Sunit Das

Treatment of Elderly Patients With Glioblastoma: A Systematic Evidence-Based Analysis

IMPORTANCEnDespite improvements in survival with aggressive chemoradiation, outcomes for patients diagnosed as having glioblastoma multiforme (GBM) remain poor. Survival is further limited in elderly patients, who are often unable to tolerate multimodality therapy. The appropriate treatment approach for elderly patients (aged >65 years) with GBM remains unclear. While the literature supports the use of standard radiotherapy (60 Gy), several recent studies have suggested that treatment with temozolomide monotherapy or short-course radiotherapy may be a reasonable alternative.nnnOBJECTIVEnTo review literature reporting survival data related to treatment of elderly patients with GBM using either temozolomide alone or radiotherapy alone.nnnEVIDENCE REVIEWnWe performed a systematic review to identify articles from the temozolomide era (2005-present) that reported survival data related to treatment of elderly patients with GBM using either temozolomide alone or radiotherapy alone, with consideration of O6-methylguanine-DNA-methyltransferase gene (MGMT) promoter methylation status. PubMed was searched for articles between January 1, 2005, and August 31, 2013, using the search terms glioblastoma, elderly, temozolomide, radiation, hypofractionated, and survival, and references from relevant articles were searched. Selected articles reported overall survival data associated with either temozolomide alone or radiotherapy alone in elderly patients (aged ≥60 years) with GBM; articles were excluded if they did not report survival data from radiotherapy alone or temozolomide alone, were not restricted to an elderly population, did not report original data, were not restricted to patients with primary GBM, were a subgroup analysis of a prior article, were a case report, or could not be located in entirety. Articles were interrogated as per the criteria designated by the Oxford Centre for Evidence-Based Medicine to determine the level of evidence presented, and data from level 1 and 2 studies were used for analysis. From a review of 185 articles, 23 were selected for inclusion and final analysis. From these, we identified 2 level 1 studies and 1 level 2 study that reported overall survival in elderly patients treated with temozolomide alone, and 4 level 1 studies and 2 level 2 studies that reported overall survival in elderly patients treated with radiotherapy alone.nnnFINDINGSnThis review of the literature revealed several limitations. First, there is a paucity of randomized clinical studies comparing temozolomide alone with radiotherapy alone in elderly patients with GBM. Second, there is a lack of coherence in the literature for the definition of elderly. Third, the treatment paradigms used are not consistent from study to study. Regardless, the available data did allow the formulation of a recommendation based on level 1 and 2 data.nnnCONCLUSIONS AND RELEVANCEnThe literature supports the use of hypofractionated radiotherapy or temozolomide monotherapy in the treatment of elderly patients with GBM. In patients with MGMT promoter methylation, temozolomide monotherapy may have greater benefit than radiotherapy.

Spatial heterogeneity in medulloblastoma

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Hypofractionated Stereotactic Radiotherapy in Five Daily Fractions for Post-Operative Surgical Cavities in Brain Metastases Patients with and without Prior Whole Brain Radiation

Our purpose was to report efficacy of hypofractionated cavity stereotactic radiotherapy (HCSRT) in patients with and without prior whole brain radiotherapy (WBRT). 32 surgical cavities in 30 patients (20 patients/21 cavities had no prior WBRT and 10 patients/11 cavities had prior WBRT) were treated with image-guided linac stereotactic radiotherapy. 7 of the 10 prior WBRT patients had “resistant” local disease given prior surgery, post-operative WBRT and a re-operation, followed by salvage HCSRT. The clinical target volume was the post-surgical cavity, and a 2-mm margin applied as planning target volume. The median total dose was 30 Gy (range: 25–37.5 Gy) in 5 fractions. In the no prior and prior WBRT cohorts, the median follow-up was 9.7 months (range: 3.0–23.6) and 15.3 months (range: 2.9–39.7), the median survival was 23.6 months and 39.7 months, and the 1-year cavity local recurrence progression-free survival (LRFS) was 79 and 100%, respectively. At 18 months the LRFS dropped to 29% in the prior WBRT cohort. Grade 3 radiation necrosis occurred in 3 prior WBRT patients. We report favorable outcomes with HCSRT, and well selected patients with prior WBRT and “resistant” disease may have an extended survival favoring aggressive salvage HCSRT at a moderate risk of radiation necrosis.

Efficacy and Safety of Pedunculopontine Nuclei (PPN) Deep Brain Stimulation in the Treatment of Gait Disorders: A Meta-Analysis of Clinical Studies

BACKGROUNDnPedunculopontine nucleus (PPN) has complex reciprocal connections with basal ganglia, especially with internal globus pallidus and substantia nigra, and it has been postulated that PPN stimulation may improve gait instability and freezing of gait. In this meta-analysis, we will assess the evidence for PPN deep brain stimulation in treatment of gait and motor abnormalities especially focusing on Parkinson disease patients.nnnMETHODSnPubMed and Scopus electronic databases were searched for related studies published before February 2014. Medline (1966-2014), Embase (1974-2010), CINAHL, Web of Science, Scopus bibliographic, and Google Scholar databases (1960-2014) were also searched for studies investigating effect of PPN deep brain stimulation in treatment of postural and postural instability and total of ten studies met the inclusion criteria for this analysis.nnnRESULTSnOur findings showed a significant improvement in postural instability (p<0.001) and motor symptoms of Parkinson disease on and off medications (p<0.05), but failed to show improvement in freezing of gait.nnnCONCLUSIONSnDespite significant improvement in postural instability observed in included studies, evidence from current literature is not sufficient to generalize these findings to the majority of patients.

Cadherin-11 Regulates Motility in Normal Cortical Neural Precursors and Glioblastoma

Metastasizing tumor cells undergo a transformation that resembles a process in normal development when non-migratory epithelial cells modulate the expression of cytoskeletal and adhesion proteins to promote cell motility. Here we find a mesenchymal cadherin, Cadherin-11 (CDH11), is increased in cells exiting the ventricular zone (VZ) neuroepithelium during normal cerebral cortical development. When overexpressed in cortical progenitors in vivo, CDH11 causes premature exit from the neuroepithelium and increased cell migration. CDH11 expression is elevated in human brain tumors, correlating with higher tumor grade and decreased patient survival. In glioblastoma, CDH11-expressing tumor cells can be found localized near tumor vasculature. Endothelial cells stimulate TGFβ signaling and CDH11 expression in glioblastoma cells. TGFβ promotes glioblastoma cell motility, and knockdown of CDH11 expression in primary human glioblastoma cells inhibits TGFβ-stimulated migration. Together, these findings show that Cadherin-11 can promote cell migration in neural precursors and glioblastoma cells and suggest that endothelial cells increase tumor aggressiveness by co-opting mechanisms that regulate normal neural development.

Reliability of Task-Based fMRI for Preoperative Planning: A Test-Retest Study in Brain Tumor Patients and Healthy Controls

Background Functional magnetic resonance imaging (fMRI) continues to develop as a clinical tool for patients with brain cancer, offering data that may directly influence surgical decisions. Unfortunately, routine integration of preoperative fMRI has been limited by concerns about reliability. Many pertinent studies have been undertaken involving healthy controls, but work involving brain tumor patients has been limited. To develop fMRI fully as a clinical tool, it will be critical to examine these reliability issues among patients with brain tumors. The present work is the first to extensively characterize differences in activation map quality between brain tumor patients and healthy controls, including the effects of tumor grade and the chosen behavioral testing paradigm on reliability outcomes. Method Test-retest data were collected for a group of low-grade (n = 6) and high-grade glioma (n = 6) patients, and for matched healthy controls (n = 12), who performed motor and language tasks during a single fMRI session. Reliability was characterized by the spatial overlap and displacement of brain activity clusters, BOLD signal stability, and the laterality index. Significance testing was performed to assess differences in reliability between the patients and controls, and low-grade and high-grade patients; as well as between different fMRI testing paradigms. Results There were few significant differences in fMRI reliability measures between patients and controls. Reliability was significantly lower when comparing high-grade tumor patients to controls, or to low-grade tumor patients. The motor task produced more reliable activation patterns than the language tasks, as did the rhyming task in comparison to the phonemic fluency task. Conclusion In low-grade glioma patients, fMRI data are as reliable as healthy control subjects. For high-grade glioma patients, further investigation is required to determine the underlying causes of reduced reliability. To maximize reliability outcomes, testing paradigms should be carefully selected to generate robust activation patterns.

ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells

Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1lo GSCs do not. Increasing ASCL1 levels in ASCL1lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.

Mouse models of glioblastoma: lessons learned and questions to be answered

AbstractGlioblastoma is the most common primary brain tumour in adults. While many patients achieve disease remission following treatment with surgical resection, radiation therapy and chemotherapy, this remission is brief and invariably followed by tumour recurrence and progression. Recent work using mouse models of the disease, coupled with data generated by The Cancer Genome Atlas, have given us new insights into the mechanisms that underlie gliomagenesis and result in glioblastoma heterogeneity. These findings suggest that the treatment of glioblastoma will require a more nuanced understanding of their biology and the employment of targeted therapeutic approaches. In this review, we will summarize the current state of mouse modeling in glioma, with a focus on how these models may inform our understanding of this disease and its treatment.n

The Role of ATRX in Glioma Biology

The current World Health Organization classification of CNS tumors has made a tremendous leap from past editions by incorporating molecular criteria in addition to the pre-existing histological parameters. The revised version has had a particular impact on the classification of diffuse low-grade gliomas and their high-grade variants. The ATRX status is one of the critical markers that define the molecular classification of gliomas. In this review, we will first provide an overview of the role of ATRX in regular cell biology. Furthermore, the role of ATRX in tumorigenesis, specifically gliomas, is comprehensively elucidated. The possible correlation of ATRX status with other genetic/epigenetic modifications is also presented. We conclude by discussing some of the challenges associated with incorporating ATRX status assessment into routine clinical practice while also exploring opportunities for future diagnostics/therapeutics in gliomas based on ATRX status.

Optimized Mass Spectrometry Analysis Workflow with Polarimetric Guidance for ex vivo and in situ Sampling of Biological Tissues

Spatially Targeted Mass Spectrometry (MS) analysis using survey scans with an imaging modality often requires consecutive tissue slices, because of the tissue damage during survey scan or due to incompatible sample preparation requirements between the survey modality and MS. We report two spatially targeted MS analysis workflows based on polarized light imaging guidance that use the same tissue sample for survey and targeted analysis. The first workflow is applicable for thin-slice analysis, and uses transmission-polarimetry-guided Desorption ElectroSpray Ionization Mass Spectrometry (DESI-MS), and confirmatory H&E histopathology analysis on the same slice; this is validated using quantitative digital pathology methods. The second workflow explores a polarimetry-guided MS platform for thick tissue assessment by developing reflection-mode polarimetric imaging coupled with a hand-held Picosecond InfraRed Laser (PIRL) MS ablation probe that requires minimal tissue removal to produce detectable signal. Tissue differentiation within 5–10u2009s of sampling with the hand-held probe is shown using multivariate statistical methods of the MS profiles. Both workflows were tasked with differentiating necrotic cancer sites from viable cancers using a breast tumour model, and their performance was evaluated. The use ofxa0the same tissue surface addresses mismatches in guidance due to intrinsic changes in tissue morphology over consecutive sections.