tbuckley/cabot-search huggingface dataset:
SURG-21. ENDO- AND EXOSCOPIC SURGERY FOR PEDIATRIC NEUROSURGICAL OPERATION
Authors: Kazuhiko Kurozumi, Masahiro Kameda, Kentarou Fujii, Yosuke Shimazu, Takao Yasuhara, Isao Date
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Recently endo- and exoscopic surgeries have been gradually performed in neurosurgery. To improve the accuracy and safety of our endoscopic procedures, we are currently trialing 4K or 8K systems. Here we report our experience of endo- and exoscopic procedures for pediatric neurosurgery. METHODS We retrospectively identified 22 patients (15 males, 7 females; mean age, 9.2 years) who underwent surgery for sellar lesions and intraventricular or intraparenchymal lesions with an endo- or exoscopic procedure at our institute between 2010 and 2020. We used a full HD endoscope system (Storz) and an organic electroluminescence (EL) monitor (Sony), and a 4K system (Sony and Olympus). VITOM 3D (Storz) was used as the exoscope. Videoscope (Olympus) was used as a flexible scope for intraventricular tumors. RESULTS We performed surgical procedures as 11 biopsies, 6 third ventriculostomies, 5 resections, and 3 fenestrations. The full HD system with organic EL monitor presented high color contrast. We could easily distinguish between tumor microstructure and the normal structure with the 4K system comparing to full HD. Moreover, electronic zoom function enabled us to discriminate tumor boundaries without having to move the endoscope closer. As a result, we could delineate the surgical working space. VITOM 3D was simple to sharpen the focus on the wider surgical field, similar to the application of an operating microscope. CONCLUSION In pediatric neurosurgery, an endo- or exoscope enables clear visual recognition of a boundary between tumor and normal area.
EPCO-31. EPIGENOMIC INTRATUMORAL HETEROGENEITY OF GLIOBLASTOMA IN THREE-DIMENSIONAL SPACE
Authors: Radhika Mathur, Sriranga Iyyanki, Stephanie Hilz, Chibo Hong, Joanna Phillips, Susan Chang, Feng Yue, Joseph Costello
Journal: Neuro-Oncology (2020)

Abstract Treatment failure in glioblastoma is often attributed to intratumoral heterogeneity (ITH), which fosters tumor evolution and generation of therapy-resistant clones. While ITH in glioblastoma has been well-characterized at the genomic and transcriptomic levels, the extent of ITH at the epigenomic level and its biological and clinical significance are not well understood. In collaboration with neurosurgeons, neuropathologists, and biomedical imaging experts, we have established a novel topographical approach towards characterizing epigenomic ITH in three-dimensional (3-D) space. We utilize pre-operative MRI scans to define tumor volume and then utilize 3-D surgical neuro-navigation to intra-operatively acquire 10+ samples representing maximal anatomical diversity. The precise spatial location of each sample is mapped by 3-D coordinates, enabling tumors to be visualized in 360-degrees and providing unprecedented insight into their spatial organization and patterning. For each sample, we conduct assay for transposase-accessible chromatin using sequencing (ATAC-Seq), which provides information on the genomic locations of open chromatin, DNA-binding proteins, and individual nucleosomes at nucleotide resolution. We additionally conduct whole-exome sequencing and RNA sequencing for each spatially mapped sample. Integrative analysis of these datasets reveals distinct patterns of chromatin accessibility within glioblastoma tumors, as well as their associations with genetically defined clonal expansions. Our analysis further reveals how differences in chromatin accessibility within tumors reflect underlying transcription factor activity at gene regulatory elements, including both promoters and enhancers, and drive expression of particular gene expression sets, including neuronal and immune programs. Collectively, this work provides the most comprehensive characterization of epigenomic ITH to date, establishing its importance for driving tumor evolution and therapy resistance in glioblastoma. As a resource for further investigation, we have provided our datasets on an interactive data sharing platform – The 3D Glioma Atlas – that enables 360-degree visualization of both genomic and epigenomic ITH.
Incidental 18F-Fluciclovine Uptake in a Desmoid Tumor Detected in a Patient Undergoing PET/CT Imaging for Prostate Cancer
Authors: Ali Baiomy, Corey T. Jensen, John F. Ward, Beth A. Chasen, Gregory C. Ravizzini
Journal: Clinical Nuclear Medicine (2020)

Abstract A 74-year-old man with biochemical recurrent prostate cancer underwent 18 F-fluciclovine PET/CT for restaging to determine subsequent treatment strategy. 18 F-fluciclovine PET/CT imaging demonstrated incidental focal heterogeneous increased 18 F-fluciclovine uptake corresponding to a soft tissue nodule within the musculature of the left anterior abdominal wall. Subsequent ultrasound-guided biopsy of the lesion revealed histopathology compatible with a desmoid tumor. Consequently, the patient underwent surgical resection with wide local excision of the lesion.
CTNI-66. ONE-YEAR FOLLOW-UP DATA OF PHASE I/II STUDY OF TIRABRUTINIB IN PATIENTS WITH RELAPSED OR REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Kazuhiko Mishima, Yoshitaka Narita, Motoo Nagane, Yasuhito Terui, Yoshiki Arakawa, Hajime Yonezawa, Katsunori Asai, Noriko Fukuhara, Kazuhiko Sugiyama, Naoki Shinojima, Arata Aoi, Ryo Nishikawa
Journal: Neuro-Oncology (2020)

Abstract Primary central nervous system lymphoma (PCNSL) is known as one of the incurable brain tumors. In March 2020, Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the indication of relapsed or refractory PCNSL (rrPCNSL) based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646). In this study, 44 Japanese patients with rrPCNSL were treated with TIR QD at 320 mg, 480 mg, or 480 mg in the fasted condition (480 mg fasted QD). The primary endpoint was overall response rate (ORR) assessed by an independent review committee according to International PCNSL Collaborative Group criteria. We previously reported the results of this study with data cutoff on June 13, 2019 (Nagane et al., the 61st American Society of Hematology Annual Meeting and Exposition in 2019). In the report, 17 of 44 patients were treated with TIR at 480 mg fasted QD which is an approved dose, and had ORR of 52.9%, median progression-free survival of 5.8 months, and median overall survival of not reached (median follow-up: 3.8 months). In 44 patients, ORR was similar among patients harboring either of the oncogenic mutants CARD11, MYD88, CD79B, or wild type. Throughout the whole patients, most common adverse events (AEs) at any grade were rash (32%), neutropenia (23%), leukopenia (18%), and lymphopenia (16%), and grade ≥3 AEs were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg QD had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). We will present one-year follow-up data of this study at the meeting. As of data cutoff (February 25, 2020), 11 of 44 patients continued to receive TIR, including 6 patients with 480 mg fasted QD. Updated data for OS, duration of response, and time to onset of AEs will also be presented.
Functional and genetic markers of niche partitioning among enigmatic members of the human oral microbiome
Authors: Alon Shaiber, Amy D. Willis, Tom O. Delmont, Simon Roux, Lin-Xing Chen, Abigail C. Schmid, Mahmoud Yousef, Andrea R. Watson, Karen Lolans, Özcan C. Esen, Sonny T. M. Lee, Nora Downey, Hilary G. Morrison, Floyd E. Dewhirst, Jessica L. Mark Welch, A. Murat Eren
Journal: Genome biology (2020)

Abstract Introduction Microbial residents of the human oral cavity have long been a major focus of microbiology due to their influence on host health and intriguing patterns of site specificity amidst the lack of dispersal limitation. However, the determinants of niche partitioning in this habitat are yet to be fully understood, especially among taxa that belong to recently discovered branches of microbial life. Results Here, we assemble metagenomes from tongue and dental plaque samples from multiple individuals and reconstruct 790 non-redundant genomes, 43 of which resolve to TM7, a member of the Candidate Phyla Radiation, forming six monophyletic clades that distinctly associate with either plaque or tongue. Both pangenomic and phylogenomic analyses group tongue-specific clades with other host-associated TM7 genomes. In contrast, plaque-specific TM7 group with environmental TM7 genomes. Besides offering deeper insights into the ecology, evolution, and mobilome of cryptic members of the oral microbiome, our study reveals an intriguing resemblance between dental plaque and non-host environments indicated by the TM7 evolution, suggesting that plaque may have served as a stepping stone for environmental microbes to adapt to host environments for some clades of microbes. Additionally, we report that prophages are widespread among oral-associated TM7, while absent from environmental TM7, suggesting that prophages may have played a role in adaptation of TM7 to the host environment. Conclusions Our data illuminate niche partitioning of enigmatic members of the oral cavity, including TM7, SR1, and GN02, and provide genomes for poorly characterized yet prevalent members of this biome, such as uncultivated Flavobacteriaceae.
Panniculitis in a Woman With Opportunistic Pulmonary Coinfection by Pneumocystis jirovecii and Cryptococcus neoformans
Authors: Billal Tedbirt, Anne-Benedicte Duval-Modeste, Philippe Courville, Stéphane Dominique, Pierre Vera, Hamza Regaieg
Journal: Clinical Nuclear Medicine (2020)

Abstract A 56-year-old woman, with history of psoriasis well controlled on ustekinumab, underwent 18 F-FDG PET/CT to explore first onset of histologically proven skin panniculitis of unknown origin. PET/CT showed high uptake in panniculitis lesions in limbs and in a lung opacity suggestive of pneumonia. Based on PET/CT findings, a bronchoalveolar lavage revealed pulmonary coinfection by P neumocystis jirovecii and C ryptococcus neoformans . Thus, hematogenous dissemination of infection was suspected as etiology of panniculitis. She was treated with fluconazole and trimethoprim-sulfamethoxazole, leading to total resolution of skin lesions. Posttherapeutic PET/CT showed complete metabolic response of skin and pulmonary lesions.
CBIO-12. THE ROLES OF lncRNAs IN GBM RADIATION RESISTANCE AND TUMOR RECURRENCE
Authors: Christian Stackhouse, James Rowland, Joshua Anderson, Jelai Wang, Thanh Nguyen, Zongliang Yue, Jake Chen, Lara Ianov, Yancey Gillespie, Christopher Willey
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma multiforme (GBM) almost invariably recurs and tumors exhibit resistance to conventional therapies. One mechanism of resistance is enhanced DNA damage response (DDR) to alkylating chemotherapy or radiation therapy (RT). We have generated 8 novel GBM patient-derived xenograft (PDX) models of tumor recurrence following serial in vivo irradiation (6 x 2Gy fractions over 2 weeks for 6+ rounds). RNA sequencing has revealed enrichment of a number of DDR pathways in the RT selected (RTS) PDX. Differential enrichment across the RTS PDX suggests multiple molecular routes to acquired RT resistance. We have also identified differential enrichment of molecular signatures for cell cycle progression, stemness, and chromatin remodeling all suggesting decreased proliferation, increased stemness, and more compacted chromatin states associated with RTS PDX. We have identified altered kinase signaling in RTS PDX that may suggest targetable signaling pathways using small molecule inhibitors. Integrated ‘–omics’ analysis has identified SRC family kinases and altered expression of collagens related to the RTS profile. Long non-coding RNAs (lncRNA) have the potential to regulate molecular phenotypes through nucleic acid binding. We have identified 269 lncRNAs significantly differentially expressed in the RTS condition. We have determined that a number of these transcripts have DNA binding potential in gene regulatory regions proximal to kinase, DDR, cell cycle, stemness, and chromatin remodeling genes. Analysis of lncRNAs and genes proximal to their binding sites has revealed regulatory networks potentially governing cell fate and phenotype. We have observed complex correlations of some of these transcripts, such as ZFAS1, which has a positive correlation with expression of stemness-promoting genes and simultaneous inverse correlation with cell cycle genes. This suggests ZFAS1 could be a phenotypic switch between a RT-sensitive proliferating cell and a RT-resistant non-proliferating stem-like cell. LncRNAs may represent a novel therapeutic target for the treatment of therapy resistant, recurrent GBM.
MODL-03. ADAPTING PALBOCICLIB FOR MEDULLOBLASTOMA THERAPY BY IMPROVING DRUG DELIVERY AND ADDRESSING RESISTANCE
Authors: Taylor Dismuke, Timothy Gershon
Journal: Neuro-Oncology (2020)

Abstract CDK4/6 inhibition may be a promising therapy for medulloblastoma. All medulloblastoma subgroups show D-cyclin/CDK4/RB pathway activity, suggesting broad potential for efficacy. To address drug delivery and systemic toxicity limitations, we developed a nanoparticle formulation of CDK 4/6 inhibitor, palbociclib, in poly (2-oxazoline) micelles (POx-palbo). POx-palbo showed reduced systemic toxicity in transgenic mice engineered to develop medulloblastoma, allowing for higher dosing. Pharmacodynamic studies showed POx-palbo suppressed RB phosphorylation acutely and after 24hrs, the effect diminished. This inhibition produced a longer lasting suppression of SHH pathway activity, demonstrated by Gli-luc reporter tumor mice. Importantly, POx-palbo therapy, administered daily, reduced tumor growth and improved the survival of mice with medulloblastoma. While POx-palbo was clearly effective as a single agent, all mice treated with POx-palbo eventually developed progressive disease, as resistant populations of tumors cells emerged. To understand the mechanisms of resistance, we compared tumors early and late in the course of therapy. We found that after 5 days of treatment, palbociclib altered cell cycle progression to produce an extended period of S-phase and that the fractions of cell expressing the stem cell marker Olig2 were markedly increased. Based on these data, we propose that tumors respond to the initial suppressive effect of palbociclib by increasing the pool of Olig2+ stem cells, that these cells show discernably different cell cycle kinetics and are resistant to CDK4/6 inhibition. Combining POx-palbo with additional therapies that target Olig2+ stem cells, by disrupting their prolonged S-phase, or by disrupting Olig2 function, may lead to newly effective medulloblastoma treatment.
AIE-active two-photon fluorescent nanoprobe with NIR-II light excitability for highly efficient deep brain vasculature imaging
Authors: Soham Samanta, Meina Huang, Shaoqiang Li, Zhigang Yang, Ying He, Zhenyu Gu, Jianguo Zhang, Dan Zhang, Liwei Liu, Junle Qu
Journal: Theranostics (2020)

Aggregation induced emission (AIE)-active bright two-photon fluorescent probes with second near-infrared (NIR-II) light excitability can be used for efficient brain bioimaging studies, wherein the fabrication of water-dispersible nanoparticles by encapsulating the hydrophobic probes with amphiphilic polymer holds the key to ensuring biocompatibility and in vivo adaptability. However, barely any study has evaluated the structural requirements that can substantially affect the water-dispersible nanoparticle formation ability of an organic AIE-active dye with amphiphilic polymers. The present study systematically assessed the structural dependency of a well-known acrylonitrile based AIE system/fluorogenic core upon the formation of water-dispersible nanoparticles and elucidated how the structural modifications can impact the in vivo two-photon imaging. Methods: A total of four acrylonitrile-based aggregation induced emission (AIE)-active two-photon (TP) fluorescent probes (AIETP, AIETP C1, AIETP C2 and AIETP C3) have been judiciously designed and synthesized with structural variations to realize how the structural alterations could substantially influence the water-dispersible nanoparticle formation ability (with amphiphilic polymers) and photo-stability to impact the in vivo imaging. Results: It has been found that the incorporation of the phenyl-thiazole unit in AIETP, AIETP C2 and AIETP C3 facilitated the formation of water-dispersible nanoparticles (NPs) with amphiphilic polymers (Pluronic F127) whereas the presence of only phenyl moiety instead in AIETP C1 could not meet the suitable condition to form the NPs with good aqueous dispersibility. Rationally designed AIETP NPs that exhibited higher brightness, improved photostability and good two-photon absorption cross section was successfully employed for in vivo brain vasculature imaging. Conclusions: Robust noninvasive 2D and 3D two-photon (NIR-II light, 1040 nm) brain vasculature imaging with beneficial attributes such as outstanding penetration depth (800 µm) and exceptional spatial resolution (1.92 µm), were achieved by utilizing AIETP NPs in this study.
QOLP-02. PATIENT-REPORTED OUTCOMES FOLLOWING PERTUZUMAB PLUS HIGH-DOSE TRASTUZUMAB IN PATIENTS WITH HER2-POSITIVE METASTATIC BREAST CANCER (MBC) AND CENTRAL NERVOUS SYSTEM (CNS) PROGRESSION POST-RADIOTHERAPY
Authors: Priya Kumthekar, Solmaz Sahebjam, Mark Pegram, Nuhad Ibrahim, Jesse Sussell, Alan Nicholas, Anita Fung, Anna Cheng, Nancy U Lin
Journal: Neuro-Oncology (2020)

Abstract Effective therapies are needed for the treatment of patients with HER2-positive MBC who develop brain metastases. In the open-label, phase II PATRICIA study (NCT02536339), 40 patients with HER2-positive MBC with CNS metastases and CNS progression post-radiotherapy (median age 48 years [range, 34–69]; prior CNS treatment [whole brain radiotherapy 71%, stereotactic radiosurgery 59%, both 31%]) were enrolled to receive pertuzumab plus high-dose trastuzumab (6-mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Following a median (range) treatment duration of 4.5 (0.3–37.3) months, the CNS-confirmed objective response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria (primary endpoint) was 11% (95% confidence interval: 3.03, 25.42), and the clinical benefit rate at 4 months was 68%, indicating sustained clinical stability. Patient-reported outcomes (PROs) were evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT), which includes sub-scales for symptom severity (average of 13 core symptom and 9 brain-tumor specific items) and symptom interference (average of 6 interference-with-life items representing overall symptom distress). Among 36 patients included in the PRO analyses, mean (standard deviation [SD]) symptom severity scores at baseline and weeks 12 and 28 were 1.65 (1.62), 2.24 (2.14), and 1.94 (2.55), respectively. Mean (SD) symptom interference scores at baseline and weeks 12 and 28 were 2.51 (2.63), 2.81 (3.39), and 1.76 (2.43), respectively. Mean (SD) changes in symptom severity and interferences scores from baseline to week 12 were 0.34 (1.54) and 0.33 (3.08), respectively. On average, patients who did not achieve stable disease or better in the CNS following treatment had worsened symptom severity and symptom interference scores over 12 weeks, while those with stable disease or better in the CNS exhibited stable or improving scores. Pertuzumab plus high-dose trastuzumab provided clinical benefit to the majority (68%) of patients in PATRICIA, without a decrement in quality of life.
Learning the Points of COMPASS-HF: Assessing Implantable Hemodynamic Monitoring in Heart Failure Patients⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: John R. Teerlink
Journal: Journal of the American College of Cardiology (2008)
IMMU-27. ANALYSIS OF IMMUNE SIGNATURES IN PEDIATRIC GLIOBLASTOMAS FOR PATIENT STRATIFICATION TO IMMUNOTHERAPY
Authors: Vidyalakshmi Chandramohan, Tyler Evangelous, Eric S Lipp, Bhavna Hora, Darell D Bigner, Roger E McLendon, David M Ashley
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pediatric glioblastoma (pGBM), despite being relatively rare (incidence rate: 0.5/100,000), are a leading cause of cancer deaths in children with a median overall survival of 9–15 months. In recent years, immunotherapy has emerged as one of the more promising advances in oncology, with impressive response rates reported in several malignancies. Effective application of immunotherapy in brain tumors depends upon a better understanding of the immune cell phenotype and mechanisms of immunosuppression in these tumors. This understanding will allow for the selection of patient population who are most likely to benefit from immunotherapeutic approaches. MATERIAL AND METHODS In order to determine the frequency, distribution, and phenotype of tumor-infiltrating immune cells in pGBMs, we undertook an immunohistochemical survey on 19 recurrent pGBMs for CD3, CD8, CD4, CD163, PD-1, PD-L1, and FoxP3; RNA-Seq was also performed on a subset of 9 cases. Distribution of lymphocytes (LYMPHS) was recorded as intratumoral (IT) or perivascular (PV). RESULTS The analysis indicates intratumoral CD3+ LYMPHS are commonly &amp;lt;5% of tumor cell mass; however, approximately half (10/19) of these recurrent pGBM have infiltrates that range from 5 to 30% CD3+ LYMPHS. Of these, 4/10 CD3+ tumors exhibit brisk CD8+ infiltrates that are associated with PD-L1+ tumor cells. These tumors with brisk CD3+/CD8+ LYMPHS and PD-L1+ tumor cells were associated with longer survivals. The data were confirmed by RNA-seq analysis. CONCLUSION PD-L1+ pGBMs associated with CD3+/CD8+ LYMPH infiltrates deserve further investigation as candidates for immunotherapy.
DIPG-56. EXPLORATION OF TUMOR/STROMA INTERACTIONS IN DIPG XENOGRAFT BY SPECIES-SPECIFIC RNA-SEQ DECONVOLUTION INDICATES A ROLE OF MICROGLIA CELL IN DIPG DEVELOPMENT
Authors: Jane Merlevede, Alexandre Plessier, Arthur Felix, Cathy Philippe, Ludivine Le Dret, David Hardy, Kevin Beccaria, Jacques Grill, David Castel, Pascale Varlet, Marie-Anne Debily
Journal: Neuro-Oncology (2020)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) and more largely Diffuse Midline Gliomas H3 K27M-mutant (DMG) harbor a unique property of infiltration. Our objective is to elucidate/describe the cellular and molecular determinants of micro-environmental modifications resulting from the tumour/stroma dialogue as it might provide pro-invasive conditions that favour the development of the disease. To this end, we performed RNA-seq analyses to characterize exhaustively the bidirectional molecular modifications of the stroma/tumour in DIPG xenograft models. Gene expression changes in murine microenvironment compartment were investigated as continuous or semi-continuous traits of tumor load by measuring transcriptome in zone with high vs. low infiltration. We observed substantial modulations in gene expression in the microenvironment associated with increasing tumor cell content, pointing to a modification of the macrophage/microglial infiltrate. The expression or overexpression of several modulated genes was validated by IHC in the stroma of DMG primary tumors. Among them, overexpression of the cytokine CCL3 was confirmed, reflecting the activation status of microglial cells. Moreover, we observed in patients that the density of IBA-1 positive microglial cells increases according to the extent of tumor infiltration and that a significant part of them harbor a mitotic status, supporting their interaction with DMG cells. The involvement of this interaction in DMG development needs further evaluation and might represent opportunity to slow down DIPG extension.