BACKGROUND AND OBJECTIVES:Molecularly defined oligodendrogliomas are rare tumors whose prognosis has improved over time because of more effective treatments. However, several aspects of management are still controversial, and studies with long-term follow-up are needed. The main aim of this study was to analyze and compare the natural history and management of patients with OG2 and OG3 and define which factors have the strongest effect on outcome. METHODS:We reviewed an institutional retrospective cohort (1996-2024) of patients with molecularly defined OG2 and OG3 according to World Health Organization 2021. We retrieved information on baseline clinical features, MRI characteristics (i.e., presence and pattern of contrast enhancement), extent of resection, initial treatment modalities after surgery, and management at progression. The relationships of these factors with progression-free survival (PFS) and overall survival (OS) were studied with univariate and multivariate analyses. RESULTS:Among 240 patients with IDH-mutant 1p/19q-codeleted oligodendrogliomas, grade 2 tumors were 149 (62.1%) and grade 3 were 91 (37.9%) with a median age of 42 and 44 years, respectively. Male/female ratio was 73/76 (49%/51%). Among patients with OG3, 70/91 (77%) exhibited a diffuse grade 3 histology (OG3d), whereas 21/91 (23%) had focal grade 3 areas only (OG3f). Overall, patients with OG2 and OG3 had similar median PFS (57.6 months, CI 53.2-61.9, vs 59.8 months, CI 41.9-77.6, p = 0.25), and prolonged median OS (274 months vs not reached). However, patients with OG3 exhibited a shorter time to radiotherapy at progression and their survival probability declined more rapidly within the first decade after surgery. The extent of resection was the only factor that significantly affected both PFS and OS in a multivariate analysis (for PFS, hazard ratio [HR] 0.90, 0.62-0.99, p = 0.026; for OS, HR 0.29, 0.13-0.79, p = 0.016), whereas tumor grade did not. Temozolomide alone as initial treatment of high-risk OG2 and OG3 with large residual tumor after surgery was not detrimental for survival. The same was true for observation in a small group of young patients with nonenhancing OG3 who have undergone complete resection and with only focal areas of malignancy (OG3f). DISCUSSION:This large retrospective cohort of IDH-mutant 1p/19q-codeleted oligodendrogliomas receiving standard treatments could serve as a benchmark for comparison with new IDH inhibitors in future clinical studies.

Background and ObjectivesMolecularly defined oligodendrogliomas are rare tumors whose prognosis has improved over time because of more effective treatments. However, several aspects of management are still controversial, and studies with long-term follow-up are needed. The main aim of this study was to analyze and compare the natural history and management of patients with OG2 and OG3 and define which factors have the strongest effect on outcome.MethodsWe reviewed an institutional retrospective cohort (1996-2024) of patients with molecularly defined OG2 and OG3 according to World Health Organization 2021. We retrieved information on baseline clinical features, MRI characteristics (i.e., presence and pattern of contrast enhancement), extent of resection, initial treatment modalities after surgery, and management at progression. The relationships of these factors with progression-free survival (PFS) and overall survival (OS) were studied with univariate and multivariate analyses.ResultsAmong 240 patients with IDH-mutant 1p/19q-codeleted oligodendrogliomas, grade 2 tumors were 149 (62.1%) and grade 3 were 91 (37.9%) with a median age of 42 and 44 years, respectively. Male/female ratio was 73/76 (49%/51%). Among patients with OG3, 70/91 (77%) exhibited a diffuse grade 3 histology (OG3d), whereas 21/91 (23%) had focal grade 3 areas only (OG3f). Overall, patients with OG2 and OG3 had similar median PFS (57.6 months, CI 53.2-61.9, vs 59.8 months, CI 41.9-77.6, p = 0.25), and prolonged median OS (274 months vs not reached). However, patients with OG3 exhibited a shorter time to radiotherapy at progression and their survival probability declined more rapidly within the first decade after surgery. The extent of resection was the only factor that significantly affected both PFS and OS in a multivariate analysis (for PFS, hazard ratio [HR] 0.90, 0.62-0.99, p = 0.026; for OS, HR 0.29, 0.13-0.79, p = 0.016), whereas tumor grade did not. Temozolomide alone as initial treatment of high-risk OG2 and OG3 with large residual tumor after surgery was not detrimental for survival. The same was true for observation in a small group of young patients with nonenhancing OG3 who have undergone complete resection and with only focal areas of malignancy (OG3f).DiscussionThis large retrospective cohort of IDH-mutant 1p/19q-codeleted oligodendrogliomas receiving standard treatments could serve as a benchmark for comparison with new IDH inhibitors in future clinical studies.

PURPOSE OF REVIEW:Rare gliomas, including circumscribed astrocytic, glioneuronal, and neuronal central nervous system (CNS) tumours, though collectively uncommon, present significant clinical challenges due to their heterogeneity and limited therapeutic evidence. Conventional management has relied predominantly on surgery and radiotherapy. Advances in molecular profiling have revealed actionable targets, prompting a timely reassessment of treatment paradigms. This review aims to describe current standard treatments and recent advances in molecularly targeted approaches for rare gliomas. RECENT FINDINGS:Gross total surgical resection remains the primary therapeutic modality for rare gliomas, providing optimal tumour control and symptom relief. Radiotherapy offers additional benefit in case of subtotal resection or recurrent disease, particularly in WHO grade 3 tumours. In contrast, conventional chemotherapy has shown limited efficacy and is typically reserved for refractory or progressive cases.The discovery of actionable molecular alterations in a substantial subset of rare gliomas has led to increasing integration of targeted therapies into clinical management. Notable recent advances include the use of BRAF/MAPK pathway inhibitors (e.g., dabrafenib/trametinib, tovorafenib), NTRK inhibitors (e.g., larotrectinib, entrectinib), FGFR inhibitors (e.g., erdafitinib, pemigatinib), and mTOR inhibitors (e.g., everolimus), which have demonstrated meaningful clinical activity in select patient populations. SUMMARY:Precision oncology is rapidly transforming the treatment landscape for rare CNS tumours. Integration of targeted therapies into clinical protocols - ideally guided by multidisciplinary molecular tumour boards - is increasingly warranted. Future research must optimise timing, combination strategies, and overcome resistance, while new biomarkers and liquid biopsy tools are needed to guide the choice of therapy and monitor response in this underserved population.

Consistent data support the efficacy of BRAF and MEK inhibitors in paediatric patients with low-grade gliomas, while data in adults are more limited, and the clinical benefit is to be defined. We retrospectively collected data of adult patients with BRAF-mutant gliomas treated between 2004 and 2024 in our Institution. Twelve patients received dabrafenib plus trametinib at recurrence after standard radiotherapy and chemotherapy. Histo-molecular diagnoses were reviewed according to WHO 2021. Radiological response was re-evaluated according to RANO criteria. We identified 12 patients (5 males and 7 females), with age ranging from 21 to 53 years. At baseline, all patients had contrast-enhancing tumours and were neurologically symptomatic. Three out of 12 patients (25%) displayed a complete response: 1 pilocytic astrocytoma (PA), 1 anaplastic pleomorphic xanthoastrocytoma (PXA), and 1 glioblastoma (GBM). Two patients achieved either seizure reduction >50% or seizure freedom. A F-DOPA PET confirmed a metabolic response in the GBM patient. Four out of 12 patients (33%) displayed a partial response (2 PA, 1 ganglioglioma - GG, 1 GBM), together with neurological improvement. Two (1 PXA, 1 GBM) out of 12 patients (17%) displayed a stable disease, with seizure freedom in 1. Three patients (25%) (1 PXA, 2 GBM) displayed an early tumour progression. PFS ranged from 7 to 24 months and OS from 8 to 46 months. Five patients are still on treatment. Adverse effects included headache (7/12) fever (4/12) and cutaneous reactions (3/12), leading to dose reduction in 2 patients. This cohort of recurrent and/or disseminated BRAF-mutant gliomas displayed a high response rate on MRI following dabrafenib plus trametinib (CR+PR 58%), with improvement of seizures (3/8, 37%). More data are needed to assess the long-term duration of response, and to investigate molecular factors influencing the probability of response.

Given the role of IDH mutations and D-2-hydroxyglutarate (D2HG) in epileptogenesis, the impact of IDH inhibitors on seizure control is of interest. This prospective study assessed patterns and timing of seizure response in patients with grade 2 IDH-mutant gliomas enrolled in a vorasidenib Expanded Access Programme (EAP) after surgery. Seizures were recorded at the end of each 28-day cycle with a dedicated diary. MRI, [18F]fluorodopa (F-DOPA) PET, and LC-MS/MS determination of D2HG plasma levels were performed at baseline and every 3 cycles. Of 50 patients enrolled in the EAP, 10 (6 astrocytomas, 4 oligodendrogliomas) had persistent seizures prior to vorasidenib initiation (mean frequency: 4.8/month); 7/10 had measurable F-DOPA PET uptake (mean SUVmax, TBRmax, MTV: 3.2, 2.8, 6.5 cm³); median D2HG plasma concentration was 39.7 ng/mL. Over a median treatment duration of 6.6 months, 8/10 achieved seizure freedom within 2 cycles, whereas one improved gradually. One patient, after initial improvement, worsened by cycle 4. All patients showed stable disease (SD) per RANO criteria on MRI after 3 and 6 cycles. 6/9 patients with seizure reduction showed reduced PET uptake by cycle 3 (mean changes: SUVmax –6.3%; TBRmax –7.5%; MTV –4.7 cm³) and 6 (SUVmax –20.9%; TBRmax –10.9%; MTV –35.9 cm³), translating into 3 partial responses and 3 SD by PET RANO. All 9 patients with durable seizure response showed reduced D2HG at both cycle 3 (mean change: –57%) and cycle 6 (–45%). In contrast, the only patient who experienced seizure worsening over time showed D2HG reduction at cycle 3 (-53%), but no further reduction, and PET progression disease, at cycle 6. In our study, vorasidenib was associated with early seizure control. Seizure improvement correlated with decreased F-DOPA PET uptake and reduced D2HG plasma concentration. These findings suggest that F-DOPA PET and D2HG plasma levels may be sensitive tools for assessing treatment efficacy.

Purpose Neuro-oncology is a multidisciplinary subspecialty that has evolved and expanded tremendously over the last 20 years. In Europe, notwithstanding a number of commendable initiatives, neither a specific neuro-oncology training curriculum nor a consensus on the ideal training tools have been set. In this context, the Youngster Committee of the Italian Association for Neuro-Oncology (AINO) has run a nationwide survey to take a snapshot of the current situation of neuro-oncology education in Italy. Methods Between July and November 2023, we distributed through AINO a 34-question survey addressed to all Italian care providers dealing with neuro-oncology, irrespective of specialty and level of experience, as per AINO mission. The questionnaire was disseminated using an open link. We analyzed and stratified answers according to epidemiological characteristics of the respondents, i.e. age, gender, role, years of experience, type and case load of their work Institutions, geographical region. Results We collected 254 valid questionnaires. The majority of respondents were under 40 years old (62.6%); neurosurgeons formed the largest specialty group (48%). Residency was a key step for neuro-oncology education according to 33% of participants; notably, younger respondents gave a significantly more positive assessment of residency programs compared to older ones (72% vs. 56%, p = 0.0193). PhD programs in Italy are focused only on research, according to 30% of respondents. Regarding the tools for continuing medical education in neuro-oncology, a striking contrast between the ideal ones, which should be the frequent participation in dedicated courses (59% responses), and the actual one, which is scientific literature (55%), was recorded. Mentorship programs are rare and inconsistent and should be strengthened. More than 90% of participants declared multidisciplinary collaboration as fundamental. Multispecialty societies like AINO have a key role in strengthening education in neuro-oncology through the organization of structured post-graduate programs. Conclusion The results of this survey, by describing the status of the neuro-oncology training paths in Italy, can lay the foundation for initiatives aimed at harmonizing neuro-oncology education in Italy and Europe. The creation of a shared neuro-oncology curriculum and of a network of mentors is suggested.

INTRODUCTION:Adult-type IDH-mutant diffuse gliomas grade 2 are rare tumors mainly affecting young patients, classified by WHO 2021 into IDH-mutant astrocytomas and IDH-mutant 1p/19q codeleted oligodendrogliomas. IDH-mutant grade 2 gliomas are slowly growing tumors; however, they grow continuously, and almost all patients will ultimately recur. Surgical resection is the first option, followed by observation with MRI in low-risk patients and radio-chemotherapy in high-risk patients. Early clinical trials and phase 3 INDIGO trial have demonstrated the efficacy of vorasidenib, a dual IDH1/2 inhibitor, in prolonging imaging-based progression-free survival and time-to-next-intervention. AREAS COVERED:This review covers the following areas: importance of surgical resection, traditional treatments after surgery, mechanisms of IDH mutations and IDH inhibitors in preclinical models, early clinical studies on ivosidenib and vorasidenib, INDIGO trial, the future role of vorasidenib, open issues beyond INDIGO trial, and novel IDH targeting strategies. EXPERT OPINION:IDH1/2 mutations are ideal targets of therapy and early clinical studies and INDIGO phase 3 trial confirmed the clinical efficacy of vorasidenib. Long-term follow-up is needed to better define the efficacy across different subgroups of patients. Overall, vorasidenib will replace observation with MRI for low-risk patients and allow to delay radiotherapy and chemotherapy and their adverse effects.

Vorasidenib, a dual isocitrate dehydrogenase 1/2 (IDH1/2) inhibitor, showed superior efficacy in prolonging progression-free survival and time to next intervention in IDH-mutant grade 2 gliomas. This case is part of an ongoing institutional study exploring the impact of vorasidenib on seizure control and the potential of [18F]fluorodopa (F-DOPA) positron emission tomography (PET) to detect treatment response earlier than magnetic resonance imaging (MRI). A 52-year-old patient with grade 2 IDH-mutant 1p19q-codeleted oligodendroglioma and persistent postoperative seizures received vorasidenib. He achieved early seizure freedom from the first month of therapy without any change of antiseizure medication (ASM). At 3 and 6 months after treatment, MRI showed stable disease (with a slight progressive reduction in tumor volume), whereas F-DOPA PET revealed a significant decrease in tracer uptake starting from the third month, which was confirmed at 6 months, corresponding to a partial response according to PET Response Assessment in Neuro-Oncology 1.0 criteria. This is the first report of an IDH-mutant grade 2 glioma patient achieving early seizure control and metabolic response on F-DOPA PET after vorasidenib. It highlights the potential of vorasidenib for seizure management and the value of F-DOPA PET for early treatment assessment. Further studies are required to evaluate long-term seizure control and potential reduction of ASM in IDH-mutant low-grade gliomas treated with vorasidenib.

Abstract BACKGROUND The 2021 WHO Classification defines IDH-wildtype (IDHwt) astrocytomas with either EGFR amplification, pTERT mutation or +7/-10 chromosomal changes as molecularly-defined glioblastomas (mGBMs), even if histologically grade 2. However, it is not clear whether mGBMs share the same clinical characteristics, response to treatments and prognosis of histologically-defined (grade 4) IDHwt GBMs (hGBMs). The Italian Association of Neuro-Oncology (AINO) performed a multicentric study to address this issue. PATIENTS AND METHODS A retrospective AINO database was created to collect clinical data of patients with mGBM with grade 2 histological features from 2010 to 2023. Exclusion criteria were the presence of mitoses, necrosis and/or microvascular proliferation in tumour specimens, and strong ring-enhancement on MRI at onset. A historical cohort of 66 hGBM patients was used for comparison. RESULTS We collected 70 patients with mGBMs. Median age was 59 years (vs 60 years of hGBM patients). All mGBM and hGBM patients had KPS>70. 46/70 mGBMs (66%) and 13/66 hGBMs (20%) presented with seizures. Methylation of pMGMT was found in 23/53 mGBMs (43%) and 30/66 hGBMs (45%). Among mGBMs, EGFR amplification was found in 23/59 (39%), and pTERT mutation in 55/66 (83%). Gross-total resection was achieved in 20/70 mGBM (29%) patients, and 21/66 hGBMs (32%). Among mGBMs, post-surgical modalities were radiotherapy (RT) +/- concomitant temozolomide (TMZ) followed by TMZ in 39 (56%), observation in 15 (21%), upfront TMZ in 13 (19%); conversely, all hGBMs underwent concomitant RT/TMZ followed by TMZ. Patients with mGBMs vs hGBMs had longer median progression-free survival (mPFS) (13 vs 9 months, p=0.011) and overall survival (mOS) (27 vs 22 months, p=0.036). Unlike hGBMs, pMGMT methylation did not affect the outcome of mGBM patients undergoing chemoradiation, mPFS being 13 months for both pMGMT-methylated and unmethylated mGBM patients (p=0.471), and mOS 38 vs 25 months (p=0.291) - conversely, among hGBM patients with vs without pMGMT methylation, mPFS was 12 vs 8 months, p<0.001, and mOS 32 vs 15 months, p<0.001). Also, mGBM patients with isolated pTERT mutation, vs those with EGFR amplification, had similar mPFS (12 vs 8 months, p=0.780), and mOS (32 vs 22 months, p=0.175). However, mGBM patients with isolated pTERT mutation showed a trend for a better mOS after chemoradiation (45 months) as compared to TMZ upfront (17 months), p=0.06. CONCLUSION Although sharing some similar characteristics (median age, KPS), mGBM patients included in our study differed hGBMs: they had a higher incidence of seizures and significantly longer mPFS and mOS; also, pMGMT methylation did not affect the outcome of mGBMs. A trend for better mOS was seen in mGBM patients with isolated pTERT mutation after chemoradiation. The study is ongoing, to confirm these findings in a larger cohort.

High-grade gliomas (HGGs) constitute the most common malignant primary brain tumor with a poor prognosis despite the standard multimodal therapy. In recent years, immunotherapy has changed the prognosis of many cancers, increasing the hope for HGG therapy. We conducted a comprehensive search on PubMed, Scopus, Embase, and Web of Science databases to include relevant studies. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Fifty-two papers were finally included (44 phase II and eight phase III clinical trials) and further divided into four different subgroups: 14 peptide vaccine trials, 15 dendritic cell vaccination (DCV) trials, six immune checkpoint inhibitor (ICI) trials, and 17 miscellaneous group trials that included both “active” and “passive” immunotherapies. In the last decade, immunotherapy created great hope to increase the survival of patients affected by HGGs; however, it has yielded mostly dismal results in the setting of phase III clinical trials. An in-depth analysis of these clinical results provides clues about common patterns that have led to failures at the clinical level and helps shape the perspective for the next generation of immunotherapies in neuro-oncology.

Background and ObjectivesPatients with IDH1/2-mutant lower-grade glioma have a high frequency of seizures. We aimed to investigate the correlations between seizures and tumor/patient characteristics and the impact of surgery and adjuvant treatments (AT) on seizure control along the disease trajectory. MethodsWe retrospectively included patients with IDH1/2-mutant lower-grade glioma who underwent surgery at the neurosurgery divisions of the University of Turin and Milan and were treated at the Division of Neuro-Oncology of Turin. Inclusion criteria were a diagnosis according to the 2021 WHO Classification and presentation with seizures; exclusion criteria were presence of CDKN2A/B homozygous deletion, intense/ring contrast enhancement on MRI at presentation, and small tissue biopsy. We evaluated seizure freedom for 2 months after surgery, 6 months from starting observation or AT, at recurrence, and for 6 months after treatments of recurrence. ResultsWe included 150 patients. There were 77 (51%) and 31 (21%) patients with IDH-mutant/1p19q-codeleted grade 2 and 3 oligodendroglioma and 30 (20%) and 12 (8%) with IDH-mutant grade 2 and 3 astrocytoma, respectively. Total resection was accomplished in 68 (45%). Seventy-five patients (50%) received AT while the remaining 75 were observed with MRI. After 6 months after AT, 28 of 29 patients (96.5%) displayed seizure reduction, 5 of 28 (18%) being seizure-free. 66 of 124 patients (53%) had seizures at recurrence. After 6 months after second-line treatments, 60 of 66 patients (91%) had seizure reduction, 11 (17%) being seizure-free. In multivariable analyses, grade 3 histology positively correlated with seizure freedom at 2 months after surgery (OR 3.5, 1.4-8.9, p = 0.008), 6 months after AT (OR 9.0, 1.5-54.9, p = 0.017), and 6 months after treatment of recurrence (OR 4.9, 1.5-16.5, p = 0.009). Adjuvant radiotherapy reduced seizures at recurrence in a univariate analysis (OR 0.14, 0.03-0.7, p = 0.020). Patients with seizure freedom after surgery and AT displayed longer progression-free survival (PFS) (65, 24.5-105, vs 48 months, 32-63.5, p = 0.037). DiscussionThis study analyzed seizure control in patients with IDH1/2-mutant lower-grade glioma across multiple time points. Grade 3 correlated with better seizure control throughout the entire disease trajectory, and seizure freedom after surgery and AT correlated with a longer PFS regardless of tumor grade. These results could serve as an external control arm in clinical trials evaluating the efficacy on seizures of antitumor agents in patients with IDH-mutant lower-grade glioma.

Introduction: Recent anticoagulant intake represents a contraindication for thrombolysis in acute ischemic stroke. Idarucizumab reverses the anticoagulant effect of dabigatran, potentially allowing for thrombolysis. This nation-wide observational cohort study, systematic review, and meta-analysis evaluated the efficacy and safety of thrombolysis preceded by dabigatran-reversal in people with acute ischemic stroke. Patients and methods: We recruited people undergoing thrombolysis following dabigatran-reversal at 17 stroke centers in Italy (reversal-group), people on dabigatran treated with thrombolysis without reversal (no-reversal group), and age, sex, hypertension, stroke severity, and reperfusion treatment-matched controls in 1:7 ratio (control-group). We compared groups for symptomatic intracranial hemorrhage (sICH, main outcome), any brain hemorrhage, good functional outcome (mRS 0-2 at 3 months), and death. The systematic review followed a predefined protocol (CRD42017060274), and odds ratio (OR) meta-analysis was implemented to compare groups. Results: Thirty-nine patients in dabigatran-reversal group and 300 matched controls were included. Reversal was associated with a non-significant increase in sICH (10.3% vs 6%, aOR = 1.32, 95% CI = 0.39-4.52), death (17.9% vs 10%, aOR = 0.77, 95% CI = 0.12-4.93) and good functional outcome (64.1% vs 52.8%, aOR = 1.41, 95% CI = 0.63-3.19). No hemorrhagic events or deaths were registered in no-reversal group (n = 12). Pooling data from 3 studies after systematic review (n = 1879), reversal carried a non-significant trend for sICH (OR = 1.53, 95% CI = 0.67-3.50), death (OR = 1.53, 95% CI = 0.73-3.24) and good functional outcome (OR = 2.46, 95% CI = 0.85-7.16). Discussion and conclusion: People treated with reperfusion strategies after dabigatran reversal with idarucizumab seem to have a marginal increase in the risk of sICH but comparable functional recovery to matched patients with stroke. Further studies are needed to define treatment cost-effectiveness and potential thresholds in plasma dabigatran concentration for reversal.

Abstract INTRODUCTION Most patients with IDH-mutant grade 2 gliomas suffer from seizures. Recently, the INDIGO trial showed that vorasidenib prolonged progression-free-survival (PFS) and time-to-next-intervention in IDH-mutant grade 2 gliomas after surgery. We investigated which factors influence seizure-control in patients with the same characteristics of those of INDIGO. Patients and METHODS We retrospectively collected data of non-enhancing IDH-mutant grade 2 glioma patients (as per WHO-2021) who presented with seizures, and evaluated seizure-freedom at 2 months after surgery, 6 months from starting either observation or adjuvant treatments, at recurrence, and 6 months after treatment of recurrence. RESULTS Ninety-five patients were included. Oligodendrogliomas IDH-mutant/1p19q-codeleted grade 2 were 69 (72.6%), astrocytomas IDH-mutant grade 2 were 26 (27.4%). Thirty-five (36.8%) received gross-total resection (GTR). After surgery, 49 (51.6%) achieved seizure-freedom, more frequently after GTR vs non-GTR (57.9% vs 35.1%, p=0.048). Sixty-eight (71.6%) low-risk patients underwent observation, while 27 (28.4%) high-risk patients received adjuvant radiotherapy (RT) and/or chemotherapy (CT). Among the latter, 17/27 (63.0%) had persistent seizures before treatment initiation and, after 6 months, all of them displayed seizure-reduction, with 2/17 (7.4%) seizure-free. In a multivariable analysis on PFS, ≥ 50% seizure-reduction (vs < 50%) after 6 months of adjuvant treatment reduced the risk of progression (HR 0.048, 0.004-0.585, p=0.017). Eighty-six (90.5%) patients recurred, and 51/86 (59.3%) displayed seizures. After 6 months of treatment of recurrence, 50/51 (98.0%) achieved seizure-reduction, with 10/51 (19.6%) seizure-free. In a multivariable analysis, either CT or RT increased the probability of seizure-freedom at 6 months after recurrence (HR 5.316, 1.582-17.869, p=0.007). CONCLUSION We defined the entity of seizure-control after standard treatments throughout the disease course. Two findings are noteworthy: the prognostic importance of seizure-reduction after adjuvant treatments; the possibility to achieve seizure-control also with treatment of recurrence. This study could serve as a benchmark for future evaluation of seizure-control with IDH inhibitors.

INTRODUCTION:The diagnosis and monitoring of leptomeningeal metastases (LM) from solid tumors are challenging, and the combination of neurological symptoms, MRI findings, and cerebrospinal fluid (CSF) cytology does not always allow to achieve a definitive diagnosis.AREAS COVERED:This review summarizes the studies that have investigated CSF liquid biopsy to improve the initial diagnosis of LM in case the CSF cytology is negative or only suspicious for tumor cells, and monitoring of tumor response following targeted therapies or immunotherapy. In this regard, the early detection of LM recurrence and the development of resistant mutations are critical issues. Moreover, the early identification of subgroups of patients with a higher risk of LM progression, as well as the correlation of LM burden with survival, are discussed.EXPERT OPINION:There is an urgent need of prospective studies to monitor longitudinally LM using CSF liquid biopsy and investigate the role of CTC, ctDNA or novel assays. The optimal setting for the longitudinal CSF and blood collection can be clinical trials focused on the molecular diagnosis of LM as well as the response and monitoring following targeted agents.

Abstract BACKGROUND Vismodegib is a SHH-inhibitor that proved to be effective in locally-recurrent SHH-activated medulloblastoma. However, whether vismodegib is effective in case of neoplastic meningitis (NM) as well has not been assessed so far. Here, we present a case of a patient with NM from SHH-activated medulloblastoma who showed a dramatic response to vismodegib. Case Report: A 34-year-old patient was diagnosed with a SHH-activated cerebellar medulloblastoma in 2015. He underwent gross-total resection, cranio-spinal radiotherapy (RT) and 5 cycles of lomustine, vincristine and cisplatin. Then, he remained disease-free until October 2021, when the MRI showed a new single contrast-enhanced nodule in the spine (T10), which was treated with stereotactic RT. However, the following MRI showed a diffuse leptomeningeal involvement, with new multiple linear and nodular lesions. The CSF cytology confirmed the presence of neoplastic cells. Therefore, in April 2022 vismodegib (150 mg daily) was started. The treatment was well tolerated, except for increased creatine phosphokinase (CTCAE v3.0 grade 1). After only 2 months of therapy, a reduction of the meningeal enhancement was seen on MRI, and after 4 months all nodular and linear lesions disappeared. Similarly, CSF cytology became negative after 4 months of treatment. However, after 8 months of treatment (December 2022), the MRI of the spine showed the new appearance of meningeal contrast-enhanced lesions, and CSF cytology confirmed the presence of neoplastic cells. Therefore, vismodegib was dismissed. In few days, the patient (who did not have any symptoms so far) developed severe meningeal symptoms, and palliative care was started, until his death in February 2023. CONCLUSION To our knowledge, this is the first report of an adult patient with NM from SHH-activated medulloblastoma achieving a complete response with vismodegib, even if temporary. Data from larger series are needed to confirm the effectiveness and safety of vismodegib in case of leptomeningeal spread.