tbuckley/cabot-search huggingface dataset:
Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies
Authors: Julius Strauss, Margaret E Gatti-Mays, Byoung Chul Cho, Andrew Hill, Sébastien Salas, Edward McClay, Jason M Redman, Houssein A Sater, Renee N Donahue, Caroline Jochems, Elizabeth Lamping, Andrea Burmeister, Jennifer L Marté, Lisa M Cordes, Marijo Bilusic, Fatima Karzai, Laureen S Ojalvo, Genevieve Jehl, P Alexander Rolfe, Christian S Hinrichs, Ravi A Madan, Jeffrey Schlom, James L Gulley
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa. Methods In these phase 1 ( NCT02517398 ) and phase 2 trials ( NCT03427411 ), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety. Results As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred. Conclusion Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.
Author Correction: c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis
Authors: Jack Leslie, Marina García Macia, Saimir Luli, Julie C. Worrell, William J. Reilly, Hannah L. Paish, Amber Knox, Ben S. Barksby, Lucy M. Gee, Marco Y. W. Zaki, Amy L. Collins, Rachel A. Burgoyne, Rainie Cameron, Charlotte Bragg, Xin Xu, Git W. Chung, Colin D. A. Brown, Andrew D. Blanchard, Carmel B. Nanthakumar, Morten Karsdal, Stuart M. Robinson, Derek M. Manas, Gourab Sen, Jeremy French, Steven A. White, Sandra Murphy, Matthias Trost, Johannes L. Zakrzewski, Ulf Klein, Robert F. Schwabe, Ingmar Mederacke, Colin Nixon, Tom Bird, Laure-Anne Teuwen, Luc Schoonjans, Peter Carmeliet, Jelena Mann, Andrew J. Fisher, Neil S. Sheerin, Lee A. Borthwick, Derek A. Mann, Fiona Oakley
Journal: Nature Metabolism (2020)
DDEL-08. CONVECTION-ENHANCED DELIVERY OF NIMUSTINE HYDROCHLORIDE (ACNU) AGAINST PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Ryuta Saito, Masayuki Kanamori, Teiji Tominaga
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Intracerebral infusion technique of convection-enhanced delivery (CED) for patients with brain tumors could offer a novel approach for effective chemotherapy. We have been working to develop an effective chemotherapy using nimustine hydrochloride (ACNU) with this drug delivery method. After several studies targeting supratentorial recurrent malignant gliomas and recurrent gliomas affecting brainstem, we conducted phase 1 study to evaluate the safety of combination of convection-enhanced delivery of nimustine hydrochloride and systemic temozolomide against recurrent gliomas affecting brainstem. In this study, we demonstrated the safety and feasibility of CED of ACNU as well as real time monitoring of drug distribution by mixing ACNU with contrast agent; Gd-DOTA. We also defined the maximum tolerable concentration in this study and proceeded to phase 2 trial against recurrent gliomas affecting brain stem. However, these trials revealed the difficulty of treating pediatric DIPG at the time of recurrence. Therefore, we decided to treat pediatric DIPG cases at their initial diagnosis in the subsequent study. Aiming at obtaining Shonin approval both for intraparenchymal infusion catheter and drug to infuse into brain parenchyma, we are now conducting Phase II physician-led trial against initially diagnosed pediatric DIPG cases.
Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury
Authors: Yi Hu, Chun Yang, Tania Amorim, Mohsin Maqbool, Jenny Lin, Chen Li, Chuanfeng Fang, Li Xue, Ariel Kwart, Hua Fang, Mei Yin, Allison J. Janocha, Daisuke Tsuchimoto, Yusaku Nakabeppu, Xiaofeng Jiang, Alex Mejia-Garcia, Faiz Anwer, Jack Khouri, Xin Qi, Qing Y. Zheng, Jennifer S. Yu, Shan Yan, Thomas LaFramboise, Kenneth C. Anderson, Leal C. Herlitz, Nikhil C. Munshi, Jianhong Lin, Jianjun Zhao
Journal: Cancer Research (2020)

Abstract Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease. Significance: These results reveal and highlight an unexpected role of APE2 via its interaction with MYH9 and suggest that APE2 has the potential to prevent acute kidney injury in patients with cisplatin-treated cancer.
OTHR-16. CONCURRENT USE OF APREPITANT AND IFOSFAMIDE IN PEDIATRIC CANCER PATIENTS
Authors: Shelby Winzent, Nathan Dahl, Molly Hemenway, Rachel Lovria, Kathleen Dorris
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Aprepitant, a selective neurokinin-1 receptor antagonist, is commonly used for prevention of chemotherapy-induced nausea and vomiting. Its use with ifosfamide is controversial due to the putative risk of potentiating neurotoxicity via inhibition of cytochrome P450 3A4 (CYP3A4). The current literature examining this interaction is inconclusive, and little data exists in pediatrics. We seek to describe a single-institution experience with concurrent aprepitant and ifosfamide administration. METHODS A retrospective review of patients treated with ifosfamide and aprepitant from 2009–2018 was conducted. Data collected included demographics, tumor type, number of days of concurrent therapy, dosing, and documented of neurotoxicity. RESULTS Twenty patients aged 7–21 years (median 17 years) were identified. Diagnoses included thirteen sarcomas and seven CNS tumors (6 germ cell tumors; 1 intracranial sarcoma). Five patients received high dose ifosfamide (&amp;gt;2,000mg/m2/day). The number of concurrent ifosfamide and aprepitant doses ranged from 2–18 (median, 8.5). Only one patient (5%) developed ifosfamide-induced neurotoxicity: a 7-year-old female with a nongerminomatous germ cell tumor who presented with seizures and somnolence. She received methylene blue and returned to her neurologic baseline. She completed her ifosfamide course without incident. She was the only patient to require weight-based aprepitant dosing and to receive the liquid formulation. CONCLUSIONS Aprepitant should be used with caution when administered concurrently with ifosfamide due to the risk of neurotoxicity. However, the incidence of neurotoxicity in this retrospective pediatric cohort was low. This interaction may be more significant in younger patients due to age-related differences in hepatic metabolism, but further study is required.
DIPG-80. CLINICAL AND RADIOGRAPHIC RESPONSE TO ONC201 IN A PEDIATRIC PATIENT WITH A THALAMIC H3K27M AND BRAFV600E MUTANT DIFFUSE MIDLINE HIGH GRADE GLIOMA
Authors: Elizabeth Duke, Jonathan Murnick, Rohinton Tarapore, Joshua Allen, Lindsay Kilburn
Journal: Neuro-Oncology (2020)

Abstract Recent improved understanding of the molecular markers of high grade glioma has shifted the approach to these aggressive CNS tumors to increasingly use molecularly guided targeted therapies. Treatment of patients with BRAFV600E mutant high grade gliomas with BRAF inhibitors has shown efficacy, however the impact of concomitant H3K27M mutation is unknown. ONC201 targets dopamine receptor D2 (DRD2), which is shown to be broadly overexpressed in the thalamus as well as multiple tumor types; its antagonism has demonstrated anti-tumor efficacy and immunomodulatory properties in preclinical studies. ONC201 has also demonstrated clinical efficacy in patients with H3K27M mutant gliomas. We present the case of a 9-year-old male with a right thalamic H3.3K27M mutant diffuse midline glioma with a concomitant BRAFV600E mutation with an ongoing partial response to ONC201 treatment. The patient was diagnosed in May 2018. He underwent biopsy, followed by standard focal proton radiation therapy (54Gy) and subsequent treatment with dasatinib, bevacizumab and everolimus over the course of five months. After continued radiographic progression on serial imaging, in April 2019 he started ONC201 375mg orally once per week through an expanded access trial. He has tolerated the medication well with grade 1 nausea and fatigue. Over the next nine months, he demonstrated clinical and radiographic improvement with modest increased use of his left side and MRIs showing progressive decrease in size of the thalamic lesion with a 70 % decrease in the target lesion (measuring 53x62mm prior to treatment, decreased to 38x26mm in January 2020).
High eosinophil counts predict decline in FEV<sub>1</sub>: results from the CanCOLD study
Authors: Wan C. Tan, Jean Bourbeau, Gilbert Nadeau, Wendy Wang, Neil Barnes, Sarah H. Landis, Miranda Kirby, James C. Hogg, Don D. Sin
Journal: European Respiratory Journal (2020)

Introduction The aim of this study was to examine the association between blood eosinophil levels and the decline in lung function in individuals aged &gt;40 years from the general population. Methods The study evaluated the eosinophil counts from thawed blood in 1120 participants (mean age 65 years) from the prospective population-based Canadian Cohort of Obstructive Lung Disease (CanCOLD) study. Participants answered interviewer-administered respiratory questionnaires and performed pre-/post-bronchodilator spirometric tests at 18-month intervals; computed tomography (CT) imaging was performed at baseline. Statistical analyses to describe the relationship between eosinophil levels and decline in forced expiratory volume in 1 s (FEV 1 ) were performed using random mixed-effects regression models with adjustments for demographics, smoking, baseline FEV 1 , ever-asthma and history of exacerbations in the previous 12 months. CT measurements were compared between eosinophil subgroups using ANOVA. Results Participants who had a peripheral eosinophil count of ≥300 cells·µL −1 (n=273) had a greater decline in FEV 1 compared with those with eosinophil counts of &lt;150 cells·µL −1 (n=430; p=0.003) (reference group) and 150–&lt;300 cells·µL −1 (n=417; p=0.003). The absolute change in FEV 1 was −32.99 mL·year −1 for participants with eosinophil counts &lt;150 cells·µL −1 ; −38.78 mL·year −1 for those with 150–&lt;300 cells·µL −1 and −67.30 mL·year −1 for participants with ≥300 cells·µL −1 . In COPD, higher eosinophil count was associated with quantitative CT measurements reflecting both small and large airway abnormalities. Conclusion A blood eosinophil count of ≥300 cells·µL −1 is an independent risk factor for accelerated lung function decline in older adults and is related to undetected structural airway abnormalities.
Stepwise cell fate decision pathways during osteoclastogenesis at single-cell resolution
Authors: Masayuki Tsukasaki, Nam Cong-Nhat Huynh, Kazuo Okamoto, Ryunosuke Muro, Asuka Terashima, Yoshitaka Kurikawa, Noriko Komatsu, Warunee Pluemsakunthai, Takeshi Nitta, Takaya Abe, Hiroshi Kiyonari, Tadashi Okamura, Mashito Sakai, Toshiya Matsukawa, Michihiro Matsumoto, Yasuhiro Kobayashi, Josef M. Penninger, Hiroshi Takayanagi
Journal: Nature Metabolism (2020)
IMMU-17. SINGLE-CELL RNA-SEQ REVEALS HIGH-GRADE GLIOMA ASSOCIATED MICROGLIA WITH PROINFLAMMATORY AND STEM-LIKE FEATURES SUPPORT TUMOR PROGRESSION
Authors: Hailong Liu, Yongqiang Liu, Janusz Franco-Barraza, Xinguang Yu, Shiyu Feng
Journal: Neuro-Oncology (2020)

Abstract Poor response of human glioblastoma to current therapies are influenced by tumor microenvironment. Although glioblastoma is recognized by large enrichment of microglia, characterization of diverse cell subsets and their functions remain challenging because of high heterogenicity. Here, we analyzed single-cell transcriptomics to comprehensively map the cell populations and determine the roles of microglia in IDH1/2 wild-type (IDH-wt) glioblastoma progression. Besides finding microglia were significantly enriched in IDH-wt glioblastoma compared to IDH1/2 mutant (IDH-mut) gliomas, we identified a unique high-grade glioma microglia (HGAM) subtype characterized by proinflammatory and stem-like features. In particular, HGAM’s pro-tumoral IL1β secretion is mediated via ApoE-induced activation of NLRP1 inflammasome. HGAM phagocytosed OPC-like malignant cells forming the neoplastic microglia, which presented the stem-like potential giving rise to activated microglia. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation. Additionally, an intricated evaluation of glioma patients revealed that SETD2 mutation/low-expression correlated with adverse prognosis. Further analysis showed that SETD2 -dificient tumor cells presented hypersensitivity to HGAM-derived IL1β via epigenetic dysregulation of PHF6. Also, SETD2 -deficient tumor cells produced TGF-β1 contributing to microglia activation. Finally, targeting the TGF-β1/TβRI signaling impaired HGAM activation and tumor growth. Our studies identify a unique neoplastic microglia subpopulation and establish cellular basis of interactions with tumor cells important for disease progression.
Prevalence of Insomnia in an Oncology Patient Population: An Irish Tertiary Referral Center Experience
Authors: Emily C. Harrold, Ahmad F. Idris, Niamh M. Keegan, Lynda Corrigan, Min Yuen Teo, Martin O’Donnell, Sean Tee Lim, Eimear Duff, Dearbhaile M. O’Donnell, M. John Kennedy, Sue Sukor, Cliona Grant, David G. Gallagher, Sonya Collier, Tara Kingston, Ann Marie O’Dwyer, Sinead Cuffe
Journal: Journal of the National Comprehensive Cancer Network (2020)

The NCCN Guidelines for Survivorship recommend dedicated sleep assessment. Reported insomnia prevalence in the general Irish population is 6% to 15%. Reported insomnia prevalence internationally among new/recently diagnosed patients with cancer varies from 30.9% to 54.3%. Insomnia prevalence has not been previously quantified in an Irish oncology cohort.A 40-item questionnaire was prospectively administered to ambulatory patients with cancer aged ≥18 years. Prespecified criteria to define insomnia syndrome combined those of the International Classification of Sleep Disorders, version 1, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The Hospital Anxiety and Depression Scale-Depression/Anxiety (HADS-D/A) was used to screen for potential confounding variables.The response rate to the questionnaire was 87% (294/337). The predominant respondent age group was 55 to 64 years (26%; 77/294), 70.7% were female (208/294), and the most common cancer subtypes were breast (37.4%), colorectal (12.9%), and lung (12.2%). A total of 62% (183/294) of patients reported sleep disturbance after diagnosis, 63% (115/183) reported moderate/severe distress related to this disturbance, and 37% (61/183) reported a significant impact on physical function. Although 33% (98/294) met insomnia syndrome criteria, only 34% (33/98) of these patients had a preexisting history of sleep disturbance. Female sex, age <65 years, cancer subtype, alcohol consumption, and HADS-D/A ≥11 were associated with statistically significant higher odds ratios (OR) of insomnia syndrome. Multivariate analysis identified breast cancer (OR, 3.17; P=.01), age <65 years (OR, 1.8; P=.03), and alcohol consumption (OR, 2.3; P=.005) as independent predictors of insomnia syndrome.Insomnia syndrome prevalence in this cohort is comparable to that reported previously and supports dedicated sleep assessment. This study identifies potentially modifiable risk factors for insomnia and demonstrates additional utility of the HADS score in identifying patients at risk.
LGG-55. OUTCOME OF BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION
Authors: Liana Nobre, Michal Zapotocky, Vijay Ramaswamy, Scott Ryall, Julie Bennet, Daniel Alderete, Julia Balaguer Guill, Lorena Baroni, Ute Bartels, Abhishek Bavle, Miriam Bornhorst, Daniel R Boue’, Adela Canete, Murali Chintagumpala, Scott L Coven, Ofelia Cruz, Sonika Dahiya, Peter Dirks, Ira J Dunkel, David Eisenstat, Cecile Faure Conter, Elizabeth Finch, Jonathan L Finlay, Didier Frappaz, Maria Luisa Garre, Karen Gauvain, Anne Grete Bechensteen, Jordan R Hansford, Inga Harting, Peter Hauser, Lili-Naz Hazrati, Annie Huang, Sarah G Injac, Valentina Iurilli, Matthias Karajannis, Gurcharanjeet Kaur, Martin Kyncl, Lenka Krskova, Normad Laperriere, Valerie Larouche, Alvaro Lassaletta, Sarah Leary, Frank Lin, Samantha Mascelli, Tara McKeown, Till Milde, Andres Morales La Madrid, Giovanni Morana, Helena Morse, Naureen Mushtaq, Diana S Osorio, Roger Packer, Zdenek Pavelka, Eduardo Quiroga-Cantero, James Rutka, Magnus Sabel, Duarte Salgado, Palma Solano, Jaroslav Sterba, Jack Su, David Sumerauer, Michael D Taylor, Helen Toledano, Derek S Tsang, Mariana Valente Fernandes, Frank van Landeghem, Cornelis M van Tilburg, Bev Wilson, Olaf Witt, Josef Zamecbik, Eric Bouffet, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2020)

Abstract Children with pediatric gliomas harboring BRAF V600E mutation have a poor outcome with current chemoradiation strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. We collected clinical, imaging, molecular and outcome information from BRAF V600E glioma patients treated with BRAFi across 29 centers from multiple countries. Sixty-seven patients were treated with BRAFi (56 pediatric low grade gliomas, PLGG and 11 pediatric high grade gliomas, PHGG) for up to 5.6 years. Objective responses were observed in 80% of PLGGs compared to 28% with conventional chemotherapy (p&amp;lt;0.001). These responses were rapid (median, 4 months), and sustained in 86% of tumors up to 5 years while on therapy. PLGG which discontinued BRAFi, 76.5% (13/17) progressed rapidly after discontinuation (median 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with a lack of response to BRAFi. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95%CI, 35.3% to 69.5%) vs 29.8% (95% CI, 20% to 44.4%) for BRAFi vs chemotherapy respectively (p=0.02). The use of BRAFi results in robust and durable responses while on therapy in BRAF V600E PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAFi therapy in childhood gliomas.
ETMR-10. EARLY FOCAL RADIOTHERAPY AND TEMOZOLOMIDE FOLLOWING COMPLETE RESECTION APPEAR SUPERIOR TO INTENSIVE CHEMOTHERAPY AND DELAYED RADIOTHERAPY IN CHILDREN WITH EMBRYONAL TUMORS WITH MULTILAYERED ROSETTES (ETMR)
Authors: Lisa Mayr, Johannes Gojo, Andreas Peyrl, Amedeo Azizi, Karin Dieckmann, Christine Haberler, Thomas Czech, Irene Slavc
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Embryonal tumor with multilayered rosettes (ETMR) is a rare, aggressive embryonal central nervous system tumor characterized by LIN28A expression and alterations in the C19MC locus. ETMRs predominantly occur in young children, have a dismal prognosis, and no definitive treatment guidelines have been established. We report on our experience in nine consecutive patients. METHODS Between 2006 and 2017, nine patients were diagnosed with ETMR. Median age was 25 months (5–38), seven were treated for primary diagnosis, two referred with progressing tumors, seven diagnosed prospectively, two retrospectively, five were located supratentorially, three pineal, one in the brainstem. RESULTS Seven patients had a gross total resection, one a partial resection and one a biopsy at initial diagnosis, followed by second resections at progression. Six patients were treated with intensive chemotherapy regimens including high-dose chemotherapy in three patients and all recurred after a median of 6 months (range 2–11) and all except one patient who died after high-dose chemotherapy, succumbed to their disease after a median of 13 months (range 7–28). Two patients were treated with gross total tumor resection, early focal radiotherapy and concomitant temozolomide followed by temozolomide and intrathecal therapy for one year and both are in continuous complete remission 51 and 46 months after diagnosis. CONCLUSION Gross total resection followed by early focal radiotherapy, temozolomide, and intrathecal chemotherapy seem to be superior to intensive chemotherapy including high-dose chemotherapy. Steady progression was observed in both patients with initial biopsy and PR only despite intensive therapy. Radiotherapy at recurrence/progression was not successful.
SURG-20. DIENCEPHALIC SYNDROME IN PEDIATRIC NEUROSURGERY
Authors: Felipe Hada Sanders, Hamilton Matushita, Alessandra Azambuja, Fernando Frasseto
Journal: Neuro-Oncology (2020)

Abstract This report details the histories of twelve patients with clinical diencephalic syndrome who collectively demonstrate the variability found in the syndrome with respect to: (1) clinical course, (2) site of the tumor, and (3) ease of obtaining radiologic confirmation of the presence of a tumor. Timely diagnosis of diencephalic syndrome is not often the case for patients presenting with failure to thrive (FTT) because of its rarity and lack of specific symptoms. These cases illustrate the importance of cranial imaging and consideration of diencephalic syndrome for children presenting with FTT despite normal or increased caloric intake.