Glioma groups, including lower-grade glioma (LGG) and glioblastoma multiforme (GBM), are the most common primary brain tumor. Malignant gliomas, especially glioblastomas, are associated with a dismal prognosis. Hypoxia is a driver of the malignant phenotype in glioma groups; it triggers a cascade of immunosuppressive processes and malignant cellular responses (tumor progression, anti-apoptosis, and resistance to chemoradiotherapy), which result in disease progression and poor prognosis. However, approaches to determine the extent of hypoxia in the tumor microenvironment are still unclear. Here, we downloaded 575 LGG patients and 354 GBM patients from Chinese Glioma Genome Atlas (GGGA), and 530 LGG patients and 167 GBM patients from The Cancer Genome Atlas (TCGA) with RNA sequence and clinicopathological data. We developed a hypoxia risk model to reflect the immune microenvironment in glioma and predict prognosis. High hypoxia risk score was associated with poor prognosis and indicated an immunosuppressive microenvironment. Hypoxia signature significantly correlated with clinical and molecular features and could serve as an independent prognostic factor for glioma patients. Moreover, Gene Set Enrichment Analysis showed that gene sets associated with the high-risk group were involved in carcinogenesis and immunosuppression signaling. In conclusion, we developed and validated a hypoxia risk model, which served as an independent prognostic indicator and reflected overall immune response intensity in the glioma microenvironment.
Peritumoral edema (PTE), one of the main characteristics of malignant glioma, is a significant contributor to the morbidity and mortality from glioma, however, a recent systematic review suggested that controversy remains with regard to its prognostic value. To further determine whether PTE was a potential prognostic factor on routine pre-operative magnetic resonance imaging (MRI) for malignant glioma, the association between survival and PTE was investigated in the present retrospective review of 109 patients with newly diagnosed supratentorial malignant glioma using MRI data from these routine scans. The Kaplan-Meier method was used to calculate overall survival (OS) in univariate analysis, and COX proportional hazards model was applied to evaluate the effect of pre-operative MRI features on OS in multivariate analysis. The PTE extent, edema shape, degree of necrosis, enhancement extent, pathological grade, patient age, Karnofsky performance status (KPS) and post-operative chemoradiotherapy were associated with OS in the patients with malignant glioma on univariate analysis. Multivariate analysis indicated that the extent of PTE and degree of necrosis shown by pre-operative MRI were independent predictors of OS, in addition to pathological grade, patient age, KPS and post-operative chemoradiotherapy. Moreover, patients with two unfavorable factors (major edema and severe necrosis) exhibited a poorer OS compared with the remainder. In summary, PTE and degree of necrosis, which are easily determined from routine MRI, can be useful for predicting a poor clinical outcome in patients with newly diagnosed malignant glioma.
Background Glioblastoma (GBM) is a highly virulent tumor of the central nervous system, with a median survival < 15 months. Clearly, an improvement in treatment outcomes is needed. However, the emergence of these malignancies within the delicate brain parenchyma and their infiltrative growth pattern severely limit the use of aggressive local therapies. The particle therapy represents a new promising therapeutic approach to circumvent these prohibitive conditions with improved treatment efficacy. Methods and design Patients with newly diagnosed malignant gliomas will have their tumor tissue samples submitted for the analysis of the status of O-6-methylguanine-DNA methyltransferase ( MGMT ) promoter methylation. In Phase I, the patients will undergo an induction carbon ion radiotherapy (CIRT) boost followed by 60 GyE of proton irradiation with concurrent temozolomide (TMZ) at 75 mg/m 2 . To determine the maximal dose of safe induction boost, the tolerance, and acute toxicity rates in a dose-escalation manner from 9 to 18 GyE in three fractions will be used. In Phase III, GBM-only patients will be randomized to receive either 60 GyE (2 GyE per fraction) of proton irradiation with concurrent TMZ (control arm) or a CIRT boost (dose determined in Phase I of this trial) followed by 60 GyE of proton irradiation with concurrent TMZ. The primary endpoints are overall survival (OS) and toxicity rates (acute and long-term). Secondary endpoints are progression-free survival (PFS), and tumor response (based upon assessment with C-methionine/fluoro-ethyl-tyrosine positron emission tomography [MET/FET PET] or magnetic resonance imaging [MRI] and detection of serologic immune markers). We hypothesize that the induction CIRT boost will result in a greater initial tumor-killing ability and prime the tumor microenvironment for enhanced immunologic tumor clearance, resulting in an expected 33% improvement in OS rates. Discussion The prognosis of GBM remains grim. The mechanism underpinning the poor prognosis of this malignancy is its chronic state of tumor hypoxia, which promotes both immunosuppression/immunologic evasion and radio-resistance. The unique physical and biological properties of CIRT are expected to overcome these microenvironmental limitations to confer an improved tumor-killing ability and anti-tumor immune response, which could result in an improvement in OS with minimal toxicity. Trial registration number This trial has been registered with the China Clinical Trials Registry, and was allocated the number ChiCTR-OID-17013702.
PurposeTo evaluate the short-term outcomes in terms of tumor control and toxicity of patients with skull base or cervical spine chordoma and chondrosarcoma treated with intensity-modulated proton or carbon-ion radiation therapy.MethodsBetween 6/2014 and 7/2018, a total of 91 patients were treated in our Center. The median age was 38 (range, 4–70) years. Forty-six (50.5%) patients were treated definitively for their conditions as initial diagnosis, 45 (49.5%) patients had recurrent tumors including 14 had prior radiotherapy. The median gross tumor volume was 37.0 (range, 1.6–231.7) cc. Eight patients received proton therapy alone, 28 patients received combined proton and carbon ion therapy, 55 patients received carbon-ion therapy alone.ResultsWith a median follow-up time of 28 (range, 8–59) months, the 2-year local control (LC), progression free (PFS) and overall survival (OS) rates was 86.2, 76.8, and 87.2%, respectively. Those rates for patients received definitive proton or carbon-ion therapy were 86.7, 82.8, and 93.8%, respectively. On multivariate analyses, tumor volume of > 60 cc was the only significant factor for predicting PFS (p = 0.045), while re-irradiation (p = 0.012) and tumor volume (> vs < 60 cc) (p = 0.005) were significant prognosticators for OS. Grade 1–2 late toxicities were observed in 11 patients, and one patient developed Grade 3 acute mucositis.ConclusionsLarger tumor volume and re-irradiation were related to inferior survival for this group of patients. Further follow-up is needed for long-term efficacy and safety.
Background Reirradiation for locoregionally recurrent nasopharyngeal carcinoma (LR‐NPC) after high‐dose radiotherapy (RT) is challenging and usually is associated with poor survival and severe toxicities. Because of its physical and biological advantages over photon‐beam RT, carbon‐ion RT (CIRT) could be a potential treatment option for patients with LR‐NPC. Methods Patients with LR‐NPC who underwent salvage therapy using CIRT at the Shanghai Proton and Heavy Ion Center between May 2015 and June 2019 were analyzed. CIRT doses were 50 to 69 gray equivalent (GyE) (2.0‐3.0 GyE per fraction). Overall survival (OS), local control, regional control, distant control, and acute and late toxicities were analyzed. Univariable and multivariable analyses of OS and local control were performed using the Cox regression model. Results Among the 206 patients included, 139 patients (67.5%) had recurrent American Joint Committee on Cancer stage III or stage IV disease. With a median follow‐up of 22.8 months, the 2‐year OS, local control, regional control, and distant control rates were 83.7%, 58.0%, 87.3%, and 94.7%, respectively. Multivariable analysis revealed that older age (P = .017) was predictive of worse OS, whereas a larger tumor volume (P = .049) and a lower biological equivalent dose (P = .029) were associated with inferior local control. No patient developed an acute toxicity of ≥grade 3 during CIRT. Severe (≥grade 3) late toxicities included temporal lobe necrosis (0.97%), cranial neuropathy (0.49%), hearing loss (1.46%), xerostomia (0.49%), and mucosal necrosis (16.02%) (toxicities were graded using the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer criteria). Conclusions Salvage treatment using CIRT is efficacious for patients with LR‐NPC and its toxicities are acceptable. CIRT may improve the survival and toxicity profiles substantially for patients with LR‐NPC compared with the reported results after photon‐based intensity‐modulated RT.
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