Current Radiopharmaceuticals - Volume 15, Issue 3, 2022

Clinical imaging equipment technological advancements offer insight into the evolution of mathematical techniques used to estimate parameters necessary to characterize the microvasculature and, thus, differentiate normal tissues from abnormal ones. These parameters are blood flow (F), capillary endothelial permeability surface area product (PS), vascular fraction (vp), and extravascular extracellular space size (EES,ve). There are a number of well-established approaches that exist in the literature; however, their analysis is restricted by complexity and is heavily influenced by noise. On the other hand, these characteristics can also be calculated using simpler and straightforward approaches such as Up-Slope Method (USM) and Graphical Analysis (GA). The review looks into the theoretical background and clinical uses of these methodologies, as well as the applicability of these techniques in various sections of the human body.

Background:4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated with a bifunctional chelator 2,2'-(7-(1-carboxy-4-((2,5-dioxopyrrolidin-1-yl)oxy)-4- oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODAGA) (hereafter referred to as Cell Death Indicator [CDI]), enters dead and dying cells and binds to 90kDa heat shock proteins (hsp90). Objective: This study assesses stability, biodistribution, imaging, and radiation dosimetry of [68Ga]- Ga-CDI for positron emission tomography (PET). Methods: Preparation of [⁶⁸Ga]Ga-CDI was performed as previously described. Product stability and stability in plasma were assessed using high-performance liquid chromatography. Biodistribution and imaging were conducted in ten healthy male Lewis rats at 1 and 2 h following intravenous [⁶⁸Ga]Ga-CDI injection. Human radiation dosimetry was estimated by extrapolation for a standard reference man and calculated with OLINDA/EXM 1.1. Results: Radiochemical purity of [⁶⁸Ga]Ga-CDI averaged 93.8% in the product and 86.7% in plasma at 4 h post-synthesis. The highest concentration of [⁶⁸Ga]Ga-CDI is observed in the kidneys; [⁶⁸Ga]Ga-CDI is excreted in the urine, and mean retained activity was 32.4% and 21.4% at 1 and 2 h post-injection. Lower concentrations of [⁶⁸Ga]Ga-CDI were present in the small bowel and liver. PET CT was concordant and additionally demonstrated focal growth plate uptake. The effective dose for [⁶⁸Ga]Ga-CDI is 2.16E-02 mSv/MBq, and the urinary bladder wall received the highest dose (1.65E-02 mSv/Mbq). Conclusion: [⁶⁸Ga] Ga-CDI is stable and has favourable biodistribution, imaging, and radiation dosimetry for imaging of dead and dying cells. Human studies are underway.

Background: Transarterial chemoembolization is the most widely used palliative treatment for unresectable hepatocellular carcinoma; however, arterioportal shunt represents a contraindication to this treatment. Objective: The study aims to assess the feasibility of balloon-occluded radiofrequency ablation in the transitory resolution of an extensive arterioportal shunt in patients with advanced hepatocellular carcinoma as a bridge to safe and effective transarterial chemoembolization. Methods: 12 consecutive patients advanced multinodular unilobar unresectable hepatocellular carcinoma with a target lesion larger than 5 cm (mean diameter 7.7 ± 1.4 cm), not suitable to transarterial chemoembolization due to extensive arterioportal shunt, were recruited. Balloon-occluded radiofrequency ablation of the hepatic area surrounding the shunt during occlusion of the artery supplying the shunt was performed, followed by lobar conventional chemoembolization. Intra/periprocedural complications were evaluated. Technical success was defined by the result of radiofrequency ablation in terms of immediate disappearance, reduction, or persistence of the shunt. Local efficacy of chemoembolization was evaluated at 1-month computed tomography according to m-RECIST criteria. Results: Technical success was achieved in all patients. No major complications were observed. 1- month follow-up showed a mean necrotic diameter of 6.3 cm (range: 3.8-8.7 cm), with an acceptable procedural result and persistence of the shunt. An overall response rate was obtained in all patients, with 25% complete response and 75% partial response. Conclusion: Balloon-occluded radiofrequency ablation of an arterioportal shunt in patients with advanced hepatocellular carcinoma can temporarily reduce shunting, allowing to perform safe and therapeutically useful chemoembolization, with satisfactory control of tumor growth.

Introduction: Pulmonary embolism (PE) can be diagnosed by perfusion lung scintigraphy using human albumin macroaggregates labelled ^99mTc (^99mTc-MAA). When PE is suspected, subcutaneous Low Molecular Weight Heparin (LMWH) should be administered even before the results of the PE diagnostic flowchart. In our study, we aimed to evaluate a possible interaction (in vitro interference) between ^99mTc-MAA and LMWH. Methods: The reconstitution of MAA kit was performed according to the manufacturer's instruction. After labelling, we carried out the following preparations: a standard dose of ^99mTc-MAA alone, as control; ^99mTc-MAA and enoxaparin at different ratios. According to the manufacturer's instruction, the radiochemical purity was performed and evaluated immediately (T0), after 15 and 30 minutes after incubation (T15 and T30). Results: We compared the radiochemical purity of ^99mTc-MAA with: (i) radiochemical purity of ^99mTc-MAA and enoxaparin (11 ratio), (ii) radiochemical purity of ^99mTc-MAA and enoxaparin (0.5 ratio), and (iii) radiochemical purity of ^99mTc-MAA and enoxaparin (ratio 2). No significant differences were found between all the measured parameters at each time point for each ratio. We also tested the stability of ^99mTc-MAA in physiological conditions (at 37°C in PBS): the initial radiochemical purity of ^99mTc-MAA was 99.78%. The values of 99mTc-MAA radiochemical purity were high in all conditions of possible interaction with LMWH, with values ranging from 98.00% at T0 to 95% at T30. Conclusion: We found no statistically significant change in the in vitro stability of ^99mTc-MAA in the presence of enoxaparin, excluding a possible direct interference. Future studies will be needed to check the ^99mTc-MAA stability under physiological conditions.

Background: An accurate measurement of the target volume is of primary importance in theragnostics of hyperthyroidism. Objective: Our purpose was to evaluate the accuracy of a threshold-based isocontour extraction procedure for thyroid tissue volumetry from SPECT-CT. Methods: Cylindrical vials with a fixed volume of 99mTcO4 at different activities were inserted into a neck phantom in two different thickness settings. Images were acquired by orienting the phantom in different positions, i.e., 40 planar images and 40 SPECT-CT. The fixed values of the isocontouring threshold for SPECT and SPECT-CT were calculated by means of linear and spline regression models. Mean, Median, Standard Deviation, Standard Error, Mean Absolute Percentage Error and Root Mean-Square Error were computed. Any difference between the planar method, SPECT and SPECT-CT and the effective volume was evaluated by means of ANOVA and posthoc tests. Moreover, planar and SPECT-CT acquisitions were performed in 8 patients with hyperthyroidism, considering relevant percentage differences greater than > 20% from the CT gold standard. Results: Concerning phantom studies, the planar method shows higher values of each parameter than the other two methods. SPECT-CT shows lower variability. However, no significant differences were observed between SPECT and SPECT-CT measurements. In patients, relevant differences were found in 7 out of 9 lesions with the planar method, in 6 lesions with SPECT, but in only one with SPECT-CT. Conclusion: Our study confirms the superiority of SPECT in volume measurement if compared with the planar method. A more accurate measurement can be obtained from SPECT-CT.

Aims: The aim of this retrospective study was to investigate SUVs variability with respect to lesion size, administered dose, and reconstruction algorithm. Background: SUVmax and SUVpeak are influenced by technical factors as count statistics and reconstruction algorithms. Objective: To fulfill the aim, we evaluated the SUVs variability with respect to lesion size, administered dose, and reconstruction algorithm (ordered - subset expectation maximization plus point spread function option - OSEM+PSF, regularized Bayesian Penalized Likelihood - BPL) in a 5 - rings BGO PET/CT scanner. Methods: Discovery IQ scanner (GE Healthcare, Milwaukee, Wisconsin, US) was used for list mode acquisition of 25 FDG patients, 12 injected with 3.7 MBq/kg (Standard Dose protocol - SD) and 13 injected with 1.8 MBq/kg (Low Dose protocol - LD). Each acquisition was reconstructed at different time/FOV with both OSEM+PSF algorithm and BPL using seven different beta factors. SUVs were calculated in 70 lesions and analysed in function of time/FOV and Beta. Image quality was evaluated as a coefficient of variation of the liver (CV - liver). Results: SUVs were not considerably affected by time/FOV. However, SUVs were influenced by beta: differences were higher in small lesions (37% for SUVmax, 15% for SUVpeak) compared to larger ones (14% and 6%). CV - liver ranged from 6% with Beta-500 (LD and SD) to 13% with Beta- 200 (LD). CV - liver of BPL with Beta-350 (optimized for clinical practice in our institution) in LD was lower than CV - liver of OSEM+PSF in SD. Conclusion: When a high sensitivity 5 - rings BGO PET/CT scanner is used with the same reconstruction algorithm, quantification by means of SUVmax and SUVpeak is a robust standard compared to the activity and scan duration. However, both SUVs and image quality are influenced by reconstruction algorithms and the related parameters should be considered to obtain the best compromise between detectability, quantification, and noise.

Background: This work aims to present a nuclear medicine imaging service’s data regarding applying positron emission–computing tomography (PET/CT) scans with the radiopharmaceutical ⁶⁸Ga-PSMA-HBED-CC (⁶⁸Ga-PSMA-11) to diagnose prostate cancer clinical relapse. Methods: Eighty patients with a mean age of 68.26 years and an average prostatic-specific antigen blood level of 7.49 ng/ml (lower concentration = 0.17 ng/ml) received ⁶⁸Ga-PSMA-11 intravenously, and full-body images of PET-CT scan were obtained. Of the total of patients admitted to the imaging service, 87.5% were examined for disease’s biochemical recurrence and clinical relapse, and 70.0% had a previous radical prostatectomy (RP). Results: Of the patients without RP, 95.8% were detected with intra-glandular disease. The ⁶⁸Ga- PSMA-11 PET/CT imaging results revealed small lesions, even in patients with low blood levels of prostatic-specific antigen, mainly in metastatic cancer cases in lymph nodes and bones. Conclusion: The ⁶⁸Ga-PSMA-11 PET/CT imaging was essential in detecting prostate cancer, with significantly high sensitivity in detecting recurrent cases. Due to its inherent reliability and sensitivity, PET/CT scanning with ⁶⁸Ga-PSMA-11 received an increasing number of medical requests throughout the present follow-up study, confirming the augmented demand for this clinical imaging procedure in the regional medical community.

Background: Breast cancer is one of the most common types of malignancies in the world. Cancer resistance is an unavoidable consequence of therapy with radiation or other modalities. Ongoing research aims to improve cancer response to therapy. Aim: The aim of this study was to evaluate the possible sensitization effect of imperatorin (IMP) in combination with external radiotherapy (ERT) or HT. Methods: After treatment of MCF-7 breast cancer cells with IMP, cells were exposed to 4 Gy X-rays or HT (42 °C for 1 hour). The viability of MCF-7 cells was measured using an MTT assay. Furthermore, the expression of pro-apoptotic genes, including Bax, Bcl-2, caspase-3, caspase-8, and caspase- 9, was investigated using real-time PCR. The sensitizing effect of IMP in combination with ERT or HT was calculated and compared to ERT or HT alone. Results: Results showed an increase in the expression of pro-apoptotic genes and downregulation of anti-apoptotic Bcl-2 following ERT and HT. Furthermore, cell viability was reduced following these treatments. IMP was able to augment these effects of ERT and HT. Conclusion: IMP could increase the efficiency of HT and ERT. This effect of IMP may suggest it as an adjuvant for increasing the therapeutic efficiency of ERT.

Background: Radioresistance is found to be the main therapeutic restriction in colorectal radiation therapy. The aim of this study was to investigate the synergistic effect of Etodolac (ET) and ionizing radiation on human colorectal cancer cells. Methods: Pretreated HT-29 cells with ET were exposed to ionizing radiation. The radiosensitizing effect of ET was evaluated using MTT, flow cytometry, and clonogenic assay. The amount of nitrite oxide (NO) in irradiated cells was also measured with the Griess reagent. Results: The present study found that pretreatment of HT-29 cells with ET decreases their survival and colony formation. Higher concentrations of ET cause total apoptosis and an increase in NO levels in irradiated cells. Conclusion: Applying ET in a concentration-dependent manner had an incremental effect on the amount of apoptosis and cell death induced by radiation.

Background: Chitosan is a cationic biopolymer obtained from deacetylating chitin, a natural compound present in crustacean shell, fungi and exoskeleton of insects. Chitosan involves various applications, including as drug and gene delivery systems, as wound dressing material and scaffolds for tissue engineering, agriculture, textile, food and feed nanotechnology, and in wastewater treatments. Chitosan-TPP particle has been figured out as the most important and stable nanoparticle for chitosan application in various fields. Objective: In this study, chitosan was chemically modified by sodium tripolyphosphate (TPP). Afterward, TPP-chitosan was radiolabeled with the gallium-67 radionuclide. The effect of several factors on labeling yield, such as chitosan solubility, acidity and concentration of TPPchitosan solution, and incubation time with gallium-67, were investigated. Methods: To prepare [⁶⁷Ga] gallium-chitosan complex, chitosan (0.5 ml) was dissolved in 2.2 mCi of [⁶⁷Ga] gallium chloride solution. The obtained solution was stirred for 5 min and then kept for 30 min at room temperature. The radiochemical purity and radiolabeling yield were measured via radiochromatography, which was performed by using a radio thin-layer chromatography (TLC) scanner instrument. To investigate the effect of chitosan kind and concentration on the labeling yield, two kinds of chitosan (acid-soluble chitosan and water-soluble chitosan) at two different concentrations (1% and 0.5%) and different pH were used. In addition, labeling efficiency and stability of the ⁶⁷Ga-TPP-chitosan complex (acidic/water soluble chitosan) at both concentrations (0.5 and 1%) and at room temperature were assessed for 30, 45 and 60 min. Results: The incubation time did not have any significant effect on labeling yield. The acidic soluble chitosan exhibited the highest radiolabeling yield at pH=9.3-10.4, while water-soluble chitosan showed the highest radiolabeling yield at pH > 5. Also, the prepared complex was stable in the final solution at room temperature and could even be used 24 hours after preparation for further application. Conclusion: Taken together, the TPP-modified water-soluble chitosan at the concentration of 0.5 % depicted the highest radiochemical yield (>95 %) in the optimized condition (pH= 6.2– 7.6). Therefore, TPP modified water-soluble chitosan can prove to be an effective carrier for therapeutic radionuclides in tumor treatment.