scholarly journals DIPG-80. CLINICAL AND RADIOGRAPHIC RESPONSE TO ONC201 IN A PEDIATRIC PATIENT WITH A THALAMIC H3K27M AND BRAFV600E MUTANT DIFFUSE MIDLINE HIGH GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii303-iii303
Author(s):  
Elizabeth Duke ◽  
Jonathan Murnick ◽  
Rohinton Tarapore ◽  
Joshua Allen ◽  
Lindsay Kilburn
Keyword(s):  
High Grade Glioma ◽  
Target Lesion ◽  
Subsequent Treatment ◽  
Thalamic Lesion ◽  
High Grade ◽  
Proton Radiation ◽  
Multiple Tumor ◽  
Tumor Types ◽  
The Impact ◽  
Diffuse Midline Glioma

Abstract Recent improved understanding of the molecular markers of high grade glioma has shifted the approach to these aggressive CNS tumors to increasingly use molecularly guided targeted therapies. Treatment of patients with BRAFV600E mutant high grade gliomas with BRAF inhibitors has shown efficacy, however the impact of concomitant H3K27M mutation is unknown. ONC201 targets dopamine receptor D2 (DRD2), which is shown to be broadly overexpressed in the thalamus as well as multiple tumor types; its antagonism has demonstrated anti-tumor efficacy and immunomodulatory properties in preclinical studies. ONC201 has also demonstrated clinical efficacy in patients with H3K27M mutant gliomas. We present the case of a 9-year-old male with a right thalamic H3.3K27M mutant diffuse midline glioma with a concomitant BRAFV600E mutation with an ongoing partial response to ONC201 treatment. The patient was diagnosed in May 2018. He underwent biopsy, followed by standard focal proton radiation therapy (54Gy) and subsequent treatment with dasatinib, bevacizumab and everolimus over the course of five months. After continued radiographic progression on serial imaging, in April 2019 he started ONC201 375mg orally once per week through an expanded access trial. He has tolerated the medication well with grade 1 nausea and fatigue. Over the next nine months, he demonstrated clinical and radiographic improvement with modest increased use of his left side and MRIs showing progressive decrease in size of the thalamic lesion with a 70 % decrease in the target lesion (measuring 53x62mm prior to treatment, decreased to 38x26mm in January 2020).

scholarly journals Defining tumor-associated vascular heterogeneity in pediatric high-grade and diffuse midline gliomas

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xin Wei ◽  
Michaël H. Meel ◽  
Marjolein Breur ◽  
Marianna Bugiani ◽  
Esther Hulleman ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Neurovascular Unit ◽  
High Grade Glioma ◽  
Model Systems ◽  
High Grade ◽  
Transcriptional Program ◽  
Vascular Phenotype ◽  
Tumor Types ◽  
Tumor Pathogenesis ◽  
Diffuse Midline Glioma

AbstractThe blood–brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using patient derived xenografts and natively forming glioma mouse models. We show tumor-associated vascular differences between these glioma subtypes, and parallels between PDX and mouse model systems, with DMG models maintaining a more normal vascular architecture, BBB function and endothelial transcriptional program relative to pHGG models. Unlike prior work in angiogenic brain tumors, we find that expression of secreted Wnt antagonists do not alter the tumor-associated vascular phenotype in DMG tumor models. Together, these findings highlight vascular heterogeneity between pHGG and DMG and differences in their response to alterations in developmental BBB signals that may participate in driving these pathological differences.

scholarly journals Brain atlas for assessing the impact of tumor location on perioperative quality of life in patients with high-grade glioma: A prospective population-based cohort study

2019 ◽  
Vol 21 ◽  
pp. 101658 ◽  
Author(s):  
Lisa Millgård Sagberg ◽  
Daniel Høyer Iversen ◽  
Even Hovig Fyllingen ◽  
Asgeir Store Jakola ◽  
Ingerid Reinertsen ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Cohort Study ◽  
High Grade Glioma ◽  
Tumor Location ◽  
Population Based ◽  
Brain Atlas ◽  
High Grade ◽  
The Impact

scholarly journals COT-21 EFFECT OF BEVACIZUMAB FOR PEDIATRIC HIGH GRADE GLIOMA

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii44-ii44
Author(s):  
Yoshihiro Tsukamoto ◽  
Manabu Natsumeda ◽  
Masayasu Okada ◽  
Takeyoshi Eda ◽  
Junichi Yoshimura ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Therapeutic Agent ◽  
High Grade Glioma ◽  
Wound Complication ◽  
Symptomatic Improvement ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Rapid Progression ◽  
High Grade ◽  
Diffuse Midline Glioma ◽  
Pediatric High Grade Glioma

Abstract INTRODUCTION Bevacizumab (BEV) therapy has been used for pediatric high grade glioma,however the evidence and effectiveness are not understood yet. METHODS We report 7 cases (age 2 to 10 years old) of pediatric high grade glioma treated with BEV. One case is thalamic diffuse midline glioma H3K27 mutant (DMGH3K27M),one case is brain stem DMGH3K27M,one case is cerebellar high grade glioma,and 4 cases are diffuse intrinsic pontine glioma (DIPG) diagnosed clinically without biopsy. 5 cases were treated with BEV when diagnosed as recurrence after chemo-radiotherapy. One case was treated for rapid tumor progression during radiotherapy. One case was started on BEV therapy with radiation and concomitant temozolomide therapy. RESULT The number of times of BEV was 2 to 13 times (median 7 times). The period of BEV was 1 to 9 months (median 4 months). One case which was treated with BEV at rapid progression during radiation showed good response on imaging and improvement of symptoms. 4 of 5 cases who were treated at recurrence clinically showed mild symptomatic improvement. One case treated with BEV and radiotherapy initially was not evaluated. The adverse effects of BEV included wound complication of tracheostomy and rash. CONCLUSION BEV showed good response for rapid progression during radiotherapy,and mild response for recurrence cases. BEV is thought to be an effective therapeutic agent for pediatric HGG at recurrence and rapid tumor progression during radiotherapy.

scholarly journals Navigated Intraoperative 2-Dimensional Ultrasound in High-Grade Glioma Surgery: Impact on Extent of Resection and Patient Outcome

2019 ◽  
Author(s):  
Alessandro Moiraghi ◽  
Francesco Prada ◽  
Alberto Delaidelli ◽  
Ramona Guatta ◽  
Adrien May ◽  
...  
Keyword(s):  
Real Time ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Intraoperative Ultrasound ◽  
High Grade Glioma ◽  
Extent Of Resection ◽  
High Grade ◽  
Glioma Surgery ◽  
Supratentorial Gliomas ◽  
The Impact

Abstract BACKGROUND Maximizing extent of resection (EOR) and reducing residual tumor volume (RTV) while preserving neurological functions is the main goal in the surgical treatment of gliomas. Navigated intraoperative ultrasound (N-ioUS) combining the advantages of ultrasound and conventional neuronavigation (NN) allows for overcoming the limitations of the latter. OBJECTIVE To evaluate the impact of real-time NN combining ioUS and preoperative magnetic resonance imaging (MRI) on maximizing EOR in glioma surgery compared to standard NN. METHODS We retrospectively reviewed a series of 60 cases operated on for supratentorial gliomas: 31 operated under the guidance of N-ioUS and 29 resected with standard NN. Age, location of the tumor, pre- and postoperative Karnofsky Performance Status (KPS), EOR, RTV, and, if any, postoperative complications were evaluated. RESULTS The rate of gross total resection (GTR) in NN group was 44.8% vs 61.2% in N-ioUS group. The rate of RTV > 1 cm3 for glioblastomas was significantly lower for the N-ioUS group (P < .01). In 13/31 (42%), RTV was detected at the end of surgery with N-ioUS. In 8 of 13 cases, (25.8% of the cohort) surgeons continued with the operation until complete resection. Specificity was greater in N-ioUS (42% vs 31%) and negative predictive value (73% vs 54%). At discharge, the difference between pre- and postoperative KPS was significantly higher for the N-ioUS (P < .01). CONCLUSION The use of an N-ioUS-based real-time has been beneficial for resection in noneloquent high-grade glioma in terms of both EOR and neurological outcome, compared to standard NN. N-ioUS has proven usefulness in detecting RTV > 1 cm3.

ONC201 in previously irradiated pediatric H3 K27M-mutant glioma or newly diagnosed DIPG.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3619-3619
Author(s):  
Sharon L. Gardner ◽  
Carl Johannes Koschmann ◽  
Rohinton Tarapore ◽  
Jeffrey C. Allen ◽  
Wafik Tharwat Zaky ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Single Agent ◽  
High Grade Glioma ◽  
Biologically Active ◽  
High Grade ◽  
Newly Diagnosed ◽  
Preclinical Models ◽  
Open Label ◽  
The Impact

3619 Background: ONC201 is a first-in-class DRD2 antagonist and ClpP agonist that has demonstrated promising activity in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 in recurrent H3 K27M-mutant glioma patients . The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients as well tolerated and biologically active. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This open-label, multi-center trial for pediatric H3 K27M-mutant glioma or non-biopsied DIPG employed a 3+3 dose-escalation and dose-expansion design with 6 arms. Arms A and E, which have completed accrual, determined the RP2D of ONC201 using oral capsule and liquid formulations in post-radiation pediatric H3 K27M-mutant glioma patients ONC201, respectively. Arm B aims to determine the RP2D for ONC201 in combination with radiotherapy in patients with newly diagnosed DIPG. Arms C and D aim to measure intratumoral ONC201 concentrations in midline glioma patients and the impact of ONC201 on H3 K27M DNA levels in CSF, respectively. Arm F was recently opened to study ONC201 as a single agent in patients with progressive H3 K27M-mutant tumors (excluding DIPG and spinal cord tumors) following radiotherapy. After determining the RP2D, a dose-expansion cohort will evaluate the safety, radiographic response, and activity of ONC201. Results: An RP2D of weekly 625mg ONC201 scaled by body weight as a capsule or in liquid formulation was established in the primary endpoints of arms A, B and E alone or in combination with radiation, without incidence of dose-limiting toxicity (DLT). Pharmacokinetic profiles were similar to those observed in adults (T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL), with similar exposure across body weights. Conclusions: ONC201 was well tolerated without DLTs at the same adult RP2D scaled by body weight as monotherapy or in combination with radiotherapy in pediatric H3 K27M-mutant glioma patients. Further investigation of ONC201 to treat H3 K27M-mutant glioma and DIPG is warranted. Clinical trial information: NCT03416530 .

The effect of anti-IGF1 therapy on muscle mass in metastatic pancreatic cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4064-4064
Author(s):  
David R. Fogelman ◽  
Mohamed Aly Khalil ◽  
Manal Hassan ◽  
Naveen Garg ◽  
Milind M. Javle ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mass Loss ◽  
Muscle Mass ◽  
Drop Out ◽  
Metastatic Pancreatic Cancer ◽  
Muscle Area ◽  
Multiple Tumor ◽  
Muscle Mass Loss ◽  
Tumor Types ◽  
The Impact

4064 Background: IGF-1 plays a role in the growth of multiple tumor types, including pancreatic cancer. IGF-1 also serves as a growth factor for muscle. The impact of therapeutic targeting of IGF-1 on muscle mass is unknown. Methods: We evaluated muscle mass at L3 in patients enrolled in a randomized phase II study of MK-0646 (M), a monoclonal antibody directed against the IGF-1 protein, in patients with metastatic pancreatic cancer (MPC). We used the Slice-o-matic (ver 4.3) software to segregate CT images into muscle and fat components and measured muscle area (cm2) at baseline and after 2 and 4 months of treatment. Patients received either gemcitabine with erlotinib (G+E), G+E+M, or G+M. Differences between the groups were compared using t-tests. Results: 58 patients had both baseline and 2 month imaging available for analysis. Of these, 44 received M and 14 had G+E only. Baseline muscle mass between the two groups was similar: 146 cm2 and 142 cm2, respectively (P=0.47). After two months of treatment, both groups demonstrated decrease in muscle mass: 134 cm2 (8% loss) vs. 130 cm2 (6% loss) (P= 0.19). Of the 37 patients who had either PR or SD at 2 months, there was a non-significant increase in muscle mass loss among the patients receiving M (7.8% vs. 4.5%, p=.31). At 4 months, those remaining patients in the M group lost 6% (n=14) of muscle mass compared to 3% in the non-M group (n=5) (P=0.54). Each 1% loss of muscle mass increased the odds of dropout by 13% (p=.03, CI 1.0-27%) and predicted for poor survival (p=HR 1.08, p=.02). Conclusions: MPC patients can be expected to lose muscle mass even while having clinical benefit (PR or SD) from chemotherapy. Muscle loss correlated with a risk of study drop-out and death. There was a non-significant trend towards greater muscle mass loss in patients on anti-IGF-1R therapy. However, it is unclear if this loss translates into functional differences between patients. Clinical trial information: NCT00769483.

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