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Background: In POLA cohort, three pathological groups of CNS WHO grade 3 oligodendroglioma IDH-mutant and 1p/19q co-deleted have been described: group 1 (high mitotic count only), group 2 (microvascular proliferation MVP and no necrosis), and group 3 (MVP and necrosis)., Methods: 494 patients from the POLA cohort, with a median follow up of 96 months were included. To identify the impact of the pathological groups and contrast enhancement in group 1 on overall survival (OS) or progression free survival (PFS), survival curves were obtained (Kaplan-Meier method) and compared (log-rank test). Prognostic value of clinical factors and CDKN2A homozygous deletion HD were also tested. Multivariate analysis was performed., Results: Survival analysis demonstrated that the pathological groups were associated with both progression-free survival (PFS P=0.01) and overall survival (OS P=0.001). In group 1, patients with contrast enhancement (1CE+) had a poorer prognosis compared to those without (OS P=0.028, PFS P=0.006). Further stratification into group 1CE-, group 1CE+, group 2, and group 3 provided clearer prognostic distinctions (OS P=0.002, PFS P<0.0001). Other prognostic factors included age (OS P<0.0001, PFS P=0.002), extent of surgical resection (OS P=0.001, PFS P=0.003), KPS (OS P<0.0001, PFS P=0.002), postoperative treatment (OS P=0.007, PFS P<0.0001), and CDKN2A HD (OS and PFS P<0.0001). The pathological groups remained of prognostic significance for PFS in multivariate analysis., Conclusion: Necrosis and CDKN2A HD are adverse prognostic factors of WHO grade 3 oligodendrogliomas, IDH mutant and 1p/19q co-deleted. Besides, in group 1 patients, lack of contrast enhancement is a factor of better prognosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Patients with IDH-mutant 1p/19q-codeleted grade 3 oligodendroglioma (O3 IDHmt/Codel ) benefit from adding alkylating agent chemotherapy to radiotherapy (RT). However, the optimal chemotherapy regimen between procarbazine, 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and vincristine (PCV) and temozolomide (TMZ) remains unclear given the lack of randomized trial data comparing both regimens., Methods: The objective was to assess the overall survival (OS) and progression-free survival (PFS) associated with first-line PCV/RT versus TMZ/RT in patients newly diagnosed with O3 IDHmt/Codel . We included patients with histologically proven O3 IDHmt/Codel (according to WHO criteria) from the French national prospective cohort Prise en charge des OLigodendrogliomes Anaplasiques (POLA). All tumors underwent central pathological review. OS and PFS from surgery were estimated using the Kaplan-Meier method and Cox regression model., Results: 305 newly diagnosed patients with O3 IDHmt/Codel treated with RT and chemotherapy between 2008 and 2022 were included, of which 67.9% of patients (n = 207) were treated with PCV/RT and 32.1% with TMZ/RT (n = 98). The median follow-up was 78.4 months (IQR, 44.3-102.7). The median OS was not reached (95% CI, Not reached [NR] to NR) in the PCV/RT group and was 140 months (95% CI, 110 to NR) in the TMZ/RT group (log-rank P = .0033). On univariable analysis, there was a significant difference in favor of PCV/RT in both 5-year (PCV/RT: 89%, 95% CI, 85 to 94; TMZ/RT: 75%, 95% CI, 66 to 84) and 10-year OS (PCV/RT: 72%, 95% CI, 61 to 85; TMZ/RT: 60%, 95% CI, 49 to 73), which was confirmed using the multivariable Cox model adjusted for age, type of surgery, gender, Eastern Cooperative Oncology Group performance status, and CDKN2A homozygous deletion (hazard ratio, 0.53 for PCV/RT, 95% CI, 0.30 to 0.92, P = .025)., Conclusion: In patients with newly diagnosed O3 IDHmt/Codel from the POLA cohort, first-line PCV/RT was associated with better OS outcomes compared with TMZ/RT. Our data suggest that the improved safety profile associated with TMZ comes at the cost of inferior efficacy in this population. Further investigation using prospective randomized studies is warranted.

Background: Novel effective treatments are needed for recurrent IDH mutant high-grade gliomas (IDHm HGGs). The aim of the multicentric, single-arm, phase II REVOLUMAB trial (NCT03925246) was to assess the efficacy and safety of the anti-PD1 Nivolumab in patients with recurrent IDHm HGGs., Patients and Methods: Adult patients with IDHm WHO grade 3-4 gliomas recurring after radiotherapy and ≥ 1 line of alkylating chemotherapy were treated with intravenous Nivolumab until end of treatment (12 months), progression, unacceptable toxicity, or death. The primary endpoint was the 24-week progression-free survival rate (24w-PFS) according to RANO criteria., Results: From July 2019 to June 2020, 39 patients with recurrent IDHm HGGs (twenty-one grade 3, thirteen grade 4, five grade 2 with radiological evidence of anaplastic transformation; 39% 1p/19q codeleted) were enrolled. Median time since diagnosis was 5.7 years, and the median number of previous systemic treatments was two. The 24w-PFS was 28.2% (11/39, CI95% 15-44.9%). Median PFS and OS were 1.84 (CI95% 1.81-5.89) and 14.7 months (CI95% 9.18-NR), respectively. Four patients (10.3%) achieved partial response according to RANO criteria. There were no significant differences in clinical or histomolecular features between responders and non-responders. The safety profile of Nivolumab was consistent with prior studies., Conclusions: We report the results of the first trial of immune checkpoint inhibitors in IDHm gliomas. Nivolumab failed to achieve its primary endpoint. However, treatment was well tolerated, and long-lasting responses were observed in a subset of patients, supporting further evaluation in combination with other agents (e.g. IDH inhibitors)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The following authors have disclosed financial relationships with commercial entities that may be impacted by this work: CD (BMS, travel support). The other authors have declared no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Strokes are the main cause of aphasia, a language disorder that makes it difficult to communicate with others. In the acute phase, patients are cared for in neurovascular departments. In this acute care context, conducting research among caregivers to gather their experiences of caregiver-patient relationships with regard to aphasic patients can be complex., Purpose of Research: To propose a participatory research methodology utilizing knowledge arising from the lived experiences of nurses and care assistants in a neurovascular department., Method: A qualitative study based on observation was carried out with a view to ensuring that all the stakeholders involved were fully integrated into the field research. The analysis was carried out in a participatory manner with a nurse and a care assistant, using the grounded theory approach., Results: Twenty-one care situations were observed over a three-month period. Following an initial report, eight situations from this group were selected and analyzed following the six stages of grounded theory analysis, four of which were carried out in a participatory manner with a nurse and a care assistant., Conclusions: Discussing caregivers&#8217; involvement in the research with them beforehand, given their professional constraints, helped maximize their participation throughout the study. The dynamics of the reporting and analysis stages were conducive to utilizing the nurses&#8217; and care assistants&#8217; lived experiences.

Purpose: The COVID-19 pandemic affected medical practice worldwide due to interventions to prevent spreading. Its effect on ophthalmology practices in Latin America has not yet been explored. We aimed to assess the perceptions about the pandemic from countries' ophthalmological national and subspecialty retina societies affiliated to the Pan-American Association of Ophthalmology (PAAO)., Patients and Methods: A survey-based study of leaders of national ophthalmological and retinal societies was conducted. The survey was sent by email to 30 societies, from which 20 responded (12 countries, 66.6% response rate). It included closed- and open-ended questions about (1) operational capacity and precautions, (2) telemedicine and virtual care, (3) procedures, and (4) post-pandemic considerations., Results: There was a marked decline in ophthalmology patient visits (80-95%) and elective surgeries (90%) during 2020 compared to before the pandemic. Precautions like temperature checks, mask usage, and social distancing were widely implemented while personal protective equipment (PPE) availability varied. Telemedicine use was limited due to lack of experience with it. Reopening plans focused on maintaining precautions and gradually resuming activities. Economic and security concerns were raised, and adherence to guidelines was emphasized. Respondents acknowledged the need to adapt to a "new normal". Long duration drugs, fewer imaging studies, and shorter wait times were preferred; however, availability of long duration drugs was limited., Conclusion: The pandemic impacted ophthalmology in Latin America, with reduced patient visits, procedures, and surgeries. Delayed treatment and complications were likely the result of the pandemic., Competing Interests: Dr Gerardo Garcia-Aguirre reports grants/personal fees and/or non-financial support from Alcon, AbbVie/Allergan, Bayer, Heidelberg Engineering, Nidek, Novartis, Roche Genentech, and Zeiss, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Bonilla-Escobar et al.)

Background: Pseudoprogression in gliomas has been extensively described after radiotherapy with or without chemotherapy, but not after chemotherapy alone. Here we describe the occurrence of pseudoprogression in patients with anaplastic oligodendrogliomas treated with postoperative procarbazine, lomustine and vincristine (PCV) chemotherapy alone., Methods: We retrospectively reviewed the medical and radiological files of patients with 1p/19q codeleted, IDH-mutant anaplastic oligodendrogliomas treated with PCV chemotherapy alone who presented magnetic resonance imaging (MRI) modifications suggestive of tumour progression and in whom the final diagnosis was a pseudoprogression., Results: We identified six patients. All patients underwent a surgical resection and were treated with PCV chemotherapy without radiotherapy. After a median of 11 months following the initiation of chemotherapy (range: 3-49 months), the patients developed asymptomatic white matter MRI modifications around the surgical cavity leading to the suspicion of a tumour progression. These modifications appeared as hyperintense on T2-fluid-attenuated inversion recovery (FLAIR) sequence, hypointense on T1 sequence, and lacked mass effect (0/6), contrast enhancement (0/6), restriction on diffusion-weighted imaging (0/4), relative cerebral blood volume (rCBV) increase on perfusion MRI (0/4), and hypermetabolism on 18 F-fluoro-L-dopa positron emission tomography ( 18 F-DOPA PET) scan (0/3). One patient underwent a surgical resection demonstrating no tumour recurrence; the five other patients were considered as having post-therapeutic modifications based on imaging characteristics. After a median follow-up of 4 years all patients were progression-free., Conclusions: Anaplastic oligodendroglioma patients treated with postoperative PCV chemotherapy alone occasionally develop T2/FLAIR hyperintensities around the surgical cavity that can wrongly suggest tumour progression. Multimodal imaging and close follow-up should be considered in this situation., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Immune checkpoint inhibitors (ICI) represent the cornerstone for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease, highlighting the need to precisely understand the plasticity of cancer cells and their cross-talk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial-to-mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public data sets and data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAF), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered the spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. These data highlight the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance., Significance: Single-cell and spatial transcriptomics reveal the proximity of mesenchymal tumor cells to myofibroblastic cancer-associated fibroblasts and their association with disease outcome and immune checkpoint inhibitor response in clear cell renal cell carcinoma., (©2023 American Association for Cancer Research.)

Aims: The distinction between CNS WHO grade 2 and grade 3 is instrumental in choosing between observational follow-up and adjuvant treatment for resected astrocytomas IDH-mutant. However, the criteria of CNS WHO grade 2 vs 3 have not been updated since the pre-IDH era., Methods: Maximal mitotic activity in consecutive high-power fields corresponding to 3 mm 2 was examined for 118 lower-grade astrocytomas IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity and other putative prognostic factors (including age, performance status, pre-surgical tumour volume, multilobar involvement, post-surgical residual tumour volume and midline involvement) was assessed for tumours with ATRX loss and the absence of CDKN2A homozygous deletion or CDK4 amplification, contrast enhancement, histological necrosis and microvascular proliferation., Results: Seventy-one per cent of the samples had <6 mitoses per 3 mm 2 . Mitotic activity, residual volume and multilobar involvement were independent prognostic factors of TTT. The threshold of ≥6 mitoses per 3 mm 2 identified patients with a shorter TTT (median 18.5 months). A residual volume ≥1 cm 3 also identified patients with a shorter TTT (median 24.5 months). The group defined by <6 mitoses per 3 mm 2 and a residual volume <1 cm 3 had the longest TTT (median 73 months) and OS (100% survival at 7 years). These findings were confirmed in a validation cohort of 52 tumours., Conclusions: Mitotic activity and post-surgical residual volume can be combined to evaluate the prognosis for patients with resected astrocytomas IDH-mutant. Patients with <6 mitoses per 3 mm 2 and a residual volume <1 cm 3 were the best candidates for observational follow-up., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Purpose: The Lynch syndrome (LS)-glioma association is poorly documented. As for mismatch repair deficiency (MMRd) in glioma, a hallmark of LS-associated tumors, there are only limited data available. We determined MMRd and LS prevalence in a large series of unselected gliomas, and explored the associated characteristics. Both have major implications in terms of treatment, screening, and prevention., Methods: Somatic next-generation sequencing was performed on 1,225 treatment-naive adult gliomas referred between 2017 and June 2022. For gliomas with ≥1 MMR pathogenic variant (PV), MMR immunohistochemistry (IHC) was done. Gliomas with ≥1 PV and protein expression loss were considered MMRd. Eligible patients had germline testing. To further explore MMRd specifically in glioblastomas, isocitrate dehydrogenase (IDH)-wild type (wt), we performed IHC, and complementary sequencing when indicated, in a series of tumors diagnosed over the 2007-2021 period., Results: Nine gliomas were MMRd (9/1,225; 0.73%). Age at glioma diagnosis was <50 years for all but one case. Eight were glioblastomas, IDH-wt, and one was an astrocytoma, IDH-mutant. ATRX (n = 5) and TP53 (n = 8) PV were common. There was no TERT promoter PV or EGFR amplification. LS prevalence was 5/1,225 (0.41%). One 77-year-old patient was a known LS case. Four cases had a novel LS diagnosis, with germline PV in MSH2 (n = 3) and MLH1 (n = 1). One additional patient had PMS2 -associated constitutional mismatch repair deficiency. Germline testing was negative in three MSH6-deficient tumors. In the second series of glioblastomas, IDH-wt, MMRd prevalence was 12.5% in the <40-year age group, 2.6% in the 40-49 year age group, and 1.6% the ≥50 year age group., Conclusion: Screening for MMRd and LS should be systematic in glioblastomas, IDH-wt, diagnosed under age 50 years.

Background: Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described., Methods: We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression., Results: In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions., Conclusion: In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after RT, the possibility of a pseudoprogression should be carefully considered., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells are identified in patient and mouse GBMs. Partial removal of p16 Ink4a -expressing malignant senescent cells, which make up less than 7 % of the tumor, modifies the tumor ecosystem and improves the survival of GBM-bearing female mice. By combining single cell and bulk RNA sequencing, immunohistochemistry and genetic knockdowns, we identify the NRF2 transcription factor as a determinant of the senescent phenotype. Remarkably, our mouse senescent transcriptional signature and underlying mechanisms of senescence are conserved in patient GBMs, in whom higher senescence scores correlate with shorter survival times. These findings suggest that senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM., (© 2023. The Author(s).)

Objective: Daily aspirin, started in the first trimester of pregnancy, is commonly used for the prevention of preeclampsia and fetal growth restriction in multiple gestation. However, the optimal dose remains controversial and the evidence for the use of aspirin in multiple pregnancies is scarce. We aimed to estimate the impact of 80 mg of aspirin in twin pregnancies., Study Design: We performed a pilot double-blind randomized trial of women with twin pregnancies recruited between 8 and 14 weeks of gestation. Fifty participants (25 in each group) were randomized to 80 mg of aspirin daily at bedtime or a placebo from randomization until 36 weeks of gestation. Primary and secondary outcomes included the birth weight of live infants, preeclampsia, and aspirin responsiveness evaluated by a platelet aggregation test (platelet function assay [PFA]-100)., Results: All participants were followed until birth, including 48 and 47 live newborns in the aspirin and the placebo groups, respectively. The mean birth weight difference between the aspirin (2,385 ± 529 g) and placebo (2,224 ± 706 g) groups was of 179 g (95% confidence interval [CI]: -172-531 g, p  = 0.32). We observed two (8%) cases of preeclampsia in the aspirin group and no case with placebo ( p  = 0.49). Most importantly,16 of 24 participants who received aspirin (67%; 95% CI: 45-84%) had a normal PFA-100 test at 22 to 23 weeks, including the two cases of preeclampsia, suggesting that the majority of the participants were nonresponsive to 80 mg of aspirin., Conclusion: Our results suggest that the majority of women with twin pregnancies showed a lack of response to a daily dose of 80 mg of aspirin according to the PFA-100 test, compared with the expected 29% of nonresponsiveness in singleton pregnancies. A daily dose of 80 mg of aspirin is likely to be insufficient for the prevention of preeclampsia and other placenta-mediated complications in twin pregnancies., Key Points: · Most women with twin pregnancies are nonresponsive to a daily dose of 80-mg aspirin.. · An 80 mg aspirin dose is insufficient to prevent placenta-mediated complications in twin pregnancies.. · Randomized trials using 100 to 160 mg of aspirin in twin pregnancies are needed.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: In the COVID-19 crisis context, the main objective of the study is to investigate factors associated with perceived concerns of change in long-term cancer care in patients currently under treatment., Methods: A French population-based cross-sectional study was performed using an online questionnaire in April 2020. All persons currently receiving cancer treatment and belonging to the Seintinelles Association (https://www.seintinelles.com) were included in this present analysis. Individual sociodemographic characteristics, medical status and information regarding cancer care were collected. Multivariate binomial logistic regression analysis was performed., Results: We included 298 women in the analysis. Younger participants (OR = 0.96 [0.94-0.99]), the need to visit healthcare facilities to receive treatment (OR = 2.93 [1.16-8.52]), deterioration in the quality of communication with the medical team since the beginning of the COVID-19 crisis (OR = 3.24 [1.61-7.02]) and being cared for by a university hospital or a public hospital (OR = 2.19 [1.16-4.23] versus comprehensive cancer centre) were associated with a perceived fear of change in long-term cancer care., Conclusion: To address patients' concerns regarding changes in their long-term cancer care, medical teams should consider the patients' own perceptions of the situation and provide clear, appropriate, precise information on cancer care, especially in the centres mostly affected by the COVID-19 crisis., (© 2022 John Wiley & Sons Ltd.)

Objective: New therapeutic approaches are needed to improve the prognosis of glioblastoma (GBM) patients., Methods: With the objective of identifying alternative oncogenic mechanisms to abnormally activated epidermal growth factor receptor (EGFR) signalling, one of the most common oncogenic mechanisms in GBM, we performed a comparative analysis of gene expression profiles in a series of 54 human GBM samples. We then conducted gain of function as well as genetic and pharmocological inhibition assays in GBM patient-derived cell lines to functionnally validate our finding., Results: We identified that growth hormone receptor (GHR) signalling defines a distinct molecular subset of GBMs devoid of EGFR overexpression. GHR overexpression was detected in one third of patients and was associated with low levels of suppressor of cytokine signalling 2 (SOCS2) expression due to SOCS2 promoter hypermethylation. In GBM patient-derived cell lines, GHR signalling modulates the expression of proteins involved in cellular movement, promotes cell migration, invasion and proliferation in vitro and promotes tumourigenesis, tumour growth, and tumour invasion in vivo. GHR genetic and pharmacological inhibition reduced cell proliferation and migration in vitro., Conclusion: This study pioneers a new field of investigation to improve the prognosis of GBM patients., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Cardiovascular disease (CVD) and nontraumatic lower-limb amputation (LLA) each results in reduced life expectancy in patients with type 1 diabetes, but the differential burden between these conditions is unknown. We compared the effects of CVD and LLA on the risk of mortality in people with type 1 diabetes., Methods: We used pooled data from the SURGENE, GENEDIAB, and GENESIS prospective cohorts. Data were divided into: 1/absence of CVD (myocardial infarction and/or stroke) nor LLA, 2/history of CVD alone without LLA, 3/LLA alone without CVD or 4/both conditions at baseline. Participants with baseline history of peripheral artery disease were excluded from groups 1 and 2. The study endpoint was any death occurring during follow-up, regardless of the causes., Results: Among 1169 participants (male 55%, age 40 ± 13 years, diabetes duration 23 ± 11 years), CVD, LLA or both were present at baseline in 49 (4.2%), 62 (5.3%) and 20 (1.7%) subjects, respectively. All-cause death occurred in 304 (26%) participants during 17-year follow-up, corresponding to 18,426 person-years and an incidence rate of 16 (95%CI, 15-18) per 1000 person-years. The risk of death increased in individuals with baseline history of CVD (adjusted HR 2.00 [95% CI 1.34-3.01], p = 0.0008) or LLA (2.26 [1.56-3.28], p < 0.0001), versus no condition, with an additive effect in people with both conditions (5.32 [3.14-9.00], p < 0.0001). No incremental risk of death was observed in people with CVD versus LLA (0.87 [0.54-1.41]). Compared with no condition, CVD and LLA were similarly associated with reduced life expectancy during follow-up: 2.79 (95% CI 1.26-4.32) and 3.38 (1.87-4.88) years, respectively. Combined conditions expose to 7.04 (4.76-9.31) less years of life expectancy (all p < 0.0001)., Conclusions: CVD and LLA conferred a similar burden regarding mortality in type 1 diabetes population. Our findings encourage a careful consideration of people with type 1 diabetes and LLA as usually recommended for those with CVD, in terms of management of risk factors, treatments and prevention., (© 2022. The Author(s).)

Background: Anaplastic oligodendrogliomas IDH-mutant and 1p/19q codeleted (AO) occasionally have a poor outcome. Herein we aimed at analyzing their characteristics., Methods: We retrospectively analyzed the characteristics of 44 AO patients with a cancer-specific survival <5 years (short-term survivors, STS) and compared them with those of 146 AO patients with a survival ≥5 years (classical survivors, CS) included in the POLA network., Results: Compared to CS, STS were older (P = .0001), less frequently presented with isolated seizures (P < .0001), more frequently presented with cognitive dysfunction (P < .0001), had larger tumors (P = .= .003), a higher proliferative index (P = .= .0003), and a higher number of chromosomal arm abnormalities (P = .= .02). Regarding treatment, STS less frequently underwent a surgical resection than CS (P = .= .0001) and were more frequently treated with chemotherapy alone (P = .= .009) or with radiotherapy plus temozolomide (P = .= .05). Characteristics independently associated with STS in multivariate analysis were cognitive dysfunction, a number of mitosis > 8, and the absence of tumor resection. Based on cognitive dysfunction, type of surgery, and number of mitosis, patients could be classified into groups of standard (18%) and high (62%) risk of <5 year survival., Conclusion: The present study suggests that although STS poor outcome appears to largely result from a more advanced disease at diagnosis, surgical resection may be particularly important in this population., (© The Author(s) 2022. Published by Oxford University Press.)

Background: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups., Methods: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment., Findings: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib., Interpretation: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma., Funding: Bristol Myers Squibb, ARTIC., Competing Interests: Declaration of interests Y-AV has received research funding from Bristol Myers Squibb (BMS) and Ipsen (all fees for institution); has been on an advisory board or data safety monitoring board for BMS and Roche; has received honoraria for lectures and presentations from BMS, MSD, Ipsen, Merck, Pfizer, Roche, Novartis, Janssen, Astellas, and Viatris; and has received support for travel or meetings from BMS, MSD, Pfizer, Ipsen, and Roche. MB has received honoraria for lectures or presentations from Janssen, AstraZeneca, Ipsen, and Astellas. CC has been on an advisory board or data safety monitoring committee for Ipsen, Pfizer, Esaï, and GSK; and has received support for travel or meetings from Pfizer. DB has received research funding from BMS, Roche, MSD, Astellas, AstraZeneca, Janssen, Exelixis, and Infinity; has received consultancy fees from MSD, Astellas, AstraZeneca, Pfizer, Ipsen, BMS, Janssen, and Sanofi; and has received support for travel or meetings from BMS, Pfizer, Roche, and Ipsen. MG-G has been on an advisory board or data safety monitoring committee for BMS, MSD, Ipsen, and Pfizer; has received honoraria for lectures or presentations from BMS, MSD, Ipsen, and Pfizer; and has received support for travel or meetings from Ipsen and Janssen. CT has received honoraria for lectures or presentations from MSD and BMS; and support for travel or meetings from MSD. BL has received honoraria for lectures or presentations from Pfizer, BMS, and Ipsen; and support for travel or meetings from Pfizer. PBa has received consultancy fees from BMS, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas, and Amgen; honoraria for lectures or presentations from BMS, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas, Bayer, Sanofi, Seagen, and Novartis; and support for travel or meetings from BMS, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas, Sanofi, Seagen, and Novartis. EC has received honoraria for lectures or presentations from AstraZeneca, MSD, BMS, and Ipsen. GG has been on an advisory board or data safety monitoring committee for BMS, Janssen, Ipsen Sanofi/Aventis, MSD Oncology, Pfizer, Bayer, and AstraZeneca; has received honoraria for lectures or presentations from Janssen Oncology, Ipsen, BMS, Amgen, Sanofi/Aventis, MSD Oncology, and Astellas Pharma (all fees for institution); and has received support for travel or meetings from Janssen Oncology, BMS, Astellas Pharma, Pfizer, Ipsen, Sanofi, and AstraZeneca. OH has received honoraria for lectures or presentations from BMS, AstraZeneca, Sanofi, Pfizer, Merck, Ipsen, Novartis, and MSD. LF has been on an advisory board or data safety monitoring committee for Pandas Prodige, Joint French Clinical Practice Guidelines issued by FRANCOGYN, CNGOF, SFOG, and GINECO-ARCAGY, and endorsed by INCa French Guidelines on management of ovarian cancer, European Organisation for Research and Treatment in Cancer, European Society of Oncological Imaging, and European Society of Urogenital Radiology; has received honoraria for lectures or presentations from General Electric, Median Technologies, and Sanofi; and received support for travel or meetings from Guerbet. AdlT has received honoraria for lectures or presentations from Janssen, AstraZeneca, Ipsen, and Astellas. KB has received honoraria for lectures or presentations from Ipsen, BMS, MSD, and Intuitive Surgical. TW has received support for travel or meetings from Astellas. GP has received consultancy fees from Roche, Astellas, Bayer, Janssen, and Bouchara-Recordati; and support for travel or meetings from Janssen and Ipsen. SO has received consultancy fees from BMS and Pfizer; and honoraria for lectures or presentations from BMS and Pfizer. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Eosinophil-mediated endomyocardial damage is a well-known complication in patients with hypereosinophilic syndromes (HES). Although management and survival have improved significantly, some patients continue to develop severe cardiomyopathy as a direct consequence of uncontrolled hypereosinophilia. Cardiologists play a key role in early detection and treatment. At the early generally asymptomatic stage, related to subendocardial eosinophilic infiltrates, elevation of the biomarker of cardiac damage (serum troponin) and cardiac MRI are the best tools for diagnosis. As disease progresses, patients typically develop intracardiac mural thrombi and may experience variable degrees of heart failure due to valve damage and/or subendocardial fibrosis, all of which are more readily detectable with traditional echocardiographic investigation. New imaging modalities such as strain imaging and specific sequences in MRI offer the perspective of detecting subtle perturbations and distinguishing inflammatory versus fibrotic stages. Endomyocardial biopsy may help in difficult settings, namely, when blood eosinophilia is not prominent, but may be non-contributive due to sampling issues or eosinophil degranulation or replacement by fibrosis, and must always be performed after careful consideration of the risk:benefit ratio. Although treatment of the HES itself should be managed by clinicians with expertise in this rare disorder with the aim of lowering eosinophil counts to prevent and treat eosinophil-mediated organ damage and dysfunction, cardiologists play a key role in managing the associated cardiopathy. There are no consensual disease-specific guidelines for treating eosinophil-mediated thrombotic complications and cardiopathy, which should be managed according to classical international recommendations., Competing Interests: Competing interests: AB has received consultancy fees from Amicus, Baeyer, Boehringer Ingelheim, Sanofi, Pfizer, Novartis and Alnylam; speaker fees from Pfizer, Sanofi and Alnylam. FR has received consultancy fees from GlaxoSmithKline and AstraZeneca for expertise in hypereosinophilic syndromes and royalties from UpToDate., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The ACE insertion/deletion (I/D) polymorphism has been widely studied in people with diabetes, albeit not with regard to lower-limb amputation (LLA). We examined associations among this polymorphism, plasma ACE concentration, and LLA in people with type 1 diabetes., Research Design and Methods: ACE I/D genotype and plasma ACE were assessed in three prospective cohorts of participants with type 1 diabetes. LLA was defined as minor (below-the-ankle amputation consisting of at least one ray metatarsal resection) or major (transtibial or transfemoral) amputation. Linear, logistic, and Cox regression models were computed to evaluate the likelihood of prevalent and incident LLA by ACE genotype (XD [ID or ID] vs. II) and plasma ACE, after adjusting for confounders., Results: Among 1,301 participants (male 54%, age 41 ± 13 years), 90 (6.9%) had a baseline history of LLA. Baseline LLA was more prevalent in XD (7.4%) than in II genotype (4.5%, odds ratio [OR] 2.17 [95 %CI 1.03-4.60]). Incident LLA occurred in 53 individuals during the 14-year follow-up and was higher in XD versus II carriers (hazard ratio 3.26 [95% CI 1.16-13.67]). This association was driven by excess risk of minor, but not major, LLA. The D allele was associated with increased prevalent LLA at the end of follow-up (OR 2.48 [1.33-4.65]). LLA was associated with higher mean (95% CI) ACE levels in II (449 [360, 539] vs. 354 [286, 423] ng/mL), but not XD (512 [454, 570] vs. 537 [488, 586]), carriers., Conclusions: This report is the first of an independent association between ACE D allele and excess LLA risk, mainly minor amputations, in patients with type 1 diabetes., (© 2022 by the American Diabetes Association.)

Introduction: People living with HIV (PLHIV) who may have experienced biographical disruptions in their life trajectory may have a vulnerability to risk that differs from the general population, particularly in the context of an infectious health crisis. This study aimed to understand the factors associated with concerns about being infected with COVID-19 among PLHIV during the first period of the health crisis., Methods: This was an online cross-sectional study using an online self-administered questionnaire in the context of the COVID-19 epidemic in France among a population of PLHIV. The recruitment was done via social networks and through various actors in the fight against HIV. The self-questionnaire was available from July 2020 to September 2020., Results: The ACOVIH study collected 249 responses, 202 men and 47 women, with a mean age of 46.6 ± 12.9 years. The most represented socio-professional categories were employees (n=73.29%), followed by managers, professionals and artists (n=59.24%). The PLHIV most worried about being infected by COVID-19 had a level of education lower than or equal to the baccalaureate, family difficulties related to HIV and a deterioration in the relationship of trust with the HIV medical team., Conclusion: Feelings of anxiety can have a health and psychosocial impact on PLHIV. It is necessary to consider these negative factors by proposing adapted support and by carrying out preventive actions aiming in particular at improving the literacy of the PLHIV.

Background: In glioma, TERT promoter mutation and loss of ATRX (ATRX loss) are associated with reactivation of telomerase or alternative lengthening of telomeres (ALT), respectively, i.e. the two telomere maintenance mechanisms (TMM). Strangely, 25% of gliomas have been reported to display neither or both of these alterations., Materials and Methods: The C-circle (CC) assay was adapted to tumor (formalin-fixed paraffin-embedded and frozen) and blood samples to investigate the TMM., Results: We constructed a CC-based algorithm able to identify the TMM and reported a sensitivity of 100% and a specificity of 97.3% (n = 284 gliomas). By combining the TMM, the mutational status of the isocitrate dehydrogenase 1/2 (IDH) gene (IDHmt), and the histological grading, we propose a new classification tool: TeloDIAG. This classification defined five subtypes: tOD, tLGA, tGBM&#95;IDHmt, tGBM, and tAIV, corresponding to oligodendroglioma, IDHmt low-grade astrocytoma, IDHmt glioblastoma, and IDHwt glioblastoma (GBM), respectively; the last class gathers ALT+ IDHwt gliomas that tend to be related to longer survival (21.2 months) than tGBM (16.5 months). The TeloDIAG was 99% concordant with the World Health Organization classification (n = 312), and further modified the classification of 55 of 144 (38%) gliomas with atypical molecular characteristics. As an example, 14 of 69 (20%) of TERTwt, ATRXwt, and IDHwt GBM were actually tAIV. Outstandingly, CC in blood sampled from IDHmt astrocytoma patients was detected with a sensitivity of 56% and a specificity of 97% (n = 206 gliomas and 30 healthy donors)., Conclusion: The TeloDIAG is a new, simple, and effective tool helping in glioma diagnosis and a promising option for liquid biopsy., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Our understanding of cell fate decisions in hematopoietic stem cells is incomplete. Here, we show that the transcription factor Helios is highly expressed in murine hematopoietic stem and progenitor cells (HSPCs), where it is required to suppress the separation of the platelet/megakaryocyte lineage from the HSPC pool. Helios acts mainly in quiescent cells, where it directly represses the megakaryocyte gene expression program in cells as early as the stem cell stage. Helios binding promotes chromatin compaction, notably at the regulatory regions of platelet-specific genes recognized by the Gata2 and Runx1 transcriptional activators, implicated in megakaryocyte priming. Helios null HSPCs are biased toward the megakaryocyte lineage at the expense of the lymphoid and partially resemble cells of aging animals. We propose that Helios acts as a guardian of HSPC pluripotency by continuously repressing the megakaryocyte fate, which in turn allows downstream lymphoid priming to take place. These results highlight the importance of negative and positive priming events in lineage commitment., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Cova et al.)

For 50 years, ecologists have examined how the number of interactions (links) scales with the number of species in ecological networks. Here, we show that the way the number of links varies when species are sequentially removed from a community is fully defined by a single parameter identifiable from empirical data. We mathematically demonstrate that this parameter is network-specific and connects local stability and robustness, establishing a formal connection between community structure and two prime stability concepts. Importantly, this connection highlights a local stability-robustness trade-off, which is stronger in mutualistic than in trophic networks. Analysis of 435 empirical networks confirmed these results. We finally show how our network-specific approach relates to the classical across-network approach found in literature. Taken together, our results elucidate one of the intricate relationships between network structure and stability in community networks., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: To assess the users' characteristics, discussion contents, and the atmosphere of virtual peer communities., Methods: A qualitative, prospective study was conducted using the Netnography method. The most popular, publicly accessible French discussion forums were investigated. The web users' quotes were collected from May to October 2018. Data analysis triangulation was performed by two researchers using the NVivo 12® software., Results: The users discussed their experience with Parkinson's disease (PD) in a warm atmosphere. 23 discussion threads were analysed: 302 messages posted by 70 users (70% were females; the average illness duration was 6 years); 115 encoded nodes were created. Five user profiles appeared: leader, follower, expert, mixed, and undetermined. Common preoccupations were a lack of time and listening from the physicians' side. Three themes emerged: managing symptoms, living with PD, and sharing illness experiences. Users sought actively for a cure to limit or stop disease evolution, using alternative and complementary therapies to optimize their daily condition., Conclusions: Online forums foster person's informal learnings about coping with PD. Healthcare professionals can use these learnings to optimize person-centred support., Practice Implications: During consultations, healthcare professionals should invite persons to discuss their online activity, informal learnings, beliefs and expectations towards therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors have no competing interest to declare., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Identification of patients with lymphocytic variant hypereosinophilic syndrome (L-HES) is challenging, and has important prognostic and therapeutic implications., Objective: This study was undertaken to assess diagnostic tools for L-HES and to develop evidence-based diagnostic recommendations., Methods: Biomarkers of T-cell-driven disease were compared between patients with L-HES versus idiopathic HES (I-HES) variants. Those performed routinely (serum immunoglobulin levels, T-cell phenotyping, T-cell receptor [TCR] gene rearrangement patterns) were collected from medical files, whereas others were prospectively assessed on stored blood samples (serum CCL17/thymus and activation regulated chemokine [TARC] levels, in vitro cytokine production)., Results: This study included 48 patients with I-HES and 20 with L-HES associated with a CD3 - CD4 + T-cell subset, including 7 with less than 5% aberrant cells. Neither increased serum immunoglobulin levels nor clonal TCR gene rearrangements were sufficiently sensitive or specific for L-HES. In contrast, systematically enhanced expression of the T-cell surface antigens CD2, CD5, CD45RO, and CD95 by these cells allowed for accurate detection by flow cytometry. Serum CCL17/TARC levels were significantly higher in patients with L-HES compared with those with I-HES, and a threshold of 3000 pg/mL allowed for detection of all subjects with L-HES with 75% specificity. Quantification of intracytoplasmic cytokine production by flow cytometry is the most reliable method for detection of enhanced type 2 cytokine expression, most notably for IL-4 and IL-13., Conclusion: Adapting the standard of procedure for T-cell phenotyping in patients with unexplained hypereosinophilia is currently the most reliable means of identifying those with CD3 - CD4 + L-HES., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: The deletion (D) allele of the ACE insertion/deletion (I/D) polymorphism is a risk factor for diabetic kidney disease. We assessed its contribution to long-term kidney outcomes and all-cause death in patients with long-standing type 1 diabetes., Research Design and Methods: A total of 1,155 participants from three French and Belgian cohorts were monitored for a median duration of 14 (interquartile range 13) years. The primary outcome was the occurrence of end-stage kidney disease (ESKD) or a 40% drop in the estimated glomerular filtration rate (eGFR). Secondary outcomes were the individual components of the primary outcome, rapid decline in eGFR (steeper than -3 mL/min/1.73 m 2 per year), incident albuminuria, all-cause death, and a composite ESKD or all-cause death. Hazard ratios (HRs) for XD versus II genotype and for baseline plasma ACE levels were computed by Cox analysis. Genotype performance in stratifying the primary outcome was tested., Results: Genotype distribution was 954 XD and 201 II. The primary outcome occurred in 20% of XD and 13% of II carriers: adjusted HR 2.07 (95% CI 1.32-3.40; P = 0.001). Significant associations were also observed for rapid decline in eGFR, incident albuminuria, ESKD, all-cause death, and ESKD or all-cause death. Baseline plasma ACE levels were higher in XD carriers and significantly associated with an increased risk of the primary outcome. The ACE genotype enhanced net reclassification improvement (0.154, 95% CI 0.007-0.279; P = 0.04) and integrated discrimination improvement (0.012, 95%CI 0.001-0.021; P = 0.02) for primary outcome stratification., Conclusions: The D-allele of the ACE I/D polymorphism was associated with an increased risk of major kidney events and all-cause death in patients with long-standing type 1 diabetes., (© 2021 by the American Diabetes Association.)

Background: IDH-mutant anaplastic astrocytomas (AAs) are chemosensitive tumors for which the best choice of adjuvant chemotherapy between procarbazine, lomustine, and vincristine (PCV) or temozolomide (TMZ) after radiotherapy (RT) remains unclear., Methods: In a large cohort of patients with histologically proven 2016 World Health Organization classification AA with IDH1/2 mutations included in the French national POLA cohort (n = 355), the primary objective was to compare progression-free survival (PFS) between the two treatment regimens (n = 311). Secondary endpoints were overall survival (OS), progression type, pseudoprogression rate, and toxicity., Results: The 4-year PFS in the RT + PCV arm was 70.8% versus 53.5% in the RT + TMZ arm, with a hazard ratio (HR) of 0.58 (95% confidence interval [CI], 0.38-0.87; p = .0074) in univariable analysis and 0.63 (95% CI, 0.41-0.97; p = .0348) in multivariable analysis. The 4-year OS in the RT + PCV arm was 84.3% versus 76.6% in the RT + TMZ arm, with an HR of 0.57 (95% CI, 0.30-1.05; p = .0675) in univariable analysis. Toxicity was significantly higher in the RT + PCV arm with more grade ≥3 toxicity (46.7% vs. 8.6%, p < .0001)., Conclusion: RT + PCV significantly improved PFS compared with RT + TMZ for IDH-mutant AA. However, RT + TMZ was better tolerated., Implications for Practice: In the absence of fully conducted randomized trials comparing procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) in adjuvant treatment after radiotherapy (RT) for the management of IDH-mutant anaplastic astrocytoma (AA) and a similar level of evidence, these two chemotherapies are both equally recommended in international guidelines. This study in a national cohort of IDH-mutant AA defined according the 2016 World Health Organization (WHO) classification shows for the first time that the RT + PCV regimen significantly improves progression-free survival in comparison with the RT + TMZ regimen. Even if at the time of analysis the difference in overall survival was not significant, this result provides new evidence for the debate about the chemotherapy regimen to prescribe in adjuvant treatment to RT for WHO 2016 IDH-mutant AA., (© 2021 AlphaMed Press.)

Background: Approximately 10% of IDH-mutant gliomas harbour non-canonical IDH mutations (non-p.R132H IDH1 and IDH2 mutations)., Objective: The aim of this study was to analyse the characteristics of non-canonical IDH-mutant gliomas., Materials and Methods: We retrospectively analysed the characteristics of 166 patients with non-canonical IDH mutant gliomas and compared them to those of 155 consecutive patients with IDH1 p.R132H mutant gliomas., Results: The median age at diagnosis was 38 years in patients with non-canonical IDH mutant gliomas and 43 years in glioma patients with IDH1 p.R132H-mutant tumours. Family history of cancer was more frequent among glioma patients harbouring non-canonical IDH mutations than in patients with IDH1 p.R132H mutations (22.2% vs 5.1%; P < 0.05). Tumours were predominantly localised in the frontal lobe regardless of the type of IDH mutation. Compared to IDH1 p.R132H-mutant gliomas, tumours with non-canonical IDH mutations were more frequently found in the infratentorial region (5.5% vs 0%; P < 0.05) and were often multicentric (4.8% vs 0.9%; P < 0.05). Compared to IDH1 P.R132H-mutant gliomas, tumours with non-canonical IDH1 mutations were more frequently astrocytomas (65.6% vs 43%, P < 0.05), while those with IDH2 mutations were more frequently oligodendrogliomas (85% vs 48.3%; P < 0.05). The median overall survival was similar in patients with IDH1 p.R132H-mutant gliomas and patients with non-canonical IDH-mutant gliomas., Conclusion: Gliomas with non-canonical IDH mutations have distinct radiological and histological characteristics. The presence of such tumours seems to be associated with genetic predisposition to cancer development.

Background: Despite maximum medical treatment and endoscopic sinus surgery (ESS), chronic rhinosinusitis with nasal polyps (CRSwNP) can require revision surgery. With a growing literature on the diversity of cytokine inflammation patterns in CRSwNP, an endotype-driven approach could lead to the identification of cytokine profiles that predict recurrence., Methods: A monocentric longitudinal study was carried out until June 2019 following CRSwNP patients who underwent surgery for the first time between December 2010 and January 2012. The biomarker profiles were established on blood and nasal secretions at the time of the first surgery (Interleukin (IL)-5, IgE, IgA, eosinophilic cationic protein (ECP) and eosinophilic- derived neurotoxin (EDN)). Profiles were compared between the patients still controlled by medical treatment and the patients requiring revision surgery during the course of the follow-up period., Results: Among the 48 patients initially enrolled in our study, 8 required revision surgery (16,7%). Clinical features (asthma, allergy, aspirin intolerance, active smoking) and levels of blood markers measured at the time of the first surgery were comparable between the 2 groups of patients. Levels of IL-5, IgE and ECP in nasal secretions were significantly increased in the group of patients needing revision surgery., Conclusions: Based on simple approach of nasal secretions sampling, we showed that a predominant T helper 2 proteins expression profile can be associated with recurrent CRSwNP after ESS. Initial immunoprofiling in CRSwNP disease may contribute to better predict the therapeutic response to optimal medical and surgical treatment, and help define the role of innovative targeted treatment, beside corticosteroids and ESS.

Background: Lymphocytic variant hypereosinophilic syndrome is characterized by marked over-production of eosinophilopoietic factor(s) by dysregulated T cells leading to eosinophil expansion. In most cases, these T cells are clonal and express a CD3 - CD4 + phenotype. As this is a rare disorder, presenting manifestations, disease course, treatment responses, and outcome are not well-characterized. Materials and Methods: In this retrospective single-center observational study, we reviewed medical files of all patients with persistent hypereosinophilia seen between 1994 and 2019 in whom CD3 - CD4 + T cells were detected. Data collection included clinical and biological findings at presentation, treatment responses, disease course, and serial CD3 - CD4 + T cell counts. Results: Our cohort comprises 26 patients, including 2 with hypereosinophilia of undetermined significance. All 24 symptomatic patients had cutaneous lesions and/or angioedema, and fasciitis was present in several cases. The aberrant T cell subset represented 2% or less total lymphocytes in 11 subjects. TCR gene rearrangement patterns on whole blood were polyclonal in these cases, while they all had serum CCL17/TARC levels above 1,500 pg/ml. Disease manifestations were mild and did not require maintenance therapy in roughly one third of the cohort, while two thirds required long-term oral corticosteroids and/or second-line agents. Among these, interferon-alpha was the most effective treatment option with a response observed in 8/8 patients, one of whom was cured of disease. Treatment had to be interrupted in most cases however due to poor tolerance and/or development of secondary resistance. Anti-interleukin-5 antibodies reduced blood eosinophilia in 5/5 patients, but clinical responses were disappointing. A sub-group of 5 patients had severe treatment-refractory disease, and experienced significant disease- and treatment-related morbidity and mortality, including progression to T cell lymphoma in three. Conclusions: This retrospective longitudinal analysis of the largest monocentric cohort of CD3 - CD4 + T cell associated lymphocytic variant hypereosinophilic syndrome published so far provides clinicians confronted with this rare disorder with relevant new data on patient presentation and outcome that should help tailor therapy and follow-up to different levels of disease severity. It highlights the need for novel therapeutic options, especially for the subset of patients with severe treatment-refractory disease. Future research efforts should be made toward understanding CD3 - CD4 + T cell biology in order to develop new treatments that target primary pathogenic mechanisms., (Copyright © 2020 Carpentier, Verbanck, Schandené, Heimann, Trépant, Cogan and Roufosse.)

β-N-Methylamino-l-alanine (BMAA), a neurotoxin naturally produced by cyanobacteria, diatoms and dinoflagellates, constitutes a serious environmental and health threat especially during acute blooms, which are becoming more frequent. This neurotoxin is implicated in several neurodegenerative diseases (ND) in humans through contaminated water or food consumption. Even low doses of neurotoxic compounds (NCs) can have lasting effects later in life. In this sense, early stages of development constitute a period of high sensitivity to environmental influence, particularly for the central nervous system. To understand the mechanisms underlying the delayed effects of NCs, newly hatched larvae of the mangrove rivulus fish, Kryptolebias marmoratus, were exposed to two sub-lethal doses of BMAA (20 μg/L and 15 mg/L) for 14 days. This fish naturally produces isogenic lineages due to its self-fertilizing reproduction, which is unique case among vertebrates. It thus provides genetic characteristics that allow scientists to study organisms' true reaction norm, minimizing genetic variability and focusing exclusively on the effects of the environment. Effect assessment was performed at different levels of biological organization to detect inconspicuous effects of BMAA, since this molecule displays long retention in organisms. BMAA effects on life history traits as well as behavioral traits such as boldness and aggressiveness were assessed more than 100 days after exposure. In addition, the relative expression of 7 potential BMAA target genes was studied, given their involvement in neurotransmission or their association with individual variation in boldness and aggressiveness. Selected genes code for reticulon 4 (RTN4), glutamate vesicular transporter 1 (Slc17a7), glutamine synthetase a (Glula), dopamine receptor D4 (DRD4), monoamine oxidase A (MAOA), calmodulin (CaM) and epedymine (Epd). Despite observing no effects of BMAA on growth, reproduction and behavioral traits, BMAA induced a significant increase of the expression of CaM and MAOA genes at 20 μg/L BMAA compared to the control group. A significant decrease of expression was observed between this lowest BMAA dose and 15 mg/L for DRD4, MAOA and CaM genes. Our results suggest disruption of glutamate turnover, intracellular dopamine depletion and activation of astrocyte protective mechanisms, indicating that BMAA might be excitotoxic. Our study revealed that BMAA can have long-lasting effects on the brain that are suspected to affect phenotypic traits with aging. Furthermore, it highlights the importance of studying delayed effects in ecotoxicological studies., Competing Interests: Declaration of Competing Interest The authors declare that no competing interests exist., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Anaplastic oligodendroglioma (AO), IDH-mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high-grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki-67, in a large series of IDHmut+/1p19qcodel AO included in the POLA ("Prise en charge des Oligodendrogliomes Anaplasiques") French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labeling indices (LI) of MCM6 and Ki-67 were obtained via computer-assisted color image analyses on immunostained AO tissues of the cohort (n = 220). Furthermore, a subgroup of AO (n = 68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki-67 (≥15%) correlated with shorter overall survival, both in univariate (P = 0.013 and P = 0.004, respectively) and multivariate analyses (P = 0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki-67). MCM6 and Ki-67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro-neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta-amyloid binding and postsynaptic specialization. In conclusion, the overexpression of MCM6 and/or Ki-67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy-to-use and cost-effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down-regulated immune response and lower microglial cells activation, and bears pro-neural phenotype., (© 2019 International Society of Neuropathology.)

Drug resistance limits the therapeutic efficacy in cancers and leads to tumor recurrence through ill-defined mechanisms. Glioblastoma (GBM) are the deadliest brain tumors in adults. GBM, at diagnosis or after treatment, are resistant to temozolomide (TMZ), the standard chemotherapy. To better understand the acquisition of this resistance, we performed a longitudinal study, using a combination of mathematical models, RNA sequencing, single cell analyses, functional and drug assays in a human glioma cell line (U251). After an initial response characterized by cell death induction, cells entered a transient state defined by slow growth, a distinct morphology and a shift of metabolism. Specific genes expression associated to this population revealed chromatin remodeling. Indeed, the histone deacetylase inhibitor trichostatin (TSA), specifically eliminated this population and thus prevented the appearance of fast growing TMZ-resistant cells. In conclusion, we have identified in glioblastoma a population with tolerant-like features, which could constitute a therapeutic target.

Background: The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification., Methods: In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas., Results: CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas., Conclusions: Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, and a fortiori its quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative "C-circle" assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age (p < 0.001), the younger the patient, the higher the intensity of ALT. Strikingly, glioblastomas having progressed from anaplastic astrocytomas did not exhibit this correlation. ALT activity level in the tumor did not depend on telomere length in healthy tissue cells from the same patient. In summary, we have uncovered the existence, in anaplastic astrocytomas but not in glioblastomas with the same IDH and ATRX mutations, of a correlation between patient age and the level of activity of ALT, a telomerase-independent pathway of telomere maintenance.

Objective: Enteroendocrine cells (EECs) of the gastro-intestinal tract sense gut luminal factors and release peptide hormones or serotonin (5-HT) to coordinate energy uptake and storage. Our goal is to decipher the gene regulatory networks controlling EECs specification from enteroendocrine progenitors. In this context, we studied the role of the transcription factor Rfx6 which had been identified as the cause of Mitchell-Riley syndrome, characterized by neonatal diabetes and congenital malabsorptive diarrhea. We previously reported that Rfx6 was essential for pancreatic beta cell development and function; however, the role of Rfx6 in EECs differentiation remained to be elucidated., Methods: We examined the molecular, cellular, and metabolic consequences of constitutive and conditional deletion of Rfx6 in the embryonic and adult mouse intestine. We performed single cell and bulk RNA-Seq to characterize EECs diversity and identify Rfx6-regulated genes., Results: Rfx6 is expressed in the gut endoderm; later, it is turned on in, and restricted to, enteroendocrine progenitors and persists in hormone-positive EECs. In the embryonic intestine, the constitutive lack of Rfx6 leads to gastric heterotopia, suggesting a role in the maintenance of intestinal identity. In the absence of intestinal Rfx6, EECs differentiation is severely impaired both in the embryo and adult. However, the number of serotonin-producing enterochromaffin cells and mucosal 5-HT content are increased. Concomitantly, Neurog3-positive enteroendocrine progenitors accumulate. Combined analysis of single-cell and bulk RNA-Seq data revealed that enteroendocrine progenitors differentiate in two main cell trajectories, the enterochromaffin (EC) cells and the Peptidergic Enteroendocrine (PE) cells, the differentiation programs of which are differentially regulated by Rfx6. Rfx6 operates upstream of Arx, Pax6 and Isl1 to trigger the differentiation of peptidergic EECs such as GIP-, GLP-1-, or CCK-secreting cells. On the contrary, Rfx6 represses Lmx1a and Tph1, two genes essential for serotonin biosynthesis. Finally, we identified transcriptional changes uncovering adaptive responses to the prolonged lack of enteroendocrine hormones and leading to malabsorption and lower food efficiency ratio in Rfx6-deficient mouse intestine., Conclusion: These studies identify Rfx6 as an essential transcriptional regulator of EECs specification and shed light on the molecular mechanisms of intestinal failures in human RFX6-deficiencies such as Mitchell-Riley syndrome., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: As acute stroke services improve, more persons experience mild stroke and need to cope daily with hidden disabilities, which may be influenced by how they perceive stroke, cognitively and emotionally., Objective: To investigate cognitive illness beliefs and emotional responses in persons with mild stroke and their possible influences on daily coping., Methods: Semi-structured interviews were conducted with 24 persons with mild stroke, on average 7.5 months (±0.89) after stroke occurrence. A thematic analysis on verbatim transcripts was guided by the Common-Sense Model of Self-Regulation., Results: All participants experienced difficulties constructing an illness identity at both acute and chronic phase. Behavioral risk factors were less accepted as causes of stroke. Lack (or inappropriate timing) of information from healthcare providers led to limited medication knowledge and low perceived control of stroke recurrence which generated anxiety, fear, and low involvement in coping. Participants who considered stroke a chronic condition experienced more difficulties. Perceived support from relatives and healthcare providers was beneficial for participation in recovery and health behaviour change., Conclusion: Despite having mildly disabilities, participants reported difficulties developing illness beliefs conducive to coping, and dealing with their emotional responses. These elements should be considered in tailored programs to improve coping with hidden disabilities post-stroke., Competing Interests: The authors have declared that no competing interests exist.

Background: Hyperglycaemia impairs tubulo-glomerular feedback. We tested whether variable tubulo-glomerular feedback during hyperglycaemia contributes to renal risk heterogeneity seen in Type 1 diabetes., Methods: During the period 1990-92, we studied the tubulo-glomerular feedback in Type 1 diabetic patients at high or low renal risk [21 of 54 with glomerular hyperfiltration and/or microalbuminuria against 11 of 55 with normal glomerular filtration rate (GFR) and urinary albumin despite uncontrolled diabetes]. The GFR, effective renal plasma flow, mean arterial pressure and fractional reabsorptions of glucose, osmols, sodium and lithium were measured sequentially during normo- and hyperglycaemia. All patients were followed up until 2016 for incident proteinuria, estimated GFR <60 mL/min/1.73 m2, doubling of serum creatinine, end-stage renal disease or all-cause death., Results: Glycaemia increased from 6.1 ± 1.3 to 15.1 ± 1.9 mmol/L in both high-risk and low-risk patients. Glycosuria was lower in the high- versus low-risk patients: 0.34 ± 0.25 versus 0.64 ± 0.44 mmol/min (P = 0.03). Both groups displayed similar kidney function during normoglycaemia. Hyperglycaemia increased more importantly GFR and fractional reabsorptions, and pre-glomerular vasodilatation in the high- than in the low-risk patients (all P < 0.05). Over 21 years, 31.5% high- versus 12.7% low-risk patients developed endpoints (adjusted P = 0.006). In a multi-adjusted survival analysis of patients having undergone renal tests, each 0.10 mmol/min glycosuria during hyperglycaemia reduced the outcome risk by 0.72 (95% confidence interval 0.49-0.97, P = 0.03)., Conclusions: Reduced tubulo-glomerular feedback and glycosuria during hyperglycaemia indicate high renal risk for Type 1 diabetic patients. Inter-individual variability in tubulo-glomerular feedback activity determines renal risk in Type 1 diabetes., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: The quality of life of people living with chronic conditions is highly dependent on self-management behaviors. Mobile health (mHealth) apps could facilitate self-management and thus help improve population health. To achieve their potential, apps need to target specific behaviors with appropriate techniques that support change and do so in a way that allows users to understand and act upon the content with which they interact., Objective: Our objective was to identify apps targeted toward the self-management of chronic conditions and that are available in France. We aimed to examine what target behaviors and behavior change techniques (BCTs) they include, their level of understandability and actionability, and the associations between these characteristics., Methods: We extracted data from the Google Play store on apps labelled as Top in the Medicine category. We also extracted data on apps that were found through 12 popular terms (ie, keywords) for the four most common chronic condition groups-cardiovascular diseases, cancers, respiratory diseases, and diabetes-along with apps identified through a literature search. We selected and downloaded native Android apps available in French for the self-management of any chronic condition in one of the four groups and extracted background characteristics (eg, stars and number of ratings), coded the presence of target behaviors and BCTs using the BCT taxonomy, and coded the understandability and actionability of apps using the Patient Education Material Assessment Tool for audiovisual materials (PEMAT-A/V). We performed descriptive statistics and bivariate statistical tests., Results: A total of 44 distinct native apps were available for download in France and in French: 39 (89%) were found via the Google Play store and 5 (11%) were found via literature search. A total of 19 (43%) apps were for diabetes, 10 for cardiovascular diseases (23%), 8 for more than one condition in the four groups (18%), 6 for respiratory diseases (14%), and 1 for cancer (2%). The median number of target behaviors per app was 2 (range 0-7) and of BCTs per app was 3 (range 0-12). The most common BCT was self-monitoring of outcome(s) of behavior (31 apps), while the most common target behavior was tracking symptoms (30 apps). The median level of understandability was 42% and of actionability was 0%. Apps with more target behaviors and more BCTs were also more understandable (ρ=.31, P=.04 and ρ=.35, P=.02, respectively), but were not significantly more actionable (ρ=.24, P=.12 and ρ=.29, P=.054, respectively)., Conclusions: These apps target few behaviors and include few BCTs, limiting their potential for behavior change. While content is moderately understandable, clear instructions on when and how to act are uncommon. Developers need to work closely with health professionals, users, and behavior change experts to improve content and format so apps can better support patients in coping with chronic conditions. Developers may use these criteria for assessing content and format to guide app development and evaluation of app performance., Trial Registration: PROSPERO CRD42018094012; https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=94012., (©Luiza Siqueira do Prado, Camille Carpentier, Marie Preau, Anne-Marie Schott, Alexandra Lelia Dima. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 26.08.2019.)

mHealth apps use is rapidly increasing and has high potential value for people with chronic conditions, supporting behaviour change for self-management and improving patient-provider communication. To build a well-functioning app development environment, we need to examine the range of available apps according to their variability and content. A review of Google Play apps revealed limited availability for chronic self-management in France among substantial unrelated content. Most apps' content was difficult to understand and act upon.

Background: Cervical spondylodiscitis is a rare but severe complication of pharyngeal surgery., Material and Methods: This multicenter retrospective study reported all patients in the database of the French head and neck tumor study group (GETTEC) affected by cervical spondylodiscitis after transoral robotic surgery (TORS) for malignant pharyngeal tumor from January 2010 to January 2017., Objectives: To describe cases of post-TORS cervical spondylodiscitis, identify alarm signs, and determine optimal management of these potentially lethal complications., Results: Seven patients from 6 centers were included. Carcinomas were located in the posterior pharyngeal wall. Tumor stage was T1 or T2. All patients had risk factors for spondylodiscitis. Mean time to diagnosis was 12.6days. The interval between surgery and spondylodiscitis diagnosis ranged from 20days to 4.5months, for a mean 2.1months. The most common symptom was neck pain (87%). Infections were polymicrobial; micro-organisms were isolated in 5 cases and managed by intravenous antibiotics, associated to medullary decompression surgery in 3 cases. Follow-up found favorable progression in 4 cases, and 3 deaths (mortality, 43%)., Conclusion: This French multicenter study found elevated mortality in post-TORS spondylodiscitis, even in case of limited resection. Surgeons must be aware of this complication and alerted by persistent neck pain, fever, asthenia, impaired or delayed posterior pharyngeal wall wound healing or elevation of inflammatory markers. MRI is the most effective diagnostic radiological examination., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Herein we report the anti-inflammatory activity of lobaric acid and pseudodepsidones isolated from the nordic lichen Stereocaulon paschale. Lobaric acid (1) and three compounds (2, 7 and 9) were found to inhibit the NF-κB activation and the secretion of pro-inflammatory cytokines (IL-1β and TNF-α) in LPS-stimulated macrophages. Inhibition and docking simulation experiments provided evidence that lobaric acid and pseudodepsidones bind to PPAR-γ between helix H3 and the beta sheet, similarly to partial PPAR-γ agonists. These findings suggest that lobaric acid and pseudodepsidones reduce the expression of pro-inflammatory cytokines by blocking the NF-κB pathway via the activation of PPAR-γ., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Viticulture is of high socio-economic importance; however, its prevalent practices severely impact the environment and human health, and criticisms from society are raising. Vine managements systems are further challenged by climatic changes. Of the 8 million hectares grown worldwide, conventional and organic practices cover 90% and 9% of acreage, respectively. Biodynamic cultivation accounts for 1%. Although economic success combined with low environmental impact is widely claimed by biodynamic winegrowers from California, to South Africa, and France, this practice is still controversial in viticulture and scientific communities. To rethink the situation, we encouraged stakeholders to confront conventional and biodynamic paradigms in a Participative-Action-Research. Co-designed questions were followed up by holistic comparison of conventional and biodynamic vineyard managements. Here we show that the amplitude of plant responses to climatic threats was higher in biodynamic than conventional management. The same stood true for seasonal trends and pathogens attacks. This was associated with higher expression of silencing and immunity genes, and higher anti-oxidative and anti-fungal secondary metabolite levels. This suggests that sustainability of biodynamic practices probably relies on fine molecular regulations. Such knowledge should contribute to resolving disagreements between stakeholders and help designing the awaited sustainable viticulture at large.

Diffuse gliomas are classified according to the 2016 WHO Classification of Tumors of the Central Nervous System, which now defines entities by both histology and molecular features. Somatostatin receptor subtype 2A (SSTR2A) expression has been reported in various solid tumors as associated with favorable outcomes. Its expression has been reported in gliomas with uncertain results regarding its prognostic value. The objective of this study was to assess the prognostic impact of SSTR2A protein expression in a large cohort of grade III and IV gliomas classified according to the updated 2016 WHO classification. We further validated our result with an independent cohort of low grade glioma using dataset generated by The Cancer Genome Atlas (TCGA) Research Network.We analyzed clinical and molecular data from 575 patients. SSTR2A protein expression was evaluated using immunohistochemistry on tissue microarrays. High expression of SSTR2A protein associated with the anaplastic oligodendroglioma IDH-mutant and 1p/19q-codeleted subgroup (p < 0.001). Among these tumors, SSTR2A protein expression was significantly associated with a lower proliferative index, the absence of microvascular proliferation and the absence of necrosis (p < 0.001). Furthermore SSTR2A protein expression associated with better overall survival (p = 0.007) and progression-free survival (p = 0.01) in both univariate and multivariate analysis when adjusted by the age, the presence of necrosis and the mitotic index. Similar results were obtained regarding SSTR2 mRNA expression in the TCGA low grade glioma, subtype IDH-mutant and 1p/19q-codeleted, dataset.SSTR2A might represent an attractive biomarker and therapeutic target in anaplastic oligodendroglioma IDH-mutant and 1p/19q-codeleted specific subgroup. Understanding the implicated molecular pathways may represent a step forward to improve therapeutic approaches.