Identification of New Genes Involved in Germline Predisposition to Early-Onset Gastric Cancer.

The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, APC, FAT4, CTNND1 and TLR2 seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and Helicobacter pylori recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition.

Double dissociation between syntactic gender and picture naming processing: a brain stimulation mapping study.

Neural foundations of syntactic gender processing remain poorly understood. We used electrostimulation mapping in nine right-handed awake patients during surgery for a glioma within the left hemisphere, to study whether the cortico-subcortical structures involved in naming versus syntactic gender processing are common or distinct. In French, the article determines the grammatical gender. Thus, the patient was asked to perform a picture naming task and to give the appropriate article for each picture, with and without stimulation. Cortical stimulation elicited reproducible syntactic gender disturbances in six patients, in the inferior frontal gyrus (three cases), and in the posterior middle temporal gyrus (three cases). Interestingly, no naming disorders were generated during stimulation of the syntactic sites, while cortical areas inducing naming disturbances never elicited grammatical gender errors when stimulated. Moreover, at the subcortical level, stimulation of the white matter lateral to the caudate nucleus induced gender errors in three patients, with no naming disorders. Using cortico-subcortical electrical mapping in awake patients, we demonstrate for the first time (1) a double dissociation between syntactic gender and naming processing, supporting independent network model rather than serial theory, (2) the involvement of the left inferior frontal gyrus, especially the pars triangularis, and the posterior left middle temporal gyrus in grammatical gender processing, (3) the existence of white matter pathways, likely a sub-part of the left superior longitudinal fasciculus, underlying a large-scale distributed cortico-subcortical circuit which might selectively sub-serve syntactic gender processing, even if interconnected with parallel sub-networks involved in naming (semantic and phonological) processing.

Direct observation of human microcirculation during decompressive craniectomy after stroke.

OBJECTIVES: Most knowledge related to the pathophysiology of microcirculation in ischemic stroke comes from experimental research. Unfortunately, data on microcirculation in the human brain are limited, partially as a result of the lack of appropriate investigational techniques. The objective of our study was to test the hypothesis that cortical microcirculatory alterations in the brain, in terms of blood flow and vessel density, occur in patients with stroke who require surgical decompression compared with a control group. DESIGN: Prospective and observational study. SETTING: Third-level university hospital. PATIENTS: Six patients who had undergone decompressive surgery as a result of a space-occupying hemispheric infarction. These patients were compared with five patients who had undergone craniotomy for a disease not affecting the cortex. INTERVENTIONS: Cortical microcirculation in the brain was directly observed using sidestream dark-field imaging. All images were analyzed offline. MEASUREMENTS AND MAIN RESULTS: In patients with stroke with a space-occupying hemispheric infarction, 18 good-quality movie images were compared with 25 control group images. In the control group, cortical vessels showed a continuous flow in small, medium, and large vessels compared with patients with stroke who presented intermittent or no flow in all vessels. The proportion of perfused vessels was near 100% in control subjects and 63.44% in patients with stroke. The perfused vessel density index was also higher in control subjects (6.16 1/mm; interquartile range, 5.65-7.56) than in patients with stroke (2.77 1/mm; interquartile range, 1.75-3.86). CONCLUSION: Sidestream dark-field imaging allowed direct visualization of cerebral microcirculatory alterations in the operating room. This technique allowed the documentation of a significant blood flow reduction in the cortical microvascular and a decreased vascular density in patients with stroke compared with control subjects.

Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study.

BACKGROUND: During the last decade, the use of 5-aminolevulinic acid (5-ALA) has been steadily increasing in neurosurgery. The study's main objectives were to prospectively evaluate the effectiveness and safety of 5-ALA when used in clinical practice setting on high-grade gliomas' patients. METHODS: National, multicenter and prospective observational study. INCLUSION CRITERIA: authorized conditions of use of 5-ALA. EXCLUSION CRITERIA: contraindication to 5-ALA, inoperable or partial resected tumors, pregnancy and children. Epidemiological, clinical, laboratory, radiological, and safety data were collected. Effectiveness was assessed using complete resection of the tumor, and progression-free and overall survival probabilities. RESULTS: Between May 2010 and September 2014, 85 patients treated with 5-ALA were included, and 77 were suitable for the effectiveness analysis. Complete resection was achieved in 41 patients (54%). Surgeons considered suboptimal the fluorescence of 5-ALA in 40% of the patients assessed. The median duration of follow-up was 12.3 months. The progression-free survival probability at 6 months was 58%. The median duration overall survival was 14.2 months. Progression tumor risk factors were grade of glioma, age and resection degree; and death risk factors were grade of glioma and gender. No severe adverse effects were reported. At one month after surgery, new or increased neurological morbidity was 6.5%. Hepatic enzymes were frequently increased within the first month after surgery; however, they subsequently normalized, and this was found to have no clinical significance. CONCLUSION: In clinical practice, the 5-ALA showed a good safety profile, but the benefits related to 5-ALA have not been yet clearly shown. The improved differentiation expected by fluorescence between normal and tumor cerebral tissue was suboptimal in a relevant number of patients; in addition, the expected higher degree of resection was lower than in clinical trials as well as incomplete resection was not identified as a prognostic factor risk for death. Because optimal fluorescence was correlated to higher complete resection rate, further research is needed to identify patients (or tumors) with more surgery benefits when using the 5-ALA.