A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer.

PURPOSE: To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation. PATIENTS AND METHODS: A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq-150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months. RESULTS: Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3-4 AEs in 7 patients. CONCLUSIONS: Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.

Redifferentiation-facilitated radioiodine therapy in thyroid cancer.

Based on experimental data, the inhibition of the MAPkinase pathway in patients with radioiodine-refractory thyroid cancer was capable of inducing a redifferentiation. Preliminary data obtained in a small series of patients were encouraging and this strategy might become an alternative treatment in those patients with a druggable mutation that induces a stimulation of the MAP kinase pathway. This is an active field of research to answer many still unresolved questions.

Nanostructured lipid carriers accumulate in atherosclerotic plaques of ApoE-/- mice.

Nanostructured lipid carriers (NLC) might represent an interesting approach for the identification and targeting of rupture-prone atherosclerotic plaques. In this study, we evaluated the biodistribution, targeting ability and safety of 64Cu-fonctionalized NLC in atherosclerotic mice. 64Cu-chelating-NLC (51.8±3.1 nm diameter) with low dispersity index (0.066±0.016) were produced by high pressure homogenization at tens-of-grams scale. 24 h after injection of 64Cu-chelated particles in ApoE-/- mice, focal regions of the aorta showed accumulation of particles on autoradiography that colocalized with Oil Red O lipid mapping. Signal intensity was significantly greater in aortas isolated from ApoE-/- mice compared to wild type (WT) control (8.95 [7.58, 10.16]×108 vs 4.59 [3.11, 5.03]×108 QL/mm2, P < 0.05). Moreover, NLC seemed safe in relevant biocompatibility studies. NLC could constitute an interesting platform with high clinical translation potential for targeted delivery and imaging purposes in atherosclerosis.

Cleaved CD31 as a target for in vivo molecular imaging of inflammation.

There is a need for new targets to specifically localize inflammatory foci, usable in a wide range of organs. Here, we hypothesized that the cleaved molecular form of CD31 is a suitable target for molecular imaging of inflammation. We evaluated a bioconjugate of D-P8RI, a synthetic peptide that binds all cells with cleaved CD31, in an experimental rat model of sterile acute inflammation. Male Wistar rats were injected with turpentine oil into the gastrocnemius muscle two days before 99mTc-HYNIC-D-P8RI (or its analogue with L-Proline) SPECT/CT or [18F]FDG PET/MRI. Biodistribution, stability study, histology, imaging and autoradiography of 99mTc-HYNIC-D-P8RI were further performed. Biodistribution studies revealed rapid elimination of 99mTc-HYNIC-D-P8RI through renal excretion with almost no uptake from most organs and excellent in vitro and in vivo stability were observed. SPECT/CT imaging showed a significant higher 99mTc-HYNIC-D-P8RI uptake compared with its analogue with L-Proline (negative control) and no significant difference compared with [18F]FDG (positive control). Moreover, autoradiography and histology revealed a co-localization between 99mTc-HYNIC-D-P8RI uptake and inflammatory cell infiltration. 99mTc-HYNIC-D-P8RI constitutes a new tool for the detection and localization of inflammatory sites. Our work suggests that targeting cleaved CD31 is an attractive strategy for the specific in vivo imaging of inflammatory processes.

Early angiogenesis detected by PET imaging with 64Cu-NODAGA-RGD is predictive of bone critical defect repair.

Therapies using stem cells may be applicable to all fields of regenerative medicine, including craniomaxillofacial surgery. Dental pulp stem cells (DPSCs) have demonstrated in vitro and in vivo osteogenic and proangiogenic properties. The aim of the study was to evaluate whether early angiogenesis investigated by nuclear imaging can predict bone formation within a mouse critical bone defect. Two symmetrical calvarial critical-sized defects were created. Defects were left empty or filled with i) DPSC-containing dense collagen scaffold, ii) 5% hypoxia-primed DPSC-containing dense collagen scaffold, iii) acellular dense collagen scaffold, or iv) left empty. Early angiogenesis assessed by PET using 64Cu-NODAGA-RGD as a tracer was found to be correlated with bone formation determined by micro-CT within the defects from day 30, and to be correlated to the late calcium apposition observed at day 90 using 18F-Na PET. These results suggest that nuclear imaging of angiogenesis, a technique applicable in clinical practice, is a promising approach for early prediction of bone grafting outcome, thus potentially allowing to anticipate alternative regenerative strategies. STATEMENT OF SIGNIFICANCE: Bone defects are a major concern in medicine. As life expectancy increases, the number of bone lesions grows, and occurring complications lead to a delay or even lack of consolidation. Therefore, to be able to predict healing or the absence of scarring at early times would be very interesting. This would not "waste time" for the patient. We report here that early nuclear imaging of angiogenesis, using 64Cu-NODAGA-RGD as a tracer, associated with nuclear imaging of mineralization, using 18F-Na as a tracer, is correlated to late bone healing objectivized by classical histology and microtomography. This nuclear imaging represents a promising approach for early prediction of bone grafting outcome in clinical practice, thus potentially allowing to anticipate alternative regenerative strategies.

Targeting mannose receptor expression on macrophages in atherosclerotic plaques of apolipoprotein E-knockout mice using 111In-tilmanocept.

BACKGROUND: Atherosclerotic plaque phenotypes are classified based on the extent of macrophage infiltration into the lesions, and the presence of certain macrophage subsets might be a sign for plaque vulnerability. The mannose receptor (MR) is over-expressed in activated macrophages. Tilmanocept is a tracer that targets MR and is approved in Europe and the USA for the detection of sentinel lymph nodes. In this study, our aim was to evaluate the potential of 111In-labelled tilmanocept for the detection of MR-positive macrophages in atherosclerotic plaques of apolipoprotein E-knockout (ApoE-KO) mouse model. METHODS: Tilmanocept was labelled with 111In. The labelling stability and biodistribution of the tracer was first evaluated in control mice (n = 10) 1 h post injection (p.i.). For in vivo imaging studies, 111In-tilmanocept was injected into ApoE-KO (n = 8) and control (n = 8) mice intravenously (i.v.). The mice were scanned 90 min p.i. using a dedicated animal SPECT/CT. For testing the specificity of 111In-tilmanocept uptake in plaques, a group of ApoE-KO mice was co-injected with excess amount of non-labelled tilmanocept. For ex vivo imaging studies, the whole aortas (n = 9 from ApoE-KO and n = 4 from control mice) were harvested free from adventitial tissue for Sudan IV staining and autoradiography. Cryosections were prepared for immunohistochemistry (IHC). RESULTS: 111In radiolabelling of tilmanocept provided a yield of greater than 99%. After i.v. injection, 111In-tilmanocept accumulated in vivo in MR-expressing organs (i.e. liver and spleen) and showed only low residual blood signal 1 h p.i. MR-binding specificity in receptor-positive organs was demonstrated by a 1.5- to 3-fold reduced uptake of 111In-tilmanocept after co-injection of a blocking dose of non-labelled tilmanocept. Focal signal was detected in atherosclerotic plaques of ApoE-KO mice, whereas no signal was detected in the aortas of control mice. 111In-tilmanocept uptake was detected in atherosclerotic plaques on autoradiography correlating well with Sudan IV-positive areas and associating with subendothelial accumulations of MR-positive macrophages as demonstrated by IHC. CONCLUSIONS: After i.v. injection, 111In-tilmanocept accumulated in MR-expressing organs and was associated with only low residual blood signal. In addition, 111In-tilmanocept uptake was detected in atherosclerotic plaques of mice containing MR-expressing macrophages suggesting that tilmanocept represents a promising tracer for the non-invasive detection of macrophages in atherosclerotic plaques.

Repeatability of Radiotracer Uptake in Normal Abdominal Organs with ¹¹¹In-Pentetreotide Quantitative SPECT/CT.

UNLABELLED: With an increasing emphasis on quantitation of SPECT imaging and its use in dosimetry to guide therapies, it is desirable to understand the repeatability in normal-organ SPECT uptake values (SPECT-UVs). We investigated the variability of normal abdominal organ uptake in repeated (111)In-pentetreotide SPECT studies. METHODS: Nine patients with multiple (111)In-pentetreotide SPECT/CT studies for clinical purposes were evaluated. Volumes of interest were drawn for the abdominal organs and applied to SPECT-UVs. The variability of those values was assessed. RESULTS: The average SPECT-UV for the liver (1.7 ± 0.6) was much lower than for the kidneys (right, 8.0 ± 2.4; left, 7.5 ± 1.7). Interpatient and intrapatient variability was similar (intraclass correlation coefficients, 0.40-0.59) for all organs. The average coefficients of variation for each organ for each patient were obtained and averaged across all patients (0.26 for liver, 0.22 for right kidney, and 0.20 for left kidney). The coefficients of variation for the organs across all scans were 0.33 (liver), 0.30 (right kidney), and 0.22 (left kidney). CONCLUSION: Variability across all patients and all scans for the liver was higher than reported with (18)F-FDG PET, though left kidney variability was similar to PET liver variability and left kidney uptake may be able to serve as an internal metric for determining the quantifiability of an (111)In-pentetreotide SPECT study.

Factors affecting the stability and repeatability of gamma camera calibration for quantitative imaging applications based on a retrospective review of clinical data.

BACKGROUND: Absolute quantitative single-photon emission computed tomography (SPECT) has several important applications including monitoring tumor response after treatment and dose estimation for targeted radionuclide therapy treatment planning. Obtaining quantitative SPECT images in absolute activity units requires the use of a calibration factor, and the repeatability of this directly affects the repeatability of image quantification. This study focused on evaluating the factors affecting the repeatability of a calibration factor measured using a planar image of an in-air calibration source. METHODS: The calibration factors calculated as part of (131)I-tositumomab patient dosimetry scans used in treatment planning performed over a 4-year period were retrospectively analyzed. Raw data included total counts in whole-body images of a radioactive calibration source, the activity of the source measured in a radionuclide activity meter (often referred to as a dose calibrator), and the background count rate obtained at three time points for each patient. The count rate from extrinsic flood source acquisitions and radionuclide activity meter constancy obtained on the same day as each image were also used. The data were analyzed statistically using a mixed-effects model to determine the factors affecting variations in the measured calibration factors. RESULTS: The global variability in the calibration factor was equal to 2.3% and was decreased by 20% to 1.8%, when the decay-corrected measurements of calibration source activity were averaged over the three time points for each patient. Camera sensitivity variation measured using a (57)Co sheet source was small and had a weak relationship to calibration factor variations. When the averaged source activity was used, the main source of variance was related to preparation and measurement of the source (77%). Radionuclide activity meter constancy had a smaller but statistically significant impact on the calibration factor. CONCLUSIONS: This study indicates that calibration factors based on planar measurements have good reproducibility. The findings of this study indicate (1) the importance of accurate and precise preparation and measurement of the calibration source activity, (2) the need to carefully control background activity during calibration factor assessment and patient data acquisition, and (3) that the calibration factor and camera sensitivity were stable over time, indicating that careful but less frequent calibration is needed.

dAcquisition setting optimization and quantitative imaging for 124I studies with the Inveon microPET-CT system.

BACKGROUND: Noninvasive multimodality imaging is essential for preclinical evaluation of the biodistribution and pharmacokinetics of radionuclide therapy and for monitoring tumor response. Imaging with nonstandard positron-emission tomography [PET] isotopes such as 124I is promising in that context but requires accurate activity quantification. The decay scheme of 124I implies an optimization of both acquisition settings and correction processing. The PET scanner investigated in this study was the Inveon PET/CT system dedicated to small animal imaging. METHODS: The noise equivalent count rate [NECR], the scatter fraction [SF], and the gamma-prompt fraction [GF] were used to determine the best acquisition parameters for mouse- and rat-sized phantoms filled with 124I. An image-quality phantom as specified by the National Electrical Manufacturers Association NU 4-2008 protocol was acquired and reconstructed with two-dimensional filtered back projection, 2D ordered-subset expectation maximization [2DOSEM], and 3DOSEM with maximum a posteriori [3DOSEM/MAP] algorithms, with and without attenuation correction, scatter correction, and gamma-prompt correction (weighted uniform distribution subtraction). RESULTS: Optimal energy windows were established for the rat phantom (390 to 550 keV) and the mouse phantom (400 to 590 keV) by combining the NECR, SF, and GF results. The coincidence time window had no significant impact regarding the NECR curve variation. Activity concentration of 124I measured in the uniform region of an image-quality phantom was underestimated by 9.9% for the 3DOSEM/MAP algorithm with attenuation and scatter corrections, and by 23% with the gamma-prompt correction. Attenuation, scatter, and gamma-prompt corrections decreased the residual signal in the cold insert. CONCLUSIONS: The optimal energy windows were chosen with the NECR, SF, and GF evaluation. Nevertheless, an image quality and an activity quantification assessment were required to establish the most suitable reconstruction algorithm and corrections for 124I small animal imaging.