Vincent Boudousq

Major increase in brain natriuretic peptide indicates right ventricular systolic dysfunction in patients with heart failure.

This study sought to investigate whether the presence of right ventricular systolic dysfunction with pre‐existing left ventricular systolic dysfunction is associated with higher plasma brain natriuretic peptide (BNP) levels, compared with patients with isolated left ventricular dysfunction. Eighty‐five patients referred for evaluation of isotopic ventricular function were prospectively included in the study. Left (LVEF) and right (RVEF) ventricular ejection fractions were evaluated by gated blood pool scintigraphy and compared with plasma BNP levels. BNP correlated negatively with LVEF, except in patients with ischaemic heart disease (P=0.09) and in patients with LVEF<40% (P=0.11). In contrast, BNP levels correlated negatively with RVEF for all subgroups. Among patients with RVEF<40%, no significant BNP difference was found between patients with or without additional left ventricular systolic dysfunction (P=0.51). Among patients with LVEF<40%, plasma BNP levels were significantly higher in patients with RVEF<40% than in patients with RVEF≥40% (P=0.004) whereas age, renal function, clinical findings, ventricular volumes, LVEF or medication were not significantly different. In conclusion, an important increase in BNP levels in patients with left ventricular systolic dysfunction should be considered by cardiologists as an indication of high risk of right ventricular dysfunction and should justify further investigation.

Relevance of 2D radiographic texture analysis for the assessment of 3D bone micro-architecture.

Although the diagnosis of osteoporosis is mainly based on dual x-ray absorptiometry, it has been shown that trabecular bone micro-architecture is also an important factor in regard to fracture risk. In vivo, techniques based on high-resolution x-ray radiography associated to texture analysis have been proposed to investigate bone micro-architecture, but their relevance for giving pertinent 3D information is unclear. Thirty-three calcaneus and femoral neck bone samples including the cortical shells (diameter: 14mm, height: 30-40mm) were imaged using 3D-synchrotron x-ray micro-CT at the ESRF. The 3D reconstructed images with a cubic voxel size of 15μm were further used for two purposes: (1) quantification of three-dimensional trabecular bone micro-architecture, (2) simulation of realistic x-ray radiographs under different acquisition conditions. The simulated x-ray radiographs were then analyzed using a large variety of texture analysis methods (co-occurrence, spectral density, fractal, morphology, etc.). The range of micro-architecture parameters was in agreement with previous studies and rather large, suggesting that the population was representative. More than 350 texture parameters were tested. A small number of them were selected based on their correlation to micro-architectural morphometric parameters. Using this subset of texture parameters, multiple regression allowed one to predict up to 93% of the variance of micro-architecture parameters using three texture features. 2D texture features predicting 3D micro-architecture parameters other than BV/TV were identified. The methodology proposed for evaluating the relationships between 3D micro-architecture and 2D texture parameters may also be used for optimizing the conditions for radiographic imaging. Further work will include the application of the method to physical radiographs. In the future, this approach could be used in combination with DXA to refine osteoporosis diagnosis.

A comparative study of Powell's and Downhill simplex algorithms for a fast multimodal surface matching in brain imaging

Multimodal images registration can be very helpful for diagnostic applications. However, even if a lot of registration algorithms exist, only a few really work in clinical routines. We developed a method based on surface matching and compared two minimization algorithms: Powells and Downhill Simplex. We studied the influence of some factors (chamfer map computation, number and order of parameters to determine, minimization criteria) on the final accuracy of the algorithm. Using this comparison, we improved some processing steps to allow a clinical use, and selected the simplex algorithm which presented the best results.

Noninternalizing Monoclonal Antibodies Are Suitable Candidates for 125I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis

We have previously shown that, in vitro, monoclonal antibodies (mAbs) labeled with the Auger electron emitter 125I are more cytotoxic if they remain at the cell surface and do not internalize in the cytoplasm. Here, we assessed the in vivo biologic efficiency of internalizing and noninternalizing 125I-labeled mAbs for the treatment of small solid tumors. Methods: Swiss nude mice bearing intraperitoneal tumor cell xenografts were injected with 37 MBq (370 MBq/mg) of internalizing (anti-HER1) 125I-m225 or noninternalizing (anti-CEA) 125I-35A7 mAbs at days 4 and 7 after tumor cell grafting. Nonspecific toxicity was assessed using the irrelevant 125I-PX mAb, and untreated controls were injected with NaCl. Tumor growth was followed by bioluminescence imaging. Mice were sacrificed when the bioluminescence signal reached 4.5 × 107 photons/s. Biodistribution analysis was performed to determine the activity contained in healthy organs and tumor nodules, and total cumulative decays were calculated. These values were used to calculate the irradiation dose by the MIRD formalism. Results: Median survival (MS) was 19 d in the NaCl-treated group. Similar values were obtained in mice treated with unlabeled PX (MS, 24 d) and 35A7 (MS, 24 d) or with 125I-PX mAbs (MS, 17 d). Conversely, mice treated with unlabeled or labeled internalizing m225 mAb (MS, 76 and 77 d, respectively) and mice injected with 125I-35A7 mAb (MS, 59 d) showed a significant increase in survival. Irradiation doses were comparable in all healthy organs, independently from the mAb used, whereas in tumors the irradiation dose was 7.4-fold higher with 125I-labeled noninternalizing than with internalizing mAbs. This discrepancy might be due to iodotyrosine moiety release occurring during the catabolism of internalizing mAbs associated with high turnover rate. Conclusion: This study indicates that 125I-labeled noninternalizing mAbs could be suitable for radioimmunotherapy of small solid tumors and that the use of internalizing mAbs should not be considered as a requirement for the success of treatments with 125I Auger electrons.

Introduction to Radiobiology of Targeted Radionuclide Therapy

During the last decades, new radionuclide-based targeted therapies have emerged as efficient tools for cancer treatment. Targeted radionuclide therapies (TRTs) are based on a multidisciplinary approach that involves the cooperation of specialists in several research fields. Among them, radiobiologists investigate the biological effects of ionizing radiation, specifically the molecular and cellular mechanisms involved in the radiation response. Most of the knowledge about radiation effects concerns external beam radiation therapy (EBRT) and radiobiology has then strongly contributed to the development of this therapeutic approach. Similarly, radiobiology and dosimetry are also assumed to be ways for improving TRT, in particular in the therapy of solid tumors, which are radioresistant. However, extrapolation of EBRT radiobiology to TRT is not straightforward. Indeed, the specific physical characteristics of TRT (heterogeneous and mixed irradiation, protracted exposure, and low absorbed dose rate) differ from those of conventional EBRT (homogeneous irradiation, short exposure, and high absorbed dose rate), and consequently the response of irradiated tissues might be different. Therefore, specific TRT radiobiology needs to be explored. Determining dose–effect correlation is also a prerequisite for rigorous preclinical radiobiology studies because dosimetry provides the necessary referential to all TRT situations. It is required too for developing patient-tailored TRT in the clinic in order to estimate the best dose for tumor control, while protecting the healthy tissues, thereby improving therapeutic efficacy. Finally, it will allow to determine the relative contribution of targeted effects (assumed to be dose-related) and non-targeted effects (assumed to be non-dose-related) of ionizing radiation. However, conversely to EBRT where it is routinely used, dosimetry is still challenging in TRT. Therefore, it constitutes with radiobiology, one of the main challenges of TRT in the future.

Apoptosis and p53 are not involved in the anti-tumor efficacy of 125I-labeled monoclonal antibodies targeting the cell membrane

INTRODUCTION (125)I-labeled monoclonal antibodies ((125)I-mAbs) can efficiently treat small solid tumors. Here, we investigated the role of apoptosis, autophagy and mitotic catastrophe in (125)I-mAb toxicity in p53(-/-) and p53(+/+) cancer cells. METHODS We exposed p53(-/-) and p53(+/+) HCT116 cells to increasing activities of internalizing (cytoplasmic location) anti-HER1 (125)I-mAbs, or non-internalizing (cell surface location) anti-CEA (125)I-mAbs. For each targeting model we established the relationship between survival and mean nucleus absorbed dose using the MIRD formalism. RESULTS In both p53(-/-) and p53(+/+) HCT116 cells, anti-CEA (125)I-mAbs were more cytotoxic per Gy than anti-HER1 (125)I-mAbs. Sensitivity to anti-CEA (125)I-mAbs was p53-independent, while sensitivity to anti-HER1 (125)I-mAbs was higher in p53(-/-) HCT 116 cells, suggesting that they act through different signaling pathways. Apoptosis was only induced in p53(+/+) HCT116 cells and could not explain cell membrane radiation sensitivity. Inhibition of autophagy did not modify the cell response to (125)I-mAbs. By contrast, mitotic death was similarly induced in both p53(-/-) and p53(+/+) HCT116 cells by the two types of (125)I-mAbs. We also showed using medium transfer experiments that γ-H2AX foci were produced in bystander cells. CONCLUSION Cell membrane sensitivity to (125)I-mAbs is not mediated by apoptosis and is p53-independent. Bystander effects-mediated mitotic death could be involved in the efficacy of (125)I-mAbs binding cell surface receptors.

Glucose metabolism in nine patients with probable sporadic Creutzfeldt–Jakob disease: FDG-PET study using SPM and individual patient analysis

Only one large series using statistical parametric mapping (SPM) reports on FDG-PET in sporadic (Heidenhain and non-Heidenhain variant) Creutzfeldt–Jakob disease (sCJD), describing hypometabolism in bilateral parietal, frontal, and occipital cortices. Our aim was to study FDG-PET in non-Heidenhain probable sCJD patients in order to assess the most pertinent FDG-PET pattern, and to compare FDG-PET and MRI data. We used both SPM and NeuroGam® software analysis, compared with healthy controls, to describe the FDG-PET abnormalities. Individual FDG-PET and MRI–DWI data were compared. SPM group analysis showed lateralized hypometabolism in the medial parietal cortex, the lateral and medial frontal (sparing Brodmann’s area 4 and 6 and the anterior cingulate cortex), and lateral parietal cortex, in the absence of basal ganglia or cerebellar hypometabolism. The most severe hypometabolism was seen in Brodmann’s area 31, and to a lesser degree area 23 (both areas correspond to the posterior cingulate cortex) and the precuneus. On individual analysis using NeuroGam® software, additional variable temporal cortex and frequent basal ganglia (with caudate nucleus as the most frequently involved structure) hypometabolism was seen, in the absence of cerebellar hypometabolism. The cerebral lobe cortex was more frequently and more severely hypometabolic than basal ganglia structures. Concordance between FDG-PET and MRI abnormalities was most often present for both the cerebral lobe cortex and the basal ganglia. In the case of discordance, FDG-PET was more sensitive than MRI for the cortex, whereas MRI was more sensitive than FDG-PET for the basal ganglia. When pathological, both cortical lobe cortex and basal ganglia involvement were slightly more often lateralized on FDG-PET than on MRI. Despite the presence of overlapping features with other diseases presenting with rapidly progressive dementia, the FDG-PET pattern we found in our non-Heidenhain sCJD patients may help in the differential diagnosis of rapidly progressive dementia.

DNA damage-centered signaling pathways are effectively activated during low dose-rate Auger radioimmunotherapy

INTRODUCTION Low dose-rate radioimmunotherapy (RIT) using (125)I-labelled monoclonal antibodies ((125)I-mAbs) is associated with unexpected high cytotoxicity per Gy. METHODS We investigated whether this hypersensitivity was due to lack of detection of DNA damage by the targeted cells. DNA damage was measured with the alkaline comet assay, gamma-H2AX foci and the micronucleus test in p53(-/-) and p53(+/+) HCT116 cells exposed to increasing activities of internalizing anti-HER1 (125)I-mAbs or non-internalizing anti-CEA (125)I-mAbs. The expression of proteins involved in radiation response and progression of cells through the cycle were determined. RESULTS Cell hypersensitivity to low absorbed doses of anti-CEA (125)I-mAbs was not due to defect in DNA damage detection, since ATM (ataxia telangiectasia mutated gene), gamma-H2AX, p53 and p21 were activated in RIT-treated HCT116 cells and G2/M cell cycle arrest was observed. Moreover, the alkaline comet assay showed that DNA breaks accumulated when cells were placed at 4°C during exposure but were repaired under standard RIT conditions (37°C), suggesting that lesions detected under alkaline conditions (mostly DNA single strand breaks and alkali-labile sites) are efficiently repaired in treated cells. The level of gamma-H2AX protein corroborated by the level of foci measured in nuclei of treated cells was shown to accumulate with time thereby suggesting the continuous presence of DNA double strand breaks. This was accompanied by the formation of micronuclei. CONCLUSION Hypersensitivity to non-internalizing (125)I-mAbs is not due to lack of detection of DNA damage after low absorbed dose-rates. However, DNA double strand breaks accumulate in cells exposed both to internalizing and non-internalizing (125)I-mAbs and lead to micronuclei formation. These results suggest impairment in DNA double strand breaks repair after low absorbed doses of (125)I-mAbs.

Assessment of the Stratos, a New Pencil-Beam Bone Densitometer: Dosimetry, Precision, and Cross Calibration

The goal of this study was to assess a new pencil-beam densitometer, the Stratos (Diagnostic Medical Systems, Pérols, France). Evaluation of the dosimetry and precision were done together with an in vivo cross-calibration study performed with the fan beam densitometer Discovery A (Hologic, Bedford, MA). The results indicated that the Stratos performed bone mineral density (BMD) measurements with a good precision, low radiation dose, and good agreement with the Discovery A. The air dose, measured by an ionization chamber, was 40 μGy. The effective dose was assessed using an anthropomorphic phantom and thermoluminescent detectors resulting in 1.96 and 0.31 μSv for a lumbar spine and proximal femur scan, respectively. The average scattered dose rate at a distance of 1m from the device was 1.06 and 1.21 μSv.h(-1) in the lumbar spine and left proximal femur scan mode, respectively. For the precision evaluation, 30 patients underwent 2 lumbar spine and 2 proximal femur scans with repositioning after each scan. The percentage root-mean-square coefficient of variation was 1.22%, 1.38%, 2.11%, and 0.86% for the lumbar spine (L1-L4), lumbar spine (L2-L4), femoral neck, and total hip, respectively. The cross-calibration studies were done on 57 patients (60 ± 9 yr). Lumbar spine, left neck, and left total hip mean BMD were 3.10% lower and 11.94% and 8.83% higher, respectively, with the Stratos compared with the Discovery A. Cross-calibration equations were calculated with a correlation coefficient of 98% (p<0.01) for the lumbar spine (L2-L4), 94% (p<0.01) for the left neck, and 92% (p<0.01) for the left total hip. After standardizing the Stratos measures using the cross-calibration equations, LINs concordance correlation coefficient was 0.98, 0.93, and 0.92 for the lumbar spine (L2-L4), left neck, and total hip, respectively.

Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects.

Abstract Aims: We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 (monoclonal antibodies labeled with 125I [125I-mAbs]). Results: We showed that the cytotoxicity of 125I-mAbs targeting the cell membrane of p53+/+ HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-β-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. 125I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase ½ (ERK1/2), p38 kinase, c-Jun N-terminal kinase (JNK) signaling pathways, and also of phospholipase C-γ (PLC-γ), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca2+ fluxes. Moreover, the nontargeted response induced by directing 5-[(125)I]iodo-2′-deoxyuridine to the nucleus was comparable to that of 125I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by 125I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also. Innovation: Low-energy Auger electrons, such as those emitted by 125I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with 125I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting. Conclusion: Our findings describe the mechanisms involved in the efficacy of 125I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal. 25, 467–484.