Neuronal Cholesterol Accumulation Induced by Cyp46a1 Down-Regulation in Mouse Hippocampus Disrupts Brain Lipid Homeostasis

Impairment in cholesterol metabolism is associated with many neurodegenerative disorders including Alzheimer's disease (AD). However, the lipid alterations underlying neurodegeneration and the connection between altered cholesterol levels and AD remains not fully understood. We recently showed that cholesterol accumulation in hippocampal neurons, induced by silencing Cyp46a1 gene expression, leads to neurodegeneration with a progressive neuronal loss associated with AD-like phenotype in wild-type mice. We used a targeted and non-targeted lipidomics approach by liquid chromatography coupled to high-resolution mass spectrometry to further characterize lipid modifications associated to neurodegeneration and cholesterol accumulation induced by CYP46A1 inhibition. Hippocampus lipidome of normal mice was profiled 4 weeks after cholesterol accumulation due to Cyp46a1 gene expression down-regulation at the onset of neurodegeneration. We showed that major membrane lipids, sphingolipids and specific enzymes involved in phosphatidylcholine and sphingolipid metabolism, were rapidly increased in the hippocampus of AAV-shCYP46A1 injected mice. This lipid accumulation was associated with alterations in the lysosomal cargoe, accumulation of phagolysosomes and impairment of endosome-lysosome trafficking. Altogether, we demonstrated that inhibition of cholesterol 24-hydroxylase, key enzyme of cholesterol metabolism leads to a complex dysregulation of lipid homeostasis. Our results contribute to dissect the potential role of lipids in severe neurodegenerative diseases like AD

Subspecialty training in Europe:a report by the European Network of Young Gynaecological Oncologists

Backgroun

Phenotypic characterization of the Tumor-Infiltrating Lymphocytes (TILs) and prognostic impact on advanced epithelial ovarian cancer

Les cancers de l’ovaire se placent au 5ème rang pour la mortalité. La connaissance moléculaire de plus en plus fine permet de proposer une prise en charge spécifique. Le microenvironnement tumoral, avec notamment les lymphocytes T infiltrants la tumeur (TILs) est un des axes importants pour proposer de nouvelles thérapeutiques. Une étude descriptive a été menée chez 29 patientes avec l’analyse des PBMc, des TILs dans le péritoine, des TALs dans l’ascite. Une autre étude décrit les TILs par rapport à la survie sans récidive (SSR) et survie globale (SG) chez 222 patientes. Les résultats préliminaires confirment une hétérogénéité importante entre les patientes. Et révèlent que les TALs ne sont pas le reflet des TILs. Un score TPS-PD-L1≥1%, un score iFoxP3>1croix, sont associés positivement à la SG (62,9 contre 115,2 mois, p=0,01, 99,5 contre 69,2 mois, p=0,03, respectivement). Les autres marqueurs, CD8, CD20, sFoxP3, s/iIL-17, IC-PD-L1 et CPS-PD-L1 ne sont pas associés à une variation de la SG. Aucun des marqueurs étudiés n’est associé à une modification de la SSR. L’hétérogénéité est également présente dans les seuils de positivité pour les différents marqueurs. Une harmonisation, ainsi que la description fine des cohortes cliniques renforceront la comparabilité entre les études.Ovarian cancers rank 5th for mortality. Increasingly detailed molecular knowledge makes it possible to offer a specific care. The tumor microenvironment, with especially tumor-infiltrating T lymphocytes (TILs) is one of the axes for proposing new therapies. A descriptive study was conducted in 29 patients with the analysis of PBMc, TILs in the peritoneum, TALs in ascites. Another study describes TIL in relation to disease-free survival (DFS) and overall survival (OS) in 222 patients. Preliminary results confirm significant heterogeneity between patients. And reveal that TALs are not a reflection of TILs. A TPS-PD-L1 score≥1%, an iFoxP3 score>1cross, are positively associated with OS (62.9 versus 115.2 months, p=0.01, 99.5 versus 69.2 months, p= 0.03, respectively). The other markers, CD8, CD20, sFoxP3, s/iIL-17, IC-PD-L1 and CPS-PD-L1 are not associated with a change in OS. None of the markers studied is associated with a change in DFS. Heterogeneity is also present in the positivity thresholds for the different markers. Harmonization and detailed description of clinical cohorts will enhance comparability between studies

Description du phénotype des lymphocytes T infiltrant la tumeur et de leur relation avec la survie des patientes atteintes d’un cancer ovarien de stade avancé.

Ovarian cancers rank 5th for mortality. Increasingly detailed molecular knowledge makes it possible to offer a specific care. The tumor microenvironment, with especially tumor-infiltrating T lymphocytes (TILs) is one of the axes for proposing new therapies. A descriptive study was conducted in 29 patients with the analysis of PBMc, TILs in the peritoneum, TALs in ascites. Another study describes TIL in relation to disease-free survival (DFS) and overall survival (OS) in 222 patients. Preliminary results confirm significant heterogeneity between patients. And reveal that TALs are not a reflection of TILs. A TPS-PD-L1 score≥1%, an iFoxP3 score>1cross, are positively associated with OS (62.9 versus 115.2 months, p=0.01, 99.5 versus 69.2 months, p= 0.03, respectively). The other markers, CD8, CD20, sFoxP3, s/iIL-17, IC-PD-L1 and CPS-PD-L1 are not associated with a change in OS. None of the markers studied is associated with a change in DFS. Heterogeneity is also present in the positivity thresholds for the different markers. Harmonization and detailed description of clinical cohorts will enhance comparability between studies.Les cancers de l’ovaire se placent au 5ème rang pour la mortalité. La connaissance moléculaire de plus en plus fine permet de proposer une prise en charge spécifique. Le microenvironnement tumoral, avec notamment les lymphocytes T infiltrants la tumeur (TILs) est un des axes importants pour proposer de nouvelles thérapeutiques. Une étude descriptive a été menée chez 29 patientes avec l’analyse des PBMc, des TILs dans le péritoine, des TALs dans l’ascite. Une autre étude décrit les TILs par rapport à la survie sans récidive (SSR) et survie globale (SG) chez 222 patientes. Les résultats préliminaires confirment une hétérogénéité importante entre les patientes. Et révèlent que les TALs ne sont pas le reflet des TILs. Un score TPS-PD-L1≥1%, un score iFoxP3>1croix, sont associés positivement à la SG (62,9 contre 115,2 mois, p=0,01, 99,5 contre 69,2 mois, p=0,03, respectivement). Les autres marqueurs, CD8, CD20, sFoxP3, s/iIL-17, IC-PD-L1 et CPS-PD-L1 ne sont pas associés à une variation de la SG. Aucun des marqueurs étudiés n’est associé à une modification de la SSR. L’hétérogénéité est également présente dans les seuils de positivité pour les différents marqueurs. Une harmonisation, ainsi que la description fine des cohortes cliniques renforceront la comparabilité entre les études

Description du phénotype des lymphocytes T infiltrant la tumeur et de leur relation avec la survie des patientes atteintes d’un cancer ovarien de stade avancé.

Ovarian cancers rank 5th for mortality. Increasingly detailed molecular knowledge makes it possible to offer a specific care. The tumor microenvironment, with especially tumor-infiltrating T lymphocytes (TILs) is one of the axes for proposing new therapies. A descriptive study was conducted in 29 patients with the analysis of PBMc, TILs in the peritoneum, TALs in ascites. Another study describes TIL in relation to disease-free survival (DFS) and overall survival (OS) in 222 patients. Preliminary results confirm significant heterogeneity between patients. And reveal that TALs are not a reflection of TILs. A TPS-PD-L1 score≥1%, an iFoxP3 score>1cross, are positively associated with OS (62.9 versus 115.2 months, p=0.01, 99.5 versus 69.2 months, p= 0.03, respectively). The other markers, CD8, CD20, sFoxP3, s/iIL-17, IC-PD-L1 and CPS-PD-L1 are not associated with a change in OS. None of the markers studied is associated with a change in DFS. Heterogeneity is also present in the positivity thresholds for the different markers. Harmonization and detailed description of clinical cohorts will enhance comparability between studies.Les cancers de l’ovaire se placent au 5ème rang pour la mortalité. La connaissance moléculaire de plus en plus fine permet de proposer une prise en charge spécifique. Le microenvironnement tumoral, avec notamment les lymphocytes T infiltrants la tumeur (TILs) est un des axes importants pour proposer de nouvelles thérapeutiques. Une étude descriptive a été menée chez 29 patientes avec l’analyse des PBMc, des TILs dans le péritoine, des TALs dans l’ascite. Une autre étude décrit les TILs par rapport à la survie sans récidive (SSR) et survie globale (SG) chez 222 patientes. Les résultats préliminaires confirment une hétérogénéité importante entre les patientes. Et révèlent que les TALs ne sont pas le reflet des TILs. Un score TPS-PD-L1≥1%, un score iFoxP3>1croix, sont associés positivement à la SG (62,9 contre 115,2 mois, p=0,01, 99,5 contre 69,2 mois, p=0,03, respectivement). Les autres marqueurs, CD8, CD20, sFoxP3, s/iIL-17, IC-PD-L1 et CPS-PD-L1 ne sont pas associés à une variation de la SG. Aucun des marqueurs étudiés n’est associé à une modification de la SSR. L’hétérogénéité est également présente dans les seuils de positivité pour les différents marqueurs. Une harmonisation, ainsi que la description fine des cohortes cliniques renforceront la comparabilité entre les études

Valeur pronostique de l'ultrastadification du ganglion sentinelle dans le cancer du sein

La prise en charge chirurgicale des cancers du sein a considérablement évolué, notamment au niveau du traitement des ganglions axillaires. Le ganglion sentinelle est désormais la règle en cas de tumeurs de petite taille. Si la procédure du ganglion sentinelle permet d éviter un certain nombre de curage axillaire, elle conduit à l ultrastadification du ou des ganglions avec la détection de micrométastases et cellules isolées. Le pronostic de cette atteinte micrométastatique a été analysée sur une population de 336 patientes, porteuse d un cancer du sein T1 ou T2 avec un suivi médian de 6,4 ans. L atteinte micrométastatique apparaît comme un élément pronostic indépendant vis-à-vis de la survie globale et survie sans récidive. L atteinte par des cellules isolées ou une micrométastase du ganglion sentinelle est de moins bon pronostic qu un ganglion indemne après une analyse par Immuno-Histo-Chimie, et de meilleur pronostic qu une atteinte macroscopique. Le curage réalisé secondairement en cas d atteinte micrométastatique retrouve une maladie ganglionnaire résiduelle dans 10% des cas, sans que cette atteinte ne modifie le traitement adjuvant proposé dans l étude. Des arguments existent dans la littérature pour proposer une abstention du curage axillaire pour certaines patientes en cas de ganglion sentinelle micrométastatique.DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Fluorescence-assisted sentinel (SND) and pelvic node dissections by single-port transvaginal laparoscopic surgery, for the management of an endometrial carcinoma (EC) in an elderly obese patient

International audienceObjective: To explore the feasibility of an oncologically acceptable management for an intermediate-risk endometrial cancer (EC) in an elderly, using the combination of transvaginal single-port laparoscopy and sentinel node policy.Methods: For this 85-years old patient, BMI 32kg/m2, with IB grade 2 endometrioid EC, a single vaginal approach was attempted [1] to perform a total hysterectomy, bilateral salpinago-oophorectomy and pelvic node assessment guided by SND [2]. Injections of indocyanine green (ICG) were performed at 3 and 9 o'clock and 2 depths [3] into the uterine cervix A simple vaginal hysterectomy was first performed using a 5mm vessel sealer (LigaSure®-Medtronics) to limit ICG leakage. As poorly accessible, adnexas were divided close to cornuas; uterine corpus was delivered vaginally. Then, a single port device (Gelpoint®-Applied), equipped with 3 trocars for optique and instruments, was installed through vagina. After transvaginal pneumoperitoneum insufflation, bowel loops were cleared from the pelvis. Latero-pelvic peritoneum was incised between external iliac pedicles and ureters. Following the algorithm, node dissection was limited to sentinel node clearly identified on the right side under color-segmented fluorescence (Pinpoint®-Novadaq), but a full pelvic dissection completed an unsatisfactory SND on the left side. Procedure was terminated with salpingo-oophorectomies. After protected vaginal specimen delivery, the single-port device was removed and vagina was closed as usual.Results: Patient was discharged on the 1st post-operative day. Final pathology confirmed the FIGO stageIB grade2 EC.Conclusions: A transvaginal laparoscopic pelvic SND after vaginal hysterectomy is feasible. This single-port "NOTES" strategy bridges the previous gaps of a pure vaginal approach and seems interesting in fragile EC patients

Patient age and breast resection weight affect immediate postmastectomy breast reconstruction in ductal carcinoma in situ

International audiencePurpose: Mastectomy is necessary for 40% of the ductal carcinoma in situ. If immediate breast reconstruction (IBR) is systematically proposed, 81% of the patients would choose immediate versus delayed breast reconstruction, but the actual IBR rate is only approximately 50% of them. Therefore, the aim of this study was to identify objective characteristics that distinguish the patients who actually underwent IBR from those who did not.Methods: Several criteria of 248 patients who have undergone mastectomy for ductal carcinoma were analyzed. Factors studied were age, body mass index, diabetes, tobacco use, and weight of the specimen of resection.Results: The rate of IBR was 43%. An increase in age and weight of the resection specimen, irrespective of the body mass index, was associated with a lower rate of IBR. Thus, an increase of 100 g in the weight of the breast induces a significant reduction of the IBR (33%).Conclusions: In our series, older patients or patients with larger breasts (irrespective of the body mass index) were less likely to undergo IBR. In order to be in line with the patient's desire, the surgeons of our unit should broaden their indications of IBR. The lack of reconstruction of large breasts should certainly be compensated in part with the recent development of free tissue transfers in our unit

Tumor-Infiltrating Lymphocytes (TILs) in Epithelial Ovarian Cancer: Heterogeneity, Prognostic Impact, and Relationship with Immune Checkpoints

Epithelial ovarian cancers (EOC) are often diagnosed at an advanced stage with carcinomatosis and a poor prognosis. First-line treatment is based on a chemotherapy regimen combining a platinum-based drug and a taxane-based drug along with surgery. More than half of the patients will have concern about a recurrence. To improve the outcomes, new therapeutics are needed, and diverse strategies, such as immunotherapy, are currently being tested in EOC. To better understand the global immune contexture in EOC, several studies have been performed to decipher the landscape of tumor-infiltrating lymphocytes (TILs). CD8+ TILs are usually considered effective antitumor immune effectors that immune checkpoint inhibitors can potentially activate to reject tumor cells. To synthesize the knowledge of TILs in EOC, we conducted a review of studies published in MEDLINE or EMBASE in the last 10 years according to the PRISMA guidelines. The description and role of TILs in EOC prognosis are reviewed from the published data. The links between TILs, DNA repair deficiency, and ICs have been studied. Finally, this review describes the role of TILs in future immunotherapy for EOC