bluuebunny/crossref_metadata_2025_split huggingface dataset:
RARE-27. UNUSUAL CASE OF TEENAGER WITH PRIMARY SPINAL GERMINOMA WITH INTRACRANIAL RELAPSE POST-THERAPY
Authors: Kooken Maria , Wait Scott , Fasola Carolina , Jacobsen Chad , Gass David 
Published: November 2019

Abstract
We present a case of a 14-year-old male who presented with back pain and difficulty walking and was found to have an intradural intramedullary germinoma in the thoracolumbar spine. After debulking, he was treated with four cycles of carboplatin and etoposide and then received local spinal radiotherapy (RT) to the initial area of disease with margin to 30 Gy in 17 fractions. Six months following completion of therapy, he was found to have an intracranial relapse. CLINICAL IMPORTANCE: Our patient is the second ever Hispanic and twelfth pediatric patient reported with primary spinal germinoma. We reviewed 54 total cases published in literature over last 35 years. Twenty-one patients (39%) were treated with surgery followed by local spinal RT (n=12) or CSI (n=9). Twenty-eight patients (52%) were treated with chemotherapy in addition to surgery and radiation. The remaining 5 patients (9%) either had surgery alone or details of their treatment plan were not reported. Six of the 54 patients experienced disease recurrence. None of the patients treated with CSI experienced disease recurrence after CSI. Ninety-six percent of patients were alive at last follow up. CLINICAL OUTCOME: Our patient had his relapsed disease resected and CSI to 23.4 GY in 13 fractions and focal boost to 21.6 Gy in 12 fractions was delivered to all sites of relapsed disease. He is undergoing surveillance of his tumor and there is no disease recurrence 3 months post-CSI. CONCLUSION: Primary spinal germinomas appear chemo responsive and radiosensitive; however, the optimal management to maximize disease control and minimize side effects is not clear. When using local spinal RT, close surveillance with brain and spine imaging seems indicated as relapses anywhere in the central nervous system are possible. Further study is needed to determine the optimum treatment approach to this tumor.
RARE-43. PRIMARY CENTRAL NERVOUS SYSTEM EWING SARCOMA: A SINGLE INSTITUTION EXPERIENCE
Authors: Yorio Florencia , Alessandro Lucas , Arakaki Naomi , Palomar Nicolas , Muggeri Alejandro , Diez Blanca 
Published: November 2019

Abstract

INTRODUCTION
Ewing Sarcoma (ES) is defined by molecular markers, being t(11,22) the most frequent. Intracranial ES/pPNET usually represent metastases from extracranial sites. Primary Central Nervous System (CNS) lesions are extremely rare.

MATERIAL AND METHODS
Retrospective review of clinical records from patients with primary CNS ES/pPNET assessed at a neurological center in Argentina between 2007–2019. All confirmed with molecular marker. Clinical characteristics, imaging, histopathology, and treatment response were evaluated. Extensive workup included whole-body CT scan, skeletal-scintigraphy, and positron-emission tomography, excluding extracranial primary lesions in all cases.

RESULTS
Total 24p. Median age 22yo (2–65); M:F 2:1. Clinical presentation: intracranial hypertension, focal neurological deficit or seizures. In brain MRI 11 supratentorial lesions, 7 infratentorial and 6 diffuse leptomeningeal. Histopathology: diffuse pattern with small round blue cells 13/24p, other patterns were also described. CD99 marked positive in all cases and T(11.22) confirmed as well: 22 PCR and 2 FISH for EWSR1-rearrangement. Misdiagnosis lead to median delay for accuracy of 7,5mo (0–124); including other CNS primary tumors (n= 13), infectious diseases (n= 5) and other diagnoses (n= 4). Most patients (n= 10) were treated with Euro99-protocol (6 cycles plus local radiotherapy (RT)), 4 with Temozolomide, Irinotecan plus RT, 7 with other regimens and 2 received no treatment. Mean overall survival (OS): 58mo (0–132) and progression-free survival 22mo (0–85). Five year OS:41%.

CONCLUSION
Clinical behavior in primary CNS ES deferred from extraosseous ES, being necessary to apply a specific regimen for this pathology as there is no standard regime for intracranial ES/pPNET. Results showed two different groups of patients with long and very short survival. Presentation, histology, and outcomes are so uneven that we propose if a more specific molecular classification should be necessary. This is, to our knowledge, the largest case series reported describing a heterogeneous group despite the presence of accurate molecular diagnosis.
RARE-52. AN EXTRA-VENTRICULAR NEUROCYTOMA PRESENTING WITH DIFFUSE LEPTOMENINGEAL DISEASE WITH OPTIC NEURITIS, A CASE REPORT
Authors: Eduardo Silva Correia Carlos , Alshiekh Nasany Ruham 
Published: November 2019

Abstract

INTRODUCTION
Neurocytoma is classically a rare intraventricular tumor that affects young adults. Due to its location, it usually presents with obstructive hydrocephalus and typically has a favorable prognosis after adequate surgical intervention. CASE: In this report, we describe the case of a 19-year-old man who developed progressive decreased visual acuity and headaches that led to a diagnosed of hydrocephalus and a ventriculoperitoneal shunt (VPS) placement. Work up at presentation revealed a thoracic spinal cord tumor which was completed resected and pathology was consistent with extra-ventricular neurocytoma. With no further intervention, he experienced signs of worsening intracranial pressure (ICP) and visual acuity, becoming steroid-dependent. Repeat imaging 3 months later showed early signs of leptomeningeal disease (LMD), optic nerve enhancement, and diffuse dural thickening. A dural biopsy was done and read as nonspecific inflammation. He then came to our center for a second opinion. We reviewed pathology from original tumor and confirmed extra-ventricular neurocytoma. We, however, read the dural biopsy as an organizing subdural hematoma. We analyzed his cerebrospinal fluid (CSF) and cytology showed neurocytoma cells, linking his LMD to initial diagnosis. He went on to receive photon craniospinal radiation (CSI) with clinical improvement and decreased steroid requirements. Most recent imaging showed improving LMD.

DISCUSSION
Extra-ventricular neurocytoma is an extremely rare disease with very few cases reported in the literature and our case is unique due to the severe leptomeningeal involvement affecting the optic nerves and the presence of neurocytoma cells on the CSF. There is no consensus on how to best treat these cases, however, our patient improved after CSI.
STEM-07. THE ATYPICAL METALLOPROTEINASE ADAMDEC1 MAINTAINS A NOVEL FGF MEDIATED SIGNALLING NETWORK IN GLIOBLASTOMA CANCER STEM CELLS
Authors: Jimenez-Pascual Ana , Hale James , Bayik Defne , Silver Daniel , Roversi Gustavo , Alban Tyler , McIntyre Thomas , Colombo Giorgio , Taraboletti Giulia , Holmberg Karl , Forsberg-Nilsson Karin , Lathia Justin , Siebzehnrubl Florian 
Published: November 2019

Abstract
Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (CSCs), but how CSCs maintain their stemness is incompletely understood and the subject of intense investigation. CSCs rely both on cell intrinsic programs and microenvironmental interactions to regulate their maintenance. Recent work has demonstrated that CSCs can modulate their surrounding microenvironment by metalloproteinase expression, allowing direct modification of the extracellular matrix that provides structural tissue integrity, and instructive signalling via engagement of key cell surface receptors and sequestration of essential growth factors. Here, we identify a novel growth factor signalling loop that induces and maintains CSCs via an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by CSCs. ADAMDEC1 solubilizes fibroblast growth factor-2 (FGF2) in the tumor microenvironment. We find that CSCs exclusively express FGF receptor 1 (FGFR1), which upon binding of FGF2 induces upregulation of Zinc finger E-box-binding homeobox 1 (ZEB1). ZEB1 is a regulator of stemness and tumor initiation, and therefore ADAMDEC1-FGF2-FGFR1 signalling promotes malignancy in GBM. We further show that ERK phosphorylation drives ZEB1, which regulates ADAMDEC1 expression, creating a positive feedback loop via repression of microRNA-203. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signalling axis for CSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. In addition, these findings provide a new paradigm for GBM growth through which key growth factors embedded within the extracellular matrix can be selectively accessed by CSC for their maintenance.
STEM-18. DISTINCT BUT PREDICTABLE MECHANISMS DRIVE GENETIC VS. EPIGENETIC RESISTANCE TO TARGETED THERAPY
Authors: George Joshy , Chen Yaohui , Abdelfattah Nourhan , Yamamoto Keiko , Adamson Scott , Rybinski Bradley , Baskin David , Chuang Jeffrey , Yun Kyuson 
Published: November 2019

Abstract
Emergence of therapy resistance greatly reduces long-term utility of effective targeted therapies, including SMO/SHH pathway inhibitors. SHH signaling is activated in ~25% of human medulloblastomas (MB) and FDA approved SMOi (to treat basal cell carcinoma (BCC)) are currently in clinical trials for MBs and acute myeloid leukemia (AML). Accumulating clinical experience suggests that a significant number of BCC patients treated with SMOi develop acquired resistance over time and some show de novo resistance. A similar pattern is observed in MB patients, indicating the need to elucidate resistance mechanisms, particularly those driving de novo vs. acquired resistance, and develop new strategies to overcome both de novo and acquired resistance to SMOi. We report that we have discovered a novel, epigenetic mechanism of therapy resistance to SMOi that underlie de novo resistance. Using two different mouse models of SHH MB, we tested our original hypothesis that the selective pressure on cancer stem cells (CSCs), but not bulk tumor cells, will determine the resistance mechanism at the molecular level. We show that acquired mutations in the SHH pathway genes (previously reported mechanism of resistance) occur only in tumors that contain CSCs that depend on the SHH pathway. In tumors where only the bulk tumor cells, but not CSCs, depend on SHH signaling, no acquired mutations in the SHH pathway genes are detected. Instead, in these tumors, epigenetic reprogramming through selective degradation of specific histone modifiers results in global changes in the epigenetic cell state and gene expression patterns. Importantly, we can predict the mechanism of resistance in individual tumors prior to treatment based on CSC phenotypes. Finally, we also report biomarkers that can be used to identify tumors with CSCs that are independent of SHH pathway, which can be exploited to design anticipatory combination therapies in the future.
STEM-22. TARGETING PYRIMIDINE SYNTHESIS ACCENTUATES MOLECULAR THERAPY RESPONSE IN GLIOBLASTOMA STEM CELLS
Authors: Yang Kailin , Wang Xiuxing , Wu Qiulian , Kim Leo , Morton Andrew , Gimple Ryan , Prager Briana , Shi Yu , Zhou Wenchao , Bhargava Shruti , Zhu Zhe , Jiang Li , Tao Weiwei , Qiu Zhixin , Zhao Linjie , Zhang Guoxing , Li Xiqing , Agnihotri Sameer , Mischel Paul , Mack Stephen , Bao Shideng , Rich Jeremy 
Published: November 2019

Abstract
Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase (CAD) or the critical downstream enzyme, dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity. Higher expression of pyrimidine synthesis genes portend poor prognosis of glioblastoma patients. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
STEM-24. THERAPEUTIC APPROACH OF STEM CELL CARRYING RETROVIRAL REPLICATING VECTORS IN HUMAN GLIOMA MODEL
Authors: Inagaki Akihito , Takahashi Masamichi , Kamijima Shuichi , Hiraoka Kei , Tam Quincy , Faure-Kumar Emmanuelle , Treger Janet , Bogan Brooke , Hacke Katrin , Collins Sara , Jolly Douglas , Kasahara Noriyuki 
Published: November 2019

Abstract
Toca 511, an improved retroviral replicating vectors (RRVs) expressing a codon-optimized cytosine deaminase, has shown highly promising evidence of therapeutic benefit in preclinical and clinical studies for gene therapy of glioma. In the present study, we engineered human mesenchymal stem cells (MSC) as tumor-homing cellular carriers that produce and release RRV, and evaluated the effect of this mode of virus delivery on the time course of intratumoral RRV dissemination. Human MSC isolates were engineered to produce RRV (MSC-RRV). Cytotoxicity assays confirmed efficient prodrug activator function in U-87 glioma cells transduced with vectors produced from MSC-RRV. To evaluate intratumoral migration activity and tumor-homing migration activity in vivo, individual MSC isolates were injected either directly into human glioma xenografts, or into the contralateral brain hemisphere. MSC-RRV isolates showing the highest levels of intratumoral migration activity were selected, and the efficiency of intratumoral dissemination and tumoricidal activity achieved by these isolates was compared against injection of RRV virus preparations in subcutaneous glioma models. Compared to virus injection, MSC-RRV achieved 1.6x-higher levels of tumor transduction (p< 0.05), and 2x-reduced tumor growth (p=0.018) at earlier time points. In short-term survival studies using lower doses of MSC-RRV cells vs. RRV virus injected 14 days post-establishment of intracranial U-87 gliomas, a small but statistically significant prolongation of median survival was seen with intracranial tumors treated with MSC-RRV as compared to RRV (26 vs. 20 days, p< 0.05) after only a single cycle of 5-FC prodrug. Thus, MSC can be employed as mobile tumor-homing RRV-producer cells, which release RRV as they migrate to tumor foci in vivo and actively penetrate into individual tumor masses, resulting in more rapid tumor transduction and earlier therapeutic efficacy, which may be advantageous particularly for multi-focal and metastatic disease. This study was funded by the California Institute for Regenerative Medicine (TR2-01791).
New insights into the neurofibroma tumor cells of origin
Authors: Li Stephen , Chen Zhiguo , Le Lu Q 
Published: November 2019

AbstractNeurofibromatosis type I (NF1) is a debilitating inherited tumor syndrome affecting around 1 in 3000 people. Patients present with a variety of tumors caused by biallelic loss of the tumor suppressor neurofibromin (NF1), a negative regulator of Ras signaling. While the mechanism of tumor formation is similar in the majority of NF1 cases, the clinical spectrum of tumors can vary depending on spatiotemporal loss of heterozygosity of NF1 in cells derived from the neural crest during development. The hallmark lesions that give NF1 its namesake are neurofibromas, which are benign Schwann cell tumors composed of nervous and fibrous tissue. Neurofibromas can be found in the skin (cutaneous neurofibroma) or deeper in body near nerve plexuses (plexiform neurofibroma). While neurofibromas have been known to be Schwann cell tumors for many years, the exact timing and initiating cell has remained elusive. This has led to difficulties in developing animal models and successful therapies for NF1. A culmination of recent genetic studies has finally begun to shed light on the detailed cellular origins of neurofibromatosis. In this review, we will examine the hunt for neurofibroma tumor cells of origin through a historical lens, detailing the genetic systems used to delineate the source of plexiform and cutaneous neurofibromas. Through these novel findings, we can better understand the cellular, temporal, and developmental context during tumor initiation. By leveraging this data, we hope to uncover new therapeutic targets and mechanisms to treat NF1 patients.
The Association Between Smoke-Free School Policies and Adolescents’ Perceived Antismoking Norms: Moderation by School Connectedness
Authors: Schreuders Michael , van den Putte Bas , Mlinarić Martin , Mélard Nora , Perelman Julian , Richter Matthias , Rimpela Arja , Kuipers Mirte A G , Lorant Vincent , Kunst Anton E 
Published: November 2019

AbstractIntroductionMany European schools implement smoke-free school policies (SFSPs). SFSPs may decrease adolescent smoking by causing adolescents to perceive stronger antismoking norms, yet there exists no quantitative evidence that indicates for which norms and for whom such effects may occur. This study therefore assessed to what extent adolescents’ perceived antismoking norms among best friends, teachers, and society at large were associated with SFSPs, and whether these associations were moderated by adolescents’ level of school connectedness.Aims and MethodsSurvey data were collected in 2016/2017 on 10,653 adolescents aged 14–16 years old and 315 staff members in 55 schools from seven European cities. Associations of adolescent-perceived SFSPs and staff-reported SFSPs with best friend, teacher, and societal antismoking norms were estimated in multilevel logistic regression models, adjusted for demographics and school-level smoking prevalence. We tested for interaction between school connectedness and SFSPs.ResultsAdolescent-perceived SFSPs were positively associated with antismoking norms by teachers (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 1.15–1.85), were negatively associated with antismoking norms by best friends (OR: 0.81, 95% CI: 0.67–0.99), but were not significantly associated with antismoking norms by society at large (OR: 0.87, 95% CI: 0.74–1.02). All interaction tests between adolescent-perceived SFSPs and school connectedness were nonsignificant. Staff-reported SFSPs were not associated with any norm and showed no significant interaction with school connectedness.ConclusionsWe found that SFSPs are associated with adolescents’ perception of more antismoking norms by teachers, but less antismoking norms by best friends, irrespective of adolescents’ level of school connectedness.ImplicationsSmoke-free school policies, just as many other tobacco control policies, are assumed to foster adolescents’ perception of antismoking norms. Still, current evidence does not demonstrate which antismoking norms may be influenced by SFSPs and whether this influence is equal for adolescents with different levels of school connectedness. This study suggests that SFSPs foster adolescents’ perception of antismoking norms by teachers, but may concurrently lead to the perception of less antismoking norms by best friends, irrespective of adolescents’ school connectedness. SFSPs may therefore need to be complemented with interventions that target antismoking norms in adolescent peer groups.
Atherosclerotic Cardiovascular Disease Risk Profile of Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate
Authors: Huhn Gregory D , Shamblaw David J , Baril Jean-Guy , Hsue Priscilla Y , Mills Brittany L , Nguyen-Cleary Thai , McCallister Scott , Das Moupali 
Published: November 2019

Abstract

Background
In human immunodeficiency virus (HIV) treatment, tenofovir alafenamide (TAF) is associated with greater increases in all fasting cholesterol subgroups compared with tenofovir disoproxil fumarate (TDF). Because lipid abnormalities may contribute to cardiovascular morbidity and mortality, cardiovascular risk assessment is integral to routine HIV care. This post hoc study evaluates the impact of lipid changes on predicted atherosclerotic cardiovascular disease (ASCVD) risk and statin eligibility in treatment-naive adults living with HIV treated with TAF or TDF.

Methods
Participants (N = 1744) were randomized (1:1) to initiate TAF or TDF, each coformulated with elvitegravir/cobicistat/emtricitabine (studies GS-US-292-0104 and GS-US-292-0111). Eligibility for statin therapy and estimated 10-year ASCVD risk among adults aged 40–79 years treated with TAF or TDF for 96 weeks (W96) were analyzed based on American College of Cardiology/American Heart Association Pooled Cohort Equations. Categorical shifts in 10-year ASCVD risk from &lt;7.5% to ≥7.5% by W96 on TAF versus TDF were calculated.

Results
Participants initiating TAF versus TDF in the overall study population showed small but significant increases in median fasting lipid parameters at W96, including total cholesterol (191 vs 177 mg/dL; P &lt; .001), low-density lipoprotein ([LDL] 119 vs 112 mg/dL; P &lt; .001), and high-density lipoprotein ([HDL] 51 vs 48 mg/dL; P &lt; .001), respectively. At baseline, 18% and 23% on TAF versus TDF had a 10-year ASCVD risk score ≥7.5%, with mean risk scores low overall for TAF versus TDF at baseline (4.9% vs 5.4%; P = .35) and W96 (6.1% vs 6.2%; P = .04). Increases in ASCVD risk from baseline to W96 were driven by both increasing age and changes in total cholesterol (TC) and HDL cholesterol. At W96, TC/HDL ratios (median) were 3.7 for both groups (P = .69). There was no difference between shifts in categorical risk for TAF versus TDF (9% vs 5%; P = .19). Eligibility for high-intensity statin therapy were similar for TAF versus TDF groups (19% vs 21%; P = .47).

Conclusions
Lipid changes with TAF as part of coformulated regimens do not substantively affect CVD risk profiles compared with TDF.
Attention to EU Affairs in the Spanish Parliament: The Role of Credit-Claiming and Issue Saliency Strategies
Authors: Palau Anna M 
Published: November 2019

AbstractRecent research demonstrates that the salience of EU affairs in domestic parliaments is mainly driven by government parties. This has been interpreted as illustrating the so-called opposition deficit thesis and mainly explained considering governments’ informational advantages and reporting duties. Drawing on a dataset on oral questions introduced in plenary meetings in the Spanish parliament, this article sheds new light on government and opposition MPs’ incentives to raise attention to the EU. Results show that in Spain, where there is no party conflict on European integration, government MPs pay attention to EU affairs following credit-claiming strategies. These strategies are likely in the context of EU events and when the perceived benefits of integration are high, and unlikely under critical junctures, when the EU cannot be framed as a governmental success. Opposition MPs pay less attention to EU affairs but they still use the EU to give visibility to issues that are of interest to their voters.