tbuckley/cabot-search huggingface dataset:
CMET-08. CEREBROSPINAL FLUID CARCINOEMBRYONIC ANTIGEN PREDICT PROGNOSIS IN LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER
Authors: Junjie Zhen, Shaoqun Li, Lei Wen, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to identify the clinicopathological features and prognostic factors related to overall survival in NSCLC patients with LM. METHODS Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Guangdong Sanjiu Brain Hospital were retrospectively reviewed. RESULTS Median KPS at diagnosis of LM were 60 (range, 20–90). Forty-seven (63.5%) patients harboring epidermal growth factor receptor (EGFR) or anaplasticlymphoma kinase (ALK) mutation while other twenty-seven patients (36.5%) were wild type or unknown status. Local treatment for LM consisted of whole-brain radiotherapy (WBRT) (52.7%), ventriculoperitoneal (VP) shunt (6.8%) and external drainage (6.8%). Systematic therapy for LM included EGFR or ALK tyrosine kinase inhibitors (TKI) (59.5%), chemotherapy (40.5%) and bevacizumab (8.1%). The median overall survival from diagnosis of LM to death was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients with high Cerebrospinal Fluid (CSF) carcinoembryonic antigen (CEA) level (＞50ng/ml) had worse prognosis compared with those low CSF CEA level (≤50ng/ml) ones (p=0.02). However, there was no significant difference in survival between patients with high serum CEA and those with low serum CEA (p=0.645). EGFR/ALK mutation and EGFR/ALK TKI after LM were also identified as variables that had prognostic influence on survival, while KPS, concurrent brain metastasis, WBRT and chemotherapy had no prognostic value for survival. CONCLUSION Median overall survival was higher than historical experience in this retrospective analysis. It is CSF CEA level, but not serum CEA level that correlated with prognosis for LM from NSCLC.
CSIG-26. IS INTRINSIC APOPTOSIS THE SIGNALING PATHWAY ACTIVATED BY TUMOR-TREATING FIELDS FOR GLIOBLASTOMA?
Authors: Kristen Carlson, Jack Tuszynski, Ze’ev Bomzon
Journal: Neuro-Oncology (2019)

Abstract Increasingly, tumor-treating fields (TTFields, 2 V/cm, 200 kHz) are accepted as the fourth treatment modality for glioblastoma. Evidence shows that substituting non-steroidal inflammation control (celecoxib) for dexamethasone increases overall survival from 4.8 to 11.0 months, and more recently, up to 60 months. Toward explaining TTFields mechanism of action (MoA), our numerical simulations indicate that TTFields disrupt functionality of microtubules, which in turn trigger the intrinsic apoptotic pathway independent of cell cycle checkpoints. We present the theory and empirical evidence. 1) TTFields act similarly to chemotherapeutic ‘spindle poisons’ by interfering with microtubule (MT) polymerization, increasing free tubulin by 20% in relative terms; 2) Finite element modeling shows TTFields amplify electric field strength, in accord with empirical results, a) along the MT when aligned with the cell axis, where field strength exceeds 10–16 N required to disrupt motor protein transit, and b) 15x at MT ends when orthogonal to cell axis; 3) Either through producing excess free tubulin, which may block voltage-dependent anion channels, or direct effects on the mitochondrial inner and outer membranes, TTFields inhibit expression of pro-survival protein Bcl-2; 4) Decreased Bcl-2 expression activates the intrinsic apoptotic pathway in a novel cell-cycle-checkpoint and caspase-independent manner; 5) Patients using low (&lt; 4.1 mg/day) vs. high (&gt;4.1 mg/day) dexamethasone doses experienced an average 8.7 vs. 3.2 months OS and up to 60 months; 6) Numerous studies in both brain and other tissues show that dexamethasone a) promotes extrinsic, immune-system apoptosis and b) inhibits intrinsic, Bcl-2/Bax mediated apoptosis; 7) Downstream effects of intrinsic apoptosis are remarkably similar to empirically-observed effects of TTFields on tumor cells. Research supported by Novocure Ltd. Dept of Neurosurgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston MA USA. carlsokw@bidmc.harvard.edu. Dept of Physics, University of Alberta, Edmonton, Canada, Novocure Ltd., Haifa, Israel.
High-Resolution Next-Generation Whole Genome Optical Mapping As a Novel Molecular Diagnostic Tool for Comprehensive Assessment of Structural Chromosomal Variations in Myelodysplastic Syndromes
Authors: Rashmi Kanagal-Shamanna, Guillermo Montalban-Bravo, Koji Sasaki, Rajyalakshmi Luthra, Hui Yang, Gokce A. Toruner, Keyur P. Patel, Saradhi Mallampati, Hagop M. Kantarjian, Carlos E. Bueso-Ramos, L. Jeffrey Medeiros, Guillermo Garcia-Manero
Journal: Blood (2019)
CMET-30. COMPREHENSIVE METHYLOME ANALYSIS OF EGFR-MUTANT PRIMARY LUNG ADENOCARCINOMA AND MATCHED BRAIN METASTASIS
Authors: Yasin Mamatjan, Michael Cabanero, Jeffrey Zuccato, Jessica Weiss, Shirin Karimi, Hadas Sorotsky, Ming Tsao, Kenneth Aldape, Frances Shepherd, Gelareh Zadeh
Journal: Neuro-Oncology (2019)

Abstract Brain metastasis (BM) in patients with EGFR-mutant lung adenocarcinoma is a major determinant of overall survival. Novel insight into the genetic and epigenetic underpinnings of BM development is lacking. The aim of this study is to compare the methylome of EGFR-mutant primary lung adenocarcinoma (EGFRM-PLA) and matched BM to identify important alterations for the mechanisms of BM. Matched EGFRM-PLA and BM tumors from seven patients were profiled using the Illumina Infinium MethylationEPIC BeadChip array. Unsupervised clustering analyses of the 14 samples showed a similar whole DNA methylation signatures between EGFRM-PLA and BM tumors. Furthermore, PCA plot highlighted that seven matched BM and lung tumor samples were clustered together closely based on matching pairs for the most variable probes (2.5K to 10K). These observations indicate high level of concordance and the same cell of origin. However, these fourteen samples clustered into two groups based on tumor site being lung or brain based on 83K differentially methylated CpG sites. Of the 83K probes, 2.4K were either hypermethylated or hypomethylated in all lung samples. A quarter of these 2.4K probes were located in promoter regions. Specifically, we identified differences in methylation status of EGFR/ALK promoter regions in lung tumors versus BM. CNV analyses showed higher deep deletions of chromosomes and genes in BM compared to EGFRM-PLA. Leukocytes unmethylation for purity (LUMP) scores which indicate immune cell infiltration were similar between lung and BM pairs (Mean LUMP_score=0.64) consistent with high immune cell infiltration. Our results indicated a similar whole DNA methylation signature of EGFRM-PLA and matched BM, while comprehensive analysis identified important differentially methylated probes. Distinct differences in CNV alterations were observed in lung versus brain samples. The BM and EGFRM-PLA showed similar tumor purity and immune cell components. Overall, tumor methylation profiling provides clinically important information regarding biology of BM in EGFRM-PLA.
<i>Vital Signs:</i> Estimated Proportion of Adult Health Problems Attributable to Adverse Childhood Experiences and Implications for Prevention — 25 States, 2015–2017
Authors: Melissa T. Merrick, Derek C. Ford, Katie A. Ports, Angie S. Guinn, Jieru Chen, Joanne Klevens, Marilyn Metzler, Christopher M. Jones, Thomas R. Simon, Valerie M. Daniel, Phyllis Ottley, James A. Mercy
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Adverse childhood experiences, such as violence victimization, substance misuse in the household, or witnessing intimate partner violence, have been linked to leading causes of adult morbidity and mortality. Therefore, reducing adverse childhood experiences is critical to avoiding multiple negative health and socioeconomic outcomes in adulthood.
IMMU-25. MAGNETIC PARTICLE IMAGING FOR NON-INVASIVE TRACKING OF ADOPTIVE CELL TRANSFER IN CANCER IMMUNOTHERAPY
Authors: Angelie Rivera-Rodriguez, Lan Hoang-Minh, Leyda Marrero-Morales, Duane Mitchell, Carlos Rinaldi
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Adoptive cell therapies (ACT) are strategies being explored to boost the immune response against cancer. ACT cancer immunotherapies are effective against metastatic melanoma, leukemia, and lymphoma, but face challenges in treating other solid tumors, such as in the brain. A critical step for the success of ACT in solid cancers is achieving trafficking and persistence of T-cells at tumor sites. Glioblastoma (GBM) is the most common and aggressive cancer of the central nervous system in adults, with a prognosis of 15-18-month average patient survival after diagnosis. Biomedical imaging is often used to track cell therapies. Magnetic Particle Imaging (MPI) is a novel biomedical imaging modality enabling non-invasive visualization of the distribution of biocompatible superparamagnetic iron oxide (SPIO) tracers. OBJECTIVE Label T-cells with SPIO to non-invasively track adoptive T cell transfer immunotherapy with MPI in the context of brain cancer. METHODS Murine pmel-DsRed T-cells were isolated from the spleen of a transgenic C57BL/6 mouse, and were exposed to different SPIO concentrations ex vivo. Cell viability, phenotype, and cytotoxic function were analyzed to determine if T-cells were affected by the SPIO labeling. Moreover, in vivo experiments were performed in a murine GBM model, and labeled T-cells were injected intravenously and tracked using MPI. RESULTS The SPIO-labeling of T-cells did not affected cell viability, phenotype, or cell cytotoxic function at all tested incubation conditions. The internalized SPIO can be quantified and spatially detected using MPI both in vitro and in vivo. In addition, MPI in vivo tracking shows T-cells accumulation in liver and lungs, as well in the spleen and brain, as showed ex vivo. CONCLUSIONS SPIO-labeling of T-cells did not affected its cytotoxic function and MPI allows for in vivo tracking of adoptively T-cell transfer. MPI will provide better understanding of ACT dynamics to accelerate development of novel treatments.
PDCT-01. BIOLOGICAL MEDICINE FOR DIFFUSE INTRINSIC PONTINE GLIOMAS ERADICATION (BIOMEDE): RESULTS OF THE THREE-ARM BIOMARKER-DRIVEN RANDOMIZED TRIAL IN THE FIRST 230 PATIENTS FROM EUROPE AND AUSTRALIA
Authors: Jacques Grill, Gwenael Le Teuff, Karsten Nysom, Klas Blomgren, Darren Hargrave, Geoff McCowage, Francisco Bautista, Dannis van Vuurden, Volodia Dangouloff-Ros, Stephanie Puget, Pascale Varlet, Marie-Anne Debily, Gilles Vassal, Marie-Cécile Le Deley
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating brain neoplasms. Despite 50 years of clinical trials, no improvement of survival has been observed and most children die within 2 years of diagnosis. Only radiotherapy transiently controls disease progression. METHODS/AIMS: BIOMEDE was conceived as a randomized multi-arm multi-stage program (drop-the-loser adaptive design). It started with an open-label phase-II trial comparing three drugs (everolimus, dasatinib, erlotinib) combined with irradiation, allocated according to the presence of their specific targets) with a planned sample size of 250 patients. A stereotactic biopsy was performed at diagnosis to centrally confirm the diagnosis of DIPG (presence of histone H3K27M mutation or loss of K27 trimethylation) and assess biomarkers/targets (PTEN-loss, EGFR-overexpression). Targeted therapies were started concomitantly with radiotherapy and were continued until disease progression. The main objective of the study was to compare the efficacy of randomized groups in terms of overall survival (OS). RESULTS At the 3rd interim analysis, based on 193 randomized patients among the 230 study patients, the IDMC concluded that the study was unlikely to meet its primary objective even if 250 patients were randomized. The median OS from the time of randomization was 10.9, 9.5 and 9 months for everolimus, dasatinib and erlotinib, respectively, which is comparable to historical controls. The median number of courses administered was 7, 5.5 and 6 respectively. Treatment was discontinued due to toxicity in 2%, 13%, and 15%, respectively. No biopsy-related death was reported and diagnostic yield was excellent, with only 5 non-informative biopsies. CONCLUSION BIOMEDE shows the feasibility of biologically-driven treatment in DIPG on a large international scale. Based on the better toxicity profile and the slightly better efficacy, although not statistically significant, the steering committee proposed that everolimus should be used as the control arm for the next step, BIOMEDE 2.0.
Annals Story Slam - What's a Life Worth?
Authors: Naheed Dosani
Journal: Annals of Internal Medicine (2019)

Web Exclusives5 November 2019Annals Story Slam - What's a Life Worth?FREENaheed Dosani, MDNaheed Dosani, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W19-0028 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - What's a Life Worth? "What's a Life Worth?" by Naheed Dosani, MD (Duration 5:42)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 5 November 2019Volume 171, Issue 9Page: SS1 ePublished: 5 November 2019 Issue Published: 5 November 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.Loading ...
RTHP-36. REIRRADIATION FOR DIFFUSE INTRINSIC PONTINE GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF PATIENT OUTCOMES
Authors: Victor Lu, John Welby, Nadia Laack, Anita Mahajan, David Daniels
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor with dismal prognosis despite initial radiation therapy (RT). The clinical consequences of attempting reirradiation (reRT) in these patients to alleviate both symptomatology and improve prognosis are currently unclear. Thus, the aim of this systematic review and meta-analysis was to clarify the efficacy and safety of reRT in DIPG. METHODS Searches of 7 electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against pre-specified criteria. The incidence and duration of clinical outcomes were then extracted and pooled by means of meta-analysis from the included studies. RESULTS A total of 7 studies satisfied all criteria, describing 90 cases of DIPG in which reRT was attempted 11.8–14 months after initial RT. Based on a random-effects model, the incidences of clinical improvement and radiologic response following reRT were 87% (95% CI, 78–95%) and 69% (95% CI, 52–84%) respectively. The incidence of acute serious toxicity was 0% (95% CI, 0–4%). Pooled overall survivals from initial diagnosis, and time of reRT, were 18.0 months (95% CI, 14.2–21.7) and 6.2 months (95% CI, 5.5–7.0) respectively. CONCLUSIONS Based on these results, the clinical consequences of reRT for DIPG when administered appropriately and safely at first progression appear acceptable, and potentially favorable, based on the limited evidence in the current literature. Concerns regarding acute serious toxicity were not realized. It is likely a sub-cohort of all DIPG diagnoses will be most amenable to improved prognosis with reRT, and greater investigation is required to identify their characteristics.
Bromodomain and Extra Terminal Domain (BET) Inhibitors Sensitize Chronic Myelomonocytic Leukemia (CMML) to PIM Inhibition Via Downregulation of Mir-33a
Authors: Christopher Letson, Alexis Vedder, Ariel Quintana, Phillip Liu, Brett Reid, Maria E Balasis, Hannah Newman, Traci Kruer, Luciana L Almada, Guolin Zhang, Martin Fernandez-Zapico, Mrinal M Patnaik, Jeffrey E. Lancet, Rami S. Komrokji, P.K. Epling-Burnette, Alan F. List, Eric B. Haura, Gary W. Reuther, Thomas A. Sellers, Holly K. Koblish, Eric Padron
Journal: Blood (2019)
Spectrum and Clinical Significance of HLA Class I Alleles and Their Somatic Mutations in Immune Aplastic Anemia
Authors: Yoshitaka Zaimoku, Sharon D. Adams, Bhavisha A Patel, Audrey Ai Chin Lee, Sachiko Kajigaya, Xingmin Feng, Olga Rios, Holly DiFebo, Lemlem Alemu, Diego Quinones Raffo, Emma M. Groarke, Willy A. Flegel, Neal S. Young
Journal: Blood (2019)
Non Invasive Evaluation of Bone Marrow Activity in Patients with Sickle Cell Disease: Correlation with Disease Features, Genotype, Markers of Erythropoiesis, Iron Metabolism and Hydroxyurea Treatment
Authors: Ioannis Papassotiriou, Pagona Flevari, Christos Poziopoulos, Sofia Zaliou, Vasilis Tsaousis, Katerina Larissi, Maria Dimopoulou, Veroniki Komninaka, Marianna Politou, Evangelos Terpos, Ersi Voskaridou
Journal: Blood (2019)
SCIDOT-43. FINAL DATA ANALYSIS OF A PILOT STUDY TESTING THE EFFICACY OF USING LASER INTERSTITIAL THERMAL THERAPY (LITT) TO INDUCE TEMPORARY DISRUPTION OF THE PERITUMORAL BLOOD BRAIN BARRIER (BBB) TO IMPROVE EFFECTIVENESS OF BBB-IMPERMEANT CHEMOTHERAPY IN RECURRENT GLIOBLASTOMA
Authors: David Tran, Jian Campian, Joshua Shimony, Albert Kim, George Ansstas, Eric Leuthardt
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Poor CNS drug delivery is a major limiting factor in GBM therapy. Since most recurrences occur peritumorally where infiltrating glioma cells reside, peritumoral BBB disruption may help improve drug delivery and efficacy. LITT, a minimally invasive cytoreductive treatment for brain tumors, may disrupt BBB as evidenced by post-ablation contrast enhancement. METHODS Patients with recurrent GBM were treated with LITT. The degree of post-LITT peritumoral BBB disruption was measured by the vascular transfer constant (Ktrans) in brain DCE-MRI. Serum levels of brain-specific enolase (BSE) were quantified as an independent measure of BBB disruption. Forty enrollments were planned with equal randomization to weekly low-dose doxorubicin, a BBB-impermeant chemotherapy, either during the BBB-permeable window (Early Dox) or after the resolution of disruption (Late Dox). The primary endpoint is 6-month PFS rate (6-PFS). RESULTS Peritumoral Ktrans peaked immediately post LITT, followed by a gradual decline for the next 4 weeks. Similarly, serum BSE concentrations peaked in 1–3 weeks after LITT before decreasing to baseline by 6 weeks. 41 patients were randomized to Early and Late Dox. 31 patients (14 Early and 17 Late Dox) were evaluable for the primary endpoint. MGMT promoter methylation rate was 28% and 47% in the Early and Late Dox arms, respectively. 6-PFS was 57.1% (8/14) in Early Dox compared to 35.3% (6/17) in Late Dox. PFS was 5.8 (95%CI: 4.1–6.3) months vs. 4.9 (95%CI: 2.4–6.3) months, while OS was 12.8 (95%CI: 7.8–14.5) months vs. 13.6 (95%CI: 10.2–17.1) months, for Early vs. Late Dox, respectively. The most common grade 3–4 toxicities were cytopenia observed in 6 (16%) patients. CONCLUSIONS LITT induces temporary peritumoral BBB disruption lasting 4–6 weeks, providing a rare opportunity to enhance local delivery of potentially efficacious but BBB-impermeant therapeutic agents. 6-PFS strongly favors dox given early during the window of BBB disruption, thus supporting the hypothesis.
Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis
Authors: Richard J. Allen, Beatriz Guillen-Guio, Justin M. Oldham, Shwu-Fan Ma, Amy Dressen, Megan L. Paynton, Luke M. Kraven, Ma'en Obeidat, Xuan Li, Michael Ng, Rebecca Braybrooke, Maria Molina-Molina, Brian D. Hobbs, Rachel K. Putman, Phuwanat Sakornsakolpat, Helen L. Booth, William A. Fahy, Simon P. Hart, Mike R. Hill, Nik Hirani, Richard B. Hubbard, Robin J. McAnulty, Ann B. Millar, Vidyia Navaratnam, Eunice Oballa, Helen Parfrey, Gauri Saini, Moira K. B. Whyte, Yingze Zhang, Naftali Kaminski, Ayodeji Adegunsoye, Mary E. Strek, Margaret Neighbors, Xuting R. Sheng, Gunnar Gudmundsson, Vilmundur Gudnason, Hiroto Hatabu, David J. Lederer, Ani Manichaikul, John D. Newell, George T. O’Connor, Victor E. Ortega, Hanfei Xu, Tasha E. Fingerlin, Yohan Bossé, Ke Hao, Philippe Joubert, David C. Nickle, Don D. Sin, Wim Timens, Dominic Furniss, Andrew P. Morris, Krina T. Zondervan, Ian P. Hall, Ian Sayers, Martin D. Tobin, Toby M. Maher, Michael H. Cho, Gary M. Hunninghake, David A. Schwartz, Brian L. Yaspan, Philip L. Molyneaux, Carlos Flores, Imre Noth, R. Gisli Jenkins, Louise V. Wain
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion.Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Measurements and Main Results: We identified and replicated three new genome-wide significant (P < 5 × 10-8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
A Novel Approach to Risk Stratification in Multiple Myeloma Using ISS Stage and FISH
Authors: Shaji K. Kumar, Patricia Greipp, Morie A Gertz, Angela Dispenzieri, Linda B Baughn, Martha Q. Lacy, Suzanne R. Hayman, Francis K. Buadi, David Dingli, Prashant Kapoor, Ronald S. Go, Yi L. Hwa, Amie Fonder, Miriam A. Hobbs, Yi Lin, Nelson Leung, Taxiarchis Kourelis, Rahma M Warsame, Mustaqeem Siddiqui, John A. Lust, Robert A. Kyle, Rhett P. Ketterling, S.Vincent Rajkumar, P. Leif Bergsagel
Journal: Blood (2019)