Publications by authors named "Fabrice Chretien"

162 Publications

Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions.

Acta Neuropathol Commun 2021 08 13;9(1):135. Epub 2021 Aug 13.

Department of Pediatric Neurosurgery, Necker Hospital, APHP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

The cIMPACT-NOW Update 7 has replaced the WHO nosology of "ependymoma, RELA fusion positive" by "Supratentorial-ependymoma, C11orf95-fusion positive". This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.
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http://dx.doi.org/10.1186/s40478-021-01238-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362233PMC
August 2021

Surgery of Insular Diffuse Gliomas-Part 1: Transcortical Awake Resection Is Safe and Independently Improves Overall Survival.

Neurosurgery 2021 Sep;89(4):565-578

Department of Neurosurgery, GHU Paris-Sainte-Anne Hospital, Paris, France.

Background: Insular diffuse glioma resection is at risk of vascular injury and of postoperative new neurocognitive deficits.

Objective: To assess safety and efficacy of surgical management of insular diffuse gliomas.

Methods: Observational, retrospective, single-institution cohort analysis (2005-2019) of 149 adult patients surgically treated for an insular diffuse glioma: transcortical awake resection with intraoperative functional mapping (awake resection subgroup, n = 61), transcortical asleep resection without functional mapping (asleep resection subgroup, n = 50), and stereotactic biopsy (biopsy subgroup, n = 38). All cases were histopathologically assessed according to the 2016 World Health Organization classification and cIMPACT-NOW update 3.

Results: Following awake resection, 3/61 patients had permanent motor deficit, seizure control rates improved (89% vs 69% preoperatively, P = .034), and neurocognitive performance improved from 5% to 24% in tested domains, despite adjuvant oncological treatments. Resection rates were higher in the awake resection subgroup (median 94%) than in the asleep resection subgroup (median 46%; P < .001). There was more gross total resection (25% vs 12%) and less partial resection (34% vs 80%) in the awake resection subgroup than in the asleep resection subgroup (P < .001). Karnofsky Performance Status score <70 (adjusted hazard ratio [aHR] 2.74, P = .031), awake resection (aHR 0.21, P = .031), isocitrate dehydrogenase (IDH)-mutant grade 2 astrocytoma (aHR 5.17, P = .003), IDH-mutant grade 3 astrocytoma (aHR 6.11, P < .001), IDH-mutant grade 4 astrocytoma (aHR 13.36, P = .008), and IDH-wild-type glioblastoma (aHR 21.84, P < .001) were independent predictors of overall survival.

Conclusion: Awake surgery preserving the brain connectivity is safe, allows larger resections for insular diffuse gliomas than asleep resection, and positively impacts overall survival.
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http://dx.doi.org/10.1093/neuros/nyab254DOI Listing
September 2021

Surgery of Insular Diffuse Gliomas-Part 2: Probabilistic Cortico-Subcortical Atlas of Critical Eloquent Brain Structures and Probabilistic Resection Map During Transcortical Awake Resection.

Neurosurgery 2021 Sep;89(4):579-590

Department of Neurosurgery, GHU Paris - Sainte-Anne Hospital, Paris, France.

Background: Insular diffuse glioma surgery is challenging, and tools to help surgical planning could improve the benefit-to-risk ratio.

Objective: To provide a probabilistic resection map and frequency atlases of critical eloquent regions of insular diffuse gliomas based on our surgical experience.

Methods: We computed cortico-subcortical "eloquent" anatomic sites identified intraoperatively by direct electrical stimulations during transcortical awake resection of insular diffuse gliomas in adults.

Results: From 61 insular diffuse gliomas (39 left, 22 right; all left hemispheric dominance for language), we provided a frequency atlas of eloquence of the opercula (left/right; pars orbitalis: 0%/5.0%; pars triangularis: l5.6%/4.5%; pars opercularis: 37.8%/27.3%; precentral gyrus: 97.3%/95.4%; postcentral and supramarginal gyri: 75.0%/57.1%; temporal pole and superior temporal gyrus: 13.3%/0%), which tailored the transcortical approach (frontal operculum to reach the antero-superior insula, temporal operculum to reach the inferior insula, parietal operculum to reach the posterior insula). We provided a frequency atlas of eloquence identifying the subcortical functional boundaries (36.1% pyramidal pathways, 50.8% inferior fronto-occipital fasciculus, 13.1% arcuate and superior longitudinal fasciculi complex, 3.3% somatosensory pathways, 8.2% caudate and lentiform nuclei). Vascular boundaries and increasing errors during testing limited the resection in 8.2% and 11.5% of cases, respectively. We provided a probabilistic 3-dimensional atlas of resectability.

Conclusion: Functional mapping under awake conditions has to be performed intraoperatively in each patient to guide surgical approach and resection of insular diffuse gliomas in right and left hemispheres. Frequency atlases of opercula eloquence and of subcortical eloquent anatomic boundaries, and probabilistic 3-dimensional atlas of resectability could guide neurosurgeons.
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http://dx.doi.org/10.1093/neuros/nyab255DOI Listing
September 2021

Toward a transitional care from childhood and adolescence to adulthood in surgical neurooncology? A lesson from the Necker-Enfants Malades and the Sainte-Anne Hospitals collaboration.

J Neurosurg Pediatr 2021 Jul 30:1-7. Epub 2021 Jul 30.

1Service de Neurochirurgie, GHU Paris-Hôpital Sainte-Anne, Paris.

Objective: Transitional care in surgical neurooncology is poorly studied. However, this period is pivotal, since it allows the patient to be empowered in his or her disease management. Here, the authors describe the experience of the Necker-Enfants Malades and the Sainte-Anne Hospital collaboration.

Methods: The mixed transitional consultations started in September 2019 in a dedicated space for transitional care, named the "La Suite" department, located in the Necker-Enfants Malades Hospital, Paris, France. The authors organized planned consultations to schedule the clinical and radiological follow-up in the adult neurosurgical department but also emergency consultations to manage tumor recurrence in young adult patients. Transitional care was performed jointly by pediatric and adult neurosurgeons who have developed clinical and research skills in the field of surgical neurooncology. Neuropathological analysis was performed by a neuropathologist who is specialized in pediatric and adult neurooncology.

Results: Fourteen patients benefited from a mixed transitional consultation. All of them accepted to start their management in an adult neurosurgical environment. Eleven patients (78.6%) for whom the disease was controlled benefited from a planned consultation. Three patients (21.4%) required rapid neurosurgical management for a tumor recurrence (n = 2) or for a new primary CNS tumor (n = 1) and benefited from an emergency consultation.

Conclusions: For adult patients harboring a brain tumor during childhood or adolescence, the authors suggest that neurosurgeons specialized in adult surgical neurooncology with a full knowledge in pediatric neurooncology will combine the required skills to optimize care management for these patients within a dedicated multidisciplinary organization framework.
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http://dx.doi.org/10.3171/2021.3.PEDS2141DOI Listing
July 2021

An integrative histopathological and epigenetic characterization of primary intracranial mesenchymal tumors, FET:CREB-fused broadening the spectrum of tumor entities in comparison with their soft tissue counterparts.

Brain Pathol 2021 Jul 27:e13010. Epub 2021 Jul 27.

Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne Hospital, Paris, France.

FET:CREB fusions have been described in a variety of tumors from various phenotypes. Recently, these fusion transcripts were reported in intracranial tumors, variably named intracranial mesenchymal myxoid tumors or angiomatoid fibrous histiocytomas. Controversy remains concerning the terminology for these tumors. Here, we report 11 cases of central nervous system mesenchymal tumors with proven FET:CREB fusion. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor or Sarcoma Classifier (v11b4/v12.2). However, by using unsupervised t-SNE and hierarchical clustering analyses, six of the cases constituted a distinct cluster. The remaining four tumors showed no obvious relation to any of the other referenced classes but were close to the clusters of extra-CNS angiomatoid fibrous histiocytomas (n = 1), clear cell sarcomas (n = 1), or solitary fibrous tumors (n = 2). Our findings confirm that intracranial FET:CREB-fused tumors do not represent a single molecular tumor entity, although most samples clustered close to each other, indicating the existence of a distinct epigenetic group that could potentially be partially masked by the low number of cases included. Further analyses are needed to characterize intracranial FET:CREB fused-defined tumors in more detail.
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http://dx.doi.org/10.1111/bpa.13010DOI Listing
July 2021

Feasibility, Safety and Impact on Overall Survival of Awake Resection for Newly Diagnosed Supratentorial -Wildtype Glioblastomas in Adults.

Cancers (Basel) 2021 Jun 10;13(12). Epub 2021 Jun 10.

Department of Neurosurgery, GHU Site Sainte-Anne, F-75014 Paris, France.

Background: Although awake resection using intraoperative cortico-subcortical functional brain mapping is the benchmark technique for diffuse gliomas within eloquent brain areas, it is still rarely proposed for IDH-wildtype glioblastomas. We have assessed the feasibility, safety, and efficacy of awake resection for IDH-wildtype glioblastomas.

Methods: Observational single-institution cohort (2012-2018) of 453 adult patients harboring supratentorial IDH-wildtype glioblastomas who benefited from awake resection, from asleep resection, or from a biopsy. Case matching (1:1) criteria between the awake group and asleep group: gender, age, RTOG-RPA class, tumor side, location and volume and neurosurgeon experience.

Results: In patients in the awake resection subgroup ( = 42), supratotal resections were more frequent (21.4% vs. 3.1%, < 0.0001) while partial resections were less frequent (21.4% vs. 40.1%, < 0.0001) compared to the asleep ( = 222) resection subgroup. In multivariable analyses, postoperative standard radiochemistry (aHR = 0.04, < 0.0001), supratotal resection (aHR = 0.27, = 0.0021), total resection (aHR = 0.43, < 0.0001), KPS score > 70 (HR = 0.66, = 0.0013), promoter methylation (HR = 0.55, = 0.0031), and awake surgery (HR = 0.54, = 0.0156) were independent predictors of overall survival. After case matching, a longer overall survival was found for awake resection (HR = 0.47, = 0.0103).

Conclusions: Awake resection is safe, allows larger resections than asleep surgery, and positively impacts overall survival of IDH-wildtype glioblastoma in selected adult patients.
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http://dx.doi.org/10.3390/cancers13122911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230499PMC
June 2021

Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study.

PLoS Med 2021 05 26;18(5):e1003632. Epub 2021 May 26.

Eijkman Institute for Molecular Biology, Jakarta, Indonesia.

Background: A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival.

Methods And Findings: We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted.

Conclusions: Immature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen.
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http://dx.doi.org/10.1371/journal.pmed.1003632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154101PMC
May 2021

Is function-based resection using intraoperative awake brain mapping feasible and safe for solitary brain metastases within eloquent areas?

Neurosurg Rev 2021 Mar 4. Epub 2021 Mar 4.

Service de Neurochirurgie, GHU Paris, Hôpital Sainte-Anne, 1, rue Cabanis, F-75014, Paris, France.

To assess feasibility and safety of function-based resection under awake conditions for solitary brain metastasis patients. Retrospective, observational, single-institution case-control study (2014-2019). Inclusion criteria are adult patients, solitary brain metastasis, supratentorial location within eloquent areas, and function-based awake resection. Case matching (1:1) criteria between metastasis group and control group (high-grade gliomas) are sex, tumor location, tumor volume, preoperative Karnofsky Performance Status score, age, and educational level. Twenty patients were included. Intraoperatively, all patients were cooperative; no obstacles precluded the procedure from being performed. A positive functional mapping was achieved at both cortical and subcortical levels, allowing for a function-based resection in all patients. The case-matched analysis showed that intraoperative and postoperative events were similar, except for a shorter duration of the surgery (p<0.001) and of the awake phase (p<0.001) in the metastasis group. A total resection was performed in 18 cases (90%, including 10 supramarginal resections), and a partial resection was performed in two cases (10%). At three months postoperative months, none of the patients had worsening of their neurological condition or uncontrolled seizures, three patients had an improvement in their seizure control, and seven patients had a Karnofsky Performance Status score increase ≥10 points. Function-based resection under awake conditions preserving the brain connectivity is feasible and safe in the specific population of solitary brain metastasis patients and allows for high resection rates within eloquent brain areas while preserving the overall and neurological condition of the patients. Awake craniotomy should be considered to optimize outcomes in brain metastases in eloquent areas.
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http://dx.doi.org/10.1007/s10143-021-01504-6DOI Listing
March 2021

[Analysis of interference criteria for the validation of a method file: HPS staining after fixation with zinc-formalin in comparison to fixation with the classical 4% buffered formalin solution].

Ann Pathol 2021 Jun 23;41(3):310-316. Epub 2021 Jan 23.

Service de neuropathologie, GHU de Paris-psychiatrie et neurosciences, centre hospitalier Sainte-Anne, 1, rue Cabanis, 75014 Paris, France.

Introduction: The department of neuropathology of Sainte-Anne Hospital uses zinc-formalin as the fixative agent for its samples. No publication referenced in Pubmed has proven the validity of this fixative agent. In the context of the accreditation of our standard staining (HPS for Hemalun-Phloxin-Saffron), we started a file for the validation of this method in which the fixative agent constitutes an « interfering » substance which can modify the quality of the technique. The aim of this study was to prove that the use of zinc-formalin as a fixative agent is as suitable as the fixation with 4 % buffered formalin.

Materials And Methods: A cohort of samples fixed by zinc-formalin and by 4 % buffered formalin was performed on fresh samples, then cut and stained by HPS. The slides were interpreted by three pathologists (one of them was outside our centre)  ``blind '' to the fixative agent and they evaluated four criteria (general quality of the staining, components of the extracellular matrix, cytoplasmic details, and nuclear details) and scored them (from 0 to 3) according to the Association française en assurance qualité (AFAQAP) recommendations.

Results: The cohort included 43 samples. The results of the analysis showed that for samples fixed by zinc-formalin, three of the four criteria obtained significantly a better score than the samples fixed by classical formalin.

Discussion And Conclusions: Our results show that the zinc-formalin fixative does not constitute an  ``interfering '' agent for the quality of the HPS staining for neuropathological samples.
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http://dx.doi.org/10.1016/j.annpat.2020.10.003DOI Listing
June 2021

Evolution of the neurosurgical management of progestin-associated meningiomas: a 23-year single-center experience.

J Neurooncol 2021 Apr 15;152(2):279-288. Epub 2021 Jan 15.

Department of Neurosurgery, Service de Neurochirurgie, GHU site Sainte-Anne, Paris, France.

Purpose: The improving knowledge of interactions between meningiomas and progestin refines the management of this specific condition. We assessed the changes over time of the management of progestin-associated meningiomas.

Methods: We retrospectively studied consecutive adult patients who had at least one meningioma in the context of progestin intake (October 1995-October 2018) in a tertiary adult Neurosurgical Center.

Results: 71 adult women with 125 progestin-associated meningiomas were included. The number of progestin-associated meningioma patients increased over time (0.5/year before 2008, 22.0/year after 2017). Progestin treatment was an approved indication in 27.0%. A mean of 1.7 ± 1.2 meningiomas were discovered per patient (median 1, range 1-6). Surgery was performed on 36 (28.8%) meningiomas and the histopathologic grading was WHO grade 1 in 61.1% and grade 2 in 38.9%. The conservative management of meningiomas increased over time (33.3% before 2008, 64.3% after 2017) and progestin treatment withdrawal increased over time (16.7% before 2008, 95.2% after 2017). Treatment withdrawal varied depending on the progestin derivative used (88.9% with cyproterone acetate, 84.6% with chlormadinone acetate, 28.6% with nomegestrol acetate, 66.7% with progestin derivative combination). The main reason for therapeutic management of meningiomas was the presence of clinical signs. Among the 54 meningiomas managed conservatively for which the progestin had been discontinued, MRI follow-up demonstrated a regression in 29.6%, a stability in 68.5%, and an ongoing growth in 1.9% of cases.

Conclusions: Conservative management, including progestin treatment discontinuation, has grown over time with promising results in terms of efficacy and safety.
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http://dx.doi.org/10.1007/s11060-021-03696-9DOI Listing
April 2021

Robot-Assisted Stereotactic Biopsies in 377 Consecutive Adult Patients with Supratentorial Diffuse Gliomas: Diagnostic Yield, Safety, and Postoperative Outcomes.

World Neurosurg 2021 04 4;148:e301-e313. Epub 2021 Jan 4.

Department of Neurosurgery, GHU site Sainte-Anne, Paris, France; Université de Paris, Paris, France; Institut de Psychiatrie et Neurosciences de Paris (IPNP), INSERM, IMA-BRAIN, Paris, France. Electronic address:

Background: Multiple biopsy samples are warranted for the histomolecular diagnosis of diffuse gliomas in the current molecular era, which possibly increases morbidity.

Objective: We assessed diagnostic yield, safety, and risk factors of postoperative morbidity after robot-assisted serial stereotactic biopsy sampling along 1 biopsy trajectory for diffuse gliomas.

Methods: Observational retrospective analysis of consecutive magnetic resonance imaging-based robot-assisted stereotactic biopsies performed at a single institution to assess the diagnosis of nonresectable newly diagnosed supratentorial diffuse gliomas in adults (2006-2016).

Results: In 377 patients, 4.2 ± 1.9 biopsy samples were obtained at 2.6 ± 1.2 biopsy sites. The histopathologic diagnosis was obtained in 98.7% of cases. Preoperative neurologic deficit (P = 0.030), biopsy site hemorrhage ≥20 mm (P = 0.004), and increased mass effect on postoperative imaging (P = 0.014) were predictors of a new postoperative neurologic deficit (7.7%). Postoperative neurologic deficit (P < 0.001) and increased mass effect on postoperative imaging (P = 0.014) were predictors of a Karnofsky Performance Status decrease ≥20 points postoperatively (4.0%). Increased intracranial pressure preoperatively (P = 0.048) and volume of the contrast-enhanced area ≥13 cm (P = 0.048) were predictors of an increased mass effect on postoperative imaging (4.4%). Preoperative Karnofsky Performance Status <70 (P = 0.045) and increased mass effect on postoperative imaging (P < 0.001) were predictors of mortality 1 month postoperatively (2.9%). Preoperative neurologic deficit (P = 0.005), preoperative Karnofsky Performance Status <70 (P < 0.001), subventricular zone contact (P = 0.004), contrast enhancement (P = 0.018), and steroid use (P = 0.003), were predictors of the inability to discharge to home postoperatively (37.0%).

Conclusions: Robot-assisted stereotactic biopsy sampling results in high diagnostic accuracy with low complication rates. Multiple biopsy sites and samples do not increase postoperative complications.
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http://dx.doi.org/10.1016/j.wneu.2020.12.127DOI Listing
April 2021

Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine.

Int J Antimicrob Agents 2021 Mar 30;57(3):106274. Epub 2020 Dec 30.

GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte-Anne, Service Hospitalo-Universitaire, Pôle Hospitalo-Universitaire Paris 15, Paris, France; Université de Paris, Paris, France; Institut Pasteur, Experimental Neuropathology Unit, Paris, France. Electronic address:

Introduction: Urgent action is needed to fight the ongoing coronavirus disease 2019 (COVID-19) pandemic by reducing the number of infected cases, contagiousness and severity. Chlorpromazine (CPZ), an antipsychotic from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and has antiviral activity against severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus. The aim of this in-vitro study was to test CPZ against SARS-CoV-2 in monkey and human cells.

Materials And Methods: Monkey VeroE6 cells and human alveolar basal epithelial A549-ACE2 cells were infected with SARS-CoV-2 in the presence of various concentrations of CPZ. Supernatants were harvested at day 2 and analysed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) for the presence of SARS-CoV-2 RNA. Cell viability was assessed in non-infected cells.

Results: CPZ was found to have antiviral activity against SARS-CoV-2 in monkey VeroE6 cells, with a half maximal inhibitory concentration (IC) of 8.2 µM, half maximal cytotoxic concentration (CC) of 13.5 µM, and selectivity index (SI) of 1.65. In human A549-ACE2 cells, CPZ was also found to have anti-SARS-CoV-2 activity, with IC of 11.3 µM, CC of 23.1 µM and SI of 2.04.

Discussion: Although the measured SI values are low, the IC values measured in vitro may translate to CPZ dosages used in routine clinical practice because of the high biodistribution of CPZ in lungs and saliva. Also, the distribution of CPZ in brain could be of interest for treating or preventing neurological and psychiatric forms of COVID-19.

Conclusions: These preclinical findings support clinical investigation of the repurposing of CPZ, a drug with mild side effects, in the treatment of patients with COVID-19.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772996PMC
March 2021

Role of astroglial Connexin 43 in pneumolysin cytotoxicity and during pneumococcal meningitis.

PLoS Pathog 2020 12 28;16(12):e1009152. Epub 2020 Dec 28.

Team Intercellular Communication and Microbial Infections, Center for Interdisciplinary Research in Biology, Collège de France, Paris, France.

Streptococcus pneumoniae or pneumococcus (PN) is a major causative agent of bacterial meningitis with high mortality in young infants and elderly people worldwide. The mechanism underlying PN crossing of the blood brain barrier (BBB) and specifically, the role of non-endothelial cells of the neurovascular unit that control the BBB function, remains poorly understood. Here, we show that the astroglial connexin 43 (aCx43), a major gap junctional component expressed in astrocytes, plays a predominant role during PN meningitis. Following intravenous PN challenge, mice deficient for aCx43 developed milder symptoms and showed severely reduced bacterial counts in the brain. Immunofluorescence analysis of brain slices indicated that PN induces the aCx43-dependent destruction of the network of glial fibrillary acid protein (GFAP), an intermediate filament protein specifically expressed in astrocytes and up-regulated in response to brain injury. PN also induced nuclear shrinkage in astrocytes associated with the loss of BBB integrity, bacterial translocation across endothelial vessels and replication in the brain cortex. We found that aCx4-dependent astrocyte damages could be recapitulated using in vitro cultured cells upon challenge with wild-type PN but not with a ply mutant deficient for the pore-forming toxin pneumolysin (Ply). Consistently, we showed that purified Ply requires Cx43 to promote host cell plasma membrane permeabilization in a process involving the Cx43-dependent release of extracellular ATP and prolonged increase of cytosolic Ca2+ in host cells. These results point to a critical role for astrocytes during PN meningitis and suggest that the cytolytic activity of the major virulence factor Ply at concentrations relevant to bacterial infection requires co-opting of connexin plasma membrane channels.
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http://dx.doi.org/10.1371/journal.ppat.1009152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793270PMC
December 2020

Meningioangiomatosis: Multimodal Analysis and Insights From a Systematic Review.

Neurology 2021 02 22;96(6):274-286. Epub 2020 Dec 22.

From the Department of Neurosurgery (A.R., M.Z., M.E.H.S., G.Z.-B., E.D., E.P, J.P.), GHU Paris-Psychiatrie et Neurosciences Sainte-Anne Hospital; Paris Descartes University (A.R., M.Z., A.T.-E., G.Z.-B., E.D., J.-F.M., E.P., F.C., P.V., C.O., E.L.-Z., J.P.), Sorbonne Paris Cité; Inserm (A.R., M.Z., G.Z.-B., E.D., J.-F.M., E.P., P.V., C.O., J.P.), U894, IMA-Brain, Centre de Psychiatrie et Neurosciences; Délégation à la Recherche Clinique et à l'Innovation (R.L.M.), GHU Paris-Psychiatrie et Neurosciences Sainte-Anne Hospital, Paris, France; University of Texas Southwestern Medical Center (M.E.H.S.), Dallas, TX; Department of Neurology (F.A.N.), Baylor College of Medicine, Houston, TX; Department of Neurology (F.A.N.), Massachusetts General Hospital, Boston, MA; Department of Neuropathology (A.T.-E., F.C., P.V., E.L.-Z.), GHU Paris-Psychiatrie et Neurosciences Sainte-Anne Hospital; Department of Neurophysiology (G.H.), Pitié-Salpêtrière Hospital, APHP, Sorbonne Université; Infantile Epilepsy and Brain Plasticity (G.H.), INSERM U1129 Paris Descartes University, PRES Sorbonne; Neuroglial Interactions in Cerebral Physiopathology (G.H.), Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR 7241, INSERM U1050, Labex Memolife, PSL Research University; Department of Neuroradiology (F.M., C.O.), GHU Paris-Psychiatrie et Neurosciences Sainte-Anne Hospital; and Department of Neurosurgery (M.B.), Necker Enfants-Malades Hospital, Paris, France.

Background: Meningioangiomatosis is a poorly studied, rare, benign, and epileptogenic brain lesion.

Objective: To demonstrate that surgical resection and a short-time interval to surgery improves epileptic seizure control, we performed a systematic review and meta-analysis of meningioangiomatosis cases.

Methods: Using PRISMA-IPD guidelines, the authors performed a systematic review and meta-analysis of histopathologically-proven meningioangiomatosis cases. Literature search in French and English languages (PubMed, Embase, the Cochrane Library, and the Science Citation Index) including all studies (January 1981 to June 2020) dealing with histopathologically-proven meningioangiomatosis, without age restriction. We assessed clinical, imaging, histomolecular, management, and outcome findings of patients with meningioangiomatosis.

Results: Two-hundred and seven cases of meningioangiomatosis from 78 studies were included. Most meningioangiomatosis was sporadic, preferentially concerned male patients, younger than 20 years old, and allowed a functionally independent status. Epileptic seizure was the main symptom, with 81.4% of patients having uncontrolled seizures at the time of surgery. Meningioangiomatosis mainly had frontal (32.3%) or temporal (30.7%) locations. Imaging presentation was heterogeneous, and the diagnosis was often missed preoperatively. The histopathologic pattern was similar whatever the clinical presentation, and immunohistochemistry had limited diagnostic value. On molecular analysis, allelic loss at 22q12 was more frequent in samples of meningioangiomatosis-associated meningioma (37.5%) than in isolated meningioangiomatosis (23.1%). Time interval from diagnosis to surgery ( = 0.011) and lack of surgical resection of the meningioangiomatosis ( = 0.009) were independent predictors of postoperative seizure control.

Conclusions: Owing to low scientific evidence, a multicentric prospective study should help refining the management of meningioangiomatosis.
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http://dx.doi.org/10.1212/WNL.0000000000011372DOI Listing
February 2021

Postoperative intracerebral haematomas following stereotactic biopsies: Poor planning or poor execution?

Int J Med Robot 2021 Apr 8;17(2):e2211. Epub 2021 Jan 8.

Service de Neurochirurgie, GHU Paris - Psychiatrie et Neurosciences - Hôpital Sainte-Anne, Paris, France.

Background: Postoperative intracerebral haematomas represent a serious complication following stereotactic biopsy. We investigated the possible underlying causes - poor planning or poor execution - of postoperative intracerebral haematomas following stereotactic biopsies.

Methods: We performed a technical investigation using a retrospective single-centre consecutive series of robot-assisted stereotactic biopsies for a supratentorial diffuse glioma in adults. Each actual biopsy trajectory was reviewed to search for a conflict with an anatomical structure at risk.

Results: From 379 patients, 12 (3.2%) presented with a postoperative intracerebral haematoma ≥20 mm on postoperative CT-scan (3 requiring surgical evacuation); 11 of them had available intraoperative imaging (bi-planar stereoscopic teleangiography x-rays at each biopsy site). The actual biopsy trajectory was similar to the planned biopsy trajectory in these 11 cases. In 72.7% (8/11) of these cases, the actual biopsy trajectory was found to contact a structure at risk (blood vessel and cerebral sulcus) and identified as the intracerebral haematoma origin.

Conclusions: Robot-assisted stereotactic biopsy is an accurate procedure. Postoperative intracerebral haematomas mainly derive from human-related errors during trajectory planning.
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http://dx.doi.org/10.1002/rcs.2211DOI Listing
April 2021

Prognostic relevance of adding MRI data to WHO 2016 and cIMPACT-NOW updates for diffuse astrocytic tumors in adults. Working toward the extended use of MRI data in integrated glioma diagnosis.

Brain Pathol 2021 Jul 15;31(4):e12929. Epub 2021 Feb 15.

Université de Paris, Sorbonne Paris Cité, Paris, France.

Assess the contribution of preoperative MRI data in improving grading of adult astrocytomas reclassified according to the WHO 2016 and cIMPACT-NOW update 3. Retrospective unicentric cohort study of 679 adult patients treated for newly diagnosed diffuse astrocytic and oligodendroglial tumors (January 2006-December 2016). We first systematically compared radiological (contrast enhancement present [CE+] vs. absent [CE-]) and histopathological findings (microvascular proliferation present [MPV+] vs. absent [MPV-]) to validate whether this comparing step of neoangiogenesis represents an efficient method to appreciate the representativity of the tumoral sampling. We focused on 629 cases of astrocytomas for radio-histological integrated analyses. In 598 cases (95.1%), neoangiogenesis evaluated by MRI or histology (CE+/MPV+ or CE-/MPV-) was identical. For the CE+/MPV- and CE-/MPV+ groups (23 cases), the radio-histological face-to-face evaluation allowed us to assess that for 13 cases (56.5%) the reason for this discrepancy was an undersampled tumor. We analyzed the group of CE+/MPV- (n = 8) and CE-/MPV+ (n = 2) in verified image-guided tumoral samples. Finally, we identified three new prognostic subgroups for molecular glioblastomas: (1) "non-representative sampling" (n = 9), (2) "Non neoangiogenic glioblastoma at the time of diagnosis, without contrast enhancement and microvascular proliferation" (n = 8), and (3) "contrast enhancing glioblastoma but without microvascular proliferation in a representative sample" (n = 4). Neoangiogenesis processes should be assessed to improve the prognosis accuracy of the current integrated diagnosis. We suggest adding imaging analyses during the neuropathological analysis of astrocytomas in adults.
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http://dx.doi.org/10.1111/bpa.12929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412115PMC
July 2021

Diagnostic Accuracy of a Reduced Immunohistochemical Panel in Medulloblastoma Molecular Subtyping, Correlated to DNA-methylation Analysis.

Am J Surg Pathol 2021 04;45(4):558-566

Departments of Neuropathology.

Medulloblastomas (MBs) are the most frequent childhood malignant brain tumor. Four histopathologic variants and 4 genetic subgroups have been defined in the World Health Organization (WHO) 2016 Classification and constitute major risk stratification items directly affecting the patient management. Although MB subgroups have been molecularly defined, immunohistochemical surrogates are needed. The aim of our retrospective study was to evaluate the concordance between immunohistochemistry, using 4 antibodies (YAP1, GAB1, OTX2, and β-catenin), and DNA-methylation profiling in MB subgrouping. From a series of 155 MBs, the κ coefficient of concordance was almost perfect (0.90), with only 8/152 discrepant cases (no DNA-methylation analysis was available in 3 cases). Interestingly, the discrepancies mostly concerned (7/8 cases) MBs with divergent differentiations (myogenic, melanotic, and others) with all of those classified into group 3 (n=6) and group 4 (n=1) by DNA-methylation profiling. Another discrepant case concerned a WNT-activated MB (showing only 1% of immunopositive tumor cell nuclei), highlighting the difficulties of determining an appropriate β-catenin immunostaining cutoff. The high concordance of the routine immunohistochemical panel (YAP1, GAB1, OTX2, and β-catenin) and DNA-methylation profiling confirm its utility as a reliable predictive marker of molecular subtype in MBs. We analyzed the accuracy of 10 different IHC combinations for the determination of MB subtype and found that a combination of 2 antibodies (YAP1 and OTX2) allows for the successful characterization of 144 cases of 152 cases. Finally, our series extends the molecular data of the rare morphologic variant of MBs with melanotic/myogenic differentiations.
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http://dx.doi.org/10.1097/PAS.0000000000001640DOI Listing
April 2021

Early abolition of cough reflex predicts mortality in deeply sedated brain-injured patients.

PeerJ 2020 26;8:e10326. Epub 2020 Nov 26.

Laboratory of Human Histopathology and Animal Models, Institut Pasteur, Paris, France.

Background: Deep sedation may hamper the detection of neurological deterioration in brain-injured patients. Impaired brainstem reflexes within the first 24 h of deep sedation are associated with increased mortality in non-brain-injured patients. Our objective was to confirm this association in brain-injured patients.

Methods: This was an observational prospective multicenter cohort study involving four neuro-intensive care units. We included acute brain-injured patients requiring deep sedation, defined by a Richmond Assessment Sedation Scale (RASS) < -3. Neurological assessment was performed at day 1 and included pupillary diameter, pupillary light, corneal and cough reflexes, and grimace and motor response to noxious stimuli. Pre-sedation Glasgow Coma Scale (GCS) and Simplified Acute Physiology Score (SAPS-II) were collected, as well as the cause of death in the Intensive Care Unit (ICU).

Results: A total of 137 brain-injured patients were recruited, including 70 (51%) traumatic brain-injured patients, 40 (29%) vascular (subarachnoid hemorrhage or intracerebral hemorrhage). Thirty patients (22%) died in the ICU. At day 1, the corneal (OR 2.69, = 0.034) and cough reflexes (OR 5.12, = 0.0003) were more frequently abolished in patients that died in the ICU. In a multivariate analysis, abolished cough reflex was associated with ICU mortality after adjustment to pre-sedation GCS, SAPS-II, RASS (OR: 5.19, 95% CI [1.92-14.1], = 0.001) or dose of sedatives (OR: 8.89, 95% CI [2.64-30.0], = 0.0004).

Conclusion: Early (day 1) cough reflex abolition is an independent predictor of mortality in deeply sedated brain-injured patients. Abolished cough reflex likely reflects a brainstem dysfunction that might result from the combination of primary and secondary neuro-inflammatory cerebral insults revealed and/or worsened by sedation.
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http://dx.doi.org/10.7717/peerj.10326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700733PMC
November 2020

Association Between Anxiety and New Organ Failure, Independently of Critical Illness Severity and Respiratory Status: A Prospective Multicentric Cohort Study.

Crit Care Med 2020 10;48(10):1471-1479

General Intensive Care Unit, APHP, Raymond Poincaré Hospital, University of Versailles Saint-Quentin en Yvelines, Garches, France.

Objectives: Anxiety results from the anticipation of a threat and might be associated with poor outcome in the critically ill. This study aims at showing that anxiety at admission in critically ill patients is associated with new organ failure over the first 7 days of ICU hospitalization independently of baseline organ failure at admission.

Design: Prospective multicenter cohort study.

Setting: Three mixed ICU from April 2014 to December 2017.

Patients: Coma-, delirium-, and invasive mechanical ventilation-free patients admitted to the ICU were included.

Interventions: None.

Measurements And Main Results: "State anxiety" was assessed using the state component of the State-Trait Anxiety Inventory State. Severity of illness was measured using Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores. Primary endpoint was a composite of occurrence of death or new organ failure in the first 7 days after admission. Three hundred ninety-one patients were included; 159 of 391 women (40.7%); median age 63 years (49-74 yr); median Simplified Acute Physiology Score II 28 (19-37). Two hundred three out of 391 patients (51.9%) reported moderate to severe anxiety (State-Trait Anxiety Inventory State ≥ 40). One hundred two out of 391 patients (26.1%) developed a new organ failure. After adjustment to Simplified Acute Physiology Score II and Sequential Organ Failure Assessment, State-Trait Anxiety Inventory State greater than or equal to 40 was associated with the primary endpoint (odds ratio, 1.94; 95% CI, 1.18-3.18; p = 0.009) and respiratory failure. In post hoc analysis, State-Trait Anxiety Inventory State greater than or equal to 40 was associated with new organ failure independently and notably of respiratory status at admission (dyspnea-Visual Analogic Scale and PaCO2 ≥ 45 mm Hg).

Conclusions: Moderate to severe anxiety at ICU admission is associated with early occurrence of new organ failure in critically ill patients, independently of respiratory status and severity of critical illness. The causality link could be addressed in an interventional trial.
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http://dx.doi.org/10.1097/CCM.0000000000004495DOI Listing
October 2020

Activation of Toll-Like Receptors Differentially Modulates Inflammation in the Human Reproductive Tract: Preliminary Findings.

Front Immunol 2020 4;11:1655. Epub 2020 Aug 4.

MISTIC Team, Virology Department, Institut Pasteur, Paris, France.

The female reproductive tract (FRT) is the main site of entry of sexually transmitted infections (STIs). Toll-like receptors (TLRs) that recognize pathogenic motifs are widely expressed in the FRT. TLR stimulation induces immune activation and local production of inflammatory mediators. In the FRT, this response should also be compatible with reproductive functions and symbiosis with host microbiota. With a view to develop efficient mucosal vaccines to prevent STI acquisition, the role of TLR ligands in the FRT needs to be explored. We have therefore investigated the cytokine profiles of the different compartments of the FRT (vagina, endocervix, ectocervix, and uterus) before and after stimulation of mononuclear cells from human tissue specimens. The comparison with PBMCs allowed us to highlight the FRT specificities. We first characterized the main immune cell populations in each compartment and observed that their distribution was different through the compartments. The CD45 cells represented a maximum of 11% in the FRT in contrast to 96% in PBMCs. We identified two main populations among the CD45 cells in the four compartments of the FRT: CD3 T cells (CD4 and CD8) and CD14 APCs. B cell populations (CD19) were much less frequent than T cells in all the FRT regions and were equally distributed. NK CD56 cells were detected in all compartments and were more abundant in the uterus. Stimulation of the mononuclear cells was then performed with TLR agonists: R848 for TLR7/8, Poly I:C for TLR3, LPS for TLR4 and ODN CpG for TLR9. Cytokine levels in unstimulated cultures of cells isolated from all FRT compartments were higher than in cultures of unstimulated PBMCs. In contrast, after stimulation with TLR agonists, cytokine responses induced by TLR agonists were moderate in the FRT and significantly lower than in PBMCs. These responses were varied with different TLR ligands and FRT compartments. The cytokine profile induced by TLR activation in the FRT supports the role of these tissues in genital anti-microbial immunity and in the control of inflammation while allowing maintenance of its reproductive function.
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http://dx.doi.org/10.3389/fimmu.2020.01655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417306PMC
April 2021

Ketamine/xylazine and barbiturates modulate microglial morphology and motility differently in a mouse model.

PLoS One 2020 6;15(8):e0236594. Epub 2020 Aug 6.

Equipe Synaptopathies et Autoanticorps (SynatAc), Institut NeuroMyoGène, INSERM U1217/UMR CNRS 5310, Lyon, France.

Microglia, the resident immune cells of the brain, are highly ramified and motile and their morphology is strongly linked to their function. Microglia constantly monitor the brain parenchyma and are crucial for maintaining brain homeostasis and fine-tuning neuronal networks. Besides affecting neurons, anesthetics may have wide-ranging effects mediated by non-neuronal cells and in particular microglia. We thus examined the effect of two commonly used anesthetic agents, ketamine/xylazine and barbiturates, on microglial motility and morphology. A combination of two-photon in vivo imaging and electroencephalography (EEG) recordings in unanesthetized and anesthetized mice as well as automated analysis of ex vivo sections were used to assess morphology and dynamics of microglia. We found that administration of ketamine/xylazine and pentobarbital anesthesia resulted in quite distinct EEG profiles. Both anesthetics reduced microglial motility, but only ketamine/xylazine administration led to reduction of microglial complexity in vivo. The change of cellular dynamics in vivo was associated with a region-dependent reduction of several features of microglial cells ex vivo, such as the complexity index and the ramification length, whereas thiopental altered the size of the cytoplasm. Our results show that anesthetics have considerable effects on neuronal activity and microglial morphodynamics and that barbiturates may be a preferred anesthetic agent for the study of microglial morphology. These findings will undoubtedly raise compelling questions about the functional relevance of anesthetics on microglial cells in neuronal physiology and anesthesia-induced neurotoxicity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236594PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410236PMC
October 2020

Central nervous system candidiasis beyond neonates: Lessons from a nationwide study.

Med Mycol 2021 Mar;59(3):266-277

Université de Paris, Service de maladies infectieuses, hôpital Universitaire Necker-Enfants malades, Assistance Publique - Hôpitaux de Paris, IHU Imagine, Paris, France.

Though candidiasis is the most frequent invasive fungal infection, Candida spp. central nervous system (CNS) infections are rare but severe. To further describe clinico-patho-radiological presentations of this entity, we report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included. Seventeen patients (70%) had CNS localization secondary to disseminated candidiasis (10 with hematologic malignancies [HM]; the seven other patients had infective endocarditis [IE]). Among patients with HM, seven previously had lumbar puncture for intrathecal chemotherapy, the three others had IE. Among patients with disseminated infection, magnetic resonance imaging (MRI) evidenced meningitis (17%), micro-abscesses (58%), or vascular complications (67%). Seven patients (30%) had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use, diabetes mellitus, or no identified predisposing condition (n = 1 each). All evaluated patients with isolated CNS involvement had meningitis on cerebrospinal fluid (CSF) and intracranial hypertension. For the latter patients, MRI evidenced meningitis (71%) or abscesses (57%). Among all patients, cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. CSF βDGlucan or mannan Ag were positive in respectively 86% and 80% of cases. Mortality attributed to CNS candidiasis was 42%: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection. CNS candidiasis are isolated or occur during disseminated infection in patients with HM and lumbar puncture for intrathecal chemotherapy or during IE. Clinical, radiological finding and outcome highly vary according to CNS localized versus disseminated candidiasis.

Lay Summary: Candida is a yeast and is the most common cause of fungal infections worldwide. Candida central nervous system (CNS) infections are rare, severe, and poorly described. We report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included (14 men, median age 51 years). Seventeen patients had CNS localization secondary to disseminated candidiasis from blood to CNS (10 with hematologic malignancies [HM], the seven other patients had infective endocarditis [IE]). Seven patients had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use (n = 1), diabetes mellitus (n = 1), or no identified risk factor (n = 1).During Candida CNS infections, brain lesions were meningitis abscesses or vascular complications. Cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. Forty-two percent of patients died from infection: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection.
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http://dx.doi.org/10.1093/mmy/myaa051DOI Listing
March 2021

Mitochondrial AIF loss causes metabolic reprogramming, caspase-independent cell death blockade, embryonic lethality, and perinatal hydrocephalus.

Mol Metab 2020 10 30;40:101027. Epub 2020 May 30.

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Cell Death and Drug Resistance in Hematological Disorders Team, F-75006, Paris, France. Electronic address:

Objectives: Apoptosis-Inducing Factor (AIF) is a protein involved in mitochondrial electron transport chain assembly/stability and programmed cell death. The relevant role of this protein is underlined because mutations altering mitochondrial AIF properties result in acute pediatric mitochondriopathies and tumor metastasis. By generating an original AIF-deficient mouse strain, this study attempted to analyze, in a single paradigm, the cellular and developmental metabolic consequences of AIF loss and the subsequent oxidative phosphorylation (OXPHOS) dysfunction.

Methods: We developed a novel AIF-deficient mouse strain and assessed, using molecular and cell biology approaches, the cellular, embryonic, and adult mice phenotypic alterations. Additionally, we conducted ex vivo assays with primary and immortalized AIF knockout mouse embryonic fibroblasts (MEFs) to establish the cell death characteristics and the metabolic adaptive responses provoked by the mitochondrial electron transport chain (ETC) breakdown.

Results: AIF deficiency destabilized mitochondrial ETC and provoked supercomplex disorganization, mitochondrial transmembrane potential loss, and high generation of mitochondrial reactive oxygen species (ROS). AIF MEFs counterbalanced these OXPHOS alterations by mitochondrial network reorganization and a metabolic reprogramming toward anaerobic glycolysis illustrated by the AMPK phosphorylation at Thr172, the overexpression of the glucose transporter GLUT-4, the subsequent enhancement of glucose uptake, and the anaerobic lactate generation. A late phenotype was characterized by the activation of P53/P21-mediated senescence. Notably, approximately 2% of AIF MEFs diminished both mitochondrial mass and ROS levels and spontaneously proliferated. These cycling AIF MEFs were resistant to caspase-independent cell death inducers. The AIF-deficient mouse strain was embryonic lethal between E11.5 and E13.5 with energy loss, proliferation arrest, and increased apoptotic levels. Contrary to AIF MEFs, the AIF KO embryos were unable to reprogram their metabolism toward anaerobic glycolysis. Heterozygous AIF females displayed progressive bone marrow, thymus, and spleen cellular loss. In addition, approximately 10% of AIF females developed perinatal hydrocephaly characterized by brain development impairment, meningeal fibrosis, and medullar hemorrhages; those mice died 5 weeks after birth. AIF with hydrocephaly exhibited loss of ciliated epithelium in the ependymal layer. This phenotype was triggered by the ROS excess. Accordingly, it was possible to diminish the occurrence of hydrocephalus AIF females by supplying dams and newborns with an antioxidant in drinking water.

Conclusions: In a single knockout model and at 3 different levels (cell, embryo, and adult mice) we demonstrated that by controlling the mitochondrial OXPHOS/metabolism, AIF is a key factor regulating cell differentiation and fate. Additionally, by providing new insights into the pathological consequences of mitochondrial OXPHOS dysfunction, our new findings pave the way for novel pharmacological strategies.
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http://dx.doi.org/10.1016/j.molmet.2020.101027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334469PMC
October 2020

Muscle Injury Induces Postoperative Cognitive Dysfunction.

Sci Rep 2020 02 17;10(1):2768. Epub 2020 Feb 17.

Institut Pasteur, Experimental Neuropathology Unit, Paris, France.

Postoperative cognitive dysfunction (POCD) is a major complication affecting patients of any age undergoing surgery. This syndrome impacts everyday life up to months after hospital discharge, and its pathophysiology still remains unclear. Translational research focusing on POCD is based on a wide variety of rodent models, such as the murine tibial fracture, whose severity can limit mouse locomotion and proper behavioral assessment. Besides, influence of skeletal muscle injury, a lesion encountered in a wide range of surgeries, has not been explored in POCD occurrence. We propose a physical model of muscle injury in CX3CR1 mice (displaying green fluorescent microglial cells) to study POCD, with morphological, behavioral and molecular approaches. We highlighted: alteration of short- and long-term memory after muscle regeneration, wide microglial reactivity in the brain, including hippocampus area, 24 hours after muscle injury, and an alteration of central brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) balance, 28 days after muscle injury. Our results suggest for the first time that muscle injury can have early as well as late impacts on the brain. Our CX3CR1 model can also facilitate microglial investigation, more specifically their pivotal role in neuroinflammation and synaptic plasticity, in the pathophysiology of POCD.
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http://dx.doi.org/10.1038/s41598-020-59639-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026159PMC
February 2020
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