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Le Kremlin-Bicêtre, France

Saliou G.,University of Western Ontario | Saliou G.,Center Hospitalier University Bicetre | Dirks P.,Hospital for Sick Children | Sacho R.H.,University of Western Ontario | And 3 more authors.
American Journal of Neuroradiology

BACKGROUND AND PURPOSE: Few clinical and imaging findings are known to be associated with poor outcome in neonates and infants with vein of Galen arteriovenous malformations. In the present consecutive series of 35 patients, we evaluated both the diameter of the superior sagittal sinus at onset and the diameter of the jugular bulb on follow-up as potential factors related to poor outcome. MATERIALS AND METHODS: Thirty-five consecutive neonates and infants who were prospectively collected in a single-center data base were included in this review. Outcome was assessed by using the Bicêtre Outcome Score. Both the absolute diameter of the superior sagittal sinus and its ratio to the biparietal diameter were measured at onset, compared with age-matched controls, and correlated to patient outcome. RESULTS: The diameter of the superior sagittal sinus at onset and its ratio to the biparietal diameter were significantly smaller in the vein of Galen arteriovenous malformation population compared with the matched population (P<.0001) and were correlated significantly with a risk of poor clinical outcome (P.008). Development of jugular bulb narrowing was also related to poor clinical outcome (P.0001). CONCLUSIONS: Decreased superior sagittal sinus diameter may reflect a decrease of cerebral blood flow due to cerebral arterial steal and intracranial hydrovenous disorders. This finding may be considered cerebral blood flow deterioration and thus taken into consideration in the management decisions for patients with vein of Galen arteriovenous malformations. Likewise, our data suggest that progressive jugular bulb narrowing may indicate earlier intervention to prevent severe narrowing. Source

Bruno A.,Paris-Sorbonne University | Bruno A.,French Institute of Health and Medical Research | Bruno A.,French National Center for Scientific Research | Boisselier B.,Paris-Sorbonne University | And 25 more authors.

Little is known about the genomic basis of primary central nervous system lymphoma (PCNSL) tumorigenesis. To investigate the mutational profile of PCNSL, we analyzed nine paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Eight genes of interest have been further investigated by focused resequencing in 28 additional PCNSL tumors to better estimate their incidence. Our study identified recurrent somatic mutations in 37 genes, some involved in key signaling pathways such as NFKB, B cell differentiation and cell cycle control. Focused resequencing in the larger cohort revealed high mutation rates for genes already described as mutated in PCNSL such as MYD88 (38%), CD79B (30%), PIM1 (22%) and TBL1XR1 (19%) and for genes not previously reported to be involved in PCNSL tumorigenesis such as ETV6 (16%), IRF4 (14%), IRF2BP2 (11%) and EBF1 (11%). Of note, only 3 somatically acquired SNVs were annotated in the COSMIC database. Our results demonstrate a high genetic heterogeneity of PCNSL and mutational pattern similarities with extracerebral diffuse large B cell lymphomas, particularly of the activated B-cell (ABC) subtype, suggesting shared underlying biological mechanisms. The present study provides new insights into the mutational profile of PCNSL and potential targets for therapeutic strategies. Source

Kasteleijn- Nolst Trenite D.,University of Rome La Sapienza | Kasteleijn- Nolst Trenite D.,University Utrecht | Parain D.,University of Rouen | Genton P.,Center Saint Paul | And 3 more authors.
Epilepsy and Behavior

A new class of drugs, the nonimidazole histamine 3 receptor (H3R) antagonists, has been developed in the past decade for treatment of various brain diseases. Pitolisant is such a drug.We studied the pharmacodynamic effect of pitolisant in patients with epilepsy in early Phase II, using the photosensitivity proof of concept model. A total of 14 adult patients (11 females and 3 males; 5 drug naïve) were studied for three days to evaluate the effect of a single oral dose of pitolisant on EEG photosensitivity ranges. All patients showed repeatedly a generalized photoparoxysmal response (PPR) prior to drug administration on placebo Day 1. A statistically significant suppressive effect (standardized photosensitive response [SPR] reduction as measured with paired t-tests) for 20-, 40-, or 60-mg doses of pitolisant was seen in 9/14 (64%) patients of whom 6/14 (43%) showed abolition of the response to intermittent photic stimulation (IPS). Patients on the highest dosage (60. mg) showed the strongest effect with an effect lasting up to 28. h. Thus, full-scale Phase II studies with this novel H3R antagonist, pitolisant, in patients with epilepsy are warranted. © 2013 Elsevier Inc. Source

Carbonne A.,Regional Coordinating Center for Nosocomial Infection Control | Thiolet J.M.,Institute of Veille Sanitaire | Fournier S.,Central Infection Control Team | Fortineau N.,Center Hospitalier University Bicetre | And 11 more authors.

An outbreak of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae type 2 was detected in September 2009 in two hospitals in a suburb south of Paris, France. In total, 13 KPC-producing K. pneumoniae type 2 cases (four with infections and nine with digestive-tract colonisations) were identified, including a source case transferred from a Greek hospital. Of the 13 cases, seven were secondary cases associated with use of a contaminated duodenoscope used to examine the source case (attack rate: 41%) and five were secondary cases associated with patient-topatient transmission in hospital. All isolated strains from the 13 patients: (i) exhibited resistance to all antibiotics except gentamicin and colistin, (ii) were more resistant to ertapenem (minimum inhibitory concentration (MIC) always greater than 4 mg/L) than to imipenem (MIC: 1-8 mg/L, depending on the isolate), (iii) carried the blaKPC-2 and blaSHV12 genes and (iv) had an indistinguishable pulsed-field gel electrophoresis (PFGE) pattern. These cases occurred in three hospitals: some were transferred to four other hospitals. Extended infection control measures implemented in the seven hospitals included: (i) limiting transfer of cases and contact patients to other wards, (ii) cohorting separately cases and contact patients, (iii) reinforcing hand hygiene and contact precautions and (iv) systematic screening of contact patients. Overall, 341 contact patients were screened. A year after the outbreak, no additional case has been identified in these seven hospitals. This outbreak emphasises the importance of rapid identification and notification of emerging highly resistant K. pneumoniae strains in order to implement reinforced control measures. Source

Gonzalez-Aguilar A.,Groupe Hospitalier Pitie Salpetriere | Gonzalez-Aguilar A.,University Pierre and Marie Curie | Idbaih A.,Groupe Hospitalier Pitie Salpetriere | Idbaih A.,University Pierre and Marie Curie | And 27 more authors.
Clinical Cancer Research

Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance. Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1 , TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival. Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies. ©2012 AACR. Source

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