tbuckley/cabot-search huggingface dataset:
RBIO-04. NEW THERAPEUTIC DELIVERY METHODS FOR TUMOR-TREATING FIELDS FOR HIGHER EFFICACY
Authors: Kristen Carlson, Zeev Bomzon, Jeffrey Arle
Journal: Neuro-Oncology (2020)

Abstract Tumor-treating fields (TTFields) are the fourth modality of glioblastoma (GBM) treatment and in conjunction with chemotherapy can increase overall survival of GBM patients up to 60 months. However, in vitro and in animal models TTFields show 100% efficacy on a variety of tumor cell types including GBM cells when field strength is 4 V/cm, versus ~2 V/cm that is the clinical delivery target, TTFields are delivered transcranially. TTFields finite element modeling studies, supported by similar transcranial electric stimulation studies, show that the principal obstacle to delivering 4 V/cm is the electrically resistive skull. Our modeling shows the biophysics is more complicated than these findings. For instance, electrically-conductive cerebrospinal fluid regions surrounding the grey matter and in ventricles shunt electric current from anode to cathode, hindering delivery of the current required to produce 4 V/cm at the tumor/peritumor target. Thus, we consider two new delivery methods for TTFields. First, the transcranial array can be made more focal and directional, following modeling and development of electrode arrays used in spinal cord and deep brain stimulation. Our finite element modeling shows that similarly-designed TTFields electrode arrays can deliver field strength focally to a tumor target approaching 4 V/cm. Second, pre- or post-resection, TTFields can be delivered via electrode arrays surgically placed in the tumor or tumor resection cavity (intra-tumoral delivery), circumventing the resistive skull and CSF shunting effects. Such intra-tumoral arrays can deliver 4 V/cm to the tumor/peritumor region, opening up the potential to replicate clinically the 100% efficacy of TTFields in vitro and in animal models. Thus, new TTFields delivery may lead to unlimited survival of GMB patients via a side-effect free treatment modality.
EZH2 activates CHK1 signaling to promote ovarian cancer chemoresistance by maintaining the properties of cancer stem cells
Authors: Yiping Wen, Yaya Hou, Xiaoqing Yi, Si Sun, Jing Guo, Xiaoqi He, Tao Li, Jing Cai, Zehua Wang
Journal: Theranostics (2020)

Background: Ovarian cancer is a fatal malignant gynecological tumor. Ovarian cancer stem cells (OCSCs) contribute to resistance to chemotherapy. The polycomb group protein enhancer of zeste homolog 2 (EZH2) plays a key role in maintaining CSCs. Here, we aimed to investigate the specific mechanism by which EZH2 regulates CSCs to result in chemoresistance and poor prognosis of ovarian cancer. Methods: We used a nude mouse model to obtain a cell line enriched for OCSCs, named SK-3rd cells. The CRISPR and Cas9 endonuclease system was used to establish an EZH2-knockout SK-3rd ovarian cancer cell line. High-throughput PCR array and bioinformatics methods were used to screen the EZH2 target involved in CSC stemness. A luciferase reporter assay and chromatin immunoprecipitation assay were performed to identify activation of CHK1 by EZH2. We evaluated associations between EZH2/CHK1 expression and the chemoresistance and prognosis of ovarian cancer patients. Results: EZH2 plays a critical role in maintaining ovarian CSC stemness and chemo-resistance. CHK1 is an EZH2 target involved in CSC stemness. Knockdown of EZH2 in ovarian CSCs decreased CHK1 expression, while CHK1 overexpression was sufficient to reverse the inhibitory effect on spheroid formation and chemoresistance caused by repression of EZH2. In addition, EZH2 was also shown to play a unique role in activating rather than repressing CHK1 signaling through binding to the CHK1 promoter in epithelial ovarian cancer cells. Finally, in clinical samples, ovarian cancer patients with high levels of EZH2 and CHK1 not only were more resistant to platinum but also had a poorer prognosis. Conclusions: Our data revealed a previously unidentified functional and mechanistic link between EZH2 levels, CHK1 signaling activation, and ovarian CSCs and provided strong evidence that EZH2 promotes ovarian cancer chemoresistance and recurrence.
Yittrium 90 Ibritumomab Tiuxetan (Zevalin®) in the Treatment of Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphoma; Integrated Analysis of Three Japanese Institution's Experience with Improvement Trend of the Long-Term Responses over a 10 Year Study Period
Authors: Ilseung Choi, Masaya Okada, Tomoki Ito
Journal: Blood (2020)
LGG-38. GENETIC ANALYSIS OF NEUROEPITHELIAL TUMORS IN THE PEDIATRIC AND ADOLESCENT AND YOUNG ADULT AGE IN A SINGLE INSTITUTE
Authors: Yasuhide Makino, Takeshi Kawauchi, Yoshiki Arakawa, Tomoko Shofuda, Ema Yoshioka, Masahiro Tanji, Yohei Mineharu, Yonehiro Kanemura, Susumu Miyamoto
Journal: Neuro-Oncology (2020)

Abstract Molecular diagnosis in brain tumors has been widely spread after the publication of WHO 2016 classification. But it become a major problem that there are some tumors not to be classified on its criteria, especially in pediatric neuroepithelial tumors. To clarify the characteristics of gliomas in pediatric and adolescent and young adult age (AYA), we picked up 131 neuroepithelial tumors under 30-year-old at Kyoto University and analyze their molecular profiles. Hot spot mutations in IDH1/2, H3F3A, HIST1H3B, TERT promoter, and BRAF were analyzed by Sanger sequencing, and 1p/19q codeletion was examined by FISH or MLPA. With the pathohistological diagnosis and genetic information, all tumors were classified based on WHO 2016 classification. The terms “not otherwise specified” (NOS) and “not elsewhere classified” (NEC) were used based on cIMPACT-NOW. There were 25 glioblastomas and 34 pilocytic astrocytomas, which accounted for a larger percentage than in adult tumors. IDH-wild type gliomas accounted for 55% in diffuse astrocytomas and 69% in anaplastic astrocytomas. The percentages of gliomas with NEC were 50% of oligodendrogliomas and 20% in anaplastic oligodendrogliomas, respectively. Most pilocytic astrocytomas were under 20-year-old (27 patients) and located in infratentorial area (21 patients). Based on WHO 2016 classification, not a few neuroepithelial tumors in pediatric and AYA ages could be classified clearly. These tumors had more different genetic abnormalities than those in adult. Therefore, it may be important to evaluate these tumors with comprehensive genetic analysis.
DIPG-51. ACVR1 MUTATIONS PROMOTE TUMOR GROWTH IN MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Jennifer Ocasio Adorno, Laura Hover, Chen He, Xiaoyan Zhu, David Goldhamer, Angel Carcaboso, Sridevi Yadavilli, Javad Nazarian, Suzanne Baker
Journal: Neuro-Oncology (2020)

Abstract Mutations in the gene encoding activin A receptor type 1 (ACVR1) are found in approximately 25% of diffuse intrinsic pontine gliomas (DIPGs), a pediatric glioma with 2-year survival rate of less than 10%. ACVR1mutations frequently coincide with activating PIK3CA or PIK3R1 mutations, indicating a potential cooperative effect of BMP and PI3K signaling in gliomagenesis. We used genetically engineered mice with inducible knock-in of Acvr1R206H or Pik3caE545K alleles, such that cre-mediated recombination resulted in expression of the gain of function mutated genes from their endogenous promoters at physiological levels. Cre-mediated deletion in GFAP-CreER;Pik3caE545K/+;p53cKO mice (Pik3ca;p53) mediated Trp53 deletion and expression of Pik3caE545K in glial progenitors, and spontaneously induced high-grade glioma (HGG) in mice with complete penetrance. Heterozygous knock-in of the Acvr1R206H allele accelerated tumorigenesis and impaired survival in Pik3ca;p53 mice (Acvr1;Pik3ca;p53). Transcriptomic analysis of Acvr1;Pik3ca;p53 tumors compared to Pik3ca;p53 littermate controls, as in patient-derived tumors, revealed broad molecular signatures associated with cell fate commitment and chromosome maintenance. Pharmacologic inhibition of ACVR1 was sufficient to impair growth in human patient-derived DIPG cell lines. Together, our studies show that ACVR1 activation promotes tumor growth in spontaneous mouse HGG and patient-derived DIPG cells, suggesting that ACVR1 inhibition may produce a clinically significant therapeutic effect in DIPG.
NCOG-49. COMBINED NECROSIS AND BRAIN INVASION PREDICT RADIO-RESISTANCE AND TUMOR RECURRENCE IN ATYPICAL MENINGIOMA
Authors: Monica Emili Garcia-Segura, Anders Erickson, Rishi Jairath, David Munoz, Sunit Das
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Meningiomas are the most common tumors in the central nervous system, with variable recurrence rates depending on WHO grading. Atypical (WHO grade II) meningioma has a higher recurrence rate than benign meningioma (WHO grade I). The efficacy of adjuvant radiotherapy (RT) to improve tumor control has been questioned. METHODS This cohort study retrospectively reviewed all patients at St. Michaels Hospital Tumor Patient Database with a diagnosis of atypical meningioma (AM) who underwent surgical resection between 1995 and 2015. Patient and tumor characteristics such as location, neuropathological diagnosis, resection extent, RT and time to reoccurrence or progression were recorded. Resection extent was defined by Simpson Grading Scale as either Gross Total (GTR) or Subtotal (STR) resection. Cox univariate regression and Kaplan-Meier survival analysis were employed to identify risk factors for recurrence and radio-resistance. RESULTS In our cohort of 181 patients, the combination of necrosis and brain invasion was associated with an increased reoccurrence risk (HR= 4.560, P=0.001) and the lowest progression-free survival relative to other histopathological predictors. This trend was maintained after GTR (P=0.001), whereas necrosis alone and combined necrosis and brain invasion were both associated with low progression-free survival in STR (P=0.001). Radiotherapy was associated with decreased progression-free survival (P=0.001), especially in patients who received GTR (P=0.001). This trend was maintained in patients with necrosis alone (P=0.002) but especially in patients with combined necrosis and brain invasion (P=0.001). CONCLUSION Combined necrosis and brain invasion is a strong predictor of tumor recurrence and radio-resistance in AM, regardless of extent of resection or RT.
<i>DMDRMR</i>-Mediated Regulation of m6A-Modified <i>CDK4</i> by m6A Reader IGF2BP3 Drives ccRCC Progression
Authors: Yinmin Gu, Shaoxi Niu, Yang Wang, Liqiang Duan, Yongbo Pan, Zhou Tong, Xu Zhang, Zhenyu Yang, Bo Peng, Xiaodong Wang, Xiaoqi Han, Yuxin Li, Tianyou Cheng, Yajuan Liu, Lina Shang, Tongfeng Liu, Xiwang Yang, Minxuan Sun, Siyuan Jiang, Chang Zhang, Ning Zhang, Qinong Ye, Shan Gao
Journal: Cancer Research (2020)

Abstract Aberrant N6-methyladenosine (m6A) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of m6A remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNAs that are potentially deregulated by DNA methylation. A novel DNA methylation–deregulated and RNA m6A reader–cooperating lncRNA (DMDRMR) facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, DMDRMR bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase CDK4 and three extracellular matrix components (COL6A1, LAMA5, and FN1), by specifically enhancing IGF2BP3 activity on them in an m6A-dependent manner. Consequently, DMDRMR and IGF2BP3 enhanced the G1–S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of DMDRMR and IGF2BP3 was associated with poor outcomes. Our findings reveal that DMDRMR cooperates with IGF2BP3 to regulate target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC. Significance: This study demonstrates that the lncRNA DMDRMR acts as a cofactor for IGF2BP3 to stabilize target genes in an m6A-dependent manner, thus exerting essential oncogenic roles in ccRCC.
ETMR-03. THE ROLE OF FOXR2 IN PEDIATRIC BRAIN CANCER
Authors: Felix Schmitt-Hoffner, Sjoerd van Rijn, Jens-Martin Hübner, Sander Lambo, Monika Mauermann, Norman Mack, Benjamin Schwalm, Stefan Pfister, Marcel Kool
Journal: Neuro-Oncology (2020)

Abstract Forkhead Box R2 (FOXR2) is a transcription factor of the Forkhead Box family that has been correlated with tumorigenesis, aberrant cell growth or tumor progression. Expression of FOXR2 in pediatric brain tumors is, besides in subsets of medullo-, pineo- and glioblastoma, primarily present in CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2), a novel entity that we in 2016 identified from the former class of primitive neuroectodermal tumors of the central nervous system (CNS-PNET). Analyzing CNS-NB-FOXR2 tumors we found that FOXR2 mRNA is expressed in an anti-correlative manner compared to the proto-oncogenes MYC and MYCN. With immunoprecipitation analyses we show that FOXR2 binds to MYC and MYCN and is thereby stabilizing these proteins. These observations on the interaction and the anti-correlative manner suggest that FOXR2 and MYC(N) may drive tumor formation in a molecularly similar fashion. To investigate this further we stably expressed FOXR2, MYCN and MYC and a combination of FOXR2 with MYC(N) in human neural stem cells (hNSC) and injected these in the striatum of NSG mice. We could show that hNSC itself do not from a tumor, whereas the expression of FOXR2 and/or MYC(N) in hNSC results in tumorigenesis. Tumors expressing both, FOXR2 and MYC(N) were growing faster than tumors with FOXR2 alone. In addition, tumors are currently being analyzed by ChIP-sequencing for FOXR2, MYC, and MYCN, to better understand the mechanisms how FOXR2 drives tumor formation compared to its interaction partners MYC and MYCN.
IMMU-19. TARGETING GLIOBLASTOMA IMMUNOSUPPRESSION AND TREATMENT RESISTANCE WITH IBRUTINIB IN COMBINATION WITH STEREOTACTIC RADIATION AND IMMUNE CHECKPOINT BLOCKADE
Authors: Jayeeta Ghose, Baisakhi Raychaudhuri, Kevin Liu, William Jiang, Pooja Gulati, Joseph Liu, Prajwal Rajappa, Manmeet Ahluwalia, Naduparambil Jacob, Arnab Chakravarti, William Carson, Raju Raval
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma (GBM) is associated with systemic and intratumoral immunosuppression. Part of this immunosuppression is mediated by myeloid derived suppressor cells (MDSCs). Preclinical evidence shows that ibrutinib, a tyrosine kinase inhibitor FDA approved for use in chronic lymphocytic leukemia and known to be CNS penetrant, can decrease MDSC generation and function. Also, focal radiation therapy (RT) synergizes with anti-PD-1 therapy in mouse GBM models. Thus, we aimed to test the combination of these approaches on immune activation and survival in a preclinical immune-intact GBM mouse model. METHODS C57BL/6 mice intracranially implanted with the murine glioma cell line GL261-Luc2 were divided into 8 groups consisting of treatments with ibrutinib, RT (10 Gy SRS), or anti-PD-1 individually or in each combination (along with a no treatment control group). Immune cell subset changes (flow-cytometry) and animal survival (Kaplan-Meier) were assessed (n=10 mice per group). RESULTS Median survival of the following groups including control (28 days), ibrutinib (27 days), RT (30 days) or anti-PD-1 (32 days) showed no significant differences. However, a significant improvement in median survival was seen in mice given combinations of ibrutinib+RT (35 days), ibrutinib+anti-PD-1 (38 days), and triple therapy with ibrutinib+RT+anti-PD-1 (48 days, p &amp;lt; 0.05) compared to controls or single treatment groups. The reproducible survival benefit of triple combination therapy was abrogated in the setting of CD4+ and CD8+ T cell depletion. Contralateral intracranial tumor re-challenge in long-term surviving mice suggested generation of tumor-specific immune memory responses. The immune profile of the tumor microenvironment (TME) showed increased cytotoxic CD8+ T cells and decreased MDSCs and regulatory T cells in the triple combination therapy mice compared to controls. CONCLUSION The combination of ibrutinib, focal RT, and anti-PD-1 immune checkpoint blockade led to a significant survival benefit compared to controls in a preclinical model of GBM.
Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy
Authors: Patrick Yu-Wai-Man, Nancy J. Newman, Valerio Carelli, Mark L. Moster, Valerie Biousse, Alfredo A. Sadun, Thomas Klopstock, Catherine Vignal-Clermont, Robert C. Sergott, Günther Rudolph, Chiara La Morgia, Rustum Karanjia, Magali Taiel, Laure Blouin, Pierre Burguière, Gerard Smits, Caroline Chevalier, Harvey Masonson, Yordak Salermo, Barrett Katz, Serge Picaud, David J. Calkins, José-Alain Sahel
Journal: Science Translational Medicine (2020)

At 96 weeks after unilateral intravitreal injection of rAAV2/2- ND4 , vision improved in both eyes in 78% of subjects affected with LHON.
TAMI-57. MEDULLOBLASTOMA UTILIZE GABA TRANSAMINASE TO SURVIVE IN THE CEREBROSPINAL FLUID MICROENVIRONMENT AND PROMOTE LEPTOMENINGEAL DISSEMINATION
Authors: Vahan Martirosian, Krutika Deshpande, Hao Zhou, Keyue Shen, Vazgen Stepanosyan, Jan Remsik, Adrienne Boire, Danielle Isakov, Henk De Feyter, Kyle Hurth, Brooke Nakamura, Ling Shao, Paul Northcott, Joe Wiemels, Shaobo Li, Josh Neman
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) is a malignant pediatric brain tumor. Studies have shown heterogeneous cells amongst the tumor bulk which mirror normal neural cells in various neurodevelopmental stages. To discern exploited mechanisms promoting MB leptomeningeal disease, we drew conclusions from developmental neurobiology. In normal differentiation, the metabolic phenotype in proliferating neural progenitor cells evolves from a glycolysis-dependent to an oxidative phosphorylation-reliant energetic profile in quiescent differentiated neurons. Cancer cells mirror this evolution, which also grants them the capability to utilize alternative nutrients in the microenvironment as an energy source. Considering metastatic cells are typically in a dormant state and primarily utilize oxidative phosphorylation, we hypothesized metastatic MB cells emulate a quiescent neuron-like cellular profile to survive in the cerebrospinal fluid and form leptomeningeal metastases. To examine this, we query the expression of GABA catabolic enzyme GABA transaminase (ABAT) in MB. GABA is found in the cerebellar and leptomeningeal microenvironments, and is utilized by metastatic cancer cells in the CNS as an energy source. We correlate an increase in ABAT expression with neurodevelopment and show heterogeneous expression of this protein in primary MB tumors. MB cells with increased expression of ABAT were slower-dividing, expressed a genetic and metabolic phenotype reminiscent of quiescent neuron-like cells, and had increased capability to metabolize GABA. Conversely, lower expression of ABAT was associated with an increased proliferation rate and correlated with a progenitor-like cellular profile. Transplantation of MB cells into the leptomeningeal compartment decreased proliferative capacity and enhanced ABAT expression. Xenograft models showed MB cells with ABAT knockdown had increased growth in the cerebellar microenvironment. Conversely, MB cells with ABAT overexpression transplanted into the cerebrospinal fluid formed leptomeningeal metastases whereas ABAT knockdown cells could not. These results suggest ABAT expression in MB cells can be modulated by the tumor microenvironment and is required to form leptomeningeal metastases.
Diabetes and COVID-19–Related Mortality in Women and Men in the UK Biobank: Comparisons With Influenza/Pneumonia and Coronary Heart Disease
Authors: Marit de Jong, Mark Woodward, Sanne A.E. Peters
Journal: Diabetes Care (2020)

Individuals with diabetes are at increased risk of poor outcomes from coronavirus disease 2019 (COVID-19) (1–4). Whether the excess risk of COVID-19 mortality associated with impaired glucose tolerance and diabetes is different between women and men is uncertain. We used data from the UK Biobank to investigate the sex-specific associations, and sex differences, between diabetes status, HbA1c, and risk of COVID-19 mortality. As comparison, we also examined sex-specific associations of death by influenza/pneumonia, a major cause of death from respiratory disease prior to COVID-19, and fatal coronary heart disease (CHD), a condition for which sex differences are well established.

The UK Biobank is a prospective cohort study including ∼500,000 participants aged 40–69 years at baseline between 2006 and 2010 (5). Follow-up for cause-specific mortality was conducted to 30 June 2020 through linkage with the national death register. Cox regression was used to obtain sex-specific hazard ratios (HRs) and 95% CIs for mortality from COVID-19, influenza/pneumonia, and CHD by diabetes status and HbA1c level. For analyses involving >2 groups, 95% CIs were estimated through floating absolute risks. Adjustments were made for age, BMI, socioeconomic status, smoking, systolic blood pressure, antihypertensive medication, total cholesterol, and lipid-lowering medication. Models for levels of HbA1c (≤6.5% [48 mmol/mol], >6.5% to ≤7.5%, …
Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting
Authors: S. Modvig, H. Hallböök, H. O. Madsen, S. Siitonen, S. Rosthøj, A. Tierens, V. Juvonen, L. T. N. Osnes, H. Vålerhaugen, M. Hultdin, R. Matuzeviciene, M. Stoskus, M. Marincevic, A. Lilleorg, M. Ehinger, U. Norén-Nystrøm, N. Toft, M. Taskinen, O. G. Jónsson, K. Pruunsild, G. Vaitkeviciene, K. Vettenranta, B. Lund, J. Abrahamsson, A. Porwit, K. Schmiegelow, H. V. Marquart
Journal: Leukemia (2020)

Abstract PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR 5y ) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p &lt; 0.0001), 29 (HzR 2.7, p &lt; 0.0001), and 79 (HzR 3.5, p &lt; 0.0001) associated with hazard of relapse adjusted for age, cytogenetics, and WBC. The early (day 15) response associated with CIR 5y adjusted for day 29 FCM-MRD, with higher levels in adults (median 2.4 × 10 −2 versus 5.2 × 10 −3 , p &lt; 0.0001). Undetectable FCM- and/or PCR-MRD on day 29 identified patients with a very good outcome (CIR 5y = 3.2%). For patients who did not undergo transplantation, day 79 FCM-MRD &gt; 10 −4 associated with a CIR 5y = 22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.