Value of PET/CT 3D visualization of head and neck squamous cell carcinoma extended to mandible.

PURPOSE: To study an original 3D visualization of head and neck squamous cell carcinoma extending to the mandible by using [18F]-NaF PET/CT and [18F]-FDG PET/CT imaging along with a new innovative FDG and NaF image analysis using dedicated software. The main interest of the 3D evaluation is to have a better visualization of bone extension in such cancers and that could also avoid unsatisfying surgical treatment later on. PATIENTS AND METHODS: A prospective study was carried out from November 2016 to September 2017. Twenty patients with head and neck squamous cell carcinoma extending to the mandible (stage 4 in the UICC classification) underwent [18F]-NaF and [18F]-FDG PET/CT. We compared the delineation of 3D quantification obtained with [18F]-NaF and [18F]-FDG PET/CT. In order to carry out this comparison, a method of visualisation and quantification of PET images was developed. This new approach was based on a process of quantification of radioactive activity within the mandibular bone that objectively defined the significant limits of this activity on PET images and on a 3D visualization. Furthermore, the spatial limits obtained by analysis of the PET/CT 3D images were compared to those obtained by histopathological examination of mandibular resection which confirmed intraosseous extension to the mandible. RESULTS: The [18F]-NaF PET/CT imaging confirmed the mandibular extension in 85% of cases and was not shown in [18F]-FDG PET/CT imaging. The [18F]-NaF PET/CT was significantly more accurate than [18F]-FDG PET/CT in 3D assessment of intraosseous extension of head and neck squamous cell carcinoma. This new 3D information shows the importance in the imaging approach of cancers. All cases of mandibular extension suspected on [18F]-NaF PET/CT imaging were confirmed based on histopathological results as a reference. CONCLUSIONS: The [18F]-NaF PET/CT 3D visualization should be included in the pre-treatment workups of head and neck cancers. With the use of a dedicated software which enables objective delineation of radioactive activity within the bone, it gives a very encouraging results. The [18F]-FDG PET/CT appears insufficient to confirm mandibular extension. This new 3D simulation management is expected to avoid under treatment of patients with intraosseous mandibular extension of head and neck cancers. However, there is also a need for a further study that will compare the interest of PET/CT and PET/MRI in this indication.

[Gastric perforation caused by a lactobezoar in an infant: a case report]. / Lactobézoard du nourrisson compliqué de perforation gastrique.

Lactobezoar is a compact mass of undigested milk concretions and mucous secretions in the gastrointestinal tract. It is usually located in the stomach, resulting in various degrees of gastric outlet obstruction. Lactobezoar is the most common type of bezoar in infancy. We report the case of rare and complicated gastric outlet obstruction secondary to lactobezoar. A female infant, 35weeks and 4days' gestation, one of dichorionic, diamniotic twins (birth weight, 1.890kg), was referred to our center at 5days of life for shock and food intolerance. She was on discontinuous oral feedings with a maltodextrin-enriched infant formula. On examination on day 4, there was a tender mass palpable in the left hypochondrium and on day 5, there was abdominal distension with signs of hemodynamic instability and sepsis. Plain abdominal X-ray showed a pneumoperitoneum associated with a heterogeneous mass in a distended stomach, consistent with a bezoar. An emergency laparotomy revealed a gastric perforation secondary to a large lactobezoar, with necrosis of the greater curvature and anterior wall of the stomach. Surgical treatment consisted of extraction of the lactobezoar, partial gastrectomy (resection of necrotic areas), and gastrostomy. Pathological examination confirmed the necrosis of the gastric mucosa. The postoperative course was complicated by prolonged sepsis. The child was kept NPO for 21days. On day 21 postsurgery, an upper gastrointestinal contrast study showed a well-dimensioned stomach, with a good pyloric passage. Gastrostomy and oral feedings were then initiated with good outcome at 6months. Etiopathogenic factors of lactobezoar are prematurity, low birth weight, altered gastric secretions and disturbed gastric emptying, hypercaloric and predominantly casein-based formulas, and inadequate milk composition. Lactobezoar should be considered in infants with symptoms of gastrointestinal obstruction with evocative images. Conservative management with nil per os, parenteral nutrition, and regular saline gastric washes has a good prognosis with rapid resolution of symptoms. Surgical indications are rare, and early and appropriate diagnosis should help limit and reduce the morbidity of lactobezoar.

Understanding the recent colonization history of a plant pathogenic fungus using population genetic tools and Approximate Bayesian Computation.

Understanding the processes by which new diseases are introduced in previously healthy areas is of major interest in elaborating prevention and management policies, as well as in understanding the dynamics of pathogen diversity at large spatial scale. In this study, we aimed to decipher the dispersal processes that have led to the emergence of the plant pathogenic fungus Microcyclus ulei, which is responsible for the South American Leaf Blight (SALB). This fungus has devastated rubber tree plantations across Latin America since the beginning of the twentieth century. As only imprecise historical information is available, the study of population evolutionary history based on population genetics appeared most appropriate. The distribution of genetic diversity in a continental sampling of four countries (Brazil, Ecuador, Guatemala and French Guiana) was studied using a set of 16 microsatellite markers developed specifically for this purpose. A very strong genetic structure was found (F(st)=0.70), demonstrating that there has been no regular gene flow between Latin American M. ulei populations. Strong bottlenecks probably occurred at the foundation of each population. The most likely scenario of colonization identified by the Approximate Bayesian Computation (ABC) method implemented in DIYABC suggested two independent sources from the Amazonian endemic area. The Brazilian, Ecuadorian and Guatemalan populations might stem from serial introductions through human-mediated movement of infected plant material from an unsampled source population, whereas the French Guiana population seems to have arisen from an independent colonization event through spore dispersal.

The chestnut blight fungus world tour: successive introduction events from diverse origins in an invasive plant fungal pathogen.

Clonal expansion has been observed in several invasive fungal plant pathogens colonizing new areas, raising the question of the origin of clonal lineages. Using microsatellite markers, we retraced the evolutionary history of introduction of the chestnut blight fungus, Cryphonectria parasitica, in North America and western Europe. Combining discriminant analysis of principal components and approximate Bayesian computation analysis, we showed that several introduction events from genetically differentiated source populations have occurred in both invaded areas. In addition, a low signal of genetic recombination among different source populations was suggested in North America. Finally, two genetic lineages were present in both invaded areas as well as in the native areas, suggesting the existence of genetic lineages with a high capacity to establish in diverse environments and host species. This study confirmed the importance of multiple introductions, but questioned the role of genetic admixture in the success of introduction of a fungal plant pathogen.

Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases.

MicroRNAs (miRNAs) carry out post-transcriptional control of a multitude of cellular processes. Aberrant expression of miRNA can lead to diseases, including cancer. Gliomas are aggressive brain tumors that are thought to arise from transformed glioma-initiating neural stem cells (giNSCs). With the use of giNSCs and human glioblastoma cells, we investigated the function of miRNAs in gliomas. We identified pro-neuronal miR-128 as a candidate glioma tumor suppressor miRNA. Decreased expression of miR-128 correlates with aggressive human glioma subtypes. With a combination of molecular, cellular and in vivo approaches, we characterize miR-128's tumor suppressive role. miR-128 represses giNSC growth by enhancing neuronal differentiation. miR-128 represses growth and mediates differentiation by targeting oncogenic receptor tyrosine kinases (RTKs) epithelial growth factor receptor and platelet-derived growth factor receptor-α. Using an autochthonous glioma mouse model, we demonstrated that miR-128 repressed gliomagenesis. We identified miR-128 as a glioma tumor suppressor that targets RTK signaling to repress giNSC self-renewal and enhance differentiation.

The genetic structure of the plant pathogenic fungus Melampsora larici-populina on its wild host is extensively impacted by host domestication.

Wild and cultivated plants represent very different habitats for pathogens, especially when cultivated plants bear qualitative resistance genes. Here, we investigated to what extent the population genetic structure of a plant pathogenic fungus collected on its wild host can be impacted by the deployment of resistant cultivars. We studied one of the main poplar diseases, poplar rust, caused by the fungus Melampsora larici-populina. A thousand and fifty individuals sampled from several locations in France were phenotyped for their virulence profile (ability to infect or not the most deployed resistant cultivar 'Beaupré'), and a subset of these was genotyped using 25 microsatellite markers. Bayesian assignment tests on genetic data clustered the 476 genotyped individuals into three genetic groups. Group 1 gathered most virulent individuals and displayed evidence for selection and drastic demographic changes resulting from breakdown of the poplar cultivar 'Beaupré'. Group 2 comprised individuals corresponding to ancestral populations of M. larici-populina naturally occurring in the native range. Group 3 displayed the hallmarks of strict asexual reproduction, which has never previously been demonstrated in this species. We discuss how poplar cultivation has influenced the spatial and genetic structure of this plant pathogenic fungus, and has led to the spread of virulence alleles (gene swamping) in M. larici-populina populations evolving on the wild host.

Invulnerability of retinal ganglion cells to NMDA excitotoxicity.

NMDA excitotoxicity has been proposed to mediate the death of retinal ganglion cells (RGCs) in glaucoma and ischemia. Here, we reexamine the effects of glutamate and NMDA on rat RGCs in vitro and in situ. We show that highly purified RGCs express NR1 and NR2 receptor subunits by Western blotting and immunostaining, and functional NMDA receptor channels by whole-cell patch-clamp recording. Nevertheless, high concentrations of glutamate or NMDA failed to induce the death of purified RGCs, even after prolonged exposure for 24 h. RGCs co-cultured together with ephrins, astrocytes, or mixed retinal cells were similarly invulnerable to glutamate and NMDA, though their NMDA currents were 4-fold larger. In contrast, even a short exposure to glutamate or NMDA induced the rapid and profound excitotoxic death of most hippocampal neurons in culture. To determine whether RGCs in an intact retina are vulnerable to excitotoxicity, we retrogradely labeled RGCs in vivo using fluorogold and exposed acutely isolated intact retinas to high concentrations of glutamate or NMDA. This produced a substantial and rapid loss of amacrine cells; however, RGCs were not affected. Nonetheless, RGCs expressed NMDA currents in situ that were larger than those reported for amacrine cells. Interestingly, the NMDA receptors expressed by RGCs were extrasynaptically localized both in vitro and in situ. These results indicate that RGCs in vitro and in situ are relatively invulnerable to glutamate and NMDA excitotoxicity compared to amacrine cells, and indicate that important, as yet unidentified, determinants downstream of NMDA receptors control vulnerability to excitotoxicity.

Schwann cells and astrocytes induce synapse formation by spinal motor neurons in culture.

Glia constitute 90% of cells in the human nervous system, but relatively little is known about their functions. We have been focusing on the potential synaptic roles of glia in the CNS. We recently found that astrocytes increase the number of mature, functional synapses on retinal ganglion cells (RGCs) by sevenfold and are required for synaptic maintenance in vitro. These observations raised the question of whether glia similarly enhance synapse formation by other neuron types. Here we have investigated whether highly purified motor neurons isolated from developing rat spinal cords are able to form synapses in the absence of glia or whether glia similarly enhance synapse number. We show that spinal motor neurons (SMNs) form few synapses unless Schwann cells or astrocytes are present. Schwann cells increase the number of functional synapses by ninefold as measured by immunostaining, and increase spontaneous synaptic activity by several hundredfold. Surprisingly, the synapses formed between spinal motor neurons were primarily glutamatergic, as they could be blocked by CNQX. This synapse-promoting activity is not mediated by direct glial-neuronal cell contact but rather is mediated by secreted molecule(s) from the Schwann cells, as we previously found for astrocytes. Interestingly, the synapse-promoting activity from astrocytes and Schwann cells was functionally similar: Schwann cells also promoted synapse formation between retinal ganglion cells, and astrocytes promoted synapse formation between spinal motor neurons. These studies show that both astrocytes and Schwann cells strongly promote synapse formation between spinal motor neurons and demonstrate that glial regulation of synaptogenesis extends to other neuron types.

[Radio-guided resection of residual metastatic lymph node from a previously resected neuroendocrine tumor]. / Exérèse radioguidée d'une adénopathie résiduelle métastatique d'une tumeur neuroendocrine antérieurement réséquée.

Neuroendocrine tumors are slowly growing and carry a high risk of recurrence. Somatostatin receptor scintigraphy is considered as the gold standard for preoperative evaluation and postoperative follow-up. The use of an intraoperative detection probe makes easier a complete resection of abdominal residual or recurrent tumor. These resections may be incomplete because of the small size of the tumor and the postoperative adhesions. Radio-guided surgery is recommended in order to reduce the need for reoperation.

Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier.

Na(v)1.6 is the main sodium channel isoform at adult nodes of Ranvier. Here, we show that Na(v)1.2 and its beta2 subunit, but not Na(v)1.6 or beta1, are clustered in developing central nervous system nodes and that clustering of Na(v)1.2 and Na(v)1.6 is differentially controlled. Oligodendrocyte-conditioned medium is sufficient to induce clustering of Na(v)1.2 alpha and beta2 subunits along central nervous system axons in vitro. This clustering is regulated by electrical activity and requires an intact actin cytoskeleton and synthesis of a non-sodium channel protein. Neither soluble- or contact-mediated glial signals induce clustering of Na(v)1.6 or beta1 in a nonmyelinating culture system. These data reveal that the sequential clustering of Na(v)1.2 and Na(v)1.6 channels is differentially controlled and suggest that myelination induces Na(v)1.6 clustering.

A role for the helix-loop-helix protein Id2 in the control of oligodendrocyte development.

Compared to neurons, the intracellular mechanisms that control glial differentiation are still poorly understood. We show here that oligodendrocyte lineage cells express the helix-loop-helix proteins Mash1 and Id2. Although Mash1 has been found to regulate neuronal development, we found that in the absence of Mash1 oligodendrocyte differentiation occurs normally. In contrast, we found that overexpression of Id2 powerfully inhibits oligodendrocyte differentiation, that Id2 normally translocates out of the nucleus at the onset of differentiation, and that absence of Id2 induces premature oligodendrocyte differentiation in vitro. These findings demonstrate that Id2 is a component of the intracellular mechanism that times oligodendrocyte differentiation and point to the existence of an as yet unidentified MyoD-like bHLH protein necessary for oligodendrocyte differentiation.

Induction of astrocyte differentiation by endothelial cells.

Here we have investigated the mechanisms that control astrocyte differentiation within the developing rat optic nerve. Astrocytes are normally generated by astrocyte precursor cells within the embryonic optic nerve. We show that there is a close temporal and spatial correlation between endothelial and astrocyte differentiation. We tested the potential role of endothelial cells in inducing astrocyte differentiation by developing an immunopanning method to highly purify endothelial cells from developing optic nerves. We show that the purified endothelial cells, but not other embryonic optic nerve cell types, strongly induce the differentiation of purified astrocyte precursor cells into astrocytes in vitro. Leukemia inhibitory factor (LIF) and LIF receptors have been implicated previously in astrocyte differentiation in vivo. We show that purified endothelial cells express LIF mRNA and that their ability to induce astrocyte differentiation is prevented by a neutralizing anti-LIF, but not anti-ciliary neurotrophic factor, antiserum. These findings demonstrate a role for endothelial cells in inducing astrocyte differentiation. The induction of astrocyte differentiation by endothelial cells makes sense phylogenetically, anatomically, and functionally, because astrocytes evolved concurrently with brain vasculature and ensheathe capillaries throughout the brain. The ability to purify and culture astrocytes and endothelial cells should provide an excellent model system for future studies of blood-brain barrier development.

Control of synapse number by glia.

Although astrocytes constitute nearly half of the cells in our brain, their function is a long-standing neurobiological mystery. Here we show by quantal analyses, FM1-43 imaging, immunostaining, and electron microscopy that few synapses form in the absence of glial cells and that the few synapses that do form are functionally immature. Astrocytes increase the number of mature, functional synapses on central nervous system (CNS) neurons by sevenfold and are required for synaptic maintenance in vitro. We also show that most synapses are generated concurrently with the development of glia in vivo. These data demonstrate a previously unknown function for glia in inducing and stabilizing CNS synapses, show that CNS synapse number can be profoundly regulated by nonneuronal signals, and raise the possibility that glia may actively participate in synaptic plasticity.

Neuronal and glial cell biology.

Here, we review progress in our understanding of neuronal and glial cell biology during the past ten years, with an emphasis on glial cell fate specification, apoptosis, the cytoskeleton, neuronal polarity, synaptic vesicle recycling and targeting, regulation of the cytoskeleton by extracellular signals, and neuron-glia interactions.