bluuebunny/crossref_metadata_2025_split huggingface dataset:
LTBK-01. INO-5401 AND INO-9012 DELIVERED INTRAMUSCULARLY (IM) WITH ELECTROPORATION (EP) IN COMBINATION WITH CEMIPLIMAB (REGN2810) IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Reardon David A , Brem Steven , Desai Arati Suvas , Bagley Stephen Joseph , Kurz Sylvia Christine , De La Fuente Macarena Ines , Nagpal Seema , Welch Mary Roberta , Hormigo Adilia , Forsyth Peter , Mandell Jacob , Khagi Simon , Aiken Robert , Walbert Tobias , Lieberman Frank , Portnow Jana , Batiste James , Carroll Nicholas , Sylvester Albert , Campbell Patricia , Lowy Israel , Dolgoter Alex , Boyer Jean , Kraynyak Kimberly , Morrow Matthew P , McMullan Trevor , Weiner David B , Skolnik Jeffrey 
Published: December 2020

Abstract

BACKGROUND
Novel T cell-enabling therapies, in combination with checkpoint inhibition, may improve OS in GBM. INO-5401 (synthetic DNA plasmids encoding hTERT, WT-1, PSMA) plus INO-9012 (synthetic DNA plasmid encoding IL-12), and the PD-1 immune checkpoint inhibitor cemiplimab, is given to patients with newly diagnosed GBM to evaluate tolerability, efficacy and immunogenicity.

METHODS
Phase I/II, single arm, 2 cohort study (A: MGMT unmethylated, B: MGMT methylated). Primary endpoint is safety; efficacy and immunogenicity are secondary. Nine mg INO-5401 plus 1 mg INO-9012 (every 3 weeks x 4 doses, then Q9W) is given IM with EP by CELLECTRA® 2000 with cemiplimab (350 mg IV Q3W). RT is given as 40 Gy over 3 weeks. TMZ is given with radiation (all patients), and adjuvantly (Cohort B only).

RESULTS
Fifty-two subjects enrolled: 32 in Cohort A; 20 in Cohort B. 35% women; median age 60 years (19–78 years). The adverse event profile is consistent with single-agent (INO-5401, INO-9012, EP and cemiplimab) reported events. OS at 12 months was 84.4% (Cohort A) and 85% (Cohort B). OS at 18 months in Cohort A is 50% (95% CI 31.9 - 68.1); median OS is 17.9 months (14.5 - NR); Cohort B OS18 and median OS will be presented. Tumor gene transcripts at diagnosis confirmed expression of INO-5401 antigens. Peripheral immune responses following INO-5401 revealed antigen-specific T cell responses by Interferon gamma ELISpot and flow cytometry, including cytokine production and expansion of antigen specific CD8+T cells with lytic potential.

CONCLUSIONS
INO-5401 + INO-9012, a novel DNA plasmid immunotherapy, demonstrates acceptable risk/benefit and generates robust systemic immune responses to encoded tumor antigens when administered with cemiplimab and RT/TMZ in newly diagnosed GBM patients. Overall survival is encouraging. Clinical trial information: NCT03491683.
ATRT-08. A PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMORS/ATYPICAL TERATOID RHABDOID TUMORS
Authors: Wood Paul , Desai Jayesh , Waldeck Kelly , Cain Jason , Gottardo Nick , Strong Robyn , Kinross Kathryn , Carr Michelle , Jones Janelle , Wong Lily , Ziegler David , Hansford Jordan , Michael Michael , Ashley David 
Published: December 2020

Abstract

BACKGROUND
Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens.

METHODS
Following cycles of induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2 following a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2.

RESULTS
Six patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44–327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC.

CONCLUSIONS
Treatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.
ATRT-13. DIFFERENT CELLS OF ORIGIN PAVE THE WAY FOR MOLECULAR HETEROGENEITY IN RHABDOID TUMORS
Authors: Graf Monika , Interlandi Marta , Moreno Natalia , Holdhof Dörthe , Melcher Viktoria , Kastrati Dennis , zu Hörste Gerd Meyer , Dugas Martin , Frühwald Michael C , Albert Thomas K , Schüller Ulrich , Kerl Kornelius 
Published: December 2020

Abstract
Rhabdoid tumors (RT) are rare but highly aggressive pediatric neoplasms. These tumors carry homozygous loss-of-function alterations of SMARCB1 in almost all cases with an otherwise low mutational load. RT arise at different intracranial (ATRT) as well as extracranial (MRT) anatomical sites. Three main molecular subgroups (ATRT-SHH, ATRT-TYR, ATRT-MYC) have been characterized for ATRT which are epigenetically and clinically diverse, while MRT show remarkable similarities with ATRT-MYC distinct from ATRT-SHH and ATRT-TYR. Even though there are hypotheses about various cells of origin among RT subgroups, precursor cells of RT have not yet been identified. Previous studies on the temporal control of SMARCB1 knockout in genetically engineered mouse models have unveiled a tight vulnerable time frame during embryogenesis with regard to the susceptibility of precursor cells to result in RT. In this study, we employed single-cell RNA sequencing to describe the intra- and intertumoral heterogeneity of murine ATRT-SHH and -MYC as well as extracranial MYC tumor cells. We defined subgroup-specific tumor markers for all RT classes but also observed a notable overlap of gene expression patterns in all MYC subgroups. By comparing these single-cell transcriptomes with available single-cell maps of early embryogenesis, we gained first insights into the cellular origin of RT. Finally, unsupervised clustering of published human RT methylation data and healthy control tissues confirmed the existence of different cells of origin for intracranial SHH tumors and MYC tumors independent of their anatomical localizations.
ATRT-15. LY6D – A CANDIDATE FOR NANOPARTICLE-BASED TARGETED THERAPIES OF ATRT
Authors: Hagemeier Lea , Sönksen Marthe , Moreno Natalia , Ettlinger Romy , Bunzen Hana , Kerl Kornelius 
Published: December 2020

Abstract
Atypical Teratoid Rhabdoid Tumors (ATRT) are aggressive brain malignancies of the infant. Despite intensive multimodal therapy, the overall prognosis remains poor, making investigations on targeted therapies crucial. Arsenic trioxide (ATO) is known to inhibit cell growth of ATRT in vitro and in vivo but its efficacy in solid tumors is limited by its adverse effects. We aimed to characterize whether a nanoparticle-based drug delivery could overcome these limitations. Therefore metal-organic frameworks containing ATO (MOF-ATO) were constructed. To improve drug specificity further, we searched for unique proteins on the surface of ATRT, in order to create antibody-drug-conjugates out of MOF-ATO and an ATRT-specific ligand. ATRT are marked by a biallelic loss of SMARCB1, which results in an activation of the repressive histone methyltransferase EZH2. After chemical inhibition of EZH2 with GSK126, a mass spectrometric based screening for differentially expressed surface proteins was performed. Treatment with ATO, as well as MOF-ATO and GSK126 each reduces the cell viability of ATRT cell lines. It results in a cell cycle arrest and an induction in apoptosis, being analysed via MTT test and flow cytometry. GSK126 treatment causes a significant upregulation of several cell surface proteins, upon them the Lymphocyte antigen 6 family member D (LY6D). Being rarely expressed on other human cells, this protein is an interesting candidate. An antibody-drug-conjugate consisting of MOF-ATO and LY6D-ligands could be a promising approach for future targeted therapies of ATRT.
ATRT-21. RHABDOID PREDISPOSITION SYNDROME: REPORT OF MOLECULAR PROFILES AND TREATMENT APPROACH IN THREE CHILDREN WITH SYNCHRONOUS ATYPICAL TERATOID/RHABDOID TUMOR AND MALIGNANT RHABDOID TUMOR
Authors: Shatara Margaret , Gupta Ajay , Arja Mohamed H Abu , Conley Suzanne E , Patel Priyal , Boué Daniel R , Pierson Christopher R , Thomas Diana L , Meyer Erin K , Shah Summit H , Jones Jeremy , Martin Lisa , McAllister Aaron , Schieffer Kathleen M , Varga Elizabeth A , Leraas Kristen , Lichtenberg Tara , LaHaye Stephanie , Miller Katherine E , Magrini Vincent , Wilson Richard K , Cottrell Catherine E , Mardis Elaine R , Aldrink Jennifer H , Auletta Jeffery J , Pindrik Jonathan , Leonard Jeffrey R , Osorio Diana S , Finlay Jonathan L , Ranalli Mark , AbdelBaki Mohamed S 
Published: December 2020

Abstract

BACKGROUND
Rhabdoid predisposition syndrome is characterized by germline alterations in SMARCB1 or SMARCA4, leading to synchronous or metachronous central nervous system (CNS) and extra-CNS rhabdoid tumors. Rare survivors have been reported to date.

METHODS
We describe the molecular profiling and treatment regimen of three patients with synchronous atypical teratoid/rhabdoid tumor (ATRT) and malignant rhabdoid tumor of the kidney (MRT-K). All patients underwent radical nephrectomy of the kidney, and gross total resection of the primary CNS tumor was achieved for two patients. An intensive chemotherapy regimen was administered; an induction phase based on the modified Third Intergroup Rhabdomyosarcoma Study (IRS-III) for ATRT followed by a consolidation phase with three cycles of high-dose chemotherapy and autologous hematopoietic progenitor cell rescue, without irradiation. All three patients were enrolled on an institutional comprehensive genomic profiling protocol.

RESULTS
A germline focal 22q deletion, including SMARCB1, was detected in two patients, while the third patient had a maternally-inherited heterozygous frameshift variant in SMARCB1. Somatic loss of heterozygosity of 22q was identified in all patients, resulting in biallelic inactivation of SMARCB1. Divergent tumor subgroups were described using DNA methylation. The three MRT-K samples were classified as MYC subtype. One ATRT was classified as SHH while the other as TYR. One patient is currently three years off-therapy without evidence of disease, while the other two patients have completed the consolidation phase without recurrent disease.

CONCLUSION
Molecular profiling of CNS and extra-CNS rhabdoid tumors revealed different epigenetic subgroups. An intensive multimodal therapeutic approach without irradiation may achieve prolonged survival.
ATRT-30. RETROSPECTIVE ANALYSIS OF CHILDREN WITH ATYPICAL TERATOID RHABDOID TUMOR TREATED ACCORDING TO ACNS0333
Authors: Hoffman Lindsey , Margol Ashley , Faulk Kelly , Hutchins Sara , Friedman Gregory , Reddy Alyssa , Dhall Girish 
Published: December 2020

Abstract
Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system tumor with poor outcome. ACNS0333, a Children’s Oncology Group phase 3 trial, enrolled 65 evaluable patients who received two cycles of induction chemotherapy, three cycles of consolidative high-dose chemotherapy (HDCT), and focal radiation therapy (RT) pre- or post-consolidation. Craniospinal irradiation (CSI) was left to clinician discretion. We retrospectively analyzed medical records of 27 children treated at our institutions according to ACNS0333. Median age at diagnosis was 14 months (range 4–165); 13 (48%) were male. M-stage was M0, M2, and M3 for 18 (66%), 5 (19%), and 4 (15%), respectively. Tumor location was supratentorial (n=14, 52%), infratentorial (n=12, 44%), or both (n=1, 4%). Complete resection was achieved for 17 (63%). All but one completed induction. Of 13 (51%) with residual disease at diagnosis, 5 (36%) and 7 (50%), respectively, exhibited complete and partial response to induction. Three patients progressed on therapy, and six progressed after completion of therapy at a median of 9.7 months. In all, 18 patients completed RT (16 focal/4 CSI and 6 pre-/12 post-consolidation). Three died of therapy-related toxicity (two in primary therapy and one in relapse therapy), and 8 died of disease. Sixteen patients (59%) are alive at a median follow up of 53 months (range 9–114). Of 17 with germline testing, eight (47%) had rhabdoid predisposition syndrome of whom three are alive. At the time of presentation, data for approximately 50 patients is expected, and we will compare outcomes to soon-to-be published data from ACNS0333.
ATRT-32. GENOME-WIDE CRISPR AND SMALL-MOLECULE SCREENS UNCOVER TARGETABLE DEPENDENCIES IN AT/RTs
Authors: Merk Daniel , Hirsch Sophie , Walter Bianca , Häusser Lara , Persky Nicole , Root David , Schüller Ulrich , Tabatabai Ghazaleh 
Published: December 2020

Abstract
Brain tumors are the leading cause of cancer-related deaths in children and adolescents. Embryonal brain tumors are a group of high-grade neoplasms which primarily affect young patients, and atypical teratoid rhabdoid tumors (AT/RTs) are the second most common type of tumor within this group. In spite of intensive research efforts and the knowledge of molecular mechanisms driving subgroup-specific heterogeneity within ATRTs, survival estimates stay relatively low as compared to other tumor entities with a median survival of around 17 months. More efficacious and durable therapies are urgently needed to improve the situation of patients. We here used a combination of genome-wide CRISPR dependency screens and small-molecule drug assays to identify genetic vulnerabilities and novel therapeutic targets for this tumor entity. Here, we successfully generated a chemical library that shows preferential activity in AT/RT cell lines, thereby validating our CRISPR approach to identify tumor-specific vulnerabilities. Of note, none of the identified dependencies seemed to be subgroup-specific, suggesting that targets identified here can be used as pan-AT/RT therapeutic avenues. Among others, these include inhibition of EGF signaling and CDK4/6. Our data provide a comprehensive map of dependencies for AT/RTs which will serve as a starting point in the development of targeted therapies for this tumor entity.
COVD-02. COVID-19 AND CHILDHOOD CANCER CARE - THEMATIC ANALYSIS OF PUBLISHED SCIENTIFIC AND CLINICAL LITERATURE
Authors: Barton Chris 
Published: December 2020

Abstract

INTRODUCTION
The SARS-CoV-2 pandemic has affected modern medicine and healthcare provision profoundly. National and regional experiences with COVID-19 have been hugely variable across the globe, reflecting ethnic, governmental, cultural, economic and healthcare differences. This thematic analysis was performed to identify scientific and clinical literature relating to the impact of COVID-19 on children with cancer and treatment.

METHODS
The NHS Evidence portal was used to conduct a healthcare database advanced literature search. Duplicates were removed. Remaining results were screened using clear inclusion and exclusion criteria.

RESULTS
172 results were identified and data extracted. Literature was identified from all 5 continents, with lower and middle income countries well represented. Key themes identified included: 1: Impact on patients already diagnosed, including decreased treatment regimens, impact on outpatient clinics, COVID susceptibility and travel restrictions; 2: Delays in presentation and diagnosis, and national screening programs; 3: The impact of COVID on healthcare professionals; 4: Impact on current and future research; 5: Consequence of global economic crisis on childhood cancer care; 6: Impact on long-term survivorship, late effects and surveillance monitoring.

CONCLUSION
COVID-19 has had a profound effect on health care, and the literature reflects the extent to which communities involved in childhood cancer care have worked together to minimise the impact. It is inevitable that there have been consequences of the pandemic on the treatment of existing patients, and the diagnosis of new ones, but evidence suggest these effects in the short term are minimal. The greatest concerns are for immediate and short-term research conduct.
COVD-03. IMPACT OF COVID-19 ON THERAPY PROVISION FOR CHILDREN WITH CNS TUMOURS
Authors: Hartley Helen , Pizer Barry , Kumar Ram , Owen Joanne , Paisley Helen , White Amillie 
Published: December 2020

Abstract

INTRODUCTION
The COVID-19 pandemic has led to widespread change in the delivery of rehabilitation. The Teenage Cancer Trust reported that 69% of young people with cancer saw their physiotherapist less than usual during the pandemic raising concerns about physiotherapy input.

METHODS
Retrospective analysis of all children’s therapy input managed under the Neuro Oncology Rehabilitation Team (NORT) between 1st April and 30th July 2020. Descriptive analysis of change to physiotherapy provision during this time period by Tertiary and local community services.

RESULTS
49 children were managed under the NORT Therapy Team during this timeframe. 9 children were newly diagnosed with CNS tumours. There was no impact on inpatient therapy provision, 3 had delayed local therapy provision on discharge requiring increased virtual input by the Tertiary centre. 40 children were outpatients managed under the NORT therapy team. 16 children were also receiving regular local physiotherapy input prior to the COVID-19 pandemic. 13 of these children subsequently had their local physiotherapy input suspended during this time period, 8 children were offered virtual input as an alternative by the Tertiary centre, 2 children received increased face to face appointments at the Tertiary centre. 14 of the 24 children managed solely under the Tertiary NORT Therapy Team changed to virtual therapy reviews.

DISCUSSION
There is a clear change in therapy provision as a result of the COVID-19 pandemic. Future research should consider the effectiveness of neurorehabilitation conducted virtually and the impact on physical function of reduced local therapy provision in children with CNS tumours.
DDEL-04. ENGINEERED NANOCARRIERS TO ENHANCE DRUG DELIVERY ACROSS THE BLOOD-BRAIN BARRIER
Authors: Straehla Joelle P , Hajal Cynthia , Safford Hannah , Offeddu Giovanni , Wyckoff Jeffrey , Kamm Roger D , Hammond Paula T 
Published: December 2020

Abstract
Pediatric central nervous system tumors are the leading cause of cancer death in children. Promising therapeutics have been identified, but the ability to deliver an effective concentration to the tumor without causing excessive systemic toxicity remains a challenge. To address this, we leveraged a tunable nanocarrier platform to design a brain-penetrant nanocarrier with preferential uptake into tumor cells over healthy brain cells. First, we used the layer-by-layer technique to iteratively coat liposomes with nanometers-thick layers of oppositely charged polyelectrolytes. To investigate the influence of surface chemistry on cellular trafficking, a panel of layered liposomes was tested for interactions with cancer cell lines, identifying poly-L-aspartic acid and hyaluronic acid as the highest-performing formulations across brain tumor lines. To facilitate nanocarrier transit across the blood-brain barrier (BBB), we developed a click chemistry platform to functionalize the nanocarrier with BBB shuttle ligands. To investigate trafficking in vitro, we utilized a microfluidic brain microvascular model comprising endothelial cells, astrocytes, pericytes, and glioma cells that self-assemble into a perfusable vascular network. We found that nanocarrier size influenced vascular transport, and the addition of BBB shuttle ligands improved transport in the presence of a glioma spheroid. To investigate in vivo nanocarrier trafficking, we performed intravital imaging through a cranial window in anesthetized mice. After intravenous administration, nanocarrier transit across intact brain capillaries was visualized using two photon microscopy, and vessel permeability was quantified over time. Ongoing studies in mice bearing patient-derived xenograft medulloblastoma and glioma tumors are being conducted to further characterize trafficking across tumor-associated vasculature.
DDEL-05. BLOOD-BRAIN BARRIER DISRUPTION AND ENHANCED RADIOSENSITIZERS EXTRAVASATION UPON FOCUSED ULTRASOUND FOR TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Hart Elvin ‘t , Derieppe Marc , Bruin Maaike , Besse Helena , Haumann Rianne , Hoving Eelco , Huitema Alwin , Ries Mario , van Vuurden Dannis 
Published: December 2020

Abstract
Poor prognosis of diffuse midline glioma, including diffuse intrinsic pontine glioma (DIPG), reflects the low efficacy of current treatment strategies, mainly due to (1) a largely intact blood-brain barrier (BBB) and (2) the proficiency of tumour tissues to upregulate multiple DNA repair genes, resulting into radio-resistance. In vitro studies showed therapeutic benefit by combining radiotherapy and radiosensitizers, while pre-clinical and clinical studies evidenced safe and transient opening of the BBB using microbubble mediated focused ultrasound (FUS). Previously, we demonstrated the enhanced extravasation of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor in the mouse pons. Local drug delivery was applied using an in-house built X-ray image-guided FUS system with a 1 MHz mono-element transducer delivering a tone-burst pulse with a mechanical index of 0.4. Tissue/blood drug concentrations were analysed by LC-MS/MS, 30 minutes after intraperitoneal injection of 10 mg/kg olaparib. The FUS system allowed for precise treatment of the pons, proven by local extravasation of Evans Blue-conjugated albumin. A significant 5.1 fold median increase was observed in absolute concentrations in the pons after FUS intervention compared to the control and a 4.9 fold increase of the median tissue-blood ratio (*p&lt;0.05). No significant differences were detected in brain regions outside the ultrasound focus and other organs, confirming the local intervention. With this, the 299 nM equivalent olaparib concentration found in the pons will facilitate PARP inhibition in future murine patient-derived xenograft tumour models, thus leading to a greater therapeutic effect when in combination with radiotherapy treatment of DIPG.