tbuckley/cabot-search huggingface dataset:
HGG-36. HIF-2: A NEW DRUG TARGET IN PEDIATRIC HIGH-GRADE GLIOMA WITH PROMISING PRECLINICAL RESULTS
Authors: Quentin Fuchs, Marina Pierrevelcin, Christophe Papin, Monique Dontenwill, Natacha Entz-Werlé
Journal: Neuro-Oncology (2020)

Abstract Pediatric high-grade gliomas (pHGGs) have a very dismal prognosis and need new innovative strategy for treatment. Despite the past discovery of histone H3 driver mutations, we are not able for instance to stop this induced epigenetic remodulation. Therefore, proactive translational studies wish to go further discovering new targetable proteins in pHGG. In our past clinical work, we were able to link significantly HIF-2alpha to a worse pHGG outcome and to their treatment resistance. We designed this new work to determine in several patient-derived cell lines (6 PDCLs) with or without H3.3 mutation the variation of HIF-2alpha, its role, its induction in normoxic and hypoxic microenvironment and its transcriptional targets using RNAseq, metabolomics and ChipSeq analyses. Complementary functional analyses were performed using siRNA strategy during cultures and migration assays. Finally, preclinical drug testing involving commercialized and non-commercialized HIF-2alpha specific inhibitors in the same PDCLs were evaluating their antiproliferative and pro-apoptotic effect. Our results confirmed the central role of HIF-2alpha in cell resistance to treatment, in pHGG stemness features and its direct link with metabolism adaptation and histone interaction. After the confirmation of its frequent presence in multiple PDCLs initiated from thalamic pHGGs and DIPG, we were using inhibitors in a single and combinatorial strategy targeting HIF-2alpha plus another hypoxia biomarker (mTor). This preclinical targeting was highly effective to favor cell arrest, apoptosis and to stop cell migration. In conclusion, HIF-2alpha seem to be a major biomarker in pHGGs that might be targeted giving a useful new opportunity for pHGG treatments.
GCT-23. MULTI-INSTITUTIONAL ANALYSIS OF TREATMENT MODALITIES IN BASAL GANGLIA AND THALAMIC GERMINOMA
Authors: Richard T Graham, Mohammad H Abu-Arja, Joseph Stanek, Ute Bartels, Andrea Cappellano, Susan Chi, Tabitha Cooney, Girish Dhall, Jonathan L Finlay, Michael J Fisher, Gregory Friedman, Amar Gajjar, Karen Gauvain, Lindsey M Hoffmann, Juliette Hukin, Ashley Margol, Sabine Mueller, Pournima Navalkele, Rebecca Ronsley, Stephanie Villeneuve, Kee Kiat Yeo, Jack M Su, Nicholas G Gottardo, Jeffrey Allen, Roger Packer, Mohamed AbdelBaki
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Central nervous system (CNS) germinomas are radiotherapy (RT)-sensitive tumors with excellent survival. Current treatment strategies combine chemotherapy with RT to reduce the field and dose of RT. There is no standard treatment for germinomas originating in the basal ganglia/thalami (BGTG) given their rarity and poorly-defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have been previously utilized; however, the optimal strategy remains unclear. METHODS Retrospective multi-institutional analysis was conducted across 18 institutions in four countries. RESULTS For 46 cases with non-metastatic BGTG, the event-free survival (EFS) was 86.9% at both 5 and 10 years, while overall survival (OS) was 100%, and 95.7% respectively at 5 and 10 years. Median RT dose and range for the various treatment volumes were as follows: CSI (n=10): 2340 cGy (1980–3060 cGy), WBI (n=8): 2340 (1800–3000 cGy), WVI (n=14): 2340 cGy (1800–2550 cGy), focal (n=9): 3600 cGy (3060–5400 cGy). There was no statistically significant difference in the EFS based on RT modality (p=0.57), but EFS for subjects with CSI and WBI were both 100%. The three subjects who received chemotherapy alone had significantly lower EFS than those who received chemotherapy and RT (p=0.001), but were salvageable with RT. CONCLUSION In the largest study to date for BGTG, there were no significant differences in outcomes between patients who received CSI, WBI, WVI or focal RT. This group of patients should be included in future prospective clinical trials, and a more limited RT field may be considered.
Arginine Deprivation and Autophagy Sustain Bioenergetics in Multiple Myeloma
Authors: Alessandra Romano, Laura Oliva, Jose Manuel Manteiga, Todoerti Katia, Lorenzo Canziani, Matteo Trudu, Francesca Fontana, Michela Ghizzinardi, Ugo Orfanelli, Magda Marcatti, Fabio Ciceri, Giovanni Tonon, Antonino Neri, Claudio Cerichione, Francesco Di Raimondo, Simone Cenci
Journal: Blood (2017)
IMMU-23. A NOVEL MASS CYTOMETRY-BASED MULTI-PARAMETER CHARACTERIZATION OF NEOANTIGEN-REACTIVE CD8+ T-CELLS IN PATIENTS PARTICIPATING IN PNOC007 H3.3K27M PEPTIDE VACCINE CLINICAL TRIAL
Authors: Jared Taitt, Takahide Nejo, Payal Watchmaker, Neil Almeida, Kaori Okada, Maryam Shahin, Ryan Gilbert, Annette Molinaro, Michael Prados, Sabine Mueller, Hideho Okada
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND We have identified an HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a multi-center clinical trial of the peptide vaccine through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007) for patients with diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG). We sought to characterize vaccine-reactive CD8+T-cells subpopulations using their precise activation and developmental status to find their associations with clinical outcomes. METHODS Mass cytometry (CyTOF) analysis was performed on patient-derived peripheral blood mononuclear cells collected at baseline as well as pre-specified time points throughout the study. Each cell subtype was characterized via tSNE-clustering based on their expression profiles and quantified as a fraction of total CD45+cells. H3.3K27M-reactive CD8+T-cells were evaluated using an H3.3K27M-HLA-A2 dextramer along with a panel of T-cell and myeloid markers. RESULTS Among all 29 patients enrolled, we analyzed samples from all 19 DIPG and 9 of 10 non-brainstem DMG cases, of which 18 had longitudinal samples available (range: 2–5). Utilizing a novel CyTOF-based immuno-monitoring platform, the expansion of H3.3K27M-reactive CD8+T-cells, defined as a 25% increase at any time-point relative to baseline, was observed in 7 of these 18 patients. Survival analyses indicated that the expansion of H3.3K27M-reactive CD8+T-cells, particularly the effector-memory phenotype, positively correlated with longer overall survival (OS) (median: 16.1 vs 9.7 months, p=0.03), whereas an abundance of early and monocytic myeloid-derived suppressor cells at baseline correlated with shorter OS among DIPG patients (9.5 vs 14.3 months, p=0.002). CONCLUSION Our novel immuno-monitoring approach offers insight into how vaccine-induced immune responses impact clinical outcomes.
MBCL-37. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDREN NEWLY DIAGNOSED WITH CLASSIC (CLMB) OR ANAPLASTIC/LARGE CELL (A/LCMB) MEDULLOBLASTOMA UP TO THE ERA OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMES ANALYSIS
Authors: Jonathan Finlay, Martin Mynarek, Girish Dhall, Claire Mazewski, Richard Grundy, Bruce H Cohen, Giles Robinson, David Ashley, Joseph R Stanek, Amar Gajjar, Stefan Rutkowski
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND/OBJECTIVE The introduction of German regimens, supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), report encouraging outcomes for young children with medulloblastoma. We performed a comparative outcomes analysis of treatment strategies for young children with ClMB or A/LCMB. DESIGN/ METHODS Data from 12 prospective multi-center trials published between 2005 and 2019 for children &amp;lt;six-years-old with ClMB or A/LCMB were reviewed; survivals were compared. RESULTS COG-9921, UKCCSG-CNS9204, COG-P9934 and SJYCO7 employing standard chemotherapy with either no or risk-based irradiation, reported 3-5-year event-free survival (EFS) of 17+/-5%, 33+/-28% (ClMB), 14+/-7% and 13.8+/-9% (ClMB) respectively, with reported EFS of 0% for A/LCMB in UKCCSG-CNS9204 and SJYCO7. HIT-SKK’87, HIT-SKK’92 and HIT-SKK’00 incorporating HD-MTX and IVENT-MTX reported 2-10-year EFS of 30–34+/-10–11% for ClMB and 33+/-27% (HIT-SSK’00) for A/LCMB. Head Start HS-I-II combined, CCG-99703 and HS-III employing induction chemotherapy, with or without HD-MTX, followed by single or tandem HDCx+AuHCR reported 3-5-year EFS of 42+/-14%, 50+/-11% and 27+/-6% for ClMB, with EFS for A/LCMB of 38+/-13% (HS-III). Finally, 5-year overall survivals for ACNS0334, without or with induction HD-MTX, are 39% and 69% respectively for ClMB and A/LCMB combined. CONCLUSIONS A trend towards better outcomes for young children with ClMB and A/LCMB is observed in trials including either HD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.
Nanomedicine of tyrosine kinase inhibitors
Authors: Veronika Smidova, Petr Michalek, Zita Goliasova, Tomas Eckschlager, Petr Hodek, Vojtech Adam, Zbynek Heger
Journal: Theranostics (2020)

Recent progress in nanomedicine and targeted therapy brings new breeze into the field of therapeutic applications of tyrosine kinase inhibitors (TKIs). These drugs are known for many side effects due to non-targeted mechanism of action that negatively impact quality of patients' lives or that are responsible for failure of the drugs in clinical trials. Some nanocarrier properties provide improvement of drug efficacy, reduce the incidence of adverse events, enhance drug bioavailability, helps to overcome the blood-brain barrier, increase drug stability or allow for specific delivery of TKIs to the diseased cells. Moreover, nanotechnology can bring new perspectives into combination therapy, which can be highly efficient in connection with TKIs. Lastly, nanotechnology in combination with TKIs can be utilized in the field of theranostics, i.e. for simultaneous therapeutic and diagnostic purposes. The review provides a comprehensive overview of advantages and future prospects of conjunction of nanotransporters with TKIs as a highly promising approach to anticancer therapy.
Genetic Variants Associated with Therapy-Related Cardiomyopathy among Childhood Cancer Survivors of African Ancestry
Authors: Yadav Sapkota, Na Qin, Matthew J. Ehrhardt, Zhaoming Wang, Yan Chen, Carmen L. Wilson, Jeremie Estepp, Parul Rai, Jane S. Hankins, Paul W. Burridge, John L. Jefferies, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, Gregory T. Armstrong, Daniel A. Mulrooney, Yutaka Yasui
Journal: Cancer Research (2020)

Abstract Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiotherapy; n = 246) were compared with cardiotoxic-exposed survivors of European ancestry (n = 1,645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2–4 and grade 3–4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF (rs6689879*C: EF reduction = 4.2%; P = 2.8 × 10−8) in 246 survivors of African ancestry, which was successfully replicated in 1,645 survivors of European ancestry but with attenuated magnitude (EF reduction = 0.4%; P = 0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2–4 cardiomyopathy, the PHTF1 promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2–4 cardiomyopathy. PHTF1 was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry. Significance: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry, and a novel locus at 1p13.2 is associated with therapy-related cardiomyopathy specifically in African-American survivors. See related commentary by Brown and Richard, p. 2272
Response to Front-Line Imatinib Treatment in Children and Adolescents with CML - Data from a Large Pediatric Cohort
Authors: Meinolf Suttorp, Philipp Schulze, Ingmar Glauche, Gudrun Göhring, Nils Von Neuhoff, Markus Metzler, Petr Sedlacek, Eveline S. de Bont, Adriana Balduzzi, Birgitte Lausen, Olga Aleinikova, Sabina Sufliarska, Guenter Henze, Gabriele Strauss, Angelika Eggert, Bernhard Kremens, Andreas H Groll, Frank Berthold, Christoph Klein, Ute Gross-Wieltsch, Karl-Walter Sykora, Arndt Borkhardt, Andreas E. Kulozik, Martin Schrappe, Christina Nowasz, Manuela Krumbholz, Josephine Tabea Tauer, Alexander Claviez, Jochen Harbott, Hans H Kreipe, Brigitte Schlegelberger, Christian Thiede
Journal: Blood (2017)
Response to: ‘Correspondence on ‘Risk of systemic lupus erythematosus after immune thrombocytopenia and autoimmune haemolytic anaemia: a nationwide French study’’ by Maquet<i>et al</i>
Authors: Xiao-Huan Chen, Fang-Xiao Zhu, Hsin-Hua Chen, James Cheng-Chung Wei
Journal: Annals of the Rheumatic Diseases (2021)

Table 1 Multivariable stratified analyses for the risk of SLE associated with ITP or AIHA exposure in the propensity-score matched (1:2) populations ITP AIHA Non-ITP ITP HR (95% CI) P value P for interaction Non-AIHA AIHA HR (95% CI) P value P for interaction No. of events/total no. of patients (per 10 5 person months) No. of events/total no. of patients (per 10 5 person months) Overall 5/6358 (1.36) 307/3179 (197.44)135.91 (56.16 to 328.92) <0.
RONC-19. TWO CASES OF RE-IRRADIATION FOR LATE RECURRENT OR RADIATION-INDUCED TUMOR AFTER RADIATION THERAPY FOR PEDIATRIC BRAIN TUMORS
Authors: Takashi Mori, Shigeru Yamaguchi, Rikiya Onimaru, Takayuki Hashimoto, Hidefumi Aoyama
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND As the outcome of pediatric brain tumors improves, late recurrence and radiation-induced tumor cases are more likely to occur, and the number of cases requiring re-irradiation is expected to increase. Here we report two cases performed intracranial re-irradiation after radiotherapy for pediatric brain tumors. CASE 1: 21-year-old male. He was diagnosed with craniopharyngioma at eight years old and underwent a tumor resection. At 10 years old, the local recurrence of suprasellar region was treated with 50.4 Gy/28 fr of stereotactic radiotherapy (SRT). After that, other recurrent lesions appeared in the left cerebellopontine angle, and he received surgery three times. The tumor was gross totally resected and re-irradiation with 40 Gy/20 fr of SRT was performed. We have found no recurrence or late effects during the one year follow-up. CASE 2: 15-year-old female. At three years old, she received 18 Gy/10 fr of craniospinal irradiation and 36 Gy/20 fr of boost to the posterior fossa as postoperative irradiation for anaplastic ependymoma and cured. However, a anaplastic meningioma appeared on the left side of the skull base at the age of 15, and 50 Gy/25 fr of postoperative intensity-modulated radiation therapy was performed. Two years later, another meningioma developed in the right cerebellar tent, and 54 Gy/27 fr of SRT was performed. Thirty-three months after re-irradiation, MRI showed a slight increase of the lesion, but no late toxicities are observed. CONCLUSION The follow-up periods are short, however intracranial re-irradiation after radiotherapy for pediatric brain tumors were feasible and effective.
RADT-27. ASSOCIATION BETWEEN ADJUVANT RADIATION THERAPY AND OVERALL SURVIVAL IN PLEOMORPHIC XANTHOASTROCYTOMA
Authors: Adham Khalafallah, Maureen Rakovec, Debraj Mukherjee
Journal: Neuro-Oncology (2020)

Abstract Pleomorphic Xanthoastrocytoma (PXA) is a low-grade central nervous system (CNS) tumor with a generally favorable prognosis. However, due to its rarity, optimal adjuvant treatment guidelines have not been established by large scale studies. In this study, we investigated the effect of adjuvant radiation therapy (RT) on overall survival (OS) in adult patients with PXA to help address this unanswered question. The National Cancer Database (NCDB) was used to identify adult patients (age 18 years old) diagnosed with histologically confirmed PXA (2004-2016). Patient demographics, tumor characteristics, and treatment information were collected. Kaplan-Meier curves were generated to study OS, and factors that affected OS were identified using a multivariate Cox proportional hazards (CPH) model. A total of 546 patients were identified. The average age of patients at diagnosis was 36.6 years old, and overall median survival was 128.6 months. RT was used to treat 179 (33.3%) patients. Those who received RT had a shorter median OS (33.3 months) compared to those who did not (&amp;gt; 128.6 months, p &amp;lt; 0.001). Our multivariate model demonstrated receiving RT was independently associated with a significantly higher risk of death (hazard ratio [HR]=4.28, 95% confidence interval [CI] = 1.77-10.38, p = .0013). Patients ≥ 65 years of age also demonstrated significantly higher risk of death (HR = 2.20, CI = 1.54-4.16, p = 0.006) and had a decreased median OS (26.0 months). In adults with PXA, treatment with RT is independently associated with a significantly higher risk of mortality. The routine use of this modality in treating PXA warrants further study.
DIPG-27. TARGETING FACILITATES CHROMATIN TRANSCRIPTION (FACT) AS A NOVEL STRATEGY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) THAT ENHANCES RESPONSE TO HISTONE DEACETYLASE (HDAC) INHIBITION
Authors: Anahid Ehteda, Laura Franshaw, Jie Liu, Swapna Joshi, Sandy Simon, Chi Nam Ignatius Pang, Federico Giorgi, Ruby Pandher, Caitlin Ung, Ornella Tolhurst, Chelsea Mayoh, Aaminah Khan, Elisha Hayden, Anjana Gopalakrishnan, Peter Trebilcock, Dannielle Upton, Rebecca Lehmann, Sandra George, Orazio Vittorio, Maria Tsoli, Katerina Gurova, Andrei Gudkov Gudkov, Murray D Norris, Michelle Haber, David S Ziegler
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumour for which new treatments are needed. A high throughput drug screen of 3500 pharmaceutical compounds identified anti-malarials, including quinacrine as having potent activity against DIPG neurospheres. CBL0137, a compound modelled on quinacrine, is an anti-cancer compound which targets Facilitates Chromatin Transcription (FACT), a chromatin remodelling complex involved in transcription, replication, and DNA repair. CBL0137 effectively crosses the blood-brain barrier and is currently in Phase I trials in adult cancer. CBL0137 induced apoptosis in DIPG neurospheres in vitro and had profound cytotoxic activity against a panel of DIPG cultures. In a DIPG orthotopic model, treatment with CBL0137 significantly improved survival. We found that treatment with CBL0137 up-regulated TP53 and increased histone H3.3 acetylation and tri-methylation in DIPG cells. We therefore examined the interaction between CBL0137 and the HDAC inhibitor, panobinostat. In vitro experiments showed that the two agents had profound synergistic activity against DIPG neurospheres in clonogenic assays and enhanced apoptosis. Transcriptomic analysis and immunoblotting indicated that combination treatment activated signalling pathways controlled by Retinoblastoma (RB)/E2F1 and subsequently increased phosphorylation and enzymatic activity of enhancer of zeste homolog 2 (EZH2). Consistent with the in vitro results, the combination of CBL0137 and panobinostat significantly prolonged the survival of two orthotopic models of DIPG, while histological analysis showed increased H3K27me3 and decreased Ki67 positive cells. Given these promising results, a paediatric trial of CBL0137 is planned to open through the Children’s Oncology Group with an expansion cohort for DIPG patients.
GCT-25. INNOVATIVE, INTENSIVE IRRADIATION-AVOIDING/MINIMIZING CHEMOTHERAPY FOR HIGH-RISK PRIMARY CENTRAL NERVOUS SYSTEM (CNS) MIXED MALIGNANT GERM CELL TUMORS (HR-MMGCT): A PILOT STUDY AND PROPOSED MULTI-NATIONAL PROSPECTIVE TRIAL
Authors: Jonathan L Finlay, Mohammad H Abu-Arja, Rolla Abu-Arja, Jeffery Auletta, Mohamed S AbdelBaki, Diana S Osorio, Suzanne Conley, Margaret Shatara, Daniel R Boué, Christopher R Pierson, Jerome Rusin, Lisa Martin, Jeremy Jones, Joshua D Palmer, Ralph Vatner, Annie Drapeau, Eric Sribnick, Jeffrey R Leonard
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND About one-third of children with primary CNS MMGCT experience incomplete responses to initial induction chemotherapy prior to irradiation, many of whom will subsequently relapse. Such high-risk patients are variably defined as having initial alpha-fetoprotein (AFP) elevations exceeding 1,000ng/mL, predominant histopathologies of malignant non-germinomatous GCT and incomplete responses to induction chemotherapy. Drugs targeting GCT-specific molecular markers have been identified for non-germinomatous GCT elements but have yet to be incorporated into prospective clinical trials. Four children with clearly identified HR-MMGCT characteristics have been treated on an innovative pilot regimen incorporating intensified chemotherapy and molecularly targeted agents, with avoidance or minimization of irradiation. METHODS Four children (two with pure suprasellar embryonal carcinoma (EC) - one with Down syndrome and the other with pre-diagnosis cognitive dysfunction; one with initial serum AFP exceeding 7,000ng/mL and yolk sac tumor (YST)+EC+Teratoma pathology; one with initial serum AFP exceeding 1,000ng/mL) were treated with 3 cycles of “standard” induction chemotherapy (ACNS1123), followed by 1–3 transplant cycles (thiotepa/carboplatin) each with complete radiographic and tumor marker responses. Two children with pure EC subsequently received six cycles of brentuximab-vedotin without irradiation and remain disease-free off therapy for 2–4 years. One child with YST+EC+Teratoma has subsequently received reduced dose craniospinal irradiation and pineal region boost, and will receive oral everolimus, erlotinib, palbocyclib and intravenous brentuximab-vedotin. The fourth child with YST+MT will commence everolimus, erlotinib and palbocyclib without irradiation. CONCLUSION This treatment strategy for HR-MMGCT patients provides preliminary tolerance and response data justifying extension to a multi-center trial.