scholarly journals MR imaging features of diffuse intrinsic pontine glioma and relationship to overall survival: report from the International DIPG Registry

2020 ◽  
Vol 22 (11) ◽  
pp. 1647-1657 ◽  
Author(s):  
James L Leach ◽  
James Roebker ◽  
Austin Schafer ◽  
Joshua Baugh ◽  
Brooklyn Chaney ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariable Analysis ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Imaging Features ◽  
Pontine Glioma ◽  
Distant Disease ◽  
Mutation Status ◽  
Mri Features ◽  
Multivariable Analyses ◽  
Prospective Trials

Abtract Background This study describes imaging features of diffuse intrinsic pontine glioma (DIPG) and correlates with overall survival (OS) and histone mutation status in the International DIPG Registry (IDIPGR). Methods Four hundred cases submitted to the IDIPGR with a local diagnosis of DIPG and baseline MRI were evaluated by consensus review of 2 neuroradiologists; 43 cases were excluded (inadequate imaging or alternative diagnoses). Agreement between reviewers, association with histone status, and univariable and multivariable analyses relative to OS were assessed. Results On univariable analysis imaging features significantly associated with worse OS included: extrapontine extension, larger size, enhancement, necrosis, diffusion restriction, and distant disease. On central review, 9.5% of patients were considered not to have DIPG. There was moderate mean agreement of MRI features between reviewers. On multivariable analysis, chemotherapy, age, and distant disease were predictors of OS. There was no difference in OS between wild-type and H3 mutated cases. The only imaging feature associated with histone status was the presence of ill-defined signal infiltrating pontine fibers. Conclusions Baseline imaging features are assessed in the IDIPGR. There was a 9.5% discordance in DIPG diagnosis between local and central review, demonstrating need for central imaging confirmation for prospective trials. Although several imaging features were significantly associated with OS (univariable), only age and distant disease were significant on multivariable analyses. There was limited association of imaging features with histone mutation status, although numbers are small and evaluation exploratory.

scholarly journals Prediction of BRAF mutation status of craniopharyngioma using magnetic resonance imaging features

2018 ◽  
Vol 129 (1) ◽  
pp. 27-34 ◽  
Author(s):  
Qi Yue ◽  
Yang Yu ◽  
Zhifeng Shi ◽  
Yongfei Wang ◽  
Wei Zhu ◽  
...  
Keyword(s):  
Roc Curve ◽  
Clinical Characteristics ◽  
Tumor Resection ◽  
High Sensitivity ◽  
Pituitary Stalk ◽  
Preoperative Treatment ◽  
Imaging Features ◽  
Diagnostic Features ◽  
Mutation Status ◽  
Mri Features

OBJECTIVETreatment with a BRAF mutation inhibitor might shrink otherwise refractory craniopharyngiomas and is a promising preoperative treatment to facilitate tumor resection. The aim of this study was to investigate the noninvasive diagnosis of BRAF-mutated craniopharyngiomas based on MRI characteristics.METHODSFifty-two patients with pathologically diagnosed craniopharyngioma were included in this study. Polymerase chain reaction was performed on tumor tissue specimens to detect BRAF and CTNNB1 mutations. MRI manifestations—including tumor location, size, shape, and composition; signal intensity of cysts; enhancement pattern; pituitary stalk morphology; and encasement of the internal carotid artery—were analyzed by 2 neuroradiologists blinded to patient identity and clinical characteristics, including BRAF mutation status. Results were compared between the BRAF-mutated and wild-type (WT) groups. Characteristics that were significantly more prevalent (p < 0.05) in the BRAF-mutated craniopharyngiomas were defined as diagnostic features. The minimum number of diagnostic features needed to make a diagnosis was determined by analyzing the receiver operating characteristic (ROC) curve.RESULTSEight of the 52 patients had BRAF-mutated craniopharyngiomas, and the remaining 44 had BRAF WT tumors. The clinical characteristics did not differ significantly between the 2 groups. Interobserver agreement for MRI data analysis was relatively reliable, with values of Cohen κ ranging from 0.65 to 0.97 (p < 0.001). A comparison of findings in the 2 patient groups showed that BRAF-mutated craniopharyngiomas tended to be suprasellar (p < 0.001), spherical (p = 0.005), predominantly solid (p = 0.003), and homogeneously enhancing (p < 0.001), and that patients with these tumors tended to have a thickened pituitary stalk (p = 0.014). When at least 3 of these 5 features were present, a tumor might be identified as BRAF mutated with a sensitivity of 1.00 and a specificity of 0.91. The area under the ROC curve for the sum of all 5 diagnostic criteria was 0.989 (p < 0.001).CONCLUSIONSThe BRAF mutation status of craniopharyngiomas might be predicted using certain MRI features with relatively high sensitivity and specificity, thus offering potential guidance for the preoperative administration of BRAF mutation inhibitors.

scholarly journals Progress in diffuse intrinsic pontine glioma: advocating for stereotactic biopsy in the standard of care

2020 ◽  
Vol 48 (1) ◽  
pp. E4 ◽  
Author(s):  
John R. Williams ◽  
Christopher C. Young ◽  
Nicholas A. Vitanza ◽  
Margaret McGrath ◽  
Abdullah H. Feroze ◽  
...  
Keyword(s):  
Stereotactic Biopsy ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Brainstem Tumor ◽  
T Cell Therapy ◽  
The Us ◽  
Brainstem Tumors ◽  
Prospective Trials ◽  
Brainstem Biopsy

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brainstem tumor affecting approximately 300 children in the US annually. Median survival is less than 1 year, and radiation therapy has been the mainstay of treatment for decades. Recent advances in the biological understanding of the disease have identified the H3K27M mutation in nearly 80% of DIPGs, leading to the 2016 WHO classification of diffuse midline glioma H3K27M-mutant, a grade IV brainstem tumor. Developments in epigenetic targeting of transcriptional tendencies have yielded potential molecular targets for clinical trials. Chimeric antigen receptor T cell therapy has also shown preclinical promise. Recent clinical studies, including prospective trials, have demonstrated the safety and feasibility of pediatric brainstem biopsy in the setting of DIPG and other brainstem tumors. Given developments in the ability to analyze DIPG tumor tissue to deepen biological understanding of this disease and develop new therapies for treatment, together with the increased safety of stereotactic brainstem biopsy, the authors present a case for offering biopsy to all children with suspected DIPG. They also present their standard operative techniques for image-guided, frameless stereotactic biopsy.

scholarly journals Clinicopathologic Characteristics and Outcome Descriptors of Metaplastic Breast Carcinoma

2021 ◽  
Author(s):  
Evi Abada ◽  
Fayez Daaboul ◽  
Kingsley Ebare ◽  
Hyejeong Jang ◽  
Ziad Fehmi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Breast Carcinoma ◽  
Metastatic Disease ◽  
Tumor Size ◽  
Multivariable Analysis ◽  
Breast Cancers ◽  
Clinicopathologic Characteristics ◽  
Distant Metastatic Disease ◽  
Multivariable Analyses ◽  
Metaplastic Breast Carcinoma

Context.— Metaplastic breast carcinoma is an aggressive form of breast cancer that accounts for 0.5% to 3% of all breast cancers. Objective.— To study the clinicopathologic characteristics and outcomes of this rare disease. Design.— Retrospective study of patients with a diagnosis of metaplastic breast carcinoma between 2000 and 2019. Hematoxylin-eosin–stained slides were reviewed and additional clinical data were obtained from electronic medical records. Univariable and multivariable Cox proportional hazard regression analyses were used to determine associations between overall survival and several clinicopathologic variables. Results.— Of the 125 patients with metaplastic breast carcinoma identified, only patients with high-grade disease (N = 115) were included in the data analysis. A total of 38 participants (33%) were white, 66 (57%) were African American, and 11 (10%) belonged to other ethnicities. The median age at diagnosis was 57 years. The median tumor size was 3 cm. Heterologous histology was seen in 30% of cases. Multivariable analyses showed that patients with a larger tumor size had worse overall survival (hazard ratio [HR], 1.25; 95% CI, 1.10–1.44; P &lt; .001). Distant metastatic disease was also associated with worse overall survival on multivariable analysis (HR, 10.27; 95% CI, 2.03–55.54; P = .005). In addition to treatment with either partial or complete mastectomies, 84 patients (73%) received chemotherapy. Multivariable analyses showed that chemotherapy had no effect on overall survival (HR, 0.53; 95% CI, 0.09–6.05; P = .55). Conclusions.— A larger tumor size and distant metastatic disease are associated with worse overall survival in patients with metaplastic breast carcinoma. Additional studies are needed to further characterize our findings.

scholarly journals In diffuse intrinsic pontine gliomas, non-coding RNA expression is significantly varied dependent on overall survival

2021 ◽  
Author(s):  
Rucha ◽  
Vijay S
Keyword(s):  
Overall Survival ◽  
Brain Cancer ◽  
Transcriptional Activity ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Rna Expression ◽  
Pontine Glioma ◽  
Non Coding Rna ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
New Treatments ◽  
Pediatric Brain

Abstract Diffuse intrinsic pontine glioma is a kind of pediatric brain cancer that kills 99 percent of patients within five years and for which there are no conventional chemotherapies. It is crucial for new treatments to comprehend the cancer's transcriptional activity. Using a published dataset, we compared the transcriptomes of tumors from patients who lived longer or less than six months. Among the genes whose expression changed most, we observed that numerous microRNAs and snoRNAs were present. The publication's findings are the first evidence of variable levels of non-coding RNA expression in diffuse intrinsic pontine glioma.

Phase 1 dose-escalation trial using convection-enhanced delivery of radiolabeled monoclonal antibody for diffuse intrinsic pontine glioma following external radiation therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2010-2010
Author(s):  
Mark M. Souweidane ◽  
Kim Kramer ◽  
Neeta Pandit-Taskar ◽  
Sofia Haque ◽  
Pat Zanzonico ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Overall Survival ◽  
Phase 1 ◽  
Diffuse Intrinsic Pontine Glioma ◽  
External Radiation ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
External Radiation Therapy ◽  
Grade 3 ◽  
Dose Levels

2010 Background: The prognosis of diffuse intrinsic pontine glioma (DIPG) is dire with a median overall survival less than one-year. 124I-omburtamab is a radiolabeled monoclonal antibody that targets B7-H3 epitope. We evaluated the safety of administering escalating doses and volumes of 124I-omburtamab via convection-enhanced delivery (CED) in children with DIPG. Methods: MSKCC 11-011 trial is a standard 3+3 phase 1, open-label, dose escalation study in patients with non-progressive DIPG. CED of 124I-omburtamab was performed between 4-14 weeks post-external radiation therapy. Nine dose levels of a single injection of 124I-omburtamab (Y-mAbs Therapeutics, USA) (range 0.25 to 8.0 mCi; and volume of infusion (Vi) from 250 to 8,000 µl) have been evaluated so far. Patients were assessed weekly for 30 days. Results: 46 children were evaluable for primary and secondary endpoints. The median age at enrolment was 6.5 years (range 2-17). Two patients have experienced AEs CTCAE grade 3 that were categorized as dose limiting toxicities (DLTs), which led to inclusion of three more patients at both the 4 and 6 mCi dose levels. Eight patients have reported transient AEs of grade 3 considered related to 124I-omburtamab. The acute grade 3 AEs were generally indicative of nervous system effects due to volume intolerance or radiation injury, and included hemiparesis (n = 3), dysarthria (n = 3), ataxia (n = 3), dysphagia (n = 2), muscular weakness (n = 2) and gait disturbance (n = 1). There were no related AEs CTCAE grade 4 or 5. Estimations of distribution volumes based on T2-weighted imaging were linearly related to volume with a mean volume of distribution/volume of infusion ratio (Vd/Vi) between 3 and 3.5. The mean ratio of lesion-to-whole body absorbed dose was ̃1000. Median overall survival from diagnosis across all cohorts was 14.8 months (n = 46, 95% CI 11.5, 16.8) and the survival rate estimates (with 95% confidence intervals) at 1, 2, 3 and 5 years were 0.63 (0.46;0.76); 0.13 (0.05;0.26); 0.08 (0.02;0.19); and 0.04 (0.00;0.16), respectively. Four patients have survived > 3 years; two remain alive at 46 and 96 months and two have died at 43 and 53 months, both with CNS disease outside of the treatment field and one with extra-CNS metastases. Conclusions: 124I-omburtamab via CED into the brain stem of children with DIPG and previously irradiated provides a possibility for improved treatment of DIPG. A dose of 8mCi and an infusion volume of 8,000 µl is considered safe and may provide a distribution volume large enough to cover tumor volumes up to 20 cm3. The median overall survival of all patients included in the trial appears to be increased with 3-4 months compared to historical control data from consortia trials. A phase 2 trial aiming at investigating the efficacy of radiolabeled omburtamab administered via CED is being planned. Clinical trial information: NCT01502917.

scholarly journals HG-56HISTONE K27M MUTATION IN A SERIES OF CENTRALLY REVIEWED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): CONSISTENCY WITH MRI FEATURES

2016 ◽  
Vol 18 (suppl 3) ◽  
pp. iii60.3-iii60
Author(s):  
Manila Antonelli ◽  
Piergiorgio Modena ◽  
Veronica Biassoni ◽  
Elisabetta Schiavello ◽  
Lorenza Gandola ◽  
...  
Keyword(s):  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
K27m Mutation ◽  
Mri Features

scholarly journals EXTH-40. THERAPEUTICALLY TARGETING DE NOVO PURINE BIOSYNTHESIS IN DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii95-ii96
Author(s):  
Ian Mersich ◽  
Biplab Dasgupta
Keyword(s):  
Overall Survival ◽  
Cell Lines ◽  
De Novo ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Purine Metabolism ◽  
Purine Biosynthesis ◽  
Therapeutic Window ◽  
Pontine Glioma ◽  
Genetic Ablation ◽  
De Novo Purine Biosynthesis

Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem malignancy in children with median survival less than 1 year and 5-year overall survival only 2 percent. Little progress has been made in treating this deadly disease due to its inoperable location and treatments aimed at targets defined in adult gliomas. Despite recent advances in genetic characterization of DIPGs there are still no targeted therapies that significantly improve overall survival. We recently generated a metabolic profile for DIPG elucidating an upregulation in purine metabolism, specifically in de novo purine biosynthesis (DNPB). Normally nucleotide salvage maintains cellular purine levels by recycling degraded bases, however DNPB is needed when purine levels are depleted. Purine metabolism provides the basic components of nucleotides needed for tumor proliferation and thus considered a high-priority target in cancer treatment. DNPB is a sequential ten step enzymatic process resulting in the production of inosine monophosphate. The last step in DNPB is carried out by the bifunctional enzyme ATIC which is upregulated in DIPG cell lines, and in patient tumors. Our preliminary data demonstrates DIPG cell lines are sensitive to pharmacological inhibition and genetic ablation of multiple enzymes in the DNPB pathway. Strikingly, cell viability could be rescued by purine supplementation when inhibiting this pathway except when ATIC is inhibited indicating the mechanism of cell death for ATIC inhibition is independent of purine nucleotide levels. Furthermore, there is a therapeutic window for targeting ATIC in DIPG cell lines relative to normal neural stem cells and normal human astrocytes. Metabolic flux experiments have demonstrated DNPB is upregulated in DIPG cell lines and the reason these cells are more sensitive to ATIC inhibition is likely related to the rapid accumulation of a cytotoxic metabolite upstream of ATIC. In vivo studies are currently underway in pre-clinical mouse models for DIPG.

Retrospective analysis on the consistency of MRI features with histological and molecular markers in diffuse intrinsic pontine glioma (DIPG)

2019 ◽  
Vol 36 (4) ◽  
pp. 697-704
Author(s):  
Marzia Giagnacovo ◽  
Manila Antonelli ◽  
Veronica Biassoni ◽  
Elisabetta Schiavello ◽  
Monika Warmuth-Metz ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Retrospective Analysis ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Mri Features

scholarly journals EPCT-23 PRE-CLINICAL STUDY OF FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING AND PANOBINOSTAT FOR DIFFUSE INTRINSIC PONTINE GLIOMA TREATMENT

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i52-i52
Author(s):  
Hong-Jian Wei ◽  
Antonios Pouliopoulos ◽  
Nina Yoh ◽  
Masih Tazhibi ◽  
Nicholas McQuillan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mr Imaging ◽  
Blood Brain Barrier ◽  
Treatment Efficacy ◽  
Focused Ultrasound ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Brain Barrier ◽  
Pontine Glioma ◽  
Blood Brain

Abstract Diffuse intrinsic pontine glioma (DIPG) is the lethal high-grade brain tumor in children with no effective treatment options to date. Despite excessive clinical trials, the prognosis remains poor, with a median overall survival (mOS) of less than 1 year. Genomic studies of DIPG tissue have identified highly recurrent mutations in genes encoding histone H3 resulting in the substitution of lysine to methionine at position 27 (K27M), which is found in approximately 80% of DIPG. Recent drug screening studies identified the histone deacetylase (HDAC) inhibitors panobinostat as a highly effective drug against DIPG in vitro. However, due to the poor Blood-Brain Barrier (BBB) penetration of systemic administration, to enhance the delivery of panobinostat to improve treatment efficacy is needed. Focused ultrasound (FUS) has been shown to be able to safely and non-invasively open BBB to enhance drug delivery. Hence, in this study, we hypothesize that FUS-mediated BBBO (BBBO) can enhance the delivery of panobinostat for a therapeutic benefit in DIPG. Herein we established the syngeneic DIPG model by intracranially injecting mouse DIPG cells (PDGFB+, H3.3K27M, p53−/−) and used FUS and microbubbles to open BBB and enhance the panobinostat delivery. Magnetic resonance (MR) imaging was utilized to evaluate BBBO and tumor progression. We first demonstrated that FUS-mediated BBB-opening is safe and feasible to mice with DIPG tumors by MR imaging and passive cavitation detection. Moreover, this DIPG cell line is very sensitive to panobinostat in in vitro cytotoxicity assay. The combined treatment of FUS-mediated BBBO and panobinostat showed benefits in both local control and overall survival. The current results demonstrated FUS could increase the treatment efficacy of panobinostat to DIPG animals may be due to the increase of targeted delivery of systemic panobinostat to DIPG tumors in brainstem.

scholarly journals PDTM-39. CRACKING THE HISTONE CODE: REVEALING THERAPEUTIC EPIGENETIC TARGETS THROUGH HISTONE H3 TAIL ANALYSIS OF DIFFUSE INTRINSIC PONTINE GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi196-vi196
Author(s):  
Daphne Li ◽  
Tina Huang ◽  
Jeannie Camarillo ◽  
Jin Qi ◽  
Hannah Weiss ◽  
...  
Keyword(s):  
Cell Lines ◽  
Histone H3 ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Tumor Formation ◽  
Wild Type ◽  
Pontine Glioma ◽  
Pediatric Glioma ◽  
Mutation Status ◽  
Histone Codes ◽  
The Impact

Abstract INTRODUCTION Diffuse intrinsic pontine glioma (DIPG) is a highly morbid pediatric cancer. Up to 80% harbor a Histone H3K27M mutation, which alters wild type Histone H3 protein post-translational modifications (PTMs) and genomic enrichment patterns to impact chromatin structure and transcription regulation. We previously identified tumorigenic patterns of H3K27Ac/bromodomain co-enrichment in DIPG, and demonstrated pre-clinical efficacy of bromodomain inhibition (JQ1). Here, we employ a novel proteomics platform, developed at our institution, to further elucidate the impact of H3K7M mutation on glioma histone codes and response to bromodomain inhibition. METHODS Epiproteomic analysis was performed on pediatric glioma cell lines (H3K27 WT n=2, H3K27M n=2) to characterize 95 distinct Histone H3.3 and H3.1 N-terminal tail modification states. Cells were treated with JQ1 or DMSO, and collected at 0h, 24h, 48h. Histones were extracted from isolated nuclei, immunopurified, and analyzed by LC-MS/MS. Results were integrated with RNA-Seq and ChIP Seq results (H3K27M, H3K27Ac, H3K27me3, H3K4me1, H3K4me3) from the same DIPG cell lines. Pediatric glioma tissues (H3K27M WT n=3, H3K27M n= 9) were similarly analyzed to validate cell line results. RESULTS Cell PTM profiles cluster by H3 mutation status on unsupervised analysis. Relative H3 PTM abundance were compared across cell lines by tumor location, H3 mutation status, and in response to treatment. Significant differential genomic enrichment H3K27M and H3.3 WT proteins, H3K27Me3 and H3K27Ac were observed between mutant and wild type cell lines with epigenetic-targeted therapy, correlating with cell transcriptomes. CONCLUSIONS Histone H3 tail epiproteomic analysis reveals DIPG histone codes in situ, revealing the effects of bromodomain inhibition on the tumor epigenetic landscape and providing new insight to the mechanism of tumor formation and therapy response. Further investigation of the utility of these signatures as biomarkers for diagnosis and longitudinal monitoring of treatment response are therefore currently underway.

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