Safety evaluation of immune-cell therapy for malignant tumor in the Cancer Immune-cell Therapy Evaluation Group (CITEG).

BACKGROUND AIMS: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. METHODS: Medical information, such as patients' background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. RESULTS: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13-97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients' performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αßT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αßT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. CONCLUSIONS: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.

Normal and Range Value Evaluations Using Heart Risk View-Function Based on the Japanese Societyof Nuclear Medicine Working Group Database.

Background: Gated myocardial perfusion single-photon emission computed tomography (SPECT) has been used to non-invasively evaluate the left ventricular (LV) volume and function. This study aimed to measure the normal and range values for heart risk view-function (HRV-F) software using the Japanese Society of Nuclear Medicine Working Group (JSNM-WG) normal database and clarify the characteristics of the normal database. Methods:We used 206 myocardial perfusion short-axis images from the normal database. Ejection fraction (EF), end-systolic volume (ESV), end-diastolic volume (EDV), peak filling rate (PFR), 1/3 mean filling rate (MFR), time to PFR (TTPF), and TTPF divided by RR interval (TPFR/RR) were calculated. Phase parameters of 95% histogram bandwidth and standard deviation were also computed using the phase analysis. The relationships among phase parameters, LV volumes, and body surface area (BSA) were evaluated in the age group of ≤65 years. Results: Higher EF was observed in females than in males (p<0.0001). EDV and ESV were significantly higher in males than in females (p<0.0001). Additionally, PFR and 1/3 MFR significantly differed between sexes (p≤0.075). Phase parameters were higher in males than in females, and higher at stress than at rest. All diastolic parameters showed no significant differences between sexes in any age group, whereas differences have remained in phase values. Phase parameters were weakly correlated with EDV (r=0.31), ESV (r=0.43), and BSA (r=0.27), respectively. Conclusions: Mean normal and range values of the normal database were determined using the HRV-F software. The normal and range values can help diagnose gated SPECT data in patients with cardiac diseases.

Evaluation of skeletal muscle activity during foot training exercises using positron emission tomography.

The foot exercises "rock-paper-scissors" and "towel gathering" are widely used in patients with lower limb disorders; however, there are no detailed reports on muscle activity during such training. We quantitatively evaluated the difference in skeletal muscle activity between the two exercises using positron emission tomography. Eight university student athletes were included. Four participants each were assigned to the foot rock-paper-scissors and towel gathering groups. Participants in each group underwent continuous training for 15 min, and received an intravenous injection of 18F-fluorodeoxyglucose. After retraining for 15 min, participants rested for 45 min. Regions of interest were defined in 25 muscles. The standardized uptake value (SUV) in the trained limb was compared with that in the non-trained control limb. SUVs increased in four skeletal muscles (tibialis anterior, peroneus brevis, extensor hallucis brevis, and abductor hallucis) in the rock-paper-scissors group, and in four muscles (flexor digitorum longus, extensor hallucis brevis, extensor digitorum brevis, and quadratus plantae) in the towel gathering group. Thus, foot rock-paper-scissors and towel gathering involved skeletal muscles related to the medial longitudinal arch and toe grip strength, respectively. Given that the two exercises target different skeletal muscles, they should be taught and implemented according to their respective purposes.

Skeletal muscle metabolism on whole-body positron emission tomography during pitching.

BACKGROUND: Electromyography (EMG) has been used for evaluating skeletal muscle activity during pitching. However, it is difficult to observe the influence of movement on skeletal muscle activity in deep-lying regions of the trunk and extremities using EMG. An alternative method that may be used is the measurement of glucose metabolism of skeletal muscle using positron emission tomography-computed tomography (PET-CT). This technique is a reliable measure of muscle metabolism, demonstrating a high correlation with the intensity of muscle activity. This study aimed to evaluate whole-body skeletal muscle metabolism during pitching using PET-CT. METHODS: Ten uninjured, skilled, adult pitchers, who were active at college or professional level, threw 40 baseballs at maximal effort before an intravenous injection of 37 MBq of 18F-fluorodeoxyglucose (FDG). Subsequently, additional 40 balls were pitched. PET-CT images were obtained 50 min after FDG injection, and regions of interest were defined within 72 muscles. The standardized uptake value (SUV) of FDG by muscle tissue per unit volume was calculated, and the mean SUV of the pitchers was compared with that of a healthy adult control group who did not exercise before the measurements. Statistical analysis was performed using a t-test, and P < 0.05 was considered statistically significant. RESULTS: Whole-body PET images showed a significant increase in glucose metabolism in the muscle groups of the fingers and toes in both the throwing and non-throwing sides. Additionally, asymmetric increases in glucose metabolism were observed in the muscles of the thigh. CONCLUSIONS: This is the first study to evaluate whole-body muscle metabolism during pitching using PET-CT. Our findings would be useful in determining the training required for pitchers, and can be further applied to other sporting activities that involve throwing.

Effect of adoptive T-cell immunotherapy on immunological parameters and prognosis in patients with advanced pancreatic cancer.

BACKGROUND AIMS: Immunotherapy is effective for many types of cancer, but its benefits in advanced pancreatic cancer, which has a poor prognosis, are not well established. In this study, the authors examined the effects of adoptive T-cell immunotherapy (ATI) on immune cell profiles and prognosis in patients with unresectable advanced pancreatic cancer. METHODS: Seventy-seven patients with unresectable advanced pancreatic cancer were treated with six cycles of αß T cells alone or in combination with chemotherapy or chemoradiation. Immune cell profiles in peripheral blood samples obtained before and after treatment were comprehensively evaluated by flow cytometry. Furthermore, associations between changes in immune cell frequencies and prognosis were determined. RESULTS: ATI prolonged survival to 18.7 months compared with previous estimates of 6.2-11.1 months for patients treated with chemotherapy alone. ATI decreased CD3+CD4+CD8- T cell frequency in peripheral blood and increased CD3+CD4-CD8+ T cell frequency. An increase in CD3+ T cells and CD3+TCRγδ- T cells in peripheral blood after treatment was associated with a good prognosis. CONCLUSIONS: ATI altered the immune profile in peripheral blood, including CD3+CD4-CD8+ T cells, and improved prognosis in pancreatic cancer.

Effects of adaptive immune cell therapy on the immune cell profile in patients with advanced gastric cancer.

BACKGROUND: Immunotherapy for cancer patients has been the subject of attention in recent years. In this study, we investigated whether αßT-cell therapy causes changes in the host's immune cell profile, and if so, the effect of these changes on prognosis. METHODS: Peripheral blood mononuclear cells (PBMCs) from 30 gastric cancer patients who had completed one course of αßT-cell therapy were analyzed. The peripheral blood immune cell profile was established using PBMCs by counting the frequency of CD4+ helper T cells, CD8+ killer T cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells and measuring the expression of their surface markers. The changes after treatment and their association with response to treatment were investigated. RESULTS: Immune cell profiles changed greatly after treatment. The frequency of CD4+ helper T cells decreased, but that of CD8+ killer T cells increased. The frequency of programmed cell death 1 (PD-1)+ effector Tregs increased significantly, but only in the non-progressive disease (non-PD) group, in which it was significantly higher compared with the PD group. Patients in whom the frequency of PD-1+ effector Tregs increased had a significantly better prognosis than those in whom it decreased. CONCLUSION: Our results suggested that αßT-cell therapy changes the host's immune cell profile, and an increase in PD-1+ effector Tregs may help improve prognosis.

Reliability of the muscle strength measurement and effects of the strengthening by an innovative exercise device for the abdominal trunk muscles.

OBJECTIVE: We developed an innovative exercise device for the abdominal trunk muscles (ATMs) that has a built-in system to measure muscle strength. We aimed to examine the reliability of the strength measurement as well as the effect of strengthening using the device. METHODS: Twenty healthy adults participated in a reliability study of the muscle strength measurement. The first and second measurement were done in one day with an hour rest interval by raters 1 and 2, and the third by rater 1 following a one-week interval. We calculated the intraclass correlation coefficient (ICC). Another seven healthy men participated in a training program using the device, consisting of strengthening twice a week for 5 weeks. ATM strength was measured before and after the training period, and a positron emission tomography (PET) scan series was performed, consisting of examinations during rest before training (control condition) and during exercise after training (training condition). RESULTS: The intra-rater (ICC = 0.95) and inter-rater (ICC = 0.99) reliability of the strength measurement were excellent. ATM strength was significantly higher after training than before. 18F-fluorodeoxyglucose accumulation within the diaphragm, abdominal rectus, abdominal external and internal oblique, transverse abdominal, and levator ani muscles was significantly higher in the training condition than in the control. CONCLUSIONS: Our innovative device showed excellent reliability to quantify ATM strength. Strengthening using the device increased strength and activated the abdominals, diaphragm, and pelvic floor muscles.

Comparison of muscle activity, strength, and balance, before and after a 6-month training using the FIFA11+ program (part 2).

BACKGROUND: Sports injury prevention training programs have been reported to be effective in decreasing the incidence of injuries. The aim of this study was to evaluate the effects of a 6-month training period, using part 2 of the FIFA11+ program (the Fédération Internationale de Football), on the activation and strength of core and lower limb muscles and on static and dynamic balance performance. STUDY DESIGN: Case series; level of evidence, 4. METHODS: Eight college male soccer players, aged mean 20.4 ± 0.5 years old, completed the FIFA11+ program at least three times per week for 6 months. The following variables were measured both before and after the 6-month training program: activities of more than 30 muscles (core and lower limb muscles), measured using the standardized uptake values of 18F-fluorodeoxyglucose on positron emission tomography; isokinetic strength of the knee flexor and extensor and hip abductor muscles, measured at 60° s-1; static balance over a 60-s period, measured using a gravicorder; and dynamic balance, measured using the star excursion balance test. RESULTS: Training improved the activity levels of core (obliquus externus abdominis and erector spinae) and lower limb (tibialis anterior) muscles (p ≤ 0.03), corrected the between-limb difference in the activation of the semimembranosus and improved dynamic balance, with a greater training effect on the nondominant limb (p ≤ 0.02). Training also improved the knee flexor force of the nondominant lower limb (p = 0.02). CONCLUSION: Routine performance of the FIFA11+ program can improve the activation of core and lower limb muscles, with a concomitant improvement in dynamic balance. These improvements could be beneficial in lowering the risk of sports-related injuries.

Fully automated analysis for bone scintigraphy with artificial neural network: usefulness of bone scan index (BSI) in breast cancer.

OBJECTIVE: Artificial neural network (ANN) technology has been developed for clinical use to analyze bone scintigraphy with metastatic bone tumors. It has been reported to improve diagnostic accuracy and reproducibility especially in cases of prostate cancer. The aim of this study was to evaluate the diagnostic usefulness of quantitative bone scintigraphy with ANN in patients having breast cancer. PATIENTS AND METHODS: We retrospectively evaluated 88 patients having breast cancer who underwent both bone scintigraphy and 18F-fluorodeoxyglucose (FDG) positron-emission computed tomography/X-ray computed tomography (PET/CT) within an interval of 8 weeks between both examinations for comparison. The whole-body bone images were analyzed with fully automated software that was customized according to a Japanese multicenter database. The region of interest for FDG-PET was set to bone lesions in patients with bone metastasis, while the bone marrow of the ilium and the vertebra was used in patients without bone metastasis. RESULTS: Thirty of 88 patients had bone metastasis. Extent of disease, bone scan index (BSI) which indicate severity of bone metastasis, the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and serum tumor markers in patients with bone metastasis were significantly higher than those in patients without metastasis. The Kaplan-Meier survival curve showed that the overall survival of the lower BSI group was longer than that with the higher BSI group in patients with visceral metastasis. In the multivariate Cox proportional hazard model, BSI (hazard ratio (HR): 19.15, p = 0.0077) and SUVmax (HR: 10.12, p = 0.0068) were prognostic factors in patients without visceral metastasis, while the BSI was only a prognostic factor in patients with visceral metastasis (HR: 7.88, p = 0.0084), when dividing the sample into two groups with each mean value in patients with bone metastasis. CONCLUSION: BSI, an easily and automatically calculated parameter, was a well prognostic factor in patients with visceral metastasis as well as without visceral metastasis from breast cancer.

Efficacy and Limitations of F-18-fluoro-2-deoxy-D-glucose Positron Emission Tomography to Differentiate Between Malignant and Benign Bone and Soft Tissue Tumors.

BACKGROUND/AIM: Positron emission tomography (PET) using 18fluorine-labelled fluorodeoxyglucose (FDG), is the most widely applied molecular imaging technique in oncology. The present study assessed the efficacy and limitations of FDG-PET by comparing FDG accumulation in bone and soft tissue lesions, as well as histopathological features. PATIENTS AND METHODS: The study included 122 patients with 165 lesions, as assessed by histopathological examinations. The maximum standardized uptake values (SUVmax) of benign lesions were compared to those of primary, recurrent, or metastatic sarcomas, as well as those of other malignancies. RESULTS: The sensitivity, specificity, and accuracy of SUVmax for differentiation between benign lesions and primary sarcomas were 67.9%, 92.9%, and 80.4%, respectively. There were no significant differences between benign lesions and recurrent or metastatic sarcomas. CONCLUSION: Although FDG-PET is a useful imaging modality to differentiate primary sarcomas from benign lesions, it is difficult to differentiate residual or metastatic sarcomas from benign lesions.

Penetrative trace fossils from the late Ediacaran of Mongolia: early onset of the agronomic revolution.

The Cambrian radiation of complex animals includes a dramatic increase in the depth and intensity of bioturbation in seafloor sediment known as the 'agronomic revolution'. This bioturbation transition was coupled with a shift in dominant trace fossil style from horizontal surficial traces in the late Precambrian to vertically penetrative trace fossils in the Cambrian. Here we show the existence of the first vertically penetrative trace fossils from the latest Ediacaran: dense occurrences of the U-shaped trace fossil Arenicolites from late Precambrian marine carbonates of Western Mongolia. Their Ediacaran age is established through stable carbon isotope chemostratigraphy and their occurrence stratigraphically below the first appearance of the trace fossil Treptichnus pedum. These Arenicolites are large in diameter, penetrate down to at least 4 cm into the sediment, and were presumably formed by the activity of bilaterian animals. They are preserved commonly as paired circular openings on bedding planes with maximum diameters ranging up to almost 1 cm, and as U- and J-shaped tubes in vertical sections of beds. Discovery of these complex penetrative trace fossils demonstrates that the agronomic revolution started earlier than previously considered.

Innovative exercise device for the abdominal trunk muscles: An early validation study.

BACKGROUND: Exercise is one of the few treatments that provide significant improvements in chronic low back pain (CLBP). We developed an innovative exercise device for abdominal trunk muscles. This device can be used in a sitting or standing position and contains a built-in system to measure abdominal trunk muscle strength. We examined whether subjects can adequately use the device to perform the exercises and measure their abdominal trunk muscle strength. METHODS: We collected data on the body height, body weight, body mass index, and girth of 30 healthy male volunteers, and measured their grip power and trunk extensor muscle strength using a dynamometer. The volunteers performed a sit-up test as an indicator of trunk flexor muscle strength, and we measured their abdominal muscle strength using the device. We then evaluated the correlations between abdominal trunk muscle strength and anthropometric parameters as well as the strength of other muscles. In subsequent tests, 5 of the 30 subjects participated in two positron emission tomography (PET) series consisting of examinations after a resting period (control study) and during exercise (exercise study). For the exercise study, the subjects performed 2 sets of exercises for 20 minutes using the device before and after an injection of 18F-fluorodeoxyglucose (FDG). PET-computed tomography images were obtained 60 minutes after FDG injection in each study. We compared the skeletal muscle metabolism of the participants in both studies using the standardized uptake value. RESULTS: The muscle strength measured by the device and the 30-second sit-up frequency were correlated. FDG accumulation within the diaphragm and abdominal rectus muscles was significantly higher in the exercise study. CONCLUSION: Our innovative exercise device facilitates a coordinated contraction of the abdominal trunk muscles at the anterior aspect and the roof of the core, and enables subjects to measure the strength of these muscles.

Changes in muscle activity after performing the FIFA 11+ programme part 2 for 4 weeks.

Changes in muscle activity were evaluated by positron emission tomography-computed tomography (PET-CT) after performing part 2 of the Fédération Internationale de Football Association's 11+ programme (11+) for 4 weeks. Eleven males performed part 2 of the 11+ for 20 min before and after 37 MBq of (18)F-fluorodeoxyglucose (FDG) was injected intravenously. PET-CT images were obtained 50 min after FDG injection. The participants were then instructed to perform part 2 of the 11+ 3 times per week for 4 consecutive weeks, after which another set of PET-CT images was obtained following the same procedure. Regions of interest were defined within 30 muscles. The standardised uptake value (SUV) of FDG by muscle tissue per unit volume was calculated, and FDG accumulation was compared between pre- and post-training PET-CT results. Performing part 2 of the 11+ for 4 weeks increased mean SUV in the sartorius, semimembranosus, biceps femoris, abductor hallucis, and flexor hallucis brevis muscles (P < 0.05). In conclusion, routinely performing part 2 of the 11+ for 4 weeks increased glucose uptake related to muscle activity in the hamstrings and hallux muscles. We speculate that there is some possibility of this change of muscle activity contributing to a decrease in sports-related injuries.

Effects of the belt electrode skeletal muscle electrical stimulation system on lower extremity skeletal muscle activity: Evaluation using positron emission tomography.

BACKGROUND: Lower-extremity muscle weakness in athletes after lower limb trauma or surgery can hinder their return to sports, and the associated muscle atrophy may lead to deterioration in performance after returning to sports. Recently, belt electrode skeletal muscle electrical stimulation (B-SES) which can contract all the lower limb skeletal muscles simultaneously was developed. However, no study has evaluated skeletal muscle activity with B-SES. Since only superficial muscles as well as a limited number of muscles can be investigated using electromyography, we investigated whether positron emission tomography (PET) can evaluate the activity of all the skeletal muscles in the body simultaneously. The purpose of this study was to evaluate the effectiveness of the B-SES system using PET. METHODS: Twelve healthy males (mean age, 24.3 years) were divided into two groups. The subjects in the control group remained in a sitting position for 10 min, and [(18)F] fluorodeoxyglucose (FDG) was intravenously injected. In the exercise group, subjects exercised using the B-SES system for 20 min daily for three consecutive days as a pre-test exercise. On the measurement day, they exercised for 10 min, received an injection of FDG, and exercised for another 10 min. PET-computed tomography images were obtained in each group 60 min after the FDG injection. Regions of interest were drawn in each lower-extremity muscle. We compared each skeletal muscle metabolism using the standardized uptake value. RESULTS: In the exercise group, FDG accumulation in the gluteus maximus, gluteus medius, gluteus minimus, quadriceps femoris, sartorius, and hamstrings was significantly higher than the muscles in the control (P < 0.05). CONCLUSION: Exercise with B-SES increased the skeletal muscle activity of the gluteal muscles as well as the most lower-extremity muscles simultaneously.

Whole body muscle activity during the FIFA 11+ program evaluated by positron emission tomography.

PURPOSE: This study investigated the effect of the FIFA 11+ warm-up program on whole body muscle activity using positron emission tomography. METHODS: Ten healthy male volunteers were divided into a control group and a group that performed injury prevention exercises (The 11+). The subjects of the control group were placed in a sitting position for 20 min and 37 MBq of (18)F-fluorodeoxyglucose (FDG) was injected intravenously. The subjects then remained seated for 45 min. The subjects of the exercise group performed part 2 of the 11+for 20 min, after which FDG was injected. They then performed part 2 of the 11+for 20 min, and rested for 25 min in a sitting position. Positron emission tomography-computed tomography images were obtained 50 min after FDG injection in each group. Regions of interest were defined within 30 muscles. The standardized uptake value was calculated to examine the FDG uptake of muscle tissue per unit volume. RESULTS: FDG accumulation within the abdominal rectus, gluteus medius and minimus were significantly higher in the exercise group than in the control group (P<0.05). CONCLUSION: The hip abductor muscles and abdominal rectus were active during part 2 of the FIFA 11+ program.

Usefulness of fluorine-18 fluorodeoxyglucose-positron emission tomography in management strategy for thymic epithelial tumors.

BACKGROUND: This study investigated the usefulness of fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) during the treatment of thymic epithelial tumors in combination with Ki-67 evaluation based on surgical cases in our department. METHODS: Between November 2003 and May 2011, 39 patients with thymic epithelial tumor underwent preoperative FDG-PET. The maximum standardized uptake value (SUVmax) of each category within Masaoka stage, World Health Organization classification, tumor diameter, myasthenia gravis, and Ki-67 label index were compared. To examine risk factors for relapse, SUVmax, age, sex, and surgical radicality were investigated in addition to those items. RESULTS: The mean SUVmax was 4.5 (range, 1.2 to 14.6) and was significantly higher for Masaoka stage IV than for I and II (all p < 0.008) and for World Health Organization classified thymic cancer compared with all other types (all p < 0.0001). Mean SUVmax revealed significantly higher values for large tumors than for small tumors (p = 0.02). Mean SUVmax was significantly higher for high Ki-67-positive samples (p = 0.0004), indicating a strong correlation between SUVmax and the Ki-67 label index (ρ = 0.77, p = 0.0001). SUVmax accurately reflected therapeutic efficacy in patients with induction therapy. Univariate analysis revealed Masaoka stages III and IV and pathologically incomplete resection as risk factors for relapse. On multivariate analysis, independent risk factors for relapse comprised only Masaoka stages III and IV. CONCLUSIONS: FDG-PET SUVmax does reflect proliferation and invasiveness of thymic epithelial tumors and can provide an index for diagnosis and treatment, although it is not a risk factor for relapse. FDG-PET is also useful for evaluating induction therapy efficacy and detecting relapse.

Comparison of diagnostic value of I-123 MIBG and high-dose I-131 MIBG scintigraphy including incremental value of SPECT/CT over planar image in patients with malignant pheochromocytoma/paraganglioma and neuroblastoma.

PURPOSE: to compare lesion detectability of I-123 MIBG scintigraphy with that of high-dose I-131 MIBG and to evaluate incremental benefit of SPECT/CT over planar image for the detection and localization of the lesions in patients with I-131 MIBG therapy for malignant pheochromocytoma/paraganglioma and neuroblastoma. MATERIALS AND METHODS: we retrospectively investigated 16 patients with malignant pheochromocytoma/paraganglioma and neuroblastoma, who were referred for I-131 MIBG therapy. We investigated the lesion detectability in 10 pairs of I-123 and high-dose I-131 MIBG studies of the same patient, obtained within 2 weeks. In 31 studies of I-123 MIBG scintigraphy in 16 patients and 17 studies of high-dose I-131 MIBG scintigraphy in 12 patients, we compared planar and SPECT/CT images for the lesion detectability and localization. RESULTS: the number of lesions detected by I-123 MIBG planer image and SPECT/CT and high-dose planer I-131 MIBG and SPECT/CT were 3.0 and 3.7, 7.3 and 7.7 per study, respectively. SPECT/CT images provided additional diagnostic information over planar images in 25 studies (81%) of 12 patients (75%) in I-123 MIBG scintigraphy and in 9 studies (53%) of 9 patients (75%) in high-dose I-131 MIBG scintigraphy. CONCLUSION: post-therapy high-dose I-131 MIBG scintigraphy is superior to I-123 MIBG scintigraphy in lesion detectability even in comparison with I-123 MIBG SPECT/CT images and high-dose I-131 MIBG planar images in patients with malignant neuroendocrine tumors. SPECT/CT images are helpful for accurate identification of anatomic localization compared with planar images.

Biologic correlates of intratumoral heterogeneity in 18F-FDG distribution with regional expression of glucose transporters and hexokinase-II in experimental tumor.

UNLABELLED: The biologic mechanisms involved in the intratumoral heterogeneous distribution of 18F-FDG have not been fully investigated. To clarify factors inducing heterogeneous 18F-FDG distribution, we determined the intratumoral distribution of 18F-FDG by autoradiography (ARG) and compared it with the regional expression levels of glucose transporters Glut-1 and Glut-3 and hexokinase-II (HK-II) in a rat model of malignant tumor. METHODS: Rats were inoculated with allogenic hepatoma cells (KDH-8) into the left calf muscle (n = 7). Tumor tissues were excised 1 h after the intravenous injection of 18F-FDG and sectioned to obtain 2 adjacent slices for ARG and histochemical studies. The regions of interest (ROIs) were placed on ARG images to cover mainly the central (CT) and peripheral (PT) regions of viable tumor tissues and necrotic/apoptotic (NA) regions. The radioactivity in each ROI was analyzed quantitatively using a computerized imaging analysis system. The expression levels of Glut-1, Glut-3, and HK-II were determined by immunostaining and semiquantitative evaluation. The hypoxia-inducible factor 1 (HIF-1) was also immunostained. RESULTS: ARG images showed that intratumoral 18F-FDG distribution was heterogeneous. The accumulation of 18F-FDG in the CT region was the highest, which was 1.6 and 2.3 times higher than those in the PT and NA regions, respectively (P < 0.001). The expression levels of Glut-1, Glut-3, and HK-II were markedly higher in the CT region (P < 0.001) compared with those in the PT region. The intratumoral distribution of 18F-FDG significantly correlated with the expression levels of Glut-1, Glut-3, and HK-II (r = 0.923, P < 0.001 for Glut-1; r = 0.829, P < 0.001 for Glut-3; and r = 0.764, P < 0.01 for HK-II). The positive staining of HIF-1 was observed in the CT region. CONCLUSION: These results demonstrate that intratumoral 18F-FDG distribution corresponds well to the expression levels of Glut-1, Glut-3, and HK-II. The elevated expression levels of Glut-1, Glut-3, and HK-II, induced by hypoxia (HIF-1), may be contributing factors to the higher 18F-FDG accumulation in the CT region.

Detection of apoptotic tumor response in vivo after a single dose of chemotherapy with 99mTc-annexin V.

UNLABELLED: Annexin V, a human protein with a high affinity for phosphatidylserine, has been labeled with (99m)Tc to detect apoptosis in vivo. To determine the effectiveness of imaging with this agent as a reflection of the degree of apoptosis after the first dose of chemotherapy, we studied rats with an engrafted hepatoma. METHODS: Annexin V was labeled with (99m)Tc (specific activity, 3.0 MBq/ micro g protein). Eleven days after being inoculated with allogenic hepatoma cells (KDH-8) in the left calf muscle, the rats were randomized to receive a single dose of cyclophosphamide (150 mg/kg intraperitoneally) or to serve as controls. (99m)Tc-annexin V was injected 20 h later. Radioactivity in tissues was determined 6 h after injection of (99m)Tc-annexin V. Tumor uptake of (14)C-iodoanitpyrine was determined as a marker of tumor blood flow. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) of tissue harvested at necropsy was performed to detect apoptosis in the tumor. RESULTS: Cyclophosphamide treatment significantly increased the tumor uptake (percentage activity of injected dose per gram of tissue after normalization to the animal's weight [%ID/g/kg]) of (99m)Tc-annexin V (0.070 +/- 0.007 %ID/g/kg for treated rats and 0.046 +/- 0.009 %ID/g/kg for controls, P < 0.001). (14)C-iodoantipyrine uptake was similar in the treated and untreated groups. The number of TUNEL-positive cells in the tumor was significantly larger in the treated rats (297.70 +/- 50.34 cells/mm(2)) than in the control rats (168.45 +/- 23.60 cells/mm(2), P < 0.001). Tumor uptake of (99m)Tc-annexin V correlated with the number of TUNEL-positive cells in the tumor (r = 0.712; P < 0.001). CONCLUSION: Tumor uptake of (99m)Tc-annexin V was significantly increased by a single dose of cyclophosphamide treatment, and the increase was concordant with the number of TUNEL-positive cells in the tumor. The current results are suggestive of the utility of (99m)Tc-annexin V as a noninvasive means to assess tumor response, although further testing, including clinical evaluation, is required.