Early progressive disease in IDH-mutant grade 2 and 3 astrocytoma without CDKN2A/B homozygous deletions may indicate radiation necrosis

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However, some cases show early progression on MRI, and these characteristics have not been fully reported. This study aimed to elucidate the characteristics of those cases. Methods This retrospective study included 52 primary cases with astrocytoma, IDH-mutant, CNS WHO grade 2–3, reclassified from the original diagnosis based on WHO2021 classification. Patients underwent surgery followed by radiation therapy or/and chemotherapy at our institution from 2006 to 2019. Progression-free survival (PFS) and overall survival (OS) was analyzed. Results The grade 2 and 3 astrocytomas were 24 and 28, respectively; the median age was 38 years. Forty-three patients underwent radiotherapy, with or without chemotherapy. Progression was diagnosed in 28 patients through MRI, and early progression within 2 years of initial radiotherapy occurred in 11 cases (21.2%). Histologically, radiation necrosis was confirmed in four out of these 11 patients (36.4%). Two patients with telomerase reverse transcriptase ( TERT ) promoter mutations experienced recurrence within three years of the initial surgery. The 2-year true progression-free, except radiation necrosis, at 2 years after surgery in astrocytoma grades 2 and 3 was 91.3% in grade 2 and 88.5% in grade 3 astrocytoma. Conclusion The possibility of radiation necrosis exists in the early progression of grade 2–3 astrocytoma. A second surgery should be performed to confirm true recurrence or radiation necrosis. Astrocytomas with TERT promoter mutations may relapse relatively early and should be followed up with caution. Astrocytoma radiation necrosis recurrence CDKN2A/B TERT promoter Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction According to the WHO 2021 classification, isocitrate dehydrogenase (IDH) -mutant diffuse astrocytic gliomas are now classified as astrocytomas, IDH-mutant, CNS WHO grades 2, 3, or 4. Among IDH-mutant astrocytomas, cyclin-dependent kinase inhibitor 2A/B ( CDKN2A/B ) homozygous deletion (HD) has been reported as a poor prognostic factor [ 1 – 6 ]. IDH-mutant astrocytomaswith CDKN2A/B HD are now diagnosed as grade 4 regardless of pathological findings [ 7 ]. Grade 4 IDH-mutant astrocytomas with CDKN2A/B HD have been shown to have a relatively progressive course. Before the era of molecular diagnosis, progression-free survival (PFS) of astrocytoma grade Ⅱ and anaplastic astrocytoma grade Ⅲ based on WHO2007 classification was 87.1 and 26.0 months, respectively and 2 year-PFS rate of grade 2 and 3 astrocytomas were 71.8% and 45.1%, respectively [ 8 ]. However, based on the WHO2016 classification, 2 year-PFS rate of grade 3 IDH mutant astrocytomas is approximately 65–70% [ 9 ]. Recurrence in low grade glioma is diagnosed radiologically when high signal on T2-weighted images and fluid attenuated inverse recovery (FLAIR) MRIs increases or the appearance of a new contrast effect reveals [ 10 ]. Radiation necrosis (RN) occurs response to radiotherapy and it also shows similar changes of recurrence on MRI [ 11 ]. Therefore, especially if a contrast lesion appears, it is difficult to diagnose whether it is a recurrence of low grade glioma or RN. IDH-mutant astrocytomas without CDKN2A/B HD often have a slow clinical course; however, some cases show early recurrence, and these characteristics have not been fully reported. This study aimed to elucidate the characteristics of those early recurrent cases. Material and Methods Patients This retrospective study included primary cases of astrocytoma, IDH-mutant, CNS WHO grade 2–3, and the diagnosis was reclassified from the original one according to the WHO2021 classification. The patients underwent surgery followed by simple radiation therapy (RT) equivalent to 45–60 Gy for grade 2 astrocytoma or local RT with 60 Gy and concomitant chemotherapy at our institution between January 2006 and December 2019. This study was approved by the Institutional Review Board of the National Cancer Center (No. 2012-043). Each patient was followed up with an MRI every 2–3 months for 2 years and 4–6 months for 5 years after the initial surgery. Recurrence was diagnosed using the RANO criteria for diffuse low-grade gliomas [ 10 ]; some patients underwent positron emission tomography (PET). If the tumor showed progressive disease on MRI and recurrence was suspected, we re-resected the lesion and examined the specimens pathologically. The clinical data of each patient, including sex, age, extent of surgical removal, Karnofsky performance score (KPS), IDH, telomerase reverse transcriptase ( TERT ) promoter mutation status, O-6-methylguanine deoxyribonucleic acid methyltransferase ( MGMT ) promoter methylation status, and MR changes at recurrence were collected. Molecular analysis Molecular analyses were performed as previously described [ 12 ]. Briefly, all DNA extractions were performed on frozen specimens using the DNeasy Blood & Tissue Kit (Qiagen, Tokyo, Japan), IDH and TERT promoter mutations were analyzed using pyrosequencing or Sanger sequencing, and CDKN2A/B HD and 1p19q c o-deletion were analyzed using the Multiplex Ligation-dependent Probe Amplification (MLPA) method (Falco, Tokyo, Japan). MGMT promoter methylation status was analyzed by pyrosequencing followed by the bisulfite method. The cut-off value for MGMT promoter methylation was 16.0%. Statistical analysis The PFS was defined as the time from the initial surgery to the diagnosis of recurrence on MR. The statistical software program, “EZR” -was used for all other statistical analyses. Statistical significance was set at p < 0.05. PFS was analyzed using the Kaplan–Meier method and compared using the log-rank test. Results Patient characteristics A total of 52 patients were included in the IDH-mutant astrocytoma without CDKN2A/B mutations HD group (Table 1 ). Twenty-four of the 56 patients were grade 2, and 28 were grade 3. The median age was 38 years (17–78 years), with 31 males and 21 females. The median KPS score at the time of initial surgery was 90. All patients confirmed IDH mutants without CDKN2A/B HD or 1p/19q co-deletion. Fifty patients had the wild-type TERT promoter; however, one each of the grade 2 and grade 3 patients had the TERT -124C > T mutation. Forty-six patients examined MGMT promoter methylation status; 27 (51.9%) patients had methylation status, 19 (36.5%) had unmethylated status, and 6 patients were unavailable. The initial treatment in grade 2 patients consisted mainly of radiation therapy (RT) alone in 10 patients, RT + nimustine (ACNU) in 5 patients, temozolomide alone in 4 patients, and observation in 4 patients; in grade 3, RT + temozolomide (TMZ) in 23 patients, RT + ACNU in 2 patients, and RT + other chemotherapy in 2 patients. There were no significant differences in the age at onset, KPS score at initial treatment, extent of resection, or MGMT methylation status between grade 2 and 3 astrocytomas. Table 1 Patient Characteristics Grade grade2 grade3 Total number 24 28 Age (years; median) 33 39 Sex male 14 17 female 10 11 Extent of Removal total or subtotal 5 12 partial or biopsy 19 16 KPS (mean) 90 90 MGMT promotor methylation status methylated 11 16 unmethylated 9 10 unknown 4 2 Initial Chemoradio-therapy after surgery Radiation therapy + Temozolomide 1 23 Radiation therapy alone 10 1 Radiation therapy + nimustine 5 2 Temozolomide alone 4 0 Clinical trial 0 1 PAV 0 1 observation 4 0 Progression on MRI Progression on MRI was diagnosed in 28 patients, and no recurrence was observed in 20 patients. The other four patients were not followed up because they were transferred to other hospitals. Two-year PFS on MRI was 88.2% in grade 2 and 76.0% in grade 3 astrocytomas, however, the difference of PFS was not statistically significant between grades 2 and grade 3 (p = 0.49; Fig. 1 ). Treatment after the diagnosis of recurrence varied from surgery to bevacizumab therapy. Surgery was performed in 15 of 28 patients (53.6%) at the time of progression on MRI. Of the 15 patients who underwent surgery, 5 had a recurrence of the same grade, 6 had grade 4 malignant transformation (grade 2 (n = 3), grade 3(n = 3)), and 4 cases (26.7%) confirmed RN. Radiation necrosis The initial diagnoses of the four patients who were diagnosed with RN were all grade 3. The median age was 43 years (one male and three females, 39–47 years). Only one patient had MGMT promoter methylation status, and other 3 cases had unmethylation status. The extent of tumor removal was total resection in two patients, one subtotal and one partial, and the initial treatment was RT + TMZ at a dose of 60 Gy in all cases. The median time to the diagnosis of progression on MRI in the four patients with RN was 22.5 months (18–26 months), indicating a significantly earlier appearance compared to all cases (p < 0.001; Fig. 1 ). In addition, progression on MRI was diagnosed in 12 cases within 30 months after initial surgery, 11 cases showed progression on MRI within 24 months after the end of radiotherapy, and 4 out of 8 cases (50%) who underwent surgery within 24 months after the end of radiotherapy were found to have RN. When RN was not considered a recurrence, the true PFS from initial surgery to the diagnosis of recurrence was 51 months (range, 9–142 months), with a trend toward longer PFS in grade 2 compared to in grade 3; however, the difference was not statistically significant (p = 0.82; Fig. 2 a). The 5-year true PFS was 63.2% for grade 2 and 54.7% for grades 3 (Table 2 ), and the 5-year OS was 85.7% for grade 2 and 76.4% for grade 3 (Table 2 , Fig. 2 b). Table 2 True progression free survival (PFS) and Overall survival (OS) per grade 1-y-PFS 2-y-PFS 3-y-PFS 5-y-PFS 5-y-OS grade2 95.7% 91.3% 82.6% 63.2% 85.7% grade3 96.2% 88.5% 67.7% 54.7% 76.4% The PFS of the two patients with TERT promoter mutations was relatively short: 9 months in the grade 2 case and 32 months in the grade 3 case. MRI and histopathology of illustrative cases diagnosed with RN and radiation injury are shown in Figs. 3 and 4 . Case 1 showed abnormal accumulation in the lesion on 11 C-methionine PET-CT during progressive disease (Fig. 3 e), whereas case 2 showed no accumulation on FDG-PET (Fig. 3 j). Both patients were diagnosed with grade 3 astrocytoma at first surgery (Fig. 4 , 4 a, e). The specimen of case 1 at second surgery showed brain parenchymal necrosis and fibrinoid vascular necrosis without tumor cells, and diagnosed as RN (Fig. 4 b, d). The histopathology of Case 2 at second surgery showed no tumor cells, while endothelial hyperplasia and gliosis were observed, which was thought to be caused by radiotherapy (Fig. 4 f, h). The case 2 was clinically diagnosed as a radiation injury. Discussions We present the clinical courses of 52 patients with grade 2 and 3 astrocytomas without CDKN2A/B HD. IDH-mutant astrocytomas without CDKN2A/B HD followed a more gradual course; however, 21.2% (11 cases) of patients with progression on MRI within 24 months after the end of radiotherapy and 4 cases out of 8 cases (50%) who underwent surgery showed histologically confirmed-RN. To our knowledge, this is the first report to emphasize that early progression on MRI is highly likely to indicate RN, which is a characteristic of this disease. The 2-year true PFS, except RN, of IDH-mutant astrocytoma grades 2 and 3 without CDKN2A/B HD was 91.3% in grade 2 and 88.5% in grade 3, and also no significant difference in OS. Shirahata et al. reported no significant difference in the OS between grade 2 and grade 3 IDH-mutant astrocytomas without CDKN2A/B HD which was similar to our findings [ 5 ]. In addition, the criteria for IDH-mutant grade 2 and grade 3 astrocytomas are determined by histological findings, such as the presence of anaplasia and significant mitotic activity; however, some reports indicate that the proliferative potential, as assessed by fission images, was not associated with the outcome in IDH-mutant astrocytomas [ 13 – 15 ]. Therefore, grade 2 and grade 3 IDH-mutant astrocytomas without CDKN2A/B HD have a more gradual course and rarely recur approximately 2 years after the start of treatment. RN in malignant gliomas is a marked localized tissue response to RT [ 16 , 17 ] that occurs in 3–24% of cases depending on the radiation dose [ 11 ]. It typically occurs 3–12 months after radiotherapy; however, it can also occur several years (or even decades) later [ 18 ]. It is often difficult to determine whether true recurrence or RN occurs using conventional MRI alone. FDG-PET is widely used worldwide as an adjunctive imaging diagnosis of recurrence, with a reported sensitivity of 71–86% and specificity of 62–100% [ 19 , 20 ]. Alternatively, 11 C-MET-PET has a sensitivity of 66–91% and specificity of 60–100% [ 21 – 24 ], and a meta-analysis of 11 C-MET PET reported a sensitivity of 70% and specificity of 93% for the diagnosis of recurrence in high-grade gliomas [ 25 ]. In the present study, PET was performed in only two of the four patients with RN; one patient underwent MET-PET (which revealed abnormal accumulation, Fig. 3 e), while the other underwent FDG-PET (which revealed no abnormal accumulation in the lesion, Fig. 3 k). The MET-PET case with abnormal accumulation (Fig. 3 e) was observed 21 months after initial treatment and 19 months after radiotherapy. The specificity of MET-PET increased significantly when more than 20 months had passed since radiotherapy; however, the diagnostic accuracy did not differ significantly for lower-grade gliomas [ 26 ]. Although PET is considered a useful diagnostic tool to determine whether the disease has recurred, it is important to confirm the diagnosis using a tissue specimen obtained by surgery. Grade 2 and 3 astrocytomas with TERT promoter mutation had relatively early recurrences, similar to grade 4 astrocytomas. IDH-mutant astrocytomas were morphologically graded according to the WHO 2021 classification. In addition, IDH-mutant grade 2 astrocytomas are expected to have a median OS of more than ten years [ 1 , 5 ] and grade 3 astrocytomas with anaplastic changes and significant mitotic potential have a median OS of 5–10 years [ 27 ], which explains the high incidence of early recurrence in grade 4 cases. IDH-wild-type glioblastoma with TERT promoter mutations is associated with a more progressive outcome than that in patients without TERT promoter mutations [ 28 , 29 ]. TERT promoter mutations are frequently observed in IDH-wild-type glioblastomas and oligodendrogliomas [ 30 , 31 ]; however, TERT positivity is extremely rare and reported 5.2% of IDH-mutant astrocytomas in the WHO 2016 classification [ 30 – 33 ]. Since the two TERT promoter mutation-positive cases in this study showed early recurrence, astrocytomas with IDH and TERT promoter mutations without 1p/19q co-deletion might be classified as grade 4 astrocytomas. This study had some limitations, including the small number of cases and the relatively short follow-up period. It is conceivable that a longer follow-up period would result in significant differences in PFS and OS between patients with grade 2 and grade 3 IDH-mutant astrocytomas. In addition, the treatment administered when recurrence was diagnosed varied, and many patients were treated with chemotherapy and radiotherapy for recurrence without a tissue diagnosis. It is conceivable that some patients who did not receive a tissue diagnosis may have had an RN, and in such cases, the possibility that a longer PFS could have been achieved cannot be ruled out. Further investigation of additional cases and a longer follow-up period is required. Conclusions Grades 2 and 3 astrocytomas rarely recur within 2 years after initial RT and the 2-year PFS is approximately 90%. It should be noted that early progression on MRI within 2 years after the initial RT in grade 2 and 3 astrocytomas with an IDH mutant without CDKN2A/B HD may indicate the possibility of RN. Alternatively, grade 2–3 astrocytoma with TERT promoter mutations may relapse relatively early and should be followed up with caution. Declarations Acknowledgments Funding Information: This study was supported by grants from the AMED under Grant Number 19ck0106340h0003. Conflict of interest: The authors have no relevant financial or non-financial interests related to this manuscript were received . Author contributions Material preparation, data collection and analysis were mainly performed by Yukie Ozeki and Mai Honda-Kitahara. Writing - review and editing were performed by Yukie Ozeki and Yoshitaka Narita. All authors read and approved the final manuscript. Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval This study was approved by the Institutional Review Board of the National Cancer Center (No. 2012-043). Consent to participate Informed consent was obtained from all individual participants included in the study. 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tomoyuki","middleName":"","lastName":"Nakano","suffix":""},{"id":284310764,"identity":"c4462865-ac79-4219-9b1c-a6c30a189b7a","order_by":9,"name":"Tomohiro Hosoya","email":"","orcid":"","institution":"Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tomohiro","middleName":"","lastName":"Hosoya","suffix":""},{"id":284310766,"identity":"d51ac4cf-ffe7-4a40-bf25-093dbf2f22bd","order_by":10,"name":"Hirokazu Sugino","email":"","orcid":"","institution":"Department of Diagnostic Pathology and Clinical Laboratories, National Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hirokazu","middleName":"","lastName":"Sugino","suffix":""},{"id":284310768,"identity":"2a7cf5a2-d024-494e-a662-918ea1913cc0","order_by":11,"name":"Kaishi Satomi","email":"","orcid":"","institution":"Department of Pathology, Kyorin University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kaishi","middleName":"","lastName":"Satomi","suffix":""},{"id":284310769,"identity":"34984736-5ccb-4830-a5fd-c72fb8137c56","order_by":12,"name":"Akihiko Yoshida","email":"","orcid":"","institution":"Department of Diagnostic Pathology and Clinical Laboratories, National Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Akihiko","middleName":"","lastName":"Yoshida","suffix":""},{"id":284310772,"identity":"dd5c9f19-97e3-4cf8-899d-0737679412e9","order_by":13,"name":"Hiroshi Igaki","email":"","orcid":"","institution":"Department of Radiation Oncology, National Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Igaki","suffix":""},{"id":284310774,"identity":"b9e8e7f6-f084-4234-9d71-bdaa30e91fe6","order_by":14,"name":"Yuko Kubo","email":"","orcid":"","institution":"Department of Diagnostic Radiology, National Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Kubo","suffix":""},{"id":284310778,"identity":"56cae070-7b27-4879-b4a0-e2092d447cca","order_by":15,"name":"Koichi Ichimura","email":"","orcid":"","institution":"Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Ichimura","suffix":""},{"id":284310783,"identity":"571b76db-cd56-4162-8fe7-5dbc830e3fad","order_by":16,"name":"Hiromichi Suzuki","email":"","orcid":"","institution":"Division of Brain Tumor Translational Research, National Cancer Center Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Hiromichi","middleName":"","lastName":"Suzuki","suffix":""},{"id":284310784,"identity":"e4eddd5a-5157-41b3-9b36-1409b2fdbe2e","order_by":17,"name":"Kenkichi Masutomi","email":"","orcid":"","institution":"Division of Cancer Stem Cell, National Cancer Center Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Kenkichi","middleName":"","lastName":"Masutomi","suffix":""},{"id":284310787,"identity":"d2c7ed0c-bcd4-4645-bc2a-34b996469e15","order_by":18,"name":"Akihide Kondo","email":"","orcid":"","institution":"Department of Neurosurgery, Juntendo University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Akihide","middleName":"","lastName":"Kondo","suffix":""}],"badges":[],"createdAt":"2024-03-25 09:27:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4162168/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4162168/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53682323,"identity":"58b0bd1e-e4cb-4305-9f59-75bfb483c66e","added_by":"auto","created_at":"2024-03-28 20:37:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":44309,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival on MRI of, all grade 2 and 3 astrocytoma and cases with radiation necrosis\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4162168/v1/cfb0fa30752b783216dfcb2c.jpg"},{"id":53682322,"identity":"b09834bb-f9f1-40a9-bb18-1d6791e79c8a","added_by":"auto","created_at":"2024-03-28 20:37:24","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":59552,"visible":true,"origin":"","legend":"\u003cp\u003eTrue progression-free survival (a) and overall survival (b) of grade 2, grade 3and all cases\u003c/p\u003e","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4162168/v1/0990812f9647b25b3b000000.jpg"},{"id":53682325,"identity":"8aa02b9c-bb62-452c-8f33-8bfc22c2e634","added_by":"auto","created_at":"2024-03-28 20:37:24","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":156395,"visible":true,"origin":"","legend":"\u003cp\u003eIllustrative cases 1 (a-f) and 2 (g-l) confirmed radiation necrosis\u003c/p\u003e\n\u003cp\u003ePreoperative MRI: a) G) preoperative FLAIR images, b) H) preoperative T1 images with Gd-DTPA, c) I) FLAIR images with progressive disease, d) j) T1 images with Gd-DTPA with progressive disease, e) 11C-methionine PET with progressive disease, k) FDG-PET with progressive disease, f) 9 months after the second surgery, l) 22 months after the second surgery\u003c/p\u003e","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4162168/v1/5de4656727a407bd8d02e73a.jpg"},{"id":53682324,"identity":"2c6d52f3-667d-4ec0-9df0-1bc4046bf982","added_by":"auto","created_at":"2024-03-28 20:37:24","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":187549,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological findings in case 1 (a-d) and case 2 (e-h)\u003c/p\u003e\n\u003cp\u003ea) e) Hematoxylin and eosin (HE) staining at initial diagnosis, b) f) HE staining at progressive disease, c) g) Immunohistochemistry (IHC) of IDH1 R132H at initial diagnosis, d) h) IHC of IDH1 R132H at progressive disease\u003c/p\u003e","description":"","filename":"Fig.4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4162168/v1/683ebfddaba6918bac793c6e.jpg"},{"id":58421128,"identity":"82152f56-7a02-4dcd-893f-441c89e8a913","added_by":"auto","created_at":"2024-06-15 15:21:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":926658,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4162168/v1/2fea32e6-67c5-4b6a-abed-a329ae3c4c09.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early progressive disease in IDH-mutant grade 2 and 3 astrocytoma without CDKN2A/B homozygous deletions may indicate radiation necrosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAccording to the WHO 2021 classification, isocitrate dehydrogenase (IDH) -mutant diffuse astrocytic gliomas are now classified as astrocytomas, IDH-mutant, CNS WHO grades 2, 3, or 4. Among IDH-mutant astrocytomas, cyclin-dependent kinase inhibitor 2A/B (\u003cem\u003eCDKN2A/B\u003c/em\u003e) homozygous deletion (HD) has been reported as a poor prognostic factor [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. IDH-mutant astrocytomaswith \u003cem\u003eCDKN2A/B\u003c/em\u003e HD are now diagnosed as grade 4 regardless of pathological findings [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Grade 4 IDH-mutant astrocytomas with \u003cem\u003eCDKN2A/B\u003c/em\u003e HD have been shown to have a relatively progressive course. Before the era of molecular diagnosis, progression-free survival (PFS) of astrocytoma grade Ⅱ and anaplastic astrocytoma grade Ⅲ based on WHO2007 classification was 87.1 and 26.0 months, respectively and 2 year-PFS rate of grade 2 and 3 astrocytomas were 71.8% and 45.1%, respectively [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, based on the WHO2016 classification, 2 year-PFS rate of grade 3 IDH mutant astrocytomas is approximately 65\u0026ndash;70% [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecurrence in low grade glioma is diagnosed radiologically when high signal on T2-weighted images and fluid attenuated inverse recovery (FLAIR) MRIs increases or the appearance of a new contrast effect reveals [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Radiation necrosis (RN) occurs response to radiotherapy and it also shows similar changes of recurrence on MRI [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Therefore, especially if a contrast lesion appears, it is difficult to diagnose whether it is a recurrence of low grade glioma or RN.\u003c/p\u003e \u003cp\u003eIDH-mutant astrocytomas without \u003cem\u003eCDKN2A/B\u003c/em\u003e HD often have a slow clinical course; however, some cases show early recurrence, and these characteristics have not been fully reported. This study aimed to elucidate the characteristics of those early recurrent cases.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis retrospective study included primary cases of astrocytoma, IDH-mutant, CNS WHO grade 2\u0026ndash;3, and the diagnosis was reclassified from the original one according to the WHO2021 classification. The patients underwent surgery followed by simple radiation therapy (RT) equivalent to 45\u0026ndash;60 Gy for grade 2 astrocytoma or local RT with 60 Gy and concomitant chemotherapy at our institution between January 2006 and December 2019. This study was approved by the Institutional Review Board of the National Cancer Center (No. 2012-043).\u003c/p\u003e \u003cp\u003eEach patient was followed up with an MRI every 2\u0026ndash;3 months for 2 years and 4\u0026ndash;6 months for 5 years after the initial surgery. Recurrence was diagnosed using the RANO criteria for diffuse low-grade gliomas [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]; some patients underwent positron emission tomography (PET). If the tumor showed progressive disease on MRI and recurrence was suspected, we re-resected the lesion and examined the specimens pathologically.\u003c/p\u003e \u003cp\u003eThe clinical data of each patient, including sex, age, extent of surgical removal, Karnofsky performance score (KPS), IDH, telomerase reverse transcriptase (\u003cem\u003eTERT\u003c/em\u003e) promoter mutation status, O-6-methylguanine deoxyribonucleic acid methyltransferase (\u003cem\u003eMGMT\u003c/em\u003e) promoter methylation status, and MR changes at recurrence were collected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMolecular analysis\u003c/h2\u003e \u003cp\u003eMolecular analyses were performed as previously described [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Briefly, all DNA extractions were performed on frozen specimens using the DNeasy Blood \u0026amp; Tissue Kit (Qiagen, Tokyo, Japan), IDH and \u003cem\u003eTERT\u003c/em\u003e promoter mutations were analyzed using pyrosequencing or Sanger sequencing, and \u003cem\u003eCDKN2A/B\u003c/em\u003e HD and 1p19q \u003cem\u003ec\u003c/em\u003eo-deletion were analyzed using the Multiplex Ligation-dependent Probe Amplification (MLPA) method (Falco, Tokyo, Japan). \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status was analyzed by pyrosequencing followed by the bisulfite method. The cut-off value for \u003cem\u003eMGMT\u003c/em\u003e promoter methylation was 16.0%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe PFS was defined as the time from the initial surgery to the diagnosis of recurrence on MR. The statistical software program, \u0026ldquo;EZR\u0026rdquo; -was used for all other statistical analyses. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. PFS was analyzed using the Kaplan\u0026ndash;Meier method and compared using the log-rank test.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eA total of 52 patients were included in the IDH-mutant astrocytoma without \u003cem\u003eCDKN2A/B\u003c/em\u003e mutations HD group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Twenty-four of the 56 patients were grade 2, and 28 were grade 3. The median age was 38 years (17\u0026ndash;78 years), with 31 males and 21 females. The median KPS score at the time of initial surgery was 90. All patients confirmed IDH mutants without \u003cem\u003eCDKN2A/B\u003c/em\u003e HD or 1p/19q co-deletion. Fifty patients had the wild-type \u003cem\u003eTERT\u003c/em\u003e promoter; however, one each of the grade 2 and grade 3 patients had the \u003cem\u003eTERT\u003c/em\u003e-124C\u0026thinsp;\u0026gt;\u0026thinsp;T mutation. Forty-six patients examined \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status; 27 (51.9%) patients had methylation status, 19 (36.5%) had unmethylated status, and 6 patients were unavailable. The initial treatment in grade 2 patients consisted mainly of radiation therapy (RT) alone in 10 patients, RT\u0026thinsp;+\u0026thinsp;nimustine (ACNU) in 5 patients, temozolomide alone in 4 patients, and observation in 4 patients; in grade 3, RT\u0026thinsp;+\u0026thinsp;temozolomide (TMZ) in 23 patients, RT\u0026thinsp;+\u0026thinsp;ACNU in 2 patients, and RT\u0026thinsp;+\u0026thinsp;other chemotherapy in 2 patients. There were no significant differences in the age at onset, KPS score at initial treatment, extent of resection, or \u003cem\u003eMGMT\u003c/em\u003e methylation status between grade 2 and 3 astrocytomas.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003egrade2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003egrade3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal number\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years; median)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExtent of Removal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003etotal or subtotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epartial or biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKPS (mean)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMGMT\u003c/b\u003e \u003cb\u003epromotor methylation status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emethylated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eunmethylated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eunknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInitial Chemoradio-therapy after surgery\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation therapy\u0026thinsp;+\u0026thinsp;Temozolomide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation therapy alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation therapy\u0026thinsp;+\u0026thinsp;nimustine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTemozolomide alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePAV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eobservation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eProgression on MRI\u003c/h2\u003e \u003cp\u003eProgression on MRI was diagnosed in 28 patients, and no recurrence was observed in 20 patients. The other four patients were not followed up because they were transferred to other hospitals. Two-year PFS on MRI was 88.2% in grade 2 and 76.0% in grade 3 astrocytomas, however, the difference of PFS was not statistically significant between grades 2 and grade 3 (p\u0026thinsp;=\u0026thinsp;0.49; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Treatment after the diagnosis of recurrence varied from surgery to bevacizumab therapy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSurgery was performed in 15 of 28 patients (53.6%) at the time of progression on MRI. Of the 15 patients who underwent surgery, 5 had a recurrence of the same grade, 6 had grade 4 malignant transformation (grade 2 (n\u0026thinsp;=\u0026thinsp;3), grade 3(n\u0026thinsp;=\u0026thinsp;3)), and 4 cases (26.7%) confirmed RN.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eRadiation necrosis\u003c/h2\u003e \u003cp\u003eThe initial diagnoses of the four patients who were diagnosed with RN were all grade 3. The median age was 43 years (one male and three females, 39\u0026ndash;47 years). Only one patient had \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status, and other 3 cases had unmethylation status. The extent of tumor removal was total resection in two patients, one subtotal and one partial, and the initial treatment was RT\u0026thinsp;+\u0026thinsp;TMZ at a dose of 60 Gy in all cases.\u003c/p\u003e \u003cp\u003eThe median time to the diagnosis of progression on MRI in the four patients with RN was 22.5 months (18\u0026ndash;26 months), indicating a significantly earlier appearance compared to all cases (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In addition, progression on MRI was diagnosed in 12 cases within 30 months after initial surgery, 11 cases showed progression on MRI within 24 months after the end of radiotherapy, and 4 out of 8 cases (50%) who underwent surgery within 24 months after the end of radiotherapy were found to have RN.\u003c/p\u003e \u003cp\u003eWhen RN was not considered a recurrence, the true PFS from initial surgery to the diagnosis of recurrence was 51 months (range, 9\u0026ndash;142 months), with a trend toward longer PFS in grade 2 compared to in grade 3; however, the difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.82; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The 5-year true PFS was 63.2% for grade 2 and 54.7% for grades 3 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), and the 5-year OS was 85.7% for grade 2 and 76.4% for grade 3 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTrue progression free survival (PFS) and Overall survival (OS) per grade\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1-y-PFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2-y-PFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3-y-PFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5-y-PFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5-y-OS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003egrade2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e91.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e82.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e63.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e85.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003egrade3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e96.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e88.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e67.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e54.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e76.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe PFS of the two patients with \u003cem\u003eTERT\u003c/em\u003e promoter mutations was relatively short: 9 months in the grade 2 case and 32 months in the grade 3 case.\u003c/p\u003e \u003cp\u003eMRI and histopathology of illustrative cases diagnosed with RN and radiation injury are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Case 1 showed abnormal accumulation in the lesion on \u003csup\u003e11\u003c/sup\u003eC-methionine PET-CT during progressive disease (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee), whereas case 2 showed no accumulation on FDG-PET (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ej). Both patients were diagnosed with grade 3 astrocytoma at first surgery (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea, e). The specimen of case 1 at second surgery showed brain parenchymal necrosis and fibrinoid vascular necrosis without tumor cells, and diagnosed as RN (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb, d). The histopathology of Case 2 at second surgery showed no tumor cells, while endothelial hyperplasia and gliosis were observed, which was thought to be caused by radiotherapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ef, h). The case 2 was clinically diagnosed as a radiation injury.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussions","content":"\u003cp\u003eWe present the clinical courses of 52 patients with grade 2 and 3 astrocytomas without \u003cem\u003eCDKN2A/B\u003c/em\u003e HD. IDH-mutant astrocytomas without \u003cem\u003eCDKN2A/B\u003c/em\u003e HD followed a more gradual course; however, 21.2% (11 cases) of patients with progression on MRI within 24 months after the end of radiotherapy and 4 cases out of 8 cases (50%) who underwent surgery showed histologically confirmed-RN. To our knowledge, this is the first report to emphasize that early progression on MRI is highly likely to indicate RN, which is a characteristic of this disease.\u003c/p\u003e \u003cp\u003eThe 2-year true PFS, except RN, of IDH-mutant astrocytoma grades 2 and 3 without \u003cem\u003eCDKN2A/B\u003c/em\u003e HD was 91.3% in grade 2 and 88.5% in grade 3, and also no significant difference in OS. Shirahata et al. reported no significant difference in the OS between grade 2 and grade 3 IDH-mutant astrocytomas without \u003cem\u003eCDKN2A/B\u003c/em\u003e HD which was similar to our findings [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In addition, the criteria for IDH-mutant grade 2 and grade 3 astrocytomas are determined by histological findings, such as the presence of anaplasia and significant mitotic activity; however, some reports indicate that the proliferative potential, as assessed by fission images, was not associated with the outcome in IDH-mutant astrocytomas [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, grade 2 and grade 3 IDH-mutant astrocytomas without \u003cem\u003eCDKN2A/B\u003c/em\u003e HD have a more gradual course and rarely recur approximately 2 years after the start of treatment.\u003c/p\u003e \u003cp\u003eRN in malignant gliomas is a marked localized tissue response to RT [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] that occurs in 3\u0026ndash;24% of cases depending on the radiation dose [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. It typically occurs 3\u0026ndash;12 months after radiotherapy; however, it can also occur several years (or even decades) later [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. It is often difficult to determine whether true recurrence or RN occurs using conventional MRI alone. FDG-PET is widely used worldwide as an adjunctive imaging diagnosis of recurrence, with a reported sensitivity of 71\u0026ndash;86% and specificity of 62\u0026ndash;100% [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Alternatively, \u003csup\u003e11\u003c/sup\u003eC-MET-PET has a sensitivity of 66\u0026ndash;91% and specificity of 60\u0026ndash;100% [\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], and a meta-analysis of \u003csup\u003e11\u003c/sup\u003eC-MET PET reported a sensitivity of 70% and specificity of 93% for the diagnosis of recurrence in high-grade gliomas [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In the present study, PET was performed in only two of the four patients with RN; one patient underwent MET-PET (which revealed abnormal accumulation, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee), while the other underwent FDG-PET (which revealed no abnormal accumulation in the lesion, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ek). The MET-PET case with abnormal accumulation (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee) was observed 21 months after initial treatment and 19 months after radiotherapy. The specificity of MET-PET increased significantly when more than 20 months had passed since radiotherapy; however, the diagnostic accuracy did not differ significantly for lower-grade gliomas [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Although PET is considered a useful diagnostic tool to determine whether the disease has recurred, it is important to confirm the diagnosis using a tissue specimen obtained by surgery.\u003c/p\u003e \u003cp\u003eGrade 2 and 3 astrocytomas with \u003cem\u003eTERT\u003c/em\u003e promoter mutation had relatively early recurrences, similar to grade 4 astrocytomas. IDH-mutant astrocytomas were morphologically graded according to the WHO 2021 classification. In addition, IDH-mutant grade 2 astrocytomas are expected to have a median OS of more than ten years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and grade 3 astrocytomas with anaplastic changes and significant mitotic potential have a median OS of 5\u0026ndash;10 years [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], which explains the high incidence of early recurrence in grade 4 cases. IDH-wild-type glioblastoma with \u003cem\u003eTERT\u003c/em\u003e promoter mutations is associated with a more progressive outcome than that in patients without \u003cem\u003eTERT\u003c/em\u003e promoter mutations [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. \u003cem\u003eTERT\u003c/em\u003e promoter mutations are frequently observed in IDH-wild-type glioblastomas and oligodendrogliomas [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]; however, \u003cem\u003eTERT\u003c/em\u003e positivity is extremely rare and reported 5.2% of IDH-mutant astrocytomas in the WHO 2016 classification [\u003cspan additionalcitationids=\"CR31 CR32\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Since the two \u003cem\u003eTERT\u003c/em\u003e promoter mutation-positive cases in this study showed early recurrence, astrocytomas with IDH and \u003cem\u003eTERT\u003c/em\u003e promoter mutations without 1p/19q co-deletion might be classified as grade 4 astrocytomas.\u003c/p\u003e \u003cp\u003eThis study had some limitations, including the small number of cases and the relatively short follow-up period. It is conceivable that a longer follow-up period would result in significant differences in PFS and OS between patients with grade 2 and grade 3 IDH-mutant astrocytomas. In addition, the treatment administered when recurrence was diagnosed varied, and many patients were treated with chemotherapy and radiotherapy for recurrence without a tissue diagnosis. It is conceivable that some patients who did not receive a tissue diagnosis may have had an RN, and in such cases, the possibility that a longer PFS could have been achieved cannot be ruled out. Further investigation of additional cases and a longer follow-up period is required.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eGrades 2 and 3 astrocytomas rarely recur within 2 years after initial RT and the 2-year PFS is approximately 90%. It should be noted that early progression on MRI within 2 years after the initial RT in grade 2 and 3 astrocytomas with an IDH mutant without \u003cem\u003eCDKN2A/B\u003c/em\u003e HD may indicate the possibility of RN. Alternatively, grade 2\u0026ndash;3 astrocytoma with \u003cem\u003eTERT\u003c/em\u003e promoter mutations may relapse relatively early and should be followed up with caution.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eFunding Information: This study was supported by grants from the AMED under Grant Number 19ck0106340h0003.\u003c/p\u003e\n\u003cp\u003eConflict of interest: The authors have no relevant financial or non-financial interests \u003cem\u003erelated to this manuscript were received\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eMaterial preparation, data collection and analysis were mainly performed by\u0026nbsp;Yukie Ozeki\u0026nbsp;and\u0026nbsp;Mai Honda-Kitahara. Writing - review and editing were performed by\u0026nbsp;Yukie Ozeki\u0026nbsp;and Yoshitaka Narita. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of the National Cancer Center (No. 2012-043).\u003c/p\u003e\n\u003cp\u003eConsent to participate\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInformed consent was obtained from all individual participants included in the study.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConsent to publish\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe authors affirm that human research participants provided informed consent for publication of the images in Fig.3 and 4.\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAppay R, Dehais C, Maurage CA, Alentorn A, Carpentier C, Colin C et al (2019) CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas. Neuro Oncol 21(12):1519\u0026ndash;1528\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrat DJ, Aldape K, Colman H, Figrarella-Branger D, Fuller GN, Giannini C et al (2020) cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 139(3):603\u0026ndash;608\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCimino PJ, Zager M, McFerrin L, Wirsching HG, Bolouri H, Hentschel B et al (2017) Multidimensional scaling of diffuse gliomas: application to the 2016 World Health Organization classification system with prognostically relevant molecular subtype discovery. Acta Neuropathol Commun 5(1):39\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReis GF, Pekmezci M, Hansen HM, Rice T, Marshall RE, Molinaro AM et al (2015) CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas. 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Radiology 217(2):377\u0026ndash;384\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilson CM, Gaber MW, Sabek OM, Zawaski JA, Merchant TE (2009) Radiation-induced astrogliosis and blood-brain barrier damage can be abrogated using anti-TNF treatment. Int J Radiat Oncol Biol Phys 74(3):934\u0026ndash;941\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZikou A, Sioka C, Alexiou GA, Fotopoulos A, Voulgaris S, Argyropoulou MI (2018) Radiation Necrosis, Pseudoprogression, Pseudoresponse, and Tumor Recurrence: Imaging Challenges for the Evaluation of Treated Gliomas. Contrast Media Mol Imaging 2018:6828396\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eG\u0026oacute;mez-R\u0026iacute;o M, Rodr\u0026iacute;guez-Fern\u0026aacute;ndez A, Ramos-Font C, L\u0026oacute;pez-Ram\u0026iacute;rez E, Llamas-Elvira JM (2008) Diagnostic accuracy of 201Thallium-SPECT and 18F-FDG-PET in the clinical assessment of glioma recurrence. Eur J Nucl Med Mol Imaging 35(5):966\u0026ndash;975\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoni N, Ora M, Mohindra N, Menda Y, Bathla G (2020) Diagnostic Performance of PET and Perfusion-Weighted Imaging in Differentiating Tumor Recurrence or Progression from Radiation Necrosis in Posttreatment Gliomas: A Review of Literature. AJNR Am J Neuroradiol 41(9):1550\u0026ndash;1557\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeuschl C, Kirchner J, Poeppel TD, Schaarschmidt B, Kebir S, El Hindy N et al (2018) (11)C-MET PET/MRI for detection of recurrent glioma. Eur J Nucl Med Mol Imaging 45(4):593\u0026ndash;601\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim YH, Oh SW, Lim YJ, Park CK, Lee SH, Kang KW et al (2010) Differentiating radiation necrosis from tumor recurrence in high-grade gliomas: assessing the efficacy of 18F-FDG PET, 11C-methionine PET and perfusion MRI. 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A Two-Stage Model of Tumorigenesis in IDH-Wild-Type Glioblastoma. Cancer Cell 35(4):542\u0026ndash;544\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeidenreich B, Kumar R (2017) Altered TERT promoter and other genomic regulatory elements: occurrence and impact. Int J Cancer 141(5):867\u0026ndash;876\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel B, Taiwo R, Kim AH, Dunn GP (2020) TERT, a promoter of CNS malignancies. Neurooncol Adv 2(1):vdaa025\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCancer Genome Atlas Research N, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR et al (2015) Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. 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Acta Neuropathol 129(5):679\u0026ndash;693\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Astrocytoma, radiation necrosis, recurrence, CDKN2A/B, TERT promoter","lastPublishedDoi":"10.21203/rs.3.rs-4162168/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4162168/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eIsocitrate dehydrogenase (IDH)-mutant astrocytoma without cyclin-dependent kinase inhibitor 2A/B (\u003cem\u003eCDKN2A/B\u003c/em\u003e) homozygous deletion (HD) typically follows a slow clinical course. However, some cases show early progression on MRI, and these characteristics have not been fully reported. This study aimed to elucidate the characteristics of those cases.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study included 52 primary cases with astrocytoma, IDH-mutant, CNS WHO grade 2\u0026ndash;3, reclassified from the original diagnosis based on WHO2021 classification. Patients underwent surgery followed by radiation therapy or/and chemotherapy at our institution from 2006 to 2019. Progression-free survival (PFS) and overall survival (OS) was analyzed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe grade 2 and 3 astrocytomas were 24 and 28, respectively; the median age was 38 years. Forty-three patients underwent radiotherapy, with or without chemotherapy. Progression was diagnosed in 28 patients through MRI, and early progression within 2 years of initial radiotherapy occurred in 11 cases (21.2%). Histologically, radiation necrosis was confirmed in four out of these 11 patients (36.4%). Two patients with telomerase reverse transcriptase (\u003cem\u003eTERT\u003c/em\u003e) promoter mutations experienced recurrence within three years of the initial surgery. The 2-year true progression-free, except radiation necrosis, at 2 years after surgery in astrocytoma grades 2 and 3 was 91.3% in grade 2 and 88.5% in grade 3 astrocytoma.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe possibility of radiation necrosis exists in the early progression of grade 2\u0026ndash;3 astrocytoma. A second surgery should be performed to confirm true recurrence or radiation necrosis. Astrocytomas with \u003cem\u003eTERT\u003c/em\u003e promoter mutations may relapse relatively early and should be followed up with caution.\u003c/p\u003e","manuscriptTitle":"Early progressive disease in IDH-mutant grade 2 and 3 astrocytoma without CDKN2A/B homozygous deletions may indicate radiation necrosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-28 20:37:19","doi":"10.21203/rs.3.rs-4162168/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c3d13bdf-4074-48fd-b20f-6eecd8789f81","owner":[],"postedDate":"March 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-15T15:13:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-28 20:37:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4162168","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4162168","identity":"rs-4162168","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}