Actinium-225 Targeted Agents: Where Are We Now?

α-particle targeted radionuclide therapy has shown promise for optimal cancer management, an exciting new era for brachytherapy. Alpha-emitting nuclides can have significant advantages over gamma- and beta-emitters due to their high linear energy transfer (LET). While their limited path length results in more specific tumor 0kill with less damage to surrounding normal tissues, their high LET can produce substantially more lethal double strand DNA breaks per radiation track than beta particles. Over the last decade, the physical and chemical attributes of Actinium-225 (225Ac) including its half-life, decay schemes, path length, and straightforward chelation ability has peaked interest for brachytherapy agent development. However, this has been met with challenges including source availability, accurate modeling for standardized dosimetry for brachytherapy treatment planning, and laboratory space allocation in the hospital setting for on-demand radiopharmaceuticals production. Current evidence suggests that a simple empirical approach based on 225Ac administered radioactivity may lead to inconsistent outcomes and toxicity. In this review article, we highlight the recent advances in 225Ac source production, dosimetry modeling, and current clinical studies.

Novel styrylbenzene derivatives for detecting amyloid deposits.

BACKGROUND: Various styrylbenzene compounds were synthesized and evaluated as mainly Aß amyloid sensors. These compounds, however, cannot be used for detecting amyloid deposition in peripheral nerves because of the inherent sensitivity of the compounds. These compounds often generate false positives especially in the basement membrane of blood vessels in histochemical studies. To overcome these problems, we must first synthesize other styryl compounds for detecting amyloid fibrils in tissues. METHODS: A wide variety of symmetrical and unsymmetrical styrylbenzene derivatives were synthesized and then these compounds were used to detect amyloid fibrils in autopsy and biopsy samples from patients with various systemic and localized forms of amyloidosis such as familial amyloidotic polyneuropathy (FAP), senile systemic amyloidosis (SSA), amyloid A (AA) amyloidosis, localized AL amyloidosis, and Alzheimer's disease. RESULTS: 1-Methoxy-2,5-bis-styrylbenzene and 2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-2,5-bis-styrylbenzene (EEEFSB) detected amyloid fibrils in both in vitro and in vivo histopathological studies. 1-Methoxy-2,5-bis-styrylbenzene also showed a high strength of fluorescence with amyloid deposition in peripheral nerves in a patient with FAP. CONCLUSIONS: 1-Methoxy-2,5-bis-styrylbenzene and EEEFSB may prove a useful tool for diagnosing amyloidosis, not only in a histochemical study but also in whole body amyloid positron emission tomography (PET) imaging.

11C-acetate for positron emission tomography imaging of clinical stage IA lung adenocarcinoma: comparison with 18F-fluorodeoxyglucose for imaging and evaluation of tumor aggressiveness.

BACKGROUND: To determine the usefulness of positron emission tomography (PET) with (11)C-acetate (AC) for imaging lung adenocarcinoma and evaluating its tumor aggressiveness, AC- and (18)F-fluorodeoxyglucose (FDG)-PET were compared. METHODS: One hundred and sixty-nine adenocarcinomas with clinical stage IA and 53 benign nodules were examined by both AC- and FDG-PET before surgery. The sensitivity and specificity for discriminating benign/adenocarcinoma were compared between AC- and FDG-PET. The AC and FDG uptakes were examined to determine the relationship with tumor aggressiveness, i.e., pathological tumor stage, lymphatic, vascular, or pleural involvement, and proliferative activity determined by Ki-67 staining score. RESULTS: While the sensitivity of AC-PET was significantly higher than FDG-PET for bronchioloalveolar carcinoma (BAC) and well-differentiated (W/D) adenocarcinoma (p < 0.001 and 0.006, respectively), there was no significant difference for moderately or poorly differentiated adenocarcinoma. The specificity was not different between them. While FDG uptakes were significantly higher in tumors with pathological advanced stages or those with lymphatic, vascular and/or pleural involvements than in tumors with pathological stage IA or those without these tumor involvements (p = 0.04 to p < 0.001), AC uptake did not show significant differences between the respective sub-groups except according to the tumor stage. While both AC and FDG uptakes showed a significant correlation with Ki-67 staining scores (p = 0.03 and p < 0.001, respectively), the correlation coefficient of former was lower than that of latter (p = 0.07). CONCLUSIONS: While AC-PET can image BAC and W/D adenocarcinoma with a higher sensitivity than FDG-PET, it cannot evaluate tumor aggressiveness of clinical stage IA lung adenocarcinoma as well as FDG-PET.

18F-fluorodeoxyglucose and 11C-acetate positron emission tomography are useful modalities for diagnosing the histologic type of thymoma.

BACKGROUND: The objective of this study was to clarify the usefulness of positron emission tomography (PET) using(18)F-fluorodeoxyglucose (FDG) and carbon 11-labeled acetate (AC) for predicting the histologic types and tumor invasiveness of thymoma in a multicenter study. METHODS: Forty thymomas were examined using both FDG-PET and AC-PET before surgery. The histologic types were type A in 1 thymoma, type AB in 12 thymomas, type B1 in 11 thymomas, type B2 in 7 thymomas, type B3 in 6 thymomas, and type C in 3 thymomas. Tumor invasiveness was assessed by pathologic tumor stage and was identified as stage I in 17 tumors, stage II in 17 tumors, stage III in 4 tumors, and stage IV in 2 tumors. FDG and AC uptake was measured as the maximum standard uptake value (SUV). RESULTS: The FDG-SUV in type C thymomas was significantly higher than that in the other types (A-B3; P = .001 - P = .048). The AC-SUV in type A/AB thymomas was significantly higher than that in the other tumor types (B1-C; P < .001 - P = .002). All 3 type C tumors had an FDG-SUV >or=6.3, and all 13 type A/AB tumors had an FDG-SUV <6.3 and an AC-SUV >or=5.7. All 17 thymomas that had an FDG-SUV <6.3 and an AC-SUV <5.7 were type B1, B2, or B3. Neither the FDG-SUV nor the AC-SUV differed significantly between the stages I/II tumors and stage III/IV tumors. CONCLUSIONS: Although neither the FDG-SUV nor the AC-SUV can predict the invasiveness of thymomas assessed by tumor stage, they are useful for predicting histologic types of thymoma. Thymomas with an FDG-SUV <6.3 and an AC-SUV >or=5.7 almost certainly are types A/AB, which is of considerable prognostic and management significance.

Enhancement of splenic glucose metabolism during acute malarial infection: correlation of findings of FDG-PET imaging with pathological changes in a primate model of severe human malaria.

In the current study, to elucidate the clinical features of severe malaria, we performed whole-body positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) of Plasmodium coatneyi-infected acute-phase Japanese macaques. The infected monkeys clearly exhibited increase in splenic FDG uptake indicating marked enhancement of glucose metabolism. The standardized uptake values (SUVs) of the spleen in the infected monkeys were significantly higher than those in the uninfected monkey. At autopsy, splenomegaly was clearly present in all infected monkeys, and histopathologic findings included hyperplasia of lymphoid follicles in white pulp, a large number of activated macrophage, and congestion of parasitized red blood cells (PRBCs) and malaria pigments in red pulp. We suggest that increase in splenic glucose uptake may thus be closely related to activation of splenic clearance system against blood-stage malarial parasites.

Cerebral metabolic reduction in severe malaria: fluorodeoxyglucose-positron emission tomography imaging in a primate model of severe human malaria with cerebral involvement.

Cerebral metabolic changes in Japanese macaques (Macaca fuscata) infected with Plasmodium coatneyi, a primate model of severe human malaria with cerebral involvement, were directly evaluated by fluorodeoxyglucose-positron emission tomography (FDG-PET). We observed diffuse and heterogeneous reduction of metabolism in the cerebral cortex in the acute phase of malaria infection. Neuropathologic examination showed preferential sequestration of parasitized red blood cells in the cerebral microvasculature. However, hemorrhagic change or necrosis was not observed in hematoxylin and eosin-stained and Nissl-stained brain tissues. This suggests that reduction of cerebral metabolism occurs before parenchymal changes appear in the brain. This may be one reason why more than half of the patients with cerebral malaria have no neurologic sequelae after recovery.

Carbon-11 choline positron emission tomography in musculoskeletal tumors: comparison with fluorine-18 fluorodeoxyglucose positron emission tomography.

PURPOSE: Recently, a new positron emission tomography (PET) tracer, carbon-11 choline, has been introduced in oncology investigations, but the role of choline PET in musculoskeletal tumor evaluation has not been previously examined. This is the first trial to investigate the utility of choline PET in evaluating musculoskeletal tumors in comparison with fluorine-18 fluoro-2-deoxy-D-glucose (FDG) PET. METHOD: Thirty-three patients were examined with both choline PET and FDG PET, of which standardized uptake values (SUVs) were used for evaluation of the lesions. To decide the appropriate cutoff value and compare the two PET studies, receiver operating characteristic curve analysis was used. The binomial test was used for comparison of sensitivities between choline PET and FDG PET. RESULTS: A significant correlation (r = 0.537, P = 0.0013) between choline and FDG SUVs was noted for all lesions (n = 33). Mean SUVs for malignant tumors were significantly higher than those for benign lesions in both choline PET and FDG PET. Using a cutoff value of 2.7 for choline SUVs, the sensitivity for correctly diagnosing malignancy was 92.3% (12/13) with a specificity of 90.0% (18/20), resulting in an accuracy rate of 90.9%. With use of a cutoff value of 3.3 for SUVs in FDG PET, the sensitivity was 84.6% (11/13) with a specificity of 80.0% (16/20), resulting in an accuracy rate of 81.8%. The receiver operating characteristic curves of two analyses showed that the mean area under the curve value of choline PET (0.9577 +/- 0.041) was significantly greater (P = 0.0488) than that of FDG PET (0.8192 +/- 0.0806). There was no significant difference in sensitivity and specificity between choline PET and FDG PET analysis using either the binomial test (P = 0.4531) or McNemar test (P = 0.371). CONCLUSION: Choline PET analysis may not be inferior to FDG PET analysis for differentiating malignant from benign musculoskeletal tumors. The advantages of choline PET were shorter examination time and little retention in the bladder; therefore, this modality may be useful for preoperative planning for musculoskeletal tumors, especially for lesions around the hip joints.

A shifting landscape: what will be next FDG in PET oncology?

The tumor-seeking agent most widely used in positron emission tomography (PET) is 2-(18)F-fluorodeoxy-D-glucose (FDG). The clinical usefulness of FDG PET has already been proved in detecting, staging and restaging various kinds of malignant tumors, but nuclear medicine physicians suffer from a "diagnostic dilemma," in which a relatively high false positive ratio of FDG PET in diagnosing malignant tumors prevails. To increase more specific tumor uptake or more specific tumor characterization, numerous PET radiopharmaceuticals have been developed, and some of them are being tested in clinical trials. This review will briefly survey the tumor uptake mechanism and clinical significance of representative non-FDG PET radiopharmaceuticals used in clinical trials for patients with cancers.