Proton beam therapy in a patient with secondary glioblastoma 32 years after postoperative radiotherapy for medulloblastoma: A case report and review of the literatures

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With the gradual standardization of diagnostic and therapeutic techniques for children's medulloblastoma tumors, especially the application of stratified treatment guided by its molecular typing and multidisciplinary integrated treatment such as surgery, chemotherapy, radiotherapy, the cure, and survival of children's medulloblastoma tumor patients have been significantly improved. At the same time, there has been an increase in the number of second primary tumors (SPT). According to the concept of multiple primary tumors defined by the International Agency for Research on Cancer (IARC), two or more primary tumors are found in the patient simultaneously or successively. The tumor diagnosed first is known as the primary tumor, and the tumor diagnosed later is known as the SPT. The most frequent site of SPT is the CNS, followed by endocrine and hematological systems. However, there is less data on second primary glioblastoma and treatment modality recommendations after medulloblastoma. The purpose of this article is to share a case of a patient with medulloblastoma who developed a second primary glioblastoma 32 years after receiving craniospinal irradiation as a child. Additionally, it aims to provide insights into the treatment experience and present a review of relevant literature. Figures Figure 1 Figure 2 Figure 3 Introduction Historically, the priority for treating medulloblastoma (MB) in children has been avoidance of undue side effects while achieving tumor control. As diagnostic and therapeutic techniques for such tumors increasingly have become more standardized, particularly through molecular subgroup stratification and multidisciplinary regimens (ie, surgery, chemotherapy, and radiotherapy), the potential for survival or cure has significantly improved. At the same time, there has been an upturn in subsequent occurrences of second primary tumors (SPTs) [1] . The International Agency for Research on Cancer (IARC) [2] has defined in which a patient harbors two or more primary tumors simultaneously or successively. Initially diagnosed tumors are considered primary lesions, whereas those arising later are designated SPTs. Central nervous system (CNS) is the most frequent site for SPT emergence, followed by endocrine and hematologic systems [3] . However, there is less data on glioblastoma (GB) as a SPT and its preferred mode of therapy after treatment of MB. The purpose of this article was to share our experience with a patient who developed a second primary GB. The latter occurred 32 years after previously administered craniospinal irradiation (CSI) for MB as a child. We intended to provide insights into the treatment process and review relevant publications in the literature. Case presentation In February 1991, our male patient (then 9 years old) presented with complaints of dizziness, vomiting, and loss of balance for 6 months. His condition had worsened recently, during the past month. Imaging studies disclosed a cerebellar tumor (30 × 25 × 25 mm) that was surgically removed on February 11, 1991. The pathology report confirmed MB, so cobalt-60 CSI (36 Gy/20 fractions) was delivered postoperatively, with a tumor bed boost (total of 56 Gy). He was monitored regularly thereafter, undergoing annual brain magnetic resonance imaging (MRI), but no chemotherapy was given. In March 2023 (32 years later), a space-occupying mass of left cerebellar hemisphere was detected by MRI. By June 25, 2023, loss of balance and difficulty walking had developed. A subsequent brain MRI again showed a mass of left cerebellar hemisphere, roughly 50.3 × 47 × 51.1 mm in size (Figure 1A). On July 6, 2023, left cerebellar hemispheric resection was performed using the prior incision line at left cerebellopontine angle. The tumor within was soft and richly vascularized, with no clearly demarcated borders. Once separated along its apparent boundaries, it measured approximately 50 × 50 × 45 mm. The brainstem was well protected, as were various cranial nerves (ipsilateral posterior group, facial, auditory, trigeminal, abducens) and other structures. Postsurgical recovery was event-free. Representative histologic preparations revealed a high-grade and diffusely infiltrating neuroepithelial tumor of left cerebellum. For the most part, this lesion was densely cellular, demonstrating marked pleomorphism and tumor giant cells in conjunction with microvascular proliferation and fenestrated necrosis. Its immunohistochemical and morphologic features were compatible with radiation-induced glioblastoma (RIGB), World Health Organization (WHO) Grade IV. Results of immunostaining are provided in Table 1, and additional evidence to support a diagnosis of RIGB is offered in Table 2. Table 1. Immunohistochemical features of primary and secondary glioblastoma Tumor marker Secondary GB [4] Primary GB [5] Present case GFAP Positive (GFAP+) Positive (GFAP+) Positive (GFAP+) Olig-2 Positive (Olig-2+) Positive (Olig-2+) Positive (Olig-2+) IDH1 R132H Positive (IDH1 R132H+) Negative (IDH1 R132H-) Negative (IDH1 R132H-) IDH2 R172K Positive (IDH2 R172K+) Negative (IDH2 R172K-) Negative (IDH2 R172K-) ATRX Negative (ATRX-) Positive/Negative (varies) Negative (ATRX-) p53 Positive (p53+) Negative (p53-) Negative (p53-) Ki-67 Approximately 30% Typically high (varies) Approximately 30% Synaptophysin Positive (Syn+) Positive/Negative (varies) Weak Positive (Syn weak +) H3K27M Negative (H3K27M-) Negative (H3K27M-) Negative (H3K27M-) H3K27me3 Typically retained Typically retained Partial expression missing EZH2 Positive (EZH2+) Variable (EZH2+) Negative (EZH2-) MTAP Negative (MTAP-) Negative (MTAP-) Negative (MTAP-) SOX11 Positive (SOX11+) Variable (Positive/Negative) Positive (SOX11+) MSH6 Positive (MSH6+) Positive (MSH6+) Positive (MSH6+) MSH2 Positive (MSH2+) Positive (MSH2+) Positive (MSH2+) MLH1 Positive (MLH1+) Positive (MLH1+) Positive (MLH1+) PMS2 Positive (PMS2+) Positive (PMS2+) Positive (PMS2+) MGMT promoter methylation Methylated Variable (methylated/non-methylated) Methylated IDH1/IDH2 Mutant Wild type Wild type 1p/19q deletion No deletion No deletion No deletion EGFR amplification No amplification Often amplified No amplification CDKN2A deletion Common (pure deletion) Common Pure deletion CDKN2B deletion Common (pure deletion) Common Pure deletion Table 2. Differing profiles of secondary GB (recurrent vs radiation induced) Characteristic Recurrent secondary GB [6] Radiation-induced secondary GB Etiology Progression from low-grade or intermediate-grade glioma Development after radiotherapy for other conditions (e.g., leukemia, brain tumor) IDH mutation Common (especially IDH1 R132H mutation) Rare TP53 mutation Common Possible, but less frequent ATRX inactivation Common Possible MGMT promoter methylation Common Possible TERT promoter mutation Rare Possible 1p/19q co-deletion Rare Rare Typical patient age Usually younger patients Usually older patients Medical history History of low-grade or intermediate-grade glioma History of radiotherapy for other tumors or diseases Other chromosomal abnormalities Common specific chromosomal mutation patterns May have more heterogeneous chromosomal mutations and structural variations Proton beam radiotherapy (PBT) At this juncture, the patient was a 41-year-old man scoring 90 by Kanefsky Performance Scale. His medical history and past treatment did not preclude reirradiating the same area. Based on current and previous ranges of irradiation and the dosing tolerability of brainstem, proton beam therapy (PBT) was selected, hoping to minimize brainstem and spinal cord exposure. The patient received treatment on August 7, 2023, 1 month after surgery. We defined postoperative tumor bed area and contrast-enhanced volume in T1 fat-saturated contrast-enhanced MRI scan as gross tumor volume (GTVtb), adding a 5-mm clinical target volume (CTV) margin. Treatment planning relied on a RayStation platform (RaySearch Laboratories, Stockholm, Sweden) for inversely planned intensity-controlled (raster-scanned) proton delivery using two horizontal beams. GTVtb and CTV doses were 60 Gy and 54 Gy, respectively in 30 fractions each (Figure 1). Maximum doses (Dmax values) to spinal cord and brain were 43.5 Gy and 53.5 Gy, respectively. Mean doses (Dmean values) to left and right hippocampus were 33 Gy and 0.95 Gy, respectively. Temozolomide (TMZ, 75 mg/m 2 ) was administered on days of radiotherapy, followed by postradiotherapy TMZ maintenance (200 mg/m 2 daily) for 5 days and cyclic dosing (every 28 days) for 6 months. During the 32-year course of patient monitoring, multiple meningiomas had also arisen as SPTs, the first diagnosed in December 2008. One was removed in March 2009, but several non-resected meningiomas were under continued observation. To date, there is no evidence of recurrence or size increases, indicating stable disease. Likewise, MRI views of tumor bed remain devoid of high signal intensity nearly 1 year after completing radiotherapy. Aside from mild dizziness, the patient has experienced no other discomfort. A chronologic overview of the key medical events elaborated is included as Figure 3. Discussion Herein, we have chronicled the medical course a childhood cancer survivor, including 32 years of follow-up after surgery and radiotherapy for MB and similar treatment imposed by a rare RIGB of later adult life. In this instance, PBT afforded access to high-dose, second-phase postoperative radiotherapy. Second primary tumors (SPTs) For survivors of childhood cancer, the cumulative incidence of SPTs arising within 30 years after initial tumor diagnoses ranges from 3–10% [3] . This is roughly 3–6 times higher than comparable rates in the general population. The most common SPTs encountered are breast cancer for female survivors, ranging from 12–20%; thyroid cancer, estimated at 2–7%; and skin cancer, exceeding general population risk by 2–6 times [7,8] . GB is a relatively rare SPT as such, but it is a recognized risk, particularly for recipients of cranial radiotherapy. More so than chemotherapy, irradiation is usually associated with a higher incidence of SPT (9.5% vs 2.4%) [3] , given its capacity to alter DNA methylation and methyltransferase activity and its deregulation of mRNA. MB is a common childhood tumor, the overall survival of which has improved through combined use of radiotherapy, chemotherapy, and surgery. Current survival rates are ~ 80–85% for standard risk groups and ~ 65–70% for high-risk groups. However, long-term toxic effects (especially SPTs) are increasing as a result. In the aftermath of MB, CNS is reportedly the most common site of SPTs (63/146, 43.2%), followed by endocrine and hematologic systems. Similar outcomes have been documented during the Childhood Cancer Survivor Study and its British counterpart probe, likely due to whole brain and spinal axis targeting during CSI [7,9] . The unique physical properties entailed have broadened the usage of PBT in treating childhood cancer. Proton doses are characterized by abrupt surges in energy release, called Bragg peaks. Such rapid dosing decays reduce radiation to nearby healthy tissues by a factor of 2–3. However, monitoring of treated patients for potential SPTs is a long-term proposition, and available research on SPT incidence by mode of MB treatment (proton vs photon therapy) is currently lacking. Raymond [10] has generated estimates of secondary cancer incidence using a model derived from Publication No. 60 of the International Commission on Radiologic Protection. Compared with intensity-modulated or conventional X-ray plans, proton beams lowered the expected incidence of radiation-induced secondary cancers after MB treatment by a factor of 8–15. An analysis of the SEER database from mid-2000s forward, ostensibly marked by greater PBT use, has also confirmed fewer SPTs as late effects [3] ; and in another assessment according to treatment time frames (1973–1995 vs 1995–2014), the SPT rate proved higher during earlier years (1973–1995) of more limited PBT use [11] . Matched adult populations (n = 558 each) receiving proton or photon therapy have been followed as well (median interval: proton group, 6.7 years; photon group, 6.0 years) [12] , recording SPT rates of 5.2% and 7.5%, respectively. Above findings imply a lower incidence of SPT after PBT of childhood MB. On the other hand, most present-day survivors of pediatric tumors have received photon therapy over a decade ago, so longer follow-up periods may be needed to ascertain SPT incidence in relation to PBT. Radiation-induced second primary glioblastoma (RIGB) Classification of a second primary GB as radiation induced (rather than recurrent second primary) [13–15] is based on the following criteria: (1) tumor situated within the irradiated field; (2) sufficient latency between irradiation and tumor occurrence; (3) histological type different from that of original neoplasm; and (4) no pathology, such as Von Recklinghausen disease, favoring tumor development. The most common malignancies associated with RIGB are nasopharyngeal carcinoma (37%), primary intracranial germinoma (21%), and MB (16%) [16] . At 9 years of age, our patient with MB received postoperative CSI only. In analyzing 2771 patients with MB from the SEER-18 database, there were 146 patients (5.27%) who developed SPTs at 15 years. Rates of SPTs after radiotherapy only, radio- and chemotherapy, and chemotherapy only were 9.5%, 4.3%, and 2.4%, respectively [3] . Several studies have shown a 14-year mean latency between radiotherapy and diagnosis of RIGB, unlike the 32-year span in our patient that surpassed most previously published intervals [11,14] . It is a widely held concept that the younger a patient is at primary treatment, the greater the risk of RIGB will be. Younger onset may therefore render patients especially vulnerable to radiation-induced gliomagenesis in later years due to an abundance of neurogenic stem cells and increased growth factor activity [17] . RIGB is a relatively rare SPT, with a molecular profile that distinguishes it from primary GB and recurrent secondary GB. Clinicians focus more on recurrent secondary GB, tending to overlook the specific and individualized treatment of RIGB. IDH mutation is a critical marker in glioma classification that helps differentiate recurrent and radiation-induced forms of secondary GB (Tables 1 , 2 ). IDH mutations are largely features of less ominous tumors (WHO grade II-III), whereas the IDH wild type primarily reflects aggressive disease (WHO grade IV), signaling a worse prognosis. In 2021, the latest WHO revision of GB grading was substantial, stipulating that only IDH wild-type lesions warrant a GB diagnosis [5] . Still, there are perhaps some GBs with IDH mutations. The latter have chiefly presented as secondary GBs, morphologically similar to primary GB but imparting a more favorable prognosis [18] . In patients with IDH -mutant GBs, median OS may be ~ 31 months, as opposed to 15 months for those with IDH -wildtype GBs [18,19] . Among 39 patients with secondary GBs, the IDH mutation rate was found to be 60%, and the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation rate was 68.8% [20] . MGMT is a direct DNA repair enzyme that eliminates the TMZ-produced genotoxic O6-methylguanine adduct in a single-step process. Because this restores the genomic integrity of tumors, MGMT promoter methylation denotes a better prognosis. An earlier meta-analysis has determined a median OS (mOS) of 10 months in patients with RIGBs [Peter Y. M]. Across the spectrum of grade IV GBs, survival in patients with RIGBs (mOS, 4.8 months) was shorter than in instances of de novo GB (mOS, 19.2 months; p < .001). These findings may be explained by the fact patients with IDH wild type were involved, and there was a lower percentage of MGMT promoter methylation [14] . Our patient with WHO grade IV GB exhibited both IDH mutation and MGMT promoter methylation, thus suggesting TMZ sensitivity and a better prognosis than anticipated for primary or recurrent secondary GB of IDH wild type. RIGB treatment Currently, there is no consensus on oncologic treatment in instances of RIGB. Studies have concluded that patients with secondary GBs experience significantly longer survival times if repeat resection is elected, instead of foregone [20] . Patients with good KPS scores and proper suitability for surgery should subsequently consider second-phase resection as a primary treatment option, although decisions on postoperative adjuvant therapy are comparatively more difficult. Physicians must weigh the perceived benefit of reirradiation against the risk of related brain damage. In the past, the conventional dose limit for partial brain radiotherapy has been 60 Gy. Some sources have challenged this view, suggesting that reirradiated brain tissue may tolerate a fractionated (2 Gy/fr) cumulative normalized total dose of 100 Gy before necrosis ensues [13] . Paulino et al. have noted that among patients with radiotherapy-induced high-grade gliomas, those who received reirradiation of 50 Gy (35/85, 41%) displayed a 2-year overall survival (OS) rate of 21%. This was significantly better than the 3% rate recorded at 2 years in the absence of reirradiation [21] . Similarly, a meta-analysis has found that reirradiation (mean dose, 48 Gy) conferred a better 2-year OS rate (24%) than the rate achieved (9%) through different treatment. Upon examining factors linked to survival in the setting of grade III-IV RIGB, multimodality combination therapy (including radiotherapy) was identified as an independent prognostic factor ( p = 0.002) [16] . These observations suggest that in some patients with radiation-induced gliomas, a therapeutic strategy of reirradiation may serve to prolong disease control. However, the tolerance threshold is changing due to advances in radiotherapy technology, such as PBT. These improvements stand to mitigate the risk of late radiation effects. Despite a scarcity of data on PBT use for reirradiation of RIGB, we are encouraged by its successful application in patients with recurrent gliomas or other brain tumors. Scartoni et al. [22] have investigated 33 patients who completed questionnaires before starting PBT, on last day of treatment, and at every follow-up visit until disease progression. It appears that PBT is safe and well tolerated, ensuring stable quality-of-life parameters for the duration. The Proton Collaborative Group (PCG) has examined 45 patients from 12 PBT centers in the United States, all receiving photon radiotherapy initially at doses of 60 Gy. The median time between original diagnosis and recurrence was only 20 months, and the median total reirradiation dose was 46.2 Gy (range, 25–60 Gy), with a median of 2.2 Gy per fraction. Of these 45 patients, 40 (88.9%) had received an equivalent dose in 2 Gy fractions (EQD2) of > 39 Gy. All patients had GB as their primary diagnosis. Median progression-free survival (PFS) time was 13.9 months, and median OS was 14.2 months. In terms of side effects, a total of five patients experienced grade 3 toxicity. One showed acute toxicity (ataxia), whereas late toxicity (neuropathy, cognitive disturbance, optic nerve disorder, or seizure) surfaced in the other four. No acute or delayed grade 4 or 5 toxicities were observed. During a similar multicenter study, patients with GB were reirradiated at high dose, without serious side effects over a year’s time, highlighting the utility of PBT for this purpose [23] . Another 20 patients who received proton reirradiation for recurrent gliomas also registered acceptable outcomes after high-dose radiotherapy. The mean initial dose was 59.4 Gy, and the mean reirradiation dose after a median of 15.3 months (range, 5.3-152.6 months) was 54 Gy [24] . Several earlier investigations have further reinforced the prospect of high-dose irradiation enabled by PBT. When irradiating our patient (32 years after initial radiotherapy), we used a standard postoperative dose of 60 Gy, delivering a low dose to brainstem and hippocampus. The Dmax of brain scan was 53.5 Gy, the Dmean of left hippocampus was 33 Gy, and the Dmean of right hippocampus was 0.95 Gy. Although the prognosis of a grade IV RIGB is poor, lessening our concerns over later clinically significant necrosis, it is important for physicians to optimally protect a patient's cognitive function. The incidence of radiation necrosis typically peaks around 1–3 years after radiotherapy [25] . At 1 year after reirradiation, no signs of tumor recurrence or radiation necrosis have been detected as yet. In summary, RIGB is a rare SPT determined by strategic molecular profiling and requiring individualized management. PBT is the preferred postoperative treatment. Abbreviations Second primary tumors (SPT) International Agency for Research on Cancer (IARC) Central Nervous System(CNS) Craniospinal Irradiation(CSI) Magnetic Resonance Imaging (MRI) Cerebellopontine Angle region(CPA) Immunohistochemistry (IHC) Radiation-induced Glioblastoma(RIGB) Nasopharyngeal Cancer (NPC) Not Otherwise Specified (NOS) World Health Organization (WHO) Karnofsky Performance Status (KPS) Overall Survival (OS) Progression-free Survival (PFS) Proton Collaborative Group (PCG) Proton beam therapy (PBT) Declarations Consent for publication. Written informed consent for publication was obtained from all participants. Availability of supporting data. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests The authors have no relevant financial or non-financial interests to disclose. Authors' contributions Bai Jiwei and Shousei Shimizu contributed to formulating the surgical and radiotherapy treatment programs. Data collection and the first draft of the manuscript were written by MA. All authors provided comments on previous versions of the manuscript. Wang Jie, Zhang Shuyan, Liu Chao, and Wang Zishen contributed to the diagnosis and radiotherapy treatment. All authors read and approved the final manuscript. Funding Not applicable. References Turcotte LM, Neglia JP, Reulen RC, et al: Risk, risk factors, and surveillance of subsequent malignant neoplasms in survivors of childhood cancer: a review. Journal of Clinical Oncology 36:2145, 2018 Report WG: International rules for multiple primary cancers (ICD-0 third edition). European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 14:307-308, 2005 Nantavithya C, Paulino AC, Liao K, et al: Development of second primary tumors and outcomes in medulloblastoma by treatment modality: a surveillance, epidemiology, and end results analysis. Pediatric Blood & Cancer 67:e28373, 2020 Ohgaki H, Kleihues P: The definition of primary and secondary glioblastoma. Clinical cancer research 19:764-772, 2013 Mahajan S, Suri V, Sahu S, et al: World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5): What's new? Indian Journal of Pathology and Microbiology 65:S5-S13, 2022 Kleihues P, Ohgaki H: Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-oncology 1:44-51, 1999 Reulen RC, Frobisher C, Winter DL, et al: Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. Jama 305:2311-2319, 2011 Turcotte LM, Whitton JA, Friedman DL, et al: Risk of subsequent neoplasms during the fifth and sixth decades of life in the childhood cancer survivor study cohort. Journal of Clinical Oncology 33:3568, 2015 Turcotte LM, Liu Q, Yasui Y, et al: Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970-2015. Jama 317:814-824, 2017 Miralbell R, Lomax A, Cella L, Schneider U: Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. International Journal of Radiation Oncology* Biology* Physics 54:824-829, 2002 Nantavithya C, Paulino AC, Liao K, et al: Observed‐to‐expected incidence ratios of second malignant neoplasms after radiation therapy for medulloblastoma: A Surveillance, Epidemiology, and End Results analysis. Cancer 127:2368-2375, 2021 Chung CS, Yock TI, Nelson K, et al: Incidence of second malignancies among patients treated with proton versus photon radiation. International Journal of Radiation Oncology* Biology* Physics 87:46-52, 2013 Salvati M, Artico M, Caruso R, et al: A report on radiation‐induced gliomas. Cancer 67:392-397, 1991 Woo PY, Lee JW, Lam SW, et al: Radiotherapy-induced glioblastoma: distinct differences in overall survival, tumor location, pMGMT methylation and primary tumor epidemiology in Hong Kong Chinese patients. British Journal of Neurosurgery 38:385-392, 2024 Cahan WG, Woodard HQ, Higinbotham NL, et al: Sarcoma arising in irradiated bone: report of eleven cases. Cancer: Interdisciplinary International Journal of the American Cancer Society 82:8-34, 1998 Yamanaka R, Hayano A, Kanayama T: Radiation-induced gliomas: a comprehensive review and meta-analysis. Neurosurgical Review 41:719-731, 2018 Tubiana M: Can we reduce the incidence of second primary malignancies occurring after radiotherapy? A critical review. Radiotherapy and Oncology 91:4-15, 2009 Juratli TA, Kirsch M, Geiger K, et al: The prognostic value of IDH mutations and MGMT promoter status in secondary high-grade gliomas. Journal of Neuro-Oncology 110:325-333, 2012 Yan H, Parsons DW, Jin G, et al: IDH1 and IDH2 mutations in gliomas. New England journal of medicine 360:765-773, 2009 Hamisch C, Ruge M, Kellermann S, et al: Impact of treatment on survival of patients with secondary glioblastoma. Journal of Neuro-Oncology 133:309-313, 2017 Paulino AC, Mai WY, Chintagumpala M, et al: Radiation-induced malignant gliomas: is there a role for reirradiation? International Journal of Radiation Oncology* Biology* Physics 71:1381-1387, 2008 Scartoni D, Amelio D, Palumbo P, et al: Proton therapy re-irradiation preserves health-related quality of life in large recurrent glioblastoma. Journal of Cancer Research and Clinical Oncology 146:1615-1622, 2020 Saeed AM, Khairnar R, Sharma AM, et al: Clinical outcomes in patients with recurrent glioblastoma treated with proton beam therapy reirradiation: analysis of the Multi-Institutional Proton Collaborative Group Registry. Advances in Radiation Oncology 5:978-983, 2020 Galle JO, McDonald MW, Simoneaux V, Buchsbaum JC: Reirradiation with Proton Therapy for Recurrent Gliomas. International Journal of Particle Therapy 2:11-18, 2015 Incidence and clinical course of radionecrosis in children with brain tumors. Strahlentherapie und Onkologie 189:759-764, 2013 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 05 Oct, 2024 Read the published version in Radiation Oncology → Version 1 posted Editorial decision: Accepted 01 Sep, 2024 Reviews received at journal 29 Jul, 2024 Reviewers agreed at journal 29 Jul, 2024 Reviewers agreed at journal 29 Jul, 2024 Reviewers invited by journal 27 Jul, 2024 Editor assigned by journal 27 Jul, 2024 Submission checks completed at journal 22 Jul, 2024 First submitted to journal 16 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4753144","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":336687768,"identity":"4e46938c-271a-4310-a10e-40a170dd56ca","order_by":0,"name":"Bai Jiwei","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bai","middleName":"","lastName":"Jiwei","suffix":""},{"id":336687772,"identity":"a4a7b898-5e47-4805-9610-91367256805b","order_by":1,"name":"Muyasha Abulimiti","email":"","orcid":"","institution":"University of 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Lu","suffix":""},{"id":336687787,"identity":"d9c0c9c4-ca37-4a75-a03f-57e4411a05f7","order_by":11,"name":"Shosei(Qingshui) Shimizu(Xiangxing)","email":"data:image/png;base64,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","orcid":"","institution":"Hebei Yizhou Cancer Hospital","correspondingAuthor":true,"prefix":"","firstName":"Shosei(Qingshui)","middleName":"","lastName":"Shimizu(Xiangxing)","suffix":""}],"badges":[],"createdAt":"2024-07-17 03:08:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4753144/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4753144/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13014-024-02515-5","type":"published","date":"2024-10-05T15:57:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62734794,"identity":"0846f6ce-1590-4dc4-8ec3-b2f8e866e5d0","added_by":"auto","created_at":"2024-08-19 00:16:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":240615,"visible":true,"origin":"","legend":"\u003cp\u003eMagnetic resonance imaging studies of 41-year-old male patient: \u003cstrong\u003e(A)\u003c/strong\u003e space-occupying mass of left cerebellar hemisphere (50.3 × 47 × 51.1 mm); \u003cstrong\u003e(B)\u003c/strong\u003e striated circumferential enhancement of tumor bed 1 month after surgery and 3D-arterial spin labeling (ASL) sequence showing localized, string-like, slightly hyperperfused operative margins; \u003cstrong\u003e(C)\u003c/strong\u003e less margin enhancement at operative site, compared with pretreatment baseline, but no real hyperperfusion of operative margins in 3D-ASL sequence; and \u003cstrong\u003e(D)\u003c/strong\u003e high intensity signal absent from tumor bed, 1 year after radiotherapy.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4753144/v1/d144e5bd2d37ce164a2de50f.png"},{"id":62734127,"identity":"be4ce442-d151-4c9b-a493-b9bf2ecb712c","added_by":"auto","created_at":"2024-08-19 00:08:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":143793,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4753144/v1/8bc206087a36cd27fa8c30c6.png"},{"id":62734125,"identity":"999bf7a4-3f4a-409e-86d6-d27cbe65e658","added_by":"auto","created_at":"2024-08-19 00:08:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":62826,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of events during 32-year patient surveillance period\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4753144/v1/eb5f57879501d1a22f1f3049.png"},{"id":66097239,"identity":"9efbf3d9-682f-4e4d-92ca-a4a121b250cf","added_by":"auto","created_at":"2024-10-07 16:13:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1064934,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4753144/v1/8afa256d-0488-4416-b00c-c510d0d217cc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Proton beam therapy in a patient with secondary glioblastoma 32 years after postoperative radiotherapy for medulloblastoma: A case report and review of the literatures","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHistorically, the priority for treating medulloblastoma (MB) in children has been avoidance of undue side effects while achieving tumor control. As diagnostic and therapeutic techniques for such tumors increasingly have become more standardized, particularly through molecular subgroup stratification and multidisciplinary regimens (ie, surgery, chemotherapy, and radiotherapy), the potential for survival or cure has significantly improved. At the same time, there has been an upturn in subsequent occurrences of second primary tumors (SPTs)\u003csup\u003e[1]\u003c/sup\u003e. The International Agency for Research on Cancer (IARC)\u003csup\u003e[2]\u003c/sup\u003e has defined in which a patient harbors two or more primary tumors simultaneously or successively. Initially diagnosed tumors are considered primary lesions, whereas those arising later are designated SPTs. Central nervous system (CNS) is the most frequent site for SPT emergence, followed by endocrine and hematologic systems\u003csup\u003e[3]\u003c/sup\u003e. However, there is less data on glioblastoma (GB) as a SPT and its preferred mode of therapy after treatment of MB.\u003c/p\u003e \u003cp\u003eThe purpose of this article was to share our experience with a patient who developed a second primary GB. The latter occurred 32 years after previously administered craniospinal irradiation (CSI) for MB as a child. We intended to provide insights into the treatment process and review relevant publications in the literature.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eIn February 1991, our male patient (then 9 years old) presented with complaints of dizziness, vomiting, and loss of balance for 6 months. His condition had worsened recently, during the past month. Imaging studies disclosed a cerebellar tumor (30 \u0026times; 25 \u0026times; 25 mm) that was surgically removed on February 11, 1991. The pathology report confirmed MB, so cobalt-60 CSI (36 Gy/20 fractions) was delivered postoperatively, with a tumor bed boost (total of 56 Gy). He was monitored regularly thereafter, undergoing annual brain magnetic resonance imaging (MRI), but no chemotherapy was given.\u003c/p\u003e\n\u003cp\u003eIn March 2023 (32 years later), a space-occupying mass of left cerebellar hemisphere was detected by MRI. By June 25, 2023, loss of balance and difficulty walking had developed. A subsequent brain MRI again showed a mass of left cerebellar hemisphere, roughly 50.3 \u0026times; 47 \u0026times; 51.1 mm in size (Figure 1A). On July 6, 2023, left cerebellar hemispheric resection was performed using the prior incision line at left cerebellopontine angle. The tumor within was soft and richly vascularized, with no clearly demarcated borders. Once separated along its apparent boundaries, it measured approximately 50 \u0026times; 50 \u0026times; 45 mm. The brainstem was well protected, as were various cranial nerves (ipsilateral posterior group, facial, auditory, trigeminal, abducens) and other structures. Postsurgical recovery was event-free.\u003c/p\u003e\n\u003cp\u003eRepresentative histologic preparations revealed a high-grade and diffusely infiltrating neuroepithelial tumor of left cerebellum. For the most part, this lesion was densely cellular, demonstrating marked pleomorphism and tumor giant cells in conjunction with microvascular proliferation and fenestrated necrosis. Its immunohistochemical and morphologic features were compatible with radiation-induced glioblastoma (RIGB), World Health Organization (WHO) Grade IV. Results of immunostaining are provided in Table 1, and additional evidence to support a diagnosis of RIGB is offered in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eImmunohistochemical features of primary and secondary glioblastoma\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"500\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.9999%;\"\u003e\u003cstrong\u003eTumor marker\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 25.2001%;\"\u003e\u003cstrong\u003eSecondary GB\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e[4]\u003c/strong\u003e\u003c/sup\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cstrong\u003ePrimary GB\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e[5]\u003c/strong\u003e\u003c/sup\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cstrong\u003ePresent case\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003eGFAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive (GFAP+)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive (GFAP+)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive (GFAP+)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOlig-2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (Olig-2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (Olig-2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (Olig-2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIDH1 R132H\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (IDH1 R132H+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003eNegative (IDH1 R132H-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNegative (IDH1 R132H-)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIDH2 R172K\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (IDH2 R172K+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003eNegative (IDH2 R172K-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNegative (IDH2 R172K-)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eATRX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003eNegative (ATRX-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive/Negative (varies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003eNegative (ATRX-)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep53\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (p53+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003eNegative (p53-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNegative (p53-)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKi-67\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003eApproximately 30%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003eTypically high (varies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003eApproximately 30%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSynaptophysin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (Syn+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive/Negative (varies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeak Positive (Syn weak +)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eH3K27M\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003eNegative (H3K27M-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003eNegative (H3K27M-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003eNegative (H3K27M-)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eH3K27me3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003eTypically retained\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003eTypically retained\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePartial expression missing\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEZH2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (EZH2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003eVariable (EZH2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNegative (EZH2-)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMTAP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003eNegative (MTAP-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003eNegative (MTAP-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003eNegative (MTAP-)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSOX11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (SOX11+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003eVariable (Positive/Negative)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (SOX11+)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMSH6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (MSH6+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (MSH6+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (MSH6+)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMSH2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (MSH2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (MSH2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (MSH2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMLH1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (MLH1+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (MLH1+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (MLH1+)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 23.9999%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePMS2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 25.2001%;\"\u003e\n \u003cp\u003ePositive (PMS2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (PMS2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\"\u003e\n \u003cp\u003ePositive (PMS2+)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"500\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.35129740518962%\" valign=\"top\" style=\"width: 19.1401%;\"\u003e\n \u003cp\u003eMGMT \u003cstrong\u003epromoter methylation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.954091816367267%\" valign=\"top\" style=\"width: 16.4355%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMethylated\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"top\" style=\"width: 25.3814%;\"\u003e\u003cbr\u003e\u003cstrong\u003eVariable \u0026nbsp; \u0026nbsp; \u0026nbsp;(methylated/non-methylated)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"24.35129740518962%\" valign=\"top\" style=\"width: 17.8918%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMethylated\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 19.1401%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIDH1/IDH2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 41.8169%;\"\u003e\n \u003cp\u003eMutant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\" style=\"width: 25.3814%;\"\u003e\n \u003cp\u003eWild type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 17.8918%;\"\u003e\n \u003cp\u003eWild type\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 19.1401%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1p/19q deletion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 41.8169%;\"\u003e\n \u003cp\u003eNo deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\" style=\"width: 25.3814%;\"\u003e\n \u003cp\u003eNo deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 17.8918%;\"\u003e\n \u003cp\u003eNo deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 19.1401%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEGFR amplification\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 41.8169%;\"\u003e\n \u003cp\u003eNo amplification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\" style=\"width: 25.3814%;\"\u003e\n \u003cp\u003eOften amplified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 17.8918%;\"\u003e\n \u003cp\u003eNo amplification\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 19.1401%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCDKN2A deletion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 41.8169%;\"\u003e\n \u003cp\u003eCommon (pure deletion)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\" style=\"width: 25.3814%;\"\u003e\n \u003cp\u003eCommon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 17.8918%;\"\u003e\n \u003cp\u003ePure deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 19.1401%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCDKN2B deletion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.8%\" valign=\"top\" style=\"width: 41.8169%;\"\u003e\n \u003cp\u003eCommon (pure deletion)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.4%\" valign=\"top\" style=\"width: 25.3814%;\"\u003e\n \u003cp\u003eCommon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.4%\" valign=\"top\" style=\"width: 17.8918%;\"\u003e\n \u003cp\u003ePure deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eDiffering profiles of secondary GB (recurrent vs radiation induced)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"500\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecurrent secondary GB\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e[6]\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRadiation-induced secondary GB\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eEtiology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eProgression from low-grade or intermediate-grade glioma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eDevelopment after radiotherapy for other conditions (e.g., leukemia, brain tumor)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eIDH mutation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eCommon (especially IDH1 R132H mutation)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eRare\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTP53 mutation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eCommon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003ePossible, but less frequent\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eATRX inactivation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eCommon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMGMT promoter methylation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eCommon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTERT promoter mutation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eRare\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1p/19q co-deletion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eRare\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eRare\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTypical patient age\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eUsually younger patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eUsually older patients\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedical history\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eHistory of low-grade or intermediate-grade glioma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eHistory of radiotherapy for other tumors or diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOther chromosomal abnormalities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eCommon specific chromosomal mutation patterns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"NaN%\"\u003e\n \u003cp\u003eMay have more heterogeneous chromosomal mutations and structural variations\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eProton beam radiotherapy (PBT)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt this juncture, the patient was a 41-year-old man scoring 90 by Kanefsky Performance Scale. His medical history and past treatment did not preclude reirradiating the same area. Based on current and previous ranges of irradiation and the dosing tolerability of brainstem, proton beam therapy (PBT) was selected, hoping to minimize brainstem and spinal cord exposure. The patient received treatment on\u0026nbsp;August 7, 2023, 1 month after surgery. We defined postoperative tumor bed area and contrast-enhanced volume in T1 fat-saturated contrast-enhanced MRI scan as gross tumor volume (GTVtb), adding a 5-mm clinical target volume (CTV) margin. Treatment planning relied on a RayStation platform (RaySearch Laboratories, Stockholm, Sweden) for inversely planned intensity-controlled (raster-scanned) proton delivery using two horizontal beams. GTVtb and CTV doses were 60 Gy and 54 Gy, respectively in 30 fractions each (Figure 1). Maximum doses (Dmax values) to spinal cord and brain were 43.5 Gy and 53.5 Gy, respectively. Mean doses (Dmean values) to left and right hippocampus were 33 Gy and 0.95 Gy, respectively. Temozolomide (TMZ, 75 mg/m\u003csup\u003e2\u003c/sup\u003e) was administered on days of radiotherapy, followed by postradiotherapy TMZ maintenance (200 mg/m\u003csup\u003e2\u0026nbsp;\u003c/sup\u003edaily) for 5 days and cyclic dosing (every 28 days) for 6 months.\u003c/p\u003e\n\u003cp\u003eDuring the 32-year course of patient monitoring, multiple meningiomas had also arisen as SPTs, the first diagnosed in December 2008. One was removed in March 2009, but several non-resected meningiomas were under continued observation. To date, there is no evidence of recurrence or size increases, indicating stable disease. Likewise, MRI views of tumor bed remain devoid of high signal intensity nearly 1 year after completing radiotherapy. Aside from mild dizziness, the patient has experienced no other discomfort. A chronologic overview of the key medical events elaborated is included as Figure 3.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHerein, we have chronicled the medical course a childhood cancer survivor, including 32 years of follow-up after surgery and radiotherapy for MB and similar treatment imposed by a rare RIGB of later adult life. In this instance, PBT afforded access to high-dose, second-phase postoperative radiotherapy.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSecond primary tumors (SPTs)\u003c/h2\u003e \u003cp\u003eFor survivors of childhood cancer, the cumulative incidence of SPTs arising within 30 years after initial tumor diagnoses ranges from 3\u0026ndash;10% \u003csup\u003e[3]\u003c/sup\u003e. This is roughly 3\u0026ndash;6 times higher than comparable rates in the general population. The most common SPTs encountered are breast cancer for female survivors, ranging from 12\u0026ndash;20%; thyroid cancer, estimated at 2\u0026ndash;7%; and skin cancer, exceeding general population risk by 2\u0026ndash;6 times \u003csup\u003e[7,8]\u003c/sup\u003e. GB is a relatively rare SPT as such, but it is a recognized risk, particularly for recipients of cranial radiotherapy. More so than chemotherapy, irradiation is usually associated with a higher incidence of SPT (9.5% vs 2.4%) \u003csup\u003e[3]\u003c/sup\u003e, given its capacity to alter DNA methylation and methyltransferase activity and its deregulation of mRNA.\u003c/p\u003e \u003cp\u003eMB is a common childhood tumor, the overall survival of which has improved through combined use of radiotherapy, chemotherapy, and surgery. Current survival rates are ~\u0026thinsp;80\u0026ndash;85% for standard risk groups and ~\u0026thinsp;65\u0026ndash;70% for high-risk groups. However, long-term toxic effects (especially SPTs) are increasing as a result. In the aftermath of MB, CNS is reportedly the most common site of SPTs (63/146, 43.2%), followed by endocrine and hematologic systems. Similar outcomes have been documented during the Childhood Cancer Survivor Study and its British counterpart probe, likely due to whole brain and spinal axis targeting during CSI \u003csup\u003e[7,9]\u003c/sup\u003e. The unique physical properties entailed have broadened the usage of PBT in treating childhood cancer. Proton doses are characterized by abrupt surges in energy release, called Bragg peaks. Such rapid dosing decays reduce radiation to nearby healthy tissues by a factor of 2\u0026ndash;3. However, monitoring of treated patients for potential SPTs is a long-term proposition, and available research on SPT incidence by mode of MB treatment (proton vs photon therapy) is currently lacking.\u003c/p\u003e \u003cp\u003eRaymond \u003csup\u003e[10]\u003c/sup\u003e has generated estimates of secondary cancer incidence using a model derived from Publication No. 60 of the International Commission on Radiologic Protection. Compared with intensity-modulated or conventional X-ray plans, proton beams lowered the expected incidence of radiation-induced secondary cancers after MB treatment by a factor of 8\u0026ndash;15. An analysis of the SEER database from mid-2000s forward, ostensibly marked by greater PBT use, has also confirmed fewer SPTs as late effects\u003csup\u003e[3]\u003c/sup\u003e; and in another assessment according to treatment time frames (1973\u0026ndash;1995 vs 1995\u0026ndash;2014), the SPT rate proved higher during earlier years (1973\u0026ndash;1995) of more limited PBT use \u003csup\u003e[11]\u003c/sup\u003e. Matched adult populations (n\u0026thinsp;=\u0026thinsp;558 each) receiving proton or photon therapy have been followed as well (median interval: proton group, 6.7 years; photon group, 6.0 years)\u003csup\u003e[12]\u003c/sup\u003e, recording SPT rates of 5.2% and 7.5%, respectively. Above findings imply a lower incidence of SPT after PBT of childhood MB. On the other hand, most present-day survivors of pediatric tumors have received photon therapy over a decade ago, so longer follow-up periods may be needed to ascertain SPT incidence in relation to PBT.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eRadiation-induced second primary glioblastoma (RIGB)\u003c/h2\u003e \u003cp\u003eClassification of a second primary GB as radiation induced (rather than recurrent second primary)\u003csup\u003e[13\u0026ndash;15]\u003c/sup\u003e is based on the following criteria: (1) tumor situated within the irradiated field; (2) sufficient latency between irradiation and tumor occurrence; (3) histological type different from that of original neoplasm; and (4) no pathology, such as Von Recklinghausen disease, favoring tumor development. The most common malignancies associated with RIGB are nasopharyngeal carcinoma (37%), primary intracranial germinoma (21%), and MB (16%)\u003csup\u003e[16]\u003c/sup\u003e. At 9 years of age, our patient with MB received postoperative CSI only. In analyzing 2771 patients with MB from the SEER-18 database, there were 146 patients (5.27%) who developed SPTs at 15 years. Rates of SPTs after radiotherapy only, radio- and chemotherapy, and chemotherapy only were 9.5%, 4.3%, and 2.4%, respectively \u003csup\u003e[3]\u003c/sup\u003e. Several studies have shown a 14-year mean latency between radiotherapy and diagnosis of RIGB, unlike the 32-year span in our patient that surpassed most previously published intervals \u003csup\u003e[11,14]\u003c/sup\u003e. It is a widely held concept that the younger a patient is at primary treatment, the greater the risk of RIGB will be. Younger onset may therefore render patients especially vulnerable to radiation-induced gliomagenesis in later years due to an abundance of neurogenic stem cells and increased growth factor activity \u003csup\u003e[17]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRIGB is a relatively rare SPT, with a molecular profile that distinguishes it from primary GB and recurrent secondary GB. Clinicians focus more on recurrent secondary GB, tending to overlook the specific and individualized treatment of RIGB. \u003cem\u003eIDH\u003c/em\u003e mutation is a critical marker in glioma classification that helps differentiate recurrent and radiation-induced forms of secondary GB (Tables\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e2\u003c/span\u003e). \u003cem\u003eIDH\u003c/em\u003e mutations are largely features of less ominous tumors (WHO grade II-III), whereas the \u003cem\u003eIDH\u003c/em\u003e wild type primarily reflects aggressive disease (WHO grade IV), signaling a worse prognosis. In 2021, the latest WHO revision of GB grading was substantial, stipulating that only \u003cem\u003eIDH\u003c/em\u003e wild-type lesions warrant a GB diagnosis \u003csup\u003e[5]\u003c/sup\u003e. Still, there are perhaps some GBs with \u003cem\u003eIDH\u003c/em\u003e mutations. The latter have chiefly presented as secondary GBs, morphologically similar to primary GB but imparting a more favorable prognosis\u003csup\u003e[18]\u003c/sup\u003e. In patients with \u003cem\u003eIDH\u003c/em\u003e-mutant GBs, median OS may be ~\u0026thinsp;31 months, as opposed to 15 months for those with \u003cem\u003eIDH\u003c/em\u003e-wildtype GBs \u003csup\u003e[18,19]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAmong 39 patients with secondary GBs, the \u003cem\u003eIDH\u003c/em\u003e mutation rate was found to be 60%, and the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation rate was 68.8% \u003csup\u003e[20]\u003c/sup\u003e. MGMT is a direct DNA repair enzyme that eliminates the TMZ-produced genotoxic O6-methylguanine adduct in a single-step process. Because this restores the genomic integrity of tumors, MGMT promoter methylation denotes a better prognosis. An earlier meta-analysis has determined a median OS (mOS) of 10 months in patients with RIGBs [Peter Y. M]. Across the spectrum of grade IV GBs, survival in patients with RIGBs (mOS, 4.8 months) was shorter than in instances of \u003cem\u003ede novo\u003c/em\u003e GB (mOS, 19.2 months; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001). These findings may be explained by the fact patients with \u003cem\u003eIDH\u003c/em\u003e wild type were involved, and there was a lower percentage of MGMT promoter methylation \u003csup\u003e[14]\u003c/sup\u003e. Our patient with WHO grade IV GB exhibited both \u003cem\u003eIDH\u003c/em\u003e mutation and MGMT promoter methylation, thus suggesting TMZ sensitivity and a better prognosis than anticipated for primary or recurrent secondary GB of \u003cem\u003eIDH\u003c/em\u003e wild type.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eRIGB treatment\u003c/h2\u003e \u003cp\u003eCurrently, there is no consensus on oncologic treatment in instances of RIGB. Studies have concluded that patients with secondary GBs experience significantly longer survival times if repeat resection is elected, instead of foregone \u003csup\u003e[20]\u003c/sup\u003e. Patients with good KPS scores and proper suitability for surgery should subsequently consider second-phase resection as a primary treatment option, although decisions on postoperative adjuvant therapy are comparatively more difficult. Physicians must weigh the perceived benefit of reirradiation against the risk of related brain damage.\u003c/p\u003e \u003cp\u003eIn the past, the conventional dose limit for partial brain radiotherapy has been 60 Gy. Some sources have challenged this view, suggesting that reirradiated brain tissue may tolerate a fractionated (2 Gy/fr) cumulative normalized total dose of 100 Gy before necrosis ensues \u003csup\u003e[13]\u003c/sup\u003e. Paulino et al. have noted that among patients with radiotherapy-induced high-grade gliomas, those who received reirradiation of 50 Gy (35/85, 41%) displayed a 2-year overall survival (OS) rate of 21%. This was significantly better than the 3% rate recorded at 2 years in the absence of reirradiation \u003csup\u003e[21]\u003c/sup\u003e. Similarly, a meta-analysis has found that reirradiation (mean dose, 48 Gy) conferred a better 2-year OS rate (24%) than the rate achieved (9%) through different treatment. Upon examining factors linked to survival in the setting of grade III-IV RIGB, multimodality combination therapy (including radiotherapy) was identified as an independent prognostic factor (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) \u003csup\u003e[16]\u003c/sup\u003e. These observations suggest that in some patients with radiation-induced gliomas, a therapeutic strategy of reirradiation may serve to prolong disease control. However, the tolerance threshold is changing due to advances in radiotherapy technology, such as PBT. These improvements stand to mitigate the risk of late radiation effects. Despite a scarcity of data on PBT use for reirradiation of RIGB, we are encouraged by its successful application in patients with recurrent gliomas or other brain tumors. Scartoni et al. \u003csup\u003e[22]\u003c/sup\u003e have investigated 33 patients who completed questionnaires before starting PBT, on last day of treatment, and at every follow-up visit until disease progression. It appears that PBT is safe and well tolerated, ensuring stable quality-of-life parameters for the duration.\u003c/p\u003e \u003cp\u003eThe Proton Collaborative Group (PCG) has examined 45 patients from 12 PBT centers in the United States, all receiving photon radiotherapy initially at doses of 60 Gy. The median time between original diagnosis and recurrence was only 20 months, and the median total reirradiation dose was 46.2 Gy (range, 25\u0026ndash;60 Gy), with a median of 2.2 Gy per fraction. Of these 45 patients, 40 (88.9%) had received an equivalent dose in 2 Gy fractions (EQD2) of \u0026gt;\u0026thinsp;39 Gy. All patients had GB as their primary diagnosis. Median progression-free survival (PFS) time was 13.9 months, and median OS was 14.2 months. In terms of side effects, a total of five patients experienced grade 3 toxicity. One showed acute toxicity (ataxia), whereas late toxicity (neuropathy, cognitive disturbance, optic nerve disorder, or seizure) surfaced in the other four. No acute or delayed grade 4 or 5 toxicities were observed.\u003c/p\u003e \u003cp\u003eDuring a similar multicenter study, patients with GB were reirradiated at high dose, without serious side effects over a year\u0026rsquo;s time, highlighting the utility of PBT for this purpose \u003csup\u003e[23]\u003c/sup\u003e. Another 20 patients who received proton reirradiation for recurrent gliomas also registered acceptable outcomes after high-dose radiotherapy. The mean initial dose was 59.4 Gy, and the mean reirradiation dose after a median of 15.3 months (range, 5.3-152.6 months) was 54 Gy \u003csup\u003e[24]\u003c/sup\u003e. Several earlier investigations have further reinforced the prospect of high-dose irradiation enabled by PBT.\u003c/p\u003e \u003cp\u003eWhen irradiating our patient (32 years after initial radiotherapy), we used a standard postoperative dose of 60 Gy, delivering a low dose to brainstem and hippocampus. The Dmax of brain scan was 53.5 Gy, the Dmean of left hippocampus was 33 Gy, and the Dmean of right hippocampus was 0.95 Gy. Although the prognosis of a grade IV RIGB is poor, lessening our concerns over later clinically significant necrosis, it is important for physicians to optimally protect a patient's cognitive function. The incidence of radiation necrosis typically peaks around 1\u0026ndash;3 years after radiotherapy\u003csup\u003e[25]\u003c/sup\u003e. At 1 year after reirradiation, no signs of tumor recurrence or radiation necrosis have been detected as yet.\u003c/p\u003e \u003cp\u003eIn summary, RIGB is a rare SPT determined by strategic molecular profiling and requiring individualized management. PBT is the preferred postoperative treatment.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003col\u003e\n \u003cli\u003eSecond primary tumors (SPT)\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;International Agency for Research on Cancer (IARC)\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Central Nervous System(CNS)\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Craniospinal Irradiation(CSI)\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Magnetic Resonance Imaging (MRI)\u003c/li\u003e\n \u003cli\u003eCerebellopontine Angle region(CPA)\u003c/li\u003e\n \u003cli\u003eImmunohistochemistry (IHC)\u003c/li\u003e\n \u003cli\u003eRadiation-induced Glioblastoma(RIGB)\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Nasopharyngeal Cancer (NPC)\u003c/li\u003e\n \u003cli\u003eNot Otherwise Specified (NOS)\u003c/li\u003e\n \u003cli\u003eWorld Health Organization (WHO)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKarnofsky Performance Status (KPS)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Overall Survival (OS)\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Progression-free Survival (PFS)\u003c/li\u003e\n \u003cli\u003e\u0026nbsp; Proton Collaborative Group (PCG)\u003c/li\u003e\n \u003cli\u003eProton beam therapy (PBT)\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConsent for publication.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBai Jiwei and Shousei Shimizu contributed to formulating the surgical and radiotherapy treatment programs. Data collection and the first draft of the manuscript were written by MA. All authors provided comments on previous versions of the manuscript. Wang Jie, Zhang Shuyan, Liu Chao, and Wang Zishen contributed to the diagnosis and radiotherapy treatment. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTurcotte LM, Neglia JP, Reulen RC, et al: Risk, risk factors, and surveillance of subsequent malignant neoplasms in survivors of childhood cancer: a review. Journal of Clinical Oncology 36:2145, 2018\u003c/li\u003e\n\u003cli\u003eReport WG: International rules for multiple primary cancers (ICD-0 third edition). European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 14:307-308, 2005\u003c/li\u003e\n\u003cli\u003eNantavithya C, Paulino AC, Liao K, et al: Development of second primary tumors and outcomes in medulloblastoma by treatment modality: a surveillance, epidemiology, and end results analysis. Pediatric Blood \u0026amp; Cancer 67:e28373, 2020\u003c/li\u003e\n\u003cli\u003eOhgaki H, Kleihues P: The definition of primary and secondary glioblastoma. Clinical cancer research 19:764-772, 2013\u003c/li\u003e\n\u003cli\u003eMahajan S, Suri V, Sahu S, et al: World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5): What\u0026apos;s new? Indian Journal of Pathology and Microbiology 65:S5-S13, 2022\u003c/li\u003e\n\u003cli\u003eKleihues P, Ohgaki H: Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-oncology 1:44-51, 1999\u003c/li\u003e\n\u003cli\u003eReulen RC, Frobisher C, Winter DL, et al: Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. Jama 305:2311-2319, 2011\u003c/li\u003e\n\u003cli\u003eTurcotte LM, Whitton JA, Friedman DL, et al: Risk of subsequent neoplasms during the fifth and sixth decades of life in the childhood cancer survivor study cohort. Journal of Clinical Oncology 33:3568, 2015\u003c/li\u003e\n\u003cli\u003eTurcotte LM, Liu Q, Yasui Y, et al: Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970-2015. Jama 317:814-824, 2017\u003c/li\u003e\n\u003cli\u003eMiralbell R, Lomax A, Cella L, Schneider U: Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. International Journal of Radiation Oncology* Biology* Physics 54:824-829, 2002\u003c/li\u003e\n\u003cli\u003eNantavithya C, Paulino AC, Liao K, et al: Observed‐to‐expected incidence ratios of second malignant neoplasms after radiation therapy for medulloblastoma: A Surveillance, Epidemiology, and End Results analysis. Cancer 127:2368-2375, 2021\u003c/li\u003e\n\u003cli\u003eChung CS, Yock TI, Nelson K, et al: Incidence of second malignancies among patients treated with proton versus photon radiation. International Journal of Radiation Oncology* Biology* Physics 87:46-52, 2013\u003c/li\u003e\n\u003cli\u003eSalvati M, Artico M, Caruso R, et al: A report on radiation‐induced gliomas. Cancer 67:392-397, 1991\u003c/li\u003e\n\u003cli\u003eWoo PY, Lee JW, Lam SW, et al: Radiotherapy-induced glioblastoma: distinct differences in overall survival, tumor location, pMGMT methylation and primary tumor epidemiology in Hong Kong Chinese patients. British Journal of Neurosurgery 38:385-392, 2024\u003c/li\u003e\n\u003cli\u003eCahan WG, Woodard HQ, Higinbotham NL, et al: Sarcoma arising in irradiated bone: report of eleven cases. Cancer: Interdisciplinary International Journal of the American Cancer Society 82:8-34, 1998\u003c/li\u003e\n\u003cli\u003eYamanaka R, Hayano A, Kanayama T: Radiation-induced gliomas: a comprehensive review and meta-analysis. Neurosurgical Review 41:719-731, 2018\u003c/li\u003e\n\u003cli\u003eTubiana M: Can we reduce the incidence of second primary malignancies occurring after radiotherapy? A critical review. Radiotherapy and Oncology 91:4-15, 2009\u003c/li\u003e\n\u003cli\u003eJuratli TA, Kirsch M, Geiger K, et al: The prognostic value of IDH mutations and MGMT promoter status in secondary high-grade gliomas. Journal of Neuro-Oncology 110:325-333, 2012\u003c/li\u003e\n\u003cli\u003eYan H, Parsons DW, Jin G, et al: IDH1 and IDH2 mutations in gliomas. New England journal of medicine 360:765-773, 2009\u003c/li\u003e\n\u003cli\u003eHamisch C, Ruge M, Kellermann S, et al: Impact of treatment on survival of patients with secondary glioblastoma. Journal of Neuro-Oncology 133:309-313, 2017\u003c/li\u003e\n\u003cli\u003ePaulino AC, Mai WY, Chintagumpala M, et al: Radiation-induced malignant gliomas: is there a role for reirradiation? International Journal of Radiation Oncology* Biology* Physics 71:1381-1387, 2008\u003c/li\u003e\n\u003cli\u003eScartoni D, Amelio D, Palumbo P, et al: Proton therapy re-irradiation preserves health-related quality of life in large recurrent glioblastoma. Journal of Cancer Research and Clinical Oncology 146:1615-1622, 2020\u003c/li\u003e\n\u003cli\u003eSaeed AM, Khairnar R, Sharma AM, et al: Clinical outcomes in patients with recurrent glioblastoma treated with proton beam therapy reirradiation: analysis of the Multi-Institutional Proton Collaborative Group Registry. Advances in Radiation Oncology 5:978-983, 2020\u003c/li\u003e\n\u003cli\u003eGalle JO, McDonald MW, Simoneaux V, Buchsbaum JC: Reirradiation with Proton Therapy for Recurrent Gliomas. International Journal of Particle Therapy 2:11-18, 2015\u003c/li\u003e\n\u003cli\u003eIncidence and clinical course of radionecrosis in children with brain tumors. Strahlentherapie und Onkologie 189:759-764, 2013\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4753144/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4753144/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"In the past, for children's medulloblastoma tumors, the priority of cancer treatments was to control the tumor rather than the risk of side effects. With the gradual standardization of diagnostic and therapeutic techniques for children's medulloblastoma tumors, especially the application of stratified treatment guided by its molecular typing and multidisciplinary integrated treatment such as surgery, chemotherapy, radiotherapy, the cure, and survival of children's medulloblastoma tumor patients have been significantly improved. At the same time, there has been an increase in the number of second primary tumors (SPT). According to the concept of multiple primary tumors defined by the International Agency for Research on Cancer (IARC), two or more primary tumors are found in the patient simultaneously or successively. The tumor diagnosed first is known as the primary tumor, and the tumor diagnosed later is known as the SPT. The most frequent site of SPT is the CNS, followed by endocrine and hematological systems. However, there is less data on second primary glioblastoma and treatment modality recommendations after medulloblastoma. The purpose of this article is to share a case of a patient with medulloblastoma who developed a second primary glioblastoma 32 years after receiving craniospinal irradiation as a child. Additionally, it aims to provide insights into the treatment experience and present a review of relevant literature.","manuscriptTitle":"Proton beam therapy in a patient with secondary glioblastoma 32 years after postoperative radiotherapy for medulloblastoma: A case report and review of the literatures","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-19 00:08:02","doi":"10.21203/rs.3.rs-4753144/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-09-01T11:59:57+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-29T15:24:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"187205877093429839093026255857841127098","date":"2024-07-29T13:57:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"146038866801744508942905337746073627033","date":"2024-07-29T12:10:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-27T11:35:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-27T10:39:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-22T04:57:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Radiation Oncology","date":"2024-07-17T03:04:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3a38bb92-2e4d-4fd5-bb98-7732d6b4eee3","owner":[],"postedDate":"August 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-07T16:08:13+00:00","versionOfRecord":{"articleIdentity":"rs-4753144","link":"https://doi.org/10.1186/s13014-024-02515-5","journal":{"identity":"radiation-oncology","isVorOnly":false,"title":"Radiation Oncology"},"publishedOn":"2024-10-05 15:57:02","publishedOnDateReadable":"October 5th, 2024"},"versionCreatedAt":"2024-08-19 00:08:02","video":"","vorDoi":"10.1186/s13014-024-02515-5","vorDoiUrl":"https://doi.org/10.1186/s13014-024-02515-5","workflowStages":[]},"version":"v1","identity":"rs-4753144","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4753144","identity":"rs-4753144","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}