Publications by authors named "Gianfranco Cicoria"

26 Publications

  • Page 1 of 1

An HPLC and UHPLC-HRMS approach to study PSMA-11 instability in aqueous solution.

EJNMMI Radiopharm Chem 2021 Mar 24;6(1):14. Epub 2021 Mar 24.

Department for Life Quality Studies, University of Bologna, Corso D'Augusto, 237, Rimini, 47921, Italy.

Background: The stability of precursors and reagents is of utmost importance for developing a robust radiolabelling method that provides high and constant radiochemical yield and radiochemical purity. While performing the QC of the [Ga]Ga-PSMA-11 injectable solutions according to Ph. Eur. Monograph that has recently been published, a trend to the instability of the standard PSMA-11, the same used as a precursor for [Ga]Ga-PSMA-11 radiosynthesis, has been observed. This instability led to the formation of a side product in a time-dependent manner. The formation of this compound, besides making the implementation of the Ph. Eur. analytical method more difficult, negatively influenced the radiochemical yield and the radiochemical purity by increasing gallium-68 in colloidal and ionic forms.

Results: The nature of the side product was investigated by adding chelators, such as EDTA, to PSMA-11 solutions and using the combination of UHPLC-HRMS. The results led to the definition of the side product structure, as Fe-PSMA-11, from the combination of the high-affinity chelator HBED-CC, present in the molecule of PSMA-11, and environmental Fe (III).

Conclusions: Strategies to reduce the risk of low radiolabeling yields and to increase the stability of the PSMA-11 in an aqueous solution were also discussed.
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http://dx.doi.org/10.1186/s41181-021-00122-3DOI Listing
March 2021

Radiotherapy-induced malfunctions of cardiac implantable electronic devices in cancer patients.

Intern Emerg Med 2020 09 2;15(6):967-973. Epub 2019 Dec 2.

Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico Di Modena, Via del Pozzo, 71, 41124, Modena, Italy.

The number of patients with cardiac implantable electronic devices (CIEDs) requiring radiation therapy (RT) for cancer treatment is increasing. The purpose of this study is to estimate the prevalence, possible predictors, and clinical impact of RT-related CIEDs malfunctions. We retrospectively reviewed the medical records of all pacemaker (PM)/implantable cardioverter-defibrillator (ICD) patients who underwent RT in the last 14 years. One hundred and twenty-seven patients who underwent 150 separate RT courses were analysed (99 with a PM and 27 with an ICD). Of note, 21/127 (16.6%) patients were PM-dependent. Neutron-producing RT was used in 37/139 (26.6%) courses, whereas non-neutron-producing RT was used in 102/139 (73.4%) courses. The cumulative dose (Dmax) delivered to the CIED exceeded 5 Gy only in 2/132 (1.5%) cases. Device malfunctions were observed in 3/150 (2%) RT courses, but none was life-threatening or led to a major clinical event and all were resolved by CIED reprogramming. In all cases, the Dmax delivered to the CIED was < 2 Gy. Two malfunctions occurred in the 37 patients treated with neutron-producing RT (5.4%), and 1 malfunction occurred in the 102 patients treated with non-neutron-producing RT (1%) (p = 0.17). Device relocation from the RT field was performed in 2/127 (1.6%) patients. RT in patients with CIED is substantially safe if performed in an appropriately organized environment, with uncommon CIEDs malfunctions and no major clinical events. Neutron-producing energies, rather than Dmax, seem to increase the risk of malfunctions. Device interrogation on a regular basis is advised to promptly manage CIED malfunctions.
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http://dx.doi.org/10.1007/s11739-019-02240-yDOI Listing
September 2020

In vitro thrombogenicity of drug-eluting and bare metal stents.

Thromb Res 2020 01 14;185:43-48. Epub 2019 Nov 14.

Columbia University Medical Center/New York-Presbyterian Hospital and the Cardiovascular Research Foundation, New York, NY, United States.

Aims: We sought to investigate the thrombogenicity of different DES and BMS in an in vitro system of stent perfusion.

Material And Methods: The experimental model consisted of a peristaltic pump connected to 4 parallel silicone tubes in which different stents were deployed. Blood was drawn from healthy volunteers and the amount of stent surfaced-induced thrombus deposition was determined using I-fibrinogen.

Results: Compared to Resolute, Biomatrix and Vision, Xience was associated with the lowest amount of stent surface-induced thrombus formation, with a significant difference compared to Vision (I-fibrinogen median value deposition [IQ range]: 50 ng [25-98] versus 560 ng [320-1520], respectively, p < 0.05), but not to other DES. In the second set of experiments Fluoropolymer-coated BMS not eluting drug was associated with a significant 3-fold reduction in I-fibrinogen deposition (245 ng [80-300]) compared to Vision (625 ng [320-760], p < 0.05), but a 7-fold increase compared to Xience (35 ng [20-60], p < 0.05). Finally Xience was associated with a significantly greater absorption of albumin compared to BMS.

Conclusions: In an in vitro system of stent perfusion, Xience was associated with the lowest amount of stent surface-induced thrombus formation compared with Resolute, Biomatrix and Vision, with a noted synergistic effect between the fluoropolymer and the drug.
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http://dx.doi.org/10.1016/j.thromres.2019.11.016DOI Listing
January 2020

Cu and fluorescein labeled anti-miRNA peptide nucleic acids for the detection of miRNA expression in living cells.

Sci Rep 2019 03 4;9(1):3376. Epub 2019 Mar 4.

Nuclear Medicine Unit, Oncology and Advanced Technologies Department, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42123, Reggio Emilia, Italy.

MiRNAs are single stranded RNAs of 18-22 nucleotides. They are promising diagnostic and prognostic markers for several pathologies including tumors, neurodegenerative, cardiovascular and autoimmune diseases. In the present work the development and characterization of anti-miRNA radiolabeled probes based on peptide nucleic acids (PNAs) for potential non-invasive molecular imaging in vivo of giant cell arteritis are described. MiR-146a and miR-146b-5p were selected as targets because they have been found up-regulated in this disease. Anti-miR and scramble PNAs were synthesized and linked to carboxyfluorescein or DOTA. DOTA-anti-miR PNAs were then labelled with copper-64 (Cu) to function as non-invasive molecular imaging tools. The affinity of the probes for the targets was assessed in vitro by circular dichroism and melting temperature. Differential uptake of fluorescein and Cu labeled anti-miRNA probes was tested on BCPAP and A549 cell lines, expressing different levels of miR-146a and -146b-5p. The experiments showed that the anti-miR-146a PNAs were more effective than the anti-miR-146b-5p PNAs. Anti-miR-146a PNAs could bind both miR-146a and miR-146b-5p. The uptake of fluorescein and Cu labeled anti-miR-146a PNAs was higher than that of the negative control scramble PNAs in miRNA expressing cells in vitro. Cu-anti-miR-146a PNAs might be further investigated for non-invasive PET imaging of miR-146 overexpressing diseases.
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http://dx.doi.org/10.1038/s41598-018-35800-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399270PMC
March 2019

Innovative Target for Production of Technetium-99m by Biomedical Cyclotron.

Molecules 2018 Dec 21;24(1). Epub 2018 Dec 21.

Legnaro National Laboratories, Italian National Institute for Nuclear Physics (LNL-INFN), Viale dell'Università 2, 35020 Legnaro PD, Italy.

Technetium-99m (Tc) is the most used radionuclide worldwide in nuclear medicine for diagnostic imaging procedures. Tc is typically extracted from portable generators containing Mo, which is produced normally in nuclear reactors as a fission product of highly enriched Uranium material. Due to unexpected outages or planned and unplanned reactor shutdown, significant Tc shortages appeared as a problem since 2008 The alternative cyclotron-based approach through the Mo(p,2n)Tc reaction is considered one of the most promising routes for direct Tc production in order to mitigate potential Mo shortages. The design and manufacturing of appropriate cyclotron targets for the production of significant amounts of a radiopharmaceutical for medical use is a technological challenge. In this work, a novel solid target preparation method was developed, including sputter deposition of a dense, adherent, and non-oxidized Mo target material onto a complex backing plate. The latter included either chemically resistant sapphire or synthetic diamond brazed in vacuum conditions to copper. The target thermo-mechanical stability tests were performed under 15.6 MeV proton energy and different beam intensities, up to the maximum provided by the available GE Healthcare (Chicago, IL, USA) PET trace medical cyclotron. The targets resisted proton beam currents up to 60 µA (corresponding to a heat power density of about 1 kW/cm²) without damage or Mo deposited layer delamination. The chemical stability of the proposed backing materials was proven by gamma-spectroscopy analysis of the solution obtained after the standard dissolution procedure of irradiated targets in H₂O₂.
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http://dx.doi.org/10.3390/molecules24010025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337538PMC
December 2018

Production of Ga-68 with a General Electric PETtrace cyclotron by liquid target.

Phys Med 2018 Nov 25;55:116-126. Epub 2018 Oct 25.

Medical Physics Department, University Hospital, S. Orsola-Malpighi, Bologna, Italy.

Purpose: In recent years the use of Ga (t = 67.84 min, β: 88.88%) for the labelling of different PET radiopharmaceuticals has significantly increased. This work aims to evaluate the feasibility of the production of Ga via the Zn(p,n)Ga reaction by proton irradiation of an enriched zinc solution, using a biomedical cyclotron, in order to satisfy its increasing demand.

Methods: Irradiations of 1.7 Msolution of Zn(NO) in 0.2 N HNO were conducted with a GE PETtrace cyclotron using a slightly modified version of the liquid target used for the production of fluorine-18. The proton beam energy was degraded to 12 MeV, in order to minimize the production of Ga through theZn(p,2n)Ga reaction. The product's activity was measured using a calibrated activity meter and a High Purity Germanium gamma-ray detector.

Results: The saturation yield ofGa amounts to (330 ± 20) MBq/µA, corresponding to a produced activity ofGa at the EOB of (4.3 ± 0.3) GBq in a typical production run at 46 µA for 32 min. The radionuclidic purity of theGa in the final product, after the separation, is within the limits of the European Pharmacopoeia (>99.9%) up to 3 h after the EOB. Radiochemical separation up to a yield not lower than 75% was obtained using an automated purification module. The enriched material recovery efficiency resulted higher than 80-90%.

Conclusions: In summary, this approach provides clinically relevant amounts ofGa by cyclotron irradiation of a liquid target, as a competitive alternative to the current production through theGe/Ga generators.
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http://dx.doi.org/10.1016/j.ejmp.2018.10.018DOI Listing
November 2018

In-house cyclotron production of high-purity Tc-99m and Tc-99m radiopharmaceuticals.

Appl Radiat Isot 2018 Sep 30;139:325-331. Epub 2018 May 30.

Legnaro Laboratories, Italian National Institute for Nuclear Physics (INFN), Legnaro, Padua, Italy; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.

In the last years, the technology for producing the important medical radionuclide technetium-99m by cyclotrons has become sufficiently mature to justify its introduction as an alternative source of the starting precursor [Tc][TcO] ubiquitously employed for the production of Tc-radiopharmaceuticals in hospitals. These technologies make use almost exclusively of the nuclear reaction Mo(p,2n)Tc that allows direct production of Tc-99m. In this study, it is conjectured that this alternative production route will not replace the current supply chain based on the distribution of Mo/Tc generators, but could become a convenient emergency source of Tc-99m only for in-house hospitals equipped with a conventional, low-energy, medical cyclotron. On this ground, an outline of the essential steps that should be implemented for setting up a hospital radiopharmacy aimed at the occasional production of Tc-99m by a small cyclotron is discussed. These include (1) target production, (2) irradiation conditions, (3) separation/purification procedures, (4) terminal sterilization, (5) quality control, and (6) Mo-100 recovery. To address these issues, a comprehensive technology for cyclotron-production of Tc-99m, developed at the Legnaro National Laboratories of the Italian National Institute of Nuclear Physics (LNL-INFN), will be used as a reference example.
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http://dx.doi.org/10.1016/j.apradiso.2018.05.033DOI Listing
September 2018

Modeling of a Cyclotron Target for the Production of 11C with Geant4.

Curr Radiopharm 2018 ;11(2):92-99

Medical Physics Unit, University Hospital "S. Orsola-Malpighi", Via Massarenti 9, 40138, Bologna, Italy.

Background: In medical cyclotron facilities, 11C is produced according to the 14N(p,α)11C reaction and widely employed in studies of prostate and brain cancers by Positron Emission Tomography. It is known from literature that the 11C-target assembly shows a reduction in efficiency during time, meaning a decrease of activity produced at the end of bombardment. This effect might depend on aspects which are still not completely known.

Objective: Possible causes of the loss of performance of the 11C-target assembly were addressed by Monte Carlo simulations.

Methods: Geant4 was used to model the 11C-target assembly of a GE PETtrace cyclotron. The physical and transport parameters to be used in the energy range of medical applications were extracted from literature data and 11C routine productions. The Monte Carlo assessment of 11C saturation yield was performed varying several parameters such as the proton energy and the angle of the target assembly with respect to the proton beam.

Results: The estimated 11C saturation yield is in agreement with IAEA data at the energy of interest, while it is about 35% greater than the experimental value. A more comprehensive modeling of the target system, including thermodynamic effect, is required. The energy absorbed in the inner layer of the target chamber was up to 46.5 J/mm2 under typical irradiation conditions.

Conclusion: This study shows that Geant4 is potentially a useful tool to design and optimize targetry for PET radionuclide productions. Tests to choose the Geant4 physics libraries should be performed before using this tool with different energies and materials.
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http://dx.doi.org/10.2174/1874471011666180412170219DOI Listing
October 2018

Transglutaminase-mediated conjugation and nitride-technetium-99m labelling of a bis(thiosemicarbazone) bifunctional chelator.

J Inorg Biochem 2018 06 2;183:18-31. Epub 2018 Mar 2.

ICMATE-CNR, Corso Stati Uniti 4, 35127 Padua, Italy; Dipartimento di Scienze del Farmaco, Università Degli Studi di Padova, Via F. Marzolo 5, 35131 Padua, Italy. Electronic address:

An assessment study involving the use of the transglutaminase (TGase) conjugation method and the nitride-technetium-99m labelling on a bis(thiosemicarbazone) (BTS) bifunctional chelating agent is presented. The previously described chelator diacetyl-2-(N-methyl-3-thiosemicarbazone)-3-(N-amino-3-thiosemicarbazone), HATSM/A, has been functionalized with 6-aminohexanoic acid (ε-Ahx) to generate the bifunctional chelating agent diacetyl-2-(N-methyl-3-thiosemicarbazone)-3-[N-(amino)-(6-aminohexanoic acid)-3-thiosemicarbazone], HATSM/A-ε-Ahx (1), suitable for conjugation to glutamine (Gln) residues of bioactive molecules via TGase. The feasibility of the TGase reaction in the synthesis of a bioconjugate derivative was investigated using Substance P (SP) as model peptide. Compounds 1 and HATSM/A-ε-Ahx-SP (2) were labelled with nitride-technetium-99m, obtaining the complexes [Tc][Tc(N)(ATSM/A-ε-Ahx)] (Tc1) and [Tc][Tc(N)(ATSM/A-ε-Ahx-SP)] (Tc2). The chemical identity of Tc1 and Tc2 was confirmed by radio/UV-RP-HPLC combined with ESI-MS analysis on the respective carrier-added products Tc1 and Tc2. The stability of the radiolabelled complexes after incubation in various environments was investigated. All the results were compared with those obtained for the corresponding Cu-analogues, Cu1 and Cu2. The TGase reaction allows the conjugation of 1 with the peptide, but it is not highly efficient due to instability of the chelator in the required conditions. The SP-conjugated complexes are unstable in mouse and human sera. However, indeed the BTS system can be exploited as nitride-technetium-99m chelator for highly efficient technetium labelling, thus making compound 1 worthy of further investigations for new targeted technetium and copper radiopharmaceuticals encompassing Single Photon Emission Computed Tomography and Positron Emission Tomography imaging.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.02.023DOI Listing
June 2018

Early and delayed evaluation of solid tumours with 64Cu-ATSM PET/CT: a pilot study on semiquantitative and computer-aided fractal geometry analysis.

Nucl Med Commun 2017 Apr;38(4):340-346

aResearch Doctorate Course in Specialized Medical Sciences, Alma Mater Studiorum - University of Bologna bPET Unit cDivision of Thoracic Surgery, University Hospital S. Orsola-Malpighi, Bologna dDepartment of Nuclear Medicine eDepartment of Inflammation and Immunology fDepartment of Medical Oncology, Humanitas Clinical and Research Hospital, Rozzano gMichele Rodriguez Foundation, Milan, Italy.

Objective: The aim of this study was to analyse early and delayed acquisition on copper-64 diacetyl-bisN4-methylthiosemicarbazone (Cu-ATSM) PET/CT in a small cohort of patients by comparing semiquantitative and computer-aided fractal geometry analyses.

Patients And Methods: Five cancer patients, including non-small-cell lung cancer and head and neck cancer, were investigated with Cu-ATSM PET/CT. Participants received an intravenous injection of Cu-ATSM according to body size and were imaged 60 min (early) and 16 h (delayed) later on hybrid PET/CT. Reconstructed images were visualized on advanced workstations for the definition of semiquantitative parameters: standardized uptake value (SUV)max, SUVratio-to-muscle, SUVmean, hypoxic volume (HV) and hypoxic burden (HB=HV×SUVmean). DICOM data retrieved from both scans were analysed using an ad-hoc computer program to determine the mean intensity value, SD, relative dispersion, three-dimensional histogram fractal dimension and three-dimensional fractal dimension.

Results: All tumour lesions showed increased uptake of Cu-ATSM at early evaluation, with a median SUVratio-to-muscle of 4.42 (range: 1.58-5.62), a median SUVmax of 5.3 (range: 1.9-7.3), a median SUVmean of 2.8 (range: 1.5-3.9), a median HV of 41.6 cm (range: 2.8-453.7) and a median HB of 161.5 cm (range: 4.4-1112.5). All semiquantitative data obtained at 1 h were consistent with the parameters obtained on delayed imaging (P>0.05). A borderline statistically significant difference was found only for SUVmax of the muscle (P=0.045). Fractal geometry analysis on DICOM images showed that all parameters at early imaging showed no statistically significant difference with late acquisition (P>0.05).

Conclusion: Our findings support the consistency of Cu-ATSM PET/CT images obtained at early and delayed acquisition for the assessment of tumour lesions.
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http://dx.doi.org/10.1097/MNM.0000000000000656DOI Listing
April 2017

Assessment of the neutron dose field around a biomedical cyclotron: FLUKA simulation and experimental measurements.

Phys Med 2016 Dec 3;32(12):1602-1608. Epub 2016 Dec 3.

Medical Physics Department, University Hospital "S. Orsola-Malpighi", Via Massarenti 9, 40138 Bologna, Italy.

In the planning of a new cyclotron facility, an accurate knowledge of the radiation field around the accelerator is fundamental for the design of shielding, the protection of workers, the general public and the environment. Monte Carlo simulations can be very useful in this process, and their use is constantly increasing. However, few data have been published so far as regards the proper validation of Monte Carlo simulation against experimental measurements, particularly in the energy range of biomedical cyclotrons. In this work a detailed model of an existing installation of a GE PETtrace 16.5MeV cyclotron was developed using FLUKA. An extensive measurement campaign of the neutron ambient dose equivalent H(10) in marked positions around the cyclotron was conducted using a neutron rem-counter probe and CR39 neutron detectors. Data from a previous measurement campaign performed by our group using TLDs were also re-evaluated. The FLUKA model was then validated by comparing the results of high-statistics simulations with experimental data. In 10 out of 12 measurement locations, FLUKA simulations were in agreement within uncertainties with all the three different sets of experimental data; in the remaining 2 positions, the agreement was with 2/3 of the measurements. Our work allows to quantitatively validate our FLUKA simulation setup and confirms that Monte Carlo technique can produce accurate results in the energy range of biomedical cyclotrons.
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http://dx.doi.org/10.1016/j.ejmp.2016.11.115DOI Listing
December 2016

Radiation Protection Studies for Medical Particle Accelerators using Fluka Monte Carlo Code.

Radiat Prot Dosimetry 2017 Apr;173(1-3):185-191

Medical Physics Department, S. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138 Bologna, Italy.

Radiation protection (RP) in the use of medical cyclotrons involves many aspects both in the routine use and for the decommissioning of a site. Guidelines for site planning and installation, as well as for RP assessment, are given in international documents; however, the latter typically offer analytic methods of calculation of shielding and materials activation, in approximate or idealised geometry set-ups. The availability of Monte Carlo (MC) codes with accurate up-to-date libraries for transport and interaction of neutrons and charged particles at energies below 250 MeV, together with the continuously increasing power of modern computers, makes the systematic use of simulations with realistic geometries possible, yielding equipment and site-specific evaluation of the source terms, shielding requirements and all quantities relevant to RP at the same time. In this work, the well-known FLUKA MC code was used to simulate different aspects of RP in the use of biomedical accelerators, particularly for the production of medical radioisotopes. In the context of the Young Professionals Award, held at the IRPA 14 conference, only a part of the complete work is presented. In particular, the simulation of the GE PETtrace cyclotron (16.5 MeV) installed at S. Orsola-Malpighi University Hospital evaluated the effective dose distribution around the equipment; the effective number of neutrons produced per incident proton and their spectral distribution; the activation of the structure of the cyclotron and the vault walls; the activation of the ambient air, in particular the production of 41Ar. The simulations were validated, in terms of physical and transport parameters to be used at the energy range of interest, through an extensive measurement campaign of the neutron environmental dose equivalent using a rem-counter and TLD dosemeters. The validated model was then used in the design and the licensing request of a new Positron Emission Tomography facility.
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http://dx.doi.org/10.1093/rpd/ncw302DOI Listing
April 2017

A solvent-extraction module for cyclotron production of high-purity technetium-99m.

Appl Radiat Isot 2016 Dec 5;118:302-307. Epub 2016 Oct 5.

Legnaro National Laboratories, Italian National Institute for Nuclear Physics (LNL-INFN), Italy.

The design and fabrication of a fully-automated, remotely controlled module for the extraction and purification of technetium-99m (Tc-99m), produced by proton bombardment of enriched Mo-100 molybdenum metallic targets in a low-energy medical cyclotron, is here described. After dissolution of the irradiated solid target in hydrogen peroxide, Tc-99m was obtained under the chemical form of TcO, in high radionuclidic and radiochemical purity, by solvent extraction with methyl ethyl ketone (MEK). The extraction process was accomplished inside a glass column-shaped vial especially designed to allow for an easy automation of the whole procedure. Recovery yields were always >90% of the loaded activity. The final pertechnetate saline solution NaTcO, purified using the automated module here described, is within the Pharmacopoeia quality control parameters and is therefore a valid alternative to generator-produced Tc. The resulting automated module is cost-effective and easily replicable for in-house production of high-purity Tc-99m by cyclotrons.
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http://dx.doi.org/10.1016/j.apradiso.2016.10.002DOI Listing
December 2016

Synthesis and preclinical evaluation of an AlF radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand.

Eur J Nucl Med Mol Imaging 2016 Nov 22;43(12):2122-2130. Epub 2016 Jun 22.

Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.

Purpose: The aim of this study was to synthesize and preclinically evaluate an F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.

Methods: Several conditions for the labeling of F-PSMA-11 via F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.

Results: Quantitative labeling yields could be achieved with >97 % radiochemical purity. The F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv.

Conclusion: F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050145PMC
http://dx.doi.org/10.1007/s00259-016-3437-yDOI Listing
November 2016

Engineered porphyrin loaded core-shell nanoparticles for selective sonodynamic anticancer treatment.

Nanomedicine (Lond) 2015 26;10(23):3483-94. Epub 2015 Nov 26.

Department of Drug Science & Technology, University of Torino, Via Pietro Giuria 13, Torino, Italy.

Aim: Porphyrin-loaded core-shell nanoparticles have been engineered for use as in vivo sonosensitizing systems, radio-tracers or magnetic resonance (MR) imaging agents, which may be suitable for the selective treatment of solid tumors and imaging analyses.

Materials & Methods: Polymethyl methacrylate nanoparticles (PMMANPs) have been either loaded with meso-tetrakis (4-sulphonatophenyl) porphyrin (TPPS) for sonodynamic anticancer treatment, with (64)Cu-TPPS for positron emission tomography biodistribution studies or with Mn(III)-TPPS for MR tumor accumulation evaluation.

Results: PMMANPs are easily functionalized with negatively charged molecules and show favorable biodistribution. In vivo TPPS-PMMANPs have demonstrated shock wave responsiveness in a Mat B III syngeneic rat breast cancer model as measured by MR analyses of pre- and post-treatment tumor volumes.

Conclusion: TPPS-PMMANPs are a multimodal system which can efficiently induce in vivo sonodynamic anticancer activity.
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http://dx.doi.org/10.2217/nnm.15.150DOI Listing
September 2016

Prognostic Evaluation of Disease Outcome in Solid Tumors Investigated With 64Cu-ATSM PET/CT.

Clin Nucl Med 2016 Feb;41(2):e87-92

From the *Department of Nuclear Medicine, Humanitas Clinical and Research Center, Rozzano, Milan; †Alma Mater Studiorum University of Bologna, Doctoral Course in Specialized Medical Sciences, and ‡Department of Nuclear Medicine, University Hospital S. Orsola-Malpighi, Bologna; §Department of Nuclear Medicine, Ospedale Santa Maria della Misericordia, Rovigo, Italy; ∥Department of Radiology, University of Southern California, Los Angeles, CA; ¶Department of Medical Oncology, Ospedale degli Infermi, Faenza; #Department of Radiation Oncology, Bellaria Hospital, Bologna; **Department of Medical Oncology, Istituto Oncologico Romagnolo, Ravenna; and ††Division of Thoracic Surgery, University Hospital S. Orsola-Malpighi, Bologna, Italy.

Purpose: Cu-ATSM is a very promising PET radiopharmaceutical for tumor imaging of hypoxia. One of the advantages of this compound compared with other hypoxia-avid tracers is the high tumor-to-background signal offered, which guaranties facilitated tumor delineation. This study analyzes optimal semiquantitative and quantitative parameters obtained by Cu-ATSM PET/CT in the same cohort of patients with special focus on their correlation to disease outcome.

Patients And Methods: A prospective recruitment of 18 consecutive patients (M:F, 13:5; mean age, 60.7 years) with locally advanced non-small cell lung cancer (n = 7) or head and neck cancer (HNC) was performed. Each participant received 105 to 500 MBq of tracer according to body size and was scanned in a 3-dimensional mode PET/CT 60 minutes after tracer injection. PET images were reconstructed and visualized on a GE Advanced 4.6 workstation for the definition of semiquantitative and quantitative parameters: SUVmax, SUVratio-to-muscle, hypoxic tumor volume (HTV), and hypoxic burden (HB = HTV × SUVmean). These data were subsequently correlated to disease outcome, expressed in terms of progression-free survival calculated on a follow-up period with a median of 14.6 months.

Results: All patients showed a moderately to highly increased uptake of Cu-ATSM in tumor lesions, with a mean SUVmax of 5.2 (range, 1.9-8.3) and mean SUVratio of 4.4 (range, 1.6-6.8). In addition, a broad range of HTV and HB was defined as mean values of 99.3 cm (range, 2.5-453.7 cm) and 301 (4.2-1134), respectively. Receiver operating characteristic analysis identified as reference cutoffs with respect to disease outcome with the following values: SUVmax >2.5 (AUC, 0.57; sensitivity, 88.9%; specificity, 50%), SUVratio ≤4.4 (AUC, 0.60; sensitivity, 50; specificity, 83.3%), HTV >160.7 cm (AUC, 0.61; sensitivity, 55.6%; specificity, 75%), and HB >160.7 (AUC, 0.67; sensitivity, 58.3%; specificity, 83.3%). In our cohort, HB showed a statistically significant difference in terms of mean values on the analysis of variance test with respect to disease progression (P = 0.04). On univariate analysis, Cox regression confirmed these findings and showed a significant correlation to progression-free survival for HB (P = 0.05) and HTV (P = 0.02).

Conclusions: In our cohort, the definition of optimal semiquantitative and quantitative parameters on Cu-ATSM PET/CT seems feasible and in line with previously published data. However, when considering the prognostic role with respect to disease outcome, the more robust parameters are represented by HTV and HB.
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http://dx.doi.org/10.1097/RLU.0000000000001017DOI Listing
February 2016

Experimental measurement and Monte Carlo assessment of Argon-41 production in a PET cyclotron facility.

Phys Med 2015 Dec 26;31(8):991-996. Epub 2015 Sep 26.

Medical Physics Department, University Hospital "S. Orsola-Malpighi", Via Massarenti 9, 40138, Bologna, Italy.

In a medical cyclotron facility, (41)Ar (t1/2 = 109.34 m) is produced by the activation of air due to the neutron flux during irradiation, according to the (40)Ar(n,γ)(41)Ar reaction; this is particularly relevant in widely diffused high beam current cyclotrons for the production of PET radionuclides. While theoretical estimations of the (41)Ar production have been published, no data are available on direct experimental measurements for a biomedical cyclotron. In this work, we describe a sampling methodology and report the results of an extensive measurement campaign. Furthermore, the experimental results are compared with Monte Carlo simulations performed with the FLUKA code. To measure (41)Ar activity, air samples were taken inside the cyclotron bunker in sealed Marinelli beakers, during the routine production of (18)F with a 16.5 MeV GE-PETtrace cyclotron; this sampling thus reproduces a situation of absence of air changes. Samples analysis was performed in a gamma-ray spectrometry system equipped with HPGe detector. Monte Carlo assessment of the (41)Ar saturation yield was performed directly using the standard FLUKA score RESNUCLE, and off-line by the convolution of neutron fluence with cross section data. The average (41)Ar saturation yield per one liter of air of (41)Ar, measured in gamma-ray spectrometry, resulted to be 3.0 ± 0.6 Bq/µA*dm(3) while simulations gave a result of 6.9 ± 0.3 Bq/µA*dm(3) in the direct assessment and 6.92 ± 0.22 Bq/µA*dm(3) by the convolution neutron fluence-to-cross section.
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http://dx.doi.org/10.1016/j.ejmp.2015.07.146DOI Listing
December 2015

PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence.

Am J Nucl Med Mol Imaging 2014 7;4(4):365-84. Epub 2014 Jun 7.

Department of Nuclear Medicine, University Hospital S. Orsola-Malpighi Bologna, Italy.

Hypoxia is a pathological condition arising in living tissues when oxygen supply does not adequately cover the cellular metabolic demand. Detection of this phenomenon in tumors is of the utmost clinical relevance because tumor aggressiveness, metastatic spread, failure to achieve tumor control, increased rate of recurrence, and ultimate poor outcome are all associated with hypoxia. Consequently, in recent decades there has been increasing interest in developing methods for measurement of oxygen levels in tumors. Among the image-based modalities for hypoxia assessment, positron emission tomography (PET) is one of the most extensively investigated based on the various advantages it offers, i.e., broad range of radiopharmaceuticals, good intrinsic resolution, three-dimensional tumor representation, possibility of semiquantification/quantification of the amount of hypoxic tumor burden, overall patient friendliness, and ease of repetition. Compared with the other non-invasive techniques, the biggest advantage of PET imaging is that it offers the highest specificity for detection of hypoxic tissue. Starting with the 2-nitroimidazole family of compounds in the early 1980s, a great number of PET tracers have been developed for the identification of hypoxia in living tissue and solid tumors. This paper provides an overview of the principal PET tracers applied in cancer imaging of hypoxia and discusses in detail their advantages and pitfalls.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074502PMC
July 2014

Usefulness of 64Cu-ATSM in head and neck cancer: a preliminary prospective study.

Clin Nucl Med 2014 Jan;39(1):e59-63

From the Departments of *Nuclear Medicine, †Medical Physics, and ‡Radiotherapy, Sant' Orsola-Malpighi Hospital, Bologna, Italy; §Department of Radiology, University of Southern California, Los Angeles, CA; and ¶Department of Nuclear Medicine, Santa Maria della Misericordia Hospital, Rovigo, Italy.

Aims: Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) is a hypoxia-avid, positron emitter radiotracer. The primary aim of this study is to assess the efficacy of pretherapy Cu-ATSM PET/CT as a prognostic factor of response to therapy. The secondary aims are to investigate if there is a difference between early and late PET/CT scans and if there is a difference between the biologic tumor volume (BTV) in radiotherapy treatment planning calculated between Cu-ATSM and F-FDG, and to assess if Cu-ATSM is a prognostic marker of disease progression.

Methods: Eleven patients with head and neck cancer treated with chemoradiotherapy were enrolled prospectively; both Cu-ATSM and F-FDG PET/CT scans before and after treatment were obtained. The Cu-ATSM scans were performed after 1 hour (early) and 16 hours (late).

Results: All patients had stage III or IV squamous cell head and neck cancer; 7 of 11 patients had nodal metastasis, and 22 cancer foci were detected with Cu-ATSM. SUVmax was 16.2 ± 7.9, and there was no significant SUVmax difference between early and late imaging. F-FDG SUVmax before therapy was 15.6 ± 9.4, whereas F-FDG SUVmax after therapy was 1.5 ± 1.2. Sensitivity and specificity values of Cu-ATSM calculated with receiver operating characteristic curves were 100% and 50% considering the SUVmax and 100% and 33% considering the volume, respectively. No difference has been found between the BTV contoured with Cu-ATSM and F-FDG.

Conclusions: The Cu-ATSM scans showed high sensitivity but low specificity in predicting neoadjuvant chemoradiotherapy response. No difference was noted between early and late scans. F-FDG and Cu-ATSM provided similar results about delineation of BTV.
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http://dx.doi.org/10.1097/RLU.0b013e3182a756f0DOI Listing
January 2014

Generator breakthrough and radionuclidic purification in automated synthesis of 68Ga-DOTANOC.

Curr Radiopharm 2013 Jun;6(2):72-7

Medical Physics Department, University Hospital S. Orsola-Malpighi, Bologna, Italy.

68Ga labeled radiopharmaceuticals, like 68Ga-DOATNOC and other similar peptides, are gaining relevance in PET-CT, thanks to relatively easy local generator production, that do not requires an installed cyclotron. However, generator produced 68Ga is typically of suboptimal purity, mainly due to the breakthrough of the parent radionuclide 68Ge. Modern automated synthesis modules adopt both fractionation methods and purification methods in order to get rid of 68Ge breakthrough. Purification methods are mainly based on based on cationic prepurification even if anionic purification has been adopted as well. This work studies the efficacy of cationic prepurification using commercial STRATA-X-C, as well as distribution of the 68Ge contaminant during all steps of the synthesis of labeled peptides. Generator waste, STRATA-X-C purification cartridge, synthesis waste and the final product are quantitatively analyzed by means of high resolution gamma ray spectrometry. Our results show that current method of purification is highly effective; initial 68Ge breakthrough of the order of 1 kBq is decreased by a factor greater than 100, with removal of about 61% of the contaminant 68Ge in the first purification passage; this allow an efficient labeling, since removal of the remaining impurity happens during chelation in the reactor vessel. In conclusion, the synthesis with modular automated system resulted to reliably produce 68Ga-DOTANOC, with limited if any user intervention. 68Ge content in the final formulation results lower than 2x10(-7)%, avoiding unjustified patient irradiation due to radionuclidic impurities and satisfying quality prerequisites for radiopharmaceutical preparations.
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http://dx.doi.org/10.2174/1874471011306020002DOI Listing
June 2013

Synthesis of oncological [11C]radiopharmaceuticals for clinical PET.

Nucl Med Biol 2012 May 14;39(4):447-60. Epub 2011 Dec 14.

PET Radiopharmacy, Nuclear Medicine Unit, Azienda Ospedaliero Universitaria di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy.

Positron emission tomography (PET) is a nuclear medicine modality which provides quantitative images of biological processes in vivo at the molecular level. Several PET radiopharmaceuticals labeled with short-lived isotopes such as (18)F and (11)C were developed in order to trace specific cellular and molecular pathways with the aim of enhancing clinical applications. Among these [(11)C]radiopharmaceuticals are N-[(11)C]methyl-choline ([(11)C]choline), l-(S-methyl-[(11)C])methionine ([(11)C]methionine) and 1-[(11)C]acetate ([(11)C]acetate), which have gained an important role in oncology where the application of 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) is suboptimal. Nevertheless, the production of these radiopharmaceuticals did not reach the same level of standardization as for [(18)F]FDG synthesis. This review describes the most recent developments in the synthesis of the above-mentioned [(11)C]radiopharmaceuticals aiming to increase the availability and hence the use of [(11)C]choline, [(11)C]methionine and [(11)C]acetate in clinical practice.
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http://dx.doi.org/10.1016/j.nucmedbio.2011.10.016DOI Listing
May 2012

Assessment of internal contamination hazard and fast monitoring for workers involved in maintenance operations on PET cyclotrons.

Radiat Prot Dosimetry 2011 Mar 3;144(1-4):468-72. Epub 2010 Nov 3.

Department of Energy, Nuclear and Environmental Control Engineering, University of Bologna, Bologna, Italy.

With the ever-increasing number of cyclotron installations, and therefore of the maintenance personnel involved, the possibility of swift, 'yes or no' screening for internal contamination becomes a prized asset. The present work presents one such procedure, evolved from an approximate whole body counting technique in widespread use in emergency situations. A detailed analysis of possible pathways for contamination leads to pinpointing the nuclides of interest. Different calibration methods are applied, showing moderate variation among them. The minimum detectable activity of order 1000 Bq is determined. The method proves sensitive enough to exclude significant contamination, or to identify its presence instantly  'on site' to prompt further in-depth investigation.
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http://dx.doi.org/10.1093/rpd/ncq327DOI Listing
March 2011

Development of a modular system for the synthesis of PET [(11)C]labelled radiopharmaceuticals.

Appl Radiat Isot 2009 Oct 27;67(10):1869-73. Epub 2009 May 27.

PET Radiopharmacy, Nuclear Medicine, Azienda Ospedaliero Universitaria di Bologna, Policlinico S.Orsola-Malpighi, Bologna, Italy.

[((11))C]labelled radiopharmaceuticals as N-[(11)C]methyl-choline ([(11)C]choline), l-(S-methyl-[(11)C])methionine ([(11)C]methionine) and [(11)C]acetate have gained increasing importance in clinical PET and for the routine production of these radiopharmaceuticals, simple and reliable modules are needed to produce clinically relevant radioactivity. On the other hand, flexible devices are needed not only for the routine synthesis but also for more complex applications as the development of new tracers. The aim of this work was the adaptation of an Eckert Ziegler modular system for easy routine synthesis of [(11)C]choline, [(11)C]methionine and [(11)C]acetate using components that account for straightforward scaling up and upgrades.
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http://dx.doi.org/10.1016/j.apradiso.2009.05.010DOI Listing
October 2009

Synthesis and quality control of 68Ga citrate for routine clinical PET.

Nucl Med Commun 2009 Jul;30(7):542-5

Department of Nuclear Medicine, PET Radiopharmacy, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Introduction And Aim: Scintigraphic imaging of infection and inflammation with 67Ga-citrate is an established and powerful diagnostic tool in the management of patients with infectious or inflammatory diseases. 68Ga is a short-lived positron-emitting radionuclide (half-life 67.6 min, positron energy 2.92 MeV), which allows better imaging qualities than 67Ga using the high spatial resolution and the quantitative features of PET. The aim of this study was to develop a method of synthesis for 68Ga citrate with high and reproducible radiochemical yield using a commercial 68Ga-labelling module. The resultant 68Ga citrate would be suitable for use in the detection of infectious or inflammatory diseases in routine clinical practice.

Methods: A simplified method of producing 68Ga citrate is described. Radiochemical purity, pyrogen testing were performed as per the standard protocols.

Results: After performing 10 syntheses of 68Ga citrate, the radiochemical yield was 64.1+/-6.0% (mean+/-standard deviation) with an average activity of 971.2+/-103.4 MBq available for labelling. Radiochemical purity determined by instant thin-layer chromatography-silica gel was higher than 98%. All the synthesized products were found to be sterile and pyrogen-free. In this study, the quality control step provided good and reproducible results. This is worth noting, especially in view of the stringent new rules adopted in most European countries for the in-house good manufacturing practice (GMP) synthesis of radiopharmaceuticals.

Conclusion: The high radiochemical yield and purity showed that this method is a reliable tool for the production of 68Ga citrate to be used in the detection of inflammatory and infectious diseases using high resolution and qualitative PET.
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http://dx.doi.org/10.1097/MNM.0b013e32832b9ac8DOI Listing
July 2009

Radiation emission dose from patients administered 90Y-labelled radiopharmaceuticals: comparison of experimental measurements versus Monte Carlo simulation.

Nucl Med Commun 2008 Dec;29(12):1100-5

Laboratory of Ionizing Radiation-ISPESL, Monte Porzio Catone, Roma, Italy.

Aim: To estimate the radiation dose delivered from patients injected with yttrium-90 (Y)-labelled tiuxetan (Zevalin) to parents and the general population, comparing different techniques.

Methods: The radiation dose delivered from a group of eight patients injected with Y-Zevalin to treat recurrent lymphoma was measured. The data obtained with the Monte Carlo simulation test were compared with the experimental measurements obtained with an ionization chamber detector and with a crystal NaI(Tl) detector.

Results: A good correlation was found between the Monte Carlo simulation test and the ionization chamber detector results: the air kerma dose rate was 4.2+/-0.1 and 4.4+/-0.8 microGy/h, respectively (r=0.9, P<0.01). Moreover, more than 99.7% of the air kerma dose rate measured with the ionization chamber detector was because of the contribution of electrons, whereas the contribution of photons was less than 0.3%. In contrast, the air kerma dose rate measured with the crystal NaI(Tl) detector was significantly lower (0.76+0.12 microGy/h) in comparison with the Monte Carlo simulation test. This underestimation was related to the limited crystal NaI(Tl) detector response to low energy rates at variance with the ionization chamber detector. The effective radiation dose released by patients treated with Y-labelled tiuxetan to parents and the general population was approximately 0.1 mSv per treatment cycle.

Conclusion: Using the Monte Carlo model as a benchmark to compare the experimental measurements obtained by the two different detectors, we found that the ionizing chamber detector was more accurate than the crystal Na(Tl) detector for measuring the exposure radiation dose delivered from patients administered with Y-labelled radiopharmaceuticals. Moreover, the effective radiation dose released by these patients to their parents and the general population is significantly lower than the value recommended by international reports and regulations.
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http://dx.doi.org/10.1097/MNM.0b013e328314b895DOI Listing
December 2008

Assessment of radionuclidic impurities in 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) routine production.

Appl Radiat Isot 2008 Mar 4;66(3):295-302. Epub 2007 Sep 4.

Medical Physics Department, S. Orsola-Malpighi Hospital, Bologna, Italy.

In this paper, radionuclidic impurities generated during the bombardment of [18 O]water in the routine production of 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) were studied. In order to assess such impurities and the efficacy of purification methods through the different steps of the synthesis, samples of the target filters, purification columns, [18 O]water recovered after the synthesis, and the final solution was collected and their activities measured and analyzed by means of a gamma-ray spectrometry system. The data demonstrated that purification methods adopted for the synthesis provide the [18F]FDG radionuclidically pure, as requested by the EU Pharmacopeia.
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http://dx.doi.org/10.1016/j.apradiso.2007.08.015DOI Listing
March 2008