Jing Wu

Apparent diffusion coefficient histogram analysis stratifies progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: A multi-center study

We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI’s from patients enrolled in the BRAIN study (nxa0=xa097) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan–Meier method with log-rank test. Mean ADC-L was 1,209xa0×xa010−6mm2/sxa0±xa0224 (SD), and mean LCP was 0.71xa0±xa00.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95xa0% confidence interval: 1.6, 6.1; Pxa0=xa00.001), 2.3 (95xa0% CI: 1.3, 4.0; Pxa0=xa00.002), and 2.4 (95xa0% CI: 1.4, 4.2; Pxa0=xa00.002), respectively. In patients with ADC-L <1,209 and LCP >0.71 versus ADC-L >1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.

Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients

BACKGROUNDnEpendymomas are rare CNS tumors. Previous studies describing the clinical course of ependymoma patients were restricted to small sample sizes, often with patients at a specific institution.nnnMETHODSnClinically annotated ependymoma tissue samples from 19 institutions were centrally reviewed. Patients were all adults aged 18 years or older at the time of diagnosis. Potential prognostic clinical factors identified on univariate analysis were included in a multivariate Cox proportional hazards model with backwards selection to model progression-free survival.nnnRESULTSnThe 282 adult ependymoma patients were equally male and female with a mean age of 43 years (range, 18-80y) at diagnosis. The majority were grade II (78%) with the tumor grade for 20 cases being reclassified on central review (half to higher grade). Tumor locations were spine (46%), infratentorial (35%), and supratentorial (19%). Tumor recurrence occurred in 26% (n = 74) of patients with a median time to progression of 14 years. A multivariate Cox proportional hazards model identified supratentorial location (P < .01), grade III (anaplastic; P < .01), and subtotal resection, followed or not by radiation (P < .01), as significantly increasing risk of early progression.nnnCONCLUSIONSnWe report findings from an ongoing, multicenter collaboration from a collection of clinically annotated adult ependymoma tumor samples demonstrating distinct predictors of progression-free survival. This unique resource provides the opportunity to better define the clinical course of ependymoma for clinical and translational studies.

Histological predictors of outcome in ependymoma are dependent on anatomic site within the central nervous system.

Ependymomas originate in posterior fossa (PF), supratentorial (ST) or spinal cord (SC) compartments. At present, grading schemes are applied independent of anatomic site. We performed detailed histological examination on 238 World Health Organization grade II and III ependymomas. Among PF ependymomas, the presence of hypercellular areas, necrosis, microvascular proliferation and elevated mitotic rate (all Pu2009<u20090.01) were significantly associated with worse progression‐free survival (PFS), while extensive ependymal canal formation was not (Pu2009=u20090.89). Similar to the PF tumors, microvascular proliferation (Pu2009=u20090.01) and elevated mitotic rate (Pu2009=u20090.03) were significantly associated with worse PFS in the ST tumors. However, in contrast to PF tumors, extensive ependymal canals (Pu2009=u20090.03) were associated with worse clinical outcome in ST ependymomas, but hypercellularity (Pu2009=u20090.57) and necrosis (Pu2009=u20090.47) were not. On multivariate Cox regression, after adjusting for relevant clinical variables, individual histological factors and a composite histological score remained significant among ST and PF ependymoma. In contrast to both PF and ST ependymoma, histological features were not found to be associated with PFS in SC tumors. Taken together, the clinical relevance of specific histological features in ependymoma appears to be related to the anatomic site of origin and suggests that site‐specific grading criteria be considered in future classification systems.

Chemosensitivity of IDH1 mutant gliomas due to an impairment in PARP1-mediated DNA repair

Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+ availability. Targeting the PARP DNA repair pathway extensively sensitized IDH1-mutated glioma cells to TMZ. Our findings demonstrate a novel molecular mechanism that defines chemosensitivity in IDH-mutated gliomas. Targeting PARP-associated DNA repair may represent a novel therapeutic strategy for gliomas. Cancer Res; 77(7); 1709-18. ©2017 AACR.

Biology and management of ependymomas

Ependymomas are rare primary tumors of the central nervous system in children and adults that comprise histologically similar but genetically distinct subgroups. The tumor biology is typically more associated with the site of origin rather than being age-specific. Genetically distinct subgroups have been identified by genomic studies based on locations in classic grade II and III ependymomas. They are supratentorial ependymomas with C11orf95-RELA fusion or YAP1 fusion, infratentorial ependymomas with or without a hypermethylated phenotype (CIMP), and spinal cord ependymomas. Myxopapillary ependymomas and subependymomas have different biology than ependymomas with typical WHO grade II or III histology. Surgery and radiotherapy are the mainstays of treatment, while the role of chemotherapy has not yet been established. An in-depth understanding of tumor biology, developing reliable animal models that accurately reflect tumor molecule features, and high throughput drug screening are essential for developing new therapies. Collaborative efforts between scientists, physicians, and advocacy groups will enhance the translation of laboratory findings into clinical trials. Improvements in disease control underscore the need to incorporate assessment and management of patients symptoms to ensure that treatment advances translate into improvement in quality of life.

Contemporary murine models in preclinical astrocytoma drug development

Despite 6 decades of research, only 3 drugs have been approved for astrocytomas, the most common malignant primary brain tumors. However, clinical drug development is accelerating with the transition from empirical, cytotoxic therapy to precision, targeted medicine. Preclinical animal model studies are critical for prioritizing drug candidates for clinical development and, ultimately, for their regulatory approval. For decades, only murine models with established tumor cell lines were available for such studies. However, these poorly represent the genomic and biological properties of human astrocytomas, and their preclinical use fails to accurately predict efficacy in clinical trials. Newer models developed over the last 2 decades, including patient-derived xenografts, genetically engineered mice, and genetically engineered cells purified from human brains, more faithfully phenocopy the genomics and biology of human astrocytomas. Harnessing the unique benefits of these models will be required to identify drug targets, define combination therapies that circumvent inherent and acquired resistance mechanisms, and develop molecular biomarkers predictive of drug response and resistance. With increasing recognition of the molecular heterogeneity of astrocytomas, employing multiple, contemporary models in preclinical drug studies promises to increase the efficiency of drug development for specific, molecularly defined subsets of tumors.

Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation but resistant to temozolomide

BACKGROUNDnGlioma stem cells (GSCs) from human glioblastomas (GBMs) are resistant to radiation and chemotherapy and may drive recurrence. Treatment efficacy may depend on GSCs, expression of DNA repair enzymes such as methylguanine methyltransferase (MGMT), or transcriptome subtype.nnnMETHODSnTo model genetic alterations in human GBM core signaling pathways, we induced Rb knockout, Kras activation, and Pten deletion mutations in cortical murine astrocytes. Neurosphere culture, differentiation, and orthotopic transplantation assays were used to assess whether these mutations induced de-differentiation into GSCs. Genome-wide chromatin landscape alterations and expression profiles were examined by formaldehyde-assisted isolation of regulatory elements (FAIRE) seq and RNA-seq. Radiation and temozolomide efficacy were examined in vitro and in an allograft model in vivo. Effects of radiation on transcriptome subtype were examined by microarray expression profiling.nnnRESULTSnCultured triple mutant astrocytes gained unlimited self-renewal and multilineage differentiation capacity. These cells harbored significantly altered chromatin landscapes that were associated with downregulation of astrocyte- and upregulation of stem cell-associated genes, particularly the Hoxa locus of embryonic transcription factors. Triple-mutant astrocytes formed serially transplantable glioblastoma allografts that were sensitive to radiation but expressed MGMT and were resistant to temozolomide. Radiation induced a shift in transcriptome subtype of GBM allografts from proneural to mesenchymal.nnnCONCLUSIONnA defined set of core signaling pathway mutations induces de-differentiation of cortical murine astrocytes into GSCs with altered chromatin landscapes and transcriptomes. This non-germline genetically engineered mouse model mimics human proneural GBM on histopathological, molecular, and treatment response levels. It may be useful for dissecting the mechanisms of treatment resistance and developing more effective therapies.

MerTK as a therapeutic target in glioblastoma.

BackgroundnGlioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025.nnnMethodsnWe examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo.nnnResultsnMerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein-positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%-10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples.nnnConclusionsnThese results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.

Pineal Region Glioblastoma, a Case Report and Literature Review

Introduction Pineal region glioblastoma multiforme (GBM) is a rare disease entity with a generally poor prognosis. We present a case of a patient with an unresectable pineal region GBM treated with chemoradiation with favorable outcome. Case background A 65-year-old patient who was presented with visual symptoms was found to have a pineal region tumor on imaging. A stereotactic biopsy showed a World Health Organization Grade IV GBM, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylated, isocitrate dehydrogenase 1 and 2 wild type. The patient was treated with radiotherapy with concurrent temozolomide, followed by adjuvant temozolomide. Disease progression occurred at 58u2009weeks post-biopsy, which prompted the initiation of bevacizumab. The patient was alive and functioning well as of his last follow up, 166u2009weeks from the initial biopsy. Discussion On our review of the literature, 24 cases of pineal region GBM have been reported. The median reported survival for these previously reported cases was 6u2009months (range, 2–24u2009months). This patient has the longest overall survival reported to date for a patient with this diagnosis. This is the first patient in the literature with pineal region GBM who has been reported to have MGMT promoter methylation. Concluding remarks Although pineal region GBM is a rare disease entity with a generally poor prognosis, long-term survival is achievable for select patients. MGMT promoter methylation may potentially have prognostic value. Favorable control of recurrent disease with the use of bevacizumab is possible.

Clinical decision making in the era of immunotherapy for high grade-glioma: report of four cases

BackgroundImmune checkpoint inhibitors (ICPIs) are being investigated in clinical trials for patients with glioblastoma. While these therapies hold great promise, management of the patients receiving such treatment can be complicated due to thexa0challenges in recognizing immune-related adverse events caused by checkpoint inhibitor treatment. Brain imaging changes that are the consequence of an inflammatory response may be misinterpreted as disease progression leading to inappropriate premature cessation of treatment. The aim of this study was to, by way of a series of cases, underscore the challenges in determining the nature of contrast-enhancing masses that develop during the treatment of patients with glioblastoma treated with ICPIs.Case presentationWe reviewed the clinical course and management of 4 patients on ICPIs who developed signs of tumor progression on imaging. These findings were examined in the context of Immunotherapy Response Assessment in Neuro-Oncology (iRANO) guidelines. Although all 4 patients had very similar imaging findings, 2 of the 4 patients were later found to have intense inflammatory changes (pseudoprogression) by pathologic examination.ConclusionsA high index of suspicion for pseudoprogression needs to be maintained when a patient with brain tumor on immunotherapy presents with worsening in an area of a pre-existing tumor or a new lesion in brain. Our findings strongly suggest that pathological diagnosis remains the gold standard for distinguishing tumor progression from pseudoprogression in patients receiving immunotherapy. There is a large unmet need to develop reliable non-invasive imaging diagnostic techniques.Trial registrationClinicalTrials.gov NCT02311920. Registered 8 December 2014.