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High-throughput screening of drug sensitivity of cancer cell lines (CCLs) holds the potential to unlock anti-tumor therapies. In this study, we leverage such datasets to predict drug response using cell line transcriptomics, focusing on models' interpretability and deployment on patients' data. We use large language models (LLMs) to match drug to mechanisms of action (MOA)-related pathways. Genes crucial for prediction are enriched in drug-MOAs, suggesting that our models learn the molecular determinants of response. Furthermore, by using only LLM-curated, MOA-genes, we enhance the predictive accuracy of our models. To enhance translatability, we align RNAseq data from CCLs, used for training, to those from patient samples, used for inference. We validated our approach on TCGA samples, where patients' best scoring drugs match those prescribed for their cancer type. We further predict and experimentally validate effective drugs for the patients of two highly lethal solid tumors, i.e., pancreatic cancer and glioblastoma., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Glioblastoma is the most aggressive adult primary brain cancer, characterized by significant heterogeneity, posing challenges for patient management, treatment planning, and clinical trial stratification., Methods: We developed a highly reproducible, personalized prognostication and clinical subgrouping system using machine learning (ML) on routine clinical data, MRI, and molecular measures from 2,838 demographically diverse patients across 22 institutions and 3 continents. Patients were stratified into favorable, intermediate, and poor prognostic subgroups (I, II, III) using Kaplan-Meier analysis (Cox proportional model and hazard ratios [HR])., Results: The ML model stratified patients into distinct prognostic subgroups with HRs between subgroups I-II and I-III of 1.62 (95%CI: 1.43-1.84, p<0.001) and 3.48 (95%CI: 2.94-4.11, p<0.001), respectively. Analysis of imaging features revealed several tumor properties contributing unique prognostic value, supporting the feasibility of a generalizable prognostic classification system in a diverse cohort., Conclusions: Our ML model demonstrates extensive reproducibility and online accessibility, utilizing routine imaging data rather than complex imaging protocols. This platform offers a unique approach for personalized patient management and clinical trial stratification in glioblastoma., (© 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.)

Drugs targeting mitochondrial energy metabolism are emerging as promising antitumor therapeutics. Glioma treatment is extremely challenging due to the high complexity of the tumor and the high cellular heterogeneity. From a metabolic perspective, glioma cancer cells can be classified into the oxidative metabolic phenotype (mainly depending on mitochondrial respiration for energy production) and glycolytic phenotype or "Warburg effect" (mainly depending on glycolysis). Herein, we reviewed the function of novel bio-active molecules targeting oxidative phosphorylation (OXPHOS), mitochondrial membrane potential and mitochondrial dynamics. These molecules exhibit intriguing preclinical and clinical results and have been proven to be promising candidates to be further developed for glioma therapy. However, despite these initial encouraging results, it is imperative to rigorously assess the side effects of these metabolic drugs, which have a non-negligible toxicity profile.

Background/objectives: Glioblastoma (GBM) is an aggressive brain cancer with limited treatment options. Extracellular vesicles (EVs) derived from GBM cells contain important biomarkers, such as microRNAs, proteins, and DNA mutations, which are involved in tumor progression, invasion, and resistance to treatment. Identifying surface markers on these EVs is crucial for their isolation and potential use in noninvasive diagnosis. This study aimed to use tumor-derived explants to investigate the surface markers of EVs and explore their role as diagnostic biomarkers for GBM., Methods: Tumor explants from nine GBM patients without IDH1/IDH2 mutations or 1p-19q co-deletion were cultured to preserve both tumor viability and cytoarchitecture. EVs were collected from the tumor microenvironment using differential centrifugation, filtration, and membrane affinity binding. Their surface protein composition was analyzed through multiplex protein assays. RNA-Seq data from TCGA and GTEx datasets, along with in silico single-cell RNA-seq data, were used to assess EV surface biomarker expression across large GBM patient cohorts., Results: The in vitro model successfully replicated the tumor microenvironment and produced EVs with distinct surface markers. Biomarker analysis in large datasets revealed specific expression patterns unique to GBM patients compared with healthy controls. These markers demonstrated potential as a GBM-specific signature and were correlated with clinical data. Furthermore, in silico single-cell RNA-seq provided detailed insights into biomarker distribution across different cell types within the tumor., Conclusions: This study underscores the efficacy of the tumor-derived explant model and its potential to advance the understanding of GBM biology and EV production. A key innovation is the isolation of EVs from a model that faithfully mimics the tumor's original cytoarchitecture, offering a deeper understanding of the cells involved in EV release. The identified EV surface markers represent promising targets for enhancing EV isolation and optimizing their use as diagnostic tools. Moreover, further investigation into their molecular cargo may provide crucial insights into tumor characteristics and evolution.

Introduction: Spheroids are spherical aggregates of cells that mimic the three-dimensional (3D) architecture of tissues more closely than traditional two dimensional (2D) cultures. Spheroids of adipose stem cells (SASCs) show special features such as high multilineage differentiation potential and immunomodulatory activity. These properties have been attributed to their secreted factors, such as cytokines and growth factors. Moreover, a key role is played by the extracellular vesicles (EVs), which lead a heterogeneous cargo of proteins, mRNAs, and small RNAs that interfere with the pathways of the recipient cells., Purpose: The aim of this work was to characterize the composition of the secretome and exosome from SASCs and evaluate their regenerative potential., Materials and Methods: SASCs were extracted from adipose samples of healthy individuals after signing informed consent. The exosomes were isolated and characterized by Dinamic Light Scattering (DLS), Scanning Electron Microscopy (SEM), and Western blotting analyses. The expression of mRNAs and miRNAs were evaluated through real-time PCR. Lastly, a wound-healing assay was performed to investigate their regenerative potential on different cell cultures., Results: The SASCs' exosomes showed an up-regulation of NANOG and SOX2 mRNAs, typical of stemness maintenance, as well as miR126 and miR146a, related to angiogenic and osteogenic processes. Moreover, the exosomes showed a regenerative effect., Conclusions: The SASCs' secretome carried paracrine signals involved in stemness maintenance, pro-angiogenic and pro-osteogenic differentiation, immune system regulation, and regeneration.

Background: Oncogenic FGFR-TACC fusions are present in 3-5% of high-grade gliomas (HGGs). Fexagratinib (AZD4547) is an oral FGFR1-3 inhibitor with preclinical activity in FGFR-TACC+ gliomas. We tested its safety and efficacy in patients with recurrent FGFR-TACC + HGGs., Patients and Methods: TARGET (NCT02824133) is a phase I/II open-label multicenter study that included adult patients with FGFR-TACC + HGGs relapsing after ≥1 line of standard chemoradiation. Patients received fexagratinib 80 mg bd on a continuous schedule until disease progression or unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (PFS6)., Results: Twelve patients with recurrent IDH wildtype FGFR-TACC + HGGs (all FGFR3-TACC3+) were included in the efficacy cohort (male/female ratio = 1.4, median age = 61.5 years). Most patients (67%) were included at the first relapse. The PFS6 was 25% (95% confidence interval 5-57%), with a median PFS of 1.4 months. All patients without progression at 6 months ( n  = 3) were treated at first recurrence (versus 56% of those in progression) and remained progression-free for 14-23 months. The best response was RANO partial response in 1 patient (8%), stable disease in 5 (42%), and progressive disease in 6 (50%). Median survival was 17.5 months from inclusion. Grade 3 toxicities included lymphopenia, hyperglycaemia, stomatitis, nail changes, and alanine aminotransferase increase ( n  = 1 each). No grade 4-5 toxicities were seen. A 32-gene signature was associated with the benefit of FGFR inhibition in FGFR3-TACC3 + HGGs., Conclusions: Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3-TACC3 + HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required., Competing Interests: A.P. and M.S. declare having received travel support from Astra Zeneca. The other authors have declared no conflict of interest relevant to this paper., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

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.)

Melanoma is one of the most sensitive tumors to immune modulation, and the major challenge for melanoma patients' survival is immune checkpoint inhibitor (ICI) therapy. γδ T lymphocytes play an antitumoral role in a broad variety of tumors including melanoma and they are optimal candidates for cellular immunotherapy. Thus, a comprehensive analysis of the correlation between γδ T cells and immune checkpoint receptors in the context of melanoma was conducted, with the aim of devising an innovative combined immunotherapeutic strategy. In this study, using the GEPIA2.0 database, a significant positive correlation was observed between the expression of γδ T cell-related genes (TRGC1, TRGC2, TCRD) and immune checkpoint genes (PDCD1, HAVCR2, LAG3), highlighting the potential role of γδ T cells in the immune response within melanoma. Moreover, flow cytometry analysis unveiled a significant augmentation in the population of γδ T cells within melanoma lesions, which exhibited the expression of immune checkpoint receptors including LAG3, TIM3, and PD1. Analysis of single-cell RNA sequencing data revealed a significant enrichment and functional reprogramming of γδ T cell clusters in response to ICIs. Interestingly, the effects of ICI therapy varied between Vδ1 and Vδ2 γδ T cell subsets, with distinct changes in gene expression patterns. Last, a correlation analysis between γδ T cell abundance, immune checkpoint gene expression, and clinical outcomes in melanoma patients showed that low expression of immune checkpoint genes, including LAG3, HAVCR2, and PDCD1, was associated with improved 1-year overall survival, emphasizing the significance of these genes in predicting patient outcomes, potentially outweighing the impact of γδ T cell abundance. This study offers critical insights into the dynamic interaction between γδ T cells, immune checkpoint receptors, and melanoma, providing valuable perspectives for potential therapeutic avenues and predictive markers in this intricate interplay., Competing Interests: Conflict of interest statement. The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Glioblastoma, a deadly brain tumor, shows limited response to standard therapies like temozolomide (TMZ). Recent findings from the REGOMA trial underscore a significant survival improvement offered by Regorafenib (REGO) in recurrent glioblastoma. Our study aimed to propose a 3D ex vivo drug response precision medicine approach to investigate recurrent glioblastoma sensitivity to REGO and elucidate the underlying molecular mechanisms involved in tumor resistance or responsiveness to treatment. Three-dimensional glioblastoma organoids (GB-EXPs) obtained from 18 patients' resected recurrent glioblastoma tumors were treated with TMZ and REGO. Drug responses were evaluated using NAD(P)H FLIM, stratifying tumors as responders (Resp) or non-responders (NRs). Whole-exome sequencing was performed on 16 tissue samples, and whole-transcriptome analysis on 13 GB-EXPs treated and untreated. We found 35% (n = 9) and 77% (n = 20) of tumors responded to TMZ and REGO, respectively, with no instances of TMZ-Resp being REGO-NRs. Exome analysis revealed a unique mutational profile in REGO-Resp tumors compared to NR tumors. Transcriptome analysis identified distinct expression patterns in Resp and NR tumors, impacting Rho GTPase and NOTCH signaling, known to be involved in drug response. In conclusion, recurrent glioblastoma tumors were more responsive to REGO compared to TMZ treatment. Importantly, our approach enables a comprehensive longitudinal exploration of the molecular changes induced by treatment, unveiling promising biomarkers indicative of drug response.

Background: Treatment-related changes still represent a diagnostic challenge in the management of patients with suspect of recurrent glioblastoma. The specificity of conventional MRI in detecting recurrence remains limited. Brain PET imaging provides information on tumor metabolism and can contribute to improving the diagnostic accuracy of cerebral neoplasms. We performed a retrospective analysis to evaluate the clinical value of O-(2- 18 F-fluoroethyl)-L-tyrosine ( 18 F-FET) PET in the diagnosis of glioblastoma recurrence., Methods: A retrospective analysis on patients considered suitable for salvage surgery for recurrence glioblastoma was performed. 18 F-FET-PET was performed to investigate gadolinium enhancement suspected for recurrence. Static and kinetic 18 F-FET parameters were analyzed and related to O-6-methylguanine-DNA methyltransferase (MGMT) status., Results: Forty-two of the 51 patients who underwent 18 F-FET-PET were re-operated. In each case, neuropathological diagnosis of tumor recurrence was confirmed. pMGMT hypermethylation was detected in 21 patients. Mean tumor-to-brain ratios (TBR) max was 3.87 (range 2.6-6.0). Static and kinetic 18 F-FET parameters were similar according to MGMT status., Conclusions: 18 FET-PET can be a reliable tool to improve the selection of patients suitable for salvage surgery for glioblastoma recurrence.

In 2012, whole-transcriptome sequencing analysis led to the discovery of recurrent fusions involving the FGFR3 and TACC3 genes as the main oncological driver in a subset of human glioblastomas. Since then, FGFR3-TACC3 fusions have been identified in several other solid cancers. Further studies dissected the oncogenic mechanisms of the fusion protein and its complex interplay with cancer cell metabolism. FGFR3-TACC3 fusion-driven gliomas emerged as a defined subgroup with specific clinical, histological, and molecular features. Several FGFR inhibitors were tested in FGFR3-TACC3 fusion-positive gliomas and proved some efficacy, although inferior to the results seen in other FGFR3-TACC3 fusion-driven cancers. In this review, we summarize and discuss the state-of-the-art knowledge resulting from a 10-year research effort in the field, its clinical implications for glioma patients, the potential reasons for targeted therapy failures, and the perspective of emerging treatments.

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.)

Introduction: Adipose derived stem cells (ASCs) are a mesenchymal stem cell population of great scientific interest due to their abundance and easiness in obtaining them from adipose tissue. Recently, several techniques for three dimensional (3D) ASCs cultivation have been developed to obtain spheroids of adipose stem cells (SASCs). It was already proved that ASCs are able to differentiate towards the endothelial lineage thus, for the first time, we investigated the ability of our 3D SASCs to differentiate endothelially and the effects of not differentiated SASC secreted factors on specific cultured cells., Materials and Methods: SASCs were differentiated with a specific medium towards endothelial lineage. Cell viability, gene and protein expression of typical endothelial markers were analysed. Moreover, tube formation, wound healing and migration assays were performed to investigate the ability in migration and angiogenic networks formation of endothelially differentiated cells. SASCs secretome were also tested., Results: We showed the ability of SASCs to differentiate towards the endothelial lineage with an increase in cell viability of 15-fold and 8-fold at 14 and 21 days of differentiation respectively. Moreover, we showed the upregulation of VEGF-A and CD31 mRNAs of 9-fold and 1300-fold in SASCs endothelially differentiated cells, whilst protein expression was different. VEGF-A protein expression was upregulated whilst CD31 protein wasn't translated. In addition, ICAM1, VCAM1, ANGPT1, CD62E protein levels remain unchanged. SASCs were also able to organize themselves into angiogenic networks after 7 days of culturing themon ECMatrix. Secreted factors from undifferentiated 3D SASCs acted in a paracrine way on HUVECs and endothelially differentiated ASCs seeded on ECMatrix to promote angiogenic events., Conclusions: SASCs, thanks to their multilineage differentiation potential, also possess the ability to differentiate towards endothelial lineage and to organize themselves into angiogenic networks. Moreover, they are able to promote angiogenesis through their secreted factors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Circulating tumor cells (CTCs) are one of the most important causes of tumor recurrence and distant metastases. Glioblastoma (GBM) has been considered restricted to the brain for many years. Nevertheless, in the past years, several pieces of evidence indicate that hematogenous dissemination is a reality, and this is also in the caseof GBM. Our aim was to optimize CTCs' detection in GBM and define the genetic background of single CTCs compared to the primary GBM tumor and its recurrence to demonstrate that CTCs are indeed derived from the parental tumor. We collected blood samples from a recurrent IDH wt GBM patient. We genotyped the parental recurrent tumor tissue and the respective primary GBM tissue. CTCs were analyzed using the DEPArray system. CTCs Copy Number Alterations (CNAs) and sequencing analyses were performed to compare CTCs' genetic background with the same patient's primary and recurrent GBM tissues. We identified 210 common mutations in the primary and recurrent tumors. Among these, three somatic high-frequency mutations (in PRKCB , TBX1 , and COG5 genes) were selected to investigate their presence in CTCs. Almost all sorted CTCs (9/13) had at least one of the mutations tested. The presence of TERT promoter mutations was also investigated and C228T variation was found in parental tumors and CTCs (C228T heterozygous and homozygous, respectively). We were able to isolate and genotype CTCs from a patient with GBM. We found common mutations but also exclusive molecular characteristics.

Aims: Current methods to induce tolerance following allotransplantation or in autoimmunity carry significant morbidity, and research is very active in investigating alternative methods which could minimize toxicity. Spheroids from adipose stem cells (SASCs) are increasingly gaining interest, they hold a great proliferative and differentiating potential. An immunomodulatory effect has not been investigated on SASCs yet. In this study, we analysed the immunomodulatory properties of SASCs and compared them to ADSCs., Main Methods: Adipose stem cells (SASCs and ADSCs) and peripheral blood mononuclear cells (PBMCs) were collected from healthy individuals. We analysed the cytokine production and proliferation of T cells co-cultured with adipose samples or conditioned medium., Key Findings: SASCs modulated cytokines production and proliferation of heterologous and autologous T cells. In the heterologous assays, we observed a reduction of IFNγ and IL-17 production and an increase of IL-9 in γδ T cells. The soluble factors present in SASCs sovranatants were also able to induce a slight reduction of IFNγ and an increase of IL-9, IL-10 and IL-17 while they could not modulate the proliferative ability of γδ T cells. In the autologous assays, we observed a reduction of the proliferative ability of T cells in co-culture at different ratios with SASCs. Analysis of the SASCs secretome showed an increased IL-5, IL-10, IL-4 and IL-13 production compared to the ADSCs one, demonstrating greater anti-inflammatory properties., Significance: Our preliminary results support the idea that SASCs exert more pronounced biological immune modulation compared to the classical adherent ADSCs, especially in heterologous experimental settings., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.)

Despite producing a panoply of potential cancer-specific targets, the proteogenomic characterization of human tumors has yet to demonstrate value for precision cancer medicine. Integrative multi-omics using a machine-learning network identified master kinases responsible for effecting phenotypic hallmarks of functional glioblastoma subtypes. In subtype-matched patient-derived models, we validated PKCδ and DNA-PK as master kinases of glycolytic/plurimetabolic and proliferative/progenitor subtypes, respectively, and qualified the kinases as potent and actionable glioblastoma subtype-specific therapeutic targets. Glioblastoma subtypes were associated with clinical and radiomics features, orthogonally validated by proteomics, phospho-proteomics, metabolomics, lipidomics and acetylomics analyses, and recapitulated in pediatric glioma, breast and lung squamous cell carcinoma, including subtype specificity of PKCδ and DNA-PK activity. We developed a probabilistic classification tool that performs optimally with RNA from frozen and paraffin-embedded tissues, which can be used to evaluate the association of therapeutic response with glioblastoma subtypes and to inform patient selection in prospective clinical trials., (© 2023. The Author(s).)

Background and Objectives: D-2-hydroxyglutarate (2HG) characterizes IDH -mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels., Methods: MEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS)., Results: MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm 3 ; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T 1 and FLAIR abnormalities, p = 0.04). 2HG levels were positively correlated with IDH -mutant allelic fraction ( p = 0.03) and total choline levels ( p < 0.001) and were higher in IDH2 -mutant compared with IDH1 R132H -mutant and non-R132H IDH1 -mutant patients ( p = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities., Discussion: MEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas., (© 2022 American Academy of Neurology.)

3D printing of polymeric scaffolds and autologous stem cells is a promising tool for damaged facial cartilage reconstruction surgeries. To this end, suitable bioinks are needed to generate scaffolds with the required morphological and functional features. We formulated hydrogel bioinks using k-Carrageen (kC) and poly(vinyl alcohol) (PVA) in three different weight ratios. The kC gives the systems the ability to undergo rapid sol-to-gel transitions upon cooling from 60 °C and above to body temperature, while the PVA is used as rheology modifier and porogen. The latter is crosslinked after molding or printing by freeze-thaw cycling for 1 day (FT1) or 5 days (FT5). To select the most suitable formulation for 3D printing, the sol-to-gel transition and the physico-chemical, mechanical and morphological properties of obtained hydrogels were studied. Moreover, the absence of cytotoxic effects of the material on SASCs was assessed in both stemness-preserving or chondro-inductive media. Printing trials were performed to identify optimal process parameters and co-printing and post-printing seeding approaches of SASCs were evaluated. Cells were found to be viable after co-printing and also after the FT1 treatment. Viable adherent cells were also found in the FT5 system, where cells were plated after freezing and thawing treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Three-dimensional (3D) cell cultures represent the spontaneous state of stem cells with specific gene and protein molecular expression that are more alike the in vivo condition. In vitro two-dimensional (2D) cell adhesion cultures are still commonly employed for various cellular studies such as movement, proliferation and differentiation phenomena; this procedure is standardized and amply used in laboratories, however their representing the original tissue has recently been subject to questioning. Cell cultures in 2D require a support/substrate (flasks, multiwells, etc.) and use of fetal bovine serum as an adjuvant that stimulates adhesion that most likely leads to cellular aging. A 3D environment stimulates cells to grow in suspended aggregates that are defined as "spheroids." In particular, adipose stem cells (ASCs) are traditionally observed in adhesion conditions, but a recent and vast literature offers many strategies that obtain 3D cell spheroids. These cells seem to possess a greater ability in maintaining their stemness and differentiate towards all mesenchymal lineages, as demonstrated in in vitro and in vivo studies compared to adhesion cultures. To date, standardized procedures that form ASC spheroids have not yet been established. This systematic review carries out an in-depth analysis of the 76 articles produced over the past 10 years and discusses the similarities and differences in materials, techniques, and purposes to standardize the methods aimed at obtaining ASC spheroids as already described for 2D cultures., (© 2022 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Background: Describe the characteristics, patterns of care, and predictive geriatric factors of elderly patients with IDHm high-grade glioma (HGG) included in the French POLA network. Material and Methods: The characteristics of elderly (≥70 years) patients IDHm HGG were compared to those of younger patients IDHm HGG (<70 years) and of elderly patients IDHwt HGG. Geriatric features were collected. Results: Out of 1433 HGG patients included, 119 (8.3%) were ≥70 years. Among them, 39 presented with IDHm HGG. The main characteristics of elderly IDHm HGG were different from those of elderly IDHwt HGG but similar to those of younger IDHm HGG. In contrast, their therapeutic management was different from those of younger IDHm HGG with less frequent gross total resection and radiotherapy. The median progression-free survival (PFS) and overall survival (OS) were longer for elderly patients IDHm HGG (29.3 months and 62.1 months) than elderly patients IDHwt HGG (8.3 months and 13.3 months) but shorter than those of younger patients IDHm HGG (69.1 months and not reached). Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, body mass index, and autonomy. Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, and body mass index, and autonomy. Conclusion: the outcome of IDHm HGG in elderly patients is better than that of IDHwt HGG. Geriatric assessment may be particularly important to optimally manage these patients.

Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest.

Objective: After temozolomide failure, no evidence-based treatment is available for pituitary carcinomas (PCs) and aggressive pituitary tumors (APTs). To date, only 12 cases treated with immune-checkpoint inhibitors (ICIs) have been published, showing encouraging efficacy. Predictive factors of response are lacking. Here, we aimed to assess the real-life efficacy and predictors of response to ICIs in PCs and APTs., Design and Methods: This study is a multicentric, retrospective, observational cohort study, including all PCs and APTs treated with ICIs in France up to March 2022. PD-L1 immunohistochemistry and CD8+ T cell infiltration were evaluated centrally., Results: Six PCs (four corticotroph and two lactotroph) and nine APTs (five corticotroph and four lactotroph) were included. The real-life efficacy of ICIs was lower than previously published data. Three corticotroph tumors (33.3%) showed partial response, one (11.1%) stable disease, while five (55.6%) progressed. One lactotroph tumor (16.7%) showed partial response, one (16.7%) stable disease, while four (66.7%) progressed. PCs responded far better than APTs, with 4/6 PCs showing partial response compared to 0/9 APTs. Corticotroph tumors responded slightly better than lactotroph tumors. In the four responsive corticotroph tumors, PD-L1 staining was negative and CD8+ T cell infiltration attained a maximum of 1% in the tumor center., Conclusions: Confirmation of the presence or absence of metastases is necessary before starting ICIs. After temozolomide failure, ICIs appear as a good therapeutic option for PCs, especially for corticotroph carcinomas. Negative PD-L1 staining and very low CD8+ T cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas., Significance Statement: This is the first study to assess the real-life efficacy of ICIs in pituitary carcinomas (PCs) and aggressive pituitary tumors. We also assessed potential predictors of response and are the first to assess the predictive value of CD8+ cell infiltration. We identified the tumor type as a major predictor, ICIs proving far more effective in treating PCs. Our study provides evidence that ICIs are a good option after temozolomide failure for PCs (four of six responded), especially for corticotroph carcinomas (three of four responded). We also provide evidence that negative PD-L1 staining and very low CD8+ cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Moreover, our findings point toward the need to systematically perform extension workup before starting ICIs.

Objective: 18 F‑fluoro-L‑3,4‑dihydroxyphenylalanine positron emission tomography (F‑DOPA PET) is used in glioma follow-up after radiotherapy to discriminate treatment-related changes (TRC) from tumor progression (TP). We compared the performances of a combined PET and MRI analysis with F‑DOPA current standard of interpretation., Methods: We included 76 consecutive patients showing at least one gadolinium-enhanced lesion on the T1‑w MRI sequence (T1G). Two nuclear medicine physicians blindly analyzed PET/MRI images. In addition to the conventional PET analysis, they looked for F‑DOPA uptake(s) outside T1G-enhanced areas (T1G/PET), in the white matter (WM/PET), for T1G-enhanced lesion(s) without sufficiently concordant F‑DOPA uptake (T1G+/PET), and F‑DOPA uptake(s) away from hemorrhagic changes as shown with a susceptibility weighted imaging sequence (SWI/PET). We measured lesions' F‑DOPA uptake ratio using healthy brain background (TBR) and striatum (T/S) as references, and lesions' perfusion with arterial spin labelling cerebral blood flow maps (rCBF). Scores were determined by logistic regression., Results: 53 and 23 patients were diagnosed with TP and TRC, respectively. The accuracies were 74% for T/S, 76% for TBR, and 84% for rCBF, with best cut-off values of 1.3, 3.7 and 1.25, respectively. For hybrid variables, best accuracies were obtained with conventional analysis (82%), T1G+/PET (82%) and SWI/PET (81%). T1G+/PET, SWI/PET and rCBF ≥ 1.25 were selected to construct a 3-point score. It outperformed conventional analysis and rCBF with an AUC of 0.94 and an accuracy of 87%., Conclusions: Our scoring approach combining F‑DOPA PET and MRI provided better accuracy than conventional PET analyses for distinguishing TP from TRC in our patients after radiation therapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Recent studies showed that patients with glioma can safely participate in early phase clinical trials; however, clinical benefits in this population were limited. We aimed to evaluate the benefit of molecular profiling to guide enrolment in early phase trials for patients with recurrent glioma., Methods: Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2018 were reviewed for clinico-pathological characteristics, toxicity, response, progression-free survival and overall survival (OS). The primary objective was to evaluate response rates in molecularly-oriented versus non-molecularly-oriented patients., Results: Eighty-eight patients were enrolled, of whom 45 (51.1%) patients were molecularly-oriented. Targets included IDH1/2 (n = 15), BRAF (n = 11), and FGFR1 (n = 3) mutations, FGFR2-3 fusions (n = 9), and mismatch repair deficiency (n = 7). Among patients with high-grade glioma (n = 74), the rate of stable disease ≥6 months and partial or complete response was 25.7% in molecularly-oriented versus 5.1% in non-molecularly-oriented patients (p = 0.02). Upon multivariable adjustment, baseline steroid use ≥20 mg prednisone equivalent per day was associated with shorter OS (OR 3.15 [95% CI 1.62-6.13], p = 0.0008), while molecular enrichment strategy was associated with longer OS (OR 0.40 [95% CI 0.22-0.73], p = 0.003). Nine (10.2%) patients experienced grade 3-4 toxicity and no dose limiting toxicity (DLT) occurred in both cohorts., Conclusion: The use of molecular profiling to guide enrolment in early phase trials is feasible and might provide benefits to selected patients with glioma. Further studies are warranted to confirm these results in larger randomised settings and identify the patients most likely to benefit from this approach., Competing Interests: Conflict of interest statement CB reports personal fees from BMS, Sanofi, Abbvie, Roche, Astra Zeneca. As a subinvestigator at the DITEP: Abbvie, Aduro biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Aeneca, Astra Zeneca Ab, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingel-heim, Boston Pharmaceuticals, Inc, Bristol Myers Squibb, Bristol-Myers Squibb Inter-national Corporation, Ca, Celgene Corpo-ration, Cephalon, Chugai Pharmaceutical Co, Clovis Oncology, Daiichi Sankyo, Debiopharm S.a, Eisai, Eli lilly, Exelixis, Forma, Gamamabs, Genentech, Inc, Gilead Sciences, Inc, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Incyte Corpora-tion, Innate Pharma, Institut De Recher-che Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev., Inc, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Kgaa, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Mil-lennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Nerviano Medical Sciences, Novartis Pharma, Octimet Onco-logy Nv, Oncoethix, Oncomed, Oncopep-tides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre Medicament, Plexxikon, Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Taiho Pharma, Tesaro, Tioma Therapeutics, Wyeth Pharma-ceuticals France, Xencor, Y's Therapeutics. JCS is an employee of Amgen and former employee of AstraZeneca. FB reports research funding from Abbvie and Sanofi; employment from Celgene (I); stocks from Crossject (I); travel, accommodations, expenses from Bristol-Myers Squibb for travel expenses, outside the submitted work. KHX reports consulting fees and research grant from BTG, outside the submitted work. AI reports grants and other from Carthera (September 2019); research grants from Transgene; grants from Sanofi, and Air Liquide; and travel funding from Leo Pharma, outside the submitted work. MT reports research funding from Sanofi; consulting or advisory role from Agios Pharmaceutical, Integragen, Taiho Oncology, and Servier, outside the submitted work; travel, accommodations, expenses from Merck Sharp & Dome and Servier, outside the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Diffuse gliomas, the most frequent and aggressive primary central nervous system neoplasms, currently lack effective curative treatments, particularly for cases lacking the favorable prognostic marker IDH mutation. Nonetheless, advances in molecular biology allowed to identify several druggable alterations in a subset of IDH wild-type gliomas, such as NTRK and FGFR-TACC fusions, and BRAF hotspot mutations. Multi-tyrosine kinase inhibitors, such as regorafenib, also showed efficacy in the setting of recurrent glioblastoma. IDH inhibitors are currently in the advanced phase of clinical evaluation for patients with IDH -mutant gliomas. Several immunotherapeutic approaches, such as tumor vaccines or checkpoint inhibitors, failed to improve patients' outcomes. Even so, they may be still beneficial in a subset of them. New methods, such as using pulsed ultrasound to disrupt the blood-brain barrier, gene therapy, and oncolytic virotherapy, are well tolerated and may be included in the therapeutic armamentarium soon.

Cartilage or bone regeneration approaches based on the direct injection of mesenchymal stem cells (MSCs) at the lesion site encounter several challenges, related to uncontrolled cell spreading and differentiation, reduced cell viability and poor engrafting. This work presents a simple and versatile strategy based on the synergic combination of in-situ forming hydrogels and spheroids of adipose stem cells (SASCs) with great potential for minimally invasive regenerative interventions aimed to threat bone and cartilage defects. Aqueous dispersions of partially degalactosylated xyloglucan (dXG) are mixed with SASCs derived from liposuction and either a chondroinductive or an osteoinductive medium. The dispersions rapidly set into hydrogels when temperature is brought to 37 °C. The physico-chemical and mechanical properties of the hydrogels are controlled by polymer concentration. The hydrogels, during 21 day incubation at 37 °C, undergo significant structural rearrangements that support cell proliferation and spreading. In formulations containing 1%w dXG cell viability increases up to 300% for SASCs-derived osteoblasts and up to 1000% for SASCs-derived chondrocytes if compared with control 2D cultures. The successful differentiation into the target cells is supported by the expression of lineage-specific genes. Cell-cell and cell-matrix interactions are also investigated. All formulations resulted injectable, and the incorporated cells are fully viable after injection., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600-mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort., Methods: We performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated BRAF V600-mutant GGNTs treated with RAFi/MEKi., Results: Twenty-eight adults with recurrent or disseminated BRAF V600-mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p = 0.047). Responders had better KPS score ( p = 0.018) and tended to be younger ( p = 0.061) and to be treated earlier ( p = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival., Conclusions: Our study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with BRAF V600-mutant GGNTs and encourages rechallenge in responders., Classification of Evidence: This study provides Class III evidence that, for adult patients with BRAF V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit., (© 2021 American Academy of Neurology.)

Background: Little is known about diffuse glioma patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)., Methods: We performed a descriptive and retrospective analysis of 41 diffuse glioma patients with symptomatic SARS-CoV2 infection during the first wave of the COVID-19 pandemic., Results: Confusion with or without fever was the most common neurological symptom (32%) supporting SARS-CoV2 testing in glioma patients with acute and unexplained confusion. Sixteen patients (39%) died after a median delay of 13 days. While multiple clinical, biological, and pathological features, COVID-19- or diffuse glioma-related, at hospital admission appeared to have a pejorative prognostic impact, none was significantly associated with death. Oncological treatments were interrupted at COVID-19 diagnosis and re-initiated with a median delay of 30 days after the end of COVID-19 symptoms., Conclusions: Interestingly, our retrospective study describes for the first time the characteristics of a cohort of diffuse glioma patients with symptomatic COVID-19. Diffuse glioma patients with poorly symptomatic COVID-19 did not come to the attention of physicians and were not enrolled in the study skewing the denominator for prognostic analysis. Further studies are warranted to specify prognosis of overall population of diffuse glioma patients with COVID-19, including asymptomatic patients, and interactions of prognostic factors of both COVID-19 and diffuse gliomas., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Abstract: Calvarial defects can result from several causes. Tissue engineering hold the potential to restore native form and protective function. We have recently shown that stemness and differentiation ability of spheroids from adipose-derived stem cells (S-ASCs) promotes osteoblasts growth within Integra in a small vertebral lesion. In our study, we aimed to test osteogenic potential of S-ASCs in aiding regeneration of a calvarial defect. Groups containing Integra showed increased bone regeneration at the calvarial defect-Integra interface compared with the control group. In particular, S-ASC-derived osteoblasts group showed a superior calvarial remodeling than undifferentiated S-ASCs group. Clusters of ossification were observed in these both groups with enhanced microvasculature density and fibrosis. In conclusion, seeding of S-ASCs in dermal regeneration templates enhanced bone healing in a rabbit calvarial defect model. These findings could prompt the elective use of S-ASCs with enhanced multilineage differentiation potential for tissue engineering purposes., Competing Interests: Conflicts of interest and sources of funding: This study was funded by the Italian Ministry of Health (Ministero della Salute, Progetto Giovani Ricercatori GR-2010-2321017 awarded to Dr. Angelo A. Leto Barone. The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Isocitrate dehydrogenase (IDH) wildtype (wt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined., Methods: We searched retrospectively all patients diagnosed with diffuse World Health Organization (WHO) grades II and III gliomas at our center (1989-2020)., Results: Out of 517 grade II gliomas, 47 were "diffuse astrocytomas, IDHwt." Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found telomerase reverse transcriptase (TERT) promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%), but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs 19 mo for IDHwt grade III gliomas) (P < 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update 3. Median OS in this subset was 42 months, which was shorter compared with patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 mo), but substantially longer compared with IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 mo, P < 0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 mo). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%)., Conclusions: Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation., (© The Author(s) 2020. 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.)

Purpose: Meningiomas represent the most frequent tumor of the central nervous system in adults. While most meningiomas are efficiently treated by surgery and radiotherapy/radiosurgery, there is a small portion of radiation- and surgery-refractory tumors for which there is no clear recommendation for optimal management. The French National Tumor Board Meeting on Meningiomas (NTBM) offers a glimpse on the current management of such patients., Methods: We retrospectively reviewed the charts of patients presented to the multidisciplinary Meeting between 2016 and 2019. We selected patients with a progressive disease after at least two treatments, including surgery and radiotherapy., Results: In this multicentric cohort of 86 cases, patients harbored 17 (19.8%) WHO Grade I, 48 (55.8%) WHO Grade II and 21 (24.4%) WHO Grade III tumors. The median number of treatments received before inclusion was 3 (range: 2 - 11). Following the Board Meeting, 32 patients (37.2%) received chemotherapy, 11 (12.8%) surgery, 17 (19.8%) radiotherapy, 14 (16.3%) watchful observation and 12 (13.9%) palliative care. After a mean follow-up of 13 months post-inclusion, 32 patients (37.2%) had died from their disease. The mean progression free survival was 27 months after radiotherapy, 10 months after surgery, 8.5 months after chemotherapy (Bevacizumab: 9 months - Octreotide/Everolimus: 8 months)., Conclusions: Surgery- and radiation-refractory meningiomas represent a heterogeneous group of tumors with a majority of WHO Grade II cases. If re-irradiation and redo-surgery are not possible, bevacizumab and octreotide-everolimus appear as a valuable option in heavily pre-treated patients considering the current EANO guidelines.

Adipose stem cells (ASCs) represent a reliable source of stem cells with a widely demonstrated potential in regenerative medicine and tissue engineering applications. New recent insights suggest that three-dimensional (3D) models may closely mimic the native tissue properties; spheroids from adipose derived stem cells (SASCs) exhibit enhanced regenerative abilities compared with those of 2D models. Stem cell therapy success is determined by "cell-quality"; for this reason, the involvement of stress signals and cellular aging need to be further investigated. Here, we performed a comparative analysis of genes connected with stemness, aging, telomeric length and oxidative stress, in 3D and 2D primary cultures. The expression levels of stemness-related markers and anti-aging Sirtuin1 were significantly up-regulated (P < 0.001) in SASCs-3D while gene expression of aging-related p16INK4a was increased in ASCs-2D (P < 0.001). The 3D and 2D cultures also had a different gene expression profile for genes related to telomere maintenance (Shelterin complex, RNA Binding proteins and DNA repair genes) (P < 0.01 and P < 0.001) and oxidative stress (aldehyde dehydrogenase class1 and 3) (P < 0.05, P < 0.01 and P < 0.001) and presented a striking large variation in their cellular redox state. Based on our findings, we propose a "cell quality" model of SASCs, highlighting a precise molecular expression of several genes involved with stemness (SOX2, POU5F1 and NANOG), anti-aging (SIRT1), oxidative stress (ALDH3) and telomeres maintenance., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The transcriptomic classification of glioblastoma (GBM) has failed to predict survival and therapeutic vulnerabilities. A computational approach for unbiased identification of core biological traits of single cells and bulk tumors uncovered four tumor cell states and GBM subtypes distributed along neurodevelopmental and metabolic axes, classified as proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic. Each subtype was enriched with biologically coherent multiomic features. Mitochondrial GBM was associated with the most favorable clinical outcome. It relied exclusively on oxidative phosphorylation for energy production, whereas the glycolytic/plurimetabolic subtype was sustained by aerobic glycolysis and amino acid and lipid metabolism. Deletion of the glucose-proton symporter SLC45A1 was the truncal alteration most significantly associated with mitochondrial GBM, and the reintroduction of SLC45A1 in mitochondrial glioma cells induced acidification and loss of fitness. Mitochondrial, but not glycolytic/plurimetabolic, GBM exhibited marked vulnerability to inhibitors of oxidative phosphorylation. The pathway-based classification of GBM informs survival and enables precision targeting of cancer metabolism., Competing Interests: Competing interests A.L. and A.I. are inventors of a biomarker technology that has been licensed to QIAGEN. A.I. received sponsored research funding from AstraZeneca and Taiho Pharmaceutical and has served as a paid consultant/advisor to AIMEDBIO Inc. A.L. received sponsored research funding from Celgene. All other authors declare no competing interests.

Background: Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated., Patients and Methods: In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and 11th June 2020. The primary end-point was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary end-points., Results: From April 4 to 11th June 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), The Eastern Cooperative Oncology Group Performance Scale (ECOG PS) ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except for cytotoxic chemotherapy in the subgroup of patients with detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcriptase polymerase chain reaction (RT-PCR), which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment (such as chemotherapy, targeted or immune therapy) interrupted or stopped following diagnosis of COVID-19., Conclusions: Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Competing Interests: Conflict of interest statement Pr Lièvre reports grants from BayerLilly, Merck and Novartis, personal fees from AAA, Amgen, Bayer, BMS,Celgene, HalioDx, Incyte, Ipsen, Lilly, Merck, Novartis, Pierre Fabre, Roche, Sandoz, Sanofi, Servier and non-financial support from AAA, Amgen, bayer, Incite, Ipsen, Merck, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Servier and Integragen outside of the submitted work. Dr. Turpin reports personal fees from MYLAN, personal fees from MERCK SERONO, personal fees from AMGEN, non-financial support from MERCK-SERONO, non-financial support from SANOFI, non-financial support from PFIZER outside the submitted work. Dr. Ahle reports grants from Biogen, grants from Novartis, grants from Roche, grants from Sanofi, grants from Abbvie, outside the submitted work.Dr Bouché reports personal fees from Merck KGaA, Roche Genentech, Bayer, Astra-Zeneca, Grunenthal, MSD, Amgen, Servier, and Pierre Fabre outside the submitted work. Dr. Neuzillet reports personal fees from SERVIER, other from OSE Immunotherapeutic, grants from ROCHE, personal fees and other from AstraZeneca, personal fees and other from Bristol-Myers Squibb, personal fees from Amgen, personal fees from Merck, personal fees from MSD, personal fees from Novartis, personal fees from Incyte, personal fees from Mylan, personal fees from Baxter, personal fees from Nutricia, personal fees from Fresenius-Kabi, outside the submitted work . Pr Michel reports personal fees from Bayer, Servier, Amgen, Shire and Lilly and non-personal fees from Bayer, Merck, Amgen, Shire, Roche and Lilly outside the submitted work. Dr. Canellas reports personal fees from BMS, personal fees from Aztra Zeneca, non-financial support from Boerhinger Ingheleim, non-financial support from Roche, outside the submitted work . Dr. Wislez reports personal fees from Boeringher Ingelheim, personal fees and non-financial support from ROCHE, personal fees and non-financial support from MSD, personal fees from BMS, personal fees from Astra Zeneca, personal fees from Amgen, outside the submitted work. Dr. Mansi reports personal fees from Roche, personal fees from Eisai, personal fees from Exact Science, personal fees from Novartis, outside the submitted work . Dr Colomba received personnal fees from IPSEN, BMS, Pfizer, Sanofi, GSK outside the submitted work. Pr. Idbaih reports grants and other from Carthera (september 2019), grants from Transgene, grants from Sanofi, grants from Air Liquide, other from Leo Pharma, grants from Nutritheragene, outside the submitted work. Pr. Aparicio reports personal fees and non-financial support from Roche, personal fees from Ipsen, personal fees from Amgen, personal fees from Servier, personal fees from Sanofi, outside the submitted work. All other authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Actionable fibroblast growth factor receptor 3 (FGFR3)-transforming acidic coiled-coil protein 3 fusions (F3T3) are found in approximately 3% of gliomas, but their characteristics and prognostic significance are still poorly defined. Our goal was to characterize the clinical, radiological, and molecular profile of F3T3 positive diffuse gliomas., Methods: We screened F3T3 fusion by real-time (RT)-PCR and FGFR3 immunohistochemistry in a large series of gliomas, characterized for main genetic alterations, histology, and clinical evolution. We performed a radiological and radiomic case control study, using an exploratory and a validation cohort., Results: We screened 1162 diffuse gliomas (951 unselected cases and 211 preselected for FGFR3 protein immunopositivity), identifying 80 F3T3 positive gliomas. F3T3 was mutually exclusive with IDH mutation (P < 0.001) and EGFR amplification (P = 0.01), defining a distinct molecular cluster associated with CDK4 (P = 0.04) and MDM2 amplification (P = 0.03). F3T3 fusion was associated with longer survival for the whole series and for glioblastomas (median overall survival was 31.1 vs 19.9 mo, P = 0.02) and was an independent predictor of better outcome on multivariate analysis.F3T3 positive gliomas had specific MRI features, affecting preferentially insula and temporal lobe, and with poorly defined tumor margins. F3T3 fusion was correctly predicted by radiomics analysis on both the exploratory (area under the curve [AUC] = 0.87) and the validation MRI (AUC = 0.75) cohort. Using Cox proportional hazards models, radiomics predicted survival with a high C-index (0.75, SD 0.04), while the model combining clinical, genetic, and radiomic data showed the highest C-index (0.81, SD 0.04)., Conclusion: F3T3 positive gliomas have distinct molecular and radiological features, and better outcome., (© The Author(s) 2020. 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.)

Nowadays, solid organ transplantation (SOT) is an established treatment for patients with end-organ dysfunction, which dramatically improves the quality-of-life. Vascularized composite allotransplants (VCAs) including hand and face have been reported worldwide over the last 20 years. However, VCAs, differently to SOT, are life-enhancing instead of life-saving and are not routinely performed due to the risk of immune rejection and the adverse effects of immunosuppression. Over the past decade, although considerable improvements in short-term outcomes after allotransplantation have been registered, these results have not been translated into major progress in long-term allograft acceptance and patient survival. Recently active researches in the field of biomarker discovery have been conducted to develop individualized therapies for allograft recipients. MicroRNAs (miRNAs) are a small noncoding RNAs functioning as critical regulators of gene and protein expression by RNA interference. They have been connected in numerous biological processes and diseases. Due to their immunomodulatory functions, miRNAs have been amended as potential diagnostic and prognostic biomarker for the detection of rejection in allotransplantation. Due to their specific circulating expression profile, they could act as noninvasive predictive tools for rejection that may help clinicians in an early adjustment of the immunosuppression protocol during acute rejections episodes. Indeed, specific anti-sense oligonucleotides suppressing miRNAs expressed in rejection could reduce the rejection rate in allografts and decrease the use of immunosuppressants. We present a literature review of the immunomodulatory properties and characteristics of miRNAs. We will summarize the current knowledge on miRNAs as potential biomarkers for allograft rejection and possible application in allotransplantation monitoring. Finally, we will discuss the advances in preclinical miRNA-based therapies for immunosuppression., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest with the information reported in this manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In vivo magnetic resonance spectroscopy (MRS) can provide clinically valuable metabolic information from brain tumors that can be used for prognosis and monitoring response to treatment. Unfortunately, this technique has not been widely adopted in clinical practice or even clinical trials due to the difficulty in acquiring and analyzing the data. In this work we propose a computational approach to solve one of the most critical technical challenges: the problem of quickly and accurately positioning an MRS volume of interest (a cuboid voxel) inside a tumor using MR images for guidance. The proposed automated method comprises a convolutional neural network to segment the lesion, followed by a discrete optimization to position an MRS voxel optimally within the lesion. In a retrospective comparison, the novel automated method is shown to provide improved lesion coverage compared to manual voxel placement.

Objective: To determine the efficacy of the thrombopoietin receptor agonist romiplostim for the prevention of temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma., Methods: In the PLATUM phase II open-label, multicenter, single-arm trial, patients diagnosed with Common Terminology Criteria for Adverse Events grade 3 or 4 thrombocytopenia during chemoradiotherapy received weekly subcutaneous romiplostim injections. PLATUM aimed at demonstrating that the percentage of thrombocytopenic patients treated with romiplostim able to complete 6 cycles of maintenance temozolomide chemotherapy exceeded 10% ( p 0 = 0.10; p A = 0.35). Using type I error equal to 0.05% and 95% power, 31 patients had to be recruited. According to a Fleming 2-step design with a preplanned interim analysis after recruitment of 20 patients (step 1), the trial was terminated early for success., Results: Twenty patients were enrolled in step 1. Median age was 61 years (range 33-73). Twelve patients received 6 temozolomide cycles, corresponding to a success rate of 60% (95% confidence interval 36%-81%). Four patients discontinued temozolomide because they did not respond to romiplostim, 2 for progression, and 2 for adverse events unrelated to romiplostim., Conclusion: The thrombopoietin receptor agonist romiplostim improves exposure to chemotherapy in patients with glioblastoma experiencing temozolomide-induced thrombocytopenia., Clinicaltrialsgov Identifier: NCT02227576., Classification of Evidence: This study provides Class IV evidence that for patients with glioblastoma and thrombocytopenia, romiplostim is effective for the secondary prophylaxis of temozolomide-induced thrombocytopenia., (© 2019 American Academy of Neurology.)

Background and Aims: Inflammatory bowel disease [IBD] is a complex chronic inflammatory disease of the human gut with no clear aetiology. Traditionally, dysregulated adaptive immune responses play an important role even though accumulating evidence suggests a role also for innate immunity. Because of the well-known plasticity of γδ T cells, we investigated their percentage occurrence, phenotypic features and effector functions in the intestinal mucosa of early-onset and long-standing IBD patients, as compared to healthy subjects., Methods: Fresh biopsies from 30 Crohn's disease and ulcerative colitis patients were obtained and digested, and cells were analysed by flow cytometry., Results: We found a reduced frequency of Vδ1 T cells in tissue from early and late IBD patients (2.24% and 1.95%, respectively, vs 5.44% in healthy tissue) but an increased frequency of Vδ2 T cells in the gut of late IBD patients (3.19% in late patients vs 1.5% in early patients and 1.65% in healthy tissue). The infiltrating Vδ2 T cells had predominant effector memory and terminally differentiated phenotypes and produced elevated levels of tumour necrosis factor-α [TNF-α] and interleukin-17 [IL-17]. The frequency of tissue Vδ2 T cells correlated with the extent of the inflammatory response and the severity of IBD., Conclusion: Our study shows that tissue Vδ1 T cells are decreased in IBD patients while Vδ2 T cells are increased in the gut of IBD patients and contribute to TNF-α production. Moreover, we identify an as yet unappreciated role of Vδ2 T cells in IL-17 production in the gut of long-standing IBD patients, suggesting that they also participate in the chronic inflammatory process., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Codeletion of chromosome arms 1p and 19q (1p/19q codeletion) highly benefits diagnosis and prognosis in gliomas. In this study, we investigated the effect of 1p/19q codeletion on cancer cell metabolism and evaluated possible metabolic targets for tailored therapies., Methods: We combined in vivo 1H (proton) magnetic resonance spectroscopy (MRS) measurements in human gliomas with the analysis of a series of standard amino acids by liquid chromatography-mass spectroscopy (LC-MS) in human glioma biopsies. Sixty-five subjects with low-grade glioma were included in the study: 31 underwent the MRI/MRS examination, 47 brain tumor tissue samples were analyzed with LC-MS, and 33 samples were analyzed for gene expression with quantitative PCR. Additionally, we performed metabolic tracer experiments in cell models with 1p deletion., Results: We report the first in vivo detection of cystathionine by MRS in 1p/19q codeleted gliomas. Selective accumulation of cystathionine was observed in codeleted gliomas in vivo, in brain tissue samples, as well as in cells harboring heterozygous deletions for serine- and cystathionine-pathway genes located on 1p: phosphoglycerate dehydrogenase (PHGDH) and cystathionine gamma-lyase (CTH). Quantitative PCR analyses showed 40-50% lower expression of both PHGDH and CTH in 1p/19q codeleted gliomas compared with their non-codeleted counterparts., Conclusions: Our results provide strong evidence of a selective vulnerability of codeleted gliomas to serine and glutathione depletion and point to cystathionine as a possible noninvasive marker of treatment response., (© 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.)

Angiogenesis is a crucial process for the maintenance of normal tissue physiology and it is involved in tissue remodeling and regeneration. This process is essential for adipose tissue maintenance. The adipose tissue is composed by different cell types including stromal vascular cells as well as adipose stem cells (ASCs). In particular, ASCs are multipotent somatic stem cells that are able to differentiate and secrete several growth factors; they are recently emerging as a new cell reservoir for novel therapies and strategies in many diseases. Several studies suggest that ASCs have peculiar properties and participate in different disease-related processes such as angiogenesis. Furthermore, pathological expansion of adipose tissue brings to hypoxia, a major condition of unhealthy angiogenesis. Recent evidences have shown that microRNAs (miRNAs) play a crucial role also on ASCs as they take part in stemness maintenance, proliferation, and differentiation. It has been suggested that some miRNAs (MIR126, MIR31, MIR221 MIR222, MIR17-92 cluster, MIR30, MIR100 and MIR486) are directly involved in the angiogenic process by controlling multiple genes involved in this pathway. With the present review, we aim at providing an updated summary of the importance of adipose tissue under physiological and pathological conditions and of its relationship with neovascularization process. In particular, we report an overview of the most important miRNAs involved in angiogenesis focusing on ASCs. Hopefully the data presented will bring benefit in developing new therapeutic strategies., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Hand and face transplants are becoming increasingly common, recording progressively more penile, uterus, abdominal wall, and allotransplantation cases reported worldwide. Despite current protocols allow long-term survival of the allografts, the ultimate goal of donor-specific tolerance has not been achieved yet. In fact, the harmful adverse effects related to the lifelong administration of immunosuppressive agents are the main drawbacks for vascularized composite allotransplantations. Research is very active in investigating alternative methods to induce greater tolerance while minimizing toxicity. Adipose-derived stem cells (ASCs) represent promising cell therapies for immunomodulation in preclinical and clinical settings. Their clinical appeal is due to their easy harvest in large quantities through a noninvasive and well-accepted approach; they may well promote donor-specific tolerance and potentially reduce immunosuppression. Several experimental studies exist, but lacking review articles reporting current evidence. This work proposes a literature review on the immunomodulatory role of ASCs in vascularized composite allotransplantations. In vitro and in vivo evidence will be summarized. The role that cell passaging and upstream progenitors-the so-called spheroid ASCs-may play in modulating the immune response will also be discussed. Finally, this article will summarize current knowledge on biodistribution, migration, and homing of injected stem cells. This review may well provide useful information for preclinical and clinical studies, aiming at a breakthrough for donor-specific tolerance.