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The purpose of this study was to evaluate the predictive features of baseline F-18-fluorodeoxy-D-glucose positron emission tomography (18F-FDG PET)/computed tomography (CT) parameters in patients with dedifferentiated liposarcomas (DDLPSs) and well-differentiated liposarcomas (WDLPSs) receiving systemic treatment. A total of 24 patients with liposarcoma who underwent longitudinal 18F-FDG PET/CT in systemic therapy were included. All volumetric segmentation of each tumor section and semiquantitative imaging parameters were extracted from the axial field of view from both PET and CT images. Maximum, mean, and minimum standardized uptake values (SUVmax, SUVmean, and SUVmin), Hounsfield units (HUs), and their respective changes from baseline and posttreatment were calculated. The voxel values from unenhanced CT images were correlated with PET-derived parameters. The 18F-FDG uptake decreased by more than 56% on average in responders for both SUVmax and SUVmean in DDLPS. There was a decrease in HUmax in DDLPS among responders. Using AUC > 0.8 as a reasonable predictor, we found that the ratios of SUVmaxD/HUmean, SUVmaxD/HUmedian, and SUVmeanD/HUmedian at baseline were significant indicators of the response to treatment in patients with liposarcoma. The changes in SUVmean and not just SUVmax parameters could be considered as accurate tumor response indicators. For the first time, we introduced baseline SUV/HU ratios as a valuable diagnostic tool in predicting liposarcoma treatment outcomes. This ability was not revealed by classic semiquantitative PET or CT parameters at baseline. [ABSTRACT FROM AUTHOR]

Simple Summary: This research study focuses on the P-cadherin protein, which is found in many types of tumors, and could be a potential target for therapy. FF-21101, a human–mouse chimeric monoclonal antibody that targets P-cadherin, was labeled with indium-111(111In) and investigated for biodistribution and radiation doses in six cynomolgus macaques. To assess the radiation profile distribution and clearance of FF-21101(111In), we performed whole-body imaging and generated time–activity curves. The lungs, spleen, liver, kidneys, and heart wall received the highest radiation dose estimates for FF-21101(111In). These findings led us to estimate the radiation doses that would be delivered to different organs if this antibody was labeled with yttrium-90 (90Y) and used in targeted radioimmunotherapy in patients. FF-21101 shows potential for clinical application in humans, according to biodistribution data obtained from macaques. Based on these results, an investigational new drug application was filed with the FDA for a Phase I clinical trial. P-cadherin is associated with a wide range of tumor types, making it an attractive therapeutic target. FF-21101 is a human–mouse chimeric monoclonal antibody (mAb) directed against human P-cadherin, which has been radioconjugated with indium-111 (111In) utilizing a DOTA chelator. We investigated the biodistribution of FF-21101(111In) in cynomolgus macaques and extrapolated the results to estimate internal radiation doses of 111In- and yttrium-90 (90Y)-FF-21101 for targeted radioimmunotherapy in humans. Whole-body planar and SPECT imaging were performed at 0, 2, 24, 48, 72, 96, and 120 h post-injection, using a dual-head gamma camera. Volumes of interest of identifiable source organs of radioactivity were defined on aligned reference CT and serial SPECT images. Organs with the highest estimated dose values (mSv/MBq) for FF-21101(111In) were the lungs (0.840), spleen (0.816), liver (0.751), kidneys (0.629), and heart wall (0.451); and for FF-21101(90Y) dose values were: lungs (10.49), spleen (8.21), kidneys (5.92), liver (5.46), and heart wall (2.61). FF-21101(111In) exhibits favorable biodistribution in cynomolgus macaques and estimated human dosimetric characteristics. Data obtained in this study were used to support the filing of an investigational new drug application with the FDA for a Phase I clinical trial. [ABSTRACT FROM AUTHOR]

The expression of human epidermal growth factor receptor-2 (HER2) receptors in cancers is correlated with a poor prognosis. If assessed in vivo, it could be used for selection of appropriate therapy for individual patients and for monitoring of the tumor response to targeted therapies. We have radiolabeled a HER2-binding Affibody molecule with fluorine-18 for in vivo monitoring of the HER2 expression by positron emission tomography (PET). The HER2-binding ZHER2:342–Cys Affibody molecule was conjugated with N-2-(4-[18F]fluorobenzamido)ethyl]maleimide ([18F]FBEM). The in vitro binding of the resulting radioconjugate was characterized by receptor saturation and competition assays. For in vivo studies, the radioconjugate was injected into the tail vein of mice bearing subcutaneous HER2-positive or HER2-negative tumors. Some of the mice were pre-treated with non-labeled ZHER2:342−Cys. The animals were sacrificed at different times post-injection, and the radioactivity in selected tissues was measured. PET images were obtained using an animal PET scanner. In vitro experiments indicated specific, high-affinity binding to HER2. PET imaging revealed a high accumulation of the radioactivity in the tumor as early as 20 min after injection, with a plateau being reached after 60 min. These results were confirmed by biodistribution studies demonstrating that, as early as 1 h post-injection, the tumor to blood concentration ratio was 7.5 and increased to 27 at 4 h. Pre-saturation of the receptors with unlabeled ZHER2:342–Cys lowered the accumulation of radioactivity in HER2-positive tumors to the levels observed in HER2-negative ones. Our results suggest that the [18F]FBEM-ZHER2:342 radioconjugate can be used to assess HER2 expression in vivo. [ABSTRACT FROM AUTHOR]

[¹³¹I]meta-iodobenzylguanidine ([¹³¹I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [¹²³I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [(18)F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1 ± 3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9 ± 0.6%; P<0.001). Biodistribution analysis after inhibitors treatment confirmed the PET results. The uptake of [(123)I]MIBG was significantly increased in liver metastases 9.5 ± 1.1% compared to 3.19 ± 0.4% in untreated control liver metastases (P<0.05). We found that HDAC inhibitors caused an increase in the amount of norepinephrine transporter expressed in tumors. HDAC inhibitors may enhance the therapeutic efficacy of [(131)I]MIBG treatment in patients with advanced malignant pheochromocytoma and paraganglioma.

Context: Pheochromocytomas and paragangliomas are rare catecholamine-secreting neuroendocrine tumors arising from the adrenal medulla and sympathetic tissues. When complete surgical resection is not an option, the treatment of pheochromocytoma is limited., Objective: The objective of the study was to identify and characterize overexpression of IL-13 receptor-alpha2 (IL-13Ralpha2) gene expression in human and murine tumors and verify xenograft mouse pheochromocytoma cell (MPC)-derived tumor's response to a selective cytotoxin., Design/setting/patients: Expression of IL-13Ralpha2 was evaluated in a panel of 25 human pheochromocytoma clinical samples by RT-PCR and eight MPC tumors by indirect immunofluorescence assay and RT-PCR., Intervention: The function of IL-13Ralpha2 in these tumor cells was examined by evaluating tumor sensitivity to a recombinant IL-13-Pseudomonas exotoxin (IL-13PE). Subcutaneous small and large MPC tumors in athymic nude mice (n = 10) were treated intratumorally with IL-13PE (100 m icrog/kg)., Main Outcome Measures: IC(50) and tumor size were measured., Results: IL-13PE immunotoxin was highly cytotoxic to IL-13Ralpha2-overexpressing MPC cells (IC(50) <2.5 ng/ml) in vitro. Furthermore, IL-13PE was highly cytotoxic to sc tumors. Our results showed a statistically significant decrease in tumor size as early as 3 d after initial treatment and further suppressed growth of MPC tumors. All tumors displayed a histological evidence of necrosis in response to IL-13 immunotoxin without any adverse effects in host at this dose., Conclusions: Human and murine neuroendocrine pheochromocytoma overexpress the IL-13Ralpha2 chain, and an IL-13PE-based receptor-directed anticancer approach may prove useful in treatment for metastatic pheochromocytoma patients.

Unlabelled: 6-(18)F-fluoro-l-3,4-dihydroxyphenylalanine ((18)F-DOPA) PET is a useful tool for the detection of certain neuroendocrine tumors, especially with the preadministration of carbidopa, an inhibitor of DOPA decarboxylase. Whether carbidopa also improves (18)F-DOPA PET of adrenal pheochromocytomas and extraadrenal paragangliomas is unknown. The aim of this study was to investigate the sensitivity of (18)F-DOPA PET in the detection of paraganglioma and its metastatic lesions and to evaluate whether tracer uptake by the tumors is enhanced by carbidopa., Methods: Two patients with nonmetastatic adrenal pheochromocytoma, and 9 patients with extraadrenal abdominal paraganglioma (1 nonmetastatic, 8 metastatic), underwent whole-body CT, MRI, baseline (18)F-DOPA PET, and (18)F-DOPA PET with oral preadministration of 200 mg of carbidopa. The dynamics of tracer uptake by these lesions and the physiologic distribution of (18)F-DOPA in normal tissues were recorded., Results: Seventy-eight lesions were detected by CT or MRI, 54 by baseline (18)F-DOPA PET (P = 0.0022 vs. CT/MRI), and 57 by (18)F-DOPA PET plus carbidopa (P = 0.0075 vs. CT/MRI, not statistically significant vs. baseline). In reference to findings on CT and MRI, the sensitivities of baseline (18)F-DOPA PET were 47.4% for lesions and 55.6% for positive body regions, versus 50.0% (lesions) and 66.7% (regions) for (18)F-DOPA PET plus carbidopa (neither is statistically significant vs. baseline). Compared with baseline, carbidopa detected additional lesions in 3 (27%) of 11 patients. Carbidopa increased the mean (+/-SD) peak standardized uptake value in index tumor lesions from 6.4 +/- 3.9 to 9.1 +/- 5.6 (P = 0.037). Pancreatic physiologic (18)F-DOPA uptake, which may mask adrenal pheochromocytoma, is blocked by carbidopa., Conclusion: Carbidopa enhances the sensitivity of (18)F-DOPA PET for adrenal pheochromocytomas and extraadrenal abdominal paragangliomas by increasing the tumor-to-background ratio of tracer uptake. The sensitivity of (18)F-DOPA PET for metastases of paraganglioma appears to be limited.