Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, ⁶⁴Cu (half-life, 12.7 h) and ²²⁵Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of ⁶⁴Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of ⁶⁸Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, ²²⁵Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of ⁶⁴Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of ⁶⁴Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for ⁶⁴Cu-FAPI-04 than for ⁶⁸Ga-FAPI-04, except in the heart, and excretion in the urine was higher for ⁶⁸Ga-FAPI-04 than for ⁶⁴Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. ²²⁵Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that ⁶⁴Cu-FAPI-04 and ²²⁵Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

Study Design. Cross-sectional study. Objective. To investigate the prevalence, concomitance, and distribution of various types of ossification of the spinal ligaments in healthy subjects using computed tomography (CT). Summary of Background Data. CT has better diagnostic accuracy for ossification of the spinal ligaments compared to plain radiography. Currently there is no study that examines the prevalence of ossification of the spinal ligaments using whole spine CT scans. Methods. One thousand five hundred Japanese patients (888 men and 612 women) who underwent positron emission tomography and CT (PETCT) in a private health check center between 2006 and 2013 were included. This PETCT was performed on self-paying participants as a preventive cancer screen. Existence of ossification of the posterior longitudinal ligament (OPLL), ligamentum flavum (OLF), anterior longitudinal ligament (OALL), diffuse idiopathic skeletal hyperostosis (DISH), and nuchal ligament (ONL) was examined. Results. The prevalence of spinal ligament ossifications was found to be 6.3% in cervical OPLL (8.3% in men and 3.4% in women), 23% in ONL (33% in men and 8.8% in women), 1.6% in thoracic OPLL (1.4% in men and 2.0% in women), 12% in thoracic OLF (15% in men and 7.7% in women), 37% in thoracolumbar OALL (45% in men and 26% in women), and 12% in DISH (16% in men and 6.2% in women). Thirteen percent of patients with cervical OPLL had thoracic OPLL, 34% of cervical OPLL had thoracic OLF, 45% of cervical OPLL had ONL, and 36% of cervical OPLL had DISH. The most common level was C5 for cervical OPLL, T1/2 for thoracic OPLL, T11 for thoracic OLF, and T8/9 for OALL. Conclusion. Accurate prevalence of various types of ossification of the spinal ligaments evaluated by CT was revealed. High concomitance was observed in each classification of spinal ligament ossification. Level of Evidence: 3

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.

A fibroblast activation protein (FAP) is an atypical type II transmembrane serine protease with both endopeptidase and post-proline dipeptidyl peptidase activity. FAP is overexpressed in cancer-associated fibroblasts (CAFs), which are found in most epithelial tumors. CAFs have been implicated in promoting tumor cell invasion, angiogenesis and growth and their presence correlates with a poor prognosis. However, FAP can generally be found during the remodeling of the extracellular matrix and therefore can be detected in wound healing and benign diseases. For instance, chronic inflammation, arthritis, fibrosis and ischemic heart tissue after a myocardial infarction are FAP-positive diseases. Therefore, quinoline-based FAP inhibitors (FAPIs) bind with a high affinity not only to tumors but also to a variety of benign pathologic processes. When these inhibitors are radiolabeled with positron emitting radioisotopes, they provide new diagnostic and prognostic tools as well as insights into the role of the microenvironment in a disease. In this respect, they deliver additional information beyond what is afforded by conventional FDG PET scans that typically report on glucose uptake. Thus, FAP ligands are considered to be highly promising novel tracers that offer a new diagnostic and theranostic potential in a variety of diseases.

A Geiger-mode avalanche photodiode (Si-PM) is a promising photodetector for PET, especially for use in a magnetic resonance imaging (MRI) system, because it has high gain and is less sensitive to a static magnetic field. We developed a Si-PM-based depth-of-interaction (DOI) PET system for small animals. Hamamatsu 4 × 4 Si-PM arrays (S11065-025P) were used for its detector blocks. Two types of LGSO scintillator of 0.75 mol% Ce (decay time: ∼45 ns; 1.1 mm × 1.2 mm × 5 mm) and 0.025 mol% Ce (decay time: ∼31 ns; 1.1 mm × 1.2 mm × 6 mm) were optically coupled in the DOI direction to form a DOI detector, arranged in a 11 × 9 matrix, and optically coupled to the Si-PM array. Pulse shape analysis was used for the DOI detection of these two types of LGSOs. Sixteen detector blocks were arranged in a 68 mm diameter ring to form the PET system. Spatial resolution was 1.6 mm FWHM and sensitivity was 0.6% at the center of the field of view. High-resolution mouse and rat images were successfully obtained using the PET system. We confirmed that the developed Si-PM-based PET system is promising for molecular imaging research.

Prostate-specific membrane antigen (PSMA)–ligand PET/CT is performed on patients with prostate cancer to stage the disease initially or to identify sites of recurrence after definitive therapy. On the basis of clinical results, ¹⁸F-PSMA-1007 is a promising PSMA PET tracer, but detailed histologic confirmation has been lacking. Methods: Ninety-six patients with prostate cancer underwent ¹⁸F-PSMA-1007 PET/CT followed by either radical prostatectomy with lymphadenectomy or salvage lymphadenectomy. The histologic findings of PSMA PET–positive nodes were analyzed retrospectively. A lesion-based and patient-based analysis was performed comparing all positive lesions and only lesions larger than 3 mm on histopathology. Results: Of the patients, 90.6% received ¹⁸F-PSMA-1007 PET/CT for staging before the primary treatment, whereas 9.4% underwent imaging for biochemical recurrence. In 34.4% of the cohort, positive lymph nodes were present on imaging. In total, 1,746 lymph nodes were dissected in 96 patients. ¹⁸F-PSMA-1007 PET had a lesion-based sensitivity of 81.7%, a specificity of 99.6%, a positive predictive value of 92.4%, and a negative predictive value of 98.9% for detecting positive lymph nodes larger than 3 mm. In the analysis of all malignant nodes regardless of size, the overall sensitivity, specificity, positive predictive value, and negative predictive value on lesion-based analysis were 71.2%, 99.5%, 91.3%, and 97.9%, respectively. The patient-based analysis showed a sensitivity of 85.9% and a specificity of 99.5% for lymph nodes larger than 3 mm. Conclusion:¹⁸F-PSMA-1007 PET/CT reliably detects malignant lymph nodes and has an exceptional specificity of more than 99% for nodal metastases.