bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCO-39. DICER1 SYNDROME WITH PRIMITIVE NEUROECTODERMAL TUMOR FROM SCREENING MUTATIONS OF DICER1 GENE
Authors: Wu Anhua , Jing Zhitao , Cheng Wen , Zhu Chen , Song Chao , Qin Huijuan , Zhang Xing , Ji Yuhang , Tian Minqi , Li Xiaomin , Ren Yong 
Published: December 2020

Abstract

BACKGROUND
DICER1 syndrome is a rare disorder of tumor predisposition. The DICER1 gene encodes the Dicer protein of the ribonuclease Ⅲ family and plays a critical role in miRNA creation. Patients with DICER1 syndrome-related cancer commonly harbor an additional somatic variant in exon24 or 25 of DICER1 involving one of the hotspots including p.E1705, p.D1709, p.G1809, p.D1810, or p.E1813. Herein, we firstly report the presence of hotspot missence mutation in a patient with primitive neuroectodermal tumor (PNET).

METHODS
The mutations in DIRCER1 were searched in the tumor tissue or peripheral blood from 4,349 patients with different types of cancer via next generation sequencing. Among them, comprehensive genomic profiling (CGP) with 131 CNS cancer-related genes and 4 brain tumor-related chromosome structure variations was performed in 230 cases, and CGP with 539 cancer-related genes was administrated in 4,119 cases. The histopathology diagnosis of each case was confirmed via hematoxylin and eosin staining.

RESULTS
A number of 99 mutations in the exon and intron regions of DICER1 gene were observed from 88 patients in 4,349 cases. The ratio of somatic variants located on exon 24 and 25 where both encoded the RNase Ⅲb cleavage domain to all mutations was 9.09% (9/99). There were 3 and 6 somatic variants in the exon 24 and 25, respectively. Among the 9 mutations, 4 of them were p.E1813, one class of hotspots located on exon 25 leading to DICER1 syndrome, and the other 4 hotspots were not observed. Among 4 cases of DICER1 syndrom, pleuropulmenary blastoma was common, rhabdomyosarcomas arisen in two cases were also reported before, and the last one was patient with PNET.

CONCLUSIONS
In this study, we analyze the mutation distribution of DICER1 in cancer patients, report firstly a patient with PNET harbors a hotspot, and widen and deepen the understanding of DICER1 syndrome.
EPID-06. QUANTIFYING THE POTENTIAL PUBLIC HEALTH IMPACT OF VARICELLA ZOSTER VIRUS (VZV) VACCINATION ON GLIOMA INCIDENCE
Authors: Shen Erica , Wallace Alexander , Zhang Chenan , Shannon Callie , Ashley David , Walsh Kyle 
Published: December 2020

Abstract

BACKGROUND
Varicella zoster virus (VZV) is a neurotropic a-herpesvirus that causes chickenpox and establishes latency in the dorsal root ganglion. Live attenuated VZV vaccine was approved for use in 1995, with the CDC estimating 95% of teens had been vaccinated in 2014. Prior epidemiological literature suggests an association between VZV infection and glioma risk.

METHODS
We conducted a systematic review and meta-analysis of prior studies on the association between VZV infection and glioma risk. We also identified genetic instruments for VZV infection from prior GWAS and tested these for association with glioma risk in TCGA and GliomaScan (2244 cases, 4914 controls).

RESULTS
In six previous studies, individuals with positive chickenpox history or anti-VZV IgG seropositivity had 1.8-fold lower odds of glioma (ORmeta=0.55, 95%Cl=0.39–0.77), with similar effects by grade. GWAS hits for personal history of chickenpox (HLA-A Gly107 and rs9266089) and shingles (HLA-AArg97, HLA-DRB1 PheSerHis13, rs2523591, rs41316748 and rs7047299) were not associated with glioma risk, nor were polygenic scores (P &gt;0.05).

DISCUSSION
Prior VZV infection is associated with reduced glioma risk and, based on analysis of genetic instruments, this appears to be an acquired protection caused by VZV infection rather than innate immunologic differences. VZV infection in known to elicit a broader antibody response than vaccination, but it is unknown whether VZV vaccination provides comparable protection against glioma. Because 89% of U.S. adults have had chickenpox, the “prevented fraction” of glioma due to chickenpox is ~29% of annual incidence. If VZV vaccination confers an equivalent 1.8-fold reduction in glioma risk, this prevented fraction could increase to 32%. However, if VZV vaccination is less protective, it could decrease to just 2%. This potentially drastic increase in glioma incidence in coming decades merits mechanistic studies comparing the neuro-immunologic consequences of VZV vaccination versus chickenpox infection and warrants early public health attention.
EPID-17. THE RELATIONSHIP OF HORMONE EXPOSURE IN BREAST CANCER AND SUBSEQUENT RISK OF HIGH GRADE GLIOMAS
Authors: Lopez-Garcia Carlos , Lopez-Rivera Victor , Dono Antonio , Ballester Leomar Y , Esquenazi Yoshua 
Published: December 2020

Abstract

BACKGROUND
Women have a lower incidence of high grade gliomas (HGGs), which is thought to be related to sex differences and hormone exposure. The association between hormone dependent tumors in women and HGGs remains poorly investigated.

METHODS
The Surveillance, Epidemiology, and End Results (SEER) database of 18 Registries (2000–2017) was used to assess age-adjusted incidence rates and temporal trends of breast cancer (BC) and HGG. Female BC patients 18 years of age or older and with ductal or lobular BC were then assessed for the risk of subsequent HGG, calculated as the standardized incidence ratio (SIR).

RESULTS
A total of 976,134 patients diagnosed with BC between 2000–2017 were identified. The temporal trend of BC and HGG incidence rates remained comparable throughout the study, with a higher incidence of BC and lower incidence of HGGs in females. Female BC patients had a 22% lower risk of developing a HGG (SIR 0.78 [0.69–0.87], p&lt; 0.05) compared to general population. HGG risk by age groups in BC females was significant, with a lower risk found in pre-menopausal women (Ages 18–50, SIR 0.66 [0.45–0.94] vs Ages 50+ SIR 0.79 [0.70–0.89], p&lt; 0.05 for both). Among HGG tumors, a decreased risk of developing glioblastoma (SIR 0.83 [0.75–0.93], p&lt; 0.05) and anaplastic astrocytoma (SIR 0.58 [0.35–90, p&lt; 0.05), was found, but not for anaplastic oligodendrogliomas.

CONCLUSIONS
The findings of our study allude to the protective effect of hormone exposure in the development of HGGs, as shown by the lower risk in female patients with BC compared to the general population.
EPID-32. SURVIVAL OF INTRACRANIAL TUMOR IN CIPTO MANGUNKUSUMO GENERAL HOSPITAL
Authors: Aninditha Tiara , Pratama Putra , Odilo Jonathan , Sofyan Henry , Imran Darma , Aman Renindra , Werdhani Retno , Ranakusuma Teguh 
Published: December 2020

Abstract

INTRODUCTION
Intracranial tumor is a debilitating health burden that cause sever disability. The incidence rate for intracranial tumor is 4.63 per 100,000 populations. Through the development of diagnostic and therapeutic modalities, the survival of intracranial tumor improved although modest. There were several factors such as demographic, clinical, and histopathological affect intracranial tumor survival. However, there were no study about intracranial tumors and factors affecting it survival in Indonesia. This study provides insight of intracranial tumor patients and factor affecting 1-year survival in Cipto Mangunkusumo General Hospital from 2014–2016.

METHODS
The design of this study is retrospective cohort. The subjects were followed-up 1 year after diagnosis. The data retrieved from Dept. of Neurosurgery and Dept. of Neurology Cipto Mangunkusumo General Hospital neuro-oncology registry. Subjects with intracranial tumors underwent surgery/biopsy were included in this study. The factors analyzed in this study were demography, clinical characteristics, histopathology, and treatment types. Analysis of survival were done with Kaplan-Meier curve and cox regression.

RESULTS
There were 317 subjects in this study. Overall 1-year survival of intracranial tumors were 75.4%. There was increased risk of death (HR 1.88; CI95% 1.2–2.94; p = 0.005) in subjects &gt;46 years old. There was no different of risk of death (HR 0.66; CI95% 0.92–1.03; p = 0.067) between men and women. There was no different of risk of death (HR 1.39; CI95% 0.72–2.70; p = 0.333) between supratentorial and infratentorial tumor. There was difference of survival among histopathology (p &lt; 0.001) and therapeutic approaches (p &lt; 0.001).

DISCUSSION
This is the first study in Indonesia that analyze survival of intracranial tumor. Several factors such as age, histopathology, and therapeutic approaches were found to affect 1-year survival of intracranial tumor. To get a representative insight of intracranial tumor in Indonesia, a larger cohort study should be conducted.
EXTH-55. PET, IMAGE-GUIDED HDAC INHIBITION OF PEDIATRIC DIFFUSE MIDLINE GLIOMA IMPROVES SURVIVAL IN MURINE MODELS
Authors: Tosi Umberto , Kommidi Harikrishna , Adeuyan Oluwaseyi , Guo Hua , Maachani Uday Bhanu , Chen Nandi , Su Taojunfeng , Zhang Guoan , Pisapia David , Dahmane Nadia , Ting Richard , Souweidane Mark 
Published: December 2020

Abstract
Efforts at altering the dismal prognosis of pediatric midline gliomas focus on direct-delivery strategies like convection-enhanced delivery (CED), where a cannula is implanted into tumor. Successful CED treatments require confirmation of tumor coverage, dosimetry, and longitudinal in vivo pharmacokinetics monitoring. These properties would be best determined clinically with image guided dosimetry using theranostic compounds, agents with both therapeutic and imaging properties. In this study, we combine CED with novel, molecular-grade positron emission tomography (PET) imaging. We synthesized PETobinostat, a novel PET-imageable HDAC inhibitor, and showed its effectiveness against DIPG models in vitro and in vivo. Cell studies against a library of DIPG cells show nanomolar IC50, allowing for rapid in vivo translation. When injected in mice, PET shows the need of CED to achieve high brain concentrations, as systemic delivery yields inferior brain permeation. PET also shows that CED has significant mouse-to-mouse variability: imaging is used to modulate CED infusions to maximize tumor saturation over time. By determining condition-specific clearance half-life (ranging between 60 and 120 minutes), we maximized tumor permeation above therapeutic concentrations for at least 12 hours. This PET-guided approach resulted in decrease tumor cellularity (p= 0.001), increased apoptosis (p= 0.034), decreased dividing cells (p= 0.003), and recovery of histone-3 acetylation (p &lt; 0.0001) when compared against vehicle and systemic-treated controls in tumor-bearing mice. Further, the PET-guided CED of PETobinostat resulted in survival prolongation (67.5 vs. 35 days, p = 0.0001) when compared to systemic administration of another potent HDAC inhibitor (Panobinostat). CED without PET guidance failed at improving survival (37.5 vs. 35 days, p = 0.74). No significant toxicity was observed following CED of PETobinostat. This work demonstrates how personalized image-guided drug delivery of a novel HDAC inhibitor may be useful in potentiating CED-based treatment platforms, and supports a foundation for the clinical translation of PETobinostat.
EXTH-57. INVESTIGATION OF THE TUMORICIDAL EFFECTS OF SONODYNAMIC THERAPY IN MALIGNANT GLIOBLASTOMA BRAIN TUMORS
Authors: Sheehan Kimball , Sheehan Darrah , Sulaiman Mohanad , Padilla Frederic , Sheehan Jason , Xu Zhiyuan 
Published: December 2020

Abstract

OBJECTIVE
Glioblastoma is the most common primary brain tumor; survival is typically 12–18 months after diagnosis. We sought to study the effects of sonodynamic therapy (SDT) using 5-Aminolevulinic acid hydrochloride (5-ALA) and high frequency focused ultrasound (FUS) on 2 glioblastoma cell lines.

PROCEDURE
Rat C6 and human U87 glioblastoma cells were studied under the following conditions: 1mM 5-ALA (5-ALA); Focused ultrasound (FUS); 5-ALA and focused ultrasound (SDT); control. Studied responses included cell viability using an MTT assay, microscopic changes using phase contract microscopy, apoptotic induction through a caspase-3 assay, and apoptosis staining to quantify cell death.

RESULTS
SDT led to a marked decrease in cell extension and reduction in cell size. For C6, the MTT assay showed reductions in cell viability for 5-ALA, FUS, and SDT groups of 5%, 16%, and 47%, respectively compared to control (p&lt; 0.05). Caspase 3 induction in C6 cells relative to control showed increases of 109%, 110%, and 278% for 5-ALA, FUS, and SDT groups, respectively (p&lt; 0.05). For the C6 cells, caspase 3 staining positivity was 2.1%, 6.7%, 11.2%, and 39.8% for control, 5-ALA, FUS, and SDT groups, respectively. C6 Parp-1 staining positivity was 1.9%, 6.5%, 9.0%, and 37.8% for control, 5-ALA, FUS, and SDT groups, respectively. U87 cells showed similar responses to the treatments.

CONCLUSIONS
Sonodynamic therapy resulted in appreciable glioblastoma cell death as compared to 5-ALA or FUS alone. The approach couples two already FDA approved techniques in a novel way to treat the most aggressive and malignant of brain tumors. Further study of this promising technique is planned using glioma and also brain metastasis models.
EXTH-69. INCREASED CANCER CELL PERMEABILITY FOLLOWING TUMOR TREATING FIELDS (TTFIELDS) APPLICATION IN VITRO
Authors: Voloshin Tali , Porat Yaara , Kaynan Noa , Klein-Goldberg Anat , Paz Rom , Volodin Alexandra , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: December 2020

Abstract

INTRODUCTION
Tumor Treating Fields (TTFields), encompassing alternating electric fields within the intermediate frequency range, is an anticancer treatment delivered to the tumor region through transducer arrays placed non-invasively on the skin. This novel loco-regional treatment has demonstrated efficacy and safety and is FDA-approved in patients with glioblastoma (GBM) and malignant pleural mesothelioma. TTFields are currently being investigated in other solid tumors in ongoing trials. Recently, TTFields were reported to alter the cellular membrane structure of GBM cells, rendering them more permeable. The objective of this study was to characterize TTFields-induced cellular permeability in cancerous cell lines.

METHODS
TTFields were applied to uterine sarcoma, glioblastoma, and breast adenocarcinoma cell lines across a range of frequencies (50–500 kHz). Cellular permeability was assessed by quantifying the percentages of cells with accumulated 7-aminoactinomycin D (7-AAD) using flow cytometry and cytotoxicity was assessed based on cell counts. Kinetics were determined using different 7-AAD exposure times relative to TTFields treatment end. Changes in intracellular accumulation of anthracycline chemotherapeutics were evaluated in chemotherapy-sensitive and chemotherapy-resistant cells.

RESULTS
TTFields induced cellular permeability to 7-AAD in all 4 cancer cell lines tested. The optimal frequency for TTFields-induced cellular permeability was different from the optimal cytotoxic frequency. Kinetics measurements demonstrated that TTFields-induced permeability is transient and is effective only during application of TTFields. In combination experiments, TTFields improved intracellular accumulation of chemotherapeutic agents. Furthermore, combining chemotherapy with TTFields treatment facilitated accumulation of chemotherapeutics in chemotherapy-resistant cells to levels comparable with accumulation in chemotherapy-sensitive cancer cells.

CONCLUSIONS
This study demonstrates that TTFields can transiently increase cancer cell permeability in vitro with an optimal frequency that is variable from the frequency that is used to induce cancer cell cytotoxicity. Moreover, this effect is reversible and cellular permeability is restored to a normal state upon TTFields treatment cessation.
IMMU-55. GD2 IS A MACROPHAGE CHECKPOINT MOLECULE AND COMBINED GD2/CD47 BLOCKADE RESULTS IN SYNERGISTIC EFFECTS AGAINST GD2 POSITIVE MALIGNANCIES
Authors: Theruvath Johanna , Mount Christopher , Monje Michelle , Mackall Crystal , Majzner Robbie 
Published: December 2020

Abstract
GD2 is a disialoganglioside expressed on a variety of tumors including DIPG, neuroblastoma and osteosarcoma. Anti-GD2 antibodies have demonstrated some success in neuroblastoma and they have either not proven to be effective or have not been evaluated in other GD2 positive malignancies. CD47 is the dominant “Don’t Eat Me” signal expressed by cancer cells to inhibit macrophages and blocking CD47 leads to phagocytosis of tumor cells. We hypothesized that CD47 blockade synergizes with anti-GD2. We measured in vitro phagocytosis of DIPG and NBL cells and observed a synergy of anti-GD2/CD47 compared to the single agents. In vivo, this combination led to the complete clearance of both orthotopic and metastatic models of NBL. Additionally, the combination significantly enhanced survival of OS xenografts. Finally, in a murine model of metastatic pulmonary OS, the combination led to a near elimination of all metastatic burden. To understand the underlying biologic basis, we studied the effects of GD2 crosslinking on tumor cells and the effects of GD2 blockade on macrophages. A portion of DIPG or NBL cells die when treated with dinutuximab, and those that survive upregulate surface calreticulin, an important pro-phagocytic (“Eat Me”) signal. Additionally, we have identified the ligand for GD2, a molecule expressed on macrophages known to inhibit phagocytosis. In summary, we have identified a novel combination of anti-GD2 and anti-CD47 antibodies that is highly effective in preclinical models and will soon be tested in children. Furthermore, we have shown that GD2 itself is a macrophage checkpoint or “Don’t Eat Me” signal.
NCMP-16. THE ROLE OF p38 AND JNK MAPK PATHWAYS IN CISPLATIN CHEMOTHERAPY-RELATED COGNITIVE IMPAIRMENT
Authors: Lomeli Naomi , Di Kaijun , Bota Daniela 
Published: December 2020

Abstract

OBJECTIVES
Chemotherapy-related cognitive impairment (CRCI) is an adverse sequela of cancer treatment commonly reported in cancer survivors. Cisplatin is used for the treatment of various malignancies including ovarian, testicular, head and neck cancers, and pediatric brain tumors. More than 30% of advanced ovarian cancer patients develop CRCI during and after platinum-based chemotherapy. We examined the role of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in cisplatin-induced CRCI, and whether the small molecule p38 MAPK inhibitor Neflamapimod and JNK inhibitor SP600125, can prevent cisplatin-induced neuronal damage. The p38 and JNK MAPK signaling pathways are involved in various stress response pathways in the CNS including oxidative stress.

METHODS
The effect of cisplatin on cognition in an ovarian cancer female rat model was assessed by novel object recognition (NOR). Hippocampal glutathione levels were measured post-behavioral testing. P38 and JNK MAPK signaling activation were assessed in the neural cell lines PC12 and SH-SY5Y by Western blot. Cultured hippocampal neurons were pretreated with Neflamapimod or SP600125 followed by cisplatin for 24 hours, and dendritic spine density and branch length were quantified.

RESULTS
Cisplatin increased phospho-p38 and phospho-JNK MAPK protein levels in PC12 and SH-SY5Y cells. Cisplatin reduced dendritic branching and spine density, which was prevented by Neflamapimod and SP600125 pre-treatment in hippocampal neurons, in vitro. Chronic cisplatin treatment decreased hippocampal glutathione levels and impaired cognitive function in the ovarian cancer rat model.

DISCUSSION
The cognitive deficits caused by cisplatin results in part from dendritic damage and neural apoptosis, which is mediated by oxidative stress and the p38 and JNK MAPK pathways. P38 and JNK MAPK inhibition mitigated cisplatin-induced dendritic spine loss and branching in vitro. Next, we will examine whether Neflamapimod and SP600125 administration in an ovarian cancer rat model is safe and if they can prevent cognitive impairment.
NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY
Authors: Ruiz Amber , Graber Jerome 
Published: December 2020

Abstract
Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.
NCOG-15. PREGNANCY AND GLIOMA
Authors: Rodriguez Andrew , Ruff Michael 
Published: December 2020

Abstract
Improvements in treatments and prognosis in glioma patients has led patients the opportunity for pregnancy despite their diagnosis. In this retrospective case series of 13 patients evaluated at Mayo Clinic, we identified patients who were pregnant at or after glioma diagnosis from 1998-2019. Clinical information was obtained through the electronic medical record. Tumor grade, treatments, peripartum complications, and pediatric outcomes were analyzed. Median follow-up for pregnant patients was 13.5 years (range, 0-24). Of the 13 patients, 2 patients received temozolomide and radiation during pregnancy for glioblastoma and had no peripartum complications. Median survival time in these patients after further treatments was 23.5 months (range, 23.3-23.8). Two children from these pregnancies had no fetal malformations or pediatric developmental delays with median follow-up of 8.8 years (range, 4.7-12.8). Three patients received radiation during pregnancy for high grade gliomas and had no fetal malformations or peripartum complications. Eight patients had one or multiple pregnancies with median 2 (range, 1-3) children at or after diagnosis with 14 children total. Eleven of the 14 children had no fetal malformations or peripartum complications and were conceived without reproductive assistive technologies. Two children, who were identical twins, were born with a placental malformation but otherwise had normal pediatric development. One child was born pre-term and had long-term developmental delays.