Guiding principles on the education and practice of theranostics.

PURPOSE: The recent development and approval of new diagnostic imaging and therapy approaches in the field of theranostics have revolutionised nuclear medicine practice. To ensure the provision of these new imaging and therapy approaches in a safe and high-quality manner, training of nuclear medicine physicians and qualified specialists is paramount. This is required for trainees who are learning theranostics practice, and for ensuring minimum standards for knowledge and competency in existing practising specialists. METHODS: To address the need for a training curriculum in theranostics that would be utilised at a global level, a Consultancy Meeting was held at the IAEA in May 2023, with participation by experts in radiopharmaceutical therapy and theranostics including representatives of major international organisations relevant to theranostics practice. RESULTS: Through extensive discussions and review of existing curriculum and guidelines, a harmonised training program for theranostics was developed, which aims to ensure safe and high quality theranostics practice in all countries. CONCLUSION: The guiding principles for theranostics training outlined in this paper have immediate relevance for the safe and effective practice of theranostics.

Fibroblast activation protein targeted therapy using [177Lu]FAPI-46 compared with [225Ac]FAPI-46 in a pancreatic cancer model.

PURPOSE: Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (177Lu)-labelled FAPI-46 and alpha-emitter (225Ac)-labelled FAPI-46 in pancreatic cancer models. METHODS: PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 and [225Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [225Ac]FAPI-46. Tumour sizes and body weights were followed. RESULTS: [18F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [177Lu]FAPI-46 and [225Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46. CONCLUSION: This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.

Comparison of the Therapeutic Effects of [211At]NaAt and [131I]NaI in an NIS-Expressing Thyroid Cancer Mouse Model.

Astatine (211At) is an alpha-emitter with a better treatment efficacy against differentiated thyroid cancer compared with iodine (131I), a conventional beta-emitter. However, its therapeutic comparison has not been fully evaluated. In this study, we compared the therapeutic effect between [211At]NaAt and [131I]NaI. In vitro analysis of a double-stranded DNA break (DSB) and colony formation assay were performed using K1-NIS cells. The therapeutic effect was compared using K1-NIS xenograft mice administered with [211At]NaAt (0.4 MBq (n = 7), 0.8 MBq (n = 9), and 1.2 MBq (n = 4)), and [131I]NaI (1 MBq (n = 4), 3 MBq (n = 4), and 8 MBq (n = 4)). The [211At]NaAt induced higher numbers of DSBs and had a more reduced colony formation than [131I]NaI. In K1-NIS mice, dose-dependent therapeutic effects were observed in both [211At]NaAt and [131I]NaI. In [211At]NaAt, a stronger tumour-growth suppression was observed, while tumour regrowth was not observed until 18, 25, and 46 days after injection of 0.4, 0.8, and 1.2 MBq of [211At]NaAt, respectively. While in [131I]NaI, this was observed within 12 days after injection (1, 3, and 8 MBq). The superior therapeutic effect of [211At]NaAt suggests the promising clinical applicability of targeted alpha therapy using [211At]NaAt in patients with differentiated thyroid cancer refractory to standard [131I]NaI treatment.

α-Emitting cancer therapy using 211 At-AAMT targeting LAT1.

α-Methyl-l-tyrosine (AMT) has a high affinity for the cancer-specific l-type amino acid transporter 1 (LAT1). Therefore, we established an anti-cancer therapy, with 211 At-labeled α-methyl-l-tyrosine (211 At-AAMT) as a carrier of 211 At into tumors. 211 At-AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double-stranded breaks in vitro. We evaluated the accumulation of 211 At-AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse 211 At-AAMT inhibited tumor growth in the PANC-1 tumor model and 1 MBq/mouse 211 At-AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that 211 At would be useful for anti-cancer therapy and that LAT1 is suitable as a target for radionuclide therapy.

Determination of brain tumor recurrence using 11 C-methionine positron emission tomography after radiotherapy.

We conducted a prospective multicenter trial to compare the usefulness of 11 C-methionine (MET) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both 11 C-MET and 18 F-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at 3 months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either 11 C-MET or 18 F-FDG underwent surgery; 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in one of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of 11 C-MET PET and 18 F-FDG PET were 0.97 (32/33, 95% confidence interval [CI]: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (P < .0001). The diagnostic accuracy of 11 C-MET PET was significantly better than that of 18 F-FDG PET (87.5% vs. 69.6%, P = .033). No examination-related adverse events were observed. The results of the study demonstrated that 11 C-MET PET was superior to 18 F-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis.

Clinical evaluation of neuroinflammation in child-onset focal epilepsy: a translocator protein PET study.

BACKGROUND: Neuroinflammation is associated with various chronic neurological diseases, including epilepsy; however, neuroimaging approaches for visualizing neuroinflammation have not been used in the clinical routine yet. In this study, we used the translocator protein positron emission tomography (PET) with [11C] DPA713 to investigate neuroinflammation in the epileptogenic zone in patients with child-onset focal epilepsy. METHODS: Patients with intractable focal epilepsy were recruited at the Epilepsy Center of Osaka University; those who were taking any immunosuppressants or steroids were excluded. PET images were acquired for 60 min after intravenous administration of [11C] DPA713. The PET image of [11C] DPA713 was co-registered to individual's magnetic resonance imaging (MRI), and the standardized uptake value ratio (SUVr) in regions of interest, which were created in non-lesions and lesions, was calculated using the cerebellum as a pseudo-reference region. In the case of epilepsy surgery, the correlation between SUVr in lesions and pathological findings was analyzed. RESULTS: Twenty-seven patients (mean age: 11.3 ± 6.2 years, male/female: 17/10) were included in this study. Of these, 85.1% showed increased uptake of [11C] DPA713 in the focal epileptic lesion. Three patients showed epileptic spasms, suggesting partial seizure onset, and all 18 patients with abnormal lesions on MRI were similarly highlighted by significant uptake of [11C] DPA713. DPA713-positive patients had a broad range of etiologies, including focal cortical dysplasia, tumors, infarction, and hippocampal sclerosis. Five out of nine MRI-negative patients showed abnormal [11C] DPA713 uptake. The SUVr of [11C] DPA713 in lesions was significantly higher than that in non-lesions. In seven patients who underwent epilepsy surgery, increased [11C] DPA713 uptake was associated with microglial activation. CONCLUSIONS: This study indicates that [11C] DPA713 uptake has valuable sensitivity in the identification of epileptic foci in child-onset focal epilepsy, and inflammation is implicated in the pathophysiology in the epileptic foci caused by various etiologies. Further research is required to establish diagnostic tools for identifying focal epileptogenic zones.

Intratumoral administration of astatine-211-labeled gold nanoparticle for alpha therapy.

BACKGROUND: 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally. RESULTS: AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. CONCLUSIONS: The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide.

Metabolic Tumor Volume Change Predicts Long-term Survival and Histological Response to Preoperative Chemotherapy in Locally Advanced Esophageal Cancer.

OBJECTIVE: Here, we assess the ability of metabolic tumor volume (MTV) as measured by F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-FDG PET/CT) to evaluate neoadjuvant chemotherapy response for patients with locally advanced esophageal cancer (EC). BACKGROUND: Optimal methods to evaluate treatment response for EC patients have not yet been established. Although previous studies have reported the value of standardized uptake value (SUV), the accuracy of predicting histological response or long-term survival in EC is limited. METHODS: In all, 102 EC patients without distant metastasis who underwent F-FDG PET/CT both before and after the preoperative chemotherapy series were analyzed. RESULTS: The median primary tumor MTV values before and after preoperative chemotherapy were 22.55 (range 0.4-183.1) and 2.75 (0-52.9), respectively, and the median MVT reduction rate was 86.5%. We found the most significant difference in survival between PET responders and nonresponders with a cut-off value of 60% MTV reduction, using a 10% stepwise cut-off analysis [2-year progression-free survival (PFS): 79.2 vs 44.4%; hazard ratio (HR) 3.397; P < 0.0001). With this cut-off value, histological response (P = 0.0091), tumor location (P = 0.0102), pT (P = 0.0011), and pN (P = 0.0110) were significantly associated with PET response. Univariate analysis of PFS indicated a correlation between PFS and tumor size, cT, decrease of primary lesion by CT, SUVmax reduction rate, MTV reduction rate, pT, pN, and pM. Multivariate analysis further identified pM (HR 3.063; P = 0.0279) and MTV reduction rate (HR 2.471; P = 0.0263) to be independent prognostic predictors, but not decrease of primary lesion by CT or SUVmax reduction rate. CONCLUSION: MTV change is clinically useful in predicting both long-term survival and histological response to preoperative chemotherapy in EC patients, after determining the optimal cut-off value based on survival analysis.

Quantifying the Severity of Parkinson Disease by Use of Dopaminergic Neuroimaging.

OBJECTIVE. Parkinson disease is characterized by dopaminergic neuron loss in the substantia nigra pars compacta resulting in presynaptic nigrostriatal dopamine dysfunction. The purpose of this study was to search for an optimal image biomarker to quantify the severity of Parkinson disease by comparing neuromelanin MRI and dopamine transporter SPECT. SUBJECTS AND METHODS. Forty patients with Parkinson disease (Hoehn and Yahr [HY] stage 1, four patients; stage 2, 18 patients; stage 3, eight patients; stage 4, six patients; stage 5, four patients) who underwent neuromelanin MRI and dopamine transporter SPECT were included. The signal-to-noise ratio (SNR) in the substantia nigra pars compacta on neuromelanin MR images and the striatal specific binding ratio (SBR) on dopamine transporter SPECT images were calculated on the basis of the value of each background region. The Mann-Whitney U test was used to test the significance of difference between the early-stage group (HY stages 1 and 2) and the advanced-stage group (HY stages 3-5) for each SNR and SBR. ROC analysis was used to compare intergroup discriminating performance. The correlation of each SNR and SBR with clinical rating scale was assessed. RESULTS. Both SNR and SBR were significantly greater in the early-stage group than in the advanced-stage group (p < 0.05). The ROC AUCs for differentiating the two groups were 0.73 for SNR and 0.89 for SBR. The coefficients of correlation were -0.47 for SNR versus HY stage and -0.67 for SBR versus HY stage. CONCLUSION. Dopaminergic neuroimaging, particularly dopamine transporter SPECT, is a potentially useful imaging biomarker of the severity of Parkinson disease.

Volumetric and texture analysis on FDG PET in evaluating and predicting treatment response and recurrence after chemotherapy in follicular lymphoma.

PURPOSE: The purpose of this study was to determine if quantitative SUV-related, volumetric FDG PET parameters, and texture features (SPs, VPs, and TFs, respectively) were useful to evaluate and predict response and recurrence after chemotherapy in follicular lymphoma (FL). METHODS: Pre- and posttreatment FDG PET examinations in 45 FL patients were analyzed retrospectively. In addition to SPs in the representative lesion, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated as VPs for the representative and whole-body lesions. Six TFs were calculated in the pretreatment representative lesion. Response results with reduction of SPs or VPs after treatment (Δ) were compared to the Lugano classification based on visual assessment. SPs, VPs, and Δ of them as well as TFs were also evaluated if they allow prediction of response and recurrence after chemotherapy. RESULTS: Quantitative assessment with SPs and VPs provided 89% and 93-96% concordant results, respectively, with Lugano classification. Among pretreatment PET parameters, low gray-level zone emphasis (LGZE) in TFs solely showed statistical significance to predict complete response. All of posttreatment and Δ of SPs and VPs were considered as the predictors of progression free survival in the univariate Cox regression analysis, but none of them was the predictor in the multivariate analysis. CONCLUSION: This study demonstrated that quantitative PET parameters were applicable to evaluate treatment response in FL. Texture analysis showed promise in predicting treatment response. Although posttreatment and Δ of PET parameters were the candidates, all of them proved to have limited value in predicting recurrence after chemotherapy.

Microvascular Dysfunction Related to Progressive Left Ventricular Remodeling due to Chronic Occlusion of the Left Anterior Descending Artery in an Adult Porcine Heart.

Occlusion of a major coronary artery induces myocardial infarction (MI), leading to left ventricle (LV) remodeling due to progressive microvasculature dysfunction. Irreversible impairment in microvascular function has been suggested to extend from the infarcted region into the infarct-border or remote regions, depending on the time to revascularization. Our aim was to determine whether the occlusion of a major coronary artery induces microvascular dysfunction in the adjacent area perfused by intact coronary arteries using a porcine model for chronic total occlusion of the left anterior descending artery (LAD). MI was induced via an ameroid constrictor ring around the LAD in adult Göttingen pigs (Sus scrofa domesticus, n = 5). Age-matched normal pigs were treated as controls (n = 3). Cardiac magnetic resonance showed reduced systolic regional wall motion in the left circumflex (LCx) and right coronary artery (RCA) territories, with a progressively worsening motion in the infarction-adjacent area over an eight-week period. On 13N-ammonia positron emission tomography (PET), myocardial blood flow (MBF) during hyperemia was significantly greater in the LCx and RCA territories (particularly in the infarction-adjacent area) compared to that in the LAD territory at four weeks after infarct induction. Subsequently, the flow significantly decreased, approaching that in the LAD territory at eight weeks after infarct induction. Fluoroscopy-guided pressure-wire studies showed significantly higher microvascular resistance in the LCx area at eight weeks compared to that in controls. Electron microscopy showed endothelium swelling and microvasculature disruption in areas adjacent to the LCx and RCA territories. Anterior MI caused coronary microvascular dysfunction in the adjacent area, associated with a reduced MBF and regional wall motion.

Japanese multicenter database of healthy controls for [123I]FP-CIT SPECT.

PURPOSE: The aim of this multicenter trial was to generate a [123I]FP-CIT SPECT database of healthy controls from the common SPECT systems available in Japan. METHODS: This study included 510 sets of SPECT data from 256 healthy controls (116 men and 140 women; age range, 30-83 years) acquired from eight different centers. Images were reconstructed without attenuation or scatter correction (NOACNOSC), with only attenuation correction using the Chang method (ChangACNOSC) or X-ray CT (CTACNOSC), and with both scatter and attenuation correction using the Chang method (ChangACSC) or X-ray CT (CTACSC). These SPECT images were analyzed using the Southampton method. The outcome measure was the specific binding ratio (SBR) in the striatum. These striatal SBRs were calibrated from prior experiments using a striatal phantom. RESULTS: The original SBRs gradually decreased in the order of ChangACSC, CTACSC, ChangACNOSC, CTACNOSC, and NOACNOSC. The SBRs for NOACNOSC were 46% lower than those for ChangACSC. In contrast, the calibrated SBRs were almost equal under no scatter correction (NOSC) conditions. A significant effect of age was found, with an SBR decline rate of 6.3% per decade. In the 30-39 age group, SBRs were 12.2% higher in women than in men, but this increase declined with age and was absent in the 70-79 age group. CONCLUSIONS: This study provided a large-scale quantitative database of [123I]FP-CIT SPECT scans from different scanners in healthy controls across a wide age range and with balanced sex representation. The phantom calibration effectively harmonizes SPECT data from different SPECT systems under NOSC conditions. The data collected in this study may serve as a reference database.

Correlation between hypoxic area in primary brain tumors and WHO grade: differentiation from malignancy using 18F-fluoromisonidazole positron emission tomography.

Background 18F-fluoromisonidazole positron emission tomography (FMISO-PET) has been used for identification of hypoxic areas in tumors, and since hypoxia causes hypoxia-inducible factor-1 and enhancement of tumor growth, identifying the hypoxic area in the tumor tissue is important. Purpose To evaluate the usefulness of FMISO-PET in the grading of primary brain tumors. Material and Methods FMISO-PET was performed preoperatively on 41 consecutive patients with pathologically confirmed brain tumor. A neuroradiologist retrospectively measured both maximum standardized uptake value (SUVmax) and mean SUV (SUVmean) in the tumor and normal cerebellar parenchyma. Maximum tumor/normal control ratio (T/Nmax) and mean tumor/normal control ratio (T/Nmean) were calculated and analyzed. Results There was a positive correlation between World Health Organization (WHO) grade and both T/Nmax and T/Nmean (r = 0.731 and 0.713, respectively). When all cases were divided into benign (WHO grade II) and malignant groups (III and IV), there were significant differences between the two groups in both T/Nmax and T/Nmean ( P < 0.001). If the cutoff value was defined as T/Nmax = 1.25 and T/Nmean = 1.23, T/Nmax had a sensitivity of 90.0% and a specificity of 90.9% while T/Nmean had a sensitivity of 93.3% and a specificity of 90.9% in differentiating the benign group from the malignant group. Conclusion Both T/Nmax and T/Nmean in FMISO-PET have a positive correlation with primary brain tumor grading, making FMISO-PET useful in diagnosing the malignancy of primary brain tumors.

Value of 18F-FDG PET/CT in discrimination between indolent and aggressive non-Hodgkin's lymphoma: A study of 328 patients.

OBJECTIVE: Non-Hodgkin's lymphoma (NHL) cases with inconclusive biopsy findings are not infrequently referred for fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). We searched for maximum standardized uptake value (SUVmax) cut-off values that could discriminate between indolent and aggressive NHL in conventional non-time of flight (non-TOF) 18F-FDG PET/CT and TOF 18F-FDG PET/CT. SUBJECTS AND METHODS: Retrospectively, 328 patients were selected by the following inclusion criteria: biopsy-proven NHL with no more than one histopathological type; new cases with less than 90 days between obtaining biopsy and 18F-FDG PET/CT scanning; recurrent cases with time interval more than six months since the last therapy with no history of transformation; and blood glucose less than 150mg/dL. Two hundred forty six (246) selected patients were scanned with non-TOF PET/CT, and 82 patients were scanned with TOF 18F-FDG PET/CT. RESULTS: The SUVmax of NHL tends to be higher in TOF 18F-FDG PET/CT than non-TOF 18F-FDG PET/CT. New aggressive NHL had significantly higher SUVmax than new indolent NHL in both, non-TOF 18F-FDG PET/CT (13.6±7.7g/mL vs. 5.3±3.4g/mL, P<0.0001) and TOF 18F-FDG PET/CT (20.5±9.8g/mL vs. 6.6±4.7g/mL, P<0.0001). A receiver operating characteristic curve analysis for new cases in non-TOF 18F-FDG PET/CT (n=204), demonstrated SUVmax of 10g/mL as the most balanced cut-off between aggressive and indolent NHL, with the area under the curve (AUC) of 86%, specificity of 94%, and sensitivity of 71%. While SUVmax of 13g/mL was the most balanced cut-off for new cases in TOF 18F-FDG PET/CT (n=57), with AUC of 91%, specificity of 95.5%, and sensitivity of 77%. CONCLUSION: Both SUVmax>10g/mL in non-TOF 18F-FDG PET/CT and >13g/mL in TOF 18F-FDG PET/CT were highly suggestive of an aggressive nature of NHL, while there was an overlap between indolent and aggressive NHL in the lower SUVmax levels.

Metabolic tumor volume of primary tumor predicts survival better than T classification in the larynx preservation approach.

We aimed to determine whether pretreatment metabolic tumor volume of the primary tumor (T-MTV) or T classification would be a better predictor of laryngectomy-free survival (LFS) and overall survival (OS) after chemoradiotherapy in patients with locally advanced laryngeal or hypopharyngeal cancer requiring total laryngectomy. We analyzed 85 patients using a Cox proportional hazards model and evaluated its usefulness by Akaike's information criterion. A T-MTV cut-off value was determined by time-dependent receiver operating characteristic curve analysis. Interobserver reliability for measuring T-MTV was estimated by the intraclass correlation coefficient (ICC). After adjustment for covariables, T-MTV, irrespective of whether a continuous or dichotomized variable, and T classification remained independent predictors of LFS and OS. Large T-MTV (>28.7 mL) was associated with inferior LFS (hazard ratio [HR], 4.16; 95% confidence interval [CI], 1.97-8.70; P = 0.0003) and inferior OS (HR, 3.18; 95% CI, 1.47-6.69; P = 0.004) compared with small T-MTV (≤28.7 mL). The T-MTV model outperformed the T classification model in predicting LFS and OS (P = 0.007 and 0.01, respectively). Three-year LFS and OS rates for patients with small versus large T-MTV were 68% vs 9% (P < 0.0001) and 77% vs 25% (P < 0.0001), respectively, whereas those for patients with T2-T3 versus T4a were 61% vs 31% (P = 0.003) and 71% vs 48% (P = 0.10), respectively. ICC was 0.99 (95% CI, 0.99-1.00). Given the excellent interobserver reliability, T-MTV is better than T classification to identify patients who would benefit from the larynx preservation approach.

18F-FBPA as a tumor-specific probe of L-type amino acid transporter 1 (LAT1): a comparison study with 18F-FDG and 11C-Methionine PET.

PURPOSE: The purpose of this study was to evaluate the usefulness of L-4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) as a tumor-specific probe, in comparison to 18F-FDG and 11C-methionine (Met), focusing on its transport selectivity by L-type amino acid transporter 1 (LAT1), which is highly upregulated in cancers. METHODS: Cellular analyses of FBPA were performed to evaluate the transportablity and Km value. PET studies were performed in rat xenograft models of C6 glioma (n = 12) and in rat models of turpentine oil-induced subcutaneous inflammation (n = 9). The kinetic parameters and uptake values on static PET images were compared using the one-tissue compartment model (K1, k2) and maximum standardized uptake value (SUVmax). RESULTS: The cellular analyses showed that FBPA had a lower affinity to a normal cell-type transporter LAT2 and induced less efflux through LAT2 among FBPA, Met, and BPA, while the efflux through LAT1 induced by FBPA was similar among the three compounds. The Km value of 18F-FBPA for LAT1 (196.8 ± 11.4 µM) was dramatically lower than that for LAT2 (2813.8 ± 574.5 µM), suggesting the higher selectivity of 18F-FBPA for LAT1. K1 and k2 values were significantly smaller in 18F-FBPA PET (K1 = 0.04 ± 0.01 ml/ccm/min and k2 = 0.07 ± 0.01 /min) as compared to 11C-Met PET (0.22 ± 0.09 and 0.52 ± 0.10, respectively) in inflammatory lesions. Static PET analysis based on the SUVmax showed significantly higher accumulation of 18F-FDG in the tumor and inflammatory lesions (7.2 ± 2.1 and 4.6 ± 0.63, respectively) as compared to both 18F-FBPA (3.2 ± 0.40 and 1.9 ± 0.19) and 11C-Met (3.4 ± 0.43 and 1.6 ± 0.11). No significant difference was observed between 18F-FBPA and 11C-Met in the static PET images. CONCLUSION: This study shows the utility of 18F-FBPA as a tumor-specific probe of LAT1 with low accumulation in the inflammatory lesions.

[Creation and Evaluation of Educational Programs for Additional Delayed Scan of FDG-PET/CT].

Generally, FDG-PET/CT image is acquired at the 60th minute after tracer administration. Depending on the clinical case, additional delayed scans may be useful. However, it is difficult to judge whether additional delayed scan is useful or not. The purposes of this study were creation and evaluation of educational programs to help radiological technologists to decide the usefulness of additional delayed scan of FDG-PET/CT. METHODS: Educational programs consisted of the instructional materials and the judgment test of clinical cases. The instructional materials provided the valuable findings for differentiation between uptake in the wall of the colon and colon content, distinction between uptake in the lymph node and urinary tract, and evaluation of malignancy. The judgment test of clinical cases consisted of 10 cases selected by a nuclear medicine physician (for 5 of that cases additional delayed scan was decided to be useful). Five experienced technologists and five inexperienced technologists scored the volubility of additional delayed scan pre- and post-training using the instructional materials (the full marks of score is 5). RESULTS: After the educational programs using the instructional materials, the score was improved with the significant difference in both experienced (pre: 3.6±1.4, post: 4.0±1.2) and inexperienced (pre: 2.8±1.5, post: 3.7±1.5) groups (p<0.05). CONCLUSION: According to the educational programs, technologist might be able to decide whether the additional delayed scan is useful or not. The successful results of this study may improve the interpretation or reduce the total exposure dose of the PET/CT scan.

Cell-sheet therapy with omentopexy promotes arteriogenesis and improves coronary circulation physiology in failing heart.

Cell-sheet transplantation induces angiogenesis for chronic myocardial infarction (MI), though insufficient capillary maturation and paucity of arteriogenesis may limit its therapeutic effects. Omentum has been used clinically to promote revascularization and healing of ischemic tissues. We hypothesized that cell-sheet transplantation covered with an omentum-flap would effectively establish mature blood vessels and improve coronary microcirculation physiology, enhancing the therapeutic effects of cell-sheet therapy. Rats were divided into four groups after coronary ligation; skeletal myoblast cell-sheet plus omentum-flap (combined), cell-sheet only, omentum-flap only, and sham operation. At 4 weeks after the treatment, the combined group showed attenuated cardiac hypertrophy and fibrosis, and a greater amount of functionally (CD31(+)/lectin(+)) and structurally (CD31(+)/α-SMA(+)) mature blood vessels, along with myocardial upregulation of relevant genes. Synchrotron-based microangiography revealed that the combined procedure increased vascularization in resistance arterial vessels with better dilatory responses to endothelium-dependent agents. Serial (13)N-ammonia PET showed better global coronary flow reserve in the combined group, mainly attributed to improvement in the basal left ventricle. Consequently, the combined group had sustained improvements in cardiac function parameters and better functional capacity. Cell-sheet transplantation with an omentum-flap better promoted arteriogenesis and improved coronary microcirculation physiology in ischemic myocardium, leading to potent functional recovery in the failing heart.

Correlation between apparent diffusion coefficients on diffusion-weighted MRI and standardized uptake value on FDG-PET/CT in pancreatic adenocarcinoma.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) and 2-deoxy-2-[18F]fluoro-D-glucose-positron emission tomography/computed tomography (PET/CT) is increasingly recognized as important for assessing tumor malignancy in oncology. Apparent diffusion coefficient (ADC) and standardized uptake value (SUV) are negatively correlated in some types of cancer based on tumor aggressiveness. PURPOSE: To evaluate relationships between ADC of magnetic resonance imaging and SUV of PET/CT in pancreatic adenocarcinomas. MATERIAL AND METHODS: Twenty-nine patients histopathologically diagnosed with pancreatic adenocarcinomas were evaluated. ADC maps were generated from 3 T-MRI using b values (b = 0, 800 s/mm(2)). PET/CT was performed 60 min after intravenous injection of FDG (3.7 MBq/kg). The margins of tumors on DW-MRI and PET/CT were assessed to measure ADC and SUV of tumor appropriately. For tumors considered well-marginated, minimal and mean ADC as well as maximal and mean SUV were measured. The correlation of ADC and SUV were statistically evaluated and survival period stratified on ADC and SUV also evaluated. RESULTS: Twenty-two tumors on DW-MRI and 25 on PET/CT were deemed well-marginated. Minimal ADC was significantly and negatively correlated with maximal and mean SUV (r = -0.61, P = 0.0040; r = -0.66, P = 0.0015), and mean ADC also showed significantly and negatively correlation with maximal and mean SUV (r = -0.50, P = 0.024; r = -0.54, P = 0.012). There was no significant difference on overall survival stratified on ADC and SUV. CONCLUSION: ADC and SUV were significantly correlated in pancreatic adenocarcinomas, although no significant findings were observed in overall survival.

(18)F-FBPA as a tumor specific tracer of L-type amino acid transporter 1 (LAT1): PET evaluation in tumor and inflammation compared to (18)F-FDG and (11)C-methionine.

OBJECTIVE: (18)F-FDG-PET is used worldwide for oncology patients. However, we sometimes encounter false positive cases of (18)F-FDG PET, such as moderate uptake in the inflammatory lesion, because (18)F-FDG accumulates not only in the cancer cells but also in the inflammatory cells (macrophage, granulation tissue, etc). To overcome this limitation of (18)F-FDG, we started to use (4-borono-2- [(18)F]fluoro-L-phenylalanine) (18)F-FBPA, an artificial amino acid tracer which is focusing attention as a tumor specific PET tracer. Physiological accumulation of (18)F-FBPA is limited in the kidney and urinary tract in humans, which enable preferable evaluation of uptake in the abdominal organs compared to (11)C-methionine ((11)C-MET). The purpose of this study was to evaluate (18)F-FBPA as a tumor specific tracer by in vitro cellular uptake analysis focusing on the selectivity of L-type amino acid transporter 1 (LAT1), which is specifically expressed in tumor cells, and in vivo PET analysis in rat xenograft and inflammation models compared to (18)F-FDG and (11)C-methionine. SUBJECTS AND METHODS: Uptake inhibition and efflux experiments were performed in HEK293-LAT1 and LAT2 cells using cold BPA, cold (18)F-FBPA, and hot (18)F-FBPA to evaluate LAT affinity and transport capacity. Position emission tomography studies were performed in rat xenograft model of C6 glioma 2 weeks after the implantation (n=9, body weight=197±10.5g) and subcutaneous inflammation model 4 days after the injection of turpentine oil (n=9, body weight=197±14.4g). Uptake on static PET images were compared among (18)F-FBPA at 60-70min post injection, (18)F-FDG at 60-70min, and (11)C-MET at 20-30min in the tumors and the inflammatory lesions by maximum standardized uptake value (SUVmax). RESULTS: Cellular uptake analysis showed no significant difference in inhibitory effect and efflux of LAT1 between cold (18)F-FBPA and cold BPA, suggesting the same affinity and transport capacity via LAT1. Uptake of (18)F-FBPA via LAT1 was superior to LAT2 by the concentration dependent uptake analysis. Position emission tomography analysis using SUVmax showed significantly higher accumulation of (18)F-FDG in the tumor and the inflammatory lesions (7.19±2.11 and 4.66±0.63, respectively) compared to (18)F-FBPA (3.23±0.40 and 1.86±0.19, respectively) and (11)C-MET (3.39±0.43 and 1.63±0.11, respectively) (P<0.01 by Tukey test). No significant difference was observed between (18)F-FBPA and (11)C-MET. CONCLUSIONS: (18)F-FBPA showed high selectivity of LAT1 by in vitro cellular uptake analysis, suggesting the potential as a tumor-specific substrate. In vivo PET analysis showed significantly lower uptake of (18)F-FBPA and (11)C-MET in the inflammatory lesions compared to (18)F-FDG, suggesting comparable utility of (18)F-FBPA PET to (11)C-MET PET in differentiating between the tumor and the inflammation.