tbuckley/cabot-search huggingface dataset:
Health Care Use and Costs in Individuals With Diabetes With and Without Comorbid Depression in Germany: Results of the Cross-sectional DiaDec Study
Authors: Manuela Brüne, Ute Linnenkamp, Silke Andrich, Linda Jaffan-Kolb, Heiner Claessen, Charalabos-Markos Dintsios, Imke Schmitz-Losem, Johannes Kruse, Nadja Chernyak, Mickaël Hiligsmann, Norbert Hermanns, Andrea Icks
Journal: Diabetes Care (2020)

OBJECTIVE Increased health care use and costs have been reported in individuals with diabetes with comorbid depression. Knowledge regarding cost differences between individuals with diabetes alone and those with diabetes and diagnosed/undiagnosed depression is, however, scarce. We therefore compared use and costs for patients with diabetes and no depression and patients with diabetes and documented depression diagnosis or self-reported depression symptoms for several cost components, including mental health care costs. RESEARCH DESIGN AND METHODS Data from a 2013 cross-sectional survey of randomly sampled members of a nationwide German statutory health insurance (SHI) provider with diabetes (n = 1,634) were linked individually with SHI data covering four quarters before and after the survey. Self-reported depression symptoms were assessed with the Patient Health Questionnaire-9, with depression diagnosis taken from SHI data. We analyzed health care use and costs, using regression analysis to calculate cost ratios (CRs) with adjustment for sociodemographic/socioeconomic factors and comorbidities for two groups: 1) those with no symptoms and no diagnosis and 2) those with symptoms or diagnosis. In our explorative subanalysis we analyzed subgroups with either symptoms or diagnosis separately. RESULTS Annual mean total health care costs were higher for patients with comorbid depression (EUR 5,629 [95% CI 4,987–6,407]) than without (EUR 3,252 [2,976–3,675], the CR being 1.25 [1.14–1.36]). Regression analysis showed that excess costs were highly associated with comorbidities. Mental health care costs were very low for patients without depression (psychotherapy EUR 2; antidepressants EUR 4) and still relatively low for those with depression (psychotherapy EUR 111; antidepressants EUR 76). CONCLUSIONS Costs were significantly higher when comorbid depression was present either as symptoms or diagnosed. Excess costs for mental health services were rather low.
Thrombogenesis and fibrinolysis in acute coronary syndromes: Important facets of a prothrombotic or hypercoagulable state?∗∗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: Gregory Y.H Lip, Andrew D Blann
Journal: Journal of the American College of Cardiology (2000)
A Phase II Study of Total Marrow and Lymphoid Irradiation (TMLI) in Combination with Cyclophosphamide and Etoposide in Patients with Relapsed/Refractory Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation
Authors: Anthony S. Stein, Ni-Chun Tsai, Joycelynne M. Palmer, Monzr M. Al Malki, Ibrahim Aldoss, Haris Ali, Ahmed Aribi, Len Farol, Chatchada Karanes, Samer Khaled, An Liu, Guido Marcucci, Ryotaro Nakamura, Margaret R. O'Donnell, Pablo Parker, Vinod Pullarkat, Eric Radany, Joseph Rosenthal, Amandeep Salhotra, Ricardo Spielberger, David S. Snyder, Stephen J. Forman, Jeffrey Wong
Journal: Blood (2017)
Unconventional Secretion of PKCδ Exerts Tumorigenic Function via Stimulation of ERK1/2 Signaling in Liver Cancer
Authors: Kohji Yamada, Tsunekazu Oikawa, Ryusuke Kizawa, Saya Motohashi, Saishu Yoshida, Tomotaka Kumamoto, Chisato Saeki, Chika Nakagawa, Yuya Shimoyama, Katsuhiko Aoki, Toshiaki Tachibana, Masayuki Saruta, Masaya Ono, Kiyotsugu Yoshida
Journal: Cancer Research (2020)

Expression of human protein kinase C delta (PKCδ) protein has been linked to many types of cancers. PKCδ is known to be a multifunctional PKC family member and has been rigorously studied as an intracellular signaling molecule. Here we show that PKCδ is a secretory protein that regulates cell growth of liver cancer. Full-length PKCδ was secreted to the extracellular space in living liver cancer cells under normal cell culture conditions and in xenograft mouse models. Patients with liver cancer showed higher levels of serum PKCδ than patients with chronic hepatitis or liver cirrhosis or healthy individuals. In liver cancer cells, PKCδ secretion was executed in an endoplasmic reticulum (ER)-Golgi-independent manner, and the inactivation status of cytosolic PKCδ was required for its secretion. Furthermore, colocalization studies showed that extracellular PKCδ was anchored on the cell surface of liver cancer cells via association with glypican 3, a liver cancer-related heparan sulfate proteoglycan. Addition of exogenous PKCδ activated IGF-1 receptor (IGF1R) activation and subsequently enhanced activation of ERK1/2, which led to accelerated cell growth in liver cancer cells. Conversely, treatment with anti-PKCδ antibody attenuated activation of both IGF1R and ERK1/2 and reduced cell proliferation and spheroid formation of liver cancer cells and tumor growth in xenograft mouse models. This study demonstrates the presence of PKCδ at the extracellular space and the function of PKCδ as a growth factor and provides a rationale for the extracellular PKCδ-targeting therapy of liver cancer. SIGNIFICANCE: PKCδ secretion from liver cancer cells behaves as a humoral growth factor that contributes to cell growth via activation of proliferative signaling molecules, which may be potential diagnostic or therapeutic targets.
EPID-11. A MULTI-INSTITUTIONAL COMPARATIVE ANALYSIS OF THE CLINICAL, GENOMIC, AND SURVIVAL CHARACTERISTICS OF PEDIATRIC, YOUNG ADULT AND OLDER ADULT PATIENTS WITH IDH-MUTANT GLIOMA
Authors: Mary Jane Lim-Fat, Jayne Vogelzang, Eleanor Woodward, Alana McGovern, Clement Ma, Hasan Al-sayegh, Sanda Alexandrescu, Ashley Margol, Jennifer Cotter, Kristina Cole, Marilyn Li, Emily Owens, Amy Smith, Stewart Goldman, Kristiyana Kaneva, Emily Burton, Kellie Nazemi, Karen Wright, Patrick Wen, Katherine Warren, Mehdi Touat, David Reardon, Wenya Linda Bi, Keith Ligon, Kee Kiat Yeo
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Prognostic significance of IDH-mutation in glioma is incompletely understood in children and adolescents/young adults (YAs). We compared the clinico-genomic features, outcomes and prognostic factors observed in IDH-mutant gliomas across age groups. METHODS Clinical, histologic and molecular data of patients with IDH-mutant gliomas from 8 pediatric institutions (spanning twenty years) and adult patients from two institutions (from 2013–2019) were identified. Patients were grouped as pediatric (&amp;lt; 19y), YA (19y to &amp;lt; 40y) or older adult (≥ 40y). Genomic alterations, including somatic mutations and copy number variants, were captured with institutional next generation sequencing. Factors were compared across age categories using Fisher’s exact test or analysis-of-variance. Cox proportional-hazards regression tested factors for association with overall (OS) and progression-free survival (PFS). RESULTS Of 379 patients, 48(13%) were pediatric, 204(54%) YA and 127(33%) older adult. Histological subtype differed significantly by age group (p&amp;lt; 0.0001). YAs had higher rates of malignant transformation (p=0.01) and shorter time-from-diagnosis-to-malignant transformation (p=0.01) compared to other age groups. Analysis of genomic alterations revealed an age-related difference in distribution in ATRX mutations only (p=0.0018). Median PFS and OS for the entire cohort were 4.62 and 17.19 years. In univariate models, PFS differed by age group (p=0.0012), with YAs having the worst outcomes. Lack of MGMT methylation (p=0.024) predicted poorer OS. Upfront observant management was predictive of poorer PFS. Gene mutations were not associated with PFS. In multi-variable models, YAs had shorter PFS compared to pediatric (hazard ratio [HR]=2.03, p=0.01) and older adults (HR=1.59, p=0.003) after adjusting for histology, extent of resection, and initial therapy. Age at diagnosis was not associated with OS in multi-variable analysis. CONCLUSIONS Within our cohort, YA with IDH-mutant tumors progressed more quickly compared to their pediatric counterparts. Further study of YA patients with IDH-mutant glioma is critical to better define best practices for this group.
TBIO-26. NON-CANONICAL OPEN READING FRAMES ENCODE FUNCTIONAL PROTEINS ESSENTIAL FOR CANCER CELL SURVIVAL
Authors: John Prensner, Oana Enache, Victor Luria, Karsten Krug, Karl Clauser, Joshua Dempster, Amir Karger, Li Wang, Karolina Stumbraite, Vickie Wang, Ginevra Botta, Nicholas Lyons, Amy Goodale, Zohra Kalani, Briana Fritchman, Adam Brown, Douglas Alan, Thomas Green, Xiaoping Yang, Jacob Jaffe, Jennifer Roth, Federica Piccioni, Marc Kirschner, Zhe Ji, David Root, Todd Golub
Journal: Neuro-Oncology (2020)

Abstract The brain is the foremost non-gonadal tissue for expression of non-coding RNAs of unclear function. Yet, whether such transcripts are truly non-coding or rather the source of non-canonical protein translation is unknown. Here, we used functional genomic screens to establish the cellular bioactivity of non-canonical proteins located in putative non-coding RNAs or untranslated regions of protein-coding genes. We experimentally interrogated 553 open reading frames (ORFs) identified by ribosome profiling for three major phenotypes: 257 (46%) demonstrated protein translation when ectopically expressed in HEK293T cells, 401 (73%) induced gene expression changes following ectopic expression across 4 cancer cell types, and 57 (10%) induced a viability defect when the endogenous ORF was knocked out using CRISPR/Cas9 in 8 human cancer cell lines. CRISPR tiling and start codon mutagenesis indicated that the biological impact of these non-canonical ORFs required their translation as opposed to RNA-mediated effects. We functionally characterized one of these ORFs, G029442—renamed GREP1 (Glycine-Rich Extracellular Protein-1)—as a cancer-implicated gene with high expression in multiple cancer types, such as gliomas. GREP1 knockout in &amp;gt;200 cancer cell lines reduced cell viability in multiple cancer types, including glioblastoma, in a cell-autonomous manner and produced cell cycle arrest via single-cell RNA sequencing. Analysis of the secretome of GREP1-expressing cells showed increased abundance of the oncogenic cytokine GDF15, and GDF15 supplementation mitigated the growth inhibitory effect of GREP1 knock-out. Taken together, these experiments suggest that the non-canonical ORFeome is surprisingly rich in biologically active proteins and potential cancer therapeutic targets deserving of further study.
Analyses of Risk, Racial Disparity, and Outcomes Among US Patients With Cancer and COVID-19 Infection
Authors: QuanQiu Wang, Nathan A. Berger, Rong Xu
Journal: JAMA Oncology (2020)

Patients with specific cancers may be at higher risk than those without cancer for coronavirus disease 2019 (COVID-19) and its severe outcomes. At present, limited data are available on the risk, racial disparity, and outcomes for COVID-19 illness in patients with cancer.
NFB-03. TRAMETINIB FOR ORBITAL PLEXIFORM NEUROFIBROMAS IN YOUNG CHILDREN WITH NF1
Authors: Helen Toledano, Gad Dotan, Rivka Friedland, Rony Cohen, Iftach Yassur, Hagit Toledano, Shlomi Constantini, Mika Shapira Rootman
Journal: Neuro-Oncology (2020)

Abstract Plexiform neurofibromas (PN) in NF1 are diagnosed in early childhood and may grow rapidly during this period. In 10% of patients they involve the orbital-periorbital area and may cause visual problems including glaucoma and visual loss from amblyopia (deprivational, strabismic, or refractive), optic nerve compression or keratopathy. Ptosis, proptosis and facial disfigurement lead to social problems and decreased self-esteem. Complete surgical removal is usually impossible and there is a tendency for regrowth after debulking. Recently inhibitors of the RAS/MAPK pathway have been investigated for their activity in PN. We describe 5 young children with NF1 and PN of the orbital area treated with the MEK inhibitor trametinib followed clinically and by volumetric MRI. Treatment was initiated at mean age 26.8 months (SD ±12.8) and continued for median 25 months (range 17– 48). Reasons for initiating treatment were visual compromise and progressive tumor growth. Doses were as recommended. One child reported decreased orbital pain after one week and another, with involvement of the masseters, had increased ability to chew food. Toxicities were mostly to skin and nails grades 1–2 as expected. Additionally, 60% had debulking surgery of preseptal eyelid tumor in first year of medical treatment. Volumetric MRI measurements showed reduction of 8–26% at 1 year from baseline with a maximal reduction of 45% in two patients at 22 &amp; 45 months. No change in visual function was recorded following treatment initiation. In conclusion, trametinib may decrease tumor size in young children with orbital PN and may prevent progressive disfigurement.
Good Glycemic Outcomes Following Bariatric Surgery Among Patients With Type 2 Diabetes, Obesity, and Low-Titer GAD Antibodies
Authors: Ruveena Kaur, David Kim, Richard Cutfield, Michael Booth, Lindsay Plank, Rinki Murphy
Journal: Diabetes Care (2020)

OBJECTIVE To evaluate diabetes remission after bariatric surgery by presence of GAD antibody among those with obesity and type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Screening GAD was performed in 221 patients with T2D and obesity referred for bariatric surgery. Nine of 16 patients with GAD and 112 of 205 without GAD proceeded with surgery. Diabetes remission and weight loss were compared by GAD presence. RESULTS The group with GAD had levels 16–91 IU/mL. Those with and without GAD were similar with regard to age, BMI, diabetes duration, proportion treated with insulin, HbA1c, and C-peptide (1,354 ± 548 vs. 1,358 ± 487 pmol/L). At 1 and 5 years postoperatively, the two groups achieved similar BMI reduction and diabetes remission (67% vs. 73%, P = 0.71, and 56% vs. 57%, P = 1.0). CONCLUSIONS Low-titer GAD in patients with T2D and retained C-peptide should not be a deterrent for bariatric surgery when the principal aim is diabetes remission.
TAMI-05. THE IRRADIATED BRAIN MICROENVIRONMENT SUPPORTS GLIOMA STEMNESS AND SURVIVAL VIA ASTROCYTE-DERIVED TRANSGLUTAMINASE 2
Authors: Tracy Berg, Carolina Marques, Vasiliki Pantazopoulou, Elinn Johansson, Kristoffer von Stedingk, David Lindgren, Elin Pietras, Tobias Bergström, Fredrik Swartling, Valeria Governa, Johan Bengzon, Mattias Belting, Håkan Axelson, Massimo Squatrito, Alexander Pietras
Journal: Neuro-Oncology (2020)

Abstract The highest-grade gliomas invariably recur as incurable tumors following standard of care comprising surgery, radiotherapy, and chemotherapy. The majority of the recurrent tumors form within the area of the brain receiving high-dose irradiation during treatment of the primary tumor, indicating that the recurrent tumor forms in an irradiated microenvironment. The tumor microenvironment has been demonstrated to influence the therapeutic response and stemness characteristics of tumor cells, but the influence of radiation on the microenvironment and its subsequent consequences for tumor cells are incompletely understood. Here, we used genetically engineered glioma mouse models and human glioma samples to characterize the impact of standard of care radiotherapy on the brain tumor microenvironment. We found that tumor-associated astrocytes subjected to radiation in vitro could enhance tumor cell stemness and survival of co-cultured glioma cells. More aggressive gliomas formed in vivo when mouse brains were irradiated prior to tumor cell implantation, suggesting that the irradiated brain microenvironment supports tumor growth. We isolated the effect of irradiated astrocytes to extracellular matrix secreted by these cells, and specifically found that astrocyte-derived transglutaminase 2 (TGM2) is a stromal promoter of glioma stemness and radioresistance. TGM2 levels were increased after radiation in glioma mouse models. Recombinant TGM2 enhanced, and TGM2 inhibitors blocked, glioma cell stemness. In human GBM tissue, TGM2 levels were increased in recurrent vs. primary tumors. In summary, in addition to supporting TGM2 as a potential therapeutic target in glioma, our data indicate that radiotherapy results in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.
QOL-38. USE OF COMPUTERIZED NEUROPSYCHOLOGICAL MEASURES TO ASSESS COGNITIVE MORBIDITY IN SURVIVORS OF CHILDHOOD BRAIN TUMORS
Authors: Duncan Dickson, Jessica Channell, Ashley Mettetal, Elizabeth Chick, Greta Wilkening, Arthur Liu, Todd Hankinson, Nicholas Foreman, Christa Hutaff-Lee
Journal: Neuro-Oncology (2020)

Abstract Treatment of central nervous system (CNS) tumors in pediatric populations is associated with significant cognitive morbidity. Documentation of neuropsychological deficits is vital to treatment and educational planning. We investigated the feasibility and utility of a computerized neuropsychological measure (NIH Toolbox Cognitive Battery) in differentiating individuals who received tumor treatment from healthy controls. Participants included pediatric CNS tumor survivors (N = 85; Mean Age = 13.47; SD = 4.76) at least 1-year post-completion of treatment and healthy sibling controls (N = 20; Mean Age = 10.2; SD = 3.21) who completed the NIH Toolbox. Ninety-eight percent of the participants enrolled completed the computerized tasks. The overall logistical regression model, with NIH Toolbox tests as predictors, was statistically significant [χ2 (7, N = 105) = 26.176; p &amp;lt; .001] and improved correct group classification from 81% to 82.9%. Picture Sequencing (β = -0.059; Wald = 6.942; p = .008) and Flanker (β = -0.083; Wald = 7.473; p = .006) were both statistically significant and negatively predictive of membership in the treatment group. For each 1 unit increase in standard score on measures of working memory and inhibition, odds of membership in the treatment group decreased by 6.2% and 8.7%, respectively. Consistent with the literature, worse performance on computerized measures of cognitive functioning mediated by executive functioning was correlated with a history of brain tumor treatment. Further investigation will focus on comparing computerized neuropsychological tools to traditional comprehensive neuropsychological evaluations and clarifying the trajectory of these deficits across recovery.
IMMU-03. EFFECT OF COMBINING IRRADIATION AND ANTI-CD47 TREATMENT ON THE PHAGOCYTOSIS OF NORMAL BRAIN CELLS
Authors: Forrest Hamrick, Osama Youssef, Samuel Cheshier
Journal: Neuro-Oncology (2020)

Abstract Immunotherapy using CD47 blockade has shown promise in treating adult and pediatric malignant primary central nervous system tumors. We recently demonstrated that irradiation significantly enhanced anti-CD47-dependent phagocytosis of high-grade glioma cells in vitro. Furthermore, mice engrafted with high-grade human glioma that received anti-CD47 combined with irradiation showed a significant increase in the survival rate and a significant decrease in tumor growth than those that received a single treatment. However, the use of irradiation may result in potential toxicity to normal CNS cells that are not susceptible to macrophage phagocytosis in anti-CD47 monotherapy. We have now extended these studies to test the effect of combining anti-CD47 and irradiation on macrophage-mediated phagocytosis of central nervous system cells. We analyzed phagocytosis of normal human neural stem cells exposed to different irradiation doses in combination with anti-CD47 treatment to assess for the potential toxicity that uniquely exists with this treatment combination.
NIMG-54. DIFFUSE TUMOR GROWTH PATTERN IS ASSOCIATED WITH WORSE OUTCOME ONLY IN IDH WILDTYPE BUT NOT IN IDH MUTANT GLIOMAS WHO II AND III
Authors: Jonathan Weller, Sophie Katzendobler, Dorothee Gramatzki, Hans-Georg Wirsching, Athina Pangalu, Annamaria Biczok, Viktoria Ruf, Niklas Thon, Michael Weller, Joerg-Christian Tonn, Bogdana Suchorska
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Magnetic resonance imaging (MRI) based characterization has previously shown heterogeneity in tumor appearance according to IDH mutation status. We have recently investigated the relevance of contrast enhancement to be dependent on IDH mutation status in glioma WHO II and III. Here, we aimed at further characterizing tumor growth patterns and their prognostic value in these tumors. METHODS MRI and clinical data of patients with newly diagnosed glioma WHO II and III from two different centers were retrospectively reviewed. Radiological data such as localization, presence of contrast enhancement, T2-volume as well as tumor growth pattern (“diffuse” vs. “circumscript”) were obtained. Progression-free (PFS) and overall survival (OS) were determined and correlated with clinical, radiological and molecular characteristics using univariate and multivariate regression analyses. RESULTS 390 patients were included, 69% thereof having an IDH mutation. The median T2-volume was 46.0 ml, IDH mutant tumors being larger (50.7 ml) than IDH wildtype tumors (36.0 ml), p = 0.01. A total of 172 tumors were classified as “circumscript” and 218 as “diffuse”; the majority of IDH wildtype tumors (71%) were well delineated compared to 51% in the IDH mutant group (p&amp;lt; 0.0001). Apart from clinical parameters such as younger age, lower KPS, complete resection and delayed treatment, “circumscript” tumor growth pattern was associated with improved survival in the entire group (p = 0.016). When analyzed according to IDH mutation status, “circumscript” tumor growth pattern was significantly associated with OS and PFS (p = 0.006 and p = 0.002) in the IDH wildtype, but not in the IDH mutant group (p = 0.34 and p = 0.81). CONCLUSION IDH wildtype tumors present more often with a ”circumscript” growth pattern on initial T2 MRI. However, this “circumscript” growth pattern was associated with improved survival only in the IDH wiltdtype but not in the IDH mutant group.
GCT-08. PROTON BEAM RADIOTHERAPY FOR PEDIATRIC AND YOUNG-ADULT PATIENTS WITH INTRACRANIAL GERM CELL TUMOR
Authors: Minako Sugiyama, Takayuki Hashimoto, Takashi Mori, Kazuya Hara, Yukayo Terashita, Shinsuke Hirabayashi, Yuko Cho, Akihiro Iguchi, Michinari Okamoto, Yukitomo Ishi, Hiroaki Motegi, Shigeru Yamaguchi, Atsushi Manabe
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND To reduce treatment-related adverse events in pediatric and young-adult patients with brain tumors, proton beam radiotherapy (PBT) has recently been performed instead of conventional X-ray radiotherapy. However, whether PBT is as effective as X-ray radiotherapy has not been sufficiently investigated, especially in patients receiving whole-ventricular irradiation. METHODS We report a retrospective observation of 15 patients with intracranial germ cell tumors (GCT), who received PBT at our institution from April 2014 to September 2019. We evaluated their clinical course, short-term adverse events, and prognosis. RESULTS/ CONCLUSION Fifteen patients (9 males and 6 females; median age 13 years) who received PBT following induction chemotherapy were analyzed. Nine patients received 23.4–27.0 GyE of whole-ventricular irradiation due to GCT in the pituitary gland, pineal body, or hypothalamic area. Three patients received 23.4 GyE of whole-brain irradiation: one of them had boost irradiation for basal ganglia. Three patients received 30.6 GyE of craniospinal irradiation (CSI). Six of the 15 patients experienced nausea (grade 2, according to the CTCAE version 4.0). Four patients, including two who received CSI, showed myelosuppression: decrease in white blood cell count, lymphocyte cell count, and neutrophil count (grade 3). No other severe short-term adverse events of &amp;gt;grade 2 was observed in any of the patients. At a median follow-up of 21 months (2-62 months) after irradiation. all patients are alive without recurrence. Our results may be encouraging and further investigations with a larger scale is warranted.