Summary Therapeutic outcomes for patients with brain metastases need to improve. A critical review of trials specifically addressing brain metastases shows key issues that could prevent acceptance of ...results by regulatory agencies, including enrolment of heterogeneous groups of patients and varying definitions of clinical endpoints. Considerations specific to disease, modality, and treatment are not consistently addressed. Additionally, the schedule of CNS imaging and consequences of detection of new or progressive brain metastases in trials mainly exploring the extra-CNS activity of systemic drugs are highly variable. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, collaborative effort to improve the design of trials in patients with brain tumours. In this two-part series, we review the state of clinical trials of brain metastases and suggest a consensus recommendation for the development of criteria for future clinical trials.
Lower-grade gliomas (LGGs) with isocitrate dehydrogenase 1 and/or 2 (IDH1/2) mutations have long survival times, making evaluation of treatment efficacy difficult. We investigated the volumetric ...growth rate of IDH mutant gliomas before and after treatment with established glioma therapies to determine whether a significant change in growth rate could be documented and perhaps be used in the future to evaluate treatment response to investigational agents in LGG trials.
In this multicenter retrospective study, 230 adult patients with IDH1/2 mutated LGGs (World Health Organization grade II or III) undergoing surgery, radiation, or chemotherapy for progressive non-enhancing tumor were identified. Subjects were required to have 3 MRI scans containing T2/fluid attenuated inversion recovery imaging spanning a minimum of 6 months prior to treatment. A mixed-effect model was used to estimate tumor growth prior to treatment. A subset of 95 patients who received chemotherapy, radiotherapy, or chemoradiotherapy and had 2 posttreatment imaging time points available were evaluated for change in pre- and posttreatment volumetric growth rates using a piecewise mixed model.
The pretreatment volumetric growth rate across all 230 patients was 27.37%/180 days (95% CI: 23.36%, 31.51%). In the 95 patients with both pre- and posttreatment scans available, there was a significant difference in volumetric growth rates before (26.63%/180 days, 95% CI: 19.31%, 34.40%) and after treatment (-15.24% /180 days, 95% CI: -21.37%, -8.62%) (P < 0.0001). The growth rates for patient subgroup with 1p/19q codeletion (N = 118) was significantly slower than the rate of the 1p/19q non-codeleted group (N = 68) (22.84% vs 35.49%, P = 0.0108).
In this study, we evaluated the growth rates of IDH mutant gliomas before and after standard therapy. Further study is needed to establish whether a change in growth rate is associated with patient survival and its use as a surrogate endpoint in clinical trials for IDH mutant LGGs.
Purpose
The WHO 2016 update classifies glioblastomas (WHO grade IV) according to isocitrate dehydrogenase (
IDH
) gene mutation status. We aimed to determine MRI-based metrics for predicting
IDH
...mutation in glioblastoma.
Methods
This retrospective study included glioblastoma cases (n = 199) with known
IDH
mutation status and pre-operative MRI (T1WI, T2WI, FLAIR, contrast-enhanced T1W1 at minimum). Two neuroradiologists determined the following MRI metrics: (1) primary lobe of involvement (frontal or non-frontal); (2) presence/absence of contrast-enhancement; (3) presence/absence of necrosis; (4) presence/absence of fluid attenuation in the non-contrast-enhancing tumor (nCET); (5) maximum width of peritumoral edema (cm); (6) presence/absence of multifocal disease. Inter-reader agreement was determined. After resolving discordant measurements, multivariate association between consensus MRI metrics/patient age and
IDH
mutation status was determined.
Results
Among 199 glioblastomas, 16 were
IDH
-mutant. Inter-reader agreement was calculated for contrast-enhancement (ĸ = 0.49 − 0.11–1.00), necrosis (ĸ = 0.55 0.34–0.76), fluid attenuation in nCET (ĸ = 0.83 0.68–0.99), multifocal disease (ĸ = 0.55 0.39–0.70), and primary lobe (ĸ = 0.85 0.80–0.91). Mean difference for peritumoral edema width between readers was 0.3 cm 0.2–0.5, p < 0.001. Multivariate analysis uncovered significant associations between
IDH
-mutation and fluid attenuation in nCET (OR 82.9 19.22, ∞, p < 0.001), younger age (OR 0.93 0.86, 0.98, p = 0.009), frontal lobe location (OR 11.08 1.14, 352.97, p = 0.037), and less peritumoral edema (OR 0.15 0, 0.65, p = 0.044).
Conclusions
Conventional MRI metrics and patient age predict
IDH
-mutation status in glioblastoma. Among MRI markers, fluid attenuation in nCET represents a novel marker with high inter-reader agreement that is strongly associated with Glioblastoma,
IDH
-mutant.
This volume begins with an overview of the impact and range of direct neoplastic involvement of the central and peripheral nervous system, comprehensively reviewing all aspects of brain metastases, ...from clinical, radiological and neuropathological manifestations, to the roles of surgery, radiation, systemic and palliative therapy in their management, and the complications of these interventions. The clinical manifestations, diagnosis, and treatment of leptomeningeal, dural, spinal epidural, and plexus metastases are also covered in detail.
Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was ...combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial.
Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m(2) daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m(2) daily for 5 days every 28 days). The primary end point was survival at 1 year.
Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis RPA class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival.
Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.
A prognostic index for survival was constructed and validated from patient data from two European Organisation for Research and Treatment of Cancer (EORTC) radiation trials for low-grade glioma ...(LGG). We sought to independently validate this prognostic index with a separate prospectively collected data set (Intergroup 86-72-51).
Two hundred three patients were treated in a North Central Cancer Treatment Group-led trial that randomized patients with supratentorial LGG to 50.4 or 64.8 Gy. Risk factors from the EORTC prognostic index were analyzed for prognostic value: histology, tumor size, neurologic deficit, age, and tumor crossing the midline. The high-risk group was defined as patients with more than two risk factors. In addition, the Mini Mental Status Examination (MMSE) score, extent of surgical resection, and 1p19q status were also analyzed for prognostic value.
On univariate analysis, the following were statistically significant (p<0.05) detrimental factors for both progression-free survival (PFS) and overall survival (OS): astrocytoma histology, tumor size, and less than total resection. A Mini Mental Status Examination score of more than 26 was a favorable prognostic factor. Multivariate analysis showed that tumor size and MMSE score were significant predictors of OS whereas tumor size, astrocytoma histology, and MMSE score were significant predictors of PFS. Analyzing by the EORTC risk groups, we found that the low-risk group had significantly better median OS (10.8 years vs. 3.9 years, p<0.0001) and PFS (6.2 years vs. 1.9 years, p<0.0001) than the high-risk group. The 1p19q status was available in 66 patients. Co-deletion of 1p19q was a favorable prognostic factor for OS vs. one or no deletion (median OS, 12.6 years vs. 7.2 years; p=0.03).
Although the low-risk group as defined by EORTC criteria had a superior PFS and OS to the high-risk group, this is primarily because of the influence of histology and tumor size. Co-deletion of 1p19q is a prognostic factor. Future studies are needed to develop a more refined prognostic system that combines clinical prognostic features with more robust molecular and genetic data.
Breaking down walls between genres that are usually discussed separately—classical, jazz, and popular—this highly engaging book offers a compelling new integrated view of twentieth-century music. ...Placing Duke Ellington (1899–1974) at the center of the story, David Schiff explores music written during the composer's lifetime in terms of broad ideas such as rhythm, melody, and harmony. He shows how composers and performers across genres shared the common pursuit of representing the rapidly changing conditions of modern life. The Ellington Century demonstrates how Duke Ellington's music is as vital to musical modernism as anything by Stravinsky, more influential than anything by Schoenberg, and has had a lasting impact on jazz and pop that reaches from Gershwin to contemporary R&B.
Low-grade gliomas (LGG) are not benign neoplasms. Patients with LGG eventually die as a consequence of this disease. Although the survival of patients with LGG is better than that of patients with ...higher-grade tumours, many of the treatments can produce or contribute to chronic impairment, particularly radiotherapy. Chemotherapy has emerged as a promising therapy, although definitive findings are awaited. Breakthroughs in molecular biology have improved our understanding of tumours and have led to the development of novel treatments and better prognoses. Ongoing clinical trials will help to elucidate the optimum management of patients with LGG.
Abstract Phosphatase and tensin homolog located on chromosome 10 (PTEN) is one of the most frequently mutated tumor suppressors in human cancer including in glioblastoma. Here, we show that PTEN ...exerts unconventional oncogenic effects in glioblastoma through a novel PTEN/mutant p53/c-Myc/Bcl-XL molecular and functional axis. Using a wide array of molecular, genetic, and functional approaches, we demonstrate that PTEN enhances a transcriptional complex containing gain-of-function mutant p53, CBP, and NFY in human glioblastoma cells and tumor tissues. The mutant p53/CBP/NFY complex transcriptionally activates the oncogenes c-Myc and Bcl-XL , leading to increased cell proliferation, survival, invasion, and clonogenicity. Disruption of the mutant p53/c-Myc/Bcl-XL axis or mutant p53/CBP/NFY complex reverses the transcriptional and oncogenic effects of PTEN and unmasks its tumor-suppressive function. Consistent with these data, we find that PTEN expression is associated with worse patient survival than PTEN loss in tumors harboring mutant p53 and that a small molecule modulator of p53 exerts greater antitumor effects in PTEN-expressing cancer cells. Altogether, our study describes a new signaling pathway that mediates context-dependent oncogenic/tumor-suppressive role of PTEN. The data also indicate that the combined mutational status of PTEN and p53 influences cancer prognosis and anticancer therapies that target PTEN and p53.
The role of chemotherapy for newly diagnosed anaplastic gliomas, particularly when combined with radiotherapy, has long been unresolved. Over the past few decades, despite no conclusive data, study ...findings have suggested that the addition of nitrosourea-based chemotherapy to radiotherapy could be beneficial.
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