tbuckley/cabot-search huggingface dataset:
DIPG-53. COMPREHENSIVE CLINICAL AND MOLECULAR ANALYSIS OF PEDIATRIC THALAMIC GLIOMA
Authors: Courtney Johnson, Heloisa Moser, Madhuri Kambhampati, Krutica Gaonkar, Roger Packer, Adam Resnick, Javad Nazarian
Journal: Neuro-Oncology (2018)

Childhood thalamic gliomas are rare cancers, accounting for 5% of all pediatric brain tumors and are of glial origin. The recent WHO classification places thalamic tumors in the category of midline gliomas based on discoveries that indicate histone 3 mutations as the driver genomic aberration of these cancers. Thalamic lesions may be confined to one side, spread to both thalami or to the brainstem. Despite variations in anatomical manifestation, the molecular events dictating tumor spread and pathogenesis are not well defined. A cohort of 294 specimens representing 207 subjects diagnosed gliomas with involvement of thalamus, were selected for methylation and whole genome sequencing using Illumina HIseq and EPIC bead array chips. Histological and clinical characterizations were correlated with molecular data to define unique pathways associated with tumor anatomical manifestation. Histological analysis indicated the presence of histone mutation in 46% of specimens. IHC based WHO grading indicated 44% (91/207) of patients with Grade 4, 21% (44/207) were Grade 3, 3% (6/207) were Grade 2, 22% (45/207) were Grade 1 and 10% were other types (e.g. ganglioglioma). Methylation studies conferred hypomethylation to be associated with H3 mutation status. Median age at diagnosis was 9.8 years and 56% of the cohort was male. The presence of the H3K27M mutation was associated with lower survival despite tumor grade. Molecular studies are underway to decipher specific pathways associated with LGG, HGG and TGs.
EAPH-12. CELASTROL INDUCED DEGRADATION OF FANCD2 SENSITIZES PEDIATRIC HIGH-GRADE GLIOMA TO THE DNA-CROSSLINKING AGENT CARBOPLATIN
Authors: Dennis Metselaar, Michaël Meel, Piotr Waranecki, Kenn Zwaan, Dannis van Vuurden, Gertjan Kaspers, Esther Hulleman
Journal: Neuro-Oncology (2018)

Pediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death during childhood. Due to their diffuse growth pattern, difficult to reach location during surgery and position behind the blood-brain barrier (BBB), prognosis of pHGG has barely improved, despite decades of research. Celastrol is a naturally occuring compound that crosses the BBB and seems to have several anti-inflammatory and antioxidative properties. In our and other studies, celastrol has been found to induce proteasomal degradation of FANCD2, a core component of the Fanconi DNA-repair mechanism. Publicly available gene expression datasets reveal FANCD2 to be strongly upregulated in pHGG compared to healthy brain tissues and low-grade glioma. Therefore, we hypothesized that pHGG cells are highly dependent on their Fanconi repair mechanism and that disruption of this mechanism could sensitize the tumor to DNA-crosslinking agents. In eight primary pHGG cell cultures we showed FANCD2 to be degraded both in a time and dose dependent manner upon celastrol treatment. Subsequently, we determined cell-viability after celastrol treatment in these same models. Non-toxic celastrol concentrations were combined with carboplatin, a DNA-crosslinking agent that crosses the BBB. This showed significant synergistic cytotoxicity in all our primary pHGG cell cultures. Furthermore, celastrol and carboplatin combination treatment induced a significant synergistic increase in DNA damage at a range of concentrations, as determined by y-H2AX staining compared to treatment with single agents. These results imply that FANCD2 can serve as a chemosensitizer in pHGG. Combination therapy using celastrol and carboplatin might serve as a potential treatment for pHGG.
IMMU-04. RNA-ENGINEERED T CELLS AS A BIOLOGICAL CARRIER TO DELIVER MACROMOLECULES TO INTRACRANIAL TUMORS
Authors: Fernanda Guimaraes, Catherine Flores, Changlin Yang, Jeffrey Drake, Elias Sayour, Jianping Huang, Duane Mitchell
Journal: Neuro-Oncology (2018)

With the presence of the blood-brain barrier (BBB), successful immunotherapeutic drug delivery to brain tumors remains a challenge. Immunomodulatory agents such as cytokines can reprogram the intratumoral microenvironment into an activated state; however, systemic cytokine delivery has limited access to the central nervous system (CNS). To overcome the limitations of systemically administered cytokines, we investigated if RNA-engineered T cells could deliver granulocyte macrophage colony stimulating factor (GM-CSF) directly to intracranial tumor. The ability of T cells to cross the BBB and mediate direct cytotoxic killing of brain tumor cells make them an attractive platform for exogenous drug delivery. Using T cell mRNA electroporation, we evaluated GM-CSF secretion and the function of the GM-CSF RNA-engineered T cells. Activated T cells can be modified to secrete GM-CSF protein in vitro, while retaining their inherent effector functions. GM-CSF RNA-engineered T cells effectively delivered GM-CSF to brain tumors in vivo, and significantly prolonged overall survival in a mouse brain tumor model. Importantly, GM-CSF RNA-engineered T cells demonstrated a superior anti-tumor efficacy as relative to unmodified T cells and T cells delivery with systemic administration of GM-CSF. The anti-tumor effects were associated with increased IFNγ levels locally within the tumor microenvironment, and peripherally antigen-specific T cell expansion. These findings demonstrate that RNA-modified T cells may serve as a versatile platform for the effective delivery of biological agents to CNS tumors.
Multivisceral resections for locally advanced gastric cancer
Authors: Y. Ostapenko, A. Lukashenko, O. Kolesnik, N. Chorna, A. Boiko
Journal: Annals of Oncology (2018)

Introduction: Multiple organ resection for locally advanced (T4) gastric cancer (AGC) is associated with high morbidity and mortality and poor outcomes. Our aim was to evaluate the efficacy of these surgeries in relation to surgical morbidity, mortality and survival. Methods: Medical records of 1065 patients with AGC who undergone total or subtotal gastrectomy with multivisceral resection and D2 or D3 lymphatic dissection were evaluated between 1998 – 2017 years at the Clinic of National Cancer Institute (Ukraine). Results: The figure of AGC spreading: colon – 41,9%; pancreatic body/tail and spleen – 38.9%; pancreatic head – 11.1%; liver left lobe – 8,1%. Gastrectomy with resection of three and more adjacent organs – 21%; two organs - 22%, one organ – 57%. Surgical mortality and morbidity rate were 6,8% and 23,9%, respectively. Main causes of postoperative mortality were pancreatic necrosis (5,2%) and abdominal abscesses (2,7%). The overall 5-year survival rate was 25%. Survival of patients with R0 and R1 resections was 37% and 13%, respectively (p < 0,05). Histopathologic examination has confirmed involvement of adjacent organs (pT4) in 91,2% of multivisceral resection cases, other 9,8% invasions were false-spreading due to desmoplastic tumor reaction (pT3) without differences in long term outcomes in both groups. Conclusion: Complete tumor R0 resection including adjacent organs is the key to successful treatment for AGC. Aggressive multivisceral resection for AGC is technically feasible and can be achieved with low mortality and acceptable morbidity, providing good disease free and overall survival.
HGG-29. DIFFUSE MIDLINE GLIOMA WITH OSSEOUS METASTASES AT DIAGNOSIS: A CASE REPORT
Authors: Meghan Belongia, Neel Bhatt, Kerri Houser, Andrew Foy, Jason Jarzembowski, Mariko Suchi, Teresa Kelly, Mohit Maheshwari, Jeffrey Knipstein
Journal: Neuro-Oncology (2018)

High grade glioma with extraneural disease is a rare presentation with a dismal prognosis. We report the case of a pediatric patient who was found to have osseous metastases at diagnosis. A 15-year-old female presented with paraplegia and urinary retention. In addition, she reported dyspnea on exertion, anxiety, chest pain, back pain, and headaches for 10 days prior to presentation. MR brain and spine demonstrated innumerable intradural lesions causing spinal cord compression, a fourth ventricular lesion, and leptomeningeal seeding throughout the neuraxis. She also had numerous osteoblastic lesions involving the spine, ribs, sternum, pelvic bones, proximal humerus and proximal femurs noted on MR and CT. She underwent a laminectomy for biopsy of the intradural lesion. Histology showed a high grade astrocytic neoplasm consistent with diffuse midline glioma, H3 K27M mutant. Bone and marrow biopsies of the iliac crest revealed metastatic disease. The patient did not receive further adjuvant therapy due to rapid clinical deterioration. She died 13 days following presentation. Autopsy was performed, and no tumor was found in other visceral organs. Extraneural metastases of high grade glioma are extremely rare and, when reported, occur mostly after surgical sampling and usually at the time of disease progression. There are only 3 previously reported cases of extraneural metastases at diagnosis, only one of which was in a pediatric patient. H3K27M-mutated diffuse midline glioma carries a poor prognosis, and this case illustrates that this is particularly so when it presents with extraneural disease.
EPEN-17. METRONOMIC THERAPY FOR RECURRENT EPENDYMOMA; PRELIMINARY RESULTS
Authors: Eileen Gillan, Markus Bookland
Journal: Neuro-Oncology (2018)

Recurrent ependymomas have a dismal prognosis (2 year survival rates 29% OS and 23% EFS) and are relatively resistant to conventional chemotherapy. An alternative approach to conventional chemotherapy can be antiangiogenic or metronomic chemotherapy which inhibits endothelial cell function and resultant neovascularization. From November 2011 to Feb 2018 five patients (median age:28 months) with recurrent (3 first, 2 multiple) anaplastic ependymomal brain tumors were treated with an antiangiogenic multidrug combination regimen (bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide, and cyclophophamide) and additional intraventricular therapy (etoposide and liposomal cytarabine) for a median of 12 months. Currently all patients are alive without evidence of recurrent disease at a median of 14 months. Toxicities were manageable and therapy was generally well tolerated with the exception of 1 patient who suffered developmental regression necessitating discontinuation of treatment. Our results suggest that the chosen antiangiogenic drug combination is particularly beneficial for patients with recurrent ependymoma and warrants further investigation as an alternative to conventional chemotherapy in relapsed patients.
Individual Treatment of Posttraumatic Stress Disorder Using Mantram Repetition: A Randomized Clinical Trial
Authors: Jill E. Bormann, Steven R. Thorp, Eric Smith, Mark Glickman, Danielle Beck, Dorothy Plumb, Shibei Zhao, Princess E. Ackland, Carie S. Rodgers, Pia Heppner, Lawrence R. Herz, A. Rani Elwy
Journal: American Journal of Psychiatry (2018)

Previous studies suggest that group "mantram" (sacred word) repetition therapy, a non-trauma-focused complementary therapy for posttraumatic stress disorder (PTSD), may be an effective treatment for veterans. The authors compared individually delivered mantram repetition therapy and another non-trauma-focused treatment for PTSD.The study was a two-site, open-allocation, blinded-assessment randomized trial involving 173 veterans diagnosed with military-related PTSD from two Veterans Affairs outpatient clinics (January 2012 to March 2014). The mantram group (N=89) learned skills for silent mantram repetition, slowing thoughts, and one-pointed attention. The comparison group (N=84) received present-centered therapy, focusing on currently stressful events and problem-solving skills. Both treatments were delivered individually in eight weekly 1-hour sessions. The primary outcome measure was change in PTSD symptom severity, as measured by the Clinician-Administered PTSD Scale (CAPS) and by self-report. Secondary outcome measures included insomnia, depression, anger, spiritual well-being, mindfulness, and quality of life. Intent-to-treat analysis was conducted using linear mixed models.The mantram group had significantly greater improvements in CAPS score than the present-centered therapy group, both at the posttreatment assessment (between-group difference across time, -9.98, 95% CI=-3.63, -16.00; d=0.49) and at the 2-month follow-up (between-group difference, -9.34, 95% CI=-1.50, -17.18; d=0.46). Self-reported PTSD symptom severity was also lower in the mantram group compared with the present-centered therapy group at the posttreatment assessment, but there was no difference at the 2-month follow-up. Significantly more participants in the mantram group (59%) than in the present-centered therapy group (40%) who completed the 2-month follow-up no longer met criteria for PTSD (p<0.04). However, the percentage of participants in the mantram group (75%) compared with participants in the present-centered therapy group (61%) who experienced clinically meaningful changes (≥10-point improvements) in CAPS score did not differ significantly between groups. Reductions in insomnia were significantly greater for participants in the mantram group at both posttreatment assessment and 2-month follow-up.In a sample of veterans with PTSD, individually delivered mantram repetition therapy was generally more effective than present-centered therapy for reducing PTSD symptom severity and insomnia.
多剤耐性蛋白質(MRP)3とMRP1によるメトトレキセート(MTX)と葉酸塩の輸送 ポリグルタミル化がMTX輸送に及ぼす効果
Authors: Zeng H, Chen Z-S, Belinsky M G, Rea P A, Kruh G D
Journal: Cancer Research (2001)
A novel patient derived orthotopic xenograft model of gastro-esophageal junction cancer: Key platform for translational discoveries
Authors: O. Veeranki, Z. Tong, A. Mejia, R. Katkhuda, B. Mino, J. Canales, A. Garcia, W. Lang, R. Bassett, J. Ajani, J. Wu, S. Kopetz, M. Blum, W. Hofstetter, C. Kingsley, W. Norton, D. Maru
Journal: Annals of Oncology (2018)

Introduction: Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. GEJ cancers remain to be a therapeutic challenge due to a lack of reliable mouse model for preclinical drug testing. Methods: A novel patient derived tumor orthotopic xenograft (PDOX) was established from GEJ cancer via transabdominal surgical implantation in athymic and NSG-SCID mice. Patient tumor was compared to subcutaneously implanted patient derived tumor xenograft (PDX) and PDOX by H&E, IHC, and next generation sequencing (T200.1 panel). Drug efficacy studies of CDK9 inhibitors with and without radiotherapy are being performed. Results: Mechanical abrasion of mouse GEJ prior to surgical implantation of patient derived tumor in situ promotes tumor engraftment. Complete PDOX engraftment was observed with rapid intra and extra luminal tumor growth as evidenced by serial Magnetic Resonance Imaging. Patient derived stroma co-engrafts with tumor cells in GEJ-PDOX. PDOXs contain fibroblasts, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJs are recapitulated in GEJ-PDOX mouse model. PDOXs demonstrates tumor invasion into vasculature. GEJ-PDOXs is a clinically relevant model for metastases and immunological studies. Conclusion: Murine models have been instrumental in advancing our understanding of gastroesophageal cancers. However, these models have limited applications in tumor microenvironment, immune oncology and metastatic studies. A GEJ-PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture facilitating it as a novel tool in translating findings from such studies. This model can be applied to address importance of tumor microenvironment in metastatic and immunological studies, and to develop novel therapeutic approaches for the treatment of GEJ cancer.
RONC-17. DOES THE EFFICACY OF SALVAGE RE-IRRADIATION IN RECURRENT MEDULLOBLASTOMA DEPEND UPON RISK-STRATIFICATION, SITE OF RELAPSE, AND MOLECULAR SUBGROUP?
Authors: Tejpal Gupta, Madan Maitre, GodaJayant Sastri, Rahul Krishnatry, Neelam Shirsat, Sridhar Epari, Girish Chinnaswamy, Vijay Patil, Aliasgar Moiyadi, Rakesh Jalali
Journal: Neuro-Oncology (2018)

To report outcomes of salvage re-irradiation in the multi-modality management of recurrent medulloblastoma. Medical records of all patients with recurrent medulloblastoma treated with curative-intent re-irradiation at a single institution were analyzed. A total of 24 patients (median age of 14 years) were included. Median time to recurrence was 38 months (range 15-99 months). Of 13 patients with SHH subgroup medulloblastoma, 11 (85%) developed local recurrence while 5 of 7 (71%) group 4 patients developed focal recurrence outside the tumor bed. Neuraxial dissemination was seen in 2 patients each of SHH and group 4, while the lone patient with WNT-pathway experienced leptomeningeal dissemination. Molecular subgrouping was not known in 3 patients. Re-irradiation was focal in 58%, extended-field in 17%, and craniospinal re-irradiation in 25% patients. Median interval from primary course of irradiation was 49 months (range 24-98 months) and median cumulative biologically effective dose (BED) was 117 Gy (range 78-132 Gy). All patients received platinum-based salvage chemotherapy either before or after re-irradiation. At a median follow-up of 16.5 months, the 2-year post-re-irradiation progression-free survival and overall survival was 45% and 61% respectively. Patients with average-risk medulloblastoma at initial diagnosis fared better than high-risk disease, while site of relapse, and molecular subgrouping did not impact upon outcomes after re-irradiation. Two of 16 failures were in-field of re-irradiation indicating excellent local control. One patient developed symptomatic radiation necrosis. Re-irradiation provides excellent local control and encouraging survival outcomes with acceptable toxicity in carefully selected patients with recurrent medulloblastoma.
Molecular characterization of immune microenvironment in colorectal cancers with microsatellite instability by digital RNA counting
Authors: M. Giordano, R. Moretto, R. Giannini, G. Zucchelli, F. Pietrantonio, C. Antoniotti, C. Ugolini, F. Morano, F. Marmorino, E. Sensi, A. Belfiore, D. Rossini, C. Lupi, G. Masi, B. Borelli, E. Ongaro, A. Boccaccino, A. Falcone, C. Cremolini, G. Fontanini
Journal: Annals of Oncology (2018)

Introduction: Alterations in the mismatch repair (MMR) mechanism in colorectal cancers (CRCs) lead to high levels of microsatellite instability (MSI-h) causing considerable endogenous immune anti-tumor response, counterbalanced by immune inhibitory signals. We evaluated the mRNA immune-profile of a series of MSI-h CRCs to identify new potential targets for future CRC immunotherapy trials by combining an extensive gene expression analysis and the clinicopathological characteristics such as presence of metastases, staging, genotype and primary tumor sidedness. Methods: Fifty primary MSI-h CRCs were analysed. Among these, 24 were non-metastatic, 13 had metachronous metastases and 13 had synchronous metastases. According to tumor staging 26 were stage I – II, 10 stage III and 14 stage IV at the time of diagnosis. Mutational status was as follows: 12 samples were RAS mutated, 22 BRAF mutated and 16 RAS and BRAF wild type. Finally, 36 tumors were right-sided and 14 left-sided. NanoString nCounter® PanCancer Immune Profiling Panel (Seattle, WA, USA), covering 730 immune-related genes, was employed to measure gene expression. A linear regression analysis was performed to investigate the differential gene expression related to above mentioned clinicopathological characteristics. The Benjamini-Yekutieli false discovery rate (FDR) was used for adjusting p-values. In this study we set a FDR<0.05 to select differentially expressed genes. Results: Several immune-related genes resulted differentially expressed according to primary tumor sidedness. Most of the deregulated genes showed higher expression in right-sided compared to left-sided MSI-h CRCs and belong to the following "immune response categories": chemokines (STAT1, CXCL10, CXCL13), innate immune response (ATG5, MAP2K1), T-cell functions (IDO1, LAG3, PTPRC), antigen processing (HLA-DPA1, HLA-DPB1, PSMB7), cytotoxicity (GNLY, GZMA), adhesion (ITGAE), NK cell functions (KLRC2) and cell cycle check point (CASP3). No significant differences based on presence of metastases, tumor stage or mutational status were observed. Conclusion: Immune-related genes investigated in this study are heterogeneously expressed in MSI-h CRCs. Interestingly, genes mainly implicated in the inhibition of the immune system are more expressed among right- than left-sided CRCs, thus suggesting a potential different responsiveness to checkpoint inhibitors. According to their putative role in the clinical practice, these preliminary results deserve further validation.
LGG-44. A PHASE I DOSE ESCALATION TRIAL OF THE MEK1/2 INHIBITOR MEK162 (BINIMETINIB) IN CHILDREN WITH LOW-GRADE GLIOMAS AND OTHER RAS/RAF PATHWAY-ACTIVATED TUMORS
Authors: Nathan Robison, Jasmine Pauly, Jemily Malvar, Mariella Gruber-Filbin, Rebecca Loret de Mola, Kathleen Dorris, Anne Bendel, Daniel Bowers, Miriam Bornhorst, Karen Gauvain, Sarah Leary, Patricia Diaz, Yi Juin Tan, Ashley Margol, Girish Dhall, Tena Rosser, Pratiti Bandopadhayay, Tom Davidson, Nicole Ullrich, Mark Borchert, Marvin Nelson, Claire Sinai, Keith Ligon, Richard Sposto, Mark Kieran
Journal: Neuro-Oncology (2018)

Ras/Raf/MEK/ERK pathway activation is the primary driver of most pediatric low-grade gliomas (LGG). MEK162 is an orally bioavailable MEK1/2 inhibitor. The primary objective of this first-in-children multi-institutional open-label dose-escalation trial was to determine the maximum tolerated dose (MTD) of MEK162 oral suspension in children. Children aged 1-18 years with recurrent, refractory or progressive LGG and other non-hematologic malignancies associated with Ras/Raf pathway activation were enrolled according to a 3 + 3 dose-escalation design. Partial response (PR) and radiographic progressive disease (PD) were defined as ≥50% decrease and ≥25% increase in 2-dimensional tumor measurements. Nineteen eligible patients, aged 2-15 (median 9) years, including 17 with LGG, were enrolled and began treatment at five dose levels, from 16 to 32mg/m2/dose twice daily. There were no dose limiting toxicities (DLTs) in 18 DLT-evaluable patients; MTD was not reached. Most common drug-attributable grade ≥2 toxicities included (all grade 2 unless specified): asymptomatic elevated creatine kinase in 9 patients (53%; 1 grade 4, 3 grade 3), acneiform or maculopapular rash in 8 (47%; 2 grade 3), dry skin in 5 (29%; 2 grade 3), and lymphopenia in 4 (24%; 1 grade 3). To date, 4 patients have had clinical or radiographic PD (3 with LGG), and 4 LGG patients have had sustained PR. Twelve LGG patients have completed at least 36 weeks therapy, with a median 29% decrease in 2-dimensional tumor measurements. MEK162 is well tolerated in this pediatric population, with evidence of antitumor activity. A phase II study is ongoing.