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Background Children ≤36 months with diffuse intrinsic pontine glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes. Methods Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed. Results Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (P = .018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation. Conclusions Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.

The first Workshop on Drug Delivery in Paediatric Brain Tumours was hosted in London by the charity Children with Cancer UK. The goals of the workshop were to break down the barriers to treating central nervous system (CNS) tumours in children, leading to new collaborations and further innovations in this under-represented and emotive field. These barriers include the physical delivery challenges presented by the blood-brain barrier, the underpinning reasons for the intractability of CNS cancers, and the practical difficulties of delivering cancer treatment to the brains of children. Novel techniques for overcoming these problems were discussed, new models brought forth, and experiences compared: OA gold

Background The literature reports a wide variation in the incidence of venous thromboembolic (VTE) disease in trauma patients. The performance of routine surveillance venous duplex ultrasound of bilateral lower extremities is controversial. Furthermore, recent examinations of the national trauma databank registry have suggested that routine duplex surveillance is associated with higher deep venous thrombosis (DVT) detection rates. Materials and Methods We examined the incidence and risk factors for VTE disease in 2827 trauma patients admitted over a 2-y period to a state-verified level I trauma center. Detailed chart review was carried out for patients with VTE disease. We then evaluated the effects of a routine bilateral lower extremity duplex surveillance guideline on VTE detection in the subset of injury patients admitted to the trauma service. Results We found an approximately 2% incidence of venous thromboembolic disease in a mostly blunt trauma population. Amongst patients with VTE disease, the most common risk factors were obesity and significant head injury. We then evaluated the 998 patients with injury who were admitted to the trauma service 1 y before and after surveillance guideline implementation. Despite a nearly 5-fold increase in the number of duplex scans, with a substantial increase in cost, we found no significant difference in the incidence of DVT. Conclusions Our preliminary data argue against the use of routine duplex surveillance of lower extremities for DVT in trauma patients. A larger, prospective analysis is necessary to confirm these findings.

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

Survival in atypical teratoid rhabdoid tumors (AT/RT) is plagued by drug resistance to platinum-intensive therapies. We have previously shown the dual mTORC1/2 inhibitor TAK228 (aka MLN0128) extends survival in orthotopic mouse models of AT/RT by enhancing cisplatin-induced apoptosis. TAK228 decreases expression of the anti-apoptotic protein MCL-1 but leads to a reflexive increase in anti-apoptotic proteins BCL-2 and BCL-X(L). We hypothesize that combining TAK228 with the BH3 mimetic, navitoclax will enhance platinum-induced cytotoxicity, reduce drug resistance, and extend survival in AT/RT. TAK228 combined with navitoclax decreases expression of MCL-1, BCL-2, and BCL-X(L); shifting toward a pro-apoptotic balance of BCL-2 family proteins. Navitoclax combines synergistically with TAK228 to slow AT/RT cell growth (MTS assay, p

Pediatric diffuse midline glioma (MLG) constitutes the deadliest childhood CNS cancers. Due to the sensitive anatomical location, lack of surgical access to the tumor has hindered molecularly informed clinical interventions; thus, there is a dire need for the development of a sensitive and accurate approach for mapping tumor DNA fingerprints and monitoring tumor response to therapy. Liquid biopsy is emerging as a minimally invasive method for detecting circulating tumor DNA (ctDNA) in patients’ biofluid. To use liquid biopsy for mapping genomic mutations in pediatric brain tumors, we designed, optimized, and validated probes, and then showed their sensitivity and specificity for clinical assessment of children diagnosed with MLGs. Specifically, we demonstrated the feasibility of generating multiplex assays for detection of multiple driver mutations in patients’ biofluid. Tumor ctDNA was detected in cyst fluid (n=1), cerebrospinal fluid (CSF, n=30) and plasma (n=77), representing 48 subjects admitted or enrolled in a clinical trial. We show that while both CSF and plasma contain ctDNA, CSF tended to be a more enriched medium for tumor-associated ctDNA. Furthermore, we have detected H3K27M in ctDNA of plasma samples in xenograft models of DIPG. Finally, we show that ctDNA analysis closely agree with tumor response, often providing similar trends compared to MR imaging. Our data are the first to indicate the clinical utility of ctDNA for monitoring tumor response, and provide a molecularly-based rapid and sensitive approach for detection and longitudinal survey of childhood CNS tumors.

BACKGROUND: Children

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.

Regional delivery of drugs can offer a pharmacokinetic advantage in the treatment of localized tumors. One method of regional delivery is by intra-arterial infusion into the basilar/vertebral artery network that provides local access to infratentorial tumors, which are frequent locations of childhood brain cancers. Proper delivery of drug by infused solutions requires adequate mixing of the infusate at the site of infusion within the artery lumen. Our mixing studies with an in vitro model of the vertebral artery network indicate that streaming of drug solution is likely to occur at low, steady infusion rates of 2 ml/min. Streaming leads to maldistribution of drug to distal perfused brain regions and may result in toxic levels in some regions while concurrently yielding subtherapeutic levels in adjacent regions. According to our model findings, distribution to both brain hemispheres is not likely following infusion into a single vertebral artery even if the infusate is well-mixed at the infusion site. This outcome results from the unique fluid flow properties of two converging channels, which are represented by the left and right vertebral branches converging into the basilar. Fluid in the model remains stratified on the side of the basilar artery served by the infused vertebral artery. Careful thought and planning of the methods of intravertebral drug infusions for treating posterior fossa tumors are required to assure proper distribution of the drug to the desired tissue regions. Improper delivery may be responsible for some noted toxicities or for failure of the treatments.

BACKGROUND: Diffuse intrinsic pontine glioma is one of the least understood pediatric tumors. We have recently identified two molecular subtypes of DIPGs (sonic hedgehog and N-Myc). Despite the existence of in vitro and in vivo models of the disease, molecular characterization of these models and their proximity to representing the disease has not been established. Here, we have done comparative protein profiling of a number of DIPG primary cells as well as protein profiles of a single specimen and specimens derived from its' in vivo and in vitro models. METHODS: Human primary DIPG (n = 4) and normal human cells derived from hindbrain (n = 2) were processed for protein profiling. Total protein was extracted and analyzed using SDS PAGE, and analyzed using Q Exactive mass spectrometer (ThermoFisher, CA, USA). Data and pathway analysis were done using the SequestHT and Ingeniuty Pathway Analysis software respectively. Protein was also extracted from a single human DIPG specimen, and its' in vitro and in vivo derived cells. Protein profiling of this specimens was performed as described above. RESULTS: In this study, we first investigated the protein profiles of four widely used DIPG primary lines, all H3.3K27M mutant. We show the overlap of the protein profile of these cells with established human DIPG subtypes. We further investigated the protein profile of a single DIPG tissue to its in vitro and in vivo models. We describe the fidelity of each model with respect to the molecular entity of the original tumor. The largest number of proteins were shared between primary tumor and murine model (846 proteins, 44%), where the primary tumor and cultured cells shared 30% (721) proteins. CONCLUSIONS: Established human DIPG cells represent tumor biology at the protein level. However, differences in molecular pathway of in vitro and in vivo models representing the disease exist.

Current management protocols for anticoagulated patients undergoing dental procedures are influenced by evidence-based guidelines. These guidelines state that the risk of significant bleeding is low in patients who have a stable INR within a therapeutic range, (2-4). The risks of interruption of anticoagulant therapy is greater than the risk of bleeding. This paper discusses the current practice of general dental practitioners (GDPs) in the West Midlands when treating patients taking warfarin and compares these findings with standard guidelines. A questionnaire was sent to 638 GDPs in West Midlands in 2010, 492 (77%) were returned. This study was carried out three years after a similar study carried out in South West Wales and after the guidance updated by the BNF and NMWIC. Thirty-three (7%) of the respondents did not treat patients on warfarin. The majority of respondents (86%) considered that a dental extraction in a patient on warfarin is a procedure associated with a high risk of bleeding. Surgical implant placement (75%), subgingival debridement (49%) and inferior dental block (40%) administration were also considered by GDPs to be associated with a high risk of bleeding. The majority (88%) of the respondents check the INR of anticoagulated patients before carrying out treatment. Of these, 244 (52%) would do so within 24 hours and 78 (17%) of them within 72 hours. Only 117 (25%) considered 4.0 as the safe upper limit for the INR for performing high-risk procedures. Clinical Relevance: The findings of this study demonstrate that there is general awareness about how to manage patients on warfarin but uncertainties still exist among general dental practitioners. Further education and training would improve the care of patients on warfarin in a primary care setting.

Regional delivery of drugs can offer a pharmacokinetic advantage in the treatment of localized tumors. One method of regional delivery is by intra-arterial infusion into the basilar/vertebral artery network that provides local access to infratentorial tumors, which are frequent locations of childhood brain cancers. Proper delivery of drug by infused solutions requires adequate mixing of the infusate at the site of infusion within the artery lumen. Our mixing studies with an in vitro model of the vertebral artery network indicate that streaming of drug solution is likely to occur at low, steady infusion rates of 2 ml/min. Streaming leads to maldistribution of drug to distal perfused brain regions and may result in toxic levels in some regions while concurrently yielding subtherapeutic levels in adjacent regions. According to our model findings, distribution to both brain hemispheres is not likely following infusion into a single vertebral artery even if the infusate is well-mixed at the infusion site. This outcome results from the unique fluid flow properties of two converging channels, which are represented by the left and right vertebral branches converging into the basilar. Fluid in the model remains stratified on the side of the basilar artery served by the infused vertebral artery. Careful thought and planning of the methods of intravertebral drug infusions for treating posterior fossa tumors are required to assure proper distribution of the drug to the desired tissue regions. Improper delivery may be responsible for some noted toxicities or for failure of the treatments.

Diffuse intrinsic pontine gliomass (DIPGss) account for 10% of pediatric brain tumors and have a universally poor prognosis. Our laboratory has shown that targeting the NOTCH pathway in glioblastoma (GBM) with gamma secretase inhibitors (GSI), inhibits the growth and viability of tumor neurospheres. Primary DIPG as well as DIPG cell lines express have very high levels of NOTCH activity as measured by western blot and qPCR assays. AKT amplification is observed in primary DIPG, and TORC1/TORC2 activation occurs in DIPG cell lines as measured by western blot. The mTOR and NOTCH pathways are known to interact and alter cancer stem cell growth, stemness, and metabolism. We hypothesized that dual targeting of NOTCH and mTOR in DIPG would lead to decreased proliferation and increased apoptosis compared to targeting either pathway in isolation. In established DIPG cell lines, we observed that GSI treatment decreases NOTCH activity in a dose dependent manner as evidenced by decreased expression of NOTCH targets expression of Hes1 and Hey1 via as measured by western blot and qPCR assays. We also observed a dose-dependent reduction in DIPG proliferation and growth after gamma-secretase inhibition as measured by BrdU (Day 7, DMSO to 5 uM MRK003 had p value Citation Format: Isabella C. Taylor, Marianne Hutt-Cabezas, Melanie Weingart, Kathy Warren, Howard Chang, Javad Nazarian, Charles G. Eberhart, Eric H. Raabe. Dual targeting of mTOR and Notch disrupts growth and promotes apoptosis in diffuse intrinsic pontine glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3099. doi:10.1158/1538-7445.AM2014-3099

Background: Satraplatin is an orally bioavailable platinum analog with preclinical activity (IC50 range in tumor cell lines 0.04 - 16 µM) in cisplatin sensitive and resistant models and clinical activity in adults with refractory cancers including prostate cancer. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.6% and 3.8%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin, which is more lipophilic than other platinum analogs, after an intravenous (IV) dose in a NHP model. Methods: Satraplatin 120 mg/m2 was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 hours. Plasma was separated immediately and ultrafiltrate (UF) was prepared by centrifugation through a Microcon 10K MWCO filter. CSF was obtained from an indwelling Ommaya reservoir (n=4) or from a temporary lumbar catheter (n=1). Platinum was quantified in the plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification of 0.03 µM in UF and CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the AUCCSF:AUCPlasma. Results: Satraplatin was well tolerated by all NHP. Pharmacokinetic parameters (median and range) for satraplatin plasma UF were Cmax 8.3 (5.7-10.6) µM, AUC0-48h 28.3 (22.6-33.2) µM·h, AUC0-inf 34.2 (24.7-38.2) µM·h, clearance 3.6 (2.4-4.3) L/h, and t1/2 18.8 (13.4-25) h. Satraplatin was detected in the CSF of all NHP. For the 4 NHP with Ommaya reservoirs PK parameters were: tmax 1.5 (1.3-2.1) h from the start of infusion, Cmax 0.07 (0.02-0.12) µM, AUC0-48h 1.2 (0.49-2.43) µM·h, ratio AUC0-48h CSF:AUC0-48h Plasma was 4.3 (2.2-7.4) %. For the NHP with lumbar catheter and limited CSF samples the tmax was 1.1 h, and Cmax was 0.62 µM. Conclusions: Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3599.