yield additional clinically impactful findings over PET/CT. PET imaging used with concurrent CT or MRI provides a unique noninvasive way to assess regional biological and biochemical features for bone and soft tissue sarcomas.

A catalytic fluoride-rebound mechanism for C(sp3)-CF3 bond formation.

The biological properties of trifluoromethyl compounds have led to their ubiquity in pharmaceuticals, yet their chemical properties have made their preparation a substantial challenge, necessitating innovative chemical solutions. We report the serendipitous discovery of a borane-catalyzed formal C(sp3)-CF3 reductive elimination from Au(III) that accesses these compounds by a distinct mechanism proceeding via fluoride abstraction, migratory insertion, and C-F reductive elimination to achieve a net C-C bond construction. The parent bis(trifluoromethyl)Au(III) complexes tolerate a surprising breadth of synthetic protocols, enabling the synthesis of complex organic derivatives without cleavage of the Au-C bond. This feature, combined with the "fluoride-rebound" mechanism, was translated into a protocol for the synthesis of 18F-radiolabeled aliphatic CF3-containing compounds, enabling the preparation of potential tracers for use in positron emission tomography.

68Ga]/[188Re] Complexed [CDTMP] Trans-1,2-Cyclohexyldinitrilotetraphosphonic Acid As a Theranostic Agent for Skeletal Metastases.

Metastasis of the osseous tissue is one of the frequent and severe aggravations as a result of several neoplastic conditions, such as metabolic disorders, infections, and cancer. The objective of this study was to evaluate the pertinence of [68Ga]-trans-1,2-cyclohexyldinitrilo tetramethylene phosphonic acid (CDTMP) as a potential bone imaging agent for positron emission tomography (PET) applications as well as to assess [188Re]-CDTMP for bone pain palliation in metastatic skeletal disorders. 68Ga complex of CDTMP was prepared at 80°C at pH 3.5, and 188Re complex of CDTMP was prepared at room temperature. [68Ga]-CDTMP complex was investigated as PET tracer while the therapeutic efficacy was assessed for [188Re]-CDTMP. Labeling efficiency, biodistribution, myelotoxicity, and imaging studies were carried out for the complexes synthesized. Both PET and MicroPET imaging studies were performed for [68Ga]-CDTMP whereas SPECT acquisitions were acquired for [188Re]-CDTMP. Data were analyzed semiquantitatively for all the scintigraphic scans obtained. The radiolabeling efficiency was observed to be >70% for [68Ga]-CDTMP. High bone uptake of [68Ga]-CDTMP as compared to contralateral tissue was found in PET imaging in Balb/C mice and New Zealand rabbit; the similar result for bone uptake was correlated in the biodistribution study of the compound in BALB/c mice at different time intervals. Biodistribution experiments carried out in mice showed maximum uptake of 6.12 ± 1.22%ID/g at 45 min postinjection. For [188Re]-CDTMP, total skeletal uptake was 8.12 ± 1.11%ID/g observed at 1 h postinjection from biodistribution data. High renal uptake confirms renal route of excretion. A good hydroxyapatite binding too was seen for both the complexes. No evidence of destruction or adverse functioning of vital organs was observed for the 188Re complex. [68Ga]-CDTMP complex can be used as a promising PET bone imaging agent and [188Re]-CDTMP as a surrogate moiety for therapeutic application. Owing to the short half-life of 68Ga (68 min), cyclotron-independent radiopharmacy, fast clearance, and rapid renal excretion as evidenced in preclinical animal models. Very low myelotoxicity and highly selective bone uptake prove the potential of [188Re]-CDTMP for therapeutic application.

Imaging of amino acid transport in brain tumours: Positron emission tomography with O-(2-[18F]fluoroethyl)-L-tyrosine (FET).

The assessment of cerebral gliomas using magnetic resonance imaging (MRI) provides excellent structural images but cannot solve all diagnostic problems satisfactorily. The differentiation of tumour tissue from non-neoplastic changes may be difficult especially in the post-treatment phase. In recent years, positron emission tomography (PET) using radiolabelled amino acids has gained considerable interest as an additional tool to improve the diagnosis of cerebral gliomas and brain metastases. A key step for this advancement was the development of the F-18 labelled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) which has spread rapidly in the last decade and replaced carbon-11 labelled amino acid tracers such as 11C-methyl-L-methionine (MET) in many centres in Europe. FET can be produced with high efficiency and distributed in a satellite concept like 2-[18F]fluoro-2-deoxy-D-glucose (FDG). Furthermore, FET exhibits favourable properties such as high in vivo stability, high tumour to background contrast and tissue specific tracer kinetics, which provides additional information for tumour grading or differential diagnosis. The Response Assessment in Neuro-Oncology (RANO) working group - an international effort to develop new standardized response criteria for clinical trials in brain tumours - has recently recommended the additional use of amino acid PET imaging for brain tumour management. FET PET can provide important diagnostic information in crucial situations such as the definition of biopsy site, the delineation of cerebral gliomas for therapy planning, sensitive monitoring of treatment response and an improved differentiation of tumour recurrence from treatment-related changes. In this article the basic information, methodological aspects and the actual status of clinical application of FET PET are reviewed.

PET imaging in heart failure: the role of new tracers.

Positron emission tomography (PET) myocardial perfusion imaging is being increasingly used for the detection of coronary artery disease. In the presence of significant left ventricle dysfunction, the assessment of myocardial ischemia and viability by PET plays a role in the identification of patients who may benefit from revascularization. In addition to these, new PET tracers may play a role in the assessment of underlying pathophysiology and therapeutic options in heart failure. Studies have shown the ability of sympathetic innervation imaging to assess the risk of cardiac death, arrhythmia, and disease progression. New tracers have been tested for the assessment of angiogenesis and other mechanisms involved in myocardial repair after infarction. Furthermore, new tracers may play a role in detection of inflammatory cardiomyopathies, especially cardiac sarcoidosis, which is a diagnostic challenge for current methods. In addition to the assessment of prognosis and etiology, the value of new PET tracers will depend on their ability to guide selection of therapies and incorporation into clinical management algorithms in heart failure. This review describes recent advances in applications of cardiac PET in heart failure with emphasis on potential roles of new tracers.

First clinical investigation of a 4D maximum likelihood reconstruction for 4D PET-based treatment verification in ion beam therapy

Background and purposeIn clinical applications of Positron Emission Tomography (PET)-based treatment verification in ion beam therapy (PT-PET), detection and interpretation of inconsistencies between Measured PET and Expected PET are mostly limited by Measured PET noise, due to low count statistics, and by Expected PET bias, especially due to inaccurate washout modelling in off-line implementations. In this work, a recently proposed 4D Maximum Likelihood (ML) reconstruction algorithm which considers Measured PET and Expected PET as two different motion phases of a 4D dataset is assessed on clinical 4D PET-CT datasets acquired after carbon ion therapy. Material and methodsThe 4D ML reconstruction algorithm estimates: (1) Measured PET of enhanced image quality with respect to the conventional Measured PET, thanks to the exploitation of Expected PET; (2) the deformation field mapping the Expected PET onto the Measured PET as a measure of the occurred displacements. ResultsResults demonstrate the desired sensitivity to inconsistencies due to breathing motion and/or setup modification, robustness to noise in different count statistics scenarios, but a limited sensitivity to Expected PET washout inaccuracy. ConclusionsThe 4D ML reconstruction algorithm supports clinical 4D PT-PET in ion beam therapy. The limited sensitivity to washout inaccuracy can be detected and potentially overcome.

Development of a 68Ge/68Ga Generator System Using Polysaccharide Polymers and Its Application in PET Imaging of Tropical Infectious Diseases.

Gallium-68 (68Ga) is a positron emitter for clinical positron emission tomography (PET) applications that can be produced by a 68Ge/68Ga generator without cyclotron. However, commercially available 68Ge/68Ga generator systems require multiple steps for the preparation of 68Ga radiopharmaceuticals and are sometimes plagued by metallic impurities in the 68Ga eluent. We developed a 68Ge/68Ga generator system using polysaccharide-based adsorbents and direct application of the generator-eluted 68Ga-citrate to PET imaging of tropical infectious diseases. N-Methylglucamine (MG) as a 68Ge-adsorbing unit (Sepha-MGs) was introduced to a series of Sephadex G-10, G-15, G-25, G-50, and G-75. In the batch method, over 97% of the 68Ge in the solution was adsorbed onto the Sepha-MG series within 15 min. In particular, 68Ge was effectively adsorbed on the Sepha(15)-MG packed columns and 70–80% of the 68Ga was eluted by 1 mL of 0.1 M trisodium citrate with low 68Ge contamination (<0.001%). The chemical form of the generator-eluted 68Ga solution was identified as 68Ga-citrate. In PET studies, affected regions in mice infected with Leishmania and severe fever with thrombocytopenia syndrome virus were clearly visualized using the 68Ga-citrate. Sepha-MGs are useful adsorbents for 68Ge/68Ga generator systems with high 68Ga elution efficiency and minimal 68Ge breakthrough. These results indicated that eluted 68Ga-citrate can be directly used for PET imaging of infectious sites in mice. This novel generator system may be useful for straightforward PET imaging of infection in clinical practice.

Proton-induced production and radiochemical isolation of 44Ti from scandium metal targets for 44Ti/44Sc generator development

Scandium-44g (half-life 3.97h) shows promise for application in positron emission tomography (PET), due to favorable decay parameters. One of the sources of 44gSc is the 44Ti/44gSc generator, which can conveniently provide this radioisotope on a daily basis at a diagnostic facility. Titanium-44 (half-life 60.0 a), in turn, can be obtained via proton irradiation of scandium metal targets. A substantial 44Ti product batch, however, requires high beam currents, long irradiation times and an elaborate chemical procedure for 44Ti isolation and purification. This study describes the production of a combined 175MBq (4.7mCi) batch yield of 44Ti in week long proton irradiations at the Los Alamos Isotope Production Facility (LANL-IPF) and the Brookhaven Linac Isotope Producer (BNL-BLIP). A two-step ion exchange chromatography based chemical separation method is introduced: first, a coarse separation of 44Ti via anion exchange sorption in concentrated HCl results in a 44Tc/Sc separation factor of 102–103. A second, cation exchange based step in HCl media is then applied for 44Ti fine purification from residual Sc mass. In summary, this method yields a 90–97% 44Ti recovery with an overall Ti/Sc separation factor of ≥106.

A comparative study of the time performance between NINO and FlexToT ASICs

Universitat de Barcelona (UB) and CIEMAT have designed the FlexToT ASIC for the front-end readout of SiPM-based scintillator detectors. This ASIC is aimed at time of flight (ToF) positron emission tomography (PET) applications. In this work we have evaluated the time performance of the FlexToT v2 ASIC compared to the NINO ASIC, a fast ASIC developped at CERN. NINO electronics give 64 ps sigma for single-photon time resolution (SPTR) and 93 ps FWHM for coincidence time resolution (CTR) with 2 × 2 × 5 mm3 LSO:Ce,Ca crystals and S13360-3050CS SiPMs. Using the same SiPMs and crystals, the FlexToT v2 ASIC yields 91 ps sigma for SPTR and 123 ps FWHM for CTR. Despite worse time performace than NINO, FlexToT v2 features lower power consumption (11 vs. 27 mW/ch) and linear ToT energy measurement.

Innovative LuYAP:Ce array for PET imaging

We present an imaging characterization of a 10 × 10 LuYAP array (2 × 2 × 10 mm3 pixels) with an innovative dielectric coating insulation (0.015 mm thick), in view of its possible use in a gamma camera for imaging positron emission tomography (PET) or in similar applications, e.g. as γ -prompt detector in hadron therapy. The particular assembly of this array was realized in order to obtain a packing fraction of 98%, improving detection efficiency and light collection. For imaging purpose, the array has been coupled with a selected Hamamatsu H10966-100 Multi Anode Photomultiplier read out by a customized 64 independent channels electronics. This tube presents a superbialkali photocathode with 38% of quantum efficiency, permitting to enhance energy resolution and consequently image quality. A pixel identification of about 0.5 mm at 662 keV was obtained, highlighting the potentiality of this detector in PET applications.

Single transmission-line readout method for silicon photomultiplier based time-of-flight and depth-of-interaction PET

We propose a novel single transmission-line readout method for whole-body time-of-flight positron emission tomography applications, without compromising on performance. The basic idea of the proposed multiplexing method is the addition of a specially prepared tag signal ahead of the scintillation pulse. The tag signal is a square pulse that encodes photon arrival time and channel information. The 2D position of a silicon photomultiplier (SiPM) array is encoded by the specific width and height of the tag signal. A summing amplifier merges the tag and scintillation signals of each channel, and the final output signal can be acquired with a one-channel digitizer. The feasibility and performance of the proposed method were evaluated using a 1:1 coupled detector consisting of 4 × 4 array of LGSO crystals and 16 channel SiPM. The sixteen 3 mm LGSO crystals were clearly separated in the crystal-positioning map with high reliability. The average energy resolution and coincidence resolving time were 11.31 ± 0.55% and 264.7 ± 10.7 ps, respectively. We also proved that the proposed method does not degrade timing performance with increasing multiplexing ratio. The two types of LGSO crystals (L0.95GSO and L0.20GSO) in phoswich detector were also clearly identified with the high-reliability using pulse shape discrimination, thanks to the well-preserved pulse shape information. In conclusion, the proposed multiplexing method allows decoding of the 3D interaction position of gamma rays in the scintillation detector with single-line readout.

Improved image quality using monolithic scintillator detectors with dual-sided readout in a whole-body TOF-PET ring: a simulation study

We have recently built and characterized the performance of a monolithic scintillator detector based on a 32 mm × 32 mm × 22 mm LYSO:Ce crystal read out by digital silicon photomultiplier (dSiPM) arrays coupled to the crystal front and back surfaces in a dual-sided readout (DSR) configuration. The detector spatial resolution appeared to be markedly better than that of a detector consisting of the same crystal with conventional back-sided readout (BSR). Here, we aim to evaluate the influence of this difference in the detector spatial response on the quality of reconstructed images, so as to quantify the potential benefit of the DSR approach for high-resolution, whole-body time-of-flight (TOF) positron emission tomography (PET) applications. We perform Monte Carlo simulations of clinical PET systems based on BSR and DSR detectors, using the results of our detector characterization experiments to model the detector spatial responses. We subsequently quantify the improvement in image quality obtained with DSR compared to BSR, using clinically relevant metrics such as the contrast recovery coefficient (CRC) and the area under the localized receiver operating characteristic curve (ALROC). Finally, we compare the results with simulated rings of pixelated detectors with DOI capability. Our results show that the DSR detector produces significantly higher CRC and increased ALROC values than the BSR detector. The comparison with pixelated systems indicates that one would need to choose a crystal size of 3.2 mm with three DOI layers to match the performance of the BSR detector, while a pixel size of 1.3 mm with three DOI layers would be required to get on par with the DSR detector.

Alcohol-Enhanced Cu-Mediated Radiofluorination.

The potential of many 18 F-labeled (hetero)aromatics for applications in positron emission tomography remains underexplored because convenient procedures for their radiosynthesis are lacking. Consequently, simple methods to prepare radiofluorinated (hetero)arenes are highly sought after. Herein, we report the beneficial effect of primary and secondary alcohols on Cu-mediated 18 F-labeling. This observation contradicts the assumption that such alcohols are inappropriate solvents for aromatic fluorination. Therefore, we developed a protocol for rapid radiolabeling of an extraordinarily broad scope of boronic and stannyl substrates under general reaction conditions. Notably, radiofluorinated indoles, phenols, and anilines were synthesized directly from the corresponding unprotected precursors. Furthermore, the novel method enabled the preparation of radiofluorinated tryptophans, [18 F]F-DPA, [18 F]DAA1106, 6-[18 F]FDA, and 6-[18 F]FDOPA.

The Landscape of Clinical Trials Evaluating the Theranostic Role of PET Imaging in Oncology: Insights from an Analysis of ClinicalTrials.gov Database.

In the war on cancer marked by personalized medicine, positron emission tomography (PET)-based theranostic strategy is playing an increasingly important role. Well-designed clinical trials are of great significance for validating the PET applications and ensuring evidence-based cancer care. This study aimed to provide a comprehensive landscape of the characteristics of PET clinical trials using the substantial resource of ClinicalTrials.gov database. We identified 25,599 oncology trials registered with ClinicalTrials.gov in the last ten-year period (October 2005-September 2015). They were systematically reviewed to validate classification into 519 PET trials and 25,080 other oncology trials used for comparison. We found that PET trials were predominantly phase 1-2 studies (86.2%) and were more likely to be single-arm (78.9% vs. 57.9%, P <0.001) using non-randomized assignment (90.1% vs. 66.7%, P <0.001) than other oncology trials. Furthermore, PET trials were small in scale, generally enrolling fewer than 100 participants (20.3% vs. 25.7% for other oncology trials, P = 0.014), which might be too small to detect a significant theranostic effect. The funding support from industry or National Institutes of Health shrunk over time (both decreased by about 5%), and PET trials were more likely to be conducted in only one region lacking international collaboration (97.0% vs. 89.3% for other oncology trials, P <0.001). These findings raise concerns that clinical trials evaluating PET imaging in oncology are not receiving the attention or efforts necessary to generate high-quality evidence. Advancing the clinical application of PET imaging will require a concerted effort to improve the quality of trials.

Imaging Central Nervous System Demyelination and Remyelination byPositron-Emission Tomography.

Positron Emission Tomography (PET), an imaging technique based on the injection of radiotracers directed against specific biological targets within brain tissues, within brain tissues, is a specific and sensitive technique which offers the unique opportunity to quantify myelin dynamics in the central nervous system. Several stilbene and benzothiazole derivatives have been repurposed to image myelin by PET. In demyelinating and dysmyelinating models, selected radiotracers were shown to reliably quantify demyelination and remyelination, allowing a translational approach in humans. A pilot study in subjects with active relapsing MS using PET and the most available benzothiazole derivative, [11C]PIB, supported the hypothesis that this technique is able to quantify myelin content in multiple sclerosis (MS) lesions and to capture dynamic demyelination and remyelination over time. This study highlighted for the first time in vivo the prognostic value of individual profiles of remyelination on the disease course. In future, the clinical application of myelin PET will be pushed forward thanks to the availability of novel fluorinated tracers for myelin, together with the setting up of non invasive quantification procedures and the use of powerful PET-MR systems. This will enable to address in vivo critical unanswered questions about the pathogenesis of remyelination, and to measure the efficacy of emerging promyelinating drugs in early-phase therapeutic trials.

Performance evaluation of a sub-millimeter spatial resolution PET detector module using a digital silicon photomultiplier coupled LGSO array

In positron emission tomography (PET) for breast, brain and small animal imaging, the spatial resolution of a PET detector is crucial to obtain high quality PET images. In this study, a PET detector for sub-millimeter spatial resolution imaging purpose was assembled using 4×4 pixels of a digital silicon photomultiplier (dSiPM, DPC-3200-22-44, Philips) coupled with a 15×15 LGSO array with BaSO4 reflector, and a 1mm thick acrylic light guide for light distribution between the dSiPM pixels. The active area of each dSiPM pixel was 3.2×3.9mm2 and the size of each LGSO scintillator element was 0.7×0.7×6mm3. In this paper, we experimentally demonstrated the performance of the PET detector by measuring the energy resolution, 2D flood map, peak to valley (P/V) ratio, and coincidence resolving time (CRT). All measurements were performed at a temperature of 10±1℃. The average energy resolution was 15.6% (without correcting for saturation effects) at 511keV and the best CRT was 242±5ps. The 2D flood map obtained with an energy window of 400–600keV demonstrated clear identification of all pixels, and the average P/V ratio of the X- and Y-directions were 7.31 and 7.81, respectively. This study demonstrated that the PET detector could be suitable for application in high resolution PET while achieving good timing resolution.

A simple method for preparation of pure 68 Ga-acetate precursor for formulation of radiopharmaceuticals: Physicochemical characteristics of the 68 Ga eluate of the SnO2 based-68 Ge/68 Ga column generator.

Gallium-68 radioisotope is an excellent source in clinical positron emission tomography application due to its ease of availability from germanium-68 (68 Ge)/gallium-68 (68 Ga) generator having a shelf life of 1year. In this paper, a modified method for purification of the primary eluate of 68 Ge-68 Ga generator by using a small cation exchange resin (Dowex-50) column has been described. The breakthrough of 68 Ge before and after purification of 68 Ga eluate was 0.014% and 0.00027%, respectively. The average recovery yield of 68 Ga after purification was 84%±8.6% (SD, n=335). The results of the physiochemical studies confirmed that the 68 Ga-acetate obtained is suitable for labeling of radiopharmaceuticals.

Acid resistant zirconium phosphate for the long term application of 68Ge/68Ga generator system

The 68Ge/68Ga generator system is an excellent source for producing ready-to-use Ga-68 in clinical Positron Emission Tomography (PET) applications. The column adsorbent is the key component for the 68Ge/68Ga generator system. Therefore, several studies have been conducted to identify column materials with a stable and superior elution yield in an acidic eluent (0.1 N HCl solution). In this study, four different zirconium phosphates were synthesized with a particle size of 200–800nm, pore-size of 55∼190Å and surface area of 0.72–268m2g−1. Synthesized and studied amorphous zirconium phosphate (ZrP-1) exhibited excellent acid resistant properties for the 0.1 N HCl eluent and a large surface area of 268m2g−1. Amorphous ZrP-1 showed a good Ga-68 elution yield of 74% in 0.1 N HCl eluent accompanying extraordinary low breakthrough of Ge-68 (0.007%).

ChemInform Abstract: Hydrogen‐Bond Promoted Nucleophilic Fluorination: Concept, Mechanism and Applications in Positron Emission Tomography

AbstractReview: recent breakthroughs in SN2‐type nucleophilic fluorination reactions using alkali metal fluorides promoted by protic solvents; 50 refs.