The international diffuse intrinsic pontine glioma registry: an infrastructure to accelerate collaborative research for an orphan disease

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

Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries.

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of 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

Late- and post-Variscan cooling and exhumation history of the northern Rhenish massif and the southern Ruhr basin: new constraints from fission-track analysis

Apatite fission-track analyses were carried out on outcrop and core samples from the Rhenish massif and the Carboniferous Ruhr Basin/Germany in order to study the late- and post-Variscan thermal and exhumation history. Apatite fission-track ages range from 291±15 Ma (lower Permian) to 136±7 Ma (lower Cretaceous) and mean track lengths vary between 11.6 μm and 13.9 μm, mostly displaying unimodal distributions with narrow standard deviations. All apatite fission-track ages are younger than the corresponding sample stratigraphic age, indicating substantial post-depositional annealing of the apatite fission-tracks. This agrees with results from maturity modelling, which indicates 3500–7000 m eroded Devonian and Carboniferous sedimentary cover. Numerical modelling of apatite fission-track data predicts onset of exhumation and cooling not earlier than 320 Ma in the Rhenish massif and 300 Ma in the Ruhr Basin, generally followed by late Carboniferous–Triassic cooling to below 50–60°C. Rapid late Variscan cooling was followed by moderate Mesozoic cooling rates of 0.1–0.2°C/Ma, converting into denudation rates of <1 mm/a (assuming a stable geothermal gradient of 30°C/km). Modelling results also give evidence for some late Triassic and early Jurassic heating and/or burial, which is supported by sedimentary rocks of the same age preserved at the rim of the lower Rhine Basin and in the subsurface of the Central and Northern Ruhr Basin. Cenozoic exhumation and cooling of the Rhenish massif is interpreted as an isostatic response to former erosion and major base-level fall caused by the subsidence in the lower Rhine Basin

Strategies for Enhancing the Electrocatalytic Activity of M-N/C Catalysts for the Oxygen Reduction Reaction

The development of highly active and durable nonprecious metal catalysts that can replace expensive Pt-based catalysts for the oxygen reduction reaction (ORR) is of pivotal importance in polymer electrolyte membrane fuel cells. In this line of research, metal and nitrogen codoped carbon (M-N/C) catalysts have emerged as the most promising alternatives to Pt-based catalysts. This review provides an overview of recently developed synthetic strategies for the preparation of M-N/C catalysts to enhance the catalytic activity of the ORR. We present five major strategies, namely the use of metal-organic frameworks as hosts or precursors, the use of sacrificial templates, the addition of heteroelements, the preferential generation of active sites, and a biomimetic approach. For each strategy, the advantages capable of boosting catalytic activity in the ORR are summarized, and notable examples and their catalytic performances are presented. The ORR activities and measurement conditions of high-performing M-N/C catalysts are also tabulated. Finally, we summarize this review with some suggestions for future studie

CD137 stimulation and p38 MAPK inhibition improve reactivity in an in vitro model of glioblastoma immunotherapy

Dendritic cell vaccination has become an interesting option for cancer immunotherapy. Tumor-lysate-pulsed dendritic cells (DC) can prime na < ve T cells and induce the regression of established tumors including gliomas as shown in various animal models. Despite hopeful results even in clinical studies, the outcome for many patients is still unsatisfying. In the present study, we tested the combination of tumor-lysate-pulsed dendritic cells (TPDC) with a monoclonal antibody against CD137, a monoclonal antibody against CD25 (daclizumab) and a specific p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580) for improving immunostimulation in an in vitro model of immunotherapy for human gliomas. We observed a higher secretion of interferon gamma by TPDC-primed peripheral blood mononuclear cells (PBMC) that were incubated with an antibody against CD137 or the p38 MAPK inhibitor. In addition, we observed higher specific lysis of tumor cells after incubation of PBMC with the p38 MAPK inhibitor or the anti-CD137 antibody. In contrast, incubation of TPDC-primed PBMC with the anti-CD25 antibody did enhance neither interferon gamma secretion nor cellular cytotoxicity. Cell depletion experiments demonstrated that the immune reaction induced by TPDC is strongly dependent on CD4-positive and CD8-positive cells. Incubation of DC during maturation and antigen loading with the anti-CD137 antibody did not enhance cytotoxicity and interferon gamma secretion in comparison with application of the anti-CD137 antibody during priming. In conclusion, our data suggest that p38 MAPK inhibition and anti-CD137 antibodies can enhance the immune response against glioblastoma cells

Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries.

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of 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