Purpose To assess amide proton transfer‐weighted (APTW) imaging features in patients with malignant gliomas after chemoradiation and the diagnostic performance of APT imaging for distinguishing true progression from pseudoprogression. Materials and Methods After approval by the Institutional Review Board, 32 patients with clinically suspected tumor progression in the first 3 months after chemoradiation were enrolled and scanned at 3T. Longitudinal routine magnetic resonance imaging (MRI) changes and medical records were assessed to confirm true progression versus pseudoprogression. True progression was defined as lesions progressing on serial imaging over 6 months, and pseudoprogression was defined as lesions stabilizing or regressing without intervention. The APTW mean and APTW max signals were obtained from three to five regions of interests for each patient and compared between the true progression and pseudoprogression groups. The diagnostic performance was assessed with receiver operating characteristic curve analysis. Results The true progression was associated with APTW hyperintensity (APTW mean = 2.75% ± 0.42%), while pseudoprogression was associated with APTW isointensity to mild hyperintensity (APTW mean = 1.56% ± 0.42%). The APTW signal intensities were significantly higher in the true progression group ( n = 20) than in the pseudoprogression group ( P < 0.001; n = 12). The cutoff APTW mean and APTW max intensity values to distinguish between true progression and pseudoprogression were 2.42% (with a sensitivity of 85.0% and a specificity of 100%) and 2.54% (with a sensitivity of 95.0% and a specificity of 91.7%), respectively. Conclusion The APTW‐MRI signal is a valuable imaging biomarker for distinguishing pseudoprogression from true progression in glioma patients. J. Magn. Reson. Imaging 2016;44:456–462.
Corticosteroids are the mainstay of treatment for peritumor edema but are often associated with significant side effects. Therapies that can reduce corticosteroid use would potentially be of significant benefit to patients. However, currently there are no standardized endpoints evaluating corticosteroid use in neuro-oncology clinical trials.
Abstract Background Despite advances in our understanding of the molecular underpinnings of meningioma progression and innovations in systemic and local treatments, recurrent meningiomas remain a substantial therapeutic challenge. The objective of this systematic review and meta-analysis is to provide a historical baseline, contemporary analysis, and propose a “rate of probable interest” to inform future clinical trial design and development on behalf of the RANO meningioma group. Methods PubMed, ClinicalTrials.gov, and ASCOpubs databases were screened for clinical trials evaluating the activity of systemic therapies for adults with recurrent meningiomas. The pooled progression-free survival at 6-months and 1-year (PFS-6 and PFS-1 year) values were calculated using the random effects technique with I-squared indices. Results The pooled PFS-6 and PFS-1 year rates for recurrent WHO grade 1 meningiomas were 43.6% (95% CI: 22.7-67.0%, I2=80%) and 21.7% (95% CI: 6.2-53.9%, I2=76%), and for grade 2-3 meningiomas, the PFS-6 was 38.0% (95% CI: 28.3-48.8%, I2=68%). In targeted therapy group, PFS-6 and PFS-1 year rates stood at 62.0% (I2=58%) and 49.0% (I2=63%) for grade 1, while for grade 2-3 tumors, the PFS-6 rate with targeted therapy and immunotherapy was 42.1% (I²=60%) and 46.0% (I²=0%), respectively. The benchmarks were set at 67% and 54% for PFS-6 and PFS-1 year for grade 1 tumors, and PFS-6 of 49% for grade 2-3 tumors. Conclusions Several studies have reported outcomes in patients with recurrent meningiomas testing a variety of agents with modest, but variable and progressively increasing activity. In this context, we recommend new benchmarks for future trials to define efficacy of future investigational therapies.
Background Despite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging. Methods Using glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug’s clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50). Results Among 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC 50 in GBM cell lines among drugs with clinical efficacy. The drugs’ half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively). Conclusion While multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.
Abstract BACKGROUND There has been increasing interest in exploring ketogenic diet therapies (KDT) in patients with glioma given the poor prognosis. The purpose of this single-arm, open label phase 2 study was to rigorously examine the feasibility, safety, systemic biological activity, and cerebral activity of a KDT in patients with glioma. METHODS 25 patients with biopsy-confirmed WHO Grade 2–4 astrocytoma with stable disease following adjuvant chemotherapy were enrolled in an 8-week GLioma Atkins-based Diet (GLAD). GLAD consisted of 2 fasting days (calories<20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates≤20 gm/day) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, IGF-1, and MR spectroscopy at baseline and week 8. RESULTS 21 patients completed the study. 80% of patients reached ≥40 mg/dL urine acetoacetate during the study. 48% of patients were adherent by food record. The diet was well-tolerated with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity including hemoglobin A1c, insulin, and fat body mass decreased significantly, while lean body mass increased. MR spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate (bHB) and acetone (Ace)) in both lesional and contralateral brain, compared to baseline. Higher total choline (tCho) and glutamine (Gln) levels were observed in lesional as compared to contralateral brain at baseline, and both decreased following intervention. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB Rs0.52, p=0.05). There were no differences in cerebral metabolites in IDH-mutant glioma after controlling for ketonuria. CONCLUSIONS The GLAD dietary intervention, while demanding, produced meaningful ketonuria, and significant systemic and cerebral metabolic changes in participants. Participant ketonuria correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records.
Vestibular schwannomas are the hallmark of neurofibromatosis 2 (NF2), occurring in >95% of patients. These tumors develop on the vestibulocochlear nerve and are associated with significant morbidity due to hearing loss, tinnitus, imbalance, facial weakness, and risk of early mortality from brainstem compression. Although hearing loss and facial weakness have been identified as important functional outcomes for patients with NF2, there is a lack of consensus regarding appropriate endpoints in clinical trials.The functional outcomes group reviewed existing endpoints for hearing and facial function and developed consensus recommendations for response evaluation in NF2 clinical trials.For hearing endpoints, the functional group endorsed the use of maximum word recognition score as a primary endpoint, with the 95% critical difference as primary hearing outcomes. The group recommended use of the scaled measurement of improvement in lip excursion (SMILE) system for studies of facial function.These recommendations are intended to provide researchers with a common set of endpoints for use in clinical trials of patients with NF2. The use of common endpoints should improve the quality of clinical trials and foster comparison among studies for hearing loss and facial weakness.
