Reoperation and radiotherapy improve overall survival in patients with epithelioid glioblastoma : A multi-institutional experience

Reoperation and radiotherapy improve overall survival in patients with epithelioid glioblastoma : A multi-institutional experience | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Reoperation and radiotherapy improve overall survival in patients with epithelioid glioblastoma : A multi-institutional experience Meng-nan Sun, Shao-qun Li, Yao Guo, Jiang-fen Zhou, Dan-dan Fu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4674275/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Oct, 2024 Read the published version in Neurosurgical Review → Version 1 posted 11 You are reading this latest preprint version Abstract Epithelioid glioblastoma (Ep-GBM) is a rare variant of glioblastoma characterized by a high recurrence rate and poor prognosis. Currently, there is no established standard treatment for Ep-GBM. Therefore, we identified 58 epithelioid glioblastoma cases to investigate these characteristics and identify the possible prognostic factors of survival. The study encompassed 58 patients with a mean age of 37.6±16.3 years. Gross total resection(GTR) was found to be associated with a longer median PFS compared to partial resection (PR) ( P =0.017). Univariate analysis demonstrated that individuals who received more than six cycles of adjuvant chemotherapy with temozolomide (TMZ) had a longer median PFS ( P =0.009, hazard ratio [HR]=0.404, 95% confidence interval [CI], 0.204-0.799) or OS ( P =0.020, HR=0.408, 95% CI, 0.192-0.868) than those who received fewer cycles. GTR remained significantly associated with PFS ( P =0.021, HR=0.430, 95% CI, 0.210-0.878). Additionally, patients who received radiotherapy had a significantly higher median OS than those who did not ( P < 0.001, HR=0.200, 95% CI, 0.081-0.495). In the multivariate analysis, radiotherapy remained significantly associated with improved survival ( P =0.001, HR=0.181, 95% CI, 0.065-0.502). Patients who underwent reoperation had significantly longer survival than those who did not ( P =0.003, HR=0.268, 95% CI, 0.113-0.633). Multivariate analysis confirmed an association between reoperation and prolonged survival ( P =0.009, HR=0.286, 95% CI, 0.110-0.747). In conclusion, gross total resection, radiotherapy, and adjuvant chemotherapy using TMZ enhanced PFS or OS, reoperation and simultaneous chemoradiotherapy show promise in extending the survival duration of patients with recurrent Ep-GBM. Epithelioid glioblastoma Chemoradiotherapy Reoperation Recurrence Ep-GBM Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Glioblastoma (GBM) stands as the most common malignant tumor of the central nervous system, with the highest occurrence rate among all brain tumors. In 2016, a new GBM subtype, epithelioid glioblastoma (Ep-GBM), was added to the WHO Classification of Tumors of the Central Nervous System. Ep-GBM is classified as an IDH wild-type GBM, distinguishing it from other GBM types [ 1 ] . Histologically, Ep-GBM is manifests with abundant epithelioid and melanoma-like cells, which exhibit features such as abundant cytoplasm, eccentric nuclei, prominent nucleoli, and rhabdomyosin-like attributes [ 2 ] . Unlike conventional GBM, Ep-GBM is more prevalent in children and young adults and exhibits aggressive behaviors such as cerebrospinal fluid dissemination and central nervous system metastases. Ep-GBM presents a notably poor prognosis, with significantly worse outcomes than other GBM types [ 3 ] . Presently, therapeutic recommendations for Ep-GBM do not account for histological variations [ 4 ] . Our findings suggest that Ep-GBM [ 5 ] , as characterized by histopathological features, is not a singular diagnostic entity. Instead, it comprises at least three distinct tumor subtypes that are molecularly and biologically different. These subtypes vary significantly in prevalence across different populations and exhibit distinct prognostic outcomes. Therefore, conventional GBM treatment strategies may not be suitable for managing Ep-GBM. Due to the relative rarity of Ep-GBM, comprehensive research on this tumor is limited. Most available literature consists of case reports or retrospective case series involving a relatively small number of cases. Therefore, the primary aim of this study was to thoroughly investigate and evaluate the clinicopathological features, treatment methods, and their impact on the prognosis of Ep-GBM. We anticipate that the findings of this study will provide valuable insights for facilitating the clinical diagnosis and treatment of Ep-GBM, as well as offer support and guidance to healthcare professionals and patients. 2. Materials and methods 2.1 Study participants A retrospective review was conducted on glioma patients who received treatment at the Guangdong Sanjiu Brain Hospital and the First Affiliated Hospital of Jinan University. Progression-free survival (PFS) is defined as the period from surgery to the occurrence of postoperative tumor recurrence, metastasis, or the last follow-up date. Overall survival (OS) is typically defined as the duration from the surgical procedure to either the patient’s demise or the last follow-up visit. Relapse survival time refers to the duration from surgery following recurrence to the patient's death or last follow-up. In this retrospective study, patient data were anonymized, eliminating the need for informed consent from the patients' guardians. The study was conducted in accordance with the principles of the Declaration of Helsinki and received authorization from the hospital's medical ethics committee. Patients with Ep-GBM underwent follow-up assessments involving brain MRI every 2 months after the initial radiotherapy for 2 or 3 years under the supervision of a multidisciplinary team. If a patient developed a new symptom or if the neurological symptoms deteriorated, then MRI was performed regardless of the scheduled follow-up period. When clinically indicated, surgery was performed to confirm the final diagnosis of a viable tumor. If surgery was not possible, then the viable tumor was determined using MRI in accordance with the RANO criteria and serial follow-up examinations with intervals of at least 3 months were performed. The clinicoradiological diagnosis was determined by a consensus reached during a multidisciplinary meeting involving two neuro-oncologists (all with 20 and 7 years of experience with neuro-oncology) and three neuroradiologists (with 18, 10 and 6 years of experience with neuro-oncologic imaging, respectively). When a contrast-enhancing lesion exhibited a steady increase in size during two or more successive follow-up MRI examinations within a 2- to 3-month interval. the patient was classified as having tumor recurrence. In contrast, when a contrast-enhancing lesion subsequently regressed or became stable without a change in treatment within 6 months of the index imaging, the patient was categorized as no recurrence. The extent of tumor resection was determined by comparing a 24–72 h postoperative MRI to that of preoperative imaging. Gross total resection was defined by the absence of visible residual tumors on postoperative T1-enhanced MRI findings, whereas the presence of residual tumor on these MRI results was designated as partial resection. All cases were reviewed by a multidisciplinary neuro-oncology clinic comprised of neurosurgeons, neuro-oncologists, and radiation oncologists. Patients in good clinical condition with tumors that originate near the previous cavities and do not involve eloquent cortical areas, basal ganglia, diencephalic or brainstem structures, with a PFS of at least 6 months, are generally considered candidates for reoperation. 2.2 Pathological testing Tumor tissue samples were fixed in 10% formalin and embedded in paraffin. Subsequently, the paraffin-embedded tumor sections, 3-µm thick, underwent staining using the standard hematoxylin and eosin staining method. Immunohistochemical staining was performed using the SP method and monoclonal antibodies against several markers, including glial fibrillary acidic protein (GFAP), methylguanine DNA methyltransferase (MGMT), oligodendrocyte transcription factor 2 (Olig-2), X-linked alpha-thalassemia mental retardation syndrome (ATRX), BRAF-V600E (VE1), IDH-1, H3K27m, P53, and Ki-67 proliferation index. 2.3 Statistical analysis Factors influencing patient endpoint events were analyzed using both univariate and multivariate Cox regression methods. Factors with a p-value < 0.2 in the univariate analysis were subsequently included in the multivariate analysis. Survival analysis was conducted using the Kaplan–Meier method, with intergroup comparisons facilitated by the log-rank test. The significance level was set at p < 0.05. All statistical analyses were performed using SPSS 27.0. 3. Results 3.1 Patient demographics The average age was 37.6 ± 16.4 years, ranging from of 5 to 70 years. Regarding the gender distribution, 30 patients were male and 28 female. The most frequently reported initial symptoms among the patients were headache and dizziness, which occurred in 42 cases, followed by limb weakness and sensory abnormalities in 6 cases, epilepsy in 6 cases, memory loss in 3 cases, and blurred vision in both eyes in 1 case. Except for 1 case located in the left cerebellar hemisphere, patients with Ep-GBM predominantly exhibited tumor onset inside the cerebral hemispheres. There were 25 cases in the right cerebral hemisphere, with 10 cases located in the right temporal lobe, 5 in the right frontal lobe, and 10 cases involving multiple lobes. Additionally, 31 cases were found in the left cerebral hemisphere, including 11 cases in the left temporal lobe, 5 cases in the left parietal lobe, 3 cases in the left frontal lobe, 1 case in the left occipital lobe, 1 case in the left thalamus, and 10 cases involving multiple lobes. In addition, 1 case was mentioned in the callosal pressure section. Clinical data are summarized in Table 1 . Table 1 Demographics of patients with epithelioid glioblastoma Parameter Parameter Age (years) Extent of resection (%) Mean ± SD 37.6 ± 16.3 Gross total resection 41(70.7%) Range 5–70 Partial resection 17(29.3%) Sex (%) Male 30(51.7%) Stupp regimen (%) 38(65.5%) Female 28(48.3%) Recurrence (%) 39(67.2%) Presenting symptom (%) Treatment after recurrence (%) Headaches & dizziness 42(72.4%) Surgery & simultaneous chemoradiotherapy 14(35.9%) Limb weakness 6(10.3%) Only Surgery 4(10.3%) Epileptic 6(10.3%) Only radiotherapy 5(12.8%) Other 4(6.9%) Supportive therapy 16(41.0%) Tumor location (%) Bevacizumab (%) 10(17.2%) Temporal lobe 21(36.2%) BRAF inhibitor (%) 6(10.3%) Frontal lobe 8(13.7%) State of survival (%) Parietal lobe 5(8.6%) Censored 23(39.7%) Occipital lobe 1(1.7%) Mortality 35(60.3%) Multiple lobes 20(34.5%) Corpus callosum 1(1.7%) Median PFS(months) 12.7 Left thalamus 1(1.7%) Median OS(months) 29.1 Left cerebellar hemisphere 1(1.7%) Median survival time after Recurrence(months) 12.7 PFS, progression-free survival; OS, overall survival. 3.2 Therapy In our study of patients diagnosed with Ep-GBMs, surgical resection was considered as the primary treatment approach. Gross total resection (GTR) was successfully completed in 41 patients, while 17 individuals underwent partial resection (PR). Following the surgical procedures, 39 patients were treated using the Stupp regimen. Most patients received a radiation dose of 60 Gy/30f, with temozolomide (TMZ) as the standard chemotherapeutic agent for all patients. Following simultaneous chemoradiotherapy, all patients received 2–12 cycles of TMZ chemotherapy. Throughout the follow-up period, tumor recurrence was observed in 39 patients. Among those who experienced recurrence, 14 individuals underwent surgery combined with simultaneous chemoradiotherapy, 4 patients chose surgery alone, 5 patients received radiation therapy alone, and 16 patients were solely treated with TMZ chemotherapy or other forms of supportive therapy. In the trial, 6 participants were administered a BRAF inhibitor, and 1 patient received combination therapy that included both BRAF and MEK inhibitors. 5 patients underwent a third surgical procedure after the second recurrence. Throughout the disease period, radiation therapy was administered to a total of 47 individuals, including 12 patients who underwent reirradiation. 3.3 Pathologic and immunohistochemistry Microscopically, the tumor cells exhibited infiltrative growth with densely arranged regular or round cells. Some of these cells displayed an epithelioid or rhabdomyoid shape and lacked adhesion while maintaining a clear cellular membrane and eosinophilic cytoplasm. Nuclei were frequently enlarged and irregularly shaped, often accompanied by prominent nucleoli, indicating prevalent nuclear atypia, which occasionally led to the formation of multinucleated giant tumor cells. No intratumoral microvascular or glomeruloid-like vascular hyperplasia was observed. Tumor cells exhibited a pattern of arrangement around blood vessels, forming a pseudopapillary structure. Moreover, the presence of digitiform necrosis and pseudo-fenestrated necrosis features could be observed within the tissue. Immunohistochemistry findings revealed positive expression of various markers: BRAF-V600E (56.9%, 33/58), MGMT (56.9%, 33/58), GFAP (89.6%, 52/58), Olig-2 (93.1%, 54/58), ATRX (86.2%, 50/58), P53 (72.4%, 42/58). The Ki-67 proliferation index ranged from 3–80%, with a mean of 28.7%. Notably, IDH-1 and H3K27m. 3.4 PFS The median PFS for the patients was 12.7 months (95% confidence interval [CI], 6.721–18.732). Among these patients, those who underwent GTR exhibited a significantly longer median PFS than those who underwent PR ( P = 0.017) (Fig. 1 ). Additionally, patients who received more than 6 cycles of TMZ adjuvant chemotherapy demonstrated a significantly extended median PFS compared to patients who received fewer than 6 cycles ( P = 0.007) (Fig. 2 ). In the univariate survival analysis, the PFS of the patients was examined in relation to various parameters, including age, sex, tumor stroke, extent of resection, and immunohistochemical markers such as the MGMT promoter methylation status, GFAP, ATRX, P53, and Ki-67 proliferation index. Notably, only the extent of tumor resection ( P = 0.021, hazard ratio [HR] = 0.430, 95% CI, 0.210–0.878) and the number of cycles of adjuvant chemotherapy with TMZ ( P = 0.009, HR = 0.404, 95% CI, 0.204–0.799) were significantly associated with PFS (Table 2 ). To further investigate these relationships, a multifactorial Cox proportional hazards model was constructed, which incorporated variables such as age, extent of tumor resection, number of adjuvant chemotherapy cycles with TMZ, simultaneous chemoradiotherapy, and BRAF-V600E and Olig2 mutation status. However, no statistically significant correlation was found between PFS and these factors. Table 2 Survival analyses for prognosticators of progression-free survival in epithelioid glioblastoma patients Parameter Univariate Multivariate HR 95% Confidence Interval P HR 95% Confidence Interval P Age 1.007 0.985–1.029 0.524 Sex 1.247 0.659–2.362 0.498 Tumor stroke 0.886 0.387–2.027 0.774 Extent of resection 0.430 0.210–0.878 0.021 0.515 0.238–1.114 0.140 Simultaneous chemoradiotherapy 0.572 0.284–1.154 0.119 0.901 0.412–1.968 0.794 Adjuvant chemotherapy 0.404 0.204–0.799 0.009 0.482 0.222–1.050 0.066 Ki-67 0.612 0.277–1.354 0.225 BRAF-V600E (+) 1.691 0.870–3.287 0.121 0.958 0.458–2.005 0.910 MGMT (+) 0.920 0.484–1.748 0.799 GFAP (+) 1.020 0.358–2.907 0.970 ATRX (+) 1.257 0.481–3.281 0.641 Olig-2 (+) 0.618 0.188–2.035 0.429 P53 (+) 0.897 0.460–1.750 0.750 3.5 OS The median OS of the patients was 29.1 months (95% CI, 21.318–36.920). During the first year, the survival rate was 78.4%, which declined to 56.8% in the second year and further dropped to 18.9% by the fifth year. A significant difference in the median OS was observed between patients who received radiotherapy and those who did not ( P < 0.001) (Fig. 3 ). In the univariate survival analysis, radiation therapy ( P < 0.001, HR = 0.200, 95% CI, 0.081–0.495) and the number of cycles of adjuvant chemotherapy with TMZ ( P = 0.020, HR = 0.408, 95% CI, 0.192–0.868) showed a significant relation to OS. A multifactorial Cox proportional risk model was constructed including sex, extent of tumor resection, administration of radiotherapy, and immunohistochemical markers (MGMT, Ki-67 proliferation index, and Olig2). Statistical analysis indicated that the radiotherapy administration was significantly correlated with OS ( P = 0.001, HR = 0.181, 95% CI, 0.065–0.502) (Table 3 ). Further analysis revealed that receiving simultaneous chemoradiotherapy after surgery increased OS (31.2 months) compared with not receiving simultaneous chemoradiotherapy (18 months); however, the difference was not significant ( P = 0.351). Table 3 Survival analyses for prognosticators of overall survival in epithelioid glioblastoma patients Parameter Univariate Multivariate HR 95% Confidence Interval P HR 95% Confidence Interval P Age 1.008 0.985–1.032 0.513 Sex 1.863 0.911–3.809 0.088 1.893 0.902–3.974 0.092 Extent of resection 0.574 0.272–1.209 0.144 1.256 0.501–2.757 0.710 Tumor stroke 0.919 0.397–2.129 0.844 Radiation therapy 0.200 0.081–0.495 < 0.001 0.214 0.078–0.592 0.003 Adjuvant chemotherapy 0.408 0.192–0.868 0.020 0.487 0.213–1.116 0.089 Ki-67 0.583 0.247–1.378 0.219 BRAF inhibitor 0.842 0.294–2.411 0.749 BRAF-V600E (+) 1.034 0.502–2.130 0.927 MGMT (+) 1.459 0.716–2.973 0.298 ATRX (+) 1.504 0.555–4.075 0.423 GFAP (+) 0.582 0.222–1.526 0.271 Olig-2 (+) 0.403 0.119–1.368 0.145 0.276 0.076–1.001 0.051 P53 (+) 1.027 0.488–2.160 0.944 3.6 Relapse survival The median survival time after relapse was 10.2 months (95% CI, 4.290–16.110). Patients who underwent surgical treatment had a significantly longer median survival time than those in the non-surgical group ( P = 0.001) (Fig. 4 ). The median survival time of patients who received re-irradiation was 22.5 months, compared to 9.5 months for those who did not; however, the observed change was not significant ( P = 0.089). Similarly, the median survival time for patients who received bevacizumab treatment was 9.9 months, compared to 12.6 months for those who did not; however, the difference was not significant ( P = 0.968). In the univariate and multivariate survival analyses, only reoperation demonstrated a significant correlation with survival time after recurrence ( P = 0.003, HR = 0.268, 95% CI, 0.113–0.633; P = 0.009, HR = 0.286, 95% CI, 0.110–0.747) (Table 4 ). Furthermore, the median survival time was significantly longer in patients who underwent surgery combined with simultaneous chemoradiotherapy after recurrence compared to those who received only radiation or surgery after recurrence (28.6 months vs. 14.6 months, 9.2 months; P = 0.007) (Fig. 5 ). Table 4 Survival analyses for prognosticators of survival in recurrence epithelioid glioblastoma patients Parameter Univariate Multivariate HR 95% Confidence Interval P HR 95% Confidence Interval P Sex 1.410 0.656–3.031 0.113–0.633 0.200–1.130 0.405–2.516 0.371–1.722 0.135–2.434 0.379 Reoperation 0.268 0.003 0.286 0.110–0.747 0.009 Re-irradiation 0.476 0.092 0.671 0.271–1.661 0.389 Bevacizumab 1.009 0.984 BRAF-V600E (+) 0.799 0.567 BRAF inhibitor 0.573 0.450 4. Discussion Ep-GBM is a newly classified histological subtype of GBM included in the 2016 WHO Classification of Tumors of the Central Nervous System [ 6 ] . Currently, there is a scarcity of studies focusing on the clinical and pathological characteristics, as well as treatment outcomes related to Ep-GBM subtypes, especially regarding treatment options after Ep-GBM recurrence. Therefore, this study is unique and aims to provide more specific information on the prognosis and therapeutic choices for these cancers. The mean age of the 58 patients diagnosed histologically with Ep-GBM was 37.6 ± 16.3 years (range: 5–70 years). This was consistent with the findings of Suxia et al. [ 7 ] . However, it is worth noting that Andrey et al. [ 5 ] reported a lower median age of 25 years for Ep-GBM patients, attributed to the large proportion of juvenile patients in their study (approximately 52%). In our study, only eight patients were under 18 years of age. The median age at diagnosis for all patients in the trial was 39.3 years, indicating a significantly younger population than conventional GBM, which typically have a median age at diagnosis of 65 years [ 8 ] . We found that majority of Ep-GBM tumors occurred in the supratentorial cerebral cortical areas, specifically in the temporal and frontal lobes, which supports the results reported by Khanna et al. [ 9 ] . However, a smaller number of tumors were also found in unconventional locations, such as the thalamus, corpus callosum, and cerebellar hemispheres. Additionally, we identified 20 patients with large tumors affecting multiple lobes of the brain. According to a report, Ep-GBM accounts for approximately 3% of all GBM cases [ 10 ] . The results of our study aligns with these findings, as we observed that Ep-GBMs constituted 4.5% of all cases of glioblastomas during the same period. In our study, 58 patients had a median survival time of 29.1 months. Similarly, Chatterjee et al. [ 11 ] conducted a study where they reported a median survival time of 25.5 months among 24 patients diagnosed with Ep-GBM. However, Wang et al. [ 7 ] reported a significantly lower median survival time of only 10.6 months for Ep-GBM. These differences in the survival outcomes could be attributed to the treatment approach employed in their study. Specifically, Wang et al. found that 48.4% of patients received simultaneous chemoradiotherapy, compared with that of 67.2% in our study. Additionally, the absence of a defined treatment regimen for post-tumor recurrence in their study could also contribute to the disparity in survival times. The primary objective of GBM surgery is to achieve maximum safe resection. A meta-analysis conducted by Brown et al. [ 12 ] revealed that GTR significantly improved OS and PFS in patients with GBM compared with PR. Similarly, in a study conducted by Lu et al. [ 3 ] , patients with Ep-GBM who underwent GTR had longer PFS and OS than those who underwent PR. However, a study conducted by Ansari et al. [ 13 ] failed to establish a correlation between GTR and survival outcomes. In our study, we found that patients who underwent GTR demonstrated a significantly longer median PFS than those who underwent PR ( P = 0.021). Additionally, the median OS in the GTR group was 31.2 months, which was 13.2 months higher than the median OS in the PR group (18.0 months). Although the difference was not significant ( P = 0.139), GTR tended to improve the OS. Notably, our study identified five patients who achieved an OS exceeding 65 months. This favorable outcome was strongly correlated with the attainment of GTR during their initial surgical procedure, highlighting the potential for long-term survival in patients who underwent GTR. Radiotherapy has been recognized as a crucial tool for GBM treatment because of its ability to enhance the local control and OS of tumors [14] . Sun et al. [15] reported prolonged survival after radiation therapy. However, contrasting findings have been reported by Wang et al. [ 7 ] , suggesting that radiotherapy does not significantly affect the prognosis. In our study, we found that patients who received radiotherapy experienced a significant extension in median OS compared to those who did not. Currently, the treatment approach for Ep-GBMs is closely aligned with that for conventional GBM. The standard treatment for GBM typically involves maximal surgical resection followed by radiotherapy in combination with TMZ. In our study, we noted an increase in the median PFS among patients who received the standard treatment regimen compared with those who underwent surgical treatment alone. However, none of these differences was significant ( P = 0.233), which could potentially be attributed to our study’s limited sample size. Additionally, we found a correlation between an increased number of cycles of adjuvant chemotherapy with TMZ and improved PFS and OS. Our study revealed a substantial recurrence rate of 67.2% among patients diagnosed with Ep-GBM, indicating a high likelihood of recurrence in this subtype. These findings highlight the importance of understanding and addressing challenges associated with the treatment of recurrent Ep-GBM. However, there is limited literature on the treatment of this specific subtype in its recurrent state. Therefore, further research is required to identify more effective treatment options. Our study findings suggest that patients who underwent reoperation showed trends towards improved survival compared with patients who did not undergo reoperation. with a median survival of 24.5 months vs 5.2 months ( P = 0.001). These results align with those of previous research, supporting the potential benefits of reoperation in managing recurrent GBM [16] . It is worth mentioning that among patients with recurrent Ep-GBM, five experienced relapse after their second surgery and subsequently underwent a third surgery. Notably, the average survival time for these patients was 67.2 months, ranging from 32.2 months to 89.0 months. These findings suggest that similar to conventional GBM cases, reoperation is equally relevant and applicable in the management of recurrent Ep-GBM, offering a potential avenue for improved outcomes and extended survival. Re-irradiation has been shown to be a feasible and effective treatment option for recurrent gliomas, as supported by published evidence [17] . The study suggested that combining reoperation, chemotherapy, or re-irradiation as treatment modalities leads to a substantial improvement in survival compared to using individual treatments alone [18] . Our study focused on recurrent Ep-GBM and found that the combination of re-irradiation and reoperation resulted in a significant increase in patient survival. The median survival time was 28.6 months, compared to 9.2 months with reoperation alone. This difference was statistically significant ( P = 0.007). BRAF is a critical regulator of the MAPK signaling pathway and plays significant roles in cell differentiation, proliferation, migration, and pro-tumorigenic activity. Its importance has led to its recognition as a promising molecular target for precision medicine and development of new therapeutic approaches. Among BRAF mutations, V600E is most frequently observed in gliomas [19] . Reports indicate that approximately 50% of Ep-GBM cases exhibit BRAF-V600E mutations, whereas conventional glioblastomas rarely show BRAF-V600E mutations [20, 21] . In our investigation, we observed BRAF-V600E mutant protein expression in 56.1% of cases. Previous studies have shown that gliomas with BRAF-V600E mutation have better prognoses than those without this mutation [22, 23] . In our study, patients with the BRAF-V600E mutation had a median survival time of 31.2 months, slightly longer than Ep-GBM patients without the BRAF-V600E mutation (24.8 months). However, this difference was not significant in our analysis ( P = 0.927). Vemurafenib has been approved for treating malignant melanoma, papillary thyroid carcinoma, and lung cancer. Strong clinical responses have been demonstrated in these settings, effectively reducing tumor development and progression caused by the BRAF-V600E mutation [24, 25] . The clinical efficacy of vemurafenib in the treatment of Ep-GBM has been active investigation [26–29] . According to Nakagomi et al. [30] , vemurafenib, a BRAF-V600E inhibitor, has shown remarkable efficacy in reducing tumor cell survival and suppressing the phosphorylation of crucial intracellular signaling proteins. In our trial, 6 patients were treated with vemurafenib. 2 patients received it after the initial surgery, and 4 patients received it after recurrence. 1 patient's prognosis was not assessed. In our study, the remaining patients exhibited either steady or partial remission. Research [31] has demonstrated that the combination of BRAF and MEK inhibitors effectively inhibits tumor growth by dual-targeted activation of the MAPK pathway. This finding is supported by several recent clinical studies that established combination therapy with MEK inhibitors as a recognized therapeutic strategy for treating Ep-GBM [32, 33] . In our study, 1 patient developed resistance to vemurafenib after one year of treatment. To address this issue, the patient underwent a third surgery and received simultaneous chemoradiotherapy (60 Gy/30 fractions, TMZ 75 mg/m2) with BRAF-MEK inhibitors. Consequently, the patient experienced an additional 8 months survival benefit. Methylation status of the MGMT promoter is an important prognostic factor in GBM [34] . However, few studies have investigated the methylation status of the MGMT promoter in Ep-GBM. In our study, we found a MGMT promoter methylation positivity rate of 56.9%, whereas Wang et al. [ 7 ] reported a rate of 45.4% in their study. GBM patients with a methylated MGMT promoter experience therapeutic benefits from TMZ, whereas those without the promoter do not show such advantages [35] . In contrast, we did not observe a significant effect of MGMT promoter methylation on PFS or OS. Similar findings were reported by Sun et al. [15] . These results may be attributed to the limited sample sizes analyzed in both studies. Further large-scale case studies are necessary to elucidate the underlying reasons. 5. Limitations Our study has several limitations. First, the retrospective nature of this study had inherent limitations. To overcome these limitations and provide more robust evidence, prospective studies are a more suitable approach for comparing therapeutic regimens for Ep-GBM. Additionally, only a few markers were analyzed using immunohistochemistry. Finally, the small sample size of our study should be noted. This limited sample size reduced the statistical power of our findings and may potentially limit the generalizability of the results. 6. Conclusions Analysis of treatment protocols and prognoses in 58 patients diagnosed with Ep-GBM We discovered that the Stupp treatment protocol, commonly employed for conventional glioblastomas, yielded positive outcomes in terms of PFS and OS in patients with Ep-GBM. This highlights the potential effectiveness of the Stupp regimen for the treatment of Ep-GBM. Furthermore, in patients with recurrent Ep-GBM, we observed that the combination of reoperation and re-irradiation therapy resulted in enhanced survival benefits. This approach demonstrates promising potential for improving the outcomes of patients with recurrent Ep-GBM. Finally, the emergence of targeted therapies represents a significant advancement in glioma treatment. This advancement holds promise for ushering in a new era of glioma management, including Ep-GBM. Declarations Data availability statemen: The data that support the findings of this study are available on request from the corresponding author, [Chang-zheng Shi]，upon reasonable request. Ethics statemen : This retrospective study was approved by the Ethics Committee of Guangdong Sanjiu Brain Hospital (No.202101017), and there was informed consent exemption for all patients. Funding: This study was supported by the Basic and Applied Basic Research Program of Guangzhou (Project No. 202201011741) and Guangzhou Science and Technology Project (Project Number: 2023A03J0609): Multimodal MRI Quantitative Analysis of Tumor Perfusion and Optimization of Anti-Angiogenesis Therapy Strategies Based on Tumor Microvascular Density. Author contributions: Conceptualization and design: MNS, DDF, MYL Acquisition of data: MNS, YG, JFZ, XYH, XJY. Analysis and interpretation of the data: SQL, YG, JFZ, XYH, XJY. Visualization: MNS, JFZ, XYH, XJY. Writing—original draft: MNS, SQL. Writing—review and editing: MNS, SQL, LBC, CZS. Final read and approval of the manuscript: all authors. Meng-nan Sun and Shao-qun Li contributed equally as the first authors of this study. Conflict of interest: The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Acknowledgments: The authors thank Juan Li, Li-chao Wang and Min-ting Ye, the doctors from Guangdong Sanjiu Brain Hospital, for assisting the data collection. References Nozomi M, Nozomi N, Tatsuya Y, et al. Concurrent TERT promoter and BRAF V600E mutation in epithelioid glioblastoma and concomitant low-grade astrocytoma. Neuropathology: official journal of the Japanese Society of Neuropathology. 2017; 37(1):58-63. https://doi.org/10.1111/neup.12318. Arie P, Pieter W. Histologic classification of gliomas. Handbook of clinical neurology. 2016;134:71-95. https://doi.org/10.1016/B978-0-12-802997-8.00005-0. Lu M V, George D N, Brown A D, et al. Confirming diagnosis and effective treatment for rare epithelioid glioblastoma variant: an integrated survival analysis of the literature. World Neurosurgery. 2019;131:243-251.e2. https://doi.org/ 10.1016/j.wneu.2019.08.007. Michael W, Emilie R L, Matthias P, et al. How we treat glioblastoma. ESMO open. 2019; 4(Suppl 2): e000520. https://doi.org/ 10.1136/esmoopen-2019-000520. Andrey K, Lukas C, Tanvi S, et al. Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis. Brain pathology. 2018;28(5):656-662. https://doi.org/ 10.1111/bpa.12566. N D L, Arie P, Guido R, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta neuropathologica. 2016;131(6):803-20. https://doi.org/ 10.1007/s00401-016-1545-1. Suxia W, Qiaowei H, Qianqian Z, et al. Clinicopathologic features and prognosis of epithelioid glioblastoma. International journal of clinical and experimental pathology. 2020; 13(7):1529-1539. https://doi.org/ PMC7414508. T Q O, Haley G, Gabrielle T, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015. Neuro-oncology. 2018; 20(suppl_4):iv1-iv86.https://doi.org/ 10.1093/neuonc/noy131. 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Mansour A, Hamid N, Amir-Abbas K, et al. Pediatric glioblastoma multiforme: A single-institution experience. Indian J Med Paediatr Oncol. 2012;33(3):155-60. https://doi.org/ 10.4103/0971-5851.103142 Abstract. Stupp Roger, Mason Warren P, van den Bent Martin J et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England journal of medicine. 2005;352(10):987-96. https://doi.org/ 10.1056/NEJMoa043330. Sun K, Zhou X, Li T, et al. Clinicopathological characteristics and treatment outcomes of epithelioid glioblastoma. Neurosurgical Review. 2021;44(6):3335-3348. https://doi.org/ 10.1007/s10143-021-01492-7. Bogdana S, Michael W, Ghazaleh T, et al. Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma-results from the DIRECTOR trial. Neuro-oncology. 2016;18(4):549-56. https://doi.org/ 10.1093/neuonc/nov326. Pierina N, Federico P, Elena C, et al. "Re-irradiation for recurrent high grade glioma (HGG) patients: results of a single arm prospective phase 2 study. ". Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2022;167:89-96. https://doi.org/ 10.1016/j.radonc.2021.12.019. M A, F S, G S, et al. Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: results from a single institution. Journal of neuro-oncology. 2017; 132(3):419-426. https://doi.org/ 10.1007/s11060-017-2383-2. Vincenzo N D, Lidia G, Alicia T, et al. Implications of BRAF V600E mutation in gliomas: Molecular considerations, prognostic value and treatment evolution. Frontiers in Oncology. 2023;12:1067252. https://doi.org/ 10.3389/fonc.2022.1067252. Kay B K, L D A, K D B, et al. Epithelioid GBMs show a high percentage of BRAF V600E mutation. The American journal of surgical pathology. 2013 May;37(5):685-98. https://doi.org/ 10.1097/PAS.0b013e31827f9c5e. Felix B, Alonso B, Marco S, et al. Frequency of BRAF V600E mutations in 969 central nervous system neoplasms. Diagnostic pathology. 2016;11(1):55. https://doi.org/ 10.1186/s13000-016-0506-2. Andrey K, Marina R, Volker H, et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta neuropathologica. 2015; 129(5):669-78. https://doi.org/ 10.1007/s00401-015-1405-4. Rui-Qi Z, Zhifeng S, Hong C, et al. Biomarker-based prognostic stratification of young adult glioblastoma. Oncotarget.2016; 7(4):5030-41. https://doi.org/ 10.18632/oncotarget.5456. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010; 467(7315):596-9. https://doi.org/ 10.1038/nature09454. B P C, Axel H, Caroline R, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England journal of medicine. 2011; 364(26):2507-16. https://doi.org/ 10.1056/NEJMoa1103782. F N B, Thomas C, Neil K, et al. Dabrafenib and trametinib in BRAFV600E mutated glioma. CNS oncology. 2017; 6(4):291-296. https://doi.org/ 10.2217/cns-2017-0006. Garry C, Jan-Michael W, Veronika D, et al. Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation. International journal of molecular sciences. 2018; 19(4):1090. https://doi.org/ 10.3390/ijms19041090. Kanemaru Y, Natsumeda M, Okada M, et al. Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy. Acta Neuropathologica Communications. 2019; 7(1):119. https://doi.org/ 10.1186/s40478-019-0774-7. Matthew S, Christian D, Howard C, et al. Challenges of targeting BRAF V600E mutations in adult primary brain tumor patients: a report of two cases. CNS oncology. 2019; 8(4): CNS48. https://doi.org/ 10.2217/cns-2019-0018. Nami N, Daisuke S, Takanori H, et al. Epithelioid glioblastoma with microglia features: potential for novel therapy. Brain pathology (Zurich, Switzerland). 2020; 30(6):1119-1133. https://doi.org/ 10.1111/bpa.12887. C K S, Andrew M, Guisheng Z, et al. Deconvoluting mechanisms of acquired resistance to RAF inhibitors in BRAF V600E mutant human glioma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021; 27(22):6197-6208. https://doi.org/ 10.1158/1078-0432.CCR-21-2660. Afsane B, AmirReza H, Majid K, et al. The therapeutic potential of targeting the BRAF mutation in patients with colorectal cancer. Journal of cellular physiology. 2018; 233(3):2162-2169. https://doi.org/ 10.1002/jcp.25952. Dratkiewicz E, Simiczyjew A, Pietraszek-Gremplewicz K, et al. Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment. International Journal of Molecular Sciences. 2019; 21(1):113. https://doi.org/ 10.3390/ijms21010113. Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. The New England journal of medicine. 2000; 343(19):1350-4. https://doi.org/ 10.1056/NEJM200011093431901. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. The New England journal of medicine. 2005; 352(10):997-1003. https://doi.org/ 10.1056/NEJMoa043331. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 09 Oct, 2024 Read the published version in Neurosurgical Review → Version 1 posted Editorial decision: Revision requested 07 Aug, 2024 Reviews received at journal 06 Aug, 2024 Reviews received at journal 02 Aug, 2024 Reviews received at journal 31 Jul, 2024 Reviewers agreed at journal 26 Jul, 2024 Reviewers agreed at journal 21 Jul, 2024 Reviewers agreed at journal 21 Jul, 2024 Reviewers invited by journal 21 Jul, 2024 Editor assigned by journal 21 Jul, 2024 Submission checks completed at journal 03 Jul, 2024 First submitted to journal 02 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. 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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-4674275","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":330949072,"identity":"d94468e1-f393-4988-b77c-90bbdd566d1f","order_by":0,"name":"Meng-nan Sun","email":"","orcid":"","institution":"The First Affiliated Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Meng-nan","middleName":"","lastName":"Sun","suffix":""},{"id":330949073,"identity":"14b390cf-2ff0-426e-9c90-74a1c65ff28d","order_by":1,"name":"Shao-qun Li","email":"","orcid":"","institution":"Guangdong Sanjiu Brain 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University","correspondingAuthor":true,"prefix":"","firstName":"Chang-zheng","middleName":"","lastName":"Shi","suffix":""}],"badges":[],"createdAt":"2024-07-02 12:37:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4674275/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4674275/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10143-024-02957-1","type":"published","date":"2024-10-09T15:57:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":61346910,"identity":"c99c531b-7354-4418-ae12-abbca9629d48","added_by":"auto","created_at":"2024-07-29 18:14:05","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":197292,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of the extent of resection on progression-free survival (months) in patients with epithelioid glioblastoma.\u003c/p\u003e","description":"","filename":"FIG1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4674275/v1/ce6e24b7b31f769a9a331311.jpg"},{"id":61346907,"identity":"795409de-6ad8-4f81-bf6a-2a368df32df8","added_by":"auto","created_at":"2024-07-29 18:14:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":205885,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of the number of cycles of adjuvant temozolomide chemotherapy on progression-free survival (months) in patients with epithelioid glioblastoma.\u003c/p\u003e","description":"","filename":"FIG2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4674275/v1/8ba89d462d4cb5d76ac4e54b.jpg"},{"id":61346905,"identity":"957c8a49-67df-47de-8ba5-c0c40195ea6b","added_by":"auto","created_at":"2024-07-29 18:14:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":197015,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of radiotherapy on overall survival (months) in patients with epithelioid glioblastoma.\u003c/p\u003e","description":"","filename":"FIG3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4674275/v1/f0d7b7ab5f644b5b0a1bfc99.jpg"},{"id":61346906,"identity":"1c0084af-cc13-45a5-b864-844eee7b6204","added_by":"auto","created_at":"2024-07-29 18:14:05","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":184690,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of reoperation on recurrent survival (months) in patients with recurrent epithelioid glioblastoma.\u003c/p\u003e","description":"","filename":"FIG4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4674275/v1/f44f3cdd85473d46c3eef751.jpg"},{"id":61349335,"identity":"96a811e8-c0d6-4c97-9a54-af633f3a8f3d","added_by":"auto","created_at":"2024-07-29 18:30:05","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":220683,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of surgery combined with radiotherapy on recurrent survival (months) in patients with recurrent epithelioid glioblastoma.\u003c/p\u003e","description":"","filename":"FIG5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4674275/v1/3323ac1e332fcd75d569946b.jpg"},{"id":66597050,"identity":"b12f3dcc-68d4-4447-8e08-843259455eae","added_by":"auto","created_at":"2024-10-14 16:06:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1669965,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4674275/v1/851f2b99-46ea-47db-803a-199f791ad386.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Reoperation and radiotherapy improve overall survival in patients with epithelioid glioblastoma : A multi-institutional experience","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eGlioblastoma (GBM) stands as the most common malignant tumor of the central nervous system, with the highest occurrence rate among all brain tumors. In 2016, a new GBM subtype, epithelioid glioblastoma (Ep-GBM), was added to the WHO Classification of Tumors of the Central Nervous System. Ep-GBM is classified as an IDH wild-type GBM, distinguishing it from other GBM types\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Histologically, Ep-GBM is manifests with abundant epithelioid and melanoma-like cells, which exhibit features such as abundant cytoplasm, eccentric nuclei, prominent nucleoli, and rhabdomyosin-like attributes\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Unlike conventional GBM, Ep-GBM is more prevalent in children and young adults and exhibits aggressive behaviors such as cerebrospinal fluid dissemination and central nervous system metastases. Ep-GBM presents a notably poor prognosis, with significantly worse outcomes than other GBM types\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Presently, therapeutic recommendations for Ep-GBM do not account for histological variations\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur findings suggest that Ep-GBM\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, as characterized by histopathological features, is not a singular diagnostic entity. Instead, it comprises at least three distinct tumor subtypes that are molecularly and biologically different. These subtypes vary significantly in prevalence across different populations and exhibit distinct prognostic outcomes. Therefore, conventional GBM treatment strategies may not be suitable for managing Ep-GBM.\u003c/p\u003e \u003cp\u003eDue to the relative rarity of Ep-GBM, comprehensive research on this tumor is limited. Most available literature consists of case reports or retrospective case series involving a relatively small number of cases. Therefore, the primary aim of this study was to thoroughly investigate and evaluate the clinicopathological features, treatment methods, and their impact on the prognosis of Ep-GBM. We anticipate that the findings of this study will provide valuable insights for facilitating the clinical diagnosis and treatment of Ep-GBM, as well as offer support and guidance to healthcare professionals and patients.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study participants\u003c/h2\u003e \u003cp\u003e A retrospective review was conducted on glioma patients who received treatment at the Guangdong Sanjiu Brain Hospital and the First Affiliated Hospital of Jinan University. Progression-free survival (PFS) is defined as the period from surgery to the occurrence of postoperative tumor recurrence, metastasis, or the last follow-up date. Overall survival (OS) is typically defined as the duration from the surgical procedure to either the patient\u0026rsquo;s demise or the last follow-up visit. Relapse survival time refers to the duration from surgery following recurrence to the patient's death or last follow-up. In this retrospective study, patient data were anonymized, eliminating the need for informed consent from the patients' guardians. The study was conducted in accordance with the principles of the Declaration of Helsinki and received authorization from the hospital's medical ethics committee.\u003c/p\u003e \u003cp\u003ePatients with Ep-GBM underwent follow-up assessments involving brain MRI every 2 months after the initial radiotherapy for 2 or 3 years under the supervision of a multidisciplinary team. If a patient developed a new symptom or if the neurological symptoms deteriorated, then MRI was performed regardless of the scheduled follow-up period. When clinically indicated, surgery was performed to confirm the final diagnosis of a viable tumor. If surgery was not possible, then the viable tumor was determined using MRI in accordance with the RANO criteria and serial follow-up examinations with intervals of at least 3 months were performed. The clinicoradiological diagnosis was determined by a consensus reached during a multidisciplinary meeting involving two neuro-oncologists (all with 20 and 7 years of experience with neuro-oncology) and three neuroradiologists (with 18, 10 and 6 years of experience with neuro-oncologic imaging, respectively). When a contrast-enhancing lesion exhibited a steady increase in size during two or more successive follow-up MRI examinations within a 2- to 3-month interval. the patient was classified as having tumor recurrence. In contrast, when a contrast-enhancing lesion subsequently regressed or became stable without a change in treatment within 6 months of the index imaging, the patient was categorized as no recurrence.\u003c/p\u003e \u003cp\u003eThe extent of tumor resection was determined by comparing a 24\u0026ndash;72 h postoperative MRI to that of preoperative imaging. Gross total resection was defined by the absence of visible residual tumors on postoperative T1-enhanced MRI findings, whereas the presence of residual tumor on these MRI results was designated as partial resection. All cases were reviewed by a multidisciplinary neuro-oncology clinic comprised of neurosurgeons, neuro-oncologists, and radiation oncologists. Patients in good clinical condition with tumors that originate near the previous cavities and do not involve eloquent cortical areas, basal ganglia, diencephalic or brainstem structures, with a PFS of at least 6 months, are generally considered candidates for reoperation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Pathological testing\u003c/h2\u003e \u003cp\u003eTumor tissue samples were fixed in 10% formalin and embedded in paraffin. Subsequently, the paraffin-embedded tumor sections, 3-\u0026micro;m thick, underwent staining using the standard hematoxylin and eosin staining method. Immunohistochemical staining was performed using the SP method and monoclonal antibodies against several markers, including glial fibrillary acidic protein (GFAP), methylguanine DNA methyltransferase (MGMT), oligodendrocyte transcription factor 2 (Olig-2), X-linked alpha-thalassemia mental retardation syndrome (ATRX), BRAF-V600E (VE1), IDH-1, H3K27m, P53, and Ki-67 proliferation index.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003eFactors influencing patient endpoint events were analyzed using both univariate and multivariate Cox regression methods. Factors with a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.2 in the univariate analysis were subsequently included in the multivariate analysis. Survival analysis was conducted using the Kaplan\u0026ndash;Meier method, with intergroup comparisons facilitated by the log-rank test. The significance level was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All statistical analyses were performed using SPSS 27.0.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Patient demographics\u003c/h2\u003e \u003cp\u003eThe average age was 37.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4 years, ranging from of 5 to 70 years. Regarding the gender distribution, 30 patients were male and 28 female. The most frequently reported initial symptoms among the patients were headache and dizziness, which occurred in 42 cases, followed by limb weakness and sensory abnormalities in 6 cases, epilepsy in 6 cases, memory loss in 3 cases, and blurred vision in both eyes in 1 case. Except for 1 case located in the left cerebellar hemisphere, patients with Ep-GBM predominantly exhibited tumor onset inside the cerebral hemispheres. There were 25 cases in the right cerebral hemisphere, with 10 cases located in the right temporal lobe, 5 in the right frontal lobe, and 10 cases involving multiple lobes. Additionally, 31 cases were found in the left cerebral hemisphere, including 11 cases in the left temporal lobe, 5 cases in the left parietal lobe, 3 cases in the left frontal lobe, 1 case in the left occipital lobe, 1 case in the left thalamus, and 10 cases involving multiple lobes. In addition, 1 case was mentioned in the callosal pressure section. Clinical data are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\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\u003eDemographics of patients with epithelioid glioblastoma\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExtent of resection (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGross total resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e41(70.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u0026ndash;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePartial resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17(29.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (%)\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 \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e30(51.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStupp regimen (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38(65.5%)\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e28(48.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRecurrence (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e39(67.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresenting symptom (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTreatment after recurrence (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadaches \u0026amp; dizziness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42(72.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurgery \u0026amp; simultaneous chemoradiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14(35.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLimb weakness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOnly Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4(10.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpileptic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOnly radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5(12.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(6.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSupportive therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16(41.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor location (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBevacizumab (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10(17.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTemporal lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(36.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBRAF inhibitor (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6(10.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrontal lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(13.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eState of survival (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParietal lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(8.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCensored\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23(39.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOccipital lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35(60.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple lobes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(34.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorpus callosum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian PFS(months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft thalamus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian OS(months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft cerebellar hemisphere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian survival time after Recurrence(months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ePFS, progression-free survival; OS, overall survival.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Therapy\u003c/h2\u003e \u003cp\u003eIn our study of patients diagnosed with Ep-GBMs, surgical resection was considered as the primary treatment approach. Gross total resection (GTR) was successfully completed in 41 patients, while 17 individuals underwent partial resection (PR). Following the surgical procedures, 39 patients were treated using the Stupp regimen. Most patients received a radiation dose of 60 Gy/30f, with temozolomide (TMZ) as the standard chemotherapeutic agent for all patients. Following simultaneous chemoradiotherapy, all patients received 2\u0026ndash;12 cycles of TMZ chemotherapy. Throughout the follow-up period, tumor recurrence was observed in 39 patients. Among those who experienced recurrence, 14 individuals underwent surgery combined with simultaneous chemoradiotherapy, 4 patients chose surgery alone, 5 patients received radiation therapy alone, and 16 patients were solely treated with TMZ chemotherapy or other forms of supportive therapy. In the trial, 6 participants were administered a BRAF inhibitor, and 1 patient received combination therapy that included both BRAF and MEK inhibitors. 5 patients underwent a third surgical procedure after the second recurrence. Throughout the disease period, radiation therapy was administered to a total of 47 individuals, including 12 patients who underwent reirradiation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Pathologic and immunohistochemistry\u003c/h2\u003e \u003cp\u003eMicroscopically, the tumor cells exhibited infiltrative growth with densely arranged regular or round cells. Some of these cells displayed an epithelioid or rhabdomyoid shape and lacked adhesion while maintaining a clear cellular membrane and eosinophilic cytoplasm. Nuclei were frequently enlarged and irregularly shaped, often accompanied by prominent nucleoli, indicating prevalent nuclear atypia, which occasionally led to the formation of multinucleated giant tumor cells. No intratumoral microvascular or glomeruloid-like vascular hyperplasia was observed. Tumor cells exhibited a pattern of arrangement around blood vessels, forming a pseudopapillary structure. Moreover, the presence of digitiform necrosis and pseudo-fenestrated necrosis features could be observed within the tissue. Immunohistochemistry findings revealed positive expression of various markers: BRAF-V600E (56.9%, 33/58), MGMT (56.9%, 33/58), GFAP (89.6%, 52/58), Olig-2 (93.1%, 54/58), ATRX (86.2%, 50/58), P53 (72.4%, 42/58). The Ki-67 proliferation index ranged from 3\u0026ndash;80%, with a mean of 28.7%. Notably, IDH-1 and H3K27m.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.4 PFS\u003c/h2\u003e \u003cp\u003eThe median PFS for the patients was 12.7 months (95% confidence interval [CI], 6.721\u0026ndash;18.732). Among these patients, those who underwent GTR exhibited a significantly longer median PFS than those who underwent PR (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Additionally, patients who received more than 6 cycles of TMZ adjuvant chemotherapy demonstrated a significantly extended median PFS compared to patients who received fewer than 6 cycles (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the univariate survival analysis, the PFS of the patients was examined in relation to various parameters, including age, sex, tumor stroke, extent of resection, and immunohistochemical markers such as the MGMT promoter methylation status, GFAP, ATRX, P53, and Ki-67 proliferation index. Notably, only the extent of tumor resection (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021, hazard ratio [HR]\u0026thinsp;=\u0026thinsp;0.430, 95% CI, 0.210\u0026ndash;0.878) and the number of cycles of adjuvant chemotherapy with TMZ (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, HR\u0026thinsp;=\u0026thinsp;0.404, 95% CI, 0.204\u0026ndash;0.799) were significantly associated with PFS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). To further investigate these relationships, a multifactorial Cox proportional hazards model was constructed, which incorporated variables such as age, extent of tumor resection, number of adjuvant chemotherapy cycles with TMZ, simultaneous chemoradiotherapy, and BRAF-V600E and Olig2 mutation status. However, no statistically significant correlation was found between PFS and these factors.\u003c/p\u003e \u003cp\u003e \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\u003eSurvival analyses for prognosticators of progression-free survival in epithelioid glioblastoma patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% Confidence Interval\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e95% Confidence Interval\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.985\u0026ndash;1.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.524\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.247\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.659\u0026ndash;2.362\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.498\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.886\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.387\u0026ndash;2.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.774\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtent of resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.430\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.210\u0026ndash;0.878\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e0.515\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.238\u0026ndash;1.114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.140\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSimultaneous chemoradiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.284\u0026ndash;1.154\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e0.901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.412\u0026ndash;1.968\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.794\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjuvant chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.404\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.204\u0026ndash;0.799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e0.482\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.222\u0026ndash;1.050\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi-67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.612\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.277\u0026ndash;1.354\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF-V600E (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.691\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.870\u0026ndash;3.287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e0.958\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.458\u0026ndash;2.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.910\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMGMT (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.920\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.484\u0026ndash;1.748\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGFAP (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.358\u0026ndash;2.907\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.970\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eATRX (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.257\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.481\u0026ndash;3.281\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.641\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlig-2 (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.618\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.188\u0026ndash;2.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.429\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP53 (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.897\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.460\u0026ndash;1.750\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0.750\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\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=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.5 OS\u003c/h2\u003e \u003cp\u003eThe median OS of the patients was 29.1 months (95% CI, 21.318\u0026ndash;36.920). During the first year, the survival rate was 78.4%, which declined to 56.8% in the second year and further dropped to 18.9% by the fifth year. A significant difference in the median OS was observed between patients who received radiotherapy and those who did not (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In the univariate survival analysis, radiation therapy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, HR\u0026thinsp;=\u0026thinsp;0.200, 95% CI, 0.081\u0026ndash;0.495) and the number of cycles of adjuvant chemotherapy with TMZ (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020, HR\u0026thinsp;=\u0026thinsp;0.408, 95% CI, 0.192\u0026ndash;0.868) showed a significant relation to OS. A multifactorial Cox proportional risk model was constructed including sex, extent of tumor resection, administration of radiotherapy, and immunohistochemical markers (MGMT, Ki-67 proliferation index, and Olig2). Statistical analysis indicated that the radiotherapy administration was significantly correlated with OS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001, HR\u0026thinsp;=\u0026thinsp;0.181, 95% CI, 0.065\u0026ndash;0.502) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Further analysis revealed that receiving simultaneous chemoradiotherapy after surgery increased OS (31.2 months) compared with not receiving simultaneous chemoradiotherapy (18 months); however, the difference was not significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.351).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurvival analyses for prognosticators of overall survival in epithelioid glioblastoma patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% Confidence Interval\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e95% Confidence Interval\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.985\u0026ndash;1.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.513\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.863\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.911\u0026ndash;3.809\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e1.893\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.902\u0026ndash;3.974\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtent of resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.574\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.272\u0026ndash;1.209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.144\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e1.256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.501\u0026ndash;2.757\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.710\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.919\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.397\u0026ndash;2.129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.844\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.081\u0026ndash;0.495\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u003c/b\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.214\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.078\u0026ndash;0.592\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjuvant chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.408\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.192\u0026ndash;0.868\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.487\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.213\u0026ndash;1.116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi-67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.583\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.247\u0026ndash;1.378\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.842\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.294\u0026ndash;2.411\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.749\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF-V600E (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.502\u0026ndash;2.130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.927\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMGMT (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.459\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.716\u0026ndash;2.973\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.298\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eATRX (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.504\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.555\u0026ndash;4.075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.423\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGFAP (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.582\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.222\u0026ndash;1.526\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.271\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlig-2 (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.403\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.119\u0026ndash;1.368\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.276\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.076\u0026ndash;1.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.051\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP53 (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.488\u0026ndash;2.160\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\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=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Relapse survival\u003c/h2\u003e \u003cp\u003eThe median survival time after relapse was 10.2 months (95% CI, 4.290\u0026ndash;16.110). Patients who underwent surgical treatment had a significantly longer median survival time than those in the non-surgical group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The median survival time of patients who received re-irradiation was 22.5 months, compared to 9.5 months for those who did not; however, the observed change was not significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.089). Similarly, the median survival time for patients who received bevacizumab treatment was 9.9 months, compared to 12.6 months for those who did not; however, the difference was not significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.968). In the univariate and multivariate survival analyses, only reoperation demonstrated a significant correlation with survival time after recurrence (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003, HR\u0026thinsp;=\u0026thinsp;0.268, 95% CI, 0.113\u0026ndash;0.633; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, HR\u0026thinsp;=\u0026thinsp;0.286, 95% CI, 0.110\u0026ndash;0.747) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Furthermore, the median survival time was significantly longer in patients who underwent surgery combined with simultaneous chemoradiotherapy after recurrence compared to those who received only radiation or surgery after recurrence (28.6 months vs. 14.6 months, 9.2 months; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurvival analyses for prognosticators of survival in recurrence epithelioid glioblastoma patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e95% Confidence Interval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e95% Confidence Interval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.410\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"5\" nameend=\"c4\" namest=\"c3\" rowspan=\"6\"\u003e \u003cp\u003e0.656\u0026ndash;3.031\u003c/p\u003e \u003cp\u003e0.113\u0026ndash;0.633\u003c/p\u003e \u003cp\u003e0.200\u0026ndash;1.130\u003c/p\u003e \u003cp\u003e0.405\u0026ndash;2.516\u003c/p\u003e \u003cp\u003e0.371\u0026ndash;1.722\u003c/p\u003e \u003cp\u003e0.135\u0026ndash;2.434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.379\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReoperation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.268\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.286\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.110\u0026ndash;0.747\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRe-irradiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.476\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.671\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.271\u0026ndash;1.661\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.389\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBevacizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.984\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF-V600E (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.567\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.450\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eEp-GBM is a newly classified histological subtype of GBM included in the 2016 WHO Classification of Tumors of the Central Nervous System\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Currently, there is a scarcity of studies focusing on the clinical and pathological characteristics, as well as treatment outcomes related to Ep-GBM subtypes, especially regarding treatment options after Ep-GBM recurrence. Therefore, this study is unique and aims to provide more specific information on the prognosis and therapeutic choices for these cancers.\u003c/p\u003e \u003cp\u003eThe mean age of the 58 patients diagnosed histologically with Ep-GBM was 37.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.3 years (range: 5\u0026ndash;70 years). This was consistent with the findings of Suxia et al.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. However, it is worth noting that Andrey et al.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e reported a lower median age of 25 years for Ep-GBM patients, attributed to the large proportion of juvenile patients in their study (approximately 52%). In our study, only eight patients were under 18 years of age. The median age at diagnosis for all patients in the trial was 39.3 years, indicating a significantly younger population than conventional GBM, which typically have a median age at diagnosis of 65 years\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe found that majority of Ep-GBM tumors occurred in the supratentorial cerebral cortical areas, specifically in the temporal and frontal lobes, which supports the results reported by Khanna et al.\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. However, a smaller number of tumors were also found in unconventional locations, such as the thalamus, corpus callosum, and cerebellar hemispheres. Additionally, we identified 20 patients with large tumors affecting multiple lobes of the brain. According to a report, Ep-GBM accounts for approximately 3% of all GBM cases \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. The results of our study aligns with these findings, as we observed that Ep-GBMs constituted 4.5% of all cases of glioblastomas during the same period.\u003c/p\u003e \u003cp\u003eIn our study, 58 patients had a median survival time of 29.1 months. Similarly, Chatterjee et al.\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e conducted a study where they reported a median survival time of 25.5 months among 24 patients diagnosed with Ep-GBM. However, Wang et al.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e reported a significantly lower median survival time of only 10.6 months for Ep-GBM. These differences in the survival outcomes could be attributed to the treatment approach employed in their study. Specifically, Wang et al. found that 48.4% of patients received simultaneous chemoradiotherapy, compared with that of 67.2% in our study. Additionally, the absence of a defined treatment regimen for post-tumor recurrence in their study could also contribute to the disparity in survival times.\u003c/p\u003e \u003cp\u003eThe primary objective of GBM surgery is to achieve maximum safe resection. A meta-analysis conducted by Brown et al.\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e revealed that GTR significantly improved OS and PFS in patients with GBM compared with PR. Similarly, in a study conducted by Lu et al.\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e, patients with Ep-GBM who underwent GTR had longer PFS and OS than those who underwent PR. However, a study conducted by Ansari et al.\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e failed to establish a correlation between GTR and survival outcomes. In our study, we found that patients who underwent GTR demonstrated a significantly longer median PFS than those who underwent PR (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021). Additionally, the median OS in the GTR group was 31.2 months, which was 13.2 months higher than the median OS in the PR group (18.0 months). Although the difference was not significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.139), GTR tended to improve the OS. Notably, our study identified five patients who achieved an OS exceeding 65 months. This favorable outcome was strongly correlated with the attainment of GTR during their initial surgical procedure, highlighting the potential for long-term survival in patients who underwent GTR.\u003c/p\u003e \u003cp\u003eRadiotherapy has been recognized as a crucial tool for GBM treatment because of its ability to enhance the local control and OS of tumors\u003csup\u003e[14]\u003c/sup\u003e. Sun et al.\u003csup\u003e[15]\u003c/sup\u003e reported prolonged survival after radiation therapy. However, contrasting findings have been reported by Wang et al.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e, suggesting that radiotherapy does not significantly affect the prognosis. In our study, we found that patients who received radiotherapy experienced a significant extension in median OS compared to those who did not. Currently, the treatment approach for Ep-GBMs is closely aligned with that for conventional GBM. The standard treatment for GBM typically involves maximal surgical resection followed by radiotherapy in combination with TMZ. In our study, we noted an increase in the median PFS among patients who received the standard treatment regimen compared with those who underwent surgical treatment alone. However, none of these differences was significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.233), which could potentially be attributed to our study\u0026rsquo;s limited sample size. Additionally, we found a correlation between an increased number of cycles of adjuvant chemotherapy with TMZ and improved PFS and OS.\u003c/p\u003e \u003cp\u003eOur study revealed a substantial recurrence rate of 67.2% among patients diagnosed with Ep-GBM, indicating a high likelihood of recurrence in this subtype. These findings highlight the importance of understanding and addressing challenges associated with the treatment of recurrent Ep-GBM. However, there is limited literature on the treatment of this specific subtype in its recurrent state. Therefore, further research is required to identify more effective treatment options. Our study findings suggest that patients who underwent reoperation showed trends towards improved survival compared with patients who did not undergo reoperation. with a median survival of 24.5 months vs 5.2 months (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). These results align with those of previous research, supporting the potential benefits of reoperation in managing recurrent GBM\u003csup\u003e[16]\u003c/sup\u003e. It is worth mentioning that among patients with recurrent Ep-GBM, five experienced relapse after their second surgery and subsequently underwent a third surgery. Notably, the average survival time for these patients was 67.2 months, ranging from 32.2 months to 89.0 months. These findings suggest that similar to conventional GBM cases, reoperation is equally relevant and applicable in the management of recurrent Ep-GBM, offering a potential avenue for improved outcomes and extended survival.\u003c/p\u003e \u003cp\u003eRe-irradiation has been shown to be a feasible and effective treatment option for recurrent gliomas, as supported by published evidence\u003csup\u003e[17]\u003c/sup\u003e. The study suggested that combining reoperation, chemotherapy, or re-irradiation as treatment modalities leads to a substantial improvement in survival compared to using individual treatments alone\u003csup\u003e[18]\u003c/sup\u003e. Our study focused on recurrent Ep-GBM and found that the combination of re-irradiation and reoperation resulted in a significant increase in patient survival. The median survival time was 28.6 months, compared to 9.2 months with reoperation alone. This difference was statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007).\u003c/p\u003e \u003cp\u003eBRAF is a critical regulator of the MAPK signaling pathway and plays significant roles in cell differentiation, proliferation, migration, and pro-tumorigenic activity. Its importance has led to its recognition as a promising molecular target for precision medicine and development of new therapeutic approaches. Among BRAF mutations, V600E is most frequently observed in gliomas\u003csup\u003e[19]\u003c/sup\u003e. Reports indicate that approximately 50% of Ep-GBM cases exhibit BRAF-V600E mutations, whereas conventional glioblastomas rarely show BRAF-V600E mutations\u003csup\u003e[20, 21]\u003c/sup\u003e. In our investigation, we observed BRAF-V600E mutant protein expression in 56.1% of cases. Previous studies have shown that gliomas with BRAF-V600E mutation have better prognoses than those without this mutation\u003csup\u003e[22, 23]\u003c/sup\u003e. In our study, patients with the BRAF-V600E mutation had a median survival time of 31.2 months, slightly longer than Ep-GBM patients without the BRAF-V600E mutation (24.8 months). However, this difference was not significant in our analysis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.927).\u003c/p\u003e \u003cp\u003e Vemurafenib has been approved for treating malignant melanoma, papillary thyroid carcinoma, and lung cancer. Strong clinical responses have been demonstrated in these settings, effectively reducing tumor development and progression caused by the BRAF-V600E mutation\u003csup\u003e[24, 25]\u003c/sup\u003e. The clinical efficacy of vemurafenib in the treatment of Ep-GBM has been active investigation\u003csup\u003e[26\u0026ndash;29]\u003c/sup\u003e. According to Nakagomi et al.\u003csup\u003e[30]\u003c/sup\u003e, vemurafenib, a BRAF-V600E inhibitor, has shown remarkable efficacy in reducing tumor cell survival and suppressing the phosphorylation of crucial intracellular signaling proteins. In our trial, 6 patients were treated with vemurafenib. 2 patients received it after the initial surgery, and 4 patients received it after recurrence. 1 patient's prognosis was not assessed. In our study, the remaining patients exhibited either steady or partial remission. Research\u003csup\u003e[31]\u003c/sup\u003e has demonstrated that the combination of BRAF and MEK inhibitors effectively inhibits tumor growth by dual-targeted activation of the MAPK pathway. This finding is supported by several recent clinical studies that established combination therapy with MEK inhibitors as a recognized therapeutic strategy for treating Ep-GBM\u003csup\u003e[32, 33]\u003c/sup\u003e. In our study, 1 patient developed resistance to vemurafenib after one year of treatment. To address this issue, the patient underwent a third surgery and received simultaneous chemoradiotherapy (60 Gy/30 fractions, TMZ 75 mg/m2) with BRAF-MEK inhibitors. Consequently, the patient experienced an additional 8 months survival benefit.\u003c/p\u003e \u003cp\u003eMethylation status of the MGMT promoter is an important prognostic factor in GBM\u003csup\u003e[34]\u003c/sup\u003e. However, few studies have investigated the methylation status of the MGMT promoter in Ep-GBM. In our study, we found a MGMT promoter methylation positivity rate of 56.9%, whereas Wang et al. \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e reported a rate of 45.4% in their study. GBM patients with a methylated MGMT promoter experience therapeutic benefits from TMZ, whereas those without the promoter do not show such advantages\u003csup\u003e[35]\u003c/sup\u003e. In contrast, we did not observe a significant effect of MGMT promoter methylation on PFS or OS. Similar findings were reported by Sun et al. \u003csup\u003e[15]\u003c/sup\u003e. These results may be attributed to the limited sample sizes analyzed in both studies. Further large-scale case studies are necessary to elucidate the underlying reasons.\u003c/p\u003e"},{"header":"5. Limitations","content":"\u003cp\u003eOur study has several limitations. First, the retrospective nature of this study had inherent limitations. To overcome these limitations and provide more robust evidence, prospective studies are a more suitable approach for comparing therapeutic regimens for Ep-GBM. Additionally, only a few markers were analyzed using immunohistochemistry. Finally, the small sample size of our study should be noted. This limited sample size reduced the statistical power of our findings and may potentially limit the generalizability of the results.\u003c/p\u003e"},{"header":"6. Conclusions","content":"\u003cp\u003eAnalysis of treatment protocols and prognoses in 58 patients diagnosed with Ep-GBM We discovered that the Stupp treatment protocol, commonly employed for conventional glioblastomas, yielded positive outcomes in terms of PFS and OS in patients with Ep-GBM. This highlights the potential effectiveness of the Stupp regimen for the treatment of Ep-GBM. Furthermore, in patients with recurrent Ep-GBM, we observed that the combination of reoperation and re-irradiation therapy resulted in enhanced survival benefits. This approach demonstrates promising potential for improving the outcomes of patients with recurrent Ep-GBM. Finally, the emergence of targeted therapies represents a significant advancement in glioma treatment. This advancement holds promise for ushering in a new era of glioma management, including Ep-GBM.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statemen:\u003c/strong\u003e The data that support the findings of this study are available on request from the corresponding author, [Chang-zheng Shi]，upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statemen\u003c/strong\u003e: This retrospective study was approved by the Ethics Committee of Guangdong Sanjiu Brain Hospital (No.202101017), and there was informed consent exemption for all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study was supported by the Basic and Applied Basic Research Program\u0026nbsp;of\u0026nbsp;Guangzhou (Project No. 202201011741) and\u0026nbsp;Guangzhou Science and Technology Project (Project Number: 2023A03J0609): Multimodal MRI Quantitative Analysis of Tumor Perfusion and Optimization of Anti-Angiogenesis Therapy Strategies Based on Tumor Microvascular Density.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization and design: MNS, DDF, MYL\u003c/p\u003e\n\u003cp\u003eAcquisition of data: MNS, YG, JFZ, XYH, XJY.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalysis and interpretation of the data: SQL, YG, JFZ, XYH, XJY.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVisualization: MNS, JFZ, XYH, XJY.\u003c/p\u003e\n\u003cp\u003eWriting—original draft: MNS, SQL.\u003c/p\u003e\n\u003cp\u003eWriting—review and editing: MNS, SQL, LBC, CZS.\u003c/p\u003e\n\u003cp\u003eFinal read and approval of the manuscript: all authors.\u003c/p\u003e\n\u003cp\u003eMeng-nan Sun and Shao-qun Li contributed equally as the first authors of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u0026nbsp;\u003c/strong\u003eThe authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e The authors thank Juan Li, Li-chao Wang and Min-ting Ye, the doctors from Guangdong Sanjiu Brain Hospital, for assisting the data collection.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNozomi M, Nozomi N, Tatsuya Y, et al. 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The New England journal of medicine. 2005; 352(10):997-1003. https://doi.org/ 10.1056/NEJMoa043331.\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":"neurosurgical-review","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nrev","sideBox":"Learn more about [Neurosurgical Review](https://www.springer.com/journal/10143)","snPcode":"10143","submissionUrl":"https://submission.nature.com/new-submission/10143/3","title":"Neurosurgical Review","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Epithelioid glioblastoma, Chemoradiotherapy, Reoperation, Recurrence Ep-GBM","lastPublishedDoi":"10.21203/rs.3.rs-4674275/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4674275/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEpithelioid glioblastoma (Ep-GBM) is a rare variant of glioblastoma characterized by a high recurrence rate and poor prognosis. Currently, there is no established standard treatment for Ep-GBM. Therefore, we identified 58 epithelioid glioblastoma cases to investigate these characteristics and identify the possible prognostic factors of survival. The study encompassed 58 patients with a mean age of 37.6±16.3 years. Gross total resection(GTR) was found to be associated with a longer median PFS compared to partial resection (PR) (\u003cem\u003eP\u003c/em\u003e=0.017). Univariate analysis demonstrated that individuals who received more than six cycles of adjuvant chemotherapy with temozolomide (TMZ) had a longer median PFS (\u003cem\u003eP\u003c/em\u003e=0.009, hazard ratio [HR]=0.404, 95% confidence interval [CI], 0.204-0.799) or OS (\u003cem\u003eP\u003c/em\u003e=0.020, HR=0.408, 95% CI, 0.192-0.868) than those who received fewer cycles. GTR remained significantly associated with PFS (\u003cem\u003eP\u003c/em\u003e=0.021, HR=0.430, 95% CI, 0.210-0.878). Additionally, patients who received radiotherapy had a significantly higher median OS than those who did not (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001, HR=0.200, 95% CI, 0.081-0.495). In the multivariate analysis, radiotherapy remained significantly associated with improved survival (\u003cem\u003eP\u003c/em\u003e=0.001, HR=0.181, 95% CI, 0.065-0.502). Patients who underwent reoperation had significantly longer survival than those who did not (\u003cem\u003eP\u003c/em\u003e=0.003, HR=0.268, 95% CI, 0.113-0.633). Multivariate analysis confirmed an association between reoperation and prolonged survival (\u003cem\u003eP\u003c/em\u003e=0.009, HR=0.286, 95% CI, 0.110-0.747). In conclusion, gross total resection, radiotherapy, and adjuvant chemotherapy using TMZ enhanced PFS or OS, reoperation and simultaneous chemoradiotherapy show promise in extending the survival duration of patients with recurrent Ep-GBM.\u003c/p\u003e","manuscriptTitle":"Reoperation and radiotherapy improve overall survival in patients with epithelioid glioblastoma : A multi-institutional experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-29 18:14:00","doi":"10.21203/rs.3.rs-4674275/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-07T10:13:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-07T01:55:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-02T13:49:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-31T07:27:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"82240736472525786500162044283535746879","date":"2024-07-27T00:40:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"331704980950493032438075372960054183538","date":"2024-07-22T02:42:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"255983621652056195994090329403513587659","date":"2024-07-22T00:43:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-22T00:33:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-22T00:32:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-03T17:25:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Neurosurgical Review","date":"2024-07-02T12:35:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"neurosurgical-review","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nrev","sideBox":"Learn more about [Neurosurgical Review](https://www.springer.com/journal/10143)","snPcode":"10143","submissionUrl":"https://submission.nature.com/new-submission/10143/3","title":"Neurosurgical Review","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e54402fd-d84a-44e2-bf05-88d0ce252401","owner":[],"postedDate":"July 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-14T15:59:12+00:00","versionOfRecord":{"articleIdentity":"rs-4674275","link":"https://doi.org/10.1007/s10143-024-02957-1","journal":{"identity":"neurosurgical-review","isVorOnly":false,"title":"Neurosurgical Review"},"publishedOn":"2024-10-09 15:57:02","publishedOnDateReadable":"October 9th, 2024"},"versionCreatedAt":"2024-07-29 18:14:00","video":"","vorDoi":"10.1007/s10143-024-02957-1","vorDoiUrl":"https://doi.org/10.1007/s10143-024-02957-1","workflowStages":[]},"version":"v1","identity":"rs-4674275","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4674275","identity":"rs-4674275","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}