bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCT-02. COMPARISON OF TARGETED AGENTS RECOMMENDED BY THE CNS-TAP TOOL TO THOSE SELECTED BY A TUMOR BOARD IN A MOLECULARLY-DRIVEN DIPG CLINICAL TRIAL
Authors: Roberts Holly , Ravi Karthik , Marini Bernard , Kline Cassie , Mueller Sabine , Koschmann Carl , Franson Andrea 
Published: June 2021

Abstract
Recently, sequencing of diffuse intrinsic pontine glioma (DIPG) biopsy specimens has revealed genomic heterogeneity of these tumors, fueling an interest in individualized, targeted treatment options. The Pacific Pediatric Neuro-Oncology Consortium recently completed enrollment onto a feasibility study PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), in which a multidisciplinary tumor board recommended molecularly-targeted agents based on genomic and molecular profiling of each patient’s tumor. Separately, our group developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to allow for numeric scoring of targeted anticancer agents to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within CNS-TAP would overlap with the agents recommended by the tumor board in this study. For each PNOC003 participant, we utilized the genomic report to identify actionable alterations and input patient-specific data into CNS-TAP to identify the highest scoring agents. We compared high-scoring agents within CNS-TAP with recommendations from the PNOC003 tumor board for each of the enrolled 28 subjects. Overall, 93% (26/28) of patients had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% (37/95) of all agents recommended by the tumor board were also selected by CNS-TAP. Furthermore, we identified factors that likely contributed to the discordance between these two methods. Without clinician input, CNS-TAP is unable to account for drug-drug interactions, includes only designated anticancer agents, and cannot easily be updated in real time. However, CNS-TAP provides an objective evaluation of targeted therapies, whereas tumor boards are inherently subjective. Given the discordance identified between these methods and the strengths of each, a prospective study incorporating both CNS-TAP and a molecular tumor board for targeted therapy selection in DIPG patients is warranted.
EPCT-08. TRIAL WORKING GROUPS FOR PAEDIATRIC BRAIN TUMOURS
Authors: Rahman Ruman , Walker David , Campbell Emma , Aquilina Kristian 
Published: June 2021

Abstract

Introduction
Brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children. These include ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial, intra-CSF and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate any of these. The science and technology underlying these developments is not traditionally embedded within the standard paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures and, in some cases, the testing and licensing of implantable devices, add difficulty at the regulatory level.

Methods
The authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this workshop and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) in 2018 and 2020, the CBTDDC and the recently developed ITCC (Innovative Therapies for Children with Cancer) brain tumour group started working together to set up a new initiative. This aims to develop CNS-delivery-focused trial working groups for paediatric brain tumours.

Results
We have assembled a prestigious steering group, comprising international researchers and clinicians with expertise in diverse aspects of translational and clinical research in CNS drug delivery. At our first group meeting in March, participants will discuss the most effective ways of translating the emerging drug delivery modalities into clinical trials. Prioritised actions will be taken forward and the group will reconvene to discuss developments and next steps at a workshop in the Autumn.

Conclusion
We present this abstract to the SNO Paediatric conference to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.
EPCT-10. DEBIO1347, AN ORAL FGFR INHIBITOR: RESULTS FROM A SINGLE CENTER STUDY IN RECURRENT/REFRACTORY FGFR ALTERED PEDIATRIC GLIOMAS
Authors: Farouk Sait Sameer , Gilheeney Stephen , Bale Tejus , Rosenblum Marc , Haque Sofia , Ibanez Katarzyna , Dinkin Marc , Vitolano Stephanie , Dunkel Ira , Karajannis Matthias 
Published: June 2021

Abstract

Background
Oncogenic driver alterations in FGFR are present in a subset of pediatric gliomas. Debio1347 is an orally available, highly selective FGFR 1–3 inhibitor that had a favorable safety profile and encouraging preliminary clinical activity in an adult phase 1 study.

Methods
Five children with progressive/refractory CNS tumors harboring an FGFR gene alteration following prior therapy were treated with Debio1347 at Memorial Sloan Kettering Cancer Center on single patient use protocols. Patients were treated using the 20 mg tablet formulation at the adult recommended phase 2 dose (80 mg/1.73 m2 * BSA once daily). Toxicities were graded using CTCAEv5.0 and imaging response assessments were performed every 8–12 weeks. RESULTS All AEs were grade 1–2. Most common treatment-related adverse events were hyperphosphatemia, ALT increased and hypoalbuminemia (4 patients). Two patients met criteria for partial response and two patients had stable disease. A 13 month-old patient with a spinal cord high-grade glioma harboring two FGFR1 mutations (V592M, K687E) had tumor reduction of 91.7% maintained for 12 months. A 26-month-old patient with a pilomyxoid astrocytoma harboring an FGFR1-TACC1 fusion had a tumor reduction of 74.5% maintained for 9 months. Molecular characterization of recurrent tumor from this patient demonstrated an NF1 deletion as a novel molecular mechanism of acquired resistance to FGFR inhibition. Prolonged disease stabilization was noted in an eight year-old patient with metastatic suprasellar pilomyxoid astrocytoma harboring an FGFR1 mutation (9 months) and in a 14 year-old patient with posterior fossa glioneuronal tumor harboring an FGFR3-TACC3 fusion (24 months and ongoing).

Conclusions
Debio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with refractory FGFR altered gliomas. Specific attention to growth velocity and clinical symptoms with incorporation of imaging assessment of bone growth is warranted. Candidate biomarkers (FGFR1 V592M and K687E SNVs, FGFR-TACC fusions) may guide patient selection. Further studies in this population are warranted.
EPCT-13. SINGLE INSTITUTION RETROSPECTIVE ANALYSIS OF TUMOR MUTATIONAL BURDEN AND SURVIVAL IN PEDIATRIC BRAIN TUMORS
Authors: Parisi Rose , Patel Roshal , Weintraub Lauren 
Published: June 2021

Abstract
Tumor mutational burden (TMB) has been studied across numerous cancer types as a means of risk stratification. To examine the prognostic relevance of TMB to pediatric central nervous system (CNS) tumors, we conducted a retrospective analysis of patients at Albany Medical Center diagnosed from 2012 to present. Patients were &lt;21 at diagnosis, had a primary CNS tumor and available genomic data. Forty-seven patients were included – 22 low-grade gliomas, 10 high-grade gliomas, 5 medulloblastomas, 3 ependymomas, 2 choroid plexus carcinomas, and 5 other CNS tumors, with a median follow up of 36 months, median age at diagnosis 10 (1–19), and 47% female. Median TMB was 1 mutation per megabase (mut/mb); range 0–6. Nine patients did not have available TMB data. Twenty-seven patients had driver mutations and other alterations implicated in cancer development including, including BRAF-KIAA1549 fusion (n=6), NF1 loss (n=5), FGFR1 amplification (n=4), TP53 inactivation (n=4), BRAF V600E mutation (n=3), and H3F3A K28M mutation (n=3). Patients with low TMB (&lt;3 muts/mb; n=24) versus high TMB (≥3 muts/mb; n=14) had a survival of 87% versus 71%, respectively, at last follow-up. Of note, all but one patient in the low TMB cohort had localized disease at diagnosis versus three in the high TMB cohort. High TMB was more prevalent in high- (45%, 9/20) versus low-grade histologies (22%, 4/18). Patients with BRAF alterations had LGGs and low TMB (0–1 muts/mb) with all patients surviving at last follow up. Of the eight deaths observed (median 18 months from diagnosis) TMB was high in 4, low in 3, and unknown in 1; all had high-grade histology. Although limited, our data suggests higher TMB may be associated with worse outcome. This analysis will be expanded via a multi-institutional review of TMB and genomic alterations in pediatric CNS patients to better identify high-risk patients requiring alternative treatment strategies.
EPCT-14. GD2 CAR T-CELLS MEDIATE CLINICAL ACTIVITY AND MANAGEABLE TOXICITY IN CHILDREN AND YOUNG ADULTS WITH H3K27M-MUTATED DIPG AND SPINAL CORD DMG
Authors: Majzner Robbie , Ramakrishna Sneha , Mochizuki Aaron , Patel Shabnum , Chinnasamy Harshini , Yeom Kristen , Schultz Liora , Richards Rebecca , Campen Cynthia , Reschke Agnes , Mahdi Jasia , Toland Angus Martin Shaw , Baggott Christina , Mavroukakis Sharon , Egeler Emily , Moon Jennifer , Landrum Kayla , Erickson Courtney , Rasmussen Lindsay , Barsan Valentin , Tamaresis John , Marcy Anne , Kunicki Michael , Fujimoto Michelle , Ehlinger Zach , Kurra Sreevidya , Cornell Timothy , Partap Sonia , Fisher Paul , Grant Gerald , Vogel Hannes , Sahaf Bita , Davis Kara , Feldman Steven , Mackall Crystal , Monje Michelle 
Published: June 2021

Abstract

Background
We previously discovered high expression of the disialoganglioside GD2 on H3K27M+ gliomas and demonstrated preclinical efficacy of intravenous (IV) GD2-targeted chimeric antigen receptor (CAR) T-cells in preclinical models of H3K27M-mutated diffuse intrinsic pontine glioma (DIPG) and diffuse midline gliomas (DMGs). We are now conducting a Phase I clinical trial (NCT04196413) of autologous GD2-targeting CAR T-cells for H3K27M+ DIPG and spinal cord DMG. Here we present the results of subjects treated at dose level 1 (DL1; 1 million GD2-CAR T-cells/kg IV).

Methods
Four patients (3 DIPG, 1 spinal DMG; ages 4–25; 1M/3F) were enrolled at DL1. Three subjects with H3K27M+ DIPG received 1e6 GD2-CAR T-cells/kg IV on study. One patient with spinal DMG enrolled but became ineligible after manufacturing and was treated on an eIND at DL1. An Ommaya reservoir was placed in all subjects for therapeutic monitoring of intracranial pressure. Subjects underwent lymphodepletion with fludarabine/cyclophosphamide and remained inpatient for at least two weeks post-infusion.

Results
All subjects developed cytokine release syndrome (Grade 1–3) manifested by fever, tachycardia and hypotension. Other toxicities included ICANS (Grade 1–2) and neurological symptoms/signs mediated by intratumoral inflammation which we have termed Tumor Inflammation-Associated Neurotoxicity (TIAN). No evidence of on-target, off-tumor toxicity was observed in any patients. No dose-limiting toxicities occurred. CAR T cells trafficked to the CNS and were detected in CSF and blood. 3/4 patients exhibited marked improvement or resolution of neurological deficits and radiographic improvement. The patient treated on an eIND exhibited &gt;90% reduction in spinal DMG volume but progressed by month 3. Re-treatment of this subject via intracerebroventricular administration resulted in a second reduction in spinal DMG volume by ~80%.

Conclusions
GD2-CAR T-cells at DL1 demonstrate a tolerable safety profile in patients with H3K27M+ DIPG/DMG with clear signs of T-cell expansion and activity including clinical responses.
EPCT-25. SMO PROTEIN DEPLETION IN SHH MEDULLOBLASTOMAS USING MICROBUBBLE-ENHANCED ULTRASOUND AND SIRNA LOADED CATIONIC NANOPARTICLES
Authors: Guo Yutong , Lee Hohyun , Fang Zhou , Velalopoulou Anastasia , Kim Jinhwan , Thomas Midhun Ben , Liu Jingbo , Abramowitz Ryan G , Kim YongTae , Coskun Ahmet F , Krummel Daniel Pomeranz , Sengupta Soma , MacDonald Tobey J , Arvanitis Costas 
Published: June 2021

Abstract
RNA-based therapies offer unique advantages for treating pediatric brain tumors. However, the systemic delivery remains a major problem due to degradation of unmodified RNA in biological fluids, poor brain accumulation, and poor cancer cell uptake or escape from the endosomal lipid bilayer barrier. While nanoparticle encapsulation can prolong circulation time and facilitate cellular uptake, their accumulation in brain tumor remains particularly poor due to their low permeability across the blood-brain barrier and limited intratumoral penetration. Focused ultrasound, when combined with circulating microbubbles (MB-FUS) provides a physical method to transiently modulate the brain tumor microenvironment (TME) and improve nanoparticle delivery. Here, we have examined the delivery of siRNA targeting the Smoothened (SMO) pathway, packaged in 50 nm cationic lipid-polymer hybrid nanoparticles (cLPH:siRNA-SMO), combined with MB-FUS in murine SmoA2 sonic hedgehog (SHH) medulloblastoma. At 30 hours after treatment, we observed the depletion of the SMO protein target, responsible for driving SHH medulloblastoma formation and growth, in mice that had received treatment with MB-FUS and cLPH:siRNA-SMO, but not with cLPH:siRNA-SMO alone. We also confirmed that SMO protein depletion was spatially achieved in the tumor regions with detected cLPH:siRNA-SMO using FISH assay, and that there was 15 fold induction of tumor cell apoptosis compared to tumors in mice that had received cLPH:siRNA-SMO alone. The limited induction of apoptosis was observed with either cLPH:siRNA (non-targeting) or MB-FUS and cLPH:siRNA (non-targeting), suggest that the observed apoptosis induction in the SmoA2 model was the direct result of SMO depletion rather than nonspecific effects of MB-FUS or cLPH:siRNA. Our findings provide a paradigm shift in drug delivery in brain tumors, where physical methods and nanotechnology are tuned together to develop rational strategies for the effective delivery of nucleic acids in brain tumors.
A Systematic Review and Meta-Analysis of Studies Evaluating the Effect of Medication Treatment for Opioid Use Disorder on Infectious Disease Outcomes
Authors: McNamara Katelyn F , Biondi Breanne E , Hernández-Ramírez Raúl U , Taweh Noor , Grimshaw Alyssa A , Springer Sandra A 
Published: June 2021

Abstract
The opioid epidemic has fueled infectious disease epidemics. We determined the impact of medications for opioid use disorder (MOUD) on treatment outcomes of opioid use disorder (OUD)-associated infectious diseases: antiretroviral therapy (ART) adherence, human immunodeficiency virus (HIV) viral suppression, hepatitis C virus (HCV) sustained virologic response, HCV reinfection, new hepatitis B virus infections, and infectious endocarditis-related outcomes. Manuscripts reporting on these infectious disease outcomes in adults with OUD receiving MOUD compared with those with OUD “not” receiving MOUD were included. Initial search yielded 8169 papers; 9 were included in the final review. The meta-analysis revealed that MOUD was associated with greater ART adherence (odds ratio [OR] = 1.55; 95% confidence interval [CI] = 1.12–2.15) and HIV viral suppression (OR = 2.19; 95% CI = 1.88–2.56). One study suggested a positive association between MOUD and HCV sustained virologic response. There is significant support for integrating MOUD with HIV treatment to improve viral suppression among persons with HIV (PWH) and OUD. Treatment of OUD among PWH should be a priority to combat the opioid and HIV epidemics.
Development of an Electronic Algorithm to Identify in Real Time Adults Hospitalized With Suspected Community-Acquired Pneumonia
Authors: Jones George , Amoah Joe , Klein Eili Y , Leeman Hannah , Smith Aria , Levin Scott , Milstone Aaron M , Dzintars Kathryn , Cosgrove Sara E , Fabre Valeria 
Published: June 2021

Abstract

Background
Community-acquired pneumonia (CAP) is a major driver of hospital antibiotic use. Efficient methods to identify patients treated for CAP in real time using the electronic health record (EHR) are needed. Automated identification of these patients could facilitate systematic tracking, intervention, and feedback on CAP-specific metrics such as appropriate antibiotic choice and duration.

Methods
Using retrospective data, we identified suspected CAP cases by searching for patients who received CAP antibiotics AND had an admitting International Classification of Diseases, Tenth Revision (ICD-10) code for pneumonia OR chest imaging within 24 hours OR bacterial urinary antigen testing within 48 hours of admission (denominator query). We subsequently explored different structured and natural language processing (NLP)–derived data from the EHR to identify CAP cases. We evaluated combinations of these electronic variables through receiver operating characteristic (ROC) curves to assess which best identified CAP cases compared to cases identified by manual chart review. Exclusion criteria were age &lt;18 years, absolute neutrophil count &lt;500 cells/mm3, and admission to an oncology unit.

Results
Compared to the gold standard of chart review, the area under the ROC curve to detect CAP was 0.63 (95% confidence interval [CI], .55–.72; P &lt; .01) using structured data (ie, laboratory and vital signs) and 0.83 (95% CI, .77–.90; P &lt; .01) when NLP-derived data from radiographic reports were included. The sensitivity and specificity of the latter model were 80% and 81%, respectively.

Conclusions
Creating an electronic tool that effectively identifies CAP cases in real time is possible, but its accuracy is dependent on NLP-derived radiographic data.
Multiomics implicate gut microbiota in altered lipid and energy metabolism in Parkinson’s disease
Authors: Pereira Pedro A. B. , Trivedi Drupad K. , Silverman Justin , Duru Ilhan Cem , Paulin Lars , Auvinen Petri , Scheperjans Filip 
Published: June 2021

ABSTRACTWe aimed to investigate the link between serum metabolites, gut bacterial community composition, and clinical variables in Parkinson’s disease (PD) and healthy control subjects (HC). 139 metabolite features were found to be differentially abundant between the PD and Control groups. No associations were found between metabolite features and within-PD clinical variables. The results suggest alterations in serum metabolite profiles in PD, and the results of correlation analysis between metabolite features and microbiota suggest that several bacterial taxa are associated with altered lipid and energy metabolism in PD.
Modern UNOS Data Reveals Septuagenarians have Inferior Heart Transplant Survival
Authors: Suryapalam Manish , Kanaparthi Jay , Kashem Mohammed , Zhao Huaqing , Toyoda Yoshiya 
Published: June 2021

AbstractBackgroundWhile heart transplantation is increasingly performed in the United States for elderly patients, survival outcomes have primarily been analyzed in single-center studies. The few existing long-term studies have indicated no difference in HTx outcomes between patients ≥70 years and 60-69 years age, but these studies only assessed to 5-years post-transplant and included data from the 1980-90s, introducing significant variance due to poorer outcomes in that era. We analyzed the UNOS database from 1987-2020, stratified by timeframe at 2000, to derive a more representative comparison of modern HTx survival outcomes.MethodsAll UNOS HTx recipients over 18 years of age (n=66,186) were divided into 3 cohorts: 18-59, 60-69 and ≥70 years old. Demographic data as well as perioperative factors were evaluated for significance using Chi-Squared and H-Tests as appropriate. Kaplan-Meier Curve and cox regressions with log-rank tests were used to assess 5 through 10 year survival outcomes.Results45,748 were 18-59 years old, 19,129 were 60-69 years old and 1,309 were ≥70 year old. The distribution of most demographic and perioperative factors significantly differed between cohorts. Pairwise survival analysis involving the 18-59 cohort always indicated significance. While there was no significance between the two older cohorts in the earlier timeframe, there was significance in the later timeframe from 6-10 years post-HTx (p<0.05). Cox regressions confirmed results.ConclusionsThe results indicate that since 2000, recipients 60-69 years of age have better 6 through 10-year post-transplant survival than older recipients, a relationship previously obscured by worse outcomes in early data.
Reliability of wastewater analysis for monitoring COVID-19 incidence revealed by a long-term follow-up study
Authors: Sanjuán Rafael , Domingo-Calap Pilar 
Published: June 2021

AbstractBackgroundWastewater-based epidemiology has been used for monitoring human activities and waterborne pathogens. Although wastewaters can also be used for tracking SARS-CoV-2 at the population level, the reliability of this approach remains to be established, especially for early warning of outbreaks.MethodsWe collected 377 samples from different treatment plants processing wastewaters of >1 million inhabitants in Valencia, Spain, between April 2020 and March 2021. Samples were cleaned, concentrated, and subjected to RT-qPCR to determine SARS-CoV-2 concentrations. These data were compared with cumulative disease notification rates over 7 and 14 day periods.ResultsWe amplified SARS-CoV-2 RNA in 75% of the RT-qPCRs, with an estimated detection limit of 100 viral genome copies per liter (gc/L). SARS-CoV-2 RNA concentration correlated strongly with disease notification rates over 14-day periods (Pearson r = 0.962, P < 0.001). A concentration >1000 gc/L showed >95% sensitivity and specificity as an indicator of more than 25 new cases per 100,000 inhabitants. Albeit with slightly higher uncertainty, these figures were reproduced using a 7-day period. Time series were similar for wastewaters data and declared cases, but wastewater RNA concentrations exhibited transient peaks that were not observed in declared cases and preceded major outbreaks by several weeks.InterpretationWastewater analysis provides a reliable tool for monitoring COVID-19, particularly at low incidence values, and is not biased by asymptomatic cases. Moreover, this approach might reveal previously unrecognized features of COVID-19 transmission.FundingConselleria d’Agricultura, Desenvolupament Rural, Emergencia Climàtica i Transició Ecològica of the Generalitat Valenciana (project OTR2020-20593SUBDI), Instituto de Salud Carlos III (FONDO-COVID19 COV20/00210), CSIC (Salud Global CSIC 202020E292), and Ministerio de Ciencia e Innovación (Ramón y Cajal contract, Call 2019).