EAPH-03. FINAL RESULTS OF THE PHASE II, SINGLE ARM TRIAL OF IRINOTECAN AND CISPLATIN IN CHILDREN WITH HIGH-RISK GLIAL TUMORS.
ABSTRACT: AbstractWe conducted an open label, single arm phase II clinical trial with with irinotecan and cisplatin (I/C) for pediatric patients with glial tumors (EudraCT:2009-010742-59).METHODSPatients diagnosed with high-risk (HR) gliomas at diagnosis (HGG, ependymomas, DIPG, or HR-LGG) received sixteen weekly outpatient iv. cycles of Cisplatin(30mg/m2) and Irinotecan(65mg/m2). Malignant gliomas received radiation at progression. Objective response was assessed with MRI plus volumetric analysis. Clinical and neurological changes were assessed.RESULTSSince November/2009 until December/2012, 39 patients (66,7% females), aged 7m-17y (mean=84-months), diagnosed with DIPG(n=7), HGG(n=5), anaplastic-ependymoma(n=6), atypical neurocytoma(n=1), LGG n=20: Pilocytic Astrocytoma(n=7), Pilomyxoid A.(n=1), Astrocytoma NOS(n=5), Grade-II astrocytoma (n=2), Ganglioglioma(n=2), LGG-NF1(n=3) were included. Most frequent events were nausea/vomiting, mostly grade 1–2, only 5/39 grade >2; 17 patients (43,6%) developed grade-1 diarrhea. At the end of follow-up 3/31 patients developed hypoacusia, all grade 1 (9,7%). Five (45.5%) patients with HGG, 1 relapsed HGG(100%), 7 DIPG(100%) and 3 LGG(15.0%) progressed during treatment, ending prematurely the study. Objective response rate (ORR) at the end of therapy (week 21), was by ITT / PP, of 54,4% for HGG, 0% for DIPG, and 85% for HR-LGG After a median follow-up time of 67.5 months, OS/EFS was 0/0% for relapsed HGG and DIPG, 62%/23% for High-grade glial tumors, and 95%/43% for HR-LGG. Radiation was avoided in 19/20 HR-LGG patients.CONCLUSIONThe I/C regimen was acceptably tolerated and shows activity for some children with HR-gliomas, mainly HR-LGG.
Project description:BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) and relapsed high grade glioma (HGG) are incurable diseases with an event free survival of 6-8 months. Anti-Programmed Death 1 (anti-PD1) antibodies have recently emerged as a promising treatment modality in multiple cancer types. Clinical studies evaluating anti PD1 antibodies in the setting of primary brain tumors have not yet been reported. Pidilizumab (CureTech, Yavne, Israel) is an anti- PD1 humanized immunoglubulin G1 monoclonal antibody. This investigator-initiated clinical trial evaluates pidilizumab in malignant gliomas (NCT01952769). METHODS: Patients older than 3 years treated with not more than 2mg/M2 of dexamethasone per day are included. Patients with newly diagnosed DIPG are recruited for biweekly pidilizumab within the first month after completion of radiotherapy. Patients with HGG relapsed after standard treatment are recruited for biweekly pidilizumab as an add-on therapy to bevacizumab within 3 months of recurrence. The study was opened in February 2014. RESULTS: To date, 6 patients have been enrolled: three with newly diagnosed DIPG, two with HGG and one with relapsed DIPG (bevacizumab + pidilizumab). A total of 30 cycles of Pidilizumab (range 2- 14) have been administered. Treatment was well tolerated with transient fatigue as the main side effect. Administration of pidilizumab less than 10 days after bevacizumab resulted in a grade 3 blood pressure elevation in one patient. This did not recur when the interval between agents was increased. One patient withdrew because of parents' decision. One patient with HGG progressed and died within 2.5 months from enrollment. Two patients had a significant tumor shrinkage along with clinical improvement. Scheduled imaging evaluation is pending in the rest. CONCLUSION: The trial is ongoing. This report is confined to schedule and initial enrollment results.
Project description:Our aim was to assess the diagnostic performance of intravoxel incoherent motion (IVIM) MR imaging for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs).Forty-five patients with diffuse glioma (age 50.9 ± 20.4 y; 26 males, 19 females) were assessed with IVIM imaging using 13 b-values (0-1000 s/mm(2)) at 3T. The perfusion fraction (f), true diffusion coefficient (D), and pseudo-diffusion coefficient (D*) were calculated by fitting the bi-exponential model. The apparent diffusion coefficient (ADC) was obtained with 2 b-values (0 and 1000 s/mm(2)). Relative cerebral blood volume was measured by the dynamic susceptibility contrast method. Two observers independently measured D, ADC, D*, and f, and these measurements were compared between the LGG group (n = 16) and the HGG group (n = 29).Both D (1.26 ± 0.37 mm(2)/s in LGG, 0.94 ± 0.19 mm(2)/s in HGG; P < .001) and ADC (1.28 ± 0.35 mm(2)/s in LGG, 1.03 ± 0.19 mm(2)/s in HGG; P < .01) were lower in the HGG group. D was lower than ADC in the LGG (P < .05) and HGG groups (P < .0001). D* was not different between the groups. The f-values were significantly larger in HGG (17.5 ± 6.3%) than in LGG (5.8 ± 3.8%; P < .0001) and correlated with relative cerebral blood volume (r = 0.85; P < .0001). Receiver operating characteristic analyses showed areas under curve of 0.95 with f, 0.78 with D, 0.73 with ADC, and 0.60 with D*.IVIM imaging is useful in differentiating HGGs from LGGs.
Project description:Gliomas, the most common primary brain tumor in humans, include a spectrum of disease. High-grade gliomas (HGG), such as glioblastoma, may arise from low-grade gliomas (LGG) that have a more indolent course. The process of malignant transformation (MT) of LGG to HGG is poorly understood but likely involves the activation of signaling programs that suppress apoptosis. We previously showed that Survivin (BIRC5) plays a role in malignant progression of glioma. Here, we investigated the role of the remaining members of the Inhibitors of Apoptosis (IAP) family on promoting MT in glioma. Utilizing expression data from the cancer genome atlas (TCGA), we identified BIRC3 as a key facilitator of MT from LGG to HGG. TCGA HGGs with high expression of BIRC 3 demonstrated a survival disadvantage and expression levels of BIRC3 were also significantly higher in TCGA HGG compared to TCGA LGG cases. We validated our findings from TCGA by using matched human specimens to show that BIRC expression is increased in HGG compared to their precursor LGG lesions. Using a unique murine model of glioma, we show that overexpression of BIRC3 promotes higher grade glioma and significantly reduces tumor-free survival in mice.
Project description:BACKGROUND: Glioma is a type of tumor that develops in the central nerve system, mainly the brain. Alterations of genomic sequence and sequence segments (such as copy number variations or CNV and copy neutral loss of heterozygosities or cnLOH) are thought to be a major determinant of the tumor grade. METHODS: We mapped genomic variations between low-grade and high-grade gliomas (LGG and HGG) in Chinese population based on Illumina's Beadchip and validated the results using real-time qPCR. RESULTS: AT THE CYTOBAND LEVEL, WE DISCOVERED: (1) unique losses in LGG on 5q, 8p and 11q, and in HGG on 6q, 11p, 13q and 19q; (2) unique gains in the LGG on 1p and in HGG at 5p, 7p, 7q and 20q; and (3) cnLOH in HGG only on 3q, 8q, 10p, 14q, 15q, 17p, 17q, 18q and 21q. Subsequently, we confirmed well-characterized oncogenes among tumor-related loci (such as EGFR and KIT) and detected novel genes that gained chromosome sequences (such as AASS, HYAL4, NDUFA5 and SPAM1) in both LGG and HGG. In addition, we found gains, losses, and cnLOH in several genes, including VN1R2, VN1R4, and ZNF677, in multiple samples. Mapping grade-associated pathways and their related gene ontology (GO) terms, we classified LGG-associated functions as "arachidonic acid metabolism", "DNA binding" and "regulation of DNA-dependent transcription" and the HGG-associated as "neuroactive ligand-receptor interaction", "neuronal cell body" and "defense response to bacterium". CONCLUSION: LGG and HGG appear to have different molecular signatures in genomic variations and our results provide invaluable information for the diagnosis and treatment of gliomas in patients with variable duration or diverse tumor differentiation.
Project description:We investigated the efficacy of the Wee1 inhibitor MK-1775 in combination with radiation for the treatment of pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine gliomas (DIPGs).Gene expression analysis was performed for 38 primary pediatric gliomas (3 grade I, 10 grade II, 11 grade III, 14 grade IV) and 8 normal brain samples using the Agilent 4 × 44 K array. Clonogenic survival assays were carried out in pediatric and adult HGG cell lines (n = 6) to assess radiosensitizing effects of MK-1775. DNA repair capacity was evaluated by measuring protein levels of ?-H2AX, a marker of double strand DNA breaks. In vivo activity of MK-1775 with radiation was assessed in 2 distinct orthotopic engraftment models of pediatric HGG, including 1 derived from a genetically engineered mouse carrying a BRAF(V600E) mutation, and 1 xenograft model in which tumor cells were derived from a patient's DIPG.Wee1 is overexpressed in pediatric HGGs, with increasing expression positively correlated with malignancy (P = .007 for grade III + IV vs I + II) and markedly high expression in DIPG. Combination treatment of MK-1775 and radiation reduced clonogenic survival and increased expression of ?-H2AX to a greater extent than achieved by radiation alone. Finally, combined MK-1775 and radiation conferred greater survival benefit to mice bearing engrafted, orthotopic HGG and DIPG tumors, compared with treatment with radiation alone (BRAF(V600E) model P = .0061 and DIPG brainstem model P = .0163).Our results highlight MK-1775 as a promising new therapeutic agent for use in combination with radiation for the treatment of pediatric HGGs, including DIPG.
Project description:Language deficits following brain tumors should consider the dynamic interactions between different tumor growth kinetics and functional network reorganization. We measured the resting-state functional connectivity of 126 patients with left cerebral gliomas involving language network areas, including 77 patients with low-grade gliomas (LGG) and 49 patients with high-grade gliomas (HGG). Functional network mapping for language was performed by construction of a multivariate machine learning-based prediction model of individual aphasia quotient (AQ), a summary score that indicates overall severity of language impairment. We found that the AQ scores for HGG patients were significantly lower than those of LGG patients. The prediction accuracy of HGG patients (R2 = 0.27, permutation P = 0.007) was much higher than that of LGG patients (R2 = 0.09, permutation P = 0.032). The rsFC regions predictive of LGG's AQ involved the bilateral frontal, temporal, and parietal lobes, subcortical regions, and bilateral cerebro-cerebellar connections, mainly in regions belonging to the canonical language network. The functional network of language processing for HGG patients showed strong dependence on connections of the left cerebro-cerebellar connections, limbic system, and the temporal, occipital, and prefrontal lobes. Together, our findings suggested that individual language processing of glioma patients links large-scale, bilateral, cortico-subcortical, and cerebro-cerebellar functional networks with different network reorganizational mechanisms underlying the different levels of language impairments in LGG and HGG patients.
Project description:To investigate the value of local image variance (LIV) as a new technique for quantification of hypointense microvascular susceptibility-weighted imaging (SWI) structures at 7 Tesla for preoperative glioma characterization.Adult patients with neuroradiologically suspected diffusely infiltrating gliomas were prospectively recruited and 7 Tesla SWI was performed in addition to standard imaging. After tumour segmentation, quantification of intratumoural SWI hypointensities was conducted by the SWI-LIV technique. Following surgery, the histopathological tumour grade and isocitrate dehydrogenase 1 (IDH1)-R132H mutational status was determined and SWI-LIV values were compared between low-grade gliomas (LGG) and high-grade gliomas (HGG), IDH1-R132H negative and positive tumours, as well as gliomas with significant and non-significant contrast-enhancement (CE) on MRI.In 30 patients, 9 LGG and 21 HGG were diagnosed. The calculation of SWI-LIV values was feasible in all tumours. Significantly higher mean SWI-LIV values were found in HGG compared to LGG (92.7 versus 30.8; p?<?0.0001), IDH1-R132H negative compared to IDH1-R132H positive gliomas (109.9 versus 38.3; p?<?0.0001) and tumours with significant CE compared to non-significant CE (120.1 versus 39.0; p?<?0.0001).Our data indicate that 7 Tesla SWI-LIV might improve preoperative characterization of diffusely infiltrating gliomas and thus optimize patient management by quantification of hypointense microvascular structures.• 7 Tesla local image variance helps to quantify hypointense susceptibility-weighted imaging structures. • SWI-LIV is significantly increased in high-grade and IDH1-R132H negative gliomas. • SWI-LIV is a promising technique for improved preoperative glioma characterization. • Preoperative management of diffusely infiltrating gliomas will be optimized.
Project description:Pediatric high-grade gliomas (HGG) are rare aggressive tumors that present a prognostic and therapeutic challenge. Diffuse midline glioma, H3K27M-mutant is a new entity introduced to HGG in the latest WHO classification. In this study we evaluated the presence of H3K27M mutation in 105 tumor samples histologically classified into low-grade gliomas (LGG) (n?=?45), and HGG (n?=?60). Samples were screened for the mutation in histone H3.3 and H3.1 variants to examine its prevalence, prognostic impact, and assess its potential clinical value in limited resource settings. H3K27M mutation was detected in 28 of 105 (26.7%) samples, and its distribution was significantly associated with midline locations (p-value?<?0.0001) and HGG (p-value?=?0.003). Overall and event- free survival (OS and EFS, respectively) of patients with mutant tumors did not differ significantly, neither according to histologic grade (OS p-value?=?0.736, EFS p-value?=?0.75) nor across anatomical sites (OS p-value?=?0.068, EFS p-value?=?0.153). Detection of H3K27M mutation in pediatric gliomas provides more precise risk stratification compared to traditional histopathological techniques. Hence, mutation detection should be pursued in all pediatric gliomas. Meanwhile, focusing on midline LGG can be an alternative in lower-middle-income countries to maximally optimize patients' treatment options.
Project description:The role of cerebellum and cerebro-cerebellar system in neural plasticity induced by cerebral gliomas involving language network has long been ignored. Moreover, whether or not the process of reorganization is different in glioma patients with different growth kinetics remains largely unknown. To address this issue, we utilized preoperative structural and resting-state functional MRI data of 78 patients with left cerebral gliomas involving language network areas, including 46 patients with low-grade glioma (LGG, WHO grade II), 32 with high-grade glioma (HGG, WHO grade III/IV), and 44 healthy controls. Spontaneous brain activity, resting-state functional connectivity and gray matter volume alterations of the cerebellum were examined. We found that both LGG and HGG patients exhibited bidirectional alteration of brain activity in language-related cerebellar areas. Brain activity in areas with increased alteration was significantly correlated with the language and MMSE scores. Structurally, LGG patients exhibited greater gray matter volume in regions with increased brain activity, suggesting a structure-function coupled alteration in cerebellum. Furthermore, we observed that cerebellar regions with decreased brain activity exhibited increased functional connectivity with contralesional cerebro-cerebellar system in LGG patients. Together, our findings provide empirical evidence for a vital role of cerebellum and cerebro-cerebellar circuit in neural plasticity following lesional damage to cerebral language network. Moreover, we highlight the possible different reorganizational mechanisms of brain functional connectivity underlying different levels of behavioral impairments in LGG and HGG patients.
Project description:In this study, we evaluated the dependence of saturation pulse length on APT imaging of diffuse gliomas using a parallel transmission-based technique. Twenty-two patients with diffuse gliomas (9 low-grade gliomas, LGGs, and 13 high-grade gliomas, HGGs) were included in the study. APT imaging was conducted at 3T with a 2-channel parallel transmission scheme using three different saturation pulse lengths (0.5 s, 1.0 s, 2.0 s). The 2D fast spin-echo sequence was used for imaging. Z-spectrum was obtained at 25 frequency offsets from -6 to +6 ppm (step 0.5 ppm). A point-by-point B0 correction was performed with a B0 map. Magnetization transfer ratio (MTRasym) and ?MTRasym (contrast between tumor and normal white matter) at 3.5 ppm were compared among different saturation lengths. A significant increase in MTRasym (3.5 ppm) of HGG was found when the length of saturation pulse became longer (3.09 ± 0.54% at 0.5 s, 3.83 ± 0.67% at 1 s, 4.12 ± 0.97% at 2 s), but MTRasym (3.5 ppm) was not different among the saturation lengths in LGG. ?MTRasym (3.5 ppm) increased with the length of saturation pulse in both LGG (0.48 ± 0.56% at 0.5 s, 1.28 ± 0.56% at 1 s, 1.88 ± 0.56% at 2 s and HGG (1.72 ± 0.54% at 0.5 s, 2.90 ± 0.49% at 1 s, 3.83 ± 0.88% at 2 s). In both LGG and HGG, APT-weighted contrast was enhanced with the use of longer saturation pulses.