Baseline [18F]FDG PET features are associated with survival and toxicity in patients treated with CAR T cells for large B cell lymphoma.

PURPOSE: Chimeric antigen receptor (CAR) T cells have established themselves as an effective treatment for refractory or relapsed large B cell lymphoma (LBCL). Recently, the sDmax, which corresponds to the distance separating the two farthest lesions standardized by the patient's body surface area, has appeared as a prognostic factor in LBCL. This study aimed to identify [18F]FDG-PET biomarkers associated with prognosis and predictive of adverse events in patients treated with CAR T cells. METHODS: Patients were retrospectively included from two different university hospitals. They were being treated with CAR T cells for LBCL and underwent [18F]FDG-PET just before CAR T cell infusion. Lesions were segmented semi-automatically with a threshold of 41% of the maximal uptake. In addition to clinico-biological features, sDmax, total metabolic tumor volume (TMTV), SUVmax, and uptake intensity of healthy lymphoid organs and liver were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The occurrence of adverse events, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), was reported. RESULTS: Fifty-six patients were included. The median follow-up was 9.7 months. Multivariate analysis showed that TMTV (cut-off of 36 mL) was an independent prognostic factor for PFS (p < 0.001) and that sDmax (cut-off of 0.15 m-1) was an independent prognostic factor for OS (p = 0.008). Concerning the occurrence of adverse events, a C-reactive protein level > 35 mg/L (p = 0.006) and a liver SUVmean > 2.5 (p = 0.027) before CAR T cells were associated with grade 2 to 4 CRS and a spleen SUVmean > 1.9 with grade 2 to 4 ICANS. CONCLUSION: TMTV and sDmax had independent prognostic values, respectively, on PFS and OS. Regarding adverse events, the mean liver and spleen uptakes were associated with the occurrence of grade 2 to 4 CRS and ICANS, respectively. Integrating these biomarkers into the clinical workflow could be useful for early adaptation of patients management.

[Inflammatory syndrome of unknown origin and PET/CT: Economic and iatrogenic impacts of false positive]. / Syndrome inflammatoire inexpliqué et TEP/CT : impacts économiques et iatrogènes des faux positifs.

INTRODUCTION: PET/CT is regularly used to investigate inflammatory syndrome of unknown origin (IUO), but hypermetabolisms found are not always consistent with the final diagnosis. The objective of the study was to assess the cost attributed to the diagnostic work-up for these false positives. MATERIALS AND METHODS: We conducted an ancillary study on a previous retrospective cohort from the internal medicine department at Amiens university hospital in patients who had a PET/CT scan between October 2004 and April 2017. Patients were included if PET/CT had been prescribed to investigate IUO. Among the 763 PET/CT performed, 144 met the inclusion criteria and a false-positive rate of 17.4% (n=25) was reported. RESULTS: Among these 25 patients, 21 underwent further investigations. The most frequently found hypermetabolic territories were digestive (n=12, mean SUVmax 8 [±4.33]) and osteoarticular (n=11, mean SUVmax 4.33 [±1.15]). The total cost of the 13 prescribed consultations was €390, the total cost of the 40 additional tests was €4,476 (mainly digestive endoscopies and radiological tests) and the total cost of medical transport was €572. The total cost of the 35 days of hospitalization specifically required to investigate these false positives was €22,952. In 23.8% (n=5), these investigations led to the incidental discovery of tumor lesions. CONCLUSION: The economic impact of false-positive PET/CT results does not appear to be negligible and merits a genuine prospective medico-economic study.

Respiratory-gated positron emission tomography and breath-hold computed tomography coupling to reduce the influence of respiratory motion: methodology and feasibility.

BACKGROUND: Respiratory motion causes uptake in positron emission tomography (PET) images of chest and abdominal structures to be blurred and reduced in intensity. PURPOSE: To compare two respiratory-gated PET binning methods (based on frequency and amplitude analyses of the respiratory signal) and to propose a "BH-based" method based on an additional breath-hold computed tomography (CT) acquisition. MATERIAL AND METHODS: Respiratory-gated PET consists in list-mode (LM) acquisition with simultaneous respiratory signal recording. A phantom study featured rectilinear movement of a 0.5-ml sphere filled with (18)F-fluorodeoxyglucose ((18)F-FDG) solution, placed in a radioactive background (sphere-to-background contrast 6:1). Two patients were also examined. Three figures of merit were calculated: the target-to-background ratio profile (TBRP) in the axial direction through the uptake (i.e., the sphere or lesion), full-width-at-half-maximum (FWHM) values, and maximized standard uptake values (SUV(max)). RESULTS: In the phantom study, the peak TBRP was 0.9 for non-gated volume, 1.83 for BH-based volume, and varied between 1.13 and 1.73 for Freq-based volumes and between 1.34 and 1.66 for Amp-based volumes. A reference volume (REF-static) was also acquired for the phantom (in a static, "expiratory" state), with a peak TBRP at 1.88. TBRPs were computed for patient data, with higher peak values for all gated volumes than for non-gated volumes. CONCLUSION: Respiratory-gated PET acquisition reduces the blurring effect and increases image contrast. However, Freq-based and Amp-based volumes are still influenced by inappropriate attenuation correction and misregistration of mobile lesions on CT images. The proposed BH-based method both reduces motion artifacts and improves PET-CT registration.

Phase-contrast MR imaging support for the diagnosis of aqueductal stenosis.

BACKGROUND AND PURPOSE: Patients with aqueductal stenosis (AS) present with various clinical and radiologic features. Conventional MR imaging provides useful information in AS but depends on a subjective evaluation by the neuroradiologist. The purpose of this study was to evaluate the support of the phase-contrast MR imaging (PC-MR imaging) technique (sensitive to CSF flows) for the diagnosis of AS. MATERIALS AND METHODS: We retrospectively considered 17 patients who underwent PC-MR imaging to explore hydrocephalus, with the absence of CSF flow at the aqueductal level. We analyzed their clinical and morphologic MR imaging data. RESULTS: None of the usually reported direct or indirect signs of aqueductal obstruction were seen in 7 patients in whom the clinical suggestion of AS was confirmed by PC-MR imaging results. Seven patients in this population had a third ventriculostomy, and 5 of them were among those in whom conventional MR imaging failed to reveal signs of aqueductal obstruction. All of these 7 patients had a positive postsurgical outcomes. The analysis of CSF and vascular dynamic data in this population was compared with an aged-matched population, and these data were found similar except for the fourth ventricular CSF flush flow latency. CONCLUSIONS: PC-MR imaging supports the diagnosis of CSF flow blockage at the aqueductal level in a reliable, reproducible, and rapid way, which aids in the diagnosis of AS in patients with clinical and/or radiologic suggestion of obstructive hydrocephalus. We, therefore, suggest using this technique in the current evaluation of hydrocephalus.

[Acute CSF changes in the mesencephalon aqueduct after subarachnoid hemorrhage as measured by PC-MRI]. / Caractérisation des perturbations du flux de LCS dans l'aqueduc du mésencéphale par IRM-CP à la phase aiguë de l'hémorragie méningée.

PURPOSE: Determining acute intracranial hydrodynamic changes after subarachnoid hemorrhage through an analysis of the CSF stroke volume (SV) as measured by phase-contrast MRI (PC-MRI) in the mesencephalon aqueduct. METHOD: A prospective study was performed in 33 patients with subarachnoid hemorrhage. A PC-MRI imaging study was performed n the acute phase (< 48 hours). CSF flow was measured in the aqueduct. The appearance of acute hydrocephalus (HCA) was then compared with data on CSF flow, and the location of the intraventricular and perimesencephalic bleeding. RESULTS: CSF analysis was performed on 27 patients, 11 of whom presented with an acute HCA. All 11 patients had an abnormal SV in the aqueduct: patients with a communicating HCA had an increased SV (n=8); and patients with a noncommunicating HCA had a nil SV (n=3). Patients with a normal SV in the aqueduct did not develop an acute HCA. Intraventricular bleeding significantly led to HCA (P=0.02), which was of the communicating type in 70% of cases. CONCLUSION: Subarachnoid hemorrhage leads to intracranial CSF hydrodynamic modifications in the aqueduct in the majority of patients. CSF flow can help us to understand the mechanism of the appearance of acute HCA. Indeed, hydrocephalus occurred - of the communicating type in most cases - even in the presence of intraventricular bleeding.

Differences in effective connectivity between dyslexic children and normal readers during a pseudoword reading task: an fMRI study.

PURPOSE: This fMRI study investigated phonological and lexicosemantic processing in dyslexic and in chronological age- and reading level-matched children in a pseudoword reading task. MATERIALS AND METHODS: The effective connectivity network was compared between the three groups using a structural model including the supramarginal cortex (BA 40; BA: Brodmann area), fusiform cortex (BA 37) and inferior frontal cortex (BA 44/45) areas of the left hemisphere. RESULTS: The results revealed differences in connectivity patterns. In dyslexic patients, in contrast with chronological age- and reading level-matched groups, no causal relationship was demonstrated between BA 40 and BA 44/45. However, a significant causal relationship was demonstrated between BA 37 and BA 44/45 both in dyslexic children and in the reading level-matched group. CONCLUSIONS: These findings were interpreted as evidence for a phonological deficit in developmental dyslexia.

[Contribution of the spectral analysis to the brain connectivity study by fMRI]. / Apport de l'analyse spectrale à l'étude de la connectivité cérébrale en IRMf Dissociation fonctionnelle de l'aire motrice supplémentaire.

AIM: To validate, through functional magnetic resonance imaging (fMRI) from spectral analysis of time series during a visuomotor task, a model of functional connectivity mainly constituted by the pre-supplementary motor area (pre-SMA), the supplementary motor area proper (SMA-proper) and the primary motor cortex (M1). MATERIALS AND METHODS: The paradigm that was tried out in young subjects (n=5) consisted of a preparation task of motor movement. We firstly proceeded with an estimate in the frequency domain of coherency coefficients and values of phase shift between these three areas. Secondly, the estimated coherency coefficients were integrated to a model of functional connectivity. Two interaction coefficients were calculated, one for the related M1 and pre-SMA regions, the other one for the related M1 and SMA-proper regions. RESULTS AND CONCLUSION: Our results demonstrate hemodynamic activity that definitely occurred earlier in the pre-SMA area during the preparatory period of the task. In the same way, a more important interaction was found between M1 and pre-SMA areas, which corroborates the assumption of the prevalent role played by these two areas in the case of a preparation task of a motor movement. Thus, this study has allowed highlighting a functional dissociation between the two portions of the SMA.

[Cerebrospinal fluid flow imaging in the meningeal hemorrhage]. / Imagerie de l'hydrodynamique cérébrale dans les hémorragies méningées.

BACKGROUND AND PURPOSES: Cerebrospinal fluid (CSF) flow oscillations are synchronized with cerebral blood flow and are also involved in the control of variations of intracranial pressure during the cardiac cycle. The aim of this study was to investigate the possible alterations of CSF flow dynamics during the acute phase of meningeal hemorrhage (MH). METHODS: Eleven patients with MH confirmed by computed tomography (CT) scan were examined by MR imaging, which comprised morphological sequences and flow dynamic sequences for quantification of CSF oscillations and cerebral blood flow rates. CSF oscillations were recorded at the cerebral aqueduct and C2-C3 subarachnoid space (SAS), where a vascular sequence was also performed to quantify artery blood flow. These results were compared to oscillations of a population of 44 control subjects and a difference of at least two standard deviation was used to define a hyperdynamic or hypodynamic appearance of CSF flow. Dilatation of the ventricular system was determined on radiographs by two neuroradiologists and a neurosurgeon. RESULTS: Only four patients presented normal ventricular CSF flow, one patient presented hypodynamic flow and five patients presented hyperdynamic flow. Five patients had normal cervical CSF flow and five patients presented hyperdynamic flow. The two patients with ventricular dilatation both presented hyperdynamic ventricular CSF flow associated with normal cervical CSF flow. One patient was excluded. CONCLUSION: Abnormal CSF flow dynamics were shown suggesting the hypothesis that bleeding increases intracranial volume and induces a reduction of cerebral compliance and an increase of intracranial pressure. The increased oscillations in the ventricular system would therefore predispose to dilatation.

Value of phase contrast magnetic resonance imaging for investigation of cerebral hydrodynamics.

OBJECTIVE: Phase Contrast Magnetic Resonance Imaging (PCMRI) is a noninvasive technique that can be used to quantify variations of flow during the cardiac cycle. PCMRI allows investigations of blood flow dynamics in the main arteries and veins of the brain but also the dynamics of cerebrospinal fluid. These cerebral flow investigations provide a description of the regulation mechanisms of intracranial pressure during the cardiac cycle. The objective of this paper is to describe the contribution of this technique in diseases related to disorders of cerebral hydrodynamics in the light of 5 clinical cases. METHOD: Flow measurements were performed using PCMRI sequences on a 1.5 Tesla MR imager in 4 patients with symptomatic ventricular dilation and 1 patient with a syringomyelic cavity. RESULTS: Flow quantification in these 5 patients, representative of the diseases mainly concerned by cerebral hydrodynamics, is useful to guide the indication for ventricular shunting in patients with hydrocephalus, to demonstrate obstruction of the cerebral aqueduct, to demonstrate recirculation of ventricular CSF after ventriculostomy and to characterize the dynamic features of CSF inside a spinal cavity. CONCLUSION: PCMRI, now available to neurosurgeons, is complementary to morphological MR and provides quantitative information on cerebral hydrodynamics. This information is mainly used to confirm alteration of CSF flow in the cerebral and spinal compartments. PCMRI is also a functional tool to better understand the pathophysiology of hydrocephalus and syringomyelia.

Ventricular dilation as an instability of intracranial dynamics.

We address the question of the ventricles' dilation as a possible instability of the intracranial dynamics. The ventricular system is shown to be governed by a dynamical equation derived from first principles. This general nonlinear scheme is linearized around a well-defined steady state which is mapped onto a pressure-volume model with an algebraic effective compliance depending on the ventricles' geometry, the ependyma's elasticity, and the cerebrospinal fluid (CSF) surface tension. Instabilities of different natures are then evidenced. A first type of structural instability results from the compelling effects of the CSF surface tension and the elastic properties of the ependyma. A second type of dynamical instability occurs for low enough values of the aqueduct's conductance. This last case is then shown to be accompanied by a spontaneous ventricle's dilation. A strong correlation with some active hydrocephalus is evidenced and discussed. The transfer function of the ventricles, compared to a low-pass filter, are calculated in both the stable and unstable regimes and appear to be very different.

Neural correlates of implicit object identification.

The present study sought to assess neural correlates of implicit identification of objects by means of fMRI, using tasks that require matching of the physical properties of objects. Behavioural data suggests that there is automatic access to object identity when observers attend to a physical property of the form of an object (e.g. the object's orientation) and no evidence for semantic processing when subjects attend to colour. We evaluated whether, in addition to neural areas associated with decisions to specific perceptual properties, areas associated with access to semantic information were activated when tasks demanded processing of the global configuration of pictures. We used two perceptual matching tasks based on the global orientation or on the colour of line drawings. Our results confirmed behavioural data. Activations in the inferior occipital cortex, fusiform and inferior temporal gyri in both tasks (orientation and colour) account for perceptual and structural processing involved in each task. In contrast, activations in the posterior and medial parts of the fusiform gyrus, shown to be involved in explicit semantic judgements, were more pronounced in the orientation-matching task, suggesting that semantic information from the pictures is processed in an implicit way even when not required by the task. Thus, this study suggests that cortical regions usually involved in explicit semantic processing are also activated when implicit processing of objects occurs.

Influence of age and osteoporosis on calcaneus trabecular bone structure: a preliminary in vivo MRI study by quantitative texture analysis.

Recent developments in high-resolution MR imaging techniques have opened up new perspectives for structural characterization of trabecular bone by non-invasive methods. In this study, 3-D MR imaging was performed on 17 healthy volunteers and 6 osteoporotic patients. Two different MR sequences were used to evaluate the impact on MR acquisition on texture analysis results. Images were analyzed with four automated methods of texture analysis (grey level histogram, cooccurrence, runlength and gradient matrices) enabling quantitative analysis of grey level intensity and distribution within three different regions of interest (ROI). Texture analysis is not very frequently used since the interpretation of the large number of calculated parameters is difficult. We applied multiparametric data analyses such as principal component analysis (CFA) and hierarchical ascending classification (HAC) to determine the relevant parameters to differentiate between three sets of images (healthy young volunteers, healthy postmenopaused and osteoporotic patients). The results suggest that relevant texture information (depending on the ROI localization in the calcaneus) can be extracted from calcaneus MR images to evaluate osteoporosis and age effects on trabecular bone structure if strictly the same acquisition sequences are used for all patients' examination.

Transmembrane and cytoplasmic domains of syndecan mediate a multi-step endocytic pathway involving detergent-insoluble membrane rafts.

Syndecan heparan sulphate proteoglycans directly mediate a novel endocytic pathway. Using Chinese hamster ovary cells expressing the human syndecan 1 core protein or a chimaeric receptor, FcR-Synd, consisting of the ectodomain of the IgG Fc receptor Ia linked to the transmembrane and cytoplasmic domains of syndecan 1, we previously reported that efficient internalization is triggered by ligand clustering, requires intact actin microfilaments and tyrosine kinases, proceeds with a t(1/2) of approx. 1 h and is distinct from coated-pit pathways. We have now examined the involvement of cholesterol-rich, detergent-insoluble membrane rafts. On clustering, (125)I-labelled IgG bound to FcR-Synd rapidly became insoluble in cold Triton X-100, well before endocytosis. Insolubility of clustered FcR-Synd ligand did not require the syndecan ectodomain, linkage of the cytoplasmic tail to the cytoskeleton, or energy-dependent cellular metabolism. Pretreatment of cells with cyclodextrin to deplete cholesterol from rafts abolished insolubility of the clustered ligand and inhibited endocytosis in a dose-responsive fashion. Similar results were obtained with (125)I-labelled lipoprotein lipase bound to authentic cell-surface syndecan. In contrast, the 39 kDa receptor-associated protein (RAP), a coated-pit ligand, was more than 80% soluble in cold Triton even after internalization; cellular cholesterol depletion failed to substantially affect the internalization of (125)I-RAP. Overall, our results indicate a multi-step endocytic process consisting of ligand binding, clustering, energy-independent lateral movement into detergent-insoluble membrane rafts and finally recruitment of actin and tyrosine kinases to bring the ligands into the cell.

Automatic object identification: an fMRI study.

Boucart and Humphreys reported an automatic access to object identity when observers attend to a physical property of the form of an object (e.g. the orientation) but not to its colour. We sought evidence for automatic identification in a brain imaging study using fMRI. In an orientation decision task participants decided whether a picture was vertical or horizontal. In the colour decision task participants decided if a picture was blue or green. Activation of areas 18-19 was found for both color and orientation. Activation of the temporal area 37 occurred more frequently in the orientation than in the colour decision task. This result suggests that automatic identification activates the same brain area as overt processing of semantic information.

The pitfalls of planar three-phase bone scintigraphy in nontraumatic hip avascular osteonecrosis.

PURPOSE: This study documented the previously reported lower sensitivity of routine planar three-phase bone scintigraphy (BS) performed using a high-resolution parallel-hole collimator compared with MRI to diagnose nontraumatic avascular necrosis of the hip (AVN). METHODS: Six observers reviewed 143 bone scintigrams obtained in patients with nontraumatic hip pain (n = 120) or a control group (n = 23). All patients had a standard radiograph and MRI within 2 months of the BS. Of 280 hips, 148 (53%) were painful on the day of the examination. The osteonecrosis group (AVN) consisted of 93 instances of AVN in 58 patients. Although it departs from the clinical situation, this method evaluated the intrinsic performance of the imaging method. The data were analyzed using a receiver operating characteristic method. RESULTS: For the six observers, the A(z) values were 0.65, 0.67, 0.66, 0.67, 0.73, and 0.79, respectively, and 0.66, 0.71, 0.75, 0.81, 0.81, 0.82, and 0.84 after removing hip diseases other than AVN through data manipulation. Bone marrow edema, as seen on MRI, was the most frequently reported misleading sign in false-positive diagnoses, especially in the early or late phases of the disease. False-negative diagnoses misclassified the scans as "asymptomatic hips" in 28 of 30 cases. Twenty-two of 30 scans appeared normal, but these AVN lesions were small (<25%) and were discovered by chance on MRIs that displayed bilateral involvement associated with radiographic evidence (stage 0 or 1). Thirteen of 20 patients were followed for 3 or more years, and only one worsened. CONCLUSIONS: BS is not indicated to diagnose possible contralateral AVN if the hip is asymptomatic. This study emphasizes the results from the literature; if indicated, a radionuclide hip investigation requires the use of a pin-hole collimator, a SPECT study with scatter correction and iterative reconstruction algorithms, or both.

Mesolimbic 7-OH-DPAT affects locomotor activities in rats.

This study tested the hypotheses that the dopamine D3 receptor is both an autoreceptor and a postsynaptic receptor and has an affinity for dopamine at the nanomolar level. The effect of bilateral microinjections of a dopamine D3-like agonist, 7-OH-DPAT, into the nucleus accumbens and into the ventral tegmental area (VTA) was tested with rats in activity monitors. Horizontal movement, rearing, and stereotypy times in seconds were automatically measured during 12 consecutive 10-min time blocks. Intraaccumbens 7-OH-DPAT (0.0001-10.0 micrograms/side) resulted in a highly significant dose by time block interactions. The dose of 0.0001 microgram/side resulted in the potentiation of horizontal movement time during the time blocks 10-40 min; whereas, 0.001-1.0 microgram/side potentiated locomotion during the early blocks following the 10-min interval. However, 10.0 micrograms/side resulted in a biphasic effect, attenuation followed by potentiation. 7-OH-DPAT (0.0001-1.0 microgram/ side) potentiated rearing time in the early time blocks and (0.001-10.0 micrograms/side) attenuated stereotypy time during the first 20 min time blocks. On the other hand, intra-VTA 7-OH-DPAT (10.0 micrograms/side) attenuated horizontal movement time during the first 20-min time blocks and (0.01 and 0.0001 microgram/side) potentiated movement time at the 20-min time block. Intraventral tegmental area 7-OH-DPAT had no effects on rearing and stereotypy times. These data support the hypothesis that the D3 receptor has an affinity for dopamine at the nanomolar level and question the hypothesis that the D3 receptors are both autoreceptors and postsynaptic receptors.

NMR relaxation rates and blood oxygenation level.

A linear relationship between the proton relaxation rates and the fraction of deoxyhemoglobin of circulating whole blood (fHb) has been established in vitro at 4.7 T. These results have been interpreted on the basis of the additivity of relaxation rates. The slope of the lines of transverse relaxation rates (R2) versus fHb was found to increase with interpulse delay in Carr-Purcell Meiboom-Gill (CPMG) experiments. The Luz-Meiboom relation applied to this interpulse delay dependence of R2 suggests a two-site chemical exchange rather than a diffusion mechanism. The 1-ms water proton exchange time derived from these observations has been interpreted in terms of exchange between exchangeable protons close to the paramagnetic center of hemoglobin and protons of bulk water.

Intra-accumbens delta 1-opioid agonist, pC1-DPDPE, differentially affects patterns of locomotor activity.

The effects of bilateral microinjections of a new potent and highly selective delta-opioid receptor agonist pCl-DPDPE (0.00, 0.1, 1.0, or 2.5 micrograms/side) were tested in rats for 60 min in activity monitors. The durations of horizontal movement time, rearing time, and stereotypy time were measured during six consecutive 10-min time blocks. The pCl-DPDPE resulted in short-lived biphasic effects of attenuation followed by potentiation for the three measures. These data in part replicate the behavioral effects of other delta-opioid receptor agonists.