tbuckley/cabot-search huggingface dataset:
DIPG-13. SENSITIVITY OF DIPG CELLS TO BMI-1 MODULATOR PTC596 IS INDEPENDENT OF EZH2 ACTIVITY
Authors: Shiva Senthil Kumar, Satarupa Sengupta, Kyungwoo Lee, Rachid Drissi
Journal: Neuro-Oncology (2018)

Despite numerous advances in understanding the biology of poor-prognosis pediatric brain tumors, DIPG remains essentially incurable. We recently validated BMI-1 as a therapeutic target in DIPG. BMI-1 is a member of the Polycomb repressive complex 1 and is highly expressed in DIPG patient tumors and patient-derived cell lines regardless of the histone H3K27 mutation status. In the current study, we used a recently developed and clinically relevant BMI-1 modulator, PTC596, to test its efficacy to treat DIPG. PTC596 induced post-translational modification of BMI-1, inhibiting its activity and selectively inhibited cell proliferation and induced apoptosis at nanomolar concentrations in all DIPG subtypes. Given the role of BMI-1 in DNA damage response, we observed an increase in γH2AX levels in DIPG cells treated with PTC596. Previous studies have shown that H3K27M mutations are disease-drivers and the presence of these mutations correlates with a global decrease in H3K27me3 levels. Here, we investigated whether the sensitivity of DIPG cells to BMI-1 modulation by PTC596 requires EZH2 activity by using an EZH2 inhibitor, EPZ011989. Our results show that the induction kinetics and the levels of γH2AX were not affected by the presence of EZH2 inhibitor regardless of H3K27 subtype, further validating our hypothesis that PTC596 is effective in all DIPG subtypes. In conclusion, to our knowledge, this is the first report providing evidence supporting the effectiveness of PTC596 in all DIPG subtypes and suggesting that BMI-1 inhibition-induced DNA damage response is independent of EZH2 activity in DIPG.
Self‐Assembling Nanoclay Diffusion Gels for Bioactive Osteogenic Microenvironments
Authors: Pujiang Shi, Yang‐Hee Kim, Mohamed Mousa, Roxanna Ramnarine Sanchez, Richard O. C. Oreffo, Jonathan I. Dawson
Journal: Advanced Healthcare Materials (2018)

Abstract Laponite nanoparticles have attracted attention in the tissue engineering field for their protein interactions, gel‐forming properties, and, more recently, osteogenic bioactivity. Despite growing interest in the osteogenic properties of Laponite, the application of Laponite colloidal gels to host the osteogenic differentiation of responsive stem cell populations remains unexplored. Here, the potential to harness the gel‐forming properties of Laponite to generate injectable bioactive microenvironments for osteogenesis is demonstrated. A diffusion/dialysis gelation method allows the rapid formation of stable transparent gels from injectable, thixotropic Laponite suspensions in physiological fluids. Upon contact with buffered saline or blood serum, nanoporous gel networks exhibiting, respectively, fivefold and tenfold increases in gel stiffness are formed due to the reorganization of nanoparticle interactions. Laponite diffusion gels are explored as osteogenic microenvironments for skeletal stem cell containing populations. Laponite films support cell adhesion, proliferation, and differentiation of human bone marrow stromal cells in 2D. Laponite gel encapsulation significantly enhances osteogenic protein expression compared with 3D pellet culture controls. In both 2D and 3D conditions, cell associated mineralization is strongly enhanced. This study demonstrates that Laponite diffusion gels offer considerable potential as biologically active and clinically relevant bone tissue engineering scaffolds.
Inflammatory bowel disease events after exposure to interleukin 17 inhibitors secukinumab and ixekizumab: Postmarketing analysis from the RADAR (“Research on Adverse Drug events And Reports”) program
Authors: Kelsey A. Orrell, Morgan Murphrey, Ryan C. Kelm, Harrison H. Lee, David R. Pease, Anne E. Laumann, Dennis P. West, Beatrice Nardone
Journal: Journal of the American Academy of Dermatology (2018)
IMMU-22. NATURAL KILLER CELL IMMUNOTHERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Javiera Bravo-Alegria, Shinji Maegawa, Keri Callegari, Bridget Kennis, Wencai Ma, William Brugmann, Arvind Rao, Dean Anthony Lee, Soumen Khatua, Wafik Zaky, David Sandberg, Stewart Goldman, Vidya Gopalakrishnan
Journal: Neuro-Oncology (2018)

Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal pediatric cancer. Immunotherapy, and specifically Natural Killer (NK) cell therapy has been investigated for glioma and other brain malignancies. Indeed, our group is the first to demonstrate safety of loco-regional infusion of ex vivo expanded and activated NK cells in a Phase-I trial of patients with recurrent/refractory fourth ventricular tumors. But their effectiveness against DIPG has not been assessed. Here, we show that NK cells have cytolytic activity against DIPG cells in vitro. In vivo, DIPG tumors implanted in the forebrain were lysed by intratumoral injections of ex vivo expanded NK cells. In addition, NK cells infused through the fourth ventricle trafficked to and promoted shrinkage of DIPG tumors in their orthotopic location. In work from other investigators, epigenetic modulation of tumors by Histone Deacetylate Inhibitors (HDACIs) is being investigated as a potential therapeutic approach for this disease. However, the effect of HDACIs on immune cell activity has not been examined. We observed that pre-treatment of NK cells with the HDACI, MS-275, enhanced NK cell mediated cytolysis of DIPG cells in vitro. This was associated with significantly enhanced expression of genes controlling motility and cytolysis. The ability of MS-275 primed NK cells to traffic and promote cytolysis of tumors implanted proximal and distal to the site of NK cell introduction will be discussed. In summary, we suggest that the use of epigenetic therapy as an ex vivo primer of NK cells could increase the effectiveness of NK cell therapy against DIPG tumors.
GERM-13. PITUITARY FAILURES IN CNS GERMINOMA. EXPERIENCE GENERATED IN SIOP CNS GCT 96
Authors: Christian Asmus Kuhrt, Claire Alapetite, Rolf Dieter Kortmann, James C Nicholson, Jans-Enno Müller, Maria Luisa Garre, Thomas Czech, Umberto Ricardi, Frank Saran, Didier Frappaz, Gabriele Calaminus
Journal: Neuro-Oncology (2018)

CNS Germinoma occur predominently in suprasellar and/or pineal sites. Combination chemo-radiotherapy is highly effective, but pituitary failures (PF) are recognised complications. We examined the presence of PF in survivors of SIOP CNSGCT96. PATIENTS AND We evaluated 235 patients treated between 01/10/1996 and 31/12/2005. 180/235 were treated according to protocol and were alive with no recurrence at follow up in November 2009 (137 male, 43 female: mean age 13 years, observation time median 6.5 years). Of 180 patients examined, 69 had PF in follow-up, 5 showed diabetes insipidus only, 37 had anterior PF and 27 had both. PF at follow-up was distributed according to RT dose to the pituitary area (PA) as follows: 2 cases in the 26/180 with no prescribed RT dose to the PA; 9 of 65 receiving 24Gy to the PA; 58 of 89 receiving 40Gy to PA. 36 of the 69 patients with PF at follow-up, had no anterior PF at diagnosis; two of these 36 patients had no prescribed RT to PA, 4/36 had 24Gy to PA (11%) and 30/36 received 40Gy to PA (83%). Pituitary failures are a major long-term risk of CNS germinoma. 83% of patients who developed PF following treatment were treated with 40Gy prescribed RT dose to PA. Our results support the need to develop treatment strategies with a lower total RT dose to the PA, particularly with respect to the size of the tumor boost. (supported in part by German Cancer Aid)
HGG-20. DNA METHYLATION ANALYSIS OF HIGH-GRADE GLIOMA IN PATIENTS WITH MISMATCH REPAIR DEFICIENCIES
Authors: Andrew Dodgshun, Kohei Fukuoka, Brittany Campbell, Melissa Edwards, Alexandra Sexton-Oates, Valérie Larouche, Vanan Magimairajan, Scott Lindhorst, Michal Oren, Gary Mason, Bruce Crooks, Shlomi Constantini, Maura Massimino, Stefano Chiaravalli, Jagadeesh Ramdas, Warren Mason, Ashraf Shamvil, Roula Farah, An van Damme, Enrico Opocher, Syed Ahmer Hamid, David Ziegler, David Samuel, Kristina A Cole, Patrick Tomboc, Duncan Stearns, Gregory Thomas, Alexander Lossos, Richard Saffery, Michael Sullivan, Jordan R Hansford, David Jones, Uri Tabori
Journal: Neuro-Oncology (2018)

Patients with constitutional mismatch repair deficiency (CMMRD) are prone to developing high-grade glioma (HGG). These tumours acquire DNA polymerase mutations and become ultra-hypermutant harbouring hundreds of mutations per megabase. The impact of these mutations on methylation profile and the ability of the tool to differentiate MMRD tumours from others is unknown. In order to answer these questions, we performed either 450k/850K methylation analysis on a cohort of 52 CMMRD-HGG and compared them to 148 non-CMMRD HGG and normal brain controls. CMMRD HGG harbouring classic mutations in histone 3 or IDH genes had a methylation profile which clustered closely with non-MMRD tumours harbouring these mutations. Tumours without these alterations exhibited a tendency to hypomethylation with some tumours being extremely hypomethylated in comparison to other HGG. Hypomethylation was unrelated to mutational burden and type of DNA polymerase mutation present. Gene set analysis of methylation patterns revealed enrichment of hypomethylation for cellular pathways involved in cellular metabolism, organelle maintenance, mitotic cell cycle and gene expression. This pattern persisted in subgroup analysis of IDH mutant tumours in patients with and without MMRD. Importantly, this pattern was present in MMRD HGG with mutational burdens <10 mutations/MB and shared between primary and recurrent tumours suggesting that hypomethylation is an early event. CMMR-HGG have unique pattern of hypomethylation which can distinguish them from other paediatric HGG. Several plausible explanations include that hypomethylation in specific pathways confer a survival advantage on the cells which acquire it, or that hypermutations in specific CpG affect methylation patterns in these genes.
MBCL-47. OTOTOXICITY IN MEDULLOBLASTOMA SURVIVORS FOLLOWING PROTON RADIATION
Authors: John Byun, Clayton B Hess, Benjamin V M Bajaj, Elizabeth A Weyman, Miranda P Lawell, Sara L Gallotto, David H Ebb, Shannon M MacDonald, Nancy J Tarbell, Torunn I Yock
Journal: Neuro-Oncology (2018)

Radiotherapy to the cochlea and cisplatin exposure are both associated with hearing loss (HL) in medulloblastoma survivors. Here we report late outcomes in survivors with ≥1 year audiogram testing. Prospective medulloblastoma trial participants (clinicaltrials.gov: NCT01063114/NCT00105560) with ≥1 years of audiogram follow-up (FU, n=110 pts) comprised the study cohort. HL was graded using the SIOP-Boston ototoxicity scales (0-4) for each ear. Associations between grade 3 HL and mean cochlear radiation dose and cumulative cisplatin dose were evaluated. Target cisplatin dose was 450 mg/m2 but most patients did not receive full dose as dose reductions were used when ototoxicity was detected during chemotherapy. Median follow-up was 4.0 years (range 1-10). At baseline, 10 ears (4.5%) had grade 3 HL. At latest FU, an additional 49 ears developed grade 3 HL (23.3%). There was no grade 4 HL. Median average cochlear dose across both ears was 29.9 Gy (20.8-50.6) and median cisplatin dose was 375.0 mg/m2 (60.0-583.0). Mean cochlear radiation dose for grade 3 HL (n=56) was 32.5Gy (24.1-47.0), compared with 31.8Gy (20.8-50.6, p=0.19). Mean cisplatin dose for grade 3 HL was 347.3mg/m2 (180.0-450.0), compared with 374.2mg/m2 for grade 0-2 ears (60.0-583.0, p=0.05). Significant hearing deficits (SIOP-Boston grade 3) develop in approximately 23.3% of medulloblastoma patients. In this cohort, higher mean radiation dose did not affect HL rates. The lower mean cumulative cisplatin dose in pts with grade 3 HL suggests cisplatin ototoxicity is driving HL, and that host susceptibility may play a role.
IMMU-14. KICKSTARTING THE CANCER IMMUNITY CYCLE BY INNATE CHECKPOINT INHIBITION TO TARGET PEDIATRIC BRAIN TUMORS
Authors: Siddhartha Mitra, Samuel Cheshier
Journal: Neuro-Oncology (2018)

Recently we published the effect of a humanized anti-CD47 antibody, on five aggressive and etiologically distinct pediatric brain tumors: Group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrates therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Disabling the inhibitory signals transduced by SIRPa by blocking anti- CD47 antibodies we promote phagocytic response driven by tumor-specific antibodies. These phagocytic innate cells are also professional antigen-presenting cells (APC), providing a link from innate to adaptive antitumor immunity. Consequently, we tested a number of approaches to augment immune checkpoint immunotherapy. We hypothesized that by activating immunogenic phagocytosis we could kickstart the cancer immunity cycle and hence augment adaptive checkpoint inhibitors against cold tumors such as medulloblastoma and pediatric glioma. To determine the in vivo efficacy of combinatorial anti-CD47 and anti-PD1 therapies, spontaneous SHH medulloblastoma mouse models were treated by, i.p. injections with either PBS (control), anti-CD47, anti-PD1 or in combination. To test the cancer immunity hypothesis combination treatment was carried out either in sequence or simultaneously. Mice receiving anti-CD47 anti-PD1 duotherapy demonstrated increased survival when treated sequentially as compared to both monotherapies and control cohorts. Immunohistochemical and Flowcytometry analysis with the macrophage marker F4/80 and T-cell subset immune panel demonstrated varying patterns of macrophage and T-cell infiltration. Addition of anti-CTLA4 mAb did not enhance the efficacy of this effect suggesting the lack of infiltrating T-regulatory cells.
SWRK-04. FAMILY HUDDLE – ONE FAMILY’S PERSONAL EXPERIENCE
Authors: Kate Fernandez, Kate Cameron
Journal: Neuro-Oncology (2018)

The Family Huddle Framework was developed in 2016 to facilitate consumer engagement in the Women’s and Children’s Health Network (WCHN) care settings. It aims to understand what the consumer believes to be important to enhancing quality, comfort and safety of care provided on inpatient wards. The Family Huddle was piloted in early 2016 in a Medical/Surgical babies ward (birth to 1 year) and subsequently implemented and evaluated in the Michael Rice Centre for Haematology and Oncology (MRCHO) from October 2016. Parent/Caregiver consumers are invited to a regular (three weekly), semi-formal group meeting with a staff member to exchange information and ideas. The purpose is to improve care through sharing information, providing feedback, informing consumers of upcoming events, and giving opportunity for direct input on issues relevant to the area. In the MRCHO there have been ten huddles held with an average of five parents per meeting. Key outcomes that have been able to be addressed from the huddles include much improved internet access across the ward area, more comfortable seating in the waiting area and an increase in the variety of hospital food for inpatients. The impact this meeting had on a family whose child had been diagnosed with a central nervous system tumour will be explored in a case study.
Hearing loss in adults, assessment and management: summary of NICE guidance
Authors: Saoussen Ftouh, Katherine Harrop-Griffiths, Martin Harker, Kevin J Munro, Ted Leverton
Journal: BMJ (2018)

### What you need to know

Hearing loss is common— Over 9 million people in England123 have hearing loss and this is increasing with the ageing population (fig 1).4 Hearing loss ranks third for disease burden in England (years lived with disability).5 The average GP sees at least four patients every day who have hearing loss sufficient to interfere with their ability to communicate with ease.



Fig 1 
Estimated prevalence of people with hearing loss in the better hearing ear of ≥25 dB by age band in England4



Hearing loss is disabling— It affects communication at work and home, affecting educational attainment, employment opportunities, personal relationships, enjoyment of music, and social independence. It can lead to significant reduction in people’s quality of life and is associated with mental health problems including depression and dementia.

Hearing loss is expensive— The overall economic burden associated with hearing loss in adults in the UK is estimated to be more than £30bn per year.67

Hearing loss can be managed successfully— Early and effective intervention can minimise the …
Abstract 12075: Telecommunicator CPR Intervention Improves Recognition of Cardiac Arrest and Time to First Chest Compression
Authors: John Sutter, Blake Langlais, Christian Dameff, Jeffrey Tully, Micah Panczyk, Vatsal Chikani, Tyler F Vadeboncoeur, Daniel W Spaite, Bentley J Bobrow
Journal: Circulation (2015)

Background: Bystander cardiopulmonary resuscitation (BCPR) significantly improves survival from out-of-hospital cardiac arrest (OHCA). Telecommunicator CPR (TCPR) has been shown to increase BCPR rates, yet TCPR performance varies widely. We assess whether a bundled TCPR protocol, training, and continuous quality improvement (CQI) intervention improves TCPR performance. Methods: The intervention was implemented at a regional 9-1-1 dispatch center and had three main components: (1) the installation of the AHA-recommended 2-question TCPR protocol, (2) training to enhance telecommunicator OHCA recognition and (3) CQI with system and case-level feedback. Training included a two-hour lecture, 30 minutes of video training, and one hour of simulation training. Audio recordings of suspected OHCAs from pre (P1, 10/5/10 - 11/6/11) and post-intervention (P2, 11/7/11 - 11/4/13) periods were collected by searching center archives for calls originally processed as cardiac arrests. Recordings were analyzed according to six key TCPR metrics. Times to telecommunicator recognition of cardiac arrest, start of TCPR instructions, and initiation of chest compressions were measured using a standardized timestamp format. Results: Rates of OHCA recognition (80% to 95%, p&lt;0.0001), TCPR instructions started (32% to 72%, p&lt;0.0001), and bystander chest compressions initiated (18% to 70%, p&lt;0.001) all increased significantly. Reductions in the time from call receipt to the start of TCPR instructions (176s to 133s, p&lt;0.0001) and to the start of compressions (265s to 162s, p&lt;0.0001) were also observed. Conclusion: This bundled protocol, training and CQI intervention was associated with a significant increase in TCPR rates and a reduction in the time to first chest compression.
NFM-15. BUILDING A NEUROFIBROMATOSIS THERAPEUTICS PROGRAM
Authors: Molly Hemenway, Nicholas Foreman, Melissa Waters
Journal: Neuro-Oncology (2018)

Neurofibromatosis (NF) therapeutics is an emerging and growing field as more and more children are diagnosed with neurofibromatosis due to better awareness of the disease and diagnostic criteria. Patients with NF have an increased incidence of central nervous system (CNS) tumors and plexiform neurofibromas. Recent developments in the treatment of plexiform neurofibromas have significantly increased the numbers of patients seen for therapy. In order to provide high-quality care to these patients, a Neurofibromatosis Therapeutics Program (NFTP) should be developed and utilized. The program at Children’s Hospital Colorado has grown over the past few years and now includes a physician, nurse practitioner, nurse, and social worker. We collaborate closely with other disciplines that are vital in the care of the NF patient with plexiform neurofibromas and/or CNS tumors including: neuro-oncology, neurosurgery, neuroradiology, otolaryngology, orthopedics, plastic surgery, ophthalmology, neurology, dental, urology, dermatology, genetics, neuropsychology, and rehabilitation. Key players are identified in each subspecialty and then the NFTP is publicized to both primary care and subspecialty programs in order to identify patients who would be best cared for in this setting. Along with collaborating disciplines, the NFTP has developed protocols and standards of care for treatment, research, adverse reaction management, and data gathering to obtain prior authorizations for medications. The NFTP is actively conducting epigenetic research on plexiform neurofibroma tissue obtained during surgery. The NFTP is a strong and vibrant area of growth with the aim to provide high quality of care for the whole child and conduct lab and clinical research.
NURS-13. REFINING OUR NEURO-ONCOLOGY MULTIDISCIPLINARY CLINIC
Authors: Erin Kissell, Jenny Raybin
Journal: Neuro-Oncology (2018)

Children with brain tumors require multi-disciplinary subspecialty care. Unlike other childhood cancers, subspecialty care is needed both during survivorship and also during active treatment. Although most major pediatric neuro-oncology centers provide a multidisciplinary clinic, we describe our unique bi-monthly clinic as an example for other centers. We also present the nurse coordinator position in detail. In the prior 2 years, our clinic had 346 patient visits. We have 8 subspecialty providers (ophthalmology, endocrinology, neurosurgery, rehabilitation, radiation oncology, neuro-oncology, neuropsychology, social work, dietician) in order to support the complex care these children need. Anecdotal reports show patient satisfaction to receiving all care including follow up MRI in one day. The coordinator role for the clinic is combined between a nurse practitioner, nurse, and scheduler who meet bi-weekly to ensure the correct providers and scans are ordered for each patient. The nurse orders the follow up visit and scans and provides a patient summary handout as the patient leaves. The nurse practitioner combines all of the providers’ notes into a summary letter for the primary care provider. Successes and pitfalls will be presented to inform other multi-disciplinary clinic nurse coordinators.
Rituximab in ANCA-associated vasculitis: fewer infusions or ultra low-dose maintenance therapy?
Authors: Sergey V Moiseev, Nikolai M Bulanov, Anastasiia S Zykova, Pavel I Novikov
Journal: Annals of the Rheumatic Diseases (2018)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a life-threatening disease characterised by a recurrent course and progressive accumulation of irreversible damage of vital organs, that is, kidney and lungs. Before the advent of immunosuppression, AAV was usually fatal, that is, up to 80%–90% of patients were expected to die within 1 to 2 years after diagnosis. Aggressive immunosuppressive treatment with cyclophosphamide and high-dose corticosteroids has improved the outcomes in patients with AAV at the cost of significant toxicity.1 Not surprisingly, the researchers are focused on exploring the new regimens of immunosuppression that can provide a similar efficacy with an improved safety. These attempts were at least partly successful particularly due to the introduction of rituximab both for remission induction and maintenance treatment. Moreover, current evidence suggests that a proportion of patients with AAV are overtreated with rituximab and may benefit from an optimised maintenance therapy.

In the recently published multicentre, randomised controlled, phase III trial (MAINRITSAN2), the investigators from the French Vasculitis Study Group compared the efficacy and safety of a tailored rituximab regimen, based on monitoring of ANCA titre and CD19+ B-cell counts, with fixed-schedule rituximab infusions in 162 patients with granulomatosis with polyangiitis or microscopic polyangiitis, who were in complete remission at the time of enrolment.2 Patients from the first group were scheduled to receive 500 mg of rituximab at randomisation, while rituximab infusions were repeated only when serial monitoring showed an increase in ANCA titre …