Assessment of Therapeutic Outcome and Role of Reirradiation in Patients With Radiation-induced Glioma

Background: We retrospectively reviewed the clinical characteristics and treatment outcomes to clarify the optimal therapeutic strategy, especially the role of reirradiation in patients with radiation-induced glioma (RIG). Methods: We identified patients with high-grade glioma who satisfied Cahan’s criteria for RIG in our database during 2001–2021 and analyzed the outcomes.Results: We identified 11 patients with RIG. The primary diseases included germinomas (n=2), acute lymphoblastic lymphomas (n=2), medulloblastomas (n=3), diffuse astrocytoma with isocitrate dehydrogenase (IDH) 2 mutant (n=1), pilocytic astrocytoma (n=1), pituitary adenoma (n=1), and a metastatic tumor from lung cancer (n=1). The median latency period was 17 years (range: 9–30 years). The RIGs included glioblastoma with IDH 1/2 wild-type (n=7), glioblastoma not otherwise specified (n=2), anaplastic astrocytoma with IDH1/2 wild-type (n=1), and anaplastic astrocytoma not otherwise specified (n=1). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and overall survival times were 11.3 and 28.3 months, respectively. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n=5) tended to be longer than that of patients that received chemotherapy alone (n=6) (17.0 vs 8.1 months; p=0.45); the median survival time was similar (29.6 vs 27.4 months; p=0.28). Local recurrences were observed less frequently in patients who received reirradiation combined with chemotherapy (50%) than in those who received chemotherapy alone (100%; p=0.046). None of the patients developed radiation necrosis. In one case, the different IDH2 mutational states between the primary and secondary tumors were useful for diagnosing the secondary tumor as RIG. Conclusions: RIG can occur more than 20 years after successful treatment of the primary disease using radiotherapy; thus, follow-up times should be extended to 30 years. Reirradiation combined with chemotherapy appears to be feasible and have favorable outcomes. Identifying the IDH1/2 mutational status can have a diagnostic effect on establishing RIG in recurrent gliomas.

NI-16 Verification of APT image and relationship with T2/FLAIR mismatch sign in WHO2016 brain tumor pathology classification

Introduction: Amide Proton Transfer Imaging(APT)is an MRI imaging method that images the increased concentration of amide groups in tumors and is expected to be clinically applied to the diagnostic imaging of gliomas.On the other hand,T2/FLAIR mismatch sign(T2/FLms)has been proposed as an MRI finding specific to astrocytoma with IDH gene mutation.This time,in the WHO2016 Brain Tumor Pathological Classification,we report the verification of the pathological gene classification of APT and the retrospective verification based on the pathological diagnosis results of whether there is a relationship between APT and T2/FLms. Method: We examined 88 cases of preoperative glioma (Grade:G2/3/4)in which APT/T2/FLAIR was imaged.resultIt showed a high value in high malignancy and a significant difference was observed.In the verification of genetic classification, the measured APT values were 1.91 ±0.71 for oligodendroglioma(16 cases),2.58±0.17 for astrocytoma(2 cases),2.40±0.90 for anaplastic oligodendroglioma(12 cases),Anaplastic astrocytoma(20 cases)2.63±0.42,The oligodendroglioma system showed lower values than the astrocytoma system.For anaplastic astrocytoma IDH mutant and glioblastoma IDH mutant,APT measurement values were measured after evaluating the presence or absence of T2/FL ms. APT measured values are anaplastic astrocytoma IDH mutant T2/FL ms present(7 cases) 2.63±0.38,T2/FL ms not (5 cases) 2.76±0.37, glioblastoma IDH mutant T2/FL ms present(5 cases)2.67±0.50, no T2/FL ms(3 cases)3.48±0.27,suggesting low APT measured values with T2/FL ms,respectively.ConclusionIn the verification of genetic classification, the oligodendroglioma system shows a lower value than the astrocytoma system,and it is considered that it can be one of the options such as treatment policy.Regarding the relationship between T2/FL ms and APT,it was suggested that the APT measured value with T2/FL ms tended to be low,but since it wasreported that the sensitivity of T2/FL ms was 30%,it was verified by accumulating cases.is required.

Fractal analysis of 11C-methionine PET in patients with newly diagnosed glioma

Background The present study tested the possible utility of fractal analysis from l-[methyl-11C]-methionine (MET) uptake in patients with newly diagnosed gliomas for differentiating glioma, especially in relation to isocitrate dehydrogenase 1 (IDH1) mutation status, and as compared with the conventional standardized uptake value (SUV) parameters. Methods Investigations of MET PET/CT were performed retrospectively in 47 patients with newly diagnosed glioma. Tumors were divided into three groups: lower grade glioma (IDH1-mutant diffuse astrocytoma and IDH1-mutant anaplastic astrocytoma), higher grade glioma (IDH1-wildtype diffuse astrocytoma and IDH1-wildtype anaplastic astrocytoma), and glioblastoma. The fractal dimension for tumor, maximum SUV (SUVmax) for tumor (T) and mean SUV for normal contralateral hemisphere (N) were calculated, and the tumor-to-normal (T/N) ratio was determined. Metabolic tumor volume (MTV) and total lesion MET uptake (TLMU) were also measured. Results There were significant differences in SUVmax (p = 0.006) and T/N ratio (p = 0.02) between lower grade glioma and glioblastoma. There were no significant differences among any of the three groups in MTV or TLMU. Significant differences were obtained in the fractal dimension between lower grade glioma and higher grade glioma (p = 0.006) and glioblastoma (p < 0.001). Conclusions The results of this preliminary study in a small patient population suggest that the fractal dimension using MET PET in patients with newly diagnosed gliomas is useful for differentiating glioma, especially in relation to IDH1 mutation status, which has not been possible with SUV parameters.

PATH-27. MGMT PROMOTER STATUS IN IDH1/2 MUTANT ANAPLASTIC ASTROCYTOMA PATIENTS ASSESSED BY DNA METHYLATION PROFILING AND QMS-PCR: A REPORT FROM THE EORTC BRAIN TUMOR GROUP

BACKGROUND Temozolomide efficacy in high-grade glioma is related to MGMTp methylation. We compared the prognostic and predictive effect of MGMTp between DNA methylation profiling (MGMT-STP27 model) and qMS-PCR in IDH1/2mt anaplastic astrocytoma patients. METHODS The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4Gy radiotherapy, radiotherapy with concurrent temozolomide, radiotherapy with 12 cycles of adjuvant temozolomide, or radiotherapy with concurrent and adjuvant temozolomide. MGMTp methylation status was assessed with the MGMT-STP27 model using 850k EPIC data, and qMS-PCR. IDH1/2 mutation status was determined with next-generation sequencing. OS was measured from randomization date. RESULTS We identified 444 IDH1/2mt anaplastic astrocytoma patients. MGMTp was methylated in 365/440 patients (83.0%) with MGMT-STP27 data, and 168/361 patients (46.5%) with qMS-PCR data. The agreement between both modalities is 59.9% (Cohen’s Kappa score 0.229). At database lock, 289 patients with MGMT-STP27 data were alive and 236 patients with qMS-PCR data. The median OS of MGMTp methylated glioma patients was 9.1 yrs [95%CI 7.5-not reached] for the MGMT-STP27 model, and not reached [95%CI 9.1-not reached] for qMS-PCR. For MGMTp unmethylated glioma patients, the median OS was 6.9 yrs [95%CI 6.2-not reached] for the MGMT-STP27 model, and 6.8 yrs [95%CI 6.2-9.7] for qMS-PCR. The HR for OS based on MGMTp methylation was 0.88 [95%CI 0.58-1.31] for the MGMT-STP27 model, and 0.72 [95%CI 0.50-1.03]) for qMS-PCR. The HR for OS after radiotherapy with any temozolomide vs radiotherapy alone for the MGMT-STP27 model was 0.53 [95%CI 0.37-0.78] for MGMTp methylated, and 0.54 [95%CI 0.25-1.18] for MGMTp unmethylated glioma patients; and for MS-PCR was 0.34 [95%CI 0.19-0.61] for MGMTp methylated, and 0.53 [95%CI 0.33-0.85] for MGMTp unmethylated glioma patients. CONCLUSION MGMTp methylation, regardless of assay, was neither prognostic nor predictive for outcome to temozolomide in IDH1/2mt anaplastic astrocytoma patients.

777 Personalized DNA vaccine in combination with plasmid encoded IL-12 for the treatment of a patient with anaplastic astrocytoma

BackgroundTumor neoantigens are epitopes derived from tumor-specific mutations. Such mutations can be incorporated in personalized vaccines to prime T cell responses against tumor specific antigens. DNA vaccines delivered with electroporation have recently shown strong CD8 and CD4 T cell responses in clinical trials. In preclinical studies, DNA-encoded neoantigen vaccines have shown induction of CD8 T cells against 50% of predicted high affinity epitopes with the ability to impact tumor growth.MethodsTwo resection samples from a patient with IDH+ MGMT-methylated anaplastic astrocytoma were subject to whole exome and transcriptome sequencing. Epitopes derived from 27 neoantigens and 3 shared tumor-associated antigens were prioritized and included in a personalized vaccine. The patient was treated with surgery, radiotherapy and temozolomide starting June 2018 and received the first dose of the personalized vaccine in June 2019 under a compassionate use single patient IND application with the FDA.ResultsAs of July 23rd, 2021, the patient has received 11 doses of the DNA personalized vaccine. No serious adverse events have been reported. Related adverse events are limited to grade 1 injection site reactions. The patient remains progression-free 37 months after surgery and 25 months after starting vaccination. Three weeks following the 3rd dose, a hyperintense image on the tumor bed was identified, which disappeared on the following MRI, 2 weeks following dose 5, being catalogued as pseudo progression. Ex vivo ELISpot have identified T cell responses to 28/30 epitopes (93.3%), including 25/27 (92.6%) neoantigens and 3/3 (100%) shared antigens. Flow cytometry analysis has determined that T cell responses are 92.3% CD8 and 69.2% CD4 (30.8% CD8 only; 61.5% both CD8 and CD4; and 7.7% CD4 only).ConclusionsThis compassionate use treatment in an adjuvant setting demonstrates manufacturing feasibility, safety, tolerability, immunogenicity, and suggests potential for persistent clinical response of DNA encoded personalized vaccines. The data supports further investigation of DNA-encoded personalized vaccines into newly diagnosed high-grade gliomas.Ethics ApprovalThe study was approved by Washington University's IRB. The participant gave informed consent before taking part in the study.

Approaches for the prevention and treatment of venous thromboembolism in a patient with anaplastic astrocytoma: a case report

Venous thromboembolism occurs in 48–200 out of 1,000 patients with brain cancer per year, which is significantly more frequent than in general population.Case report. A female patient had surgical treatment of anaplastic astrocytoma following radiotherapy and chemotherapy (temozolomide, irinotecan, bevacizumab) at the age of 17 years old. She also received dexamethasone. At the age of 20 years, she developed cancer recurrence, that required chemotherapy. After chemotherapy had been initiated, the patient developed deep vein thrombosis of the legs. Rivaroxaban 20 mg/d for 2.5 months with the subsequent switch to enoxaparin 60 mg/d showed no recanalization. Enoxaparin dose increasing up to 160 mg/d demonstrated incomplete recanalization, however, superficial venous thrombosis of the legs developed. Combination therapy with enoxaparin plus warfarin resulted in further deep and superficial veins recanalization.Discussion. In cancer-associated venous thromboembolism that is resistant to low molecular weight heparin monotherapy, short-term combination therapy with low molecular weight heparin and vitamin K antagonists can be considered. However, in recurrent cancer standard treatment protocols can be ineffective.

Aggressively recurring cervical intramedullary anaplastic astrocytoma in a pregnant patient

Background: Many patients with spinal juvenile pilocytic astrocytoma can experience prolonged remission after resection. However, some reports suggest that pregnancy may be associated with progression. Case Description: The authors provide an image report highlighting a case of rapid and aggressive transformation of an intramedullary astrocytoma of the cervical spine in a pregnant patient. Over the course of 1 year, the lesion progressed from a juvenile pilocytic astrocytoma to an anaplastic astrocytoma. Genetic testing revealed mutations associated with aggressive behavior. Conclusion: The case and associated imaging demonstrate the importance of close neurologic monitoring and counseling regarding risk of progression in pregnant patients with spinal gliomas.

OS05.2.A MGMT promoter status in IDH1/2 mutant anaplastic astrocytoma patients assessed by DNA methylation profiling and qMS-PCR: a report from the EORTC Brain Tumor Group

BACKGROUND Temozolomide (TMZ) efficacy in high-grade glioma is related to O 6-methylguanine DNA methyltransferase promoter (MGMTp) methylation. We compared the prognostic and predictive effect of MGMTp between DNA methylation profiling (the MGMT-STP27 model) and quantitative methylation specific polymerase chain reaction (qMS-PCR) in isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant (mt) anaplastic astrocytoma patients. MATERIAL AND METHODS The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy (RT), RT with concurrent TMZ, RT with 12 cycles of adjuvant TMZ, or RT with concurrent and adjuvant TMZ. MGMTp methylation status was assessed with the MGMT-STP27 model using 850k EPIC data, and qMS-PCR. IDH1/2 mutation status was determined with a next-generation sequencing panel. Overall survival (OS) was measured from date of randomization. RESULTS We identified 444 IDH1/2mt anaplastic astrocytoma patients of which MGMT-STP27 data was available for 440 patients (99.1%), qMS-PCR data for 361 patients (81.3%), and both for 357 patients (80.4%). MGMTp was methylated in 365 patients (83.0%) for the MGMT-STP27 model, and 168 patients (46.5%) for qMS-PCR. The agreement between the MGMT-STP27 model and qMS-PCR is 59.9% with a Cohen’s Kappa score of 0.229. At database lock, 289 patients with MGMT-STP27 data were still alive and 236 patients with qMS-PCR data. The median OS of MGMTp methylated glioma patients was 9.1 yrs [95 % confidence interval (CI) 7.5-not reached] for the MGMT-STP27 model, and not reached [95 % CI 9.1-not reached] for the qMS-PCR data. For MGMTp unmethylated glioma patients, the median OS was 6.9 yrs [95% CI 6.2-not reached] for the MGMT-STP27 model, and 6.8 yrs [95% CI 6.2–9.7] for the qMS-PCR data. The hazard ratio (HR) for OS based on MGMTp methylation was 0.88 [95% CI 0.58–1.31] for the MGMT-STP27 data, and 0.72 [95% CI 0.50–1.03]) for the qMS-PCR data. The HR for OS after RT with any TMZ vs RT alone for the MGMT-STP27 model was 0.53 [95% CI 0.37–0.78] for MGMTp methylated, and 0.54 [95% CI 0.25–1.18] for MGMTp unmethylated glioma patients; and for the MS-PCR data was 0.34 [95% CI 0.19–0.61] for MGMTp methylated, and 0.53 [95% CI 0.33–0.85] for MGMTp unmethylated glioma patients. CONCLUSION MGMTp methylation, regardless of assay, was neither prognostic nor predictive for outcome to temozolomide in IDH1/2mt anaplastic astrocytoma patients.