Franck Lacoeuille

Tumor eradication in rat glioma and bypass of immunosuppressive barriers using internal radiation with (188)Re-lipid nanocapsules

To date, glioblastoma treatments have only been palliative. In this context, locoregional drug delivery strategies, which allow for blood--brain barrier bypass and reduced systemic toxicity, are of major significance. Recent progress in nanotechnology has led to the development of colloidal carriers of radiopharmaceutics, such as lipid nanocapsules loaded with rhenium-188 (LNC(188)Re-SSS) that are implanted in the brain. In our study, we demonstrated that fractionated internal radiation using LNC(188)Re-SSS triggered remarkable survival responses in a rat orthotopic glioma model (cure rates of 83%). We also highlighted the importance of the radioactivity activity gradient obtained by combining a simple stereotactic injection (SI) with convection-enhanced delivery (CED).We assumed that the immune system played a role in the treatments efficacy on account of the overproduction of peripheral cytokines, recruitment of immune cells to the tumor site, and memory response in long-term survivor animals. Hence, nanovectorized internal radiation therapy with activity gradients stimulating immune responses may represent a new and interesting alternative for the treatment of solid tumors such as glioblastomas.

Lipid nanocapsules loaded with rhenium-188 reduce tumor progression in a rat hepatocellular carcinoma model.

Background Due to their nanometric scale (50 nm) along with their biomimetic properties, lipid nanocapsules loaded with Rhenium-188 (LNC188Re-SSS) constitute a promising radiopharmaceutical carrier for hepatocellular carcinoma treatment as its size may improve tumor penetration in comparison with microspheres devices. This study was conducted to confirm the feasibility and to assess the efficacy of internal radiation with LNC188Re-SSS in a chemically induced hepatocellular carcinoma rat model. Methodology/Principal Findings Animals were treated with an injection of LNC188Re-SSS (80 MBq or 120 MBq). The treated animals (80 MBq, n = 12; 120 MBq, n = 11) were compared with sham (n = 12), blank LNC (n = 7) and 188Re-perrhenate (n = 4) animals. The evaluation criteria included rat survival, tumor volume assessment, and vascular endothelial growth factor quantification. Following treatment with LNC188Re-SSS (80 MBq) therapeutic efficiency was demonstrated by an increase in the median survival from 54 to 107% compared with control groups with up to 7 long-term survivors in the LNC188Re-SSS group. Decreased vascular endothelial growth factor expression in the treated rats could indicate alterations in the angiogenesis process. Conclusions/Significance Overall, these results demonstrate that internal radiation with LNC188Re-SSS is a promising new strategy for hepatocellular carcinoma treatment.

Calibration Test of PET Scanners in a Multi-Centre Clinical Trial on Breast Cancer Therapy Monitoring Using 18F-FLT

A multi-centre trial using PET requires the analysis of images acquired on different systems We designed a multi-centre trial to estimate the value of 18F-FLT-PET to predict response to neoadjuvant chemotherapy in patients with newly diagnosed breast cancer. A calibration check of each PET-CT and of its peripheral devices was performed to evaluate the reliability of the results. Material and Methods 11 centres were investigated. Dose calibrators were assessed by repeated measurements of a 68Ge certified source. The differences between the clocks associated with the dose calibrators and inherent to the PET systems were registered. The calibration of PET-CT was assessed with an homogeneous cylindrical phantom by comparing the activities per unit of volume calculated from the dose calibrator measurements with that measured on 15 Regions of Interest (ROIs) drawn on 15 consecutive slices of reconstructed filtered back-projection (FBP) images. Both repeatability of activity concentration based upon the 15 ROIs (ANOVA-test) and its accuracy were evaluated. Results There was no significant difference for dose calibrator measurements (median of difference −0.04%; min = −4.65%; max = +5.63%). Mismatches between the clocks were less than 2 min in all sites and thus did not require any correction, regarding the half life of 18F. For all the PET systems, ANOVA revealed no significant difference between the activity concentrations estimated from the 15 ROIs (median of difference −0.69%; min = −9.97%; max = +9.60%). Conclusion No major difference between the 11 centres with respect to calibration and cross-calibration was observed. The reliability of our 18F-FLT multi-centre clinical trial was therefore confirmed from the physical point of view. This type of procedure may be useful for any clinical trial involving different PET systems.

Visualization of cardiac metastasis from medullary thyroid carcinoma on F-18 DOPA PET/CT scan.

Cardiac metastases are frequent (10%–12%) at autopsy of patients who have died of advanced cancers, but are usually clinically unrecognized. Melanoma, lymphoma, lung, and breast cancers are the main tumors inducing cardiac metastases. We present a case of cardiac metastasis which accumulated F-18 fluorodeoxyglucose and F-18 fluorodihydroxyphenylalanine in a 56-year-old woman with recurrent medullary thyroid carcinoma.

Delayed ( 18 F)FDG PET imaging of central nervous system lymphoma: is PET better than MRI?

The use of [F]FDG PET in primary central nervous system lymphoma was the subject of a recent article in this journal [1]. The authors concluded that MRI plays a crucial role in CNS lymphoma, but that [F]FDG PET could yield additional information. It is well known that the use of [F]FDG to study brain tumour is hindered by the high glucose affinity for the grey matter. Recently, Spence [2] proved that delayed imaging of brain tumours could enhance the tumour to background contrast. In our institution we currently perform early (1 h post injection) and late (6 h) images for every patient with suspected malignant brain disease. This 73-year-old woman was referred for the evaluation of relapse of a diffuse large B-cell lymphoma initially localised in the abdomen and bone (T3–T11). She was treated with apparent success with six courses of RMBACOD [rituximab (Mabthera, Rituxan)–methotrexate, bleomycin, adriamycin, cyclophosphamide, oncovin, dexamethasone]. Ten months later, the patient experienced numbness of her right arm and a cerebellar syndrome. MRI revealed a tumour in the cerebellum, and a possible second lesion in the right part of the tentorium cerebelli. A PET scan was performed 14 days thereafter, using 350 MBq [F]FDG. For early acquisition, scanning was performed in seven bed positions, at 4 min per bed position, in 2D mode using a GE Discovery ST. The late acquisition consisted of a 45 min bed position in 3D mode. Figure a shows the maximum intensity projection (MIP) image of the brain in the early phase. Thoracic and abdominal examination did not reveal any abnormality. Figure b shows the late MIP image. The tomogram (c) confirmed the three lesions suspected on MIP imaging, in the left cerebellum, left temporal pole and right tentorium cerebelli. A small lesion at the anterior edge of the right cerebellum could also be suspected. The use of [F]FDG PET in CNS Lymphoma has already been advocated, but most of these articles used only early imaging [1, 3–6].

American consensus recommendations for gastric scintigraphy: curve fitting with only a few points remains an easy and accurate method to obtain reliable and reproducible gastric emptying estimates.

BackgroundIn 2008, American consensus recommendations for performing gastric emptying (GE) scintigraphy were published. It was recommended that data are acquired only at 0, 1, 2, and 4 h and that the results are expressed as percentages of meal retention. Until now, it was established that the GE time–activity curves should have many points (every 10, 15, or 20 min) to reflect the GE process accurately and to be optimally adjusted by a mathematical model. In this study, we have evaluated the curve fitting using only a few points as proposed by the consensus protocol. Materials and methodsGE scintigraphy tests of 224 patients were retrospectively analyzed. Two curve fittings were done for each patient, either using data acquired every 20 min or using data acquired every hour. A comparison of these two methods was made based on the values of the computed GE parameters. ResultsWe observed strong correlations between the two methods (r=0.81–0.99, P<0.05). Using the Bland–Altman analysis, more than 95% of the differences were included in the mean difference 95% confidence interval. The mean differences were weak with a relatively small SD and Cohens k coefficients ranging from 0.84 to 0.93, indicating an excellent agreement between the two methods. ConclusionOur results showed the feasibility and accuracy of curve fitting using only a few points. The curve fitting is easy to perform and allows the computation of reliable and reproducible parameters that reflect the whole GE process.

68Ga and 188Re Starch-Based Microparticles as Theranostic Tool for the Hepatocellular Carcinoma: Radiolabeling and Preliminary In Vivo Rat Studies

Purpose This work aims to develop, validate and optimize the radiolabeling of Starch-Based Microparticles (SBMP) by 188Re and 68Ga in the form of ready-to-use radiolabeling kits, the ultimate goal being to obtain a unique theranostic vector for the treatment of Hepatocellular Carcinoma. Methods Optimal labeling conditions and composition of freeze-dried kits were defined by monitoring the radiochemical purity while varying several parameters. In vitro stability studies were carried out, as well as an in vivo biodistribution as a preliminary approach with the intra-arterial injection of 68Ga radiolabeled SBMP into the hepatic artery of DENA-induced rats followed by PET/CT imaging. Results Kits were optimized for 188Re and 68Ga with high and stable radiochemical purity (>95% and >98% respectively). The in vivo preliminary study was successful with more than 95% of activity found in the liver and mostly in the tumorous part. Conclusion SBMP are a promising theranostic agent for the Selective Internal Radiation Therapy of Hepatocellular carcinoma.

Isotopic Scintigraphy Coupled With Computed Tomography for the Investigation of Intrathecal Baclofen Device Malfunction

OBJECTIVE To assess the potential use of indium-111 diethylenetriamine pentaacetic acid ((111)In-DTPA) scintigraphy coupled with computed tomography (CT) for the investigation of intrathecal baclofen (ITB) device malfunction. DESIGN Retrospective study of a case series of patients. SETTING Neurosurgical and physical and rehabilitation medicine departments. PARTICIPANTS Patients (N=7) with reduced ITB effectiveness in whom prior conventional radiographs were inconclusive. INTERVENTION Nine (111)In-DTPA scintigraphic studies and 8 CT scans. Planar acquisitions were followed by tomoscintigraphy combined with CT. MAIN OUTCOME MEASURE Progression of the radiotracer in the pump, catheters, and in the subarachnoid space. RESULTS In 7 cases, scintigraphy coupled with CT showed leakage behind the pump, lack of activity outside the pump reservoir, abrupt interruption of activity in the catheter, or abnormal distribution of the radiotracer, thus demonstrating that the drug did not reach its target. Surgical revision confirmed these findings in 5 cases. In 1 case, combined imagery ruled out device dysfunction. In the remaining case, only planar acquisitions were performed, showing correct diffusion of the radiotracer. CONCLUSIONS The combination of scintigraphy and CT provides simultaneous functional and anatomic imagery of the device. The slow infusion of the radioisotope mimics the diffusion of baclofen, and this could be a useful method to explore intrathecal device malfunction. Further studies are required to compare scintigraphy coupled with CT, to radiopaque injection followed by fluoroscopy or CT.

Absence of lung fibrosis after a single pulmonary delivery of lipid nanocapsules in rats

Lipid nanocapsules (LNCs) are potential drug carriers for pulmonary delivery since they can be nebulized without any structural or functional changes, and the aerosols produced are highly compatible with pulmonary drug delivery in human beings. The alveolar surface tension, in vitro cytotoxicity, biodistribution and pulmonary toxicity in rats of a single endotracheal spray of LNCs or paclitaxel-loaded LNCs were studied. In vitro cytotoxicity of LNCs after a spray remained unchanged. Biodistribution study showed a homogeneous repartition in the lungs in rats with an improvement in lung retention of the radiolabeled tracer loaded in LNCs compared to the absence of LNCs with a lung half-time of 8.8±0.7 hours. Bronchoalveolar fluid analysis revealed transient 7-day alveolar inflammation, reaching a maximum between days 2 and 4, characterized by a peak of granulocytes at day 1 followed by a peak of lymphocytes at day 3. Alveolar protein levels were increased at days 3 and 7. Acute inflammation was increased with paclitaxel-loaded LNCs in comparison with blank LNCs but dropped out at day 7. No histological pulmonary lesion was observed at day 60. LNCs lowered surface tension to a greater degree than Curosurf® in a physicochemical model of the pulmonary alveolus. A single pulmonary delivery of LNCs induces a short-term alveolar inflammation with no residual lesions in rats at day 60. These data permit to start the study of LNCs in surfactant replacement therapy.