Frequent FGFR1 hotspot alterations in driver-unknown low-grade glioma and mixed neuronal-glial tumors

Purpose Low-grade gliomas (LGG) and mixed neuronal-glial tumors (MNGT) show frequent MAPK pathway alterations. Oncogenic fibroblast growth factor receptor 1 (FGFR1) tyrosinase kinase domain has been reported in brain tumors of various histologies. We sought to determine the frequency of FGFR1 hotspot mutations N546 and K656 in driver-unknown LGG/MNGT and examined FGFR1 immunohistochemistry as a potential tool to detect those alterations. Methods We analyzed 476 LGG/MNGT tumors for KIAA-1549-BRAF fusion, IDH1/2, TERT promotor, NF1, H3F3A and the remaining cases for FGFR1 mutation frequency and correlated FGFR1 immunohistochemistry in 106 cases. Results 368 of 476 LGG/MNGT tumors contained non-FGFR1 alterations. We identified 9 FGFR1 p.N546K and 4 FGFR1 p.K656E mutations among the 108 remaining driver-unknown samples. Five tumors were classified as dysembryoplastic neuroepithelial tumor (DNT), 4 as pilocytic astrocytoma (PA) and 3 as rosette-forming glioneuronal tumor (RGNT). FGFR1 mutations were associated with oligodendroglia-like cells, but not with age or tumor location. FGFR1 immunohistochemical expression was observed in 92 cases. FGFR1 immunoreactivity score was higher in PA and DNT compared to diffuse astrocytoma, but no correlation between FGFR1 mutation in tumors and FGFR1 expression level was observed. Conclusion FGFR1 hotspot mutations are the fifth most prevailing alteration in LGG/MNGT. Performing FGFR1 sequencing analysis in driver-unknown low-grade brain tumors could yield up to 12% FGFR1 N546/K656 mutant cases.

Experience in treatment of glial tumors using the CyberKnife device

The study objective is to determine the effectiveness of stereotactic radiotherapy in treatment of glial cerebral tumors.Materials and methods. Results of using stereotactic radiotherapy in treatment of recurrent cerebral gliomas in 30 patients and primary glial tumor in 1 patient who couldn’t receive traditional radiotherapy were analyzed. Treatment was administered both to adults (n = 22) and children (n = 9). Prior to treatment all patients underwent pre-radiotherapy preparation in the form of contrast-enhanced magnetic resonance topometry of the brain, computed tomography with topometry, as well as positron emission tomography/computed tomography with amino acids (n = 21).Results. During treatment 2 patient developed grade II toxic reactions requiring emergency medical help. In 29 patients, treatment did not cause any complications. At the time of article preparation, 7 patients were alive; maximal follow-up period was 55 months, median follow-up duration was 8 months.Conclusion. Stereotactic radiotherapy can be used for disease stabilization. The results show effectiveness and safety of stereotactic radiotherapy as a salvage method of local treatment in patients with recurrent glial tumors of the brain.

BIOM-22. RELEVANCE OF TUMOR MUTATION BURDEN (TMB) IN HIGH-GRADE GLIOMAS

BACKGROUND Efforts have been directed toward searching for molecular biomarkers predicting response to immunotherapy in glial tumors. Recently, FDA granted accelerated approval of pembrolizumab for treatment patients with solid tumors with high mutational burden (TMB-H; ≥ 10 mut/Mb). There are conflicting results regarding the use of this parameter in glial tumors. OBJECTIVE to review NGS examinations of patients with glial tumors and high TMB and to analyze their response to immunotherapy. METHODS we retrospectively reviewed NGS examinations from patients with glial tumors treated in Tel-Aviv Medical Center from 2016-2021. Cases with TMB-H were retrieved and analyzed. RESULTS We identified nine high-grade glioma patients with TMB-H. The median age was 38 (19-65). There were 4 patients with glioblastoma; three with anaplastic oligodendroglioma; and two with anaplastic astrocytoma. All but one received radiation prior to the biopsy used for NGS examination, and all were treated with temozolomide. The median TMB was 54 (19-252). Only one glioblastoma patient with a family history of Lynch syndrome had microsatellite instability (MSI)-high; all other patients were MSI stable (MSS). Nevertheless, in all cases, mutated mismatch repair (MMR) genes were detected (MSH6 in 3 patients, MSH2 in one patient, MLH1 in one patient, PMS 2 in one patient, and both MSH2 and 6 in one patient). Six patients received immunotherapy. Only one patient with recurrent glioblastoma and the highest TMB in the group (252) demonstrated a near complete response to pembrolizumab and remains on treatment more than three years. All other patients did not respond to immunotherapy. CONCLUSION TMB-H in primary glioma is associated with mutations of MMR genes. It is typically associated with MSS in these patients (MSI-high was seen in only one syndromic patient). In contrast to systemic neoplasms with TMB-H, the majority of our patients did not respond to immunotherapy.

Glial Tumors

Glial tumors are primary brain and spinal cord tumors arising from supporting cells of the central nervous system, including oligodendrocytes, astrocytes, microglia, and ependymal cells. Collectively, glial tumors are the most common category of primary brain tumors. They may be infiltrative or well circumscribed. Prognosis ranges from surgical cure to survival of less than 2 years, depending on tumor type. Age is the strongest risk factor for glioma in adults, with incidence rates increasing from a low of 3.2 per 100,000 person-years among persons age 20 to 34 years to a high of 19.3 per 100,000 person-years among those age 75 to 84 years.

TO ESTABLISH THE CORRELATION BETWEEN P53 AND HISTOPATHOLOGICAL GRADING OF GLIAL TUMORS

Glial tumors occupy approximately 70% of the spectrum of all brain tumors with astrocytoma’s being the most common primary. High grade glial tumors have a poor outcome with limited survival rate. To establish the correlation between p53 status and histological grading of glial tumors. Objectives: To diagnose glial tumors on histopathological examination, to evaluate histological grade, to evaluate p53 expression and to assess the correlation between p53 expression and histological grade of gliomas. The study investigated 52 cases of gliomas. Histological grade was determined by WHO Grading System. Nuclear expression of p53 was evaluated by immunohistochemistry. A direct correlation between the histological grade and the p53 expression was observed. High grade gliomas exhibit high p53 expression. Thus, p53 as an adjunct to histological grade can provide a supportive clue to the clinicians, to predict the biological behaviour of gliomas.

A Systematic Review of the Tumor-Infiltrating CD8+ T-Cells/PD-L1 Axis in High-Grade Glial Tumors: Toward Personalized Immuno-Oncology

Based on preclinical findings, programmed death-ligand 1 (PD-L1) can substantially attenuate CD8+ T-cell-mediated anti-tumoral immune responses. However, clinical studies have reported controversial results regarding the significance of the tumor-infiltrating CD8+ T-cells/PD-L1 axis on the clinical picture and the response rate of patients with high-grade glial tumors to anti-cancer therapies. Herein, we conducted a systematic review according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements to clarify the clinical significance of the tumor-infiltrating CD8+ T-cells/PD-L1 axis and elucidate the impact of this axis on the response rate of affected patients to anti-cancer therapies. Indeed, a better understanding of the impact of this axis on the response rate of affected patients to anti-cancer therapies can provide valuable insights to address the futile response rate of immune checkpoint inhibitors in patients with high-grade glial tumors. For this purpose, we systematically searched Scopus, Web of Science, Embase, and PubMed to obtain peer-reviewed studies published before 1 January 2021. We have observed that PD-L1 overexpression can be associated with the inferior prognosis of glioblastoma patients who have not been exposed to chemo-radiotherapy. Besides, exposure to anti-cancer therapies, e.g., chemo-radiotherapy, can up-regulate inhibitory immune checkpoint molecules in tumor-infiltrating CD8+ T-cells. Therefore, unlike unexposed patients, increased tumor-infiltrating CD8+ T-cells in anti-cancer therapy-exposed tumoral tissues can be associated with the inferior prognosis of affected patients. Because various inhibitory immune checkpoints can regulate anti-tumoral immune responses, the single-cell sequencing of the cells residing in the tumor microenvironment can provide valuable insights into the expression patterns of inhibitory immune checkpoints in the tumor micromovement. Thus, administrating immune checkpoint inhibitors based on the data from the single-cell sequencing of these cells can increase patients’ response rates, decrease the risk of immune-related adverse events development, prevent immune-resistance development, and reduce the risk of tumor recurrence.