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.

[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.

Repression of the alpha-fetoprotein gene promoter by progesterone and chimeric receptors in the presence of hormones and antihormones.

Using transient transfection assays, we showed that repression of the alpha-fetoprotein promoter by intact and deletion mutants of the progesterone receptor and by chimeric progesterone/glucocorticoid-estrogen receptors in the presence of their cognate hormones was closely correlated with their ability to bind to a progesterone/glucocorticoid-responsive element. This negative regulation was also observed in the presence of antihormones, providing evidence that receptor-antihormone complexes can bind to their responsive elements in vivo.

[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.

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.

[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.

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.

Progestin receptors: isoforms and antihormone action.

We present evidence that the two isoforms of A and B of the chicken (cPR) and human progesterone receptor (hPR) originate from two different mRNA populations. One of these encodes the isoforms A which originate by initiation of translation at an in-frame AUG found 127 (cPR) and 165 (hPR) codons downstream of the AUG which gives rise to the isoforms B. Two estrogen-inducible hPR promoters were identified which are responsible for the generation of these two classes of transcripts. Characterization of the cPR promoter suggested the possible existence of cell-type and isoform-specific auto-regulation of cPR transcription and provided evidence that estrogen-induction of cPR expression occurs at a post-transcriptional level. Finally, we demonstrate promoter-specific transcriptional activation by the hPR isoforms A and B, and we discuss the mechanism of action of the anti-progestin RU486.

Mechanisms of antihormone action.

The mechanisms of action of two types of anti-hormones is discussed. Type I anti-hormones comprise the antiestrogen hydroxy-tamoxifen and the antiprogestin RU486, both of which promote DNA binding of the cognate receptors and, due to the activity of one of the two transcription activation functions of the estrogen and progesterone receptors, act as mixed agonist/antagonists. Evidence supporting that ICI 164,384 is also a member of the same group is presented. Type II antagonists impair DNA binding of the corresponding receptor in vitro and, in some cases, also in vivo. Ligand-mapping, an approach to identify the site of interaction of a steroid substitution within the hormone-binding domain of the receptor has been used to identify the 11 beta-pocket of the progesterone receptor and revealed that a single amino acid is responsible for the differential antagonistic effect of RU486 in man, chicken and hamster.

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.

Labyrinthine and visual involvement in the dorsal immobility response of adult rats.

The dorsal immobility response (DIR) is typically seen in the infants of many altricial mammalian species. Lifting the animal into the air by the nape of the neck is the primary releasing stimulus. Functionally, this response appears to facilitate carrying of the infants by the adults. When grasped by the nape and lifted into the air, adult rats will also exhibit the DIR. In this paper, the role of the labyrinths in the DIR of adult male rats was examined. Vestibular stimulation produced by vertical circular acceleration increased the duration of the DIR, while labyrinthectomy greatly diminished the DIR. In rats with intact labyrinths, visual occlusion greatly potentiated the DIR, whereas, in labyrinthectomized rats, visual occlusion had little effect. These data indicate that the vestibular system plays a major role in mediating the DIR of adult rats. The retention of the DIR into adulthood and the possible increased role of the labyrinths in the control of the adult DIR, are discussed with respect to the possible role of the DIR as an anti-predator mechanism.

Effects of intrastriatal hormones on the dorsal immobility response in the rat.

Previous research has shown that the dorsal immobility response (DIR) changes significantly in duration across the estrous cycle. In order to test whether gonadal steroid hormones act directly on the striatum to modulate this behavior, ovariectomized female Long-Evans hooded rats were given bilateral intrastriatal implants of 17 beta-estradiol, 2-hydroxyestradiol, progesterone, or cholesterol. These implants were made at one-week intervals, each animal receiving each treatment in a Latin square design. Four hours after each hormone implant, the animals were tested for the DIR. Only rats receiving the intrastriatal 17 beta-estradiol implant were significantly different from those receiving cholesterol, and showed greatly potentiated DIR's.

Effects of intracerebral quinpirole on locomotion in rats.

The effects of the dopamine D2 receptor agonist quinpirole (LY 171555) on locomotor activity and margin time (thigmotaxis or wall-hugging) were measured for 2 h in rats injected either s.c. (vehicle, 0.02, 2.0 mg/kg) or directly into either the dorsal striatum or nucleus accumbens (vehicle, 0.1, 1.0, 10, 20 or 40 micrograms bilaterally in each site). In all groups, margin time decreased as drug dose increased. As in previous research, quinpirole given s.c. decreased locomotor activity at a low dose and had a biphasic effect on locomotor activity at the high dose. Both of these effects were also elicited by quinpirole injected directly into the dorsal striatum; 10 and 20 micrograms decreased locomotion immediately, while 40 micrograms led to both the immediate decrease and a later increase. In contrast, the lowest doses of quinpirole (0.1 and 1.0 microgram) injected into the nucleus accumbens led to an increase in locomotion from 20 to 60 min, while the higher doses led only to the early decrease. Thus, both the locomotor activating and inhibiting effects of quinpirole are found in both the nucleus accumbens and the dorsal striatum, but the differing dose-response relationships indicate that the mechanisms are not the same in these two brain regions.

The effects of bilateral and unilateral vibrissotomy on behavior within aquatic and terrestrial environments.

Introducing an untreated rat to a novel environment typically results in thigmotaxis or wall-seeking behavior and the unilateral removal of the vibrissae induces an asymmetry in thigmotaxis. The present study investigated the effects of bilateral and unilateral removal of the vibrissae (vibrissotomy) upon the rat exhibiting thigmotaxis within aquatic and terrestrial environments. Unilateral vibrissotomy resulted in directional thigmotaxis asymmetry toward the intact vibrissae side within both environments. Within the aquatic environment, the unilateral vibrissotomy group swam a significantly longer distance than the other two groups. The data are discussed in terms of activation and sensory information.

Dorsal pressure potentiates the duration of tonic immobility and catalepsy in rats.

This study tested the generalizations that cutaneous pressure will elicit immobility, that there is a relationship between the intensity of cutaneous pressure and the duration of immobility, and that the localization or body surfaces, particularly the upper dorsal area or the nape of the neck, is more susceptible to immobility. Immobility was measured by the duration in sec of tonic immobility, bar grasp and vertical cling behaviors or catalepsy. It was shown in the first experiment that dorsal pressure immobility can be elicited in the adult rat. The application of a 9-kg pressure elicited a significant potentiation of the duration of tonic immobility and the bar grasp catalepsy and both 5 and 9 kg of pressure potentiated the duration of vertical cling catalepsy. In the second experiment, only pressure applied to the midline of the dorsal surface at the nape of the neck significantly potentiated the duration of these measures. These results were compared with other experimentally and naturally occurring immobilities.