Ryuichi Nishii

Objective. Real-time imaging of alpha-particle tracks in scintillators is promising for microdosimetric studies of alpha-emitting radionuclides in targeted radionuclide therapy. However, when inorganic scintillators such as Gd ₃ Al ₂ Ga ₃ O ₁₂ (GAGG) are used, the observed track characteristics differ from those in biological tissues. This study aimed to validate the GATE (geant4 application for tomographic emission) simulation framework using experimentally obtained alpha-particle track images and to compare track characteristics in GAGG and biological tissue-equivalent media. Such analysis is essential for quantitatively interpreting track images obtained with scintillator-based imaging systems in microdosimetry. Approach. Alpha-particle track images were obtained using a real-time high-resolution imaging system based on a GAGG scintillator and an Am-241 source. Simulated track ranges were compared with experimental images. The finalRange parameter in GATE was optimized because it affects the Bragg peak shape of alpha particles. Furthermore, simulated track characteristics in biological tissue-equivalent media were quantitatively compared with those in GAGG. Main Results. A bright endpoint artifact was identified in simulated alpha-particle tracks, originating from the particle transport mechanism implemented in Geant4/GATE and depending on the finalRange value. The simulated and experimental ranges of alpha particles in GAGG were 8.20 μ m and 8.05 μ m, respectively, demonstrating good agreement. Linear energy transfer (LET) values in GAGG were 2.8 and 1.8 times higher than those in adipose and bone, respectively. Significance. Recognizing this artifact is important for correct interpretation of LET distributions in microdosimetric evaluations. Our results demonstrated that GATE can accurately reproduce alpha-particle track characteristics and provides a useful framework for interpreting track structures observed in inorganic scintillators in terms of energy deposition in biological tissues. Nevertheless, optimization of the finalRange parameter is required for reliable microdosimetric evaluation.

Recent progress in nuclear medicine has been driven by continuous advances in radiotracers, imaging technologies, and radiopharmaceutical therapies, leading to an expansion of clinical applications supported by an increasing body of evidence. In particular, systematic reviews and meta-analyses have played an important role in quantitatively evaluating the clinical value of these developments. This narrative review provides an overview of recent meta-analytic evidence in nuclear medicine, with a primary focus on oncologic applications, while briefly addressing developments in cardiology and neurology. In oncology, positron emission tomography (PET)/computed tomography (CT) using fluorodeoxyglucose (FDG) has become an established imaging modality for post-treatment assessment across various malignancies. Meta-analyses indicate that volumetric metabolic parameters, such as metabolic tumor volume and total lesion glycolysis, are more consistently associated with clinical outcomes than conventional single-voxel metrics. In addition, the interim and post-therapy metabolic response, assessed by FDG PET/CT, provides clinically relevant prognostic information and may contribute to treatment monitoring. Beyond FDG, tumor-targeted PET tracers, including prostate-specific membrane antigen and somatostatin receptor ligands, have demonstrated improved diagnostic performance in specific malignancies, and emerging tracers such as fibroblast activation protein inhibitors represent promising future directions. Radiopharmaceutical therapy has also shown notable progress, with meta-analytic evidence supporting the effectiveness and acceptable safety of peptide receptor radionuclide therapy for neuroendocrine tumors, as well as for advanced prostate cancer. In nuclear cardiology and neurology, advances in PET and single photon emission CT technologies have enabled more precise disease characterization, although their clinical roles continue to evolve. Overall, accumulating meta-analytic evidence supports the growing clinical importance of nuclear medicine. Continued methodological refinement and further evidence generation will be essential to optimize patient management in routine clinical practice.

The rare abscopal effect during radiotherapy is thought to be caused by the release of immune-stimulated damage-associated molecular patterns, such as high mobility group box-1 protein (HMGB1), from cancer cells. Although external irradiation of cancer cells increases HMGB1 release, it is not clear if HMGB1 is released from cells after administering 131I-labeled m-iodobenzylguanidine (131I-MIBG) as an internal targeted radiotherapeutic agent. This study aimed to determine if HMGB1 is released from human-derived cancer and normal cells after administering 131I-MIBG. Methods: Extracellular lactate dehydrogenase (LDH) and HMGB1 released from H441 (human-derived lung adenocarcinoma cell line) and HaCaT (human keratinocyte cell line) 1 day after 2- and 10-Gy X-ray irradiation were measured. Accumulations of 131I-MIBG in SH-SY5Y (human-derived neuroblastoma cell line) and HaCaT were measured 60 min after administering 131I-MIBG (0.37, 1.85, 3.7 MBq/well). Extracellular LDH and HMGB1 released from SH-SY5Y and HaCaT 1 day after administering 131I-MIBG were also measured. Results: The extracellular LDH and HMGB1 released from H441 after 10-Gy X-ray irradiation were significantly increased. However, the extracellular LDH and HMGB1 released from HaCaT after 2-Gy and 10-Gy X-ray irradiation were not increased. After administering 1.85 MBq and 3.7 MBq 131I-MIBG, the extracellular LDH and HMGB1 released from SH-SY5Y were both significantly increased, but only the extracellular LDH released from HaCaT was significantly increased. Conclusions: HMGB1 was released from neuroblastomas but not from normal cells after 131I-MIBG administration, suggesting that a combination of 131I-MIBG and immunotherapy may be feasible.

[¹²³I]β-methyl-p-iodophenyl-pentadecanoic acid ([¹²³I]BMIPP), which is used for nuclear medicine imaging of myocardial fatty acid metabolism, accumulates in cancer cells. However, the mechanism of accumulation remains unknown. Therefore, this study aimed to elucidate the accumulation and accumulation mechanism of [¹²³I]BMIPP in cancer cells. We compared the accumulation of [¹²³I]BMIPP in cancer cells with that of [¹⁸F]FDG and found that [¹²³I]BMIPP was a much higher accumulation than [¹⁸F]FDG. The accumulation of [¹²³I]BMIPP was evaluated in the presence of sulfosuccinimidyl oleate (SSO), a CD36 inhibitor, and lipofermata, a fatty acid transport protein (FATP) inhibitor, under low-temperature conditions and in the presence of etomoxir, a carnitine palmitoyl transferase I (CPT1) inhibitor. The results showed that [¹²³I]BMIPP accumulation was decreased in the presence of SSO and lipofermata in H441, LS180, and DLD-1 cells, suggesting that FATPs and CD36 are involved in [¹²³I]BMIPP uptake in cancer cells. [¹²³I]BMIPP accumulation in all cancer cell lines was significantly decreased at 4 °C compared to that at 37 °C and increased in the presence of etomoxir in all cancer cell lines, suggesting that the accumulation of [¹²³I]BMIPP in cancer cells is metabolically dependent. In a biological distribution study conducted using tumor-bearing mice transplanted with LS180 cells, [¹²³I]BMIPP highly accumulated in not only LS180 cells but also normal tissues and organs (including blood and muscle). The tumor-to-intestine or large intestine ratios of [¹²³I]BMIPP were similar to those of [¹⁸F]FDG, and the tumor-to-large-intestine ratios exceeded 1.0 during 30 min after [¹²³I]BMIPP administration in the in vivo study. [¹²³I]BMIPP is taken up by cancer cells via CD36 and FATP and incorporated into mitochondria via CPT1. Therefore, [¹²³I]BMIPP may be useful for imaging cancers with activated fatty acid metabolism, such as colon cancer. However, the development of novel imaging radiotracers based on the chemical structure analog of [¹²³I]BMIPP is needed.

Background Fibroblast activation protein-α (FAP), a type-II transmembrane serine protease, is expressed during wound healing, in cancer-associated fibroblasts, and in chronic fibrosing diseases. However, its expression in deep vein thrombus (DVT) remains unclear. Therefore, in this study, we investigated FAP expression and localization in DVT. Methods First, we pathologically accessed aspirated thrombi of patients with DVT (n=14), classifying thrombotic areas as follows; fresh, cellular lysis, endothelialization, fibroblastic reaction. Endothelialization and fibroblastic reaction were defined as organizing reactions. We immunohistochemically examined FAP-expressed areas and expressed cells. Second, we analyzed FAP expression in cultured dermal fibroblasts. Results All the aspirated thrombi showed a mixture of at least three of the four thrombotic areas. Specifically, 83 % of aspirated thrombi showed fresh and organizing reactions within each thrombus. Immunohistochemical expression of FAP was restricted in organizing area. Further, FAP expression in the thrombi was mainly found in vimentin-positive or α-smooth muscle actin-positive fibroblasts in double immunofluorescence. Some CD163-positive macrophages also showed FAP expression. FAP mRNA and protein levels significantly increased in cultured fibroblasts with low- proliferative activity under 0.1% fetal bovine serum (FBS) than that in fibroblasts under 10% FBS. Fibroblasts cultured in 10% FBS showed a significant decrease in FAP mRNA levels following supplementation with hemin, but not with thrombin. Conclusions The heterogeneous composition of the venous thrombi suggests the existence of a multistep thrombus formation process in human DVT. Further, fibroblasts or myofibroblasts may express FAP in organizing process in DVT. FAP expression may increase in fibroblasts with low-proliferative activity.

Purpose: N-benzyl-N-methyl-2-[7, 8-dihydro-7-(2-[¹⁸F] fluoroethyl) -8-oxo-2-phenyl-9H-purin-9-yl] acetamide ([¹⁸F] FEDAC) is a novel positron emission tomography (PET) tracer that targets the translocator protein (TSPO; 18 kDa) in the mitochondrial outer membrane, which is known to be upregulated in various diseases such as malignant tumors, neurodegenerative diseases, and neuroinflammation. This study presents the first attempt to use [¹⁸F]FEDAC PET/CT and evaluate its biodistribution as well as the systemic radiation exposure to the radiotracer in humans. Materials and Methods: Seventeen whole-body [¹⁸F]FEDAC PET/CT (injected dose, 209.1 ± 6.2 MBq) scans with a dynamic scan of the upper abdomen were performed in seven participants. Volumes of interest were assigned to each organ, and a time–activity curve was created to evaluate the biodistribution of the radiotracer. The effective dose was calculated using IDAC-Dose 2.1. Results: Immediately after the intravenous injection, the radiotracer accumulated significantly in the liver and was subsequently excreted into the gastrointestinal tract through the biliary tract. It also showed high levels of accumulation in the kidneys, but showed minimal migration to the urinary bladder. Thus, the liver was the principal organ that eliminated [¹⁸F] FEDAC. Accumulation in the normal brain tissue was minimal. The effective dose estimated from biodistribution in humans was 19.47 ± 1.08 µSv/MBq, and was 3.60 mSV for 185 MBq dose. Conclusion: [¹⁸F]FEDAC PET/CT provided adequate image quality at an acceptable effective dose with no adverse effects. Therefore, [¹⁸F]FEDAC may be useful in human TSPO-PET imaging.

Purpose N-benzyl-N-methyl-2 - [7, 8-dihydro-7 - (2 - [¹⁸F] fluoroethyl) -8-oxo-2-phenyl-9H-purin-9-yl] acetamide ([¹⁸F] FEDAC) is a novel positron emission tomography (PET) tracer that targets the translocator protein (TSPO; 18 kDa) in the mitochondrial outer membrane, which is known to be upregulated in various diseases such as malignant tumors, neurodegenerative diseases, and neuroinflammation. This study presents the first attempt to use [¹⁸F]-FEDAC PET/CT and evaluate its biodistribution as well as the systemic radiation exposure to the radiotracer in humans. Materials and Methods Seventeen whole-body [¹⁸F]-FEDAC PET/CT (injected dose, 209.1 ± 6.2 MBq) scans with a dynamic scan of the upper abdomen were performed in seven participants. Volumes of interest were assigned to each organ, and a time–activity curve was created to evaluate the biodistribution of the radiotracer. The effective dose was calculated using IDAC-Dose 2.1. Results Immediately after the intravenous injection, the radiotracer accumulated significantly in the liver and was subsequently excreted into the gastrointestinal tract through the biliary tract. It also showed high levels of accumulation in the kidneys, but showed minimal migration to the urinary bladder. Thus, the liver was the principal organ that eliminated [¹⁸F] FEDAC. Accumulation in the normal brain tissue was minimal. The effective dose estimated from biodistribution in humans was 19.47 ± 1.08 µSv/MBq, and was 3.60 ± 0.20 µSV for 185 MBq dose. Conclusion [¹⁸F]FEDAC PET/CT provided adequate image quality at an acceptable effective dose with no adverse effects. Therefore, [¹⁸F]FEDAC may be useful in human TSPO-PET imaging.

The World Health Organization has cautioned that antimicrobial resistance (AMR) will be responsible for an estimated 10 million deaths annually by 2050. To facilitate prompt and accurate diagnosis and treatment of infectious disease, we investigated the potential of amino acids for use as indicators of bacterial growth activity by clarifying which amino acids are taken up by bacteria during the various growth phases. In addition, we examined the amino acid transport mechanisms that are employed by bacteria based on the accumulation of labeled amino acids, Na⁺ dependence, and inhibitory effects using a specific inhibitor of system A. We found that ³H-L-Ala accurately reflects the proliferative activity of Escherichia coli K-12 and pathogenic EC-14 in vitro. This accumulation in E. coli could be attributed to the amino acid transport systems being different from those found in human tumor cells. Moreover, biological distribution assessed in infection model mice with EC-14 using ³H-L-Ala showed that the ratio of ³H-L-Ala accumulated in infected muscle to that in control muscle was 1.20. By detecting the growth activity of bacteria in the body that occurs during the early stages of infection by nuclear imaging, such detection methods may result in expeditious diagnostic treatments for infectious diseases.

We evaluated the whole-body distribution of orally-administered radioiodine-125 labeled acetaminophen (¹²⁵I-AP) to estimate gastrointestinal absorption of anionic drugs. ¹²⁵I-AP was added to human embryonic kidney (HEK)293 and Flp293 cells expressing human organic anion transporting polypeptide (OATP)1B1/3, OATP2B1, organic anion transporter (OAT)1/2/3, or carnitine/organic cation transporter (OCTN)2, with and without bromosulfalein (OATP and multidrug resistance-associated protein (MRP) inhibitor) and probenecid (OAT and MRP inhibitor). The biological distribution in mice was determined by oral administration of ¹²⁵I-AP with and without bromosulfalein and by intravenous administration of ¹²⁵I-AP. The uptake of ¹²⁵I-AP was significantly higher in HEK293/OATP1B1, OATP1B3, OATP2B1, OAT1, and OAT2 cells than that in mock cells. Bromosulfalein and probenecid inhibited OATP- and OAT-mediated uptake, respectively. Moreover, ¹²⁵I-AP was easily excreted in the urine when administered intravenously. The accumulation of ¹²⁵I-AP was significantly lower in the blood and urinary bladder of mice receiving oral administration of both ¹²⁵I-AP and bromosulfalein than those receiving only ¹²⁵I-AP, but significantly higher in the small intestine due to inhibition of OATPs and/or MRPs. This study indicates that whole-body distribution after oral ¹²⁵I-AP administration can be used to estimate gastrointestinal absorption in the small intestine via OATPs, OATs, and/or MRPs by measuring radioactivity in the urinary bladder.

Background There is currently no established imaging method for assessing liver reserve capacity prior to carbon-ion radiotherapy (CIRT) for liver tumors. In order to perform safe CIRT, it is essential to estimate the post-therapeutic residual reserve capacity of the liver. Purpose To evaluate the ability of pre-treatment ^99mTc-galactosyl human serum albumin (^99mTc-GSA) scintigraphy to accurately estimate the residual liver reserve capacity in patients treated with CIRT for liver tumors. Materials and methods This retrospective study evaluated patients who were performed CIRT for liver tumors between December 2018 and September 2020 and underwent ^99mTc-GSA scintigraphy before and 3 months after CIRT, and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI within 1 month before CIRT were evaluated. The maximal removal rate of ^99mTc-GSA (GSA-Rmax) was analyzed for the evaluation of pre-treatment liver reserve capacity. Then, the GSA-Rmax of the estimated residual liver (GSA-RL) was calculated using liver SPECT images fused with the Gd-EOB-DTPA-enhanced MRI. GSA-RL before CIRT and GSA-Rmax at 3 months after CIRT were compared using non-parametric Wilcoxon signed-rank test and linear regression analysis. Results Overall, 50 patients were included (mean age ± standard deviation, 73 years ± 11; range, 29–89 years, 35 men). The median GSA-RL was 0.393 [range, 0.057–0.729] mg/min, and the median GSA-Rmax after CIRT was 0.369 [range, 0.037–0.780] mg/min (P = .40). The linear regression equation representing the relationship between the GSA-RL and GSA-Rmax after CIRT was y = 0.05 + 0.84x (R² = 0.67, P < .0001). There was a linear relationship between the estimated and actual post-treatment values for all patients, as well as in the group with impaired liver reserve capacity (y = − 0.02 + 1.09x (R² = 0.62, P = .0005)). Conclusions ^99mTc-GSA scintigraphy has potential clinical utility for estimating the residual liver reserve capacity in patients undergoing carbon-ion radiotherapy for liver tumors. Trial registration UMIN000038328, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000043545.