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
64
Cu and
...225
Ac-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 (
177
Lu)-labelled FAPI-46 and alpha-emitter (
225
Ac)-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
18
FFAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of
177
LuFAPI-46 and
225
AcFAPI-46 were evaluated in the xenograft model (total
n
= 12). For the determination of treatment effects,
177
LuFAPI-46 and
225
AcFAPI-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
177
LuFAPI-46, and 3 kBq (
n
= 3), 10 kBq (
n
= 2), 30 kBq (
n
= 6), control (
n
= 7) for
225
AcFAPI-46. Tumour sizes and body weights were followed.
Results
18
FFAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration.
177
LuFAPI-46 and
225
AcFAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both
177
LuFAPI-46 and
225
AcFAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of
177
LuFAPI-46 were relatively slow but lasted longer than those of
225
AcFAPI-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.
We present the guideline for use of
211
At sodium astatide (NaAt) for targeted alpha therapy in clinical trials on the basis of radiation safety issues in Japan. This guideline was prepared by a ...study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine on 8th Feb, 2021. The study showed that patients receiving
211
AtNaAt do not need to be admitted to a radiotherapy room and outpatient treatment is possible. The radiation exposure from the patient is within the safety standards of the ICRP and IAEA recommendations for the general public and caregivers. Precautions for patients and their families, safety management associated with the use of
211
AtNaAt, education and training, and disposal of medical radioactive contaminants are also included in this guideline. Treatment using
211
AtNaAt in Japan should be carried out according to this guideline. Although this guideline is applied in Japan, the issues for radiation protection and evaluation methodology shown here are considered internationally useful as well.
Objective
18
F-labeled prostate-specific membrane antigen (PSMA) ligand,
18
FPSMA-1007, has the benefit of a higher synthetic yield and minimal excretion in the urine. High detection efficacy was ...reported in biochemical recurrence (BCR) of prostate cancer after radical prostatectomy. Thus, we evaluated the preliminary diagnostic utility of
18
FPSMA-1007 PET in patients with prostate cancer, focusing on the BCR which is not detected on conventional imaging.
Methods
We enrolled a total of 28 patients (age 51–79 years) with BCR of prostate cancer. BCR was defined as a continuous increase in PSA after radical prostatectomy or radiation therapy without any apparent recurrent lesions on conventional diagnostic imaging (CT and bone scintigraphy). PSMA-PET scanning was performed approximately 60 min after intravenous injection of
18
FPSMA-1007 (259 ± 37 MBq). PSMA-PET images were evaluated for lesion detection as well as its relation to PSA values and location.
Results
Abnormal uptake, which was suspected to be recurrence or metastasis, was detected in 92.9% (26/28) of patients with BCR. The SUVmax was 8.4 ± 6.4 in local recurrence, 11.5 ± 11.8 in pelvic lymph nodes (LN), and 4.1 ± 1.6 in bone metastasis. The detection rates were 66.7% in the PSA group-1 (0.1–0.5 ng/mL), 85.7% in the PSA group-2 (0.5–1.0 ng/mL), and 100% in the PSA group-3 (above 1.0 ng/mL). Among the PET-positive BCR patients (
n
= 26), local recurrence was detected in 57.7% (15/26), pelvic LN in 42.3% (11/26), and bone metastasis in 15.4% (4/26). In 53% (8/15) of BCR patients who were suspected of local recurrence, focal uptake was detected adjacent to the bladder on
18
FPSMA-1007 PET. This suggested the significant advantage of having minimal physiological urine excretion.
Conclusions
18
FPSMA-1007 PET showed a high detection rate in recurrent and metastatic lesions. In patients with BCR, its high detection led to suitable treatment strategies, such as salvage radiation therapy or surgical removal of recurrent lymph nodes.
Trial registration
(UMIN Clinical Trials Registry) UMIN000037697.
We investigated the prognostic significance and the underlying mechanism of increased bone marrow (BM) 2-(
F) fluoro-2-deoxy-D-glucose as a tracer (FDG)-uptake in patients with gynecological cancer. ...A list of patients diagnosed with cervical, endometrial, and ovarian cancer from January 2008 to December 2014 were identified. Then, through chart reviews, 559 patients who underwent staging by FDG-positron emission tomography (PET)/computed tomography (CT) and subsequent surgical resection were identified, and their clinical data were reviewed retrospectively. BM FDG-uptake was evaluated using maximum standardized uptake value (SUVmax) and BM-to-aorta uptake ratio (BAR). As a result, we have found that increased BAR was observed in 20 (8.7%), 21 (13.0%), 21 (12.6%) of cervical, endometrial, and ovarian cancer, respectively, and was associated with significantly shorter survival. Increased BAR was also closely associated with increased granulopoiesis. In vitro and in vivo experiments revealed that tumor-derived granulocyte colony-stimulating factor (G-CSF) was involved in the underlying causative mechanism of increased BM FDG-uptake, and that immune suppression mediated by G-CSF-induced myeloid-derived suppressor cells (MDSCs) is responsible for the poor prognosis of this type of cancer. In conclusion, increased BM FDG-uptake, as represented by increased BAR, is an indicator of poor prognosis in patients with gynecological cancer.
Resting-state networks (RSNs) exhibit spontaneous functional connectivity in the resting state. Previous studies have evaluated RSNs mainly based on spontaneous fluctuations in blood oxygenation ...level-dependent (BOLD) signals during functional magnetic resonance imaging (fMRI). However, separation between regional increases in cerebral blood flow (CBF) and oxygen consumption is theoretically difficult using BOLD-fMRI. Such separation can be achieved using quantitative
O-gas and water positron emission tomography (PET). In addition,
F-FDG PET can be used to investigate functional connectivity based on changes in glucose metabolism, which reflects local brain activity. Previous studies have highlighted the feasibility and clinical usefulness of
F-FDG-PET for the analysis of RSNs, and recent studies have utilized simultaneous PET/fMRI for such analyses. While PET provides seed information regarding the focus of the abnormalities (e.g., hypometabolism and reduced target binding), fMRI is used for the analysis of functional connectivity. Thus, as PET and fMRI provide different types of information, integrating these modalities may aid in elucidating the pathological mechanisms underlying certain diseases, and in characterizing individual patients.
Objective
Astatine (
211
At) is a promising alpha emitter as an alternative to iodine (
131
I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated ...thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of
211
AtNaAt to determine the FIH dose.
Methods
211
AtNaAt solution was injected into normal 6-week-old mice (male (
n
= 50) and female (
n
= 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (
n
= 20), 20 MBq/kg (
n
= 20), 50 MBq/kg (
n
= 30), saline control (
n
= 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity:
n
= 80) or 14 days (
n
= 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups.
Results
No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of
211
AtNaAt.
Conclusions
In the extended single-dose toxicity study of
211
AtNaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.
Somatic stem cell (SC) therapy can improve cardiac performance following ischemic injury. In this study, we investigated whether induced pluripotent SC-derived cardiomyocytes (iPS-CMs) are more ...effective than somatic SCs, such as skeletal myoblasts (SM) and mesenchymal (M)SCs, in promoting functional recovery upon transplantation in a porcine model of myocardial infarction.
Myocardial injury was induced by ameroid ring placement in immunosuppressed female mini pigs; after 1 month, epicardial cell transplantation was performed with iPS-CMs (n = 7), SMs (n = 7), and MSCs (n = 7). Control pigs underwent sham operation (n = 8).
Cell therapy improved functional recovery 2 months after myocardial infarction, as evidenced by increased ejection fraction (iPS-CM, +7.3% ± 2.2% and SM, +5.8% ± 5.4% vs control, -4.4% ± 3.8%; P < 0.05). The analysis of regional contractile function in the infarcted zone revealed an increase in transverse peak strain (iPS-CM, +4.6% ± 2.2% vs control, -3.8% ± 4.7%; P < 0.05). The C-11 acetate kinetic analysis by positron emission tomography showed that the work-metabolic cardiac energy efficacy increased by the transplantation of iPS-CMs, but was reduced by the other cell types. This was accompanied by decreased myocardial wall stress in the infarcted zone (iPS-CM, -27.6 ± 32.3 Pa and SM, -12.8 ± 27 Pa vs control, +40.5 ± 33.9 Pa; P < 0.05).
The iPS-CM is superior to other somatic cell sources in terms of improving regional contractile function and cardiac bioenergetic efficiency, suggesting greater clinical benefits in severely damaged myocardium.
In 1942, eighty years ago, Dr. Hertz first conducted radioiodine (RAI) diagnosis and therapy for thyroid disorders followed later by the successful treatment of thyroid cancer patients using RAI. In ...2022, memorial 80 years later, alpha emitter astatine (
211
At), an analogue for iodine, was successfully administered to a patient with refractory thyroid cancer in Japan as a phase-1 clinical trial (first-in-human). Over the past two decades, the use of
68
Ga labeled peptides for somatostatin receptor (SSTR)-targeted PET imaging followed by beta or alpha emitters labeled SSTR-analogues for peptide receptor radionuclide therapy (PRRT) has demonstrated remarkable success in the management of neuroendocrine neoplasms. In addition, theranostics targeting prostate-specific membrane antigen (PSMA) have dramatically changed the management and treatment of advanced prostate cancer patients. Novel radionuclides and new targets, ligands targeting the tumor microenvironment, optimized peptides and antibodies, combinations of radioligands with immunotherapy, radioprotectors and radiosensitizers as well as new delivery strategies are currently systematically explored. Now the dream of conquering cancer, that Saul Hertz began eight decades ago is coming to fruition.
This study assessed the possibility of semi-automatic harmonization of standardized uptake values (SUVs) in multicenter studies. Phantom data were acquired using 16 PET/CT scanners (including 3 ...PET/CT scanners with a silicon photomultiplier detector). PET images obtained using 30-min/bed scans for optimum harmonization filter calculations and using 90-180-s/bed scans for SUV validation under clinical conditions were obtained. Time of flight and a reconstruction method with point-spread function correction were allowed. The optimal full width at half maximum of the 3D-Gaussian filter that minimizes the root mean square error with the median value of the JSNM harmonization range was calculated semi-automatically. The SUVmax and the SUVpeak of the hot spheres were measured, and the inter-scanner coefficient of variation (COV) was calculated before and after harmonization. The harmonization filter was applied to 11 of the 15 PET/CT scanners in which the SUV calibration accuracy had been verified, but not in the remaining 4 scanners. Under noiseless conditions before harmonization, the inter-scanner COVs of the SUVmax and the SUVpeak were as high as 21.57% and 12.20%, respectively, decreasing to 8.79% and 5.73% after harmonization, respectively. Harmonization brought the SUVmax of all the hot spheres to within the harmonization range. Even under clinical conditions affected by image noise, the inter-scanner COVs for the SUVmax and SUVpeak were as high as 8.83% and 5.18% after harmonization, respectively. By applying an optimal harmonization filter that is calculated semi-automatically, the harmonization of SUVs according to the JSNM strategy is possible in multicenter studies, thereby reducing inter-scanner COVs.
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