NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells.

BACKGROUND: Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Despite current therapies, the morbidity and recurrent risk remains significant. Neuropilin-1 receptor (NRP1) has been implicated in the tumor progression of MB. Our recent study showed that NRP1 inhibition stimulated MB stem cells differentiation. Consequently, we hypothesized that targeting NRP1 in medulloblastoma could improve current treatments. METHODS: NRP1 inhibition with a novel peptidomimetic agent, MR438, was evaluated with radiotherapy (RT) in MB models (DAOY, D283-Med and D341-Med) in vitro on cancer stem-like cells as well as in vivo on heterotopic and orthotopic xenografts. RESULTS: We show that NRP1 inhibition by MR438 radiosensitizes MB stem-like cells in vitro. In heterotopic DAOY models, MR438 improves RT efficacy as measured by tumor growth and mouse survival. In addition, clonogenic assays after tumor dissociation showed a significant reduction in cancer stem cells with the combination treatment. In the same way, a benefit of the combined therapy was observed in the orthotopic model only for a low cumulative irradiation dose of 10 Gy but not for 20 Gy. CONCLUSIONS: Finally, our results demonstrated that targeting NRP1 with MR438 could be a potential new strategy and could limit MB progression by decreasing the stem cell number while reducing the radiation dose.

Clinical evaluation of a device providing simultaneous white-light and fluorescence video streams as well as panoramic imaging during fluorescence assisted-transurethral resection of bladder cancer.

The current clinical study is aimed at evaluating the clinical relevance of an innovative device (called CyPaM2 device) that for the first time provides urologists with (i) a panoramic image of the bladder inner wall within the surgery time, and with (ii) a simultaneous (bimodal) display of fluorescence and white-light video streams during the fluorescence assisted-transurethral resection of bladder cancers procedure. The clinical relevance of this CyPaM2 device was evaluated on 10 patients according to three criteria (image quality, fluorescent lesions detection relevance, and ergonomics) compared with a reference medical device. Innovative features displayed by the CyPaM2 device were evaluated without any possible comparison: (i) simultaneous bimodal display of white-light and fluorescence video streams, (ii) remote light control, and (iii) time delay for the panoramic image building. The results highlight the progress to achieve in order to obtain a fully mature device ready for commercialization and the relevance of the innovative features proposed by the CyPaM2 device confirming their interest.

Heart rate and respiration influence on macroscopic blood and CSF flows.

Background Changes in blood volume in the intracranial arteries and the resulting oscillations of brain parenchyma have been presumed as main initiating factors of cerebrospinal fluid (CSF) pulsations. However, respiration has been recently supposed to influence CSF dynamics via thoracic pressure changes. Purpose To measure blood and CSF cervical flow and quantify the contribution of cardiac and respiratory cycles on the subsequent signal evolution. Material and Methods Sixteen volunteers were enrolled. All participant underwent two-dimensional fast field echo echo planar imaging (FFE-EPI). Regions of interest were placed on internal carotids, jugular veins, and rachidian canal to extract temporal profiles. Spectral analysis was performed to extract respiratory and cardiac frequencies. The contribution of respiration and cardiac activity was assessed to signal evolution by applying a multiple linear model. Results Mean respiratory frequency was 14.6 ± 3.9 cycles per min and mean heart rate was 66.8 ± 9 cycles per min. Cardiac contribution was higher than breathing for internal carotids, explaining 74.68% and 10.27% of the signal variance, respectively. For the jugular veins, respiratory component was higher than the cardiac one contributing 44.28% and 6.53% of the signal variance, respectively. For CSF, breathing and cardiac component contributed less than half of signal variance (12.61% and 23.23%, respectively). Conclusion Respiration and cardiac activity both influence fluid flow at the cervical level. Arterial inflow is driven by the cardiac pool whereas venous blood aspiration seems more due to thoracic pressure changes. CSF dynamics acts as a buffer between these two blood compartments.

Relationship between cerebrospinal fluid flow, ventricles morphology, and DTI properties in internal capsules: differences between Alzheimer's disease and normal-pressure hydrocephalus.

BACKGROUND: Normal-pressure hydrocephalus (NPH) and Alzheimer's disease (AD) have some similar clinical features and both involve white matter and cerebrospinal fluid (CSF) disorders. PURPOSE: To compare putative relationships between ventricular morphology, CSF flow, and white matter diffusion in AD and NPH. MATERIAL AND METHODS: Thirty patients (18 with AD and 12 with suspected NPH) were included in the study. All patients underwent a 3-Tesla MRI scan, which included phase-contrast MRI of the aqueduct (to assess the aqueductal CSF stroke volume) and a DTI session (to calculate the fractional anisotropy [FA] and apparent diffusion coefficient [ADC]) in the internal capsules). RESULTS: FA was correlated with ventricular volume in the suspected NPH population (P < 0.001; rs = 0.88), whereas the ADC was highly correlated with the aqueductal CSF stroke volume in AD (P < 0.001; rs = 0.79). CONCLUSION: Although AD and NPH both involve CSF disorders, the two diseases do not have the same impact on the internal capsules. The magnitude of the ADC is related to the aqueductal CSF stroke volume in AD, whereas FA is related to ventricular volume in NPH.

Added Value of Scintillating Element in Cerenkov-Induced Photodynamic Therapy.

Cerenkov-induced photodynamic therapy (CR-PDT) with the use of Gallium-68 (68Ga) as an unsealed radioactive source has been proposed as an alternative strategy to X-ray-induced photodynamic therapy (X-PDT). This new strategy still aims to produce a photodynamic effect with the use of nanoparticles, namely, AGuIX. Recently, we replaced Gd from the AGuIX@ platform with Terbium (Tb) as a nanoscintillator and added 5-(4-carboxyphenyl succinimide ester)-10,15,20-triphenylporphyrin (P1) as a photosensitizer (referred to as AGuIX@Tb-P1). Although Cerenkov luminescence from 68Ga positrons is involved in nanoscintillator and photosensitizer activation, the cytotoxic effect obtained by PDT remains controversial. Herein, we tested whether free 68Ga could substitute X-rays of X-PDT to obtain a cytotoxic phototherapeutic effect. Results were compared with those obtained with AGuIX@Gd-P1 nanoparticles. We showed, by Monte Carlo simulations, the contribution of Tb scintillation in P1 activation by an energy transfer between Tb and P1 after Cerenkov radiation, compared to the Gd-based nanoparticles. We confirmed the involvement of the type II PDT reaction during 68Ga-mediated Cerenkov luminescence, id est, the transfer of photon to AGuIX@Tb-P1 which, in turn, generated P1-mediated singlet oxygen. The effect of 68Ga on cell survival was studied by clonogenic assays using human glioblastoma U-251 MG cells. Exposure of pre-treated cells with AGuIX@Tb-P1 to 68Ga resulted in the decrease in cell clone formation, unlike AGuIX@Gd-P1. We conclude that CR-PDT could be an alternative of X-PDT.

Targeting Glioblastoma-Associated Macrophages for Photodynamic Therapy Using AGuIX®-Design Nanoparticles.

Glioblastoma (GBM) is the most difficult brain cancer to treat, and photodynamic therapy (PDT) is emerging as a complementary approach to improve tumor eradication. Neuropilin-1 (NRP-1) protein expression plays a critical role in GBM progression and immune response. Moreover, various clinical databases highlight a relationship between NRP-1 and M2 macrophage infiltration. In order to induce a photodynamic effect, multifunctional AGuIX®-design nanoparticles were used in combination with a magnetic resonance imaging (MRI) contrast agent, as well as a porphyrin as the photosensitizer molecule and KDKPPR peptide ligand for targeting the NRP-1 receptor. The main objective of this study was to characterize the impact of macrophage NRP-1 protein expression on the uptake of functionalized AGuIX®-design nanoparticles in vitro and to describe the influence of GBM cell secretome post-PDT on the polarization of macrophages into M1 or M2 phenotypes. By using THP-1 human monocytes, successful polarization into the macrophage phenotypes was argued via specific morphological traits, discriminant nucleocytoplasmic ratio values, and different adhesion abilities based on real-time cell impedance measurements. In addition, macrophage polarization was confirmed via the transcript-level expression of TNFα, CXCL10, CD-80, CD-163, CD-206, and CCL22 markers. In relation to NRP-1 protein over-expression, we demonstrated a three-fold increase in functionalized nanoparticle uptake for the M2 macrophages compared to the M1 phenotype. The secretome of the post-PDT GBM cells led to nearly a three-fold increase in the over-expression of TNFα transcripts, confirming the polarization to the M1 phenotype. The in vivo relationship between post-PDT efficiency and the inflammatory effects points to the extensive involvement of macrophages in the tumor zone.

Importance of Rose Bengal Loaded with Nanoparticles for Anti-Cancer Photodynamic Therapy.

Rose Bengal (RB) is a photosensitizer (PS) used in anti-cancer and anti-bacterial photodynamic therapy (PDT). The specific excitation of this PS allows the production of singlet oxygen and oxygen reactive species that kill bacteria and tumor cells. In this review, we summarize the history of the use of RB as a PS coupled by chemical or physical means to nanoparticles (NPs). The studies are divided into PDT and PDT excited by X-rays (X-PDT), and subdivided on the basis of NP type. On the basis of the papers examined, it can be noted that RB used as a PS shows remarkable cytotoxicity under the effect of light, and RB loaded onto NPs is an excellent candidate for nanomedical applications in PDT and X-PDT.

Respiratory-gated 18F-FDG PET imaging in lung cancer: effects on sensitivity and specificity.

BACKGROUND: Respiratory motion is known to deteriorate positron emission tomography (PET) images and may lead to potential diagnostic errors when a standardized uptake value (SUV) cut-off threshold is used to discriminate between benign and malignant lesions. PURPOSE: To evaluate and compare ungated and respiratory-gated 18F-fluorodeoxyglucose PET/computed tomography (CT) methods for the characterization of pulmonary nodules. MATERIAL AND METHODS: The list-mode acquisition during respiratory-gated PET was combined with a short breath-hold CT scan to form the CT-based images. We studied 48 lesions in 43 patients. PET images were analyzed in terms of the maximum SUV (SUV(max)) and the lesion location. RESULTS: Using receiver-operating characteristic (ROC) curves, the optimal SUV cut-off thresholds for the ungated and CT-based methods were calculated to be 2.0 and 2.2, respectively. The corresponding sensitivity values were 83% and 92%, respectively, with a specificity of 67% for both methods. The two methods gave equivalent performance levels for the upper and middle lobes (sensitivity 93%, specificity 62%). They differed for the lower lobes, where the CT-based method outperformed the ungated method (sensitivity values of 90% and 70%, respectively, and a specificity of 73% with both methods) - especially for lesions smaller than 15 mm. CONCLUSION: The CT-based method increased sensitivity and did not diminish specificity, compared with the ungated method. It was more efficient than the ungated method for imaging the lower lobes and smallest lesions, which are most affected by respiratory motion.

Ophthalmic Artery and Superior Ophthalmic Vein Blood Flow Dynamics in Glaucoma Investigated by Phase Contrast Magnetic Resonance Imaging.

PRECIS: Ophthalmic artery (OA) and superior ophthalmic vein (SOV) blood flow were quantified by phase contrast magnetic resonance imaging (PC MRI) and seemed lower in glaucoma. Venous flow dynamics was different in glaucoma patients with a significantly decreased pulsatility. INTRODUCTION: Studies using color Doppler imaging and optical coherence tomography flowmetry strongly suggested that vascular changes are involved in the pathophysiology of glaucoma, but the venous outflow has been little studied beyond the episcleral veins. This study measured the OA and the SOV flow by PC MRI in glaucoma patients compared with controls. METHODS: Eleven primary open-angle glaucoma patients, with a mean±SD visual field deficit of -2.3±2.7 dB and retinal nerve fiber layer thickness of 92±13 µ, and 10 controls of similar age, were examined by PC MRI. The mean, maximal and minimal flow over cardiac cycle were measured. The variation of flow (ΔQ) was calculated. RESULTS: The OA mean±SD mean flow was 13.21±6.79 in patients and 15.09±7.62 mL/min in controls (P=0.35) and the OA maximal flow was 25.70±12.08 mL/min in patients, and 28.45±10.64 mL/min in controls (P=0.22). In the SOV the mean±SD mean flow was 6.46±5.50 mL/min in patients and 7.21±6.04 mL/min in controls (P=0.81) and the maximal flow was 9.06±6.67 in patients versus 11.96±9.29 mL/min in controls (P=0.47). The ΔQ in the SOV was significantly lower in patients (5.45±2.54 mL/min) than in controls (9.09±5.74 mL/min) (P=0.04). DISCUSSION: Although no significant difference was found, the mean and maximal flow in the OA and SOV seemed lower in glaucoma patients than in controls. The SOV flow waveform might be affected in glaucoma, corroborating the hypothesis of an impairment of venous outflow in those patients.

Terbium-Based AGuIX-Design Nanoparticle to Mediate X-ray-Induced Photodynamic Therapy.

X-ray-induced photodynamic therapy is based on the energy transfer from a nanoscintillator to a photosensitizer molecule, whose activation leads to singlet oxygen and radical species generation, triggering cancer cells to cell death. Herein, we synthesized ultra-small nanoparticle chelated with Terbium (Tb) as a nanoscintillator and 5-(4-carboxyphenyl succinimide ester)-10,15,20-triphenyl porphyrin (P1) as a photosensitizer (AGuIX@Tb-P1). The synthesis was based on the AGuIX@ platform design. AGuIX@Tb-P1 was characterised for its photo-physical and physico-chemical properties. The effect of the nanoparticles was studied using human glioblastoma U-251 MG cells and was compared to treatment with AGuIX@ nanoparticles doped with Gadolinium (Gd) and P1 (AguIX@Gd-P1). We demonstrated that the AGuIX@Tb-P1 design was consistent with X-ray photon energy transfer from Terbium to P1. Both nanoparticles had similar dark cytotoxicity and they were absorbed in a similar rate within the cells. Pre-treated cells exposure to X-rays was related to reactive species production. Using clonogenic assays, establishment of survival curves allowed discrimination of the impact of radiation treatment from X-ray-induced photodynamic effect. We showed that cell growth arrest was increased (35%-increase) when cells were treated with AGuIX@Tb-P1 compared to the nanoparticle doped with Gd.

Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma.

BACKGROUND: Local recurrences of glioblastoma (GBM) after heavy standard treatments remain frequent and lead to a poor prognostic. Major challenges are the infiltrative part of the tumor tissue which is the ultimate cause of recurrence. The therapeutic arsenal faces the difficulty of eradicating this infiltrating part of the tumor tissue while increasing the targeting of tumor and endogenous stromal cells such as angiogenic endothelial cells. In this aim, neuropilin-1 (NRP-1), a transmembrane receptor mainly overexpressed by endothelial cells of the tumor vascular system and associated with malignancy, proliferation and migration of GBM, highlighted to be a relevant molecular target to promote the anti-vascular effect of photodynamic therapy (VTP). METHODS: The multiscale selectivity was investigated for KDKPPR peptide moiety targeting NRP-1 and a porphyrin molecule as photosensitizer (PS), both grafted onto original AGuIX design nanoparticle. AGuIX nanoparticle, currently in Phase II clinical trials for the treatment of brain metastases with radiotherapy, allows to achieve a real-time magnetic resonance imaging (MRI) and an accumulation in the tumor area by EPR (enhanced permeability and retention) effect. Using surface-plasmon resonance (SPR), we evaluated the affinities of KDKPPR and scramble free peptides, and also peptides-conjugated AGuIX nanoparticles to recombinant rat and human NRP-1 proteins. For in vivo selectivity, we used a cranial window model and parametric maps obtained from T2*-weighted perfusion MRI analysis. RESULTS: The photophysical characteristics of the PS and KDKPPR molecular affinity for recombinant human NRP-1 proteins were maintained after the functionalization of AGuIX nanoparticle with a dissociation constant of 4.7 µM determined by SPR assays. Cranial window model and parametric maps, both revealed a prolonged retention in the vascular system of human xenotransplanted GBM. Thanks to the fluorescence of porphyrin by non-invasive imaging and the concentration of gadolinium evaluated after extraction of organs, we checked the absence of nanoparticle in the brains of tumor-free animals and highlighted elimination by renal excretion and hepatic metabolism. CONCLUSION: Post-VTP follow-ups demonstrated promising tumor responses with a prolonged delay in tumor growth accompanied by a decrease in tumor metabolism.

A practical way to improve contrast-to-noise ratio and quantitation for statistical-based iterative reconstruction in whole-body PET imaging.

In whole-body positron emission tomography (PET) imaging, the detection of small uptake foci (i.e., around two or three times the tomograph's spatial resolution) is a critical issue. Indeed, spatial resolution is altered by postreconstruction smoothing operations used to reduce the noise introduced by (among other things) an inaccurate system matrix. The authors previously proposed a device-dedicated projector, easily applicable on a clinical gantry, based on point-source measurements, which introduces less noise than a geometrical model. In the present study, they took advantage of the lower noise levels by reducing the postfilter and then quantified the approach's impact on image quality. This study was performed on an IEC Body Phantom Set filled with 18F (sphere-to-background activity ratio: 4:1). The same 3 min acquisition was reconstructed with either (i) a clinical system based on a geometrical tomographic operator (OSEM_CL) or (ii) an OSEM algorithm using the suggested system matrix (OSEM_DR). In order to compare the resulting images, they set the 3D Gaussian postfilter (3DGPF) for OSEM_DR so as to obtain similar background signal-to-noise ratio (SNR) to that of OSEM_CL with a Gaussian postfilter full width at half maximum of 5 mm (as recommended for whole-body imaging on a Biograph6). They then assessed the contrast-to-noise ratio (CNR) and quantitation [contrast recovery (CR)] for the phantom's four smallest spheres (with internal diameters of 10, 13, 17, and 22 mm). Evaluation of 3DGPFs ranging from 2.2 to 2.6 mm showed that a value of 2.4 mm in OSEM_DR gave the closest background SNR to that of OSEM_CL with a 3DGPF of 5 mm. For all studied targets, the CNR was higher with OSEM_DR than with OSEM_CL. For the 10 and 13 mm spheres, OSEM_DR increased the size of the CNR peaks by 37% and 20%, relative to OSEM_CL. The OSEM_DR technique yielded higher CR values than OSEM_CL did. For the 10, 13, 17, and 22 mm spheres, the CR values at eight iterations were 0.5, 0.6, 1.1, and 1.0 for OSEM_DR and 0.3, 0.4, 0.9, and 0.8 for OSEM_CL. They evaluated a practical method for determining a device-dedicated system matrix based on point-source acquisitions. This tomographic operator is more realistic than geometrical system matrix and introduces less noise into PET images during statistical reconstruction; it thus reduces the extent of postfiltering operations required. Thus, spatial resolution is better maintained with OSEM_DR than with clinical reconstruction. They showed that this method improves the contrast-to-noise ratio and quantification of uptake foci (especially those that are at the system's limit of detection) and, in a clinical context, could allow better detection and earlier diagnosis.

Radiation-Induced Mitotic Catastrophe Enhanced by Gold Nanoparticles: Assessment with a Specific Automated Image Processing Workflow.

In recent years, the use of gold-based nanoparticles in radiotherapy has been extensively studied, and the associated radiosensitization mechanism has been evaluated in a variety of in vitro studies. Given that mitotic catastrophe is widely involved in radiation-induced cell death, we evaluated the effect of gold nanoparticles on this key event. Most of the methods currently used to visualize and quantify morphological changes and multinucleation are manual. To circumvent this time-consuming step, we developed and optimized an image processing workflow (based on freely accessible software and plugins) for the automated quantification of mitotic catastrophes. We validated this approach in three cell lines by comparing the number of radiation-induced mitotic catastrophes detected using the automated and manual methods in the presence and absence of nanoparticles. With the Bland-Altman analysis, the automated and manual counting methods were found to be fully interchangeable. The ultimate goal of this work was to determine whether mitotic catastrophe was critically involved in radiationinduced cell death after prior exposure to gold nanoparticles. In the radioresistant U87 cell line, exposure to gold nanoparticles was associated with a shorter time course for the events related to mitotic catastrophe, which peaked at 96 h postirradiation. Mitotic catastrophe was dose-dependent in both the presence and absence of gold nanoparticles. These results demonstrate that cell exposure to gold nanoparticles led to an increase in mitotic catastrophe events, and confirm the marked radiosensitizing effect observed in clonogenic assays.

Initial clinical results for breath-hold CT-based processing of respiratory-gated PET acquisitions.

PURPOSE: Respiratory motion causes uptake in positron emission tomography (PET) images of chest structures to spread out and misregister with the CT images. This misregistration can alter the attenuation correction and thus the quantisation of PET images. In this paper, we present the first clinical results for a respiratory-gated PET (RG-PET) processing method based on a single breath-hold CT (BH-CT) acquisition, which seeks to improve diagnostic accuracy via better PET-to-CT co-registration. We refer to this method as "CT-based" RG-PET processing. METHODS: Thirteen lesions were studied. Patients underwent a standard clinical PET protocol and then the CT-based protocol, which consists of a 10-min List Mode RG-PET acquisition, followed by a shallow end-expiration BH-CT. The respective performances of the CT-based and clinical PET methods were evaluated by comparing the distances between the lesions' centroids on PET and CT images. SUV(MAX) and volume variations were also investigated. RESULTS: The CT-based method showed significantly lower (p = 0.027) centroid distances (mean change relative to the clinical method = -49%; range = -100% to 0%). This led to higher SUV(MAX) (mean change = +33%; range = -4% to 69%). Lesion volumes were significantly lower (p = 0.022) in CT-based PET volumes (mean change = -39%: range = -74% to -1%) compared with clinical ones. CONCLUSIONS: A CT-based RG-PET processing method can be implemented in clinical practice with a small increase in radiation exposure. It improves PET-CT co-registration of lung lesions and should lead to more accurate attenuation correction and thus SUV measurement.

Improved attenuation correction via appropriate selection of respiratory-correlated PET data.

PURPOSE: We propose a respiratory-correlated PET data processing method (called "BH-CT-based") based on breath-hold CT acquisition to reduce the smearing effect and improve the attenuation correction. The resulting images are compared with the ungated PET images acquired using a standard, free-breathing clinical protocol. METHODS: The BH-CT-based method consisted of a list-mode acquisition with simultaneous respiratory signal recording. An additional breath-hold CT acquisition was also performed in order to define a tissue position from which PET events can be selected. A phantom study featured a 0.5-ml sphere (filled with 18F-fluorodeoxyglucose ((18)F-FDG) solution) pushed onto a rubber balloon (filled with (18)F-FDG solution and iodinated contrast agent). The feasibility of the BH-CT-based method was also assessed in two patients. RESULTS: In the phantom study, the contrast-to-noise ratios (CNRs) were -1.6 for the Ungated volume and 5.1 for the BH-CT-based volume. For patients, CNRs were higher for BH-CT-based volumes than those for Ungated volumes (17.3 vs. 6.3 and 7.3 vs. 3.8, for patients 1 and 2, respectively). Bias-variance measurements were performed and yielded bias reduction of 40% with BH-CT-based. CONCLUSION: The application of a BH-CT-based method decreases motion bias in PET images. This method resolves issues related to both PET-to-CT misregistration and erroneous attenuation correction and increases lesion detectability.

Benefits of respiratory-gated 18F-FDG PET acquisition in lung disease.

BACKGROUND: Fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) is a reliable imaging modality for the diagnosis of malignant lung nodules and to assess the latter's prognosis. However, physiological respiratory motion deteriorates PET images and thus decreases the technique's diagnostic and prognostic values. This issue can be overcome by applying respiratory gating to the F-FDG PET/CT acquisitions. PURPOSE: The aim of this study was to evaluate the ability of respiratory-gated F-FDG PET/CT to diagnose malignant lung nodules and to predict recurrence and patient survival. PATIENTS AND METHODS: A total of 103 prospectively enrolled patients with solid lung nodules underwent both ungated and gated F-FDG PET/CT acquisitions. The maximum standardized uptake value (SUVmax) was used to differentiate benign from malignant nodules. Patients have been followed up for at least 36 months to confirm imaging results and assess survival. RESULTS: Gated F-FDG PET/CT was significantly more sensitive than ungated PET/CT for the diagnosis of malignant lung nodules located in the lower lobes (92 vs. 58%; P<0.001) and in patients aged older than 60 years (73 vs. 48%; P<0.001). The same gain was observed for stage I cancers with tumors from 10 to 20 mm. When considering patients aged older than 60 years, those with a low SUVmax on gated PET images had a significantly higher 3-year disease-free survival rate than those with a high SUVmax (76 vs. 47%; P=0.03). CONCLUSION: F-FDG PET/CT is advisable for the assessment of lung nodules in patients aged older than 60 years and/or in the lower lobes.

Is VLSM a valid tool for determining the functional anatomy of the brain? Usefulness of additional Bayesian network analysis.

OBJECTIVES: The ability of voxel-based lesion-symptom mapping (VLSM) to define the functional anatomy of the human brain has not been fully assessed. With a view to assessing VLSM's validity, the present study analyzed the technique's ability to determine the known clinical-anatomic correlates of hemiparesis in stroke patients. DESIGN: Lesions (damaged in at least 5 patients) associated with transformed limb motor score (after adjustment on lesion volume) at 6 months were examined in 272 patients using VLSM. The value of additional multivariable linear, logistic and Bayesian analyses was examined. RESULTS: We first checked that motor hemiparesis was fully accounted for by corticospinal tract (CST) lesions (sensitivity = 100%; p = 0.0001). Conventional VLSM analysis flagged up 2 regions corresponding to the CST, but also 8 regions located outside the CST. All 10 brain regions achieving statistical significance in the VLSM analysis were submitted to 3 additional analyses. The backward linear regression analysis selected 5 regions, one only corresponding to the CST (R2: 0.03, p = 0.0008). The logistic regression analysis selected correctly the CST (OR: 2.39, 95%CI: 1.44-3.96; 0.001). The Bayesian network analysis selected regions including the CST (in 92% of 3000 bootstrap replications) and identified the source of multicollinearity. These lesions evaluated by structural equation modeling resulted in an excellent fit (p-value = 0.228, chi/df = 1.19, RMSEA = 0.032, CFI = 0.999). Analyses of confusion factors showed that conventional VLSM analyses were strongly influenced by lesion frequency (R2 = 0.377; p = 0.0001) and multicollinearity. CONCLUSIONS: Conventional VLSM analyses are sensitive but weakened by a type I error due to the combined effects of multicollinearity and lesion frequency. We demonstrate that the addition of a Bayesian network analysis, and to a lesser extent of logistic regression, controlled for this type I error and constituted a reliable means of defining the functional anatomy of the motor system in stroke patients.

Effect of tomographic operator inaccuracies and respiratory motion on PET/CT lung nodule images smearing.

BACKGROUND: In thoracic PET/computed tomography (CT) imaging, uptake foci usually appear smeared because of postreconstruction smoothing and respiratory motion. OBJECTIVE: The aim of the present study was to assess the respective contributions of the reconstruction process and respiratory motion on PET/CT images. MATERIALS AND METHODS: Thirty-one pulmonary lesions were studied. Free-breathing PET/CT acquisitions were followed by a 10-min respiratory-gated PET/CT acquisition. Four different reconstructions were performed by combining two different tomographic operators (TOs) (i.e. the geometric clinical system matrix or a system matrix including the detector response) and taking account (or not) of respiratory motion using a previously developed 'CT-based' technique. For each reconstruction method, lesion segmentation was performed with an adaptive threshold. Next, we computed the volume differences between each reconstruction. Finally, we applied a multiple linear model to compute the relative contributions of TO-based and CT-based respiratory compensation to lesion volume. RESULTS: The three groups, combining the reconstruction methods and the respiratory compensation (or not), differed significantly in terms of the volume differences. For all lesions, the full linear model yielded a regression coefficient R of 76.10%. The partial R values were 65.58 and 10.52% for the detector response operator and the CT-based method, respectively. For lesions in the upper/middle lobes, blurring was mainly because of TO (partial R=78.53%), whereas, for lower lobe lesions, smearing was mainly because of respiratory motion (partial R=56.76%). CONCLUSION: Our results showed that image reconstruction, by TO accuracy, was the main explanatory factor for lesion smearing when considering the chest as a whole. Respiration had a major impact on the lower lobes.

Ocular blood flow and cerebrospinal fluid pressure in glaucoma.

Disease mechanism underlying glaucoma remains unclear. Extensive research on this pathology has highlighted changes in vascular parameters and in circulation of the cerebrospinal fluid (CSF). Here, we review the most recent research on alterations in ocular blood flow and/or CSF flow in glaucoma. Ultrasound Doppler imaging studies have shown an increased resistive index in ophthalmic artery's in glaucoma. Furthermore, changes in optic nerve CSF circulation, which can be assessed with magnetic resonance imaging, may lead to a greater translaminar pressure difference, mechanical stress, and poor clearance of toxic substances. This constitutes a new approach for understanding blood-CSF interactions involved in glaucoma.

Use of dynamic (18)F-fluorodeoxyglucose positron emission tomography to investigate choroid plexus function in Alzheimer's disease.

Choroid plexuses (CPs) are structures involved in CSF production and cerebral regulation and present atypical glucose metabolism. In addition, CPs impairment may be related to Alzheimer disease (AD). In the present study, we present the first results pointing out glucose metabolism in the CP with dynamic fluorodeoxyglucose positron emission tomography (dynamic (18)F-FDG-PET). We studied 47 elderly adults who were classified into three classes: healthy subjects (HS), amnestic mild cognitive impairment (aMCI) and AD. All participants have undergone dynamic (18)F-FDG-PET for 45 min. Acquisitions were divided into 34 frames to extract tissue time-activity curves (TTACs) in various structures including CSF and CPs. Results showed a decreased CPs (18)F-FDG metabolism in AD compared with aMCI and HS. Conversely, dynamic uptake was higher in CSF for AD compared with the other groups. ROC analysis showed that CPs TTACs are a promising tool as it yielded sensitivity of 85.7% and a specificity of 83.3%. Our study showed a disturbance of glucose exchange at the blood-CSF barrier level which is in favour of a key-role of the CPs in AD.