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Purpose: In addition to established prognostic factors in low-grade glioma (LGG), studies suggest a sexual dimorphism with male sex portending worse prognosis. Our objective was to identify the effect of sex on presentation and outcomes in LGG.Methods and Materials: We conducted a retrospective cohort study of adults (aged ≥18 years) diagnosed with LGG (World Health Organization 2016 grade 2 glioma). Patients with IDH wild-type tumors were excluded. Patients were matched between male and female sex by age, treatment, and surgery via propensity score matching. Patient, tumor, and treatment characteristics were analyzed by sex. Endpoints included overall survival (OS), next intervention-free survival (NIFS), progression-free survival, and malignant transformation-free survival. Kaplan-Meier analyses and Cox proportional hazards regression multivariable analysis with backward elimination were completed.Results: Of the 532 patients identified, 258 (48%) were men. Men were more likely to present with seizure (69.38% vs 56.57%, P = .002), but no other statistically significant differences between sexes at presentation were identified. Five-year OS was higher in women at 87% (95% confidence interval [CI], 83%-91%) versus 78% (95% CI, 73%-84%) in men (P = .0045). NIFS was significantly higher in female patients at 68% (95% CI, 62%-74%) versus 57% (95% CI, 51%-64%) in men (P = .009). On multivariable analysis, female sex was independently associated with improved OS (hazard ratio [HR], 1.54; 95% CI, 1.16-2.05; P = .002), NIFS (HR, 1.42; 95% CI, 1.42; P = .004), and malignant transformation-free survival (HR, 1.62; 95% CI, 1.24-2.12; P = .0004). In patients with molecularly defined LGG (IDH and 1p19q status; n = 291), female sex remained independently associated with improved OS (HR, 1.79; 95% CI, 1.16-2.77; P = .008) and NIFS (HR, 1.45; 95% CI, 1.07-1.96; P = .016).Conclusions: In this study, female sex was independently associated with improved outcomes. These findings support intrinsic sex-specific differences in LGG behavior, justifying further studies to optimize management and therapeutics based on sex. [ABSTRACT FROM AUTHOR]

Purpose: Malignant transformation (MT) of adult grade 2 glioma (low-grade glioma [LGG]) is associated with adverse survival. We sought to describe the incidence, outcomes, and risk factors for MT of molecularly classified LGG.Methods and Materials: We reviewed a single-institutional database of adults who received a diagnosis of LGG with data allowing for molecular classification from 1980 to 2018 to evaluate time to MT and its associated risk factors. MT was defined as pathologic confirmation of grade 3-4 glioma and/or imaging characteristics consistent with MT by multidisciplinary consensus.Results: Among the included 486 adults with molecularly classified LGG, median age was 39 years (range, 18-78), median tumor size was 3.9 cm (range, 0.3-13.0), and 262 (54%) were male. Molecular classification was IDHmut1p/19qcodel in 169 (35%), IDHmut1p/19qintact in 125 (26%), and IDHwt in 192 (40%) patients. Adjuvant management was observation in 246 (51%) patients, temozolomide alone in 82 (16%), radiation therapy alone in 63 (13%), and radiation therapy concurrent with temozolomide in 81 (17%). Temozolomide monotherapy was more likely to be given to IDHmut1p/19qcodel patients (P < .001). Median follow-up was 5.3 years. MT occurred in 84 (17%) patients, with a 5-year freedom from MT of 86% (95% confidence interval [CI], 82%-90%). Median overall survival after MT was 2.4 years (95% CI, 1.5-3.3) and was associated with molecular classification (P = .03) and grade at MT (P < .001). Factors associated with MT were male sex (hazard ratio [HR], 2.1; 95% CI, 1.2-3.6; P = .009), tumor size ≥5 cm (HR, 3.5; 95% CI, 2.0-6.2; P < .001), IDHmut1p/19qintact (HR, 2.7; 95% CI, 1.3-5.6; P = .009) or IDHwt classification (HR, 5.5; 95% CI, 2.5-11.8; P < .001), and adjuvant temozolomide monotherapy (HR, 3.8; 95% CI, 1.4-10.3; P = .008).Conclusions: MT of LGG has a poor prognosis associated with unfavorable molecular groups. Analysis of our large cohort identified adjuvant temozolomide monotherapy as the only modifiable risk factor for MT and provides the first clinical evidence of temozolomide-associated MT among molecularly classified adult LGG. This novel finding supplements our understanding of temozolomide-induced hypermutation and informs precision management of LGG. [ABSTRACT FROM AUTHOR]

Purpose: To identify risk factors for progression-free survival (PFS) in the molecular era among patients with low-grade glioma (LGG) who undergo gross total resection (GTR) followed by initial observation.Methods and Materials: We reviewed patients with World Health Organization grade 2 LGG treated at a single institution. We included only those who underwent magnetic resonance imaging (MRI)-confirmed GTR followed by initial observation. Molecular classification was obtained at either the time of diagnosis or pathology review. Cox proportional hazards regression, the Kaplan-Meier method, and the log-rank test were used. P values <.05 were considered statistically significant.Results: We included 144 patients who underwent MRI-confirmed GTR between 1994 and 2014 followed by initial observation. Median age was 29 years (interquartile range [IQR], 18-41), median tumor size was 2.7 cm (IQR, 1.8-4.0), and median follow-up was 81 months (IQR, 36-132). Molecular classification was 13% IDH-mutant 1p19q-codeleted; 21% IDH-mutant 1p19q-intact; 39% IDH1-R132H-wildtype; and 28% undetermined. For the entire cohort, 5- and 10-year PFS and overall survival were 71% and 53%, and 98% and 90%, respectively. On multivariate analysis, factors associated with worse PFS included increasing age at diagnosis (hazard ratio [HR], 1.05; 95% CI, 1.00-1.09; P = .03), increasing preoperative tumor size (HR, 1.07; 95% CI, 1.04-1.10; P < .0001), and IDH-mutant 1p19q-intact classification (HR, 3.18; 95% CI, 1.15-8.74, P = .025). Median PFS for patients with IDH-mutant 1p19q-codeleted, IDH-mutant 1p19q-intact, and IDH1-R132H-wildtype tumors were 113 months, 56 months, and not reached, respectively. Molecular classification was significantly associated with PFS (P < .0001) but not overall survival (P = .20).Conclusions: Among patients with LGG who undergo MRI-confirmed GTR and initial observation in the molecular era, increasing age, increasing tumor size, and IDH-mutant 1p19q-intact classification are associated with worse PFS. Because tumor progression is associated with adverse health-related quality of life, these factors may aid clinicians and patients in the shared decision-making process regarding goals of surgery and timing of postoperative therapy. Further study is required to elucidate why IDH-mutant 1p19q-intact LGGs are at higher risk for early progression. [ABSTRACT FROM AUTHOR]

Purpose: The incidence, risk factors, and outcomes of low-grade glioma patients who undergo malignant transformation (MT) in the era of temozolomide are not well known. This study evaluates these factors in a large group of World Health Organization grade 2 glioma patients treated at a tertiary-care institution.Methods and Materials: Patient, tumor, and treatment factors were analyzed using an institutional review board-approved low-grade glioma database. Characteristics were compared using χ2 and Wilcoxon signed rank tests. Time to event was summarized using proportional hazards models. Univariate and multivariate survival analyses were performed.Results: Of a total of 599 patients, 124 underwent MT; 76 (61.3%) had biopsy-proven MT. The MT incidence was 21%, and the median time to MT was 56.4 months. The 5- and 10-year progression-free survival rates were 30.6% ± 4.2% and 4.8% ± 1.9%, respectively, for MT patients and 60% ± 2.4% and 38% ± 2.7%, respectively, for non-MT patients. The 5- and 10-year overall survival rates were 75% ± 4.0% and 46% ± 5.0%, respectively, for MT patients and 87% ± 1.7% and 78% ± 2.3%, respectively, for non-MT patients. On multivariate analysis, older age (P = .001), male sex (P = .004), multiple tumor locations (P = .004), chemotherapy alone (P = .012), and extent of resection (P = .045) remained significant predictors of MT.Conclusions: MT affects survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our finding that initial interventions could affect the rate of MT is provocative, but these data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT. [ABSTRACT FROM AUTHOR]

The incidence of radiation necrosis has increased secondary to greater use of combined modality therapy for brain tumors and stereotactic radiosurgery. Given that its characteristics on standard imaging are no different that tumor recurrence, it is difficult to diagnose without use of more sophisticated imaging and nuclear medicine scans, although the accuracy of such scans is controversial. Historically, treatment had been limited to steroids, hyperbaric oxygen, anticoagulants, and surgical resection. A recent prospective randomized study has confirmed the efficacy of bevacizumab in treating radiation necrosis. Novel therapies include using focused interstitial laser thermal therapy. This article will review the diagnosis and treatment of radiation necrosis. [ABSTRACT FROM AUTHOR]

Purpose: The Radiation Therapy Oncology Group (RTOG) developed a prognostic classification based on a recursive partitioning analysis (RPA) of patient pretreatment characteristics from three completed brain metastases randomized trials. Clinical trials for patients with brain metastases generally exclude small-cell lung cancer (SCLC) cases. We hypothesize that the RPA classes are valid in the setting of SCLC brain metastases. Methods and Materials: A retrospective review of 154 SCLC patients with brain metastases treated between April 1983 and May 2005 was performed. RPA criteria used for class assignment were Karnofsky performance status (KPS), primary tumor status (PT), presence of extracranial metastases (ED), and age. Results: Median survival was 4.9 months, with 4 patients (2.6%) alive at analysis. Median follow-up was 4.7 months (range, 0.3–40.3 months). Median age was 65 (range, 42–85 years). Median KPS was 70 (range, 40–100). Number of patients with controlled PT and no ED was 20 (13%) and with ED, 27 (18%); without controlled PT and ED, 34 (22%) and with ED, 73 (47%). RPA class distribution was: Class I: 8 (5%); Class II: 96 (62%); Class III: 51 (33%). Median survivals (in months) by RPA class were: Class I: 8.6; Class II: 4.2; Class III: 2.3 (p = 0.0023). Conclusions: Survivals for SCLC-only brain metastases replicate the results from the RTOG RPA classification. These classes are therefore valid for brain metastases from SCLC, support the inclusion of SCLC patients in future brain metastases trials, and may also serve as a basis for historical comparisons. [Copyright &y& Elsevier]

Purpose: There have been conflicting reports in the literature regarding the prognostic significance of epidermal growth factor receptor (EGFR) amplification in patients with glioblastoma multiforme (GBM). The purpose of this study is to determine the prognostic significance of EGFR amplification in patients with GBM treated at the Cleveland Clinic Foundation. Methods and Materials: A retrospective review of GBM patients treated with surgery at the Cleveland Clinic Foundation was performed. Amplification of EGFR was evaluated with fluorescence in situ hybridization in a total of 107 patients diagnosed between December 1995 and May 2003. In addition to EGFR status, various prognostic factors were evaluated to determine the factors that influenced survival and radiographic response rate. The median follow-up was 9 months. Results: The overall median survival was 9.8 months, with a 1-year survival of 40%. Of the 107 patients in whom EGFR status was evaluated, 36 (33.6%) were found to have EGFR amplification. On multivariate analysis, median survival was found to be significantly improved for patients with age <60 (12.6 months vs. 8 months, p = 0.0061), patients with Karnofsky Performance Status ≥70 (12.1 months vs. 4.4 months, p < 0.0001), patients who had undergone subtotal resection or gross total resection (11.1 months vs. 4.1 months, p = 0.002), and patients who received a radiation dose ≥60 Gy compared with no radiation (12.7 months vs. 3 months, p < 0.0001). There was no association of EGFR amplification with survival. When stratified by age (<60 vs. ≥60), EGFR status still did not reach statistical significance in predicting for survival. For the 81 patients who had radiographic follow-up, the 1-year overall local control was 14%. On univariate analysis, only treatment with radiation (<60 Gy vs. ≥60 Gy vs. no radiation, p = 0.03) was found to predict for improved local control. Treatment with radiation did not remain statistically significant on multivariate analysis. Conclusion: Epidermal growth factor receptor amplification was not found to be a significant prognostic indicator of overall survival or radiographic local control in patients with GBM treated with surgery at the Cleveland Clinic Foundation. Further studies are needed to fully delineate the significance of this molecular marker in patients with GBM. [Copyright &y& Elsevier]

: PurposeTo determine the benefit of whole brain radiotherapy (WBRT) and the use of the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classification system in patients with brain metastases from renal cell carcinoma.: Methods and materialsWe identified 46 consecutive patients with brain metastases from renal cell carcinoma who were treated with WBRT at the Cleveland Clinic Foundation between 1983 and 2000. We reviewed their charts for patient and tumor characteristics and categorized them according to the RTOG RPA classes.: ResultsThe median follow-up and survival time for all 46 patients (15 women and 31 men) was 3.0 months. The median radiation dose was 3000 cGy in 10 fractions. Patients who received higher radiation doses (>3000 cGy) survived longer than those who received 3000 cGy or less than 3000 cGy (8.5 months vs. 2.7 months vs. 0.4 months, p = 0.0289). However, the Karnofsky performance status and RPA class were confounding factors in these data. The median survival for patients by RTOG RPA class was 8.5 months for Class I (n = 2), 3 months for Class II (n = 37), and 0.6 months for Class III (n = 7, p = 0.0834).: ConclusionDespite the relatively poor prognosis of patients who receive WBRT alone, it appears that they benefit from this palliative treatment. The RTOG RPA classification system may be a useful tool in assessing prognosis in this patient population. [Copyright &y& Elsevier]