tbuckley/cabot-search huggingface dataset:
QOLP-08. UNDERSTANDING THE EXPERIENCE OF YOUNG ADULTS (YAS) DIAGNOSED WITH AN EPENDYMOMA FROM THE ADULT EPENDYMOMA OUTCOMES PROJECT AND RARE CNS OUTCOMES AND RISK STUDY
Authors: Alvina Acquaye, Kathleen Wall, Mark Gilbert, Terri Armstrong
Journal: Neuro-Oncology (2019)

Abstract Research in young adult (YA) patients is novel, particularly in central nervous system tumors like ependymomas. Stagnant survival outcomes in YAs are concerning compared to improvements within pediatric and older adults. Additionally, uncertainty of the impact of treatment on psychosocial and behavioral outcomes during an essential developmental stage warrants attention. The purpose of this report is to explore ependymoma YA outcomes data to inform care. Adult ependymoma (n=191) patients participating in a web-based outcomes study completed clinical data and validated questionnaires (EQ-5D, MDASI-BT). YAs 18–39 (n= 58) were compared to older adults (OAs) &gt;40 (n=133). Participants were predominantly female (68%), with tumor location in brain (29%) or spine (71%). The majority of YAs (67%) reported seeing a physician within 6 months from symptom onset, whereas OAs were more likely to delay for 7 months or longer. Headaches (brain tumor 70%) and numbness (spine tumor73%) were common presenting symptoms for both age groups. 76% of YAs were working before diagnosis, however 27% stopped work, 18% reduced hours, 7% switched jobs and 2% lost their job after diagnosis. At time of participation, most participants were not on active treatment (61%), but both YA and OA frequently endorsed use of pain medication (37%). Tumor recurrence was more common in YAs (30%) compared to OAs (19%). Common moderate to severe symptoms in YAs included distress (27%) and fatigue/sadness (18%) with brain tumors compared to fatigue (56%) and distress/disturbed sleep/drowsiness (36%) with spine tumors. Over a third of YAs reported some impact on general health (usual activities, pain/discomfort, and anxiety/depression). Despite stable disease, YAs with ependymoma experienced mood and lifestyle challenges and reported significant symptoms and use of pain medication. Further exploration is needed on the impact of cancer-related effects on YAs to gain insight on appropriate management and care.
Erratum: Corrigenda: Genomic signatures to guide the use of chemotherapeutics
Authors: Anil Potti, Holly K Dressman, Andrea Bild, Richard F Riedel, Gina Chan, Robyn Sayer, Janiel Cragun, Hope Cottrill, Michael J Kelley, Rebecca Petersen, David Harpole, Jeffrey Marks, Andrew Berchuck, Geoffrey S Ginsburg, Phillip Febbo, Johnathan Lancaster, Joseph R Nevins
Journal: Nature Medicine (2007)
Outcomes of IDH-Mutated Advanced Phase Ph-Negative Myeloproliferative Neoplasms Treated with IDH Inhibitors
Authors: Kirk Cahill, Anand Ashwin Patel, Hongtao Liu, Sandeep Gurbuxani, Michael Thirman, Satyajit Kosuri, Andrew S. Artz, Richard A. Larson, Wendy Stock, Jeremy Segal, Olatoyosi Odenike
Journal: Blood (2019)
A Phase 1 Study of Carfilzomib-Thalidomide-Dexamethasone in Patients with Relapsed/Refractory AL Amyloidosis - Catalyst Trial Results
Authors: Mamta Garg, Andrew Hall, Matthew Jenner, Bhuvan Kishore, Helen J Lachmann, Julian D Gillmore, Alexandra Pitchford, Louise Flanagan, Jamie B Oughton, Shameem Mahmood, Sajitha Sachchithanantham, Sarah R Brown, Ashutosh D Wechalekar
Journal: Blood (2019)
PDTM-31. INVESTIGATING THE EFFECT OF H3G34V MUTATION ON DISTINCT GENOMIC H3K36 METHYLATION PATTERNS IN PEDIATRIC GLIOMA
Authors: Tina Huang, Andrea Piunti, Patrick Ozark, Elizabeth Barton, Jin Qi, Rintaro Hashizume, Ali Shilatifard, Amanda Saratsis
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Histone H3.3 mutation (H3F3A) occurs in 50% of cortical pediatric high-grade gliomas (pHGGs). This mutation replaces glycine 34 with arginine or valine (G34R/V), impairing SETD2 activity (H3K36-specific trimethyltransferase). Consequently, reduced H3K36me is observed on H3G34V nucleosomes relative to wild-type, contributing to genomic instability and driving a distinct gene expression signature associated with tumorigenesis. However, it is not known if this differential H3K36me3 enrichment is due to H3G34V mutant protein alone. Therefore, we set to elucidate the effect of H3G34V mutation in pediatric glioma on genomic H3K36me3 enrichment in vitro. METHODS Doxycycline-inducible short hairpin RNA (shRNA) against H3F3A was delivered via lentivirus to established H3G34V mutant pediatric glioma cell line KNS42, and H3G34V introduced into H3.3 wild type normal human astrocytes (NHA). Transfections were confirmed by western blot, fluorescent imaging, and flow cytometry, with resulting H3.3WT and H3K36me3 expression determined by western blot. H3.3WT, H3K36me3, and H3G34V ChIP-Seq was performed to evaluate effects of H3G34V mutation on genomic enrichment patterns. RESULTS Complete knockdown of H3G34V was achieved with DOX-induced shRNA, with no change in total H3.3, suggesting disproportionate allelic frequency of genes encoding H3.3 (H3F3A and H3F3B). Modest increase in H3K36me3 expression occurred after H3F3A-knockdown from KNS42, suggesting H3G34V alone impacts observed H3K36me3 levels. H3G34V knock-in to NHAs was verified via western blot. Distinct H3K36me3 genomic enrichment was observed with H3G34V on ChIP-Seq. CONCLUSIONS We demonstrate that DOX-inducible knockdown of H3F3A in an H3G34V mutant pediatric glioma cell line, and H3G34V mutation transduction in wild-type NHAs, directly impacts H3K36me3 expression level. Further evaluation by ChIP-Seq analysis for restoration of wild-type genomic H3K36me3 enrichment patterns with H3G34V knockdown, and mutant H3K36me3 patterns with H3G34V transduction, is currently underway.
Management of Meningitis
Authors: H. G. Easton
Journal: BMJ (1964)

ment selectively for over a decade without seeing any of the theoretical ill-effects so often mentioned.Conversely we have read and heard of patients dying from pneumococcal meningitis without having received any intrathecal penicillin.McKendrick5 pleaded strongly for its regular use, quoting mortality rates of 25-30% without (vide the 29% mortality in Heycock and Noble's series) and 9-12% with its use for five to seven days.Intrathecal therapy with streptomycin also has a valuable role in the management of relapsing haemophilus meningitis, for intramuscular dosage alone does not usually give an adequate C.S.F.level.In McKendrick's' series of 17 cases where this additional measure was employed routinely there was only one death.This compares favourably with the Sunderland figures of four deaths in 21 cases, of whom only a third received intrathecal streptomycin." Rarely, if ever," should intrathecal therapy be omitted from the management of pneumococcal or relapsing haemophilus meningitis.Finally, is it not general experience that aseptic virus meningitis is now more, and not less, common than pyogenic meningitis; and that tuberculous meningitis has become some- thing of a rarity in most centres ?-I am, etc., J. P. ANDERSON.
Evaluation of the Prognostic Significance and Effect of NT5E-Adenosine Axis, a Novel Immune Checkpoint, in Diffuse Large B-Cell Lymphoma
Authors: Xianhuo Wang, Tingting Zhang, Lanfang Li, Lihua Qiu, Zhengzi Qian, Shiyong Zhou, Bin Meng, Xiubao Ren, Huilai Zhang, Kai Fu
Journal: Blood (2019)
TMOD-13. MODELING THE GENETIC, TRANSCRIPTOMIC, AND CELLULAR HETEROGENEITY OF GLIOBLASTOMA USING TUMOR ORGANOIDS
Authors: Daniel Zhang, Fadi Jacob, Ryan Salinas, Phuong Nguyen, Guo-li Ming, Hongjun Song
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma exhibits enormous genetic, transcriptional, and cellular heterogeneity at the macroscopic level across regions of the tumor as well as at the microscopic level between neighboring cells, all of which present significant challenges towards creating a definitive treatment for this devastating disease. We have developed a method of generating glioblastoma organoids (GBOs) from fresh tissue obtained directly from surgical resection and maintaining them in a defined medium without bFGF/EGF. Whole exome sequencing revealed that GBOs maintain the genomic landscape of their parent tumors. Somatic and copy number variants are present in the GBOs at similar allele frequencies or copy ratios as in the parent tumor, suggesting that the relative proportions of clonal populations are largely maintained in the organoids. Bulk transcriptomic analysis demonstrated strong gene expression correlations between the parent tumor and corresponding GBOs through 12 weeks of culture. Some tumors were sampled at multiple different anatomic regions, and the corresponding GBOs maintained region-specific gene expression signatures and genomic variants. EGFRvIII, a tumor-specific variant targeted in a number of emerging therapies, also remains present in the GBOs at similar transcript frequencies, reflecting the native heterogeneity of the parent tumor. Finally, we used single cell transcriptomics to examine cellular heterogeneity and find that GBOs contain many different cell types that exhibit similar gene expression profiles as the matching cell type in the corresponding parent tumor. Notably, these GBOs retain neoplastic as well as non-neoplastic cells, such as tumor associated macrophages / microglia, T-cells, endothelial cells, stromal cells, and oligodendrocytes. These GBOs preserve complex tumor heterogeneity an in vitro environment, creating opportunities for extended manipulation, characterization, and functional study for mechanistic investigation and therapeutic testing.
The shift of obesity burden by socioeconomic status between 1998 and 2017 in Latin America and the Caribbean: a cross-sectional series study
Authors: Safia S Jiwani, Rodrigo M Carrillo-Larco, Akram Hernández-Vásquez, Tonatiuh Barrientos-Gutiérrez, Ana Basto-Abreu, Laura Gutierrez, Vilma Irazola, Ramfis Nieto-Martínez, Bruno P Nunes, Diana C Parra, J Jaime Miranda
Journal: The Lancet Global Health (2019)

The burden of obesity differs by socioeconomic status. We aimed to characterise the prevalence of obesity among adult men and women in Latin America and the Caribbean by socioeconomic measures and the shifting obesity burden over time.
Outcome of Autologous Stem Cell Transplantation Following PD-(L)1 Based Salvage Therapy for Multiply Relapsed Patients with Classic Hodgkin Lymphoma
Authors: Reid W Merryman, Robert A. Redd, Yago Nieto, Uttam Rao, Michael T Byrne, David A. Bond, Kami J. Maddocks, Hatcher J. Ballard, Jakub Svoboda, Anurag K. Singh, Joseph P. McGuirk, Justin Darrah, Michael A Spinner, Ranjana H Advani, Jason Romancik, Jonathon B. Cohen, Matthew J. Frigault, Yi-Bin Chen, Maryam Rahimian, Robin M. Joyce, Mansi Shah, Kevin A. David, Ryan C. Lynch, Stephen D. Smith, Vincent T. Ho, Philippe Armand, Alex F. Herrera
Journal: Blood (2019)
Multiple Pathways Targeting CD25 or TNFRSF25 Affect CD4+FoxP3+ Regulatory T Cell Phenotype and Suppressive Function
Authors: Sabrina N. Copsel, Henry Barreras, Casey O. Lightbourn, Cameron S. Bader, Dietlinde Wolf, Brandon Kale, Warren Alperstein, Krishna V Komanduri, Robert B. Levy
Journal: Blood (2019)
GENE-62. IDENTIFICATION OF FGFR4 p.G388R VARIANT IN CEREBELLAR HEMANGIOBLASTOMAS
Authors: Matija Snuderl, Kasthuri Kannan, Jean-Pierre Gagner, Elad Mashiach, Matthias Karajannis, Adriana Heguy, David Zagzag
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND While most hemangioblastomas (~70%) are sporadic and occur predominantly in the cerebellum, they may present as well as familial form associated with von Hippel-Lindau (VHL) syndrome, an autosomal dominant disorder caused by germline mutations of the VHL gene that trigger nuclear translocation of hypoxia-inducible factor (HIF)-1α and angiogenesis. Although inactivation of VHL, a tumor suppressor gene, has been observed in hemangioblastomas, the underlying pathogenic mechanisms responsible for familial and sporadic hemangioblastomas remain incompletely understood. METHODS Whole exome sequencing of cerebellar hemangioblastoma tumors and matched blood leukocytes from 24 patients, age 24–63, was performed. After preparation and amplification of barcoded libraries, exomes were captured using Kapa Biosystems methodology and paired-end sequenced on Illumina HiSeq 2500 to an average 100-fold coverage. Following read alignment to hg19 genome, tumor and germline (leukocyte) sequences were compared, and pathogenic single nucleotide variants (SNVs) identified and validated by re-sequencing followed by pathway analysis. Additionally, tumor RNA isolated using Maxwell Promega was sequenced on Illumina instrument and the expression counts determined and normalized. RESULTS We found 314 pathogenic and/or highly deleterious mutations (both germline and somatic) with a median of 13 mutations per patient. Five patients had VHL syndrome (germline VHL mutation) and 4 carried somatic VHL mutations. Among the VHL tumors, 82 mutations were identified, including HNF1B, NOTCH1 and TCF7L1, suggesting a potential contribution of altered RNA metabolism based upon pathway analysis. Among all hemangioblastomas, germline growth factor receptor variants (FGFR4 p.G388R (14/23 (61%) patients), IGF1R, PDGFRA and TYK2) known to activate STAT3 signaling and induce HIF-1α and angiogenesis, were identified. Non-hierarchical clustering of RNA sequencing data revealed two transcriptionally-distinct subtypes of hemangioblastomas. CONCLUSIONS Our findings indicate that hemangioblastomas can also occur by germline mutations known to activate STAT3 signaling, which may have significant implication in genetic testing and counseling of patients with hemangioblastomas.
Prognostic Significance of Cytogenetic Abnormalities for Patients with Acute Lymphoblastic Leukemia, a Region-Wide Retrospective Study
Authors: Keito Suto, Akio Shigematsu, Shuichi Ota, Ryoji Kobayashi, Takeshi Kondo, Tomoyuki Endo, Yutaka Tsutsumi, Hajime Kobayashi, Yasutaka Kakinoki, Satoshi Yamamoto, Yuichi Konuma, Takuto Miyagishima, Tetsuyuki Igarashi, Takanori Oda, Hajime Sakai, Toshimichi Ishihara, Masahiro Yoshida, Takahiro Nagashima, Kazuya Sato, Yuji Kanisawa, Yoshihito Haseyama, Yasuo Hirayama, Mitsutoshi Kurosawa
Journal: Blood (2019)
Effect of revealing authors’ conflicts of interests in peer review: randomized controlled trial
Authors: Leslie K John, George Loewenstein, Andrew Marder, Michael L Callaham
Journal: BMJ (2019)

Abstract Objective To assess the effect of disclosing authors’ conflict of interest declarations to peer reviewers at a medical journal. Design Randomized controlled trial. Setting Manuscript review process at the Annals of Emergency Medicine. Participants Reviewers (n=838) who reviewed manuscripts submitted between 2 June 2014 and 23 January 2018 inclusive (n=1480 manuscripts). Intervention Reviewers were randomized to either receive (treatment) or not receive (control) authors’ full International Committee of Medical Journal Editors format conflict of interest disclosures before reviewing manuscripts. Reviewers rated the manuscripts as usual on eight quality ratings and were then surveyed to obtain “counterfactual scores”—that is, the scores they believed they would have given had they been assigned to the opposite arm—as well as attitudes toward conflicts of interest. Main outcome measure Overall quality score that reviewers assigned to the manuscript on submitting their review (1 to 5 scale). Secondary outcomes were scores the reviewers submitted for the seven more specific quality ratings and counterfactual scores elicited in the follow-up survey. Results Providing authors’ conflict of interest disclosures did not affect reviewers’ mean ratings of manuscript quality (M control =2.70 (SD 1.11) out of 5; M treatment =2.74 (1.13) out of 5; mean difference 0.04, 95% confidence interval –0.05 to 0.14), even for manuscripts with disclosed conflicts (M control = 2.85 (1.12) out of 5; M treatment =2.96 (1.16) out of 5; mean difference 0.11, –0.05 to 0.26). Similarly, no effect of the treatment was seen on any of the other seven quality ratings that the reviewers assigned. Reviewers acknowledged conflicts of interest as an important matter and believed that they could correct for them when they were disclosed. However, their counterfactual scores did not differ from actual scores (M actual =2.69; M counterfactual =2.67; difference in means 0.02, 0.01 to 0.02). When conflicts were reported, a comparison of different source types (for example, government, for-profit corporation) found no difference in effect. Conclusions Current ethical standards require disclosure of conflicts of interest for all scientific reports. As currently implemented, this practice had no effect on any quality ratings of real manuscripts being evaluated for publication by real peer reviewers.
Single-Cell Transcriptomic and Proteomic Diversity in Multiple Myeloma
Authors: Reyka G Jayasinghe, Yige Wu, Ying Zhu, Ruiyang Liu, Mark A. Fiala, Daniel R. Kohnen, Chia-Feng Tsai, Smrithi Mani, Justin King, Michael P. Rettig, Julie O'Neal, Tianjiao Wang, Steven M. Foltz, Lijun Yao, Hua Sun, Catrina Fronick, Scott R. Goldsmith, John F. DiPersio, Ravi Vij, Liu Tao, Li Ding
Journal: Blood (2019)
Mortality After Invasive Second Breast Cancers Following Prior Radiotherapy for DCIS
Authors: Puyao C. Li, Zilu Zhang, Angel M. Cronin, Rinaa S. Punglia
Journal: Journal of the National Comprehensive Cancer Network (2019)

Women with a history of ductal carcinoma in situ (DCIS) are at increased risk for developing a second breast cancer (SBC). A prior meta-analysis of randomized studies of radiotherapy (RT) for DCIS has shown a trend toward increased breast cancer-specific mortality after SBC, but it did not have the power needed to detect a significant difference, due to a limited number of recurrences. This study sought to evaluate the impact of RT for DCIS on mortality after SBC in a larger cohort.Using the SEER database, 3,407 patients were identified who received breast-conserving therapy with or without RT for primary DCIS in 2000 through 2013 and subsequently developed a stage I-III invasive SBC within the same time period. Fine-Gray competing risk models were used to study the association between receipt of RT and mortality after SBC.Prior RT was found to be associated with higher rates of breast cancer-specific mortality (hazard ratio [HR], 1.70; 95% CI, 1.18-2.45; P=.005), even after controlling for cancer stage. Interaction analysis suggested that this risk trended higher in patients with ipsilateral versus contralateral SBC (HR, 2.07 vs 1.26; P=.16). Furthermore, compared with patients who developed contralateral SBC, those with ipsilateral SBC were younger (P<.001) and more often lacked estrogen receptor expression (P<.001).Patients who previously received RT for DCIS had higher mortality after developing an invasive SBC than those who did not receive RT. This finding may have implications for initial treatment decisions in the management of DCIS.
RTHP-12. NATIONWIDE DISTRIBUTION OF LINEAR ACCELERATOR VERSUS GAMMA KNIFE STEREOTACTIC RADIOSURGERY UTILIZATION FOR METASTATIC BRAIN DISEASE IN ACADEMIC VERSUS COMMUNITY HOSPITALS
Authors: Shearwood McClelland III, Catherine Degnin, Yiyi Chen, Gordon Watson, Jerry Jaboin
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Single-fraction stereotactic radiosurgery (SRS) is often the preferred treatment modality for metastatic brain disease, particularly when patients have a small enough volume of disease to preclude whole brain radiation therapy and its associated permanent cognitive morbidity. The two predominant SRS treatment modalities are Gamma Knife and linear accelerator (LINAC). The recent impact of SRS modality in academic versus community hospital settings in the United States (US) since the 2013 implementation of the American Tax Payer Relief Act (ATRA) has yet to be examined. METHODS Brain metastases patients from non-small cell lung cancer (NSCLC) throughout the United States having undergone SRS were identified using the 2010–2016 National Cancer Data Base (NCDB). SRS utilization in academic versus community (non-academic) hospitals was identified and assessed. RESULTS Of the 4,012 SRS patients examined, the majority (64%) were treated at academic hospitals. Beginning in 2014, LINAC SRS rapidly increased in popularity compared to GKRS, reversing an annual decline in utilization originating from 2011. The 63% LINAC composition of SRS cases at non-academic centers in 2016 was an all-time high, a 12% increase from a year earlier. This was markedly different than SRS utilization at academic hospitals, where despite a steady increase in LINAC SRS since 2013, GKRS remained the predominant SRS modality, comprising 73% of cases in 2016. CONCLUSIONS The implementation of LINAC over Gamma Knife SRS in the non-academic hospital setting has markedly increased in the timespan since ATRA implementation, comprising more than 60% of SRS cases compared to only 27% of academic hospital SRS cases in 2016. These findings indicate that without the substantially increased Medicare reimbursement advantage formerly associated with Gamma Knife compared to LINAC prior to ATRA, the non-academic setting may be more sensitive than academic centers to conditions optimizing reimbursement.
Elotuzumab As Post-Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Myeloma
Authors: Nikhita Gadi, Linda Schmidt, Jaeil Ahn, Tianmin Wu, Scott D. Rowley, Elli Gourna Paleoudis, Michele L. Donato, David H. Vesole, Stuart L. Goldberg, David S. Siegel, Noa Biran
Journal: Blood (2019)
CSIG-14. PROTEIN KINASE CK2 REGULATES THE EXPRESSION OF NERVE/GLIAL ANTIGEN (NG)2 IN GLIOBLASTOMA
Authors: Beate Schmitt, Christoph Sippl, Steffi Urbschat, Joachim Oertel, Matthias Laschke, Michael Menger, Emmanuel Ampofo
Journal: Neuro-Oncology (2019)

Abstract Nerve/glial antigen (NG)2 enhances cell proliferation, migration as well as chemoresistance and is associated with a poor clinical outcome in glioblastoma. Since regulatory mechanisms of NG2 expression are still largely unknown, we herein investigated the impact of protein kinase CK2 inhibition on NG2 expression in human glioblastoma cells. CK2 was inhibited in NG2-positive human glioblastoma cell lines (A1207, U87) and primary human glioblastoma cells by pharmacological treatment (CX-4945, TBB) or siRNA. NG2 expression was analyzed by flow cytometry, Western Blot and qRT-PCR. Cytotoxicity and viability were assessed by WST-1, LDH and BrdU assays. Scratch, sprouting and BrdU assays as well as growth curves were performed to examine cell migration and proliferation. Truncated fragments of the human NG2 promotor were generated and their transcriptional activity was assessed using reporter gene assays. The effect of CK2 inhibition on tumor growth was investigated in xenografts within the flanks of NOD/SCID mice. Finally, effects of CK2 inhibition were analyzed in primary human glioblastoma cells. We found that inhibition of CK2 significantly reduces NG2 protein levels in A1207 (19%±6.2; Mean±SD), U87 (35%±11.3) and primary human glioblastoma cells (41%) when compared to controls. Further analyses revealed that this is due to a decreased NG2 mRNA level. Of note, we identified a 200 base pair fragment, including a binding site for the CK2-dependent transcription factor SP-1. Functional assays showed no cytotoxic effects of the decreased NG2 expression after CK2 inhibition, whereas cell migration and proliferation were markedly reduced. Moreover, we found that CX-4945 treatment decreases tumor growth, which is associated with a diminished NG2 expression (56%±13.0) when compared to controls. In conclusion, we identified CK2 as a novel regulator of NG2 gene expression in human glioblastoma cells. Hence, pharmacological inhibition of CK2 may represent a novel strategy in the therapy of NG2-positive glioblastoma.