CNS tumors with PLAGL1-fusion: beyond ZFTA and YAP1 in the genetic spectrum of supratentorial ependymomas.

A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

Fluid suppression in amide proton transfer-weighted (APTw) CEST imaging: New theoretical insights and clinical benefits.

PURPOSE: Amide proton transfer-weighted (APTw) MRI at 3T provides a unique contrast for brain tumor imaging. However, APTw imaging suffers from hyperintensities in liquid compartments such as cystic or necrotic structures and provides a distorted APTw signal intensity. Recently, it has been shown that heuristically motivated fluid suppression can remove such artifacts and significantly improve the readability of APTw imaging. THEORY AND METHODS: In this work, we show that the fluid suppression can actually be understood by the known concept of spillover dilution, which itself can be derived from the Bloch-McConnell equations in comparison to the heuristic approach. Therefore, we derive a novel post-processing formula that efficiently removes fluid artifact, and explains previous approaches. We demonstrate the utility of this APTw assessment in silico, in vitro, and in vivo in brain tumor patients acquired at MR scanners from different vendors. RESULTS: Our results show a reduction of the CEST signals from fluid environments while keeping the APTw-CEST signal intensity almost unchanged for semi-solid tissue structures such as the contralateral normal appearing white matter. This further allows us to use the same color bar settings as for conventional APTw imaging. CONCLUSION: Fluid suppression has considerable value in improving the readability of APTw maps in the neuro-oncological field. In this work, we derive a novel post-processing formula from the underlying Bloch-McConnell equations that efficiently removes fluid artifact, and explains previous approaches which justify the derivation of this metric from a theoretical point of view, to reassure the scientific and medical field about its use.

Exploring the mechanism of 18F-fluorodopa uptake in recurrent high-grade gliomas: A comprehensive histomolecular-positron emission tomography analysis.

BACKGROUND: Dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-FDOPA) positron emission tomography (PET) is a valuable tool for managing high-grade gliomas (HGGs), but there is a lack of literature on its relationship with glioma subtypes since the 2021 reclassification of brain tumors. There is also debate surrounding the mechanism of 18F-FDOPA uptake, particularly after chemoradiation therapy. This study aimed to investigate the correlation between 18F-FDOPA uptake and histomolecular characteristics, particularly L-amino acid transporter 1 (LAT1) expression, in recurrent gliomas, and examine their impact on survival in HGGs. METHODS: Thirty-nine patients with recurrent HGGs (14 isocitrate dehydrogenase [IDH]-mutant, 25 IDH-wildtype) who underwent a brain 18F-FDOPA PET/computed tomography (CT) or PET/magnetic resonance imaging (MRI) followed by surgical resection of the 18F-FDOPA-avid lesion within 6 months, were retrospectively reviewed. PET results were compared with histological examination and for SCL7A5/LAT1 immunostaining. The study also examined the relationship between PET parameters, LAT1 expression, and survival outcomes. RESULTS: Astrocytoma IDH-mutant G4 had higher 18F-FDOPA uptake than glioblastoma IDH-wildtype G4 (maximum tumor-to-normal brain ratio [TBRmax] 5 [3.4-9] vs. 3.8 [2.8-5.9], p = 0.02). IDH-mutant gliomas had higher LAT1 expression than IDH-wildtype gliomas (100 [14-273] vs. 15.5 [0-137], p < 0.05) as well as higher TBRmax (5 [2.4-9] vs. 3.8 [2.8-6], p < 0.05). In survival analysis, LAT1 score >100 was a predictor for longer progression-free survival in IDH-mutant HGGs. CONCLUSIONS: To our knowledge, our study is the first to suggest a link between LAT1 expression and IDH mutation status. We showed that higher TBRmax was associated with higher LAT1 expression and IDH mutation status. Further studies are needed to better understand the mechanisms underlying amino acid PET tracers uptake, especially in the post-radiation and chemotherapy settings.

APT weighted imaging in diffuse gliomas.

Amide proton transfer-weighted (APTw) imaging is a non-invasive molecular MRI technique with a wide range of applications in neuroradiology and particularly neuro-oncology imaging. More than 15 years of pre-clinical experiments and clinical studies have demonstrated that APTw metrics are reproducible and reliable, leading to large-scale clinical acceptance. At present, major vendors of MRI scanners provide APTw sequences upon request. However, most neuroradiologists are unfamiliar with this advanced MRI contrast, its related metrics, and its established added value to patient care. In this manuscript, we present the APTw contrast and illustrate its clinical potential for glioma patients, before and after tumor therapy. We also show common artifacts of APTw imaging and discuss potential limitations and future refinements. Our goal is to suggest how this emerging technique can aid in diffuse gliomas work-up.

Advances in molecular and imaging biomarkers in lower-grade gliomas.

INTRODUCTION: Lower-grade (grade 2-3) gliomas (LGGs) constitutes a group of primary brain tumors with variable clinical behaviors and treatment responses. Recent advancements in molecular biology have redefined their classification, and novel imaging modalities emerged for the noninvasive diagnosis and follow-up. AREAS COVERED: This review comprehensively analyses the current knowledge on molecular and imaging biomarkers in LGGs. Key molecular alterations, such as IDH mutations and 1p/19q codeletion, are discussed for their prognostic and predictive implications in guiding treatment decisions. Moreover, the authors explore theranostic biomarkers for the potential of tailored therapies. Additionally, they also describe the utility of advanced imaging modalities, including widely available techniques, as dynamic susceptibility contrast perfusion-weighted imaging and less validated, emerging approaches, for the noninvasive LGGs characterization and follow-up. EXPERT OPINION: The integration of molecular markers enhanced the stratification of LGGs, leading to the new concept of integrated histomolecular classification. While the IDH mutation is an established key prognostic and predictive marker, recent results from IDH inhibitors trials showed its potential value as a theranostic marker. In this setting, advanced MRI techniques such as 2-D-hydroxyglutarate spectroscopy are very promising for the noninvasive diagnosis and monitoring of LGGs. This progress offers exciting prospects for personalized medicine and improved treatment outcomes in LGGs.

Neurochemical Differences between 1p/19q Codeleted and Noncodeleted IDH-mutant Gliomas by in Vivo MR Spectroscopy.

Background Noninvasive identification of glioma subtypes is important for optimizing treatment strategies. Purpose To compare the in vivo neurochemical profiles between isocitrate dehydrogenase (IDH) 1-mutant 1p/19q codeleted gliomas and their noncodeleted counterparts measured by MR spectroscopy at 3.0 T with a point-resolved spectroscopy (PRESS) sequence optimized for D-2-hydroxyglutarate (2HG) detection. Materials and Methods Adults with IDH1-mutant gliomas were retrospectively included for this study from two university hospitals (inclusion period: January 2015 to July 2016 and September 2019 to June 2021, respectively) based on availability of 1p/19q codeletion status and a PRESS acquisition optimized for 2HG detection (echo time, 97 msec) at 3.0 T before any treatment. Spectral analysis was performed using LCModel and a simulated basis set. Metabolite quantification was performed using the water signal as a reference and correcting for water and metabolite longitudinal and transverse relaxation time constants. Concentration ratios were computed using total creatine (tCr) and total choline. A two-tailed unpaired t test was used to compare metabolite concentrations obtained in codeleted versus noncodeleted gliomas, accounting for multiple comparisons. Results Thirty-one adults (mean age, 39 years ± 8 [SD]; 19 male) were included, and 19 metabolites were quantified. Cystathionine concentration was higher in codeleted (n = 13) than noncodeleted (n = 18) gliomas when quantification was performed using the water signal or tCr as references (2.33 mM ± 0.98 vs 0.93 mM ± 0.94, and 0.34 mM ± 0.14 vs 0.14 mM ± 0.14, respectively; both P < .001). The sensitivity and specificity of PRESS to detect codeletion by means of cystathionine quantification were 92% and 61%, respectively. Other metabolites did not show evidence of a difference between groups (P > .05). Conclusion Higher cystathionine levels were detected in IDH1-mutant 1p/19q codeleted gliomas than in their noncodeleted counterparts with use of a PRESS sequence optimized for 2HG detection. Of 19 metabolites quantified, only cystathionine showed evidence of a difference in concentration between groups. Clinical trial registry no. NCT01703962 © RSNA, 2023 See also the editorial by Lin in this issue.

Hippocampal and neocortical BRAF mutant non-expansive lesions in focal epilepsies.

OBJECTIVE: Mesial Temporal Lobe Epilepsy-associated Hippocampal Sclerosis (MTLE-HS) is a syndrome associated with various aetiologies. We previously identified CD34-positive extravascular stellate cells (CD34+ cells) possibly related to BRAFV600E oncogenic variant in a subset of MTLE-HS. We aimed to identify the BRAFV600E oncogenic variants and characterise the CD34+ cells. METHODS: We analysed BRAFV600E oncogenic variant by digital droplet Polymerase Chain Reaction in 53 MTLE-HS samples (25 with CD34+ cells) and nine non-expansive neocortical lesions resected during epilepsy surgery (five with CD34+ cells). Ex vivo multi-electrode array recording, immunolabelling, methylation microarray and single nuclei RNAseq were performed on BRAFwildtype MTLE-HS and BRAFV600E mutant non-expansive lesion of hippocampus and/or neocortex. RESULTS: We identified a BRAFV600E oncogenic variant in five MTLE-HS samples with CD34+ cells (19%) and in five neocortical samples with CD34+ cells (100%). Single nuclei RNAseq of resected samples revealed two unique clusters of abnormal cells (including CD34+ cells) associated with senescence and oligodendrocyte development in both hippocampal and neocortical BRAFV600E mutant samples. The co-expression of the oncogene-induced senescence marker p16INK4A and the outer subventricular zone radial glia progenitor marker HOPX in CD34+ cells was confirmed by multiplex immunostaining. Pseudotime analysis showed that abnormal cells share a common lineage from progenitors to myelinating oligodendrocytes. Epilepsy surgery led to seizure freedom in eight of the 10 patients with BRAF mutant lesions. INTERPRETATION: BRAFV600E underlies a subset of MTLE-HS and epileptogenic non-expansive neocortical focal lesions. Detection of the oncogenic variant may help diagnosis and open perspectives for targeted therapies.

High perilesional T2-FLAIR signal around anterior temporal perivascular spaces: How can fluid suppressed Amide Proton Transfer weighted imaging further comfort the diagnosis.

Areas of marked T2-FLAIR hyperintensity around perivascular spaces can be misdiagnosed as tumor, especially in case of lesion evolution. In this report, we show and describe increased T2-FLAIR signal intensity around anterior temporal perivascular spaces in three patients and shortly review this poorly known entity. In addition, we discuss for the first time the added value of fluid suppressed APTw imaging, an emerging noninvasive molecular technique, in the characterization of this "do not touch" abnormality.

Central nervous system lymphomas-Assessment and treatment and prevention of central nervous system relapse.

In this review focused on lymphoma and the central nervous system (CNS), we summarize recent developments in the management of primary (PCNSL) and secondary CNS lymphoma (SCNSL), treatment of CNS lymphoma in the older population, the neuroradiological assessment of CNS lymphoma and finally highlight the ongoing debate on optimal CNS prophylaxis. The section on PCNSL focuses on the different approaches available for frontline treatment in Europe and the United States and discusses consolidation strategies. We then highlight available strategies to treat PCNSL in the elderly population, an area of unmet need. New therapies aiming at minimizing toxicity and prioritizing quality of life are emerging for these patients. Secondary CNS lymphoma, especially in the relapsed/refractory setting is another area of unmet need, and the efficacy of CAR-T cell therapy is being explored. We provide an overview of the imaging challenges in the neuroradiological assessment of CNS lymphoma. Finally, the section on CNS prophylaxis summarizes recent findings from large retrospective studies challenging the efficacy of present approaches to prophylaxis in higher-risk patients with lymphoma.

Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative.

The 2021 WHO classification of the CNS Tumors identifies as "Peripheral nerve sheath tumors" (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively.

Proton therapy for adult craniopharyngioma: Experience of a single institution in 91 consecutive patients.

BACKGROUND: Craniopharyngioma (CP) in adults is a rare benign tumor associated with many morbidities, with limited contemporary studies to define treatment, and follow-up guidelines. METHODS: A single-center retrospective study was conducted on patients aged ≥ 18 years from 2006-2018 with CP and who were treated with proton therapy (PT). Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS), local recurrence-free survival (LRFS), and toxicity were characterized using Kaplan-Meier and Cox regression analyses. RESULTS: Ninety-one patients met the criteria, with a median age of 37 years (range 18-82 years). PT was conducted after tumor resection in 88 patients (97%), in 64 patients (70.3%) as an adjuvant strategy and in 27 (29.7%) after recurrent disease. Three patients received exclusive PT. A median MRI follow-up of 39 months revealed 35.2% complete response, 49.5% partial response, and 9.9% stable disease. Five patients developed local recurrence (LR). The pattern of failure study showed that these five LR were within the GTV volume. The 5-year LRFS was 92.0% [CI 95% 84.90-99.60]. All the patients were alive at the end of the follow-up. Patients requiring treatment adaptation during PT tend to have a higher risk of LR (P = .084). Endocrinopathy was the most frequent grade ≥ 2 late toxicity. Among patients who were symptom-free before the start of treatment, none developed hearing toxicity but four (9.8%) developed visual disorders and 10 (11.3%) symptomatic memory impairment. Patients with large tumors had a higher risk of developing symptomatic memory impairment (P = .029). CONCLUSION: Adults with CP treated with PT have favorable survival outcomes, with acceptable late toxicity. Prospective quality-of-life and neurocognitive studies are needed to define late adverse effects better.

In Vivo 2-Hydroxyglutarate Monitoring With Edited MR Spectroscopy for the Follow-up of IDH-Mutant Diffuse Gliomas: The IDASPE Prospective Study.

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 cm3; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T1 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.

Roles and outcomes of stereotactic biopsy for adult patients with brainstem lesion.

PURPOSE: This study aimed to assess the benefit-risk ratio by determining diagnostic yield and safety of brainstem biopsies in adult patients. The secondary objectives were (i) to compare brainstem biopsy safety and postbiopsy patients' outcomes and survival with those of patients biopsied for a brain or cerebellar lesion, and (ii) to assess the impact of brainstem biopsy on final diagnosis and further therapeutic management. METHODS: Among 1784 stereotactic biopsies performed in adult patients at a tertiary center between April 2009 and October 2020, we retrospectively examined 50 consecutive brainstem biopsies. We compared variables regarding diagnostic yield, safety and post-biopsy outcomes between brainstem biopsy patients and brain/cerebellum biopsy patients. RESULTS: Brainstem biopsy led to a diagnosis in 86% of patients (94.6% in patients with suspected tumor). Lesion contrast enhancement on imaging was the sole predictor of obtaining a diagnosis. Rates of symptomatic complications and mortality were significantly higher in brainstem biopsy patients compared to brain/cerebellum biopsy patients (20% vs 0%; p < 0.001 and 6% vs 0%; p = 0.01, respectively). Transfrontal trajectory and prebiopsy swallowing disorders were predictors of brainstem biopsy-related symptomatic complications. Brainstem biopsy findings led to diagnostic change in 22% of patients. CONCLUSIONS: Stereotactic biopsy in adult patients with brainstem lesion has a high diagnostic yield. Although stereotactic brainstem biopsy is associated with more functional and fatal complications than biopsies targeting the brain/cerebellum, its safety profile appears acceptable. Thus, the benefit-risk ratio of stereotactic biopsy in patients with brainstem lesion is favorable but should nevertheless be carefully weighted on a case-by-case basis.

Prognostic factors in primary central nervous system lymphoma.

PURPOSE OF REVIEW: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal diffuse large B cell lymphoma. Despite its apparent immunopathological homogeneity, PCNSL displays a wide variability in outcome. Identifying prognostic factors is of importance for patient stratification and clinical decision-making. The purpose of this review is to focus on the clinical, neuroradiological and biological variables correlated with the prognosis at the time of diagnosis in immunocompetent patients. RECENT FINDINGS: Age and performance status remain the most consistent clinical prognostic factors. The current literature suggests that neurocognitive dysfunction is an independent predictor of poor outcome. Cumulating data support the prognostic value of increased interleukin-10 level in the cerebrospinal fluid (CSF), in addition to its interest as a diagnostic biomarker. Advances in neuroimaging and in omics have identified several semi-quantitative radiological features (apparent diffusion restriction measures, dynamic contrast-enhanced perfusion MRI (pMRI) pattern and 18F-fluorodeoxyglucose metabolism) and molecular genetic alterations with prognostic impact in PCNSL. SUMMARY: Validation of new biologic and neuroimaging markers in prospective studies is required before integrating future prognostic scoring systems. In the era of radiomic, large clinicoradiological and molecular databases are needed to develop multimodal artificial intelligence algorithms for the prediction of accurate outcome.

Reduced-dose WBRT as consolidation treatment for patients with primary CNS lymphoma: an LOC network study.

The optimal consolidation strategy for primary central nervous system lymphoma (PCNSL) remains controversial. Preventing radio-induced neurotoxicity of consolidation treatment through reduced-dose whole-brain radiotherapy (rdWBRT) at a dose of 23.4 Gy is an interesting alternative to conventional WBRT in patients aged <60 years. From the LOC Network (Network for Oculo-cerebral Lymphomas) database, we retrospectively selected patients with PCNSL aged <60 years who showed complete (CR) or unconfirmed CR after high-dose methotrexate-based chemotherapy and had received consolidation rdWBRT as the first-line treatment. If available, prospective neuropsychological follow-ups were reported. Twenty-nine patients diagnosed between 2013 and 2018 met the study selection criteria. Nine (31%) patients experienced relapse during the follow-up, with a median time from radiotherapy to recurrence of 8.7 months (interquartile range, 4-11.5). Five of those patients received salvage treatment and consolidation with intensive chemotherapy and autologous stem cell transplantation. Progression-free survival rates were 89% (95% confidence interval [CI] 79%-100%), 72% (95% CI, 56%-88%), and 69% (95% CI, 52%-85%) at 1, 2, and 5 years, respectively. Overall survival rates were 100%, 89% (95% CI, 79%-100%), and 86% (95% CI, 74%-99%) at 1, 2, and 5 years, respectively, and were consistent with those observed for standard-dose WBRT (sdWBRT). No prognostic factor was identified. The results of the 36-month neuropsychological follow-up for a subset of patients appeared reassuring, with most patients exhibiting maintenance of or improvements in their baseline conditions. Our results, combined with phase 2 study results, support the use of rdWBRT instead of sdWBRT as a consolidation treatment in <60-year-old patients showing CR after induction treatment.

Chemotherapy is an efficient treatment in primary CNS MALT lymphoma.

BACKGROUND: Mucosae-associated lymphoid tissue (MALT) lymphomas are a rare and poorly understood form of primary central nervous system lymphoma (PCNSL). The aim of this study was to better describe these tumors, their management and their long-term prognosis. METHODS: Patients with primary CNS MALT lymphoma (PCNSML) were retrospectively selected from the database on PCNSL of the Pitié-Salpêtrière Hospital. RESULTS: Of 662 PCNSL, 11 (1.7%) PCNSML (9 females and 2 males, median age: 56 years) were selected. The median time from first symptoms to diagnosis was 13 months. Location was dural in 8 cases and parenchymal in 3 cases. The disease was multifocal/diffuse in 7 cases. In first line, all patients received chemotherapy (high-dose methotrexate (HD-MTX) based chemotherapy (n = 4) and non-HD-MTX-based chemotherapy (n = 7)), preceded by surgery in 4 cases. None received radiotherapy. According to the IPCG (International PCNSL Collaborative Group) criteria, the overall response rate was 7/11 (64%). At latest news, 5 patients had persistent contrast enhancement, stable with no treatment since a median of 57 months, raising the question of complete response despite persisting contrast enhancement. No patient developed neurotoxicity except for one patient who subsequently received radiotherapy. The median follow-up was 109 months. The median progression-free survival was 78.0 months and the 10-year overall survival rate was 90%. CONCLUSION: This is the largest series demonstrating that chemotherapy is an efficient treatment in PCNSML, with an excellent long-term outcome and the absence of neurotoxicity, and calling into question the relevance of the IPCG criteria for the evaluation of response.

Primary CNS lymphoma of the corpus callosum: presentation and neurocognitive outcomes.

INTRODUCTION: The corpus callosum (CC) is frequently involved in primary central nervous system lymphomas (PCNSLs). In this cohort study, we described the neurocognition of patients with PCNSL-CC and its posttherapeutic evolution. METHODS: Immunocompetent patients with PCNSL-CC were identified retrospectively at the Pitié-Salpêtrière Hospital. We described their clinical presentation. Neuropsychological test scores (MMSE; digit spans; Free and Cued Selective Reminding Test; Image Oral Naming Test; Frontal Assessment Battery; Trail Making Test; Stroop and verbal fluency tests; Rey's Complex Figure test) and factors impacting them were analyzed. RESULTS: Twenty-seven patients were included (median age: 67 years, median Karnofsky Performance Status: 70); cognitive impairment and balance disorders were present in 74% and 59%, respectively. At diagnosis, neuropsychological test results were abnormal for global cognitive efficiency (63% of patients), memory (33-80% depending on the test) and executive functions (44-100%). Results for visuospatial and language tests were normal. All patients received high-dose methotrexate-based polychemotherapy, followed in one patient by whole-brain radiotherapy; 67% of patients achieved complete response (CR). With a median follow-up of 48 months (range 6-156), patients in CR had persistent abnormal test results for global cognitive efficiency in 17%, executive function in 18-60%, depending on the test, and memory in 40-60%. Splenium location and age ≥ 60 years were significantly associated with worse episodic memory scores throughout the follow-up. CONCLUSIONS: PCNSL-CC is associated with frequent cognitive dysfunctions, especially memory impairment, which may recover only partially despite CR and warrant specific rehabilitation. Older age (≥ 60) and splenium location are associated with worse neurocognitive outcomes.

Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life-experience of the French Network.

We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n = 147) or at relapse (n = 119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n = 64), thiotepa-busulfan (n = 24), BCNU-etoposide-cytarabine-melphalan (BEAM, n = 36) and thiotepa-busulfan-cyclophosphamide (n = 142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.

The influence of cystathionine on neurochemical quantification in brain tumor in vivo MR spectroscopy.

PURPOSE: To evaluate the ability of the PRESS sequence (TE  = 97 ms, optimized for 2-hydroxyglutarate detection) to detect cystathionine in gliomas and the effect of the omission of cystathionine on the quantification of the full neurochemical profile. METHODS: Twenty-three subjects with a glioma were retrospectively included based on the availability of both MEGA-PRESS and PRESS acquisitions at 3T, and the presence of the cystathionine signal in the edited MR spectrum. In eight subjects, the PRESS acquisition was performed also in normal tissue. Metabolite quantification was performed using LCModel and simulated basis sets. The LCModel analysis for the PRESS data was performed with and without cystathionine. RESULTS: All subjects with glioma had detectable cystathionine levels >1 mM with Cramér-Rao lower bounds (CRLB) <15%. The mean cystathionine concentrations were 3.49 ± 1.17 mM for MEGA-PRESS and 2.20 ± 0.80 mM for PRESS data. Cystathionine concentrations showed a significant correlation between the two MRS methods (r = 0.58, p = .004), and it was not detectable in normal tissue. Using PRESS, 19 metabolites were quantified with CRLB <50% for more than half of the subjects. The metabolites that were significantly (p < .0028) and mostly affected by the omission of cystathionine were aspartate, betaine, citrate, γ-aminobutyric acid (GABA), and serine. CONCLUSIONS: Cystathionine was detectable by PRESS in all the selected gliomas, while it was not detectable in normal tissue. The omission from the spectral analysis of cystathionine led to severe biases in the quantification of other neurochemicals that may play key roles in cancer metabolism.