REVOLUMAB: A phase II trial of nivolumab in recurrent IDH mutant high-grade gliomas.

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).

A threshold for mitotic activity and post-surgical residual volume defines distinct prognostic groups for astrocytoma IDH-mutant.

AIMS: The distinction between CNS WHO grade 2 and grade 3 is instrumental in choosing between observational follow-up and adjuvant treatment for resected astrocytomas IDH-mutant. However, the criteria of CNS WHO grade 2 vs 3 have not been updated since the pre-IDH era. METHODS: Maximal mitotic activity in consecutive high-power fields corresponding to 3 mm2 was examined for 118 lower-grade astrocytomas IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity and other putative prognostic factors (including age, performance status, pre-surgical tumour volume, multilobar involvement, post-surgical residual tumour volume and midline involvement) was assessed for tumours with ATRX loss and the absence of CDKN2A homozygous deletion or CDK4 amplification, contrast enhancement, histological necrosis and microvascular proliferation. RESULTS: Seventy-one per cent of the samples had <6 mitoses per 3 mm2 . Mitotic activity, residual volume and multilobar involvement were independent prognostic factors of TTT. The threshold of ≥6 mitoses per 3 mm2 identified patients with a shorter TTT (median 18.5 months). A residual volume ≥1 cm3 also identified patients with a shorter TTT (median 24.5 months). The group defined by <6 mitoses per 3 mm2 and a residual volume <1 cm3 had the longest TTT (median 73 months) and OS (100% survival at 7 years). These findings were confirmed in a validation cohort of 52 tumours. CONCLUSIONS: Mitotic activity and post-surgical residual volume can be combined to evaluate the prognosis for patients with resected astrocytomas IDH-mutant. Patients with <6 mitoses per 3 mm2 and a residual volume <1 cm3 were the best candidates for observational follow-up.

Mismatch Repair Deficiency and Lynch Syndrome Among Adult Patients With Glioma.

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

A Multigene Signature Associated with Progression-Free Survival after Treatment for IDH Mutant and 1p/19q Codeleted Oligodendrogliomas.

BACKGROUND: IDH mutant and 1p/19q codeleted oligodendrogliomas are the gliomas associated with the best prognosis. However, despite their sensitivity to treatment, patient survival remains heterogeneous. We aimed to identify gene expressions associated with response to treatment from a national cohort of patients with oligodendrogliomas, all treated with radiotherapy +/- chemotherapy. METHODS: We extracted total RNA from frozen tumor samples and investigated enriched pathways using KEGG and Reactome databases. We applied a stability selection approach based on subsampling combined with the lasso-pcvl algorithm to identify genes associated with progression-free survival and calculate a risk score. RESULTS: We included 68 patients with oligodendrogliomas treated with radiotherapy +/- chemotherapy. After filtering, 1697 genes were obtained, including 134 associated with progression-free survival: 35 with a better prognosis and 99 with a poorer one. Eight genes (ST3GAL6, QPCT, NQO1, EPHX1, CST3, S100A8, CHI3L1, and OSBPL3) whose risk score remained statistically significant after adjustment for prognostic factors in multivariate analysis were selected in more than 60% of cases were associated with shorter progression-free survival. CONCLUSIONS: We found an eight-gene signature associated with a higher risk of rapid relapse after treatment in patients with oligodendrogliomas. This finding could help clinicians identify patients who need more intensive treatment.

T2-Fluid-attenuated inversion recovery (FLAIR) pseudoprogression in patients with anaplastic oligodendrogliomas treated with procarbazine, lomustine and vincristine (PCV) chemotherapy alone.

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.

Incidence and characteristics of pseudoprogression in IDH-mutant high-grade gliomas: A POLA network study.

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.

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.

Characteristics, Patterns of Care and Predictive Geriatric Factors in Elderly Patients Treated for High-Grade IDH-Mutant Gliomas: A French POLA Network Study.

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.

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.

Characteristics of Anaplastic Oligodendrogliomas Short-Term Survivors: A POLA Network Study.

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

Hybrid [18F]-F-DOPA PET/MRI Interpretation Criteria and Scores for Glioma Follow-up After Radiotherapy.

OBJECTIVE: 18F­fluoro-L­3,4­dihydroxyphenylalanine positron emission tomography (F­DOPA 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 F­DOPA current standard of interpretation. METHODS: We included 76 consecutive patients showing at least one gadolinium-enhanced lesion on the T1­w MRI sequence (T1G). Two nuclear medicine physicians blindly analyzed PET/MRI images. In addition to the conventional PET analysis, they looked for F­DOPA uptake(s) outside T1G-enhanced areas (T1G/PET), in the white matter (WM/PET), for T1G-enhanced lesion(s) without sufficiently concordant F­DOPA uptake (T1G+/PET), and F­DOPA uptake(s) away from hemorrhagic changes as shown with a susceptibility weighted imaging sequence (SWI/PET). We measured lesions' F­DOPA 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 F­DOPA PET and MRI provided better accuracy than conventional PET analyses for distinguishing TP from TRC in our patients after radiation therapy.

Sustained Tumor Control With MAPK Inhibition in BRAF V600-Mutant Adult Glial and Glioneuronal Tumors.

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.

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors.

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18-69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

An AI-Powered Blood Test to Detect Cancer Using NanoDSF.

Glioblastoma is the most frequent and aggressive primary brain tumor. Its diagnosis is based on resection or biopsy that could be especially difficult and dangerous in the case of deep location or patient comorbidities. Monitoring disease evolution and progression also requires repeated biopsies that are often not feasible. Therefore, there is an urgent need to develop biomarkers to diagnose and follow glioblastoma evolution in a minimally invasive way. In the present study, we described a novel cancer detection method based on plasma denaturation profiles obtained by a non-conventional use of differential scanning fluorimetry. Using blood samples from 84 glioma patients and 63 healthy controls, we showed that their denaturation profiles can be automatically distinguished with the help of machine learning algorithms with 92% accuracy. Proposed high throughput workflow can be applied to any type of cancer and could become a powerful pan-cancer diagnostic and monitoring tool requiring only a simple blood test.

Radiotherapy Plus Procarbazine, Lomustine, and Vincristine Versus Radiotherapy Plus Temozolomide for IDH-Mutant Anaplastic Astrocytoma: A Retrospective Multicenter Analysis of the French POLA Cohort.

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

Rare Primary Central Nervous System Tumors in Adults: An Overview.

Overall, tumors of primary central nervous system (CNS) are quite common in adults with an incidence rate close to 30 new cases/100,000 inhabitants per year. Significant clinical and biological advances have been accomplished in the most common adult primary CNS tumors (i.e., diffuse gliomas). However, most CNS tumor subtypes are rare with an incidence rate below the threshold defining rare disease of 6.0 new cases/100,000 inhabitants per year. Close to 150 entities of primary CNS tumors have now been identified by the novel integrated histomolecular classification published by the World Health Organization (WHO) and its updates by the c-IMPACT NOW consortium (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy). While these entities can be better classified into smaller groups either by their histomolecular features and/or by their location, assessing their treatment by clinical trials and improving the survival of patients remain challenging. Despite these tumors are rare, research, and advances remain slower compared to diffuse gliomas for instance. In some cases (i.e., ependymoma, medulloblastoma) the understanding is high because single or few driver mutations have been defined. The European Union has launched European Reference Networks (ERNs) dedicated to support advances on the clinical side of rare diseases including rare cancers. The ERN for rare solid adult tumors is termed EURACAN. Within EURACAN, Domain 10 brings together the European patient advocacy groups (ePAGs) and physicians dedicated to improving outcomes in rare primary CNS tumors and also aims at supporting research, care and teaching in the field. In this review, we discuss the relevant biological and clinical characteristics, clinical management of patients, and research directions for the following types of rare primary CNS tumors: medulloblastoma, pineal region tumors, glioneuronal and rare glial tumors, ependymal tumors, grade III meningioma and mesenchymal tumors, primary central nervous system lymphoma, germ cell tumors, spinal cord tumors and rare pituitary tumors.

Mechanisms and therapeutic implications of hypermutation in gliomas.

A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.

Germline mutations in the new E1' cryptic exon of the VHL gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma.

BACKGROUNDS: The incidence of germline mutations in the newly discovered cryptic exon (E1') of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known. METHODS: We studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum ('Single VHL tumour' cohort), 70 patients with multiple tumours of the VHL spectrum ('Multiple VHL tumours' cohort), 76 patients with a VHL disease as described in the literature ('VHL-like' cohort) and 946 patients with a PPGL were screened for E1' genetic variants. RESULTS: Six different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (p<0.0001) suggesting that this variant might be either a recurrent mutation or a modifier mutation conferring a risk for the development of tumours and cancers of the VHL spectrum. CONCLUSIONS: VHL E1' cryptic exon mutations contribute to 1.32% (1/76) of 'VHL-like' cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice.