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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.

BACKGROUND BMI-1 is highly expressed in DIPG. Downregulation leads to inhibition of cell proliferation, cell cycle signaling, self-renewal, telomerase expression, activity, and suppression of DIPG cell migration. Targeted inhibition of BMI-1 sensitizes DIPG cells to radiation and drug-induced DNA damage. PTC596 (formulated by PTC Therapeutics, Inc.) is a novel, orally available drug that inhibits microtubule polymerization, resulting in G2/M cell cycle arrest and post-translational modification of BMI-1 protein and reduced BMI-1 protein levels. OBJECTIVES: To estimate the maximum tolerated dose and describe dose limiting toxicities, pharmacokinetics and pharmacodynamics of PTC596 in children 3–21 years of age with newly diagnosed diffuse intrinsic pontine glioma and high-grade gliomas. METHODS PTC596 is administered twice per week orally during radiotherapy and as maintenance for up to two years. The starting dose of PTC596 was 200 mg/m2, with a subsequent dose level of 260mg/m2/dose. Pharmacokinetics are performed in Cycles 1 and 2. RESULTS This study is currently ongoing. Nine patients (7 with DIPG, 2 with HGG), 8 evaluable, have been enrolled. At dose level 1, 200 mg/m2, three evaluable patients were enrolled and experienced no DLTs. At dose level 2, among 5 evaluable patients, 2 experienced dose-limiting grade 4 neutropenia. PTC596 has been otherwise well tolerated. Five patients remain in Cycles 2–11. CONCLUSION This phase I trial is ongoing. PTC596 is tolerable at dose level 1. We are amending the protocol to introduce tablets that can be dissolved in liquid to allow enrollment of younger patients and those unable to swallow whole tablets.

Established in April 2012, the mission of the IDIPGR is to provide secure integrated data sets including clinical, pathologic, radiologic and molecular genomics to the research community to promote hypothesis driven research. Over 600 data points per patient are securely stored on a CCHMC constructed web resource and domain using the open-source data mart development framework Harvest (PMID:24303304) (‘Links’). Genomic data is stored in the cloud-enabled VIVA platform and accessed through cross-platform integration and standardization algorithms for comparison across datasets. Features include source identification, data wrangling, and standardization of molecular and phenotypic data (2017), a web-enabled data mart that provides phenotype-genotype query/exploration, along with raw and processed data file downloads to authorized investigators (Harvest, 2017), additional tools for filtering and analysis of genomic datasets at the level of a phenotype, sample, gene, and variant (VIVA, 2017–2018), and uploaded digitized slides (Aperio, 2019). The IDIPGR Repository stores abstracted datasets for >1020 patients with DIPG/DMG, of whom 366 have tumor tissue available through biopsy and/or autopsy, and centrally reviewed and digitized specimens from 124 patients. The Repository contains >5000 radiology studies from >700 patients, with >550 patients centrally reviewed, and genomics data from 80 patients. Currently 27 IDIPGR approved projects utilize these datasets. The DIPG/DMG Registry constructed a robust database platform and integration system that provides the infrastructure to promote highly collaborative, international, hypothesis-driven research. Broadening collaboration among investigators for hypothesis-driven research studies will lead to better classification and more effective treatment of patients with DIPG and DMG.

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

Diffuse intrinsic pontine glioma (DIPG) is aggressive brainstem tumor with median survival of < 1 year. We queried data from the International DIPG Registry to define clinical, radiological, histological, and molecular characteristics of DIPG patients who survived < 3 months from diagnosis. Among 909 patients enrolled on the registry, 59 (6.5%) had overall survival (OS) of < 3 months. Median age at diagnosis was 5.8 years (range 0–13 years), and 12 (20%) were age < 3 years at diagnosis. Most presented with short duration of symptoms (< 6 weeks, 50/58; 86%) and at least one cranial nerve palsy, cerebellar sign, and/or pyramidal tract sign (52/54; 96%). Twenty-two (41%) presented with hydrocephalus, including 10 who required CSF diversion. All had extra-pontine extension on diagnostic imaging. Less than half of patients (25/56, 45%) received therapy; of these, 11 received radiation (RT) only, 12 received RT and chemotherapy, and 2 received chemotherapy only. Most received steroids (48/52; 92%), including 27 who received palliative steroids at the end of life. Biopsy and autopsy were performed in 11/57 (19%) and 13/58 (22%) cases, respectively. Of 22 for whom histology was known, 19 represented high-grade glioma subtypes, 2 low-grade gliomas, and 1 embryonal tumor. Six were molecularly characterized, and 3 harbored H3K27M mutations. Ongoing work will aim to further characterize the molecular features of these tumors with exceptional poor outcomes despite therapy.

We aimed to perform external validation of the recently developed survival prediction model for diffuse intrinsic pontine glioma (DIPG), and discuss its utility. The DIPG survival prediction model was developed in a cohort of patients from the Netherlands, United Kingdom and Germany, registered in the SIOPE DIPG Registry, and includes age

Diffuse intrinsic pontine glioma (DIPG), a rare, often fatal childhood brain tumor, remains a major therapeutic challenge. In 2012, investigators, funded by the DIPG Collaborative (a philanthropic partnership among 29 private foundations), launched the International DIPG Registry (IDIPGR) to advance understanding of DIPG. Comprised of comprehensive deidentified but linked clinical, imaging, histopathological, and genomic repositories, the IDIPGR uses standardized case report forms for uniform data collection; serial imaging and histopathology are centrally reviewed by IDIPGR neuro-radiologists and neuro-pathologists, respectively. Tissue and genomic data, and cell cultures derived from autopsies coordinated by the IDIPGR are available to investigators for studies approved by the Scientific Advisory Committee. From April 2012 to December 2016, 670 patients diagnosed with DIPG have been enrolled from 55 participating institutions in the US, Canada, Australia and New Zealand. The radiology repository contains 3558 studies from 448 patients. The pathology repository contains tissue on 81 patients with another 98 samples available for submission. Fresh DIPG tissue from seven autopsies has been sent to investigators to develop primary cell cultures. The bioinformatics repository contains next-generation sequencing data on 66 tumors. Nine projects using data/tissue from the IDIPGR by 13 principle investigators from around the world are now underway. The IDIPGR, a successful alliance among philanthropic agencies and investigators, has developed and maintained a highly collaborative, hypothesis-driven research infrastructure for interdisciplinary and translational projects in DIPG to improve diagnosis, response assessment, treatment and outcome for patients.

INTRODUCTION: Patients ≥10 years of age with a DIPG are reported to have a higher rate of long-term survival (≥24 months). The purpose of this study was to compare clinical, radiological, pathological and molecular characteristics between patients ≥10 years old with DIPG who were long-term survivors (LTS) vs short-term survivors (STS) and assess biological differences in this age group compared to patients

BACKGROUND: Children

Although bevacizumab has not proven effective in adults with newly diagnosed high-grade gliomas (HGG), feasibility in newly diagnosed children with diffuse intrinsic pontine gliomas (DIPG) or HGG has not been reported in a prospective study. In a safety and feasibility study, children and young adults with newly diagnosed HGG received radiotherapy (RT) with bevacizumab (10 mg/kg: days 22, 36) and temozolomide (75-90 mg/m(2)/day for 42 days) followed by bevacizumab (10 mg/kg, days 1, 15), irinotecan (125 mg/m(2), days 1, 15) and temozolomide (150 mg/m(2)/day days 1-5). DIPG patients did not receive temozolomide. Telomerase activity, quality of life (QOL), and functional outcomes were assessed. Among 27 eligible patients (15 DIPG, 12 HGG), median age 10 years (range 3-29 years), 6 discontinued therapy for toxicity: 2 during RT (grade 4 thrombocytopenia, grade 3 hepatotoxicity) and 4 during maintenance therapy (grade 3: thrombosis, hypertension, skin ulceration, and wound dehiscence). Commonest ≥grade 3 toxicities included lymphopenia, neutropenia and leukopenia. Grade 3 hypertension occurred in 2 patients. No intracranial hemorrhages occurred. For DIPG patients, median overall survival (OS) was 10.4 months. For HGG patients, 3-year progression free survival and OS were 33 % (SE ± 14 %) and 50 % (SE ± 14 %), respectively. All 3 tested tumor samples, demonstrated histone H3.3K27M (n = 2 DIPG) or G34R (n = 1 HGG) mutations. QOL scores improved over the course of therapy. A bevacizumab-based regimen is feasible and tolerable in newly diagnosed children and young adults with HGG and DIPG.

Children with diffuse intrinsic brainstem glioma (DIPG) have a median survival of less than 1 year despite radiation ± chemotherapy. The International DIPG Registry, a collaborative effort among researchers in North America and Australia has enrolled 395 patients with data for over 900 patients committed from 35 institutions. Among the 395 patients, 32 long-term survivors (LTS) (overall survival [OS] ≥2 years) have been identified. Preliminarily, we report clinical, radiographic, and histologic data for 75 of 395 patients, including the 32 LTS and 43 in the comparison (C) group. On central radiographic review, 5 were deemed not to represent DIPG (3 LTS and 2 C). Median age at diagnosis for LTS and C groups was 5.5 and 6.1 years, respectively. Fifty-seven percent of LTS had >6 weeks between onset of symptoms and diagnosis versus 28% for the comparison group (p < 0.05). Incidence of signs and symptoms at diagnosis (cranial nerve, cerebellar, or pyramidal) was similar in both groups. All patients, except 3 LTS, underwent radiation at diagnosis; all but 6 received adjunct chemotherapy. Median OS was 28.4 and 10.8 months for the LTS and C groups, respectively. Two patients (1 LTS) had an H3.3K27M mutation and 2 (1 LTS) had an H3.1K27M mutation. Biology data from 25 other patients from autopsy (n = 12) or biopsy (n = 13) are under analysis. Presence of enhancement on diagnostic imaging was associated with poorer survival (p = 0.02). There was no significant difference in radiographic evidence of hemorrhage, necrosis, diffusion restriction, or tumor size between LTS and C groups. Preliminary data in children with DIPG suggest that LTS have a longer duration of presenting signs and symptoms and less often display radiographic evidence of enhancement at diagnosis. Complete clinical, radiographic, and biology (where available) data on all 395 patients enrolled are currently being analyzed and will be presented.

Focal adhesions have been intensely studied ever since their discovery in 1971. The last three decades have seen major advances in understanding the structure of focal adhesions and the functions they serve in cellular adhesion, migration, and other biological processes. In this chapter, we begin with a historical perspective of focal adhesions, provide an overview of focal adhesion biology, and highlight recent major advances in the field. Specifically, we review the different types of matrix adhesions and the role different Rho GTPases play in their formation. We discuss the relative contributions of integrin and syndecan adhesion receptors to the formation of focal adhesions. We also focus on new insights gained from studying focal adhesions on biomaterial surfaces and from the growing field of mechanotransduction. Throughout this chapter, we have highlighted areas of focal adhesion biology where major questions still remain to be answered.

Focal adhesions have been intensely studied ever since their discovery in 1971. The last three decades have seen major advances in understanding the structure of focal adhesions and the functions they serve in cellular adhesion, migration, and other biological processes. In this chapter, we begin with a historical perspective of focal adhesions, provide an overview of focal adhesion biology, and highlight recent major advances in the field. Specifically, we review the different types of matrix adhesions and the role different Rho GTPases play in their formation. We discuss the relative contributions of integrin and syndecan adhesion receptors to the formation of focal adhesions. We also focus on new insights gained from studying focal adhesions on biomaterial surfaces and from the growing field of mechanotransduction. Throughout this chapter, we have highlighted areas of focal adhesion biology where major questions still remain to be answered.