Combined visual and quantitative assessment of somatostatin receptor scintigraphy for staging and restaging of neuroendocrine tumors.

PURPOSE: Somatostatin receptor scintigraphy (SRS) using 111In-DTPA-DPhe1-octreotide (pentetreotide) has become an integral part of neuroendocrine neoplasm management. The lack of precise quantification is a disadvantage of SRS. This study aimed to adapt the standardized uptake value (SUV) to SRS, establish the SUV range for physiological uptake in the liver, kidney, and spleen, and elucidate the utility of combined visual and quantitative SRS assessment for staging and restaging of neuroendocrine tumors (NETs). MATERIALS AND METHODS: This study included 21 patients with NETs who underwent 111In-pentetreotide SRS. The SUV of physiological and pathological uptake was calculated using bone single-photon emission computed tomography (SPECT) quantitative analysis software (GI-BONE). For visual analysis, the primary and metastatic lesions were scored visually on planar and SPECT images using a five-point scale. We assessed the relationships between the SUVs of the liver, kidney, and spleen in the dual phase, and among quantitative indices, visual score, and pathological lesions classification. RESULTS: Sixty-three NEN lesions were evaluated. The mean ± standard deviation maximum SUVs (SUVmax) were liver: 4 h, 2.6 ± 1.0; 24 h, 2.2 ± 1.0; kidney: 4 h, 8.9 ± 1.8; 24 h, 7.0 ± 2.0; and spleen; 4 h, 11.3 ± 4.5; 24 h, 11.5 ± 7.6. Higher SUVmax was significantly associated with higher visual scores on dual-phase SPECT (4 h, p < 0.001; 24 h, p < 0.001) (4 h: scores 3 and 4, p < 0.05; scores 3 and 5: p < 0.01; scores 4 and 5: p < 0.01; 24 h: scores 3 and 4, p = 0.0748; scores 3 and 5: p < 0.01; scores 4 and 5: p < 0.01). CONCLUSION: We adapted the SUV to SRS and established the range of SUV for physiological uptake in the liver, kidney, and spleen. Combined visual and quantitative assessment is useful for imaging individual lesions in greater detail, and may serve as a new tumor marker of SRS for staging and restaging of NETs.

Early Prediction of Radiotherapeutic Efficacy in a Mouse Model of Non-Small Cell Lung Carcinoma Using 18F-FLT and 18F-FDG PET/CT.

This study investigated the usefulness of [18F]-3'-deoxy-3'-fluorothymidine (18F-FLT) and [18F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) imaging for predicting the therapeutic efficacy of non-small cell lung cancer (NSCLC) irradiation at an early stage after radiation treatment. Mice were xenografted with the human lung adenocarcinoma line A549 or large cell lung cancer line FT821. Tumour uptake of 18F-FLT and 18F-FDG was imaged using PET/CT before and 1 week after irradiation. In A549 tumours, 18F-FLT uptake was significantly decreased, and 18F-FDG uptake was unchanged post-irradiation compared with pre-irradiation. In FT821 tumours, uptake of both 18F-FLT and 18F-FDG uptake was substantially decreased post-irradiation compared with pre-irradiation. In both xenografts, tumour volumes in the irradiated groups were significantly decreased compared with those in the control group. 18F-FLT is expected to contribute to individual NSCLC therapy because it accurately evaluates the decrease in tumour activity that cannot be captured by 18F-FDG. 18F-FDG may be useful for evaluating surviving cells without being affected by the inflammatory reaction at an extremely early stage, approximately 1 week after irradiation. Combined use of 18F-FLT and 18F-FDG PET/CT imaging may increase the accurate prediction of radiotherapy efficacy, which may lead to improved patient outcomes and minimally invasive personalised therapy. J. Med. Invest. 70 : 361-368, August, 2023.

New quantitative indices of cardiac amyloidosis with 99mTc-pyrophosphate scintigraphy.

PURPOSE: Amyloid light chain (AL) and transthyretin (ATTR) are the major subtypes of cardiac amyloidosis (CA). 99mTc-pyrophosphate (PYP) scintigraphy is used to differentiate ATTR from other CA subtypes. We adapted the standardized uptake value (SUV) for 99mTc-PYP and proposed two quantitative indices, amyloid deposition volume (AmyDV) and total amyloid uptake (TAU). This study aimed to evaluate the utility of these quantitative indices in differentiating ATTR from non-ATTRs. MATERIALS AND METHODS: Before the SUV measurement, the Becquerel calibration factor (BCF) of 99mTc was obtained by a phantom experiment. Thirty-two patients who had undergone hybrid SPECT/CT imaging 3 h after injection of 99mTc-PYP (370 MBq) were studied. CT attenuation correction for image reconstruction was applied in all. We calculated SUV, AmyDV, and TAU using a quantitative analysis software program for bone SPECT (GI-BONE) and analyzed AmyDV using two methods: threshold method (set 40%); and constant value method (average SUVmax of ribs). We assessed the diagnostic ability of heart-to-contralateral lung (H/CL) ratio, SUV, AmyDV, and TAU to differentiate ATTR from non-ATTR using receiver operating characteristic (ROC) analysis. RESULTS: Statistically significant differences in all quantitative indices were observed between ATTR and non-ATTR. The area under the curve of each quantitative index for discriminating between ATTR and non-ATTR were as follows: H/CL, 0.997; SUVmax, 0.953; SUVmean (M1), 0.964; SUVmean (M2), 0.969; AmyDV (M1), 0.875; AmyDV (M2), 0.974; and TAU, 0.974. The AmyDV (M2) had higher diagnostic ability than AmyDV (M1). Thus, TAU was calculated as AmyDV (M2) × SUVmean (M2). In the ROC curve, SUV, AmyDV, and TAU had almost the same diagnostic ability as H/CL in distinguishing ATTR from non-ATTRs. CONCLUSIONS: We propose two novel 3D-based quantitative parameters (AmyDV and TAU) that have almost equal ability to discriminate ATTR from non-ATTR.

Effect of different examination conditions on image quality and quantitative value of amyloid positron emission tomography using 18F-flutemetamol.

OBJECTIVE: The recommended start time for 18F-flutemetamol amyloid positron emission tomography (PET) examination is 60-120 min after 18F-flutemetamol injection, while an acquisition time of 10-30 min is generally recommended. We aimed to elucidate the effects of different examination conditions on image quality, diagnostic ability, and quantitative value of amyloid PET using 18F-flutemetamol. METHODS: We acquired data on a Discovery PET/computed tomography 710 scanner using Hoffman brain and pillar phantoms with 20 MBq of 18F for 30 min. The images were reconstructed into 10-, 20-, and 30-min periods. The ordered subset-expectation maximization algorithm was used for image reconstruction, which uses a 2- or 4-mm Gaussian filter and a combination of iteration and subset numbers. The percentage contrast and coefficient of variation (CV; as the image noise) were used as physical evaluation indices for reconstructed images, and images with superior contrast and low image noise were selected for clinical evaluation. The imaging data of 15 symptomatic patients (n = 7 and n = 8 for positive and negative diagnoses of Alzheimer's disease, respectively) were reconstructed under the phantom study conditions. Radiographers visually evaluated and ranked the clinical images based on the overall contrast and image noise, and nuclear medicine specialists diagnosed Alzheimer's disease. We compared the standardized uptake value ratio (SUVR) obtained with different acquisition conditions. RESULTS: The basic study using the phantom revealed high convergence of contrast and image noise in five patterns of acquisition time and filter strengths. Regarding visual evaluation, the use of a 2-mm Gaussian filter caused difficulties in diagnosis because the brain parenchymal accumulation was mottled with high image noise. Differences in image quality and diagnostic ability due to different examination times were not significant. Differences in the SUVR were not significant in patients with a negative Alzheimer's disease diagnosis; in patients with a positive diagnosis, the SUVR showed significant fluctuation depending on the acquisition conditions. CONCLUSION: The differences in image quality and diagnostic performance due to the differences in 10-min acquisition time were not significant; however, of note, SUVR showed significant fluctuation depending on the acquisition conditions in patients diagnosed with Alzheimer's disease.

A new quantitative index in the diagnosis of Parkinson syndrome by dopamine transporter single-photon emission computed tomography.

OBJECTIVE: Dopamine transporter single-photon emission computed tomography (DAT SPECT) has been widely used to diagnose Parkinson syndrome. Using the standardized uptake value (SUV) of DAT SPECT, we propose "functional dopamine transporter volume (f-DTV)" as a new quantitative index to evaluate the three-dimensional volume of functional dopamine transporters and assess its diagnostic ability in differentiating dopaminergic neurodegenerative diseases (dNDD) from non-dNDD. METHODS: Seventy-nine patients were enrolled (42 dNDD, 37 non-dNDD; 38 men; age 24-88 years). We analyzed seven quantitative indices. The specific binding ratio (SBR) was calculated using a program specialized for DAT SPECT (SBR_Bolt). The SUVmax, SUVpeak, and SUVmean were calculated using a quantification program for bone SPECT. SBR_SUV was calculated by dividing striatal SUVmean by the average of background SUVmean. The cutoff value of the active dopamine transporter level was examined using three methods (threshold of 40% of SUVmax, SUV 2, and SUV 3) to calculate the active dopamine transporter volume (ADV). The f-DTV was calculated by multiplying ADV and SUVmean. We assessed the correlations between SBR_Bolt and SBR_SUV, and compared the mean value of each index between the dNDD and non-dNDD groups. The abilities of SBR_Bolt, SBR_SUV, SUVmax, SUVpeak, SUVmean, ADV, and f-DTV in differentiating dNDD from non-dNDD were determined by the area under the receiver operating curve (AUC) generated by the receiver operating characteristics analysis. RESULTS: The SBR_Bolt and SBR_SUV highly correlated with each other (r = 0.71). The cutoff value of the active dopamine transporter level was determined as SUV 3. All seven quantitative indices showed lower values in the dNDD group than in the non-dNDD group, and the difference between the two groups was statistically significant (p < 0.05). Sensitivity, specificity, and AUC of f-DTV were slightly lower than those of SBR_Bolt (71%, 79%, and 0.81, respectively, for f-DTV, and 81%, 84%, 0.88, respectively, for SBR_Bolt). The difference in AUC between f-DTV and SBR_Bolt was not statistically significant. CONCLUSIONS: This study demonstrates the utility of f-DTV as a novel quantitative index for evaluating the three-dimensional volume of functional dopamine transporters, and that f-DTV has almost the same diagnostic ability to differentiate dNDD from non-dNDD using DAT SPECT.

Non­invasive monitoring of paclitaxel and lenvatinib efficacy against anaplastic thyroid cancer in orthotopic SCID mouse models using small­animal FDG­PET/CT.

Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid carcinoma with a poor prognosis. Thus, suitable preclinical tumor models are required for the development of new ATC therapies. In the present study, orthotopic tumor xenograft models were established using ATC cell lines and SCID mice, and tumor invasion and the effects of anticancer drugs were evaluated using positron emission tomography/computed tomography (PET/CT) to repeatedly and non­invasively monitor these models. Three ATC cell lines (8305c, 8505c, and ACT­1) were used. Their sensitivities to two anticancer drugs (paclitaxel and lenvatinib) were investigated. The 8505c cell line was orthotopically implanted into SCID mice, which were then divided into three groups: No chemotherapy, paclitaxel (5 mg/kg, administered intraperitoneally, every week), and lenvatinib (5 mg/kg, oral route, every day) groups. PET/CT was performed and tumor growth and the effects of anticancer drugs based on tumor volume and fludeoxyglucose (FDG) uptake were evaluated. 8505c cells exhibited the highest sensitivity to the anticancer drugs. In mice implanted with 8505c cells, continuous increases in FDG uptake associated with tumor growth were detected on PET/CT in the group that received no chemotherapy. The tumor volume and FDG uptake increased by 91.5­ and 2.4­fold, respectively, within 2 weeks. The increase observed in tumor volume was 26.9­ and 12.2­fold in the paclitaxel and lenvatinib groups, respectively, within 2 weeks. Furthermore, the increase in FDG uptake was 1.8 and 1.6­fold in the paclitaxel and lenvatinib groups, respectively, within 2 weeks. In our orthotopic SCID mouse model, tumor growth and the effects of anticancer drugs were repeatedly and non­invasively monitored using PET/CT. The present method is useful for the development of new ATC treatments.

Assessment of insulin resistance in the skeletal muscle of mice using positron emission tomography/computed tomography imaging.

Measuring glucose uptake in the skeletal muscle in vivo is an effective method to determine glucose metabolism abnormalities as the skeletal muscle is the principal tissue responsible for glucose disposal and is a major site of peripheral insulin resistance. In this study, we investigated the pathological glucose metabolism dynamics of the skeletal muscle of C57BL/6J mice in a noninvasive and time-sequential manner using positron emission tomography/computed tomography (PET/CT), an imaging technique that uses radioactive substances to visualize and measure metabolic processes in the body, with [18F]-fluoro-2-deoxy-D-glucose (FDG). FDG-PET/CT imaging revealed that insulin administration and exercise load significantly increased FDG accumulation in the skeletal muscle of C57BL/6J mice. FDG accumulation was lower in the skeletal muscle of 14-week-old db/db diabetic model mice exhibiting remarkable insulin resistance compared to that of 7-week-old db/db mice. Based on the continuous observation of FDG accumulation over time in diet-induced obese (DIO) mice, FDG accumulation significantly decreased in 17-week-old mice after the acquisition of insulin resistance. Although insulin-induced glucose uptake in the skeletal muscle was markedly attenuated in 20-week-old DIO mice that had already developed insulin resistance, exercise load effectively increased FDG uptake in the skeletal muscle. Thus, we successfully confirmed that glucose uptake accompanied by insulin administration and exercise load increased in the skeletal muscle using PET-CT. FDG-PET/CT might be an effective tool that could noninvasively capture the chronological changes of metabolic abnormalities in the skeletal muscle of mice.

Non­invasive monitoring of cisplatin and erlotinib efficacy against lung cancer in orthotopic SCID mouse models by small animal FDG­PET/CT and CT.

We established patient­like models of lung cancer metastasis by orthotopically implanting human non­small cell lung cancer cell lines into SCID mice. We evaluated the utilities of small­animal computed tomography (CT) and positron­emission tomography­computed tomography (PET/CT) in these models to non­invasively and repeatedly monitor the anticancer effects of cisplatin and erlotinib. We orthotopically implanted three non­small cell lung cancer cell lines, A549, FT821 and PC­9, into SCID mice. These mice were then divided into three groups: Control, cis­diamminedichloroplatinum (II) (CDDP) (7­mg/kg CDDP, single administration intraperitoneally), and erlotinib (25 mg/kg erlotinib/day, oral administration 5 days/week). After treatment initiation, we repeatedly performed PET/CT and CT measurements and assessed anticancer effects based on tumor volumes and FDG uptake. A549 tumors were not affected by CDDP or erlotinib. FT821 tumors were highly responsive to CDDP. PC­9 tumors, which have an epidermal growth factor receptor mutation, were highly responsive to erlotinib. Histological results and metastatic rates correlated with the anticancer effects shown by CT. In our orthotopic SCID mouse lung cancer models, 18FDG­PET/CT and CT imaging non­invasively and repeatedly monitored the efficacies of cisplatin and erlotinib against not only implanted tumors, but also mediastinal lymph node metastases.

Preparation of New Scintillation Imaging Material Composed of Scintillator-Silica Fine Powders and its Imaging of Tritium.

A new scintillation imaging material [scintillator-silica fine powder (FP)] was prepared using silica FPs and scintillator-encapsulating silica nanoparticles (NPs) (scintillator-silica NPs). The wt% values of scintillator-silica NPs on the scintillator-silica FPs were 38, 43, 36 and 44%. Scintillation images of 3H, 63Ni, 35S, 33P, 204Tl, 89Sr and 32P dropped on the scintillator-silica FPs were obtained at about 37 kBq per 0.1-10 µl with a charge-coupled device (CCD) imager for a 5 min exposure. In particular, high-intensity CCD images of 35S were selectively obtained using the 2.25, 4.77 and 10 µm silica FPs with scintillator-silica NPs owing to the residual S of dimethyl sulfoxide in the preparation. Scintillation images of 3H at 1670 ± 9 Bq/0.5 µl and 347 ± 6 Bq/0.5 µl dropped in a 2 mm hole on the scintillator-silica FPs (6.78 and 10 µm) were also obtained using the CCD imager for a 2 h exposure.

Effects of dietary phosphate on glucose and lipid metabolism.

Recent epidemiological and animal studies have suggested that excess intake of phosphate (Pi) is a risk factor for the progression of chronic kidney disease and its cardiovascular complications. However, little is known about the impact of dietary high Pi intake on the development of metabolic disorders such as obesity and type 2 diabetes. In this study, we investigated the effects of dietary Pi on glucose and lipid metabolism in healthy rats. Male 8-wk-old Sprague-Dawley rats were divided into three groups and given experimental diets containing varying amounts of Pi, i.e., 0.2 [low Pi(LP)], 0.6 [control Pi(CP)], and 1.2% [high Pi(HP)]. After 4 wk, the HP group showed lower visceral fat accumulation compared with other groups, accompanied by a low respiratory exchange ratio (V̇CO2/V̇O2) without alteration of locomotive activity. The HP group had lower levels of plasma insulin and nonesterified fatty acids. In addition, the HP group also showed suppressed expression of hepatic lipogenic genes, including sterol regulatory element-binding protein-1c, fatty acid synthase, and acetyl-CoA carboxylase, whereas there was no difference in hepatic fat oxidation among the groups. On the other hand, uncoupling protein (UCP) 1 and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression were significantly increased in the brown adipose tissue (BAT) of the HP group. Our data demonstrated that a high-Pi diet can negatively regulate lipid synthesis in the liver and increase mRNA expression related to lipid oxidation and UCP1 in BAT, thereby preventing visceral fat accumulation. Thus, dietary Pi is a novel metabolic regulator.

Tumor growth-inhibitory effect of an angiotensin-converting enzyme inhibitor (captopril) in a lung cancer xenograft model analyzed using 18F-FDG-PET/CT.

INTRODUCTION: We administered an angiotensin-converting enzyme inhibitor (captopril) to mice implanted with a human lung adenocarcinoma epithelial cell line (A549 cells) and investigated the tumor growth-inhibitory effect of captopril from the viewpoint of glucose metabolism using (18)F-fluorodeoxyglucose ((18)F-FDG)-PET/CT. METHODS: Subcutaneous implantation of A549 cells (1.9×10(6) cells) was carried out in the lower right flank of mice. Fifteen days after the transplantation of A549 cells, mice (six in each group) were treated with captopril (3.0 mg/mouse) or saline (1000 µl/mouse) for 5 days. We performed (18)F-FDG-PET/CT imaging of the mice before and after the treatment and evaluated the degree of (18)F-FDG accumulation in tumors. In both groups (the captopril-administrated and control groups), values for the metabolic tumor volume (MTV), maximum standardized uptake value, total lesion glycolysis, and tumor volume after treatment had a tendency to increase. However, tumor growth was suppressed in the captopril-administrated group compared with the control group. RESULTS: In terms of the growth rate, the MTV and tumor volume were significantly different (P<0.05). It was found that captopril exerted a potential tumor growth-inhibitory effect; this was because the captopril-administrated group showed low values of MTV, maximum standardized uptake value, total lesion glycolysis, and tumor volume in comparison with the control group.

Utility of respiratory-gated small-animal PET/CT in the chronologic evaluation of an orthotopic lung cancer transplantation mouse model.

Our aim in this study was to clarify the effects of respiratory-gated PET in the evaluation of lung cancer according to the (18)F-FDG uptake in an orthotopic transplantation mouse model. We created such a model, and we performed PET/CT. The mice were divided into two groups according to tumor volume: a small-tumor group (<20 mm(3)) and a large-tumor group (>20 mm(3)). We reconstructed the following conditions based on list-mode data: non-gated (3D) images and gated (4D) images, divided based on the respiratory cycle (expiration phase, stable phase, and inspiration phase). We calculated the maximum standardized uptake values (SUVmax) in each phase. We used the % difference [= (4D SUVmax - 3D SUVmax)/3D PET SUVmax × 100 (%)] to evaluate the differences in the 4D SUVmax and 3D SUVmax. The 4D SUVmax values were significantly higher than the 3D SUVmax, regardless of the tumor size. The % difference for the small tumors was greater than that for the large tumors, and it was highest in the stable phase. We conclude that the SUVmax in the stable phase under respiratory-gated PET are the most reliable. The SUVmax observed under non-gated PET are considered to be more frequently underestimated in cases involving small tumors than in those involving large tumors. In the chronologic study evaluating the time course of tumor development, the size of the tumor is small in early stage, and respiratory-gated PET is effective in reducing the underestimation of such tumors caused by respiratory motion.

The impact of self-shielded cyclotron operation on small-animal PET/CT equipment installed nearby, on the floor just above.

PURPOSE: The purpose of this study was to evaluate the impact of a cyclotron on small-animal PET equipment installed directly above the cyclotron. METHODS: The cyclotron equipment was HM-12, which has two targets, and the PET/CT equipment was Inveon. The equipment was installed in conformity to Japanese law and regulations. Before installation of the PET/CT equipment, the radiation dose, radio waves, and static and fluctuating magnetic fields were measured at the position where it would be placed, both when the cyclotron was in use and when it was not in use. After installation of the PET/CT, natural background and emission counts were measured at the same place under the same conditions. RESULTS: An increase of radiation dose was observed when the target nearest the PET equipment was used. There were no distinct effects of radio waves or static and fluctuating magnetic fields. A significant increase of emission counts, approximately 300 cpm, was observed when the nearest target was used. CONCLUSIONS: Though radio waves and static and fluctuating magnetic fields generated by running cyclotron had no influence, a significant increase in emission count was observed. Careful attention should be paid to this influence when very low-radioactivity PET measurements are done.