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Background: Cerebrospinal fluid (CSF) stands as an easily accessible reservoir for circulating tumor DNA (ctDNA) analysis in patients with CNS tumors, although evidence is still limited. Our aim was to prospectively evaluate the feasibility of detecting ctDNA for mutational analysis in CSF and plasma in patients with glioma., Methods: Prospective study of patients with gliomas diagnosed at four third-level hospitals in Spain. A customized next-generation sequencing (NGS) 8-gene panel (IDH1, IDH2, ATRX, TP53, PTEN, PIK3CA, EGFR, BRAF) was used in paired CSF, plasma and tumor samples. Mutation concordance occurred when the same pathogenic gene variant was detected in tumor and ctDNA. The prognostic value of ctDNA and that of its median variant allele frequency (mVAF) were analyzed., Results: Between February 2017 and March 2020, 37 patients with glioma were enrolled. Among 32 patients with analyzable CSF samples: new diagnosis (n=23); relapse (n=9). WHO 5th Ed: IDH-mut astrocytoma (n=10), IDH-mutant oligodendroglioma (n=6), IDH-wildtype glioblastoma (n=16). CSF-ctDNA-positive (ctDNA+): 19/32 (59%). CSF-ctDNA-negative (ctDNA-): 13/32 (41%). No. of mutations in CSF: 1 (10/19), 2 (7/19), 3 (2/19). Frequency of CSF-ctDNA mutated genes: EGFR (8/19: 42%), PTEN (7/19: 37%), TP53 (6/19: 32%), IDH1 (5/19: 26%), PIK3CA (4/19: 21%). Tumor-CSF mutation concordance: 16/19 (84%). Progression-free and overall survivals were significantly shorter in patients with ctDNA+ ≥ mVAF compared to ctDNA+ < mVAF. No association was found between ctDNA in CSF and distance to closest CSF reservoir, tumor size or IDH status. ctDNA was detected in 2 out 14 (14%) individual plasma samples, in both cases concordant with the primary tumor., Conclusion: CSF is a reliable reservoir for ctDNA analyses in patients with gliomas. ctDNA is detectable in plasma although at a lower rate. Larger, prospective studies should be conducted to refine the potential role of liquid biopsy in this disease., (Copyright © 2025 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

FGFR3-TACC3 fusion-positive IDH-wild-type (IDH-WT) glioblastoma (GB) is a rare GB subtype occurring in approximately 3% of cases. It is clinical behavior and molecular profile is different from those of fusion-negative IDH-WT GBs. Evidence on the role of FGFR inhibitors in FGFR-altered gliomas is limited. We present the case of a patient with a FGFR3-TACC3 fusion-positive IDH-WT GB that at its second recurrence was treated with the FGFR inhibitor erdafitinib through a compassionate use program. Although no objective response was achieved, an overt deceleration in tumor growth was evidenced and the patient remained on treatment for 5.5 months., Competing Interests: Santiago Cabezas-Camarero: Consultant for: Bristol-Myers Squibb, Merck, MSD. Speaker’s Bureau for: Bristol-Myers Squibb, Merck, MSD. Employee of: None. Grant/Research support from clinical trials: AstraZeneca, MSD, Merck. Travel and Academic work Fees from: Merck, MSD, Johnson & Johnson Innovative Medicine. Rebeca Pérez-Alfayate: Travel expenses: Prim. Pedro Pérez-Segura: Consultant for: Bristol-Myers Squibb, Merck, MSD. Speaker’s Bureau for: Bristol-Myers Squibb, Merck, MSD. Employee of: None. Grant/Research support from (Clinical Trials): Bristol-Myers Squibb, AstraZeneca, MSD. Travel and Academic work Fees from: Merck, MSD and Bristol-Myers Squibb. The rest of the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Adult medulloblastoma (MB) is a rare disease affecting 0.6 persons per million adults over 19 years of age. The SHH-activated/TP53-wild type is the most common subtype, accounting for 60% of adult MBs, being characterized by mutations in PTCH1, SMO, or the TERT promoter. Several small studies demonstrate objective but short-lived responses to SMO inhibitors such as vismodegib or sonidegib. Like other oncogene-addicted solid tumors, detection of the corresponding drivers through liquid biopsy could aid in the molecular diagnosis and monitoring of the disease through less invasive procedures. However, most studies have only evaluated cerebrospinal fluid as the ctDNA reservoir, and very limited evidence exists on the role of liquid biopsy in plasma in patients with primary central nervous system tumors, including MB. We present the case of a 26-year-old patient with a recurrent MB, in which next-generation sequencing (FoundationOne CDx) revealed a mutation in PTCH1, allowing the patient to be treated with vismodegib in second line, resulting in a durable benefit lasting for 1 year. Using an in-house digital PCR probe, the PTCH1 mutation could be tracked in ctDNA during treatment with first-line chemotherapy and while on treatment with vismodegib, demonstrating a precise correlation with the radiological and clinical behavior of the disease., (© The Author(s) 2024. Published by Oxford University Press.)

Corneal dystrophies are hereditary diseases affecting the corneal tissue; they are bilateral, symmetrical and unrelated to environmental or systemic conditions. Congenital corneal stromal dystrophy is a very rare autosomal dominant dystrophy that is caused by a mutation in the DCN gene that encodes decorin (a proteoglycan of the extracellular matrix). We herein report 4 cases of congenital stromal corneal dystrophy in 2 families, highlighting the previously undescribed histopathologic features, the possible differential diagnosis of this entity and the key role played by decorin staining in its diagnosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Molecular testing using blood-based liquid biopsy approaches has not been widely investigated in patients with glioma. A prospective single-center study enrolled patients with gliomas ranging from grade II to IV. Peripheral blood (PB) was drawn at different timepoints for circulating tumour DNA (ctDNA) monitoring. Next-generation sequencing (NGS) was used for the study of isocitrate dehydrogenase 1 (IDH1) mutations in the primary tumor. Beads, Emulsion, Amplification and Magnetics (BEAMing) was used for the study of IDH1 mutations in plasma and correlated with the NGS results in the tumor. Between February 2017 and July 2018, ten patients were enrolled, six with IDH1-mutant and four with IDH1 wild-type gliomas. Among the six IDH-mutant gliomas, three had the same IDH1 mutation detected in plasma (50%), and the IDH1-positive ctDNA result was obtained in patients either at diagnosis (no treatment) or during progressive disease. While the false-negative rate reached 86% (18/21), 15 out of the 18 (83%) plasma-negative results were from PB collected from the six IDH-mutant patients at times at which there was no accompanying evidence of tumor progression, as assessed by MRI. There were no false-positive cases in plasma collected from patients with IDH1 wild-type tumors. BEAMing detected IDH1 mutations in the plasma of patients with gliomas, with a modest clinical sensitivity (true positivity rate) but with 100% clinical specificity, with complete agreement between the mutant loci detected in tumor and plasma. Larger prospective studies should be conducted to expand on these findings, and further explore the clearance of mutations in PB from IDH1-positive patients in response to therapy.

Germline replication-repair deficient (gRRD) gliomas are exceptional events, and only a few of them have been treated with immune checkpoint inhibitors (ICIs). Contrary to sporadic gliomas, where ICIs have failed to show any objective benefit, the very few patients with gRRD gliomas treated with ICIs to date seem to benefit from programmed-death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, either in terms of durable responses or in terms of survival. T-cell immunohistochemistry (IHC) and T-cell receptor (TCR) repertoire using high-throughput next-generation sequencing (NGS) with the Oncomine TCR-Beta-SR assay (Thermo Fisher Scientific) were analyzed in pre- and post-nivolumab tumor biopsies obtained from a patient with a Lynch syndrome-associated glioma due to a germline pathogenic hMLH1 mutation. The aim was to describe changes in the T-cell quantity and clonality after treatment with nivolumab to better understand the role of acquired immunity in gRRD gliomas. The patient showed a slow disease progression and overall survival of 10 months since the start of anti-PD-1 therapy with excellent tolerance. A very scant T-cell infiltrate was observed both at initial diagnosis and after four cycles of nivolumab. The drastic change observed in TCR clonality in the post-nivolumab biopsy may be explained by the highly spatial and temporal heterogeneity of glioblastomas. Despite the durable benefit from nivolumab, the scant T-cell infiltrate possibly explains the lack of objective response to anti-PD-1 therapy. The major change in TCR clonality observed after nivolumab possibly reflects the evolving molecular heterogeneity in a highly pre-treated disease. An in-deep review of the available literature regarding the role of ICIs in both sporadic and gRRD gliomas was conducted., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Santiago Cabezas-Camarero Consultant for: Bristol-Myers Squibb, Merck, MSD. Speaker’s Bureau for: Bristol-Myers Squibb, Merck, MSD. Employee of: None. Grant/Research support from (Clinical Trials): Bristol-Myers Squibb, AstraZeneca, MSD. Travel and Academic work Fees from: Merck, MSD and Bristol-Myers Squibb. Pedro Pérez Segura Consultant for: Bristol-Myers Squibb, Merck, MSD. Speaker’s Bureau for: Bristol-Myers Squibb, Merck, MSD. Employee of: None. Grant/Research support from (Clinical Trials): Bristol-Myers Squibb, AstraZeneca, MSD. Travel and Academic work Fees from: Merck, MSD and Bristol-Myers Squibb. The rest of the authors declare no conflicts of interest relevant to the publication of this article., (© The Author(s), 2022.)