Translocator Protein 18 kDa (TSPO): A Promising Molecular Target for Image-Guided Surgery of Solid Cancers.

The translocator protein 18-kDa (TSPO) is a mitochondrial membrane protein that is previously identified as the peripheral benzodiazepine receptor (PBR). Furthermore, it plays a significant role in a diverse range of biochemical processes, including steroidogenesis, mitochondrial cholesterol transport, cell survival and death, cell proliferation, and carcinogenesis. Several investigations also reported its roles in various types of cancers, including colorectal, brain, breast, prostate, and lung cancers, as well as melanoma. According to a previous study, the expression of TSPO was upregulated in cancer cells, which corresponds to an aggressive phenotype and/or poor prognosis. Consequently, the potential for crafting diagnostic and prognostic tools with a focus on TSPO holds great potential. In this context, several radioligands designed to target this protein have been identified, and some of the candidates have advanced to clinical trials. In recent years, the use of hybrid probes with radioactive and fluorescence molecules for image-guided surgery has exhibited promising results in animal and human studies. This indicates that the approach can serve as a valuable surgical navigator during cancer surgery. The current hybrid probes are built from various molecular platforms, including small molecules, nanoparticles, and antibodies. Although several TSPO-targeted imaging probes have been developed, their development for image-guided surgery of cancers is still limited. Therefore, this review aims to highlight recent findings on the involvement of TSPO in carcinogenesis, as well as provide a new perspective on the potential application of TSPO-targeted hybrid probes for image-guided surgery.

The Chemical Scaffold of Theranostic Radiopharmaceuticals: Radionuclide, Bifunctional Chelator, and Pharmacokinetics Modifying Linker.

Therapeutic radiopharmaceuticals have been researched extensively in the last decade as a result of the growing research interest in personalized medicine to improve diagnostic accuracy and intensify intensive therapy while limiting side effects. Radiometal-based drugs are of substantial interest because of their greater versatility for clinical translation compared to non-metal radionuclides. This paper comprehensively discusses various components commonly used as chemical scaffolds to build radiopharmaceutical agents, i.e., radionuclides, pharmacokinetic-modifying linkers, and chelators, whose characteristics are explained and can be used as a guide for the researcher.

Preclinical Evaluation of Chicken Egg Yolk Antibody (IgY) Anti-RBD Spike SARS-CoV-2-A Candidate for Passive Immunization against COVID-19.

The coronavirus disease 2019 (COVID-19) has become a substantial threat to the international health sector and the global economy. As of 26 December 2021, the number of mortalities resulting from COVID-19 exceeded 5.3 million worldwide. The absence of an effective non-vaccine treatment has prompted the quest for prophylactic agents that can be used to combat COVID-19. This study presents the feasibility of chicken egg yolk antibody (IgY) anti-receptor-binding domain (RBD) spike SARS-CoV-2 as a strong candidate to neutralize the virus for application in passive immunization. For the purpose of preclinical studies, we radiolabeled IgY anti-RBD spike SARS-CoV-2 with radionuclide iodine-131. This allowed us to evaluate several biological characteristics of IgY in vitro, in vivo, and ex vivo. The preclinical data suggest that IgY anti-RBD spike SARS-CoV-2 could specifically bind to the SARS-CoV-2 antigens; however, little uptake was observed in normal cells (MRC-5) (<2%). Furthermore, the ex vivo biodistribution study revealed that IgY predominantly accumulated in the trachea of normal mice compared to other organs. We also found that IgY possessed a good safety profile when used as an intranasal agent. Taken together, we propose that IgY anti-RBD spike SARS-CoV-2 has the potential for application in passive immunization against COVID-19.

Immuno-PET imaging for non-invasive assessment of cetuximab accumulation in non-small cell lung cancer.

BACKGROUNDS: Overexpression of epidermal growth factor receptor (EGFR) has been established as a valid therapeutic target of non-small cell lung cancer (NSCLC). However, the clinical benefit of cetuximab as an EGFR-targeting drug is still controversial, partially due to the lack of effective means to identify suitable patients. This study aimed to investigate the potential of radiolabeled cetuximab as a non-invasive tool to predict cetuximab accumulation in NSCLC tumor xenografts with varying EGFR expression levels. METHODS: The NSCLC tumors in model mice were subjected to in vivo biodistribution study and positron emission tomography (PET) imaging 48 h after injection of either 111In- or 64Cu-labeled cetuximab. The EGFR expression levels of NSCLC tumors were determined by ex vivo immunoblotting. RESULTS: We found that tumors with high EGFR expression had significantly higher [111In]In-DOTA-cetuximab accumulation than tumors with moderate to low EGFR expression (P < 0.05). Strong correlations were found between [111In]In-DOTA-cetuximab tumor uptake and EGFR expression level (r = 0.893), and between [64Cu]Cu-DOTA-cetuximab tumor uptake with EGFR expression level (r = 0.915). PET imaging with [64Cu]Cu-DOTA-cetuximab allowed clear visualization of tumors. CONCLUSION: Our findings suggest that this immuno-PET imaging can be clinically translated as a tool to predict cetuximab accumulation in NSCLC cancer patients prior to cetuximab therapy.

Thin-Shelled PEGylated Perfluorooctyl Bromide Nanocapsules for Tumor-Targeted Ultrasound Contrast Agent.

Shell thickness determines the acoustic response of polymer-based perfluorooctyl bromide (PFOB) nanocapsule ultrasound contrast agents. PEGylation provides stealth property and arms for targeting moieties. We investigated a modulation in the polymer formulation of carboxy-terminated poly(d,l-lactide-co-glycolide) (PLGA) and poly(d,l-lactide-co-glycolide)-block-polyethylene glycol (PLGA-b-PEG) to produce thin-shelled PFOB nanocapsules while keeping its echogenicity, stealth property, and active targeting potential. Polymer formulation contains 40% PLGA-PEG that yields the PEGylated PFOB nanocapsules of approximately 150 nm size with average thickness-to-radius ratio down to 0.15, which adequately hindered phagocytosis. Functionalization with antibody enables in vitro tumor-specific targeting. Despite the acoustic response improvement, the in vivo tumor accumulation was inadequate to generate an observable acoustic response to the ultrasound power at the clinical level. The use of PLGA and PLGA-PEG polymer blend allows the production of thin-shelled PFOB nanocapsules with echogenicity improvement while maintaining its potential for specific targeting.

Prognostic value of metabolic tumor volume of pretreatment 18F-FAMT PET/CT in non-small cell lung Cancer.

BACKGROUND: This study aimed to determine the prognostic value of positron emission tomography (PET) metabolic parameters-namely metabolic tumor volume (MTV), total lesion glycolysis (TLG), and total lesion retention (TLR)-on fluorine-18 (18F) fluorodeoxyglucose (FDG) and L- [3-18F]-α-methyltyrosine (18F-FAMT) PET/CT in patients with non-small-cell lung cancer (NSCLC). METHODS: The study group comprised 112 NSCLC patients who underwent 18F-FDG and 18F-FAMT PET/CT prior to any therapy. The MTV, TLG, TLR, and maximum standardized uptake value (SUVmax) of the primary tumors were determined. Automatic MTV measurement was performed using PET volume computer assisted reading software. (GE Healthcare). Cox proportional hazards models were built to assess the prognostic value of MTV, TLG (for 18F-FDG), TLR (for 18F-FAMT), SUVmax, T stage, N stage, M stage, clinical stage, age, sex, tumor histological subtype, and treatment method (surgery or other therapy) on overall survival (OS). RESULTS: Higher TNM, higher clinical stage, inoperable status, and higher values for all PET parameters (both 18F-FAMT and 18F-FDG PET) were significantly associated (P < 0.05) with shorter OS. Multivariate analysis revealed that a higher MTV of 18F-FAMT (hazard ratio [HR]: 2.88, CI: 1.63-5.09, P < 0.01) and advanced clinical stage (HR: 5.36, CI: 1.88-15.34, P < 0.01) were significant predictors of shorter OS. CONCLUSIONS: MTV of 18F-FAMT is of prognostic value for OS in NSCLC cases and can help guide decision-making during patient management.

Determining patient selection tool and response predictor for outpatient 30 mCi radioiodine ablation dose in non-metastatic differentiated thyroid carcinoma: a Japanese perspective.

The lack of isolation ward throughout Japan has long been limiting the 131I radioactive iodine (RAI) ablation for differentiated thyroid cancer (DTC) cases. The 30 mCi RAI ablation was only recently permitted for outpatient basis. However, no patient selection tool nor response predictor has been proposed. This study evaluated factors to find response predictor and determinant for the suitable patients. The retrospective study reviewed 47 eligible non-metastatic papillary DTC patients whose had first 30 mCi RAI ablation after total thyroidectomy. Age, gender, clinical stage, risk category, and pre-ablation serum thyroglobulin (Tg) level were among covariates analyzed to determine the patient selection factors; while the thyroid bed uptake on initial whole body scan (WBS) was later also included in determining RAI ablation response. Thirteen (28%) patients had a low risk (T1-2) while 23 (49%) and 11 (23%) had an intermediate (T3) or high risk (T4), respectively. Twenty-five patients were responders, and 22 were non-responders. All factors were similar between responders and non-responders except pre-ablation serum Tg level (p < 0.001). In multivariate analysis, pre-ablation serum Tg level was the only significant factor for both patient selection (odd ratio (OR) = 1.52, 95% confidence interval (CI) = 1.13-2.06) and response predictor (OR = 1.48; 95% CI = 1.12-1.95). With the cut-off of 5.4 ng/mL, pre-ablation serum Tg level predicts RAI ablation response with 92% specificity and 73% sensitivity. Pre-ablation serum Tg level may help patient selection and predict the response to outpatient 30 mCi RAI ablation among post total thyroidectomy non-metastatic DTC patients.

A new approach for simple radioisotope cisternography examination in cerebrospinal fluid leakage detection.

OBJECTIVE: We developed a new quantitative interpretation technique of radioisotope cisternography (RIC) for the diagnosis of spontaneous cerebrospinal fluid hypovolemia (SCH). METHODS: RIC studies performed for suspected SCH were evaluated. (111)In-DTPA RIC images were taken at 0, 1, 3, 6, and 24-h after radioisotope injection following the current protocol. Regions of interest (ROI) were selected on 3-h images to include brain, spine, bladder or the whole body. The accumulative radioactivity counts were calculated for quantitative analysis. Final diagnoses of SCH were established based on the diagnostic criteria recently proposed by Schievink and colleagues. RESULTS: Thirty-five patients were focused on. Twenty-one (60.0%) patients were diagnosed as having SCH according to the Schievink criteria. On the 3-h images, direct cerebrospinal fluid leakage sign was detected in nine of 21 SCH patients (42.9%), as well as three patients with suspected iatrogenic leakage. Compared to non-SCH patients, SCH patients showed higher bladder accumulation at 3-h images (P = 0.0002), and higher brain clearance between the 6- and 24-h images (P < 0.0001). In particular, the 24-h brain clearance was more conclusive for the diagnosis than 24-h whole cistern clearance. The combination of direct sign and 24-h brain accumulation resulted in 100% of accuracy in the 32 patients in whom iatrogenic leakage was not observed. 1- and 6-h images did not provide any additional information in any patients. CONCLUSIONS: A new simple ROI setting method, in which only the 3-h whole body and 24-h brain images were necessary, was sufficient to diagnose SCH.

Evaluation of bone scan index change over time on automated calculation in bone scintigraphy.

OBJECTIVE: Bone scintigraphy (bone scan) is useful in detecting metastatic bone lesions through visual assessment of hot spots. A semi-quantitative analysis method that evaluates bone scan images has been eagerly anticipated. BONENAVI is software that enables automatic assessment of bone scan index (BSI). BSI is useful for stratifying cancer patients and monitoring their therapeutic response. The purpose of this study was to evaluate the BONENAVI reading in determining BSI and hot spots at different time intervals after radioisotope injection. METHODS: We evaluated 32 patients, including 22 males and 10 females. Ten patients had breast cancer, 20 patients had prostate cancer, and 2 had malignant pheochromocytoma. Patients were injected with 740 MBq of (99m)Tc-methylene diphosphonate and bone scintigraphy was performed at 2, 4, and 6 h after injection on each patient. The BSI and the number of hot spots were obtained from BONENAVI software. Bone scan images were also visually assessed to exclude false positives due to artifacts. Analyses were performed in all lesions, selected true lesions, segment based and cancer type based. Non-parametric statistical analyses for pairwise multiple group comparison were performed using Friedman test followed with post hoc analysis. RESULTS: The BSIs and the number of hot spots were significantly increased with time, with significant differences between each of time points (P < 0.001). Analysis of regional BSI (rBSI) and hot spot number changes of selected 15 true lesions also showed similar increase (P < 0.001). In general, the pelvic segment was the most prone to rBSI changes and the chest segment was the most prone to hot spot number changes. Visual assessment showed that BONENAVI diagnosed some typical artifacts as metastases (hot spots). CONCLUSION: BONENAVI reading of BSIs and hot spot numbers was highly affected by acquisition time. In serial or follow-up examinations (in particular, for monitoring therapeutic efficacy), acquisition time should be fixed for each patient. Cautious interpretation should be made on segments with high physiological uptake. BONENAVI reading was prone to misinterpretation of artifacts. Visual assessment is necessary to rule out this possibility.

In vivo molecular imaging of cancer stem cells.

A rare subpopulation of cancer cells known as cancer stem cells (CSCs) have distinct characteristics resembling stem cells, including cell renewal capability, differentiation into multiple lineages, and endless proliferation potential. Cumulating evidence has revealed that CSCs are responsible for tumorigenicity, invasion, metastasis, and therapeutic resistance. Despite continued investigation of CSCs, in vivo behavior of CSCs is not yet fully understood. The in vivo imaging modalities of optical, nuclear, and magnetic resonance are currently being employed to investigate the complexity behind the CSCs behavior. Valuable information that were previously obscured by the limitations of in vitro techniques now are currently being revealed. These studies give us a more comprehensive insight about what happen to CSCs in vivo. This review will briefly discuss the recent findings on CSCs behavior as informed by in vivo imaging studies.

Effects of intratumoral inflammatory process on 18F-FDG uptake: pathologic and comparative study with 18F-fluoro-α-methyltyrosine PET/CT in oral squamous cell carcinoma.

UNLABELLED: The accurate depiction of both biologic and anatomic profiles of tumors has long been a challenge in PET imaging. An inflammation, which is innate in the carcinogenesis of oral squamous cell carcinoma (OSCC), frequently complicates the image analysis because of the limitations of (18)F-FDG and maximum standardized uptake values (SUV(max)). New PET parameters, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as well as (18)F-fluoro-α-methyltyrosine ((18)F-FAMT), a malignancy-specific amino acid-based PET radiotracer, are considered more comprehensive in tumor image analysis. Here, we showed the substantial effects of the intratumoral inflammatory process on (18)F-FDG uptake and further study the possibility of MTV and TLG to predict both tumor biology (proliferation activity) and anatomy (pathologic tumor volume). METHODS: (18)F-FDG and (18)F-FAMT PET images from 25 OSCC patients were analyzed. SUV(max) on the tumor site was obtained. PET volume computerized-assisted reporting was used to generate a volume of interest to obtain MTV and TLG for (18)F-FDG and total lesion retention (TLR) for (18)F-FAMT. The whole tumor dissected from surgery was measured and sectioned for pathologic analysis of tumor inflammation grade and Ki-67 labeling index. RESULTS: The high SUV(max) of (18)F-FDG was related to the high inflammation grade. The SUV(max )ratio of (18)F-FDG to (18)F-FAMT was higher in inflammatory tumors (P < 0.05) whereas the corresponding value in tumors with a low inflammation grade was kept low. All (18)F-FAMT parameters were correlated with Ki-67 labeling index (P < 0.01). Pathologic tumor volume predicted from MTV of (18)F-FAMT was more accurate (R = 0.90, bias = 3.4 ± 6.42 cm(3), 95% confidence interval = 0.77-6.09 cm(3)) than that of (18)F-FDG (R = 0.77, bias = 8.1 ± 11.17 cm(3), 95% confidence interval = 3.45-12.67 cm(3)). CONCLUSION: (18)F-FDG uptake was overestimated by additional uptake related to the intratumoral inflammatory process, whereas (18)F-FAMT simply accumulated in tumors according to tumor activity as evaluated by Ki-67 labeling index in OSCC.

Fractionated radioimmunotherapy with 9°Y-labeled fully human anti-CEA antibody.

Carcinoembryonic antigen (CEA) is an attractive target molecule of radioimmunotherapy (RIT). To enhance RIT's therapeutic efficacy, the fractionation of radiolabeled antibody doses is an attractive strategy. In this study, a fully human anti-CEA monoclonal antibody (mAb) C2-45 was selected by virtue of its lack of immunogenicity, and the effectiveness of fractionated RIT with yttrium-90 (9°Y)-labeled mAb C2-45 was evaluated. In LS180 tumor-bearing mice, indium-111 (¹¹¹In)-labeled mAb C2-45 showed high and persistent tumor accumulation. Therapeutic studies were performed with single doses of 9°Y-mAb C2-45 (100 or 200 µCi) or double doses of 100 µCi 9°Y-mAb C2-45 at different intervals (5, 10, and 15 days). All 9°Y-mAb C2-45-treated mice showed inhibition of tumor progression, while the time to tumor progression was much longer in both the 200-µCi-treated group and the double 100-µCi-treated group than in the single 100-µCi-treated group. The therapeutic effect of the double 100 µCi administration at days 0 and 15 lasted significantly longer than that in the other treatment groups. These findings indicate that 9°Y-mAb C2-45 may be a promising agent for the treatment of CEA-positive cancer and that the fractionation of 9°Y-labeled antibody doses could enhance the therapeutic effect if performed according to an appropriate protocol.

Complementary roles of tumour specific PET tracer ¹8F-FAMT to ¹8F-FDG PET/CT for the assessment of bone metastasis.

PURPOSE: The usefulness of (18)F-FDG PET/CT for bone metastasis evaluation has already been established. The amino acid PET tracer [(18)F]-3-fluoro-alpha-methyl tyrosine ((18)F-FAMT) has been reported to be highly specific for malignancy. We evaluated the additional value of (18)F-FAMT PET/CT to complement (18)F-FDG PET/CT in the evaluation of bone metastasis. METHODS: This retrospective study included 21 patients with bone metastases of various cancers who had undergone both (18)F-FDG and (18)F-FAMT PET/CT within 1 month of each other. (18)F-FDG-avid bone lesions suspicious for malignancy were carefully selected based on the cut-off value for malignancy, and the SUVmax of the (18)F-FAMT in the corresponding lesions were evaluated. RESULTS: A total of 72 (18)F-FDG-positive bone lesions suspected to be metastases in the 21 patients were used as the reference standard. (18)F-FAMT uptake was found in 87.5 % of the lesions. In the lesions of lung cancer origin, the uptake of the two tracers showed a good correlation (40 lesions, r = 0.68, P < 0.01). Bone metastatic lesions of oesophageal cancer showed the highest average of (18)F-FAMT uptake. Bone metastatic lesions of squamous cell carcinoma showed higher (18)F-FAMT uptake than those of adenocarcinoma. No significant difference in (18)F-FAMT uptake was seen between osteoblastic and osteolytic bone metastatic lesions. CONCLUSION: The usefulness of (18)F-FAMT PET/CT for bone metastasis detection regardless of the lesion phenotype was demonstrated. The fact that (18)F-FAMT uptake was confirmed by (18)F-FDG uptake suggests that (18)F-FAMT PET/CT has the potential to complement (18)F-FDG PET/CT for the detection of bone metastases.

Current developments and clinical applications of bubble technology in Japan: a report from 85th Annual Scientific Meeting of The Japan Society of Ultrasonic in Medicine, Tokyo, 25-27 May, 2012.

The potentials of bubble technology in ultrasound has been investigated thoroughly in the last decade. Japan has entered as one of the leaders in bubble technology in ultrasound since Sonazoid (Daiichi Sankyo & GE Healthcare) was marketed in 2007. The 85th Annual Scientific Meeting of The Japan Society of Ultrasonics in Medicine held in Tokyo from May 25 to 27, 2012 is where researchers and clinicians from all over Japan presented recent advances and new developments in ultrasound in both the medical and the engineering aspects of this science. Even though bubble technology was originally developed simply to improve the conventional ultrasound imaging, recent discoveries have opened up powerful emerging applications. Bubble technology is the particular topic to be reviewed in this report, including its mechanical advances for molecular imaging, drug/gene delivery device and sonoporation up to its current clinical application for liver cancers and other liver, gastrointestinal, kidney and breast diseases.

Clinical significance of ¹8F-α-methyl tyrosine PET/CT for the detection of bone marrow invasion in patients with oral squamous cell carcinoma: comparison with ¹8F-FDG PET/CT and MRI.

OBJECTIVE: L-3-[(18)F]-fluoro-α-methyl tyrosine ((18)F-FAMT) is an amino acid tracer for positron emission tomography/computed tomography (PET/CT) which specifically transported into cancer cells by L-type amino acid transporter 1 (LAT1). LAT1 overexpression in tumors is significantly correlated with cell proliferation and angiogenesis. (18)F-FAMT PET/CT, fluorine-18-fluorodeoxyglucose ((18)F-FDG) PET/CT and magnetic resonance imaging (MRI) were compared for their diagnostic performance in the detection of bone marrow invasion in patients with oral squamous cell carcinoma (OSCC). METHODS: Twenty-seven patients with OSCC on the upper or lower alveolar ridge underwent staging by MRI, (18)F-FDG PET/CT and (18)F-FAMT PET/CT studies before surgery. Post-surgical pathologic examination was used as the standard to determine the final diagnoses. The possibility of bone marrow invasion on MRI, (18)F-FDG PET/CT and (18)F-FAMT PET/CT were usually graded retrospectively into five-point score. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated according to the obtained scores. RESULTS: As the sensitivity of (18)F-FDG PET/CT was highest (100 %) among that of MRI (95 %) and (18)F-FAMT PET/CT (90 %), the specificity of (18)F-FAMT PET/CT was highest (85.7 %) among that of MRI (57 %) and (18)F-FDG PET/CT (14.3 %). The size of pathological tumor was accorded with that detected by (18)F-FAMT PET/CT and was smaller than that detected by (18)F-FDG PET/CT (P < 0.01). Significant difference was not found between (18)F-FAMT PET tumor volume and pathological tumor volume. CONCLUSIONS: (18)F-FAMT PET/CT was useful and more specific than MRI or (18)F-FDG PET/CT in the detection of bone marrow invasion of OSCC and may contribute to minimize the extent of resection in oral surgery patient.

Predicting cetuximab accumulation in KRAS wild-type and KRAS mutant colorectal cancer using 64Cu-labeled cetuximab positron emission tomography.

Overexpression of epidermal growth factor receptor (EGFR) is common in colorectal cancer. However, cetuximab as an EGFR-targeting drug is useful only for a subset of patients and currently no single predictor other than V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status has been established. In the present study, we investigated cetuximab accumulation in colorectal tumors and major organs using (111)In-DOTA-cetuximab. We also evaluated the potential of positron emission tomography (PET) imaging of (64)Cu-DOTA-cetuximab. Colorectal tumor xenografts with a different EGFR expression level and KRAS mutation status were subjected to in vivo biodistribution study and PET imaging at 48 h post-injection of radiolabeled cetuximab. The EGFR expression levels on colorectal tumors were determined by ex vivo immunoblotting and ELISA. We found that KRAS wild-type tumors had significantly higher (111)In-DOTA-cetuximab accumulation than KRAS mutant tumors (P < 0.001). Based on KRAS mutation status, a strong correlation was found between (111)In-DOTA-cetuximab tumor uptake and EGFR expression level (KRAS wild type: r = 0.988; KRAS mutant: r = 0.829), and between (64)Cu-DOTA-cetuximab tumor uptake with EGFR expression level (KRAS wild type: r = 0.838; KRAS mutant: r = 0.927). Significant correlation was also found between tumor uptake of (111)In-DOTA-cetuximab and (64)Cu-DOTA-cetuximab (r = 0.920). PET imaging with (64)Cu-DOTA-cetuximab allowed clear visualization of tumors. Both radiolabeled cetuximab had effectively visualized cetuximab accumulation in colorectal tumors with a wide variety of EGFR expression levels and different KRAS mutation status as commonly encountered in the clinical setting. Our findings suggest that this radioimmunoimaging therefore can be clinically translated as an in vivo tool to predict cetuximab accumulation in colorectal cancer patients prior to cetuximab therapy.