bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B59: Cardiometabolic complications after pediatric cancer: Associations with chemotherapeutic agents and body-mass-index fluctuations
Authors: Belanger Veronique , Warin Alexandre , Tonova Elitsa , Bouchard Isabelle , Meloche Caroline , Curnier Daniel , Sultan Serge , Laverdiere Caroline , Sinnett Daniel , Marcil Valerie 
Published: August 2020

Abstract
Introduction: Survivors of childhood cancer are at risk of cardiometabolic complications including dyslipidemia, obesity, insulin resistance, and hypertension. In addition, children undergoing chemotherapy often suffer from substantial side effects including rapid weight gain, transient hypertension, and elevated blood glucose and lipids. However, little is known about the cardiometabolic health of children shortly after cancer treatment. This study aims to describe the cardiometabolic profile of children after treatment and to study the factors associated with these complications.
Methods: Participants were recruited at Sainte-Justine UHC in Montreal as part of the VIE Program (Valorization, Implication, Education). Cardiometabolic health was assessed with biochemical, clinical, and anthropometric measures. Data on treatment (diagnosis, chemotherapeutic agents, and doses) were obtained from medical files.
Results: Evaluations were performed on 71 participants (45% boys; median age: 9.8 years; 42% with acute lymphoblastic leukemia; median time since last treatment: 1.4 years, range: 0.2-3.5 years). Our assessment showed that 28% had hypertension, 27% were obese, 19% had altered glucose metabolism, and 33% had dyslipidemia. The risk of having dyslipidemia was associated with higher age [relative risk (RR): 1.28, 95%CI: 1.14-1.44, P&lt;0.01] and body mass index (BMI) (RR: 1.76, 95%CI: 1.11-2.78, P=0.02). Participants who increased their BMI during treatment were at higher risk of obesity (RR: 3.01, 95%CI: 1.44-6.29, P&lt;0.01). The increase of BMI during treatment was associated with exposure to glucocorticoids (coefficient β: 0.56, 95%CI: 0.13-0.98, P=0.01) and to methotrexate (coefficient β: 0.73, 95%CI: 0.34-1.11, P&lt;0.01).
Conclusion: We found important alterations of children’s cardiometabolic profile shortly after the end of cancer treatment. Increased BMI during and after treatment and exposure to corticosteroids and methotrexate were factors associated with cardiometabolic health. This stresses the importance of maintaining a favorable nutritional status during cancer therapy. Early nutritional interventions promoting sustainable healthy eating habits may contribute to limit cardiometabolic complications in the short and long term.
Citation Format: Veronique Belanger, Alexandre Warin, Elitsa Tonova, Isabelle Bouchard, Caroline Meloche, Daniel Curnier, Serge Sultan, Caroline Laverdiere, Daniel Sinnett, Valerie Marcil. Cardiometabolic complications after pediatric cancer: Associations with chemotherapeutic agents and body-mass-index fluctuations [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B59.
Abstract IA01: Pediatric neuro-oncology: What’s next?
Authors: Pfister Stefan M. 
Published: August 2020

Abstract
Based on recent discoveries and data integration in genomics and epigenomics, a lot more is known about the biology of childhood brain tumors today when compared to a decade ago. This has vastly benefitted brain tumor diagnostics, including classification and some predictive and prognostic biomarkers. Yet the gap between this newly defined diagnostic gold standard and routine clinical implementation largely remains to be bridged. Additionally, the cell of origin for a majority of brain tumor entities remains elusive. The increased granularity of understanding intertumor heterogeneity also comes with the challenge of accounting for this heterogeneity in our therapeutic approaches. Ever-smaller patient groups and, on the other hand, an ever-increasing portfolio of potentially available drugs, require a paradigm shift in how we run and evaluate preclinical and clinical trials. Academically rewarding proof-of-concept studies that are typically well published, which certainly have a different purpose and thus lack the rigor of thorough preclinical filtering (because they typically embark on one or two “representative” models, which certainly does not cover the heterogeneity of a disease by any means), should no longer be regarded “sufficient preclinical evidence” to justify a clinical trial. Thus, novel incentives and funding models for this “less academically attractive,” but highly patient-relevant studies need to be explored. Phase I trials just with the purpose of dose finding should not be carried without a path forward into efficacy testing. Drugs with no evidence for brain penetration should not “just” be tried in patients with brain tumors without even making the best effort to understand brain and tumor penetrance. Academic work-up of biologic material from every single patient being enrolled on a trial should be mandatory rather than “nice to have.” Hereditary cancer predisposition should no longer be ignored when it comes to treatment stratification. Reimbursement models for “next-generation diagnostics,” preclinical phase I and phase II studies, and academic clinical trials (focusing on combinations rather than monotherapies in end-stage disease) have to shift from traditional third-party funding to alternative funding models. If we do not manage to address this paradigm shift, high-risk brain tumor patients may still mostly die from their disease 10 years from now.
Citation Format: Stefan M. Pfister. Pediatric neuro-oncology: What’s next? [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA01.
Abstract IA03: Medulloblastoma predisposition according to molecular subgroup: The usual suspects and beyond
Authors: Northcott Paul A. 
Published: August 2020

Abstract
Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses, and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5-6% of all MB patients. The incidence of genetic predisposition to MB varied according to patient age and molecular subgroup status, with up to 25% of childhood SHH-MB patients predicted to harbor pathogenic germline variation. These estimates only account for known cancer predisposition genes, and ongoing studies designed to investigate unknown pathogenic events in the germline of MB patients have implicated novel MB predisposition genes. This presentation aims to summarize these recent insights into genetic predisposition to MB and contextualize these findings with their associated clinical implications.
Citation Format: Paul A. Northcott. Medulloblastoma predisposition according to molecular subgroup: The usual suspects and beyond [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA03.
Abstract IA20: Neuronal activity promotes proliferation of normal and neoplastic glial cells
Authors: Monje Michelle 
Published: August 2020

Abstract
Neuronal activity regulates the proliferation and differentiation of oligodendrocyte precursor cells during development and in adulthood. In the healthy brain, this results in activity-regulated plasticity of myelination and subsequent modulation of neural circuit function evident in oligodendrogenesis-dependent behavioral changes. The robust mitogenic effect of neuronal activity on normal neural precursor and oligodendroglial precursor cells, a putative cellular origin of pediatric high-grade gliomas (HGG), suggests that dysregulated or “hijacked” mechanisms of myelin plasticity might similarly promote proliferation in this devastating group of childhood brain cancers. Using in vivo and in situ optogenetic techniques together with patient-derived high-grade glioma cell cultures and xenograft models, we have demonstrated that neuronal activity similarly promotes proliferation and growth of both pediatric and adult high-grade glioma subtypes. Crucial mechanisms mediating activity-regulated high-grade glioma growth include secretion of Brain Derived Neurotrophic Factor (BDNF) and the synaptic protein neuroligin-3 (NLGN3), which induces multiple oncogenic signaling pathways together with robust changes in synaptic gene expression in glioma cells. Nlgn3 is necessary for the growth of high-grade glioma xenografts in the mouse brain, and NLGN3 expression levels in human HGG negatively correlate with patient overall survival. Thus, neuronal activity not only modulates the structure and function of the brain’s myelinated infrastructure, but neurons also play an important role in the brain tumor microenvironment, with activity-regulated secretion of NLGN3 emerging as an unexpected and therapeutically targetable mechanism underlying axon-glioma interactions and promoting neuronal activity-regulated cancer growth.
References: Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Inema I, Miller SE, Bieri G, Zuchero JB, Barres BA, Woo PJ, Vogel H, Monje M. Neuronal activity promotes adaptive oligodendrogenesis and myelination in the mammalian brain. Science 2014;344 (6183):487; 344:1252304. Venkatesh HS, Johung T, Caretti V, Noll A, Tang Y, Nagaraja S, Gibson EM, Mount CW, Pollepalli J, Mitra SS, Woo PJ, Malenka RM, Vogel H, Bredel M, Mallick P, Monje M. Neuronal activity promotes glioma growth through neuroligin-3 secretion, Cell 2015;161(4):803-16. Venkatesh HS, Tam LT, Woo PJ, Nagaraja S, Gillespe SM, Lennon J, Ni J, Duveau DY, Morris PJ, Zhao JJ, Thomas CJ, Monje M. Targeting neuronal activity-regulated neuroligin-3 dependency for high-grade glioma, Nature 2017;549:533-37.
Citation Format: Michelle Monje. Neuronal activity promotes proliferation of normal and neoplastic glial cells [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA20.
Abstract IA22: Tumor cells highjack diverse cellular processes to maintain redox balance
Authors: Zhang Hai-Feng , El Naggar Amal M. , Cheng Hongwei , Li Wei , Dimitrov Dimiter S. , Sorensen Poul H. 
Published: August 2020

Abstract
In aggressive sarcomas such as Ewing sarcoma (EwS) and osteosarcoma (OS), the single most powerful predictor of poor outcome is metastatic disease, highlighting the critical need to identify new factors driving metastasis in these diseases. Metastasis is widely regarded as a very inefficient process, likely due to diverse stress forms that can potentially cull premetastatic cancer cells during the metastatic cascade, including hypoxia in primary tumors, anoikis stress in the circulation, and increased oxidative stress at distant organs prior to colonization. Adaptation to such conditions requires rapid stress-alleviating plasticity to confer fitness for metastatic progression, but mechanisms remain elusive. Studies in our laboratory indicate that mitigation of oxidative stress, not only during local invasion at the primary tumor site but also in the circulation during dissemination, and potentially as part of colonization at distant sites, is critical for childhood sarcoma metastatic capacity. Indeed, EwS and OS cells appear to utilize many different strategies to maintain redox balance, such as the induction of antioxidant pathways involving NRF2 or through other mechanisms such as alterations in amino acid transporter systems to facilitate production of glutathione and other antioxidants via amino acid metabolism. Some of these pathways are transcriptionally regulated, such as by direct activation of EWS-ETS fusion targets, while others are regulated through rapid translational activation by pioneer translation factors such as YB-1. Examples of each of these processes will be discussed.
Citation Format: Hai-Feng Zhang, Amal M. El Naggar, Hongwei Cheng, Wei Li, Dimiter S. Dimitrov, Poul H. Sorensen. Tumor cells highjack diverse cellular processes to maintain redox balance [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA22.
Abstract IA23: Lessons from a rare childhood cancer syndrome on replication repair deficiency and hypermutation
Authors: Tabori Uri Y. 
Published: August 2020

Abstract
In order to divide, cells need to replicate their DNA. Replication is done by DNA polymerase epsilon and delta (POLE and POLD1) and creates thousands of mistakes per each replication cycle. The major components safeguarding our genome against such mutations are the proofreading capacity of both polymerases and the mismatch repair (MMR) genes. Germline mutations in either POLE or the MMR genes result in the most aggressive childhood cancer syndromes with high penetrance of cancers during childhood with the hallmark of extreme hypermutation. Data from the International Replication Repair Deficiency (RRD) Consortium reveal that this phenomenon is not restricted to the rare cancer syndrome and affects 5% of childhood cancers throughout many tissues. Hypermutation is observed in up to 10% of recurrent childhood cancers and 20% of adult cancers. Recent data reveal that there are a variety of mutational signatures that are associated with each cause of RRD and hypermutation. These mutations can be traced to the germline or previous therapy. Furthermore, signatures are not restricted to SNV but can be observed by insertions and deletions in microsatellites. Animal models of RRD shed new light on the process of tumorigenesis and mutation progression in RRD cancers and their impact on inter- and intratumoral heterogeneity. Together, these data provide an Achilles heel to these tumors where immunotherapy and combinations can improve survival for patients with germline RRD and children with RRD hypermutant cancers. Novel biomarkers of response to immunotherapy provide insight into the patterns of immune and tumor interactions in these patients.
Citation Format: Uri Y. Tabori. Lessons from a rare childhood cancer syndrome on replication repair deficiency and hypermutation [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA23.
Abstract IA28: Tumor uniformity
Authors: Behjati Sam 
Published: August 2020

Abstract
Intra- and intertumor heterogeneity has emerged as a near-universal feature of human cancer. The definition of heterogeneity has advanced our understanding of various biologic and clinical challenges. At the same time, however, it distracts from unifying features of tumor that may lend themselves as universal targets. Here, I outline some observations from single-cell RNA sequencing experiments of childhood and adult cancers that indicate that transcriptional cellular identity transcends intra- and intertumor heterogeneity. Accordingly, the cellular transcriptome may in some cases represent a tumor-overarching target.
Citation Format: Sam Behjati. Tumor uniformity [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA28.
Abstract IA31: Stalled developmental programs at the root of K27M mutant gliomas and other pediatric brain tumors
Authors: Jabado Nada 
Published: August 2020

Abstract
Childhood brain tumors have suspected prenatal origins. We showed that H3K27M in gliomas impairs the production and the spread of the repressive H3K27me3 mark from PRC2 high-affinity sites. Neither the recruitment of PRC2 to its nucleation sites nor the deposition of the H3K27me3 mark in the proximity of those sites was affected by the mutation. However, our findings indicate that as the marks cannot spread to establish the proper silencing landscape, further lineage specification, a major role of PRC2, is not possible, and the cell is stalled in an early epigenetic and progenitor state, indefinitely multiplying without being able to further differentiate. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of &gt;44,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 119 distinct cell populations and defined regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage, embryonal tumors with multilayered rosettes fully recapitulate a cortical neuronal lineage, atypical teratoid-rhabdoid tumors originate outside of the neuro-ectoderm, while diffuse intrinsic pontine gliomas resemble a pontine astrocytic progenitor and differentiate upon removal of driver mutation H3K27M. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies mirroring transcriptional programs of the corresponding normal lineages. We identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.
Citation Format: Nada Jabado. Stalled developmental programs at the root of K27M mutant gliomas and other pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA31.
Abstract PR04: Locoregionally administered B7H3-targeting CAR T cells mediate potent antitumor effects in atypical teratoid/rhabdoid tumor
Authors: Theruvath Johanna , Sotillo Elena , Graef Claus Moritz , Heitzeneder Sabine , Labanieh Louai , Majzner Robbie , Mackall Crystal 
Published: August 2020

Abstract
Atypical teratoid/rhabdoid tumors (ATRT) are highly malignant embryonal brain tumors, arising in very young children, and are associated with inactivation of SMARCB1. The prognosis is extremely poor. Hence new treatments are urgently needed. We show that 100% of ATRT express B7-H3 and residual SMARCA4 SWI/SNF activity drives B7-H3 expression. Further, we demonstrate that prenatal brain expresses high levels of B7-H3, but expression is absent on pediatric brain, suggesting that the cell of origin may conserve high B7-H3 expression. We recently created a 4-1BB second-generation CAR targeting B7-H3. To date, there are little data on the most efficacious route of administration of CAR T cells in malignant brain tumors. The goal of this study was to test the antitumor activity of the B7-H3 CAR in highly aggressive ATRT xenograft models and compare intracavitary (IT), intraventricular (ICV), and intravenous (IV) administration in terms of efficacy, toxicity, and persistence of CAR T cells. Locoregionally (IT and ICV) administered B7H3.BB.z-CAR T cells mediate potent antitumor effects against cerebral ATRT xenografts, with more rapid kinetics, greater potency, and diminished systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. ICV-administered CAR T cells also demonstrate robust trafficking from the CNS into the periphery, and following clearance of ATRT xenografts, ICV or IV administered B7H3.BB.z-CAR T cells mediate antigen specific protection from tumor rechallenge in the CNS or in the flank. In summary, B7H3 is a promising immune target for this largely incurable pediatric tumor. We demonstrate that CNS delivered CAR T cells cure ATRT xenografts and efficiently traffic from the CNS into the periphery and can mediate long-term immune protection from disease recurrence in the CNS or in peripheral tissues.
This abstract is also being presented as Poster A12.
Citation Format: Johanna Theruvath, Elena Sotillo, Claus Moritz Graef, Sabine Heitzeneder, Louai Labanieh, Robbie Majzner, Crystal Mackall. Locoregionally administered B7H3-targeting CAR T cells mediate potent antitumor effects in atypical teratoid/rhabdoid tumor [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr PR04.
Integrative Genomic Analysis Reveals Four Protein Biomarkers for Platelet Traits
Authors: Lee Dong Heon , Yao Chen , Bhan Arunoday , Schlaeger Thorsten , Keefe Joshua , Rodriguez Benjamin A.T. , Hwang Shih-Jen , Chen Ming-Huei , Levy Daniel , Johnson Andrew D. 
Published: August 2020

Rationale:
Mean platelet volume (MPV) and platelet count (PLT) are platelet measures that have been linked to cardiovascular disease (CVD) and mortality risk. Identifying protein biomarkers for these measures may yield insights into CVD mechanisms.

Objective:
We aimed to identify causal protein biomarkers for MPV and PLT among 71 CVD-related plasma proteins measured in FHS (Framingham Heart Study) participants.

Methods and Results:
We conducted integrative analyses of genetic variants associated with PLT/MPV with protein quantitative trait locus variants associated with plasma proteins followed by Mendelian randomization to infer causal relations of proteins for PLT/MPV. We also tested protein-PLT/MPV association in FHS participants. Using induced pluripotent stem cell-derived megakaryocyte clones that produce functional platelets, we conducted RNA-sequencing and analyzed expression differences between low- and high-platelet producing clones. We then performed small interfering RNA gene knockdown experiments targeting genes encoding proteins with putatively causal platelet effects in megakaryocyte clones to examine effects on platelet production. In protein-trait association analyses, ten proteins were associated with MPV and 31 with PLT. Mendelian randomization identified 4 putatively causal proteins for MPV and 4 for PLT. GP-5 (Glycoprotein V), GRN (granulin), and MCAM (melanoma cell adhesion molecule) were associated with PLT, while MPO (myeloperoxidase) showed significant association with MPV in both analyses. RNA-sequencing analysis results were directionally concordant with observed and Mendelian randomization-inferred associations for GP-5, GRN, and MCAM. In siRNA gene knockdown experiments, silencing GP-5, GRN, and MPO decreased PLTs. Genome-wide association study results suggest several of these may be linked to CVD risk.

Conclusions:
We identified 4 proteins that are causally linked to PLTs. These proteins may also have roles in the pathogenesis of CVD via a platelet/blood coagulation-based mechanism.