Abstract

OBJECTIVE

To assess feasibility and effect on cognitive function and Health-Related Quality of Life (HRQoL) of an iPad-based intervention in grade 2 and 3 glioma patients stable off treatment. Patients with lower grade glioma suffer significant cognitive dysfunctions that impact their HRQoL. Formal cognitive rehabilitation is a limited resource that may be more available if deployed with a mobile device such as an iPad.

METHODS

Stable, grade 2 and 3 glioma patients with subjective cognitive complaints, complete a baseline computerized battery of standardized cognitive tests using the NIH Toolbox and HRQOL assessment with the FACT-BR. Patients then completed a novel, evidence-based, iPad based, brain tumor specific, cognitive rehabilitation program called ReMind over the next 3 months (~3 hours per week). NIH Toolbox and HRQOL assessments were repeated after completion of the rehabilitation, and again 9 months after baseline. Primary endpoint was feasibility with secondary endpoints of changes in cognitive scores and HRQOL assessments.

RESULTS

To date, 10 patients have enrolled and completed baseline testing, of whom 5 have completed ReMind rehabilitation. Median age is 56 years. Median disease duration is 7.6 years. 5 patients have Oligodendrogliomas (IDH mutated and 1p19q deleted), 3 patients have Astrocytomas, IDH mutated, and 2 patients have Astrocytomas NOS. 5 are grade II and 5 are grade III. 5 had left hemisphere tumors, 4 had right hemisphere tumors, and 1 was bilateral. 10 had prior chemotherapy and 8 prior radiation. We anticipate enrolling another 5 – 10 patients and will present the updated feasibility data as well as changes in cognitive and HRQOL scores.

CONCLUSION

As patients with lower grade tumors live longer, it is important to increase availability of cognitive interventions to improve HRQOL and outcomes. This iPad based approach provides in-home access to cognitive training and compensation strategies for patients with brain tumors.

Detection of DNA copy number aberrations by shallow whole-genome sequencing (WGS) faces many challenges, including lack of completion and errors in the human reference genome, repetitive sequences, polymorphisms, variable sample quality, and biases in the sequencing procedures. Formalin-fixed paraffin-embedded (FFPE) archival material, the analysis of which is important for studies of cancer, presents particular analytical difficulties due to degradation of the DNA and frequent lack of matched reference samples. We present a robust, cost-effective WGS method for DNA copy number analysis that addresses these challenges more successfully than currently available procedures. In practice, very useful profiles can be obtained with ∼0.1× genome coverage. We improve on previous methods by first implementing a combined correction for sequence mappability and GC content, and second, by applying this procedure to sequence data from the 1000 Genomes Project in order to develop a blacklist of problematic genome regions. A small subset of these blacklisted regions was previously identified by ENCODE, but the vast majority are novel unappreciated problematic regions. Our procedures are implemented in a pipeline called QDNAseq. We have analyzed over 1000 samples, most of which were obtained from the fixed tissue archives of more than 25 institutions. We demonstrate that for most samples our sequencing and analysis procedures yield genome profiles with noise levels near the statistical limit imposed by read counting. The described procedures also provide better correction of artifacts introduced by low DNA quality than prior approaches and better copy number data than high-resolution microarrays at a substantially lower cost.

Background

Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence.

Methods

We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a 3-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites.

Results

Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account.

Conclusion

Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists.

Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

Abstract

BACKGROUND

Survival in glioblastoma patients is usually in the range of 12–15 months, and less than 5% of patients survive 5 years from diagnosis. Little is known about factors influencing long-term survival.

METHODS

A consortium generously funded by the Brain Tumor Funders’ Collaborative comprising more than 20 clinical sites in Europe, the US, and Australia registers patients with glioblastoma who survived for at least 5 years. The aim of the study is a better understanding of factors contributing to prolonged survival by assessment of (i) clinical features, (ii) molecular parameters, (iii) therapy and quality of life-related factors, and (iv) immunological parameters. The histopathological diagnosis of glioblastoma is centrally reviewed at study entry. Clinical characteristics including imaging data are collected at the European Organisation for Research and Treatment of Cancer (EORTC) in Brussels, Belgium. Comprehensive molecular analyses are performed at the German Cancer Research Center (DKFZ), Germany. Immunological parameters are analyzed in Zurich, Switzerland. Alive patients are followed by neurocognitive assessments additionally.

RESULTS

At the cut-off of May 30, 2017, 182 patients have been registered by 17 sites; 107 patients are alive, more than half of which contribute to the neurocognitive assessments and patient-related outcome studies, as well as the immunological studies. First comprehensive results of disease characteristics with a cut-off of September 30, 2017, will be presented.

CONCLUSIONS

The collaborative effort of this consortium by comprehensive characterization of molecular parameters, immunological aspects, and individual clinical and therapy-related determinants will contribute to a better understanding of factors that modulate the course of this disease.

Background

The Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures should be of high quality, both in terms of relevance and other measurement properties. This systematic review aimed to identify PRO measures that have been used in brain tumor studies to date.

Methods

A systematic literature search for articles published up to June 25, 2020 was conducted in several electronic databases. Pre-specified inclusion criteria were used to identify studies using PRO measures assessing symptoms, (instrumental) activities of daily living [(I)ADL] or health-related quality of life (HRQoL) in adult patients with glioma, meningioma, primary central nervous system lymphoma, or brain metastasis.

Results

A total of 215 different PRO measures were identified in 571 published and 194 unpublished studies. The identified PRO measures include brain tumor-specific, cancer-specific, and generic instruments, as well as instruments designed for other indications or multi- or single-item study-specific questionnaires. The most frequently used instruments were the EORTC QLQ-C30 and QLQ-BN20 (n = 286 and n = 247), and the FACT-Br (n = 167), however, the majority of the instruments were used only once or twice (150/215).

Conclusion

Many different PRO measures assessing symptoms, (I)ADL or HRQoL have been used in brain tumor studies to date. Future research should clarify whether these instruments or their scales/items exhibit good content validity and other measurement properties for use in brain tumor patients.

Background

Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier.

Methods

European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors.

Results

The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm.

Conclusions

Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.