Risk stratification in diffuse large B-cell lymphoma using lesion dissemination and metabolic tumor burden calculated from baseline PET/CT†.

BACKGROUND: We analyzed the prognostic value of a new baseline positron emission tomography (PET) parameter reflecting the spread of the disease, the largest distance between two lesions (Dmax). We tested its complementarity to metabolic tumor volume (MTV) in a large cohort of diffuse large B-cell lymphoma (DLBCL) patients from the REMARC trial (NCT01122472). PATIENTS AND METHODS: MTVs were defined using the 41% maximum standardized uptake value threshold. From the three-dimensional coordinates, the centroid of each lesion was automatically obtained and considered as the lesion location. The distances between all pairs were calculated. Dmax was obtained for each patient and normalized with the body surface area [standardized Dmax (SDmax)]. RESULTS: From the REMARC trial, 290 patients aged 60-80 years were included: 91% had an advanced stage and 71% International Prognostic Index (IPI) ≥3. High versus low SDmax significantly impacted progression-free survival (PFS) (P < 0.0001) and overall survival (OS) (P = 0.0027). Patients with SDmax > 0.32 m-1 (n = 82) had a 4-year PFS and OS of 46% and 71%, respectively, against 77% and 87%, respectively, for patients with low SDmax. High SDmax and high MTV were independent prognostic factors of PFS (P = 0.0001 and P = 0.0010, respectively) and OS (P = 0.0028 and P = 0.0004, respectively). Combining MTV and SDmax yielded three risk groups with no (n = 109), one (n = 122) or two (n = 59) factors (P < 0.0001 for both PFS and OS). The 4-year PFS were 90%, 63%, 41%, respectively, and the 4-year OS were 95%, 79%, 66%, respectively. In addition, patients with at least two of the three factors including high SDmax, high MTV, Eastern Cooperative Oncology Group (ECOG) ≥2 had a higher number of central nervous system relapse (P = 0.017). CONCLUSIONS: SDmax is a simple feature that captures lymphoma dissemination, independent from MTV. These two PET metrics, SDmax and MTV, are complementary to characterize the disease, reflecting the tumor burden and its spread. This score appeared promising for DLBCL baseline risk stratification.

Reorganization of large-scale cognitive networks during automation of imagination of a complex sequential movement.

We investigated the functional reconfiguration of the cerebral networks involved in imagination of sequential movements of the left foot, both performed at regular and fast speed after mental imagery training. Thirty-five volunteers were scanned with a 3T MRI while they imagined a sequence of ankle movements (dorsiflexion, plantar flexion, varus and valgus) before and after mental practice. Subjects were distributed in two groups: the first group executed regular movements whereas the second group made fast movements. We applied the general linear model (GLM) and model-free, exploratory tensorial independent component analytic (TICA) approaches to identify plastic post-training effects on brain activation. GLM showed that post-training imagination of movement was accompanied by a dual effect: a specific recruitment of a medial prefronto-cingulo-parietal circuit reminiscent of the default-mode network, with the left putamen, and a decreased activity of a lateral fronto-parietal network. Training-related subcortical changes only consisted in an increased activity in the left striatum. Unexpectedly, no difference was observed in the cerebellum. TICA also revealed involvement of the left executive network, and of the dorsal control executive network but no significant differences were found between pre- and post-training phases. Therefore, repetitive motor mental imagery induced specific putamen (motor rehearsal) recruitment that one previously observed during learning of overt movements, and, simultaneously, a specific shift of activity from the dorsolateral prefrontal cortex (attention, working memory) to the medial posterior parietal and cingulate cortices (mental imagery and memory rehearsal). Our data complement and confirm the notion that differential and coupled recruitment of cognitive networks can constitute a neural marker of training effects.

Oval window niche height: quantitative evaluation with CT before stapes surgery for otosclerosis.

BACKGROUND AND PURPOSE: Stapes surgery for otosclerosis can be challenging when the oval window niche is narrow. We analyzed the reliability of CT to evaluate the height of the OWN and propose a quantitative criterion to distinguish normal and narrow OWNs. MATERIALS AND METHODS: Fifty-six patients were scheduled for primary stapes surgery and, with available preoperative CT scans, were prospectively enrolled in the study at a tertiary care hospital. OWN height was measured on coronal CT and qualitatively evaluated during surgery. CT findings and surgical observations were matched to determine the preoperative imaging criterion of a narrow OWN. RESULTS: OWN was found to be narrow during surgery in 8 of 56 patients (14%). On CT, mean OWN height measurement was 1.1 mm for the narrow group and 1.8 mm for the normal OWN surgical cases. The cutoff between normal and narrow OWN was computed at 1.3 mm by using discriminant analysis and at 1.4 mm with boxplot analysis. These CT cutoff values allowed a correct classification of "normal" and "narrow" OWN, compared with visual evaluation during surgery. CONCLUSIONS: Measurements of the OWN height provide an accurate and relevant evaluation of this region before otosclerosis surgery. A width below 1.4 mm should be considered at risk for technical difficulties during the stapes footplate approach.

Functional connectivity of the human red nucleus in the brain resting state at 3T.

BACKGROUND AND PURPOSE: Previous structural data obtained with diffusion tensor imaging axonal tracking have demonstrated possible in vivo connections between the human red nucleus (RN) and the sensorimotor and associative cortical areas. However, tractographic reconstructions can include false trajectories because of, for instance, the low spatial resolution of diffusion images or the inability to precisely detect fiber crossings. The rubral network was therefore reassessed by functional connectivity during the brain resting state. Because the RN is located very close to the substantia nigra (SN), the nigral network was also studied to ensure that these 2 circuits were correctly dissociated. MATERIALS AND METHODS: Data from 14 right-handed healthy volunteers were acquired at rest and analyzed by region-of-interest (ROI)-based functional connectivity. The blood oxygen level-dependent (BOLD) signal intensity fluctuations of separate ROIs located in the RN and SN were successively used to identify significant temporal correlations with BOLD signal intensity fluctuations of other brain regions. RESULTS: Low-frequency BOLD signal intensity of the RN correlated with signal intensity fluctuations in the cerebellum; mesencephalon; SN; hypothalamus; pallidum; thalamus; insula; claustrum; posterior hippocampus; precuneus; and occipital, prefrontal, and fronto-opercular cortices. Despite some cortical and subcortical overlaps with nigral connectivity, this rubral network was clearly distinct from the nigral network, which showed a strong correlation with the striatum; cerebellar vermis; and more widespread frontal, prefrontal, and orbitofrontal cortical areas. CONCLUSIONS: During the brain resting state, the human RN participates in cognitive circuits related to salience and executive control, and that may partly represent a subclass of its structural connectivity as revealed by tractography.

[Functional MR imaging and oligodendrogliomas]. / IRM fonctionnelle et oligodendrogliomes.

The localization of functional areas obtained from functional MRI (fMRI) is useful for patients suffering from tumors contiguous to eloquent brain areas. fRMI is an efficient tool in the strategy of treatment of low grade oligodendroglioamas in the rolandic area in intact or slightly impaired patients. It can be used preoperatively to assess motor functional areas. Indeed there is a good correlation for motor cortex lesions when using comparison between fMRI and intraoperative findings. Direct integration of fMRI data into neuronavigation enables to better visualize and preserve eloquent brain areas. One must be aware of fMRI limits. It is still often used with the control of direct cortical stimulations.

[Crossed anarthria and a dissociated lateralisation of language]. / Anarthrie croisée et latéralisation dissociée du langage.

INTRODUCTION: Crossed anarthria cases are uncommon and rather old. OBSERVATION: We report the case of a right-handed 55-year-old man who presented crossed pure anarthria due to a hemorrhage in the premotor cortex (feet of F1 and F2) and in the high part of Pierre-Marie's quadrangle. CONCLUSION: The study of different tasks (articulation, verbal fluency, direct object word-generation from a verb) showed a dissociated lateralisation of his language. Lexico-semantic and grammatical tasks are processed in the left hemisphere. Articulation programming occurs in the right hemisphere.

Functional MR imaging in assessment of language dominance in epileptic patients.

The value of functional MR Imaging (fMRI) in assessing language lateralization in epileptic patients candidate for surgical treatment is increasingly recognized. However few data are available for left-handed patients. Moreover determining factors for atypical dominance in patients investigated with contemporary imaging have not been reported. We studied 20 patients (14 males, 6 females; 9 right handed, 11 left handed) aged from 9 to 48 years, investigated for intractable partial epilepsy. Epileptic focus location was temporal in 14 cases, extratemporal in 6, and lateralized in the left hemisphere in 11/20. Hemispheric dominance for language was evaluated by both Wada test and fMRI using a silent word generation paradigm in all patients. Furthermore, a postictal speech test was performed in 15 patients. An fMRI language lateralization index was calculated from the number of activated pixels (Student's t test, P < 0.0001) in the right and left hemispheres. The Wada test showed a right hemispheric dominance in 8 patients (6 were left handed and 2 right handed) and a left hemispheric dominance in 12 patients (5 were left handed and 7 right handed). These results were concordant with clinical postictal examination in 11/15 patients (73%). Clinical status did not allow a conclusion about hemispheric dominance for the remaining 4 patients. FMRI was concordant with the Wada test in 19/20 cases. For one left-handed patient, fMRI showed bilateral activation, whereas the Wada test demonstrated a right hemispheric dominance. Right language lateralization was significantly correlated with left lateralized epilepsy (P < 0.05) but was not correlated with age at epilepsy onset, early brain injury (before 6 years), and lobar localization of epileptogenic focus. However the lack of a significant relationship between these factors and atypical language lateralization may be related to the small sample size.

Using a bidimensional t test to compare simultaneous activations in functional brain MRI.

The aim of functional brain magnetic resonance imaging studies is to determine which regions of the brain are related to a given specific task. Different methods can be used to extract the functional signal and there is currently no consensus for this operation. Measures based on correlation are only relevant for a single task. In this paper, we propose a method based on a multivariable Student's t test that permits the comparison of the results of successive activations. This technique allows a qualitative analysis of complex tasks, making possible to deal with both similar and different activated cortical areas.

Sensorimotor cortical activity in patients with complete spinal cord injury: a functional magnetic resonance imaging study.

Residual activation of the cortex was investigated in nine patients with complete spinal cord injury between T6 and L1 by functional magnetic resonance imaging (fMRI). Brain activations were recorded under four conditions: (1) a patient attempting to move his toes with flexion-extension, (2) a patient imagining the same movement, (3) passive proprio-somesthesic stimulation of the big toes without visual control, and (4) passive proprio-somesthesic stimulation of the big toes with visual control by the patient. Passive proprio-somesthesic stimulation of the toes generated activation posterior to the central sulcus in the three patients who also showed a somesthesic evoked potential response to somesthesic stimulation. When performed under visual control, activations were observed in two more patients. In all patients, activations were found in the cortical areas involved in motor control (i.e., primary sensorimotor cortex, premotor regions and supplementary motor area [SMA]) during attempts to move or mental imagery of these tasks. It is concluded that even several years after injury with some local cortical reorganization, activation of lower limb cortical networks can be generated either by the attempt to move, the mental evocation of the action, or the visual feedback of a passive proprio-somesthesic stimulation.

Multimodal anatomic, functional, and metabolic brain imaging for tumor resection.

OBJECTIVE: Improvement of neurosurgical techniques with a more detailed description of brain tumors and their functional environment. METHODS: We performed: (1) anatomical magnetic resonance imaging (MRI) for reference, (2) functional sequences dedicated to the adjacent cortical structures (sensorimotor, visual, language paradigms), and (3) thallium 201 cerebral tomoscintigraphy to visualize active tumor invasion. Data were transferred to a workstation for automatic registration. RESULTS: All data were combined into one synthetic image showing the foci of high proliferative activity, which have to be completely resected, and the peritumoral functional structures, which have to be spared in order to minimize postoperative sequelae. This trimodal image is entered into a surgical neuronavigation computer for preoperative planning in order to outline tumoral target and functional risk areas. All this information is displayed in the operative microscope (Zeiss MKM) optically linked to MR images. This multimodality technique diminishes operative time by reducing electrocorticography and improves the operative short-term outcome. CONCLUSION: Multimodal imaging is useful for optimization of neurosurgical tumor resection.

Evolution of intron/exon structure of DEAD helicase family genes in Arabidopsis, Caenorhabditis, and Drosophila.

The DEAD box RNA helicase (RH) proteins are homologs involved in diverse cellular functions in all of the organisms from prokaryotes to eukaryotes. Nevertheless, there is a lack of conservation in the splicing pattern in the 53 Arabidopsis thaliana (AtRHs), the 32 Caenorhabditis elegans (CeRHs) and the 29 Drosophila melanogaster (DmRHs) genes. Of the 153 different observed intron positions, 4 are conserved between AtRHs, CeRHs, and DmRHs, and one position is also found in RHs from yeast and human. Of the 27 different AtRH structures with introns, 20 have at least one predicted ancient intron in the regions coding for the catalytic domain. In all of the organisms examined, we found at least one gene with most of its intron predicted to be ancient. In A. thaliana, the large diversity in RH structures suggests that duplications of the ancestral RH were followed by a high number of intron deletions and additions. The very high bias toward phase 0 introns is in favor of intron addition, preferentially in phase 0. Results from this comparative study of the same gene family in a plant and in two animals are discussed in terms of the general mechanisms of gene family evolution.

[Clinical application of functional MRI: a strategic tool for neurosurgery]. / Application clinique de l'IRM fonctionnelle: aide à la stratégie neurochirurgicale.

The purpose was to incorporate preoperative functional imaging data into anatomic data of operative microscope for neurosurgical procedures of patients suffering from lesions contiguous to eloquent brain areas. The day before surgery, patients bearing scalp markers underwent fMRI, just before anatomical contrast-enhanced MR images. FMRI data analysis were realised using a t test (p<0.0001). The resulting functional-anatomical images were downloaded onto a surgical neuronavigation computer in order to outline tumoral target and functional areas. At surgery, cortical stimulation has been used to confirm functional data. Functional image-guided surgery of lesions abutting functional cortex can be safely performed.

Functional MR imaging and traumatic paraplegia: preliminary report.

PURPOSE: To evaluate residual activity in the sensorimotor cortex of the lower limbs in paraplegia. METHODS: 5 patients suffering from a complete paralysis after traumatic medullar lesion (ASIA=A). Clinical evaluation of motility and sensitivity. 1. Control functional MR study of the sensorimotor cortex during simultaneous movements of hands, imaginary motor task and passive hands stimulation. 2. Concerning the lower limbs, 3 fMRI conditions: 1-patient attempts to move his toes with flexion-extension, 2-mental imagery task of the same movement, 3-peripheral passive proprio-somesthesic stimulation (squeezing) of the big toes. RESULTS: Activations were observed in the primary sensorimotor cortex (M1), premotor regions and in the supplementary motor area (SMA) during movement and mental imaginary tasks in the control study and during attempt to move and mental imaginary tasks in the study concerning the lower limbs. Passive somesthesic stimulation generated activation posterior to the central sulcus for 2 patients. CONCLUSION: Activations in the sensorimotor cortex of the lower limbs can be generated either by attempting to move or mental evocation. In spite of a clinical evaluation of complete paraplegia, fMRI can show a persistence of sensitive anatomic conduction, confirmed by Somesthesic Evoked Potentials.

Genomic exploration of the hemiascomycetous yeasts: 1. A set of yeast species for molecular evolution studies.

The identification of molecular evolutionary mechanisms in eukaryotes is approached by a comparative genomics study of a homogeneous group of species classified as Hemiascomycetes. This group includes Saccharomyces cerevisiae, the first eukaryotic genome entirely sequenced, back in 1996. A random sequencing analysis has been performed on 13 different species sharing a small genome size and a low frequency of introns. Detailed information is provided in the 20 following papers. Additional tables available on websites describe the ca. 20000 newly identified genes. This wealth of data, so far unique among eukaryotes, allowed us to examine the conservation of chromosome maps, to identify the 'yeast-specific' genes, and to review the distribution of gene families into functional classes. This project conducted by a network of seven French laboratories has been designated 'Génolevures'.

Genomic exploration of the hemiascomycetous yeasts: 3. Methods and strategies used for sequence analysis and annotation.

The primary analysis of the sequences for our Hemiascomycete random sequence tag (RST) project was performed using a combination of classical methods for sequence comparison and contig assembly, and of specifically written scripts and computer visualization routines. Comparisons were performed first against DNA and protein sequences from Saccharomyces cerevisiae, then against protein sequences from other completely sequenced organisms and, finally, against protein sequences from all other organisms. Blast alignments were individually inspected to help recognize genes within our random genomic sequences despite the fact that only parts of them were available. For each yeast species, validated alignments were used to infer the proper genetic code, to determine codon usage preferences and to calculate their degree of sequence divergence with S. cerevisiae. The quality of each genomic library was monitored from contig analysis of the DNA sequences. Annotated sequences were submitted to the EMBL database, and the general annotation tables produced served as a basis for our comparative description of the evolution, redundancy and function of the Hemiascomycete genomes described in other articles of this issue.

Genomic exploration of the hemiascomycetous yeasts: 4. The genome of Saccharomyces cerevisiae revisited.

Since its completion more than 4 years ago, the sequence of Saccharomyces cerevisiae has been extensively used and studied. The original sequence has received a few corrections, and the identification of genes has been completed, thanks in particular to transcriptome analyses and to specialized studies on introns, tRNA genes, transposons or multigene families. In order to undertake the extensive comparative sequence analysis of this program, we have entirely revisited the S. cerevisiae sequence using the same criteria for all 16 chromosomes and taking into account publicly available annotations for genes and elements that cannot be predicted. Comparison with the other yeast species of this program indicates the existence of 50 novel genes in segments previously considered as 'intergenic' and suggests extensions for 26 of the previously annotated genes.

Genomic exploration of the hemiascomycetous yeasts: 11. Kluyveromyces lactis.

Random sequencing of the Kluyveromyces lactis genome allowed the identification of 2235-2601 open reading frames (ORFs) homologous to S. cerevisiae ORFs, 51 ORFs which were homologous to genes from other species, 64 tRNAs, the complete rDNA repeat, and a few Ty1- and Ty2-like sequences. In addition, the complete sequence of plasmid pKD1 and a large coverage of the mitochondrial genome were obtained. The global distribution into general functional categories found in Saccharomyces cerevisiae and as defined by MIPS is well conserved in K. lactis. However, detailed examination of certain subcategories revealed a small excess of genes involved in amino acid metabolism in K. lactis. The sequences are deposited at EMBL under the accession numbers AL424881-AL430960.

Genomic exploration of the hemiascomycetous yeasts: 18. Comparative analysis of chromosome maps and synteny with Saccharomyces cerevisiae.

We have analyzed the evolution of chromosome maps of Hemiascomycetes by comparing gene order and orientation of the 13 yeast species partially sequenced in this program with the genome map of Saccharomyces cerevisiae. From the analysis of nearly 8000 situations in which two distinct genes having homologs in S. cerevisiae could be identified on the sequenced inserts of another yeast species, we have quantified the loss of synteny, the frequency of single gene deletion and the occurrence of gene inversion. Traces of ancestral duplications in the genome of S. cerevisiae could be identified from the comparison with the other species that do not entirely coincide with those identified from the comparison of S. cerevisiae with itself. From such duplications and from the correlation observed between gene inversion and loss of synteny, a model is proposed for the molecular evolution of Hemiascomycetes. This model, which can possibly be extended to other eukaryotes, is based on the reiteration of events of duplication of chromosome segments, creating transient merodiploids that are subsequently resolved by single gene deletion events.

Genomic exploration of the hemiascomycetous yeasts: 19. Ascomycetes-specific genes.

Comparisons of the 6213 predicted Saccharomyces cerevisiae open reading frame (ORF) products with sequences from organisms of other biological phyla differentiate genes commonly conserved in evolution from 'maverick' genes which have no homologue in phyla other than the Ascomycetes. We show that a majority of the 'maverick' genes have homologues among other yeast species and thus define a set of 1892 genes that, from sequence comparisons, appear 'Ascomycetes-specific'. We estimate, retrospectively, that the S. cerevisiae genome contains 5651 actual protein-coding genes, 50 of which were identified for the first time in this work, and that the present public databases contain 612 predicted ORFs that are not real genes. Interestingly, the sequences of the 'Ascomycetes-specific' genes tend to diverge more rapidly in evolution than that of other genes. Half of the 'Ascomycetes-specific' genes are functionally characterized in S. cerevisiae, and a few functional categories are over-represented in them.

Genomic exploration of the hemiascomycetous yeasts: 20. Evolution of gene redundancy compared to Saccharomyces cerevisiae.

We have evaluated the degree of gene redundancy in the nuclear genomes of 13 hemiascomycetous yeast species. Saccharomyces cerevisiae singletons and gene families appear generally conserved in these species as singletons and families of similar size, respectively. Variations of the number of homologues with respect to that expected affect from 7 to less than 24% of each genome. Since S. cerevisiae homologues represent the majority of the genes identified in the genomes studied, the overall degree of gene redundancy seems conserved across all species. This is best explained by a dynamic equilibrium resulting from numerous events of gene duplication and deletion rather than by a massive duplication event occurring in some lineages and not in others.