Neuro-Oncology Diet and risk of glioma

Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool Abstract Background Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985–2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors. Methods A multi-institutional retrospective institutional review board–approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively. Results The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0–1.0, 1.5–2.0, 2.5–3, and 3.5–4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively. Conclusion The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com. Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients Abstract Background Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we designed a phase I/II study to test safety and immunogenicity of the IMA950 multipeptide vaccine adjuvanted with poly-ICLC in HLA-A2 + glioma patients. Methods Adult patients with newly diagnosed glioblastoma (n=16) and grade III astrocytoma (n=3) were treated with radiochemotherapy followed by IMA950/poly-ICLC vaccination. The first 6 patients received IMA950 (9 MHC class I and 2 MHC class II peptides) i.d. and poly-ICLC i.m. After protocol amendment, IMA950 and poly-ICLC were mixed and injected s.c. (n=7) or i.m. (n=6). Primary endpoints were safety and immunogenicity. Secondary endpoints were overall survival, progression-free survival at 6 and 9 months, and vaccine-specific peripheral CD4 and CD8 T cell responses. Results The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery. For the first 6 patients, vaccine-induced CD8 T cell responses were restricted to a single peptide and CD4 responses were absent. After optimization of vaccine formulation, we observed multipeptide CD8 and sustained Th1 CD4 T cell responses. For the entire cohort, CD8 T cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients. Conclusion We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for glioma patients. Trial registration Clinicaltrials.gov NCT01920191. Recent Developments and Future Directions in Adult Lower-Grade Gliomas: Society for Neuro-Oncology (SNO) and European Association of Neuro-Oncology (EANO) Consensus Abstract The finding that most grade II and III gliomas harbor isocitrate dehydrogenase (IDH) mutations conveying a relatively favorable and fairly similar prognosis in both tumor grades highlights that these tumors represent a fundamentally different entity from IDH wild-type gliomas exemplified in most glioblastoma. Herein we review the most recent developments in molecular neuropathology leading to reclassification of these tumors based upon IDH and 1p/19q status, as well as the potential roles of methylation profiling and CDKN2A/B deletional analysis. We discuss the epidemiology, clinical manifestations, benefit of surgical resection, and neuroimaging features of lower-grade gliomas as they relate to molecular subtype, including advanced imaging techniques such as 2-hydroxyglutarate magnetic resonance spectroscopy and amino acid PET scanning. Recent, ongoing and planned studies of radiation therapy and both cytotoxic and targeted chemotherapies are summarized, including both small molecule and immunotherapy approaches specifically targeting the mutant IDH protein. Diet and risk of glioma: combined analysis of three large prospective studies in the UK and USA Abstract Background Available evidence on diet and glioma risk comes mainly from studies with retrospective collection of dietary data. To minimise possible differential dietary recall between those with and without glioma, we present findings from three large prospective studies. Methods Participants included 692,176 from (UK) Million Women Study, 470,780 from (US) NIH-AARP Study, and 99,148 from (US) PLCO Study. Cox regression yielded study-specific adjusted relative risks for glioma in relation to 15 food groups, 14 nutrients, and 3 dietary patterns, which were combined, weighted by inverse-variances of the relative risks. Separate analyses by <5 and ≥5 years follow-up assessed potential biases related to changes of diet before glioma diagnosis. Results The 1,262,104 participants, mean age 60.6 (SD5.5) at baseline, were followed for 15.4 million person-years (mean 12.2 years/participant), during which 2,313 incident gliomas occurred, at mean age 68.2 (SD6.4). Overall, there was weak evidence for increased glioma risks associated with increasing intakes of total fruit, citrus fruit, and fibre, and healthy dietary patterns, but these associations were generally null after excluding the first 5 years of follow-up. There was little evidence for heterogeneity of results by study or by sex. Conclusions The largest prospective evidence to date suggests little, if any, association between major food groups, nutrients, or common healthy dietary patterns, and glioma incidence. With the statistical power of this study and the comprehensive nature of the investigation here, it seems unlikely we have overlooked major effects of diet on risk of glioma that would be of public health concern.

Highlights from the Literature

Forthcoming Meetings Edited by Albert H. Kim and Jennie W. Taylor

Glioblastoma: a prognostic value of AMT-PET? See the article by John et al, pp. 264–273.

Old meet new—the path to combination treatments in pediatric low-grade gliomas See the article by Poore et al, pp. 252–263.

Disparities along the glioblastoma clinical trials landscape We read with interest the recent work by Vanderbeek et al1 regarding the current clinical trials landscape for glioblastoma (GBM) patients. An unexplored dimension of their analysis centers on disparities and demographic discrepancies between clinical trial participants and the broader GBM population. We therefore examined clinical trials with published results as highlighted by the authors, totaling 51 trials.1 While most of these trials reported details regarding patient age (48/51, 94%) and gender (47/51, 92%), only 14 trials (27%) provided information regarding ethnicity and/or race in either peer-reviewed publications or ClinicalTrials.gov. The rate of reporting ethnicity/race was particularly low among phase I/II studies (9/43, 21%) compared with phase III trials (5/8, 63%, chi-squared test P = 0.02).

Multimodal imaging-defined subregions in newly diagnosed glioblastoma: impact on overall survival Abstract Background Although glioblastomas are heterogeneous brain-infiltrating tumors, their treatment is mostly focused on the contrast-enhancing tumor mass. In this study, we combined conventional MRI, diffusion-weighted imaging (DWI), and amino acid PET to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value. Methods Contrast-enhanced T1, T2/fluid attenuated inversion recovery (FLAIR) MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients with newly diagnosed glioblastoma. Five tumor subregions were identified based on a combination of MRI contrast enhancement, T2/FLAIR signal abnormalities, and AMT uptake on PET. ADC and AMT uptake tumor/contralateral normal cortex (T/N) ratios in these tumor subregions were correlated, and their prognostic value was determined. Results A total of 115 MRI/PET-defined subregions were analyzed. Most tumors showed not only a high-AMT uptake (T/N ratio > 1.65, N = 27) but also a low-uptake subregion (N = 21) within the contrast-enhancing tumor mass. High AMT uptake extending beyond contrast enhancement was also common (N = 25) and was associated with low ADC (r = −0.40, P = 0.05). Higher AMT uptake in the contrast-enhancing tumor subregions was strongly prognostic for overall survival (hazard ratio: 7.83; 95% CI: 1.98–31.02, P = 0.003), independent of clinical and molecular genetic prognostic variables. Nonresected high-AMT uptake subregions predicted the sites of tumor progression on posttreatment PET performed in 10 patients. Conclusions Glioblastomas show heterogeneous amino acid uptake with high-uptake regions often extending into non-enhancing brain with high cellularity; nonresection of these predict the site of posttreatment progression. High tryptophan uptake values in MRI contrast-enhancing tumor subregions are a strong, independent imaging marker for longer overall survival.

Supratotal resection in glioma: a systematic review Abstract Background Emerging evidence suggests survival benefit from resection beyond all MRI abnormalities present on T1-enhanced and T2‒fluid attenuated inversion recovery (FLAIR) modalities in glioma (supratotal resection); however, the quality of evidence is unclear. We addressed this question via systematic review of the literature. Methods EMBASE, MEDLINE, Scopus, and Web of Science databases were queried. Case studies, reviews or editorials, non-English, abstract-only, brain metastases, and descriptive works were excluded. All others were included. Results Three hundred and nine unique references yielded 41 studies for full-text review, with 7 included in the final analysis. Studies were mostly of Oxford Center for Evidence-Based Medicine Level 4 quality. A total of 88 patients underwent supratotal resection in a combined cohort of 492 patients (214 males and 278 females, age 18 to 82 years). Fifty-one supratotal resections were conducted on high-grade gliomas, and 37 on low-grade gliomas. Karnofsky performance status, overall survival, progression-free survival, neurological deficits postoperatively, and anaplastic transformation were the main measured outcomes. No randomized controlled trials were identified. Preliminary low-quality support was found for supratotal resection in increasing overall survival and progression-free survival for both low-grade and high-grade glioma. Conclusion The literature suggests insufficient evidence for carte blanche application of supratotal resection, particularly in lower-grade gliomas where neurological deficits can result in long-term disability. While the preliminary studies discussed here, containing data from only a few centers, have reported increased progression-free and overall survival, these claims require validation in prospective research studies involving larger patient populations with clearly defined appropriate outcome metrics in order to reduce potential bias.

Uncommon low-grade brain tumors Abstract The 2016 World Health Organization (WHO) classification of primary central nervous system (CNS) tumors includes numerous uncommon (representing ≤1% of tumors) low-grade (grades I–II) brain neoplasms with varying clinical behaviors and outcomes. Generally, gross tumor or maximal safe resection is the primary treatment. Adjuvant treatments, though their exact role is unknown, may be considered individually based on pathological subtypes and a proper assessment of risks and benefits. Targetable mutations such as BRAF (proto-oncogene B-Raf), TRAIL (tumor necrosis factor apoptosis inducing ligand), and PDGFR (platelet derived growth factor receptor) have promising roles in future management.

Outcomes following stereotactic radiosurgery for small to medium-sized brain metastases are exceptionally dependent upon tumor size and prescribed dose Abstract Background At our institution, we have historically treated brain metastasis (BM) ≤2 cm in eloquent brain with a radiosurgery (SRS) lower prescription dose (PD) to reduce the risk of radionecrosis (RN). We sought to evaluate the impact of this practice on outcomes. Methods We analyzed a prospective registry of BM patients treated with SRS between 2008 and 2017. Incidences of local failure (LF) and RN were determined and Cox regression was performed for univariate and multivariate analyses (MVAs). Results We evaluated 1533 BM ≤2 cm. Median radiographic follow-up post SRS was 12.7 months (1.4–100). Overall, the 2-year incidence of LF was lower for BM treated with PD ≥21 Gy (9.3%) compared with PD ≤15 Gy (19.5%) (sub–hazard ratio, 2.3; 95% CI: 1.4–3.7; P = 0.0006). The 2-year incidence of RN was not significantly higher for the group treated with PD ≥21 Gy (9.5%) compared with the PD ≤15 Gy group (7.5%) (P = 0.16). MVA demonstrated that PD (≤15 Gy) and tumor size (>1 cm) were significantly correlated (P < 0.05) with higher rates of LF and RN, respectively. For tumors ≤1 cm, when comparing PD ≤15 Gy with ≥21 Gy, the risks of LF and RN are equivalent. However, for lesions >1 cm, PD ≥21 Gy is associated with a lower incidence of LF without significantly increasing the risk of RN. Conclusion Our results indicate that rates of LF or RN following SRS for BM are strongly correlated with size and PD. Based on our results, we now, depending upon the clinical context, consider increasing PD to 21 Gy for BM in eloquent brain, excluding the brainstem.

Sex difference of mutation clonality in diffuse glioma evolution Abstract Background Sex differences in glioma incidence and outcome have been previously reported but remain poorly understood. Many sex differences that affect the cancer risk were thought to be associated with cancer evolution. Methods In this study, we used an integrated framework to infer the timing and clonal status of mutations in ~600 diffuse gliomas from The Cancer Genome Atlas (TCGA) including glioblastomas (GBMs) and low-grade gliomas (LGGs), and investigated the sex difference of mutation clonality. Results We observed higher overall and subclonal mutation burden in female patients with different grades of gliomas, which could be largely explained by the mutations of the X chromosome. Some well-established drivers were identified showing sex-biased clonality, such as CDH18 and ATRX. Focusing on glioma subtypes, we further found a higher subclonal mutation burden in females than males in the majority of glioma subtypes, and observed opposite clonal tendency of several drivers between male and female patients in a specific subtype. Moreover, analysis of clinically actionable genes revealed that mutations in genes of the mitogen-activated protein kinase (MAPK) signaling pathway were more likely to be clonal in female patients with GBM, whereas mutations in genes involved in the receptor tyrosine kinase signaling pathway were more likely to be clonal in male patients with LGG. Conclusions The patients with diffuse glioma showed sex-biased mutation clonality (eg, different subclonal mutation number and different clonal tendency of cancer genes), highlighting the need to consider sex as an important variable for improving glioma therapy and clinical care.