NaI gamma camera performance for high energies: Effects of crystal thickness, photomultiplier tube geometry and light guide thickness.

BACKGROUND: Gamma camera imaging, including single photon emission computed tomography (SPECT), is crucial for research, diagnostics, and radionuclide therapy. Gamma cameras are predominantly based on arrays of photon multipliers tubes (PMTs) that read out NaI(Tl) scintillation crystals. In this way, standard gamma cameras can localize É£-rays with energies typically ranging from 30 to 360 keV. In the last decade, there has been an increasing interest towards gamma imaging outside this conventional clinical energy range, for example, for theragnostic applications and preclinical multi-isotope positron emission tomography (PET) and PET-SPECT. However, standard gamma cameras are typically equipped with 9.5 mm thick NaI(Tl) crystals which can result in limited sensitivity for these higher energies. PURPOSE: Here we investigate to what extent thicker scintillators can improve the photopeak sensitivity for higher energy isotopes while attempting to maintain spatial resolution. METHODS: Using Monte Carlo simulations, we analyzed multiple PMT-based configurations of gamma detectors with monolithic NaI (Tl) crystals of 20 and 40 mm thickness. Optimized light guide thickness together with 2-inch round, 3-inch round, 60 × 60 mm2 square, and 76 × 76 mm2 square PMTs were tested. For each setup, we assessed photopeak sensitivity, energy resolution, spatial, and depth-of-interaction (DoI) resolution for conventional (140 keV) and high (511 keV) energy É£ using a maximum-likelihood algorithm. These metrics were compared to those of a "standard" 9.5 mm-thick crystal detector with 3-inch round PMTs. RESULTS: Estimated photopeak sensitivities for 511 keV were 27% and 53% for 20 and 40 mm thick scintillators, which is respectively, 2.2 and 4.4 times higher than for 9.5 mm thickness. In most cases, energy resolution benefits from using square PMTs instead of round ones, regardless of their size. Lateral and DoI spatial resolution are best for smaller PMTs (2-inch round and 60 × 60 mm2 square) which outperform the more cost-effective larger PMT setups (3-inch round and 76 × 76 mm2 square), while PMT layout and shape have negligible (< 10%) effect on resolution. Best spatial resolution was obtained with 60 × 60 mm2 PMTs; for 140 keV, lateral resolution was 3.5 mm irrespective of scintillator thickness, improving to 2.8 and 2.9 mm for 511 keV with 20 and 40 mm thick crystals, respectively. Using the 3-inch round PMTs, lateral resolutions of 4.5 and 3.9 mm for 140 keV and of 3.5 and 3.7 mm for 511 keV were obtained with 20 and 40 mm thick crystals respectively, indicating a moderate performance degradation compared to the 3.5 and 2.9 mm resolution obtained by the standard detector for 140 and 511 keV. Additionally, DoI resolution for 511 keV was 7.0 and 5.6 mm with 20 and 40 mm crystals using 60 × 60 mm2 square PMTs, while with 3-inch round PMTs 12.1 and 5.9 mm were obtained. CONCLUSION: Depending on PMT size and shape, the use of thicker scintillator crystals can substantially improve detector sensitivity at high gamma energies, while spatial resolution is slightly improved or mildly degraded compared to standard crystals.

A new antiviral hypothesis and radioactive iodine therapy to other cancers, such as breast cancer, lung cancer, and glioblastoma multiforme (GBM)?

Radioactive iodine therapy (RIT) is an effective, safe, and cheap method in benign and malignant thyroid diseases. There is still an unresolved question of whether RIT treatment also plays a role in the treatment of, for example, breast cancer, lung cancer, or glioblastoma multiforme (GBM). These studies are currently being carried out in rats in combination with genes, but it may be an interesting challenge to assess "pure" RIT alone, thanks to the expression of sodium iodide symporter (NIS), is effective in other organ nodules, both benign and malignant. Cloning of the NIS in 1996 provided an opportunity to use NIS as a powerful theranostic transgene. In addition, NIS is a sensitive reporter gene that can be monitored by high-resolution PET imaging using the radiolabels [¹²4I]sodium iodide ([¹²4I]NaI) or [18F] tetrafluoroborate ([¹8F]TFB). Based on published positron emission tomography (PET) results, [¹²4I]sodium iodide and internally synthesized [18F]TFB were compared in an orthotopic animal model of NIS-expressing glioblastoma. The results showed improved image quality using [¹8F]TFB. Based on these results, we will be able to extend the NIS gene therapy approach using non-viral gene delivery vehicles to target orthotopic tumour models with low-volume disease such as GBM. Is it possible to treat RIT alone without using the NIS gene in GBM? After all, the NIS symporter was detected not only in the thyroid gland, but also in different tumours. The administration of RIT is completely harmless; the only complication is hypothyroidism. Indeed, recently it has been shown that, for example, in the case of thyroid cancer, the maximum RIT is 37000 MBq (1000 mCi). When beneficial effects of therapy in GBM are not possible (e.g. neurosurgery, modulated electro-hyperthermia, chemotherapy, immunotherapy, cancer vaccines, or oncolytic viruses), could RIT provide a "revolution" using NIS?

Dose calibration of Health Canada's Fixed Point Surveillance system for environmental radiation monitoring in terms of air kerma and H*(10).

The environmental radiation exposure in Canada has been monitored since 2002 by Health Canada's Fixed Point Surveillance network. The network consists of over eighty 7.6 cm × 7.6 cm sodium iodide spectrometers, and routinely reports to the public the environmental gamma radiation level throughout Canada. This paper describes the latest dose calibrations to air kerma and ambient dose equivalent for the future upgraded network. The calibration curves were developed using Monte Carlo techniques and further optimized via experiments in various reference fields. The dose calibration was validated over a wide range of gamma energy, dose measurement range, and angle of incidence under laboratory conditions. In environmental monitoring situations, the angular distribution of radiation exposure was analytically calculated by assuming a semi-infinite plume source, semi-infinite planar source, and infinite volume sources for the respective exposure scenarios of radioactive plume, ground contamination, and soil source. By coupling the resultant radiation angular distribution with detector's angular variation on dose response, the overall accuracy of dose measurement in each of these environmental scenarios was estimated. The accuracy is expected to be within ±3.7% for plume radiation, -5.6% for 137Cs ground contamination, and 0% to -17.1% for soil radioactive sources. The under-estimation for soil sources is mainly caused by absorption of radiation in the electronic system underneath the crystal.

Imaging-guided targeted radionuclide tumor therapy: From concept to clinical translation.

Since the first introduction of sodium iodide I-131 for use with thyroid patients almost 80 years ago, more than 50 radiopharmaceuticals have reached the markets for a wide range of diseases, especially cancers. The nuclear medicine paradigm also shifts from solely molecular imaging or radionuclide therapy to imaging-guided radionuclide therapy, which is deemed a vital component of precision cancer therapy and an emerging medical modality for personalized medicine. The imaging-guided radionuclide therapy highlights the systematic integration of targeted nuclear diagnostics and radionuclide therapeutics. Regarding this, nuclear imaging serves to "visualize" the lesions and guide the therapeutic strategy, followed by administration of a precise patient specific dose of radiotherapeutics for treatment according to the absorbed dose to different organs and tumors calculated by dosimetry tools, and finally repeated imaging to predict the prognosis. This strategy leads to significantly enhanced therapeutic efficacy, improved patient outcomes, and manageable adverse events. In this review, we provide an overview of imaging-guided targeted radionuclide therapy for different tumors such as advanced prostate cancer and neuroendocrine tumors, with a focus on development of new radioligands and their preclinical and clinical results, and further discuss about challenges and future perspectives.

Addition of polyvinyl pyrrolidone during density separation with sodium iodide solution improves recovery rate of small microplastics (20-150 µm) from soils and sediments.

The purpose of this study was to identify a method to accurately separate small microplastics (<100 µm) from soil and sediment. We initially conducted spike-and-recovery tests using polyethylene microbeads and density separation and found that the recovery rate of microplastic particles smaller than 100 µm was less than 60%. This result suggested that previous reports have underestimated the concentrations of microplastics smaller than 100 µm in soil. When polyvinyl pyrrolidone was added and dispersed in a heavy liquid, the recovery rate exceeded 90%, regardless of the microplastic particle size. This improved recovery rate was independent of the type of polymer (polyethylene, polypropylene, polystyrene, polyethylene terephthalate, or nylon 6) and the physicochemical properties of the soil (Andisols, Entisols, or Ultisols), and the method was also effective for marine and lake sediments. Using this method, we measured microplastic concentrations in paddy soil. The results showed that the most common particle size, 20-100 µm, accounted for 64% of all microplastics. Accurate separation from the soil of fractions smaller than 100 µm, which account for the majority of microplastics in soil, will enable an accurate assessment of the impact of microplastics on the soil ecosystem. The method identified in this study can serve as the basic technique for achieving that goal.

Diagnostic Performance of Cervical Ultrasound, 99mTc-Sestamibi Scintigraphy, and Contrast-Enhanced 18F-Fluorocholine PET in Primary Hyperparathyroidism.

Preoperative localization of pathologic parathyroids is crucial for minimally invasive treatment of primary hyperparathyroidism (PHPT). This study compared contrast-enhanced 18F-fluorocholine PET/CT, cervical ultrasonography (CU), and conventional scintigraphic imaging modalities (MIBI scintigraphy, consisting of 99mTc-sestamibi/123I-sodium iodide SPECT/CT, 99mTc-sestamibi/123I-sodium iodide planar subtraction imaging, and 99mTc-sestamibi planar dual-phase imaging), combined and individually, for preoperative localization of hyperfunctional parathyroids in PHPT. The gold standard was histologic examination. Methods: Data from consecutive patients with clinically suspected PHPT were retrospectively collected. All 3 imaging modalities were systematically performed. The ability of 18F-fluorocholine PET/CT, CU, and MIBI scintigraphy to identify a hyperfunctional parathyroid and specify the side or identify an ectopic location was noted. Patients underwent surgical exploration if at least 1 examination was positive. The findings of CU + MIBI scintigraphy combined were considered positive if CU and MIBI scintigraphy separately showed a hyperfunctional parathyroid gland on the same side or in the same ectopic location; any findings other than these were considered negative. The composite judgment criterion for pathologic parathyroid was a combination of histologic analysis and normalization of parathyroid hormone and calcium levels. Results: In total, 149 pathologic parathyroids were found in 143 of the 144 included patients. 18F-fluorocholine PET/CT diagnosed 148 of 149 pathologic parathyroids. Only 4 false-positives and 1 false-negative were found. The 18F-fluorocholine PET/CT sensitivity of 99.3% was superior to that of CU, at 75.2% (P < 0.0001); MIBI scintigraphy, at 65.1% (P < 0.0001); and CU + MIBI scintigraphy, at 89.9%, (P = 0.0009). Five of the 5 ectopic locations were diagnosed by 18F-fluorocholine PET/CT, 2 of the 5 by MIBI scintigraphy, and none by CU. Accuracy was better for 18F-fluorocholine PET/CT, at 98%, than for CU, at 84% (P < 0.0001); MIBI scintigraphy, at 81% (P < 0.0001); or CU + MIBI scintigraphy, at 91% (P < 0.0001). Among the 72 (50%) patients who had a negative CU + MIBI scintigraphy result, 18F-fluorocholine PET/CT correctly identified hyperfunctional thyroids in 70 (97.2%). Average uptake in the 18F-fluorocholine PET/CT hyperfunctional parathyroid was higher than that in the adjacent thyroid (SUVmax adjusted for lean body mass, 6.45 vs. 2.15) (P < 0.0001). Conclusion: The accuracy of 18F-fluorocholine PET/CT is higher than that of CU and MIBI scintigraphy for localization of hyperfunctional parathyroids, justifying the systematic use of 18F-fluorocholine PET/CT as the first-line method for PHPT diagnosis.

El tratamiento paciente específico del hipertiroidismo con radioyodo: una oportunidad a la mejora / Radioiodine treatment of hyperthyroidism with patient-specific techniques: an improvement opportunity

Introducción: La aplicación de actividades fijas en el tratamiento del hipertiroidismo con I131 (yoduro de sodio, conocido también como radioyodo), es el método más usado en nuestro país, a pesar de la individualidad morfo-funcional que caracteriza esta afección. Sin embargo, no existe aún, un consenso internacional sobre la dosis más conveniente para cada caso, y por ende, los resultados no siempre son los deseados. Objetivo: Evaluar la aplicabilidad de varios métodos de cálculo de dosis paciente-específica para el tratamiento de hipertiroidismo con yoduro de sodio. Métodos: Se realizó un análisis de los resultados de varios métodos de cálculo de dosis recomendados internacionalmente a partir de la actividad fija prescrita en 10 pacientes, con el empleo de tecnologías y herramientas ya desarrolladas y disponibles en el país. Se evaluó la variabilidad inter-especialista y su impacto en la dosis planificada para el tratamiento. Resultados: El uso de la información incompleta de la biodistribución y farmacocinética del paciente produjo diferencias entre -42 por ciento y 37 por ciento de las dosis para el mismo paciente. El resultado de la comparación del método de cálculo recomendado por la Sociedad Europea de Medicina Nuclear, manejando la masa por gammagrafía-2D / 3D y por ultrasonido, arrojó diferencias no significativas entre sí. La variabilidad inter-especialista de las actividades prescrita mostró diferencias significativas, que arrojan sobre el mismo paciente, discrepancias entre 44Gy y 243Gy de las dosis terapéuticas a recibir, situación que puede comprometer el éxito del tratamiento y producir efectos secundarios no deseados. Conclusiones: Las técnicas dosimétricas paciente-específicas se pueden implementar satisfactoriamente en nuestro país. Las diferencias numéricas encontradas, especialmente la variabilidad inter-especialista, demuestran la no estandarización terapéutica, lo que apoya el uso de la farmacocinética paciente-específica pre terapéutica y la masa por gammagrafía-3D para planificar el tratamiento siempre que sean posible(AU)

Introduction: Despite of its typical morpho-functional individuality, fixed activities remain as the most used method in Cuba for hyperthyroidism treatment with I (sodium iodide, also known as radioiodine). However, there is not yet an international consensus on the most convenient doses for each case, so, the results are not always the desired ones. Objective: To evaluate the applicability of various patient-specific dose calculation methods for the treatment of hyperthyroidism with sodium iodide. Methods: It was carried out an analysis in 10 patients of the results of some methods for dose calculation from the prescribed fixed activity recommended internationally, with the use of technologies and tools already developed and available in the country. The inter-specialist variability and its impact in the planned dose for the treatment were assessed. Results: The use of uncompleted biodistribution and pharmacokinetics information of the patient showed differences between -42 percent and 37 percent in the doses for the same patient. The outcome of the comparison of the calculation method recommended by the European Society of Nuclear Medicine managing the mass by 3D/2D gammagraphy and ultrasound, presented no significant discrepancies among them. The inter-specialist variability of prescribed activity was statistically significant, and it can produce in the same patient differences between 44Gy and 243Gy of the therapeutic doses, which could affect the treatment success and lead to unnecessary side effects. Conclusions: The patient´s personalized calculation methods can be satisfactorily applied in Cuba. The numeric differences found, especially inter-specialist variability, show the lack of therapeutic standardization, which supports the use of pre-therapeutic patient-specific pharmacokinetics and the mass by 3D-gammagraphy to plan the treatment when possible(AU)

An Efficient Conjugation Approach for Coupling Drugs to Native Antibodies via the PtII Linker Lx for Improved Manufacturability of Antibody-Drug Conjugates.

The PtII linker [ethylenediamineplatinum(II)]2+ , coined Lx, has emerged as a novel non-conventional approach to antibody-drug conjugates (ADCs) and has shown its potential in preclinical in vitro and in vivo benchmark studies. A crucial improvement of the Lx conjugation reaction from initially <15 % to ca. 75-90 % conjugation efficiency is described, resulting from a systematic screening of all relevant reaction parameters. NaI, a strikingly simple inorganic salt additive, greatly improves the conjugation efficiency as well as the conjugation selectivity simply by exchanging the leaving chloride ligand on Cl-Lx-drug complexes (which are direct precursors for Lx-ADCs) for iodide, thus generating I-Lx-drug complexes as more reactive species. Using this iodide effect, we developed a general and highly practical conjugation procedure that is scalable: our lead Lx-ADC was produced on a 5 g scale with an outstanding conjugation efficiency of 89 %.

Management and evaluation of sodium [131I] iodide contamination after oral administration.

Radioiodine therapy using oral administration of Iodine-131 (I) is a widespread employed strategy for the treatment of hyperthyroidism and thyroid cancer. Such a therapy requires well-trained staff, equipment and procedures regarding radiation safety. The aims of this work are to report an incidental experience of radioprotection with a 370 MBq sodium [I] iodide capsule, which arose following vomiting one minute after the oral administration in a nuclear medicine department and assessment of capsule leakage in a stomach like environment by in vitro experiment. Measurements of the radiation dose rate at the different steps of the decontamination procedure were performed and management of the situation described. Dose rate in vomit was 113 µSv/h [directional dose equivalent H'(0.07)] after capsule withdrawal and was decreased by 10 times after the first decontamination attempt. To evaluate the I release following administration to the patient, an in vitro experiment was designed to recap capsules degradation in a stomach like environment including acidic solution (pH 1) and temperature at 35-37°c. A significant release of I (<6%) was observed in the first 2 min of the in vitro experiment. Sodium [I] iodide capsules disruption occurred at 150 s for capsule 1 and 133 s for capsule 2. Incidental contamination with I in the clinics is of important concern in nuclear medicine and precautions that allow optimization and pertinent management of the situation should be known by the nuclear medicine and radioprotection community.

Analysis of activity uptake, effective half-life and time-integrated activity for low- and high-risk papillary thyroid cancer patients treated with 1.11 GBq and 3.7 GBq of 131I-NaI respectively.

PURPOSE: To analyse the activity uptakes, effective half-lives and time-integrated activities, of relevance for remnant dosimetry, for patients treated for papillary thyroid cancer (PTC) with a different amount of activity of 131I-NaI. METHODS: Fifty patients were included. Of those, 18 patients had low-risk PTC and were treated with 1.11 GBq of 131I-NaI (Group 1), and 32 patients had high-risk PTC and were treated with 3.7 GBq (Group 2). Radioiodine was administered after total thyroidectomy and rhTSH stimulation. Two SPECT/CT scans were performed for each patient to determine the remnant activities and effective half-lives. RESULTS: Significantly higher values (p < 0.05) were obtained for Group 1 for the remnant activity at 7 d (medians 1.4 MBq vs 0.27 MBq), the remnant activity per administered activity at 2 d (0.35% vs 0.09%) and at 7 d (0.13% vs 0.007%), and the effective half-life (93 h vs 40 h). Likewise, the time-integrated activity coefficient was significantly higher for Group 1. The time-integrated activity did not differ significantly between the two groups (p > 0.05). CONCLUSIONS: We found a significant difference in the remnant activity per administered activity, the rate of washout from thyroid remnants, and the time-integrated activity coefficient between low-risk PTC patients treated with 1.11 GBq and high-risk PTC patients treated with 3.7 GBq. On the contrary, there was no such difference in the time-integrated activity. If remnant masses were also not statistically different (reasonable assumption for this monocentric study) no difference in time-integrated activity would imply no difference in remnant absorbed dose, of relevance for treatment efficacy and the risks of stochastic effects.

Decreased All- trans Retinoic Acid-Induced Expression of Sodium-Iodide Transporter in Mammary Epithelial Cells Caused by Conjugated Linoleic Acid Isomers.

Expression of sodium-iodide symporter (NIS) is stimulated by sterol-regulatory-element-binding transcription factors (SREBFs) in mammary epithelial MCF-7 cells. Because conjugated linoleic acid (CLA) isomers have been shown to inhibit transcriptional activity of SREBFs in the mammary gland, the hypothesis was tested that CLA isomers inhibit NIS expression induced by all- trans retinoic acid (ATRA) in MCF-7 cells through inhibiting SREBF activity. c9t11-CLA and t10c12-CLA decreased ATRA-induced NIS-mRNA expression from 1.00 (ATRA alone) to 0.80 ± 0.12 (200 µM c9t11-CLA, P < 0.05) and 0.62 ± 0.10 (200 µM t10c12-CLA, P < 0.05), NIS-protein expression from 1.00 (ATRA alone) to 0.77 ± 0.08 (200 µM c9t11-CLA, P < 0.05) and 0.63 ± 0.05 (200 µM t10c12-CLA, P < 0.05), and NIS-promoter activity from 1.00 (ATRA alone) to 0.74 ± 0.13 (200 µM c9t11-CLA, P < 0.05) and 0.76 ± 0.13 (200 µM t10c12-CLA, P < 0.05); however, c9t11-CLA and t10c12-CLA increased the mRNA levels of SREBF isoforms and their target genes. In contrast, the mRNA expression of peroxisome-proliferator-activated receptor γ (PPARG) was strongly induced by ATRA alone but decreased by CLA isomers from 1.00 (ATRA alone) to 0.80 ± 0.06 (200 µM c9t11-CLA, P < 0.05) and 0.86 ± 0.06 (200 µM t10c12-CLA, P < 0.05). Overexpression of PPARγ in MCF-7 cells increased basal NIS-promoter activity, and treatment with the PPARγ ligand troglitazone stimulated ATRA-induced NIS-promoter activity. In conclusion, the results suggest that CLA isomers exert their effect on the expression of NIS by decreasing PPARG expression in MCF-7 cells.

Identification of a crucial amino acid responsible for the loss of specifying FGFR1-KLB affinity of the iodinated FGF21.

Previous studies suggest that specific binding to the complex consisting of fibroblast growth factor receptor-1 (FGFR1) and the coreceptor beta-Klotho (KLB) is the premise for human FGF19 and FGF21 activating the downstream signaling cascades, and regulating the metabolic homeostasis. However, it was found that human FGF21 loses its ability to bind to FGFR1-KLB after iodination with Na125 I and chloramine T, whereas human FGF19 retained its affinity for FGFR1-KLB even after iodination. The molecular mechanisms underlying these differences remained elusive. In this study, we first demonstrated that an intramolecular disulfide bond was formed between cysteine-102 and cysteine-121 in FGF21, implying that the oxidation of the cysteine to cysteic acid, which may interfere with the active conformation of FGF21, did not occur during the iodination procedures, and thus ruled out the possibility of the two conserved cysteine residues mediating the loss of FGF21 binding affinity to FGFR1-KLB upon iodination. Site-directed mutagenesis and molecular modeling were further applied to determine the residue(s) responsible for the loss of FGFR1-KLB affinity. The results showed that mutation of a single tyrosine-207, but not the other five tyrosine residues in FGF21, to a phenylalanine retained the FGFR1-KLB affinity of FGF21 even after iodination, whereas replacing the corresponding phenylalanine residue with tyrosine in FGF19 did not alter its binding affinity to FGFR1-KLB, but decreased the receptor binding ability of the iodinated protein, suggesting that tyrosine-207 is the crucial amino acid responsible for the loss of specifying FGFR1-KLB affinity of the iodinated FGF21.

Effect of emodin on T cell subsets in NOD mice with NaI­induced experimental autoimmune thyroiditis.

Chronic lymphocytic thyroiditis (CLT), also known as Hashimoto's thyroiditis, is an autoimmune disease in which the thyroid gland is gradually destroyed. To date, only a limited number of agents can effectively suppress thyroiditis development in CLT patients. The aim of the current study was to investigate the protective effect of emodin on experimental autoimmune thyroiditis (EAT) in mice, which is considered an excellent model for CLT. NaI was used to induce the EAT model in non­obese diabetic (NOD) mice. An ELISA method was employed to detect the TgAb level (thyroid inflammation) in the serum of the EAT mice. The T cell subsets in peripheral blood and spleen were detected by flow cytometry. The histopathological study revealed that the thyroid inflammatory cell infiltration was significantly reduced by emodin compared with the model group. In addition, ELISA assays indicated that the NaI­induced serum TgAb upregulation was dramatically revered by emodin. Moreover, the level of serum IFN­Î³ and the cell populations of CD3+CD4+IL­4+, CD3+CD4+ IFN­Î³+, CD3+CD8+IL­4+, CD3+CD8+ IFN­Î³+ T cells in peripheral blood monocytes and splenic lymphocytes were significantly increased by NaI in the model group compared with in the normal group. Nevertheless, this type of increase was markedly attenuated by emodin. To conclude, the EAT model was successfully established by treating NOD mice with NaI. Emodin indicated an inhibitory effect on the autoimmune response that was significantly different in EAT compared with control mice. Furthermore, the anti­inflammatory action of emodin on EAT mice may be mediated via the inhibition of the secretion of IFN­Î³ and the cell numbers of CD3+CD4+IL­4+, CD3+CD4+ IFN­Î³+, CD3+CD8+IL­4+ and CD3+CD8+ IFN­Î³+ T cells in the peripheral blood monocytes and splenic lymphocytes. Therefore, the data may offer valuable insight on the efficacy of treatment of CLT with emodin.

Influence of the SPECT calibration source position on the absorbed dose calculation for 131I-NaI therapy using GATE simulations.

Many research groups have studied nuclear medicine image quantification to improve its accuracy in dose estimation. This work aims to evaluate the influence of the source calibration position for absorbed dose calculation for a 131I-NaI therapy using Monte Carlo (MC) simulations. The calibration approach consisted of a cylindrical phantom filled with water. A cylindrical 131I source with 361.1 ± 3.6 kBq ml-1 was positioned at the center of the phantom and its outer part. Images were acquired with 150 00 counts per projection image acquired with SPECT detector (high counts density-HCD) and 3000 counts per projection (low counts density-LCD). MC simulations, performed with GATE code, were validated by comparing the S values of a water sphere uniformly filled with 131I, as from the sphere model of OLINDA/EXM 1.1. Calibration factors deviation between central and peripheral calibrations is more significant for HCD (18.3%) than for LCD images (3.7%). The 3D dose distribution map obtained from GATE resulted in a dose factor equal to 1.5 × 10-3 mGy/(MBq.s). For both HCD and LCD images, the commonly used approach, which employs the central source calibration to obtain the dose from a peripheral source, resulted in dose overestimation. Results suggest that organ dose calculation can be improved considering the organ position in the field of view. Finally, patients' radiation protection in dosimetry studies could be improved considering the calibration source position, due to the superior accuracy in dose calculation.

Rutin Scavenges Reactive Oxygen Species, Inactivates 5'-Adenosine Monophosphate-Activated Protein Kinase, and Increases Sodium-Iodide Symporter Expression in Thyroid PCCL3 Cells.

BACKGROUND: Thyroid iodide uptake, mediated by the sodium-iodide symporter (NIS), is essential for thyroid hormone synthesis and also for treatment of thyroid diseases, such as thyroid cancer, through radioiodine therapy. Therefore, compounds able to increase thyroid iodide uptake could be clinically useful, and it is of great importance to unravel the mechanisms underlying such an effect. It has been shown previously that the flavonoid rutin increases thyroid radioiodide uptake in vivo in rats. This study aimed to investigate the mechanisms involved in the stimulatory effect of rutin on iodide uptake. METHODS: This study evaluated iodide uptake, NIS expression and its subcellular distribution, iodide efflux, reactive oxygen species levels, and the intracellular pathways involved in NIS regulation in a rat thyroid PCCL3 cell line treated with rutin. RESULTS: Similar to previous results found in vivo, rutin increased radioiodide uptake in PCCL3 cells, which was accompanied by increased NIS expression (at both the mRNA and protein levels) and a reduction of radioiodide efflux. Moreover, the results suggest that rutin could regulate NIS subcellular distribution, leading to higher levels of NIS at the cell membrane. In addition, rutin decreased the levels of intracellular reactive oxygen species and phospho-5'-adenosine monophosphate-activated protein kinase. CONCLUSIONS: The flavonoid rutin seems to be an important stimulator of radioiodide uptake, acting at multiple levels, an effect that can be due to decreased oxidative stress, reduced 5'-adenosine monophosphate-activated protein kinase activation, or both. Since thyroid iodide uptake is crucial for effective radioiodine therapy, the results suggest that rutin could be useful as an adjuvant in radioiodine therapy.

Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene.

The theranostic sodium iodide symporter (NIS) gene allows detailed molecular imaging of transgene expression and application of therapeutic radionuclides. As a crucial step towards clinical application, we investigated tumor specificity and transfection efficiency of epidermal growth factor receptor (EGFR)-targeted polyplexes as systemic NIS gene delivery vehicles in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) that closely reflects human disease. PDAC was induced in mice by pancreas-specific activation of constitutively active KrasG12D and deletion of Trp53. We used tumor-targeted polyplexes (LPEI-PEG-GE11/NIS) based on linear polyethylenimine, shielded by polyethylene glycol and coupled with the EGFR-specific peptide ligand GE11, to target a NIS-expressing plasmid to high EGFR-expressing PDAC. In vitro iodide uptake studies in cell explants from murine EGFR-positive and EGFR-ablated PDAC lesions demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS. In vivo 123I gamma camera imaging and three-dimensional high-resolution 124I PET showed significant tumor-specific accumulation of radioiodide after systemic LPEI-PEG-GE11/NIS injection. Administration of 131I in LPEI-PEG-GE11/NIS-treated mice resulted in significantly reduced tumor growth compared to controls as determined by magnetic resonance imaging, though survival was not significantly prolonged. This study opens the exciting prospect of NIS-mediated radionuclide imaging and therapy of PDAC after systemic non-viral NIS gene delivery.

Glycyrrhizin, a Direct HMGB1 Antagonist, Ameliorates Inflammatory Infiltration in a Model of Autoimmune Thyroiditis via Inhibition of TLR2-HMGB1 Signaling.

BACKGROUND: High mobility group box-1 (HMGB1), a non-histone protein, plays an important role in autoimmune diseases. However, the significance of HMGB1 in the pathogenesis of autoimmune thyroiditis has not been reported. The purpose of this study was to explore whether HMGB1 participates in the pathogenesis of autoimmune thyroiditis, and whether glycyrrhizin (GL), a direct inhibitor of HMGB1, attenuates the severity of thyroid inflammatory infiltration in a murine model of autoimmune thyroiditis. METHODS: A total of 80 male NOD.H-2h4 mice were randomly divided into a control or iodine supplement (NaI) group at four weeks of age, and the control group was fed with regular water, whereas the NaI group was supplied with 0.005% sodium iodine water. Another 24 male NOD.H-2h4 mice were also randomized into three groups (eight mice per group) as follows: control, NaI, and GL treatment after iodine supplementation (NaI + GL). The NOD.H-2h4 mice were fed with 0.005% sodium iodide water for eight weeks to enhance autoimmune thyroiditis. After iodine treatment, the mice received intraperitoneal injections of GL for four weeks. The severity of lymphocytic infiltration in the thyroid gland was measured by histopathological studies. The serum levels of HMGB1, tumor necrosis factor alpha, interleukin (IL)-6, IL-1ß, and thyroglobulin antibody titers were measured using an enzyme-linked immunosorbent assay. HMGB1 expression was measured by immunohistochemical staining and real-time polymerase chain reaction. TLR2, HMGB1, MyD88, and nuclear transcription factor κB were measured by Western blot. RESULTS: The mRNA expression of HMGB1 was significantly higher at 8 and 16 weeks in the NaI group than it was in the control group. Serum levels of thyroglobulin antibodies, HMGB1, tumor necrosis factor alpha, IL-6, and IL-1ß were significantly increased in the NaI group, but they were dramatically attenuated with GL injection. The prevalence of thyroiditis and the infiltration of lymphocytes were significantly decreased in the NaI + GL group. GL administration also significantly reduced the protein expression of TLR2, MyD88, HMGB1 and nuclear transcription factor κB in the thyroid gland and attenuated the severity of thyroiditis. CONCLUSION: HMGB1 may play a crucial role in autoimmune thyroiditis by causing inflammatory infiltration, thus increasing the severity of autoimmune thyroiditis. GL effectively attenuated thyroiditis in the iodine-induced NOD.H-2h4 mice via a molecular mechanism related to the inhibition of TLR2-HMGB1 signaling.

Radionuclide Therapies in Molecular Imaging and Precision Medicine.

This article reviews recent advances and applications of radionuclide therapy. Individualized precision medicine, new treatments, and the evolving role of radionuclide therapy are discussed.

Whole-remnant and maximum-voxel SPECT/CT dosimetry in 131I-NaI treatments of differentiated thyroid cancer.

PURPOSE: To investigate the possible differences between SPECT/CT based whole-remnant and maximum-voxel dosimetry in patients receiving radio-iodine ablation treatment of differentiated thyroid cancer (DTC). METHODS: Eighteen DTC patients were administered 1.11 GBq of 131I-NaI after near-total thyroidectomy and rhTSH stimulation. Two patients had two remnants, so in total dosimetry was performed for 20 sites. Three SPECT/CT scans were performed for each patient at 1, 2, and 3-7 days after administration. The activity, the remnant mass, and the maximum-voxel activity were determined from these images and from a recovery-coefficient curve derived from experimental phantom measurements. The cumulated activity was estimated using trapezoidal-exponential integration. Finally, the absorbed dose was calculated using S-values for unit-density spheres in whole-remnant dosimetry and S-values for voxels in maximum-voxel dosimetry. RESULTS: The mean absorbed dose obtained from whole-remnant dosimetry was 40 Gy (range 2-176 Gy) and from maximum-voxel dosimetry 34 Gy (range 2-145 Gy). For any given patient, the activity concentrations for each of the three time-points were approximately the same for the two methods. The effective half-lives varied (R = 0.865), mainly due to discrepancies in estimation of the longer effective half-lives. On average, absorbed doses obtained from whole-remnant dosimetry were 1.2 ± 0.2 (1 SD) higher than for maximum-voxel dosimetry, mainly due to differences in the S-values. The method-related differences were however small in comparison to the wide range of absorbed doses obtained in patients. CONCLUSIONS: Simple and consistent procedures for SPECT/CT based whole-volume and maximum-voxel dosimetry have been described, both based on experimentally determined recovery coefficients. Generally the results from the two approaches are consistent, although there is a small, systematic difference in the absorbed dose due to differences in the S-values, and some variability due to differences in the estimated effective half-lives, especially when the effective half-life is long. Irrespective of the method used, the patient absorbed doses obtained span over two orders of magnitude.

PDGFRα Regulates Follicular Cell Differentiation Driving Treatment Resistance and Disease Recurrence in Papillary Thyroid Cancer.

Dedifferentiation of follicular cells is a central event in resistance to radioactive iodine and patient mortality in papillary thyroid carcinoma (PTC). We reveal that platelet derived growth factor receptor alpha (PDGFRα) specifically drives dedifferentiation in PTC by disrupting the transcriptional activity of thyroid transcription factor-1 (TTF1). PDGFRα activation dephosphorylates TTF1 consequently shifting the localization of this transcription factor from the nucleus to the cytoplasm. TTF1 is required for follicular cell development and disrupting its function abrogates thyroglobulin production and sodium iodide transport. PDGFRα also promotes a more invasive and migratory cell phenotype with a dramatic increase in xenograft tumor formation. In patient tumors we confirm that nuclear TTF1 expression is inversely proportional to PDGFRα levels. Patients exhibiting PDGFRα at time of diagnosis are three times more likely to exhibit nodal metastases and are 18 times more likely to recur within 5years than those patients lacking PDGFRα expression. Moreover, high levels of PDGFRα and low levels of nuclear TTF1 predict resistance to radioactive iodine therapy. We demonstrate in SCID xenografts that focused PDGFRα blockade restores iodide transport and decreases tumor burden by >50%. Focused PDGFRα inhibitors, combined with radioactive iodine, represent an additional avenue for treating patients with aggressive variants of PTC.